**Part 4**

**Planning for Quality Control** 

178 Modern Approaches To Quality Control

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Shaffer L.G., Ledbetter D.H. & Lupski J.R. (2001). Molecular cytogenetics of contiguous gene

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Shaffer L.G. & Bejjani B.A. (2009). Using microarray-based molecular cytogenetic methods to

Udvardi M.K., Czechowski T. & Scheible W.R. (2008). Eleven golden rules of quantitative RT-PCR. *Plant Cell*, Vol. 20. No. 7, (Jul), pp. 1736-1737, ISSN 1040-4651 VanGuilder H.D., Vrana K.E. & Freeman W.M. (2008). Twenty-five years of quantitative

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Workman C., Jensen L.J., Jarmer H., Berka R., Gautier L., Nielser H.B., Saxild H.H., Nielsen

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C., Brunak S. & Knudsen S. (2002). A new non-linear normalization method for reducing variability in DNA microarray experiments. *Genome Biol*, Vol. 3. No. 9,

**10** 

*Italy* 

Filippo G. Praticò

**QA/QC in Transport Infrastructures:** 

Transport infrastructures (road and highway networks, railways, terminal facilities, airports, mass transit systems, bicycle paths and pedestrian walkways, etc.) have significant impacts on the development of regional and national economies. However, the effectiveness of these impacts over the time has to be established based on the actual quality of all the pertaining components of the infrastructure asset (pavement, safety barriers, signals, illumination, embankment, drainage, etc.). Quality can be interpreted as the degree of excellence of a product or service, or as the degree to which a product or service satisfies the needs of a specific customer or, finally, as the degree to which a product or service conforms with a given requirement. In more detail, **quality assurance** (QA) refers to all those planned and systematic actions necessary to provide confidence that a product or facility will perform satisfactorily in service. At the same time, **quality control** (QC), also called process control, relates to those QA actions and considerations necessary to assess and adjust production and construction processes so as to control the level of quality being produced in the end product (Fig.1). Note that **QA (which includes QC) is an infrastructure (e.g. highway) agency responsibility** and involves all the process (planning, design, plan and specifications, construction, etc.), while **QC is a producer–contractor** responsibility which mainly affects construction. Furthermore, QC is not simply QA in construction, due to the fact that both independent assurance and acceptance procedures refer to QA in construction but they are NOT a part of QC. The entire QA/QC process includes: i) setting up the initial data collection or experimentation to determine typical parameters of current construction; ii) designing the acceptance plan itself, including selecting quality characteristics (and corresponding specification limits), statistical quality measure (and corresponding quality levels), buyer's and seller's risks, lot size, number of samples (sample size), specification and/or acceptance limits, and payment–adjustment provisions. As is well known (Burati et al, 2003), traditionally, highway specifications spelled out in detail the work that was to be done by the contractor under the form of **materials and methods specifications** (also called method specifications, recipe specifications, or prescriptive specifications). In this case, specifications direct the contractor to use specified materials in definite proportions and specific types of equipment and methods to place the material. On the contrary, **end result specifications** require the contractor to take the entire responsibility for supplying a product

**1. Introduction** 

or an item of construction.

**Issues and Perspectives** 

*University Mediterranea at Reggio Calabria* 

## **QA/QC in Transport Infrastructures: Issues and Perspectives**

Filippo G. Praticò *University Mediterranea at Reggio Calabria Italy* 

## **1. Introduction**

Transport infrastructures (road and highway networks, railways, terminal facilities, airports, mass transit systems, bicycle paths and pedestrian walkways, etc.) have significant impacts on the development of regional and national economies. However, the effectiveness of these impacts over the time has to be established based on the actual quality of all the pertaining components of the infrastructure asset (pavement, safety barriers, signals, illumination, embankment, drainage, etc.). Quality can be interpreted as the degree of excellence of a product or service, or as the degree to which a product or service satisfies the needs of a specific customer or, finally, as the degree to which a product or service conforms with a given requirement. In more detail, **quality assurance** (QA) refers to all those planned and systematic actions necessary to provide confidence that a product or facility will perform satisfactorily in service. At the same time, **quality control** (QC), also called process control, relates to those QA actions and considerations necessary to assess and adjust production and construction processes so as to control the level of quality being produced in the end product (Fig.1). Note that **QA (which includes QC) is an infrastructure (e.g. highway) agency responsibility** and involves all the process (planning, design, plan and specifications, construction, etc.), while **QC is a producer–contractor** responsibility which mainly affects construction. Furthermore, QC is not simply QA in construction, due to the fact that both independent assurance and acceptance procedures refer to QA in construction but they are NOT a part of QC. The entire QA/QC process includes: i) setting up the initial data collection or experimentation to determine typical parameters of current construction; ii) designing the acceptance plan itself, including selecting quality characteristics (and corresponding specification limits), statistical quality measure (and corresponding quality levels), buyer's and seller's risks, lot size, number of samples (sample size), specification and/or acceptance limits, and payment–adjustment provisions. As is well known (Burati et al, 2003), traditionally, highway specifications spelled out in detail the work that was to be done by the contractor under the form of **materials and methods specifications** (also called method specifications, recipe specifications, or prescriptive specifications). In this case, specifications direct the contractor to use specified materials in definite proportions and specific types of equipment and methods to place the material. On the contrary, **end result specifications** require the contractor to take the entire responsibility for supplying a product or an item of construction.

QA/QC in Transport Infrastructures: Issues and Perspectives 183

materials and methods specifications. **QA specification** consists of two separate functions, i.e. **quality control** or process control, and **acceptance**. As for the development of QC procedures and requirements, the QC procedures and requirements are made up of two parts: the QC requirements (tests to be performed, minimum frequency, qualified laboratories) and the quality characteristics to be measured. For HMAC (hot mix asphalt concrete, or HMA), typical quality characteristics that may be tested for QC include aggregate quality, density (see next section), gradation of critical sieve sizes, plant and discharge temperatures, degree of aggregate coating, moisture content of fine aggregate and/or of finished mix. For PCC (Portland cement concrete) , typical quality characteristics that are tested for QC include aggregate quality, gradation of critical sieve sizes, air content, water–cement ratio, mix temperature, slump. Note that three different subjects can carry out the acceptance testing: contractor, agency, third part. The agency: i) may decide **to do (itself)** the acceptance testing; ii) may assign the testing to the **contractor**; iii) may have a **combination of agency and contractor acceptance testing**; iv) or may require a **third part** to do the testing. In Italy, acceptance testing is usually carried out by a third part, following "general" and "special" Contract specifications (Capitolato special CIRS, Capitolato speciale prestazionale ANAS, etc.). Figure 2 illustrates the conceptual framework of the chapter.

By referring to density (more technically: bulk specific gravity and air voids content), this is a very crucial factor for QC/QA procedures used to evaluate contract specifications. Indeed, the life cycle of hot mix asphalt (HMA) depends on the material density. Bulk specific gravity, Gmb, measures the specific gravity of a compacted hot mix asphalt sample (core or in-lab compacted). Life cycle costs, contract requirements, and QC/QA procedures are all modeled as functions of the effective Gmb properties resulting from suitable design and construction techniques and by application of appropriate boundary conditions. A variety of methods for determining (in laboratory or on site) Gmb are available (dimensional, AASHTO T 269-EN 12697-6:2003; parafilm, ASTM D 1188; vacuum sealing principle, ASTM D 6752; paraffin coated, BU N40-1973, AASHTO T 275-A, EN 12697-6:2003; saturated Surface Dry, AASHTO T 166, ASTM D 2726, EN 12697-6:2003; non-nuclear portable device, ASTM D 7113, AASHTO TP68). In the vacuum sealing method (VSD), specimen volume is determined by a vacuum chamber that shrink-wraps the specimen in a high quality plastic bag. Surface texture effects can be appreciable, and are accounted for in by the shrink-wrap process. Archimedes' principle is then applied. The dimensional method uses height, diameter, and width measurements to estimate the volume. Surface irregularities (i.e., the rough surface texture of a typical specimen) can introduce inaccuracies, because, in practice, an "osculatory" volume is computed. The parameter P is a density estimate derived from measurements of a non-nuclear portable device, collected at the tested surface (Williams, 2008; Megali et al., 2010; Rao et al., 2007; Kvasnak et al., 2007; Romero, 2002; Sargand et al., 2005; TransTech, 2003; Gamache, 2004, 2005; Praticò et al, 2009; Praticò et al, 2009a; Praticò and Moro, 2011; Alvarez et al, 2010). In non-nuclear portable device measurements, an electrical current is transmitted from a transmitter through the asphalt concrete pavement at a given location and is detected by the receiver. Note that the current cannot flow through the isolation ring. The impedance (ohm) is measured, and the dielectric constant (dimensionless) is derived. The dielectric constant of the HMA is used to estimate the density. The dielectric constant depends on the HMA composition in that it is derived from the dielectric constants of air (~1) and bitumen &

**2. Density** 

Fig. 1. Contractor vs. agency relationship.

Fig. 2. Conceptual framework of the chapter.

The highway agency's responsibility is to either accept or reject the final product or to apply a price adjustment (PA) commensurate with the degree of compliance with the specifications. In practice, current specifications are neither solely "materials and methods" nor "end result." (Burati et al., 2003). **Quality assurance specifications** (a.k.a. QA/QC specifications or QC/QA specifications) are a combination of end result specifications and materials and methods specifications. **QA specification** consists of two separate functions, i.e. **quality control** or process control, and **acceptance**. As for the development of QC procedures and requirements, the QC procedures and requirements are made up of two parts: the QC requirements (tests to be performed, minimum frequency, qualified laboratories) and the quality characteristics to be measured. For HMAC (hot mix asphalt concrete, or HMA), typical quality characteristics that may be tested for QC include aggregate quality, density (see next section), gradation of critical sieve sizes, plant and discharge temperatures, degree of aggregate coating, moisture content of fine aggregate and/or of finished mix. For PCC (Portland cement concrete) , typical quality characteristics that are tested for QC include aggregate quality, gradation of critical sieve sizes, air content, water–cement ratio, mix temperature, slump. Note that three different subjects can carry out the acceptance testing: contractor, agency, third part. The agency: i) may decide **to do (itself)** the acceptance testing; ii) may assign the testing to the **contractor**; iii) may have a **combination of agency and contractor acceptance testing**; iv) or may require a **third part** to do the testing. In Italy, acceptance testing is usually carried out by a third part, following "general" and "special" Contract specifications (Capitolato special CIRS, Capitolato speciale prestazionale ANAS, etc.). Figure 2 illustrates the conceptual framework of the chapter.

## **2. Density**

182 Modern Approaches To Quality Control

Planning

Maintenance

Fig. 1. Contractor vs. agency relationship.

**Section 1: INTRODUCTION** 

**SECTION 2** 

Fig. 2. Conceptual framework of the chapter.

**SECTION 3** 

The highway agency's responsibility is to either accept or reject the final product or to apply a price adjustment (PA) commensurate with the degree of compliance with the specifications. In practice, current specifications are neither solely "materials and methods" nor "end result." (Burati et al., 2003). **Quality assurance specifications** (a.k.a. QA/QC specifications or QC/QA specifications) are a combination of end result specifications and

**Quality control** 

**2: Density tests** 

**Acceptance** Independent

**Quality Assurance** 

**Construction**

**Quality Assurance in construction** 

> **3: Pay Adjustment**

Design

assurance

Plans and specifications

Advertise & award of contract

By referring to density (more technically: bulk specific gravity and air voids content), this is a very crucial factor for QC/QA procedures used to evaluate contract specifications. Indeed, the life cycle of hot mix asphalt (HMA) depends on the material density. Bulk specific gravity, Gmb, measures the specific gravity of a compacted hot mix asphalt sample (core or in-lab compacted). Life cycle costs, contract requirements, and QC/QA procedures are all modeled as functions of the effective Gmb properties resulting from suitable design and construction techniques and by application of appropriate boundary conditions. A variety of methods for determining (in laboratory or on site) Gmb are available (dimensional, AASHTO T 269-EN 12697-6:2003; parafilm, ASTM D 1188; vacuum sealing principle, ASTM D 6752; paraffin coated, BU N40-1973, AASHTO T 275-A, EN 12697-6:2003; saturated Surface Dry, AASHTO T 166, ASTM D 2726, EN 12697-6:2003; non-nuclear portable device, ASTM D 7113, AASHTO TP68). In the vacuum sealing method (VSD), specimen volume is determined by a vacuum chamber that shrink-wraps the specimen in a high quality plastic bag. Surface texture effects can be appreciable, and are accounted for in by the shrink-wrap process. Archimedes' principle is then applied. The dimensional method uses height, diameter, and width measurements to estimate the volume. Surface irregularities (i.e., the rough surface texture of a typical specimen) can introduce inaccuracies, because, in practice, an "osculatory" volume is computed. The parameter P is a density estimate derived from measurements of a non-nuclear portable device, collected at the tested surface (Williams, 2008; Megali et al., 2010; Rao et al., 2007; Kvasnak et al., 2007; Romero, 2002; Sargand et al., 2005; TransTech, 2003; Gamache, 2004, 2005; Praticò et al, 2009; Praticò et al, 2009a; Praticò and Moro, 2011; Alvarez et al, 2010). In non-nuclear portable device measurements, an electrical current is transmitted from a transmitter through the asphalt concrete pavement at a given location and is detected by the receiver. Note that the current cannot flow through the isolation ring. The impedance (ohm) is measured, and the dielectric constant (dimensionless) is derived. The dielectric constant of the HMA is used to estimate the density. The dielectric constant depends on the HMA composition in that it is derived from the dielectric constants of air (~1) and bitumen &

QA/QC in Transport Infrastructures: Issues and Perspectives 185

and the quality index. Note that it is required to determine specification limits (USL, upper specification limit, and LSL, lower specification limit), and to decide on AQL (Acceptable quality level) and RQL (Rejectable quality level). USL and LSL are the limiting values placed on a quality characteristic, while AQL and RQL refer to the quality measure and are respectively the minimum level of actual quality at which the material or construction can be considered fully acceptable (for that quality characteristic) and that maximum level of actual quality at which the material or construction can be considered unacceptable (rejectable). Specification limits and quality levels are basic inputs to decide pay relationships. Performance-related pay, incentive/disincentive, minimum pay provisions, remove/replace provisions, retest provisions are examples of pay relationships. At the present several classes of models for acceptance procedures depending on input parameters and underlying principle can be listed (Praticò, 2007; Praticò et al, 2008; Praticò et al, 2010a; 2010b; Praticò et al, 2011a): 1) IRI-type models (where IRI stands for International Roughness Index) and average-type models; 2) PD-type models (where PD stands for Percent Defective); 3) LCCA based models (where LCCA stands for Life Cycle Cost Analysis). IRI-type models are based on roughness indicators, as synthetically expressive of the quality of the work and of the related costs (for example the Profile Index (PI), the International Roughness Index (IRI), etc.. In this case the Pay Adjustment (PA) is often empirically determined on the basis of the Pay Factor (PF). PF (and the payment to the contractor) decreases as IRI increases. In the average-based models (see for example typical Italian contracts such as CIRS and ANAS 2008), the pay adjustment (or/and its specific value, PA/C=PA\*) usually depends on the difference (DI), for the given j-th quality characteristic, between the average (xAC) and the design value (xAD). Sometimes the percent difference is used (%, PDI=(xAC-xAD)/ xAD)or its difference from a threshold. It results PA=abs(DI)·k (where abs(DI) indicates the absolute value of DI, while k usually ranges from 0.3 to 3 and the overall PA is the sum of the PAs of the single quality characteristics. For example, for a SFC (side force coefficient) of 36 instead of 40, it results PDI=10% and PA=10·0.5=5%. Note that these models are cumulative and only penalties are involved (no bonuses). Thickness, HMA moduli, pavement bearing, surface properties (such as SFC and sand height, SH) are usually the main quality characteristics which are considered. In PDtype models asphalt content, grading, mix in-place density, air voids, Marshall resistance, and/or thickness are often used (Deacon et al., 1997; Epps et al., 1999; Khaled, 2003; Burati, 2005; Hughes et al., 2005). In this case the PA is often (but not always) computed by taking into account the percentage within the limits (PWL), with particular probabilistic hypotheses in order to calibrate agency and contractor risks; for the i-th variable, for a given layer, from the PWLi a percent defective (PDi) and then a pay factor (PFi) are computed; by combining all the PFi a combined pay factor (CPF) is often derived. Given that, by the means of CPF and cost, the Pay Adjustment is computed. LCCA based models are models in which the concept of life cycle cost analysis (as a methodology useful to compare the total user and agency costs of competing project implementation alternatives) is explicit. Therefore, pay adjustment depends on how long the pavement will last (Weed, 2001; Weed & Tabrizi, 2005; Whiteley et al., 2005). The Pay Factor may be often referred (more or less implicitly) to an expected life. For this reason, the boundary between these different models may be difficult to define. Though many algorithms do exist for assessing pay adjustment, many classes of issues still call for research. Furthermore, note that the real OC curves (Operating Characteristic Curves) and risks will depend on sample size (number of test results used to judge the quality of a lot), lot size and sublot size (sublots are needed in

aggregates (5–6). Water and moisture, if present, strongly influence the dielectric constant estimate because the dielectric constant of water approximately 80. Densities measured in the laboratory (dimensional, parafilm, vacuum sealing principle, paraffin coated, saturated surface dry), when contract specifications are well-defined, are quite reliable and accurate but are obtained very slowly. On-site measurements (non-nuclear portable device) are made using non-nuclear portable devices and result often biased and unreliable. Researchers have attempted to find correlations between the results obtained using different procedures (Brown et al., 2004; Cooley et al., 2002; Crouch et al., 2003; Mohammad et al., 2005; Montepara & Virgili, 1996; Spellerberg & Savage, 2004; Williams et al., 2005; Megali et al., 2009). Studies have been carried out in order to propose a theoretical framework for interpreting in-lab and on-site measurements and in the aim of proposing strategies for using non-nuclear portable devices in QC/QA (Megali et al., 2010). A decrease in porosity (or effective porosity) yielded in-lab specific gravities that converged. In contrast, due to the high dielectric constant of water the divergence of in-site measures was observed. The ranking among procedures was the following: GmbSSD > GmbFIN > GmbCOR > GmbFILM > GmbDIM. Furthermore the ranking did not depend on core diameter (Praticò and Moro, 2011b). From a practical standpoint, two strategies were proposed for estimating the density of an asphalt sample: i) consideration of both W (water content) and P (density measured through non-nuclear portable devices) in an estimate for the effective porosity, which is the most crucial parameter for quality control evaluation; ii) consideration of both W and P in an estimate of density. In (Praticò and Moro, 2011), two equations were proposed for practical applications:

$$G\_{mb\text{COR}} = aP + b\mathcal{W} + c \tag{1}$$

$$m\_{eff} = dP + e\mathcal{V}V + f \tag{2}$$

where a = 0.914, b = -0.007, c = 0.303, d = -56.673, e = 0.420, f = 128.698 (coefficients are casespecific).

#### **3. Acceptance procedures**

This section deals with acceptance procedures. Premises (§3.1) illustrate how acceptance procedures can be carried out, the main indicators which are used and what are the main issues. Afterwards, section 3.2 (model) describes a model for the derivation of the price adjustment (PA) based on life cycle cost analysis. Due to the need of considering surface properties, section 3.3 addresses life expectancy of surface properties (skid resistance, texture, surface wear, drainability, acoustic performance). Bulk properties still remain the key-factor in determining the expected life of the as-constructed pavement. To this end, section 3.4 deals with several tools for the determination of the expected life of a pavement through empirical to rational models. Section 3.5 presents an example of application and provides other references. Main findings are summarized in section 3.6.

#### **3.1 Premises and symbols**

In the aim of providing a useful indicator for acceptance procedures, from each quality characteristic the corresponding value of quality measure is derived (Burati et al., 2003; Leahy et al., 2009). Quality measure is any one of several means that have been established to quantify quality. Some examples of quality measures are the mean, the standard deviation, the percent defective, the percent within limits, the average absolute deviation,

aggregates (5–6). Water and moisture, if present, strongly influence the dielectric constant estimate because the dielectric constant of water approximately 80. Densities measured in the laboratory (dimensional, parafilm, vacuum sealing principle, paraffin coated, saturated surface dry), when contract specifications are well-defined, are quite reliable and accurate but are obtained very slowly. On-site measurements (non-nuclear portable device) are made using non-nuclear portable devices and result often biased and unreliable. Researchers have attempted to find correlations between the results obtained using different procedures (Brown et al., 2004; Cooley et al., 2002; Crouch et al., 2003; Mohammad et al., 2005; Montepara & Virgili, 1996; Spellerberg & Savage, 2004; Williams et al., 2005; Megali et al., 2009). Studies have been carried out in order to propose a theoretical framework for interpreting in-lab and on-site measurements and in the aim of proposing strategies for using non-nuclear portable devices in QC/QA (Megali et al., 2010). A decrease in porosity (or effective porosity) yielded in-lab specific gravities that converged. In contrast, due to the high dielectric constant of water the divergence of in-site measures was observed. The ranking among procedures was the following: GmbSSD > GmbFIN > GmbCOR > GmbFILM > GmbDIM. Furthermore the ranking did not depend on core diameter (Praticò and Moro, 2011b). From a practical standpoint, two strategies were proposed for estimating the density of an asphalt sample: i) consideration of both W (water content) and P (density measured through non-nuclear portable devices) in an estimate for the effective porosity, which is the most crucial parameter for quality control evaluation; ii) consideration of both W and P in an estimate of density. In (Praticò and Moro, 2011), two equations were proposed for practical applications:

 *n dP eW eff f* (2) where a = 0.914, b = -0.007, c = 0.303, d = -56.673, e = 0.420, f = 128.698 (coefficients are case-

This section deals with acceptance procedures. Premises (§3.1) illustrate how acceptance procedures can be carried out, the main indicators which are used and what are the main issues. Afterwards, section 3.2 (model) describes a model for the derivation of the price adjustment (PA) based on life cycle cost analysis. Due to the need of considering surface properties, section 3.3 addresses life expectancy of surface properties (skid resistance, texture, surface wear, drainability, acoustic performance). Bulk properties still remain the key-factor in determining the expected life of the as-constructed pavement. To this end, section 3.4 deals with several tools for the determination of the expected life of a pavement through empirical to rational models. Section 3.5 presents an example of application and

In the aim of providing a useful indicator for acceptance procedures, from each quality characteristic the corresponding value of quality measure is derived (Burati et al., 2003; Leahy et al., 2009). Quality measure is any one of several means that have been established to quantify quality. Some examples of quality measures are the mean, the standard deviation, the percent defective, the percent within limits, the average absolute deviation,

provides other references. Main findings are summarized in section 3.6.

specific).

**3. Acceptance procedures** 

**3.1 Premises and symbols** 

*G aP bW c mbCOR* (1)

and the quality index. Note that it is required to determine specification limits (USL, upper specification limit, and LSL, lower specification limit), and to decide on AQL (Acceptable quality level) and RQL (Rejectable quality level). USL and LSL are the limiting values placed on a quality characteristic, while AQL and RQL refer to the quality measure and are respectively the minimum level of actual quality at which the material or construction can be considered fully acceptable (for that quality characteristic) and that maximum level of actual quality at which the material or construction can be considered unacceptable (rejectable). Specification limits and quality levels are basic inputs to decide pay relationships. Performance-related pay, incentive/disincentive, minimum pay provisions, remove/replace provisions, retest provisions are examples of pay relationships. At the present several classes of models for acceptance procedures depending on input parameters and underlying principle can be listed (Praticò, 2007; Praticò et al, 2008; Praticò et al, 2010a; 2010b; Praticò et al, 2011a): 1) IRI-type models (where IRI stands for International Roughness Index) and average-type models; 2) PD-type models (where PD stands for Percent Defective); 3) LCCA based models (where LCCA stands for Life Cycle Cost Analysis). IRI-type models are based on roughness indicators, as synthetically expressive of the quality of the work and of the related costs (for example the Profile Index (PI), the International Roughness Index (IRI), etc.. In this case the Pay Adjustment (PA) is often empirically determined on the basis of the Pay Factor (PF). PF (and the payment to the contractor) decreases as IRI increases. In the average-based models (see for example typical Italian contracts such as CIRS and ANAS 2008), the pay adjustment (or/and its specific value, PA/C=PA\*) usually depends on the difference (DI), for the given j-th quality characteristic, between the average (xAC) and the design value (xAD). Sometimes the percent difference is used (%, PDI=(xAC-xAD)/ xAD)or its difference from a threshold. It results PA=abs(DI)·k (where abs(DI) indicates the absolute value of DI, while k usually ranges from 0.3 to 3 and the overall PA is the sum of the PAs of the single quality characteristics. For example, for a SFC (side force coefficient) of 36 instead of 40, it results PDI=10% and PA=10·0.5=5%. Note that these models are cumulative and only penalties are involved (no bonuses). Thickness, HMA moduli, pavement bearing, surface properties (such as SFC and sand height, SH) are usually the main quality characteristics which are considered. In PDtype models asphalt content, grading, mix in-place density, air voids, Marshall resistance, and/or thickness are often used (Deacon et al., 1997; Epps et al., 1999; Khaled, 2003; Burati, 2005; Hughes et al., 2005). In this case the PA is often (but not always) computed by taking into account the percentage within the limits (PWL), with particular probabilistic hypotheses in order to calibrate agency and contractor risks; for the i-th variable, for a given layer, from the PWLi a percent defective (PDi) and then a pay factor (PFi) are computed; by combining all the PFi a combined pay factor (CPF) is often derived. Given that, by the means of CPF and cost, the Pay Adjustment is computed. LCCA based models are models in which the concept of life cycle cost analysis (as a methodology useful to compare the total user and agency costs of competing project implementation alternatives) is explicit. Therefore, pay adjustment depends on how long the pavement will last (Weed, 2001; Weed & Tabrizi, 2005; Whiteley et al., 2005). The Pay Factor may be often referred (more or less implicitly) to an expected life. For this reason, the boundary between these different models may be difficult to define. Though many algorithms do exist for assessing pay adjustment, many classes of issues still call for research. Furthermore, note that the real OC curves (Operating Characteristic Curves) and risks will depend on sample size (number of test results used to judge the quality of a lot), lot size and sublot size (sublots are needed in

QA/QC in Transport Infrastructures: Issues and Perspectives 187

a, ai, a1B structural layer coefficients; i refers to i-th layer and B refers to the Bearing

CP as-Constructed Pavement, actual pavement constructed by the contractor

loads without the application of a global rehabilitation.

AC, I , AD, j Parameters which take into account for successive resurfacings.

frei i-th frequency (formula for skid resistance dependence on time) G0, .., G3 Real coefficients in the recipe of the expected life (Burati et al, 2003)

I Indicator, for example percolation speed or drainability

DP as-Designed Pavement; desired pavement, as defined by the agency (buyer)

E, EB, ES Expected life of the CP, general, for only B component, for only S component,

M1B, M1 Moduli, respectively, of the first layer of DP– B component and of the first layer of

N, n Number of layers (above the subgrade) total (N) and to resurface/construct (n)

PDV, PDT Percent Defective (PD) referred to air voids and to thickness respectively.

Present Costs, referred to "B" characteristics, to "S"ones, to DP, to the i-th layer, to the 1st layer of the "B" component, to "B" characteristics as a percent of CDP,

Design life of the as-Designed Pavement; also called initial design life, it is the amount of time for which the chosen pavement design is expected to carry the traffic

real numbers, ratio between C2 and C1 (f), and ratio between C3 and C1 (f3),

Expected life of successive resurfacing/reconstruction, general, of DP, of CP,

Pay Adjustments; PA is the total one; B and D mean referred to B or S, respectively; %:expressed in percentage, i.e. referred to CDP; (1L): referred to one layer (1L) or

, refers to each periodical effect on friction (F); =max

i i-th phase of the i-th periodical effect on friction (F)

, , real numbers, coefficients

component

BPN British Pendulum Number

respectively. CBR California Bearing Ratio

DFC Dense-graded Friction Course

respectively ESALs Equivalent single Axes Loads

respectively

h real number, ratio between t1B and t2

IRI International Roughness Index

the DP MS Marshall Stability

NDT Non Destructive Test

P Pavement

PF Pay Factor

respectively OGFC Open Graded Friction Course

more (2L, etc.)

PI Profile Index (a roughness indicator)

PEM Porous European Mixes

PM Preventive Maintenance

F1, F2, F3, F Coefficients Fi in the formula of the friction F

INF, INT Inflation rate and interest rate, respectively

EXPLIF Expected life

CPF Combined Pay Factor CT equivalent Cumulative Traffic

CB, CS CDP Ci, C1B %CB

D

f, f3

O, ODP, OCP

PA, PAB, PAS, PA%, PA%(1L),..

B "bearing" component of the pavement

order to ensure that the specimens for the sample are obtained from throughout the lot, and are not concentrated in one portion or section of the lot). The operating characteristic (OC) curve is a graphic representation of an acceptance plan that shows the relationship between the actual quality of a lot and either the probability of its acceptance or the probability of its acceptance at various payment levels (for acceptance plans that include pay adjustment provisions). OCs aid in the selection of plans that are effective in reducing risks, because they provide buyer's and seller's risk.

In the abovementioned processes (state-of-the art in the field) the following critical issues can be listed (Praticò, 2008). Problem 1. As is well known (Di Benedetto et al., 1996; Domenichini et al., 1999), all the properties and characteristics influence the real and perceived economic value of the as-constructed pavement at a given time. So, when one characteristic fails, this constitutes a quality assurance problem for the state agency (Burati et al., 2003; Muench & Mahoney, 2001), and an acceptance plan, with particular acceptance procedures, is needed, in order to estimate a pay adjustment, PA. The use of **road surface condition** measurements for the acceptance of roadwork is becoming more and more relevant (Boscaino and Praticò, 2001; Boscaino et al, 2005) and calls for a synergistic approach. Problem 2. Can a friction course be treated as the remaining layers in estimating pay adjustment? In other terms, how can pay adjustment be estimated when both surface and mechanical defects are involved? Problem 3. Is it possible to apply life cycle cost analysis when **both surface and mechanical performance are involved**? Problem 4. Attention is often entirely focused on the quality of single asphalt layers, without any systemic consideration of the quality of the whole **multilayer** during the life cycle. However, it must be observed that the influence of the bottom layers on the performance of a multilayer can strongly modify both failure typology and pavement expected life. Problem 5. **Percentage of defects or average values**? Is there a connection between models based on percent defective and model/procedures based on the consideration of average values? Is there the potential for a synergetic consideration of both position and dispersion? Problem 6. Is there a **relationship between the position of the mean respect to the limits and the value of the percent of defects**? Probably yes, but it depends on the single type of set data (standard deviation, asymmetry, kurtosis, or in the simplest case on standard deviation). Many uncertainties in this field call for further research (Uddin et al, 2011). Problem 7. Given that performance are usually related to averages and not to percent defective, is it possible to relate **pavement performance and PDs** (percentage of defects)? Problem 8. The logic of percent defective is usually linked to pay factors and a **composite pay factor** must be considered. A possibility is to have a correlation between the different factors and the expected life of the pavement. But how much logical and exhaustive can be such procedures? Problem 9. Is it possible a synergetic consideration of **defects and delays** in pay adjustment models? Problem 10. A drawback of the method of percent defects is the impossibility for taking into account the extended service life due to the surplus in some of the quality indicators (for example thickness), even if other defects are detected. In other terms, **PDs are defined positive**. Is there any possibility to correct this shortcoming within the framework of the PD-models? Problem 11. Another problem does occur when one tries to apply the concept of percent defective to Open Graded Friction Courses or Porous European Mixes. In fact, in these cases, the quality indicators used in PD evaluation (thickness and air voids) seem not to provide a logical estimate of expected life (included the surface performance). This fact is due also to the uncertainties in the field of the

order to ensure that the specimens for the sample are obtained from throughout the lot, and are not concentrated in one portion or section of the lot). The operating characteristic (OC) curve is a graphic representation of an acceptance plan that shows the relationship between the actual quality of a lot and either the probability of its acceptance or the probability of its acceptance at various payment levels (for acceptance plans that include pay adjustment provisions). OCs aid in the selection of plans that are effective in reducing risks, because

In the abovementioned processes (state-of-the art in the field) the following critical issues can be listed (Praticò, 2008). Problem 1. As is well known (Di Benedetto et al., 1996; Domenichini et al., 1999), all the properties and characteristics influence the real and perceived economic value of the as-constructed pavement at a given time. So, when one characteristic fails, this constitutes a quality assurance problem for the state agency (Burati et al., 2003; Muench & Mahoney, 2001), and an acceptance plan, with particular acceptance procedures, is needed, in order to estimate a pay adjustment, PA. The use of **road surface condition** measurements for the acceptance of roadwork is becoming more and more relevant (Boscaino and Praticò, 2001; Boscaino et al, 2005) and calls for a synergistic approach. Problem 2. Can a friction course be treated as the remaining layers in estimating pay adjustment? In other terms, how can pay adjustment be estimated when both surface and mechanical defects are involved? Problem 3. Is it possible to apply life cycle cost analysis when **both surface and mechanical performance are involved**? Problem 4. Attention is often entirely focused on the quality of single asphalt layers, without any systemic consideration of the quality of the whole **multilayer** during the life cycle. However, it must be observed that the influence of the bottom layers on the performance of a multilayer can strongly modify both failure typology and pavement expected life. Problem 5. **Percentage of defects or average values**? Is there a connection between models based on percent defective and model/procedures based on the consideration of average values? Is there the potential for a synergetic consideration of both position and dispersion? Problem 6. Is there a **relationship between the position of the mean respect to the limits and the value of the percent of defects**? Probably yes, but it depends on the single type of set data (standard deviation, asymmetry, kurtosis, or in the simplest case on standard deviation). Many uncertainties in this field call for further research (Uddin et al, 2011). Problem 7. Given that performance are usually related to averages and not to percent defective, is it possible to relate **pavement performance and PDs** (percentage of defects)? Problem 8. The logic of percent defective is usually linked to pay factors and a **composite pay factor** must be considered. A possibility is to have a correlation between the different factors and the expected life of the pavement. But how much logical and exhaustive can be such procedures? Problem 9. Is it possible a synergetic consideration of **defects and delays** in pay adjustment models? Problem 10. A drawback of the method of percent defects is the impossibility for taking into account the extended service life due to the surplus in some of the quality indicators (for example thickness), even if other defects are detected. In other terms, **PDs are defined positive**. Is there any possibility to correct this shortcoming within the framework of the PD-models? Problem 11. Another problem does occur when one tries to apply the concept of percent defective to Open Graded Friction Courses or Porous European Mixes. In fact, in these cases, the quality indicators used in PD evaluation (thickness and air voids) seem not to provide a logical estimate of expected life (included the surface performance). This fact is due also to the uncertainties in the field of the

they provide buyer's and seller's risk.


QA/QC in Transport Infrastructures: Issues and Perspectives 189

resurfaced (or reconstructed, if base layers are involved): thus nN. Each of the n layers has a contract cost (i.e. present cost of the as-Designed Pavement, in €/m2) equal to Ci (i=1, 2, .. n, from the surface towards the subgrade), then the relative cost CDP of the as-Designed

CDP=C1+C2+…+Cn. (5)

where CS and CB are respectively the cost of the S component (supplementary) and of the B component of the as-designed pavement. The first layer of B will have a present cost C1B (where C stands for cost, 1 for 1st layer, B for bearing component of the pavement) and a

where C1B, referred to the first layer of the B component (which is intrinsically designed only to have mechanical properties), is generally lower than C1. Let INT and INF be the long-term annual interest rate and inflation rate respectively, given in decimal form

For the as-Designed Pavement, let Design life (D) be the expected life in years of the B component and DS of the S component. For the as-Constructed Pavement, let EB be the expected life of the B component and let ES be the expected life of the S component. In practice, ES can be interpreted as the minimum expected life (years) for supplementary

where ESi is the expected life of the i-th supplementary characteristic. Note that, in order to consider the right number of resurfacing processes the parameters (AC and AD) can be

> *)(1+ne-t/*

In practice, for t=EB-ES-DS=0 or negative, approaches 0, while for EB-ES-DS>1 it approaches 1. Note that in a first analysis of the problem can be negleted. Let us introduce the concept of expected life (years) of successive resurfacing or reconstruction (typically 10 years). For the as-Designed Pavement (DP) let ODP be this "successive" expected life, both for B (bearing) and S (supplementary). For the as-Constructed Pavement (CP) let OCP be this "successive" expected life, both for B (bearing) and S (supplementary). The reason for separating the concept of O into two different concepts ODP and OCP is that the actual expected life of a resurfacing / reconstruction depends also on the part of the pavement notresurfaced. For example, it is possible that, after reconstruction, a subgrade weaker than that set out in contract causes a lower expected life of the surfacing, or that a base stronger then that set out in contract causes a greater one. Given the above facts, it is possible to

*R=(1+INF)*

characteristics (where j represents a given supplementary characteristic):

introduced, where, for example, a=1, m=1, n=20000, =0.05, t=EB-ES-DS:

*=a(1+me-t/*

*CDP=CS+CB* (6)

*CB= C1B+C2+…+Cn.* (7)

*CS=CDP-CB=C1-C1B* (8)

*ES=min [ESi], i=1, 2, …, k* (10)

*(1+INT)-1.* (9)

*)-1 .* (11)

Pavement can be expressed as follows:

thickness t1B (in order to permit to B to last for D years). Thus:

(typically 0.08 and 0.04). The Rate R is so defined:

demonstrate the following (see table 1):


Table 1. List of symbols and acronyms.

correlations among air voids, moduli and expected life. Problem 12. Can base and subgrade be part of the considered pavement system in such algorithms? Problem 13. The density and volumetrics of as-built pavements is a vital part of QC/QA procedures.

Expected life, infrastructure management and pay adjustment strongly depend on air voids content, especially when bituminous mixes are involved. Despite this measurement process is affected by several classes of uncertainties and many issues still call for further research: influence of core diameter, reliability of non-destructive testing, etc. Table 1 lists the main symbols used in this section.

## **3.2 Model**

This section deals with model development. Equations 3-13, Fig.3, Table 1 summarize the derivation of the algorithms. Note that the algorithm here presented overcomes and refines the previous formula as stated in (Praticò, 2007) and was successively updated (Praticò et al, 2010a; Praticò et al, 2010b; Praticò et al, 2011). In summary, the model allows to estimate the pay adjustment on the basis of how long the pavement (considered in all its "qualities") will perform adequately. In order to introduce the model, let DP be the as-designed pavement and CP be the as-constructed pavement (symbols are listed in table 1). The main inputs of the model are costs and expected lives, while the output is the Pay Adjustment, PA (negative if a penalty is provided). It is well known that the friction course has supplementary characteristics (friction, fire resistance, etc., Praticò et al, 2010c). Therefore, every pavement P (both DP and CP, for example) can be divided into two main "components": Bearing characteristics, B, and Supplementary characteristics, S. By comparing, separately, the Bearing characteristics (B, addressing substantially moduli, Poisson coefficients and thicknesses) of the as-Designed Pavement (DP) and of the as-Constructed Pavement (CP), the Pay Adjustment PAB is estimated (where the subscript B means that PA is referred to the bearing characteristics). Similarly, by comparing the Supplementary characteristics (S) of as-designed (DP) and of the as-constructed pavement (CP), the pay Adjustment PAS is estimated:

$$P = B + S \tag{3}$$

$$\text{PA} = \text{PA}\_{\text{B}} + \text{PA}\_{\text{S}} \tag{4}$$

where PAS refers to S, PAB to B, and PA to all the non-conformities. To estimate PAS and PAB, it is necessary to analyze the costs of the pavement during its life. Let N be the total layers of the as-Designed Pavement (above the subgrade) and let n be the layers to be

Y, Y\* Years (real number) and time in years to reach a quasi-constant friction, respectively

correlations among air voids, moduli and expected life. Problem 12. Can base and subgrade be part of the considered pavement system in such algorithms? Problem 13. The density and

Expected life, infrastructure management and pay adjustment strongly depend on air voids content, especially when bituminous mixes are involved. Despite this measurement process is affected by several classes of uncertainties and many issues still call for further research: influence of core diameter, reliability of non-destructive testing, etc. Table 1 lists the main

This section deals with model development. Equations 3-13, Fig.3, Table 1 summarize the derivation of the algorithms. Note that the algorithm here presented overcomes and refines the previous formula as stated in (Praticò, 2007) and was successively updated (Praticò et al, 2010a; Praticò et al, 2010b; Praticò et al, 2011). In summary, the model allows to estimate the pay adjustment on the basis of how long the pavement (considered in all its "qualities") will perform adequately. In order to introduce the model, let DP be the as-designed pavement and CP be the as-constructed pavement (symbols are listed in table 1). The main inputs of the model are costs and expected lives, while the output is the Pay Adjustment, PA (negative if a penalty is provided). It is well known that the friction course has supplementary characteristics (friction, fire resistance, etc., Praticò et al, 2010c). Therefore, every pavement P (both DP and CP, for example) can be divided into two main "components": Bearing characteristics, B, and Supplementary characteristics, S. By comparing, separately, the Bearing characteristics (B, addressing substantially moduli, Poisson coefficients and thicknesses) of the as-Designed Pavement (DP) and of the as-Constructed Pavement (CP), the Pay Adjustment PAB is estimated (where the subscript B means that PA is referred to the bearing characteristics). Similarly, by comparing the Supplementary characteristics (S) of as-designed (DP) and of the as-constructed pavement

where PAS refers to S, PAB to B, and PA to all the non-conformities. To estimate PAS and PAB, it is necessary to analyze the costs of the pavement during its life. Let N be the total layers of the as-Designed Pavement (above the subgrade) and let n be the layers to be

*P=B+S* (3)

PA= PAB+PAS (4)

Thickness of the i-th layer of DP and of the first layer of the bearing component of

S supplementary component of the pavement. It hasn't bearing properties.

Tj expected life of the j-th supplementary characteristic UCS Unconfined Compressive Strength – 7 day break

volumetrics of as-built pavements is a vital part of QC/QA procedures.

PWL Percentage Within Limits PWL Percentage Within Limits

SFC Side Force Coefficient

DP

Table 1. List of symbols and acronyms.

(CP), the pay Adjustment PAS is estimated:

REH Rehabilitation

symbols used in this section.

**3.2 Model** 

ti t1B

resurfaced (or reconstructed, if base layers are involved): thus nN. Each of the n layers has a contract cost (i.e. present cost of the as-Designed Pavement, in €/m2) equal to Ci (i=1, 2, .. n, from the surface towards the subgrade), then the relative cost CDP of the as-Designed Pavement can be expressed as follows:

$$\mathbf{C}\_{\rm DP} = \mathbf{C}\_{1} + \mathbf{C}\_{2} + \dots + \mathbf{C}\_{n} \,. \tag{5}$$

$$\mathbf{C}\_{DP} \equiv \mathbf{C}\_{S} \pm \mathbf{C}\_{B} \tag{6}$$

where CS and CB are respectively the cost of the S component (supplementary) and of the B component of the as-designed pavement. The first layer of B will have a present cost C1B (where C stands for cost, 1 for 1st layer, B for bearing component of the pavement) and a thickness t1B (in order to permit to B to last for D years). Thus:

$$C\_B = C\_{1B} + C\_2 + \dots + C\_n. \tag{7}$$

$$\mathbf{C}\_S \mathbf{=} \mathbf{C}\_{DP} \mathbf{C}\_B \mathbf{=} \mathbf{C}\_{I^T} \mathbf{C}\_{IB} \tag{8}$$

where C1B, referred to the first layer of the B component (which is intrinsically designed only to have mechanical properties), is generally lower than C1. Let INT and INF be the long-term annual interest rate and inflation rate respectively, given in decimal form (typically 0.08 and 0.04). The Rate R is so defined:

$$R = (1 + INF) \cdot (1 + INT)^{-1}.\tag{9}$$

For the as-Designed Pavement, let Design life (D) be the expected life in years of the B component and DS of the S component. For the as-Constructed Pavement, let EB be the expected life of the B component and let ES be the expected life of the S component. In practice, ES can be interpreted as the minimum expected life (years) for supplementary characteristics (where j represents a given supplementary characteristic):

$$\text{ES} \equiv \min \left\{ \text{ESi} \right\}, \text{i} = 1, 2, \dots, k \tag{10}$$

where ESi is the expected life of the i-th supplementary characteristic. Note that, in order to consider the right number of resurfacing processes the parameters (AC and AD) can be introduced, where, for example, a=1, m=1, n=20000, =0.05, t=EB-ES-DS:

*=a(1+me-t/ )(1+ne-t/ )-1 .* (11)

In practice, for t=EB-ES-DS=0 or negative, approaches 0, while for EB-ES-DS>1 it approaches 1. Note that in a first analysis of the problem can be negleted. Let us introduce the concept of expected life (years) of successive resurfacing or reconstruction (typically 10 years). For the as-Designed Pavement (DP) let ODP be this "successive" expected life, both for B (bearing) and S (supplementary). For the as-Constructed Pavement (CP) let OCP be this "successive" expected life, both for B (bearing) and S (supplementary). The reason for separating the concept of O into two different concepts ODP and OCP is that the actual expected life of a resurfacing / reconstruction depends also on the part of the pavement notresurfaced. For example, it is possible that, after reconstruction, a subgrade weaker than that set out in contract causes a lower expected life of the surfacing, or that a base stronger then that set out in contract causes a greater one. Given the above facts, it is possible to demonstrate the following (see table 1):

QA/QC in Transport Infrastructures: Issues and Perspectives 191

iii) As a consequence of the previous point, when the expected life of resurfacing/reconstruction is equal for both the as-Designed and the as-Constructed Pavement, if the expected life of the S component is greater than that of the B component, then the pay adjustment can be computed by the above-mentioned Ref.Eq. after (Weed,

iv) The pay adjustment must be compatible with the cost of the layers to resurface; from this another equation to be included in the equation system is derived. This equation originates from an intrinsic limitation of the model (in common with the previous model (Weed, 2001]); for example for DB=20, EB=0, ODP=OCP=10, ES=DS, it is PA-1.7CDP (which is inconsistent); the new model agrees with common sense if, when EB=0, one puts also DB→

> *PA*

vi) PA is substantially dependent on D-E (with E=EB=ES and O=OCP=ODP); it may be

*CDP-1= -0. 02414284*

vii) PA is substantially dependent on OCP-ODP; for D=20, with E=EB=ES=15, it may be

 PACDP-1= -0. 1601 (OCP-ODP)-0.3753 (21) viii) PA% is affected by the difference (RD-RES); this relationship depends on the thickness of resurfacing/reconstruction; if f3=C3/C1, with f=C2/C1, OCP=ODP=O, D=EB, and n is the

This section deals with the estimate of the life expectancy for the different surface properties (see Figs 4-8, Tabs 2 and 3, equations 25-36 ). The author is aware that, if inadequately used, even the new model could cause misevaluations(Praticò, 2007). Some tools to optimize the estimate process are proposed below. The estimate of ES (as a minimum life expectancy for the various supplementary characteristics) can be obtained from quality control/assurance tests, if the time-dependence of the supplementary characteristics, for given traffic, is predictable. There are many effects and related indicators that can be considered eligible as supplementary characteristics (AA.VV., 2005): drainagebility, friction (polishing), noise, texture, splash & spray, raveling, reflectivity, chemical spill tolerance, faulting (difference in

*(D-E)2 - 0.0164080*

*(RD-RE)*

*EB;* (16)

*-CDP* (18)

*(RD-RES), for n=3* (22)

*(RD-RES), for n=2* (23)

*(1+f+f3)-1* (24)

*(1+f)-1>(1-fh)*

 *(D-E)* (19)

*(D-E) - 0.00202513* (20)

*(1-RO)-1* (17)

*ES*

*if ODP=OCP and ES>EB, it is PA=CDP*

and O→, or/and with D=O. This supplementary equation is:

approximated, for example, by linear or quadratic relations:

*PA(1-RO)*

approximated, for example, by this linear relation:

*CDP-1= -0.00049374*

*PA%= (1-fh)*

*PA%= (1-fh)*

*(1+f+f3)-1*

> *(1+f)-1*

*(RD-RES), for n=1, where (1-fh)>(1-fh)*

*PA(1-RO)*

number of layers resurfaced:

*PA%= (1-fh)*

**3.3 Life expectancy of surface properties** 

2001):

$$\begin{aligned} \mathbf{PA} & \mathbf{=}\_{\mathbf{S}} \text{(R^{\text{DS}} \cdot \text{R^{\text{ES}}})} + \mathbf{\hat{s}\_{\text{AC}} \cdot \mathbf{C}\_{\mathbf{S}} [- (\mathbf{R^{\text{ES}}} \mathbf{S})]} + \mathbf{\hat{s}\_{\text{AD}} \cdot \mathbf{C}\_{\mathbf{S}} [\mathbf{R^{\text{ES}}}]} + \mathbf{\hat{c}\_{\mathbf{S}}} \cdot \mathbf{\hat{f}} [(\mathbf{R^{\text{D}}}) / (1 - \mathbf{R^{\text{CD}}})) / (1 - \mathbf{R^{\text{ES}}}) / (1 - \mathbf{R^{\text{ES}}}) / (1 - \mathbf{R^{\text{ES}}}) / (1 - \mathbf{R^{\text{ES}}}) / (1 - \mathbf{R^{\text{ES}}}) / (1 - \mathbf{R^{\text{ES}}}) / (1 - \mathbf{R^{\text{ES}}}) / (1 - \mathbf{R^{\text{ES}}}) / (1 - \mathbf{R^{\text{ES}}}) / (1 - \mathbf{R^{\text{ES}}}) / (1 - \mathbf{R^{\text{ES}}}) / (1 - \mathbf{R^{\text{ES}}}) / (1 - \mathbf{R^{\text{ES}}}) / (1 - \mathbf{R^{\text{ES}}}) / (1 - \mathbf{R^{\text{ES}}}) / (1 - \mathbf{R^{\text{ES}}}) / (1 - \mathbf{R^{\text{ES}}}) / (1 - \mathbf{R^{\text{ES}}}) / (1 - \mathbf{R^{\text{ES}}}) / (1 - \mathbf{R^{\text{ES}}}) / (1 - \mathbf{R^{\text{ES}}}) \end{aligned} \tag{12}$$

Fig. 3. A synthesis of the model (symbols are listed above).

The term containing CB is the PAB, while PAS is given by the sum of the three terms containing CS. Note that, when DS=ES, EB=E, CS+CB=C, ODP=OCP=O (AD=AD=0), it follows (as in Burati et al, 2003; Weeds, 2001):

$$\text{PA} = \text{(C)} \cdot \left[ \text{(R}^{\text{D}} \text{ -} \text{R}^{\text{E}}) \right] / \text{(1} \text{-} \text{R}^{\text{O}}) \text{[} \tag{13}$$

Table 2 illustrates expenditure flows. In order to test the validity of the hypotheses and the effectiveness of the method the following focal points can be focused:

i) In the case of an as-constructed pavement capable of withstanding the design loading, there is only a pay adjustment for non-conformities of supplementary characteristics:

$$\text{if } \text{D=E}\_{\text{B}} \text{ and } \text{O}\_{\text{DP}} \equiv \text{O}\_{\text{CP}}, \text{ it is } PA\_{\text{B}} \equiv 0 \tag{14}$$

or if

$$E\_S \equiv 0, \ E\_B \equiv \mathbf{D} \to \infty, \ O\_{\mathbf{D}P} \equiv \mathbf{O\_{CP}}, \ \mathbf{PA} \to \sim \mathbf{C}\_S;\tag{15}$$

ii) The model is conceived for an expected life of the supplementary component less than that of the bearing component (as-constructed pavement); this limitation is quite obvious and agrees with the state of the art of pavement constructions. The equations system *must*  contain also this equation:

**PA**CS(RDS- RES)+ACCS(RES+DS)] +ADCSR2DS]+ (CS)[(RD))/(1-RODP)]- [(REB))/(1- ROCP)]+(CB)[(RD))/(1-RODP)]- [(REB))/(1-ROCP)] CS(RDS- RES) + (CS)[(RD))/(1-RODP)]- [(REB))/(1-ROCP)]+(CB)[(RD))/(1-RODP)]- [(REB))/(1-ROCP)] (12)

**DP** (As-Designed Pavement) **CP** (As-Constructed Pavement)

**Model Inputs Model Inputs Model Inputs Model Inputs** 

**S:** Supplementary characteristics

**ES** (expected life of the component "Supplementary" of the CP)

**B:** Bearing characteristics

**EB** (expected life of the component "B" of CP); **OCP** (expected life of successive works of CP)

The term containing CB is the PAB, while PAS is given by the sum of the three terms containing CS. Note that, when DS=ES, EB=E, CS+CB=C, ODP=OCP=O (AD=AD=0), it follows

**PA**=PAS+PAB

Table 2 illustrates expenditure flows. In order to test the validity of the hypotheses and the

i) In the case of an as-constructed pavement capable of withstanding the design loading,

ii) The model is conceived for an expected life of the supplementary component less than that of the bearing component (as-constructed pavement); this limitation is quite obvious and agrees with the state of the art of pavement constructions. The equations system *must* 

there is only a pay adjustment for non-conformities of supplementary characteristics:

 *[(RD -RE))/(1-RO)]* (13)

**PAB=** (CB)[(RD))/(1-RODP)]- [(REB))/(1-ROCP)]

*, ODP=OCP, PA→-CS;* (15)

*if D=EB and ODP=OCP, it is PAB=0* (14)

Fig. 3. A synthesis of the model (symbols are listed above).

**PAS**=CS(RDS- RES) +ACCS(RES+DS)] +ADCSR2DS]+ + (CS)[(RD))/(1-RODP)]- [(REB))/(1-ROCP)]

> *PA= (C)*

**S:** Supplementary characteristics

**CS** (cost of the component "Supplementary " of DP)

effectiveness of the method the following focal points can be focused:

*ES=0, EB=D→*

(as in Burati et al, 2003; Weeds, 2001):

**B:** Bearing characteristics

**D** (design life of DP); **CB** (cost of the component "B" of DP); **ODP** (expected life of successive works of DP)

contain also this equation:

or if

$$E\_S \triangle E\_B \text{:}\tag{16}$$

iii) As a consequence of the previous point, when the expected life of resurfacing/reconstruction is equal for both the as-Designed and the as-Constructed Pavement, if the expected life of the S component is greater than that of the B component, then the pay adjustment can be computed by the above-mentioned Ref.Eq. after (Weed, 2001):

$$\text{if } \mathcal{O}\_{\mathcal{D}P} \models \mathcal{O}\_{\mathcal{C}P} \text{ and } E\_S \rhd E\_{\mathcal{B}\_I} \text{ it is } PA \Leftarrow \mathcal{C}\_{\mathcal{D}P} \cdot \{R^D \text{-} R^E\} \cdot \{1 \neg R^O\} \cdot 1 \tag{17}$$

iv) The pay adjustment must be compatible with the cost of the layers to resurface; from this another equation to be included in the equation system is derived. This equation originates from an intrinsic limitation of the model (in common with the previous model (Weed, 2001]); for example for DB=20, EB=0, ODP=OCP=10, ES=DS, it is PA-1.7CDP (which is inconsistent); the new model agrees with common sense if, when EB=0, one puts also DB→ and O→, or/and with D=O. This supplementary equation is:

$$PA \succeq \mathsf{C}\_{DP} \tag{18}$$

vi) PA is substantially dependent on D-E (with E=EB=ES and O=OCP=ODP); it may be approximated, for example, by linear or quadratic relations:

$$\text{PA} \cdot \text{(1-R}^{\text{o}}\text{)} \cdot \text{C}\_{\text{DP}}\text{'} \text{'} = \text{-0.} \text{ 024} \text{14} \text{284} \cdot \text{(D-E)} \tag{19}$$

$$PA \cdot \text{(1-} R^{\text{O}}\text{)} \cdot \text{C}\_{D P} \text{!= -0.00049374 \text{--} (D-E)^2 - 0.0164080 \text{-} (D-E) - 0.00202513} \tag{20}$$

vii) PA is substantially dependent on OCP-ODP; for D=20, with E=EB=ES=15, it may be approximated, for example, by this linear relation:

$$\text{PA} \cdot \text{C}\_{\text{DP}'} \text{1} = \text{-0.1601} \cdot \text{(CCP-ODP)-0.3753} \tag{21}$$

viii) PA% is affected by the difference (RD-RES); this relationship depends on the thickness of resurfacing/reconstruction; if f3=C3/C1, with f=C2/C1, OCP=ODP=O, D=EB, and n is the number of layers resurfaced:

$$\text{PA}\,\% = (\text{1-}\text{fth}) \cdot (\text{1+} \text{f} + \text{f}\_{\text{3}}) \cdot \text{1} \cdot (\text{R}^{\text{D}} \text{-} \text{R}^{\text{ES}}), \text{ for } n \equiv \text{3} \tag{22}$$

$$PA\% = (1\text{-}f\text{h})\cdot(1\text{-}f)^{\text{-}1}\cdot(R^{\text{D}}\therefore R^{\text{ES}}), \text{ for } n \equiv 2\tag{23}$$

$$\text{PA\%} = (\text{1\textgreater}) \cdot (\text{R}^{\text{D}} \cdot \text{R}^{\text{ES}}), \text{ for } n \equiv 1, \text{ where } (\text{1\textgreater}) \rhd (\text{1\textdegree}) \cdot (\text{1\textdegree}) \cdot (\text{1\textdegree}) \cdot \text{1\textdegree} \cdot (\text{1\textdegree}) \cdot (\text{1\textdegree}) \cdot (\text{1\textdegree}) \cdot \text{1} \cdot \text{1} \cdot \text{/} \cdot \text{1} \cdot \text{/} \cdot \text{1} \cdot \text{/} \cdot \text{} \tag{24}$$

#### **3.3 Life expectancy of surface properties**

This section deals with the estimate of the life expectancy for the different surface properties (see Figs 4-8, Tabs 2 and 3, equations 25-36 ). The author is aware that, if inadequately used, even the new model could cause misevaluations(Praticò, 2007). Some tools to optimize the estimate process are proposed below. The estimate of ES (as a minimum life expectancy for the various supplementary characteristics) can be obtained from quality control/assurance tests, if the time-dependence of the supplementary characteristics, for given traffic, is predictable. There are many effects and related indicators that can be considered eligible as supplementary characteristics (AA.VV., 2005): drainagebility, friction (polishing), noise, texture, splash & spray, raveling, reflectivity, chemical spill tolerance, faulting (difference in

QA/QC in Transport Infrastructures: Issues and Perspectives 193

As is well known, skid resistance changes over time. Typically it increases in the first two years following construction as the roadway is worn away by traffic and rough aggregate surfaces become exposed, then decreases over the remaining pavement life as aggregates become more polished. Skid resistance is also typically higher in the fall and winter and lower in the spring and summer. This seasonal variation is quite significant and can severely skew skid resistance data if not compensated for. Skid resistance deterioration rate depends on the combination of many factors (aggregate properties and gradation, alignment, detritus build-up, rainfall and traffic characteristics, etc) and this can affect substantially any attempt at prediction and modelling. On the basis of the international literature on this topic the following equation can be here derived for skid resistance (*F*)

1

where i) Seasonal, monthly, daily effects and variations are considered by the different frequencies (*frei*) (Diringer and Barros, 1990; Wilson and Kirk, 2005); initial increase is not explicitly considered here; ii) The terminal value *F1* depends on aggregate shore hardness (both average value and coefficient of variation); this value seems to depend on Polishing Stone Value (PSV, British Standard BS 812, Italian standard CNR BU 140/92) and on Los Angeles (or micro-Deval) (Dupont and Turenq, 1993); both the Los Angeles abrasion number and the PSV, alone, do not correlate well with field performance (Dupont and Turenq, 1993); iii) time in years to reach a quasi-constant friction (Y\*) can correspond to 2 million cumulative vehicle passes (Diringer and Barros, 1990) and is usually two to four years, depending on traffic and aggregate properties; iv) F2F1-1 can be estimated in 0.8~1.1 for sedimentary rocks and 0.5~1.4 for igneous rocks (data referred to BPN); v) F3F1-1 can be estimated equal to 0.1~0.3 (Diringer and Barros, 1990). Figure 5 (left) provides a simplified depiction of these hypotheses on friction time-dependence, where Y\*=4, F1=47; F2=38, fre1=1year-1, 1=2=0; fre2=4 year-1, F3F1-1=0.22; dotted curve refers to fre2=0. Figure 5 (right) shows time-dependence for two friction indicators (initial increase is not represented (Brosseaud and Roche, 1997; Kokkalis and Panagouli, 1998). A possible relationship between SFC (Side Friction Coefficient, range 0-1) and SN (Skid Number, range 0-1) (Ullidtz, 1987) is

The minimum value of SFC over the time can be also estimated through the following

where QCV is the number of commercial vehicles/lane/day, PSV is the Polishing Stone Value (Ullidtz, 1987). For limestone, the decrease of SFC over the time as a function of N (number of heavy vehicle equivalents in millions) and SFCi (initial value of SFC) can be

(2 )

 

*SFC=-0.014+1.516 SN* (26)

*SFC=-0.48N0.373(SFCi-3)* (28)

*Min SFC=0.024-0.663\*10^-4 QCV+0.01PSV* (27)

(25)

 \* 0.001 1 2 3

*FF Fe F sen frei i*

*Y <sup>Y</sup> Ln*

drop due to pavement wear:

as follows (see figure 5):

equation (see figure 6):

expressed as (see figure7):

while for basalt as (figure 7):


Table 1. A synopsis of times and expenditures flows for AD and AC.

elevation across a joint), pitting, resistance to wearing, etc. Let Esi be the expected life in relation to the i-th characteristic. Under these hypotheses, Es will be the minimum value among the Esi. In the light of the above facts, if i=1 (for example friction) and the asdesigned target is qa, while the as-constructed value of friction is qb<qa, in the case of linear law over the time it results: a) expected life of the as-designed friction course: ESa=(T-qa)/m, where T stands for minimum level and m is the gradient (negative); b) expected life of the as-constructed friction course: ESb=(T-qb)/m, where T stands for minimum level; c) loss of expected life: ESa-ESb =(qb-qa)/m. For example, if m=-2, T=35, qa=55, qb=45, it results ESa-ESb =5 years.

Fig. 4. Expected life: tools to optimize the estimate (symbols are listed in table above).

*ACCS*

*OCP (CB+CS)*

*OCP (CB+CS)*

elevation across a joint), pitting, resistance to wearing, etc. Let Esi be the expected life in relation to the i-th characteristic. Under these hypotheses, Es will be the minimum value among the Esi. In the light of the above facts, if i=1 (for example friction) and the asdesigned target is qa, while the as-constructed value of friction is qb<qa, in the case of linear law over the time it results: a) expected life of the as-designed friction course: ESa=(T-qa)/m, where T stands for minimum level and m is the gradient (negative); b) expected life of the as-constructed friction course: ESb=(T-qb)/m, where T stands for minimum level; c) loss of expected life: ESa-ESb =(qb-qa)/m. For example, if m=-2, T=35, qa=55, qb=45, it results ESa-ESb

Quality controls, rejectable quality limits, acceptance quality limits

AV % defective (PDV)

Fig. 4. Expected life: tools to optimize the estimate (symbols are listed in table above).

i-th layer

Traffic Exp.life of

ESALs

Asphalt content %

*(REB)/(1-*

*ROCP)* 

*CS(RES)* 

*+(CB+CS)*

*[(RES+DS)]* 

*(RES) CS*

*(REB+OCP) (CB+CS)*

*(REB+2OCP) (CB+CS)*

*(REB+nOCP) (CB+CS)*

% defectivethickness (PDT)

D ES, DS , EB

D, ODP

Suggested ranges

*EXPLIF G G PDV G PDT G PDV* <sup>0</sup> <sup>1</sup> <sup>2</sup> <sup>3</sup>

*(RDS)- CS*

*CS*

*ADCSR2DS]+* 

*(CB+CS)*

*+ACCS*

*CS*

*(REB) (CB+CS)*

*(RES)* 

*(RDB-REB)* 

*(RDB+ODP-REB+OCP)* 

*(RDB+nODP -*

*(RES+DS)]+* 

*[(RDB))/(1-*

Initial values of suppl. charact.

> Aggregate properties

*ODP-*

*[(RES+DS)-R2DS]* 

*(RDB+2*

*RODP)]- [(REB))/(1-ROCP)]*

*REB+2OCP)* 

*REB+nOCP)* 

*(RDS- RES)* 

AD, As-designed pavement AC, As-constructed pavement AD vs. AC Times Expenditure Times Expenditure Pay Adjustment

*(RDS) ES CS*

*(RDB+ODP) EB+OCP (CB+CS)*

*(RDB) EB (CB+CS)*

*R2DS ES+DS* 

*ODP) EB+2*

Table 1. A synopsis of times and expenditures flows for AD and AC.

*(RDB+nODP) EB+n*

*DS CS*

*DB+ODP (CB+CS)*

*DB (CB+CS)*

*ODP (CB+CS)*

*ODP (CB+CS)*

*2DS* 

*DB+2*

*DB+n*

Sum

=5 years.

Resistances

Moduli and structural layer coefficients

Rat./empirical design

D, EB, ODP, OCD

*(RDB+2*

*(RDB)/(1-*

*RODP)* 

NDT + cores

*CS(RDS)* 

*+(CB+CS)*

*ADCS* As is well known, skid resistance changes over time. Typically it increases in the first two years following construction as the roadway is worn away by traffic and rough aggregate surfaces become exposed, then decreases over the remaining pavement life as aggregates become more polished. Skid resistance is also typically higher in the fall and winter and lower in the spring and summer. This seasonal variation is quite significant and can severely skew skid resistance data if not compensated for. Skid resistance deterioration rate depends on the combination of many factors (aggregate properties and gradation, alignment, detritus build-up, rainfall and traffic characteristics, etc) and this can affect substantially any attempt at prediction and modelling. On the basis of the international literature on this topic the following equation can be here derived for skid resistance (*F*) drop due to pavement wear:

$$F = F\_1 + F\_2 \cdot e^{\int\_{\frac{\gamma}{\sqrt{\tau}} Ln(0.001)} \Big|\_{\ r}} + F\_3 \cdot \prod\_{i=1}^{\tau t} \text{sen}(\mathbf{2} \cdot \boldsymbol{\pi} \cdot f \text{re}\_i - \phi\_i) \tag{25}$$

where i) Seasonal, monthly, daily effects and variations are considered by the different frequencies (*frei*) (Diringer and Barros, 1990; Wilson and Kirk, 2005); initial increase is not explicitly considered here; ii) The terminal value *F1* depends on aggregate shore hardness (both average value and coefficient of variation); this value seems to depend on Polishing Stone Value (PSV, British Standard BS 812, Italian standard CNR BU 140/92) and on Los Angeles (or micro-Deval) (Dupont and Turenq, 1993); both the Los Angeles abrasion number and the PSV, alone, do not correlate well with field performance (Dupont and Turenq, 1993); iii) time in years to reach a quasi-constant friction (Y\*) can correspond to 2 million cumulative vehicle passes (Diringer and Barros, 1990) and is usually two to four years, depending on traffic and aggregate properties; iv) F2F1-1 can be estimated in 0.8~1.1 for sedimentary rocks and 0.5~1.4 for igneous rocks (data referred to BPN); v) F3F1 -1 can be estimated equal to 0.1~0.3 (Diringer and Barros, 1990). Figure 5 (left) provides a simplified depiction of these hypotheses on friction time-dependence, where Y\*=4, F1=47; F2=38, fre1=1year-1, 1=2=0; fre2=4 year-1, F3F1-1=0.22; dotted curve refers to fre2=0. Figure 5 (right) shows time-dependence for two friction indicators (initial increase is not represented (Brosseaud and Roche, 1997; Kokkalis and Panagouli, 1998). A possible relationship between SFC (Side Friction Coefficient, range 0-1) and SN (Skid Number, range 0-1) (Ullidtz, 1987) is as follows (see figure 5):

$$\text{SFC=-0.014+1.516 SN} \tag{26}$$

The minimum value of SFC over the time can be also estimated through the following equation (see figure 6):

$$\text{Min } SFC \equiv 0.024 \text{--} 0.663 \, ^\circ 10^\circ \text{--} 4 \, \text{QCV} \, \dagger \text{-} 0.01 \text{PSV} \, \tag{27}$$

where QCV is the number of commercial vehicles/lane/day, PSV is the Polishing Stone Value (Ullidtz, 1987). For limestone, the decrease of SFC over the time as a function of N (number of heavy vehicle equivalents in millions) and SFCi (initial value of SFC) can be expressed as (see figure7):

$$\text{ASFC} \equiv 0.48 \text{N}^{0.373} \text{(SFCi-3)} \tag{28}$$

while for basalt as (figure 7):

QA/QC in Transport Infrastructures: Issues and Perspectives 195

formula is strongly dependent on the differences D-E and OCP-ODP. This can help to reduce the possible conflicts between contractor and buyer without using simple but empirical

PEM 0.469 -0.778 0.862 Percolation speed (cm/s) 0.79~1.5 0~3 PEM 0.449 -2.435 0.795 Percolation speed (cm/s) 0.57~1.6 0~3 PEM 1.049 -0.778 0.248 Permeability (cm/s) 0.3~1.3 0~3.75 PEM - EL 1.119 -1.312 0.168 Permeability (cm/s) 0.15~1.3 0~3.75

> > **MIN SFC**

**MPD (mm)**

Indicator *<sup>I</sup> <sup>I</sup>* Range *<sup>Y</sup>* Range (years)

100000 1000000 10000000

BPN

0 25 50 75 100

0 20 40 60 80 100

**PSV**

8 12

**N (x1000)**

**CT**

SFC

**SFC, BPN**

formulas and models not well-grounded in logic.

Table 2. Time-dependence of drainability (example).

**Y, Years**

**SN**

Fig. 6. Example of relationship SN vs. SFC and PSV vs. MINSFC.

**N**

Fig. 7.Example of relationships N vs. SFC and MPD vs. number of axes.

Note: F: Friction indicator; SFC: Side Friction Coefficient; BPN: British Pendulum Number Fig. 5. Skid resistance (F=BPN) vs. time (Years) and skid resistance (SFC, BPN) versus

F1

F2

**F**

024

equivalent Cumulative Traffic (CT).

**SFC**

**SFC**

0 25 50 75 100

Limestone-SFCi=60 Basalt; SFCi=60 MINSFC(PSV=50) MINSFC(PSV=30)

02468

Y\*

Pavement

$$\text{ASFC=-0.30N}^{0.50N} \text{(SFC}\_{i}\text{-3)} \tag{29}$$

(Flintsch et al, 2001) proposed the following model:

$$\text{SN(64)}\_{8}\text{=}26.865 + 2.079 \cdot \text{Binde} + 1.601 \cdot \text{PP200} + 1.03 \cdot \text{VTM} \tag{30}$$

$$\text{SN(64)}\_{\text{R}} \text{=} 104.211 \text{--} 4..356 \cdot \text{N}MS \text{+} 0.1833 \cdot \text{VTM} \tag{31}$$

where SN(64)S stands for Skid Number measured at 64Km/h for smooth tires, Binder stands for binder code (-1 for PG 64-22, 0 for PG 70-22, 1 for PG 76-22), PP200 is the percentage of material passing the #200 sieve, VTM represents the total voids in the mix, SN(64)R stands for Skid Number measured at 64Km/h for ribbed ( R) tires, NMS is the Nominal Maximum Size. Note that the model after Flintsch et alia refers to the starting point of diagrams (asconstructed value). In particular, for Binder=-1, NMS=12.5, PP200=5, VTM=20 it results SN64S= SN64R=53 and for Binder=-1, NMS=19, PP200=5, VTM=6, it results SN64S= 39 and SN64R=23. As for texture, (Flintsch et al, 2001) proposed the following model:

#### *MPD=-2.896+0.2993NMS+0.0698VMA* (32)

where MPD stands for Mean Profile Depth, NMS for Nominal Maximum Size and VMA for Voids in Mineral Aggregates. Note that in this case the law doesn't provide the variation over the time. Another model for texture depth was developed (Arnold et al, 2005) according to the following algorithm:

$$\text{MPD} = \text{k1} - \text{k2} \dots \text{log(N)},\tag{33}$$

where *k1* and *k2* are constants and *N* is number of wheel passes. The constants *k1* and *k2* in the equation (the Patrick equation) have been calculated for two different cases (see figure 7). The Surface wear due to the combined action of salt and traffic can be estimated through the following model (Ullidtz, 1987, Praticò et al, 2010):

$$\text{RNDW} = 2.48 \cdot 10^{\text{-}5} \cdot \text{PASS} \cdot 0.02 \cdot \text{CVW} \cdot 0.46 \cdot \text{S} \cdot \text{22} \cdot \text{SALT} \cdot 0.52 \tag{34}$$

Where RDW is the rut depth due to studded tires in mm, PASS is the number of vehicles with studded tires in one direction expressed in thousand, CW is the carriageway width in m, S is the vehicle speed in Km/h, and SALT is a variable for salting (2 salted, 1 unsalted, see figure). Based on other authors (Smith, 1979), with studded tires in the range 7-23%, concrete pavement wear can be considered as follows:

$$P\text{V}\approx 0, \text{5}^{\ast}\text{Y}\tag{35}$$

Where PW is the wear in mm, while Y stands for number of years. Also drainability values depend on the chosen indicator (Praticò and Moro, 2007a, 2008a). On the basis of the international literature on this topic, a typical curve for drainability is as follows (where I is drainability indicator, Y stands for years, and are positive and is negative; PEM indicates porous European mixes; EM: emergency lane):

$$I = \alpha \cdot e^{\beta \cdot Y} + \chi \tag{36}$$

It is important to note that, although some of these estimates may be considered approximate, all the inputs may be "conditioned" by the same methodology and the PA

where SN(64)S stands for Skid Number measured at 64Km/h for smooth tires, Binder stands for binder code (-1 for PG 64-22, 0 for PG 70-22, 1 for PG 76-22), PP200 is the percentage of material passing the #200 sieve, VTM represents the total voids in the mix, SN(64)R stands for Skid Number measured at 64Km/h for ribbed ( R) tires, NMS is the Nominal Maximum Size. Note that the model after Flintsch et alia refers to the starting point of diagrams (asconstructed value). In particular, for Binder=-1, NMS=12.5, PP200=5, VTM=20 it results SN64S= SN64R=53 and for Binder=-1, NMS=19, PP200=5, VTM=6, it results SN64S= 39 and

where MPD stands for Mean Profile Depth, NMS for Nominal Maximum Size and VMA for Voids in Mineral Aggregates. Note that in this case the law doesn't provide the variation over the time. Another model for texture depth was developed (Arnold et al, 2005)

where *k1* and *k2* are constants and *N* is number of wheel passes. The constants *k1* and *k2* in the equation (the Patrick equation) have been calculated for two different cases (see figure 7). The Surface wear due to the combined action of salt and traffic can be estimated through

Where RDW is the rut depth due to studded tires in mm, PASS is the number of vehicles with studded tires in one direction expressed in thousand, CW is the carriageway width in m, S is the vehicle speed in Km/h, and SALT is a variable for salting (2 salted, 1 unsalted, see figure). Based on other authors (Smith, 1979), with studded tires in the range 7-23%,

> *PW*

*<sup>Y</sup> I e* 

It is important to note that, although some of these estimates may be considered approximate, all the inputs may be "conditioned" by the same methodology and the PA

Where PW is the wear in mm, while Y stands for number of years. Also drainability values depend on the chosen indicator (Praticò and Moro, 2007a, 2008a). On the basis of the international literature on this topic, a typical curve for drainability is as follows (where I is drainability indicator, Y stands for years, and are positive and is negative; PEM

SN64R=23. As for texture, (Flintsch et al, 2001) proposed the following model:

*SFC=-0.30N0.503(SFCi-3)* (29)

*SN(64)S=26.865+2.079·Binder+1.601·PP200+1.03·VTM* (30)

*SN(64)R=104.211-4.356·NMS+0.1833·VTM* (31)

*MPD=-2.896+0.2993NMS+0.0698VMA* (32)

*RDW= 2.48·10-5·PASS1.02·CW-0.46· S1.22·SALT0.32* (34)

MPD = k1 – k2 **.** log(N), (33)

*0,5\*Y* (35)

(36)

(Flintsch et al, 2001) proposed the following model:

according to the following algorithm:

the following model (Ullidtz, 1987, Praticò et al, 2010):

concrete pavement wear can be considered as follows:

indicates porous European mixes; EM: emergency lane):

formula is strongly dependent on the differences D-E and OCP-ODP. This can help to reduce the possible conflicts between contractor and buyer without using simple but empirical formulas and models not well-grounded in logic.


Table 2. Time-dependence of drainability (example).

Note: F: Friction indicator; SFC: Side Friction Coefficient; BPN: British Pendulum Number

Fig. 5. Skid resistance (F=BPN) vs. time (Years) and skid resistance (SFC, BPN) versus equivalent Cumulative Traffic (CT).

Fig. 6. Example of relationship SN vs. SFC and PSV vs. MINSFC.

Fig. 7.Example of relationships N vs. SFC and MPD vs. number of axes.

QA/QC in Transport Infrastructures: Issues and Perspectives 197

which corresponds to a given laboratory resistance (Unconstrained Compressive Strength – 7-day break) can vary to a great extent in relation to many factors (time from base construction, traffic, subgrade drainage, shrinkage cracks, etc). Figure 9 shows the relationship between resistances and structural layer coefficients according to (Van Til et al, 1972). Note that in the following figures MS indicates Marshall stability, M the modulus, a the structural layer coefficient, UCS is the unconstrained compressive strength- 7 day break, CBR is the california bearing ratio; ESAL indicates equivalent single axle load, AC stands for as-constructed. In principle, EB, expected life of the bearing component of the as-Constructed Pavement, can be estimated as D (except where D is derived from thresholds in contracts or from design report). Moreover, it must be noted that for the asphalt layers there are empirical formulas that can be used to estimate D and EB in function of Percent Defective of air voids and thickness (PDV, PDT, (Burati et al, 2003)), or in function of the air voids and asphalt content of the as-Constructed Pavement. Both for EB and D, reliable information can be obtained from Non-Destructive Tests, NDT (e.g. Falling Weight Deflectometer), or /and laboratory tests on cores (resilient moduli – test methods AASHTO TP9-94-1B, ASTM D 4123, LTPP P07) (Giannattasio and Pignataro, 1983; Ullidtz, 1987). The estimate of ODP and OCP can be approached by the same methodologies above-mentioned for D and EB respectively (see also tables 4 and 5). All these values can be modified (and costs upgraded) if extended service life gains for preventive maintenance treatment are considered (overband crack filling, crack sealing, single or double chip seal, slurry seal, microsurfacing, ultrathin, hot-mix asphalt overlay, hot-mix asphalt mill and overlay, etc.) and in relation to particular design philosophies.

> 1.E+06 2.E+06 3.E+06 4.E+06

> > 0 500 1000

**MS (daN)**

surface course - M surface course - a

**M (KPa) a**

0 0.1 0.2 0.3 0.4 0.5

Fig. 9. Example of MS-M-a relationships, for surface courses and base courses.

1.E+06 2.E+06 3.E+06 4.E+06

0 500 1000

**MS (daN)**

base course -M base course - a

**M (KPa) a**

0 0.1 0.2 0.3 0.4

Fig. 8. Example of relationships years vs. wear (mm) or permeability.

As for noise mitigation, based on the international literature the following information is available:


Table 3. Duration of noise mitigation (SPB method).

#### **3.4 Life expectancy of bulk properties**

Both for unbound and HMA/PCC layers, volumetrics, mechanistic performance and related indicators are often correlated and vary over the time. Equations 37-38, Figs 9-13, Tables 4 and 5 summarize several practical relationships. In the M-E PDG, the HMA layer modulus is characterized using the dynamic modulus (or backcalulated modulus from FWD data). In more detail, the dynamic modulus at a given loading time and temperature is assumed to be the elastic modulus in the response computation. PCC materials need a static modulus of elasticity adjusted with time. For chemically stabilized materials the elastic modulus or the resilient modulus is needed (lime-stabilized typical value: 45000psi). For unbound materials the resilient modulus is needed (39000 psi: very good; 10000psi: very poor). In the AASHTO guide 1993 the structural layer coefficients and the resilient modulus (subgrade) are used. Design life (D) of the as-Designed Pavement (DP), can be estimated from contract specifications. D can also be estimated on the basis of the design report (in which it is usually specified). Empirical or rational design can be used after having estimated structural layer coefficients or moduli from resistance thresholds set out in the contract (Marshall Stability, MS, for surface course, base course and bituminous treated bases, California Bearing Ratio (CBR), for untreated bases or subbases, Unconfined Compressive Strength – 7 day break (UCS) for cement treated bases, (Huang, 2003), see figures 9 to 13); by knowing thickness and traffic loading it is therefore possible to estimate D. Importantly, on the basis of the international literature (Van Til et al, 1972; Gaspard, 2000; Sebesta, 2005) and current practice, the modulus of cement treated bases

As for noise mitigation, based on the international literature the following information is

Solution E IN FINAL DAC (dense asphalt concrete) Variable 0 -2 PA (porous asphalt) 10-12 4 <3 (?) TPA (two-layer porous asphalt) 9 6 4 SMA-like thin layers 9.5 4.7 3 Porous-type thin layers 8.5 5 3

E: Expected lifetime (years); IN: Initial noise reduction (db(A)); FINAL: Final/minimum

Both for unbound and HMA/PCC layers, volumetrics, mechanistic performance and related indicators are often correlated and vary over the time. Equations 37-38, Figs 9-13, Tables 4 and 5 summarize several practical relationships. In the M-E PDG, the HMA layer modulus is characterized using the dynamic modulus (or backcalulated modulus from FWD data). In more detail, the dynamic modulus at a given loading time and temperature is assumed to be the elastic modulus in the response computation. PCC materials need a static modulus of elasticity adjusted with time. For chemically stabilized materials the elastic modulus or the resilient modulus is needed (lime-stabilized typical value: 45000psi). For unbound materials the resilient modulus is needed (39000 psi: very good; 10000psi: very poor). In the AASHTO guide 1993 the structural layer coefficients and the resilient modulus (subgrade) are used. Design life (D) of the as-Designed Pavement (DP), can be estimated from contract specifications. D can also be estimated on the basis of the design report (in which it is usually specified). Empirical or rational design can be used after having estimated structural layer coefficients or moduli from resistance thresholds set out in the contract (Marshall Stability, MS, for surface course, base course and bituminous treated bases, California Bearing Ratio (CBR), for untreated bases or subbases, Unconfined Compressive Strength – 7 day break (UCS) for cement treated bases, (Huang, 2003), see figures 9 to 13); by knowing thickness and traffic loading it is therefore possible to estimate D. Importantly, on the basis of the international literature (Van Til et al, 1972; Gaspard, 2000; Sebesta, 2005) and current practice, the modulus of cement treated bases

0 0,5 1 1,5

**I (cm/s)**

01234

**Y (years)**

1 2 3 4

available:

noise reduction (db(A))

0 2 4 6 8 10

**years**

Table 3. Duration of noise mitigation (SPB method).

**3.4 Life expectancy of bulk properties** 

Fig. 8. Example of relationships years vs. wear (mm) or permeability.

RDW (salt=2) **mm**

RDW (salt=1)

which corresponds to a given laboratory resistance (Unconstrained Compressive Strength – 7-day break) can vary to a great extent in relation to many factors (time from base construction, traffic, subgrade drainage, shrinkage cracks, etc). Figure 9 shows the relationship between resistances and structural layer coefficients according to (Van Til et al, 1972). Note that in the following figures MS indicates Marshall stability, M the modulus, a the structural layer coefficient, UCS is the unconstrained compressive strength- 7 day break, CBR is the california bearing ratio; ESAL indicates equivalent single axle load, AC stands for as-constructed. In principle, EB, expected life of the bearing component of the as-Constructed Pavement, can be estimated as D (except where D is derived from thresholds in contracts or from design report). Moreover, it must be noted that for the asphalt layers there are empirical formulas that can be used to estimate D and EB in function of Percent Defective of air voids and thickness (PDV, PDT, (Burati et al, 2003)), or in function of the air voids and asphalt content of the as-Constructed Pavement. Both for EB and D, reliable information can be obtained from Non-Destructive Tests, NDT (e.g. Falling Weight Deflectometer), or /and laboratory tests on cores (resilient moduli – test methods AASHTO TP9-94-1B, ASTM D 4123, LTPP P07) (Giannattasio and Pignataro, 1983; Ullidtz, 1987). The estimate of ODP and OCP can be approached by the same methodologies above-mentioned for D and EB respectively (see also tables 4 and 5). All these values can be modified (and costs upgraded) if extended service life gains for preventive maintenance treatment are considered (overband crack filling, crack sealing, single or double chip seal, slurry seal, microsurfacing, ultrathin, hot-mix asphalt overlay,

hot-mix asphalt mill and overlay, etc.) and in relation to particular design philosophies.

Fig. 9. Example of MS-M-a relationships, for surface courses and base courses.

QA/QC in Transport Infrastructures: Issues and Perspectives 199

**ESALs to 10% Fatigue Cracking (\*)**

56789

**AC Average Air Void Content (%)**

**Relative Modulus**

0.5 0.6 0.7 0.8 0.9 1.0 1.1 AC Std Dev 0.6 AC Std Dev 1.2 AC Std Dev 1.8

0 5 10 15 **AC Average Air Void Content (%)**

years to 4th

10~12 (mill and overlay)

*a1* (37)

rehabilitation (ODP)

**Relative fatigue life**

0.00 0.25 0.50 0.75 1.00 1.25 1.50 1.75 2.00

years to 1st

drained)

rehabilitation (D)

12~16 (base layer undrained)

15~20 (base layer

**ESALs to 10mm ruth depth (\*)**

4.5 5 5.5 6 6.5 7

**AC Average Asphalt content (%)**

3 5 7 9 11 13 15 **AC Average Air Void Content (%)**

AC Std Dev 0.095 AC Std Dev 0.19 AC Std Dev 0.285

(Surface courses (Epps et al. , 1999)) (\*) expressed as multiple of target ESALs.

**Relative Rutting rate**

rehabilitation (ODP)

Modulus (right) - Surface courses (Austroroads, 1999).

years to 2nd

Table 4. Estimates of years to the n-th rehabilitation.

10~12 (mill and overlay)

> *t1BM1B1/3 t1*

Fig. 12. Left: ESALs to 10mm vs. asphalt content. Right: ESALs to 10% vs. air void content

0 5 10 15 **AC Average Air Void Content (%)**

Fig. 13. Air Voids vs. Relative Fatigue Life (left) or Relative Rutting Rate (center) or . Relative

Note that the application of the PA formula depends on the ability to split the surface course into two parts. A tentative method to estimate t1B, C1B, CB and CS is to identify the component B of DP in a pavement with a design life D, but with a different friction course (this time with negligible surface properties, for example just the binder course). In

*M11/3 ; t1B*

where the modulus M1B of the first layer of the B component of the as-Designed Pavement can be tentatively identified in M2, the structural layer coefficient a1B can be considered equal to a2, and the thicknesses t1 and t2 are known. As above-mentioned, M1, M2 (moduli of the 1st and 2nd layer of the DP) and a1, a2 (structural layer coefficients of the 1st and 2nd layer of the DP) may be estimated by using correlation charts and algorithms in literature

particular, two tentative values of t1B may be obtained by the following expressions:

years to 3rd

and overlay)

10~12 (mill and overlay)

> *a1Bt1*

rehabilitation (ODP)

12~16 (full depth mill

Fig. 10. Cement treated base courses, untreated bases, subbases, subgrades.

Fig. 11. Left (untreated bases): CBR vs. M and a. Right (surface course - fine gradation): ESALs to 10mm Ruth Depth vs. asphalt content (Epps et al. , 1999).

**Mr (psi) a a a UCS, Mpa UCS,psi MD, Mpa CBR MD, Mpa CBR MD, Mpa CBR MD, Mpa**  all CTB (1) UB (2) SB (3) CTB (4) CTB CTB (5) UB (6) UB (7) SB SB (8) SUB (9) SUB (10) **9,128 0.06** 6 31 6 29 **12,628** 0.09 17 **80** 8 40 **15,000 0.11** 30 144 10 48 **15,750 0.07** 0.11 10 47 40 192 11 **50 18,300** 0.08 0.13 17 **80** 64 309 12 59 **20,548** 0.10 **0.14** 25 122 100 479 14 66 **25,000** 0.12 52 248 **17** 80 **30,000 0.14** 100 480 20 96 **33,582 0.15** 150 722 22 107 **39,000 26** 125 **45,000 30** 144

Equations:

0.0E+00 5.0E+06 1.0E+07 1.5E+07 2.0E+07

**ESALs to 10mm ruth depth**

(1): a=0.499\*LOG10(Mr)-2.7324; (2): a=0.249\*LOG10(Mr)-0.977; (3):a=0.227\*LOG10(Mr)-0.839; (4): UCS=(a-0.0935)/0.02282609; (5): MD= 4667.3\*a - 552.6; (6): CBR=10^(a/0.0689); (7, 8): MD=CBR\*4.8; (9): CBR=Mr/1500.

Symbols: CTB: Cement treated base; UB: Untreated base; SB: Subbase; MD: Modulus of deformation; SUB: Subgrade (bolded characters refer to a very good subgrade support); Mr: resilient modulus; a: structural layer coefficient; UCS: unconfined compressive strength; MD: Modulus of deformation;

CBR: California bearing ratio.

air void content 5% air void content 6% air void content 7%

4.5 5 5.5 6 6.5 7

**Asphalt content (%)**

**599,081 0.15 2.5** 362 **150 752,581 0.20** 4.7 676 381 **864,318 0.23** 6.0 867 521

**Cement treated bases**

Fig. 10. Cement treated base courses, untreated bases, subbases, subgrades.

0.05 0.07 0.09 0.11 0.13 0.15

ESALs to 10mm Ruth Depth vs. asphalt content (Epps et al. , 1999).

Fig. 11. Left (untreated bases): CBR vs. M and a. Right (surface course - fine gradation):

100

1.E+04 2.E+05 4.E+05 6.E+05 8.E+05

0.12 0.14 0.16 0.18 0.20 0.22 0.24 0.26 0.28

**a, structural layer coefficient**

untreated bases -M untreated bases - a

**M (KPa) a**

0 50 100

**CBR**

UCS, Kpa MD, Mpa

1000

10000

Fig. 12. Left: ESALs to 10mm vs. asphalt content. Right: ESALs to 10% vs. air void content (Surface courses (Epps et al. , 1999)) (\*) expressed as multiple of target ESALs.

Fig. 13. Air Voids vs. Relative Fatigue Life (left) or Relative Rutting Rate (center) or . Relative Modulus (right) - Surface courses (Austroroads, 1999).


Table 4. Estimates of years to the n-th rehabilitation.

Note that the application of the PA formula depends on the ability to split the surface course into two parts. A tentative method to estimate t1B, C1B, CB and CS is to identify the component B of DP in a pavement with a design life D, but with a different friction course (this time with negligible surface properties, for example just the binder course). In particular, two tentative values of t1B may be obtained by the following expressions:

$$t\_{1B} \cdot M\_{1B}{}^{1\beta} \cong t\_1 \cdot M\_1{}^{1\beta} \; ; \; \; t\_{1B} \; \; a\_{1B} \cong t\_1 \; \; a\_1 \tag{37}$$

where the modulus M1B of the first layer of the B component of the as-Designed Pavement can be tentatively identified in M2, the structural layer coefficient a1B can be considered equal to a2, and the thicknesses t1 and t2 are known. As above-mentioned, M1, M2 (moduli of the 1st and 2nd layer of the DP) and a1, a2 (structural layer coefficients of the 1st and 2nd layer of the DP) may be estimated by using correlation charts and algorithms in literature

QA/QC in Transport Infrastructures: Issues and Perspectives 201

sub-grade 0.10106 0.10106 0.13106 0.10106 0.11<sup>106</sup>

Life (years) D=22 D=22 EB=18 ODP=12 OCP=14

Output D t1B/t2=0.50 EB ODP OCP

Table 7. Case-history (years are rounded to the nearest integer; moduli in KPa).

Table 8. PA determination –Inputs and outputs *(the percentages are referred to CDP).*

the high dielectric constant of water (divergence of in-site measures).

In the light of above facts, the main findings of the study can be summarized in terms of drawbacks and point of strengths. Air void content has a vital role in QC/QA. A decrease in porosity (or effective porosity) yields in-lab specific gravities that converge toward the maximum theoretical specific gravity Gmm (convergence of in-lab measurements). In contrast, gravities determined through non-nuclear portable devices often increase due to

Uncertainties in the determination of the expected life of the different characteristics and complexity are the main drawbacks of the models of PA based on LCCA. On the contrary,

PA (€/m2) -2.51 PAB (€/m2) -0.52 PAS (€/m2) -1.99 PA% -13.70 PAB % -2.85 PAS % -10.85

Asphalt (27

Cement treated (20 cm)

Subbase +

Input

Output

**4. Main findings** 

or 25.5\* cm) 2.29<sup>106</sup> 2.65<sup>106</sup>

DP (@0) DP, B(@0) CP(@0) DP(@EB) CP(@EB)

1.00106 1.00106 1.30106 0.50106 0.70106

INT 0.08 C2, asphalt, €/ m2 4,25 INF 0.04 C3, asphalt, €/ m2 7,27 R 0.963 Cost of the cement treated, €/ m2 6,92 D (years) 22 Cost of the granular sub-base, €/ m2 3,83 EB (years) 18 Overall Cost €/m2 29,09 ES (years) 3 Asphalt cost €/ m2 18,34 ODP (years) 12 CB, €/ m2 13.65 OCP (years) 14 CS, €/ m2 4.69 t1B/t2 0,5 CB% 74.42 C1, asphalt, €/m2 6,82 CS% 25.58

(\*) 1.00106 2.29106 2.29<sup>106</sup>

references (Van Til et al, 1972; Huang, 2003) in function of the traditional resistance tests. Similarly, C1B, CB and CS (€/m2), for a given t1B, can be easily estimated by comparing the costs of the 1st and 2nd layer of the DP, given that the cost of the unit of volume of the layers 1B and 2 of the DP are the same. For example, if C2 and t2 are the cost and thickness of the second layer of the as-Designed Pavement respectively, then for h=0.5, f=0.6: if

$$\mathbf{t}\_{1\overline{\mathsf{B}}} = \mathbf{h} \cdot \mathbf{t}\_2 \; \mathsf{C}\_2 \; \mathsf{C}\_2 \; \mathsf{C}\_{1\nu} \; \mathsf{C}\_{1\overline{\mathsf{B}}} \cdot \mathsf{t}\_{1\overline{\mathsf{B}}} \cdot \mathsf{t} = \mathsf{C}\_2 \cdot \mathsf{t}\_2 \; \mathsf{t} \; \mathsf{(C/m\overline{\mathsf{y}})} \implies \mathsf{C}\_{1\overline{\mathsf{B}}} = f\mathsf{h} \cdot \mathsf{C}\_{1\nu} \; \mathsf{C}\_{\overline{\mathsf{C}}} = \mathsf{C}\_1 \cdot \begin{pmatrix} \mathtt{1} \ \mathsf{f} \ \mathsf{h} \end{pmatrix}$$

$$\mathsf{C}\_{\overline{\mathsf{S}}} = \mathbf{0}.7 \cdot \mathsf{C}\_{\mathsf{L}} \quad \mathsf{C}\_{1\overline{\mathsf{B}}} = \mathbf{0}.3 \; \mathsf{C}\_1 \quad \mathsf{C}\_{\overline{\mathsf{B}}} = \mathbf{0}.3 \; \mathsf{C}\_1 + \mathsf{C}\_2 + \dots + \mathsf{C}\_n \tag{38}$$


Table 5. Summary of a variety of maintenance and rehabilitation life expectancy and costs.

#### **3.5 Experimental application**

An experimental application was performed on a motorway in Southern Italy. Traditional quality characteristics of the mixes, for single lane and given layer, have been organized in function of the progressive abscissa. Many experimental devices were used in order to measure the actual characteristics of the as-constructed pavement. From the comparison between the requirements of the as-designed pavement (DP) and the actual characteristics of the as-constructed pavement (CP) the moduli for DP(@0) and CP(@0) were derived (see table 7). The ratio t1B/t2 was about 0.5; asphalt concrete thickness was 27 cm for DP and about 27-5+3.5=25.5cm for the B component of the pavement. Results were obtained by Kenpave [Huang, 2003] and successfully compared with the AASHTO Guide 1993 equation. By analyzing the drainability and friction data, ES=3 was estimated, caused by insufficient drainability. Pay adjustments (in absolute and in percentage, as referred to the cost CDP) are summarized in table 8.

references (Van Til et al, 1972; Huang, 2003) in function of the traditional resistance tests. Similarly, C1B, CB and CS (€/m2), for a given t1B, can be easily estimated by comparing the costs of the 1st and 2nd layer of the DP, given that the cost of the unit of volume of the layers 1B and 2 of the DP are the same. For example, if C2 and t2 are the cost and thickness of the

*-1 (€/m3)* 

*C1, C1B=0.3 C1 CB=0.3*

Crack seals (PM) 2 3 1.7 0.66 Fog Seals (PM) 3 4 0.8 0.24 Slurry seal (PM) 4 9 1.5 0.23 Microsurfacing (PM) 5 14 2.3 0.24 Chip seals (PM) 4 6 1.3 0.26 Thin hot mix overlay (PM/REH) 2 10 2.8 0.47 HMA– Dense Graded (5cm) (PM/REH)- (ODP) 5 15 5.3 0.53

(ODP) 10 20 5.9 0.40 37.5mm mill+37.5mm overlay (PM/REH) - (ODP) 8 12 7.2 0.72 Milling (37.5mm) +100mm overlay (REH) - (ODP) 18 22 9.5 0.48 Milling+thick overlay (75-180mm) (REH) - (ODP) 18 25 10.9 0.51

Table 5. Summary of a variety of maintenance and rehabilitation life expectancy and costs.

An experimental application was performed on a motorway in Southern Italy. Traditional quality characteristics of the mixes, for single lane and given layer, have been organized in function of the progressive abscissa. Many experimental devices were used in order to measure the actual characteristics of the as-constructed pavement. From the comparison between the requirements of the as-designed pavement (DP) and the actual characteristics of the as-constructed pavement (CP) the moduli for DP(@0) and CP(@0) were derived (see table 7). The ratio t1B/t2 was about 0.5; asphalt concrete thickness was 27 cm for DP and about 27-5+3.5=25.5cm for the B component of the pavement. Results were obtained by Kenpave [Huang, 2003] and successfully compared with the AASHTO Guide 1993 equation. By analyzing the drainability and friction data, ES=3 was estimated, caused by insufficient drainability. Pay adjustments (in absolute and in percentage, as referred to the

 *C1B= fh* 

*C1, CS=C1*

 *(1- fh)* 

(Years, Y) Cost

*C1+C2+…+Cn* (38)

(€/ m2)

€/(m2 min max Y)

Cost for year

second layer of the as-Designed Pavement respectively, then for h=0.5, f=0.6:

Treatment expected Life

if

*t1B=ht2 , C2=fC1, C1Bt1B-1=C2t2*

**3.5 Experimental application** 

cost CDP) are summarized in table 8.

*CS=0.7*

Asph. Rubber Hot Mix – Gap Graded (4-5cm) (PM/REH)-

Note. PM: Preventive Maintenance treatment; REH: REHabilitation

After (Moulthrop et al, 1998; Hicks and Epps, 2005; Shober and Friedrichs, 2002)


Table 7. Case-history (years are rounded to the nearest integer; moduli in KPa).


Table 8. PA determination –Inputs and outputs *(the percentages are referred to CDP).*

## **4. Main findings**

In the light of above facts, the main findings of the study can be summarized in terms of drawbacks and point of strengths. Air void content has a vital role in QC/QA. A decrease in porosity (or effective porosity) yields in-lab specific gravities that converge toward the maximum theoretical specific gravity Gmm (convergence of in-lab measurements). In contrast, gravities determined through non-nuclear portable devices often increase due to the high dielectric constant of water (divergence of in-site measures).

Uncertainties in the determination of the expected life of the different characteristics and complexity are the main drawbacks of the models of PA based on LCCA. On the contrary,

QA/QC in Transport Infrastructures: Issues and Perspectives 203

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Transportation, 2007.

DC 20418, April.

874-886.

January, 1998.

Seattle, WA.

October -2008.

05-233, Final Report, Iowa State University, Ames; Iowa Department of

Highway Quality Assurance terms, Transportation Research Circular number E-C037, TRB National research Board, 2101 Constitution Avenue, NW, Washington,

109; b) L. 18 novembre 1998, n. 415 - c.d. L. Merloni ter; c) Capitolato Speciale d'appalto ANAS 1998 e succ.– artt.12, 13, 19; d)D.P.R. 21.12.99 n. 554 (Reg. di attuazione); e) Norme tecniche di tipo prestazionale per capitolati speciali d'appalto (CIRS, Centro sperimentale Interuniversitario di Ricerca Stradale), 2000;

reliability and potentiality of nonnuclear portable devices for asphalt mixture density measurement, 2010, Journal of Materials in Civil Engineering 22 (9), pp.

influencing the permeability of hot-mix asphalt mixtures. Volume 74E Electronic

maintenance, 1998 Western Pavement maintenance Forum, Sacramento, CA, USA,

Mix Asphalt Concrete Statistical Acceptance Specification. WA-RD 517.1. Washington State Department of Transportation, Transportation Center (TRAC).

mechanical defects are involved? a synergetic study on theory and experiments, SURF 08 – 6th Symposium on surface characteristics, Portoroz, Slovenia, 20/22

model based on both mechanical and surface performance of flexible pavements, Construction Management and Economics, Volume 25, Issue 3, pages 305 – 313,

and Experimental Investigation. International Journal of Pavement Research and

core diameter dependence, 2011b, Construction and Building Materials, doi:


**Part 5** 

**Quality Control** 

**for Medical Research and Process** 


http://www.transtechsys.com/products/pro\_lib\_pqi.htm.


## **Part 5**

**Quality Control for Medical Research and Process** 

206 Modern Approaches To Quality Control

Shober S.F., Friedrichs D.A. (2002). A Pavement Preservation Strategy, Wisconsin

Siegwart, R. (2001). Indirect Manipulation of a Sphere on a Flat Disk Using Force

Smith R.D. (1979) Pavement wear and studded tire use in Iowa, Final Report, Iowa highway

Spellerberg P, Savage D. An investigation of the cause of variation in HMA Bulk Specific

State of Florida Department of Transportation (2004). Asphalt concrete friction courses,

TransTech Systems Inc. Effect of Water and Temperature on Hot Mix Asphalt Density

Uddin, M., Mohboub, K.C., Goodrum, P.M. (2011). "Effects of Nonnormal Distributions on

Construction Engineering and Management, volume 137, n° 2, pp. 108-118.

Van Til, C.J., McCullough B.F., Vallerga B.A., Hicks R.G., Evaluation of AASHO Interim

Weed Richard M. (2001). "Derivation of equation for cost of premature pavement failure",

Weed Richard M., Kaz Tabrizi , Conceptual framework for pavement smoothness

Western Federal Lands Highway Division FP Specification Change (2004). "Pavement

Whiteley Leanne, Susan Tighe, Zhanmin Zhang, Incorporating Variability into Pavement

Williams SG. Non-Nuclear Methods for HMA Density Measurements. MBTC 2075, Final

Performance, Life Cycle Cost Analysis and Specification Pay Factors, 84th Annual

specification, TRB 2005 Annual Meeting, January, 2005.

Information. *International Journal of Advanced Robotic Systems,* Vol.6, No.4,

Gravity test results using non-absorptive aggregates. National Cooperative Highway Research Program Web Document 66 (Project 9-26 (Phase 2), July

Measurement using Electromagnetic Sensing. TransTech Technical Note 0301,

Highway Construction acceptance Pay Factor Calculations", Journal of

guides for of pavement structures, NCHRP 128, Highway Research Board,

Department of ransportation Library, USA.

(December 2009), pp. 12-16, ISSN 1729-8806

Schenectady, January 15, 2003. Available online: http://www.transtechsys.com/products/pro\_lib\_pqi.htm.

Ullidtz, P. (1987). Pavement Analysis. Elsevier, Amsterdam.

80th TRB annual meeting.

Smoothness/Roughness".

Meeting - January 9-13, 2005.

Report, University of Arkansas, June 2008.

research Board, Project HR-148.

2004.

1972.

December.

**11** 

*Spain* 

**by ISO 15189** 

**Procedures for Validation of Diagnostic** 

Silvia Izquierdo Álvarez and Francisco A. Bernabeu Andreu

*Hospital Universitario Príncipe de Asturias, Alcalá de Henares, Madrid,* 

**Methods in Clinical Laboratory Accredited** 

*Servicio de Bioquímica Clínica, Hospital Universitario Miguel Servet, Zaragoza* 

Actually, each clinical and/or biochemical laboratory has responsibility for demonstrating its competence and therefore must obtain results of good quality. Medical laboratories provide vital medical services to different clients: clinicians requesting a test, patients from whom the sample was collected, public health and medical-legal instances, referral laboratories and authoritative bodies. All expect results that are accurate and obtained in an effective manner, within a suitable time frame and at acceptable cost. There are different ways of achieving the end results, but compliance with International Organization for Standardization (ISO) 15189, the international standard for the accreditation of medical laboratories, is becoming progressively accepted as the optimal approach to assuring quality in medical testing. As result, the accreditation of clinical laboratories is shifting from being a "recommendation" to becoming a "requirement" in many countries throughout Europe and in the other countries around the world (Berwouts, 2010). *Accreditation* is defined by ISO as the "Procedure by which an authoritative body gives formal recognition that a body or person is competent to carry out specific tasks". Although accreditation also considers the quality management system (QMS), it has additional formal requirements of technical competence, including initial and continuous training of personnel, *validation of methods and* 

A good QMS in the laboratory has a lot of advantages such as increased transparency, traceability, uniformity, work satisfaction and better focus on critical points. On the contrary, it will require extra time on aspects such as document control and there is a danger of losing critical attitude and curbing innovation and changes. Therefore, a formal accreditation and the linked periodical audits are stimulant for keeping the quality system (QS) alive. Without accreditation, there is a danger of giving less attention to quality improvement. In addition, accreditation is a good way to demonstrate and attest competence and a worldwide tool to recognize laboratories. Finally, all parties (patients, families, the laboratory and clinicians) are benefited through better processes and quality of

All essential elements of QS are covered by the ISO 15189 accreditation standard in two distinct chapters: management requirements and technical requirements. Technical elements

**1. Introduction** 

results (Berwouts, 2010).

*instruments*, and internal and external quality control.

## **Procedures for Validation of Diagnostic Methods in Clinical Laboratory Accredited by ISO 15189**

Silvia Izquierdo Álvarez and Francisco A. Bernabeu Andreu *Servicio de Bioquímica Clínica, Hospital Universitario Miguel Servet, Zaragoza Hospital Universitario Príncipe de Asturias, Alcalá de Henares, Madrid, Spain* 

## **1. Introduction**

Actually, each clinical and/or biochemical laboratory has responsibility for demonstrating its competence and therefore must obtain results of good quality. Medical laboratories provide vital medical services to different clients: clinicians requesting a test, patients from whom the sample was collected, public health and medical-legal instances, referral laboratories and authoritative bodies. All expect results that are accurate and obtained in an effective manner, within a suitable time frame and at acceptable cost. There are different ways of achieving the end results, but compliance with International Organization for Standardization (ISO) 15189, the international standard for the accreditation of medical laboratories, is becoming progressively accepted as the optimal approach to assuring quality in medical testing. As result, the accreditation of clinical laboratories is shifting from being a "recommendation" to becoming a "requirement" in many countries throughout Europe and in the other countries around the world (Berwouts, 2010). *Accreditation* is defined by ISO as the "Procedure by which an authoritative body gives formal recognition that a body or person is competent to carry out specific tasks". Although accreditation also considers the quality management system (QMS), it has additional formal requirements of technical competence, including initial and continuous training of personnel, *validation of methods and instruments*, and internal and external quality control.

A good QMS in the laboratory has a lot of advantages such as increased transparency, traceability, uniformity, work satisfaction and better focus on critical points. On the contrary, it will require extra time on aspects such as document control and there is a danger of losing critical attitude and curbing innovation and changes. Therefore, a formal accreditation and the linked periodical audits are stimulant for keeping the quality system (QS) alive. Without accreditation, there is a danger of giving less attention to quality improvement. In addition, accreditation is a good way to demonstrate and attest competence and a worldwide tool to recognize laboratories. Finally, all parties (patients, families, the laboratory and clinicians) are benefited through better processes and quality of results (Berwouts, 2010).

All essential elements of QS are covered by the ISO 15189 accreditation standard in two distinct chapters: management requirements and technical requirements. Technical elements

Procedures for Validation of

**Precise, but inaccurate IQC OK EQA fails**

IQC: Internal Quality Control EQA: External Quality assessment Fig. 1. Accuracy and precision.

one or more of the following:

including the following:



principles of the method and practical experience.


element, which makes this method, does not meet customer requirements.

**2. Validation design of a method** 

Diagnostic Methods in Clinical Laboratory Accredited by ISO 15189 211

*Diagnostic validation* is a formal requirement of accreditation standards, including ISO 17025 and ISO 15189, those tests/methods and instruments must be validated before diagnostic use to ensure reliable results for patients, clinicians or referring laboratories and their quality must be maintained throughout use. In other words, the laboratory must demonstrate that their tests/methods are fit for the intended use before application to patient samples. Figure 2 shows a summary of what ISO 15189 states with regard to validation (Berwouts, 2010; Burnett & C. Blair, 2001, Burnett et al., 2002; Burnett, 2006). Although the concept of validation makes explicit reference to the purely analytical aspects may also include preanalytical and sampling procedures, handling and transport. At a minimum, the techniques used to determine the performance of a method should be



In any case, analytical methods must be those that meet customer requirements, that is, those that provide clinically useful information. Thus, an analytical method for determination of aluminium in serum based on the complexation of this element with 8 hydroxyquinoline and quantification by fluorimetry can have high reliability but its detection limit is at least an order of magnitude above the upper limit of the reference

There are publications that provide general methods of evaluation of analytical methods

**Precise, and accurate IQC OK EQA OK**

enclose personnel and training, accommodation, equipment, *validation* and assuring quality of examination procedures by internal quality control (IQC), external quality control (EQA), maintenance and calibration.

ISO 15189 standard emphasizes so in the quality of contributions to patient care as in laboratory and management procedures and specifies the quality management system requirements, in particular to medical laboratories and stages:

<<The laboratory shall use only validated procedures for confirming that the examination procedures are suitable for intended use>>, <<The validation shall be as extensive as are necessary to meet the needs in the given application or field of application>>, and <<Procedures need to be periodically revalidated in view if changing conditions and technical advances>>.

IQC is an internal verification that the test yields consistent results day after day; in the other words, the identification measure of *precision*, but not necessarily of *accuracy*. ISO 15189 requires that "the laboratory shall design IQC systems that verify the attainment of the intended quality of results". On the hand, the laboratory should avoid mistakes (ISO 15189, 5.6.1.) in the process of handling samples, requests, examinations, reports and so on; on the other, the laboratory should determine *uncertainty* (ISO 15189, 5.6.2) where relevant and possible. For each test, the laboratory should identify and define potential errors, risks and challenges (typically, during the validation phase); subsequently, specific IQC should be defined to assure each risk and potential problem.

EQA is an important complement to IQC in which a large number of laboratories are provided with the same material and required to return results to a coordinating centre. The results are compared to determine the *accuracy* of the individual laboratory. In addition, EQA provides continuous education and training for laboratories as well. Accredited laboratories are required to "participate in interlaboratory comparisons such as those organized by EQA schemes" (ISO 15189, 5.6.4). EQA should, as far as possible, cover the entire range of tests, and the entire examination process, from sample reception, preparation and analysis to interpretation and reporting (ISO 15189 5.6.5). For some specific tests, no EQA scheme exists. ISO 15189 (5.6.5) states "whenever a formal laboratory comparison programme is not available, the laboratory shall develop a mechanism for determining the acceptability of procedures nor otherwise evaluated"; examples include reference materials or interlaboratory exchange. Interlaboratory comparisons should cover the scope of services offered and there should be a formal mechanism of review and comparison of results.

Used together, IQC and EQA provide a method of ensuring accuracy and consistency of results and are vital tools in the laboratory. The relation between precision and accuracy may be illustrated by the familiar example of shooting arrows at a target (Berwouts, 2010; Burnett, 2006) (figure 1).

The results provided by the clinical/medical laboratory must be accurate to allow a correct clinical interpretation and to be comparable with earlier or later and between laboratories. So the purpose of this chapter is to establish a set of guidelines and recommendations to help personnel carry out their work in clinical/medical laboratories that are accredited or under accreditation by ISO 15189. It is necessary to establish and define the different procedures validation, the fundamental guidelines for the proper design of the validation, the recommendations to validate an established method in the laboratory, and the different parameters to be assessed.

EQA: External Quality assessment

enclose personnel and training, accommodation, equipment, *validation* and assuring quality of examination procedures by internal quality control (IQC), external quality control (EQA),

ISO 15189 standard emphasizes so in the quality of contributions to patient care as in laboratory and management procedures and specifies the quality management system

<<The laboratory shall use only validated procedures for confirming that the examination procedures are suitable for intended use>>, <<The validation shall be as extensive as are necessary to meet the needs in the given application or field of application>>, and <<Procedures need to be periodically revalidated in view if changing conditions and

IQC is an internal verification that the test yields consistent results day after day; in the other words, the identification measure of *precision*, but not necessarily of *accuracy*. ISO 15189 requires that "the laboratory shall design IQC systems that verify the attainment of the intended quality of results". On the hand, the laboratory should avoid mistakes (ISO 15189, 5.6.1.) in the process of handling samples, requests, examinations, reports and so on; on the other, the laboratory should determine *uncertainty* (ISO 15189, 5.6.2) where relevant and possible. For each test, the laboratory should identify and define potential errors, risks and challenges (typically, during the validation phase); subsequently, specific IQC should

EQA is an important complement to IQC in which a large number of laboratories are provided with the same material and required to return results to a coordinating centre. The results are compared to determine the *accuracy* of the individual laboratory. In addition, EQA provides continuous education and training for laboratories as well. Accredited laboratories are required to "participate in interlaboratory comparisons such as those organized by EQA schemes" (ISO 15189, 5.6.4). EQA should, as far as possible, cover the entire range of tests, and the entire examination process, from sample reception, preparation and analysis to interpretation and reporting (ISO 15189 5.6.5). For some specific tests, no EQA scheme exists. ISO 15189 (5.6.5) states "whenever a formal laboratory comparison programme is not available, the laboratory shall develop a mechanism for determining the acceptability of procedures nor otherwise evaluated"; examples include reference materials or interlaboratory exchange. Interlaboratory comparisons should cover the scope of services offered and there should be a formal mechanism of review and comparison of results. Used together, IQC and EQA provide a method of ensuring accuracy and consistency of results and are vital tools in the laboratory. The relation between precision and accuracy may be illustrated by the familiar example of shooting arrows at a target (Berwouts, 2010;

The results provided by the clinical/medical laboratory must be accurate to allow a correct clinical interpretation and to be comparable with earlier or later and between laboratories. So the purpose of this chapter is to establish a set of guidelines and recommendations to help personnel carry out their work in clinical/medical laboratories that are accredited or under accreditation by ISO 15189. It is necessary to establish and define the different procedures validation, the fundamental guidelines for the proper design of the validation, the recommendations to validate an established method in the laboratory, and the different

requirements, in particular to medical laboratories and stages:

be defined to assure each risk and potential problem.

maintenance and calibration.

technical advances>>.

Burnett, 2006) (figure 1).

parameters to be assessed.

Fig. 1. Accuracy and precision.

## **2. Validation design of a method**

*Diagnostic validation* is a formal requirement of accreditation standards, including ISO 17025 and ISO 15189, those tests/methods and instruments must be validated before diagnostic use to ensure reliable results for patients, clinicians or referring laboratories and their quality must be maintained throughout use. In other words, the laboratory must demonstrate that their tests/methods are fit for the intended use before application to patient samples. Figure 2 shows a summary of what ISO 15189 states with regard to validation (Berwouts, 2010; Burnett & C. Blair, 2001, Burnett et al., 2002; Burnett, 2006).

Although the concept of validation makes explicit reference to the purely analytical aspects may also include preanalytical and sampling procedures, handling and transport. At a minimum, the techniques used to determine the performance of a method should be one or more of the following:


In any case, analytical methods must be those that meet customer requirements, that is, those that provide clinically useful information. Thus, an analytical method for determination of aluminium in serum based on the complexation of this element with 8 hydroxyquinoline and quantification by fluorimetry can have high reliability but its detection limit is at least an order of magnitude above the upper limit of the reference element, which makes this method, does not meet customer requirements.

There are publications that provide general methods of evaluation of analytical methods including the following:

Procedures for Validation of

a. Planning:

c. Control:

reference standard.

selectivity, etc.

ensure that the results come to fruition.

operators and results).

Verification of compliance with targets.

a. *Planning* consists of the following phases:

Diagnostic Methods in Clinical Laboratory Accredited by ISO 15189 213

A validation process like any other requires a series of planning, execution and control to

 Definition of objectives and internal requirements applied the method to validate (purpose, parameters to measure in the matrix or matrices to be determined).

1) Assign responsibility. In this phase it will be defined a person responsible for carrying out the validation process and deciding the outcome. This person can count on help from others, but he is responsible for making decisions so, he must have a proper qualification; 2) Definition of the characteristics and requirements applied to the method: The definition of requirements has to do with the intended use of the method ( i.e. as property or analyte, the matrix or matrices in which they will determine the use that will make the test results and legal requirements or economic policy to be applied to test results), from the specified requirements and based on a literature search using other standards, etc. There is a design and optimization phase of the procedure that is performed by laboratory. This is the stage where, for example for an instrumental method, you must establish a priori the linearity of the method, the working range, the limit of detection and quantification is desired, the accuracy and precision fit. In short what features the laboratory can apply the method to the intended use; 3) Description documented procedure: It should be sufficiently detailed to ensure its proper performance and repeatability. This ensures that all laboratory personnel

To accomplish this phase can be helpful in establishing a suitable index of the case as the

b. *Implementation*: Outcome is based on the realization of a series of tests and experiments that occur as a result values for the parameters defined in the requirements. These parameters can be variable depending on the type of method applied and the requirements and can include accuracy, precision, limit of detection, limit of quantization,

c. *Control*: The control is the verification of compliance and the final declaration. 1) Verification of compliance: As a result of the implementation of activities will be decided whether the values meet the specified requirements, in which case proceed to establish which checks should be made to the method as regular monitoring to confirm that remain requirements requested at the time of validation, e.g. using a control pattern periodically check the parameters of the regression line, etc., proceeding to their inclusion in the proceedings and preparing a final edition of the same. Otherwise you may be assessed if an amendment to the previously established requirements. 2) Final Statement: All the validation process should conclude with a formal statement of the adequacy of the procedure defined as stated is suitable for their intended use, according to specified

 Definition and documentation of the method (procedure for validation). b. Implementation: implementation of activities, results obtained and recorded (date,

Final Declaration of the appropriateness of the procedure defined.

that are qualified can do just as the method with comparable results.

requirements (Burnett & C. Blair, 2001; Burnett et al., 2001; Burnett, 2006).

Definition responsible for performing the validation process.


Fig. 2. Validation requirements according ISO 15189:2007.

Regarding the validation and control of analytical procedures, paragraph 5.5 of ISO 15189: 2007 specifies to be used those procedures "that have been published by experts or international guidelines, national or regional". Own procedures "must be properly validated for its intended use and fully documented".

So, ISO 15189: 2007 says "as appropriate, the documentation should include the following: technical specifications (e.g., linearity, precision, accuracy, expressed as a measurement uncertainty limit of detection, measurement, sensitivity and specificity, and interference)" (ISO 15189, 5.5.3).

When a unit or section of a clinical/medical laboratory chooses to engage in the accreditation ISO 15189, must be aware that although the analytical methods which usually works have been validated in its implementation must be validated in time.

A validation process like any other requires a series of planning, execution and control to ensure that the results come to fruition.

a. Planning:

212 Modern Approaches To Quality Control

4. To determine the accuracy through recovery studies before a definitive method or

1. Definition of the evaluation protocol that registers the results of the measurements.

2. Determining the range of application and dilution mechanisms, if any.

6. Estimate the limit of detection and quantification (and others if applicable).

3. Identify the components of precision in the day, every day.

7. To study the specificity of the method, checking for interference.

Fig. 2. Validation requirements according ISO 15189:2007.

for its intended use and fully documented".

(ISO 15189, 5.5.3).

Regarding the validation and control of analytical procedures, paragraph 5.5 of ISO 15189: 2007 specifies to be used those procedures "that have been published by experts or international guidelines, national or regional". Own procedures "must be properly validated

So, ISO 15189: 2007 says "as appropriate, the documentation should include the following: technical specifications (e.g., linearity, precision, accuracy, expressed as a measurement uncertainty limit of detection, measurement, sensitivity and specificity, and interference)"

When a unit or section of a clinical/medical laboratory chooses to engage in the accreditation ISO 15189, must be aware that although the analytical methods which usually

works have been validated in its implementation must be validated in time.

reference, if any. 5. To determine the sensitivity.

8. Establishing the reference range. 9. Document the validity of the method.

	- Verification of compliance with targets.
	- Final Declaration of the appropriateness of the procedure defined.

a. *Planning* consists of the following phases:

1) Assign responsibility. In this phase it will be defined a person responsible for carrying out the validation process and deciding the outcome. This person can count on help from others, but he is responsible for making decisions so, he must have a proper qualification; 2) Definition of the characteristics and requirements applied to the method: The definition of requirements has to do with the intended use of the method ( i.e. as property or analyte, the matrix or matrices in which they will determine the use that will make the test results and legal requirements or economic policy to be applied to test results), from the specified requirements and based on a literature search using other standards, etc. There is a design and optimization phase of the procedure that is performed by laboratory. This is the stage where, for example for an instrumental method, you must establish a priori the linearity of the method, the working range, the limit of detection and quantification is desired, the accuracy and precision fit. In short what features the laboratory can apply the method to the intended use; 3) Description documented procedure: It should be sufficiently detailed to ensure its proper performance and repeatability. This ensures that all laboratory personnel that are qualified can do just as the method with comparable results.

To accomplish this phase can be helpful in establishing a suitable index of the case as the reference standard.

b. *Implementation*: Outcome is based on the realization of a series of tests and experiments that occur as a result values for the parameters defined in the requirements. These parameters can be variable depending on the type of method applied and the requirements and can include accuracy, precision, limit of detection, limit of quantization, selectivity, etc.

c. *Control*: The control is the verification of compliance and the final declaration. 1) Verification of compliance: As a result of the implementation of activities will be decided whether the values meet the specified requirements, in which case proceed to establish which checks should be made to the method as regular monitoring to confirm that remain requirements requested at the time of validation, e.g. using a control pattern periodically check the parameters of the regression line, etc., proceeding to their inclusion in the proceedings and preparing a final edition of the same. Otherwise you may be assessed if an amendment to the previously established requirements. 2) Final Statement: All the validation process should conclude with a formal statement of the adequacy of the procedure defined as stated is suitable for their intended use, according to specified requirements (Burnett & C. Blair, 2001; Burnett et al., 2001; Burnett, 2006).

Procedures for Validation of

about the detailed requirements or procedures.

5.4.2 "Laboratory-developed methods or methods adopted by the laboratory may also be used if they are appropiate for the intended use

5.4.5.2 "The laboratory shall validate non-standard methods, laboratorydesigned/developed methods, standard methods used outside their intended scope, and amplifications and modifications of standard methods to confirm that methods are fit for the intended use. The validation shall be as extensive as is necessary to meet the needs of the given application or field or application.The laboratory shall record the results obtained, the procedure used for validation, and a statement as to

5.4.5.3 "NOTE 1 validation includes specification of the requirements, determination of the characteristics of the methods, a check that the requirements can be fulfilled by using the method, and a statement on the validity. NOTE 3 Validation is always a balance between costs, risks and technical possibilities, There are many cases in which the range and uncertainty of the values (eg accuracy, detection limit, selectivity, linearity, repeatability, robutness and cross-sensivity) can only be given in a

and if they are validated".

wether the method is fit for the intended use".

simplified way due to lack of information".

verification.

correct analyte(s), are measured.

Diagnostic Methods in Clinical Laboratory Accredited by ISO 15189 215

The validation or verification of methods, as defined in figure 4, is a normal requirement for the accreditation of laboratories according to the two major international standards applicable to clinical/medical laboratories, ISO 15189 and ISO 17025. Although the general requirements are clearly stablished (figure 4), the standards provide very little guidance

Before a test/method can be validated, it is necessary to establish (a) that the particular measurements are diagnostically useful and (b) that the correct analyte(s), and only the

Full validation is required when is no suitable performance specification available, for example, with novel tests/methods or technologies. This process involves assessing the performance of the test/method in comparison with a "gold standard" or reference test/method that is capable of assigning the sample status without error. In simple terms, validation can be seen as a process to determine whether the laboratory is "performing the correct test/method". Validation data can be used to assess the accuracy of either the technology or the specific test/method. Generally speaking, the generic validation of a novel technology should be performed on a larger scale, ideally in multiple laboratories (interlaboratory validation), and should include a much more comprehensive investigation of the critical parameters relevant to the specific technology to provide the highest chance of

*Principle requirements of ISO 157025:2005 Principle requirements od ISO 15189:2007*

Fig. 4. Principle requirements of ISO 15189: 2007 and ISO 17025:2005 about validation and

intervals".

relevant and possible".

5.5.1 "[….]If in-house procedures are used, they shall be appropriately validated for their intended use and fully documented". 5.5.2 "The methods and procedures selected for use shall be evaluated and found to give satisfactory results before used for medical examinations. A review of procedures by the laboratory director or designated person shall be understaken initially and at defined

5.6.2 "The laboratory shall determine the uncertainty of results, where

detecting sources of variation and interference (Berwouts, 2010; Burnett, 2006).

## **2.1 Types and methods of validation**

The laboratory shall validate examination procedures from non standard methods, laboratory designed or development methods, standard methods used outside their intended scope and modified validated methods.

When examination procedures have been validated by the method developer (i.e., the manufacturer or author of a published procedure), the laboratory shall obtain information from the method developer to confirm that the performance characteristics of the method are appropriate for its intended use. When changes are made to a validated examination procedure, the influence of such changes shall be documented and, if appropriate, a new validation shall be carried out.

Examination procedures from method developers that used without modification shall be subject to verification before being introduced into routine use. The verification shall confirm, through provision of objective evidence (performance characteristics), that the performance claims for the examination method have been met. The performance claims for the examination method confirmed during the verification process shall be those relevant to the intended use of the examination results.

Verification and validation are two slightly different procedures (figure 3). By default, all new laboratory procedures must be validated before application to clinical testing. In addition, a validation is necessary when major technical modifications to existing methods are carried out or when the performance of existing methods has been shown to be unsatisfactory (Berwouts, 2010; Hauck et al., 2008).

Fig. 3. Validation vs verification in diagnostic methods.

The laboratory shall validate examination procedures from non standard methods, laboratory designed or development methods, standard methods used outside their

When examination procedures have been validated by the method developer (i.e., the manufacturer or author of a published procedure), the laboratory shall obtain information from the method developer to confirm that the performance characteristics of the method are appropriate for its intended use. When changes are made to a validated examination procedure, the influence of such changes shall be documented and, if appropriate, a new

Examination procedures from method developers that used without modification shall be subject to verification before being introduced into routine use. The verification shall confirm, through provision of objective evidence (performance characteristics), that the performance claims for the examination method have been met. The performance claims for the examination method confirmed during the verification process shall be those relevant to

Verification and validation are two slightly different procedures (figure 3). By default, all new laboratory procedures must be validated before application to clinical testing. In addition, a validation is necessary when major technical modifications to existing methods are carried out or when the performance of existing methods has been shown to be

> *VALIDATION VS VERIFICATION OF A METHOD IN A CLINICAL/MEDICAL LABORATORY*

•Existing METHOD with defined performance •Existing METHOD used after repair

> VERIFICATION Before use as diagnostic test/method

**COMPARE** PERFORMANCE CHARACTERISTICS, with specifications. Be aware of and respect specified requirements

DOCUMENT and record the results obtained and the procedure used for the validation

CONTINUOUS VALIDATION

**2.1 Types and methods of validation** 

validation shall be carried out.

•Non standard method

•Modified validated method

•Laboratory designed by developed method •Standard method used outside their intended scope

intended scope and modified validated methods.

the intended use of the examination results.

VALIDATION Before use as diagnostic test/method

**DEFINE** PERFORMANCE CHARACTERISTICS, As extensive as is necessary to confirm, Throug the provision of objective evidence, That the specific requirements for the intended use have been fulfilled

DOCUMENT and record the results obtained and the procedure used for the validation

CONTINUOUS VALIDATION

Fig. 3. Validation vs verification in diagnostic methods.

unsatisfactory (Berwouts, 2010; Hauck et al., 2008).

The validation or verification of methods, as defined in figure 4, is a normal requirement for the accreditation of laboratories according to the two major international standards applicable to clinical/medical laboratories, ISO 15189 and ISO 17025. Although the general requirements are clearly stablished (figure 4), the standards provide very little guidance about the detailed requirements or procedures.

Before a test/method can be validated, it is necessary to establish (a) that the particular measurements are diagnostically useful and (b) that the correct analyte(s), and only the correct analyte(s), are measured.

Full validation is required when is no suitable performance specification available, for example, with novel tests/methods or technologies. This process involves assessing the performance of the test/method in comparison with a "gold standard" or reference test/method that is capable of assigning the sample status without error. In simple terms, validation can be seen as a process to determine whether the laboratory is "performing the correct test/method". Validation data can be used to assess the accuracy of either the technology or the specific test/method. Generally speaking, the generic validation of a novel technology should be performed on a larger scale, ideally in multiple laboratories (interlaboratory validation), and should include a much more comprehensive investigation of the critical parameters relevant to the specific technology to provide the highest chance of detecting sources of variation and interference (Berwouts, 2010; Burnett, 2006).


Fig. 4. Principle requirements of ISO 15189: 2007 and ISO 17025:2005 about validation and verification.

Procedures for Validation of

international units.

Systematic error

Total error

Random error

Type of error

**2.2.2 Qualitative methods** 

methods (adapted from Menditto et al., 2007).

Diagnostic Methods in Clinical Laboratory Accredited by ISO 15189 217

should be considered in the validation as well. Robustness can be considered as a useful

As trueness and precision represent two different forms of error, they need to be treated in different ways. In practice, systematic error or bias can often be resolved by using a correction factor; constant bias requires an additive correction factor, whereas proportional

For quantitative methods, particularly those requiring absolute quantification, it is most effective to estimate analytical accuracy on an ongoing basis by running a set of calibration standards (standard curve) with each batch or run. In this case, it is important that linearity be evaluated and that the lower and upper standards are respectively below and above the expected range of the results as precision cannot be assessed on extrapolated results. Where possible, calibration standards should be traceable to absolute numbers or to recognized

Other factors that may need to be evaluated include the limit of detection defined as the lowest quantity of analyte that can be reliably detected above background noise levels and the limits of quantification that define the extremities at which the measurement response to

Trueness

Bias

Measurement uncertainty

Standard deviation

Precision Repeatability, intermediate precision, reproducibility

Performance

Fig. 5. Performance characteristics, error types and measurement metrics uses for qualitative

This is an extreme form of a categorical test/method, in which there are only two result categories, positive and negative. This binary categorization can be based either on a cut-off

characteristic Description (Metric)

Accuracy

prediction of expected intermediate precision (Berwouts, 2010).

bias requires a multiplicative correction factor.

changes in the analyte remains linear (Berwouts, 2010).

#### **2.2 Recommendations to validate a method developed in the laboratory 2.2.1 Quantitative methods**

Two components of analytical accuracy are required to characterize a quantitative method: trueness and precision. Trueness expresses how close the methods result is to the reference value. Typically, multiple measurements are made for each point and the rest method result is taken to be the mean of the replicate results (excluding outliers if necessary). As quantitative assays measure a continuous variable, mean results are often represented by a regression of data (a regression line is a linear average). Any deviation of this regression from the reference indicates a systematic error, which expressed as a bias (i.e., a number indicating the size and direction of the deviation from the true result). There are two general forms of bias. With constant bias, method results deviate from the reference value by the same amount, regardless of that value. With proportional bias, the deviation is proportional to the reference value. Both forms of bias can exist simultaneously. Although measurement of bias is useful, it is only one component of the measurement uncertainty and gives no indication of how dispersed the replicate results are. This dispersal is called precision and can be measured by imprecision, that provides an indication of how well a single method results is representative of a number of replicates or repetitions. Imprecision is commonly expressed as the standard deviation of the replicate results, but is often more informative to describe a confidence interval (CI) around the mean result. Precision is subdivided according to how replicate analyses are handled an evaluated.

Repeatability refers to the closeness of agreement between results of test performed on the same method items, by the same analyst, on the same instrument, under the same conditions in the same location and repeated over a short period of time. Repeatability represents "within-run precision".

Intermediate precision refers to closeness of agreement between results of methods performed on the same method items in a single laboratory but over an extended period of time, taking account of normal variation in laboratory conditions such as different operators, different equipment and different days. Intermediate precision therefore represents "withinlaboratory, between-run precision" and is therefore a useful measure for inclusion in ongoing validation.

Reproducibility refers to closeness of agreement between results of methods carried out on the same method items, taking into account the broadest range of variables encountered in real laboratory conditions, including different laboratories. Reproducibility therefore represents "inter-laboratory precision".

In practical terms, internal laboratory validation will only be concerned with repeatability and intermediate precision and in many cases both can be investigated in a single series of well-designed experiments. Reduced precision indicates the presence of random error. The relationship between the components of analytical accuracy, types of error and the metrics used to describe them is illustrated in figure 5.

Any validation should also consider robustness, which, in the context of a quantitative method, could be considered as a measure of precision. However, robustness expresses how well a method maintains precision when faced by a specific designed "challenge", in the form of precision does not represent random error. Typical variables in the laboratory include sample type, sample handling, sample quality, instrument make and model, reagent lots and environmental conditions (e.g., humidity, temperature). Appropriate variables should be considered and tested for each specific method. The principle of purposefully challenging methods is also applicable to both categorical and qualitative methods and

Two components of analytical accuracy are required to characterize a quantitative method: trueness and precision. Trueness expresses how close the methods result is to the reference value. Typically, multiple measurements are made for each point and the rest method result is taken to be the mean of the replicate results (excluding outliers if necessary). As quantitative assays measure a continuous variable, mean results are often represented by a regression of data (a regression line is a linear average). Any deviation of this regression from the reference indicates a systematic error, which expressed as a bias (i.e., a number indicating the size and direction of the deviation from the true result). There are two general forms of bias. With constant bias, method results deviate from the reference value by the same amount, regardless of that value. With proportional bias, the deviation is proportional to the reference value. Both forms of bias can exist simultaneously. Although measurement of bias is useful, it is only one component of the measurement uncertainty and gives no indication of how dispersed the replicate results are. This dispersal is called precision and can be measured by imprecision, that provides an indication of how well a single method results is representative of a number of replicates or repetitions. Imprecision is commonly expressed as the standard deviation of the replicate results, but is often more informative to describe a confidence interval (CI) around the mean result. Precision is subdivided

Repeatability refers to the closeness of agreement between results of test performed on the same method items, by the same analyst, on the same instrument, under the same conditions in the same location and repeated over a short period of time. Repeatability

Intermediate precision refers to closeness of agreement between results of methods performed on the same method items in a single laboratory but over an extended period of time, taking account of normal variation in laboratory conditions such as different operators, different equipment and different days. Intermediate precision therefore represents "withinlaboratory, between-run precision" and is therefore a useful measure for inclusion in

Reproducibility refers to closeness of agreement between results of methods carried out on the same method items, taking into account the broadest range of variables encountered in real laboratory conditions, including different laboratories. Reproducibility therefore

In practical terms, internal laboratory validation will only be concerned with repeatability and intermediate precision and in many cases both can be investigated in a single series of well-designed experiments. Reduced precision indicates the presence of random error. The relationship between the components of analytical accuracy, types of error and the metrics

Any validation should also consider robustness, which, in the context of a quantitative method, could be considered as a measure of precision. However, robustness expresses how well a method maintains precision when faced by a specific designed "challenge", in the form of precision does not represent random error. Typical variables in the laboratory include sample type, sample handling, sample quality, instrument make and model, reagent lots and environmental conditions (e.g., humidity, temperature). Appropriate variables should be considered and tested for each specific method. The principle of purposefully challenging methods is also applicable to both categorical and qualitative methods and

**2.2 Recommendations to validate a method developed in the laboratory** 

according to how replicate analyses are handled an evaluated.

**2.2.1 Quantitative methods** 

represents "within-run precision".

represents "inter-laboratory precision".

used to describe them is illustrated in figure 5.

ongoing validation.

should be considered in the validation as well. Robustness can be considered as a useful prediction of expected intermediate precision (Berwouts, 2010).

As trueness and precision represent two different forms of error, they need to be treated in different ways. In practice, systematic error or bias can often be resolved by using a correction factor; constant bias requires an additive correction factor, whereas proportional bias requires a multiplicative correction factor.

For quantitative methods, particularly those requiring absolute quantification, it is most effective to estimate analytical accuracy on an ongoing basis by running a set of calibration standards (standard curve) with each batch or run. In this case, it is important that linearity be evaluated and that the lower and upper standards are respectively below and above the expected range of the results as precision cannot be assessed on extrapolated results. Where possible, calibration standards should be traceable to absolute numbers or to recognized international units.

Other factors that may need to be evaluated include the limit of detection defined as the lowest quantity of analyte that can be reliably detected above background noise levels and the limits of quantification that define the extremities at which the measurement response to changes in the analyte remains linear (Berwouts, 2010).

Fig. 5. Performance characteristics, error types and measurement metrics uses for qualitative methods (adapted from Menditto et al., 2007).

#### **2.2.2 Qualitative methods**

This is an extreme form of a categorical test/method, in which there are only two result categories, positive and negative. This binary categorization can be based either on a cut-off

Procedures for Validation of

business (controls to the truth).

of external quality assessment.

participating laboratories.

correction factors.

**programs** 

as diagnostic daily reality for clinical laboratories.

**3.1 Estimation of the accuracy using reference materials** 

Diagnostic Methods in Clinical Laboratory Accredited by ISO 15189 219

the laboratory. You can validate the micro-range or specific concentration range, applicable

ISO 15189 accreditation for clinical laboratories require a verification of the accuracy of the measurement procedures. The study of the accuracy, by estimating the systematic error, should be in the validation of the measurement. To study the accuracy of a measurement procedure is necessary to compare average values obtained with a conventional true value. In the clinical laboratory can be used as true values considered, mainly 3 types: value assigned to a reference material, the consensus value obtained in a program of external

The accuracy is expressed numerically by systematic error, which is the difference between the average measurement results obtained and a conventional true value. The values

The reference materials used in the study must have a value assigned to the magnitude that is measured and the corresponding value of uncertainty. You should also know the traceability of the assigned value. It is preferable that the material has a matrix similar to human samples. The main types of materials: certified reference materials, prepared by metrology institutes or other organizations related to metrology and reference materials

The reference material manufacturer must provide the traceability and uncertainty of assigned values; the latter expressed as standard uncertainty or expanded uncertainty.

The results of accuracy studies should be used to validate the accuracy of the measurement procedures, ensures the absence of relevant and introduce systematic errors in the calculation of uncertainty of measurement uncertainty components associated with any

The external quality control includes different activities aimed at assessing the accuracy of the results through the intervention of an organization outside the laboratory. The most common form of external quality control is comparisons between laboratories or programs

These programs are organized by professional associations, government agencies or manufacturers of control materials that have a similar function. Participating laboratories measured once a magnitude of a control material of unknown value. Organization of the program collects the results of laboratory and a study of the data then forwarded to each participating laboratory, informing about the error of its outcome. The duration of the program, the number of measurements that are performed and the number of different materials are used, depending on the different programs. To study the accuracy is recommended that the program in which you participate fulfill the following conditions: high number of participants, the laboratory has a minimum of 12 results for participation and that you know the standard deviation characterizes the dispersion of results among

**3.2 Estimation of the accuracy from participation in external quality assessment** 

quality assessment, the value obtained with a reference measurement procedure.

assigned to some reference materials may be considered conventionally true values.

Along with the uncertainty value must also specify the coverage factor used.

to a quantitative result. The diagnostic accuracy of a qualitative method can be characterized by two components, both of which can be calculated: sensitivity (the proportion of positive results correctly identified by the method), and specificity (the proportion of negative results correctly identified by the method).

## **3. Parameters required for considering in the validation or revalidation of a method**

There are several measurable parameters that should be taken into account during validation or verification. The estimation of *accuracy* is a key parameter. Accuracy consists of both precision and trueness for quantitative and semiquantitative test/method. *Precision* or "closeness of agreement between results of replicate measurements" includes the following: *Repeatability:* within-run variation (same sample, same conditions).

*Intermediate precision*: between-run variation within a single laboratory (different samples, operators, equipments).

*Reproducibility:* between-run variation in different laboratories (different samples, operator).

*Robustness:* variation when confronted with relevant challenges (e.g., sample type, environmental conditions and so on).

*Trueness* is the "closeness of agreement with a reference value". Appropriate reference materials are, therefore, essential and could include positive and negative/normal controls, certified reference materials, EQA materials, synthetic samples or material characterized by another technique.

The components of accuracy for quality tests/methods are *sensitivity* and *specificity*. *Sensitivity* is a measure of how well the test/method detects positive results, whereas *specificity* describes how well negatives are detected.

Thorough documentation during a validation process is essential, especially in the context of accreditation process pragmatic approaches, reconciling the formal requirements of accreditation standards while respecting the aim that "validation must be practical", such as the design of IQC based on validation results, making full use of data that laboratories are already collecting, for example from IQC or EQA, for continuous validation. There are no detailed practical guides for validation of diagnostic methods in medical laboratories; moreover, the accreditation standards have no specific details about how to fulfil their requirements. The laboratory must decide on this, on the basis of their experience and performance requirements; it is duty of the laboratory to provide evidence that tests results provided are reliable, and that the performance claims are correct (Burnett, 2006; Hauck et al., 2008).

In the end, validation is never finished. The implementation of quality indicators for systematically monitoring and evaluating the laboratory's contribution to patient care is good way to continuously validate diagnostic tests/methods, apart from IQC, EQA and other data (Eurachem, 2010; Hauck et al., 2008).

But when the method has already implemented several years and with performance and optimal quality specifications, we recommend periodic revalidation through the information provided by the treatment program reports or international interlaboratory comparison or testing fitness, programs or external quality control, in which the laboratory has been involved for years. The advantage of this validation methodology described above, is to estimate the imprecision, bias and uncertainty, without much effort and without having to make a lot of trials and experimental trials that would mean stopping the routine work in

to a quantitative result. The diagnostic accuracy of a qualitative method can be characterized by two components, both of which can be calculated: sensitivity (the proportion of positive results correctly identified by the method), and specificity (the proportion of negative results

**3. Parameters required for considering in the validation or revalidation of a** 

*Repeatability:* within-run variation (same sample, same conditions).

There are several measurable parameters that should be taken into account during validation or verification. The estimation of *accuracy* is a key parameter. Accuracy consists of both precision and trueness for quantitative and semiquantitative test/method. *Precision* or "closeness of agreement between results of replicate measurements" includes the following:

*Intermediate precision*: between-run variation within a single laboratory (different samples,

*Reproducibility:* between-run variation in different laboratories (different samples, operator). *Robustness:* variation when confronted with relevant challenges (e.g., sample type,

*Trueness* is the "closeness of agreement with a reference value". Appropriate reference materials are, therefore, essential and could include positive and negative/normal controls, certified reference materials, EQA materials, synthetic samples or material characterized by

The components of accuracy for quality tests/methods are *sensitivity* and *specificity*. *Sensitivity* is a measure of how well the test/method detects positive results, whereas

Thorough documentation during a validation process is essential, especially in the context of accreditation process pragmatic approaches, reconciling the formal requirements of accreditation standards while respecting the aim that "validation must be practical", such as the design of IQC based on validation results, making full use of data that laboratories are already collecting, for example from IQC or EQA, for continuous validation. There are no detailed practical guides for validation of diagnostic methods in medical laboratories; moreover, the accreditation standards have no specific details about how to fulfil their requirements. The laboratory must decide on this, on the basis of their experience and performance requirements; it is duty of the laboratory to provide evidence that tests results provided are reliable, and that the performance claims are correct (Burnett, 2006; Hauck et

In the end, validation is never finished. The implementation of quality indicators for systematically monitoring and evaluating the laboratory's contribution to patient care is good way to continuously validate diagnostic tests/methods, apart from IQC, EQA and

But when the method has already implemented several years and with performance and optimal quality specifications, we recommend periodic revalidation through the information provided by the treatment program reports or international interlaboratory comparison or testing fitness, programs or external quality control, in which the laboratory has been involved for years. The advantage of this validation methodology described above, is to estimate the imprecision, bias and uncertainty, without much effort and without having to make a lot of trials and experimental trials that would mean stopping the routine work in

correctly identified by the method).

**method** 

operators, equipments).

another technique.

al., 2008).

environmental conditions and so on).

*specificity* describes how well negatives are detected.

other data (Eurachem, 2010; Hauck et al., 2008).

the laboratory. You can validate the micro-range or specific concentration range, applicable as diagnostic daily reality for clinical laboratories.

#### **3.1 Estimation of the accuracy using reference materials**

ISO 15189 accreditation for clinical laboratories require a verification of the accuracy of the measurement procedures. The study of the accuracy, by estimating the systematic error, should be in the validation of the measurement. To study the accuracy of a measurement procedure is necessary to compare average values obtained with a conventional true value. In the clinical laboratory can be used as true values considered, mainly 3 types: value assigned to a reference material, the consensus value obtained in a program of external quality assessment, the value obtained with a reference measurement procedure.

The accuracy is expressed numerically by systematic error, which is the difference between the average measurement results obtained and a conventional true value. The values assigned to some reference materials may be considered conventionally true values.

The reference materials used in the study must have a value assigned to the magnitude that is measured and the corresponding value of uncertainty. You should also know the traceability of the assigned value. It is preferable that the material has a matrix similar to human samples. The main types of materials: certified reference materials, prepared by metrology institutes or other organizations related to metrology and reference materials business (controls to the truth).

The reference material manufacturer must provide the traceability and uncertainty of assigned values; the latter expressed as standard uncertainty or expanded uncertainty. Along with the uncertainty value must also specify the coverage factor used.

The results of accuracy studies should be used to validate the accuracy of the measurement procedures, ensures the absence of relevant and introduce systematic errors in the calculation of uncertainty of measurement uncertainty components associated with any correction factors.

#### **3.2 Estimation of the accuracy from participation in external quality assessment programs**

The external quality control includes different activities aimed at assessing the accuracy of the results through the intervention of an organization outside the laboratory. The most common form of external quality control is comparisons between laboratories or programs of external quality assessment.

These programs are organized by professional associations, government agencies or manufacturers of control materials that have a similar function. Participating laboratories measured once a magnitude of a control material of unknown value. Organization of the program collects the results of laboratory and a study of the data then forwarded to each participating laboratory, informing about the error of its outcome. The duration of the program, the number of measurements that are performed and the number of different materials are used, depending on the different programs. To study the accuracy is recommended that the program in which you participate fulfill the following conditions: high number of participants, the laboratory has a minimum of 12 results for participation and that you know the standard deviation characterizes the dispersion of results among participating laboratories.

Procedures for Validation of

d. Measurement procedure.

**3.3.2 Imprecision** 

Diagnostic Methods in Clinical Laboratory Accredited by ISO 15189 221

c. Type size and unity. For example, substance concentration (mmol/L), mass

The existence of different molecular forms of the analyte can introduce uncertainty in the results. This source of uncertainty can be reduced or eliminated by careful definition of the

Another source of uncertainty regarding the definition of the measurand are possible crossreactions and interference that can occur with some samples and must be identified and

In short, uncertainty caused by the uncertainty of the measurand can not be quantified, but

Most of the components of measurement uncertainty of the analytical phase are contained in

This assessment should be a sufficient number of data to collect the different sources of uncertainty apply, i.e., a minimum of six months of data and new estimation every year. In the period of data collection should include several calibrations to collect the uncertainty generated by the calibration process. Moreover it is necessary to use different batches of

The estimate of *CVid* is made for a measurement value close to the values of clinical decision.

The clinical laboratory must know the uncertainty and metrological traceability of values assigned to calibration materials used. As usual it is commercial material the manufacturer must provide such data (Directive 98/79/EC). Along with the uncertainty value must also specify the coverage factor used. Typically, uncertainty is expressed as expanded

The standard uncertainty (*u*) is calculated by dividing *U* by the coverage factor. *U* on (%) of the value assigned to the gauge should not vary excessively batch to batch and

The estimation of measurement uncertainty is assumed that any significant systematic error of the measurement procedure has been deleted, corrected or ignored. The identification of a possible systematic error should be done during the validation of the measurement

When systematic error is corrected by a factor, the correction has an associated uncertainty (*ucf*) that should be considered in calculating the combined measurement uncertainty. Systematic errors caused in the routine use of the measurement by the inevitable differences between different calibrations behave randomly in the long term, so this component of

The uncertainty is calculated by combining various sources. For this reason, clinical laboratories should identify each measurand, specifying the measurement procedure, and

the estimation of imprecision (*CVid*). It is usually obtained using control materials.

measurement, so they may react differently to some or other molecular forms.

may be reduced or eliminated by detailed specification of the measurand.

concentration (g/L), catalyst concentration (nkat/L), etc.

documented to prevent, where possible, their influence.

calibrator if you have the uncertainty of the assigned value.

uncertainty (*U*) for a confidence level of 95% (coverage factor = 2).

**3.3.3 Value assigned to the calibrator** 

should generally be lower than *CVid*.

**3.3.4 Systematic error (bias)** 

uncertainty is reflected in *CVid*.

**3.3.5 Uncertainty calculation** 

procedure.

## **3.3 Estimation of measurement uncertainty**

The results provided by the clinical laboratory must be accurate (true and precise) to allow a correct clinical interpretation and to be comparable with earlier or later and between laboratories.

The error of measurement of clinical laboratory results is almost always unknown. Instead, it is possible to ascribe a measurement uncertainty and metrological traceability of each result. The uncertainty is a numerical expression of the degree of doubt of the result. Traceability relates the result with reference values established allowing reproducibility over time and between laboratories (Eurachem, 2010).

In the estimation of measurement uncertainty is assumed that any systematic error is eliminated, corrected or ignored, random effects are assessed on the outcome of an action and establishing a range within which lies the true value of the measured magnitude a certain level of confidence. The standard for laboratory accreditation ISO 15189 requires an estimate of the uncertainty of the results. The appropriate methodology for estimating the uncertainty described in the Guide to the Expression of Uncertainty in Measurement (GUM). The GUM was developed jointly by several international organizations for standardization and metrology for use in calibration and testing laboratories and measures applied to physical or chemical analysis. Currently, the GUM is difficult to apply to measures that are performed in clinical laboratories, although they maintained their principles. Moreover, the complexity and cost of obtaining an estimate of the uncertainty of measurement must be commensurate with the quality requirements applicable to the clinical use of the results.

Sources are contributing to the uncertainty of a result as follows: sample collection, sample preparation, calibrators or reference materials, input quantities (e.g., absorbance), computer equipment used, environmental conditions, sample stability and changes in workers.

The uncertainty associated with the collection and sample preparation is difficult to estimate and should be reduced through rigorous standardization of procedures. In this paper only consider the sources of uncertainty in the analytical phase, which begins when the sample interacts with the first technical step of the measurement (for example, placing the sample into an analyzer) and ends with obtaining a value numerical measurement result.

The main components of the uncertainty of the analytical phase correspond to the uncertainty of the measured, the stability of the sample in the measurement system calibration, the volume dispensed, the batch of reagents, instrumentation equipment, operators and environmental conditions. In the following paragraphs, are discussed in more detail the main components.

Measurement uncertainty is a parameter that is specifically associated with each outcome. In clinical laboratories, it is impossible to estimate particular measurement uncertainty for each measurand of each sample, so it makes a rough estimate of the uncertainty of measurement for a measurand defined and values of the same close to decision clinic. Measurement uncertainty does not apply to qualitative tests, in which the result is a numeric value.

## **3.3.1 Definition of measurand**

The measurand is defined by the following parameters:


The results provided by the clinical laboratory must be accurate (true and precise) to allow a correct clinical interpretation and to be comparable with earlier or later and between

The error of measurement of clinical laboratory results is almost always unknown. Instead, it is possible to ascribe a measurement uncertainty and metrological traceability of each result. The uncertainty is a numerical expression of the degree of doubt of the result. Traceability relates the result with reference values established allowing reproducibility

In the estimation of measurement uncertainty is assumed that any systematic error is eliminated, corrected or ignored, random effects are assessed on the outcome of an action and establishing a range within which lies the true value of the measured magnitude a certain level of confidence. The standard for laboratory accreditation ISO 15189 requires an estimate of the uncertainty of the results. The appropriate methodology for estimating the uncertainty described in the Guide to the Expression of Uncertainty in Measurement (GUM). The GUM was developed jointly by several international organizations for standardization and metrology for use in calibration and testing laboratories and measures applied to physical or chemical analysis. Currently, the GUM is difficult to apply to measures that are performed in clinical laboratories, although they maintained their principles. Moreover, the complexity and cost of obtaining an estimate of the uncertainty of measurement must be commensurate with the quality requirements applicable to the

Sources are contributing to the uncertainty of a result as follows: sample collection, sample preparation, calibrators or reference materials, input quantities (e.g., absorbance), computer

The uncertainty associated with the collection and sample preparation is difficult to estimate and should be reduced through rigorous standardization of procedures. In this paper only consider the sources of uncertainty in the analytical phase, which begins when the sample interacts with the first technical step of the measurement (for example, placing the sample

The main components of the uncertainty of the analytical phase correspond to the uncertainty of the measured, the stability of the sample in the measurement system calibration, the volume dispensed, the batch of reagents, instrumentation equipment, operators and environmental conditions. In the following paragraphs, are discussed in more

Measurement uncertainty is a parameter that is specifically associated with each outcome. In clinical laboratories, it is impossible to estimate particular measurement uncertainty for each measurand of each sample, so it makes a rough estimate of the uncertainty of measurement for a measurand defined and values of the same close to decision clinic. Measurement

a. Analyte to be measured. For example, protein, sodium ion, cholesterol, ASO,

uncertainty does not apply to qualitative tests, in which the result is a numeric value.

equipment used, environmental conditions, sample stability and changes in workers.

into an analyzer) and ends with obtaining a value numerical measurement result.

**3.3 Estimation of measurement uncertainty** 

over time and between laboratories (Eurachem, 2010).

laboratories.

clinical use of the results.

detail the main components.

**3.3.1 Definition of measurand** 

The measurand is defined by the following parameters:

b. System. For example, serum, urine, venous blood, pleural fluid, etc.

hemoglobin, white blood cell counts, etc.

The existence of different molecular forms of the analyte can introduce uncertainty in the results. This source of uncertainty can be reduced or eliminated by careful definition of the measurement, so they may react differently to some or other molecular forms.

Another source of uncertainty regarding the definition of the measurand are possible crossreactions and interference that can occur with some samples and must be identified and documented to prevent, where possible, their influence.

In short, uncertainty caused by the uncertainty of the measurand can not be quantified, but may be reduced or eliminated by detailed specification of the measurand.

## **3.3.2 Imprecision**

Most of the components of measurement uncertainty of the analytical phase are contained in the estimation of imprecision (*CVid*). It is usually obtained using control materials.

This assessment should be a sufficient number of data to collect the different sources of uncertainty apply, i.e., a minimum of six months of data and new estimation every year. In the period of data collection should include several calibrations to collect the uncertainty generated by the calibration process. Moreover it is necessary to use different batches of calibrator if you have the uncertainty of the assigned value.

The estimate of *CVid* is made for a measurement value close to the values of clinical decision.

#### **3.3.3 Value assigned to the calibrator**

The clinical laboratory must know the uncertainty and metrological traceability of values assigned to calibration materials used. As usual it is commercial material the manufacturer must provide such data (Directive 98/79/EC). Along with the uncertainty value must also specify the coverage factor used. Typically, uncertainty is expressed as expanded uncertainty (*U*) for a confidence level of 95% (coverage factor = 2).

The standard uncertainty (*u*) is calculated by dividing *U* by the coverage factor. *U* on (%) of the value assigned to the gauge should not vary excessively batch to batch and should generally be lower than *CVid*.

#### **3.3.4 Systematic error (bias)**

The estimation of measurement uncertainty is assumed that any significant systematic error of the measurement procedure has been deleted, corrected or ignored. The identification of a possible systematic error should be done during the validation of the measurement procedure.

When systematic error is corrected by a factor, the correction has an associated uncertainty (*ucf*) that should be considered in calculating the combined measurement uncertainty.

Systematic errors caused in the routine use of the measurement by the inevitable differences between different calibrations behave randomly in the long term, so this component of uncertainty is reflected in *CVid*.

#### **3.3.5 Uncertainty calculation**

The uncertainty is calculated by combining various sources. For this reason, clinical laboratories should identify each measurand, specifying the measurement procedure, and

Procedures for Validation of

the operator's experience are recommended.

required for fulfilling statistical criteria.

correct the cause of the discrepancy.

**method in the clinical laboratory** 

competence of clinical laboratories.

must develop a set of documents or records.

variation.

additional".

conducted.

criteria are recommended to estimate a minimum of 30 days.

Diagnostic Methods in Clinical Laboratory Accredited by ISO 15189 223

The accuracy can be studied under conditions of repeatability, reproducibility and intermediate. The study conditions that are more interested in the clinical laboratory are the

Before starting the study a period of familiarization with the measurement procedure and

Also for this study is recommended that samples for this study were commercial materials or control samples. We recommend using at least two samples with different concentrations of the magnitude under study, with a value within the physiological range or close to a discriminate value, and one with a pathological value. When it sees fit, they can not be tested with values close to the limits of the measuring range of the procedure. Samples should be stable during the duration of the study. If using commercial control materials,

The run imprecision were obtained under the same conditions of repeatability, ie the same samples, the same operator, the same components of the measurement system for a short time and without calibrations between measurements. A minimum of 30 measurements are

If the results of the run imprecision are not consistent with previous results, either supplied by the manufacturer or obtained in the literature, the study should be stopped to find and

Imprecision is obtained under certain conditions. Each laboratory should perform the estimation with standard calibration frequency (daily weekly, etc), and changes of operator, calibrator lot, reagent lot, etc, which are common in everyday work. Following the statistical

Before calculating the mean, standard deviation and coefficient of variation of the results must be detected the presence of possible outliers. An abnormal result will be removed provided that it is related to a documented error or has demonstrated statistically that is an outlier. After the removal of outliers, if any, imprecision is calculated by the coefficient of

**4. Documentation: procedures and instructions needed for the validation of a** 

International Standard ISO 15189:2007 clearly identifies the documentation requirements necessary to determine compliance with the requirements referred to for quality and

Standard clinical laboratory means (paragraph 3.8) that "laboratory devoted to biological, microbiological, immunological, chemical, immunohematological, biophysical, cytological, pathological or other material derived from the human body in order to provide diagnostic information, prevention and treatment of diseases or the assessment of human health and can provide a consultant advisory service covering all aspects of laboratory analysis, including interpretation of the findings and recommendations on any proper analysis

The implications of documentary that suggests the validation of a method, it follows that it

Registration means that documentary evidence of a fact that has occurred and is understood by documentary evidence to document that describes how the activities should be

whenever possible, they should be interchangeable with samples of human origin.

kind of repeatability and intermediate terms, which vary from day to day.

calculate for each of them calculate the combined uncertainty from the data of internal quality control and other data, using the following equation:

$$
\mu\_c = \sqrt{C V\_{id}^2 + \mu\_{cd}^2 + \mu\_{\phi}^2}
$$

Where:

*uc*: relative combined standard uncertainty (%); *CVid*: imprecision (coefficient of variation) interday; *Ucal*: relative standard uncertainty (%) of the value assigned to the calibrator; *ucf*: relative standard uncertainty (%) of the factor used to correct a systematic error. It is recommended to express the combined uncertainty for a confidence level of 95% (expanded uncertainty, *Uc*). To do this, multiply the value of uc for k = 2.

$$\mathcal{U}\_c = 2 \times \sqrt{C V\_{id}^2 + \mu\_{cal}^2 + \mu\_{\hat{c}}^2}$$

The relative expanded uncertainty should be expressed to two significant figures, for example: 4.2%, 16%.

#### **3.3.6 Interpretation**

The estimation of measurement uncertainty provides a quantitative indication of the level of doubt that the laboratory has in each result and is therefore a key element in the system of analytical quality in clinical laboratories.

The relative expanded uncertainty of a measurand should be less than one third of the Maximum Permitted Error (MPE). If it was superior, should be studied in greater detail the different sources of uncertainty, identify the most significant and perform the appropriate actions to reduce them.

#### **3.3.7 Applications**

The uncertainty of measurement should be used primarily for:


#### **3.3.8 Limitations**

The value of the measurement uncertainty varies with the concentration of the measurand and may be substantially different for very low or very high analyte. For this reason it is recommended that the estimate for a concentration closes to clinical decision values.

#### **3.4 Estimation of precision**

Precision is one of the most important metrological characteristics to be considered for selection and implementation of a measurement procedure in the clinical laboratory. In addition, the quantitative understanding of this feature is essential for establishing tolerance intervals of internal control materials for the objective interpretation of the significance of a change between two consecutive values of magnitude biochemistry, and the calculation of uncertainty.

calculate for each of them calculate the combined uncertainty from the data of internal

2 22 *u CV u u <sup>c</sup> id cal cf*

*uc*: relative combined standard uncertainty (%); *CVid*: imprecision (coefficient of variation) interday; *Ucal*: relative standard uncertainty (%) of the value assigned to the calibrator; *ucf*: relative standard uncertainty (%) of the factor used to correct a systematic error. It is recommended to express the combined uncertainty for a confidence level of 95%

2 22 *U CV u u <sup>c</sup>* 2 *id cal fc*

The relative expanded uncertainty should be expressed to two significant figures, for

The estimation of measurement uncertainty provides a quantitative indication of the level of doubt that the laboratory has in each result and is therefore a key element in the system of

The relative expanded uncertainty of a measurand should be less than one third of the Maximum Permitted Error (MPE). If it was superior, should be studied in greater detail the different sources of uncertainty, identify the most significant and perform the appropriate



The value of the measurement uncertainty varies with the concentration of the measurand and may be substantially different for very low or very high analyte. For this reason it is

Precision is one of the most important metrological characteristics to be considered for selection and implementation of a measurement procedure in the clinical laboratory. In addition, the quantitative understanding of this feature is essential for establishing tolerance intervals of internal control materials for the objective interpretation of the significance of a change between two consecutive values of magnitude biochemistry, and the calculation of

recommended that the estimate for a concentration closes to clinical decision values.


quality control and other data, using the following equation:

(expanded uncertainty, *Uc*). To do this, multiply the value of uc for k = 2.

The uncertainty of measurement should be used primarily for:

Where:

example: 4.2%, 16%.

**3.3.6 Interpretation** 

actions to reduce them.

magnitude biochemistry.

**3.4 Estimation of precision** 

**3.3.7 Applications** 

decision.

**3.3.8 Limitations** 

uncertainty.

analytical quality in clinical laboratories.

The accuracy can be studied under conditions of repeatability, reproducibility and intermediate. The study conditions that are more interested in the clinical laboratory are the kind of repeatability and intermediate terms, which vary from day to day.

Before starting the study a period of familiarization with the measurement procedure and the operator's experience are recommended.

Also for this study is recommended that samples for this study were commercial materials or control samples. We recommend using at least two samples with different concentrations of the magnitude under study, with a value within the physiological range or close to a discriminate value, and one with a pathological value. When it sees fit, they can not be tested with values close to the limits of the measuring range of the procedure. Samples should be stable during the duration of the study. If using commercial control materials, whenever possible, they should be interchangeable with samples of human origin.

The run imprecision were obtained under the same conditions of repeatability, ie the same samples, the same operator, the same components of the measurement system for a short time and without calibrations between measurements. A minimum of 30 measurements are required for fulfilling statistical criteria.

If the results of the run imprecision are not consistent with previous results, either supplied by the manufacturer or obtained in the literature, the study should be stopped to find and correct the cause of the discrepancy.

Imprecision is obtained under certain conditions. Each laboratory should perform the estimation with standard calibration frequency (daily weekly, etc), and changes of operator, calibrator lot, reagent lot, etc, which are common in everyday work. Following the statistical criteria are recommended to estimate a minimum of 30 days.

Before calculating the mean, standard deviation and coefficient of variation of the results must be detected the presence of possible outliers. An abnormal result will be removed provided that it is related to a documented error or has demonstrated statistically that is an outlier. After the removal of outliers, if any, imprecision is calculated by the coefficient of variation.

## **4. Documentation: procedures and instructions needed for the validation of a method in the clinical laboratory**

International Standard ISO 15189:2007 clearly identifies the documentation requirements necessary to determine compliance with the requirements referred to for quality and competence of clinical laboratories.

Standard clinical laboratory means (paragraph 3.8) that "laboratory devoted to biological, microbiological, immunological, chemical, immunohematological, biophysical, cytological, pathological or other material derived from the human body in order to provide diagnostic information, prevention and treatment of diseases or the assessment of human health and can provide a consultant advisory service covering all aspects of laboratory analysis, including interpretation of the findings and recommendations on any proper analysis additional".

The implications of documentary that suggests the validation of a method, it follows that it must develop a set of documents or records.

Registration means that documentary evidence of a fact that has occurred and is understood by documentary evidence to document that describes how the activities should be conducted.

Procedures for Validation of

LAB LOGO

**Date of procedure of validation**

Additional data

Declaration:

Validation criteria:

Validated method No validated method Validated method with restrictions

Fig. 7. Template record: Report of validation.

to be followed in the validation.

necessary for the validation of a method:

 Template record: Report of validation (figure 7). Registration: Plan quality control method (figure 8).

Technical Registration. Spreadsheets (Excel) (figure 10).

Parameter Result /value Observations

Date of validation of the method: Signature: (Responsible of validation)

Diagnostic Methods in Clinical Laboratory Accredited by ISO 15189 225

of the method validation, quality control plan method. They detail steps for each procedure

Here are a few examples of formats and / or templates of records that are considered

Code: VALIDATION REPORT

**Register Observations Personnel**

"Name of the laboratory"

Date:

Review Page X of Y

Template record: Design / planning of the method validation (figure 6).

Title page of a validation procedure in clinical laboratory methods (figure 9).

According to these definitions it is able to state that the laboratory should have a defined overall validation procedure (document) that describes: What activities will be performed; responsibility to perform; records to retain; how to be performed.

To confirm the verification of compliance, apply the method to real matrices, records to keep are: 1. Requirements applied to the method (Must be defined prior to conducting the tests, indicating preserved based on what have been defined); 2.Records of previous tests. (Straight calibration standards used, results obtained from different computers, etc.); 3. Written procedure (approved by qualified personnel); 4. Results of tests for checking compliance with requirements (The laboratory must clearly indicate the results of the parameters and the comparison with the specified requirements); 5. Statement by the head of the validation of the procedure is suitable for their intended use based on the evidence (All these records should include dates, personnel and equipment used in ways that can be reconstructed).

It must have an overall validation procedure describing the activities undertaken; those responsible for conducting, records to keep (the method established requirements, records of tests: calibration lines, patterns, etc.).


Fig. 6. Template record: Design / planning of the method validation.

It must be developed and used a generic template so that it is not necessary to have to develop a validation process for each method, but simply change the data in the template. Thus, for any method in the laboratory which will continue to want to validate one of the two ways described: the classical or from the results of inter-comparison programs. It is used for the models listed in the Annexes to this case: report validation, design / planning

According to these definitions it is able to state that the laboratory should have a defined overall validation procedure (document) that describes: What activities will be performed;

To confirm the verification of compliance, apply the method to real matrices, records to keep are: 1. Requirements applied to the method (Must be defined prior to conducting the tests, indicating preserved based on what have been defined); 2.Records of previous tests. (Straight calibration standards used, results obtained from different computers, etc.); 3. Written procedure (approved by qualified personnel); 4. Results of tests for checking compliance with requirements (The laboratory must clearly indicate the results of the parameters and the comparison with the specified requirements); 5. Statement by the head of the validation of the procedure is suitable for their intended use based on the evidence (All these records should include dates, personnel and equipment used in ways that can be

It must have an overall validation procedure describing the activities undertaken; those responsible for conducting, records to keep (the method established requirements, records

> Page X of Y Review: CODE: Date: Registration "Name of the Laboratory"

Design/planning of the method validation

Parameter Value Observations

Fig. 6. Template record: Design / planning of the method validation.

It must be developed and used a generic template so that it is not necessary to have to develop a validation process for each method, but simply change the data in the template. Thus, for any method in the laboratory which will continue to want to validate one of the two ways described: the classical or from the results of inter-comparison programs. It is used for the models listed in the Annexes to this case: report validation, design / planning

responsibility to perform; records to retain; how to be performed.

reconstructed).

of tests: calibration lines, patterns, etc.).

Lab logo

Objectives:

References: Used:

Method:

Procedure/codification:

Responsible for validation:

of the method validation, quality control plan method. They detail steps for each procedure to be followed in the validation.

Here are a few examples of formats and / or templates of records that are considered necessary for the validation of a method:



Fig. 7. Template record: Report of validation.

Procedures for Validation of

LAB LOGO

**CONTENTS**

2. DEFINITIONS

4. PROCEDURE

5. ANNEXES

**5. Conclusion** 

**6. References** 

1. OBJECTIVE AND SCOPE

3. REFERENCE DOCUMENTS

4.1. Accuracy 4.2.Precision 4.3.Trueness 4.4. Repeateability 4.5.Reproducibility 4.6. Uncertainty

4.7. Another validation parameters

technical competence to offer quality results.

No.18, pp. 1-19.

No. 55, pp. 729-733.

Fig. 10. Contents in a validation procedure in clinical laboratory.

It is important to have documented procedures for the validation of different diagnostic methods available within a clinical laboratory. There is a need to develop practical guidelines for method validation procedures in clinical laboratories through the various tools available to the laboratory. There is no single way to validate a diagnostic and clinical laboratory validate and verify the validation of their methods over time to meet the requirements of the existing accreditation standards and to demonstrate the laboratory's

Berwouts, S.; Morris, M.A. & Dequeker, E. (2010).Approaches to quality management and

Burnett, D. (2006). ISO 15189:2003-quality management, evaluation and continual

Burnett, D. & Blair, C. (2001). Standards for the medical laboratory-harmonization and

Burnett, D.; Blair C.; Haeney, M.R.; Jeffcoate, S.L.; Scott, K.W. & Williams, D.L. (2002).

improvement. *Clin Chem Lab Med.* No. 44, pp. 133-739.

subsidiarity. *Clin Chem Acta.* No. 309, pp. 137-145.

accreditation in a genetic testing laboratory. *European Journal of Human Genetics.*

Clinical pathology accreditation: standards for the medical laboratory. *J Clin Pathol.* 

Diagnostic Methods in Clinical Laboratory Accredited by ISO 15189 227

Code: PROCEDURE FOR VALIDATION METHODS

MANUAL OF PROCEDURES "Name of the laboratory"

Date:

Review Page X of Y


#### Fig. 8. Registration: Plan quality control method.

Fig. 9. Title page of a validation procedure in clinical laboratory methods


Fig. 10. Contents in a validation procedure in clinical laboratory.

## **5. Conclusion**

226 Modern Approaches To Quality Control

Lab logo Registration "Name of the Laboratory"

CODE: Quality control plan method

MANUAL OF PROCEDURES "Name of the laboratory"

Code: PROCEDURE FOR VALIDATION METHODS

PROCEDURE FOR VALIDATION METHODS

*Developed Revised Approved*

*Technical Manager Quality Manager Lab Director*

Fig. 9. Title page of a validation procedure in clinical laboratory methods

Date:

Review Page X of Y

**Method for validation (Description)**

*Accuracy*

*Trueness Precision*

*Repeateability*

*Reproducibility*

*Uncertainty* Robutness Specificity LOQ

Fig. 8. Registration: Plan quality control method.

LAB LOGO

*Date*

Date:

Review: Page X of Y

**Quality Control** *Periodicity Acceptance criteria*

It is important to have documented procedures for the validation of different diagnostic methods available within a clinical laboratory. There is a need to develop practical guidelines for method validation procedures in clinical laboratories through the various tools available to the laboratory. There is no single way to validate a diagnostic and clinical laboratory validate and verify the validation of their methods over time to meet the requirements of the existing accreditation standards and to demonstrate the laboratory's technical competence to offer quality results.

## **6. References**


**1. Introduction** 

regulations and are effectively adhering to them.

government agencies which regulate human experimentation.

**12** 

**Quality Control and** 

Stahl, Edmundo *LatAmScience, LLC* 

*U.S.A.* 

**Quality Assurance in** 

**Human Experimentation** 

During the 20th, century the awareness of the need for the ethical treatment of human subjects participating in experimentation has evolved. Various incidents over the years have sparked the creation of government entities dedicated to the regulation of human experimentation. This has brought about the creation of regulations whose objective is the protection human subjects throughout the experimentation process. These regulations call for many checks and balances with the objective of protecting the individual under experimentation through quality control procedures in the monitoring process of the experiment. The quality is assured through auditing the process by independent professionals. This chapter will describe the history of the development of Good Clinical Practices (GCP) and an analysis of some applicable documents and practices developed by the Food and Drug Administration of the USA, and the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). FDA (USA), EMA (EU) and Pharmaceutics and Medicines Safety Bureau (Japan) as well as pharmaceutical industry representatives of the USA, EU and Japan form the ICH. ICH guidelines provide a unified standard for designing, conducting, recording and reporting clinical trials involving the participation of human subjects and other necessary activities related to human experimentation. ICH is especially concerned with harmonizing the regulatory requirements of its sponsor countries; USA, EU and Japan. It describes the necessary activities and documentation that would allow the evaluation of the ethical conduct of a clinical trial and assure the quality of the information derived from such a study. Many countries all over the world are now including these guidelines in their

A significant part of human experimentation is conducted in the development of new drugs for the treatment of human disease as well as devices and instruments used in medical practice. This chapter will also describe the development process, the logic behind it, the non-clinical testing that is necessary for the drug/device development process, the clinical phases of drug development, the role of the ethics committees and Institutional Review Boards in the approval process to conduct human experimentation as well as the role of the


## **Quality Control and Quality Assurance in Human Experimentation**

Stahl, Edmundo *LatAmScience, LLC U.S.A.* 

## **1. Introduction**

228 Modern Approaches To Quality Control

Eurachem. (May 2010). The firness for purpose of analytical methods a laboratory guide to

Hauck, W.W.; Kock, W.; Abernethy, D. &Williams, R.L. (2008). Making sense of trueness, precision, accuracy and uncertainty. *Pharmacopeial Forum.* No.34, pp.838-842. International Organization for Standardization. Medical laboratories-Particular

International Organization for Standardization: General requirements for the competence of

Menditto, A.; Patriarca, M. & Magnusson, B. (2007). Understanding the meaning of accuracy, trueness and precision. *Accred Qual Assur*. No. 12, pp.45-47.

method validation and related topics, Avaliable from:

requirements for quality and competence. ISO 15189:2007.

testing and calibration laboratories.ISO/IEC 17025:2005.

http://www.eurachem.org/guides/valid.pdf

During the 20th, century the awareness of the need for the ethical treatment of human subjects participating in experimentation has evolved. Various incidents over the years have sparked the creation of government entities dedicated to the regulation of human experimentation. This has brought about the creation of regulations whose objective is the protection human subjects throughout the experimentation process. These regulations call for many checks and balances with the objective of protecting the individual under experimentation through quality control procedures in the monitoring process of the experiment. The quality is assured through auditing the process by independent professionals. This chapter will describe the history of the development of Good Clinical Practices (GCP) and an analysis of some applicable documents and practices developed by the Food and Drug Administration of the USA, and the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). FDA (USA), EMA (EU) and Pharmaceutics and Medicines Safety Bureau (Japan) as well as pharmaceutical industry representatives of the USA, EU and Japan form the ICH. ICH guidelines provide a unified standard for designing, conducting, recording and reporting clinical trials involving the participation of human subjects and other necessary activities related to human experimentation. ICH is especially concerned with harmonizing the regulatory requirements of its sponsor countries; USA, EU and Japan. It describes the necessary activities and documentation that would allow the evaluation of the ethical conduct of a clinical trial and assure the quality of the information derived from such a study. Many countries all over the world are now including these guidelines in their regulations and are effectively adhering to them.

A significant part of human experimentation is conducted in the development of new drugs for the treatment of human disease as well as devices and instruments used in medical practice. This chapter will also describe the development process, the logic behind it, the non-clinical testing that is necessary for the drug/device development process, the clinical phases of drug development, the role of the ethics committees and Institutional Review Boards in the approval process to conduct human experimentation as well as the role of the government agencies which regulate human experimentation.

Quality Control and Quality Assurance in Human Experimentation 231

impoverished Black individuals from Macon county, Alabama, who thought they were receiving free health care from the government were never told they had syphilis nor were they treated for it. The Belmont Report incorporates the principles of the Nuremberg Code, the Declaration of Geneva and the Declaration of Helsinki. These documents influenced significantly the legislation and creation of regulations for the ethical conduct of human experimentation in the USA. Sections 45 (government sponsored studies, 45 CFR) and 21 (private and industry sponsored studies, 21 CFR) of the Code of Federal Regulations (CFR) base many of their regulations on these important ethical documents and have influenced in

The U.S. Food and Drug Administration (FDA) 6 was created in 1906 by the Federal Food, Drug, and Cosmetic Act, the Wiley Act. The purpose was to prevent the manufacturing, sale, or transportation of adulterated or misbranded or poisonous or deleterious foods, drugs, medicines, and liquors. The FDA evolved over the years to require manufacturers to submit a New Drug Application (NDA) for each newly introduced drug and provide data that demonstrates the safety of the product (1938), and later (1962) to establish efficacy, in order to show that the products were effective for their claimed indication. Several amendments to the law have followed to reflect the evolution and emerging issues in the drug development and approval process, which remain today in the crossroads where science, medicine, politics and business intersect. Because a new drug approval is based largely on clinical data obtained by experiments in humans, the FDA has vested significant effort in ensuring the quality of the clinical data and the conditions under which they are obtained. The set of regulations and guidelines the FDA publishes constitute what is collectively known as good clinical practices or GCP. Through these FDA sets the minimum standards for the conduct of clinical trials, the collection of data and data management and

The European Medicine Agency, EMA7 (formerly known as EMEA, European Agency for the Evaluation of Medicinal Products), was founded in 1995 and is a decentralized agency of the European Union responsible for the scientific evaluation of medicines developed by pharmaceutical companies for use in the European Union. Its main function is the promotion and protection of public human and animal health, through the evaluation and supervision of medicines for human and animal use. They are responsible for the evaluation of European Marketing Authorizations for human and veterinary use medicines. The agency monitors the safety of marketed products and provides scientific advice to companies on the development of new medicines. The agency constantly works to forge close ties with partner organizations around the world, including the World Health

In Japan the Pharmaceuticals and Medical Devices Agency (PMDA) 8 working with the Ministry of Health implements measures for securing the efficacy and safety of drugs, cosmetics and medical devices. The PMDA also has forged close ties with other regulatory agencies, namely the EMA and FDA as partners in the formation of the International

The International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) 9 was created in 1990. This organization brings together the regulatory authorities and pharmaceutical industry of Europe, Japan and the

Organization, the FDA and the other regulatory authorities.

many important ways human experimentation in the US and around the world.

**3. Regulatory environment** 

reporting of clinical studies.

Conference on Harmonization (ICH).

### **2. Evolution of ethical conduct in human experimentation**

Since the 5th century B.C. the most prevalent code of ethical conduct for the medical profession has been and still is the "Hippocratic Oath"1. It is widely believed to have been written by Hippocrates, often regarded as the father of western medicine. The original text of the Hippocratic Oath is usually interpreted as one of the first statements of a moral of conduct to be used by physicians, assuming the respect for all human life. It has been modified over time in many occasions but the spirit of the concept has been preserved.

It was not until after the end of World War II that the United States authorities conducted in their occupied zone several trials for war crimes committed by the Nazis in Nüremberg2. The trials were formally named the "Trials of War Criminals before the Nuremberg Military Tribunals". They were held before US military courts, not before the International Military Tribunal. The defendants were accused of unethical human experimentation and other atrocities. On August 19th, 1947 the tribunal delivered its verdict including their opinion on human experimentation. The Nüremberg Code that emerged from these trials consists of 10 points that represent a set of ethical research principles for human experimentation. The Nüremberg Code includes concepts like: voluntary consent of the research subject; experimentation with clear fruitful objectives; experimentation in humans should be preceded by animal experimentation; the conduct of research in humans should not produce physical or mental injury nor results in death of the study subjects; the experimentation should be conducted with a view of introducing the minimal possible risk to the individual during the experimentation and conducted by a qualified person. It also includes the concept that the subject should be at liberty to stop the experiment at any time for any reason. Likewise, the experimenter should be prepared to terminate the experiment if in their judgment there is any reasonable chance that it may harm the research subject. Subsequently in 1948 the World Medical Association introduced the Declaration of Geneva 3 as a modernization of the Hippocratic Oath. It was designed as a formulation of that oath's moral truths that could be comprehended and acknowledged modernly. The Declaration of Geneva has been amended in 1968, 1984, 1994, 2005 and 2006.

Another important historical document addressing human experimentation is the Declaration of Helsinki4 adopted in 1964 by the World Medical Association in Helsinki, Finland. It is a set of ethical principles for the medical community specifically related to human experimentation and is widely regarded as a cornerstone document for human research. It has been revised six times since its adoption, the last revision being in 2008. The Declaration of Helsinki adopted the ten principles first stated in the Nüremberg Code and tied them to the Declaration of Geneva. It addresses clinical research reflecting the changes in medical practice. Its various revisions introduced the concept of independent review committees, now known as Institutional Review Board or Independent Ethics Committees; the management of the inclusion of minors in clinical research and the recognition of vulnerable groups; addressed the use of placebos; and the inclusion of human volunteers in clinical trials. This document was not meant to be legally binding but has influenced national and regional regulation and legislation around the world. It introduced the concept that ethical considerations must take precedence over laws and regulations.

In the USA, the Belmont Report5 was created by the now named Department of Health and Human Services with the title "Ethical Principles and Guidelines for the Protection of Human Subjects of Research". The report was issued in April 1979 prompted in part by problems arising from the Tuskegee Syphilis Study (1932-1972). The Tuskegee Syphilis Study was designed to observe the clinical evolution of syphilis. The patients, 399 impoverished Black individuals from Macon county, Alabama, who thought they were receiving free health care from the government were never told they had syphilis nor were they treated for it. The Belmont Report incorporates the principles of the Nuremberg Code, the Declaration of Geneva and the Declaration of Helsinki. These documents influenced significantly the legislation and creation of regulations for the ethical conduct of human experimentation in the USA. Sections 45 (government sponsored studies, 45 CFR) and 21 (private and industry sponsored studies, 21 CFR) of the Code of Federal Regulations (CFR) base many of their regulations on these important ethical documents and have influenced in many important ways human experimentation in the US and around the world.

## **3. Regulatory environment**

230 Modern Approaches To Quality Control

Since the 5th century B.C. the most prevalent code of ethical conduct for the medical profession has been and still is the "Hippocratic Oath"1. It is widely believed to have been written by Hippocrates, often regarded as the father of western medicine. The original text of the Hippocratic Oath is usually interpreted as one of the first statements of a moral of conduct to be used by physicians, assuming the respect for all human life. It has been modified over time in many occasions but the spirit of the concept has been preserved. It was not until after the end of World War II that the United States authorities conducted in their occupied zone several trials for war crimes committed by the Nazis in Nüremberg2. The trials were formally named the "Trials of War Criminals before the Nuremberg Military Tribunals". They were held before US military courts, not before the International Military Tribunal. The defendants were accused of unethical human experimentation and other atrocities. On August 19th, 1947 the tribunal delivered its verdict including their opinion on human experimentation. The Nüremberg Code that emerged from these trials consists of 10 points that represent a set of ethical research principles for human experimentation. The Nüremberg Code includes concepts like: voluntary consent of the research subject; experimentation with clear fruitful objectives; experimentation in humans should be preceded by animal experimentation; the conduct of research in humans should not produce physical or mental injury nor results in death of the study subjects; the experimentation should be conducted with a view of introducing the minimal possible risk to the individual during the experimentation and conducted by a qualified person. It also includes the concept that the subject should be at liberty to stop the experiment at any time for any reason. Likewise, the experimenter should be prepared to terminate the experiment if in their judgment there is any reasonable chance that it may harm the research subject. Subsequently in 1948 the World Medical Association introduced the Declaration of Geneva 3 as a modernization of the Hippocratic Oath. It was designed as a formulation of that oath's moral truths that could be comprehended and acknowledged modernly. The Declaration of

Another important historical document addressing human experimentation is the Declaration of Helsinki4 adopted in 1964 by the World Medical Association in Helsinki, Finland. It is a set of ethical principles for the medical community specifically related to human experimentation and is widely regarded as a cornerstone document for human research. It has been revised six times since its adoption, the last revision being in 2008. The Declaration of Helsinki adopted the ten principles first stated in the Nüremberg Code and tied them to the Declaration of Geneva. It addresses clinical research reflecting the changes in medical practice. Its various revisions introduced the concept of independent review committees, now known as Institutional Review Board or Independent Ethics Committees; the management of the inclusion of minors in clinical research and the recognition of vulnerable groups; addressed the use of placebos; and the inclusion of human volunteers in clinical trials. This document was not meant to be legally binding but has influenced national and regional regulation and legislation around the world. It introduced the concept

In the USA, the Belmont Report5 was created by the now named Department of Health and Human Services with the title "Ethical Principles and Guidelines for the Protection of Human Subjects of Research". The report was issued in April 1979 prompted in part by problems arising from the Tuskegee Syphilis Study (1932-1972). The Tuskegee Syphilis Study was designed to observe the clinical evolution of syphilis. The patients, 399

**2. Evolution of ethical conduct in human experimentation** 

Geneva has been amended in 1968, 1984, 1994, 2005 and 2006.

that ethical considerations must take precedence over laws and regulations.

The U.S. Food and Drug Administration (FDA) 6 was created in 1906 by the Federal Food, Drug, and Cosmetic Act, the Wiley Act. The purpose was to prevent the manufacturing, sale, or transportation of adulterated or misbranded or poisonous or deleterious foods, drugs, medicines, and liquors. The FDA evolved over the years to require manufacturers to submit a New Drug Application (NDA) for each newly introduced drug and provide data that demonstrates the safety of the product (1938), and later (1962) to establish efficacy, in order to show that the products were effective for their claimed indication. Several amendments to the law have followed to reflect the evolution and emerging issues in the drug development and approval process, which remain today in the crossroads where science, medicine, politics and business intersect. Because a new drug approval is based largely on clinical data obtained by experiments in humans, the FDA has vested significant effort in ensuring the quality of the clinical data and the conditions under which they are obtained. The set of regulations and guidelines the FDA publishes constitute what is collectively known as good clinical practices or GCP. Through these FDA sets the minimum standards for the conduct of clinical trials, the collection of data and data management and reporting of clinical studies.

The European Medicine Agency, EMA7 (formerly known as EMEA, European Agency for the Evaluation of Medicinal Products), was founded in 1995 and is a decentralized agency of the European Union responsible for the scientific evaluation of medicines developed by pharmaceutical companies for use in the European Union. Its main function is the promotion and protection of public human and animal health, through the evaluation and supervision of medicines for human and animal use. They are responsible for the evaluation of European Marketing Authorizations for human and veterinary use medicines. The agency monitors the safety of marketed products and provides scientific advice to companies on the development of new medicines. The agency constantly works to forge close ties with partner organizations around the world, including the World Health Organization, the FDA and the other regulatory authorities.

In Japan the Pharmaceuticals and Medical Devices Agency (PMDA) 8 working with the Ministry of Health implements measures for securing the efficacy and safety of drugs, cosmetics and medical devices. The PMDA also has forged close ties with other regulatory agencies, namely the EMA and FDA as partners in the formation of the International Conference on Harmonization (ICH).

The International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) 9 was created in 1990. This organization brings together the regulatory authorities and pharmaceutical industry of Europe, Japan and the

Quality Control and Quality Assurance in Human Experimentation 233

progresses, additional animal studies are conducted. These animal studies include longterm drug administration, and specialized animal tests are conducted to support longer administration in humans. These experiments allow the observation of drug effects that would be impractical or unethical to study in humans. Researchers can observe the effects of the compound over the lifespan of an animal, test dose responses and maximum doses; assess the effects on reproduction, pregnancy and the embryos; effects on genes; assess potential for carcinogenicity; evaluate mechanisms of action of the drug; and characterize the site, degree and duration of action of the compound. Regulatory agencies are involved in determining the amount and type of animal testing required to initiate drug development in humans as well as the requirements to support the whole clinical

The regulatory agencies, specifically FDA, set the minimum standards for laboratories conducting these nonclinical tests through the publication and enforcement of Good Laboratory Practice (GLP)10. To ensure the quality and integrity of the data derived, nonclinical laboratories are required to implement quality systems to conduct their experiments and to abide by the animal welfare laws of the country. GLPs establish basic standards for the conduct and reporting of non clinical safety testing, including the organization of the laboratory, personnel qualifications, physical structure of the facility, equipment, maintenance procedures, and operating procedures. It requires the use of a written protocol and its structure, including its purpose, who is sponsoring the study, procedure for identification and evaluation of the test animals or test system. GLP details how to report nonclinical studies, the storage and retrieval of records and data, and the retention of records. FDA conducts inspections to monitor compliance with GLP requirements. Nonclinical laboratories may be disqualified if the laboratory facility fails to comply with the regulations, and the noncompliance affects adversely the results of the

In addition, FDA may provide advice to sponsors on the adequacy of the nonclinical testing plans before animal testing has begun, and evaluate independently the results and conclusions of the nonclinical testing. FDA has developed guidances for nonclinical testing also. Other regulatory authorities, namely European Community and Japan, have also developed their testing standards. ICH has stepped in in an effort to harmonize these

The basic toxicology studies undertaken to identify and measure a drug's adverse effects in the short- and long-term may include any or all of the studies shown in table 1 depending

The responsibility of the conduction of these animal experiments falls on the sponsor, the animal laboratory and the regulatory authorities. Quality systems are required to guarantee the quality of the data generated. The Sponsor monitors the study and conducts audits, the laboratory needs to have proper standard operating procedures and guidelines in accordance with the regulations and prevailing laws as well as a quality group to ensure compliance with said regulations and laws, and the regulatory authorities perform

In the FDA regulations and regulations by health authorities around the world accept 3 phases of drug development11. A fourth phase is frequently included during the post

on the drug, intended use and duration of exposure in clinical trials (Table 1).

inspections to make sure the regulations and laws are being complied with.

development program.

standards with the Safety guidelines (S).

**5. The clinical phases of drug development** 

study.

US. The purpose is to discuss scientific and technical aspects of drug registration with the goal of harmonizing drug development and registration across the world. The Global Cooperation Group of this organization has been working to harmonize the increasingly global approach to drug development, so that the benefits of international harmonization for better global health can be realized worldwide. ICH's mission is to achieve greater harmonization to ensure that safe, effective, and high quality medicines are developed and registered in the most resource-efficient manner. ICH has developed a series of guidelines to help regulate the clinical drug development process. The instruments developed include a standardized medical terminology system (MedDRA) to use in the capturing, registering, documenting and reporting adverse events during human experimentation. ICH maintains, develops and distributes MedDRA. ICH also developed a standardized package for the submission of new drug applications, the Common Technical Document (CTD) which has been adopted around the world as the gold standard for new medical products submissions. The CTD assembles all the quality, safety and efficacy information required for regulatory submissions in a common format to facilitate the regulatory review process. The CTD has simplified the assembly of the regulatory packages since reformatting for submissions to different regulatory agencies is not necessary anymore. Another area where ICH has worked to improve is international electronic communication by evaluating and recommending Electronic Standards for the Transfer of Regulatory Information (ESTRI). ESTRI has developed recommendations for electronic individual case safety reports and electronic CTDs. Furthermore, ICH has developed guidelines to standardize and harmonize the areas involved in the drug development process. These include guidelines on quality of the product being developed; on safety focusing on nonclinical studies to uncover potential risks for humans; on efficacy, which is concerned with the design, conduct and safety clinical trials; and other guideless like the ones developed by ESTRI. The clinical guidelines include clinical safety (E1-2), clinical study reports (E3), dose response studies (E4), ethnic factors (E5), Good Clinical Practice (E6), clinical trials (E7-11), clinical evaluation by therapeutic category (12), clinical evaluation (E14), and pharmacogenomics (E15-16). The GCP (E6) document describes the responsibilities and expectations of all participants in the conduct of clinical trials, including investigators, monitors, sponsors and IRBs. It is one of several GCP guidelines published by various organizations, like the World Health Organization (WHO), Pan American Health Organization (PAHO), FDA and EMA. ICH's E6 is the GCP guideline most commonly accepted worldwide. It has been adopted by many countries in their regulations and accepted as the gold standard of GCP for clinical drug development. We will discuss E6 in more detail.

#### **4. Nonclinical drug testing**

Animal testing is an imperfect predictor of drug activity in humans. It constitutes the best practical experimental models for identifying and measuring the pharmacologic activity of the drug and predicting its effects in humans. *In vivo* and *in vitro* animal testing is the first major activity in the drug development process. The purpose is to characterize the toxicology, pharmacokinetic activity, and pharmacological activity of the candidate compounds prior to administration to human beings. FDA (21CFR58) as well as ICH (S guidelines) have developed standards for such testing. Initially, short-term effects are evaluated to decide if the drug is sufficiently safe for administration to humans and at what dose should the human testing start. As the drug development in human beings

US. The purpose is to discuss scientific and technical aspects of drug registration with the goal of harmonizing drug development and registration across the world. The Global Cooperation Group of this organization has been working to harmonize the increasingly global approach to drug development, so that the benefits of international harmonization for better global health can be realized worldwide. ICH's mission is to achieve greater harmonization to ensure that safe, effective, and high quality medicines are developed and registered in the most resource-efficient manner. ICH has developed a series of guidelines to help regulate the clinical drug development process. The instruments developed include a standardized medical terminology system (MedDRA) to use in the capturing, registering, documenting and reporting adverse events during human experimentation. ICH maintains, develops and distributes MedDRA. ICH also developed a standardized package for the submission of new drug applications, the Common Technical Document (CTD) which has been adopted around the world as the gold standard for new medical products submissions. The CTD assembles all the quality, safety and efficacy information required for regulatory submissions in a common format to facilitate the regulatory review process. The CTD has simplified the assembly of the regulatory packages since reformatting for submissions to different regulatory agencies is not necessary anymore. Another area where ICH has worked to improve is international electronic communication by evaluating and recommending Electronic Standards for the Transfer of Regulatory Information (ESTRI). ESTRI has developed recommendations for electronic individual case safety reports and electronic CTDs. Furthermore, ICH has developed guidelines to standardize and harmonize the areas involved in the drug development process. These include guidelines on quality of the product being developed; on safety focusing on nonclinical studies to uncover potential risks for humans; on efficacy, which is concerned with the design, conduct and safety clinical trials; and other guideless like the ones developed by ESTRI. The clinical guidelines include clinical safety (E1-2), clinical study reports (E3), dose response studies (E4), ethnic factors (E5), Good Clinical Practice (E6), clinical trials (E7-11), clinical evaluation by therapeutic category (12), clinical evaluation (E14), and pharmacogenomics (E15-16). The GCP (E6) document describes the responsibilities and expectations of all participants in the conduct of clinical trials, including investigators, monitors, sponsors and IRBs. It is one of several GCP guidelines published by various organizations, like the World Health Organization (WHO), Pan American Health Organization (PAHO), FDA and EMA. ICH's E6 is the GCP guideline most commonly accepted worldwide. It has been adopted by many countries in their regulations and accepted as the gold standard of GCP for clinical drug

Animal testing is an imperfect predictor of drug activity in humans. It constitutes the best practical experimental models for identifying and measuring the pharmacologic activity of the drug and predicting its effects in humans. *In vivo* and *in vitro* animal testing is the first major activity in the drug development process. The purpose is to characterize the toxicology, pharmacokinetic activity, and pharmacological activity of the candidate compounds prior to administration to human beings. FDA (21CFR58) as well as ICH (S guidelines) have developed standards for such testing. Initially, short-term effects are evaluated to decide if the drug is sufficiently safe for administration to humans and at what dose should the human testing start. As the drug development in human beings

development. We will discuss E6 in more detail.

**4. Nonclinical drug testing** 

progresses, additional animal studies are conducted. These animal studies include longterm drug administration, and specialized animal tests are conducted to support longer administration in humans. These experiments allow the observation of drug effects that would be impractical or unethical to study in humans. Researchers can observe the effects of the compound over the lifespan of an animal, test dose responses and maximum doses; assess the effects on reproduction, pregnancy and the embryos; effects on genes; assess potential for carcinogenicity; evaluate mechanisms of action of the drug; and characterize the site, degree and duration of action of the compound. Regulatory agencies are involved in determining the amount and type of animal testing required to initiate drug development in humans as well as the requirements to support the whole clinical development program.

The regulatory agencies, specifically FDA, set the minimum standards for laboratories conducting these nonclinical tests through the publication and enforcement of Good Laboratory Practice (GLP)10. To ensure the quality and integrity of the data derived, nonclinical laboratories are required to implement quality systems to conduct their experiments and to abide by the animal welfare laws of the country. GLPs establish basic standards for the conduct and reporting of non clinical safety testing, including the organization of the laboratory, personnel qualifications, physical structure of the facility, equipment, maintenance procedures, and operating procedures. It requires the use of a written protocol and its structure, including its purpose, who is sponsoring the study, procedure for identification and evaluation of the test animals or test system. GLP details how to report nonclinical studies, the storage and retrieval of records and data, and the retention of records. FDA conducts inspections to monitor compliance with GLP requirements. Nonclinical laboratories may be disqualified if the laboratory facility fails to comply with the regulations, and the noncompliance affects adversely the results of the study.

In addition, FDA may provide advice to sponsors on the adequacy of the nonclinical testing plans before animal testing has begun, and evaluate independently the results and conclusions of the nonclinical testing. FDA has developed guidances for nonclinical testing also. Other regulatory authorities, namely European Community and Japan, have also developed their testing standards. ICH has stepped in in an effort to harmonize these standards with the Safety guidelines (S).

The basic toxicology studies undertaken to identify and measure a drug's adverse effects in the short- and long-term may include any or all of the studies shown in table 1 depending on the drug, intended use and duration of exposure in clinical trials (Table 1).

The responsibility of the conduction of these animal experiments falls on the sponsor, the animal laboratory and the regulatory authorities. Quality systems are required to guarantee the quality of the data generated. The Sponsor monitors the study and conducts audits, the laboratory needs to have proper standard operating procedures and guidelines in accordance with the regulations and prevailing laws as well as a quality group to ensure compliance with said regulations and laws, and the regulatory authorities perform inspections to make sure the regulations and laws are being complied with.

## **5. The clinical phases of drug development**

In the FDA regulations and regulations by health authorities around the world accept 3 phases of drug development11. A fourth phase is frequently included during the post

Quality Control and Quality Assurance in Human Experimentation 235

approval period. These are not mandates that determine the specific structure or design of clinical trials. Although these phases are in general to be conducted sequentially, frequently they overlap. Clinical development programs commonly proceed in the following stages:

This is the phase where initial introduction of an investigational product to humans. The drug is administered cautiously to a few patients or normal human volunteers (usually less than 80), to gain an understanding of the pharmacology, and basic safety of the drug, including tolerability, activity, pharmacodynamics, pharmacokinetics, mechanism of action in humans and optimal route of administration. Drug metabolism, structure-activity relationships and studies in which investigational drugs are used as research tools to explore biological phenomena or disease processes are also included in this phase. The first evidence of the drug efficacy in humans may also be observed in these phase. Subjects are monitored very closely. The studies in Phase II are designed based on the results obtained

In this phase a small group of patients are tested, usually 100 to 200, who suffer from the condition the drug is intended to treat or diagnose. The studies include well controlled, closely monitored trials. The investigational product is administered with the objective of increasing the understanding of the safety profile and the initial observations on the efficacy of the drug in the proposed disease. In this phase the aim is to establish a foundation for the phase III trials. The information gathered includes dose, dose regimen and fine tuning of the

The drug in this phase is used in much larger groups of patients, several hundred or thousands, who suffer from the condition that the compound is supposed to treat. This phase includes controlled and uncontrolled studies. The idea is to gather additional safety and efficacy information to determine the benefit-risk ratio of the drug. In this phase the trials follow more rigorous standards since they will serve as the primary basis for the

In addition to these 3 phases, regulatory authorities may require additional studies after approval to clarify some finding observed during the development program or to produce additional safety data, or treat special populations (e.g. the elderly, patients with renal function impairment, children, etc.). In a general sense the clinical development process continues long after the drug has been approved for marketing. Collection and evaluation of adverse experiences and other information collected while the drug is in the market provides the sponsor and regulatory authorities of a continuous flow of data that allows ongoing review and reassessment of safety and efficacy of the drug. The concept of risk minimization action plans have been introduced recently. Risk minimization action plans are strategic plans to minimize a drug's known risks and for the regulatory agency to monitor the sponsor's implementation of the plan. These postmarketing commitments range from comprehensive literature reviews to large controlled trials. These post marketing

**5.1 Phase I** 

during this phase.

target population.

approval of the drug to be marketed.

**5.3 Phase III** 

**5.4 Phase IV** 

**5.2 Phase II** 


approval period. These are not mandates that determine the specific structure or design of clinical trials. Although these phases are in general to be conducted sequentially, frequently they overlap. Clinical development programs commonly proceed in the following stages:

## **5.1 Phase I**

234 Modern Approaches To Quality Control

exposure.

development.

cancer development.

Measure the short-term adverse effects of one of more doses administered over no more than 24 hours. Provide information on appropriate dosage for multiple dose studies, potential target organs, timeline of drug induced effects, species specific toxicity, potential acute toxicity in humans and estimate the safe acute dose for humans.

Evaluate toxic potential over 14 to 90 days depending on

Determine the risk in relation to the anticipated dose and

reversibility of observed toxicity and the no observed effect level. These studies last 180 days to 1 year of

To observe the generation of malignant tumors in animals. Generally they are required for drugs which are intended to be used for chronic conditions for 6 months or more, or to be intermittently used over the years for chronic or intermittent conditions. These studies are usually in rodents and last for 2 years.

These are studies appropriate for specific formulations, route of administration, or conducted in particular animal models relevant to a human condition, disease or

For drugs to be used in women of childbearing potential.

Mutagenicity studies. Are used to assess the likelihood of the drug causing genomic damage that could induce

Used to describe the systemic exposure achieved in animals and its relationship to the drug concentration, dose and time course of the toxic effect. The purpose is to contribute in the assessment of the relevance of these findings to clinical safety, and support the choice of species and dose regimen in other nonclinical studies as well as the design of subsequent nonclinical studies.

age. They include immunotoxicity studies.

They include fertility and general reproductive performance, teratology and perinatal/postnatal

the proposed clinical indication and duration of exposure. They are designed to assess the progression

duration of treatment, potential target organs,

and regression of drug induced lesions.

Acute toxicity studies

Subacute or subchronic

Chronic toxicity studies

Carcinogenicity studies

Special toxicity studies

Genotoxicity studies

Toxicokinetic studies

Table 1. Basic Nonclinical Toxicology Studies.

Reproductive toxicity studies

toxicity studies

This is the phase where initial introduction of an investigational product to humans. The drug is administered cautiously to a few patients or normal human volunteers (usually less than 80), to gain an understanding of the pharmacology, and basic safety of the drug, including tolerability, activity, pharmacodynamics, pharmacokinetics, mechanism of action in humans and optimal route of administration. Drug metabolism, structure-activity relationships and studies in which investigational drugs are used as research tools to explore biological phenomena or disease processes are also included in this phase. The first evidence of the drug efficacy in humans may also be observed in these phase. Subjects are monitored very closely. The studies in Phase II are designed based on the results obtained during this phase.

#### **5.2 Phase II**

In this phase a small group of patients are tested, usually 100 to 200, who suffer from the condition the drug is intended to treat or diagnose. The studies include well controlled, closely monitored trials. The investigational product is administered with the objective of increasing the understanding of the safety profile and the initial observations on the efficacy of the drug in the proposed disease. In this phase the aim is to establish a foundation for the phase III trials. The information gathered includes dose, dose regimen and fine tuning of the target population.

#### **5.3 Phase III**

The drug in this phase is used in much larger groups of patients, several hundred or thousands, who suffer from the condition that the compound is supposed to treat. This phase includes controlled and uncontrolled studies. The idea is to gather additional safety and efficacy information to determine the benefit-risk ratio of the drug. In this phase the trials follow more rigorous standards since they will serve as the primary basis for the approval of the drug to be marketed.

#### **5.4 Phase IV**

In addition to these 3 phases, regulatory authorities may require additional studies after approval to clarify some finding observed during the development program or to produce additional safety data, or treat special populations (e.g. the elderly, patients with renal function impairment, children, etc.). In a general sense the clinical development process continues long after the drug has been approved for marketing. Collection and evaluation of adverse experiences and other information collected while the drug is in the market provides the sponsor and regulatory authorities of a continuous flow of data that allows ongoing review and reassessment of safety and efficacy of the drug. The concept of risk minimization action plans have been introduced recently. Risk minimization action plans are strategic plans to minimize a drug's known risks and for the regulatory agency to monitor the sponsor's implementation of the plan. These postmarketing commitments range from comprehensive literature reviews to large controlled trials. These post marketing

Quality Control and Quality Assurance in Human Experimentation 237

difference is that monitoring occurs only during the execution of the clinical study, auditing occurs at any time during or after the clinical study is completed. In addition to quality audits there are inspections conducted by the regulatory authority(ies). An inspection is the act of conducting an official review of documents, facilities, records, and any other resources the authorities deem related to the clinical study. The inspection may be at the clinical trial site, at the sponsor's facilities, and/or at the Contract Research Organization (CRO) facilities, or at any other establishment the authorities deem appropriate. CROs are organizations which are normally contracted by sponsors to monitor their clinical studies. CROs may also conduct a complete development program for a sponsor on occasions, or deliver part of the activities related to the development of the investigational product. The purpose of monitoring is to determine if the research was conducted in compliance with national and local laws and regulations for the conduct of research and the protection of

All parties involved in human experimentation (sponsors, clinical investigators, Institutional Review Boards/Independent Ethics Committees, and regulatory authorities) need to adopt and implement quality systems for the processes and activities they are responsible for. This includes clinical research facilities. Clinical research should include **Quality Systems** to measure the quality of clinical research through the use of standard operating procedures (SOPs), study protocol compliance, internal monitoring and the sponsor's monitoring activities. This is accomplished through training of the personnel involved in clinical trial

A Typical quality system would include production and process control, equipment and facilities control; records, documents and change controls; material controls, design controls and corrective and preventive action. (Figure 1). This system can easily be adapted for the

Fig. 1. Typical quality system. This system can easily be adapted to a medical device

MANAGEMENT

CONTROL PRODUCTION

RECORDS, DOCUMENT AND CHANGE CONTROL

CORRECTIVE AND PREVENTIVE

ACTION FACILITY AND

EQUIPMENT CONTROL

> AND PROCESS CONTROL

activities, internal and external audits, and accountability of the personnel.

human subjects.

development of medical devices.

DESIGN CONTROL

MATERIALS

development facility.

studies are usually called post approval trials or phase IV trials. Phase IV trials can be undertaken at the request of the regulatory agency as part of a postapproval commitment, as a specific regulatory agency requirement, or at a company's own decision to learn more about their product.

## **6. Quality systems in clinical research<sup>12</sup>**

Many aspects of Good Manufacturing Practice (GMP) apply to the drug development process. Quality is a measure of the ability of a product, process, or service to satisfy stated or implied needs. A high quality product is one that meets these needs. For human experimentation, quality may apply to data generation and management, or, the processes involved in the implementation of the trials. Quality systems for human experimentation are the formalized practices, e.g. monitoring programs, auditing programs, complaint handling systems, etc., for periodically reviewing the adequacy of the activities and practices during human experimentation, and for revising such activities and practices so that data and process quality are maintained. For human experimentation GCPs are the basis for implementation of quality systems through quality management. This is done through the coordination of activities by the sponsors of the experiments, the clinical investigators and their staff, the institutional review boards and independent ethics committees, and by regulators to direct and control the operations with respect to quality. Quality management consists of three components: quality control, quality assurance, and quality improvement.

In the case of human experimentation, **Quality Control** is the steps taken during the implementation of the clinical trial to ensure the quality of the data generated and the processes involved. These include investigator supervision, sponsor monitoring, and any review by the regulatory authorities, to ensure that the trial meets the protocol and procedural requirements and is reproducible. **Quality Assurance** is the systematic process to determine whether the quality control system is working and effective. In clinical trials this is usually done by the sponsor through independent auditing of quality control activities, and also by the regulatory authorities through inspection of the quality systems and activities.

With the knowledge obtained from the quality assurance, audits and activities changes are made to the systems and activities with the purpose of increasing the ability to fulfill the quality requirements for the moment and in the future. This process can be called **Quality Improvement**.

Another activity central to maintaining and improving quality in clinical trial is the process of monitoring. Monitoring is a quality control activity conducted by the sponsor or a representative of the sponsor. The purpose is to ensure that the research data are accurate, complete, and verifiable from source documents. GCP guidelines (ICH E6)9 defines monitoring as "the act of overseeing the progress of a clinical trial, and of ensuring that it is conducted, recorded, and reported in accordance with the protocol, standard operating procedures, good clinical practices, and the applicable regulatory requirements." Monitors usually compare the data in the case report forms designed for the study and the source documents, i.e., with the medical chart of the patient, physician notes, laboratory results, etc. Monitors also make sure that the activities related to protecting the rights and welfare of the study subjects were carried out appropriately. On the other hand, auditing is an independent quality assurance activity used by the sponsor to evaluate the effectiveness of the monitoring program. Auditing procedures are similar to the monitoring activities. The

studies are usually called post approval trials or phase IV trials. Phase IV trials can be undertaken at the request of the regulatory agency as part of a postapproval commitment, as a specific regulatory agency requirement, or at a company's own decision to learn more

Many aspects of Good Manufacturing Practice (GMP) apply to the drug development process. Quality is a measure of the ability of a product, process, or service to satisfy stated or implied needs. A high quality product is one that meets these needs. For human experimentation, quality may apply to data generation and management, or, the processes involved in the implementation of the trials. Quality systems for human experimentation are the formalized practices, e.g. monitoring programs, auditing programs, complaint handling systems, etc., for periodically reviewing the adequacy of the activities and practices during human experimentation, and for revising such activities and practices so that data and process quality are maintained. For human experimentation GCPs are the basis for implementation of quality systems through quality management. This is done through the coordination of activities by the sponsors of the experiments, the clinical investigators and their staff, the institutional review boards and independent ethics committees, and by regulators to direct and control the operations with respect to quality. Quality management consists of three components: quality control, quality assurance, and quality improvement. In the case of human experimentation, **Quality Control** is the steps taken during the implementation of the clinical trial to ensure the quality of the data generated and the processes involved. These include investigator supervision, sponsor monitoring, and any review by the regulatory authorities, to ensure that the trial meets the protocol and procedural requirements and is reproducible. **Quality Assurance** is the systematic process to determine whether the quality control system is working and effective. In clinical trials this is usually done by the sponsor through independent auditing of quality control activities, and also by the regulatory authorities through inspection of the quality systems

With the knowledge obtained from the quality assurance, audits and activities changes are made to the systems and activities with the purpose of increasing the ability to fulfill the quality requirements for the moment and in the future. This process can be called **Quality** 

Another activity central to maintaining and improving quality in clinical trial is the process of monitoring. Monitoring is a quality control activity conducted by the sponsor or a representative of the sponsor. The purpose is to ensure that the research data are accurate, complete, and verifiable from source documents. GCP guidelines (ICH E6)9 defines monitoring as "the act of overseeing the progress of a clinical trial, and of ensuring that it is conducted, recorded, and reported in accordance with the protocol, standard operating procedures, good clinical practices, and the applicable regulatory requirements." Monitors usually compare the data in the case report forms designed for the study and the source documents, i.e., with the medical chart of the patient, physician notes, laboratory results, etc. Monitors also make sure that the activities related to protecting the rights and welfare of the study subjects were carried out appropriately. On the other hand, auditing is an independent quality assurance activity used by the sponsor to evaluate the effectiveness of the monitoring program. Auditing procedures are similar to the monitoring activities. The

about their product.

and activities.

**Improvement**.

**6. Quality systems in clinical research<sup>12</sup>**

difference is that monitoring occurs only during the execution of the clinical study, auditing occurs at any time during or after the clinical study is completed. In addition to quality audits there are inspections conducted by the regulatory authority(ies). An inspection is the act of conducting an official review of documents, facilities, records, and any other resources the authorities deem related to the clinical study. The inspection may be at the clinical trial site, at the sponsor's facilities, and/or at the Contract Research Organization (CRO) facilities, or at any other establishment the authorities deem appropriate. CROs are organizations which are normally contracted by sponsors to monitor their clinical studies. CROs may also conduct a complete development program for a sponsor on occasions, or deliver part of the activities related to the development of the investigational product. The purpose of monitoring is to determine if the research was conducted in compliance with national and local laws and regulations for the conduct of research and the protection of human subjects.

All parties involved in human experimentation (sponsors, clinical investigators, Institutional Review Boards/Independent Ethics Committees, and regulatory authorities) need to adopt and implement quality systems for the processes and activities they are responsible for.

This includes clinical research facilities. Clinical research should include **Quality Systems** to measure the quality of clinical research through the use of standard operating procedures (SOPs), study protocol compliance, internal monitoring and the sponsor's monitoring activities. This is accomplished through training of the personnel involved in clinical trial activities, internal and external audits, and accountability of the personnel.

A Typical quality system would include production and process control, equipment and facilities control; records, documents and change controls; material controls, design controls and corrective and preventive action. (Figure 1). This system can easily be adapted for the development of medical devices.

Fig. 1. Typical quality system. This system can easily be adapted to a medical device development facility.

Quality Control and Quality Assurance in Human Experimentation 239

clinical trials; verify the accuracy and reliability of clinical trial data submitted to FDA in support of research or marketing applications; and assess compliance with FDA's regulations governing the conduct of clinical trials. The purpose of the program is to

BIMO developed compliance programs to provide uniform guidance and specific instructions for inspections of clinical investigators, sponsors and monitors, in-vivo bioequivalence facilities, Institutional Review Boards, and nonclinical laboratories involved in the testing of investigational products. The purpose of these programs is to adapt a

The most useful elements of a quality system that applies to clinical studies are: corrective and preventive action (CAPA) and management controls. CAPA procedures can be adapted



Management controls involve the appointment of a management representative responsible for the research, in this case the investigator or sub Investigator, and to conduct

Figure 3 shows the relationship between CAPA, management reviews and audits, external (sponsor monitoring, third party or FDA) and internal through monitoring internal

Although FDA inspections are focused on clinical investigators, they are of great importance to sponsors. The inspections are designed to determine how well sponsors performed their responsibilities for the conduct of the study; should the inspections uncover serious problems it may result in rejection of the data essential for drug approval. As a result the sponsor may face inspections and compliance actions if it is found to have worked with


provide instructions for FDA's field personnel for conducting such inspections.

Quality System framework for the oversight and management of clinical studies.

to ensure effective and efficient clinical study management. The application of CAPA to clinical research activities involve:



AUDITS MANAGEMENT

Fig. 3 Relationship between CAPA, Management Reviews and Audits.

REVIEW

noncompliant investigators and did not take corrective action.


CAPA

transcription.

actions taken

management reviews.

activities.


A **Quality System** for an investigational clinical center may be also adapted from this diagram to include the following areas under the control of the clinical investigator (Figure 2):


Fig. 2. The organization of a clinical investigational site.

These represent the activities required in a well run clinical investigational site. The investigator is responsible for all activities. The site should have guidelines and/or standard operating procedures for each these areas and activities. In addition, the investigator should have sufficient personnel who are properly trained and qualified to conduct these activities. It is also important that the facility are appropriate in size and configuration to accommodate all these areas.

## **7. FDA Bioresearch monitoring 12**

The Food and Drug Administration's (FDA) bioresearch monitoring program (BIMO) was established in 1977 with input from the drug, biologics, medical device, veterinary medicine, and food areas. Chapter 48 of the FDA's Compliance Program Guidance Manual is dedicated to Bioresearch Monitoring and delineates the inspection and reporting procedures for studies under FDA jurisdiction. The stated objectives of the bioresearch monitoring program are: to protect the rights, safety, and welfare of subjects involved in FDA-regulated

A **Quality System** for an investigational clinical center may be also adapted from this diagram to include the following areas under the control of the clinical investigator

These represent the activities required in a well run clinical investigational site. The investigator is responsible for all activities. The site should have guidelines and/or standard operating procedures for each these areas and activities. In addition, the investigator should have sufficient personnel who are properly trained and qualified to conduct these activities. It is also important that the facility are appropriate in size and configuration to

CLINICAL INVESTIGATOR

CORRECTIVE AND PREVENTIVE ACTION DEVELOPMENT AND IMPLEMENTATION

FACILITY AND EQUIPMENT EVALUATION AND DOCUMENTATION

SOURCE DOCUMENTATION GENERATION, INTEGRITY AND RETENTION

CONSENT PROCESS AND DOCUMENTATION

The Food and Drug Administration's (FDA) bioresearch monitoring program (BIMO) was established in 1977 with input from the drug, biologics, medical device, veterinary medicine, and food areas. Chapter 48 of the FDA's Compliance Program Guidance Manual is dedicated to Bioresearch Monitoring and delineates the inspection and reporting procedures for studies under FDA jurisdiction. The stated objectives of the bioresearch monitoring program are: to protect the rights, safety, and welfare of subjects involved in FDA-regulated



Fig. 2. The organization of a clinical investigational site.

SAFETY MANAGEMENT AND REPORTING PROCESS AND DOCUMENTATION

accommodate all these areas.

**7. FDA Bioresearch monitoring 12** 




SITE STAFF QUALIFICATION, TRAINING AND DOCUMENTATION

IP ACCOUNTABILITY AND INTEGRITY AND DOCUMENTATION

(Figure 2):

clinical trials; verify the accuracy and reliability of clinical trial data submitted to FDA in support of research or marketing applications; and assess compliance with FDA's regulations governing the conduct of clinical trials. The purpose of the program is to provide instructions for FDA's field personnel for conducting such inspections.

BIMO developed compliance programs to provide uniform guidance and specific instructions for inspections of clinical investigators, sponsors and monitors, in-vivo bioequivalence facilities, Institutional Review Boards, and nonclinical laboratories involved in the testing of investigational products. The purpose of these programs is to adapt a Quality System framework for the oversight and management of clinical studies.

The most useful elements of a quality system that applies to clinical studies are: corrective and preventive action (CAPA) and management controls. CAPA procedures can be adapted to ensure effective and efficient clinical study management.

The application of CAPA to clinical research activities involve:


Management controls involve the appointment of a management representative responsible for the research, in this case the investigator or sub Investigator, and to conduct management reviews.

Figure 3 shows the relationship between CAPA, management reviews and audits, external (sponsor monitoring, third party or FDA) and internal through monitoring internal activities.

Fig. 3 Relationship between CAPA, Management Reviews and Audits.

Although FDA inspections are focused on clinical investigators, they are of great importance to sponsors. The inspections are designed to determine how well sponsors performed their responsibilities for the conduct of the study; should the inspections uncover serious problems it may result in rejection of the data essential for drug approval. As a result the sponsor may face inspections and compliance actions if it is found to have worked with noncompliant investigators and did not take corrective action.

Quality Control and Quality Assurance in Human Experimentation 241

The IRB/IEC should consider the qualifications of the investigator, ensure that all subjects have freely provided their informed consent to be included in the study, ensure that payments to the subject for participation in the trial are not coercive or exercise undue influence, and continuously review the progress of the experimentation at intervals appropriate to the degree of risk to human subjects, but at least once per year. The IRB can request additional information if in the judgment of the IRB members the additional information would add meaningfully to the protection of rights, safety and/or well-being of the trial subjects. The IRB should always determine that a protocol or the information provided adequately addresses relevant ethical concerns and meets applicable regulatory

The IRB is usually composed of at least 5 members, at least one member whose primary area of interest is nonscientific, and at least one member who is independent of the trial site. The investigator may provide information on any aspect of the trial but should not participate in

For the implementation of the informed consent the investigator should comply with all regulatory requirements and adhere to GCP and the ethical principles originating in the Declaration of Helsinki. The subject should be thoroughly informed of the experiment to be conducted, the risks and the potential benefits. Ample time should be given to the subject to make his/her decision to participate in the study. It should be very clear what the experimentation is all about. No coercion should be applied on the potential study subject.





The informed consent document should include explanations of the following:




**8.2 Independent Ethics Committees (IECs) and Institutional Review Boards (IRBs)**  Their main responsibility is to safeguard the rights, safety, and wellbeing of all trial subjects, with special attention to the inclusion of vulnerable subjects to the trial. The IRB/IEC is required to have standard operating procedures and maintain written records of their meeting and decisions. The composition and authority under which the IRB was established should be documented in writing. All meetings, notification to members, and schedules should be disseminated in writing. In summary all information and documentation of

activities should be documented and transparent.

deliberations or in the vote, or opinion of the IRB.

**8.3 The informed consent process** 

being administered.

nursing infant, if applicable. - Reasonable expected benefits.


consequences.

risks and benefits.

requirements.

## **8. Good clinical practice (E6)<sup>9</sup>**

Good Clinical Practices (GCP) is not a set of instructions on how to develop a product or how to design human experiments. GCP is a series of general principles that must be observed during the conduct of human experimentation. This GCP guideline provides a unified standard for designing, conducting, recording, and reporting clinical trials that involve human subjects. Compliance with this guideline provides public assurance that the rights, well-being, and confidentiality of the trial subjects are protected and that the results of the study are credible. GCP are part of the quality systems to cover testing of medicinal products and devices, and conducting clinical studies in human beings. Their objective is to provide a unified standard for the European Union, Japan, and the United States, with consideration to existing GCPs of Australia, Canada, the Nordic countries as well as the World Health Organization, and to facilitate the mutual acceptance of clinical data by the regulatory authorities. It includes also the minimum information that should be included in the information to the investigator, which are the documents considered essential, their purpose, and how to file them. Many countries around the world have adopted these guidelines as their own. The ICH guideline on GCP (E6) outlines the 13 principles of good clinical practices. These principles are in line with the Nüremberg Code, the Declaration of Helsinki and the Belmont Report. These guidelines should be adopted by IRBs/IECs, sponsors, and clinical investigators as well as regulatory authorities who oversee or conduct clinical trials.

## **8.1 Principles of GCP**


The GCP outline the duties of the IRBs/IECs, sponsors, and the clinical investigators.

Good Clinical Practices (GCP) is not a set of instructions on how to develop a product or how to design human experiments. GCP is a series of general principles that must be observed during the conduct of human experimentation. This GCP guideline provides a unified standard for designing, conducting, recording, and reporting clinical trials that involve human subjects. Compliance with this guideline provides public assurance that the rights, well-being, and confidentiality of the trial subjects are protected and that the results of the study are credible. GCP are part of the quality systems to cover testing of medicinal products and devices, and conducting clinical studies in human beings. Their objective is to provide a unified standard for the European Union, Japan, and the United States, with consideration to existing GCPs of Australia, Canada, the Nordic countries as well as the World Health Organization, and to facilitate the mutual acceptance of clinical data by the regulatory authorities. It includes also the minimum information that should be included in the information to the investigator, which are the documents considered essential, their purpose, and how to file them. Many countries around the world have adopted these guidelines as their own. The ICH guideline on GCP (E6) outlines the 13 principles of good clinical practices. These principles are in line with the Nüremberg Code, the Declaration of Helsinki and the Belmont Report. These guidelines should be adopted by IRBs/IECs, sponsors, and clinical investigators as well as regulatory authorities who oversee or conduct

1. Clinical studies should be conducted according to ethical principles

consideration and prevail over scientific or societal interests.

the responsibility of a qualified physician or qualified dentist.

training, and experience to perform his/her respective tasks.

allows accurate reporting, interpretation, and verification.

11. The confidentiality of the records should be protected

accordance with the approved protocol.

2. Foreseeable risks and inconveniences should be weighed against anticipated benefit to

3. The rights, safety and well-being of the trial subjects should be the most important

4. Available preclinical and clinical information on a product should be adequate to

5. A clinical trial should be scientifically sound and described in a clear detailed protocol. 6. A clinical trial should be conducted in compliance with a protocol previously approved

7. Medical care given to, and decisions made on behalf of, trial subjects should be always

8. Each individual involved in conducting the trial should be qualified by education,

9. Freely given informed consent should be obtained from every study subject prior to

10. All clinical trial information should be recorded, handled, and stored in a way that

12. The investigational products should be manufactured, handled, and stored in accordance with applicable good manufacturing practices (GMP), and used in

13. Systems with procedures that assure the quality of every aspect of the trial should be

The GCP outline the duties of the IRBs/IECs, sponsors, and the clinical investigators.

**8. Good clinical practice (E6)<sup>9</sup>**

clinical trials.

**8.1 Principles of GCP** 

the subjects

by an IRB/IEC.

implemented.

support the proposed trial

clinical trial participation.

### **8.2 Independent Ethics Committees (IECs) and Institutional Review Boards (IRBs)**

Their main responsibility is to safeguard the rights, safety, and wellbeing of all trial subjects, with special attention to the inclusion of vulnerable subjects to the trial. The IRB/IEC is required to have standard operating procedures and maintain written records of their meeting and decisions. The composition and authority under which the IRB was established should be documented in writing. All meetings, notification to members, and schedules should be disseminated in writing. In summary all information and documentation of activities should be documented and transparent.

The IRB/IEC should consider the qualifications of the investigator, ensure that all subjects have freely provided their informed consent to be included in the study, ensure that payments to the subject for participation in the trial are not coercive or exercise undue influence, and continuously review the progress of the experimentation at intervals appropriate to the degree of risk to human subjects, but at least once per year. The IRB can request additional information if in the judgment of the IRB members the additional information would add meaningfully to the protection of rights, safety and/or well-being of the trial subjects. The IRB should always determine that a protocol or the information provided adequately addresses relevant ethical concerns and meets applicable regulatory requirements.

The IRB is usually composed of at least 5 members, at least one member whose primary area of interest is nonscientific, and at least one member who is independent of the trial site. The investigator may provide information on any aspect of the trial but should not participate in deliberations or in the vote, or opinion of the IRB.

## **8.3 The informed consent process**

For the implementation of the informed consent the investigator should comply with all regulatory requirements and adhere to GCP and the ethical principles originating in the Declaration of Helsinki. The subject should be thoroughly informed of the experiment to be conducted, the risks and the potential benefits. Ample time should be given to the subject to make his/her decision to participate in the study. It should be very clear what the experimentation is all about. No coercion should be applied on the potential study subject. The informed consent document should include explanations of the following:


Quality Control and Quality Assurance in Human Experimentation 243

involved parties to ensure direct access to clinical trial related sites, source documents, and reports for the purpose of monitoring and auditing by the sponsor, CRO and regulatory authorities. Agreement with the investigators or any other party involved in the study

Quality control should be applied to each stage of data handling to ensure that all data are reliable and have been properly processed, for securing the services of monitors to ensure compliance of clinical investigators and verify that the study is carried out according to the approved study protocol. Sponsors also audit the monitor's performance, other quality control activities and systems to ensure performance. The monitors hired by the sponsor to review the records at the clinical centers, and report their finding to the sponsor in written

Sponsors may transfer in writing any or all their obligations to a contract research organization (CRO), but the ultimate responsibility for the quality and integrity of the data

The sponsor is responsible for the medical expertise. Qualified medical personnel should be readily available to advise on trial related matters. An external consultant may be appointed

Sponsors are responsible for the trial design, trial management, trial data handling, and retention of documents for the specified period required by law and regulations. They are also responsible for the selection of qualified investigators and to apply with the regulatory

Finally, the sponsor is responsible to provide insurance or indemnification to the investigator against claims arising from the trials, except for claims arising from malpractice

The regulators may inspect all parties who conduct or oversee clinical research and verify the information submitted to the regulatory authorities. Regulatory agencies inspect specifically clinical investigators, pharmaceutical companies, device companies, CROs, IRBs/IECs, as well as nonclinical laboratories, to ensure the accuracy and validity of the data generated, and to ensure that the rights and welfare of the research subjects are protected. The regulatory inspectors evaluate how well sponsors, monitors, clinical and non clinical investigators, CROs, and IRBs/IECs comply with the regulations. They may require certain conditions for a study to proceed. They develop policies and procedures for reviewing product applications and for the conduct of GCP inspections as exemplified by

Over the last century the scientific community has developed a better understanding of how to protect and respect the rights, safety and wellbeing of research subjects. For centuries the Hippocratic Oath was the only ethical guidance for physicians and scientists on how to treat subjects, and specifically research subjects. The development of Good Clinical Practice was the result of various incidents that resulted in the Nuremberg Code, the Declaration of Geneva, the Declaration of Helsinki and the Belmont Report. ICH is an attempt to harmonize GCP in the most advanced democracies. Today, many regulatory agencies around the globe use these principles to regulate human experimentation in their countries.

always resides with the sponsor. CROs have the same obligations as the sponsor.

should be in writing.

for this function.

and/or negligence.

**8.6 Regulators** 

**9. Conclusion** 

authorities to conduct the trial.

the FDA's BIMO compliance programs.

reports of all visits and trial related communications.


## **8.4 The investigator**

The investigators supervise the study staff to ensure they follow established procedures for the conduct of the study. They should be qualified by training, education and experience to conduct clinical trials. The investigators should be thoroughly familiar with GCP, the product under investigation and the study protocol. Investigators are responsible for all medical decisions. In their role they obtain approval to conduct the study from the IRB/IEC; ensure that informed consent is obtained freely and without coercion before the study starts; establish and maintain the subjects' case histories; transcribe the subjects' medical data from the medical files to a case report form for the sponsor; ensure the accuracy, completeness, legibility, and timeliness of the data reported; promptly report all adverse events and other problems; document and explain any deviations from the study protocol; be responsible for the accountability and proper storage as well as the use according to the protocol of the investigational product; and provide all required reports at the end of the study to the sponsor.

Investigators should be in contact with the IRB/IEC and the sponsor frequently. Communications involve,


Upon completion of the trial the investigator should inform the sponsor, the IRB/IEC and the regulatory authorities with a summary of the trial outcome, and any other report required by applicable regulation.

#### **8.5 The sponsor**

Sponsors are responsible implementing and maintaining quality assurance and quality control systems with written SOPs to ensure that the trials are conducted, and data are generated, documented and reported in compliance with the protocol, GCP, and applicable regulatory requirements. Sponsors are also responsible for securing agreement from all involved parties to ensure direct access to clinical trial related sites, source documents, and reports for the purpose of monitoring and auditing by the sponsor, CRO and regulatory authorities. Agreement with the investigators or any other party involved in the study should be in writing.

Quality control should be applied to each stage of data handling to ensure that all data are reliable and have been properly processed, for securing the services of monitors to ensure compliance of clinical investigators and verify that the study is carried out according to the approved study protocol. Sponsors also audit the monitor's performance, other quality control activities and systems to ensure performance. The monitors hired by the sponsor to review the records at the clinical centers, and report their finding to the sponsor in written reports of all visits and trial related communications.

Sponsors may transfer in writing any or all their obligations to a contract research organization (CRO), but the ultimate responsibility for the quality and integrity of the data always resides with the sponsor. CROs have the same obligations as the sponsor.

The sponsor is responsible for the medical expertise. Qualified medical personnel should be readily available to advise on trial related matters. An external consultant may be appointed for this function.

Sponsors are responsible for the trial design, trial management, trial data handling, and retention of documents for the specified period required by law and regulations. They are also responsible for the selection of qualified investigators and to apply with the regulatory authorities to conduct the trial.

Finally, the sponsor is responsible to provide insurance or indemnification to the investigator against claims arising from the trials, except for claims arising from malpractice and/or negligence.

## **8.6 Regulators**

242 Modern Approaches To Quality Control




The investigators supervise the study staff to ensure they follow established procedures for the conduct of the study. They should be qualified by training, education and experience to conduct clinical trials. The investigators should be thoroughly familiar with GCP, the product under investigation and the study protocol. Investigators are responsible for all medical decisions. In their role they obtain approval to conduct the study from the IRB/IEC; ensure that informed consent is obtained freely and without coercion before the study starts; establish and maintain the subjects' case histories; transcribe the subjects' medical data from the medical files to a case report form for the sponsor; ensure the accuracy, completeness, legibility, and timeliness of the data reported; promptly report all adverse events and other problems; document and explain any deviations from the study protocol; be responsible for the accountability and proper storage as well as the use according to the protocol of the investigational product; and provide all required reports at the end of the study to the

Investigators should be in contact with the IRB/IEC and the sponsor frequently.




Sponsors are responsible implementing and maintaining quality assurance and quality control systems with written SOPs to ensure that the trials are conducted, and data are generated, documented and reported in compliance with the protocol, GCP, and applicable regulatory requirements. Sponsors are also responsible for securing agreement from all

written report with any additional information requested.

IRB/IEC, the monitor and auditors for verification of the information.





subject.

may be terminated.

**8.4 The investigator** 

sponsor.

Communications involve,

the IRB/IEC to start the study

required by applicable regulation.

**8.5 The sponsor** 

The regulators may inspect all parties who conduct or oversee clinical research and verify the information submitted to the regulatory authorities. Regulatory agencies inspect specifically clinical investigators, pharmaceutical companies, device companies, CROs, IRBs/IECs, as well as nonclinical laboratories, to ensure the accuracy and validity of the data generated, and to ensure that the rights and welfare of the research subjects are protected. The regulatory inspectors evaluate how well sponsors, monitors, clinical and non clinical investigators, CROs, and IRBs/IECs comply with the regulations. They may require certain conditions for a study to proceed. They develop policies and procedures for reviewing product applications and for the conduct of GCP inspections as exemplified by the FDA's BIMO compliance programs.

## **9. Conclusion**

Over the last century the scientific community has developed a better understanding of how to protect and respect the rights, safety and wellbeing of research subjects. For centuries the Hippocratic Oath was the only ethical guidance for physicians and scientists on how to treat subjects, and specifically research subjects. The development of Good Clinical Practice was the result of various incidents that resulted in the Nuremberg Code, the Declaration of Geneva, the Declaration of Helsinki and the Belmont Report. ICH is an attempt to harmonize GCP in the most advanced democracies. Today, many regulatory agencies around the globe use these principles to regulate human experimentation in their countries.

**13** 

*Spain* 

Javier Arrieta

**Quality and Quality Indicators** 

Physicians have historically shared an intuitive concept of Quality, concerning the care we provide to our patients. Our academic education and practice have been focused on Quality as a technical concept, assessable only by technicians and with no strong correlation with outcomes. The concept of Medicine as an Art is related to the values of vocation, dedication

In the XXI Century, we all now accept the scientific nature of Medicine and, therefore, its dependence on the objective assessment of outcomes. In contrast, the patient's perception of Quality strongly depends on the culture and the environment. The current definition of disease given by the World Health Organization (WHO) focuses on self-perceived health and wellbeing. In this context, quality-based medicine should also be oriented towards the

Quality is one of the strategic elements on which the transformation and improvement of modern health systems is based. The effort made in recent years towards quality assurance in this field –including in the particular case of nephrology-, entails recognition of the need for objective and standardized measurement tools for health activities: Quality is not just

There are many definitions of Quality, which in itself suggests that none of them are comprehensive. Definitions focused on Quality in Health, mainly date from the 1980's, when Palmer, Donabedian (Donabedian, 1980), the American Medical Association and many other authors tried to develop an adequate definition. As early as 1990, the Institute of Medicine adapted the definition given by the ISO (International Organization for Standardization), which does not specifically refer to Health: "Quality is the degree to which the characteristics of a product or service meet the objectives for which it was created", defining Quality in Medicine as "the degree to which health services for individuals and populations increase the likelihood of desired health outcomes and are consistent with current professional knowledge"(Lohr, 1990). This is the current philosophy of Medical Quality, which assesses the results, both objective and perceived by the patient (Committee on Quality of Health Care in America, 2001), assuming a degree of uncertainty with respect

and good practice, recognizing that results can after all be negative

health and welfare as perceived by the patient.

**1. Introduction** 

good intentions.

**2. Definitions of quality** 

to processes and the final outcomes.

**in Peritoneal Dialysis** 

*Hospital Universitario de Basurto – Bilbao* 

The responsibility of GCP is shared by all parties involved in human experimentation, investigators, sponsors, ethics commitees, regulatory authorities, and research subjects. To guarantee the quality and accuracy of the data generated during human experimentation Quality Systems have been developed and are applied around the world.

## **10. References**


## **Quality and Quality Indicators in Peritoneal Dialysis**

Javier Arrieta *Hospital Universitario de Basurto – Bilbao Spain* 

## **1. Introduction**

244 Modern Approaches To Quality Control

The responsibility of GCP is shared by all parties involved in human experimentation, investigators, sponsors, ethics commitees, regulatory authorities, and research subjects. To guarantee the quality and accuracy of the data generated during human experimentation

[1] Markel, H. (2004) Perspective. Becoming a Physician. "I Swear by Apollo"- On Taking

[2] Shuster, E. (1997) Fifty Years Later: The Significance of the Nuremberg Code. N Engl J

[3] Jones, D.A. (2006) The Hippocratic Oath II. The Declaration of Geneva and other modern

[4] WMA Declaration of Helsinki – Ethical Principles for Medical Research Involving

[5] The Belmont Report. (1979) Ethical Principles and Guidelines for the Protection of

[8] Japanese Regulatory Agency: Pharmaceutical and Medical Devices Agency available in

[9] International Conference on Harmonization and Technical Requirements for the

[12] Bioresearch Monitoring in Compliance Program Guidance Manual, Chapter 48

adaptation of the classical doctor's oath. Catholic Medical Quarterly, February 2006

Human Subjects of Research. Department of Health, Education, and Welfare

Registration of Pharmaceuticals for Human Use (ICH) available in http://www.

Quality Systems have been developed and are applied around the world.

the Hippocratic Oath. N Engl J Med 2004; 350:2026-2029

http://www.wma.net/en/30publications/10policies/b3/index.html

available in http://ohrs.od.nih.gov/guidelines/belmont.html [6] U.S. Food and Drug Administration available in http://www.FDA.gov [7] European Medicines Agency available in http://www.EMA.europa.eu

[10] Good Laboratory Practice (GLP), 21CFR58 available in http:// www.fda.gov [11] Phases of Drug Development, 21CFR312.21 available in http:// www.fda.gov

Med 1997; 337: 1436-1440, Nov 13, 1997

Human Subjects. October 2008 available from

http://www.pmda.go.jp/english/index.html

ICH.org/home.html

available in: http://www.fda.gov

**10. References** 

Physicians have historically shared an intuitive concept of Quality, concerning the care we provide to our patients. Our academic education and practice have been focused on Quality as a technical concept, assessable only by technicians and with no strong correlation with outcomes. The concept of Medicine as an Art is related to the values of vocation, dedication and good practice, recognizing that results can after all be negative

In the XXI Century, we all now accept the scientific nature of Medicine and, therefore, its dependence on the objective assessment of outcomes. In contrast, the patient's perception of Quality strongly depends on the culture and the environment. The current definition of disease given by the World Health Organization (WHO) focuses on self-perceived health and wellbeing. In this context, quality-based medicine should also be oriented towards the health and welfare as perceived by the patient.

Quality is one of the strategic elements on which the transformation and improvement of modern health systems is based. The effort made in recent years towards quality assurance in this field –including in the particular case of nephrology-, entails recognition of the need for objective and standardized measurement tools for health activities: Quality is not just good intentions.

## **2. Definitions of quality**

There are many definitions of Quality, which in itself suggests that none of them are comprehensive. Definitions focused on Quality in Health, mainly date from the 1980's, when Palmer, Donabedian (Donabedian, 1980), the American Medical Association and many other authors tried to develop an adequate definition. As early as 1990, the Institute of Medicine adapted the definition given by the ISO (International Organization for Standardization), which does not specifically refer to Health: "Quality is the degree to which the characteristics of a product or service meet the objectives for which it was created", defining Quality in Medicine as "the degree to which health services for individuals and populations increase the likelihood of desired health outcomes and are consistent with current professional knowledge"(Lohr, 1990). This is the current philosophy of Medical Quality, which assesses the results, both objective and perceived by the patient (Committee on Quality of Health Care in America, 2001), assuming a degree of uncertainty with respect to processes and the final outcomes.

Quality and Quality Indicators in Peritoneal Dialysis 247

Finally, the European model can theoretically be implemented with no additional economic cost (the only requirement being training in use of the model), while those who pursue international accreditation need to pay the evaluators. There is a cost calculator on the Joint Commission's website, and it should be noted that the center's accreditations have to be

In this context, we note that dialysis is a high cost therapy that can rarely be paid for by the patient. Funders have the authority -and obligation- to monitor the quality of the Healthcare for which they pay. Therefore, they increasingly demand the accreditation of Dialysis Units. Evaluators are usually independent from the payer, and they act as intermediaries between the payer and the health provider. Nevertheless, even in the accreditation systems, evaluation is considered as an element to guide these units in making improvements. In this chapter, we will consider a quality system focused on a continuous improvement

(rather than quality accreditation) that every dialysis unit could adopt if so desired.

Fig. 1. European Foundation for Quality Management. Model of Excellence.

be correlated with those two endpoints: survival and quality of life.

Initially, quality systems have been used in acute care processes (mainly surgical), as well as general services such as laboratories, radiology units, etc. Quality indicators in these cases are derived from different patients who undergo a procedure at different points in time. However in dialysis, patients continue treatment over periods of months and years, and this implies several conceptual changes. It is clear that dialysis is not a curative procedure, but rather a life support technique. Its purpose is then to prolong life and improve its quality. Accordingly, indicators that seek to measure the quality of a certain dialysis therapy should

Quality systems in hemodialysis have been implemented for two decades, fundamentally, due to accreditation requirements. However, peritoneal dialysis (PD) is performed at the patient's home under clinical guidance depending on the general hospital, itself already

renewed every three years.

**2.1.1 Quality systems in dialysis** 

**2.1.2 Quality systems in peritoneal dialysis** 

Quality in patient care depends on a large number of factors, but doctors tend to consider only a few, such as efficacy and effectiveness, more recently including accessibility, efficiency, privacy, and safety, among others as respect for the environment. Some factors are of great interest to Society as a whole - like those just listed - while others may be interesting primarily for patients, such as timeliness, convenience, patient participation, etc. The restrictive view of Quality used by doctors explains the differences we find between the technical quality and the quality perceived by the patients (JCAHO: Agenda for change, 1989).

### **2.1 Quality models**

Although all models of quality are based on common ideas, such as reducing the variability in medical practice through standardization -using standards and indicators-, two types of quality models can be distinguished with respect to their underlying purpose. On the one hand, some models pursue standardization. This involves assessment by a qualified and independent entity that will accredit or certify us for providing high quality medical care. On the other hand, there are models that aim for continuous quality improvement based on self-monitoring. These produce continuous feedback that should help eliminate errors and lead to improvements in outcomes.

These two types of models are by no means exclusive. In Europe, public hospitals commonly use the European Foundation for Quality Management (EFQM) model, which not health specific:

(http://www.efqm.org/en/Home/aboutEFQM/tabid/108/Default.aspx); while, providers in the United Stated and private centers in Europe have chosen accreditations based on the standards of the Joint Commission on Accreditation of Healthcare Organizations (JCAHO, 1989; JCAHO update, 1990; JCAHO, 2011). Meanwhile, in Latin America the EFQM model is adopted more widely through the Latin American Foundation for Quality Management (FUNDIBEQ; www.fundibeq.org ).

The Joint Commission uses a wide range of indicators and standards from the National Institute of Standards and Technology (NIST) -355 in the international version, of which 171 are mandatory for accreditation-, divided into medical and organizational indicators. They can be accessed from www.jointcommission.org or www.quality.nist/gov/.

The EFQM model allows centers to choose their indicators and standards -as long are they are logical and supported by scientific evidence- and pays greater attention to the evolution of the indicator towards "Excellence", than to the achievement of a standard at a given time. In other words, centers are not valued for their good work, but for their year-on-year improvement.

Another important difference from an operational point of view is that the Joint Commission certifies Centers -although it may also test Units- and assesses both clinical and other organizational, structural, plant safety and accessibility indicators. On the other hand, the European model can readily be applied to processes. For example, it is possible to apply the EFQM to a chronic hemodialysis process, peritoneal dialysis, nephrology hospitalization ward or kidney transplantation unit. Therefore, we can first apply it to one of the processes in our Service or Hospital, and within a few years extend it to other processes. It should be noted that processes are only one part of the EFQM (Figure 1), a useful aspect of the model is that we can start by applying it into individual processes, based on the priorities of clients and employees. Later on, the analysis can evolve to address common issues for the Hospital, such as leadership and strategy.

Quality in patient care depends on a large number of factors, but doctors tend to consider only a few, such as efficacy and effectiveness, more recently including accessibility, efficiency, privacy, and safety, among others as respect for the environment. Some factors are of great interest to Society as a whole - like those just listed - while others may be interesting primarily for patients, such as timeliness, convenience, patient participation, etc. The restrictive view of Quality used by doctors explains the differences we find between the technical quality and the quality perceived by the patients (JCAHO: Agenda for change,

Although all models of quality are based on common ideas, such as reducing the variability in medical practice through standardization -using standards and indicators-, two types of quality models can be distinguished with respect to their underlying purpose. On the one hand, some models pursue standardization. This involves assessment by a qualified and independent entity that will accredit or certify us for providing high quality medical care. On the other hand, there are models that aim for continuous quality improvement based on self-monitoring. These produce continuous feedback that should help eliminate errors and

These two types of models are by no means exclusive. In Europe, public hospitals commonly use the European Foundation for Quality Management (EFQM) model, which

(http://www.efqm.org/en/Home/aboutEFQM/tabid/108/Default.aspx); while, providers in the United Stated and private centers in Europe have chosen accreditations based on the standards of the Joint Commission on Accreditation of Healthcare Organizations (JCAHO, 1989; JCAHO update, 1990; JCAHO, 2011). Meanwhile, in Latin America the EFQM model is adopted more widely through the Latin American Foundation for Quality Management

The Joint Commission uses a wide range of indicators and standards from the National Institute of Standards and Technology (NIST) -355 in the international version, of which 171 are mandatory for accreditation-, divided into medical and organizational indicators. They

The EFQM model allows centers to choose their indicators and standards -as long are they are logical and supported by scientific evidence- and pays greater attention to the evolution of the indicator towards "Excellence", than to the achievement of a standard at a given time. In other words, centers are not valued for their good work, but for their year-on-year

Another important difference from an operational point of view is that the Joint Commission certifies Centers -although it may also test Units- and assesses both clinical and other organizational, structural, plant safety and accessibility indicators. On the other hand, the European model can readily be applied to processes. For example, it is possible to apply the EFQM to a chronic hemodialysis process, peritoneal dialysis, nephrology hospitalization ward or kidney transplantation unit. Therefore, we can first apply it to one of the processes in our Service or Hospital, and within a few years extend it to other processes. It should be noted that processes are only one part of the EFQM (Figure 1), a useful aspect of the model is that we can start by applying it into individual processes, based on the priorities of clients and employees. Later on, the analysis can evolve to address common issues for the Hospital,

can be accessed from www.jointcommission.org or www.quality.nist/gov/.

1989).

**2.1 Quality models** 

not health specific:

improvement.

lead to improvements in outcomes.

(FUNDIBEQ; www.fundibeq.org ).

such as leadership and strategy.

Finally, the European model can theoretically be implemented with no additional economic cost (the only requirement being training in use of the model), while those who pursue international accreditation need to pay the evaluators. There is a cost calculator on the Joint Commission's website, and it should be noted that the center's accreditations have to be renewed every three years.

In this context, we note that dialysis is a high cost therapy that can rarely be paid for by the patient. Funders have the authority -and obligation- to monitor the quality of the Healthcare for which they pay. Therefore, they increasingly demand the accreditation of Dialysis Units. Evaluators are usually independent from the payer, and they act as intermediaries between the payer and the health provider. Nevertheless, even in the accreditation systems, evaluation is considered as an element to guide these units in making improvements.

In this chapter, we will consider a quality system focused on a continuous improvement (rather than quality accreditation) that every dialysis unit could adopt if so desired.

Fig. 1. European Foundation for Quality Management. Model of Excellence.

## **2.1.1 Quality systems in dialysis**

Initially, quality systems have been used in acute care processes (mainly surgical), as well as general services such as laboratories, radiology units, etc. Quality indicators in these cases are derived from different patients who undergo a procedure at different points in time. However in dialysis, patients continue treatment over periods of months and years, and this implies several conceptual changes. It is clear that dialysis is not a curative procedure, but rather a life support technique. Its purpose is then to prolong life and improve its quality. Accordingly, indicators that seek to measure the quality of a certain dialysis therapy should be correlated with those two endpoints: survival and quality of life.

## **2.1.2 Quality systems in peritoneal dialysis**

Quality systems in hemodialysis have been implemented for two decades, fundamentally, due to accreditation requirements. However, peritoneal dialysis (PD) is performed at the patient's home under clinical guidance depending on the general hospital, itself already

Quality and Quality Indicators in Peritoneal Dialysis 249

Fig. 2. Dialysis Process.

under global assessment and accreditations. That dependence explains why quality systems in PD have not been prioritized. The EFQM model can be applied to isolated processes, so it can be used in Peritoneal Dialysis Units.

The full EFQM model (Total Quality Management) includes the assessment of multiple criteria, grouped into facilitators (5 types) and results (4 types).

In this chapter, we will only describe the PD process (as a part of the Dialysis Process) and the most appropriate indicators and standards for its evaluation..

## **3. The peritoneal dialysis process**

The process includes information concerning the alternative techniques of dialysis offered to patients from which they can choose, and withdrawal from the PD program due to death, transplantation, changing to hemodialysis or recovery of renal function. As hemodialysis and PD have a similar start and end, and the same therapeutic purpose, we have grouped them under a single process of chronic dialysis, with its two main variants (Figure 2). Logically, the dialysis process is part of a series of support processes including those of the laboratory, pharmacy, maintenance, etc. The description of each activity in the process (Table 1) should not be exhaustive but rather refer to specific protocols that need to be written, accessible to all staff and regularly updated. However, it is important that there is a designated person in charge of each activity in the process and a record of the activity that could be consulted if necessary (Lopez-Revuelta et al., 2002; Arenas, 2006).

The process of peritoneal dialysis is a part of a more complex dialysis process that includes all the renal replacement therapies (Figure 2). Patients' opinions and medical contraindications determine the decision between the three main alternatives for dialysis, whether as a definitive therapy or as life support waiting for kidney transplantation. In this chapter we consider only the indicators of quality for the home peritoneal dialysis option.

#### **3.1 Characteristics of clinical quality indicators**

A clinical indicator is a quantitative measure that can help us monitor and evaluate quality in care activities and support services. It is not a direct marker of quality, but rather can serve to alert to areas which require specific action within a healthcare organization

Indicators express information as numbers of events or ratios. In the latter case, the denominator is the number of patients among whom the event could potentially occur. Although the event selected is undesirable, in general it should occur commonly enough to be used as an index. There is, however, a special kind of indicator that cannot be expressed as an index or a ratio: the Sentinel Event Indicator, that measures events which are undesirable, preventable, rare and have serious outcomes. When detected, such indicators warrant a thorough investigation and urgent action (even if there is just one case).

Indicators can measure either processes or results. The best process indicators are those closely linked to patient outcomes, and for which there is scientific evidence that indicates that the care provided will lead to a specific result. In the event that the result of a process cannot be measured, or there is an excessive delay for corrective action, process indicators are the only type that can be used.

Further, indicators can measure desirable or undesirable results. In the former case, the objective is that the vast majority of patients meet the criteria; while in the latter case, the aim is just the opposite. Ideally, the quality systems used by a given Unit should select only those indicators that represent desirable objectives, in order to avoid confusion. For instance,

under global assessment and accreditations. That dependence explains why quality systems in PD have not been prioritized. The EFQM model can be applied to isolated processes, so it

The full EFQM model (Total Quality Management) includes the assessment of multiple

In this chapter, we will only describe the PD process (as a part of the Dialysis Process) and

The process includes information concerning the alternative techniques of dialysis offered to patients from which they can choose, and withdrawal from the PD program due to death, transplantation, changing to hemodialysis or recovery of renal function. As hemodialysis and PD have a similar start and end, and the same therapeutic purpose, we have grouped them under a single process of chronic dialysis, with its two main variants (Figure 2). Logically, the dialysis process is part of a series of support processes including those of the laboratory, pharmacy, maintenance, etc. The description of each activity in the process (Table 1) should not be exhaustive but rather refer to specific protocols that need to be written, accessible to all staff and regularly updated. However, it is important that there is a designated person in charge of each activity in the process and a record of the activity that

The process of peritoneal dialysis is a part of a more complex dialysis process that includes all the renal replacement therapies (Figure 2). Patients' opinions and medical contraindications determine the decision between the three main alternatives for dialysis, whether as a definitive therapy or as life support waiting for kidney transplantation. In this chapter we consider only the indicators of quality for the home peritoneal dialysis option.

A clinical indicator is a quantitative measure that can help us monitor and evaluate quality in care activities and support services. It is not a direct marker of quality, but rather can

Indicators express information as numbers of events or ratios. In the latter case, the denominator is the number of patients among whom the event could potentially occur. Although the event selected is undesirable, in general it should occur commonly enough to be used as an index. There is, however, a special kind of indicator that cannot be expressed as an index or a ratio: the Sentinel Event Indicator, that measures events which are undesirable, preventable, rare and have serious outcomes. When detected, such indicators

Indicators can measure either processes or results. The best process indicators are those closely linked to patient outcomes, and for which there is scientific evidence that indicates that the care provided will lead to a specific result. In the event that the result of a process cannot be measured, or there is an excessive delay for corrective action, process indicators

Further, indicators can measure desirable or undesirable results. In the former case, the objective is that the vast majority of patients meet the criteria; while in the latter case, the aim is just the opposite. Ideally, the quality systems used by a given Unit should select only those indicators that represent desirable objectives, in order to avoid confusion. For instance,

serve to alert to areas which require specific action within a healthcare organization

warrant a thorough investigation and urgent action (even if there is just one case).

can be used in Peritoneal Dialysis Units.

**3. The peritoneal dialysis process** 

**3.1 Characteristics of clinical quality indicators** 

are the only type that can be used.

criteria, grouped into facilitators (5 types) and results (4 types).

the most appropriate indicators and standards for its evaluation..

could be consulted if necessary (Lopez-Revuelta et al., 2002; Arenas, 2006).

Fig. 2. Dialysis Process.

Quality and Quality Indicators in Peritoneal Dialysis 251

"peritonitis rate with a negative culture" is an indicator of low quality, a high rate suggesting poor quality in sample collection, transport or laboratory processing of peritoneal effluent. As this may not be intuitive, it is preferable to use the "peritonitis rate

In addition, indicators must be valid. This means they should identify situations in which quality in the healthcare provided can be improved (reflected in final outcomes). Validity is often only apparent and the indicator has to be "validated" afterwards. Lastly, indicators must be sensitive, able to identify real problems with care, avoiding "false positives", and

The selection of a set of indicators is a complicated task. It is preferable to select only a few, avoiding an increase in workload related to maintaining the database that would have no direct translation into improvements. From the selected recommendations, the quality indicators were drawn up according to a format which includes: their definition, criterion, equation, units, frequency of the assessment, standard, bibliographical references and comments. The methodologies proposed by the Joint Commission and the Standing Committee of the Hospitals of the European Union were followed by systems for monitoring healthcare processes. These have been complemented by the specific HD methodology that is followed by the American ESRD Special Project and implemented by the Centres for Medicare and Medicaid Services (CMS) -such as in the ESRD Clinical Performance Measures (CPM) Project-. Initially, quality criteria were selected from each recommendation for measurement of performance. The indicator is a quantitative measurement to evaluate a criterion. A "standard" was set for each indicator (namely, the required degree of performance to ensure an acceptable level of quality) based on scientific evidence or, in its absence, by consensus. On many occasions, sufficient scientific evidence was not available, but experience derived from the follow-up of indicators will help us adjust and redefine them in the future. Those interested in understanding the subject more

Traditionally (Donabedian 1980; JCAHO, 1989), we distinguish between structure, process and outcome indicators. Variations in the quality of the structure or the process tend to influence the outcomes. Structure Indicators are highly valued for accreditation, as adverse results caused by structural defects imply a greater responsibility if patients file lawsuits. However, we assume process indicators are a more accurate reflection of quality than those directly related to outcomes, as they detect systematic errors and their correction more

commonly produces improved outcomes (Williams et al, 2006; Ballard, 2003).

with a positive culture", aiming for this indicator to exceed 80% of cases.

they must also be specific, so that they detect only these real problems.

deeply, should consult the 1989 and 1990 JCAHO references.

**3.2 Quality indicators in peritoneal dialysis** 

PERITONEAL DIALYSIS PROTOCOL Nephrologist Lab Reports

Clinical Record

**ACTIVITY DESCRIPTION RESPONSIBLE REGISTRY** 

Discharge from PD due to partial improvement of renal function, change to hemodialysis, transplant or patient's

Table 1. Peritoneal Dialysis: Activities in the Process.

death.


PD nurse

or surgeon

Nephrologist

Nephrologist

and premedication PD nurse Nursing record

PERITONEAL DIALYSIS PROTOCOL PD nurse Nursing record

at patient's home from specific date PD nurse Nursing record

asking for possible problems or doubts. PD nurse Nursing record

PERITONEAL DIALYSIS PROTOCOL PD nephrologist PD Graphics

PROTOCOL Nephrologist PD Graphics

PD nurse

PD nephrologist

Clinical Record Nursing record Consent Form

Lab Reports Clinical Record

RRT Registry. Waiting List for kidney transplant

E-mail and letter of approval

PD Graphics Nursing record Clinical Record

PD Graphics Nursing record Clinical Record

Clinical Record

Clinical Record

PD Graphics Clinical Record RRT Registry

PD physician Clinical Record

**ACTIVITY DESCRIPTION RESPONSIBLE REGISTRY** 

about RRT techniques DIALYSIS GENERAL PROTOCOL Nephrologist

PD DIALYSIS GENERAL PROTOCOL Nephrologist

Written appointment, with date, time

Catheter insertion PERITONEAL DIALYSIS PROTOCOL PD nephrologist

Waiting List

(CAPD or APD)

Call the PD provider To finalize the supply of PD equipment

On line data communication to RRT Registry Database, including

Identification, Clinical and Serological Data, and required data for Kidney

To be done by email about patient information and chosen PD technique

permeability PERITONEAL DIALYSIS PROTOCOL PD nurse Nursing record

Patient PD training PERITONEAL DIALYSIS PROTOCOL PD nurse Nursing record

PERITONEAL DIALYSIS PROTOCOL PD nephrologist

PROTOCOL Nephrologist

After starting PD at home, some contacts

In case of patient's decision or unsolvable problems. PD PROTOCOL

PRE-TRASPLANT STUDIES

PRE-TRASPLANT STUDIES

Patient information

Indication for starting

Appointment for PD catheter insertion

Incorporate in the RRT Registry and waiting list for renal transplant

Administration and PD material provider about

Home visit or phone call to patient's home

Regular controls at hospital, or by phone, mail, web-cam, etc.

To consider change in dialysis technique

Regular controls about studies and treatments of associated illnesses

Regular control's studies about Waiting List for kidney transplant

Reconsider situation in Waiting List for kidney

transplant

Check PD catheter

Deliver to patient Information about appointment for catheter

insertion

Convey to

the patient


Table 1. Peritoneal Dialysis: Activities in the Process.

"peritonitis rate with a negative culture" is an indicator of low quality, a high rate suggesting poor quality in sample collection, transport or laboratory processing of peritoneal effluent. As this may not be intuitive, it is preferable to use the "peritonitis rate with a positive culture", aiming for this indicator to exceed 80% of cases.

In addition, indicators must be valid. This means they should identify situations in which quality in the healthcare provided can be improved (reflected in final outcomes). Validity is often only apparent and the indicator has to be "validated" afterwards. Lastly, indicators must be sensitive, able to identify real problems with care, avoiding "false positives", and they must also be specific, so that they detect only these real problems.

The selection of a set of indicators is a complicated task. It is preferable to select only a few, avoiding an increase in workload related to maintaining the database that would have no direct translation into improvements. From the selected recommendations, the quality indicators were drawn up according to a format which includes: their definition, criterion, equation, units, frequency of the assessment, standard, bibliographical references and comments. The methodologies proposed by the Joint Commission and the Standing Committee of the Hospitals of the European Union were followed by systems for monitoring healthcare processes. These have been complemented by the specific HD methodology that is followed by the American ESRD Special Project and implemented by the Centres for Medicare and Medicaid Services (CMS) -such as in the ESRD Clinical Performance Measures (CPM) Project-. Initially, quality criteria were selected from each recommendation for measurement of performance. The indicator is a quantitative measurement to evaluate a criterion. A "standard" was set for each indicator (namely, the required degree of performance to ensure an acceptable level of quality) based on scientific evidence or, in its absence, by consensus. On many occasions, sufficient scientific evidence was not available, but experience derived from the follow-up of indicators will help us adjust and redefine them in the future. Those interested in understanding the subject more deeply, should consult the 1989 and 1990 JCAHO references.

#### **3.2 Quality indicators in peritoneal dialysis**

Traditionally (Donabedian 1980; JCAHO, 1989), we distinguish between structure, process and outcome indicators. Variations in the quality of the structure or the process tend to influence the outcomes. Structure Indicators are highly valued for accreditation, as adverse results caused by structural defects imply a greater responsibility if patients file lawsuits. However, we assume process indicators are a more accurate reflection of quality than those directly related to outcomes, as they detect systematic errors and their correction more commonly produces improved outcomes (Williams et al, 2006; Ballard, 2003).

Quality and Quality Indicators in Peritoneal Dialysis 253

We use Global Indicators and Comorbidity Indicators to describe patients (Table 2). Most of these are not quality indicators but Registry data, local practice frameworks or terms of reference which enable us to identify certain patient and PD unit characteristics that may influence outcomes and modify other indicators. It is interesting to see how their evolution pans out over time. In some cases, they do indicate aspects of the quality of medical attention before starting PD, but our intention is to use them to adjust the evaluation of Outcome Indicators. The modified Charlson Index (Bedhu et al., 2000) extends the item "Documented History of Myocardial Infarction" to include another one namely "Ischemic Heart Disease (CHD)", which includes all forms of coronary heart disease (angina, myocardial infarction, angiographic evidence of coronary artery disease history of angioplasty or bypass surgery). For this reason, we consider it more appropriate for the usual profile of PD patients. Global and Comorbidity Indicators are collected annually, as they are not used to make improvements. The Charlson Index is measured at the start of PD

Outcome Indicators (Table 3) (Arrieta et al., 2009; Bajo et al., 2010) include more up-to-date data, such as the rate of infections associated with the technique, the adequacy of the dialysis dose, test results and medications taken. These Indicators can alert us to deficiencies in the initial stages of treatment, and early correction can rapidly improve outcomes. Usually, they are compiled twice a year, but with a good IT system they can be calculated and consulted as often as is agreed to be appropriate in each unit, though clearly this

Other indicators such as rates of hospitalization or withdrawals from DP should be explored more carefully, as they are influenced by local characteristics, the socio-cultural context and

Period Prevalence (prevalents at begin of period + incidents)

" of incidents with a signed Informed Consent about all RRT

" of prevalents on CAPD (vs total in PD techniques)

Median of Modified Charlson Index in incidents Median of Modified Charlson Index in prevalents

**3.3 Classification of peritoneal dialysis indicators** 

and, as it can only increase, it is reassessed once or twice a year.

involves additional work.

the availability of replacement therapy.

PD Incidence

techniques

Table 2. Quality Indicators at starting PD.

**GLOBAL INDICATORS** 

Sex rate of incidents y prevalents

**COMORBIDITY INDICATORS** 

Mean time in PD treatment of prevalents Percent of diabetics among incidents " of incidents not dialyzed before " " coming from HD " " coming from TX

Mean age of incidents Mean age of prevalents

Indicators must monitor quality. Therefore, they should be correlated to survival or quality of life of the patients, and be based on scientific evidence. In our case, we based them on the Clinical Practice Guidelines in PD, recently published by the Spanish Society of Nephrology (Arrieta, 2006). Following the publication of these guidelines, a panel of peritoneal dialysis, with the support of the Quality Management in Nephrology Group (a working group of Spanish Society of Nephrology), designed a definition for quality indicators and standards that can be used by all the nephrology community -especially those dedicated to PD-. The new definitions would also serve as a framework or terms of reference for future areas of improvement, filling the gap between the development of guidelines and subsequent monitoring.

Often, we found that there was not sufficient scientific evidence to define a standard. In these cases, we proposed a provisional framework that should be evaluated later. Earlier in this chapter, we have explained that continuous improvement objectives should be set by each unit, based on local outcomes.

Whatever the result of applying an indicator in a given unit, what is important is that they guide improvement activities, and there will then be ongoing monitoring of whether such measures are effective. In fact, indicators are basically an internal tool that permits comparisons with our own previous performance and helps us assess our own improvement. In the future, the pooling of results from different institutions would determine the appropriate quality standards in peritoneal dialysis for the Spanish population.

Having similar quality criteria in all centers is a medium-term objective, as we are all interested in comparing our results and assessing whether variations in clinical practice lead to different final outcomes (Jha et al., 2005).

On the other hand, it has been shown that regular measurement of quality indicators –and the fact of having set up targets and standards- encourages monitoring and improves the outcomes of the process (Williams, 2005; Fink, 2002).

The initial list of indicators, standards and objectives selected includes a large number of indicators that have been already established for hemodialysis. As the most prevalent renal replacement technique, many Quality Systems have already been developed in that field (Lopez-Revuelta et al., 2007). Nevertheless, we should always consider those indicators or standards that have not been specifically validated for PD patients as provisional, and focus on the survival and quality of life outcomes instead.

There are usually too many indicators. Each unit should select those that seem most relevant to its daily routine. In addition, data management technologies become a priority. A wide range of computer software (Renalsoft®, Nefrolink®, Nefrosoft®, Versia® etc.) is used in peritoneal dialysis and hemodialysis units in Spain. In some cases, more advanced programs are being developed and adopted than enable quality indicators to be estimated automatically and rapidly.

In the following sections, we will describe the initial selection of Quality Indicators used by the Spanish Society of Nephrology (currently, at the evaluation stage). They are Clinical Indicators, so they have to be supplemented with Structure Indicators, Satisfaction Surveys and Quality of Life Questionnaires for patients. From a business point of view, and in order to obtain Accreditations of our units, it is also a good idea to carry out Satisfaction Surveys of our staff and suppliers.

Indicators must monitor quality. Therefore, they should be correlated to survival or quality of life of the patients, and be based on scientific evidence. In our case, we based them on the Clinical Practice Guidelines in PD, recently published by the Spanish Society of Nephrology (Arrieta, 2006). Following the publication of these guidelines, a panel of peritoneal dialysis, with the support of the Quality Management in Nephrology Group (a working group of Spanish Society of Nephrology), designed a definition for quality indicators and standards that can be used by all the nephrology community -especially those dedicated to PD-. The new definitions would also serve as a framework or terms of reference for future areas of improvement, filling the gap between the development of guidelines and subsequent

Often, we found that there was not sufficient scientific evidence to define a standard. In these cases, we proposed a provisional framework that should be evaluated later. Earlier in this chapter, we have explained that continuous improvement objectives should be set by

Whatever the result of applying an indicator in a given unit, what is important is that they guide improvement activities, and there will then be ongoing monitoring of whether such measures are effective. In fact, indicators are basically an internal tool that permits comparisons with our own previous performance and helps us assess our own improvement. In the future, the pooling of results from different institutions would determine the appropriate quality standards in peritoneal dialysis for the Spanish

Having similar quality criteria in all centers is a medium-term objective, as we are all interested in comparing our results and assessing whether variations in clinical practice lead

On the other hand, it has been shown that regular measurement of quality indicators –and the fact of having set up targets and standards- encourages monitoring and improves the

The initial list of indicators, standards and objectives selected includes a large number of indicators that have been already established for hemodialysis. As the most prevalent renal replacement technique, many Quality Systems have already been developed in that field (Lopez-Revuelta et al., 2007). Nevertheless, we should always consider those indicators or standards that have not been specifically validated for PD patients as provisional, and focus

There are usually too many indicators. Each unit should select those that seem most relevant to its daily routine. In addition, data management technologies become a priority. A wide range of computer software (Renalsoft®, Nefrolink®, Nefrosoft®, Versia® etc.) is used in peritoneal dialysis and hemodialysis units in Spain. In some cases, more advanced programs are being developed and adopted than enable quality indicators to be estimated

In the following sections, we will describe the initial selection of Quality Indicators used by the Spanish Society of Nephrology (currently, at the evaluation stage). They are Clinical Indicators, so they have to be supplemented with Structure Indicators, Satisfaction Surveys and Quality of Life Questionnaires for patients. From a business point of view, and in order to obtain Accreditations of our units, it is also a good idea to carry out Satisfaction Surveys

monitoring.

population.

each unit, based on local outcomes.

to different final outcomes (Jha et al., 2005).

outcomes of the process (Williams, 2005; Fink, 2002).

on the survival and quality of life outcomes instead.

automatically and rapidly.

of our staff and suppliers.

## **3.3 Classification of peritoneal dialysis indicators**

We use Global Indicators and Comorbidity Indicators to describe patients (Table 2). Most of these are not quality indicators but Registry data, local practice frameworks or terms of reference which enable us to identify certain patient and PD unit characteristics that may influence outcomes and modify other indicators. It is interesting to see how their evolution pans out over time. In some cases, they do indicate aspects of the quality of medical attention before starting PD, but our intention is to use them to adjust the evaluation of Outcome Indicators. The modified Charlson Index (Bedhu et al., 2000) extends the item "Documented History of Myocardial Infarction" to include another one namely "Ischemic Heart Disease (CHD)", which includes all forms of coronary heart disease (angina, myocardial infarction, angiographic evidence of coronary artery disease history of angioplasty or bypass surgery). For this reason, we consider it more appropriate for the usual profile of PD patients. Global and Comorbidity Indicators are collected annually, as they are not used to make improvements. The Charlson Index is measured at the start of PD and, as it can only increase, it is reassessed once or twice a year.

Outcome Indicators (Table 3) (Arrieta et al., 2009; Bajo et al., 2010) include more up-to-date data, such as the rate of infections associated with the technique, the adequacy of the dialysis dose, test results and medications taken. These Indicators can alert us to deficiencies in the initial stages of treatment, and early correction can rapidly improve outcomes. Usually, they are compiled twice a year, but with a good IT system they can be calculated and consulted as often as is agreed to be appropriate in each unit, though clearly this involves additional work.

Other indicators such as rates of hospitalization or withdrawals from DP should be explored more carefully, as they are influenced by local characteristics, the socio-cultural context and the availability of replacement therapy.


Table 2. Quality Indicators at starting PD.

Quality and Quality Indicators in Peritoneal Dialysis 255

Calculation of the rate of occurrence of a certain outcome may present problems in units with few patients. We recommend estimating the prevalence of "at-risk" patients per month, to determine the "real" total number of patients to be used in the denominator of the

Every indicator should have a clear definition, a target or objective (threshold or range), and a standard for assessing compliance. We have defined objectives when there is a reasonable amount of scientific evidence to support them. However, such evidence is often not sufficiently tested in PD (though it may have been tested in HD patients or in the general population, as is the case of LDL cholesterol levels). The original standard is commonly set at the percentage of patients who meet the target. For clarity, we prefer to express the degree

It is important that targets are always to be established based on scientific evidence. For instance, the hemoglobin target is set at 11 mg/dL or above because the Guidelines for Good Clinical Practice (based on hemodialysis) agree on this level; nevertheless; PD patients may have Hb higher than 13 in the absence of EPO. Accordingly, we will not set a maximum target as we do in HD. The standard is a given rate of compliance with objectives -usually 80% to 85%-, and is later adapted to the real results obtained and the real possibilities of

When we initially apply an indicator in our units, we may find that our compliance rates are very low. This could mean that the target was too high, the indicator was not appropriate or, even, that the sample of patients on which the assessment if based are really ill. The objective must be based on high-grade evidence. If it is well established, we must strive to achieve it over time and accept a low compliance rate, re-evaluating the rate once or twice a

I insist that a good progress is more important than a good result. Evidence is often drawn from clinical trials involving highly selected patients, with a high rates of adherence to prescribed medication (which is often free during the trial) and under close medical supervision. These results would be very difficult to achieve in routine practice. In any case, it is absolutely not permissible for the threshold for compliance with an objective to be lowered as a means of achieving a better rate of compliance, unless on reconsideration it is judged that the target is not supported by current evidence, or that the effort required to achieve the target is not justified by real improvements in the final outcome measures

Finally, we must remember that just measuring outcomes tends to produce an improvement in clinical practice (Williams et al., 2005; Fink et al., 2002). It has also been proven that, in hemodialysis, the level of compliance with quality standards is directly related to mortality and morbidity, although most of the standards applied have not yet been validated (Rocco et al., 2006; Plantiga et al., 2007). From a theoretical standpoint, this introduces a bias towards the validation of an Indicator or a Standard, but it should also encourage doctors to use the quality control systems as tools for continuous improvement of our daily practice, rather than consider them as management tools with little relevance

ratios (Jager et al., 2007).

year.

**3.4 Standards and objectives of quality indicators** 

of compliance than the rate of "non-compliance".

achieving the Standard in our healthcare context.

(namely, survival and quality of life).

to medical practice.


Table 3. Quality Indicators of Outcomes.

percent of patients in Kidney Tx Waiting List (WL) (among prevalents in PD)

annual rate of transplants in PD patients (among patients in WL)

**OUTCOME INDICATORS (2) (SEMESTER INDICATORS)** 

mean time between Tx and PD catheter extraction ¿< 1-3 months?

rate of peritonitis ¿< 0.5 / pte / yr?

rate of patients with nasal cultures (positive or not) >80%

 percent of patients with an urea KT/V measured in the semester >80% " of patients with urea KT/V > 1.7 >80% " of patients not anurics with Renal Residual Function measured >80% " of patients with a daily UF rate > 1000ml/ day >80% " of patients using daily one or more hypertonic bags (3.86 / 4.25%) <20% " of patients with a PET performed in the 3 months alter starting PD >80% " of patients with a PET performed annually >80%

 percent of patients within Hb objective (11 to 13) >80% " of patients with serum ferritin > 100 >80% " of patients with Index of Resistance to EPO < 9 >80% " of patients with I.R. to darboepoetin < 0.045 >80% " of patients with serum cholesterol LDL < 100 >80% " of patients with serum albumin > 3.5 >80% " of patients with serum phosphate < 5.5 >80% " of patients with serum corrected calcium > 8.4 and < 9.5 >80% " of patients with Ca x P < 55 (in mg/dL) >80% " of patients with PTH < 300 >80%

percent of peritonitis with a positive culture (identified germ)

" of patients resulting High Absorbers in PET. (D/P Cr 4h > 0.81)

**OUTCOME INDICATORS (1) (ANNUAL INDICATORS)** 

mean time in PD before inclusion in WL

mean time in PD before kidney Tx

partial rates in APD and CAPD

" of peritonitis by Gram +

 " of peritonitis "catheter dependent" rate of infections of catheter exit site

Infections (limited to PD technique)

 by Gram – by fungus

Adequacy and membrane function

Analysis and medication

Table 3. Quality Indicators of Outcomes.

Hospitalization

Exits from PD

Transplants

admissions

 totals change to HD deaths transplants

average days by admission

Calculation of the rate of occurrence of a certain outcome may present problems in units with few patients. We recommend estimating the prevalence of "at-risk" patients per month, to determine the "real" total number of patients to be used in the denominator of the ratios (Jager et al., 2007).

#### **3.4 Standards and objectives of quality indicators**

Every indicator should have a clear definition, a target or objective (threshold or range), and a standard for assessing compliance. We have defined objectives when there is a reasonable amount of scientific evidence to support them. However, such evidence is often not sufficiently tested in PD (though it may have been tested in HD patients or in the general population, as is the case of LDL cholesterol levels). The original standard is commonly set at the percentage of patients who meet the target. For clarity, we prefer to express the degree of compliance than the rate of "non-compliance".

It is important that targets are always to be established based on scientific evidence. For instance, the hemoglobin target is set at 11 mg/dL or above because the Guidelines for Good Clinical Practice (based on hemodialysis) agree on this level; nevertheless; PD patients may have Hb higher than 13 in the absence of EPO. Accordingly, we will not set a maximum target as we do in HD. The standard is a given rate of compliance with objectives -usually 80% to 85%-, and is later adapted to the real results obtained and the real possibilities of achieving the Standard in our healthcare context.

When we initially apply an indicator in our units, we may find that our compliance rates are very low. This could mean that the target was too high, the indicator was not appropriate or, even, that the sample of patients on which the assessment if based are really ill. The objective must be based on high-grade evidence. If it is well established, we must strive to achieve it over time and accept a low compliance rate, re-evaluating the rate once or twice a year.

I insist that a good progress is more important than a good result. Evidence is often drawn from clinical trials involving highly selected patients, with a high rates of adherence to prescribed medication (which is often free during the trial) and under close medical supervision. These results would be very difficult to achieve in routine practice. In any case, it is absolutely not permissible for the threshold for compliance with an objective to be lowered as a means of achieving a better rate of compliance, unless on reconsideration it is judged that the target is not supported by current evidence, or that the effort required to achieve the target is not justified by real improvements in the final outcome measures (namely, survival and quality of life).

Finally, we must remember that just measuring outcomes tends to produce an improvement in clinical practice (Williams et al., 2005; Fink et al., 2002). It has also been proven that, in hemodialysis, the level of compliance with quality standards is directly related to mortality and morbidity, although most of the standards applied have not yet been validated (Rocco et al., 2006; Plantiga et al., 2007). From a theoretical standpoint, this introduces a bias towards the validation of an Indicator or a Standard, but it should also encourage doctors to use the quality control systems as tools for continuous improvement of our daily practice, rather than consider them as management tools with little relevance to medical practice.

Quality and Quality Indicators in Peritoneal Dialysis 257

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Valdecasas, J. et al. (2007). Developing a Clinical Performance Measures System for hemodialysis. Quality Group, Spanish Society of Nephrology. *Nefrología,* Vol 27, No 5, pp. 542-559. Online ISSN: 2013-2514. Print ISSN: 0211-

Attainment of clinical performance targets and improvement in clinical outcomes and resource use in hemodialysis care: a prospective cohort study. *BMC Health* 

Clinical Performance Measures and Outcomes among Patients Receiving long-term Hemodialysis. *Annals of Internal Medicine*, Vol 145, pp. 512-519. On line ISSN: 1539-

U.S. hospitals as reflected by standardized measures, 2002-2004. *New England Journal of Medicine,* Vol 353, pp. 255-264. On line ISSN 1533-4406 Print ISSN 0028-

Health Administration Press. ISBN: 0914904477, 0914904485

Online ISSN: 1533-3450, Print ISSN: 1046-6673.

Online ISSN: 1523-1755, Print ISSN: 0085-2538

ISSN 1533-4406 Print ISSN 0028-4793.

No 11, pp 330-339. ISSN: 0097-5990.

11, pp. 6-7. ISSN: 0747-7376.

ISSN: 0211-6995.

3704. Print ISSN: 0003-4819.

6995.

4793.

## **4. Conclusion**

It has already been demonstrated that the regular measurement of quality indicators –as well as having standards and establishing objectives-, helps to improve the monitoring and results of the dialysis process, and contributes to improving outcomes in terms of patient morbidity and mortality. Access to management software becomes a priority. A Quality System should be focused on achieving Continuous Improvement of Quality expressed in terms of Survival and Quality of Life. Patients' opinion about self-perceived health and wellbeing and about quality of health care must be considered. Accreditation of the Unit should not be a final objective.

## **5. Acknowledgment**

Groups of Quality in Hemodialysis and Peritoneal Dialysis of Spanish Society of Nephrology have played an essential role in the process of selecting indicators and testing the suitability of proposed standards of Quality in PD.

## **6. References**


It has already been demonstrated that the regular measurement of quality indicators –as well as having standards and establishing objectives-, helps to improve the monitoring and results of the dialysis process, and contributes to improving outcomes in terms of patient morbidity and mortality. Access to management software becomes a priority. A Quality System should be focused on achieving Continuous Improvement of Quality expressed in terms of Survival and Quality of Life. Patients' opinion about self-perceived health and wellbeing and about quality of health care must be considered. Accreditation of the Unit

Groups of Quality in Hemodialysis and Peritoneal Dialysis of Spanish Society of Nephrology have played an essential role in the process of selecting indicators and testing

Arenas, MD.; Lorenzo, S.; Alvarez-Ude, F.; Angoso, M.; López- Revuelta, K. &Aranaz, J.

Arrieta, J.; Bajo, MA.; Caravaca, F.; Coronel, F.; García-Perez, H.; Gonzalez-Parra, E.; et al.

Arrieta, J. (2009). Calidad en Diálisis Peritoneal. In: *Tratado de Diálisis Peritoneal.* (Chapter

Bajo, MA.; Selgas, R.; Remón, C.; Arrieta, J.; Alvarez-Ude, F.; Arenas, MD.; Borrás, M.;

Ballard, DJ. (2003). Indicators to improve clinical quality across an integrated health care

Bedhu, S.; Bruns, FJ.; Saul, M.; Seddon, P. & Zeidel, ML. (2000). A simple comorbidity scale

Committee on Quality of Health Care in America. (2001). Crossing the quality chasm: a new

(2006). Quality control systems implementation in the Spanish Dialysis Units. *Nefrología,* Vol 26, No.2, pp. 234-245. Online ISSN: 2013-2514. Print ISSN: 0211-

(2006). Guidelines of the Spanish Society of Nephrology. Clinical practice guidelines for peritoneal dialysis. *Nefrología*. Vol 26. Suppl 4, pp 1-184. Online

31). Montenegro, J.; Correa-Rotter, R & Riella, MC., pp 573-582. Elsevier. ISBN: 978-

Coronel, F.; García-Ramón, R.; Minguela, I.; Pérez-Bañasco, V.; Pérez-Contreras, J.; Fontán, MP.; Teixidó, J.; Tornero, F. & Vega N. (2010). Scientifictechnical quality and ongoing quality improvement plan in peritoneal dialysis. *Nefrologia*. Vol 30, No. 1, pp. 28-45. : 2013-2514. Print ISSN: 0211-

system. International Journal of Quality in Health Care. Vol. 15, Suppl 1, pp i13-i23,

predicts clinical outcomes and costs in dialysis patients. *American Journal of* 

health system for the 21st Century. Washington, DC: National Academy Press.

**4. Conclusion** 

should not be a final objective.

the suitability of proposed standards of Quality in PD.

ISSN: 2013-2514. Print ISSN: 0211-6995.

Online ISSN 1464-3677 - Print ISSN 1353-4505.

*Medicine,* Vol 108, pp 609-613, ISSN 0002-9343.

84-8086-394-0, Madrid.

ISBN: 0-309-07280-8.

**5. Acknowledgment** 

**6. References** 

6995.

6995.


**14** 

*Israel* 

**From a Quality Assurance and Control** 

**to a Nationwide Health Project** 

*2Weizmann Institute of Science, Rehovot,* 

*6Chief Medical Officer, Medical Corps, IDF,* 

*1Quality Assurance and Control Committee, Medical Corps, IDF,* 

*3Head of Standards and Regulation Department in the Division* 

*of Community Medicine, Ministry of Health, Tel Aviv,* 

**System for Medical Processes, Through** 

**Epidemiological Trends of Medical Conditions,** 

Elio Palma1,4, Orna Tal5, Nachman Ash6, Avi Cohen1 and Yoram Chaiter1

A health policy is an integral part of the general welfare policy in every state. According to Dye (1987), interior public policy constitutes the same action as a government that chooses to "do or not do" (Dye, 1987), and thus it is assumed that any governmental action is derived from its will to preserve and provide quality services to the public. Quality of patient health care is defined by two principal dimensions: access and effectiveness (Campbell *et al.*, 2000). Over the last few decades, quality control has been gaining a central place in public organizations in order to improve the quality of services and treatment (Blumenthal, 1996; Landon, *et al.*, 2003; Mandel, *et al.*, 2003; 2004). Quality assurance is a key component in the

The quality index in the health system is a criterion that shows measurable values in morbidity and service levels (Campbell *et al.*, 2000). Since the 1960s, the quality indices in health systems were divided into three main levels: infrastructure and structure, process, and outcome. The last two are usually included as preferred measures (Donabedian, 2005). Infrastructure and structure indices are related to organizational issues of the health services, the attending person's nature, and the procedures and medical policy that are being implemented by the organization on both the private and public levels. The assumption is that any health organization should be capable of providing quality health services according to its resources, which are made up of human, economical, and

processes aimed at improving the quality of service and medical care.

**1.1 Quality control and the health system** 

**1. Introduction** 

Yossy Machluf1,2, Amir Navon1, Avi Yona1, Avinoam Pirogovsky1,3,

*4Head of Department of Occupational Medicine, Clalit Health Services, Afula, 5Israeli Center for Technology Assessment in Health Care; The Gertner Institute for Epidemiology and Health Policy Research, Head of Emerging Technologies Unit, Tel Aviv,* 

Williams, SC.; Watt, A.; Schmaltz, SP.; Koss, RG. & Loeb, JM. (2006). Assessing the reliability of standardized performance indicators. *International Journal of Quality in Health Care,* Vol 18, pp. 246-255. Online ISSN 1464-3677 - Print ISSN 1353- 4505.

## **From a Quality Assurance and Control System for Medical Processes, Through Epidemiological Trends of Medical Conditions, to a Nationwide Health Project**

Yossy Machluf1,2, Amir Navon1, Avi Yona1, Avinoam Pirogovsky1,3, Elio Palma1,4, Orna Tal5, Nachman Ash6, Avi Cohen1 and Yoram Chaiter1 *1Quality Assurance and Control Committee, Medical Corps, IDF, 2Weizmann Institute of Science, Rehovot, 3Head of Standards and Regulation Department in the Division of Community Medicine, Ministry of Health, Tel Aviv, 4Head of Department of Occupational Medicine, Clalit Health Services, Afula, 5Israeli Center for Technology Assessment in Health Care; The Gertner Institute for Epidemiology and Health Policy Research, Head of Emerging Technologies Unit, Tel Aviv, 6Chief Medical Officer, Medical Corps, IDF, Israel* 

## **1. Introduction**

258 Modern Approaches To Quality Control

Williams, SC.; Watt, A.; Schmaltz, SP.; Koss, RG. & Loeb, JM. (2006). Assessing the reliability

4505.

of standardized performance indicators. *International Journal of Quality in Health Care,* Vol 18, pp. 246-255. Online ISSN 1464-3677 - Print ISSN 1353-

> A health policy is an integral part of the general welfare policy in every state. According to Dye (1987), interior public policy constitutes the same action as a government that chooses to "do or not do" (Dye, 1987), and thus it is assumed that any governmental action is derived from its will to preserve and provide quality services to the public. Quality of patient health care is defined by two principal dimensions: access and effectiveness (Campbell *et al.*, 2000). Over the last few decades, quality control has been gaining a central place in public organizations in order to improve the quality of services and treatment (Blumenthal, 1996; Landon, *et al.*, 2003; Mandel, *et al.*, 2003; 2004). Quality assurance is a key component in the processes aimed at improving the quality of service and medical care.

#### **1.1 Quality control and the health system**

The quality index in the health system is a criterion that shows measurable values in morbidity and service levels (Campbell *et al.*, 2000). Since the 1960s, the quality indices in health systems were divided into three main levels: infrastructure and structure, process, and outcome. The last two are usually included as preferred measures (Donabedian, 2005).

Infrastructure and structure indices are related to organizational issues of the health services, the attending person's nature, and the procedures and medical policy that are being implemented by the organization on both the private and public levels. The assumption is that any health organization should be capable of providing quality health services according to its resources, which are made up of human, economical, and

From a Quality Assurance and Control

System for Medical Processes, Through Epidemiological Trends of Medical Conditions… 261

Fig. 1. Schematic representation of the medical process at the recruitment centers.

accumulated medical documentation and forms to the medical committee.

describe disorders, their severity, and determine the profile (Chaiter *et al.*, 2010).

The administrative medical department employees at the recruitment centers constitute the administrative shell of the medical process, are thought of as medical facility workers, and serve as an extension of the medical process. They are exposed to medical information and follow strict laws of keeping medical confidentiality. They are in charge of the appointments of the recruits for various medical procedures at the recruitment centers and at medical facilities outside the recruitment centers; queue regulations; exchanges of letters and documents, and submitting requests from clinics, hospitals, and government facilities. The technical medical assistants are part of the medical committee. Prior to medical committee examinations, they measure vital signs and anthropometric values (such as height, weight, blood pressure, and pulse) and check visual acuity and color vision according to Ishihara color tables. Urinalysis testing is done by a laboratory technician. They also collect all previously sent documents, add all required forms, and provide all of this

The physician's work on the medical committee consists of a thorough medical anamnesis, including family history, habits, and a psychological evaluation. A systematic and comprehensive physical examination is performed. According to the findings, the committee chairman decides whether additional tests, such as a specialist consultation, laboratory tests, imaging, or other measures, are required or if the information is sufficient to apply functional classification codes (FCCs) and complete a recruit's medical profile. The medical profile reflects the recruit's current health status and is used by the Personnel Directorate to assign a military position that is consistent with that health status. Similar to coding systems like the International Classification of Diseases (ICD), Medical FCCs

infrastructure components. Process indices are aimed at examining the extent of the medical actions that are taken to achieve the desired target, assuming that well performed operations increase the chance of accomplishing the desired effects. By contrast, outcome indices focus on the individual level rather than on the organization level. Outcome measurements provide an indirect measure of the overall quality assessment and may provide a benchmark for tracking progress. In general, the more the first two indices (the infrastructure and structure and the process indices) are involved in measuring quality, the greater the reliability of the outcome measures (Donabedian, 2005).

Many approaches were developed to assess the quality of health care and to improve both medical and patient processes, such as the Six Sigma, which utilizes the DMAIC model (Define, Measure, Analyze, Improve, and Control); ISO (International Organization for Standardization); BOS (Business Operating System); CI (Continuous Improvement); TQM (Total Quality Management); etc. (Donabedian, 2003; Munro, 2009; Ovretveit, 1992; Ransom *et al.*, 2008). Many of these approaches are derived and adapted from quality assurance systems in industry, where processes are straightforward and the implementation of such methods is easier. Yet, the medical process represents an intricately interwoven and dynamic process (Donabedian, 2003, Ovretveit, 1992) where many variables are interconnected. For instance, in medical committees, managing authorities, health care medical professionals, technical and administrative personnel, and patients, as well as medical policy, regulations, and goals are all part of medical processes. Therefore, difficulties may arise while applying these methods to medical procedures.

Although there are many models of health care quality control and assurance, most focus on specific issues and are a tool for managerial decisions and not for the day-to-day surveillance of the processes on a clinical level. They may address a specific issue at a local medical facility and may try to improve the specific circumstances, such as the high rates of certain infections at a specific ward or at a specific medical center. Most of the quality assurance processes measure outcomes rather than the completeness and intactness of the continuous process and use a set of tracers or specific indicators, such as Hemoglobin A1C levels in diabetics, cholesterol levels, blood pressure, etc. There are also many economical issues addressed by such quality assurance systems and only rarely do they achieve an optimal resolution of the processes that they aim to control. Many decisions are made in an effort to save expenses and by that to achieve control, while the clinical issues of the processes are not addressed in detail. Most quality systems deal with a limited aspect of the health care process, rather than dealing with the whole process and its various components, including both personnel (policy makers, managers, medical professionals, technical staff, administrative shell, patients) and non-personnel (policy, regulations, infrastructure, economy). In this chapter, the design, application, and outcomes of a unique quality control and assurance program within the framework of medical committees will be described.

#### **1.2 Overview of medical processes at recruitment centers**

In Israel, adolescents aged 16-19 are obligated by law to enlist for military service and are examined by medical committees at conscription centers in order to determine their medical status. The medical process at the recruitment centers necessitates the coordinated action of medical professionals, technical and administrative personnel, and managing authorities, on both the local and national levels. The medical process is based mainly on a medical interview and an examination by a medical committee and is supplemented and supported by information from the family physician, medical consultants, and experts (Fig. 1).

infrastructure components. Process indices are aimed at examining the extent of the medical actions that are taken to achieve the desired target, assuming that well performed operations increase the chance of accomplishing the desired effects. By contrast, outcome indices focus on the individual level rather than on the organization level. Outcome measurements provide an indirect measure of the overall quality assessment and may provide a benchmark for tracking progress. In general, the more the first two indices (the infrastructure and structure and the process indices) are involved in measuring quality, the

Many approaches were developed to assess the quality of health care and to improve both medical and patient processes, such as the Six Sigma, which utilizes the DMAIC model (Define, Measure, Analyze, Improve, and Control); ISO (International Organization for Standardization); BOS (Business Operating System); CI (Continuous Improvement); TQM (Total Quality Management); etc. (Donabedian, 2003; Munro, 2009; Ovretveit, 1992; Ransom *et al.*, 2008). Many of these approaches are derived and adapted from quality assurance systems in industry, where processes are straightforward and the implementation of such methods is easier. Yet, the medical process represents an intricately interwoven and dynamic process (Donabedian, 2003, Ovretveit, 1992) where many variables are interconnected. For instance, in medical committees, managing authorities, health care medical professionals, technical and administrative personnel, and patients, as well as medical policy, regulations, and goals are all part of medical processes. Therefore,

Although there are many models of health care quality control and assurance, most focus on specific issues and are a tool for managerial decisions and not for the day-to-day surveillance of the processes on a clinical level. They may address a specific issue at a local medical facility and may try to improve the specific circumstances, such as the high rates of certain infections at a specific ward or at a specific medical center. Most of the quality assurance processes measure outcomes rather than the completeness and intactness of the continuous process and use a set of tracers or specific indicators, such as Hemoglobin A1C levels in diabetics, cholesterol levels, blood pressure, etc. There are also many economical issues addressed by such quality assurance systems and only rarely do they achieve an optimal resolution of the processes that they aim to control. Many decisions are made in an effort to save expenses and by that to achieve control, while the clinical issues of the processes are not addressed in detail. Most quality systems deal with a limited aspect of the health care process, rather than dealing with the whole process and its various components, including both personnel (policy makers, managers, medical professionals, technical staff, administrative shell, patients) and non-personnel (policy, regulations, infrastructure, economy). In this chapter, the design, application, and outcomes of a unique quality control and assurance program within the framework of medical committees will be described.

In Israel, adolescents aged 16-19 are obligated by law to enlist for military service and are examined by medical committees at conscription centers in order to determine their medical status. The medical process at the recruitment centers necessitates the coordinated action of medical professionals, technical and administrative personnel, and managing authorities, on both the local and national levels. The medical process is based mainly on a medical interview and an examination by a medical committee and is supplemented and supported

by information from the family physician, medical consultants, and experts (Fig. 1).

greater the reliability of the outcome measures (Donabedian, 2005).

difficulties may arise while applying these methods to medical procedures.

**1.2 Overview of medical processes at recruitment centers** 

Fig. 1. Schematic representation of the medical process at the recruitment centers.

The administrative medical department employees at the recruitment centers constitute the administrative shell of the medical process, are thought of as medical facility workers, and serve as an extension of the medical process. They are exposed to medical information and follow strict laws of keeping medical confidentiality. They are in charge of the appointments of the recruits for various medical procedures at the recruitment centers and at medical facilities outside the recruitment centers; queue regulations; exchanges of letters and documents, and submitting requests from clinics, hospitals, and government facilities.

The technical medical assistants are part of the medical committee. Prior to medical committee examinations, they measure vital signs and anthropometric values (such as height, weight, blood pressure, and pulse) and check visual acuity and color vision according to Ishihara color tables. Urinalysis testing is done by a laboratory technician. They also collect all previously sent documents, add all required forms, and provide all of this accumulated medical documentation and forms to the medical committee.

The physician's work on the medical committee consists of a thorough medical anamnesis, including family history, habits, and a psychological evaluation. A systematic and comprehensive physical examination is performed. According to the findings, the committee chairman decides whether additional tests, such as a specialist consultation, laboratory tests, imaging, or other measures, are required or if the information is sufficient to apply functional classification codes (FCCs) and complete a recruit's medical profile. The medical profile reflects the recruit's current health status and is used by the Personnel Directorate to assign a military position that is consistent with that health status. Similar to coding systems like the International Classification of Diseases (ICD), Medical FCCs describe disorders, their severity, and determine the profile (Chaiter *et al.*, 2010).

From a Quality Assurance and Control

process (Machluf *et al.*, 2011).

recruitment centers.

**2. Quality assurance and control system** 

reflect the real daily health care activity in medical departments.

System for Medical Processes, Through Epidemiological Trends of Medical Conditions… 263

system improves the control and management of the medical processes and informatics from the point of view of both the patients and the system operators. Implementation and automation of medical regulations and procedures within the computerized system also make this system play a key role and serve as a control tool during the decision-making

During 1997, a quality assurance and control system was set up (Chaiter *et al.*, 2008; 2010; 2011; The State Comptroller and Ombudsman Office, 2002). This unique system, unlike most policies or systems for quality assurance of medical care, originated from within the medical profession, rather than from industry or academia, and its regulation and modes of action

Fig. 2. Scheme of the quality assurance and control project of medical processes at the

The goals of the quality assurance and control committee are not solely to assess and improve the medical committee outcomes. They are also to identify the limitations and needs of whole medical process regarding the medical, technical, administrative, procedural, and physical aspects and to evaluate knowledge, skills, judgement and working patterns, which count for quality care (Holmboe *et al*., 2008), among all medical personnel; to develop and implement intervention programs to answer the needs of all of the parties participating in the medical process; and to achieve a higher quality of patient care and patient satisfaction (Fig. 2). Accordingly, the quality assurance and control system evaluates

For a complete and successful medical process, a close collaboration between the medical, administrative and technical personnel and harmony in their working relationship are needed.

#### **1.3 Complex and dynamic medical processes at recruitment centers**

Based on our annual analysis of the last decade (Conscription Administration Data, 2001-9), each year about 100,000 new recruits start the medical processes, and more than 400,000 medical encounters are performed at the recruitment centers. About 50% and approximately 13% of the recruits have ≥2 and ≥4 encounters, respectively, mostly with specialists or in hospitals. Most recruits (≥75%) have at least one FCC, while many (~20%) have 3 or more co-existent medical conditions, in spite of their age. Furthermore, it is not just the prevalence of medical conditions but also their severity and morbidity. For instance, ~8% of recruits suffer from chronic asthma, while ~1.5% and ~10% suffer from various cardiac anomalies and mental disorders, respectively (Machluf *et al.*, 2011). In about 10% of the recruits, the discovery of new conditions (following accidents, operations, or a change in the severity of the medical conditions from the first check-up) leads to the modification, addition, or cancellation of FCCs. This may result in the determination of a new medical profile. The thorough examination at a recruitment center might reveal a new, previously unknown, medical problem that warrants further follow-up or treatments at a primary clinic by the primary care physician. Among these conditions, we have revealed even cases of severe disorders, such cardiac anomalies, nephropathies, cancer, etc. In these cases, the diagnostictreatment loops need to be closed.

#### **1.4 Databases**

The information acquired during the medical process in stored, organized, and archived in a database. Computer-based tools allow analysis and visualization of data. With regard to the administrative aspects of the medical process, the computerized system consists of three main components (Machluf *et al.*, 2011):

*A status system:* a specific status code is assigned to each file/recruit using code numbers reflecting the specific specialist, test, or documentation needed. A status code and its beginning and end dates allow the administrative medical department to actively and dynamically follow up and manage the medical and administrative processes on both the individual and collective levels.

*An appointment system:* this system is used to assign a specific date for an appointment to a certain specialist or medical procedure, to generate invitations, and to document the appointment outcome. Its design principles allow better control and management of human and medical resources according to the capacities and limitations of the medical system.

*A directing, monitoring, and controlling system:* a local smart card-based system for real-time follow-up and regulation of waiting lists of patients at each station. It automatically directs recruits either to an available station or according to priorities pre-set by the medical personnel that the specific recruit is required to pass. It provides the medical administrative personnel and the medical committee members with relevant information on both the individual (recruit) and collective (queues) levels.

Each component system is directed toward answering a particular need and, although each is independent, they are all compatible with each other and provide the user with a comprehensive view of the medical process and information. The combined computerized system improves the control and management of the medical processes and informatics from the point of view of both the patients and the system operators. Implementation and automation of medical regulations and procedures within the computerized system also make this system play a key role and serve as a control tool during the decision-making process (Machluf *et al.*, 2011).

## **2. Quality assurance and control system**

262 Modern Approaches To Quality Control

For a complete and successful medical process, a close collaboration between the medical, administrative and technical personnel and harmony in their working relationship are

Based on our annual analysis of the last decade (Conscription Administration Data, 2001-9), each year about 100,000 new recruits start the medical processes, and more than 400,000 medical encounters are performed at the recruitment centers. About 50% and approximately 13% of the recruits have ≥2 and ≥4 encounters, respectively, mostly with specialists or in hospitals. Most recruits (≥75%) have at least one FCC, while many (~20%) have 3 or more co-existent medical conditions, in spite of their age. Furthermore, it is not just the prevalence of medical conditions but also their severity and morbidity. For instance, ~8% of recruits suffer from chronic asthma, while ~1.5% and ~10% suffer from various cardiac anomalies and mental disorders, respectively (Machluf *et al.*, 2011). In about 10% of the recruits, the discovery of new conditions (following accidents, operations, or a change in the severity of the medical conditions from the first check-up) leads to the modification, addition, or cancellation of FCCs. This may result in the determination of a new medical profile. The thorough examination at a recruitment center might reveal a new, previously unknown, medical problem that warrants further follow-up or treatments at a primary clinic by the primary care physician. Among these conditions, we have revealed even cases of severe disorders, such cardiac anomalies, nephropathies, cancer, etc. In these cases, the diagnostic-

The information acquired during the medical process in stored, organized, and archived in a database. Computer-based tools allow analysis and visualization of data. With regard to the administrative aspects of the medical process, the computerized system consists of three

*A status system:* a specific status code is assigned to each file/recruit using code numbers reflecting the specific specialist, test, or documentation needed. A status code and its beginning and end dates allow the administrative medical department to actively and dynamically follow up and manage the medical and administrative processes on both the

*An appointment system:* this system is used to assign a specific date for an appointment to a certain specialist or medical procedure, to generate invitations, and to document the appointment outcome. Its design principles allow better control and management of human and medical resources according to the capacities and limitations of the medical system. *A directing, monitoring, and controlling system:* a local smart card-based system for real-time follow-up and regulation of waiting lists of patients at each station. It automatically directs recruits either to an available station or according to priorities pre-set by the medical personnel that the specific recruit is required to pass. It provides the medical administrative personnel and the medical committee members with relevant information on both the

Each component system is directed toward answering a particular need and, although each is independent, they are all compatible with each other and provide the user with a comprehensive view of the medical process and information. The combined computerized

**1.3 Complex and dynamic medical processes at recruitment centers** 

needed.

treatment loops need to be closed.

main components (Machluf *et al.*, 2011):

individual (recruit) and collective (queues) levels.

individual and collective levels.

**1.4 Databases** 

During 1997, a quality assurance and control system was set up (Chaiter *et al.*, 2008; 2010; 2011; The State Comptroller and Ombudsman Office, 2002). This unique system, unlike most policies or systems for quality assurance of medical care, originated from within the medical profession, rather than from industry or academia, and its regulation and modes of action reflect the real daily health care activity in medical departments.

Fig. 2. Scheme of the quality assurance and control project of medical processes at the recruitment centers.

The goals of the quality assurance and control committee are not solely to assess and improve the medical committee outcomes. They are also to identify the limitations and needs of whole medical process regarding the medical, technical, administrative, procedural, and physical aspects and to evaluate knowledge, skills, judgement and working patterns, which count for quality care (Holmboe *et al*., 2008), among all medical personnel; to develop and implement intervention programs to answer the needs of all of the parties participating in the medical process; and to achieve a higher quality of patient care and patient satisfaction (Fig. 2). Accordingly, the quality assurance and control system evaluates

From a Quality Assurance and Control

samples of completed medical files.

an evaluation of basic measurement techniques.

necessary.

decision making according to clinical criteria and regulations.

System for Medical Processes, Through Epidemiological Trends of Medical Conditions… 265

and evaluates the completeness and adequacy of the anamnesis, physical examination, and decision-making process (using a pre-designed form), as well as the quality of the communication and service to the recruits. For each of these components, quantitative (a numerical scale following specific criteria) and qualitative (description and comments) assessments are used. For example, for each issue in the anamnesis or physical examination, codes are used to determine whether and how the issue was addressed (according to regulations and clinical merits as determined in the medical literature). The decision-making process is also assessed for the quality of referrals to further investigation and the quality of

For each medical committee, 5-10 cases are observed. Findings are shared and discussed with the observed physicians, and proper instructions and guidance are provided, if

*Sampling for recruits' re-examination and record evaluation:* With a recruits' consent, physicians from the quality and assurance system re-examine a random sampling (8-10 on average) of recruits immediately following their examination by the medical committee. The findings of the complete re-examination, including the "assigning" of a medical profile and FCCs, are compared to those of the local medical committee, and discrepancies are recorded and discussed for each case. In addition, a random sampling of files (30-50 files from each recruitment center), where the profiling process was completed, are re-checked by a physician from the quality and assurance system to assess the anamnesis, the medical findings and

*Questionnaire (patients' survey)*: In each recruitment center, questionnaires are randomly distributed to recruits (15-20 on average) following their examination by the medical committee to gain more insight regarding the medical processes (basic measurements, anamnesis, and physical examination), preserving medical confidentiality and right of privacy, as well as the recruits' rates of satisfaction with the service, during the medical process. Recruits are also asked to express their general impression of the medical process.

There are many similarities that are shared by the work of administrative staff and the technical assistants and also by their quality control and assessment. Direct assessment of each person's performance consists of direct observation and evaluation of their work, distribution of questionnaires to professional personnel, interviews, and analysis of random

*Observation (audit):* The work of all of the technical medical staff is assessed prior to, during, and after the medical committee examinations. First, medical equipment (scales, altimeters, chart tables for the visual acuity examination, sphyngomanometers, and Ishihara color tables) and its use are examined during the process of taking basic measurements. Also, documentation handling, data recording, and proper directing to further processes are checked. When required, correct instructions are provided to prevent future mistakes. Similarly, observation of the administrative staff involves the same parameters, except for

*Questionnaire:* A detailed questionnaire is used in order to evaluate the skills of all technical assistants in measurement techniques (weight, height, etc.), knowledge of the normal range and abnormal findings regarding different measurements and the corresponding FCCs (blood pressure, pulse, urinalysis, etc.), and administrative issues (recording of measurements and medical history, signatures, etc.). By contrast, questionnaires are given to

documents, the decision-making process, and the assignment of profiles and FCCs.

**2.2.2 Direct assessment of technical and administrative medical staff** 

and analyzes in detail the various facets of the activities of the medical policy makers, managers, administrative staff, medical professionals (physicians, experts, consultants), and technical assistants, utilizing different complementary methods (Fig. 2). Experts from all these fields (and others), with their high skills and experience, are incorporated into the quality assurance and control system. Of note, performance measures are evidence-based and valid, feasible to collect, applicable to a large enough population of patients, attributed to the performance of individuals, adjustable to the patient level, and representative of the activities of a specialty (Landon *et al.*, 2003).

## **2.1 Approach**

Two main approaches are deployed by the quality assurance and control committee: (i) physical visits to recruitment centers, during which the procedures, work, decision-making processes, and outcomes are directly assessed, and (ii) data mining and processing from the computerized databases. The different means used in each approach to assess the work and results of the different medical process-related staff are summarized in Table 1. Incorporation of such complementary assessment methodologies provides both quantitative and qualitative analyses of daily activities and practices in the medical departments.


\* -distributed to recruits; #-distributed to soldiers

Table 1. The various methodologies used to assess components of the medical process.

## **2.2 Direct assessment**

Direct assessment during the physical visits to the recruitment centers provides an opportunity to evaluate the work of the medical process as a whole. It also enables direct interaction and brainstorming with local medical department members, from administrative staff though technicians, physicians and experts to managers.

### **2.2.1 Direct assessment of medical committee performance**

The medical committee is central to the medical process. Direct assessment of the medical committee's performance consists of direct observation and clinical evaluation of the physicians' work, random samplings, re-examination of recruits that were examined by the medical committee, distribution of questionnaires to recruits following their examination by the medical committee, and analysis of random samples of completed medical files.

*Observation and clinical assessment (clinical audit):* Upon receiving a recruit's consent, a physician from the quality and assurance system joins the medical committee as an observer

and analyzes in detail the various facets of the activities of the medical policy makers, managers, administrative staff, medical professionals (physicians, experts, consultants), and technical assistants, utilizing different complementary methods (Fig. 2). Experts from all these fields (and others), with their high skills and experience, are incorporated into the quality assurance and control system. Of note, performance measures are evidence-based and valid, feasible to collect, applicable to a large enough population of patients, attributed to the performance of individuals, adjustable to the patient level, and representative of the

Two main approaches are deployed by the quality assurance and control committee: (i) physical visits to recruitment centers, during which the procedures, work, decision-making processes, and outcomes are directly assessed, and (ii) data mining and processing from the computerized databases. The different means used in each approach to assess the work and results of the different medical process-related staff are summarized in Table 1. Incorporation of such complementary assessment methodologies provides both quantitative

Methodology Components of the medical process

Technical assistants

Observation - Re-examination \* - - - Record evaluation - Interviews - Questionnaires \* # #

Epidemiology-like -

Administrative

staff Recruits

and qualitative analyses of daily activities and practices in the medical departments.

physicians

Data mining Reports-QC -

Table 1. The various methodologies used to assess components of the medical process.

Direct assessment during the physical visits to the recruitment centers provides an opportunity to evaluate the work of the medical process as a whole. It also enables direct interaction and brainstorming with local medical department members, from administrative

The medical committee is central to the medical process. Direct assessment of the medical committee's performance consists of direct observation and clinical evaluation of the physicians' work, random samplings, re-examination of recruits that were examined by the medical committee, distribution of questionnaires to recruits following their examination by

*Observation and clinical assessment (clinical audit):* Upon receiving a recruit's consent, a physician from the quality and assurance system joins the medical committee as an observer

the medical committee, and analysis of random samples of completed medical files.

activities of a specialty (Landon *et al.*, 2003).

Approach Tools Medical


staff though technicians, physicians and experts to managers.

**2.2.1 Direct assessment of medical committee performance** 

**2.1 Approach** 

Direct assessment

**2.2 Direct assessment** 

\*

and evaluates the completeness and adequacy of the anamnesis, physical examination, and decision-making process (using a pre-designed form), as well as the quality of the communication and service to the recruits. For each of these components, quantitative (a numerical scale following specific criteria) and qualitative (description and comments) assessments are used. For example, for each issue in the anamnesis or physical examination, codes are used to determine whether and how the issue was addressed (according to regulations and clinical merits as determined in the medical literature). The decision-making process is also assessed for the quality of referrals to further investigation and the quality of decision making according to clinical criteria and regulations.

For each medical committee, 5-10 cases are observed. Findings are shared and discussed with the observed physicians, and proper instructions and guidance are provided, if necessary.

*Sampling for recruits' re-examination and record evaluation:* With a recruits' consent, physicians from the quality and assurance system re-examine a random sampling (8-10 on average) of recruits immediately following their examination by the medical committee. The findings of the complete re-examination, including the "assigning" of a medical profile and FCCs, are compared to those of the local medical committee, and discrepancies are recorded and discussed for each case. In addition, a random sampling of files (30-50 files from each recruitment center), where the profiling process was completed, are re-checked by a physician from the quality and assurance system to assess the anamnesis, the medical findings and documents, the decision-making process, and the assignment of profiles and FCCs.

*Questionnaire (patients' survey)*: In each recruitment center, questionnaires are randomly distributed to recruits (15-20 on average) following their examination by the medical committee to gain more insight regarding the medical processes (basic measurements, anamnesis, and physical examination), preserving medical confidentiality and right of privacy, as well as the recruits' rates of satisfaction with the service, during the medical process. Recruits are also asked to express their general impression of the medical process.

#### **2.2.2 Direct assessment of technical and administrative medical staff**

There are many similarities that are shared by the work of administrative staff and the technical assistants and also by their quality control and assessment. Direct assessment of each person's performance consists of direct observation and evaluation of their work, distribution of questionnaires to professional personnel, interviews, and analysis of random samples of completed medical files.

*Observation (audit):* The work of all of the technical medical staff is assessed prior to, during, and after the medical committee examinations. First, medical equipment (scales, altimeters, chart tables for the visual acuity examination, sphyngomanometers, and Ishihara color tables) and its use are examined during the process of taking basic measurements. Also, documentation handling, data recording, and proper directing to further processes are checked. When required, correct instructions are provided to prevent future mistakes. Similarly, observation of the administrative staff involves the same parameters, except for an evaluation of basic measurement techniques.

*Questionnaire:* A detailed questionnaire is used in order to evaluate the skills of all technical assistants in measurement techniques (weight, height, etc.), knowledge of the normal range and abnormal findings regarding different measurements and the corresponding FCCs (blood pressure, pulse, urinalysis, etc.), and administrative issues (recording of measurements and medical history, signatures, etc.). By contrast, questionnaires are given to

From a Quality Assurance and Control

personnel within the medical departments.

on recruitment centers with bigger populations.

minor ones, are now only rarely detected.

differences were observed between recruitment centers.

(p=0.003) and from 8.7% to 50% (p=0.01) during the years 2006 and 2007).

**3.1 Medical committee performance** 

System for Medical Processes, Through Epidemiological Trends of Medical Conditions… 267

identify difficulties concerning physical conditions, administrative or medical procedural deficiencies, and insufficient knowledge or skills of medical/technical/administrative

In general, during the years 1997-2010, more than sixty visits to the different recruitment centers were carried out. Regarding the performance of the medical committees, the work of more than 110 chairmen (of medical committees) was assessed by different means. Six hundred and fifty-five recruits were re-examined, 452 filled out questionnaires, and approximately 1700 records (medical files) were examined and evaluated, providing a 3 pronged approach to observational findings. For the sake of clarity, we will present the findings from the first years and from the period after the intervention programs, focusing

During the first years of the program, we found that at most of the recruitment centers there was an inadequate amount or a lack of medical equipment, and often it was found that the equipment was used inappropriately (Chaiter *et al.*, 2008). The following were among the more common medical equipment-related faults that were found: broken altimeters, inadequately balanced scales, unsuitable Ishihara books for color vision examination, incomplete regulation manuals, and inadequate equipment for visual acuity examinations. Following our visits, a major effort was made to improve the physical conditions and equipment at the medical committee examinations. Examination rooms were redesigned according to the needs of the physician and the patients. Inadequate and old medical equipment were replaced by new machines, complete manuals and regulations were provided, and attention was paid to the physical surroundings and environment. After a gradual improvement in this area throughout the recruitment centers, such faults, even

Among the physicians, we observed inadequacies in anamnesis quality, insufficient physical examinations, and errors in decision making (Chaiter *et al.*, 2008). Furthermore, significant

Anamnesis includes both specific tracer questions and general systematic queries. The tracer questions are all obligatory and refer to night vision, refractive eye surgery, dyslexia, drug use, gynaecological issues among female recruits, prolonged staying abroad at specific areas that are endemic to HIV, and psychological/psychiatric treatments. The main findings show a lack of anamnesis about most of these tracers, except the last two. Yet, differences were observed between recruitment centers. For instance (Chaiter *et al.*, 2008), in 2002, complete anamnesis for refractive surgery was found to range between 12.5% of recruits at center 2 to 90% of recruits at center 5 (p<0.001). Anamnesis of drug use was found to be only 25% of the cases at center 2 as compared to 100% of the recruits at center 5 (p=0.04). Similarly, at center 3, 10% of recruits there were asked about dyslexia, while at center 2 the rate was 100% (p<0.001). During and especially following the intervention program, a clear improvement in the anamnesis process was evident by the completion of anamneses and specific tracer questions at all of the recruitment centers. For example (Chaiter *et al.*, 2008), at center 1, the rates of recruits who were asked about the night vision trace and about prolonged stays abroad at specific areas that are endemic to HIV significantly increased (from 4.35% to 50%

Noted findings concerning physical examinations included a lack of examination of the lateral motion range of the spine and an incomplete examination of heart auscultation (at

the administrative staff to evaluate their knowledge of regulations (status, appointments, and the smart card-based system) and administrative issues (special populations, reports, etc.). Correct instructions are given and even demonstrations are done to promote an increase in knowledge and skills.

*Interviews*: The technical assistants and administrative personnel are interviewed about their work, the findings of the control system are discussed individually, and ideas of how to improve the infrastructure, process, and procedures are shared.

*Sampling for records evaluation*: a random sampling of files (10 on average of each kind, at each recruitment center), where the profiling process was completed, are re-checked by members of the quality and assurance system to assess the documentation and administrative processes.

## **2.3 Data mining and processing**

The demographic information and medical-administrative data are stored, organized, and archived in a database. This data can be visualized and retrieved. Computerized tools, such as reports and regulation-based automated procedures, allow in-depth data analysis. Computerized databases and tools, when integrated into the medical process, allow efficient follow-up and management of medical processes and informatics (Machluf *et al.*, 2011). These databases and reports can also serve as quality control and assessment means (Chaiter *et al.*, 2008; 2010; Machluf *et al.*, 2011; Navon *et al.*, 2011). Using the reports, one can assess the work of medical professionals (physicians and experts, for example), technical assistants, and administrative staff members. For example, reports are aimed at identifying discrepancies between the medical information (such as anthropometric and basic measurement data) and FCCs or medical profiles, inconsistencies in the medicaladministrative information between the status and appointment systems, inadequate or incomplete medical processes (deviations from defined regulations), etc. (Chaiter *et al*., 2008; Machluf *et al*., 2011; Navon *et al*., 2011). Such populations, at the individual level, are monitored, and reports are distributed monthly to the relevant personnel at each recruitment center and to the managing authorities.

Reports also support the design, planning, monitoring, and use of human and medical resources and are a component of the decision making that is made by the medicaladministrative managers. For instance, various aspects of the availability and need for medical services, such as specialists, consultants, medical procedures, waiting queues, and various causes of congestion that need to be taken care of, are all assessed regularly by reports. The findings are distributed to the relevant personnel at the recruitment centers and to the managing authorities.

Reports also allow a comparison between the performance of the medical personnel within and between the recruitment centers and across a longitudinal time axis. Furthermore, since medical profiles and FCCs are indicators of medical conditions among recruits, an epidemiological investigation of the profile distribution and prevalence of FCCs can be performed, providing inter- and intra-recruitment center analysis (Chaiter *et al.*, 2010). This valuable information can be related to or crossed with gender, geographical area, country of origin, ethnicity, socio-economic background, education, and morbidity trends in the general population in Israel and other countries.

## **3. Findings**

Using these tools, we analyzed key parameters related to the performance, integrity, and completeness of the medical processes and procedures. Furthermore, we were able to identify difficulties concerning physical conditions, administrative or medical procedural deficiencies, and insufficient knowledge or skills of medical/technical/administrative personnel within the medical departments.

## **3.1 Medical committee performance**

266 Modern Approaches To Quality Control

the administrative staff to evaluate their knowledge of regulations (status, appointments, and the smart card-based system) and administrative issues (special populations, reports, etc.). Correct instructions are given and even demonstrations are done to promote an

*Interviews*: The technical assistants and administrative personnel are interviewed about their work, the findings of the control system are discussed individually, and ideas of how to

*Sampling for records evaluation*: a random sampling of files (10 on average of each kind, at each recruitment center), where the profiling process was completed, are re-checked by members of the quality and assurance system to assess the documentation and

The demographic information and medical-administrative data are stored, organized, and archived in a database. This data can be visualized and retrieved. Computerized tools, such as reports and regulation-based automated procedures, allow in-depth data analysis. Computerized databases and tools, when integrated into the medical process, allow efficient follow-up and management of medical processes and informatics (Machluf *et al.*, 2011). These databases and reports can also serve as quality control and assessment means (Chaiter *et al.*, 2008; 2010; Machluf *et al.*, 2011; Navon *et al.*, 2011). Using the reports, one can assess the work of medical professionals (physicians and experts, for example), technical assistants, and administrative staff members. For example, reports are aimed at identifying discrepancies between the medical information (such as anthropometric and basic measurement data) and FCCs or medical profiles, inconsistencies in the medicaladministrative information between the status and appointment systems, inadequate or incomplete medical processes (deviations from defined regulations), etc. (Chaiter *et al*., 2008; Machluf *et al*., 2011; Navon *et al*., 2011). Such populations, at the individual level, are monitored, and reports are distributed monthly to the relevant personnel at each

Reports also support the design, planning, monitoring, and use of human and medical resources and are a component of the decision making that is made by the medicaladministrative managers. For instance, various aspects of the availability and need for medical services, such as specialists, consultants, medical procedures, waiting queues, and various causes of congestion that need to be taken care of, are all assessed regularly by reports. The findings are distributed to the relevant personnel at the recruitment centers and

Reports also allow a comparison between the performance of the medical personnel within and between the recruitment centers and across a longitudinal time axis. Furthermore, since medical profiles and FCCs are indicators of medical conditions among recruits, an epidemiological investigation of the profile distribution and prevalence of FCCs can be performed, providing inter- and intra-recruitment center analysis (Chaiter *et al.*, 2010). This valuable information can be related to or crossed with gender, geographical area, country of origin, ethnicity, socio-economic background, education, and morbidity trends in the

Using these tools, we analyzed key parameters related to the performance, integrity, and completeness of the medical processes and procedures. Furthermore, we were able to

improve the infrastructure, process, and procedures are shared.

increase in knowledge and skills.

**2.3 Data mining and processing** 

recruitment center and to the managing authorities.

general population in Israel and other countries.

administrative processes.

to the managing authorities.

**3. Findings** 

In general, during the years 1997-2010, more than sixty visits to the different recruitment centers were carried out. Regarding the performance of the medical committees, the work of more than 110 chairmen (of medical committees) was assessed by different means. Six hundred and fifty-five recruits were re-examined, 452 filled out questionnaires, and approximately 1700 records (medical files) were examined and evaluated, providing a 3 pronged approach to observational findings. For the sake of clarity, we will present the findings from the first years and from the period after the intervention programs, focusing on recruitment centers with bigger populations.

During the first years of the program, we found that at most of the recruitment centers there was an inadequate amount or a lack of medical equipment, and often it was found that the equipment was used inappropriately (Chaiter *et al.*, 2008). The following were among the more common medical equipment-related faults that were found: broken altimeters, inadequately balanced scales, unsuitable Ishihara books for color vision examination, incomplete regulation manuals, and inadequate equipment for visual acuity examinations. Following our visits, a major effort was made to improve the physical conditions and equipment at the medical committee examinations. Examination rooms were redesigned according to the needs of the physician and the patients. Inadequate and old medical equipment were replaced by new machines, complete manuals and regulations were provided, and attention was paid to the physical surroundings and environment. After a gradual improvement in this area throughout the recruitment centers, such faults, even minor ones, are now only rarely detected.

Among the physicians, we observed inadequacies in anamnesis quality, insufficient physical examinations, and errors in decision making (Chaiter *et al.*, 2008). Furthermore, significant differences were observed between recruitment centers.

Anamnesis includes both specific tracer questions and general systematic queries. The tracer questions are all obligatory and refer to night vision, refractive eye surgery, dyslexia, drug use, gynaecological issues among female recruits, prolonged staying abroad at specific areas that are endemic to HIV, and psychological/psychiatric treatments. The main findings show a lack of anamnesis about most of these tracers, except the last two. Yet, differences were observed between recruitment centers. For instance (Chaiter *et al.*, 2008), in 2002, complete anamnesis for refractive surgery was found to range between 12.5% of recruits at center 2 to 90% of recruits at center 5 (p<0.001). Anamnesis of drug use was found to be only 25% of the cases at center 2 as compared to 100% of the recruits at center 5 (p=0.04). Similarly, at center 3, 10% of recruits there were asked about dyslexia, while at center 2 the rate was 100% (p<0.001). During and especially following the intervention program, a clear improvement in the anamnesis process was evident by the completion of anamneses and specific tracer questions at all of the recruitment centers. For example (Chaiter *et al.*, 2008), at center 1, the rates of recruits who were asked about the night vision trace and about prolonged stays abroad at specific areas that are endemic to HIV significantly increased (from 4.35% to 50% (p=0.003) and from 8.7% to 50% (p=0.01) during the years 2006 and 2007).

Noted findings concerning physical examinations included a lack of examination of the lateral motion range of the spine and an incomplete examination of heart auscultation (at

From a Quality Assurance and Control

Symptomatic

Allergic rhinitis/

Knee joint

n.s. – not significant

System for Medical Processes, Through Epidemiological Trends of Medical Conditions… 269

recruitment center 1 (Table 2). Interestingly, a trend toward a significant increase in prevalence until the year 2005 and then a significant decrease in prevalence until the year

Medical condition Year Correlation

Chronic headache 4.31 4.82 4.88 5.77 6.66 6.21 6.06 6.24 6.17 0.820,

scoliosis/kyphosis 1.90 3.41 3.93 5.35 5.52 4.88 4.91 5.16 4.72 0.709,

Active asthma 11.29 9.29 8.66 9.62 9.94 9.54 8.52 8.94 8.12 0.684,

Under-weight 4.44 4.56 4.91 5.49 4.79 3.57 3.44 3.85 4.14 0.558,

Chronic back pain 8.32 7.99 8.27 8.52 9.03 8.50 7.28 7.63 7.50 0.515,

sinusitis 11.89 11.75 11.19 12.39 12.86 12.31 11.18 11.19 10.30 0.471,

disorders 3.62 3.19 3.79 4.37 4.94 4.16 4.24 4.02 3.09 0.082,

Mental conditions 9.83 8.17 9.14 8.94 11.13 10.20 10.03 9.75 8.10 0.040,

Table 2. Percentages of main medical conditions contributing to a difference in profiling at recruitment center 1 from 2001 to 2009 (Modified with permission from Chaiter *et al.*, 2010). Some of these 26 FCCs were found to vary significantly between sub-districts in all of the recruitment centers (data not shown and Chaiter *et al.*, 2010). This may be attributed to both demographic-environmental parameters and professional-human causes. Across recruitment centers, and over the years, clear and significant disparities were found in the prevalence of how a majority of these FCCs were assigned by different medical committee chairmen in the year 2006 (data not shown and Chaiter *et al.*, 2010). This further strengthens the supposition that there are differences among recruitment centers and among the chairmen's reporting of medical histories, performing physical examinations, and interpreting various medical conditions, all of which lead to differential assignments of FCCs. Differences in FCC assignment by different chairmen at the same recruitment center indicate decision-making disparities or lack of experience and expertise in specific fields. The intervention program led to an improvement in certain aspects of the chairmen's knowledge and skills and, as a result, to an improvement in the performance of the committees; while variations between chairmen and between recruitment centers still exist, it is to a slightly lesser extent. The impact of professional development and understanding of the whole medical process (see below), as well as the establishment of a uniform working platform, resulted in decreased variability of medical conditions in the various conscription centers and among physicians. However, it could have been greater if the turnover of

It is noteworthy that a subset of the 26 most commonly assigned FCCs were found to vary significantly among all three stratification criteria (recruitment centers, sub-districts, and

professional medical human resources would have been lower.

2001 2002 2003 2004 2005 2006 2007 2008 2009 p value

<0.01

<0.05

<0.05

n.s.

n.s.

n.s.

n.s.

n.s.

2009 was common to all other FCCs, except for that of underweight (Table 2).

one point only - left sternal border), lung auscultation (one or two points on each side), the abdomen (partial palpation of one or two quadrants), the lower extremities (especially the feet), and male genitalia (lack of examination of the inguinal canal for possible inguinal hernia or incomplete examination of testicles) (Chaiter *et al.*, 2008). Moreover, similar to anamnesis, clear differences were observed between recruitment centers. In 2002, the rate of complete examination of the abdomen ranged from 25% (center 2) to 90% (center 5) of recruits (p=0.048), while complete foot examinations were carried out on 38% (center 4) to 70% (center 5) of recruits. During the years following the intervention program, noticeable progress was observed in the physical examinations. For example, at center 1, a significant improvement was noted from 2006 to 2007 in abdominal examinations (from 8.7% to 75% (p<0.001)), foot examinations (from 47.8% to 100% (p=0.01)), and in male genitalia examinations (from 4.35% to 75% (p<0.01)).

Decision-making processes are integral and central to the medical process. Over the years, no clear trends were observed in the rates of correct decision-making procedures (Chaiter *et al.*, 2008). This may be attributed to the turnover of human resources (chairmen, physicians), and the persistence of local medical procedures at recruitment centers which are not in line with the general guidance. Nevertheless, an improvement in the decision-making processes at specific time points, or over several years, at specific centers was associated with cooperation with the quality control and assurance system.

Together, better medical history recording, physical examinations, and decision-making processes by the physicians of the medical committees were noted.

Data mining and processing by computerized reports revealed a major decrease in the rate of discrepancies between the medical information (such as anthropometric and basic measurements data) and FCCs or medical profiles (Chaiter *et al.*, 2008).

Analysis of medical profile distribution and the prevalence of FCCs, the indicators of medical conditions among recruits, uncovered significant differences between recruitment centers (Chaiter *et al.*, 2010). Analyzing all of the FCCs revealed the 26 most common FCCs, which comprised approximately 90% of all assigned FCCs. Almost 90% of these common FCCs (23 out of 26) were found to vary significantly between different recruitment centers. Data stratification according to ethnic origin did not affect the results (Conscription Administration Data, 2001-9). These 26 FCCs include overweight, underweight, anemia, asthma, cardiac anomalies (either valvular or non-valvular), hypertension, varicocele/hydrocele, epilepsy, mental illness conditions (personality disorders, neurosis, psychosis, depression, mental retardation, and autism), hernia, visual acuity, allergic rhinitis/sinusitis, and flat feet. Some of these FCCs (such as bee sting allergy; anemia; valvular and non-valvular cardiac anomalies, including mitral valve prolapse; hypertension; hydrocele/varicocele; flat feet; hernia; hearing loss; visual acuity problems; and color blindness) were found not to significantly affect the final profile outcome. Yet, a set of only 8 FCCs (those indicating recruits who were underweight or suffered from asthma, chronic headache/migraine, mental illness, scoliosis/kyphosis, chronic back pain, knee joint disorders, or rhinitis/sinusitis) accounted for 90% of the medical profiling differences between recruitment centers (Conscription Administration Data, 2001-9). Of these key profile-affecting FCCs, the prevalence of all of them except scoliosis/kyphosis and mental conditions was found to be 1.5 to 2.5 times higher at recruitment center 1 as compared to the other centers (Chaiter *et al.*, 2010).

Over the years, significant trends were observed: the prevalence of chronic headaches (increased), symptomatic scoliosis/kyphosis (increased), and active asthma (decreased) in recruitment center 1 (Table 2). Interestingly, a trend toward a significant increase in prevalence until the year 2005 and then a significant decrease in prevalence until the year 2009 was common to all other FCCs, except for that of underweight (Table 2).


n.s. – not significant

268 Modern Approaches To Quality Control

one point only - left sternal border), lung auscultation (one or two points on each side), the abdomen (partial palpation of one or two quadrants), the lower extremities (especially the feet), and male genitalia (lack of examination of the inguinal canal for possible inguinal hernia or incomplete examination of testicles) (Chaiter *et al.*, 2008). Moreover, similar to anamnesis, clear differences were observed between recruitment centers. In 2002, the rate of complete examination of the abdomen ranged from 25% (center 2) to 90% (center 5) of recruits (p=0.048), while complete foot examinations were carried out on 38% (center 4) to 70% (center 5) of recruits. During the years following the intervention program, noticeable progress was observed in the physical examinations. For example, at center 1, a significant improvement was noted from 2006 to 2007 in abdominal examinations (from 8.7% to 75% (p<0.001)), foot examinations (from 47.8% to 100% (p=0.01)), and in male genitalia

Decision-making processes are integral and central to the medical process. Over the years, no clear trends were observed in the rates of correct decision-making procedures (Chaiter *et al.*, 2008). This may be attributed to the turnover of human resources (chairmen, physicians), and the persistence of local medical procedures at recruitment centers which are not in line with the general guidance. Nevertheless, an improvement in the decision-making processes at specific time points, or over several years, at specific centers was associated with

Together, better medical history recording, physical examinations, and decision-making

Data mining and processing by computerized reports revealed a major decrease in the rate of discrepancies between the medical information (such as anthropometric and basic

Analysis of medical profile distribution and the prevalence of FCCs, the indicators of medical conditions among recruits, uncovered significant differences between recruitment centers (Chaiter *et al.*, 2010). Analyzing all of the FCCs revealed the 26 most common FCCs, which comprised approximately 90% of all assigned FCCs. Almost 90% of these common FCCs (23 out of 26) were found to vary significantly between different recruitment centers. Data stratification according to ethnic origin did not affect the results (Conscription Administration Data, 2001-9). These 26 FCCs include overweight, underweight, anemia, asthma, cardiac anomalies (either valvular or non-valvular), hypertension, varicocele/hydrocele, epilepsy, mental illness conditions (personality disorders, neurosis, psychosis, depression, mental retardation, and autism), hernia, visual acuity, allergic rhinitis/sinusitis, and flat feet. Some of these FCCs (such as bee sting allergy; anemia; valvular and non-valvular cardiac anomalies, including mitral valve prolapse; hypertension; hydrocele/varicocele; flat feet; hernia; hearing loss; visual acuity problems; and color blindness) were found not to significantly affect the final profile outcome. Yet, a set of only 8 FCCs (those indicating recruits who were underweight or suffered from asthma, chronic headache/migraine, mental illness, scoliosis/kyphosis, chronic back pain, knee joint disorders, or rhinitis/sinusitis) accounted for 90% of the medical profiling differences between recruitment centers (Conscription Administration Data, 2001-9). Of these key profile-affecting FCCs, the prevalence of all of them except scoliosis/kyphosis and mental conditions was found to be 1.5 to 2.5 times higher at recruitment center 1 as compared to the

Over the years, significant trends were observed: the prevalence of chronic headaches (increased), symptomatic scoliosis/kyphosis (increased), and active asthma (decreased) in

examinations (from 4.35% to 75% (p<0.01)).

other centers (Chaiter *et al.*, 2010).

cooperation with the quality control and assurance system.

processes by the physicians of the medical committees were noted.

measurements data) and FCCs or medical profiles (Chaiter *et al.*, 2008).

Table 2. Percentages of main medical conditions contributing to a difference in profiling at recruitment center 1 from 2001 to 2009 (Modified with permission from Chaiter *et al.*, 2010).

Some of these 26 FCCs were found to vary significantly between sub-districts in all of the recruitment centers (data not shown and Chaiter *et al.*, 2010). This may be attributed to both demographic-environmental parameters and professional-human causes. Across recruitment centers, and over the years, clear and significant disparities were found in the prevalence of how a majority of these FCCs were assigned by different medical committee chairmen in the year 2006 (data not shown and Chaiter *et al.*, 2010). This further strengthens the supposition that there are differences among recruitment centers and among the chairmen's reporting of medical histories, performing physical examinations, and interpreting various medical conditions, all of which lead to differential assignments of FCCs. Differences in FCC assignment by different chairmen at the same recruitment center indicate decision-making disparities or lack of experience and expertise in specific fields. The intervention program led to an improvement in certain aspects of the chairmen's knowledge and skills and, as a result, to an improvement in the performance of the committees; while variations between chairmen and between recruitment centers still exist, it is to a slightly lesser extent. The impact of professional development and understanding of the whole medical process (see below), as well as the establishment of a uniform working platform, resulted in decreased variability of medical conditions in the various conscription centers and among physicians. However, it could have been greater if the turnover of professional medical human resources would have been lower.

It is noteworthy that a subset of the 26 most commonly assigned FCCs were found to vary significantly among all three stratification criteria (recruitment centers, sub-districts, and

From a Quality Assurance and Control

medical database and system.

System for Medical Processes, Through Epidemiological Trends of Medical Conditions… 271

As a result of the intervention program (Navon *et al.*, 2011), improvements were found in all of these aspects of knowledge, skills, working procedures, professional collaboration, and management. This led to a considerable decrease in the rates of errors in records, such as inconsistencies in medical-administrative information between the status and appointment systems, and a significant increase in the rate of proper and complete administrative medical processes and profiling processes. Nevertheless, a significant increase was observed in the rate of recruits with medical profile that did not take into account the information written in the medical questionnaires that were filled out by their primary care physicians.

The quality control and assurance system and the local medical departments at the recruitment centers continuously analyze data from the computerized system (mainly by means of reports) in order to assess and evaluate the performance of the medical and administrative processes, as well as to identify errors and discrepancies in individual medical files. In light of the findings, the medical committees and departments take action to correct mistakes, follow up specific populations, etc. Moreover, reports can uncover difficulties and vulnerabilities in global processes, which in turn lead to further improvements or modifications of either the medical procedure or the computerized

The combined computerized system (including the appointment system, the status system, and the directing, monitoring, and controlling system) improves the control and management of the medical processes and informatics from the point of view of both the patients and the system operators (Machluf *et al.*, 2011). Different parameters of quality control regarding the medical and administrative processes are assessed (such as efficiency), and solutions are sought. Computerized system-based design and re-allocation of human and medical resources are implemented according to the capacities and limitations of the medical system. For instance, at recruitment center 1, reports during late '90s revealed a significant number of recruits waiting for specific medical processes (ophthalmologist, cardiologist, pulmonologist, orthopede, neurologist, etc.), and the intervention led to a reduction of at least 50% in the number of recruits holding a specific status over a period of 16 months; this reduction was achieved for most (12) of these statuses (15) (Machluf *et al.*, 2011). In addition, analysis revealed the specialists in each recruitment center for which recruits wait long periods of time for successful completion of the process. In all of the recruitment centers, a higher number of recruits who were waiting for more than 3 months was found with recruits who were in the process of medical documentation (centers 1 and 5) or who were waiting to see a neurologist (centers 2-4). Also in this case, computer-aided planning and re-allocation of human and medical resources played a key role in the intervention and in the solutions found for the specific specialists and recruits at each center (Machluf *et al.*, 2011). Another parameter regarding both quality control of the medical process and quality service to the recruits is the number of attendances at a recruitment center for each recruit until the final profile is assigned. Among the recruits who received their medical profile during 2010, approximately two-thirds of the recruits were required to report to the medical departments up to two times (Fig. 3). This rate was better in recruitment centers 2, 4, and 5 (>70% of recruits). On the other hand, a considerable fraction of recruits were obligated to attend six times or more, especially in recruitment centers 1 and 5 (2.5% and 2.3% of recruits, respectively) (Fig. 3). In some cases, the profile was assigned but no arrival to a recruitment center was recorded. These findings, and others, are the basis

**3.4 Computer-based tools – not just for quality control and assurance** 

chairmen assigning the profiles) (data not shown and Chaiter *et al.*, 2010). The common characteristic of these FCCs (such as underweight, asthma, chronic headache, symptomatic scoliosis/hypnosis, chronic back pain, knee joint disorders, and allergic rhinitis/sinusitis) is that their assignment procedure is prone to a relatively high degree of variation in anamnesis, examination, chairman discretion, and interpretation.

#### **3.2 Technical assistant staff performance**

The work of more than 110 technician assistants and laboratory staff members was assessed by questionnaires, interviews, and direct observation of their performance before, during, and after the medical committee examinations (Conscription Administration Data, 2006-9; Chaiter *et al.*, 2010; 2011). Prior to the intervention program, insufficient knowledge was revealed mainly with regard to the normal range of values for blood pressure and pulse, urinalysis, visual acuity, and color vision and to the interpretation of abnormal values of these measurements. Furthermore, some technician soldiers suffered from inadequate execution of the techniques, such as incorrect weight and height measurements. Inadequate knowledge regarding the relationship of all of the above mentioned measurements to specific medical FCCs was found. Some of these findings (insufficient knowledge, technical skill, and their relationships and meanings) were common to the technical staff at all of the recruitment centers, while other aspects were evident at specific recruitment centers.

After the intervention program, a higher level of expertise, increased skills in measuring medical parameters, and a more accurate interpretation of these values were observed among the technical staff. Improvements were found in the measurement techniques of weight, height, color vision tests, and determining of visual acuity, as well as an increased understanding of the normal parameters of these and other measurements, such as pulse and urinalysis, and their interpretation and relationship to medical FCCs (Chaiter *et al.*, 2011). For example, in recruitment center 2, a significant and sustained improvement was observed in the interpretation of low systolic or diastolic blood pressure and in the determination of color blindness and other issues, and in recruitment center 1 there was a higher rate of correct measurements for weight, height, and visual acuity. The number of medical inconsistencies was progressively and dramatically reduced.

#### **3.3 Administrative staff**

During the years 2007 to 2009, 23 visits were carried out to assess the work of the administrative medical departments at the recruitment centers. During these visits, the work of almost 200 medical administrative personnel and managers was analyzed. The main findings (Navon *et al.*, 2011) include incomplete knowledge of medical-administrative processes (such as appointments and statuses), a lack of professional collaboration between medical departments at different recruitment centers that was inevitably caused by differences in working patterns and operational procedures at all of the centers, a partial management of diaries with abnormal laboratory results, and local procedures which deviated and were not in line with regulations and instructions (such as those related to recruit identification or the management of medical questionnaires that were received from primary care physicians). Furthermore, in some cases, the managers of the medical administrative departments were only partially or inappropriately trained for their duty, and therefore their performance was far from optimal during the first period with regard to the professional-administrative-medical aspects and the management of human resources.

chairmen assigning the profiles) (data not shown and Chaiter *et al.*, 2010). The common characteristic of these FCCs (such as underweight, asthma, chronic headache, symptomatic scoliosis/hypnosis, chronic back pain, knee joint disorders, and allergic rhinitis/sinusitis) is that their assignment procedure is prone to a relatively high degree of variation in

The work of more than 110 technician assistants and laboratory staff members was assessed by questionnaires, interviews, and direct observation of their performance before, during, and after the medical committee examinations (Conscription Administration Data, 2006-9; Chaiter *et al.*, 2010; 2011). Prior to the intervention program, insufficient knowledge was revealed mainly with regard to the normal range of values for blood pressure and pulse, urinalysis, visual acuity, and color vision and to the interpretation of abnormal values of these measurements. Furthermore, some technician soldiers suffered from inadequate execution of the techniques, such as incorrect weight and height measurements. Inadequate knowledge regarding the relationship of all of the above mentioned measurements to specific medical FCCs was found. Some of these findings (insufficient knowledge, technical skill, and their relationships and meanings) were common to the technical staff at all of the

recruitment centers, while other aspects were evident at specific recruitment centers.

medical inconsistencies was progressively and dramatically reduced.

**3.3 Administrative staff** 

After the intervention program, a higher level of expertise, increased skills in measuring medical parameters, and a more accurate interpretation of these values were observed among the technical staff. Improvements were found in the measurement techniques of weight, height, color vision tests, and determining of visual acuity, as well as an increased understanding of the normal parameters of these and other measurements, such as pulse and urinalysis, and their interpretation and relationship to medical FCCs (Chaiter *et al.*, 2011). For example, in recruitment center 2, a significant and sustained improvement was observed in the interpretation of low systolic or diastolic blood pressure and in the determination of color blindness and other issues, and in recruitment center 1 there was a higher rate of correct measurements for weight, height, and visual acuity. The number of

During the years 2007 to 2009, 23 visits were carried out to assess the work of the administrative medical departments at the recruitment centers. During these visits, the work of almost 200 medical administrative personnel and managers was analyzed. The main findings (Navon *et al.*, 2011) include incomplete knowledge of medical-administrative processes (such as appointments and statuses), a lack of professional collaboration between medical departments at different recruitment centers that was inevitably caused by differences in working patterns and operational procedures at all of the centers, a partial management of diaries with abnormal laboratory results, and local procedures which deviated and were not in line with regulations and instructions (such as those related to recruit identification or the management of medical questionnaires that were received from primary care physicians). Furthermore, in some cases, the managers of the medical administrative departments were only partially or inappropriately trained for their duty, and therefore their performance was far from optimal during the first period with regard to the professional-administrative-medical aspects and the management of human resources.

anamnesis, examination, chairman discretion, and interpretation.

**3.2 Technical assistant staff performance** 

As a result of the intervention program (Navon *et al.*, 2011), improvements were found in all of these aspects of knowledge, skills, working procedures, professional collaboration, and management. This led to a considerable decrease in the rates of errors in records, such as inconsistencies in medical-administrative information between the status and appointment systems, and a significant increase in the rate of proper and complete administrative medical processes and profiling processes. Nevertheless, a significant increase was observed in the rate of recruits with medical profile that did not take into account the information written in the medical questionnaires that were filled out by their primary care physicians.

#### **3.4 Computer-based tools – not just for quality control and assurance**

The quality control and assurance system and the local medical departments at the recruitment centers continuously analyze data from the computerized system (mainly by means of reports) in order to assess and evaluate the performance of the medical and administrative processes, as well as to identify errors and discrepancies in individual medical files. In light of the findings, the medical committees and departments take action to correct mistakes, follow up specific populations, etc. Moreover, reports can uncover difficulties and vulnerabilities in global processes, which in turn lead to further improvements or modifications of either the medical procedure or the computerized medical database and system.

The combined computerized system (including the appointment system, the status system, and the directing, monitoring, and controlling system) improves the control and management of the medical processes and informatics from the point of view of both the patients and the system operators (Machluf *et al.*, 2011). Different parameters of quality control regarding the medical and administrative processes are assessed (such as efficiency), and solutions are sought. Computerized system-based design and re-allocation of human and medical resources are implemented according to the capacities and limitations of the medical system. For instance, at recruitment center 1, reports during late '90s revealed a significant number of recruits waiting for specific medical processes (ophthalmologist, cardiologist, pulmonologist, orthopede, neurologist, etc.), and the intervention led to a reduction of at least 50% in the number of recruits holding a specific status over a period of 16 months; this reduction was achieved for most (12) of these statuses (15) (Machluf *et al.*, 2011). In addition, analysis revealed the specialists in each recruitment center for which recruits wait long periods of time for successful completion of the process. In all of the recruitment centers, a higher number of recruits who were waiting for more than 3 months was found with recruits who were in the process of medical documentation (centers 1 and 5) or who were waiting to see a neurologist (centers 2-4). Also in this case, computer-aided planning and re-allocation of human and medical resources played a key role in the intervention and in the solutions found for the specific specialists and recruits at each center (Machluf *et al.*, 2011). Another parameter regarding both quality control of the medical process and quality service to the recruits is the number of attendances at a recruitment center for each recruit until the final profile is assigned. Among the recruits who received their medical profile during 2010, approximately two-thirds of the recruits were required to report to the medical departments up to two times (Fig. 3). This rate was better in recruitment centers 2, 4, and 5 (>70% of recruits). On the other hand, a considerable fraction of recruits were obligated to attend six times or more, especially in recruitment centers 1 and 5 (2.5% and 2.3% of recruits, respectively) (Fig. 3). In some cases, the profile was assigned but no arrival to a recruitment center was recorded. These findings, and others, are the basis

From a Quality Assurance and Control

adjustments to specific local needs.

designed. It utilizes various means:

in the course.

System for Medical Processes, Through Epidemiological Trends of Medical Conditions… 273

were made, the same procedure was carried out as a large-scale intervention program that was gradually implemented at other recruitment centers, until full implementation of the system was achieved throughout the whole organization. The gradual implementation process allowed for both the full support of each recruitment center and an assimilation of

It is noteworthy that acceptance of and cooperation with the quality control and assurance system were not trivial. During the first years of the program, physicians and policy makers, and to a lesser extent technical assistants and administrative staff members, were reluctant to comply with the quality control and assurance activities, during all of the stages and particularly during the intervention. The main reasons for that were professional autonomy and time/procedural requirements. This phenomenon and its causes were found also in France (Giraud-Roufast & Chabot, 2008). To build trust and cooperation, except for the fact that it was an obligatory process, few key actions were taken. First, the main goals of performance assessment were to improve professional competence, rather than to take sanctions. Medical personnel were considered partners, taking part in activities and brainstorming (mainly during the design and implementation stages). During intensive educational activity, the benefits (professional development, money, time, resources, quality care, etc.) to the individual service-providing staff (physicians, managers, etc.) and to the patients (quality of service and care, safety, etc.), to the medical departments, and to the organization were highlighted. Gradually, quality control and assessment became an integral component of the medical department's work, both routinely by the medical

Except for the physical condition issues, three main needs were acknowledged in every aspect of the medical processes, in the medical department: uniform medical and administrative processes at all recruitment centers; proper and comprehensive acquisition of medical, technical, and administrative knowledge, expertise, and skills; and sharing between all conscription centers. In light of these needs, an intervention program was

*Forums of organization leaders*: A forum was established, which includes leading physicians, medical administrative personnel, and the managers of the medical departments. Meetings are held on a regular basis in order to update all involved personnel on the novelties introduced into the medical system, to exchange ideas, and to formulate recommendations (and thereafter their implementation) for ongoing quality assessment and improved working procedures. This led to the development and production of manuals for administrative and technician soldiers, the printing of a catalogue of medical equipment,

*Training and simulation center for physicians*: A training program was implemented for physicians, which includes lectures, clinical training at a simulation center, and continuous observation and feedback on their work. Each chairman physician is invited once a year to participate in a workshop that provides simulated scenarios of patient-physician encounters. Each scenario is played by specially trained actors performing the role of the recruits. A detailed anamnesis, a recording of the findings, and further investigation is performed by the physician. Each encounter is recorded on video and is then discussed in detail with the special training team to point out mistakes and inconsistencies in the process. Each physician receives a personal feedback summary and accreditation is given for participation

personnel and occasionally by the quality control and assessment system.

and the initiation of theoretical and practical training programs.

to analyze the medical and administrative aspects of the medical process, such as coordinated invitations, unnecessary or insufficient investigations, and the proper recording of arrivals.

Fig. 3. Analysis of the number of attendances to a recruitment center in completed records during 2010.

The combined computerized system together with reports and automated tools allows the management of populations with special needs, such as mentally retarded and cerebral palsy patients. According to the regulations, these special populations are exempt from reporting to the recruitment centers, and their files are managed with maximum discretion and sensitivity to the individual, thus respecting them and their families' wishes.

Based on data mining findings, modifications were also introduced in working procedures. A reduction in the daily number of invited recruits improved the quality of the medical encounters. Specific combined status codes were introduced for the efficient planning of the medical encounters. Implementation and automation of medical regulations and procedures within the computerized system cause this system to play a key role and serve as a control tool during the decision-making process.

## **4. Intervention**

The quality control and assurance system operates via an analysis design implementation evaluation modification loop.

First, all medical processes were mapped and analyzed, and particular infrastructure, medical, technical, management, and administrative needs were characterized by experts. The design principles of the intervention program with regard to the components, mode of action, time lines, etc. were determined to address those needs, in line with the general medical processes and goals. Then, a small-scale pilot program was launched in one recruitment center and was systematically analyzed. Throughout these steps, the quality control and assurance system personnel collaborated with the experts and experienced staff members from the medical departments and with policy makers. This collaboration allowed for better intervention planning, an efficient feedback process, contributed to the participants' sense of ownership and commitment to the process, increased their confidence, and made them receptive to the intervention program. After the required modifications

to analyze the medical and administrative aspects of the medical process, such as coordinated invitations, unnecessary or insufficient investigations, and the proper recording

Fig. 3. Analysis of the number of attendances to a recruitment center in completed records

The combined computerized system together with reports and automated tools allows the management of populations with special needs, such as mentally retarded and cerebral palsy patients. According to the regulations, these special populations are exempt from reporting to the recruitment centers, and their files are managed with maximum discretion

Based on data mining findings, modifications were also introduced in working procedures. A reduction in the daily number of invited recruits improved the quality of the medical encounters. Specific combined status codes were introduced for the efficient planning of the medical encounters. Implementation and automation of medical regulations and procedures within the computerized system cause this system to play a key role and serve as a control

The quality control and assurance system operates via an analysis design

First, all medical processes were mapped and analyzed, and particular infrastructure, medical, technical, management, and administrative needs were characterized by experts. The design principles of the intervention program with regard to the components, mode of action, time lines, etc. were determined to address those needs, in line with the general medical processes and goals. Then, a small-scale pilot program was launched in one recruitment center and was systematically analyzed. Throughout these steps, the quality control and assurance system personnel collaborated with the experts and experienced staff members from the medical departments and with policy makers. This collaboration allowed for better intervention planning, an efficient feedback process, contributed to the participants' sense of ownership and commitment to the process, increased their confidence, and made them receptive to the intervention program. After the required modifications

and sensitivity to the individual, thus respecting them and their families' wishes.

of arrivals.

during 2010.

**4. Intervention** 

tool during the decision-making process.

implementation evaluation modification loop.

were made, the same procedure was carried out as a large-scale intervention program that was gradually implemented at other recruitment centers, until full implementation of the system was achieved throughout the whole organization. The gradual implementation process allowed for both the full support of each recruitment center and an assimilation of adjustments to specific local needs.

It is noteworthy that acceptance of and cooperation with the quality control and assurance system were not trivial. During the first years of the program, physicians and policy makers, and to a lesser extent technical assistants and administrative staff members, were reluctant to comply with the quality control and assurance activities, during all of the stages and particularly during the intervention. The main reasons for that were professional autonomy and time/procedural requirements. This phenomenon and its causes were found also in France (Giraud-Roufast & Chabot, 2008). To build trust and cooperation, except for the fact that it was an obligatory process, few key actions were taken. First, the main goals of performance assessment were to improve professional competence, rather than to take sanctions. Medical personnel were considered partners, taking part in activities and brainstorming (mainly during the design and implementation stages). During intensive educational activity, the benefits (professional development, money, time, resources, quality care, etc.) to the individual service-providing staff (physicians, managers, etc.) and to the patients (quality of service and care, safety, etc.), to the medical departments, and to the organization were highlighted. Gradually, quality control and assessment became an integral component of the medical department's work, both routinely by the medical personnel and occasionally by the quality control and assessment system.

Except for the physical condition issues, three main needs were acknowledged in every aspect of the medical processes, in the medical department: uniform medical and administrative processes at all recruitment centers; proper and comprehensive acquisition of medical, technical, and administrative knowledge, expertise, and skills; and sharing between all conscription centers. In light of these needs, an intervention program was designed. It utilizes various means:

*Forums of organization leaders*: A forum was established, which includes leading physicians, medical administrative personnel, and the managers of the medical departments. Meetings are held on a regular basis in order to update all involved personnel on the novelties introduced into the medical system, to exchange ideas, and to formulate recommendations (and thereafter their implementation) for ongoing quality assessment and improved working procedures. This led to the development and production of manuals for administrative and technician soldiers, the printing of a catalogue of medical equipment, and the initiation of theoretical and practical training programs.

*Training and simulation center for physicians*: A training program was implemented for physicians, which includes lectures, clinical training at a simulation center, and continuous observation and feedback on their work. Each chairman physician is invited once a year to participate in a workshop that provides simulated scenarios of patient-physician encounters. Each scenario is played by specially trained actors performing the role of the recruits. A detailed anamnesis, a recording of the findings, and further investigation is performed by the physician. Each encounter is recorded on video and is then discussed in detail with the special training team to point out mistakes and inconsistencies in the process. Each physician receives a personal feedback summary and accreditation is given for participation in the course.

From a Quality Assurance and Control

computerized system.

**5. Effects of intervention** 

level reported by recruits.

**6. Epidemiological aspects** 

tools and modes of action to achieve these goals.

identify risk factors that can affect present and future morbidity.

System for Medical Processes, Through Epidemiological Trends of Medical Conditions… 275

The quality control and assurance system also gives complementary support to the medical department with implementation, adjustments, and instruction in the proper use of the computerized tools in the medical processes for the purpose of higher quality of control, management, and service. The computerized system, through its implementation and automation of medical regulations and procedures, plays a central role and serves as a control tool during the decision-making process and as a way to prevent inconsistencies in the medical information. In addition, electronic medical files were incorporated into the

*Certification*: Certification is virtually awarded for the completion of requisite training/instruction by accredited authorities, including the quality control and assurance system. It is important to note that, unlike most licensures and board certifications (Landon *et al.*, 2003), the qualification process and examinations are periodic and specific to particular medical fields and ensure professional competency according to pre-determined standards.

During the years of intervention, benefits were observed in the quality of all of the areas that were examined. As these effects were described before (see the section entitled Findings) or earlier (Chaiter *et al.*, 2008; 2010; 2011; Machluf *et al.*, 2011; Navon *et al.*, 2011), we can summarize them in a few main categories: 1) infrastructure and physical conditions; 2) consistent improvement in the knowledge, skills, and performance of the physicians (anamnesis, examination, decision-making processes, etc.), technicians (measurements, recording, interpretation, etc.), and administrative staff (procedures, regulations, etc.); 3) uniform working platforms and procedures in terms of the medical and administrative processes at all of the recruitment centers; and 4) a launching of the framework and forums

One important contribution of the quality control and assurance system is in terms of the diagnosis, design, and implementation of the intervention program and its analysis. The impact on the medical department's performance is clear and evident. Furthermore, after the intervention program's implementation, the satisfaction rate, sense of belonging, and responsibility were higher among all of the medical department personnel. It led to the increased perception of the administrative and technical medical staff to feel that their work was part of the medical profiling process, acting as case managers and part of quality assurance aimed at providing the best medical service for recruits. Therefore, it is only natural that this would consequently lead to a consistent, major increase in the satisfaction

As mentioned above, not all of the goals were achieved fully, and in some respects there was a disparity between what was achieved and the desired objectives. Clearly, some changes are time-dependent, and the benefits of current efforts will be evident in the near future. Other challenges may require different solutions. We are always looking for new and better

The medical processes for the adolescent population of Israel present a unique opportunity to assess the health status of the young Israeli population on a nationwide level and to

for sharing knowledge and skills between all of the conscription centers.

*Instruction of physicians*: After being observed, the physicians are instructed and trained in all issues assessed by the quality control and assurance system. Proper physical examination, partial or complete, is demonstrated upon request or, if necessary, is based on the findings.

*Manual for technical medical staff performance*: A comprehensive manual was written describing measurement techniques that are carried out by the technical assistants (and laboratory staff) at the medical committee examinations. It was distributed to relevant personnel and is used on a daily basis. The manual also contains information about the normal range of systolic and diastolic blood pressure and pulse measurements and correct interpretation of visual acuity and color vision tests (Ishihara and D15), as well as about the interpretation of abnormal values with instructions of how to act if an abnormal value is encountered during measurement or is written in the medical committee protocol. The manual contains information that involves the technician soldiers in the coordination and quality assurance processes of the medical committee examinations. For instance, the technician soldiers are instructed to return a file to the physician if they find an abnormal blood pressure value recorded in the protocol of the medical committee without any instructions from the examining physician on how to proceed or if the physician determines the profile of the recruit without assigning a FCC that indicates hypertension.

*Frontal lectures*: All technical medical personnel and administrative staff at all of the recruitment centers were given lectures at each recruitment center and in special meetings arranged at the medical assessment branch of the IDF Medical Corps. The issues discussed in the lectures further stressed what was described in the written manuals and also emphasized cases of risk management in order to strengthen the notion about the importance of the technical medical staff's work and the administrative processes as part of the quality assurance of the medical committee examinations and as assistants of the physicians in the process of medical profiling. During some of the lectures at the recruitment centers, training in measurement techniques, such as blood pressure measurements, was performed. In addition, the relationships and links between the medical, technical, and administrative processes were highlighted.

*Instruction of technical medical staff*: After the observations, questionnaires, and interviews were conducted, the technician soldiers were given detailed feedback and were instructed and trained in all of the issues that were assessed by the quality control and assurance system. In addition, all problematic areas that were identified by the system were discussed with the medical department managers.

*Instruction of administrative staff*: After the observations, questionnaires, and interviews were completed, the administrative staff were given detailed feedback and were instructed and trained in all of the issues that were assessed by the quality control and assurance system. In addition, all problematic areas that were identified by the system were discussed with the administrative staff's managers.

*Written reports*: Written reports summarized the findings with an emphasis on the recommendations required to make improvements and to correct the mistakes found in each recruitment center. The reports were distributed to the relevant medical and management authorities at the local recruitment centers and at headquarters. These reports also allowed a comparative overview between medical departments at different recruitment centers and between different time periods or specific assessments.

*Computerized tools*: The quality control and assurance system plays a key role in the design and planning of computerized systems or in their modifications so that the medical department's needs, mainly with regard to procedures and regulations, will be answered. The quality control and assurance system also gives complementary support to the medical department with implementation, adjustments, and instruction in the proper use of the computerized tools in the medical processes for the purpose of higher quality of control, management, and service. The computerized system, through its implementation and automation of medical regulations and procedures, plays a central role and serves as a control tool during the decision-making process and as a way to prevent inconsistencies in the medical information. In addition, electronic medical files were incorporated into the computerized system.

*Certification*: Certification is virtually awarded for the completion of requisite training/instruction by accredited authorities, including the quality control and assurance system. It is important to note that, unlike most licensures and board certifications (Landon *et al.*, 2003), the qualification process and examinations are periodic and specific to particular medical fields and ensure professional competency according to pre-determined standards.

## **5. Effects of intervention**

274 Modern Approaches To Quality Control

*Instruction of physicians*: After being observed, the physicians are instructed and trained in all issues assessed by the quality control and assurance system. Proper physical examination, partial or complete, is demonstrated upon request or, if necessary, is based on the findings. *Manual for technical medical staff performance*: A comprehensive manual was written describing measurement techniques that are carried out by the technical assistants (and laboratory staff) at the medical committee examinations. It was distributed to relevant personnel and is used on a daily basis. The manual also contains information about the normal range of systolic and diastolic blood pressure and pulse measurements and correct interpretation of visual acuity and color vision tests (Ishihara and D15), as well as about the interpretation of abnormal values with instructions of how to act if an abnormal value is encountered during measurement or is written in the medical committee protocol. The manual contains information that involves the technician soldiers in the coordination and quality assurance processes of the medical committee examinations. For instance, the technician soldiers are instructed to return a file to the physician if they find an abnormal blood pressure value recorded in the protocol of the medical committee without any instructions from the examining physician on how to proceed or if the physician determines

the profile of the recruit without assigning a FCC that indicates hypertension.

administrative processes were highlighted.

with the medical department managers.

between different time periods or specific assessments.

administrative staff's managers.

*Frontal lectures*: All technical medical personnel and administrative staff at all of the recruitment centers were given lectures at each recruitment center and in special meetings arranged at the medical assessment branch of the IDF Medical Corps. The issues discussed in the lectures further stressed what was described in the written manuals and also emphasized cases of risk management in order to strengthen the notion about the importance of the technical medical staff's work and the administrative processes as part of the quality assurance of the medical committee examinations and as assistants of the physicians in the process of medical profiling. During some of the lectures at the recruitment centers, training in measurement techniques, such as blood pressure measurements, was performed. In addition, the relationships and links between the medical, technical, and

*Instruction of technical medical staff*: After the observations, questionnaires, and interviews were conducted, the technician soldiers were given detailed feedback and were instructed and trained in all of the issues that were assessed by the quality control and assurance system. In addition, all problematic areas that were identified by the system were discussed

*Instruction of administrative staff*: After the observations, questionnaires, and interviews were completed, the administrative staff were given detailed feedback and were instructed and trained in all of the issues that were assessed by the quality control and assurance system. In addition, all problematic areas that were identified by the system were discussed with the

*Written reports*: Written reports summarized the findings with an emphasis on the recommendations required to make improvements and to correct the mistakes found in each recruitment center. The reports were distributed to the relevant medical and management authorities at the local recruitment centers and at headquarters. These reports also allowed a comparative overview between medical departments at different recruitment centers and

*Computerized tools*: The quality control and assurance system plays a key role in the design and planning of computerized systems or in their modifications so that the medical department's needs, mainly with regard to procedures and regulations, will be answered. During the years of intervention, benefits were observed in the quality of all of the areas that were examined. As these effects were described before (see the section entitled Findings) or earlier (Chaiter *et al.*, 2008; 2010; 2011; Machluf *et al.*, 2011; Navon *et al.*, 2011), we can summarize them in a few main categories: 1) infrastructure and physical conditions; 2) consistent improvement in the knowledge, skills, and performance of the physicians (anamnesis, examination, decision-making processes, etc.), technicians (measurements, recording, interpretation, etc.), and administrative staff (procedures, regulations, etc.); 3) uniform working platforms and procedures in terms of the medical and administrative processes at all of the recruitment centers; and 4) a launching of the framework and forums for sharing knowledge and skills between all of the conscription centers.

One important contribution of the quality control and assurance system is in terms of the diagnosis, design, and implementation of the intervention program and its analysis. The impact on the medical department's performance is clear and evident. Furthermore, after the intervention program's implementation, the satisfaction rate, sense of belonging, and responsibility were higher among all of the medical department personnel. It led to the increased perception of the administrative and technical medical staff to feel that their work was part of the medical profiling process, acting as case managers and part of quality assurance aimed at providing the best medical service for recruits. Therefore, it is only natural that this would consequently lead to a consistent, major increase in the satisfaction level reported by recruits.

As mentioned above, not all of the goals were achieved fully, and in some respects there was a disparity between what was achieved and the desired objectives. Clearly, some changes are time-dependent, and the benefits of current efforts will be evident in the near future. Other challenges may require different solutions. We are always looking for new and better tools and modes of action to achieve these goals.

## **6. Epidemiological aspects**

The medical processes for the adolescent population of Israel present a unique opportunity to assess the health status of the young Israeli population on a nationwide level and to identify risk factors that can affect present and future morbidity.

From a Quality Assurance and Control

of body height (Jaeger *et al.*, 2001).

now under investigation.

**6.2 Medical conditions** 

Israeli population.

System for Medical Processes, Through Epidemiological Trends of Medical Conditions… 277

General population data and military records suggest that US heights essentially remained stable after World War II (mainly in birth cohorts of 1955-74), which is concurrent with continual rapid increases in height in Western and Northern Europe (Komlos & Lauderdale, 2007). A historical retrospect of German military male recruits found an increase in both the average body weight and height, where the changes in body weight were greater than those

The implications of these findings with regard to different demographic parameters, socioeconomic status, anthropometric indices, medical conditions, and other risk factors are

Analysis of the prevalence of specific FCCs provided the opportunity to gain knowledge about the trends of different medical conditions. Such an analysis in recruits from center 5 uncovered an increase in the prevalence of valvular and non-valvular congenital heart anomalies among male recruits (Fig. 5. upper panel). Referring to cardiac diseases, the prevalence of congenital valvular heart disorders was higher than the prevalence of nonvalvular heart disorders. Furthermore, an increase in the prevalence of solid tumors in both

Fig. 5. Prevalence of solid tumors and congenital heart anomalies among the 16-19 year old

males and females was also demonstrated (Fig. 5. lower panel).

A pilot study, including over 105,000 adolescents, has been carried out using data from one of the recruitment centers to assess trends in weight, height, and other medical parameters (e.g., blood pressure) and conditions (e.g., congenital heart disease) among 16-19 year olds in Israel (born in 1971-1992). Our preliminary analysis suggests that variability between recruitment centers may affect the consistency and reliability of nationwide analysis, as opposed to information from a single recruitment center. Furthermore, in one selected center, the differences between chairmen in assigning profiles and FCCs were much smaller than in other centers. Clear trends were demonstrated, and their association with demographic variables was examined. The findings are out of the scope of this manuscript, yet we wish to illustrate two possible insights drawn from such analysis.

#### **6.1 Anthropometric values**

Among the young (16-19 year olds) Israeli population born between 1971 and 1992, a significant increase in average body weight was demonstrated in females and mainly in males (Fig. 4, upper panel). In both genders, the increase in average weight is more dramatic in teenagers who were born during 1982-1992. On the other hand, no dramatic change was observed in average height in females or in males (Fig. 4, lower panel). This might be an indication of an increase in the body-mass index (BMI).

Fig. 4. Trends of average weight and height among the 16-19 year old Israeli population.

General population data and military records suggest that US heights essentially remained stable after World War II (mainly in birth cohorts of 1955-74), which is concurrent with continual rapid increases in height in Western and Northern Europe (Komlos & Lauderdale, 2007). A historical retrospect of German military male recruits found an increase in both the average body weight and height, where the changes in body weight were greater than those of body height (Jaeger *et al.*, 2001).

The implications of these findings with regard to different demographic parameters, socioeconomic status, anthropometric indices, medical conditions, and other risk factors are now under investigation.

## **6.2 Medical conditions**

276 Modern Approaches To Quality Control

A pilot study, including over 105,000 adolescents, has been carried out using data from one of the recruitment centers to assess trends in weight, height, and other medical parameters (e.g., blood pressure) and conditions (e.g., congenital heart disease) among 16-19 year olds in Israel (born in 1971-1992). Our preliminary analysis suggests that variability between recruitment centers may affect the consistency and reliability of nationwide analysis, as opposed to information from a single recruitment center. Furthermore, in one selected center, the differences between chairmen in assigning profiles and FCCs were much smaller than in other centers. Clear trends were demonstrated, and their association with demographic variables was examined. The findings are out of the scope of this manuscript,

Among the young (16-19 year olds) Israeli population born between 1971 and 1992, a significant increase in average body weight was demonstrated in females and mainly in males (Fig. 4, upper panel). In both genders, the increase in average weight is more dramatic in teenagers who were born during 1982-1992. On the other hand, no dramatic change was observed in average height in females or in males (Fig. 4, lower panel). This might be an

Fig. 4. Trends of average weight and height among the 16-19 year old Israeli population.

yet we wish to illustrate two possible insights drawn from such analysis.

indication of an increase in the body-mass index (BMI).

**6.1 Anthropometric values** 

Analysis of the prevalence of specific FCCs provided the opportunity to gain knowledge about the trends of different medical conditions. Such an analysis in recruits from center 5 uncovered an increase in the prevalence of valvular and non-valvular congenital heart anomalies among male recruits (Fig. 5. upper panel). Referring to cardiac diseases, the prevalence of congenital valvular heart disorders was higher than the prevalence of nonvalvular heart disorders. Furthermore, an increase in the prevalence of solid tumors in both males and females was also demonstrated (Fig. 5. lower panel).

Fig. 5. Prevalence of solid tumors and congenital heart anomalies among the 16-19 year old Israeli population.

From a Quality Assurance and Control

teenagers or by active medical intervention.

**8. Concluding remarks** 

a medical organization.

System for Medical Processes, Through Epidemiological Trends of Medical Conditions… 279

about further findings and about any change in the medical condition and status of the recruit by the primary physicians. Beyond the issue of medical informatics and process, recruits are provided with better medical service, which might contribute to early diagnosis, quick and appropriate treatment, and better and faster recovery. In the future, if this information sharing is combined with an epidemiological study, we believe it may also contribute to the prevention of health conditions, either via the medical education of

Quality assessment, control, and improvement in a health system should include the infrastructure and structure, process, and outcome levels. The quality control and assurance system for medical committees at recruitment centers operates via an analysis design implementation evaluation modification loop. It first relies upon the identification of the limitations and needs of the whole medical process and of each department with regard to the medical, technical, administrative, procedural, and physical aspects and with regard to official policy, including the systematic evaluation of the knowledge, skills, judgement, and working patterns of all of the medical personnel. To this end, complementary methodologies are utilized to provide both quantitative and qualitative analyses of daily activities and practices. Among the main tools utilized are observations and assessment, a sampling of recruits for re-examination and of records for evaluation, questionnaires, interviews, data mining and analysis by reports, and patients' surveys. Then, intervention programs are designed and implemented to answer the needs of all of the parties participating in the medical process in order to improve their quality and performance; to increase the quality of patient care; and to achieve a higher patient satisfaction rate. Intervention programs include the establishment of a training and simulation center, lectures and instruction to all of the medical department's personnel, a forum of organization leaders, production of manuals, certification, written reports, and the design of computerized tools. These intervention programs and their impact need to be continuously evaluated and modified according to the specific needs and effects in particular recruitment centers. Significant improvements have been observed in various key parameters, such as the knowledge, skills, and judgement of the personnel and their professional performance, the conditions of their working environment, uniform working platforms, and the patients' satisfaction rate. Incessant monitoring and intervention are important to maintain quality in

Quality improvement at the individual (physicians, assistant technicians, administrative staff, managers, etc.) and global levels (performance, outcomes, physical conditions, procedures and regulations, etc.) is a goal in and of itself but is also a means of improving patient care and safety. Furthermore, the collaboration of all the participants in the process, on all levels – medical professionals (physicians, experts, etc.), technical assistants, administrative staff, and the active support and involvement of the managing authorities

The successful application of a quality control and assurance project can lay the foundation for a population-based investigation, namely an assessment of the health status of the young Israeli population, by measuring anthropometric values and the prevalence of various medical conditions among recruits on a nationwide level. They may result in the identification of risk factors that can affect present and future morbidity. A national project

and policy makers – is a critical determinant for a successful outcome.

Previous analyses of specific morbidity prevalence in Israeli conscripts from all recruitment centers also revealed an increase in the prevalence of heart defects among male recruits (Farfel *et al.*, 2007), as well as a higher prevalence of congenital valvular heart disease compared to non-valvular heart disease (Bar-Dayan *et al.*, 2005).

## **7. A nationwide program**

These findings demonstrate the need for a nationwide intervention program to reduce morbidity, future illness, and even mortality. Furthermore, a project of information sharing and cooperation was established with family physicians at primary clinics on a nationwide basis, the Ministry of Health, the National Insurance Institute, the Israeli National Cancer Registry, and the Ministry of Social Affairs and Social Services. This national project (Fig. 6) is aimed at education, prevention, and early intervention in target populations.

Fig. 6. Scheme of national project for information sharing and collaboration.

So far, although this information-sharing project was only initiated on a small-scale pilot format, covering only a minor fraction of the relevant population, bi-directional benefits are evident. For example, medical investigations in recruitment centers uncover medical conditions that were unknown before to the civilian authorities and vice-versa. These medical conditions include vision and hearing problems, essential hypertension, asthma, cardiac anomalies, tumors, urological conditions (hernia, varicocele, hydrocele, etc.), nephrological disorders (nephropathies, microscopic hematoria, severe proteinuria, etc.), orthopaedic problems, neurological problems, and mental disorders. Such findings are then reported to the primary care physician for further investigation with a referral to specialists and/or for treatment. The medical departments at the recruitment centers are then informed about further findings and about any change in the medical condition and status of the recruit by the primary physicians. Beyond the issue of medical informatics and process, recruits are provided with better medical service, which might contribute to early diagnosis, quick and appropriate treatment, and better and faster recovery. In the future, if this information sharing is combined with an epidemiological study, we believe it may also contribute to the prevention of health conditions, either via the medical education of teenagers or by active medical intervention.

## **8. Concluding remarks**

278 Modern Approaches To Quality Control

Previous analyses of specific morbidity prevalence in Israeli conscripts from all recruitment centers also revealed an increase in the prevalence of heart defects among male recruits (Farfel *et al.*, 2007), as well as a higher prevalence of congenital valvular heart disease

These findings demonstrate the need for a nationwide intervention program to reduce morbidity, future illness, and even mortality. Furthermore, a project of information sharing and cooperation was established with family physicians at primary clinics on a nationwide basis, the Ministry of Health, the National Insurance Institute, the Israeli National Cancer Registry, and the Ministry of Social Affairs and Social Services. This national project (Fig. 6)

is aimed at education, prevention, and early intervention in target populations.

Fig. 6. Scheme of national project for information sharing and collaboration.

So far, although this information-sharing project was only initiated on a small-scale pilot format, covering only a minor fraction of the relevant population, bi-directional benefits are evident. For example, medical investigations in recruitment centers uncover medical conditions that were unknown before to the civilian authorities and vice-versa. These medical conditions include vision and hearing problems, essential hypertension, asthma, cardiac anomalies, tumors, urological conditions (hernia, varicocele, hydrocele, etc.), nephrological disorders (nephropathies, microscopic hematoria, severe proteinuria, etc.), orthopaedic problems, neurological problems, and mental disorders. Such findings are then reported to the primary care physician for further investigation with a referral to specialists and/or for treatment. The medical departments at the recruitment centers are then informed

compared to non-valvular heart disease (Bar-Dayan *et al.*, 2005).

**7. A nationwide program** 

Quality assessment, control, and improvement in a health system should include the infrastructure and structure, process, and outcome levels. The quality control and assurance system for medical committees at recruitment centers operates via an analysis design implementation evaluation modification loop. It first relies upon the identification of the limitations and needs of the whole medical process and of each department with regard to the medical, technical, administrative, procedural, and physical aspects and with regard to official policy, including the systematic evaluation of the knowledge, skills, judgement, and working patterns of all of the medical personnel. To this end, complementary methodologies are utilized to provide both quantitative and qualitative analyses of daily activities and practices. Among the main tools utilized are observations and assessment, a sampling of recruits for re-examination and of records for evaluation, questionnaires, interviews, data mining and analysis by reports, and patients' surveys. Then, intervention programs are designed and implemented to answer the needs of all of the parties participating in the medical process in order to improve their quality and performance; to increase the quality of patient care; and to achieve a higher patient satisfaction rate. Intervention programs include the establishment of a training and simulation center, lectures and instruction to all of the medical department's personnel, a forum of organization leaders, production of manuals, certification, written reports, and the design of computerized tools. These intervention programs and their impact need to be continuously evaluated and modified according to the specific needs and effects in particular recruitment centers. Significant improvements have been observed in various key parameters, such as the knowledge, skills, and judgement of the personnel and their professional performance, the conditions of their working environment, uniform working platforms, and the patients' satisfaction rate. Incessant monitoring and intervention are important to maintain quality in a medical organization.

Quality improvement at the individual (physicians, assistant technicians, administrative staff, managers, etc.) and global levels (performance, outcomes, physical conditions, procedures and regulations, etc.) is a goal in and of itself but is also a means of improving patient care and safety. Furthermore, the collaboration of all the participants in the process, on all levels – medical professionals (physicians, experts, etc.), technical assistants, administrative staff, and the active support and involvement of the managing authorities and policy makers – is a critical determinant for a successful outcome.

The successful application of a quality control and assurance project can lay the foundation for a population-based investigation, namely an assessment of the health status of the young Israeli population, by measuring anthropometric values and the prevalence of various medical conditions among recruits on a nationwide level. They may result in the identification of risk factors that can affect present and future morbidity. A national project

From a Quality Assurance and Control

No.1, pp. 19-30.

No.4, pp. 691–729.

149-52.

pp. 251-73.

System for Medical Processes, Through Epidemiological Trends of Medical Conditions… 281

Bar-Dayan, Y.; Elishkevits, K.; Goldstein, L.; Goldberg, A.; Ohana, N.; Onn, E.; Levi, Y. &

Campbell, S.M.; Roland, M.O. & Buetow, S.A. (2000). Defining quality of care. *Social Science* 

Chaiter, Y.; Machluf, Y.; Pirogovsky. A.; Palma, E.; Yona, A.; Shohat, T.; Yitzak, A.; Tal, O. &

Chaiter, Y., Palma, E., Machluf, Y., Yona, A.; Cohen, A.; Pirogovsky, A.; Shohat, T.; Ytzhak,

Chaiter, Y.; Pirogovsky, A.; Palma, E.; Yona, A.; Machluf, Y.; Shohat, T.; Farraj, N.; Tal, O.,

Conscription Administration Data. (2001-9), *Biannual control on medical profiles in recruitment centers*, Personnel Directorate, IDF, Israel (unpublished data analysis). Donabedian, A. (2003). *An introduction to quality assurance in health care*, Oxford University

Donabedian, A. (2005). Evaluating the quality of medical care. *Milbank Quarterly*, Vol.83,

Dye, T.R. (1987). *Understanding Public Policy* (6th edition), Prentice-Hall, ISBN 0139369732,

Farfel, A.; Green, M.S.; Shochat, T.; Noyman.; Levy, Y. & Afek, A. (2007). Trends in specific

Giraud-Roufast, A. & Chabot, J.M. (2008). Medical acceptance of quality assurance in health care, *The Journal of the American Medical Association*, Vol.300, No.22, pp. 2663-5. Holmboe, E.S.; Lipner, R. & Greiner, A. (2008). Assessing quality of care: knowledge matters, *The Journal of the American Medical Association*, Vol.299, NO.3, pp. 338-40. Iverson, T. & Wren, A. (1998). Equality, employment, and budgetary restraint: the trilemma

Jaeger, U.; Zellner, K.; Kromeyer-Hauschild, K.; Lüdde, R.; Eisele, R. & Hebebrand, J. (2001).

Komlos, J. & Lauderdale, B.E. (2007). The mystery trend in American heights in the 20th

Landon, B.E.; Normand, S.L.; Blumenthal, D. & Daley, J. (2003). Physician clinical

Machluf, Y.; Pirogovsky, A.; Palma, E.; Yona, A.; Navon, A.; Shohat, T.; Ytzhak, A.; Tal, O.;

Body height, body weight and body mass index of German military recruits. Historical retrospect and current status. *Anthropologischer Anzeiger*, Vol.59, No.3,

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of the service economy. *World Politics*, Vol.50, No.4, pp. 507-46.

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morbidity prevalence in male adolescents in Israel over a 50 year period and the impact of recent immigration. *The Israel Medical Association Journal*, Vol.9, No.3, pp.

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A. & Ash, N. (2011). Quality assuring intervention for technical medical staff at medical committees. *International Journal of Health Care Quality Assurance*, Vol.24,

Campino-Abbebe, G. & Levy, Y. (2008). Medical quality control in conscription centers- ten years of activity. *Journal of Israeli Military Medicine*, Vol.5 No.2, pp. 75-9.

of information sharing and cooperation was set up, aimed at screening, education, prevention, and early intervention in target populations.

There are multi-directional effects and relationships between the quality assurance and control process and its implications on improving the quality of health care and nationwide projects of preventative medicine through collaboration and information sharing (Fig. 7).

Recently, Zalmanovitch and Vashdi (2010) proposed an inherent trilemma, a trade-off between three desirable objectives (Iverson & Wren, 1998), in any debate on health care policy. In this context, the critical broad objectives are quality, funding, and coverage. In this context, quality refers to the efficiency and effectiveness of the health care services provided; funding refers to the public expenditures for health care that are incurred by taxpayers; and coverage refers to the percentage of a country's population eligible for state health care services and the comprehensiveness of these services. A trade-off means that, at most, only two of the three objectives can be satisfied simultaneously, and satisfying any two will always come at the expense of the third (Zalmanovitch & Vashdi, 2010). The cumulative experience of the quality assurance and control system and its effects suggest that it is central to the successful balancing between the three objectives, at least in the context of the medical departments at the recruitment centers. Considering the common characteristics of medical processes at the recruitment centers and at primary medical facilities, implementation of multi-armed quality assurance and control systems at clinics and hospitals holds great promise in finding the best solution to the trilemma, beyond the direct and clear impact on the medical staff's performance, medical process outcomes, service quality, and patient safety. Together with an epidemiologic investigation and preventive action, this system may contribute to the identification of risk factors and a reduction in future morbidity.

Fig. 7. Establishment of a quality control and assurance system for medical processes in recruitment centers led to an epidemiological study and a nationwide health project.

It remains to be seen in future studies whether the system can efficiently address these issues.

#### **9. References**

Blumenthal, D. (1996). Quality of health care part 1: Quality of health care - what is it?. *The New England Journal of Medicine*, Vol.335, No.12, pp. 891-4.

of information sharing and cooperation was set up, aimed at screening, education,

There are multi-directional effects and relationships between the quality assurance and control process and its implications on improving the quality of health care and nationwide projects of preventative medicine through collaboration and information sharing (Fig. 7). Recently, Zalmanovitch and Vashdi (2010) proposed an inherent trilemma, a trade-off between three desirable objectives (Iverson & Wren, 1998), in any debate on health care policy. In this context, the critical broad objectives are quality, funding, and coverage. In this context, quality refers to the efficiency and effectiveness of the health care services provided; funding refers to the public expenditures for health care that are incurred by taxpayers; and coverage refers to the percentage of a country's population eligible for state health care services and the comprehensiveness of these services. A trade-off means that, at most, only two of the three objectives can be satisfied simultaneously, and satisfying any two will always come at the expense of the third (Zalmanovitch & Vashdi, 2010). The cumulative experience of the quality assurance and control system and its effects suggest that it is central to the successful balancing between the three objectives, at least in the context of the medical departments at the recruitment centers. Considering the common characteristics of medical processes at the recruitment centers and at primary medical facilities, implementation of multi-armed quality assurance and control systems at clinics and hospitals holds great promise in finding the best solution to the trilemma, beyond the direct and clear impact on the medical staff's performance, medical process outcomes, service quality, and patient safety. Together with an epidemiologic investigation and preventive action, this system may contribute to the identification of risk factors and a reduction in

Fig. 7. Establishment of a quality control and assurance system for medical processes in recruitment centers led to an epidemiological study and a nationwide health project.

It remains to be seen in future studies whether the system can efficiently address these

Blumenthal, D. (1996). Quality of health care part 1: Quality of health care - what is it?. *The* 

*New England Journal of Medicine*, Vol.335, No.12, pp. 891-4.

prevention, and early intervention in target populations.

future morbidity.

issues.

**9. References** 


**15** 

**The Significance of Board-Certified Registered** 

Noriyuki Tohnosu1,2, Jun Hasegawa2,3, Yosio Masuda2,4, Taku Kato5,

*2Breast cancer screening committee of Funabashi Municipal Medical Association,* 

**Society in Regional Medical Activities** 

*5Laboratory Section of Cytology, Funabashi Municipal Medical Center, 6Radiotechnical Department, Funabashi Municipal Medical Center 7Department of Pharmacy, Funabashi Municipal Medical Center* 

*1Department of Surgery,Funabashi Municipal Medical Center* 

Satoru Ishii6 and Kanae Iwata7

*4Masuda Clinic of breast and thyroid diseases,* 

*3Funabashi Futawa Hospital,* 

*Funabashi, Chiba,* 

*Japan* 

**Breast Specialist of the Japanese Breast Cancer** 

Although the mortality of breast cancer patients in the Western countries has declined due to high screening rate, the number of Japanese breast cancer patients has seen a sharp rise and the most common cause of death of middle-aged women. Since one of every sixteen Japanese women have been diagnosed with breast cancer and more than 10,000 patients die from breast cancer every year, it is a goal to reduce the mortality through detection and treatment in its early stages. Board certified breast specialists of the Japanese Breast Cancer Society have been established in 1997 to contribute for the benefit of welfare of the nation and meet the social needs. In addition, The Ministry of Health, Welfare and Labor authorized the advertisement of specialists via the home page ( http://www.jbcs.gr.jp/ ) in October, 2004 (Sonoo, 2005). As our institution has been designated as the region-based affiliated hospital for cancer treatment since January, 2007, the significance of the breast

**2. Breast specialists, board certified institutions and its affiliated institutions** 

It is the minimum requirement for breast specialists to be authorized experts or qualified doctors in any one of the fields of surgery, oncological internal medicine, radiology and gynecology. The standards for qualifying breast specialists are different depending on each field. The standards for surgeons is: (1) It is required to be specialists in surgery and authorized breast doctors whose titles can possibly be acquired 4 years after graduation. (2) It is necessary to deal with breast diseases for over 7 years and experience the treatment

**1. Introduction** 

specialists was surveyed.

**2.1.Breast specialists** 

informatics. *International Journal of Health Care Quality Assurance*, Accepted for publication.


The State Controller and Ombudsman Office. (2002). *Annual Report 53a*, Israel.

Zalmanovitch, Y. & Vashdi, D.R. (2010). Trade-offs are unavailable. *British Medical Journal*, Vol.340, pp. c1259.

## **The Significance of Board-Certified Registered Breast Specialist of the Japanese Breast Cancer Society in Regional Medical Activities**

Noriyuki Tohnosu1,2, Jun Hasegawa2,3, Yosio Masuda2,4, Taku Kato5, Satoru Ishii6 and Kanae Iwata7 *1Department of Surgery,Funabashi Municipal Medical Center 2Breast cancer screening committee of Funabashi Municipal Medical Association, 3Funabashi Futawa Hospital, 4Masuda Clinic of breast and thyroid diseases, 5Laboratory Section of Cytology, Funabashi Municipal Medical Center, 6Radiotechnical Department, Funabashi Municipal Medical Center 7Department of Pharmacy, Funabashi Municipal Medical Center Funabashi, Chiba, Japan* 

## **1. Introduction**

282 Modern Approaches To Quality Control

Mandel, D.; Amital, H.; Zimlichman, E.; Wartenfeld, R.; Benyamini, L.; Shochat, T.;

Mandel, D.; Zimlichman, E.; Ash, N., Mimouni, F.B.; Ezra, Y. & Kreiss, Y. (2003). Quality

Munro, R.A. (2009). *Lean six Sigma for the healthcare practice: A pocket guide*, Amer Society for

Navon, A.; Machluf, Y.; Cohen, A.; Pirogovsky, A.; Palma, E.; Tal, O.; Frenkel-Nir, Y.; Ash,

Ovretveit, J. (1992). *Health service quality: An introduction to quality methods for health services*, Blackwell Scientific Publications, ISBN 0632032790, Oxford, England. Ransom, E.R.; Joshi, M.S.; Nash, D.B. & Ransom, S.B. (2008). *The Healthcare Quality Book:* 

Zalmanovitch, Y. & Vashdi, D.R. (2010). Trade-offs are unavailable. *British Medical Journal*,

Quality Press, ISBN 0873897609, Milwaukee, Wisconsin, USA.

The State Controller and Ombudsman Office. (2002). *Annual Report 53a*, Israel.

publication.

No.11, pp. 890-2.

*Care*, Vol.16, No.2, pp. 175-80.

*Medicine*, Accepted for publication.

1567933017, Chicago, USA.

Vol.340, pp. c1259.

informatics. *International Journal of Health Care Quality Assurance*, Accepted for

Mimouni, F.B. & Kreiss, Y. (2004). Quality assessment program in primary care clinics: a tool for quality improvement. *International Journal for Quality in Health* 

assessment of primary health care in a military setting, *Milltary Medicine*, Vol.168,

N. & Chaiter, Y. (2011). Quality Assurance of Administrative Aspects of Medical Processes within the Framework of Medical Committees. *Journal of Israeli Military* 

*Vision, strategy, and tools* (2nd edition), Health Administration Press, ISBN

Although the mortality of breast cancer patients in the Western countries has declined due to high screening rate, the number of Japanese breast cancer patients has seen a sharp rise and the most common cause of death of middle-aged women. Since one of every sixteen Japanese women have been diagnosed with breast cancer and more than 10,000 patients die from breast cancer every year, it is a goal to reduce the mortality through detection and treatment in its early stages. Board certified breast specialists of the Japanese Breast Cancer Society have been established in 1997 to contribute for the benefit of welfare of the nation and meet the social needs. In addition, The Ministry of Health, Welfare and Labor authorized the advertisement of specialists via the home page ( http://www.jbcs.gr.jp/ ) in October, 2004 (Sonoo, 2005). As our institution has been designated as the region-based affiliated hospital for cancer treatment since January, 2007, the significance of the breast specialists was surveyed.

## **2. Breast specialists, board certified institutions and its affiliated institutions**

#### **2.1.Breast specialists**

It is the minimum requirement for breast specialists to be authorized experts or qualified doctors in any one of the fields of surgery, oncological internal medicine, radiology and gynecology. The standards for qualifying breast specialists are different depending on each field. The standards for surgeons is: (1) It is required to be specialists in surgery and authorized breast doctors whose titles can possibly be acquired 4 years after graduation. (2) It is necessary to deal with breast diseases for over 7 years and experience the treatment

The Significance of Board-Certified Registered Breast

3. Laboratories and libraries are well-equipped.

Table 2. Standards of board certified institutions.

instruct.

5. Autopsy room is equipped.

occupying most in the latter (Fig. 2).

3.9%

6.4%

31.7%

Institutions (n=357) (Nov.1998-Jul.2009)

17.9%

19.9%

in Japan.

9.5%

Specialist of the Japanese Breast Cancer Society in Regional Medical Activities 285

1. It is required to have beds for surgical treatment or diagnosis and/or non surgical

2. Board -certified registered breast specialists have to regularly work and adequately

8. It is compulsory that board-certified registered breast specialists belonged to certified institutions instruct at the certified affiliated institutions and report its contents.

It is impossible for doctors who aim at breast specialists to be qualified although they even practice hard in the non-certified institutions where non-certified but skillful surgeons treat many breast cancer patients. Therefore, considering the present small number of breast specialists in Japan, it is necessary for non-certified institutions to be affiliated with the regional certified institutions so that the doctors could be qualified. If the number of breast specialists is large in the future, the affiliated institutions may possibly be abolished (Sonoo, 2005,2008). The standards of the affiliated institutions are shown in Table3. The number of board-certified institutions and its affiliated institutions are 357 and 410, respectively, Kanto bloc occupying most in the former and Chubu bloc

treatment of more than 20 breast cancer patients in a year.

6. Instructive events on breast diseases are regularly held.

4. Records of anamnesis are well-written and preserved in ample care.

7. Publications or presentations on breast diseases have to be continued.

Hokkaido

Hokkaido

Tohoku

Kanto

6.6%

19.0%

Chubu

Kinki

Chugoku・ Shikoku Kyusyu・

Tohoku

10.6% 6.8%

Kanto

Chubu

Kinki

Chugoku・ Shikoku Kyusyu・ Okinawa

Nos. of board-cetified Nos. of board-cetified

Okinawa No.of board-certified

Fig. 2. Distribution of the number of board-certified institutions and its affiliated institutions

No.of board-certified affiliated institutions

18.3% 21.5%

(Jan.2007-Jul.2009)

(n=410)

12.2%

19.0%

15.6%

and/or diagnosis of more than 100 breast cancer patients. (3) It is mandatory to be engaged in clinical works at the certified institutions. (4) Academic achievements on breast diseases ( publications or presentations ) have to exceed the compulsory score. (5) Passing the written and oral examinations is needed (Table 1). The qualification has to be renewed every 5 year.


Table 1. Standards of board-certified registered breast specialist.

The breast specialists have been registered from seven regional blocs in Japan: Hokkaido, Tohoku, Kanto, Kinki, Chubu, Chugoku-Shikoku and Kyusyu-Okinawa. The present number of the nationwide breast specialists has been still as small as 837 and 303 in Kanto bloc or eastern part of Japan, 40 in Chiba prefecture of Kanto bloc and 2 in Funabashi city of Chiba prefecture, respectively (Fig.1.)

Fig. 1. Distribution of the numbers of board-certified registered breast specialists in Japan.

#### **2.2 Board certified institutions and its affiliated institutions**

)

In1998, the Japanese Breast Cancer Society has designated certified institutions and its affiliated institutions in the seven blocs of Hokkaido, Tohoku, Kanto, Chubu, Kinki, Chugoku-Shikoku and Kyusyu-Okinawa throughout Japan and our hospital has acted as the certified institution since then. Certified institutions have to meet the following standards (Tab. 2).


and/or diagnosis of more than 100 breast cancer patients. (3) It is mandatory to be engaged in clinical works at the certified institutions. (4) Academic achievements on breast diseases ( publications or presentations ) have to exceed the compulsory score. (5) Passing the written and oral examinations is needed (Table 1). The qualification has to be renewed every 5 year. 1.Concerning surgeons, it is required to be specialists in surgery and authorized breast doctors whose titles can possibly be acquired 4 years after graduation. 2.It is necessary to deal with breast diseases for over 7 years and experience the treatment and/or diagnosis of more than 100 breast cancer patients. 3. It is mandatory to be engaged in clinical works at the certified institutions. 4. Academic achievements on breast diseases ( publications or presentations ) have

The breast specialists have been registered from seven regional blocs in Japan: Hokkaido, Tohoku, Kanto, Kinki, Chubu, Chugoku-Shikoku and Kyusyu-Okinawa. The present number of the nationwide breast specialists has been still as small as 837 and 303 in Kanto bloc or eastern part of Japan, 40 in Chiba prefecture of Kanto bloc and 2 in Funabashi city of

33 (3.9%)

303 (36.2%)

Fig. 1. Distribution of the numbers of board-certified registered breast specialists in Japan.

In1998, the Japanese Breast Cancer Society has designated certified institutions and its affiliated institutions in the seven blocs of Hokkaido, Tohoku, Kanto, Chubu, Kinki, Chugoku-Shikoku and Kyusyu-Okinawa throughout Japan and our hospital has acted as the certified institution since then. Certified institutions have to meet the following

51 (6.1%)

Hokkaido Tohoku Kanto Chubu Kinki

Chiba Pref. 40 (Funabashi city 2)


> Chugoku・Shikoku Kyusyu・Okinawa

to exceed the compulsory score.

Chiba prefecture, respectively (Fig.1.)

78 (9.3%)

158(18.9%)

133 (15.9%)

**2.2 Board certified institutions and its affiliated institutions** 

81(9.7%)

)

standards (Tab. 2).

5. Passing the written and oral examinations is needed.

Table 1. Standards of board-certified registered breast specialist.


Table 2. Standards of board certified institutions.

It is impossible for doctors who aim at breast specialists to be qualified although they even practice hard in the non-certified institutions where non-certified but skillful surgeons treat many breast cancer patients. Therefore, considering the present small number of breast specialists in Japan, it is necessary for non-certified institutions to be affiliated with the regional certified institutions so that the doctors could be qualified. If the number of breast specialists is large in the future, the affiliated institutions may possibly be abolished (Sonoo, 2005,2008). The standards of the affiliated institutions are shown in Table3. The number of board-certified institutions and its affiliated institutions are 357 and 410, respectively, Kanto bloc occupying most in the former and Chubu bloc occupying most in the latter (Fig. 2).

Fig. 2. Distribution of the number of board-certified institutions and its affiliated institutions in Japan.

The Significance of Board-Certified Registered Breast

▲

6.8

8.9

▲

7.3

who are indicated to screening are referred to the hospital also.

12.1

● ● Percentage of examinees

● ●

11.4

6.2

Fig. 3. Change in percentage of breast cancer examinees and detailed examinations in

hospitals. Doctors including gynecologists, cytologists and technologist attend to share knowledge and information on breast cancer. In addition, breast cancer patients who want to undergo surgery at an earlier date are referred to the affiliated hospital. Those women

In our hospital activities on breast cancer patients, patient and the family-centered team management has been carried out and comedical staffs play an important role in each field. Apart from nurses, a pharmacist not only immediately reacts to advise doctors on optimal use of drugs whenever asked but also kindly responds to the patients soon after adverse events particularly of chemotherapy are seen. She is well informed about recent drug news both domestic and abroad on breast cancer and often has presentations even in the Japanese Breast Cancer Society. An experienced cytologist who plays a leading part in Japan is specifically of great help in the diagnosis of breast diseases both on the outpatient and intraoperative basis to contribute much for the benefit of not only our hospital but also the

Education of trainee doctors contain mammography reading, academic presentation and surgery of breast cancer. On mammographic reading ability, a third-year trainee doctor in our hospital was the first successful candidate in Chiba prefecture in the nationwide examination several years ago and it was also quite rare in Japan. Six trainee doctors of 2 general surgeons, 2 lung surgeons and 2 gynecologists have been accredited up until now. Since present team management basically requires certified nurses ( breast care nurse ) in particular, it is an urgent task to have the staffs in our team although the nationwide examination is relatively difficult to pass. As for the accredited pharmacist for cancer drug, The Japanese Society of Pharmatheutical Health Care and Sciences has also adopted a board-certified system since 2006 and the standards of certified pharmacist for cancer drugs

community hospitals or clinics which ask consultations of microscopic specimen.

▲ ▲ Percentage of detailed examinations

5

Funabashi city.

**3.3 Team management** 

are as follows (Table 4).

10

15

20

%

Specialist of the Japanese Breast Cancer Society in Regional Medical Activities 287


2004 2005 2006 2007 2008 2009

▲ ▲

● ▲

▲

10.0

13.7

●

7.7

17.0

● ●

14.0

6.7

year


Table 3. Standards of board-certified affiliated institution.

#### **3. Medical activities as region-based affiliated hospital for cancer treatment**

Japanese government has issued an Act of Strategy for Cancer in June, 2006 to treat the Japanese major cancers of lung, stomach, liver, colorectum and breast with equal high medical quality throughout the nation. For that purpose, affiliated hospitals for cancer treatment have been designated in each region and our institution has been the hospital since January, 2007.

The present number of the hospitals is 13 in Chiba Prefecture and the qualification has to be renewed every 5 year. The main works for breast specialists in our region are raising the percentage of examinees, reducing the percentage of detailed examinations, maintaining quality control in breast cancer screening, promoting close cooperation with the board certified affiliated hospital and community hospitals or clinics, optimal team management for breast cancer, an education of trainee doctors and providing citizens with information on breast cancer including extension lectures.

#### **3.1 Breast cancer screening**

As for breast cancer screening in Funabashi city, a mammography has been applied to women aged 40 and over since 2004. The percentage of examinees has annually risen from 8.9% in 2004 to 17.0% in 2009, whereas the percentage of detailed examinations has been almost constantly 6-7% exept in 2008 due to the effect of good quality control, the detection rate of breast cancer being 0.28% (Fig.3).

Although there were only four qualified doctors to read mammography when mammographic screening started, there have been 10 qualified doctors at present to form five teams in which a pair of two doctors reads alternately every week. On mammographic technics and knowledge, a qualified technologist at our hospital who plays a leading role in Japan has called a monthly meeting to educate technologists involved in screening mammography in Funabashi city. Breast cancer screening using stereotactic guided Mammotome has begun in our hospital by request of the community hospitals and clinics in March, 2011.

#### **3.2 Coordination with the affiliated hospital**

As far as coordination with the affiliated hospital is concerned, a conference has been held monthly to compare mammography with pathology of the postoperative cases of both

Fig. 3. Change in percentage of breast cancer examinees and detailed examinations in Funabashi city.

hospitals. Doctors including gynecologists, cytologists and technologist attend to share knowledge and information on breast cancer. In addition, breast cancer patients who want to undergo surgery at an earlier date are referred to the affiliated hospital. Those women who are indicated to screening are referred to the hospital also.

## **3.3 Team management**

286 Modern Approaches To Quality Control

1. It is required to have beds for surgical treatment or diagnosis and/or non surgical

2. Board -certified registered breast specialists have to regularly work and adequately

8. It is compulsory that board-certified registered breast specialists belonged to certified institutions instruct at the certified affiliated institutions and report its contents.

**3. Medical activities as region-based affiliated hospital for cancer treatment**  Japanese government has issued an Act of Strategy for Cancer in June, 2006 to treat the Japanese major cancers of lung, stomach, liver, colorectum and breast with equal high medical quality throughout the nation. For that purpose, affiliated hospitals for cancer treatment have been designated in each region and our institution has been the hospital

The present number of the hospitals is 13 in Chiba Prefecture and the qualification has to be renewed every 5 year. The main works for breast specialists in our region are raising the percentage of examinees, reducing the percentage of detailed examinations, maintaining quality control in breast cancer screening, promoting close cooperation with the board certified affiliated hospital and community hospitals or clinics, optimal team management for breast cancer, an education of trainee doctors and providing citizens with information on

As for breast cancer screening in Funabashi city, a mammography has been applied to women aged 40 and over since 2004. The percentage of examinees has annually risen from 8.9% in 2004 to 17.0% in 2009, whereas the percentage of detailed examinations has been almost constantly 6-7% exept in 2008 due to the effect of good quality control, the detection

Although there were only four qualified doctors to read mammography when mammographic screening started, there have been 10 qualified doctors at present to form five teams in which a pair of two doctors reads alternately every week. On mammographic technics and knowledge, a qualified technologist at our hospital who plays a leading role in Japan has called a monthly meeting to educate technologists involved in screening mammography in Funabashi city. Breast cancer screening using stereotactic guided Mammotome has begun in our hospital by request of the community hospitals and clinics in

As far as coordination with the affiliated hospital is concerned, a conference has been held monthly to compare mammography with pathology of the postoperative cases of both

treatment of more than 20 breast cancer patients in a year.

6. Instructive events on breast diseases are regularly held.

4. Records of anamnesis are well-written and preserved in ample care.

7. Publications or presentations on breast diseases have to be continued.

3. Laboratories and libraries are well-equipped.

Table 3. Standards of board-certified affiliated institution.

instruct.

since January, 2007.

5. Autopsy room is equipped.

breast cancer including extension lectures.

rate of breast cancer being 0.28% (Fig.3).

**3.2 Coordination with the affiliated hospital** 

**3.1 Breast cancer screening** 

March, 2011.

In our hospital activities on breast cancer patients, patient and the family-centered team management has been carried out and comedical staffs play an important role in each field. Apart from nurses, a pharmacist not only immediately reacts to advise doctors on optimal use of drugs whenever asked but also kindly responds to the patients soon after adverse events particularly of chemotherapy are seen. She is well informed about recent drug news both domestic and abroad on breast cancer and often has presentations even in the Japanese Breast Cancer Society. An experienced cytologist who plays a leading part in Japan is specifically of great help in the diagnosis of breast diseases both on the outpatient and intraoperative basis to contribute much for the benefit of not only our hospital but also the community hospitals or clinics which ask consultations of microscopic specimen.

Education of trainee doctors contain mammography reading, academic presentation and surgery of breast cancer. On mammographic reading ability, a third-year trainee doctor in our hospital was the first successful candidate in Chiba prefecture in the nationwide examination several years ago and it was also quite rare in Japan. Six trainee doctors of 2 general surgeons, 2 lung surgeons and 2 gynecologists have been accredited up until now.

Since present team management basically requires certified nurses ( breast care nurse ) in particular, it is an urgent task to have the staffs in our team although the nationwide examination is relatively difficult to pass. As for the accredited pharmacist for cancer drug, The Japanese Society of Pharmatheutical Health Care and Sciences has also adopted a board-certified system since 2006 and the standards of certified pharmacist for cancer drugs are as follows (Table 4).

The Significance of Board-Certified Registered Breast

50s, younger than the age group at the previous lectures.

**3.5 Extension lectures** 

**4. Discussion** 

(Sonoo, 2007, 2008).

Specialist of the Japanese Breast Cancer Society in Regional Medical Activities 289

Together with the affiliated hospital, community hospitals and clinics, we have held fourtime extension lectures for citizens on breast cancer each with certain theme at every other year since 2006 (Tab. 5.). Specifically, a lecture on liaison clinical path was given for the first time in October 2010, and the majority of the audience including men was in their 40s and

Date Support organization Attendant institutions

Sep. 2006 A private enterprise Our hospital and three

Jun. 2008 A private enterprise Our hospital, two ommunity

Quite different from Western countries, Japanese specialist system has been privately established to improve and maintain the quality of the members in each society. In 1962, specialist system for anesthetists started for the first time in the Japanese Anestheology Society followed by those for radiologists and brain surgeons in 1964. Since around mid-1970, the Japanese Society of Internal Medicine has taken the iniative not only to let the board-certified doctors and specialists be socially accepted but also to enable them to advertise in April, 2004 (Sakai, 2005). Health, Welfare and Labor Ministry has also authorized the advertisement of breast specialists through the home page in October, 2004. Although the field of breast cancer is related to not only surgery but also radiology, gynecology and oncological internal medicine, surgeons occupy 95% of breast specialists in Japan, quite unlike Western countries. Therefore, Japanese breast specialists are busy working even for rapidly-advancing chemotherapy, however, they can possibly acquire a broad range of knowledge and experience through medical activities in team management. Since there are few emergency patients, even woman doctors including surgeons and gynecologists could work by taking advantage of being female while they rear children. As the number of breast specialists is still small in Japan, they will turn out to be important human resources for Japanese breast cancer patients who have continued to rise in number

Before applying to the examination for breast specialist, the following curriculum has to be finished; 1) to master general knowledge on breast diseases, clinical judgement, the ability to

Oct. 2010 ✱ A private enterprise 〃 〃

Table 5. Extension lectures ever held. \*A theme 'clinical path ' was included.

Mar. 2008 Funabashi city Our hospital

Year Sponsored Attended

community hospitals

hospitals and a breast clinic


Table 4. Standars of board certified pharmacist for cancer drugs.

Strengthening a supportive system of cancer consultation is so important also that we started the team formed of a nurse who serves exclusively and three social workers in November, 2008. Concerning best supportive care, a specialist of former lung surgeon has gone into action in a newly built ward with 20 beds since April, 2009.

As the region-based affiliated hospital for cancer treatment, we will have to achieve the goal to have common clinical path of breast cancer among the community hospitals or clinics in our city and carry out breast cancer screening using ultrasound especially for the examinees aged 30-40 years.

#### **3.4 Clinical path**

A clinical path is useful for low-risk postoperative breast cancer patients in shortening time to visit and wait for receiving the same standard treatment without concentrating only in the region-based affiliated hospital . It is also beneficial for the region-based affiliated hospital to have more ample time on treating more seriously ill patients with metastases or recurrence. When the patients are operated on at the region-based hospitals and found to be at low risk ( i.e. node negative, positive hormone receptors for prescription of oral medicines alone and no chemotherapy or no therapy ), they are treated there with or without hormonal medicines for 1- 6 months, then are referred to community hospitals or clinics if they consent the use of path. They are checked up only with prescription and blood collection and then return to the region-based affiliated hospitals every 6-12 month for detailed examinations like mammography, ultrasound and CT or bone scan if required. If some emergencies, recurrence and/or metastases happen, the region-based affiliated hospitals have to respond immediately not only for the patients but also the community physicians (Fig. 4).

Fig. 4. Flowchart of clinical path for postoperative breast cancer patients.

## **3.5 Extension lectures**

288 Modern Approaches To Quality Control

1. It is required to have a career as a pharmacist for over five years and have to be a member of the Society for over five years when applied for the examination. 2. It is necessary to attend the Society or symposium of the Society more than two

3. Academic presentation on medical pharmacy has to be carried out as a coauthor over three times in meetings and one of them must be given as an author. 4. Publishing more than three papers on medical pharmacy is needed.

Strengthening a supportive system of cancer consultation is so important also that we started the team formed of a nurse who serves exclusively and three social workers in November, 2008. Concerning best supportive care, a specialist of former lung surgeon has

As the region-based affiliated hospital for cancer treatment, we will have to achieve the goal to have common clinical path of breast cancer among the community hospitals or clinics in our city and carry out breast cancer screening using ultrasound especially for the examinees

A clinical path is useful for low-risk postoperative breast cancer patients in shortening time to visit and wait for receiving the same standard treatment without concentrating only in the region-based affiliated hospital . It is also beneficial for the region-based affiliated hospital to have more ample time on treating more seriously ill patients with metastases or recurrence. When the patients are operated on at the region-based hospitals and found to be at low risk ( i.e. node negative, positive hormone receptors for prescription of oral medicines alone and no chemotherapy or no therapy ), they are treated there with or without hormonal medicines for 1- 6 months, then are referred to community hospitals or clinics if they consent the use of path. They are checked up only with prescription and blood collection and then return to the region-based affiliated hospitals every 6-12 month for detailed examinations like mammography, ultrasound and CT or bone scan if required. If some emergencies, recurrence and/or metastases happen, the region-based affiliated hospitals have to respond immediately not only for the patients but also the community physicians

(Breast specialist) Patient・Family

Mail (or brought by patient)

Fig. 4. Flowchart of clinical path for postoperative breast cancer patients.

Issue

Preservation of clinical path (original print)

Community hospital or clinic

●Preservation of clinical path for patient (copy) ●Preservation of clinical path for doctor (original print)

**Return to region-based hospital every 6 ~ 12months for detailed examinations**

Table 4. Standars of board certified pharmacist for cancer drugs.

gone into action in a newly built ward with 20 beds since April, 2009.

Region-based hospital

Clinical path for patient (copy) Clinical path for doctor

●Follow-up for 1~6 months ●Decision-making on referral community hospital or clinic ●Obtaining informed consent

on clinical path

times.

aged 30-40 years.

**3.4 Clinical path** 

(Fig. 4).

Together with the affiliated hospital, community hospitals and clinics, we have held fourtime extension lectures for citizens on breast cancer each with certain theme at every other year since 2006 (Tab. 5.). Specifically, a lecture on liaison clinical path was given for the first time in October 2010, and the majority of the audience including men was in their 40s and 50s, younger than the age group at the previous lectures.


Table 5. Extension lectures ever held. \*A theme 'clinical path ' was included.

## **4. Discussion**

Quite different from Western countries, Japanese specialist system has been privately established to improve and maintain the quality of the members in each society. In 1962, specialist system for anesthetists started for the first time in the Japanese Anestheology Society followed by those for radiologists and brain surgeons in 1964. Since around mid-1970, the Japanese Society of Internal Medicine has taken the iniative not only to let the board-certified doctors and specialists be socially accepted but also to enable them to advertise in April, 2004 (Sakai, 2005). Health, Welfare and Labor Ministry has also authorized the advertisement of breast specialists through the home page in October, 2004. Although the field of breast cancer is related to not only surgery but also radiology, gynecology and oncological internal medicine, surgeons occupy 95% of breast specialists in Japan, quite unlike Western countries. Therefore, Japanese breast specialists are busy working even for rapidly-advancing chemotherapy, however, they can possibly acquire a broad range of knowledge and experience through medical activities in team management. Since there are few emergency patients, even woman doctors including surgeons and gynecologists could work by taking advantage of being female while they rear children. As the number of breast specialists is still small in Japan, they will turn out to be important human resources for Japanese breast cancer patients who have continued to rise in number (Sonoo, 2007, 2008).

Before applying to the examination for breast specialist, the following curriculum has to be finished; 1) to master general knowledge on breast diseases, clinical judgement, the ability to

The Significance of Board-Certified Registered Breast

Endo, 2009).

Specialist of the Japanese Breast Cancer Society in Regional Medical Activities 291

seminars frequently including examinations since November, 2000 (Tsunoda, 2008 &

The examination of reading mammography includes 100 cases half with two views and candidates have to fill out the marksheets for judging categories within a limited time of 100 minutes. The results of examinations are classified into the ranks of A, B, C , D and A+B are certified. Rank A is accepted as the ability of reading and teaching of screening mammography. The possibility of obtaining rank A in a review of rigorous testing is less than 10 percent of the total candidates. The Committee has not only accredited the doctors and technologists involved in breast cancer screening program but also given the members examinations every five year for the renewal of accreditation. Futhermore, the lecturer's and staff member's meeting has also been held once a year for keeping the knowledge and information about mammography screening system (Tsunoda, 2008). Although there has been legally-authorized Mammography Quality Standard ACT (MQSA) of the United States, the Japanese committee is considered the pioneer system in the world to evaluate the

Although ultrasound screening has been strongly recommended for examinees with dense breast particularly in their 40s or younger (Hashimoto & Ban 2010 ), there has been no worldwide evidence to prove whether ultrasound screening would have a potential to reduce the mortality of breast cancer for women aged 40-49. Therefore, in order to clarify sensitivity, specificity and detection rate as primary endpoint and cumulative advanced breast cancer incidence rate as secondary endpoint, 5-year Japan Strategic Anti-Cancer Randomized Trial (J-START) (http://jsrtfall.umin.jp/) has been conducted between the two groups of mammography combined with ultrasound and mammography alone in the respective number of 100,000 examinees in their 40s since 2006 with the initiative of The Ministry of Health, Welfare and Labor and the outcome will be shown in 2012. If effectiveness of ultrasound is confirmed, ultrasound screening would start in Japan for the first time in the world and we will have to prepare for the screening to especially secure a

As far as clinical path in Japan is concerned, The Ministry of Health, Welfare and Labor authorized the payment for using paths for neck of femur fracture for the first time in 2006. Then, the Ministry issued Stragetic Anti-Cancer Promotion Project in 2007 to oblige the use of clinical paths of the five major cancers of stomach, colorectum, liver, lung and breast. According to the Ministry's survey in 2010, the number of the clinical paths used and patients enrolled has been larger in a comparison between before-2008 and 2009. Specifically, breast cancer patients increased even five-fold, largest in number compared to the other cancer patients. However, questionnaires to 410 hospitals by Health, Welfare and Labor Ministry in 2010 revealed that those patients including their families who understand paths have occupied only 30% even in the hospitals using paths. In other words, hospital staffs seem unlikely to give ample explanation or enlighten on paths considering that there actually have been many other path-using community hospitals throughout Japan. Likewise, the number of Chiba prefecture-based common paths used has been still as small as four, similar to lung cancer (1) and liver cancer (4) from April 2010 to January 2011. According to the other questionnaire by a certain group formed of breast cancer patients and their families, there have been the following anxieties for patients; 1) Whether the physicians of the community hospitals or clinics can treat enough or not, as well as the breast specialists in the region-based hospitals. 2) When clinical path is suddenly mentioned under treatment, some patients feel like losing a relationship of mutual trust. 3) Without

ability of individuals who engage in mammographic screening (Ohuchi, 2007).

certain number of well-trained breast sonographers in Funabashi city also.

solve problems without regard to each expertise, 2) to master basic knowledge on anatomy, physiology, hormonal environment, epidemiology, pathology, biology of the mammary gland and breast cancer screening and to be able to clinically respond, 3) to master basic treatment technics on diagnosis by imaging modalities, aspiration cytology, core needle biopsy, biopsy using Mammotome, surgical biopsy , sentinel lymphnode biopsy and treatment with surgery, radiation, anticancer drugs, hormonal medicines, best supportive care and postoperative rehabilitation, medical ethics including informed consent, second opinion and clinical trials. 4) to master special treatment technics on breast diseases required for each expertise. 5) to actively attend conference or academic meetings, research or treat via evidence based medicine and give academic presentations on case reports or clinical study. 6) to understand the importance of medical administration involving risk management, medical cost, team management, etc. for carrying out practical medical activities (Sawai, 2006).

The number of board certified institutions and their affiliated institutions has seen a gradual rise and the largest number is centered on Kanto bloc or eastern part of Japan as well as breast specialists. There have been only two breast specialists in Funabashi city with a population of 600,000, therefore it is essential to increase the number of breast specialists for treating the steadily increasing breast cancer patients.

Under a guidance of The Ministry of Health, Welfare and Labor, nationwide mammographic breast cancer screening for women aged 50 and over has been introduced at intervals of two years since April, 2000 followed by the screening for women aged 40-49 since 2003 (Ohuchi, 2007). However, the percentage of examinees aged 40 and over has still been as low as 20.3% in Japan and the percentage of mammographic screening at the age of 50-69 was 23.8% compared to 60-90% in Western countries in 2006 ( OECD Health Data 2009). According to the Japanese government statistics in fiscal year 2008, the nationwide average percentage of examinees is as low as 1.5% at mammography screening alone and 7.6% at combined mammography screening with palpation. The Ministry of Health, Welfare and Labor has started to distribute free coupons to raise the percentage up to 50% since October, 2009. The average rate of using coupons has been approximately 30% at the age of 40-69 (Japanese government bulletin, 2009). There have been some reports showing the effect of distributing free coupons to improve the percentage of examinees (Komoto & Ishiyama, 2010 ). Similarly, the percentage of examinees was raised from 81% to 88% in some age groups after the introduction of free of charge in Finland (Kauhava, 2008). Whereas the percentage was improved from 18.8% to 40.7% in Sendai, 2011's quake and tsunami-hit Miyagi prefecture, northern part of Japan through not using coupons but making various efforts of increase in consultations with universities or institutions to exchange views, women's cancer screening promotion project and distribution of application form to all houses (Satake, 2011). The percentage of detailed examinations and the detection rate of breast cancer screening in 2008 in Japan is 8.6% and 0.32%, respectively (Japanese government report, 2010). Our series have shown almost same as the nationwide data.

In order to maintain a quality control not only on facility but also personnel qualification of mammography reading ability for doctors and mammographic skills for technologists, The Central Committee on Quality Control of Mammographic Screening was launched as a non-profit organization in November, 1997 and has offered nationwide training

solve problems without regard to each expertise, 2) to master basic knowledge on anatomy, physiology, hormonal environment, epidemiology, pathology, biology of the mammary gland and breast cancer screening and to be able to clinically respond, 3) to master basic treatment technics on diagnosis by imaging modalities, aspiration cytology, core needle biopsy, biopsy using Mammotome, surgical biopsy , sentinel lymphnode biopsy and treatment with surgery, radiation, anticancer drugs, hormonal medicines, best supportive care and postoperative rehabilitation, medical ethics including informed consent, second opinion and clinical trials. 4) to master special treatment technics on breast diseases required for each expertise. 5) to actively attend conference or academic meetings, research or treat via evidence based medicine and give academic presentations on case reports or clinical study. 6) to understand the importance of medical administration involving risk management, medical cost, team management, etc. for carrying out practical medical

The number of board certified institutions and their affiliated institutions has seen a gradual rise and the largest number is centered on Kanto bloc or eastern part of Japan as well as breast specialists. There have been only two breast specialists in Funabashi city with a population of 600,000, therefore it is essential to increase the number of breast specialists for

Under a guidance of The Ministry of Health, Welfare and Labor, nationwide mammographic breast cancer screening for women aged 50 and over has been introduced at intervals of two years since April, 2000 followed by the screening for women aged 40-49 since 2003 (Ohuchi, 2007). However, the percentage of examinees aged 40 and over has still been as low as 20.3% in Japan and the percentage of mammographic screening at the age of 50-69 was 23.8% compared to 60-90% in Western countries in 2006 ( OECD Health Data 2009). According to the Japanese government statistics in fiscal year 2008, the nationwide average percentage of examinees is as low as 1.5% at mammography screening alone and 7.6% at combined mammography screening with palpation. The Ministry of Health, Welfare and Labor has started to distribute free coupons to raise the percentage up to 50% since October, 2009. The average rate of using coupons has been approximately 30% at the age of 40-69 (Japanese government bulletin, 2009). There have been some reports showing the effect of distributing free coupons to improve the percentage of examinees (Komoto & Ishiyama, 2010 ). Similarly, the percentage of examinees was raised from 81% to 88% in some age groups after the introduction of free of charge in Finland (Kauhava, 2008). Whereas the percentage was improved from 18.8% to 40.7% in Sendai, 2011's quake and tsunami-hit Miyagi prefecture, northern part of Japan through not using coupons but making various efforts of increase in consultations with universities or institutions to exchange views, women's cancer screening promotion project and distribution of application form to all houses (Satake, 2011). The percentage of detailed examinations and the detection rate of breast cancer screening in 2008 in Japan is 8.6% and 0.32%, respectively (Japanese government report, 2010). Our series have shown

In order to maintain a quality control not only on facility but also personnel qualification of mammography reading ability for doctors and mammographic skills for technologists, The Central Committee on Quality Control of Mammographic Screening was launched as a non-profit organization in November, 1997 and has offered nationwide training

activities (Sawai, 2006).

treating the steadily increasing breast cancer patients.

almost same as the nationwide data.

seminars frequently including examinations since November, 2000 (Tsunoda, 2008 & Endo, 2009).

The examination of reading mammography includes 100 cases half with two views and candidates have to fill out the marksheets for judging categories within a limited time of 100 minutes. The results of examinations are classified into the ranks of A, B, C , D and A+B are certified. Rank A is accepted as the ability of reading and teaching of screening mammography. The possibility of obtaining rank A in a review of rigorous testing is less than 10 percent of the total candidates. The Committee has not only accredited the doctors and technologists involved in breast cancer screening program but also given the members examinations every five year for the renewal of accreditation. Futhermore, the lecturer's and staff member's meeting has also been held once a year for keeping the knowledge and information about mammography screening system (Tsunoda, 2008). Although there has been legally-authorized Mammography Quality Standard ACT (MQSA) of the United States, the Japanese committee is considered the pioneer system in the world to evaluate the ability of individuals who engage in mammographic screening (Ohuchi, 2007).

Although ultrasound screening has been strongly recommended for examinees with dense breast particularly in their 40s or younger (Hashimoto & Ban 2010 ), there has been no worldwide evidence to prove whether ultrasound screening would have a potential to reduce the mortality of breast cancer for women aged 40-49. Therefore, in order to clarify sensitivity, specificity and detection rate as primary endpoint and cumulative advanced breast cancer incidence rate as secondary endpoint, 5-year Japan Strategic Anti-Cancer Randomized Trial (J-START) (http://jsrtfall.umin.jp/) has been conducted between the two groups of mammography combined with ultrasound and mammography alone in the respective number of 100,000 examinees in their 40s since 2006 with the initiative of The Ministry of Health, Welfare and Labor and the outcome will be shown in 2012. If effectiveness of ultrasound is confirmed, ultrasound screening would start in Japan for the first time in the world and we will have to prepare for the screening to especially secure a certain number of well-trained breast sonographers in Funabashi city also.

As far as clinical path in Japan is concerned, The Ministry of Health, Welfare and Labor authorized the payment for using paths for neck of femur fracture for the first time in 2006. Then, the Ministry issued Stragetic Anti-Cancer Promotion Project in 2007 to oblige the use of clinical paths of the five major cancers of stomach, colorectum, liver, lung and breast. According to the Ministry's survey in 2010, the number of the clinical paths used and patients enrolled has been larger in a comparison between before-2008 and 2009. Specifically, breast cancer patients increased even five-fold, largest in number compared to the other cancer patients. However, questionnaires to 410 hospitals by Health, Welfare and Labor Ministry in 2010 revealed that those patients including their families who understand paths have occupied only 30% even in the hospitals using paths. In other words, hospital staffs seem unlikely to give ample explanation or enlighten on paths considering that there actually have been many other path-using community hospitals throughout Japan. Likewise, the number of Chiba prefecture-based common paths used has been still as small as four, similar to lung cancer (1) and liver cancer (4) from April 2010 to January 2011. According to the other questionnaire by a certain group formed of breast cancer patients and their families, there have been the following anxieties for patients; 1) Whether the physicians of the community hospitals or clinics can treat enough or not, as well as the breast specialists in the region-based hospitals. 2) When clinical path is suddenly mentioned under treatment, some patients feel like losing a relationship of mutual trust. 3) Without

The Significance of Board-Certified Registered Breast

*Surgery,* vol.69, No.4, pp. 396-401

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Endo, T. (2009). Progress of quality control in breast cancer screening and future problems

Hashimoto,H. (2010). Present and future of ultrasound breast cancer screening (in Japanese).

Ban, K. et al. (2010). Consideration of apporopriate scrutiny of concurrent ultrasound

http://jsrtfall.umin.jp/. Present status and perspective of J-START (in Japanese). *Proceeding* 

Ando, T. et al. (2004). Breast cancer surgery and clinical path (in Japanese). *Surgical* 

Aogi, K. et al. (2008). Breast cancer surgery-The present status of development of clinical

path (in Japanese). *Surgical Treatment* , vol.99, No.1, pp.48-56

handbook (in Japanese). *Proceeding of J. Jpn Assoc. Breast Cancer Screen*, vol.19, No.3,

after introduction of free coupons (in Japanese). *Proceeding of J Jpn. Assoc. Breast* 

special reference to activity of Sendai city (in Japanese). *J. Jpn. Assoc. Breast Cancer* 

problems (in Japanese with English abstract). *Jpn J Breast Cancer*, vol.23, No.3, 2008,

(in Japanese). *J Jpn. Assoc. Breast Cancer Screen*, vol.18, No.2, 2009, pp.107-

screening with mammography screening (in Japanese). *J Jpn. Assoc. Breast Cancer* 

Japanese). *Surgical Treatment,* vol.98, No.3, 2008, pp. 260-266

http://www.gankenshin50.go.jp/. OECD Health Data 2009 (in Japanese).

*of J. Jpn.Assoc. Breast Cancer Screen,* vol7, No.3, 2008, pp.341

*Health Project Report FY* 2009 (in Japanese), 2010, pp. 1

*breast cancer,* Nagai Book Co. 2006, pp. 515-519.

screening in 1990 article (in Japanese), pp. 5

*Cancer Screen*, vol.19, No.3, 2010, pp. 357

*Screen.* Vol.20, No.2, 2011, pp.102-105

*Inner Vision* , vol.25,No.8, 2010, pp.27-29

*Screen,* vol.25, No.6, 2010, pp.649-656

*of an instructive lecture*, 2010, pp.1-2

*Treatment* , vol.90, No.5, pp.937-943

close communication between the breast specialists and the community physicians, patients may possibly think to forcedly be sent out.

Region-based affiliated hospitals for cancer treatment have now been required to more closely cooperate to promote coordination with the community hospitals or clinics using clinical paths for the purpose of improving and maintaining treatment quality (Ando, 2004 & Aogi, 2008).

Since The Ministry of Health, Welfare and Labor revised the score of payment for treatment in fiscal year 2010, the region-based affiliated hospitals and community hospitals or clinics can get a certain additional score if the patients requiring a 10-year follw-up are treated using the common clinical path. Apart from the low-risk breast cancer patients, a path for postoperative chemotherapy using trastuzumab has been applied in Kitakyusyu city, Fukuoka prefecture, southern part of Japan (Ohno, 2008). For success of the path, Ohno et al stress the importance and benefit of close communication with the community physicians by holding regular meetings three times a year before starting its use.

We have had regular meetings since 2009 like Ohno et al to start Funabashi city-based clinical path in April, 2011. In addition to the meetings, it is required for success to fully inform the patients both before and after admission for surgery and citizens through regular extension lectures like ours, bulletins or website.

## **5. Conclusion**

It is essential to have a more number of breast specialists in order to treat the steadily increasing Japanese breast cancer patients. To raise the percentage of examinees in breast cancer screening, the efforts must be continued including various campaigns by non-profit organization or consecutive distribution of free coupons by the government. Mammographic reading ability for doctors and mammographic skills for technologists have to be renewed every five year as before to maintain quality control. Evidence-based ultrasound breast cancer screening may possibly start in Japan for women aged 30-40. Clinical path has to be popular for low-risk breast cancer patients via adequate information before and/or after admission for surgery, regular extension lectures for citizens and bulletins or website.

## **6. Acknowledgement**

I wish to thank Dr. Hasegawa for collecting continuous data on breast cancer screening in Funabashi city, Dr. Masuda for referring many early breast cancer patients, cyotologist Mr. Kato for diagnosing quickly on the outpatient and intraoperative basis, pharmacist Ms. Iwata for offering quick assistance on drug information and radiotechnologist Mr. Ishii for maintaining quality control on mammography as well as continuing technical education to other technologists involved in municipal breast cancer screening.

## **7. References**

Sonoo, H. (2005). Certification system of breast diseases of the Japanese Breast Cancer Society (in Japanese with English abstract). *Jpn J Breast Cancer*, vol.20, No.1, 2005, pp. 59-63

close communication between the breast specialists and the community physicians, patients

Region-based affiliated hospitals for cancer treatment have now been required to more closely cooperate to promote coordination with the community hospitals or clinics using clinical paths for the purpose of improving and maintaining treatment quality (Ando, 2004

Since The Ministry of Health, Welfare and Labor revised the score of payment for treatment in fiscal year 2010, the region-based affiliated hospitals and community hospitals or clinics can get a certain additional score if the patients requiring a 10-year follw-up are treated using the common clinical path. Apart from the low-risk breast cancer patients, a path for postoperative chemotherapy using trastuzumab has been applied in Kitakyusyu city, Fukuoka prefecture, southern part of Japan (Ohno, 2008). For success of the path, Ohno et al stress the importance and benefit of close communication with the community physicians

We have had regular meetings since 2009 like Ohno et al to start Funabashi city-based clinical path in April, 2011. In addition to the meetings, it is required for success to fully inform the patients both before and after admission for surgery and citizens through regular

It is essential to have a more number of breast specialists in order to treat the steadily increasing Japanese breast cancer patients. To raise the percentage of examinees in breast cancer screening, the efforts must be continued including various campaigns by non-profit organization or consecutive distribution of free coupons by the government. Mammographic reading ability for doctors and mammographic skills for technologists have to be renewed every five year as before to maintain quality control. Evidence-based ultrasound breast cancer screening may possibly start in Japan for women aged 30-40. Clinical path has to be popular for low-risk breast cancer patients via adequate information before and/or after admission for surgery, regular extension lectures for citizens and

I wish to thank Dr. Hasegawa for collecting continuous data on breast cancer screening in Funabashi city, Dr. Masuda for referring many early breast cancer patients, cyotologist Mr. Kato for diagnosing quickly on the outpatient and intraoperative basis, pharmacist Ms. Iwata for offering quick assistance on drug information and radiotechnologist Mr. Ishii for maintaining quality control on mammography as well as continuing technical education

Sonoo, H. (2005). Certification system of breast diseases of the Japanese Breast Cancer

Society (in Japanese with English abstract). *Jpn J Breast Cancer*, vol.20, No.1, 2005,

to other technologists involved in municipal breast cancer screening.

by holding regular meetings three times a year before starting its use.

may possibly think to forcedly be sent out.

extension lectures like ours, bulletins or website.

& Aogi, 2008).

**5. Conclusion** 

bulletins or website.

**7. References** 

pp. 59-63

**6. Acknowledgement** 


**16** 

Mana Sezdi *Istanbul University* 

*Turkey* 

**Dose Optimization for the** 

**Quality Control Tests of X-Ray Equipment** 

Radiation is a major risk in diagnostic and therapeutic medical imaging. The problem is caused from incorrect use of radiography equipment and from the radiation exposure to patients much more than required. Exposure of different dose values for the same clinical

International Commission on Radiation Protection (ICRP), the International Atomic Energy Agency (IAEA) and other various independent institutions have been making publications in relation to ionizing radiation protection for more than fifty years. Report 60 of the ICRP and the Basic Safety Standards that was published in the IAEA report have three basic

The most important issue in these principles is the optimization of radiation. In the mentioned policy, the lowest dose is aimed by considering the country's economic and social factors for acceptable applications. Personnel already receive low dose with protection systems in the working areas. However, the patient doses must be taken under control

The second point indicates that the patient's radiation dose level must be kept at the lowest possible dose. In other words, it indicates dose optimization. The dose optimization meaning "the minimum radiation dose of the optimum image quality", is achieved by

In the Radiology Quality Control systems, the biggest problem is dose control and dose optimization. Neither patient nor users knows how much dose is exposed because there is

Since there is no dose adjustment on the equipment, the systems are operated by using the usual parameters; kVp and mAs. Because dose can not be adjusted, the patient may receive

For dose optimization, all exposures should be kept at the minimum dose level in according to the ALARA principle (ALARA-as low as reasonably achievable). The aim of the optimization is not to download the risks of irradiation to zero. It is to reduce them to an acceptable level. This can be possible only by examining all parameters that affect the X-ray, by investigating the relationship between dose and these parameters, on the basis of this

examination, is an enough reason to draw attention to this issue.

based on the principle of optimization as much as possible.

relationship, by performing the necessary regulations.

more dose than the aimed dose.

principles related to the radiation protection (ICRP, 1991; IAEA, 1996).

There are two important points when performing a radiological procedure: To obtain the best possible image for a clear diagnosis of the disease,

To apply the lowest dose for protecting the patient while getting the best image.

applying quality control procedures, calibration and dosimetric measurements.

no any system in the x-ray device for measuring or showing dose during exposure.

**1. Introduction** 

Ohno S. et al. (2008) Present status and problems of introduction of regional medicine clinical path of breast cancer (in Japanese). *J New Rem. & Clin,* vol.57, No.12 , pp.12- 21

## **Dose Optimization for the Quality Control Tests of X-Ray Equipment**

Mana Sezdi *Istanbul University Turkey* 

## **1. Introduction**

294 Modern Approaches To Quality Control

Ohno S. et al. (2008) Present status and problems of introduction of regional medicine

21

clinical path of breast cancer (in Japanese). *J New Rem. & Clin,* vol.57, No.12 , pp.12-

Radiation is a major risk in diagnostic and therapeutic medical imaging. The problem is caused from incorrect use of radiography equipment and from the radiation exposure to patients much more than required. Exposure of different dose values for the same clinical examination, is an enough reason to draw attention to this issue.

International Commission on Radiation Protection (ICRP), the International Atomic Energy Agency (IAEA) and other various independent institutions have been making publications in relation to ionizing radiation protection for more than fifty years. Report 60 of the ICRP and the Basic Safety Standards that was published in the IAEA report have three basic principles related to the radiation protection (ICRP, 1991; IAEA, 1996).

The most important issue in these principles is the optimization of radiation. In the mentioned policy, the lowest dose is aimed by considering the country's economic and social factors for acceptable applications. Personnel already receive low dose with protection systems in the working areas. However, the patient doses must be taken under control based on the principle of optimization as much as possible.

There are two important points when performing a radiological procedure:


The second point indicates that the patient's radiation dose level must be kept at the lowest possible dose. In other words, it indicates dose optimization. The dose optimization meaning "the minimum radiation dose of the optimum image quality", is achieved by applying quality control procedures, calibration and dosimetric measurements.

In the Radiology Quality Control systems, the biggest problem is dose control and dose optimization. Neither patient nor users knows how much dose is exposed because there is no any system in the x-ray device for measuring or showing dose during exposure.

Since there is no dose adjustment on the equipment, the systems are operated by using the usual parameters; kVp and mAs. Because dose can not be adjusted, the patient may receive more dose than the aimed dose.

For dose optimization, all exposures should be kept at the minimum dose level in according to the ALARA principle (ALARA-as low as reasonably achievable). The aim of the optimization is not to download the risks of irradiation to zero. It is to reduce them to an acceptable level. This can be possible only by examining all parameters that affect the X-ray, by investigating the relationship between dose and these parameters, on the basis of this relationship, by performing the necessary regulations.

Dose Optimization for the Quality Control Tests of X-Ray Equipment 297

effect on patient dose and image quality. The focus of this study is on the relationship

Absorbed dose is the quantity that expresses the radiation concentration delivered to a point, such as the entrance surface of patient's body. Absorbed dose in air is recognized as air kerma and it is a measure of the amount of radiation energy, in the unit of joules (J), actually deposited in or absorbed in a unit mass (kg) of air. Therefore, the quantity, kerma, is expressed in the units of J/kg which is also the radiation unit, the gray (G) (Sprawls, 1987;

In this study, the word of "dose" will be used instead of air kerma (absorbed dose in air).

The high energy of the x-ray spectrum is determined by the kilovoltage applied to the x-ray tube. The maximum photon energy is numerically equal to the maximum applied potential in kilovolts. The maximum photon energy is determined by the voltage during the exposure time. This value is generally referred as the kilovolt peak (kVp) and is one of the adjustable

The x-ray cathode is heated electrically by a current from a separate low voltage power supply. The output of this supply is controlled by the mA selector on the x-ray unit. Additionally, the duration of the x-ray exposure is controlled by the time selector. mAs is

Half value layer describes both the penetrating ability of specific radiations and the penetration through specific objects. HVL is the thickness of material that reduces the intensity of an x-ray beam by half, and is expressed in unit of distance (mm) (Sprawls, 1987).

The purpose of the radiographic image is to provide information about the medical condition of the patient. A quality image is one that provides all the information required

Image quality is not a single factor but is described with beam alignment, collimation alignment, contrast and resolution. Contrast means differences in the form of gray scales or light intensities, whereas the resolution is a measure of its ability to differentiate between

The radiographic measurements were performed in ten stationary X-ray units in five hospitals. The X-ray units including: Siemens, Philips, Toshiba, General Electric and Shimadzu were participated in this study. The reason for chosing these x-ray units is that their age is between 5 and 7 years old and the machines have 3 phase generators, thus their

two objects a small distance apart; such that they appear distinct from one another. An image is acceptable as qualified only if it has high resolution and high contrast.

HVL value is kept in a narrow range, such as between 3 and 3,2mmAl.

described by multiplying of these two values (mA x second) (Hendee et al., 1984).

for diagnosis of the patient's condition (Hendee et al., 1984).

between dose, image quality and other radiographic parameters.

**2.1 Absorbed dose** 

Hendee et al., 1984).

factors of x-ray equipment (Sprawls, 1987).

**2.4 Half Value Layer (HVL)** 

**3. Material and method** 

**2.5 Image quality** 

**2.2 kVp** 

**2.3 mAs** 

In all x-ray equipment, the operator can control the quantity and the quality of the radiation with kVp and mAs controls. If the equipment is not properly controlled, it will not be possible to control the radiation output. For this reason, optimization consists of not only improving of image quality and low dose but also establishing quality assurance and quality control programmes to ensure a proper performance of the x-ray equipment.

As frequently documented in the scientific literature, patient dose and image quality are basic aspects of any quality control (QC) tests in diagnostic radiology. Image quality must be adequate for diagnosis and it must be obtained with low doses.

The following QC tests are performed for both patient dose and image quality evaluation;


The quality control tests' methods, as well as the criteria for scoring the results, are in full agreement with those specified in the American Association of Physicists in Medicine (AAPM) Report No.4 and IEC 61223-3-1 (AAPM, 1981; IEC 61223-3-1, 1999).

There are a number of recent studies about dose optimization. Some of them are the surveys about image quality and patient dose in radiographic examinations in the authors' countries (Bouzarjomehri, 2004; Ciraj et al., 2005; Ramanandraibe, 2009; Papadimitriou, 2001; Shahbazi-Gahrouei, 2006). Some investigators focused only patient dose optimization (Brix et al., 2005; Vano & Fernandez, 2007; Seibert, 2004; Williams & Catling, 1998), whereas the others examined both the patient dose and image quality in radiographic devices (Aldrich et al., 2006; Schaefer-Prokop et al., 2008; Geijer, 2002). There are also studies that give reference values for clinical x-ray examinations by measuring phantom dose (Gray et al., 2005). But there is no any study focused to the dose optimization during quality control tests of x-ray devices. Dose optimization is very important because of the quality and quantity of quality control tests of x-ray equipments.

The aim of this study is to provide optimal x-ray parameters that may be used for quality control tests in order to make quality control activities more efficient and can be controlled. The staff know how the quality control tests are performed, but they don't know which parameters' values give which qualified image. They have problems during evaluation of test results, although there are some recommendations in the standards (AAPM, 1981; IEC 61223-3-1, 1999). They need proven parameter values for comparison. In this study, it was examined during quality control tests which parameters give a high quality image and how much dose is measured when these parameters were applied.

This study was performed by investigating the effects of X-ray parameters' changes on dose and by modeling of dose related to these parameters. After the modeling, in according to the related parameters, the dose level can be controlled, and in different x-ray units the dose levels that are obtained by applying the same parameter setting, can be compared.

Thus, in addition to obtain optimal parameters, controlling of the accuracy of the measured dose values may be possible by calculating the dose value during quality control tests.

#### **2. Parameters of x-ray**

In radiography, dose and image quality are dependent on radiographic parameters. This study is concerned with the quantification of these parameters and an assessment of their effect on patient dose and image quality. The focus of this study is on the relationship between dose, image quality and other radiographic parameters.

## **2.1 Absorbed dose**

Absorbed dose is the quantity that expresses the radiation concentration delivered to a point, such as the entrance surface of patient's body. Absorbed dose in air is recognized as air kerma and it is a measure of the amount of radiation energy, in the unit of joules (J), actually deposited in or absorbed in a unit mass (kg) of air. Therefore, the quantity, kerma, is expressed in the units of J/kg which is also the radiation unit, the gray (G) (Sprawls, 1987; Hendee et al., 1984).

In this study, the word of "dose" will be used instead of air kerma (absorbed dose in air).

## **2.2 kVp**

296 Modern Approaches To Quality Control

In all x-ray equipment, the operator can control the quantity and the quality of the radiation with kVp and mAs controls. If the equipment is not properly controlled, it will not be possible to control the radiation output. For this reason, optimization consists of not only improving of image quality and low dose but also establishing quality assurance and quality

As frequently documented in the scientific literature, patient dose and image quality are basic aspects of any quality control (QC) tests in diagnostic radiology. Image quality must

The following QC tests are performed for both patient dose and image quality evaluation;

Image Quality (Beam alignment, collimation alignment, contrast and resolution)

(AAPM) Report No.4 and IEC 61223-3-1 (AAPM, 1981; IEC 61223-3-1, 1999).

much dose is measured when these parameters were applied.

The quality control tests' methods, as well as the criteria for scoring the results, are in full agreement with those specified in the American Association of Physicists in Medicine

There are a number of recent studies about dose optimization. Some of them are the surveys about image quality and patient dose in radiographic examinations in the authors' countries (Bouzarjomehri, 2004; Ciraj et al., 2005; Ramanandraibe, 2009; Papadimitriou, 2001; Shahbazi-Gahrouei, 2006). Some investigators focused only patient dose optimization (Brix et al., 2005; Vano & Fernandez, 2007; Seibert, 2004; Williams & Catling, 1998), whereas the others examined both the patient dose and image quality in radiographic devices (Aldrich et al., 2006; Schaefer-Prokop et al., 2008; Geijer, 2002). There are also studies that give reference values for clinical x-ray examinations by measuring phantom dose (Gray et al., 2005). But there is no any study focused to the dose optimization during quality control tests of x-ray devices. Dose optimization is very important because of the quality and quantity of quality

The aim of this study is to provide optimal x-ray parameters that may be used for quality control tests in order to make quality control activities more efficient and can be controlled. The staff know how the quality control tests are performed, but they don't know which parameters' values give which qualified image. They have problems during evaluation of test results, although there are some recommendations in the standards (AAPM, 1981; IEC 61223-3-1, 1999). They need proven parameter values for comparison. In this study, it was examined during quality control tests which parameters give a high quality image and how

This study was performed by investigating the effects of X-ray parameters' changes on dose and by modeling of dose related to these parameters. After the modeling, in according to the related parameters, the dose level can be controlled, and in different x-ray units the dose

Thus, in addition to obtain optimal parameters, controlling of the accuracy of the measured dose values may be possible by calculating the dose value during quality control tests.

In radiography, dose and image quality are dependent on radiographic parameters. This study is concerned with the quantification of these parameters and an assessment of their

levels that are obtained by applying the same parameter setting, can be compared.

control programmes to ensure a proper performance of the x-ray equipment.

be adequate for diagnosis and it must be obtained with low doses.

kVp Accuracy and Repeatability

X-ray Tube Output-kVp Relation

 Dose-kVp Linearity Test Dose-mAs Linearity Test

HVL (Half Value Layer)

control tests of x-ray equipments.

**2. Parameters of x-ray** 

The high energy of the x-ray spectrum is determined by the kilovoltage applied to the x-ray tube. The maximum photon energy is numerically equal to the maximum applied potential in kilovolts. The maximum photon energy is determined by the voltage during the exposure time. This value is generally referred as the kilovolt peak (kVp) and is one of the adjustable factors of x-ray equipment (Sprawls, 1987).

## **2.3 mAs**

The x-ray cathode is heated electrically by a current from a separate low voltage power supply. The output of this supply is controlled by the mA selector on the x-ray unit. Additionally, the duration of the x-ray exposure is controlled by the time selector. mAs is described by multiplying of these two values (mA x second) (Hendee et al., 1984).

### **2.4 Half Value Layer (HVL)**

Half value layer describes both the penetrating ability of specific radiations and the penetration through specific objects. HVL is the thickness of material that reduces the intensity of an x-ray beam by half, and is expressed in unit of distance (mm) (Sprawls, 1987).

## **2.5 Image quality**

The purpose of the radiographic image is to provide information about the medical condition of the patient. A quality image is one that provides all the information required for diagnosis of the patient's condition (Hendee et al., 1984).

Image quality is not a single factor but is described with beam alignment, collimation alignment, contrast and resolution. Contrast means differences in the form of gray scales or light intensities, whereas the resolution is a measure of its ability to differentiate between two objects a small distance apart; such that they appear distinct from one another.

An image is acceptable as qualified only if it has high resolution and high contrast.

## **3. Material and method**

The radiographic measurements were performed in ten stationary X-ray units in five hospitals. The X-ray units including: Siemens, Philips, Toshiba, General Electric and Shimadzu were participated in this study. The reason for chosing these x-ray units is that their age is between 5 and 7 years old and the machines have 3 phase generators, thus their HVL value is kept in a narrow range, such as between 3 and 3,2mmAl.

Dose Optimization for the Quality Control Tests of X-Ray Equipment 299

Test tool ETR1 (Iba Dosimetry, 2008) was used for image quality tests. The ETR1 is a multipurpose test tool. With a single exposure on X-ray film made by using this tool, all criterias

Before exposure, a cassette with x-ray film was placed on the patient table. The distance between the film and the focal spot was set to 100cm. The test tool was placed over the cassette and the collimator was adjusted to ensure that the light beam covers exactly the inner pattern of the test tool. An exposure was performed with 50kVp and 20mAs. The exposure was repeated for each setting value adjusted for dose measurements mentioned in

After developing the film, the image on the film was compared with the real test tool image. Beam alignment, collimation alignment, contrast and resolution factors were determined

During the quality control of x-ray equipment, it is essential to know the effects of x-ray parameters to the image quality. The x-ray parameters' effects were measured by using

In result, the optimized dose in which parameters' value gave the high quality image was

The measured doses by changing kVp are given in Table 1. During measurements, mAs was firstly kept stable (20mAs) and kVp was changed as 50, 70, 80 and 100kVp to investigate the

After this, the same measurement procedure was applied to other mAs values (40 and

Graphical representations of the relationship between dose and kVp value for constant mAs (20, 40 and 50mAs) at 100cm and 60cm are given in Fig. 1, 2, 3 and Fig. 4, 5, 6, respectively.

Fig. 1. Measured dose values of 10 x-ray units versus kVp for 20mAs at distance of 100cm.

(alignments, contrast and resolution) can be checked for quality control of image.

Section 3.1 and 3.2 (50kVp-40mAs, 50mAs; 70kVp-20mAs, 40mAs, 50mAs; etc…).

quality control test procedures and they were analysed graphically.

50mAs). All measurements were performed at distance of 100 and 60cm.

**4.1 Assessment of X-ray dose variation with kVp** 

effects of kVp to the dose at stable mAs.

**3.5 Observing of image quality** 

and recorded.

**4. Results** 

determined.

Dosimax Plus A (Wellhöfer, Scanditronix, IBA, Germany) dosimeter was used to measure radiation dose. Dosimax Plus A dosimeter is a universal basic device and is designed according to IEC 61674 for acceptance tests and for quality checks at radiographic X-ray units. In Dosimax Plus A, dose measurements are performed by using solid state detectors (RQA). The dose range is from 200nGy to 9999mGy (Iba Dosimetry, 2008). It was calibrated by the Iba Laboratory of Germany and found to be capable of performing within recommended level of precision and accuracy.

Dose measurement applications has been included in recent recommendations (AAPM, 1981; IEC 61223-3-1, 1999). The measurement procedures that were realized in this study, are explained below step by step.

Before starting dose measurements, kVp accuracy tests were performed for 10 units and it was seen that they have acceptable accuracy in according to the standards (AAPM, 2002).

### **3.1 Measurement procedure of X-ray dose variation with kVp**

The dosimeter was positioned in central beam axis such that the X-ray tube focal spotdedector distance (FDD) was 100cm for the measurements. The radiation field size was set to cover the dosimeter in order to avoid the possible scatter radiation to the dosimeter.

In order to investigate the effect of kVp to the dose, the unit was set at 20mAs and 50kVp value. An X-ray exposure was made and the dosimeter reading was recorded. This step was repeated at same constant mAs and different kVp settings (50, 70, 80 and 100kVp) and dosimeter reading was determined. Similar X-ray dose measurements were also determined for 40 and 50mAs settings for each kVp value (50, 70, 80 and 100kVp). All measurements were repeated for 60cm (FDD). The measured dose values were plotted against the corresponding kVp for each X-ray unit separately.

#### **3.2 Measurement procedure of X-ray dose variation with mAs**

The dosimeter was positioned at 100cm (FDD) from the focal spot of the X-ray tube.

In order to determine the effect of mAs to the dose, the exposures were performed with constant kVp (50kVp), but with gradually increasing mAs (10, 20, 40 and 50mAs). Similar X-ray dose measurements were also determined for 70 and 100kVp settings for each mAs value (10, 20, 40 and 50mAs). All measurements were repeated for distance of 60cm. The measurement results for each X-ray unit were plotted against the corresponding mAs.

#### **3.3 Measurement procedure of X-ray tube output variation with kVp**

The X-ray tube output was determined as the ratio of dose reading to the mAs setting. The values of X-ray tube output were plotted against kVp by using dose values obtained from two measurement procedures (Section 3.1 and 3.2).

#### **3.4 Measurement procedure for Half Value Layer (HVL)**

For dose measurements, filtration was realized by using aluminum (Al) filters with 1mm and 0,5mm.

During the measurements, mAs and kVp were stable (20mAs, 50kVp) and the distance was determined as 100cm. Initially, the dose measurement without the filter was generalized. After this, the dose measurement was repeated by using filter with different thickness. Each filter thickness was obtained by adding 1mmAl and 0,5mmAl. The dose measurements were taken in the conditions; without filter, 1mmAl, 2mmAl, 3mmAl and 3,5mmAl.

#### **3.5 Observing of image quality**

Test tool ETR1 (Iba Dosimetry, 2008) was used for image quality tests. The ETR1 is a multipurpose test tool. With a single exposure on X-ray film made by using this tool, all criterias (alignments, contrast and resolution) can be checked for quality control of image.

Before exposure, a cassette with x-ray film was placed on the patient table. The distance between the film and the focal spot was set to 100cm. The test tool was placed over the cassette and the collimator was adjusted to ensure that the light beam covers exactly the inner pattern of the test tool. An exposure was performed with 50kVp and 20mAs. The exposure was repeated for each setting value adjusted for dose measurements mentioned in Section 3.1 and 3.2 (50kVp-40mAs, 50mAs; 70kVp-20mAs, 40mAs, 50mAs; etc…).

After developing the film, the image on the film was compared with the real test tool image. Beam alignment, collimation alignment, contrast and resolution factors were determined and recorded.

## **4. Results**

298 Modern Approaches To Quality Control

Dosimax Plus A (Wellhöfer, Scanditronix, IBA, Germany) dosimeter was used to measure radiation dose. Dosimax Plus A dosimeter is a universal basic device and is designed according to IEC 61674 for acceptance tests and for quality checks at radiographic X-ray units. In Dosimax Plus A, dose measurements are performed by using solid state detectors (RQA). The dose range is from 200nGy to 9999mGy (Iba Dosimetry, 2008). It was calibrated by the Iba Laboratory of Germany and found to be capable of performing within

Dose measurement applications has been included in recent recommendations (AAPM, 1981; IEC 61223-3-1, 1999). The measurement procedures that were realized in this study, are

Before starting dose measurements, kVp accuracy tests were performed for 10 units and it was seen that they have acceptable accuracy in according to the standards (AAPM, 2002).

The dosimeter was positioned in central beam axis such that the X-ray tube focal spotdedector distance (FDD) was 100cm for the measurements. The radiation field size was set to cover the dosimeter in order to avoid the possible scatter radiation to the dosimeter. In order to investigate the effect of kVp to the dose, the unit was set at 20mAs and 50kVp value. An X-ray exposure was made and the dosimeter reading was recorded. This step was repeated at same constant mAs and different kVp settings (50, 70, 80 and 100kVp) and dosimeter reading was determined. Similar X-ray dose measurements were also determined for 40 and 50mAs settings for each kVp value (50, 70, 80 and 100kVp). All measurements were repeated for 60cm (FDD). The measured dose values were plotted against the

recommended level of precision and accuracy.

corresponding kVp for each X-ray unit separately.

two measurement procedures (Section 3.1 and 3.2).

and 0,5mm.

**3.4 Measurement procedure for Half Value Layer (HVL)** 

**3.1 Measurement procedure of X-ray dose variation with kVp** 

**3.2 Measurement procedure of X-ray dose variation with mAs** 

**3.3 Measurement procedure of X-ray tube output variation with kVp** 

The dosimeter was positioned at 100cm (FDD) from the focal spot of the X-ray tube.

In order to determine the effect of mAs to the dose, the exposures were performed with constant kVp (50kVp), but with gradually increasing mAs (10, 20, 40 and 50mAs). Similar X-ray dose measurements were also determined for 70 and 100kVp settings for each mAs value (10, 20, 40 and 50mAs). All measurements were repeated for distance of 60cm. The measurement results for each X-ray unit were plotted against the corresponding mAs.

The X-ray tube output was determined as the ratio of dose reading to the mAs setting. The values of X-ray tube output were plotted against kVp by using dose values obtained from

For dose measurements, filtration was realized by using aluminum (Al) filters with 1mm

During the measurements, mAs and kVp were stable (20mAs, 50kVp) and the distance was determined as 100cm. Initially, the dose measurement without the filter was generalized. After this, the dose measurement was repeated by using filter with different thickness. Each filter thickness was obtained by adding 1mmAl and 0,5mmAl. The dose measurements were

taken in the conditions; without filter, 1mmAl, 2mmAl, 3mmAl and 3,5mmAl.

explained below step by step.

During the quality control of x-ray equipment, it is essential to know the effects of x-ray parameters to the image quality. The x-ray parameters' effects were measured by using quality control test procedures and they were analysed graphically.

In result, the optimized dose in which parameters' value gave the high quality image was determined.

## **4.1 Assessment of X-ray dose variation with kVp**

The measured doses by changing kVp are given in Table 1. During measurements, mAs was firstly kept stable (20mAs) and kVp was changed as 50, 70, 80 and 100kVp to investigate the effects of kVp to the dose at stable mAs.

After this, the same measurement procedure was applied to other mAs values (40 and 50mAs). All measurements were performed at distance of 100 and 60cm.

Graphical representations of the relationship between dose and kVp value for constant mAs (20, 40 and 50mAs) at 100cm and 60cm are given in Fig. 1, 2, 3 and Fig. 4, 5, 6, respectively.

Fig. 1. Measured dose values of 10 x-ray units versus kVp for 20mAs at distance of 100cm.

Dose Optimization for the Quality Control Tests of X-Ray Equipment 301

Fig. 2. Measured dose values of 10 x-ray units versus kVp for 40mAs at distance of 100cm.

Fig. 3. Measured dose values of 10 x-ray units versus kVp for 50mAs at distance of 100cm.

Fig. 4. Measured dose values of 10 x-ray units versus kVp for 20mAs at distance of 60cm.


Table 1. Measured doses (µGy) for constant mAs but increasing kVp at different distances.

**Dose (µGy)** 

**Unit 50 kVp 70 kVp 80 kVp 100 kVp 50 kVp 70 kVp 80 kVp 100 kVp** 

736,0 1439 1766 2420 1950 4230 5450 8050 710,7 1388 1707 2357 1883 3955 5243 7588 824,3 1538 1866 2538 2327 4640 5905 8608 894,4 1605 1935 2601 2478 4915 6181 8909 690,4 1324 1642 2282 1554 3717 4981 7268 1048 1734 2101 2757 3310 5758 7006 9498 792,1 1481 1826 2483 2077 4353 5627 8277 988,4 1704 2070 2726 2999 5477 6722 9300 934,7 1657 2017 2652 2796 5157 6445 9062 1101 1784 2136 2792 3484 5872 7195 9741

1482 2938 3622 5056 4190 8260 10800 15600

1493 2863 3580 4912 3774 7983 10511 15123 1587 3129 3797 5276 4511 8588 11383 15515 1600 3136 3872 5335 4684 8981 11515 16089 1400 2738 3460 4861 3464 7613 10099 14656 1923 3461 4207 5716 5468 10097 12415 17247 1528 3082 3702 5185 4271 8716 10984 15797 1858 3335 4104 5561 5249 9773 12037 16986 1692 3290 3946 5405 4870 9408 11788 16487 2053 3581 4320 5855 5805 10618 12869 17610

1790 3612 4590 6380 5350 12548 15800 22700

1722 3443 4384 6194 4991 12168 15553 22313 1933 3678 4609 6608 6144 13528 15973 23548 1985 3697 4481 6652 6588 13249 16348 23704 1604 3345 4185 6008 4585 11712 15033 21972 2245 4020 4965 6995 8101 14631 17750 24808 1853 3665 4575 6518 5574 12999 15799 23255 2198 3813 4759 6823 7623 14240 17234 24484 2091 3799 4691 6712 7064 13751 16857 23892 2391 4213 5167 7194 8724 15027 18203 25283

Table 1. Measured doses (µGy) for constant mAs but increasing kVp at different distances.

**60cm - 20mAs** 

**60cm - 40mAs** 

**60cm - 50mAs** 

**100cm - 20mAs** 

**100cm - 40mAs** 

**100cm - 50mAs** 

Fig. 2. Measured dose values of 10 x-ray units versus kVp for 40mAs at distance of 100cm.

Fig. 3. Measured dose values of 10 x-ray units versus kVp for 50mAs at distance of 100cm.

Fig. 4. Measured dose values of 10 x-ray units versus kVp for 20mAs at distance of 60cm.

Dose Optimization for the Quality Control Tests of X-Ray Equipment 303

The dose values obtained from 10 x-ray units were analysed statistically and the mean dose

For different distance and mAs settings, the mean dose values were plotted against kVp (Fig. 7). Hence, the small differences that are caused from unit changes were eliminated, and

**(µGy) 50kVp 70kVp 80kVp 100kVp 50kVp 70kVp 80kVp 100kVp Mean** 872,0 1565,4 1906,5 2560,7 2485,8 4807,5 6075,5 8630,2 **std** 144,3 155,9 172,4 174,8 645,3 753,0 760,0 823,6

**(µGy) 50kVp 70kVp 80kVp 100kVp 50kVp 70kVp 80kVp 100kVp Mean** 1661,6 3155,3 3861,1 5316,0 4628,7 9003,7 11440,1 16110,9 **std** 215,4 266,5 283,4 329,3 742,1 962,9 866,6 957,6

**(µGy) 50kVp 70kVp 80kVp 100kVp 50kVp 70kVp 80kVp 100kVp Mean** 1981,3 3728,4 4640,7 6608,4 6474,2 13385,3 16455,0 23595,8 **std** 249,7 254,1 280,0 356,4 1387,9 1069,0 1024,1 1075,5

The obtained dose values at constant kVp by increasing mAs can be seen in Table 3. The dose measurements were performed at 50, 70 and 100kVp with changing mAs (10, 20, 40

Graphical representations of the relationship between dose and mAs for constant kVp (50, 70 and 100kVp) at 100 and 60cm are shown in Fig. 8, 9, 10 and Fig. 11, 12, 13, respectively.

Fig. 8. Measured dose values of 10 x-ray units versus mAs for 50kVp at distance of 100cm.

values for each setting parameter were defined with standard deviation in Table 2.

**Dose 100cm - 20mAs 60cm - 20mAs** 

**Dose 100cm - 40mAs 60cm - 40mAs** 

**Dose 100cm - 50mAs 60cm - 50mAs** 

Table 2. The statistic analysis of dose from 10 units for different kVp at constant mAs.

the effect of kVp to dose variation was focused.

**4.2 Assessment of X-ray dose variation with mAs** 

and 50mAs) in distance of 100 and 60cm.

Fig. 5. Measured dose values of 10 x-ray units versus kVp for 40mAs at distance of 60cm.

Fig. 6. Measured dose values of 10 x-ray units versus kVp for 50mAs at distance of 60cm.

Fig. 7. Mean dose values of 10 x-ray units versus kVp for different mAs and distance setting.

Fig. 5. Measured dose values of 10 x-ray units versus kVp for 40mAs at distance of 60cm.

Fig. 6. Measured dose values of 10 x-ray units versus kVp for 50mAs at distance of 60cm.

Fig. 7. Mean dose values of 10 x-ray units versus kVp for different mAs and distance setting.

The dose values obtained from 10 x-ray units were analysed statistically and the mean dose values for each setting parameter were defined with standard deviation in Table 2.

For different distance and mAs settings, the mean dose values were plotted against kVp (Fig. 7). Hence, the small differences that are caused from unit changes were eliminated, and the effect of kVp to dose variation was focused.


Table 2. The statistic analysis of dose from 10 units for different kVp at constant mAs.

#### **4.2 Assessment of X-ray dose variation with mAs**

The obtained dose values at constant kVp by increasing mAs can be seen in Table 3. The dose measurements were performed at 50, 70 and 100kVp with changing mAs (10, 20, 40 and 50mAs) in distance of 100 and 60cm.

Graphical representations of the relationship between dose and mAs for constant kVp (50, 70 and 100kVp) at 100 and 60cm are shown in Fig. 8, 9, 10 and Fig. 11, 12, 13, respectively.

Fig. 8. Measured dose values of 10 x-ray units versus mAs for 50kVp at distance of 100cm.

Dose Optimization for the Quality Control Tests of X-Ray Equipment 305

Fig. 9. Measured dose values of 10 x-ray units versus mAs for 70kVp at distance of 100cm.

Fig. 10. Measured dose values of 10 x-ray units versus mAs for 100kVp at distance of 100cm.

Fig. 11. Measured dose values of 10 x-ray units versus mAs for 50kVp at distance of 60cm.


Table 3. Measured doses (µGy) for constant kVp but increasing mAs at different distances.

**Dose (µGy)** 

**Unit 10 mAs 20 mAs 40 mAs 50 mAs 10 mAs 20 mAs 40 mAs 50 mAs** 

378,0 736,0 1432 1810 1050 2089 4188 5120 339,8 695,4 1397 1773 932 1940 4056 5075 402,2 796,4 1527 1886 1202 2231 4276 5245 464,0 786,5 1554 1911 1247 2333 4329 5394 321,1 632,5 1344 1717 826 1846 3975 5026 565,8 934,5 1688 2068 1494 2532 4680 5715 370,2 712,0 1483 1834 1123 2152 4245 5206 530,9 879,0 1641 2006 1342 2402 4516 5657 510,4 844,6 1610 1952 1272 2342 4447 5551 606,9 987,6 1711 2091 1597 2614 4801 5862

714,4 1469 2871 3652 2310 4180 8140 10077

641,8 1372 2787 3528 2187 4040 7966 9846 801,0 1618 3055 3874 2604 4401 8428 10480 874,9 1687 3180 3902 2799 4675 8672 10585 574,9 1292 2683 3414 1993 3828 7692 9613 1001 1881 3401 4157 3317 5186 9123 10959 754,2 1558 2955 3773 2580 4309 8359 10228 987,4 1764 3387 4084 3221 4956 8972 10745 956,6 1718 3292 3952 2989 4936 8832 10645 1075 1926 3515 4219 3503 5387 9280 11210

1404 2808 5616 7020 3250 7288 15435 19426

1198 2623 5387 6819 3006 6870 14811 18926 1641 2927 5751 7255 3870 8097 15872 20058 1690 2922 5964 7285 4278 8296 16080 20415 1045 2444 5308 6622 2421 6342 14354 18465 1854 3182 6215 7558 4940 8955 17157 21594 1582 2885 5703 7131 3537 7601 15343 19500 1797 3060 6070 7429 4509 8735 17102 21306 1717 3055 6070 7407 4448 8584 16399 20958 1889 3343 6266 7638 5290 9310 17697 21944

Table 3. Measured doses (µGy) for constant kVp but increasing mAs at different distances.

**60cm - 50kVp** 

**60cm - 70kVp** 

**60cm - 100kVp** 

**100cm - 50kVp** 

**100cm - 70kVp** 

**100cm - 100kVp** 

Fig. 9. Measured dose values of 10 x-ray units versus mAs for 70kVp at distance of 100cm.

Fig. 10. Measured dose values of 10 x-ray units versus mAs for 100kVp at distance of 100cm.

Fig. 11. Measured dose values of 10 x-ray units versus mAs for 50kVp at distance of 60cm.

Dose Optimization for the Quality Control Tests of X-Ray Equipment 307

The dose values obtained from 10 x-ray units were analysed statistically and the mean dose

For different distance and kVp settings, the mean dose values were plotted against mAs (Fig. 14). Hence, the small differences that are caused from unit changes were eliminated,

**(µGy) 10mAs 20mAs 40mAs 50mAs 10mAs 20mAs 40mAs 50mAs Mean** 448,9 800,5 1538,6 1904,9 1208,4 2248,1 4351,4 5385,1 **std** 100,5 111,8 125,0 125,0 238,3 246,1 262,3 295,3

**(µGy) 10mAs 20mAs 40mAs 50mAs 10mAs 20mAs 40mAs 50mAs Mean** 838,2 1628,5 3112,6 3855,6 2750,4 4589,7 8546,2 10438,6 **std** 167,4 208,6 285,7 266,1 526,1 518,1 519,6 498,2

**(µGy) 10mAs 20mAs 40mAs 50mAs 10mAs 20mAs 40mAs 50mAs Mean** 1581,7 2924,9 5835,1 7216,4 3954,8 8008,0 16025,0 20259,2 **std** 281,9 261,2 334,7 322,8 903,1 960,3 1079,2 1180,2

In order to investigate the relationship between the x-ray tube output and kVp, firstly the xray tube outputs for 10 x-ray units, were calculated by dividing the measured dose values to the mAs values. It was seen that there is a dose distribution because of the measured different doses of each x-ray unit. Therefore, the mean of the x-ray tube output values for

Additionally, the graphics show that there is a different distribution that are caused from

For each different distance, the mean of the calculated tube output for different mAs were

Fig. 15. X-ray tube output changes with kVp (dose values from procedure in Section 3.1).

values for each setting parameter were defined with standard deviation in Table 4.

**Dose 100cm - 50kVp 60cm - 50kVp** 

**Dose 100cm - 70kVp 60cm - 70kVp** 

**Dose 100cm - 100kVp 60cm - 100kVp** 

Table 4. The statistic analysis of dose from 10 units for different mAs at constant kVp.

each mAs values were used for plotting of the x-ray tube output against the kVp.

different distances although all distributions were similar for each mAs value.

and the effect of mAs to dose variation was focused.

**4.3 Assessment of X-ray tube output variation with kVp** 

plotted with equations.

Fig. 12. Measured dose values of 10 x-ray units versus mAs for 70kVp at distance of 60cm.

Fig. 13. Measured dose values of 10 x-ray units versus mAs for 100kVp at distance of 60cm.

Fig. 14. Mean dose values of 10 x-ray units versus mAs for different kVp and distances.

Fig. 12. Measured dose values of 10 x-ray units versus mAs for 70kVp at distance of 60cm.

Fig. 13. Measured dose values of 10 x-ray units versus mAs for 100kVp at distance of 60cm.

Fig. 14. Mean dose values of 10 x-ray units versus mAs for different kVp and distances.

The dose values obtained from 10 x-ray units were analysed statistically and the mean dose values for each setting parameter were defined with standard deviation in Table 4.

For different distance and kVp settings, the mean dose values were plotted against mAs (Fig. 14). Hence, the small differences that are caused from unit changes were eliminated, and the effect of mAs to dose variation was focused.


Table 4. The statistic analysis of dose from 10 units for different mAs at constant kVp.

## **4.3 Assessment of X-ray tube output variation with kVp**

In order to investigate the relationship between the x-ray tube output and kVp, firstly the xray tube outputs for 10 x-ray units, were calculated by dividing the measured dose values to the mAs values. It was seen that there is a dose distribution because of the measured different doses of each x-ray unit. Therefore, the mean of the x-ray tube output values for each mAs values were used for plotting of the x-ray tube output against the kVp.

Additionally, the graphics show that there is a different distribution that are caused from different distances although all distributions were similar for each mAs value.

For each different distance, the mean of the calculated tube output for different mAs were plotted with equations.

Fig. 15. X-ray tube output changes with kVp (dose values from procedure in Section 3.1).

Dose Optimization for the Quality Control Tests of X-Ray Equipment 309

selected. kVp and mAs values were plugged into the Equations 3, 4, and Equations 7, 8 to predict the dose values for applied kVp and mAs values of measurement procedures (Section 3.1 and 3.2). The results were then compared with the measured dose values, as

It is seen from Table 5, the predicted dose values are within the measured dose value with standard deviations for each measurement procedure (in different distance, firstly constant mAs with increasing kVp, afterly constant kVp with increasing mAs). The predicted dose values obtained from equations that shows the relationship between x-ray tube output and kVp during measurement procedure (mAs is increased with constant kVp), are approximately similar with the predicted dose values that were derived from measurement procedure of constant mAs and increasing kVp. Relatively it can be said that dose measurements are not affected from the application style of parameters (kVp and mAs). Not only keeping mAs as constant and increasing kVp, but also keeping kVp as constant and increasing mAs doesn't affect the measured dose values for the same kVp and mAs. For example, the dose value obtained from measurement of 50kVp-40mAs are approximately similar during application of both constant 50kVp with increasing mAs and constant 40mAs with increasing kVp. This result showed that taking into account the results that were obtained from only one measurement procedure is sufficient. Especially, Equation 3 and

> **Dose calculated from Equation 3 (µGy)**

**Dose calculated from Equation 7 (µGy)**

**Dose calculated from Equation 4 (µGy)** 

**Dose calculated from Equation 8 (µGy)**

Equation 7 can be preferred for dose estimation because of their best R2.

**Mean dose from direct measurement (µGy)** 

**Mean dose from direct measurement (µGy)**

**10mAs-50kVp** 448,9 ± 100,5 415,39 377,84 **10mAs-70kVp** 838,2 ± 167,4 773,25 805,76 **10mAs-100kVp** 1581,7 ± 281,9 1310,04 1447,64

**10mAs-50kVp** 1208,4 ± 238,3 1217,2 1059,60 **10mAs-70kVp** 2750,4 ± 526,1 2468,08 2234,24 **10mAs-100kVp** 3954,8 ± 903,1 4344,4 3996,20

Testing of half value layer is performed by measuring dose values with different Al thickness and it verifies that half value layer is sufficient to reduce patient exposure to low energy radiation. The obtained dose measurement results of each x-ray unit in this study for

The dose measurement results were plotted against the aluminum (Al) thickness (Fig. 17). Dose (µGy) equations were obtained as a function of Al thickness and from these equations, the Al thickness in which the dose decreased to its half value was calculated (Table 7).

shown in Table 5.

**Distance 100cm**

**Distance 60cm** 

Table 5. Measured and calculated dose values.

**4.4 Assessment of Half Value Layer (HVL)** 

stable mAs and kVp are given in Table 6.

In Figure 15, the dose values that were obtained by applying the procedure mentioned in Section 3.1 and the procedure settings (mAs, kVp), were plotted, whereas in Figure 16 the values obtained from procedure in section 3.2, were used.

Fig. 16. X-ray tube output changes with kVp (dose values from procedure in Section 3.2).

The tube output which is derived from direct measurement can be expressed in equations obtained from Figure 15 and Figure 16, because kVp is related to tube output directly. For distance of 100cm, tube output can be written separately in different two equations that were obtained from graphics in Fig. 15 and Fig. 16.

$$\text{Tube output (\mu Gy/mAs)} = 1,7893 \text{kVp - 47,926} \qquad \text{R2} = 1 \tag{1}$$

$$\text{Tube output (\mu Gy/mAs)} = 2,1396\text{kVp - 69,196} \qquad \mathbb{R}^2 = 0,9992\tag{2}$$

Dose can be determined from tube output, and mAs can be placed in Equations 1 and 2.

$$\text{Dose } (\mu \text{Gy}) = (1,7893 \text{kVp} - 47,926) \times \text{mAs} \tag{3}$$

$$\text{Dose } (\mu \text{Gy}) = (2, 1396 \text{kVp } -69, 196) \times \text{mAs} \tag{4}$$

For distance of 60 cm, again tube output can be written separately in different two equations obtained from Figure 15 and Figure 16, respectively.

$$\text{Table output (\mu Gy/mAs)} = 6,2544\text{kVp - 191,0} \quad \text{R}^2 = 0,9998 \tag{5}$$

$$\text{Tube output (\mu Gy/mAs)} = 5,8732 \text{kVp} - 187.7 \qquad \text{R2} = 0,9987 \tag{6}$$

When mAs is placed in Equations 5 and 6, the following Equations 7 and 8 are derived.

$$\text{Dose } (\mu \text{Gy}) = (6, 2544 \text{kVp } -191, 0) \times \text{mAs} \tag{7}$$

$$\text{Dose } (\mu\text{Gy}) = (5.8732\,\text{kVp} - 187.7) \times \text{mAs} \tag{8}$$

To test the validity of these equations, an external set of dose values obtained from measurements (10mAs-50kVp, 10mAs-70kVp and 10mAs-100kVp for 100cm and 60cm) was

In Figure 15, the dose values that were obtained by applying the procedure mentioned in Section 3.1 and the procedure settings (mAs, kVp), were plotted, whereas in Figure 16 the

Fig. 16. X-ray tube output changes with kVp (dose values from procedure in Section 3.2).

The tube output which is derived from direct measurement can be expressed in equations obtained from Figure 15 and Figure 16, because kVp is related to tube output directly. For distance of 100cm, tube output can be written separately in different two equations that

Tube output (µGy/mAs) = 2,1396kVp – 69,196 R2 = 0,9992 (2)

For distance of 60 cm, again tube output can be written separately in different two equations

Tube output (µGy/mAs) = 5,8732kVp – 187,7 R2 = 0,9987 (6)

Dose (µGy) = (6,2544kVp – 191,0) × mAs (7)

 Dose (µGy) = (5,8732kVp – 187,7) × mAs (8) To test the validity of these equations, an external set of dose values obtained from measurements (10mAs-50kVp, 10mAs-70kVp and 10mAs-100kVp for 100cm and 60cm) was

When mAs is placed in Equations 5 and 6, the following Equations 7 and 8 are derived.

Dose can be determined from tube output, and mAs can be placed in Equations 1 and 2.

Tube output (µGy/mAs) = 1,7893kVp – 47,926 R2 = 1 (1)

Dose (µGy) = (1,7893kVp – 47,926) × mAs (3)

Dose (µGy) = (2,1396kVp – 69,196) × mAs (4)

Tube output (µGy/mAs) = 6,2544kVp – 191,0 R2 = 0,9998 (5)

values obtained from procedure in section 3.2, were used.

were obtained from graphics in Fig. 15 and Fig. 16.

obtained from Figure 15 and Figure 16, respectively.

selected. kVp and mAs values were plugged into the Equations 3, 4, and Equations 7, 8 to predict the dose values for applied kVp and mAs values of measurement procedures (Section 3.1 and 3.2). The results were then compared with the measured dose values, as shown in Table 5.

It is seen from Table 5, the predicted dose values are within the measured dose value with standard deviations for each measurement procedure (in different distance, firstly constant mAs with increasing kVp, afterly constant kVp with increasing mAs). The predicted dose values obtained from equations that shows the relationship between x-ray tube output and kVp during measurement procedure (mAs is increased with constant kVp), are approximately similar with the predicted dose values that were derived from measurement procedure of constant mAs and increasing kVp. Relatively it can be said that dose measurements are not affected from the application style of parameters (kVp and mAs). Not only keeping mAs as constant and increasing kVp, but also keeping kVp as constant and increasing mAs doesn't affect the measured dose values for the same kVp and mAs. For example, the dose value obtained from measurement of 50kVp-40mAs are approximately similar during application of both constant 50kVp with increasing mAs and constant 40mAs with increasing kVp. This result showed that taking into account the results that were obtained from only one measurement procedure is sufficient. Especially, Equation 3 and Equation 7 can be preferred for dose estimation because of their best R2.


Table 5. Measured and calculated dose values.

### **4.4 Assessment of Half Value Layer (HVL)**

Testing of half value layer is performed by measuring dose values with different Al thickness and it verifies that half value layer is sufficient to reduce patient exposure to low energy radiation. The obtained dose measurement results of each x-ray unit in this study for stable mAs and kVp are given in Table 6.

The dose measurement results were plotted against the aluminum (Al) thickness (Fig. 17). Dose (µGy) equations were obtained as a function of Al thickness and from these equations, the Al thickness in which the dose decreased to its half value was calculated (Table 7).

Dose Optimization for the Quality Control Tests of X-Ray Equipment 311

**Unit Dose (µGy) = f(Al (mm)) Calculated HVL (mm)** 

As it is seen from the table, the observed x-ray units' HVL values change from 3,0 to 3,2 mmAl. Because it is required that the HVL of an acceptable x-ray unit with 3 phase generator must exceed 2,9mm, the observed 10 x-ray units were appropriate to the

Image quality tests were performed by controlling of beam alignment, collimation

As a result of the beam aligment and collimation alignment tests, it was seen that beam alignment and collimation alignment are only related to the quality of x-ray tube, are not dependent to the x-ray parameters, such as kVp, mAs and dose. For this reason, the test results that were obtained from only one measurement setting (50kVp, 20mAs, 100cm), are

Beam alignment test gives the deviation of the centre from the middle of the exposed film to the middle of the test tool (point "a" in Figure 18). The test's results that were given in Table

In the collimation alignment test, the vertical misalignment was defined as the sum of the deviation of the top and bottom edges, horizontal as the sum of the deviation of the right and left edges (point "b" in Figure 18). In according to the international standards, the misalignment must each be less than 25mm (AAPM, 1981). As it is seen from Table 8, all

For the measurement of the resolution, parallel lead strips separated by a distance equal to the width of the strips, that are placed on the test tool (point "c" in Figure 18) were used. The common practice is to describe the line width and separation distance in terms of line pairs (lp) per unit distance (millimeters) (Lp/mm). One line pair consists of one lead strip and adjacent separation space. The number of line pairs per millimeter is actually an expression of spatial frequency. As the lines get smaller and closer together, the spatial frequency increases (Sprawls, 1987). The test pattern contains areas with different spatial frequencies. To evaluate an imaging system, the visible line group is recorded as line pairs per mm. In according to the international standards, resolution below 0,8Lp/mm is not acceptable (AAPM, 1981). The obtained test results in this study, are shown in Table 9.

sufficient to obtain information about alignments of each x-ray units (Table 8).

8 show that the beam misalignments were less than 10mm for 10 x-ray units.

misalignmenst for 10 units are appropriate to the standards.

y = 693,18 e-0,208x R2 = 0,9714 3,0 y = 678,13 e-0,204x R2 = 0,9819 3,1 y = 811,49 e-0,212x R2 = 0,9979 3,2 y = 848,79 e-0,208x R2 = 0,9775 3,1 y = 658,65 e-0,207x R2 = 0,9812 3,1 y = 1002,5 e-0,211x R2 = 0,9830 3,1 y = 769,50 e-0,220x R2 = 0,9940 3,0 y = 929,33 e-0,212x R2 = 0,9723 3,0 y = 907,66 e-0,219x R2 = 0,9939 3,0 y = 1035,5 e-0,212x R2 = 0,9722 3,0

Table 7. Dose=*f*(Al) equations and calculated HVL values.

international standards (AAPM, 1981).

alignment, contrast and resolution of image.

**4.5 Image quality** 


Table 6. Dose measurements for different aluminum thickness (mm).

Fig. 17. Al(mm)-Dose(µGy) graphic for each X-ray unit.


Table 7. Dose=*f*(Al) equations and calculated HVL values.

As it is seen from the table, the observed x-ray units' HVL values change from 3,0 to 3,2 mmAl. Because it is required that the HVL of an acceptable x-ray unit with 3 phase generator must exceed 2,9mm, the observed 10 x-ray units were appropriate to the international standards (AAPM, 1981).

#### **4.5 Image quality**

310 Modern Approaches To Quality Control

kVp = 50, mAs = 20, Distance = 100cm

736,0 520,9 451,8 374,0 342,8 710,7 519,9 446,8 370,1 337,7 824,3 647,5 522,0 431,6 388,9 894,4 643,1 554,2 462,3 415,7 690,4 502,1 431,8 359,5 322,0 1047,8 767,3 654,0 524,1 493,8 792,1 598,8 485,7 401,8 360,0 988,0 702,1 588,9 499,6 454,9 934,7 704,2 577,1 474,8 425,2 1101,0 782,2 656,0 556,6 506,8

**0mmAl 1mmAl 2mmAl 3mmAl 4mmAl** 

**Unit Dose (µGy)** 

Table 6. Dose measurements for different aluminum thickness (mm).

Fig. 17. Al(mm)-Dose(µGy) graphic for each X-ray unit.

Image quality tests were performed by controlling of beam alignment, collimation alignment, contrast and resolution of image.

As a result of the beam aligment and collimation alignment tests, it was seen that beam alignment and collimation alignment are only related to the quality of x-ray tube, are not dependent to the x-ray parameters, such as kVp, mAs and dose. For this reason, the test results that were obtained from only one measurement setting (50kVp, 20mAs, 100cm), are sufficient to obtain information about alignments of each x-ray units (Table 8).

Beam alignment test gives the deviation of the centre from the middle of the exposed film to the middle of the test tool (point "a" in Figure 18). The test's results that were given in Table 8 show that the beam misalignments were less than 10mm for 10 x-ray units.

In the collimation alignment test, the vertical misalignment was defined as the sum of the deviation of the top and bottom edges, horizontal as the sum of the deviation of the right and left edges (point "b" in Figure 18). In according to the international standards, the misalignment must each be less than 25mm (AAPM, 1981). As it is seen from Table 8, all misalignmenst for 10 units are appropriate to the standards.

For the measurement of the resolution, parallel lead strips separated by a distance equal to the width of the strips, that are placed on the test tool (point "c" in Figure 18) were used. The common practice is to describe the line width and separation distance in terms of line pairs (lp) per unit distance (millimeters) (Lp/mm). One line pair consists of one lead strip and adjacent separation space. The number of line pairs per millimeter is actually an expression of spatial frequency. As the lines get smaller and closer together, the spatial frequency increases (Sprawls, 1987). The test pattern contains areas with different spatial frequencies. To evaluate an imaging system, the visible line group is recorded as line pairs per mm. In according to the international standards, resolution below 0,8Lp/mm is not acceptable (AAPM, 1981). The obtained test results in this study, are shown in Table 9.

Dose Optimization for the Quality Control Tests of X-Ray Equipment 313

As it is seen from Table 8, both beam alignments and collimation alignments of 10 x-ray units are appropriate to the international standards and there is no unwanted effect on the

Although beam alignment and collimation alignment are not dependent to the kVp and mAs value, resolution and contrast are directly related to these parameters. On Table 9, it is seen that resolution increases with increasing parameter setting values, especially with kVp. From Table 10, it can be said that contrast is good on the values of 70kVp, especially on 70kVp-40mAs for 10 x-ray units. At this value of parameters, all copper steps on the test tool can be seen definitely. While the values on the Table 10 decreases from 0,6 to 0,1, the

In this study, the x-ray units with ages between 5 and 7 years old were selected to prevent the wide distribution of measured dose because the x-ray tubes don't produce the same

Again, in this study, three phase generators were preferred because they produces more radiation exposure per unit mAs. This characteristic is essential for modeling of dose. A difference in tube output among tubes is often caused by variations in the filtration. For this reason, this study were performed on the x-ray units with HVL values that changes approximately from 3,0 to 3,1mmAl. It also prevented the wide distribution of measured dose. The obtained HVL values in this study are acceptable in according to the international

It is known that dose is more sensitive to the kVp changes than mAs changes. Exposure errors can occur if the actual kVp generated by the x-ray generator is different from the adjusting kVp value. Before dose measurements, kVp accuracy testing were performed correctly and it was seen that the kVp during exposure was the close within the acceptable

All dose measurements were performed at different distance of 100cm and 60cm. With this application, the distance effects on dose were investigated and it was used for dose

For dose measurements, two different measurement procedures were used. In the first procedure, mAs value was kept constant and kVp values were changed to investigate the dose variation with kVp. In the second procedure, kVp value was kept constant and mAs values were changed to investigate the dose variation with mAs. Thus, the effects of kVp

Because the x-ray units were selected in according to the criterias mentioned above, the measured dose values didn't show wide distribution for each measurement setup in all 10 xray units. In this condition, the mean of the dose values of 10 x-ray units for each measurement setup was used to show the tube output variations with kVp. Plotting of tube output to kVp (Figure 15 and 16) were performed by using dose values obtained from two different measurement procedures. By this way, it was seen that the tube output variations related to kVp were approximately similar at different mAs value. Hence, the mean

Modeling was realized twice for dose values at different distances of 100cm and 60cm, because the different variations were seen between measurement values obtained different distances. By using equations (Equation 3 and Equation 7) in the models related to the

contrast also decreases and the seeable points on the film loss step by step.

exposure and the output decreases with age of x-ray unit.

image quality.

**5. Discussion** 

standards (AAPM, 1981).

deviation to the selected kVp value.

and mAs were examined separately.

variations were used for modeling of dose.

modeling because of the inverse-square effect.

Evaluating the contrast was performed by looking at the copper step wedge from the test pattern that are placed on the test tool (point "d" in Figure 18). The visible copper step wedges were recorded in order to describe the resolution quality (Table 10). In according to the international standards, all copper steps have to be clearly visible (AAPM, 1981).

Fig. 18. ETR1 test tool used for image quality test.


Table 8. Beam alignment and collimation alignment test results.

As it is seen from Table 8, both beam alignments and collimation alignments of 10 x-ray units are appropriate to the international standards and there is no unwanted effect on the image quality.

Although beam alignment and collimation alignment are not dependent to the kVp and mAs value, resolution and contrast are directly related to these parameters. On Table 9, it is seen that resolution increases with increasing parameter setting values, especially with kVp. From Table 10, it can be said that contrast is good on the values of 70kVp, especially on 70kVp-40mAs for 10 x-ray units. At this value of parameters, all copper steps on the test tool can be seen definitely. While the values on the Table 10 decreases from 0,6 to 0,1, the contrast also decreases and the seeable points on the film loss step by step.

## **5. Discussion**

312 Modern Approaches To Quality Control

Evaluating the contrast was performed by looking at the copper step wedge from the test pattern that are placed on the test tool (point "d" in Figure 18). The visible copper step wedges were recorded in order to describe the resolution quality (Table 10). In according to

the international standards, all copper steps have to be clearly visible (AAPM, 1981).

**Unit Beam Alignment (mm) Collimation Alignment (mm) <sup>1</sup>**< 10mm OK Top: 3mm Bottom: 2mm Total: 5mm

**<sup>2</sup>**< 10mm OK Top: 5mm Bottom: 3mm Total: 8mm

**<sup>3</sup>**< 10mm OK Top: 1mm Bottom: 1mm Total: 2mm

**<sup>4</sup>**< 10mm OK Top: 3mm Bottom: 2mm Total: 5mm

**<sup>5</sup>**< 10mm OK Top: 2mm Bottom: 1mm Total: 3mm

**<sup>6</sup>**< 10mm OK Top: 6mm Bottom: 4mm Total: 10mm

**<sup>7</sup>**< 10mm OK Top: 2mm Bottom: 2mm Total: 4mm

**<sup>8</sup>**< 10mm OK Top: 4mm Bottom: 3mm Total: 7mm

**<sup>9</sup>**< 10mm OK Top: 5mm Bottom: 4mm Total: 9mm

**<sup>10</sup>**< 10mm OK Top: 7mm Bottom: 5mm Total: 12mm

Table 8. Beam alignment and collimation alignment test results.

Right: 1mm Left: 1mm Total: 2mm OK

**a**

**d**

**c**

**b**

Right: 3mm Left: 1mm Total: 4mm OK

Right: 2mm Left: 1mm Total: 3mm OK

Right: 2mm Left: 3mm Total: 5mm OK

Right: 2mm Left: 2mm Total: 4mm OK

Right: 3mm Left: 3mm Total: 6mm OK

Right: 3mm Left: 1mm Total: 4mm OK

Right: 1mm Left: 1mm Total: 2mm OK

Right: 2mm Left: 2mm Total: 4mm OK

Right: 4mm Left: 3mm Total: 7mm OK

Fig. 18. ETR1 test tool used for image quality test.

In this study, the x-ray units with ages between 5 and 7 years old were selected to prevent the wide distribution of measured dose because the x-ray tubes don't produce the same exposure and the output decreases with age of x-ray unit.

Again, in this study, three phase generators were preferred because they produces more radiation exposure per unit mAs. This characteristic is essential for modeling of dose.

A difference in tube output among tubes is often caused by variations in the filtration. For this reason, this study were performed on the x-ray units with HVL values that changes approximately from 3,0 to 3,1mmAl. It also prevented the wide distribution of measured dose. The obtained HVL values in this study are acceptable in according to the international standards (AAPM, 1981).

It is known that dose is more sensitive to the kVp changes than mAs changes. Exposure errors can occur if the actual kVp generated by the x-ray generator is different from the adjusting kVp value. Before dose measurements, kVp accuracy testing were performed correctly and it was seen that the kVp during exposure was the close within the acceptable deviation to the selected kVp value.

All dose measurements were performed at different distance of 100cm and 60cm. With this application, the distance effects on dose were investigated and it was used for dose modeling because of the inverse-square effect.

For dose measurements, two different measurement procedures were used. In the first procedure, mAs value was kept constant and kVp values were changed to investigate the dose variation with kVp. In the second procedure, kVp value was kept constant and mAs values were changed to investigate the dose variation with mAs. Thus, the effects of kVp and mAs were examined separately.

Because the x-ray units were selected in according to the criterias mentioned above, the measured dose values didn't show wide distribution for each measurement setup in all 10 xray units. In this condition, the mean of the dose values of 10 x-ray units for each measurement setup was used to show the tube output variations with kVp. Plotting of tube output to kVp (Figure 15 and 16) were performed by using dose values obtained from two different measurement procedures. By this way, it was seen that the tube output variations related to kVp were approximately similar at different mAs value. Hence, the mean variations were used for modeling of dose.

Modeling was realized twice for dose values at different distances of 100cm and 60cm, because the different variations were seen between measurement values obtained different distances. By using equations (Equation 3 and Equation 7) in the models related to the

Dose Optimization for the Quality Control Tests of X-Ray Equipment 315

**Contrast (mmCu)** 

**Unit 50kVp 70kVp 80kVp 100kVp 50kVp 70kVp 80kVp 100kVp** 

0,3 0,5 0,4 0,1 0,4 0,5 0,3 0,1 0,4 0,4 0,3 0,2 0,3 0,5 0,3 0,1 0,3 0,5 0,4 0,1 0,4 0,4 0,4 0,2 0,4 0,5 0,3 0,1 0,4 0,4 0,4 0,1 0,4 0,4 0,3 0,3 0,5 0,5 0,3 0,2 0,3 0,5 0,3 0,2 0,4 0,5 0,4 0,1 0,4 0,5 0,4 0,3 0,3 0,6 0,4 0,3 0,5 0,6 0,4 0,1 0,4 0,5 0,3 0,1 0,4 0,5 0,3 0,2 0,5 0,6 0,3 0,1 0,3 0,4 0,4 0,2 0,4 0,4 0,4 0,2

0,5 0,6 0,5 0,3 0,4 0,6 0,5 0,2

0,5 0,6 0,4 0,2 0,5 0,6 0,4 0,2 0,4 0,6 0,4 0,2 0,3 0,6 0,5 0,3 0,4 0,6 0,5 0,3 0,5 0,6 0,5 0,2 0,5 0,6 0,5 0,3 0,4 0,6 0,4 0,2 0,4 0,6 0,5 0,2 0,4 0,6 0,5 0,3 0,5 0,6 0,4 0,1 0,5 0,6 0,4 0,1 0,5 0,6 0,4 0,2 0,5 0,6 0,5 0,2 0,4 0,6 0,5 0,3 0,3 0,6 0,5 0,3 0,4 0,6 0,4 0,2 0,5 0,6 0,4 0,2

0,4 0,6 0,5 0,3 0,5 0,5 0,4 0,3

0,5 0,6 0,5 0,2 0,5 0,6 0,5 0,2 0,5 0,5 0,4 0,3 0,4 0,5 0,4 0,3 0,4 0,6 0,5 0,3 0,4 0,6 0,5 0,3 0,4 0,6 0,5 0,4 0,4 0,6 0,5 0,4 0,5 0,6 0,5 0,3 0,5 0,6 0,4 0,3 0,4 0,6 0,5 0,2 0,5 0,6 0,5 0,2 0,5 0,5 0,4 0,2 0,4 0,6 0,4 0,2 0,5 0,6 0,5 0,3 0,4 0,6 0,5 0,3 0,5 0,6 0,5 0,3 0,5 0,6 0,5 0,3 **60cm - 20mAs** 

**60cm - 40mAs** 

**60cm - 50mAs** 

**100cm - 20mAs** 

**100cm - 40mAs** 

**100cm - 50mAs** 

Table 10. Contrast test results for 10 x-ray units.


Table 9. Resolution test results for 10 x-ray units

**Resolution (Lp/mm)** 

**Unit 50kVp 70kVp 80kVp 100kVp 50kVp 70kVp 80kVp 100kVp** 

2,2 3,1 3,4 4,0 2,2 3,4 3,4 4,0 2,2 3,4 3,7 4,3 2,2 3,1 3,4 4,0 2,5 3,1 3,7 4,0 2,0 2,8 3,0 3,7 2,5 3,4 3,4 4,0 2,2 3,1 3,4 4,3 2,5 3,4 3,4 4,3 2,5 3,4 3,4 4,3 2,0 2,8 3,7 4,3 2,2 3,1 3,4 4,0 2,5 3,1 3,7 4,3 2,2 3,1 3,4 4,3 2,0 2,8 3,4 4,0 2,0 2,8 3,1 4,0 2,0 2,8 3,4 4,0 2,2 3,1 3,4 4,3 2,2 3,1 3,7 4,3 2,2 3,1 3,7 4,3

2,2 3,4 3,7 4,3 2,5 3,4 3,7 4,3

2,2 3,4 3,7 4,3 2,0 3,1 3,4 4,0 2,5 3,4 4,0 4,3 2,5 3,4 3,7 4,3 2,5 3,1 3,4 4,0 2,2 3,1 3,4 4,0 2,2 3,4 3,7 4,3 2,5 3,4 3,7 4,0 2,8 3,4 3,7 4,3 2,8 3,7 4,0 4,3 2,8 3,7 4,0 4,3 2,5 3,4 3,7 4,0 2,2 3,4 3,7 4,0 2,5 3,4 3,7 4,0 2,5 3,4 3,7 4,3 2,2 3,1 3,7 4,3 2,2 3,1 4,0 4,3 2,2 3,4 4,0 4,3

2,5 3,1 4,0 4,3 2,2 3,1 3,7 4,3

2,8 3,4 4,0 4,6 2,5 3,1 3,7 4,3 2,8 3,4 4,0 4,6 2,8 3,4 4,0 4,6 2,5 3,1 3,7 4,3 2,2 3,1 3,7 4,3 2,5 2,8 3,7 4,3 2,2 3,1 3,7 4,6 2,8 3,1 4,0 4,6 2,0 2,8 3,7 4,3 3,1 3,4 4,3 4,6 2,8 3,1 4,0 4,6 2,8 3,1 4,0 4,3 2,0 2,8 3,7 4,0 2,8 3,1 4,0 4,6 2,5 3,1 4,0 4,6 3,1 3,7 4,3 4,6 3,1 3,4 4,3 4,3 **60cm - 20mAs** 

**60cm - 40mAs** 

**60cm - 50mAs** 

**100cm - 20mAs** 

**100cm - 40mAs** 

**100cm - 50mAs** 

Table 9. Resolution test results for 10 x-ray units


Table 10. Contrast test results for 10 x-ray units.

Dose Optimization for the Quality Control Tests of X-Ray Equipment 317

I would like to thank the co-operation of radiographers at all of the radiological departments

Aldrich, J., Duran, E., Dunlop, P., & Mayo, J. (2006). Optimization of dose and image quality

Bouzarjomehri, F. (2004). Patient dose in routine X-ray examinations in Yazd state. *Iran. J.* 

Brix, G., Nekolla, E., & Griebel, J. (2005). Radiation exposure of patients from diagnostic and interventional X-ray procedures. *Radiologe,* Vol.45, No.4, (April 2005), pp. 340-349 Ciraj, O., Markovic, S., & Kosutic, D. (2005). First results on patient dose measurements

*Radiation Protection Dosimetry,* Vol.113, No.3, (March 2005), pp. 330-335 Geijer, H. (2002). Radiation dose and image quality in diagnostic radiology. Optimization of

Gray, J., Archer, B., Butler, P., Hobbs, B., Mettler, F., Pizzutiello, R., Schueler, B., Strauss, K.,

Application and impact. *Radiology,* Vol.235, No.2, (May 2005), pp. 354-358 Hendee, W., Chaney, E., & Rossi, R. (1984). *Radiologic Physics, Equipment and Quality Control*,

IAEA (1996). *International Basic Safety Standards for Protection against Ionizing Radiation and for* 

Iba Dosimetry (2008). Dosimax Plus A User Manual, 21 March 2011, Available from:

ICRP (1991). 1990 Recommendations of the international commission on radiological protection. ICRP Publication 60, *Annals of the ICRP*, Vol.21, No.1-3, (1991) IEC 61223-3-1:1999 (1999). *Evaluation and routine testing in medical imaging departments.* 

Papadimitriou, D., Perris, A., Molfetas, M., Panagiotakis, A., Manetou, A., Tsourouflis, G.,

Ramanandraibe, M., Andriambololona, R., Rakotoson, E., Tsapaki, V., & Gfirtner, H. (2009).

AAPM (1981). Basic quality control in diagnostic radiology. *AAPM Report No. 4*, (1981) AAPM (2002). Quality control in diagnostic radiology. *AAPM Report No. 74*, (2002)

for computed radiography and digital radiography. *Journal of Digital Imaging,* 

from conventional diagnostic radiology procedures in Serbia and Montenegro.

the dose-image quality relationship with clinical experience from scoliosis radiography, coronary intervention and a flat-panel digital detector. *Acta Radiol.* 

Suleiman, O., & Yaffe, M. (2005). Reference values for diagnostic radiology:

*the Safety of Radiation Sources*. IAEA Safety Series 15, ISBN 92-0-104295-7, Vienna,

*Acceptance tests. Imaging performance of X-ray equipment for radiographic and radiscopic* 

Vassileva, J., Chronopoulos, P., Karapanagiotou, O., & Kottou, S. (2001). Patient dose, image quality and radiographic techniques for common X-ray examinations in two Greek hospitals and comparison with European guidelines. *Radiation* 

Survey of image quality and patient dose in simple radiographic examinations in Madagascar: Initial results, *Proceedings of HEP-MAD 09,* Antananarivo,

**7. Acknowledgment** 

participating in this study.

Austria

www.iba-dosimetry.com

Vol.19, No.2, (June 2006), pp. 126-131

*Suppl.,* Vol.43, (March 2002), pp. 1-43

Year Book Medical Publishers, Chicago, USA

*systems*, BSI, ISBN 0-580-32753-1, London, England

*Protection Dosimetry,* Vol.95, No.1, (2001), pp. 43-48

Madagascar, August 21-28, (2009)

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**8. References** 

distances, the dose was calculated for the parameter settings that are different from the parameter settings used for dose modeling. After estimation, the measured and calculated dose values were compared. And, it was seen that the dose estimation was very successful.

For observing of image quality, a film was exposed during each dose measurement, after this, it was developed. Contrast and resolution tests were performed on these films. From Table 10, it can be said that contrast decreased with increasing kVp. It was seen that the best contrast is possible at the values of 70kVps, especially at 70kVp-40mAs. Although the other mAs values with constant 70kVp show good contrast, the best contrast with low dose is determined at 70kVp-40mAs.

In the resolution tests, from Table 9, it can be said that resolution increased related to increasing kVp. Because of this, the resolution is good in kVp values of 100kVp with different mAs.

But, in this study, because our aim is to obtain high image quality (both good contrast and good resolution), the optimum parameter values were selected as recommendation. The parameter setting values of 70kVp-40mAs can be accepted as the recommended technical parameters to obtain high quality image and low dose. If it is wanted to increase the number of recommended parameters, all mAs changes with constant 70kVp (20, 40, 50mAs) can be used as quality control test parameters.

If a radiographic staff adjusts these recommended parameters in an x-ray device, he/she will know which characteristics will appear on the image and how much dose will be measured. Hence, by this way, the staff can control and evaluate his/her tests' results during quality control tests of x-ray units.

## **6. Conclusion**

The technical x-ray parameters are very important to reduce the dose and to obtain the image with good quality. The dose reduction can be obtained by adequate changes of physical parameters without lose of image quality. The optimal radiation dose for optimal image quality can be achieved by understanding of the parameters that affect radiation dose and image quality. The dose optimization process also consists of quality control programs to test radiographic devices periodically. In this study, it was studied in which parameters' values were appropriate to obtain high quality image and to reduce dose, in other words, dose optimization, during quality control tests of x-ray units.

This study shows that optimization of technical factors may lead to a substantial dose reduction. If the optimized parameters are applied to X-ray equipment during quality control tests, it is possible to determine how much good image quality will be obtained with this optimized parameters and how much dose will be measured when this qualified image is developed.

The results show the importance of radiographic staff training about the recommended parameters that are applied to the x-ray units for a qualified quality control system. It is essential to provide relevant education and training to staff in the radiology departments.

It can be sure that with such a study the questions on many professional staff's mind will be answered, and the dose and the image characteristics will be parameters that are controlled and managed.

## **7. Acknowledgment**

I would like to thank the co-operation of radiographers at all of the radiological departments participating in this study.

## **8. References**

316 Modern Approaches To Quality Control

distances, the dose was calculated for the parameter settings that are different from the parameter settings used for dose modeling. After estimation, the measured and calculated dose values were compared. And, it was seen that the dose estimation was very

For observing of image quality, a film was exposed during each dose measurement, after this, it was developed. Contrast and resolution tests were performed on these films. From Table 10, it can be said that contrast decreased with increasing kVp. It was seen that the best contrast is possible at the values of 70kVps, especially at 70kVp-40mAs. Although the other mAs values with constant 70kVp show good contrast, the best contrast with low dose is

In the resolution tests, from Table 9, it can be said that resolution increased related to increasing kVp. Because of this, the resolution is good in kVp values of 100kVp with

But, in this study, because our aim is to obtain high image quality (both good contrast and good resolution), the optimum parameter values were selected as recommendation. The parameter setting values of 70kVp-40mAs can be accepted as the recommended technical parameters to obtain high quality image and low dose. If it is wanted to increase the number of recommended parameters, all mAs changes with constant 70kVp (20, 40, 50mAs) can be

If a radiographic staff adjusts these recommended parameters in an x-ray device, he/she will know which characteristics will appear on the image and how much dose will be measured. Hence, by this way, the staff can control and evaluate his/her tests' results

The technical x-ray parameters are very important to reduce the dose and to obtain the image with good quality. The dose reduction can be obtained by adequate changes of physical parameters without lose of image quality. The optimal radiation dose for optimal image quality can be achieved by understanding of the parameters that affect radiation dose and image quality. The dose optimization process also consists of quality control programs to test radiographic devices periodically. In this study, it was studied in which parameters' values were appropriate to obtain high quality image and to reduce dose, in other words,

This study shows that optimization of technical factors may lead to a substantial dose reduction. If the optimized parameters are applied to X-ray equipment during quality control tests, it is possible to determine how much good image quality will be obtained with this optimized parameters and how much dose will be measured when this qualified image

The results show the importance of radiographic staff training about the recommended parameters that are applied to the x-ray units for a qualified quality control system. It is essential to provide relevant education and training to staff in the radiology departments. It can be sure that with such a study the questions on many professional staff's mind will be answered, and the dose and the image characteristics will be parameters that are controlled

successful.

different mAs.

**6. Conclusion** 

is developed.

and managed.

determined at 70kVp-40mAs.

used as quality control test parameters.

during quality control tests of x-ray units.

dose optimization, during quality control tests of x-ray units.


**17** 

Shahid Pervez

*Pakistan* 

*Professor, Section of Histopathology, Department of Pathology & Microbiology, Aga Khan University Hospital Karachi,* 

**Infectious Aetiology of Cancer:** 

**Developing World Perspective** 

Infection attributable cancers contribute over 1/4th of all cancers in the developing countries (26.3%) compared to the developed countries (7.7%), (Parkin, 2006). Overwhelming majority are related to viral infections. In contrast to other carcinogens where it is usually a *'hit and run'* kind of situation, with infectious agents particularly viruses one may precisely demonstrate and prove its presence and integration within host neoplastic cells. Oncogenic DNA viral genome incorporates itself directly into host cells DNA while oncogenic RNA viral genome is transcribed into host cell DNA by reverse transcriptase. Neoplastic transformation usually follows. Oncogenic mechanisms include acting as promoter, transforming protooncogenes into oncogenes. Credit goes to Dr Peyton Rous, a noble laureate pathologist who demonstrated that it was possible to transmit tumours from one

Human tumours with proven or proposed viral aetiology include 'Human papillomavirus (HPV)', Epstein-Barr Virus (EBV), Hepatitis B and C viruses, RNA retroviruses like 'Human T-lymphotropic virus (HTLV1)', 'Human Herpes Virus-8 (HHV-8). Bacteria with proven carcinogenic potential include 'Helicobacter pylori'. Among fungi aflatoxins produced by 'Aspergillus flavus' are potent carcinogens. Among parasites 'Schistosoma' and 'Clonorchis

HPV is a small epitheliotropic, non enveloped DNA virus belonging to papovaviridae family. Its genome comprises 7000-8000 base pairs of double-stranded closed-circular DNA. At least 70 genetically distinct types of HPV have been identified in humans. According to their oncogenic potential HPV is classified in a high oncogenic risk group (i.e., HPV16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 65, 66) and low oncogenic risk group (i.e., HPV6, 11, 42, 43, 44). High risk HPV association with cervical and anogenital cancers is established beyond doubt. HPV16 and 18 are declared as human carcinogens by 'international Agency for Research on Cancer (IARC)'. HPV association with other cancers in particular with *'oral* 

*cancer'* is also being investigated with evidence of significant association.

**1. Introduction** 

animal to other like transmission of an infection.

sinensis' are implicated in the causation of cancer.

**2. Human papillomavirus (HPV)** 


## **Infectious Aetiology of Cancer: Developing World Perspective**

## Shahid Pervez

*Professor, Section of Histopathology, Department of Pathology & Microbiology, Aga Khan University Hospital Karachi, Pakistan* 

## **1. Introduction**

318 Modern Approaches To Quality Control

Schaefer-Prokop, C., Neitzel, U., Venema, H., Uffmann, M., & Prokop, M. (2008). Digital

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Shahbazi-Gahrouei, D. (2006). Entrance surface dose measurements for routine X-ray

Sprawls, P. (1987). *Physical Principles of Medical Imaging*, Aspen, ISBN 0-87189-644-3,

Vano, E., & Fernandez Soto, J. (2007). Patient dose management in digital radiography.

Williams, J., & Catling, M. (1998). An investigation of X-ray equipment factors influencing

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*Biomedical Imaging and Intervention Journal,* Vol.3, No.2, (2007)

(2004), pp. 183-195

Maryland, USA

1998), pp. 1192-1198

No.1, (2006), pp. 29-33

chest radiography: an update on modern technology, dose containment and control

examinations in Chaharmahal and Bakhtiari hospitals. *Iran. J. Radiat. Res.,* Vol.4,

patient dose in radiography. *The British Journal of Radiology,* Vol.71, (November

Infection attributable cancers contribute over 1/4th of all cancers in the developing countries (26.3%) compared to the developed countries (7.7%), (Parkin, 2006). Overwhelming majority are related to viral infections. In contrast to other carcinogens where it is usually a *'hit and run'* kind of situation, with infectious agents particularly viruses one may precisely demonstrate and prove its presence and integration within host neoplastic cells. Oncogenic DNA viral genome incorporates itself directly into host cells DNA while oncogenic RNA viral genome is transcribed into host cell DNA by reverse transcriptase. Neoplastic transformation usually follows. Oncogenic mechanisms include acting as promoter, transforming protooncogenes into oncogenes. Credit goes to Dr Peyton Rous, a noble laureate pathologist who demonstrated that it was possible to transmit tumours from one animal to other like transmission of an infection.

Human tumours with proven or proposed viral aetiology include 'Human papillomavirus (HPV)', Epstein-Barr Virus (EBV), Hepatitis B and C viruses, RNA retroviruses like 'Human T-lymphotropic virus (HTLV1)', 'Human Herpes Virus-8 (HHV-8). Bacteria with proven carcinogenic potential include 'Helicobacter pylori'. Among fungi aflatoxins produced by 'Aspergillus flavus' are potent carcinogens. Among parasites 'Schistosoma' and 'Clonorchis sinensis' are implicated in the causation of cancer.

## **2. Human papillomavirus (HPV)**

HPV is a small epitheliotropic, non enveloped DNA virus belonging to papovaviridae family. Its genome comprises 7000-8000 base pairs of double-stranded closed-circular DNA. At least 70 genetically distinct types of HPV have been identified in humans. According to their oncogenic potential HPV is classified in a high oncogenic risk group (i.e., HPV16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 65, 66) and low oncogenic risk group (i.e., HPV6, 11, 42, 43, 44). High risk HPV association with cervical and anogenital cancers is established beyond doubt. HPV16 and 18 are declared as human carcinogens by 'international Agency for Research on Cancer (IARC)'. HPV association with other cancers in particular with *'oral cancer'* is also being investigated with evidence of significant association.

Infectious Aetiology of Cancer: Developing World Perspective 321

countries. In Karachi it ranked 2nd with an identical risk in both genders (Bhurgri et al, 2003). However if combined with pharynx and larynx cancers which have the same histologic type (squamous cell carcinoma) & risk factors it ranks number 1. Major risk factors in the developed world include *'smoking'* and *'alcohol;* however in the developing world though smoking is a common major risk factor, role of alcohol drinking is possibly a minor risk factor particularly in developing muslim countries. In subcontinent (Pakistan, India & Bangladesh) alternate chewing habits like betel quid and areca nut are major risk factors. Areca nut is now declared by WHO as a bonafide carcinogen. People using paan (betel leaf) are about 8- 9 times more likely to develop oral cancers as compared to non-users (Merchant et al, 2000). Smokeless tobacco, including '*gudka'* and '*niswar'* is an extremely addictive substance with a high rate of use in younger age groups, as well is contributing toward endemic rise of oral cancers in Pakistan (Ali et al, 2009 & Nair et al, 2004). (Figure 1) This habit commonly leads to a pre-malignant condition *'Submucosal fibrosis'* which commonly transforms into OSCC. Poor oral hygiene is another contributory factor in this population. A significant proportion of OSCC patients however deny exposure to conventional and well known risk factors. This has led to search of other risk factors and associations including microbes (Scully et al, 1985). The striking commonality between oral cavity and cervical cavity paved the way to look for epitheliotropic viruses like HPV. Although these two areas are anatomically different, the squamous epithelium found in both areas has several similarities. For instance the squamous epithelium of ecto-cervix and oral cavity including pharynx and larynx are composed of squamous epithelium with a thin layer of keratin or no keratin. In both areas the epithelium is subject to microtrauma of various types as well as to bacteria and varying chemical irritants. Most common malignancy at both anatomic sites is also SCC with varied differentiation. (Figure 2) These factors may directly expose to HPV infections of cells resulting in malignant transformation. Furthermore the HPV subtypes isolated from lesions of squamous epithelium of cervix are similar to the type found in both normal epithelium and various lesions of the oral cavity, pharynx and larynx. These include

The reported prevalence of HPV in OSCC varies widely in various studies depending on the population and ethnicity studied and/or sensitivity of the methods used and viral DNA sequence targeted. HPV in particular HPV-16, like in cervix is implicated in the aetiology of OSCC (Gillison, 2004; Miller & Johnstone, 2001) About 40 – 60% of patients with tumours of oropharynx are reported to be positive for HPV infection (Gillison, 2004; Kreimer et al, 2005). HPV-positive tumours are distinct from HPV-negative tumours in their biological characteristics and clinical behaviour. Data from retrospective analyses as well as a prospective clinical trial demonstrated that HPV-positive oropharyngeal tumours are more sensitive to chemotherapy and radiation treatment and have a markedly improved prognosis and favourable clinical outcome compared with HPV-negative tumours (Fakhry

Recently, another significant observation has emerged in terms of HPV status of oropharyngeal tumours and racial disparities. Black Americans are known to have a higher incidence of and mortality from head and neck squamous cell carcinoma (HNSCC) than the whites and present with more advanced disease at a younger age (Goodwin et al, 2008; Morse & Kerr 2006; Ryerson et al, 2008; Shiboski et al, 2007). The greatest survival difference between blacks and whites was detected specifically in oropharyngeal cancers, but there was no racial difference between the overall survival rates of patients with nonoropharyngeal tumours (Settle et al, 2009). Most importantly, the recently published

HPV subtypes16, 18, 31 & 33.

et al, 2008; Settle et al, 2009)

## **2.1 HPV & cervical carcinoma**

Cervical carcinoma is one of the most common malignancies in women worldwide. However with effective preventive measures like *'cervical screening'* programs in developed countries more and more cases are picked at an early stage where complete cure is possible. A significant recent breakthrough has come in the form of *'HPV vaccine'* against high risk HPV16 & 18. This is gaining momentum in developed countries with high risk and burden of disease. It is administered at age 11-13, three shots are given intramuscularly. In contrast in the developing countries data is patchy or non-existent. In most countries no cervical screening programs are in place. In developing muslim countries situation is even worse. For instance in Pakistan, a populous muslim country of about 170 million inhabitants there is no cervical screening program and the only source of cervical smears are the sporadic smears obtained at the time of consultation in obstetrics & gynecology clinics. The problem is further compounded by the social taboos on matters of sexual practices and sexually transmitted infections (STI). These socio-cultural prohibitions create a substantial barrier to such investigations.

Recently a study was carried out with the help of IARC in women of Karachi, Pakistan (largest port city of Pakistan with an estimated population of 15 million from diverse ethnic backgrounds), (Raza et al, 2010). A sum of 899 married women aged 15-59 years living in a densely populated suburb of Karachi consented to participate. HPV prevalence was found to be 2.8%. Cervical abnormalities were diagnosed in 2.4% of whom 27.3% were HPV positive. HPV16 was detected as the most common type among women with both normal (0.5%) and abnormal (9.1%) cytology. This study also included 91 invasive cervical carcinomas (ICC) from two major university hospitals of Karachi, Pakistan. HPV16 was also the predominant HPV type (75.8%) in ICC followed by HPV18 (6.6%). This study led to the suggestion of very low burden of HPV infection in general female population, considerably lower than neighboring India (17%, Franceschi et al, 2005), China (15-18%, Dai et al, 2006, Wu et al, 2007) and Nepal (9%, Sherpa et al, 2010).

In another study from Karachi, Pakistan (Khan et al, 2007) women visiting two major tertiary care hospitals in Karachi, diagnosed with ICC, sixty (60) paraffin-embedded biopsies were analysed for HPV subtypes by PCR. Out of the 60 samples only one was negative for HPV, the rest were positive excluding two samples where subtype could not be determined. Fifty six (56) were HPV16 positive and only one was HPV18 positive.

## **2.1.1 Conclusion**


## **3. HPV and oral cancer**

Oral cancer (OC) / Oral squamous cell carcinoma (OSCC) excluding salivary gland cancers ranks 6th overall in the world in both sexes with much higher incidence in the developing

Cervical carcinoma is one of the most common malignancies in women worldwide. However with effective preventive measures like *'cervical screening'* programs in developed countries more and more cases are picked at an early stage where complete cure is possible. A significant recent breakthrough has come in the form of *'HPV vaccine'* against high risk HPV16 & 18. This is gaining momentum in developed countries with high risk and burden of disease. It is administered at age 11-13, three shots are given intramuscularly. In contrast in the developing countries data is patchy or non-existent. In most countries no cervical screening programs are in place. In developing muslim countries situation is even worse. For instance in Pakistan, a populous muslim country of about 170 million inhabitants there is no cervical screening program and the only source of cervical smears are the sporadic smears obtained at the time of consultation in obstetrics & gynecology clinics. The problem is further compounded by the social taboos on matters of sexual practices and sexually transmitted infections (STI). These socio-cultural prohibitions create a substantial barrier to

Recently a study was carried out with the help of IARC in women of Karachi, Pakistan (largest port city of Pakistan with an estimated population of 15 million from diverse ethnic backgrounds), (Raza et al, 2010). A sum of 899 married women aged 15-59 years living in a densely populated suburb of Karachi consented to participate. HPV prevalence was found to be 2.8%. Cervical abnormalities were diagnosed in 2.4% of whom 27.3% were HPV positive. HPV16 was detected as the most common type among women with both normal (0.5%) and abnormal (9.1%) cytology. This study also included 91 invasive cervical carcinomas (ICC) from two major university hospitals of Karachi, Pakistan. HPV16 was also the predominant HPV type (75.8%) in ICC followed by HPV18 (6.6%). This study led to the suggestion of very low burden of HPV infection in general female population, considerably lower than neighboring India (17%, Franceschi et al, 2005), China (15-18%, Dai et al, 2006,

In another study from Karachi, Pakistan (Khan et al, 2007) women visiting two major tertiary care hospitals in Karachi, diagnosed with ICC, sixty (60) paraffin-embedded biopsies were analysed for HPV subtypes by PCR. Out of the 60 samples only one was negative for HPV, the rest were positive excluding two samples where subtype could not be





Oral cancer (OC) / Oral squamous cell carcinoma (OSCC) excluding salivary gland cancers ranks 6th overall in the world in both sexes with much higher incidence in the developing

determined. Fifty six (56) were HPV16 positive and only one was HPV18 positive.

sexually transmitted infections (STI) is either non-existent or sparse.

programs & HPV vaccination in resource constrained economies.

women of Karachi, Pakistan revealed very low incidence of HPV (2.8%).

**2.1 HPV & cervical carcinoma** 

such investigations.

**2.1.1 Conclusion** 

**3. HPV and oral cancer** 

Wu et al, 2007) and Nepal (9%, Sherpa et al, 2010).

showed overwhelming predominance of HPV16.

countries. In Karachi it ranked 2nd with an identical risk in both genders (Bhurgri et al, 2003). However if combined with pharynx and larynx cancers which have the same histologic type (squamous cell carcinoma) & risk factors it ranks number 1. Major risk factors in the developed world include *'smoking'* and *'alcohol;* however in the developing world though smoking is a common major risk factor, role of alcohol drinking is possibly a minor risk factor particularly in developing muslim countries. In subcontinent (Pakistan, India & Bangladesh) alternate chewing habits like betel quid and areca nut are major risk factors. Areca nut is now declared by WHO as a bonafide carcinogen. People using paan (betel leaf) are about 8- 9 times more likely to develop oral cancers as compared to non-users (Merchant et al, 2000). Smokeless tobacco, including '*gudka'* and '*niswar'* is an extremely addictive substance with a high rate of use in younger age groups, as well is contributing toward endemic rise of oral cancers in Pakistan (Ali et al, 2009 & Nair et al, 2004). (Figure 1) This habit commonly leads to a pre-malignant condition *'Submucosal fibrosis'* which commonly transforms into OSCC. Poor oral hygiene is another contributory factor in this population.

A significant proportion of OSCC patients however deny exposure to conventional and well known risk factors. This has led to search of other risk factors and associations including microbes (Scully et al, 1985). The striking commonality between oral cavity and cervical cavity paved the way to look for epitheliotropic viruses like HPV. Although these two areas are anatomically different, the squamous epithelium found in both areas has several similarities. For instance the squamous epithelium of ecto-cervix and oral cavity including pharynx and larynx are composed of squamous epithelium with a thin layer of keratin or no keratin. In both areas the epithelium is subject to microtrauma of various types as well as to bacteria and varying chemical irritants. Most common malignancy at both anatomic sites is also SCC with varied differentiation. (Figure 2) These factors may directly expose to HPV infections of cells resulting in malignant transformation. Furthermore the HPV subtypes isolated from lesions of squamous epithelium of cervix are similar to the type found in both normal epithelium and various lesions of the oral cavity, pharynx and larynx. These include HPV subtypes16, 18, 31 & 33.

The reported prevalence of HPV in OSCC varies widely in various studies depending on the population and ethnicity studied and/or sensitivity of the methods used and viral DNA sequence targeted. HPV in particular HPV-16, like in cervix is implicated in the aetiology of OSCC (Gillison, 2004; Miller & Johnstone, 2001) About 40 – 60% of patients with tumours of oropharynx are reported to be positive for HPV infection (Gillison, 2004; Kreimer et al, 2005). HPV-positive tumours are distinct from HPV-negative tumours in their biological characteristics and clinical behaviour. Data from retrospective analyses as well as a prospective clinical trial demonstrated that HPV-positive oropharyngeal tumours are more sensitive to chemotherapy and radiation treatment and have a markedly improved prognosis and favourable clinical outcome compared with HPV-negative tumours (Fakhry et al, 2008; Settle et al, 2009)

Recently, another significant observation has emerged in terms of HPV status of oropharyngeal tumours and racial disparities. Black Americans are known to have a higher incidence of and mortality from head and neck squamous cell carcinoma (HNSCC) than the whites and present with more advanced disease at a younger age (Goodwin et al, 2008; Morse & Kerr 2006; Ryerson et al, 2008; Shiboski et al, 2007). The greatest survival difference between blacks and whites was detected specifically in oropharyngeal cancers, but there was no racial difference between the overall survival rates of patients with nonoropharyngeal tumours (Settle et al, 2009). Most importantly, the recently published

Infectious Aetiology of Cancer: Developing World Perspective 323

Fig. 2. Photomicrograph of H & E stained (A) well differentiated oral squamous cell carcinoma showing diffuse sheets of squamous cell with prominent keratinization and keratin pearl formations , Magnification X 10. (B) poorly differentiated oral Squamous

**A B**

Fig. 3. PCR amplification of HPV general, HPV type 16 and HPV type 18 in OSCC samples. The products were electophoresed on 2% agarose gel and stained with ethidium bromide. Lane N: negative control, lane P: positive control, lanes 1-4 HPV (general primer) positive tumour samples, lanes 5-6 HPV 16 positive tumour samples, lanes 7-8 HPV 18 positive

Fig. 4. Result of sequence analysis of PCR products, (A), Gene Sequencing HPV General.

Fig. 5. Kaplan-Meier curves of overall survival (OS) of (A) human papillomavirus (HPV) positive patients as compared with HPV-negative patients. (B) Disease Free Survival of human papillomavirus (HPV) positive patients as compared with HPV-negative patients.

tumour samples, Lane L: molecular size marker (50-bp ladder marker).

A.

B.

C.

(B), Gene Sequencing HPV Type 16. (C), Gene Sequencing HPV Type 18.

cell carcinoma, Magnification X 20.

prospective analysis demonstrated that a marked difference exists between black and white Americans in terms of HPV infection. HPV positivity was about 9-fold higher in white (34%) than in black (4%) patients, directly correlating HPV infection with significant survival disparities between the two populations (Settle et al, 2009). Clearly, the HPV status of patients with OSCC would be an important determinant for prognosis and treatment options in the future.

Recently, in a retrospective study of 140 patients with primary OSCC and a long-term follow up, Ali et al reported from Karachi, Pakistan, 68% of cases to be positive for HPV (Ali et al, 2008). Approximately 90% of these cases were infected with HPV16, (Figure 3 & 4) the predominant subtype in the US population as well. HPV infection was detected entirely in tumours of the cheek and tongue in the oral cavity; this was consistent with the occurrence frequency in the Karachi population for oral cancers which is as follows: 55.9% for cheek, 28.4% for tongue, 6.8% for palate, 4.4% for gum, 3.1% for lip and 1.4% for floor of the mouth (Bhurgri et al, 2003). Furthermore, though HPV positive patients had comparatively prolonged overall survival when compared with HPV negative patients but the difference was not statistically significant (P=0.97) (Figure 5). Betel quid chewers were comparatively more prone to HPV positivity (OR=2.34; 95 CI= 1.1-4.31). These findings are in contrast with the results from US studies where the ratio of oropharyngeal tumours with respect to other sites was 2:1 and the HPV-positive tumours were consistently associated with a better clinical outcome in terms of both overall and disease-free survival (Fakhry et al, 2008; Settle et al, 2009). The reason(s) for these different findings are not clear.

#### **3.1 Oncogenic HPV pathways**

The chief oncoproteins of HPV16 are encoded by the genes E6 and E7. The E6 protein targets the tumour suppressor gene p53 for degradation. In fact, degradation of p53 in HPV positive cells is fully dependent on the presence of E6 (Ali et al, 2010, Figure 6). The E7 oncoprotein is involved in suppression of retinoblastoma protein (pRb) function. Reduced pRb expression is common in HPV-positive tonsillar cancer.

#### **3.2 Mode of transmission**

Two questions immediately come to mind, first how HPV gets there and second why patients with HPV association will have better survival. In response to question 1, haematogenous spread from genital tract is proposed besides atypical sexual habits. In response to question 2 one possible explanation is that HPV infection may lead to genome instability, paradoxically making tumour cells more susceptible to radiotherapy.

Fig. 1. Clinical presentations of patients with oral squamous cell carcinoma (OSCC) in Pakistani patients (Photographs were taken with patient's consent).

prospective analysis demonstrated that a marked difference exists between black and white Americans in terms of HPV infection. HPV positivity was about 9-fold higher in white (34%) than in black (4%) patients, directly correlating HPV infection with significant survival disparities between the two populations (Settle et al, 2009). Clearly, the HPV status of patients with OSCC would be an important determinant for prognosis and treatment

Recently, in a retrospective study of 140 patients with primary OSCC and a long-term follow up, Ali et al reported from Karachi, Pakistan, 68% of cases to be positive for HPV (Ali et al, 2008). Approximately 90% of these cases were infected with HPV16, (Figure 3 & 4) the predominant subtype in the US population as well. HPV infection was detected entirely in tumours of the cheek and tongue in the oral cavity; this was consistent with the occurrence frequency in the Karachi population for oral cancers which is as follows: 55.9% for cheek, 28.4% for tongue, 6.8% for palate, 4.4% for gum, 3.1% for lip and 1.4% for floor of the mouth (Bhurgri et al, 2003). Furthermore, though HPV positive patients had comparatively prolonged overall survival when compared with HPV negative patients but the difference was not statistically significant (P=0.97) (Figure 5). Betel quid chewers were comparatively more prone to HPV positivity (OR=2.34; 95 CI= 1.1-4.31). These findings are in contrast with the results from US studies where the ratio of oropharyngeal tumours with respect to other sites was 2:1 and the HPV-positive tumours were consistently associated with a better clinical outcome in terms of both overall and disease-free survival (Fakhry et al, 2008; Settle

The chief oncoproteins of HPV16 are encoded by the genes E6 and E7. The E6 protein targets the tumour suppressor gene p53 for degradation. In fact, degradation of p53 in HPV positive cells is fully dependent on the presence of E6 (Ali et al, 2010, Figure 6). The E7 oncoprotein is involved in suppression of retinoblastoma protein (pRb) function. Reduced

Two questions immediately come to mind, first how HPV gets there and second why patients with HPV association will have better survival. In response to question 1, haematogenous spread from genital tract is proposed besides atypical sexual habits. In response to question 2 one possible explanation is that HPV infection may lead to genome

instability, paradoxically making tumour cells more susceptible to radiotherapy.

**A B**

**C D**

Fig. 1. Clinical presentations of patients with oral squamous cell carcinoma (OSCC) in

Pakistani patients (Photographs were taken with patient's consent).

et al, 2009). The reason(s) for these different findings are not clear.

pRb expression is common in HPV-positive tonsillar cancer.

options in the future.

**3.1 Oncogenic HPV pathways** 

**3.2 Mode of transmission** 

Fig. 2. Photomicrograph of H & E stained (A) well differentiated oral squamous cell carcinoma showing diffuse sheets of squamous cell with prominent keratinization and keratin pearl formations , Magnification X 10. (B) poorly differentiated oral Squamous cell carcinoma, Magnification X 20.

Fig. 3. PCR amplification of HPV general, HPV type 16 and HPV type 18 in OSCC samples. The products were electophoresed on 2% agarose gel and stained with ethidium bromide. Lane N: negative control, lane P: positive control, lanes 1-4 HPV (general primer) positive tumour samples, lanes 5-6 HPV 16 positive tumour samples, lanes 7-8 HPV 18 positive tumour samples, Lane L: molecular size marker (50-bp ladder marker).

Fig. 4. Result of sequence analysis of PCR products, (A), Gene Sequencing HPV General. (B), Gene Sequencing HPV Type 16. (C), Gene Sequencing HPV Type 18.

Fig. 5. Kaplan-Meier curves of overall survival (OS) of (A) human papillomavirus (HPV) positive patients as compared with HPV-negative patients. (B) Disease Free Survival of human papillomavirus (HPV) positive patients as compared with HPV-negative patients.

Infectious Aetiology of Cancer: Developing World Perspective 325

internal repeats in the Bam HI, E, K, N and Z regions. We also studied the extent of polymorphism in EBV genome by *'single stranded conformation polymorphism (SSCP)'* technique for '*Bam HI E, K, N and Z regions'*. Hypervariability in Bam HI, K and N regions was noticeably higher compared to *E or Z* regions. All in all no association was established between EBV variants differentiated on the basis sequence heterogeneity in *Bam HI, K, N, E* 

Mode of infection of T-cells by EBV is complex and poorly understood. Nazaruk et al, 1998 proposed that initially virus infects the B-cells and remains in the latent phase but under immunosuppressive conditions IL10 is secreted by EBV specific CD8+ T-cells activating Bcells. Subsequently reactivation of EBV lytic cycle occurs that may contribute to the

Fig. 7. Ethidium Bromide stained agarose gel showing PCR products of EBV-DNA amplified

AILT is an uncommon form of mature T-NHL characterised by systemic disease that occurs predominantly in middle-aged and elderly patients. The clinico-pathologic syndrome is characterised by fever, night sweats, weight loss, generalised lymphadenopathy, hepatomegaly and splenomegaly. Histologic examination of lymph nodes typically shows effacement of lymph nodes architecture, a polymorphous infiltrate including immunoblasts, lymphocytes, plasma cells, eosinophils, epithelioid histiocytes and a prominent arborizing postcapillary vasculature (Figure 8). In a study conducted by us a total of 13 well characterised cases of AILT based on morphology, IHC and TcR gene rearrangement studies were analysed for EBV by PCR and ISH (EBER). Association of EBV was seen in 11 out of 13 cases (84.6%) by PCR. By ISH (EBER), EBV was detected in 8 out of 9 cases (88.8%) cases. (Figure 8) So all in all strongest correlation of EBV was seen in this type of T-NHL. (Noorali

Fig. 8. I*n situ hybridization* photomicrograph of a lymph node showing the localisation of EBV in the nuclei of neoplastic lymphocytes indicated by blackish signal (↑) (B), H& E of the

**A B**

development of EBV-associated T-cell lymphoproliferative disorders.

*and Z regions* in different subsets of T-NHL.

with primers specific for gp200 region.

et al, 2005).

same (A).

**4.2 EBV & angioimmunoblastic T-cell lymphoma (AILT)** 

Fig. 6. Photomicrograph of a well-differentiated OSCC demonstrating diffuse strong nuclear TP53 staining. The arrows indicate positive dark brown intranuclear staining (magnification x 10 (A) & 20 (B)).

## **3.3 Conclusions**


## **4. Epstein-Barr virus (EBV)**

EBV was initially discovered from cell cultures of a high grade B-cell lymphoma *'Endemic (African) Burkitt Lymphoma (BL)'*, which is highly prevalent in paraequatorial Africa and New Guinea. The disease affects children and adolescents and has strong association with malaria. Endemic BL commonly involves extra-nodal sites particularly jaw. In rest of the world '*sporadic form of BL'* is seen having a weaker association with EBV and commonly affecting gastro-intestinal tract (GIT) particularly small intestine.

EBV associated other lymphomas include 'classic Hodgkin lymphoma (cHL)' particularly 'mixed cellularity' type (60%), 'B-cell lymphoma in immunosuppressed', 'mature T-cell lymphoproliferative disorders' in particular 'Angioimmunoblastic T-cell lymphoma (AILT)', 'Angiocentric (Nasal) T-cell lymphoma'. Non-lymphoid associations include 'Nasopharyngeal carcinoma'.

## **4.1 EBV & mature T-cell non-Hodgkin lymphoma (T-NHL)**

EBV association with certain subsets of T-NHL is now well established. In a study conducted by us in Pakistan (Noorali et al, 2003), mature T-NHL comprised 22.2% of total mature NHLs. These cases were characterised on the basis of morphology, immunohistochemistry and T-cell receptor (TCR) gene rearrangement studies. This study demonstrated frequent presence of EBV in mature T-NHL cases (55.4%) by '*PCR'* (Figure 7) and *'in-situ hybridization (ISH)'*. While analysing various subsets of mature T-NHL 'Peripheral T-cell lymphoma (PTCL) - unspecified' (n=88) showed 51.2% EBV positive cases. EBV can be differentiated according to size polymorphism depending on the number of

Fig. 6. Photomicrograph of a well-differentiated OSCC demonstrating diffuse strong nuclear TP53 staining. The arrows indicate positive dark brown intranuclear staining (magnification





EBV was initially discovered from cell cultures of a high grade B-cell lymphoma *'Endemic (African) Burkitt Lymphoma (BL)'*, which is highly prevalent in paraequatorial Africa and New Guinea. The disease affects children and adolescents and has strong association with malaria. Endemic BL commonly involves extra-nodal sites particularly jaw. In rest of the world '*sporadic form of BL'* is seen having a weaker association with EBV and commonly

EBV associated other lymphomas include 'classic Hodgkin lymphoma (cHL)' particularly 'mixed cellularity' type (60%), 'B-cell lymphoma in immunosuppressed', 'mature T-cell lymphoproliferative disorders' in particular 'Angioimmunoblastic T-cell lymphoma (AILT)', 'Angiocentric (Nasal) T-cell lymphoma'. Non-lymphoid associations include

EBV association with certain subsets of T-NHL is now well established. In a study conducted by us in Pakistan (Noorali et al, 2003), mature T-NHL comprised 22.2% of total mature NHLs. These cases were characterised on the basis of morphology, immunohistochemistry and T-cell receptor (TCR) gene rearrangement studies. This study demonstrated frequent presence of EBV in mature T-NHL cases (55.4%) by '*PCR'* (Figure 7) and *'in-situ hybridization (ISH)'*. While analysing various subsets of mature T-NHL 'Peripheral T-cell lymphoma (PTCL) - unspecified' (n=88) showed 51.2% EBV positive cases. EBV can be differentiated according to size polymorphism depending on the number of

of Karachi (Pakistan) with 90% containing HPV 16.

**A B**

statistical significance as seen in American whites.

affecting gastro-intestinal tract (GIT) particularly small intestine.

**4.1 EBV & mature T-cell non-Hodgkin lymphoma (T-NHL)** 

x 10 (A) & 20 (B)).

**3.3 Conclusions** 

of the world.

highest in the world.

**4. Epstein-Barr virus (EBV)** 

'Nasopharyngeal carcinoma'.

internal repeats in the Bam HI, E, K, N and Z regions. We also studied the extent of polymorphism in EBV genome by *'single stranded conformation polymorphism (SSCP)'* technique for '*Bam HI E, K, N and Z regions'*. Hypervariability in Bam HI, K and N regions was noticeably higher compared to *E or Z* regions. All in all no association was established between EBV variants differentiated on the basis sequence heterogeneity in *Bam HI, K, N, E and Z regions* in different subsets of T-NHL.

Mode of infection of T-cells by EBV is complex and poorly understood. Nazaruk et al, 1998 proposed that initially virus infects the B-cells and remains in the latent phase but under immunosuppressive conditions IL10 is secreted by EBV specific CD8+ T-cells activating Bcells. Subsequently reactivation of EBV lytic cycle occurs that may contribute to the development of EBV-associated T-cell lymphoproliferative disorders.

Fig. 7. Ethidium Bromide stained agarose gel showing PCR products of EBV-DNA amplified with primers specific for gp200 region.

## **4.2 EBV & angioimmunoblastic T-cell lymphoma (AILT)**

AILT is an uncommon form of mature T-NHL characterised by systemic disease that occurs predominantly in middle-aged and elderly patients. The clinico-pathologic syndrome is characterised by fever, night sweats, weight loss, generalised lymphadenopathy, hepatomegaly and splenomegaly. Histologic examination of lymph nodes typically shows effacement of lymph nodes architecture, a polymorphous infiltrate including immunoblasts, lymphocytes, plasma cells, eosinophils, epithelioid histiocytes and a prominent arborizing postcapillary vasculature (Figure 8). In a study conducted by us a total of 13 well characterised cases of AILT based on morphology, IHC and TcR gene rearrangement studies were analysed for EBV by PCR and ISH (EBER). Association of EBV was seen in 11 out of 13 cases (84.6%) by PCR. By ISH (EBER), EBV was detected in 8 out of 9 cases (88.8%) cases. (Figure 8) So all in all strongest correlation of EBV was seen in this type of T-NHL. (Noorali et al, 2005).

Fig. 8. I*n situ hybridization* photomicrograph of a lymph node showing the localisation of EBV in the nuclei of neoplastic lymphocytes indicated by blackish signal (↑) (B), H& E of the same (A).

Infectious Aetiology of Cancer: Developing World Perspective 327






Nasopharyngeal carcinomas are particularly common in some parts of Africa and southern China. In former they constitute most frequent childhood cancer while in the later adults are mostly affected. Association of EBV with nasopharyngeal carcinoma is well established. In fact this association is literally 100%. EBV associated protein LMP-1 is expressed in most

Fig. 11. Photomicrograph of a case of Nasopharyngeal carcinoma (H& E, A) stained with an

Relatively recently in 1994 *'Human Herpesvirus-8 (HHV-8)* was identified in an AIDS patient with cutaneous *'Kaposi sarcoma (KS)'*. Later it was found that over 95% KS are associated with HHV-8. This virus is largely transmitted sexually. An antibody against HHV-8 shows positive reactivity in about 100% of cases and is a useful tool to confirm the diagnosis. Although *'Kaposi sarcoma'* is uncommon in our practice in Pakistan, it is highly prevalent in developing world with high AIDS incidence. (Figure 12) Four forms are recognized based primarily on population demographics and risk factors. These include a) *'Chronic KS'*, also called European KS b) *'Lymphoadenopathic KS'* also called African or endemic KS c)

while association with *'sporadic BL'* is relatively weak.

*(EBER)'* are commonly used in routine diagnostic pathology

Caribbean is insignificant in our experience in Pakistan.

antibody to LMP-1 (B), note cytoplasmic staining of neoplastic cells.

**A B**


*'Transplant associated KS'* and d) '*AIDs-associated KS'*.



**7. EBV & nasopharyngeal carcinoma** 

**6.1 Conclusions** 

*'mixed cellularity variant'*

ALCL subtypes.

cases. (Figure 11)

**7.1 Conclusions** 

**8.1 Conclusions** 

**8. HHV8 & Kaposi sarcoma** 

## **4.3 EBV & Mycosis fungoides (MF)**

MF is an indolent T-cell lymphoma of skin. In a study conducted by us a total of 14 well characterised cases of MF were analysed for EBV by PCR and ISH (EBER). EBV was identified in 3 out of 6 cases (50%) by PCR but all these were negative on ISH (EBER). This discrepancy is most likely caused by low copy number of infected cells in tissue sections not amplified as in PCR based studies (Noorali et al, 2002).

## **4.4 EBV & anaplastic large cell lymphoma (ALCL)**

ALCL is a peculiar type of T-NHL. In a recent study by us (Syed et al, 2011) ALCL was turned out to be the most common T-NHL in the archives of the largest referral centre of Pakistan. This variant of T-NHL however has the weakest association with EBV (Noorali et al 2004).

## **5. HTLV-1 & T-NHL**

HTLV1 is a RNA oncogenic virus which is associated with *'adult T-cell leukemia /lymphoma*' and is endemic in southern Japan and Caribbean basin. Like HIV which causes AIDS, HTLV1 also shows tropism for CD4+ T cells, hence this subset is the main victim for neoplastic transformation. In our local studies HTLV1 association was absent in mature Tlymphoproliferative disorders. This is in line with relatively low burden of HIV-AIDS in Pakistan so far (Noorali et al, 2004). (Figure 9)

Fig. 9. Agarose gel showing samples of mature T-NHL negative for HTLV-1 DNA by PCR.

## **6. Role of EBV detection by PCR, ISH & IHC in diagnostic pathology**

The ability to amplify specific regions of DNA from paraffin-embedded tissue by PCR has a profound impact on diagnostic pathology. For routine histopathological diagnosis of various lymphoproliferative disorders EBV-ISH (EBV-encoded nuclear RNA -1(EBER-1) and IHC by using an antibody to 'Latent Membrane Protein-1 (LMP-1) are frequently used in diagnostic dilemmas. For instance in the differential diagnosis of cHL and ALCL, EBER or LMP-1 positivity in neoplastic cells will strongly favour cHL as EBV association with ALCL is very *weak*. (Figure 10)

Fig. 10. Photomicrograph of a case of Hodgkin lymphoma (mixed cellularity, H&E, A ↑) stained with an antibody to LMP-1, note cytoplasmic staining of large Hodgkin cells (↑ B).

## **6.1 Conclusions**

326 Modern Approaches To Quality Control

MF is an indolent T-cell lymphoma of skin. In a study conducted by us a total of 14 well characterised cases of MF were analysed for EBV by PCR and ISH (EBER). EBV was identified in 3 out of 6 cases (50%) by PCR but all these were negative on ISH (EBER). This discrepancy is most likely caused by low copy number of infected cells in tissue sections not

ALCL is a peculiar type of T-NHL. In a recent study by us (Syed et al, 2011) ALCL was turned out to be the most common T-NHL in the archives of the largest referral centre of Pakistan. This variant of T-NHL however has the weakest association with EBV (Noorali et

HTLV1 is a RNA oncogenic virus which is associated with *'adult T-cell leukemia /lymphoma*' and is endemic in southern Japan and Caribbean basin. Like HIV which causes AIDS, HTLV1 also shows tropism for CD4+ T cells, hence this subset is the main victim for neoplastic transformation. In our local studies HTLV1 association was absent in mature Tlymphoproliferative disorders. This is in line with relatively low burden of HIV-AIDS in

Fig. 9. Agarose gel showing samples of mature T-NHL negative for HTLV-1 DNA by PCR.

The ability to amplify specific regions of DNA from paraffin-embedded tissue by PCR has a profound impact on diagnostic pathology. For routine histopathological diagnosis of various lymphoproliferative disorders EBV-ISH (EBV-encoded nuclear RNA -1(EBER-1) and IHC by using an antibody to 'Latent Membrane Protein-1 (LMP-1) are frequently used in diagnostic dilemmas. For instance in the differential diagnosis of cHL and ALCL, EBER or LMP-1 positivity in neoplastic cells will strongly favour cHL as EBV association with ALCL

Fig. 10. Photomicrograph of a case of Hodgkin lymphoma (mixed cellularity, H&E, A ↑) stained with an antibody to LMP-1, note cytoplasmic staining of large Hodgkin cells (↑ B).

**A B**

**6. Role of EBV detection by PCR, ISH & IHC in diagnostic pathology** 

**4.3 EBV & Mycosis fungoides (MF)** 

al 2004).

**5. HTLV-1 & T-NHL** 

is very *weak*. (Figure 10)

amplified as in PCR based studies (Noorali et al, 2002).

**4.4 EBV & anaplastic large cell lymphoma (ALCL)** 

Pakistan so far (Noorali et al, 2004). (Figure 9)


## **7. EBV & nasopharyngeal carcinoma**

Nasopharyngeal carcinomas are particularly common in some parts of Africa and southern China. In former they constitute most frequent childhood cancer while in the later adults are mostly affected. Association of EBV with nasopharyngeal carcinoma is well established. In fact this association is literally 100%. EBV associated protein LMP-1 is expressed in most cases. (Figure 11)

Fig. 11. Photomicrograph of a case of Nasopharyngeal carcinoma (H& E, A) stained with an antibody to LMP-1 (B), note cytoplasmic staining of neoplastic cells.

## **7.1 Conclusions**


## **8. HHV8 & Kaposi sarcoma**

Relatively recently in 1994 *'Human Herpesvirus-8 (HHV-8)* was identified in an AIDS patient with cutaneous *'Kaposi sarcoma (KS)'*. Later it was found that over 95% KS are associated with HHV-8. This virus is largely transmitted sexually. An antibody against HHV-8 shows positive reactivity in about 100% of cases and is a useful tool to confirm the diagnosis. Although *'Kaposi sarcoma'* is uncommon in our practice in Pakistan, it is highly prevalent in developing world with high AIDS incidence. (Figure 12) Four forms are recognized based primarily on population demographics and risk factors. These include a) *'Chronic KS'*, also called European KS b) *'Lymphoadenopathic KS'* also called African or endemic KS c) *'Transplant associated KS'* and d) '*AIDs-associated KS'*.

## **8.1 Conclusions**


Infectious Aetiology of Cancer: Developing World Perspective 329


Fig. 13. Photomicrograph of gastric biopsy showing abundant '*Helicobacter pylori*' organisms on epithelial surface (←A), Figure B & C shows gastric MALT lymphoma arising from the marginal zone of lymphoid follicle ←. Figure D shows well differentiated adenocarcinoma

**A B**

**C D**

**10. Immunoproliferative small intestinal disease (IPSID) &** *Campylobacter* 

fluids. It can be treated with broad spectrum antibiotics at its early stages.

paramount importance, particularly in endemic regions.

Immunoproliferative small intestinal disease (IPSID) is a special variant of*, 'Extranodal marginal zone B cell lymphoma'*, which affects the small intestine. In early to mid 1960s it was referred to as *'Mediterranean lymphomas'*, during late 1960s the term *'α-heavy chain disease'* was also used for patients with similar clinico-pathological presentations. Later it was realized that both *'Mediterranean lymphomas'* and *'α-heavy chain disease'* represented a spectrum of the same disease which presents in different stages i.e., benign, intermediate and overtly malignant (stage A, B & C) and the disease was named IPSID (Fine & Stone 2000). IPSID is predominantly found in patients of '*Mediterranean origin'*; however a few cases of IPSID are also diagnosed in the subcontinent (Pervez et al, 2011). IPSID involves the production of truncated alpha heavy chains which may appear in the serum and other body

It is postulated that IPSID occurs in patients with repeated intestinal infections. Recent studies suggest association with *Campylobacter jejuni* (Lecuit et al, 2004). It is postulated that this results in continuous chronic antigenic stimulation of IgA secreting lymphoid tissue common in small intestine with a resultant clonal proliferation of IgA secreting lymphoid cells. Subsequently most cases lose the ability to synthesize light chain. In early stages it may be very difficult to differentiate IPSID, from chronic inflammatory process by the reporting pathologists. In such circumstances it may be impossible to diagnose without the help of clonal studies for IgH chain gene rearrangement (Figure 14). The other close mimicry includes '*Coeliac disease'* as both IPSID and '*Coeliac disease'* are characterised by lymphoplasmacytic infiltrate and villous atrophy. In these cases demographics are important; also gluten free diet will lead to improvement of '*Coeliac disease'* cases. Intra-intraepithelial lymphocytosis with surface epithelial damage shall also favour Coeliac disease. As some cases of IPSID particularly if untreated may transform into aggressive lymphomas like '*Diffuse large B-cell lymphoma' (DLBCL)*, recognition of subtle features and follow-up is of

MALT lymphoma is low.

of stomach (intestinal type ←).

*jejuni***:**


Fig. 12. Photomicrograph of Kaposi sarcoma resected from skin (H&E, A & B). Figure C shows lymph node metastases of the same (↑) highlighted on immunohistochemistry with CD31 (↑D).

## **9.** *Helicobacter pylori* **& gastric MALT lymphoma**

*'MALT lymphomas'* were first described in 1983 by Peter Isaacson and Dennis Wright. They noted that primary low grade gastric B cell lymphomas recapitulate the histology of *'Mucosa Associated Lymphoid Tissue (MALT)'* exemplified by the Peyer patches and coined the term *'MALT lymphoma'*. These lymphomas are currently recognized as '*Extranodal marginal zone B cell lymphomas of MALT type'* according to the *'WHO Classification for Tumours of Haematopoietic and Lymphoid Tissues'* (Issaacson et al, 2008) (Figure 13). The stomach is the most reported and best studied site of '*MALT Lymphomas'*. An intimate relationship has been reported between the presence of '*Helicobacter pylori (HP)'* in the stomach and the development of '*MALT Lymphoma'* (Figure 13). In fact the pathogenesis of gastric '*MALT Lymphoma'* is believed to be caused by repeated antigenic stimulation of the immune system in the stomach by HP. The role of HP in the pathogenesis of *'gastric MALTomas'* can be illustrated by the fact that 75% of the patients who have gastric MALToma undergo remission if treated with antibiotics to eradicate HP (Ono et al, 2008). About half the people in the world have HP colonized in their gastrointestinal tract. Of these most remain asymptomatic. Despite the fact that, a high prevalence of HP is reported from Pakistan (Pervez et al, 2011), the prevalence of *'gastric MALTomas'* is very low in our experience. Seroprevalence of HP infection in the Pakistani population has been reported as high as 58%. This correlates with the *'Asian enigma'* described by various authors where less developed Asian countries like Pakistan, India, Bangladesh and Thailand have lower rates of gastric carcinoma compared to well developed countries like Japan and China, despite a higher prevalence of HP infection in the population. HP has been established to have a role in the aetiology of gastric carcinoma and its paradoxical high prevalence in areas with few cases of gastric carcinoma has long puzzled researchers. Available evidences do not support difference in HP strains as the sole explanation for this enigma.

#### **9.1 Conclusions**



Fig. 12. Photomicrograph of Kaposi sarcoma resected from skin (H&E, A & B). Figure C shows lymph node metastases of the same (↑) highlighted on immunohistochemistry with

*'MALT lymphomas'* were first described in 1983 by Peter Isaacson and Dennis Wright. They noted that primary low grade gastric B cell lymphomas recapitulate the histology of *'Mucosa Associated Lymphoid Tissue (MALT)'* exemplified by the Peyer patches and coined the term *'MALT lymphoma'*. These lymphomas are currently recognized as '*Extranodal marginal zone B cell lymphomas of MALT type'* according to the *'WHO Classification for Tumours of Haematopoietic and Lymphoid Tissues'* (Issaacson et al, 2008) (Figure 13). The stomach is the most reported and best studied site of '*MALT Lymphomas'*. An intimate relationship has been reported between the presence of '*Helicobacter pylori (HP)'* in the stomach and the development of '*MALT Lymphoma'* (Figure 13). In fact the pathogenesis of gastric '*MALT Lymphoma'* is believed to be caused by repeated antigenic stimulation of the immune system in the stomach by HP. The role of HP in the pathogenesis of *'gastric MALTomas'* can be illustrated by the fact that 75% of the patients who have gastric MALToma undergo remission if treated with antibiotics to eradicate HP (Ono et al, 2008). About half the people in the world have HP colonized in their gastrointestinal tract. Of these most remain asymptomatic. Despite the fact that, a high prevalence of HP is reported from Pakistan (Pervez et al, 2011), the prevalence of *'gastric MALTomas'* is very low in our experience. Seroprevalence of HP infection in the Pakistani population has been reported as high as 58%. This correlates with the *'Asian enigma'* described by various authors where less developed Asian countries like Pakistan, India, Bangladesh and Thailand have lower rates of gastric carcinoma compared to well developed countries like Japan and China, despite a higher prevalence of HP infection in the population. HP has been established to have a role in the aetiology of gastric carcinoma and its paradoxical high prevalence in areas with few cases of gastric carcinoma has long puzzled researchers. Available evidences do not support


**9.** *Helicobacter pylori* **& gastric MALT lymphoma** 

**A B**

**C D**

difference in HP strains as the sole explanation for this enigma.

AIDS is very low

CD31 (↑D).

**9.1 Conclusions** 

is well established.


Fig. 13. Photomicrograph of gastric biopsy showing abundant '*Helicobacter pylori*' organisms on epithelial surface (←A), Figure B & C shows gastric MALT lymphoma arising from the marginal zone of lymphoid follicle ←. Figure D shows well differentiated adenocarcinoma of stomach (intestinal type ←).

## **10. Immunoproliferative small intestinal disease (IPSID) &** *Campylobacter jejuni***:**

Immunoproliferative small intestinal disease (IPSID) is a special variant of*, 'Extranodal marginal zone B cell lymphoma'*, which affects the small intestine. In early to mid 1960s it was referred to as *'Mediterranean lymphomas'*, during late 1960s the term *'α-heavy chain disease'* was also used for patients with similar clinico-pathological presentations. Later it was realized that both *'Mediterranean lymphomas'* and *'α-heavy chain disease'* represented a spectrum of the same disease which presents in different stages i.e., benign, intermediate and overtly malignant (stage A, B & C) and the disease was named IPSID (Fine & Stone 2000). IPSID is predominantly found in patients of '*Mediterranean origin'*; however a few cases of IPSID are also diagnosed in the subcontinent (Pervez et al, 2011). IPSID involves the production of truncated alpha heavy chains which may appear in the serum and other body fluids. It can be treated with broad spectrum antibiotics at its early stages.

It is postulated that IPSID occurs in patients with repeated intestinal infections. Recent studies suggest association with *Campylobacter jejuni* (Lecuit et al, 2004). It is postulated that this results in continuous chronic antigenic stimulation of IgA secreting lymphoid tissue common in small intestine with a resultant clonal proliferation of IgA secreting lymphoid cells. Subsequently most cases lose the ability to synthesize light chain. In early stages it may be very difficult to differentiate IPSID, from chronic inflammatory process by the reporting pathologists. In such circumstances it may be impossible to diagnose without the help of clonal studies for IgH chain gene rearrangement (Figure 14). The other close mimicry includes '*Coeliac disease'* as both IPSID and '*Coeliac disease'* are characterised by lymphoplasmacytic infiltrate and villous atrophy. In these cases demographics are important; also gluten free diet will lead to improvement of '*Coeliac disease'* cases. Intra-intraepithelial lymphocytosis with surface epithelial damage shall also favour Coeliac disease. As some cases of IPSID particularly if untreated may transform into aggressive lymphomas like '*Diffuse large B-cell lymphoma' (DLBCL)*, recognition of subtle features and follow-up is of paramount importance, particularly in endemic regions.

Infectious Aetiology of Cancer: Developing World Perspective 331

Fig. 15. Photomicrograph of a liver biopsy in a patient infected with Hepatitis C. Note fibrous band dividing the liver parenchyma into varying size nodules (↑A, Trichrome). Figure B shows a well differentiated hepatocellular carcinoma (HCC) arising in this patient

**A B**



Dr Samina Noorali & Dr Syed Adnan Ali who completed their PhD under my supervision and participated in experimental work & original work on EBV and HPV in T-NHL & Oral cancer respectively included in this chapter are duly acknowledged. Ms. Shamsha Punjwani

Ali M, Idress M, Ali L, Hussain A & Rehman I U, Saleem S, Afzal S & Butt S. (2011).

Ali NS, Khuwaja AK, Ali T & Hameed R. (2009). Smokeless tobacco use among adult

Ali SM., Awan MS., Ghaffar S,., Slahuddin I., Khan S., Mehraj V & Pervez S. (2008). Human

Ali SM, Awan MS, Ghaffar S, Azam SI & Pervez S. (2010). TP53 protein overexpression in

Bhurgri Y, Bhurgri A, Hussainy AS, Usman A, Faridi N, Malik J, Zaidi ZA, Muzaffar S,

awareness status and genotypes. *Virology journal*, 8:102-110.

survival oucome in Pakistani patients. *Oral Surgery*, 3, 83-95.

Hepatitis B virus in Pakistan: A systematic review of prevalence, risk factors,

patients who visited family practice clinics in Karachi, Pakistan*. J Oral Pathol Med.*

Papillomavirus infection in oral squamous cell carcinomas: Correlation with histologic variables and survival outcome in a high risk population, *Oral Surgery*, 1,

oral squamous cell carcinomas (OSCC);correlation with histologic variables and

Kayani N, Pervez S & Hasan SH.(2003). Cancer of oral cavity and pharynx in Karachi-identification of potential risk factors. *Asia Pacific J Cancer Prevention,* Apr-

(H&E).

**11.1 Conclusions** 

secondary to Hepatitis B & C.

May;38(5):416-421.

96-105

Jun, 4:125-130.

**12. Acknowledgement** 

**13. References** 


is acknowledged for her help in formatting this manuscript.

Fig. 14. Photomicrograph of duodenal biopsy from an IPSID patient diagnosed at stage A. Note flattening of mucosa with loss of villous architecture. Lamina propria shows diffuse sheets of plasma cells (H&E A & B).

## **10.1 Conclusions**


## **11. Hepatitis B virus (HBV), Hepatitis C virus (HCV) & Hepatocellular carcinoma (HCC)**

Developing countries bear major burden of 'Hepatitis B & C' for the obvious reasons i.e., insufficient or no screening of transfused blood, multiple use of contaminated needles, drug abuse and overall poor safety standards (Jafri et al, 2006). Pakistan for instance carries a very high burden of hepatitis B & C. There are estimated 7-9 million carriers of hepatitis B with a carrier rate of 3-5% (Ali et al, 2011). Genotype D (63.71%) is the most prevalent genotype in Pakistani population (Ali et al, 2011). The overall anti-HCV prevalence rate is 14-15% in general population of Pakistan (Idrees et al, 2009). Though hepatitis C is a major culprit for the reasons including increased potential to cause '*chronic liver disease*' and '*no vaccination*'; hepatitis B is still highly prevalent as well. A large proportion of population is still not vaccinated for hepatitis B, though now it is included in EPI (Extended Program of Immunization) program by the government and all newborns do get it.

In a recent study from Pakistan out of 161 subjects with HCC, chronic HCV infection was identified as a major risk factor (63.44% of tested HCC patients) for the development of HCC (Idrees et a, 2009). The time from HCV infection to the clinical appearance of cancer ranged from 10-50 years. In this population with HCC among various genotypes of HCV, genotype 3a was predominant (40.96%), followed by 3b in 15.66%, 1a in 9.63% and 1b in 2.40%.

On the face of such a high burden of Hepatitis B & C, hepatocellular carcinoma (HCC) is one of the common malignancies in our practice arising in a background of liver cirrhosis (Figure 15). Besides several other environmental factors are also playing their role in the causation of HCC. In Karachi, a port city of about 15 million inhabitants with hot and humid climate, it is reported that in wholesale markets selling food commodities without proper packing and preservation, a very high content of *'aspergillus flavus'* is isolated which is a known cause of HCC. Unfortunately HCC is a bad cancer and in our experience life expectancy at the time of diagnosis is not more than six months.

Fig. 15. Photomicrograph of a liver biopsy in a patient infected with Hepatitis C. Note fibrous band dividing the liver parenchyma into varying size nodules (↑A, Trichrome). Figure B shows a well differentiated hepatocellular carcinoma (HCC) arising in this patient (H&E).

## **11.1 Conclusions**

330 Modern Approaches To Quality Control

Fig. 14. Photomicrograph of duodenal biopsy from an IPSID patient diagnosed at stage A. Note flattening of mucosa with loss of villous architecture. Lamina propria shows diffuse



Developing countries bear major burden of 'Hepatitis B & C' for the obvious reasons i.e., insufficient or no screening of transfused blood, multiple use of contaminated needles, drug abuse and overall poor safety standards (Jafri et al, 2006). Pakistan for instance carries a very high burden of hepatitis B & C. There are estimated 7-9 million carriers of hepatitis B with a carrier rate of 3-5% (Ali et al, 2011). Genotype D (63.71%) is the most prevalent genotype in Pakistani population (Ali et al, 2011). The overall anti-HCV prevalence rate is 14-15% in general population of Pakistan (Idrees et al, 2009). Though hepatitis C is a major culprit for the reasons including increased potential to cause '*chronic liver disease*' and '*no vaccination*'; hepatitis B is still highly prevalent as well. A large proportion of population is still not vaccinated for hepatitis B, though now it is included in EPI (Extended Program of

In a recent study from Pakistan out of 161 subjects with HCC, chronic HCV infection was identified as a major risk factor (63.44% of tested HCC patients) for the development of HCC (Idrees et a, 2009). The time from HCV infection to the clinical appearance of cancer ranged from 10-50 years. In this population with HCC among various genotypes of HCV, genotype

On the face of such a high burden of Hepatitis B & C, hepatocellular carcinoma (HCC) is one of the common malignancies in our practice arising in a background of liver cirrhosis (Figure 15). Besides several other environmental factors are also playing their role in the causation of HCC. In Karachi, a port city of about 15 million inhabitants with hot and humid climate, it is reported that in wholesale markets selling food commodities without proper packing and preservation, a very high content of *'aspergillus flavus'* is isolated which is a known cause of HCC. Unfortunately HCC is a bad cancer and in our experience life

3a was predominant (40.96%), followed by 3b in 15.66%, 1a in 9.63% and 1b in 2.40%.

found in Mediterranean region with sporadic cases in sub-continent.

**11. Hepatitis B virus (HBV), Hepatitis C virus (HCV) & Hepatocellular** 


**A B**

Immunization) program by the government and all newborns do get it.

expectancy at the time of diagnosis is not more than six months.

sheets of plasma cells (H&E A & B).

**10.1 Conclusions** 

**carcinoma (HCC)** 


## **12. Acknowledgement**

Dr Samina Noorali & Dr Syed Adnan Ali who completed their PhD under my supervision and participated in experimental work & original work on EBV and HPV in T-NHL & Oral cancer respectively included in this chapter are duly acknowledged. Ms. Shamsha Punjwani is acknowledged for her help in formatting this manuscript.

## **13. References**


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**18** 

*Turkey* 

**Blood Irradiation** 

*1Istanbul University, Oncology Institute,* 

*2Istanbul University, Oncology Institute, Department of Medical Pyhsics, Fatih, Istanbul 3Istanbul University, Oncology Institute, Department of Medical Pyhsics, Fatih, Istanbul,* 

*Department of Medical Oncology, Fatih, Istanbul* 

Sezer Saglam1, Aydin Cakir2 and Seyfettin Kuter3

Transfusion-associated graft-versus-host disease (TA-GVHD) is a possible complication of blood transfusion that occurs when viable donor T-lymphocytes proliferate and engraft in immunodeficient patients after transfusion. Presently, the only method accepted to prevent TA-GVHD is the irradiation of blood and its components before transfusion (Moroff and Luban 1997)). Ionizing irradiation eliminates the functional and proliferative capacities of Tlymphocytes leaving other blood components, especially erythrocytes, granulocytes and platelets, functional and viable. This is possible because T-lymphocytes are more radiosensitive than other blood components (Masterson and Febo, 1992).To carry out the irradiation of blood specially designed commercial irradiators exist, usually localized in

Blood and blood components may be treated with ionizing radiation, such as gamma rays from 137Cs or 60Co sources, and from self-contained X-ray (bremsstrahlung) units and medical linear X-ray (bremsstrahlung) and electron accelerators used primarily for radiotherapy. However, teletherapy machines, such as linear accelerators or 60Co units already available at the hospital, may also be used for the same purpose (Moroff 1997),

Blood irradiation specifications include a lower limit of absorbed dose, and may include an upper limit or central target dose. For a given application, any of these values may be prescribed by regulations that have been established on the basis of available scientific data. The absorbed dose range for blood irradiation is typically 15 Gy to 50 Gy. In some jurisdictions, the absorbed dose range for blood irradiation is 25 Gy to 50 Gy. The energy range is typically from approximately 40 keV to 5 MeV for photons, and up to 10 MeV for electrons. For each blood irradiator, an absorbed-dose rate at a reference position within the canister is measured by the manufacturer as part of acceptance testing using a reference-standard dosimetry system. That reference-standard measurement is used to calculate the timer setting required to deliver the specified absorbed dose to the center of the canister with blood and blood components, or other reference position. Either relative or absolute absorbed dose measurements are performed within the blood or blood-equivalent volume for determining the absorbed-dose distribution. Accurate radiation dosimetry at a reference position which

**1. Introduction** 

blood banks, and dedicated exclusively to this task.

improving the cost/benefit ratio of the process.


## **Blood Irradiation**

Sezer Saglam1, Aydin Cakir2 and Seyfettin Kuter3

*1Istanbul University, Oncology Institute, Department of Medical Oncology, Fatih, Istanbul 2Istanbul University, Oncology Institute, Department of Medical Pyhsics, Fatih, Istanbul 3Istanbul University, Oncology Institute, Department of Medical Pyhsics, Fatih, Istanbul, Turkey* 

## **1. Introduction**

334 Modern Approaches To Quality Control

Settle K, Posner MR, Schumaker LM, Tan M. Suntharalingam M. Goloubeva O, Strome SE,

Settle K, Taylor R, Wolf J, Kwok Y, Cullen K, Carter K, Ord R, Zimrin A, Strome S,

Sherpa ATL, Clifford G, Vaccarella S, Shrestha S, Nygard N, Karki BS, Snijders PJ, Meijer CJ,

Syed S, Khalil S & Pervez S. (2011). Anaplastic Large Cell Lymphoma: The most common Tcell lymphoma in Pakistan, Asia Pacific J Cancer Prev, 12(3):685-689. Wu RF, Dai M, Qiao YL, Clifford GM, Liu ZH, Arslan A, Li N, Shi JF, Snijders PJ, Meijer CJ

urbanisation. *Int J Cancer*, Sept, 121(6):1306-1311.

(Philadel) Sept, 2(9) 776-781.

April, 115 (8) 1744-1752.

June, 35(3):233-240.

Haddad RI, Patel SS, Cambell EV 3rd, Sarlis N, Lorch J & Cullen KJ. (2009). Racial survival disparity in head and neck cancer results from low prevalence of human papillomavirus infection in black oropharyngeal cancer patients. *Cancer Prev Res*

Suntharalingam M. (2009). Race impacts outcome in stage III/IV squamous cell carcinomas of the head and neck after concurrent chemoradiation therapy. *Cancer*,

& Franceschi S.. (2010). Human papillomavirus infection in women with and without cervical cancer in Nepal. *Cancer Causes Control, March,* 21 (3):313-330. Shiboski CH, Schmidt BL & Jordan RC. (2007). Racial disparity in stage at diagnosis and

survival among adults with oral cancer in the US. Community. *Dent Oral Epidemiol*,

&, Franceschi S. (2007). Human papillomavirus infection in women in Shenzhen city, People's republic of China, a population typical of recent Chinese

Transfusion-associated graft-versus-host disease (TA-GVHD) is a possible complication of blood transfusion that occurs when viable donor T-lymphocytes proliferate and engraft in immunodeficient patients after transfusion. Presently, the only method accepted to prevent TA-GVHD is the irradiation of blood and its components before transfusion (Moroff and Luban 1997)). Ionizing irradiation eliminates the functional and proliferative capacities of Tlymphocytes leaving other blood components, especially erythrocytes, granulocytes and platelets, functional and viable. This is possible because T-lymphocytes are more radiosensitive than other blood components (Masterson and Febo, 1992).To carry out the irradiation of blood specially designed commercial irradiators exist, usually localized in blood banks, and dedicated exclusively to this task.

Blood and blood components may be treated with ionizing radiation, such as gamma rays from 137Cs or 60Co sources, and from self-contained X-ray (bremsstrahlung) units and medical linear X-ray (bremsstrahlung) and electron accelerators used primarily for radiotherapy. However, teletherapy machines, such as linear accelerators or 60Co units already available at the hospital, may also be used for the same purpose (Moroff 1997), improving the cost/benefit ratio of the process.

Blood irradiation specifications include a lower limit of absorbed dose, and may include an upper limit or central target dose. For a given application, any of these values may be prescribed by regulations that have been established on the basis of available scientific data.

The absorbed dose range for blood irradiation is typically 15 Gy to 50 Gy. In some jurisdictions, the absorbed dose range for blood irradiation is 25 Gy to 50 Gy. The energy range is typically from approximately 40 keV to 5 MeV for photons, and up to 10 MeV for electrons.

For each blood irradiator, an absorbed-dose rate at a reference position within the canister is measured by the manufacturer as part of acceptance testing using a reference-standard dosimetry system. That reference-standard measurement is used to calculate the timer setting required to deliver the specified absorbed dose to the center of the canister with blood and blood components, or other reference position. Either relative or absolute absorbed dose measurements are performed within the blood or blood-equivalent volume for determining the absorbed-dose distribution. Accurate radiation dosimetry at a reference position which

Blood Irradiation 337

quantified in such reports. In addition, investigators have suggested that the number of T lymphocytes present in a product that causes GVHD may depend on the extent of patient immunocompetence at the time of transfusion . It is likely that the greater the degree of immunosuppression, the fewer the viable T lymphocytes that will be required to produce GVHD in susceptible patients. In a recent review, it was suggested that cytotoxic T lymphocytes, or interleukin-2-secreting precursors of helper T lymphocytes,may be more predictive of GVHD than the number of proliferating T cells alone. Accordingly,this suggests that until further data are available to confirm adequate removal of these T-cell subtypes by leucoreduction, irradiation should be used for blood products destined for patients at risk for GVHD. Irradiated red cells undergo an enhanced efflux of potassium during storage at 10 to 60 C.Comparable levels of potassium leakage occur with or without prestorage leucoreduction. Washing units of red cells before transfusion to reduce the supernatant potassium load does not seem to be warranted for most red cell transfusions because posfinfusion dilution prevents the increase in plasma potassium. On the other hand, when irradiated red cells are used for neonatal exchange transfusion or the equivalent of a whole blood exchange is anticipated, red cell washing should be considered to prevent the possible adverse effects caused by hyperkalemia associated with irradiation and storage. Blood components given to recipients, whether immunocompromised or immunocompetent, that contain lymphocytes that are homozygous for an HLA haplotype that is shared with the recipient, pose a specific risk for TA-GVHD. This circumstance occurs when first and second degree relatives serve as directed donors s-ll and when HLA matched platelet components donated by related or unrelated individuals are being transfused.

Irradiation of blood components has been recommended in these situations.

has not yet been delineated.

**4. Quality assurance guidelines** 

plasma.

Platelet components that have low levels of leucocytes because of the apheresis process and/or leucofiltration should also be irradiated if intended for transfusion to susceptible patients. This is because the minimum number of T lymphocytes that induces TA-GVHD

Fresh frozen plasma does not need to be irradiated routinely because it is generally accepted that the freezing and thawing processes destroy the T lymphocytes that are present in such

During the past 2 years, there have been two brief articles suggesting that immunocompetent progenitor cells may be present in frozen-thawed plasma; the authors therefore suggested that frozen-thawed plasma may need to be irradiated. Further studies are needed to validate these findings and to assess whether the number of immunocompetent cells, that may be present in thawed fresh frozen plasma, is sufficient to induce GVHD. In rare instances, when nonfrozen plasma (termed *fresh plasma)* is transfused, it should be irradiated because of the presence of a sizable number of viable lymphocytes,

Various dosimetry techniques have been used to measure the dose to blood products. These include thermoluminescent dosimeters (TLD); alanine, ferrous sulphate, red perspex, metaloxide semiconductor field effect transistors (MOSFETs) and chloroform */*dithoizone*/*parafin mixture (Hillyer *et al* 1993). Recently radiochromic film was shown to be an adequate dosimeter for blood irradiation (Butson *et al* 1999). The most prevalent method relies on TLDs and tries to ascertain the causes and variations in delivered *in vitro* 

approximately 1 x10 7 cells in a component prepared from a unit of whole blood.

could be the position of the maximum absorbed dose (Dmax) or minimum absorbed dose (Dmin) offers a quantitative, independent method to monitor the radiation process.

Dosimetry is part of a measurement quality assurance program that is applied to ensure that the radiation process meets predetermined specifications.

#### **2. Blood irradiators**

The basic operating principles and configurations of a free-standing irradiator with either 137Cs source or a linear accelerator are shown schematically in Figure 1. With a freestanding 137Cs irradiator, the blood components are contained within a metal canister that is a rotating turntable. Continuous rotation allows for the rays, originating from one to four closely positioned pencil sources, to penetrate all portions of the blood component. The number of sources and their placement depend on the instrument and model. The speed of rotation of the turntable also depends on the make or model of the instrument. A lead shield encloses the irradiation chamber. Free standing irradiators employing 60 Co as the source of rays are comparable except that the canister containing the blood component does not rotate during the irradiation process; rather, tubes of 60 Co are placed in a circular array around the entire canister within the lead chamber. When free standing irradiators are used, the rays are attenuated as they pass through air and blood but at different rates. The magnitude of attenuation is greater with 137Cs than with 60 Co.

Linear accelerators generate a beam of X-rays over a field of given dimension. Routinely, the field is projected on a table-top structure. The blood component is placed (flat) between two sheets of biocompatible plastic several centimeters thick.The plastic on the top of the blood component (ie,nearer to the radiation source) generates electronic equilibrium of the secondary electrons at the point where they pass through the component container.The plastic sheet on the bottom of the blood component provides for irradiation back-scattering that helps to ensure the homogenous delivery of the x-rays. The blood component is usually left stationary when the entire x-ray dose is being delivered. Alternatively it may be flipped over when one half of the dose has been delivered; this process involves turning off and restarting the linear accelerator during the irradiation procedure. Although it seems as if the practice of flipping is not required,further data are needed.

#### **3. Blood components**

The risk of GVHD for patients, all components that might contain viable T lymphocytes should be irradiated. These include units of whole blood and cellular components (red cells, platelets, granulocytes),whether prepared from whole blood or by apheresis. All types of red cells should be irradiated, whether they are suspended in citrated plasma or in an additive solution. There are recent data supporting the retention of the quality of irradiated red cells after freezing and thawing.If frozen thawed units are intended for GVHDsusceptible individuals and have not been previously irradiated,they should be irradiated because it is known that such components contain viable T lymphocytes.Filtered red cell products should also be irradiated.Extensive leucoreduction through filtration may decrease the potential for GVHD and serve as an alternative to irradiation in the future when questions about the minimum level of viable T lymphocytes that can lead to GVHD are resolved. There are reports of TA-GVHD in patients who received leucodepleted (filtered) red cells; however,the extent of leucoreduction of the components was not uniformly

could be the position of the maximum absorbed dose (Dmax) or minimum absorbed dose

Dosimetry is part of a measurement quality assurance program that is applied to ensure that

The basic operating principles and configurations of a free-standing irradiator with either 137Cs source or a linear accelerator are shown schematically in Figure 1. With a freestanding 137Cs irradiator, the blood components are contained within a metal canister that is a rotating turntable. Continuous rotation allows for the rays, originating from one to four closely positioned pencil sources, to penetrate all portions of the blood component. The number of sources and their placement depend on the instrument and model. The speed of rotation of the turntable also depends on the make or model of the instrument. A lead shield encloses the irradiation chamber. Free standing irradiators employing 60 Co as the source of rays are comparable except that the canister containing the blood component does not rotate during the irradiation process; rather, tubes of 60 Co are placed in a circular array around the entire canister within the lead chamber. When free standing irradiators are used, the rays are attenuated as they pass through air and blood but at different rates. The

Linear accelerators generate a beam of X-rays over a field of given dimension. Routinely, the field is projected on a table-top structure. The blood component is placed (flat) between two sheets of biocompatible plastic several centimeters thick.The plastic on the top of the blood component (ie,nearer to the radiation source) generates electronic equilibrium of the secondary electrons at the point where they pass through the component container.The plastic sheet on the bottom of the blood component provides for irradiation back-scattering that helps to ensure the homogenous delivery of the x-rays. The blood component is usually left stationary when the entire x-ray dose is being delivered. Alternatively it may be flipped over when one half of the dose has been delivered; this process involves turning off and restarting the linear accelerator during the irradiation procedure. Although it seems as if the

The risk of GVHD for patients, all components that might contain viable T lymphocytes should be irradiated. These include units of whole blood and cellular components (red cells, platelets, granulocytes),whether prepared from whole blood or by apheresis. All types of red cells should be irradiated, whether they are suspended in citrated plasma or in an additive solution. There are recent data supporting the retention of the quality of irradiated red cells after freezing and thawing.If frozen thawed units are intended for GVHDsusceptible individuals and have not been previously irradiated,they should be irradiated because it is known that such components contain viable T lymphocytes.Filtered red cell products should also be irradiated.Extensive leucoreduction through filtration may decrease the potential for GVHD and serve as an alternative to irradiation in the future when questions about the minimum level of viable T lymphocytes that can lead to GVHD are resolved. There are reports of TA-GVHD in patients who received leucodepleted (filtered) red cells; however,the extent of leucoreduction of the components was not uniformly

(Dmin) offers a quantitative, independent method to monitor the radiation process.

the radiation process meets predetermined specifications.

magnitude of attenuation is greater with 137Cs than with 60 Co.

practice of flipping is not required,further data are needed.

**2. Blood irradiators** 

**3. Blood components** 

quantified in such reports. In addition, investigators have suggested that the number of T lymphocytes present in a product that causes GVHD may depend on the extent of patient immunocompetence at the time of transfusion . It is likely that the greater the degree of immunosuppression, the fewer the viable T lymphocytes that will be required to produce GVHD in susceptible patients. In a recent review, it was suggested that cytotoxic T lymphocytes, or interleukin-2-secreting precursors of helper T lymphocytes,may be more predictive of GVHD than the number of proliferating T cells alone. Accordingly,this suggests that until further data are available to confirm adequate removal of these T-cell subtypes by leucoreduction, irradiation should be used for blood products destined for patients at risk for GVHD. Irradiated red cells undergo an enhanced efflux of potassium during storage at 10 to 60 C.Comparable levels of potassium leakage occur with or without prestorage leucoreduction. Washing units of red cells before transfusion to reduce the supernatant potassium load does not seem to be warranted for most red cell transfusions because posfinfusion dilution prevents the increase in plasma potassium. On the other hand, when irradiated red cells are used for neonatal exchange transfusion or the equivalent of a whole blood exchange is anticipated, red cell washing should be considered to prevent the possible adverse effects caused by hyperkalemia associated with irradiation and storage. Blood components given to recipients, whether immunocompromised or immunocompetent, that contain lymphocytes that are homozygous for an HLA haplotype that is shared with the recipient, pose a specific risk for TA-GVHD. This circumstance occurs when first and second degree relatives serve as directed donors s-ll and when HLA matched platelet components donated by related or unrelated individuals are being transfused. Irradiation of blood components has been recommended in these situations.

Platelet components that have low levels of leucocytes because of the apheresis process and/or leucofiltration should also be irradiated if intended for transfusion to susceptible patients. This is because the minimum number of T lymphocytes that induces TA-GVHD has not yet been delineated.

Fresh frozen plasma does not need to be irradiated routinely because it is generally accepted that the freezing and thawing processes destroy the T lymphocytes that are present in such plasma.

During the past 2 years, there have been two brief articles suggesting that immunocompetent progenitor cells may be present in frozen-thawed plasma; the authors therefore suggested that frozen-thawed plasma may need to be irradiated. Further studies are needed to validate these findings and to assess whether the number of immunocompetent cells, that may be present in thawed fresh frozen plasma, is sufficient to induce GVHD. In rare instances, when nonfrozen plasma (termed *fresh plasma)* is transfused, it should be irradiated because of the presence of a sizable number of viable lymphocytes, approximately 1 x10 7 cells in a component prepared from a unit of whole blood.

## **4. Quality assurance guidelines**

Various dosimetry techniques have been used to measure the dose to blood products. These include thermoluminescent dosimeters (TLD); alanine, ferrous sulphate, red perspex, metaloxide semiconductor field effect transistors (MOSFETs) and chloroform */*dithoizone*/*parafin mixture (Hillyer *et al* 1993). Recently radiochromic film was shown to be an adequate dosimeter for blood irradiation (Butson *et al* 1999). The most prevalent method relies on TLDs and tries to ascertain the causes and variations in delivered *in vitro* 

Blood Irradiation 339

Dose mapping measures the delivery of radiation within a simulated blood component or over an area in which a blood component is placed. This applies to an irradiation field when a linear accelerator is used or to the canister of a free-standing irradiator. Dose mapping is the primary means of ensuring that the irradiation process is being conducted correctly. It documents that the intended dose of irradiation is being delivered at a specific location (such as the central midplane of a canister), and it describes how the delivered irradiation dose varies within a simulated component or over a given area. This allows conclusions to be drawn about the maximum and minimum doses being delivered. Dose mapping should be performed with sensitive dosimetry techniques. A number of commercially available systems have been developed in recent years. Other quality assurance measures that need to be done include the routine confirmation that the turntable is operating correctly (for 137Cs rradiators), measurements to ensure that the timing device is accurate, and the periodic lengthening of the irradiation time to correct for source decay. With linear accelerators, it is necessary to measure the characteristics of the x-ray beam to ensure consistency of delivery. Confirming that a blood component has, in actuality, been irradiated is also an important part of a quality assurance program. At least one commercial firm has developed an

For free-standing irradiators, a dose-mapping procedure will measure the delivered dose throughout the circular canister in which the blood component is placed. To establish a twodimensional map, a dosimetry system is placed in a canister that is completely filled with a blood/tissue-compatible phantom composed of water or an appropriate plastic such as polystyrene. The dosimetry material is placed within the phantom in a predetermined way. This approach provides data that describe the minimum levels of irradiation that would be absorbed by a blood component placed in the canister and recognizes that maximum attenuation will occur when the canister is completely filled with a blood-compatible material. Relevantly, it was shown recently that the absorbed dose at the central midplane of a canister (ie, at the center point) decreased by approximately 25% (from 3100 to 2500 cGy) in a 137Cs irradiator (JL Shepherd and Associates, San Francisco, CA) when the loading of the canister was changed from 0% (air) to 100% (with blood components). An irradiationsensitive film dosimetry system (International Speciality Products) that will be described later in this report was used for this purpose. A linear relationship was observed between the amount of fill and the measured central dose. With 1 and 2 units of blood components, the central dose relative to air was 0.98 and 0.93. The minimum and maximum levels were influenced in the same manner as the central dose on decreasing the proportion of the canister that contained air. Other studies have shown that the extent of variability in the dose delivered to the interior of simulated blood units (water or saline in plastic blood storage containers) depended on the model of the 137Cs free-standing irradiator. An immobilized grid of thennoluminescent dosimeters in a plastic sheet were placed within the simulated blood units to measure dose delivery. See the section on dosimetry systems in use. It was also shown that a spacer into the bottom of the canister increases the minimum level of radiation within the simulated blood units as expected from the results of fullcanister dose mapping involving a phantom.The extent of variability with 137Cs irradiations is influenced by a number of factors, including the number of sources, turntable speed, and the presence of a spacer at the bottom of the canister.These studies underscore the need for

indicator label for this purpose.

**5. Dose mapping with free-standing irradiators** 

dose across an 'active' treatment volume in a dedicated blood box for standard x-ray beams.

Most dosimeters have significant energy dependence at photon and electron energies less than 100 keV, so great care must be exercised when measuring absorbed dose in that energy range.

This practice outlines irradiator installation qualification, operational qualification, performance qualification, and routine product processing dosimetric procedures to be followed in the irradiation of blood and blood components by the blood-banking community. If followed, these procedures will help to ensure that the products processed with ionizing radiation from gamma, X-rays (bremsstrahlung), or electron sources receive absorbed doses within a predetermined range.

One must document that the instrument being used for irradiation is operating appropriately and confirm that blood components had been irradiated.To assure that the irradiation process is being conducted correctly, specific procedures are recommended for free-standing irradiators and linear accelerators, which are summarized in Tables 1 and 2. The procedures to be used with free-standing irradiators are an update to the guidelines provided several years ago by Anderson. Included are current recommendations from the FDA.


Table 1. Recommended Quality Assurance Measures to be Used with Free-Standing Gamma Irradiators.

Fig. 1. With a freestanding 137Cs irradiator, the blood components are contained within a metal canister that is positioned on a rotating turntable.

dose across an 'active' treatment volume in a dedicated blood box for standard x-ray

Most dosimeters have significant energy dependence at photon and electron energies less than 100 keV, so great care must be exercised when measuring absorbed dose in that energy

This practice outlines irradiator installation qualification, operational qualification, performance qualification, and routine product processing dosimetric procedures to be followed in the irradiation of blood and blood components by the blood-banking community. If followed, these procedures will help to ensure that the products processed with ionizing radiation from gamma, X-rays (bremsstrahlung), or electron sources receive

One must document that the instrument being used for irradiation is operating appropriately and confirm that blood components had been irradiated.To assure that the irradiation process is being conducted correctly, specific procedures are recommended for free-standing irradiators and linear accelerators, which are summarized in Tables 1 and 2. The procedures to be used with free-standing irradiators are an update to the guidelines provided several years

ago by Anderson. Included are current recommendations from the FDA.

Isotop decay factor Annually for 137Cs ;montly for 60Co Dose map Annualy for 137Cs; annually for 60Co

Table 1. Recommended Quality Assurance Measures to be Used with Free-Standing Gamma

Fig. 1. With a freestanding 137Cs irradiator, the blood components are contained within a

Measure Frequency

Radiation leakage daily Timer accuracy montly Turntable daily

metal canister that is positioned on a rotating turntable.

beams.

range.

Irradiators.

absorbed doses within a predetermined range.

Dose mapping measures the delivery of radiation within a simulated blood component or over an area in which a blood component is placed. This applies to an irradiation field when a linear accelerator is used or to the canister of a free-standing irradiator. Dose mapping is the primary means of ensuring that the irradiation process is being conducted correctly. It documents that the intended dose of irradiation is being delivered at a specific location (such as the central midplane of a canister), and it describes how the delivered irradiation dose varies within a simulated component or over a given area. This allows conclusions to be drawn about the maximum and minimum doses being delivered. Dose mapping should be performed with sensitive dosimetry techniques. A number of commercially available systems have been developed in recent years. Other quality assurance measures that need to be done include the routine confirmation that the turntable is operating correctly (for 137Cs rradiators), measurements to ensure that the timing device is accurate, and the periodic lengthening of the irradiation time to correct for source decay. With linear accelerators, it is necessary to measure the characteristics of the x-ray beam to ensure consistency of delivery. Confirming that a blood component has, in actuality, been irradiated is also an important part of a quality assurance program. At least one commercial firm has developed an indicator label for this purpose.

## **5. Dose mapping with free-standing irradiators**

For free-standing irradiators, a dose-mapping procedure will measure the delivered dose throughout the circular canister in which the blood component is placed. To establish a twodimensional map, a dosimetry system is placed in a canister that is completely filled with a blood/tissue-compatible phantom composed of water or an appropriate plastic such as polystyrene. The dosimetry material is placed within the phantom in a predetermined way. This approach provides data that describe the minimum levels of irradiation that would be absorbed by a blood component placed in the canister and recognizes that maximum attenuation will occur when the canister is completely filled with a blood-compatible material. Relevantly, it was shown recently that the absorbed dose at the central midplane of a canister (ie, at the center point) decreased by approximately 25% (from 3100 to 2500 cGy) in a 137Cs irradiator (JL Shepherd and Associates, San Francisco, CA) when the loading of the canister was changed from 0% (air) to 100% (with blood components). An irradiationsensitive film dosimetry system (International Speciality Products) that will be described later in this report was used for this purpose. A linear relationship was observed between the amount of fill and the measured central dose. With 1 and 2 units of blood components, the central dose relative to air was 0.98 and 0.93. The minimum and maximum levels were influenced in the same manner as the central dose on decreasing the proportion of the canister that contained air. Other studies have shown that the extent of variability in the dose delivered to the interior of simulated blood units (water or saline in plastic blood storage containers) depended on the model of the 137Cs free-standing irradiator. An immobilized grid of thennoluminescent dosimeters in a plastic sheet were placed within the simulated blood units to measure dose delivery. See the section on dosimetry systems in use. It was also shown that a spacer into the bottom of the canister increases the minimum level of radiation within the simulated blood units as expected from the results of fullcanister dose mapping involving a phantom.The extent of variability with 137Cs irradiations is influenced by a number of factors, including the number of sources, turntable speed, and the presence of a spacer at the bottom of the canister.These studies underscore the need for

Blood Irradiation 341

predominant irradiation source for blood. More recently, they have been developed also for use with 60Co irradiators. Thermolumeniscent dosimeters (TLD chips) are one type of routine dosimeter. TLD chips are small plastic chips with millimeter dimensions having a crystal lattice that absorbs ionizing radiation. Specialized equipment is used to release and measure the energy absorbed by the TLD chip at the time of the test irradiation. In one commercially available system, chips are placed at nine different locations within a polystyrene phantom that fits into the canister of the IBL 437C irradiator (CIS US, Inc,Bedford, MA). The timer setting used routinely for an instrument is used in the test

Method Measurement type Thermoluminescent Dosimetry Emission of light Radiochromic(GafChromic) film Optic density Mosfet(metal –oxide field effect transistors) Voltage detection

Table 3. Dosimetric systems in different clinics.

Alanine/ESR ESR signal-Magnetic field

There are two systems that use radiochromic film. On exposure to irradiation, the film darkens, resulting in an increase in optical density. The optical density, determined at various locations on the film, is linearly proportional to the absorbed irradiation dose. Standard films that are irradiated at a given dose level with a calibrated source at a national reference laboratory provide the means to assess the absolute level of absorbed irradiation.This type of dosimeter is basically an x-ray film comparable with that used in clinical practice. With this device, the map that is developed identifies the absorbed irradiation dose that is measured at a large number of locations. In one system, a film contained in a thin water-tight casement is placed into the canister (International Specialty Products,Wayne, NJ), This approach is being used with a variety of irradiators. The canister is filled completely with water before the irradiation procedure.This system provides a direct readout of the dose that is delivered throughout the canister. The timer setting used routinely is employed for the test procedure. In a second system, a film having different radiation sensitive characteristics is embedded between two halves of a circular-fitting polystyrene plastic phantom (Nordion Internation, Canada, Ontario). Irradiation of specialized films is performed with a number of timer settings, each being larger than that used routinely. The map produced is normalized for a central midplane dose of 2500 cGy. The time to produce the 2500 cGy will have been predetermined with a different dosimeter system, the Fricke system, in which absorbed radiation causes a change in the state of a iron salt that can be assessed spectrophotometrically. Another approach to irradiation dose mapping employs a solid-state electronic dosimeter that is technically referred to as a *metaloxide silicon field effect transistor* (MOSFET). A board contains a number of small transistors in an arrangement that provides data for a dose map. This board is placed between two halves of a circular polystyrene phantom that fits into the canister. This dosimeter absorbs and stores the radiation dose imparted to it electronically . The radiation causes the formation of holes in the metal-oxide layer that becomes trapped within the transistor. The magnitude of the holes is evaluated by measuring the voltage across the transistor with a voltmeter. The voltages measured are converted to absorbed dose. With each dosimetry system, measurements are used to express the absorbed irradiation dose of cGrays. All dosimetry

procedure.

consistency in loading the canister.Attenuation of the irradiation dose delivered is a function of physical density, electronic density, and atomic number with three major processes: photoelectric, Compton, and pair production. In practical terms, attenuation is caused when the irradiation enters a liquid, such as water or blood. The extent of attenuation depends on a number of factors,including the dimensions of the canister. In a fully filled canister, as is used for dose mapping, the attenuation will increase as the irradiation transverses to the center point. The dose map that is generated describes the dose distribution. As depicted in the theoretical dose map shown in Figure 2, the edges of the canister are exposed to a greater dose of irradiation compared with the center line because the attenuation is less in the periphery. The attenuation with 60 Co is less than that seen with 137Cs.

When an irradiator is purchased, the distributor will provide a central dose level that is determined in a blood-compatible environment. In the 1970s and 1980s manufacturers provided a central dose that was determined in air, resulting in the use of timer settings that provided for a dose level that was somewhat less than what was expected. Subsequent to the issuing of the FDA guidelines in July 1993 and the use of dose mapping, it has been necessary to readjust irradiation times with some instruments because the attenuation effect had not been considered previously.

A theoretical two-dimensional dose map describing the irradiation dose distribution through a fully filled canister of a free-standing 137Cs irradiator is shown in Figure 2. To obtain this dose map,dosimeters would have been positioned in the central axis and the edge of circular canister from the top to the bottom of the canister. The y dimension of the map depicts the top to bottom axis of the canister, whereas the x dimension depicts the cross-sectional axis. For the theoretical situation described in Figure 2, the central midplane dose is 2560 cGy, slightly above the minimum standard of 2500 cGy, and the minimum dose is 1750 cGy. In this irradiation dose map, the minimum dose is at the central bottom of the canister, a common finding in actual practice.

The dose map can also be used to assess whether the turntable of a 137Cs irradiator is rotating in an appropriate manner. The occurrence of comparable readings at the two edges of the two-dimensional map, as depicted in the theoretical dose map, indicates that the canister is rotating evenly in front of the 137Cs source. If the turntable were not rotating, the dose levels at the edge of the map closest to the source would be much higher than that found on the opposite edge, ie, the side located distant to the source. According to the 1993 recommendations from the FDA, dose mapping should be performed routinely on an annual basis and after a major repair, especially one involving the sample handling apparatus such as the turntable.

#### **6. Dosimetry systems**

The delivered irradiation dose can be measured by a variety of dosimetry systems. In recent years, several commercial interests have developed complete systems for use with freestanding irradiators; each system consists of a phantom that fills the canister and a sensitive dosimetry system. Three main types of dosimetry measurement systems are available (Table 3).

These dosimeters are referred to as routine dosimeters. They are calibrated against standard systems, usually at national reference laboratories such as the National Institute of Standards and Technology in the United States. The routine dosimeter measurement systems were initially developed for use with 137Cs irradiators because this is the

consistency in loading the canister.Attenuation of the irradiation dose delivered is a function of physical density, electronic density, and atomic number with three major processes: photoelectric, Compton, and pair production. In practical terms, attenuation is caused when the irradiation enters a liquid, such as water or blood. The extent of attenuation depends on a number of factors,including the dimensions of the canister. In a fully filled canister, as is used for dose mapping, the attenuation will increase as the irradiation transverses to the center point. The dose map that is generated describes the dose distribution. As depicted in the theoretical dose map shown in Figure 2, the edges of the canister are exposed to a greater dose of irradiation compared with the center line because the attenuation is less in

When an irradiator is purchased, the distributor will provide a central dose level that is determined in a blood-compatible environment. In the 1970s and 1980s manufacturers provided a central dose that was determined in air, resulting in the use of timer settings that provided for a dose level that was somewhat less than what was expected. Subsequent to the issuing of the FDA guidelines in July 1993 and the use of dose mapping, it has been necessary to readjust irradiation times with some instruments because the attenuation effect

A theoretical two-dimensional dose map describing the irradiation dose distribution through a fully filled canister of a free-standing 137Cs irradiator is shown in Figure 2. To obtain this dose map,dosimeters would have been positioned in the central axis and the edge of circular canister from the top to the bottom of the canister. The y dimension of the map depicts the top to bottom axis of the canister, whereas the x dimension depicts the cross-sectional axis. For the theoretical situation described in Figure 2, the central midplane dose is 2560 cGy, slightly above the minimum standard of 2500 cGy, and the minimum dose is 1750 cGy. In this irradiation dose map, the minimum dose is at the central bottom of the

The dose map can also be used to assess whether the turntable of a 137Cs irradiator is rotating in an appropriate manner. The occurrence of comparable readings at the two edges of the two-dimensional map, as depicted in the theoretical dose map, indicates that the canister is rotating evenly in front of the 137Cs source. If the turntable were not rotating, the dose levels at the edge of the map closest to the source would be much higher than that found on the opposite edge, ie, the side located distant to the source. According to the 1993 recommendations from the FDA, dose mapping should be performed routinely on an annual basis and after a major repair, especially one involving the sample handling

The delivered irradiation dose can be measured by a variety of dosimetry systems. In recent years, several commercial interests have developed complete systems for use with freestanding irradiators; each system consists of a phantom that fills the canister and a sensitive dosimetry system. Three main types of dosimetry measurement systems are available

These dosimeters are referred to as routine dosimeters. They are calibrated against standard systems, usually at national reference laboratories such as the National Institute of Standards and Technology in the United States. The routine dosimeter measurement systems were initially developed for use with 137Cs irradiators because this is the

the periphery. The attenuation with 60 Co is less than that seen with 137Cs.

had not been considered previously.

canister, a common finding in actual practice.

apparatus such as the turntable.

**6. Dosimetry systems** 

(Table 3).

predominant irradiation source for blood. More recently, they have been developed also for use with 60Co irradiators. Thermolumeniscent dosimeters (TLD chips) are one type of routine dosimeter. TLD chips are small plastic chips with millimeter dimensions having a crystal lattice that absorbs ionizing radiation. Specialized equipment is used to release and measure the energy absorbed by the TLD chip at the time of the test irradiation. In one commercially available system, chips are placed at nine different locations within a polystyrene phantom that fits into the canister of the IBL 437C irradiator (CIS US, Inc,Bedford, MA). The timer setting used routinely for an instrument is used in the test procedure.


Table 3. Dosimetric systems in different clinics.

There are two systems that use radiochromic film. On exposure to irradiation, the film darkens, resulting in an increase in optical density. The optical density, determined at various locations on the film, is linearly proportional to the absorbed irradiation dose. Standard films that are irradiated at a given dose level with a calibrated source at a national reference laboratory provide the means to assess the absolute level of absorbed irradiation.This type of dosimeter is basically an x-ray film comparable with that used in clinical practice. With this device, the map that is developed identifies the absorbed irradiation dose that is measured at a large number of locations. In one system, a film contained in a thin water-tight casement is placed into the canister (International Specialty Products,Wayne, NJ), This approach is being used with a variety of irradiators. The canister is filled completely with water before the irradiation procedure.This system provides a direct readout of the dose that is delivered throughout the canister. The timer setting used routinely is employed for the test procedure. In a second system, a film having different radiation sensitive characteristics is embedded between two halves of a circular-fitting polystyrene plastic phantom (Nordion Internation, Canada, Ontario). Irradiation of specialized films is performed with a number of timer settings, each being larger than that used routinely. The map produced is normalized for a central midplane dose of 2500 cGy. The time to produce the 2500 cGy will have been predetermined with a different dosimeter system, the Fricke system, in which absorbed radiation causes a change in the state of a iron salt that can be assessed spectrophotometrically. Another approach to irradiation dose mapping employs a solid-state electronic dosimeter that is technically referred to as a *metaloxide silicon field effect transistor* (MOSFET). A board contains a number of small transistors in an arrangement that provides data for a dose map. This board is placed between two halves of a circular polystyrene phantom that fits into the canister. This dosimeter absorbs and stores the radiation dose imparted to it electronically . The radiation causes the formation of holes in the metal-oxide layer that becomes trapped within the transistor. The magnitude of the holes is evaluated by measuring the voltage across the transistor with a voltmeter. The voltages measured are converted to absorbed dose. With each dosimetry system, measurements are used to express the absorbed irradiation dose of cGrays. All dosimetry

Blood Irradiation 343

are treated with x-rays, the instrument settings are very different than those used to treat oncology patients. Hence, additional periodic quality control measures, primarily to assess the dose delivered to blood components, are needed to ensure that linear accelerators are being operated appropriately when used for blood irradiation. Currently, there are no commercially available systems for assessing the dose delivered throughout the area of an irradiation field in which blood components are placed for treatment with x-rays. An ideal dosimeter for this purpose would be made of a tissue-compatible plastic phantom, containing appropriate dosimeter material and a covering that could be placed at the appropriate distance from the source. An alternative approach might involve the use of a blood bag filled with water (simulating a blood unit) containing TLD chips, as described earlier. In comparative studies using such simulated blood units, it was determined that radiation delivery was more uniform with linear accelerators than with 137Cs free-standing irradiators. This reflects the relative homogeneity of x-ray beams. In the absence of an available system modified for the irradiation of blood bags, the dose delivered throughout an irradiation field should be mapped with the dosimetric measuring system known as an *ionization chamber.* The ionization chamber is used to calibrate linear accelerators for patient use. In addition, on a yearly basis, dose mapping should be performed using a tissue-

In view of the widely divergent conditions that are used during the operation of linear accelerators, other parameters pertaining to the x-ray beam should be evaluated on at least a quarterly basis to provide assurance that the instrument is being used appropriately for the irradiation of blood components. The goal is to ensure that the instrument is being set in a consistent fashion. When setting a linear accelerator for blood component irradiation, the following should be measured: the distance between the x-ray source and the position where the blood components are to be placed; consistency in the strength of the x-ray beam; and (3) the intensity of the x-ray beam. The distance between the source and position on the table where blood components will be placed (referred to as the *target)* can be evaluated easily with a calibrated measuring device. This is a simple task that can be performed on a routine basis. The consistency of beam output can be evaluated by measuring the beam current. Beam intensity can be evaluated by measuring the ionization current in a monitoring ionization chamber array that can be expressed in terms of the number of photons delivered per square centimeter. These parameters should be assessed routinely as part of quality control programs used by radiation physicists. A code of practice was published in 1994 by the Radiation Therapy Committee of the American Association of Physicists in Medicine for the quality control of radiotherapy accelerators. The described practices are used routinely by radiation physicists. It would he prudent to ensure that an institution using a linear accelerator for blood irradiation follow these quality assurance

It is important to have positive confirmation that the irradiation process has taken place. This is to identify whether an operator fails to initiate the electronically controlled irradiation process or when the irradiation process is not performed because of instrumentation malfunction. A radiation-sensitive indicator label has been developed specifically for this purpose by International Speciality Products,Wayne, NJ. The label containing a radiationsensitive film strip is placed on the external surface of the blood

compatible phantom.

guidelines and recommendations.

**9. Confirming that irradiation occurred** 

measurements are associated with a degree of uncertainty or possible error. The magnitude of the uncertainty depends on the kind of dosimeter used. For most dosimeters, the level is 5% of the measured value. For a central absorbed dose level of 2560 cGy (see theoretical dose map in Fig 2) the value could be as high as 2788 cGy or as low as 2432 cGy. Correspondingly, a measured value of 2400 cGy could be as high as 2520 cGy or as low as 2380 cGy. Because the measured value could in actuality meet the 2500 cGy standard, it is appropriate to accept a value of 2400 cGy as meeting the current standard. The same approach should be used when evaluating the minimum value on a dose map. Albeit arbitrary and cautious, the actual minimum on an irradiation dose map should not be below 1500 cGy.

## **7. Precautions with free-standing irradiators**

It is important periodically to lengthen the time of irradiation to correct for decay of the isotopic source that emits the gamma irradiation. Until recently, this was the only major quality assurance measure that was performed routinely. With the half-life for 137Cs being 30 years, annual lengthening of the timer setting is appropriate.On the other hand, with the half-life of 60Co being only 5,27 years, the time of irradiation should be increased on a quarterly basis. The additional seconds of irradiation that are needed can be calculated using formulae that can be found in any physics text. Alternatively, distributors of irradiators provide a chart that specifies the appropriate setting as a function of calendar time.

## **7.1 Turntable rotation**

For 137Cs irradiators, it is essential that the turntable operates at a constant speed in a circular pattern to ensure that each part of a blood component is exposed equally to the source. Daily verification of turntable rotation is an appropriate quality assurance measure. With some free-standing irradiator models rotation of the turntable can be observed before the door of the compartment in which the canister is positioned is closed. In other models, this can be done only indirectly by ensuring that an indicator light is operating appropriately. With some older models, there have been occasional reports that the turntable failed to rotate because of mechanical problems. Such problems should not be encountered with the newer models because of changes in the turntable mechanisms. In any event, daily verification of turntable rotation is a prudent quality assurance measure.

### **7.2 Radioactivity leakage**

Irradiators are constructed so that the isotopic sources are contained in a chamber heavily lined with a protective lead shield to prevent leakage of radioactivity. Accordingly, gamma irradiators are considered to be very safe instruments. Although there have been no reports of source leakage of radioactivity, periodic measurements are warranted to ensure that this is the case. Attaching a film badge to the outside of the irradiator, using a Geiger counter periodically, and performing a wipe test of the inside of the chamber where the canister is positioned at least semiannually are measures that are being used.

## **8. Dose mapping with linear accelerators**

Linear accelerators that are used therapeutically to provide radiation therapy are carefully monitored to ensure appropriateness of dose to an irradiation field. When blood components

measurements are associated with a degree of uncertainty or possible error. The magnitude of the uncertainty depends on the kind of dosimeter used. For most dosimeters, the level is 5% of the measured value. For a central absorbed dose level of 2560 cGy (see theoretical dose map in Fig 2) the value could be as high as 2788 cGy or as low as 2432 cGy. Correspondingly, a measured value of 2400 cGy could be as high as 2520 cGy or as low as 2380 cGy. Because the measured value could in actuality meet the 2500 cGy standard, it is appropriate to accept a value of 2400 cGy as meeting the current standard. The same approach should be used when evaluating the minimum value on a dose map. Albeit arbitrary and cautious, the actual minimum on an irradiation dose map should not be below

It is important periodically to lengthen the time of irradiation to correct for decay of the isotopic source that emits the gamma irradiation. Until recently, this was the only major quality assurance measure that was performed routinely. With the half-life for 137Cs being 30 years, annual lengthening of the timer setting is appropriate.On the other hand, with the half-life of 60Co being only 5,27 years, the time of irradiation should be increased on a quarterly basis. The additional seconds of irradiation that are needed can be calculated using formulae that can be found in any physics text. Alternatively, distributors of irradiators provide a chart that specifies the appropriate setting as a function of calendar

For 137Cs irradiators, it is essential that the turntable operates at a constant speed in a circular pattern to ensure that each part of a blood component is exposed equally to the source. Daily verification of turntable rotation is an appropriate quality assurance measure. With some free-standing irradiator models rotation of the turntable can be observed before the door of the compartment in which the canister is positioned is closed. In other models, this can be done only indirectly by ensuring that an indicator light is operating appropriately. With some older models, there have been occasional reports that the turntable failed to rotate because of mechanical problems. Such problems should not be encountered with the newer models because of changes in the turntable mechanisms. In any

event, daily verification of turntable rotation is a prudent quality assurance measure.

positioned at least semiannually are measures that are being used.

**8. Dose mapping with linear accelerators** 

Irradiators are constructed so that the isotopic sources are contained in a chamber heavily lined with a protective lead shield to prevent leakage of radioactivity. Accordingly, gamma irradiators are considered to be very safe instruments. Although there have been no reports of source leakage of radioactivity, periodic measurements are warranted to ensure that this is the case. Attaching a film badge to the outside of the irradiator, using a Geiger counter periodically, and performing a wipe test of the inside of the chamber where the canister is

Linear accelerators that are used therapeutically to provide radiation therapy are carefully monitored to ensure appropriateness of dose to an irradiation field. When blood components

1500 cGy.

time.

**7.1 Turntable rotation** 

**7.2 Radioactivity leakage** 

**7. Precautions with free-standing irradiators** 

are treated with x-rays, the instrument settings are very different than those used to treat oncology patients. Hence, additional periodic quality control measures, primarily to assess the dose delivered to blood components, are needed to ensure that linear accelerators are being operated appropriately when used for blood irradiation. Currently, there are no commercially available systems for assessing the dose delivered throughout the area of an irradiation field in which blood components are placed for treatment with x-rays. An ideal dosimeter for this purpose would be made of a tissue-compatible plastic phantom, containing appropriate dosimeter material and a covering that could be placed at the appropriate distance from the source. An alternative approach might involve the use of a blood bag filled with water (simulating a blood unit) containing TLD chips, as described earlier. In comparative studies using such simulated blood units, it was determined that radiation delivery was more uniform with linear accelerators than with 137Cs free-standing irradiators. This reflects the relative homogeneity of x-ray beams. In the absence of an available system modified for the irradiation of blood bags, the dose delivered throughout an irradiation field should be mapped with the dosimetric measuring system known as an *ionization chamber.* The ionization chamber is used to calibrate linear accelerators for patient use. In addition, on a yearly basis, dose mapping should be performed using a tissuecompatible phantom.

In view of the widely divergent conditions that are used during the operation of linear accelerators, other parameters pertaining to the x-ray beam should be evaluated on at least a quarterly basis to provide assurance that the instrument is being used appropriately for the irradiation of blood components. The goal is to ensure that the instrument is being set in a consistent fashion. When setting a linear accelerator for blood component irradiation, the following should be measured: the distance between the x-ray source and the position where the blood components are to be placed; consistency in the strength of the x-ray beam; and (3) the intensity of the x-ray beam. The distance between the source and position on the table where blood components will be placed (referred to as the *target)* can be evaluated easily with a calibrated measuring device. This is a simple task that can be performed on a routine basis. The consistency of beam output can be evaluated by measuring the beam current. Beam intensity can be evaluated by measuring the ionization current in a monitoring ionization chamber array that can be expressed in terms of the number of photons delivered per square centimeter. These parameters should be assessed routinely as part of quality control programs used by radiation physicists. A code of practice was published in 1994 by the Radiation Therapy Committee of the American Association of Physicists in Medicine for the quality control of radiotherapy accelerators. The described practices are used routinely by radiation physicists. It would he prudent to ensure that an institution using a linear accelerator for blood irradiation follow these quality assurance guidelines and recommendations.

#### **9. Confirming that irradiation occurred**

It is important to have positive confirmation that the irradiation process has taken place. This is to identify whether an operator fails to initiate the electronically controlled irradiation process or when the irradiation process is not performed because of instrumentation malfunction. A radiation-sensitive indicator label has been developed specifically for this purpose by International Speciality Products,Wayne, NJ. The label containing a radiationsensitive film strip is placed on the external surface of the blood

Blood Irradiation 345

[2] Roberts GT, Luban NLC: Transfusion-associated graftversus-host disease, in Rossi EC,

[3] Linden JV, Pisciotto PT: Transfusion-associated graftversus-host disease and blood

[4] Anderson KC: Clinical indications for blood component irradiation, in Baldwin ML,

[5] Brubaker DB: Transfusion-associated graft-versus-host disease, in Anderson KC, Ness

[7] Davey RJ: Transfusion-associated graft-versus-host disease and the irradiation of blood

[8] Kanter MH: Transfusion-associated graft-versus-host disease disease: Do transfusions

[9] McMilan KD, Johnson RL: HLA-homozygosity and the risk of related-donor transfusionassociated graft-versus-host disease. Transfus Med Rev.1993; 7:37-41 [10] Petz LD, Calhoun L, Yam P, et al: Transfusion-associated graft-versus-host disease in

[11] Williamson LM, Warwick RM: Transfusion-associated graft-versus-host disease and its

[12] Ohto H, Anderson KC: Survey of transfusion-associated graft-versus-host disease in

[13] Davey RJ: The effect of irradiation on blood components, in Baldwin ML and Jefferies

[14] Fearon TC, Luban NLC: Practical dosimetric aspects of blood and blood product

[15] Suda BA, Leitman SF, Davey RJ: Characteristics of red cells irradiated and subsequently

[16] Miraglia CC, Anderson G, Mintz PD: Effect of freezing on the in vivo recovery of

[17] Crowley JR Skrabut EM, Valeri CR: Immunocompetent lymphocytes in previously

[18] Akahoshi M, Takanashi M, Masuda M, et al: A case of transfusion-associated graft-

[19] Heim MU, Munker R, Saner H, et at: Graft-versus-host Kranldleit(GVH mit letalem

versus-host disease not prevented by white cell-reduction filters.

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immunocompetent recipients. Transfus Med Rev .1996;10:31-43

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MD,Williams and Wilkins, 1996, pp 785-801

irradiation. Transfus Med Rev .1992;6:116-123

Association of Blood Banks, 1992, pp 31-49

relatives? Transfusion.1992;32:323-327

prevention. Blood Reviews.1995; 9:251-261

irradiation. Transfusion .1986.26:457-459

Transfusion .1993;33:742-750

of Blood Banks, 1992, pp 51-62

Transfusion.1992;32:169-172

Infusionstherapie.1991; 18:8-9

.1995;16:135-137

Simon TL, Moss GC, Goldis A(eds): Principles of Transfusion Medicine. Baltimore

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PM (eds): Scientific Basis of Transfusion Medicine. Implications for Clinical

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component. Irradiation causes distinct visually observable changes: The appearance changes from clear red to opaque with obliteration of the word "NOT." When the label is placed on a blood component, there is a visual record that the irradiation process took place. The reliability of this type of indicator was documented recently in a multisite study.

Two versions of the indicator label have been manufactured. The difference is the range of radiation needed to cause a change in the radiationsensitive film. The ratings for these indicators are 1500 cGy or 2500 cGy. The ratings serve as an approximate guideline for the amount of absorbed radiation that will be needed to completely change the window from reddish to opaque with complete obliteration of the word "NOT." Because the indicator labels are designed for and are used to confirm that the irradiation process has occurred, we have concluded that the 1500 cGy label is the most appropriate tool to perform this quality control measure. This is based on the routinely observed pattern of dose distribution to a blood component in a canister of a free-standing irradiator. Despite a targeted central dose of 2500 cGy, there will be spots at which the dose will be less. If the theoretical dose map presented in Figure 2 is used as an example, there will be a spot that will receive only 1800 cGy. If the 2500 cGy-rated label were to be located on the external surface of a component, there may be minimal changes in the appearance of the radiation-sensitive film window.This would result in a judgment that the blood component was not irradiated, when in actuality it was treated satisfactorily.


Table 4. Guidelines for irradiating blood components.

## **10. References**

[1] Anderson KC, WeinsteinHJ: Transfusion-associated graftversus-host disease. New Eng J Med .1994;323:315-321

component. Irradiation causes distinct visually observable changes: The appearance changes from clear red to opaque with obliteration of the word "NOT." When the label is placed on a blood component, there is a visual record that the irradiation process took place. The

Two versions of the indicator label have been manufactured. The difference is the range of radiation needed to cause a change in the radiationsensitive film. The ratings for these indicators are 1500 cGy or 2500 cGy. The ratings serve as an approximate guideline for the amount of absorbed radiation that will be needed to completely change the window from reddish to opaque with complete obliteration of the word "NOT." Because the indicator labels are designed for and are used to confirm that the irradiation process has occurred, we have concluded that the 1500 cGy label is the most appropriate tool to perform this quality control measure. This is based on the routinely observed pattern of dose distribution to a blood component in a canister of a free-standing irradiator. Despite a targeted central dose of 2500 cGy, there will be spots at which the dose will be less. If the theoretical dose map presented in Figure 2 is used as an example, there will be a spot that will receive only 1800 cGy. If the 2500 cGy-rated label were to be located on the external surface of a component, there may be minimal changes in the appearance of the radiation-sensitive film window.This would result in a judgment that the blood component was not irradiated,

> Dose *Linear accelerators Free standing irradiators*

> Dose mapping *Linear accelerators Free Standing irradiators*

Correction for radioisotopic decay Cs-137; annually Co-60; every 3 month Turntable rotation(Free standing Cs-137 irradiators) Daily should be checked. Storage time (after irradiation) *Red cells Platelets*

[1] Anderson KC, WeinsteinHJ: Transfusion-associated graftversus-host disease. New Eng J

2500 cGy to the central midplane of a canister with a minumum of 1500 cGy elsewhere.

Routinely,once a year Cs-137 or twice a year Co-60 and after major repairs;the irradiation procedure should be tested using a fully filled canister with a dosimetry system to map the distrubition of the absorbed dose.

No change due to the irradiation.

reliability of this type of indicator was documented recently in a multisite study.

when in actuality it was treated satisfactorily.

2500 cGy to the center of an irradiation field with a minumum of 1500 cGy elsewhere.

Yearly dose mapping with an ionization chamber and a water phantom.More frequent evaluation of instrument conditions to ensure consistency of x-rays.

For up to 28 days;total storage time cannot exceed maximum stroga time for unirradiated red cells

Med .1994;323:315-321

**10. References** 

Table 4. Guidelines for irradiating blood components.


Blood Irradiation 347

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egulatoryInformation/OtherRecommendationsforManufacturers/Memorandumto

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transfusions of HLAmatched,HLA-homozygous platelets from unrelated donors.

host disease due to apheresis platelets matched for HLA class`, I antigens.

associated graft-versus-host disease.Transfus Sci .1995;16:265-268

blood. Transfusion .1997;27:444-445

irradiation. Vox Sang .1996;70:117-118

Transfusion. 1994; 34:432-437

Transfusion.1993; 33:910-914

31:50S(abstr)

Transfusion.1996;26:453-456

Transfusion .1988;28:451-455

unwarranted. Transfusion.1990; 30:675-677

29:185

disease caused by leukocyte fltered stored blood. Anesthesiology.1993;79:1419-1421


**Part 6** 

**Examples for Different Quality** 

**Control Processes** 


## **Part 6**

## **Examples for Different Quality Control Processes**

348 Modern Approaches To Quality Control

[57] Kutcher GJ, Coia L, Gillin M et al.: Comprehensive QA for radiation oncology: report of

[58] Nath R, Biggs PJ, Bova FJ, et al: AAPM code of practice for radiotherapy accelerators:

[59] Leitman SF, Silberstein L, Fairman RM, et al: Use of a radiation-sensitive film label in

618

1121

(abstr)

AAPM radiation therapy committee task group 40. Med Phys.1994; 21:581-

report of AAPM radiation therapy task group no 45. Med Phys.1994; 21:1093-

the quality control of irradiated blood components. Transfusion.1992;32:4S

**19** 

**R&D: Foundation Stone of Quality** 

There are many definitions of quality. The oldest based on simple fulfilling of desired technical parameters developed into nowadays agreement, that the pivot of interest should be customer and his needs. Modern quality systems define quality as a degree of fulfilling of customers´ demands, or the degree of customers´ satisfaction by goods or services that he

Quality management systems have been developing since the beginning of industrial goods production. Producers of goods with higher quality had advantages for fight with competitors and high quality products were the main way how to satisfy customers. Although quality products are still necessary for success on the market, quality itself does not make nowadays business. Since the end of eighties new kind of companies appeared. These companies were orientated not only on quality goods production, but mainly on

For these companies quality product was just one fourth of their marketing mix, whose management under certain brand was to satisfy customers. The resting parts of marketing mix are e.g. the price, place of purchase and accompanying services, or promotion quality. The original sense of brand was to label product with the place of origin and name of

Due to sophisticated marketing methods can brand nowadays bring to customer whole battery of emotional values, which can sort customers into varying social groups. The satisfaction of customers is not brought only by the product quality, but also by emotions

Brand management added to product new value, which allowed brand keepers to sell for much higher prices than would be the prices of their products without brand. Because not all customers could afford to pay extra price for emotional values and engaging to higher social classes, the byproduct of branding was the polarization of marked and origin of new distribution channels selling products without strong brands. These products are sold for much lower prices and usually have good enough quality to satisfy demands of its users. These so called cheap brands e.g. made up 40 % of German beer marked in 2005 (Verstl,

Brand management is also the reason why contact of quality department with customers is nowadays mediated by marketing department and quality improvement is often managed

**1. Introduction** 

branding.

2005).

by marketing manager.

had paid for (Juran, 2000).

**1.1 The role of quality in success on the market** 

producer, which together had served as a guarantee of quality.

connected with social enlistment of brand (Klein, 2005; Olins 2009).

Petr Košin, Jan Šavel and Adam Brož

*Budweiser Budvar, N.C.* 

*Czech Republic* 

## **R&D: Foundation Stone of Quality**

Petr Košin, Jan Šavel and Adam Brož

*Budweiser Budvar, N.C. Czech Republic* 

## **1. Introduction**

There are many definitions of quality. The oldest based on simple fulfilling of desired technical parameters developed into nowadays agreement, that the pivot of interest should be customer and his needs. Modern quality systems define quality as a degree of fulfilling of customers´ demands, or the degree of customers´ satisfaction by goods or services that he had paid for (Juran, 2000).

#### **1.1 The role of quality in success on the market**

Quality management systems have been developing since the beginning of industrial goods production. Producers of goods with higher quality had advantages for fight with competitors and high quality products were the main way how to satisfy customers. Although quality products are still necessary for success on the market, quality itself does not make nowadays business. Since the end of eighties new kind of companies appeared. These companies were orientated not only on quality goods production, but mainly on branding.

For these companies quality product was just one fourth of their marketing mix, whose management under certain brand was to satisfy customers. The resting parts of marketing mix are e.g. the price, place of purchase and accompanying services, or promotion quality. The original sense of brand was to label product with the place of origin and name of producer, which together had served as a guarantee of quality.

Due to sophisticated marketing methods can brand nowadays bring to customer whole battery of emotional values, which can sort customers into varying social groups. The satisfaction of customers is not brought only by the product quality, but also by emotions connected with social enlistment of brand (Klein, 2005; Olins 2009).

Brand management added to product new value, which allowed brand keepers to sell for much higher prices than would be the prices of their products without brand. Because not all customers could afford to pay extra price for emotional values and engaging to higher social classes, the byproduct of branding was the polarization of marked and origin of new distribution channels selling products without strong brands. These products are sold for much lower prices and usually have good enough quality to satisfy demands of its users. These so called cheap brands e.g. made up 40 % of German beer marked in 2005 (Verstl, 2005).

Brand management is also the reason why contact of quality department with customers is nowadays mediated by marketing department and quality improvement is often managed by marketing manager.

R&D: Foundation Stone of Quality 353

Quality characteristics can be defined technically as inherent property of product that serves for identification, description and differentiation of product form other products and has a quantity and unit. Customer orientated definition of quality characteristic would be a

Quality characteristics can be divided into two groups: real characteristics and measurable attributes. Real characteristics directly correspond to the customer orientated definition of quality and are the reason why customers buy selected product. These characteristics should be evaluated in the fourth step of PDCA or Juran´s quality spiral. Their disadvantage is problematic measurement and evaluation and that is why real characteristics are usually translated into measurable attributes in the first step of quality improvement process. Measurable attribute suit more the technical definition of quality and although not corresponding directly to customers' satisfaction they can be quite easily measured and evaluated during production and by feedback effect serve in the second and third step of

The case study of this chapter for illustration of quality improvement in practice will be beer foam stability. It is a measurable attribute, which closely describes real quality characteristic called foam appearance. Foam appearance is one of the most important quality parameters of beer, because it is a visual parameter and visual parameters are ease to evaluate by almost

Foam stability is not the only attribute describing foam appearance; the others are e.g. foam density, creaminess, color, or ability to cling on beer glass. Although these technical parameters have their meaning for foam appearance, stability is the most important parameter because when foam is not stable, it disappears and there is nothing to judge.

all customers, who are much surer by what they see than what they taste.

Fig. 2. Juran´s quality spiral.

**1.3 Quality characteristics** 

quality management.

property of product, that satisfy customer.

**2. Case study: beer foam stability** 

## **1.2 Quality improvement**

Quality manager can never be satisfied with quality. It is because quality is not static; it is developing together with the development of customers´ needs. The process of developing quality is called quality improvement and it is integral part of modern quality management. As any other management systems, the management of quality improvement is based on the flow of information. There are several model systems for information flow in quality improvement management; of the most famous is Deming´s PDCA cycle (fig. 1) or Juran's quality spiral (fig. 2).

These model systems have in common four basic steps, which also represent four levels where quality is managed in practice. The first level of quality management called "plan" or "product development" step is usually secured by the R&D department or by external consulting expert. This step includes designing of the product with all technical parameters and proposing of production processes with all operation steps and control points.

The second step ("Do" or "Production & process control), usually secured by production department in close cooperation with quality control department, includes production of products by production processes, which are carefully operated by feedback regulation in originally proposed control steps.

The third step where quality is managed is the "Check" or "Final inspection". This step is usually secured by the Quality control department and sampling or evaluation of the results are usually planed and processed with the help of statistical tools, like control charts or histograms.

The last step of information flow at the quality improvement management ("Act" or "Market research") is secured by quality assurance or marketing department. At this step customers´ satisfaction with product is measured. Method can be common market research, like statistic study with questionnaires, or with direct interviews.

Fig. 1. PDCA cycle.

Quality manager can never be satisfied with quality. It is because quality is not static; it is developing together with the development of customers´ needs. The process of developing quality is called quality improvement and it is integral part of modern quality management. As any other management systems, the management of quality improvement is based on the flow of information. There are several model systems for information flow in quality improvement management; of the most famous is Deming´s PDCA cycle (fig. 1) or Juran's

These model systems have in common four basic steps, which also represent four levels where quality is managed in practice. The first level of quality management called "plan" or "product development" step is usually secured by the R&D department or by external consulting expert. This step includes designing of the product with all technical parameters

The second step ("Do" or "Production & process control), usually secured by production department in close cooperation with quality control department, includes production of products by production processes, which are carefully operated by feedback regulation in

The third step where quality is managed is the "Check" or "Final inspection". This step is usually secured by the Quality control department and sampling or evaluation of the results are usually planed and processed with the help of statistical tools, like control charts or

The last step of information flow at the quality improvement management ("Act" or "Market research") is secured by quality assurance or marketing department. At this step customers´ satisfaction with product is measured. Method can be common market research,

like statistic study with questionnaires, or with direct interviews.

and proposing of production processes with all operation steps and control points.

**1.2 Quality improvement** 

quality spiral (fig. 2).

histograms.

Fig. 1. PDCA cycle.

originally proposed control steps.

Fig. 2. Juran´s quality spiral.

## **1.3 Quality characteristics**

Quality characteristics can be defined technically as inherent property of product that serves for identification, description and differentiation of product form other products and has a quantity and unit. Customer orientated definition of quality characteristic would be a property of product, that satisfy customer.

Quality characteristics can be divided into two groups: real characteristics and measurable attributes. Real characteristics directly correspond to the customer orientated definition of quality and are the reason why customers buy selected product. These characteristics should be evaluated in the fourth step of PDCA or Juran´s quality spiral. Their disadvantage is problematic measurement and evaluation and that is why real characteristics are usually translated into measurable attributes in the first step of quality improvement process.

Measurable attribute suit more the technical definition of quality and although not corresponding directly to customers' satisfaction they can be quite easily measured and evaluated during production and by feedback effect serve in the second and third step of quality management.

## **2. Case study: beer foam stability**

The case study of this chapter for illustration of quality improvement in practice will be beer foam stability. It is a measurable attribute, which closely describes real quality characteristic called foam appearance. Foam appearance is one of the most important quality parameters of beer, because it is a visual parameter and visual parameters are ease to evaluate by almost all customers, who are much surer by what they see than what they taste.

Foam stability is not the only attribute describing foam appearance; the others are e.g. foam density, creaminess, color, or ability to cling on beer glass. Although these technical parameters have their meaning for foam appearance, stability is the most important parameter because when foam is not stable, it disappears and there is nothing to judge.

R&D: Foundation Stone of Quality 355

saying that beer can be only made from water, barley malt and hops. Improving foam quality by simple increase of natural hop components would have negative effect in change

The role of proteins in foam stability has been the most studied part of foam quality in academic research. There have been described several proteins that influence foam quality, mainly hydrophobic proteins like protein Z, or lipid transfer proteins (LTP). Protein Z represents proteins with high molecular weight (relative molecular weight 35 000 – 50 000) and LTP have relative molecular weight 5 000 – 15 000. Proteins, which together with bitter acids and ions build up the framework of foam bubble walls, come to beer from malt. A lot of studies on which malt contains more of these foam promoting proteins were driven by the idea, that change of malt specifications could be a way for a brewer how to fix problems with foam. The problem of this approach is that changing malt specifications can substantially change some of the other important parameters of beer, e.g. color, fermentability and final degree of attenuation, or the essential character of beer taste, which

Although foam stability has been in focus of academic research for quite a long time, there have not been found a practical recipe how to improve foam quality and not change any of

There are far less papers written from applied research compared to academic research. The reason is not only the evaluation of academic research quality by the quantity of published papers, but also historic transfer of applied research from goods producers to service and suppliers companies, who more carefully guard their knowhow and do not publish much of

Although it is quite hard to come across this kind of publication, they are of great use because they usually look for practical solutions. Contrary to academic research, which usually looks for answers on questions "how does it work", applied research usually solves

For our case study of foam stability can be found sporadic publications recommending some practical solutions like optimization of the malt grinding, correct choice of lauthering tun, sufficient separation of sediment after wort boiling, or consistent rinsing of bottles at the end

The assignment of the research was to improve foam without changing any other quality characteristics, especially beer appearance and taste, which is secured by constant specifications of raw materials. That is why trials with alternative malt specification, hop dosage or use of any additive to beer as discussed in the academic research was excluded

Foam collapse can be divided into three stages from the macroscopic point of view. The first is the drainage of beer out of wet foam, where significant upward movement of beer-foam interface can be observed. The second stage is the collapse of dry foam and is accompanied by significant decrease of foam surface. The third stage is the break-up of the last foam layer,

which results in the appearance of a "bald patch" on the surface of the beer.

of bitterness intensity, one of the most sensed sensory attribute of beer.

is hidden in the unfermented remainder of malt in the beer body.

Applied sources

technical papers.

of washing (Haukeli, 1993).

from the design of this study.

**3.1 Foam stability measurement** 

**3. Improvement of foam stability** 

the other beer parameters, including beer raw materials and composition.

questions concerning what can one do to economically solve a problem.

Assignment for this study is was to improve beer foam stability without changing any other beer quality and production parameters, which most often include raw materials. Complexity of this quality parameter much differs from common example situations like screw production.

## **2.1 Procedure of foam quality improvement**

The general procedure of quality improvement has several steps. Whole process starts with bibliographic research, because many of the basic questions have been solved before by someone else.

The second step should be the verification of bibliographic result under the specific conditions of the company. With good luck this can be the end of quality improvement.

If bibliographic results do not help, the third step should be the start of own primary research. There cannot be given general instruction on this step, but there is one way that occasionally helps and was useful also in the case study of this chapter. It is to develop your own analytical method, of which results closely corresponds to customers sensation of the quality parameter and simultaneously can be used all over whole production line to evaluate how the quality attribute develops during production.

The fourth step can then be to use the new analytical method to find weak points of the production line and find a way how to control these processes to improve the quality problem. Results of the method can then be used for feed-back regulation of selected processes parameters in second step of the quality improvement information flow described by PDCA or Juran´s quality spiral.

The last step of the research would be identical with the third or fourth step of quality management. With the help of sophisticated statistical tools should be precisely evaluated the extent of quality improvement and the economical balance of quality profits and costs.

#### **2.2 Bibliographic search**

The research usually starts with bibliographic search. In many cases the same problem has already been discussed either in academic or applied research.

Academic sources

Academic research offers several solutions for foam quality improvement, mostly based on reductionist analytical approach. The idea is that foam stability can be increased by addition of foam stabilizing material to beer. There have been described several foam stabilizing substances, but less methods how to increase the content of these and not change beer taste or composition. Of the most discussed are bitter acids and proteins (Evans, 2002).

All of hop bitter acids can increase foam stability, but the most effective are chemically reduced derivates. Their production stars with extraction of α-bitter acids from hop by organic solvent or supercritical CO2. The second step is isomerization of α-bitter acids in alkali and high temperature conditions and the third step chemical reduction of iso-α-bitter acids into di-, tetra- or hexa-hydro-iso-α-bitter acids. Most often discussed are tetrahydroiso-α-bitter acids, produced under the brand Tetrahop.

Tetrahop is used in downstream processes as additive in milligrams per liters of beer. There are several problem of this way of improving foam quality. Major is that although foam stability is increased, foam structure at the end of foam collapse has unnatural appearance resembling polystyrene foam. Next problem is harsh character of Tetrahop's taste, which is far away from fine taste of natural hops. Probably the least important problem is that the chemical preparation of Tetrahop collides with Reinheitsgebot, German beer purity law

Assignment for this study is was to improve beer foam stability without changing any other beer quality and production parameters, which most often include raw materials. Complexity of this quality parameter much differs from common example situations like

The general procedure of quality improvement has several steps. Whole process starts with bibliographic research, because many of the basic questions have been solved before by

The second step should be the verification of bibliographic result under the specific conditions of the company. With good luck this can be the end of quality improvement. If bibliographic results do not help, the third step should be the start of own primary research. There cannot be given general instruction on this step, but there is one way that occasionally helps and was useful also in the case study of this chapter. It is to develop your own analytical method, of which results closely corresponds to customers sensation of the quality parameter and simultaneously can be used all over whole production line to

The fourth step can then be to use the new analytical method to find weak points of the production line and find a way how to control these processes to improve the quality problem. Results of the method can then be used for feed-back regulation of selected processes parameters in second step of the quality improvement information flow described

The last step of the research would be identical with the third or fourth step of quality management. With the help of sophisticated statistical tools should be precisely evaluated the extent of quality improvement and the economical balance of quality profits and costs.

The research usually starts with bibliographic search. In many cases the same problem has

Academic research offers several solutions for foam quality improvement, mostly based on reductionist analytical approach. The idea is that foam stability can be increased by addition of foam stabilizing material to beer. There have been described several foam stabilizing substances, but less methods how to increase the content of these and not change beer taste

All of hop bitter acids can increase foam stability, but the most effective are chemically reduced derivates. Their production stars with extraction of α-bitter acids from hop by organic solvent or supercritical CO2. The second step is isomerization of α-bitter acids in alkali and high temperature conditions and the third step chemical reduction of iso-α-bitter acids into di-, tetra- or hexa-hydro-iso-α-bitter acids. Most often discussed are tetrahydro-

Tetrahop is used in downstream processes as additive in milligrams per liters of beer. There are several problem of this way of improving foam quality. Major is that although foam stability is increased, foam structure at the end of foam collapse has unnatural appearance resembling polystyrene foam. Next problem is harsh character of Tetrahop's taste, which is far away from fine taste of natural hops. Probably the least important problem is that the chemical preparation of Tetrahop collides with Reinheitsgebot, German beer purity law

or composition. Of the most discussed are bitter acids and proteins (Evans, 2002).

screw production.

someone else.

**2.1 Procedure of foam quality improvement** 

by PDCA or Juran´s quality spiral.

**2.2 Bibliographic search** 

Academic sources

evaluate how the quality attribute develops during production.

already been discussed either in academic or applied research.

iso-α-bitter acids, produced under the brand Tetrahop.

saying that beer can be only made from water, barley malt and hops. Improving foam quality by simple increase of natural hop components would have negative effect in change of bitterness intensity, one of the most sensed sensory attribute of beer.

The role of proteins in foam stability has been the most studied part of foam quality in academic research. There have been described several proteins that influence foam quality, mainly hydrophobic proteins like protein Z, or lipid transfer proteins (LTP). Protein Z represents proteins with high molecular weight (relative molecular weight 35 000 – 50 000) and LTP have relative molecular weight 5 000 – 15 000. Proteins, which together with bitter acids and ions build up the framework of foam bubble walls, come to beer from malt.

A lot of studies on which malt contains more of these foam promoting proteins were driven by the idea, that change of malt specifications could be a way for a brewer how to fix problems with foam. The problem of this approach is that changing malt specifications can substantially change some of the other important parameters of beer, e.g. color, fermentability and final degree of attenuation, or the essential character of beer taste, which is hidden in the unfermented remainder of malt in the beer body.

Although foam stability has been in focus of academic research for quite a long time, there have not been found a practical recipe how to improve foam quality and not change any of the other beer parameters, including beer raw materials and composition.

#### Applied sources

There are far less papers written from applied research compared to academic research. The reason is not only the evaluation of academic research quality by the quantity of published papers, but also historic transfer of applied research from goods producers to service and suppliers companies, who more carefully guard their knowhow and do not publish much of technical papers.

Although it is quite hard to come across this kind of publication, they are of great use because they usually look for practical solutions. Contrary to academic research, which usually looks for answers on questions "how does it work", applied research usually solves questions concerning what can one do to economically solve a problem.

For our case study of foam stability can be found sporadic publications recommending some practical solutions like optimization of the malt grinding, correct choice of lauthering tun, sufficient separation of sediment after wort boiling, or consistent rinsing of bottles at the end of washing (Haukeli, 1993).

## **3. Improvement of foam stability**

The assignment of the research was to improve foam without changing any other quality characteristics, especially beer appearance and taste, which is secured by constant specifications of raw materials. That is why trials with alternative malt specification, hop dosage or use of any additive to beer as discussed in the academic research was excluded from the design of this study.

#### **3.1 Foam stability measurement**

Foam collapse can be divided into three stages from the macroscopic point of view. The first is the drainage of beer out of wet foam, where significant upward movement of beer-foam interface can be observed. The second stage is the collapse of dry foam and is accompanied by significant decrease of foam surface. The third stage is the break-up of the last foam layer, which results in the appearance of a "bald patch" on the surface of the beer.

R&D: Foundation Stone of Quality 357

the second stage of foam collapse. This method has much higher reproducibility than the pouring test, but is quite far away from the customer perceived foam stability, as can be

Disadvantage of both of these methods, NIBEM and pouring test, is that it cannot be used to measure foam stability of samples that do not contain sufficient amount of CO2 to create foam. NIBEM is slightly less sensitive to CO2 content of sample than pouring test, because

The new method for foam stability measurement, which was optimized and tested for foam stability improvement, is called the matrix foaming potential (MFP) and is measured by Foam stability tester type FA by 1-CUBE, Havlickuv Brod, Czech Republic (fig. 4). Foam is created by introducing of a gas into liquid sample and mixing with stirrer. By the combination of gas type, gas flow rate and revolution speed of the mixer there can be prepared foam of various structures, eg. by introducing 0,25 mL/min of air and mixing at 1200 RPM creates very fine foam resembling foam created on draught beer, or introducing 0,5 ml/min of air and mixing at 900 RPM creates medium coarse foam resembling foam on

Foam stability is evaluated as a time from the end foam generation to the decrease of foam surface over a set distance, which is a distance of electrodes that are in the place of measurement. The MFP value expressed in seconds covers the height of created foam under standard conditions, which corresponds to foaming ability of the sample, time to foam drainage in the first stage of foam collapse and the whole second stage of foam collapse. As can be seen from the measurement principal, MFP can be used all over the whole beer production line, because even samples without CO2 can be evaluated. Samples that contain CO2 have to be degassed prior to the measurement. The MFP measurement has lower reproducibility due to various reasons, e.g. the temperature sensitivity (fig. 6). Regardless the reproducibility this method is much close to real foam quality as sensed by consumers,

> **250 300 350 400 450 500 bald patch appearance (s)**

Fig. 3. Scatter plot and regression analysis of NIBEM with customer perceived stability

**R2**

 **= 0,0129**

as can be seen from satisfactory correlation with pouring test (fig. 7).

seen from the low correlation with pouring test (fig. 3).

foam is created by flushing of the sample through the jet.

**3.2 Matrix foaming potential** 

beer poured from the bottle (fig. 5).

measured by the pouring test.

**NIBEM**

This division corresponds to measurement strategy focused on the second stage of foam decay. The collapse of the foam accordance to first order kinetic equation is usually expressed as the time dependency of beer volume remaining in dry foam after initial beer drainage.

Kinetic equation can also connect the first two phases of foam collapse as expressed in formula (1),

$$\mathbf{c} = \mathbf{c}\_{\rm o} - a\_0 \cdot \frac{k\_2}{k\_2 - k\_1} \cdot e^{-k\_1 \mathbf{c}} + (a\_0 \cdot \frac{k\_1}{k\_2 - k\_1} - b\_0) \cdot e^{-k\_2 \mathbf{c}} \tag{1}$$

where *c* is the beer volume or its height under the foam, *c∞* is the total volume of beer after complete foam decay, *a* is volume of beer bound in dry foam, *b* is beer freely present in the foam and *τ* is time. The constants *k1, k2* describe the foam collapse in the first and second stage of decay, index 0 indicates the beginning of foam degradation (Savel, 1986).

How customers evaluate foam quality was uncovered by qualitative research at which 30 random customers were asked about their satisfaction with beer foam on the beer they were drinking in pubs or bars in the Czech Republic. In contrast to similar investigations, interviewees were not asked a long series of questions about foam quality or served any adjusted beer samples. The intention was to discretely interview the drinkers in their normal pub or bar drinking situation and gauge their opinion of the foam on the beer they were being served. The only question asked by the interviewers during drinking was the unforced question "is everything OK or not with the foam?" At this point, according to the interviewee's opinion, if there was something wrong with the foam, we visually evaluated the stage of foam collapse, in particular noting the presence of a "bald patch" in the foam, on the surface of the beer.

According to this qualitative assessment of customer perception of foam quality, customers in did not pay much attention to the foam until a problem with the foam is perceived. The beer was seen as problem free so long as there was a sufficient amount of foam to cover the beer surface in the glass. Customers start to be concerned about the foam quality in their glass only once they perceive that there was something wrong with the foam in their glass. This was at the end of foam collapse, when bald patches start to appear on the beer surface. At this point, approximately a quarter of the customers started to pay attention to the quality of beer foam in their glasses. The other three quarters of customers did not have any problems with the foam quality, even at this point. As the break-up of the last foam layer proceeded to produce a substantial bald patch on the beer surface, more customers started to be concerned with foam quality. Once the beer surface was almost completely bald, almost all customers commented that the foam quality was not satisfactory. Thus it can be concluded that for beer drinkers, the early appearance of this bald patch indicates a poor quality beer.

Close to this sensation of foam quality is a method for foam stability measurement called pouring test, which measures foam stability through whole collapse curve and includes the last collapse stages where bald patch appears. It is based on pouring atemperated (8 °C) beer from the bottle to a standard tasting glass and time from pouring to the first bald patch larger than 5 mm appearance is recorded. Although this test is principally very close to the customer sensation of foam quality, it has a disadvantage of low reproducibility.

One of the most spread methods among brewing laboratories is a method called NIBEM. This method is based on recording of the speed of downward movement of foam surface in

This division corresponds to measurement strategy focused on the second stage of foam decay. The collapse of the foam accordance to first order kinetic equation is usually expressed as the time dependency of beer volume remaining in dry foam after initial beer

Kinetic equation can also connect the first two phases of foam collapse as expressed in

0 00 2 1 2 1 ( ) *k k k k cc a e a b e kk kk*

where *c* is the beer volume or its height under the foam, *c∞* is the total volume of beer after complete foam decay, *a* is volume of beer bound in dry foam, *b* is beer freely present in the foam and *τ* is time. The constants *k1, k2* describe the foam collapse in the first and second

How customers evaluate foam quality was uncovered by qualitative research at which 30 random customers were asked about their satisfaction with beer foam on the beer they were drinking in pubs or bars in the Czech Republic. In contrast to similar investigations, interviewees were not asked a long series of questions about foam quality or served any adjusted beer samples. The intention was to discretely interview the drinkers in their normal pub or bar drinking situation and gauge their opinion of the foam on the beer they were being served. The only question asked by the interviewers during drinking was the unforced question "is everything OK or not with the foam?" At this point, according to the interviewee's opinion, if there was something wrong with the foam, we visually evaluated the stage of foam collapse, in particular noting the presence of a "bald patch" in the foam, on

According to this qualitative assessment of customer perception of foam quality, customers in did not pay much attention to the foam until a problem with the foam is perceived. The beer was seen as problem free so long as there was a sufficient amount of foam to cover the beer surface in the glass. Customers start to be concerned about the foam quality in their glass only once they perceive that there was something wrong with the foam in their glass. This was at the end of foam collapse, when bald patches start to appear on the beer surface. At this point, approximately a quarter of the customers started to pay attention to the quality of beer foam in their glasses. The other three quarters of customers did not have any problems with the foam quality, even at this point. As the break-up of the last foam layer proceeded to produce a substantial bald patch on the beer surface, more customers started to be concerned with foam quality. Once the beer surface was almost completely bald, almost all customers commented that the foam quality was not satisfactory. Thus it can be concluded that for beer drinkers, the early appearance of this bald patch indicates a poor

Close to this sensation of foam quality is a method for foam stability measurement called pouring test, which measures foam stability through whole collapse curve and includes the last collapse stages where bald patch appears. It is based on pouring atemperated (8 °C) beer from the bottle to a standard tasting glass and time from pouring to the first bald patch larger than 5 mm appearance is recorded. Although this test is principally very close to the

One of the most spread methods among brewing laboratories is a method called NIBEM. This method is based on recording of the speed of downward movement of foam surface in

customer sensation of foam quality, it has a disadvantage of low reproducibility.

stage of decay, index 0 indicates the beginning of foam degradation (Savel, 1986).

2 1 1 2

(1)

drainage.

formula (1),

the surface of the beer.

quality beer.

the second stage of foam collapse. This method has much higher reproducibility than the pouring test, but is quite far away from the customer perceived foam stability, as can be seen from the low correlation with pouring test (fig. 3).

Disadvantage of both of these methods, NIBEM and pouring test, is that it cannot be used to measure foam stability of samples that do not contain sufficient amount of CO2 to create foam. NIBEM is slightly less sensitive to CO2 content of sample than pouring test, because foam is created by flushing of the sample through the jet.

#### **3.2 Matrix foaming potential**

The new method for foam stability measurement, which was optimized and tested for foam stability improvement, is called the matrix foaming potential (MFP) and is measured by Foam stability tester type FA by 1-CUBE, Havlickuv Brod, Czech Republic (fig. 4). Foam is created by introducing of a gas into liquid sample and mixing with stirrer. By the combination of gas type, gas flow rate and revolution speed of the mixer there can be prepared foam of various structures, eg. by introducing 0,25 mL/min of air and mixing at 1200 RPM creates very fine foam resembling foam created on draught beer, or introducing 0,5 ml/min of air and mixing at 900 RPM creates medium coarse foam resembling foam on beer poured from the bottle (fig. 5).

Foam stability is evaluated as a time from the end foam generation to the decrease of foam surface over a set distance, which is a distance of electrodes that are in the place of measurement. The MFP value expressed in seconds covers the height of created foam under standard conditions, which corresponds to foaming ability of the sample, time to foam drainage in the first stage of foam collapse and the whole second stage of foam collapse.

As can be seen from the measurement principal, MFP can be used all over the whole beer production line, because even samples without CO2 can be evaluated. Samples that contain CO2 have to be degassed prior to the measurement. The MFP measurement has lower reproducibility due to various reasons, e.g. the temperature sensitivity (fig. 6). Regardless the reproducibility this method is much close to real foam quality as sensed by consumers, as can be seen from satisfactory correlation with pouring test (fig. 7).

Fig. 3. Scatter plot and regression analysis of NIBEM with customer perceived stability measured by the pouring test.

R&D: Foundation Stone of Quality 359

**250 300 350 400 450 500**

**Bald patch appearance (s)**

Fig. 7. Correlation of pouring test with Matrix Foaming Potential (MFP).

**R2 = 0,3425**

Fig. 6. Temperature dependance of Matrix foaming potential.

**0**

**50**

**100**

**150**

**MFP (s)**

**200**

**250**

Fig. 4. Foam stability tester type FA by 1-CUBE.

Fig. 5. Fine (right) and medium coarse foam.

Fig. 4. Foam stability tester type FA by 1-CUBE.

Fig. 5. Fine (right) and medium coarse foam.

Fig. 6. Temperature dependance of Matrix foaming potential.

Fig. 7. Correlation of pouring test with Matrix Foaming Potential (MFP).

R&D: Foundation Stone of Quality 361

(A)

(B) Fig. 9. Scatter plot and regression analysis of protein content of beer with NIBEM value (A),

Previous investigations using a "foam tower" have shown that hydrophobic and foam positive components such as LTP1 and iso-α-acids are preferentially concentrated in the foam. To study if the content of beer foam positive proteins/components were limiting, a serial re-foaming experiment as depicted in figure 10 was designed. Degassed beer, created

and time to bald patch appearance (B).

## **3.3 Foam positive and negative substances**

As discussed above, brewers or researchers looking to improve foam quality typically take a reductionist analytical approach. Accordingly, the quality of beer foam generated is tried to be evaluated by measuring the content of foam positive components in beer, and then attempting to modify the brewing process to increase the content of these foam positive compounds to improve foam quality. Most often targeted with such an approach are foam positive components including protein Z, LTP1 and other proteins, and iso-α-acids or their reduced forms. Much more infrequently, the role of foam negative components such as lipids is considered in the technical literature.

It was observed that beer, even with the lowest content of proteins, could be foamed to 100 % of volume of relatively stable foam by simple foaming technique (Fig 8). A simple approach was to correlate the content of foam positive proteins assessed by the Bradford Coommassie blue binding assay (CBB) with foam stability measured by both NIBEM value and by pouring the beer to a glass from the bottle and measuring the time to bald patch appearance (Fig 9). This experiment was conducted with 15 brands of commercial lagers and showed no association between the level of foam positive proteins in beer or its foam stability with NIBEM (Fig 9A), although there was some association with bald patch formation (Fig 9B) although the slope was relatively low. On the basis of these results it was questioned whether the content of foam positive compounds was as important for the beer foam quality of beer as found in previous studies.

This suggests that the content of foam positive proteins/components may not be limiting with respect to foam quality, a similar conclusion that can perhaps be drawn from the beer dilution experiments of Roberts over 30 years ago (Roberts, 1978).

Fig. 8. whole volume of low protein beer converted into foam.

As discussed above, brewers or researchers looking to improve foam quality typically take a reductionist analytical approach. Accordingly, the quality of beer foam generated is tried to be evaluated by measuring the content of foam positive components in beer, and then attempting to modify the brewing process to increase the content of these foam positive compounds to improve foam quality. Most often targeted with such an approach are foam positive components including protein Z, LTP1 and other proteins, and iso-α-acids or their reduced forms. Much more infrequently, the role of foam negative components such as

It was observed that beer, even with the lowest content of proteins, could be foamed to 100 % of volume of relatively stable foam by simple foaming technique (Fig 8). A simple approach was to correlate the content of foam positive proteins assessed by the Bradford Coommassie blue binding assay (CBB) with foam stability measured by both NIBEM value and by pouring the beer to a glass from the bottle and measuring the time to bald patch appearance (Fig 9). This experiment was conducted with 15 brands of commercial lagers and showed no association between the level of foam positive proteins in beer or its foam stability with NIBEM (Fig 9A), although there was some association with bald patch formation (Fig 9B) although the slope was relatively low. On the basis of these results it was questioned whether the content of foam positive compounds was as important for the beer

This suggests that the content of foam positive proteins/components may not be limiting with respect to foam quality, a similar conclusion that can perhaps be drawn from the beer

**3.3 Foam positive and negative substances** 

lipids is considered in the technical literature.

foam quality of beer as found in previous studies.

dilution experiments of Roberts over 30 years ago (Roberts, 1978).

Fig. 8. whole volume of low protein beer converted into foam.

(B)

Fig. 9. Scatter plot and regression analysis of protein content of beer with NIBEM value (A), and time to bald patch appearance (B).

Previous investigations using a "foam tower" have shown that hydrophobic and foam positive components such as LTP1 and iso-α-acids are preferentially concentrated in the foam. To study if the content of beer foam positive proteins/components were limiting, a serial re-foaming experiment as depicted in figure 10 was designed. Degassed beer, created

R&D: Foundation Stone of Quality 363

beginning. It follows that foam stability was not just determined by the level of foam positive compounds, but it was more the result of compromise or balance between foam positive and negative components. Moreover, as the foam stability increased with refoaming, it was apparent that both negative and positive foam components were presumably concentrated in the foam, thus separated from the beer to be re-foamed in the next cycle. This unexpected and contrary result could be explained by the following hypotheses. Firstly, Bamforth proposed that "hydrolyzed hordein appears to selectively enter beer foams at the expense of the more foam-stabilising albuminous polypeptides" such as protein Z (Bamforth, 2004). As such, as the level of hydrolyzed hordein is depleted relative to the albuminous polypeptides, foam stability would be seen to improve. However, Lusk et al. found in their foam tower experiments, as the content of LTP1 was depleted, the foam became less "creamy" and contained coarse bubbles, that were not observed in this experiment (Lusk, 1999). Secondly, as LTP1 is concentrated in beer foam and is thought to play a lipid-binding role in beer, both the LTP1 and the foam stabilizing lipids would be removed with the separated foam. An improvement in foam stability would occur if the level of lipids were limiting in the beer relative to LTP1, other lipid

> **1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Sample order in refoaming**

Fig. 11. Results of foaming capacity and foam stability during a serial refoaming experiment with 15 iterations. The volume of beer foam formed was exactly the same for each refoaming

The insights gained from these experiments recommend several practical approaches to foam quality improvement in commercial production. These are based on the premise that

**0**

**1**

**2**

**3**

**Volume of beer in foam (ml)**

**4**

**5**

binding components and foam positive proteins/components.

**volume of beer in foam**

**time to bald patch**

**0**

iteration, when using a constant time of foaming.

**3.4 Practical approach to foam stability** 

**100**

**200**

**300**

**400**

**Time to bald patch (s)**

**500**

**600**

**700**

foam by stirrer as in MFP measurement with foaming time kept constant so as to measure the quantity of foam produced. The foam and beer phases were separated by pouring beer from under the foam, refilled the beer phase to original volume by "fresh" degassed beer to keep standard foaming conditions and again created foam with the mixer. The refilled amount was less than 10 % of the total volume. This cycle of foaming and separation was repeated 15 times.

The basic premise of the experiment was that if the content of foam positive proteins/components content was limiting in beer foam, foam capacity (amount of generated foam) and foam stability would decrease with sample order number in the experiment as these foam active components were concentrated in the foam and depleted from the beer. Thus foam positive proteins/components would migrate and concentrate in the foam phase in the earlier foaming and separation steps and so that there would not be a sufficient amount in beer phase in the later steps to generate sufficient amounts of stable foam.

Fig. 10. Schematic of the design of experiment for the serial re-foaming of beer. Fifteen iterations of re-foaming of the beer were undertaken.

Figure 11 clearly shows that with serial re-foaming, foam capacity throughout the experiment was unchanged and foam stability, in terms of time till bald patch formation, was substantially increased, being five times higher at the end of experiment than at the

foam by stirrer as in MFP measurement with foaming time kept constant so as to measure the quantity of foam produced. The foam and beer phases were separated by pouring beer from under the foam, refilled the beer phase to original volume by "fresh" degassed beer to keep standard foaming conditions and again created foam with the mixer. The refilled amount was less than 10 % of the total volume. This cycle of foaming and separation was

The basic premise of the experiment was that if the content of foam positive proteins/components content was limiting in beer foam, foam capacity (amount of generated foam) and foam stability would decrease with sample order number in the experiment as these foam active components were concentrated in the foam and depleted from the beer. Thus foam positive proteins/components would migrate and concentrate in the foam phase in the earlier foaming and separation steps and so that there would not be a sufficient amount in beer phase in the later steps to generate sufficient amounts of stable

Fig. 10. Schematic of the design of experiment for the serial re-foaming of beer. Fifteen

Figure 11 clearly shows that with serial re-foaming, foam capacity throughout the experiment was unchanged and foam stability, in terms of time till bald patch formation, was substantially increased, being five times higher at the end of experiment than at the

iterations of re-foaming of the beer were undertaken.

repeated 15 times.

foam.

beginning. It follows that foam stability was not just determined by the level of foam positive compounds, but it was more the result of compromise or balance between foam positive and negative components. Moreover, as the foam stability increased with refoaming, it was apparent that both negative and positive foam components were presumably concentrated in the foam, thus separated from the beer to be re-foamed in the next cycle. This unexpected and contrary result could be explained by the following hypotheses. Firstly, Bamforth proposed that "hydrolyzed hordein appears to selectively enter beer foams at the expense of the more foam-stabilising albuminous polypeptides" such as protein Z (Bamforth, 2004). As such, as the level of hydrolyzed hordein is depleted relative to the albuminous polypeptides, foam stability would be seen to improve. However, Lusk et al. found in their foam tower experiments, as the content of LTP1 was depleted, the foam became less "creamy" and contained coarse bubbles, that were not observed in this experiment (Lusk, 1999). Secondly, as LTP1 is concentrated in beer foam and is thought to play a lipid-binding role in beer, both the LTP1 and the foam stabilizing lipids would be removed with the separated foam. An improvement in foam stability would occur if the level of lipids were limiting in the beer relative to LTP1, other lipid binding components and foam positive proteins/components.

Fig. 11. Results of foaming capacity and foam stability during a serial refoaming experiment with 15 iterations. The volume of beer foam formed was exactly the same for each refoaming iteration, when using a constant time of foaming.

#### **3.4 Practical approach to foam stability**

The insights gained from these experiments recommend several practical approaches to foam quality improvement in commercial production. These are based on the premise that

R&D: Foundation Stone of Quality 365

By this approach there were found several control points for foam stability, of which some fulfilled the demand for not changing of any other beer quality parameter, including raw materials. The effectiveness of these new control points has to be validated by statistical methods, which also serve for control of constancy of other quality parameters after setting

The most suitable statistic tool is regulation chart, which illustrates the change of foam stability in figure 14 by NIBEM value. Foam stability increased from values around lower specification limit into optimal central zone for NIBEM, MFP increased approximately three

Fig. 14. Regulation chart of foam stability measured by NIBEM during process optimization.

Integral part of modern quality management is improving quality. For the task of improving beer foam quality, more successful strategy appeared to be employing own R&D, compared to external consulting expert, even with deep knowledge of bibliographic results on given

The quality improvement procedure included optimization of new method with results close to customer sensation of quality, which could be used even for evaluation of intermediate product all over the production line. By this method weak points were

Bamforth, C.W. (2004). A critical control point analysis for flavour stability of beer*. Master Brewers Association of the American Technical Quarterly*, Vol.41, (2004), pp. 97-103 Evans, E. & Sheehan, M. C. (2002). Don´t be fobbed off: The substance of beer foam - a

Haukeli, A. D.; Wulff, T. O. & Lie, S. (1993). Practical experiments to improve foam stability,

Juran, J.M. & Godfrey, A.B. (2000). *Juran´s quality handbook, fifth edition,* McGraw Hill, ISBN

review. *Journal of the American Society of Brewing Chemists*, Vol.60, No.2, (2002), pp.

*Proceedings of 1993 24th European Brewery Convention Congress,* p. 40, Oslo, Norway,

discovered and the success of new regulation was evaluated by control charts.

Before regulation After regulation

new control points.

**4. Conclusion** 

**5. References** 

47-57

1993

0-07-116539-8, Singapore, Singapore

topic.

times.

by measuring the MFP during and within each production stage, critical points can be identified in the process that reduce foam stability and indicates process parameters that can be modified to improve foam stability, particularly the limiting of the inclusion of foam negative components. One example was to apply MFP measurement during the course of lautering and sparging process. Figure 12 shows, that extended sparging was one of the steps that reduces foam stability. It has long been known that although extended sparging recovers more extract, it also results in the extraction of increasing amounts of undesirable substances such as polyphenols, husk bitter substances, etc , and foam negative materials. Similarly, the MFP analysis was applied during the course of main fermentation (Fig 13). During fermentation, foam stability was decreased to almost a third.

Fig. 12. Matrix foaming potential of wort samples taken during the course of lautering and sparging.

Fig. 13. Matrix foaming potential of "beer" samples during the course of main fermentation.

by measuring the MFP during and within each production stage, critical points can be identified in the process that reduce foam stability and indicates process parameters that can be modified to improve foam stability, particularly the limiting of the inclusion of foam negative components. One example was to apply MFP measurement during the course of lautering and sparging process. Figure 12 shows, that extended sparging was one of the steps that reduces foam stability. It has long been known that although extended sparging recovers more extract, it also results in the extraction of increasing amounts of undesirable substances such as polyphenols, husk bitter substances, etc , and foam negative materials. Similarly, the MFP analysis was applied during the course of main fermentation (Fig 13).

During fermentation, foam stability was decreased to almost a third.

**0**

**33 % of lautering**

**0**

**50**

**100**

**150**

**MFP**

**200**

**250**

**300**

**66 % of lautering**

**100 % of lautering**

**33 % of sparging**

Fig. 12. Matrix foaming potential of wort samples taken during the course of lautering and

**stage in the brewhouse**

**1 2 3 4 5 6 7 8 9 10 11 12 day of fermentation**

Fig. 13. Matrix foaming potential of "beer" samples during the course of main fermentation.

**66 % of sparging**

**99 % of sparging** **sweet wort full kettle**

**hopped wort**

**50**

**100**

**150**

**MFP (s)**

sparging.

**200**

**250**

By this approach there were found several control points for foam stability, of which some fulfilled the demand for not changing of any other beer quality parameter, including raw materials. The effectiveness of these new control points has to be validated by statistical methods, which also serve for control of constancy of other quality parameters after setting new control points.

The most suitable statistic tool is regulation chart, which illustrates the change of foam stability in figure 14 by NIBEM value. Foam stability increased from values around lower specification limit into optimal central zone for NIBEM, MFP increased approximately three times.

Fig. 14. Regulation chart of foam stability measured by NIBEM during process optimization.

## **4. Conclusion**

Integral part of modern quality management is improving quality. For the task of improving beer foam quality, more successful strategy appeared to be employing own R&D, compared to external consulting expert, even with deep knowledge of bibliographic results on given topic.

The quality improvement procedure included optimization of new method with results close to customer sensation of quality, which could be used even for evaluation of intermediate product all over the production line. By this method weak points were discovered and the success of new regulation was evaluated by control charts.

## **5. References**


**20** 

*Zaria, Nigeria* 

**Herbal Drug Regulation Illustrated with** 

Sunday J. Ameh1, Obiageri O. Obodozie1, Mujitaba S. Abubakar2,

*2Department of Pharmacognosy and Drug Development, Ahmadu Bello University, Zaria, 3Department of Pharmaceutical and Medicinal Chemistry, Ahmadu Bello University,* 

Quality system is defined as arrangements, procedures, processes and resources; and the systematic actions necessary to ensure that a manufactured product will meet given specifications. On the other hand, quality control is defined as measures taken, including sampling and testing, to ensure that raw materials, intermediates, packaging materials and finished goods conform to given specifications. Quality specification refers to a written procedure and requirements that a raw material, intermediate or finished good must meet for approval. On the other hand, standard operating procedure (SOP) refers a written procedure, giving step-by-step directions on how a particular operation is to be carried out. Quality manual means, a document that describes the various elements of the system used in assuring the quality of results or products generated by a laboratory or factory. The term quality assurance refers to the totality of all the arrangements made with the objective of ensuring that products are of the quality required for their intended use. Good manufacturing practice (GMP), on the other hand, is that aspect of quality control that deals directly with manufacturing and testing of raw materials, intermediates and finished goods to ensure a product of consistent quality. Essentially, GMP involves two types of control analytical and inspection, and both require: i) clear instructions for every manufacturing process; ii) a means of controlling and recording every manufacturing process; iii) a means of ensuring that the complete history of a batch can be traced; iv) a mechanism for recalling any batch of product from circulation; v) a system for attending to complaints on quality of product or service; and vii) a programme for training operators to carry out and to document procedures. The foregoing definitions and description of GMP conform to those of WHO (2000). It is also clear from the foregoing that GMPs are not prescriptive instructions on how a manufacturer can produce, but are rather a series of principles that must be observed for quality products, services or results to emerge. Invariably, GMPs are approved and enforced by an appropriate National Agency, but the onus of preparing and

**1. Introduction** 

**Niprifan® Antifungal Phytomedicine** 

Magaji Garba3 and Karnius S. Gamaniel1

*Research and Development (NIPRD), Garki, Abuja,* 

*National Institute for Pharmaceutical* 

*1Department of Medicinal Chemistry and Quality Control,* 

Klein, N. (2005). *Bez loga*, Dokořán, ISBN 80-7363-010-9, Prague, Czech Republic


## **Herbal Drug Regulation Illustrated with Niprifan® Antifungal Phytomedicine**

Sunday J. Ameh1, Obiageri O. Obodozie1, Mujitaba S. Abubakar2, Magaji Garba3 and Karnius S. Gamaniel1 *1Department of Medicinal Chemistry and Quality Control,* 

*National Institute for Pharmaceutical* 

*Research and Development (NIPRD), Garki, Abuja, 2Department of Pharmacognosy and Drug Development, Ahmadu Bello University, Zaria, 3Department of Pharmaceutical and Medicinal Chemistry, Ahmadu Bello University,* 

*Zaria, Nigeria* 

## **1. Introduction**

366 Modern Approaches To Quality Control

Lusk, L.T.; Ting, P.; Goldstein, H.; Ryder, D. & Navarro, A. (1999). Foam tower fractionation

Roberts, R.T.; Keeney, P.J. & Wainwright, T. (1978). The effects of lipids and related materials on beer foam. *Journal of the Institute of Brewing*, Vol.84, (1978), pp. 9-12 Verstl, I. (2005). The servant of two masters or how to keep your customers satisfied : the

Šavel, J. (1986). Dva modely rozpadu pivní pěny, *Kvasný Průmysl*, Vol.32, No.4, (1986), pp.

of beer proteins and bittering acids, In: *European Brewery Convention Monograph*, 166

European brewing industry, the Zeitgeist and Tradition, *Proceedings of 2005 30th European Brewery Convention Congress*, p. 171, Prague, Czech Republic, May 14-19,

Klein, N. (2005). *Bez loga*, Dokořán, ISBN 80-7363-010-9, Prague, Czech Republic

Olins, W. (2009) *O Značkách*, Argo, ISBN 978-80-257-0158-4, Prague, Czech Republic

– 187, ISBN 3-418-00774-0, Amsterdam, Netherlands

2005

76-78

Quality system is defined as arrangements, procedures, processes and resources; and the systematic actions necessary to ensure that a manufactured product will meet given specifications. On the other hand, quality control is defined as measures taken, including sampling and testing, to ensure that raw materials, intermediates, packaging materials and finished goods conform to given specifications. Quality specification refers to a written procedure and requirements that a raw material, intermediate or finished good must meet for approval. On the other hand, standard operating procedure (SOP) refers a written procedure, giving step-by-step directions on how a particular operation is to be carried out. Quality manual means, a document that describes the various elements of the system used in assuring the quality of results or products generated by a laboratory or factory. The term quality assurance refers to the totality of all the arrangements made with the objective of ensuring that products are of the quality required for their intended use. Good manufacturing practice (GMP), on the other hand, is that aspect of quality control that deals directly with manufacturing and testing of raw materials, intermediates and finished goods to ensure a product of consistent quality. Essentially, GMP involves two types of control analytical and inspection, and both require: i) clear instructions for every manufacturing process; ii) a means of controlling and recording every manufacturing process; iii) a means of ensuring that the complete history of a batch can be traced; iv) a mechanism for recalling any batch of product from circulation; v) a system for attending to complaints on quality of product or service; and vii) a programme for training operators to carry out and to document procedures. The foregoing definitions and description of GMP conform to those of WHO (2000). It is also clear from the foregoing that GMPs are not prescriptive instructions on how a manufacturer can produce, but are rather a series of principles that must be observed for quality products, services or results to emerge. Invariably, GMPs are approved and enforced by an appropriate National Agency, but the onus of preparing and

Herbal Drug Regulation Illustrated with Niprifan® Antifungal Phytomedicine 369

Posology and method of administration.

Contraindications/ special warnings.

Quantity of active ingredient (Example: 25 mg *P. guineense*). List of excipients (Example: *P. guineense, E. caryophyllata* etc., etc).

These data are used as the basis for inserts, packaging, or advertisement. Inserts must pass "readability testing."

Drug must be produced with validated/ reproducible formula

The product must be manufactured at least on pilot scale and

Stability studies should be carried out on the product packaged in

A summary of the stability studies undertaken must be provided. From stability data shelf life/ storage precautions should be

A quality dossier must be provided for raw and finished materials The product must be produced from herbs that have been cultivated and harvested in accordance with GACP. 10. The starting material must be evaluated for risk of any

Review of any potential interactions with other drugs, side effects, and any proposed contraindications/ precautions in the product

Any information concerning special groups such as children, the

It is interesting to note that in the US, where herbal medicines are regulated as dietary supplements, manufacturers are not required to prove safety or efficacy, but the FDA can withdraw a product

Instead data must provide reference that the product has been in

The data must be presented in a special format, called: *Common* 

Recognized monographs on the material or product with

Production must be in a GMP compliant facility

There must be a finished product specification.

three batches used for stability studies.

the container proposed for marketing.

environmental contamination.

Published animal or human studies.

Name of the product.

Strength. Dosage form.

Shelf life.

method.

proposed.

information.

information on safety.

elderly or pregnant women.

from sale if it proves harmful.

*Technical Document Format*. The Table was drawn based on data gathered from references including (DSHEA 1994; Goldman, 2001;

There is no requirement to prove efficacy.

Of 30 or more years, the last 15 must be in Europe.

use as medicine for 30 years or more.

Indications.

Precautions for use.

S/No. **Regulatory aspect Requirement**

**Product information**: Summary of product characteristics

**Quality control** 

**Safety data requirements**: Refers to safety pharmacology, including animal and human studies

**Traditional use evidence**: Refers to history and prevalence.

De Smet, 2005; Ann Godsell Regulatory, 2008).

Table 2. EMEA requirements for registering herbal medicines.

**data**: Refer to GMP requirements for production.

1

2

3

4

executing GMPs rests with the manufacturer. In Nigeria (population ~ 150 million), GMPs are enforced by NAFDAC – established by decree in 1992/93.

The tests carried out for this study were according to official procedures - mostly BP (2004) and WHO (1998). The results are discussed within the context of requirements for herbal drug regulation as per WHO, EMEA and NAFDAC. It is noted that herbal drug regulation in Nigeria (Table 1) as compared that in Europe (Table 2) is paradoxically hampered not by the rigor and "stringency" of rules, but by the fact that the rules are only merely cumbersome, being neither adequate nor enforceable (Table 3), unlike those of EMEA.


The above information were drawn from NAFDAC's leaflets and website: www.nafdacnigeria.org

Table 1. NAFDAC requirements for registering herbal medicines.

Essentially, the NAFDAC rules seem perhaps affected, or rather made cumbersome without being truly rigorous or "stringent" as actually claimed in the Agency's website. It is further noted that, like in China, where the head of the drug regulatory agency was sentenced to death for corruption (Gross and Minot, 2007), drastic actions, including the wholesale reorganization of NAFDAC management, had to take place in 2000 to straighten things out. The high frequency of confiscation and public destruction of counterfeit products by NAFDAC strongly testifies to the inadequacy of the rules and policies guiding drug regulation in Nigeria. Unfortunately, this worrisome state of affairs is equally true of many countries, as stated in the case of china. There is thus, the need for drug regulatory agencies in these countries to brace up. The aim of this article therefore, is to further an earlier advocacy (Ameh et al., 2010a) that includes alerting and encouraging Drug Regulatory Agencies, Health Ministries, and Parliamentary Health Committees, especially those in developing countries, to enact laws and evolve policies that will better regulate the

executing GMPs rests with the manufacturer. In Nigeria (population ~ 150 million), GMPs

The tests carried out for this study were according to official procedures - mostly BP (2004) and WHO (1998). The results are discussed within the context of requirements for herbal drug regulation as per WHO, EMEA and NAFDAC. It is noted that herbal drug regulation in Nigeria (Table 1) as compared that in Europe (Table 2) is paradoxically hampered not by the rigor and "stringency" of rules, but by the fact that the rules are only merely cumbersome, being neither adequate nor enforceable (Table 3), unlike those of EMEA.

The above information were drawn from NAFDAC's leaflets and website: www.nafdacnigeria.org

Essentially, the NAFDAC rules seem perhaps affected, or rather made cumbersome without being truly rigorous or "stringent" as actually claimed in the Agency's website. It is further noted that, like in China, where the head of the drug regulatory agency was sentenced to death for corruption (Gross and Minot, 2007), drastic actions, including the wholesale reorganization of NAFDAC management, had to take place in 2000 to straighten things out. The high frequency of confiscation and public destruction of counterfeit products by NAFDAC strongly testifies to the inadequacy of the rules and policies guiding drug regulation in Nigeria. Unfortunately, this worrisome state of affairs is equally true of many countries, as stated in the case of china. There is thus, the need for drug regulatory agencies in these countries to brace up. The aim of this article therefore, is to further an earlier advocacy (Ameh et al., 2010a) that includes alerting and encouraging Drug Regulatory Agencies, Health Ministries, and Parliamentary Health Committees, especially those in developing countries, to enact laws and evolve policies that will better regulate the

The applicant must be certified by the Corporate Affairs Commission as a registered business in Nigeria. A marketer or distributor must show evidence of Power of Attorney issued by

Manufacturing, storage and distribution premises must be GXP compliant. Marketers must provide convincing

Applicant may be required to provide a

the manufacturer.

The product must :

Safety, among others.

plan for reporting on: The use of the product. Any adverse reactions.

evidence of GDP and GSP.

information on: Ingredients. Method of analysis.

Stability. Dosage.

Have a certificate of analysis. Be accompanied by a dossier with

are enforced by NAFDAC – established by decree in 1992/93.

S/No. **Regulatory aspect Requirement**

Legal status of applicant, who may be:

Manufacturer. Marketer. Distributor.

registration.

<sup>2</sup>Analytical status of the product for

3 Pre-registration inspection of premises.

4 Post marketing surveillance plan/ report

Table 1. NAFDAC requirements for registering herbal medicines.

1


The Table was drawn based on data gathered from references including (DSHEA 1994; Goldman, 2001; De Smet, 2005; Ann Godsell Regulatory, 2008).

Table 2. EMEA requirements for registering herbal medicines.

Herbal Drug Regulation Illustrated with Niprifan® Antifungal Phytomedicine 371

growing use in the West, it is held that some 80 % of the populace in many developing countries still relies predominantly on herbs and other alternative remedies (WHO, 2008). Indeed, in some parts of Africa, for example, Ethiopia, a dependence of up to 90% has been

The study applied official procedures – mainly WHO (1998) and BP (2004) to: evaluate the quality parameters of the raw materials and their extracts; and the changes in these parameters during dark, dry storage in capped glass bottles under tropical room temperature and humidity (RTH) as obtain in a typical Nigerian Traditional Apothecary (NTA). The parameters evaluated were: appearance, loss on drying, ash values, extractability, solubility, pH, TLC features, light absorption and foaming index. Basic morphological studies were carried out as per WHO (1998). Appropriate phytochemical tests were also conducted by official methods as described elsewhere (Ameh et al., 2010c;

The aerial parts of *Mitracarpus scaber* obtained during the months of October and November from the botanical garden of the National Institute for Pharmaceutical Research and Development (NIPRD) were air-dried in a well-ventilated shade, designed for drying medicinal plant materials. The materials were subsequently comminuted to coarse powder with a grinding machine. The procedure for sampling was as per WHO (1998) as had been described in detail earlier (Ameh et al., 2010c). Three (3) original samples from each batch or container were combined into a pooled sample and subsequently used to prepare the average sample. The average sample was prepared by "quartering" the pooled sample as follows: each pooled sample was mixed thoroughly, and constituted into a square-shaped heap. The heap was then divided diagonally into 4 equal parts. Any 2 diagonally opposite parts were taken and mixed carefully. This step was repeated 2 to 4 times to obtain the required quantity of sample. Any material remaining was returned to the batch. The final samples were obtained from an average sample by quartering, as described above. This means that an average sample gave rise to 4 final samples. Each final sample was divided into 2 portions. One portion was retained as reference material, while the other was tested in duplicate or triplicate. The samples for stability study were stored at room temperature and

humidity (RTH) in capped glass bottles and placed in a shelf protected from light.

**2.2 Macroscopic examination and phytochemical tests on the fresh and air-dried** 

The procedures adopted were as per WHO (1998). Shape and size were determined with the aid of a ruler and a pair of calipers. Diffuse day light was used on the untreated sample to determine its colour. The texture and surface/ fracture characteristics of the untreated sample were examined, where necessary, with x10 magnification hand lens to reveal the characteristics of cut surfaces. The material was felt by touch, to determine if it was soft or hard. Or was bent and ruptured, to obtain information on brittleness and appearance of fracture planes – whether it was fibrous, smooth, rough or granular. Odour was determined by placing a pinch in a 50-ml beaker, and then slowly and repeatedly the air above the material was inhaled. If no distinct odour was perceived, the material was crushed between

claimed (BBC, 2006).

**2. Experimental** 

**2.1 Treatment and sampling of material** 

2010d).

**materials** 


The information on NAFDAC were drawn from leaflets and NAFDAC's website (2010): www.nafdacnigeria.org/ The remarks are informed by current affairs and public perception of NAFDAC's role and activities including the wholesale reorganization of its Management in 2000.

Table 3. NAFDAC's extra requirements for registering herbal medicines.

production, distribution and use of herbal drugs. This is in view of the ever increasing use of herbs notably after the Alma-Ata Declaration (Ameh et al, 2010b) which paved the way for the stupendous growth of herbal drug use worldwide, particularly in North America where that growth had been stymied by the Flexner Report of 1910. That Report, which coincided with Paul Ehrlich's introduction of Salvarsan and the term "chemotherapy" in 1909, had favoured chemical medicine over herbal (Pelletier, 2006). Furthermore, apart from the said

growing use in the West, it is held that some 80 % of the populace in many developing countries still relies predominantly on herbs and other alternative remedies (WHO, 2008). Indeed, in some parts of Africa, for example, Ethiopia, a dependence of up to 90% has been claimed (BBC, 2006).

## **2. Experimental**

370 Modern Approaches To Quality Control

Clearly unreasonable for all categories of applicants

Probably unreasonable for all categories of applicants

Clearly unreasonable for all categories of applicants

Clearly unreasonable for all categories of applicants

Clearly unreasonable for all categories of applicants

Only probably reasonable

Probably unreasonable for all categories of applicants

A sketch of the minor variations should be provided in print no matter how brief. Any information provided by NAFDAC should be printable for sake of transparency.

Likely to be abused if the amount is high. The fee should be a token amount paid by all

applicants

1 Five (5) copies of the product dossier. Probably unreasonable <sup>2</sup>Three (3) packs of the products samples. Probably reasonable

S/No. **Extra requirement Remark** 

<sup>3</sup>Notarized original copy of the duly executed Power of Attorney from the product manufacturer.

> Certificate of Manufacture issued by the competent health or regulatory authority in country of origin and authenticated by the Nigerian Mission in that country. Where there is no Nigerian mission, The British High Commission or an ECOWAS country Mission will

If contract-manufactured, Contract Manufacturing Agreement, properly executed and notarized by a Notary Public in the country of manufacture.

manufacturer, authenticated by the Nigerian Mission.

9 Premises Registration License from PCN Only probably reasonable

Current World Health Organization Good Manufacturing Practice Certificate for the

<sup>7</sup>Certificate of Pharmaceutical Products (COOP) duly

Current Superintendent Pharmacists license to practice issued by the Pharmacists Council of Nigeria

Certificate of Registration of brand name with trademark registry in the Ministry of Commerce here in Nigeria; Letter of invitation from manufacturer to inspect factory abroad, stating full name and location

Nutraceuticals, medical devices and other regulated drug products have similar requirements, with minor variations. Specific details can be obtained from

The information on NAFDAC were drawn from leaflets and NAFDAC's website (2010): www.nafdacnigeria.org/ The remarks are informed by current affairs and public perception of NAFDAC's role and activities including the wholesale reorganization of its Management

production, distribution and use of herbal drugs. This is in view of the ever increasing use of herbs notably after the Alma-Ata Declaration (Ameh et al, 2010b) which paved the way for the stupendous growth of herbal drug use worldwide, particularly in North America where that growth had been stymied by the Flexner Report of 1910. That Report, which coincided with Paul Ehrlich's introduction of Salvarsan and the term "chemotherapy" in 1909, had favoured chemical medicine over herbal (Pelletier, 2006). Furthermore, apart from the said

Table 3. NAFDAC's extra requirements for registering herbal medicines.

<sup>11</sup>The applicable fee payable only if documents are confirmed to be satisfactory.

issued and authenticated.

4

5

6

8

10

12

in 2000.

authenticate.

(PCN).

of plant.

NAFDAC.

The study applied official procedures – mainly WHO (1998) and BP (2004) to: evaluate the quality parameters of the raw materials and their extracts; and the changes in these parameters during dark, dry storage in capped glass bottles under tropical room temperature and humidity (RTH) as obtain in a typical Nigerian Traditional Apothecary (NTA). The parameters evaluated were: appearance, loss on drying, ash values, extractability, solubility, pH, TLC features, light absorption and foaming index. Basic morphological studies were carried out as per WHO (1998). Appropriate phytochemical tests were also conducted by official methods as described elsewhere (Ameh et al., 2010c; 2010d).

## **2.1 Treatment and sampling of material**

The aerial parts of *Mitracarpus scaber* obtained during the months of October and November from the botanical garden of the National Institute for Pharmaceutical Research and Development (NIPRD) were air-dried in a well-ventilated shade, designed for drying medicinal plant materials. The materials were subsequently comminuted to coarse powder with a grinding machine. The procedure for sampling was as per WHO (1998) as had been described in detail earlier (Ameh et al., 2010c). Three (3) original samples from each batch or container were combined into a pooled sample and subsequently used to prepare the average sample. The average sample was prepared by "quartering" the pooled sample as follows: each pooled sample was mixed thoroughly, and constituted into a square-shaped heap. The heap was then divided diagonally into 4 equal parts. Any 2 diagonally opposite parts were taken and mixed carefully. This step was repeated 2 to 4 times to obtain the required quantity of sample. Any material remaining was returned to the batch. The final samples were obtained from an average sample by quartering, as described above. This means that an average sample gave rise to 4 final samples. Each final sample was divided into 2 portions. One portion was retained as reference material, while the other was tested in duplicate or triplicate. The samples for stability study were stored at room temperature and humidity (RTH) in capped glass bottles and placed in a shelf protected from light.

### **2.2 Macroscopic examination and phytochemical tests on the fresh and air-dried materials**

The procedures adopted were as per WHO (1998). Shape and size were determined with the aid of a ruler and a pair of calipers. Diffuse day light was used on the untreated sample to determine its colour. The texture and surface/ fracture characteristics of the untreated sample were examined, where necessary, with x10 magnification hand lens to reveal the characteristics of cut surfaces. The material was felt by touch, to determine if it was soft or hard. Or was bent and ruptured, to obtain information on brittleness and appearance of fracture planes – whether it was fibrous, smooth, rough or granular. Odour was determined by placing a pinch in a 50-ml beaker, and then slowly and repeatedly the air above the material was inhaled. If no distinct odour was perceived, the material was crushed between

Herbal Drug Regulation Illustrated with Niprifan® Antifungal Phytomedicine 373

and with 100 parts of solvent methanol: water 80:20, v/v filtering, and diluting the filtrates by 150x with the same solvent. Absorbencies were measured at λ227 nm, using the solvent as the blank. Florescent, precoated plates were used for normal phase TLC, utilizing silica K6, and hexane: ethylacetate as mobile phase. Solutions of analytes were prepared and applied as follows: To 1 mg of the analyte, 2 drops of ethanol were added and mixed well (~1 %w/v solution). The plates used were 5 cm wide x 20 cm long. With a ruler and a pencil, a distance of 5 mm was measured from the bottom of the plate, and a line of origin was lightly drawn across the plate, without disturbing the adsorbent. The analyte was applied to the origin as a 1 μl droplet. The spot was allowed to dry. Subsequently, the plate was developed in a developing tank saturated with the vapour of the solvent system to be used as mobile phase. The level of the solvent in the tank was adjusted to a level 2 to 3 mm below the line of origin on the plate. The plate was considered developed when the solvent front reached a predetermined line, not less than 5 mm below the top of the plate. The air-dried plate was visualized using a viewing cabinet (Cammag) and a UV-lamp (Cammag – equipped to emit light at 254 or 366 nm). The resulting chromatogram was photographed

**2.7 Determinations of pH of preparations – herb and the dry extract** 

10; and freshly distilled water were used for the study.

Determination of pH values was with a Jenway pH Meter. Standard pH solutions: 4, 7 and

**2.8 Determination of foaming indices of preparations – herb and the dry extract**  Decoctions of plant materials foam due to the presence of saponins. This ability is measured as foaming index, and is an important quality control parameter. The requirements for the test include: conical flasks (500-ml); volumetric flasks (100-ml); test tubes (16cm x 16mm); ruler; and stop-clock. The procedure was as follows: Exactly 1.0 g of powdered material was accurately transferred into a 500-ml conical flask containing 100 ml of boiling water, and maintained at moderate boiling for 30 minutes. The mixture was then cooled and filtered into a 100-ml volumetric flask. The volume was made up to 100 ml with water. Successive portions of 1 ml, 2 ml, 3 ml etc up to 10 ml of the filtrate was poured into ten stoppered tubes having the following dimensions: height, 16 cm; diameter, 16 mm. Subsequently, the volume of each tube was adjusted to 10 ml with water, stoppered and shaken in lengthwise motion for 15 seconds, at 2 shakes per second. The tubes were allowed to stand for 15 minutes, and the height of the foam in each tube was measured. The results were assessed

Foaming index is ≤ 100, if the height of foam in all the tubes is less than 1 cm.

If the height of the foam is > 1 cm in every tube, the foaming index is over 1000.

expressed as expressed as a quantity [Q] per ml or as [Q]ml-1.

used to determine the foaming index, as = 1000/V.

to obtain a more precise result.

If a height of 1 cm is obtained in any tube, the volume [V] of the decoction in that tube, is

But if the tube above is the first or the second in the series, prepare an intermediate dilution

To obtain a more precise result, repeat the determination using a new series of dilutions of the decoction. Note the tube in which the height of foam is 1 cm, and the volume [V] of the decoction therein, and calculate the foaming index, as = 1000/V. Results are

and subsequently drawn to scale.

as follows:

the thumb and index finger, and inhaled as above. The strength of the odour was determined as: odourless, weak, distinct, or strong. The sensation of the odour was determined as: aromatic, fruity, rancid, etc. etc. When possible, the odour was compared with that of a defined substance, such as menthol, sulphur dioxide, eugenol, etc. etc. Taste: In tasting the material, as recommended by our experience with the material, the following procedure was applied: a pinch of the material was mixed with water and savored, or chewed without swallowing, to determine the strength and the sensation of the taste. The strength is recorded as: tasteless, weak, distinct, or strong; and the sensation, as: sweet, sour, saline, or bitter. Phytochemical tests for tannins, saponins, terpenoids, anthraquinones and alkaloids were carried out on samples by procedures as described in detail elsewhere (Ameh et al., 2010c, d).

#### **2.3 Loss on drying**

This was carried out using a minimum of 0.5 – 1.0 g of material. Drying was effected in a Lindberg/Blue M gravity-convention oven maintained at 105-110 0C, for 3 h, after which the sample was allowed to cool to room temperature in a desiccator, and subsequently weighed. The time interval from the oven to point of weighing was usually about 30 minutes. The results are expressed as a range or as mean ± standard deviation.

#### **2.4 Evaluation of extractive matter**

About 4 g of accurately weighed coarsely powdered, air-dried sample was transferred into a glass-stoppered, 250-ml reflux conical flask, followed by the addition of 100 ml of solvent. The flask was weighed along with its contents, and recorded as W1. The flask was well shaken, and allowed to stand for 1 h. Subsequently a reflux condenser was attached to the flask, and gently brought to boiling and maintained thereat boiled 20 – 60 minutes depending upon the solvent. The mixture was subsequently cooled and weighed again. The weight was recorded as W2, and then readjusted to W1 with the solvent. The flask was shaken well once again and its contents rapidly filtered through a dry filter paper. By means a pipette, 25 ml of the filtrate was transferred to a previously dried and tarred glass dish and then gently evaporated to dryness on a hot plate. Subsequently, the dish was dried at 105 ºC for 1-6 hours, cooled in a desiccator for 30 min, and weighed. The extractable matter was calculated as %w/w of the air-dried sample.

#### **2.5 Determination of solubility of material in a given solvent – Methods I and II**

The solubility of a material was determined at room temperature ~ 25ºC and expressed in terms of "parts', representing the number of milliliter of solvent, in which 1 g of the material is soluble. Vials of appropriate sizes: ~4-ml, ~ 12-ml and ~20-ml capacities were used. The mixtures were thoroughly shaken for at least 30 min before inspection for un-dissolved solute. In methods I, each vial received 100 mg of sample and the volume of solvent indicated. In method II, a vial received 100 mg and increasing volumes of solvent. The methods give the same results.

#### **2.6 Light absorption and thin layer chromatography (TLC)**

UV-VIS Spectrophotometer (Jenway or Shimadzu) and quartz 1-cm cells were used for the study. Solutions of herb and extract were made by thoroughly mixing 1 part of the solute

the thumb and index finger, and inhaled as above. The strength of the odour was determined as: odourless, weak, distinct, or strong. The sensation of the odour was determined as: aromatic, fruity, rancid, etc. etc. When possible, the odour was compared with that of a defined substance, such as menthol, sulphur dioxide, eugenol, etc. etc. Taste: In tasting the material, as recommended by our experience with the material, the following procedure was applied: a pinch of the material was mixed with water and savored, or chewed without swallowing, to determine the strength and the sensation of the taste. The strength is recorded as: tasteless, weak, distinct, or strong; and the sensation, as: sweet, sour, saline, or bitter. Phytochemical tests for tannins, saponins, terpenoids, anthraquinones and alkaloids were carried out on samples by procedures as described in detail elsewhere (Ameh

This was carried out using a minimum of 0.5 – 1.0 g of material. Drying was effected in a Lindberg/Blue M gravity-convention oven maintained at 105-110 0C, for 3 h, after which the sample was allowed to cool to room temperature in a desiccator, and subsequently weighed. The time interval from the oven to point of weighing was usually about 30 minutes. The

About 4 g of accurately weighed coarsely powdered, air-dried sample was transferred into a glass-stoppered, 250-ml reflux conical flask, followed by the addition of 100 ml of solvent. The flask was weighed along with its contents, and recorded as W1. The flask was well shaken, and allowed to stand for 1 h. Subsequently a reflux condenser was attached to the flask, and gently brought to boiling and maintained thereat boiled 20 – 60 minutes depending upon the solvent. The mixture was subsequently cooled and weighed again. The weight was recorded as W2, and then readjusted to W1 with the solvent. The flask was shaken well once again and its contents rapidly filtered through a dry filter paper. By means a pipette, 25 ml of the filtrate was transferred to a previously dried and tarred glass dish and then gently evaporated to dryness on a hot plate. Subsequently, the dish was dried at 105 ºC for 1-6 hours, cooled in a desiccator for 30 min, and weighed. The extractable matter was

**2.5 Determination of solubility of material in a given solvent – Methods I and II** 

The solubility of a material was determined at room temperature ~ 25ºC and expressed in terms of "parts', representing the number of milliliter of solvent, in which 1 g of the material is soluble. Vials of appropriate sizes: ~4-ml, ~ 12-ml and ~20-ml capacities were used. The mixtures were thoroughly shaken for at least 30 min before inspection for un-dissolved solute. In methods I, each vial received 100 mg of sample and the volume of solvent indicated. In method II, a vial received 100 mg and increasing volumes of solvent. The

UV-VIS Spectrophotometer (Jenway or Shimadzu) and quartz 1-cm cells were used for the study. Solutions of herb and extract were made by thoroughly mixing 1 part of the solute

results are expressed as a range or as mean ± standard deviation.

et al., 2010c, d).

**2.3 Loss on drying** 

**2.4 Evaluation of extractive matter** 

calculated as %w/w of the air-dried sample.

**2.6 Light absorption and thin layer chromatography (TLC)** 

methods give the same results.

and with 100 parts of solvent methanol: water 80:20, v/v filtering, and diluting the filtrates by 150x with the same solvent. Absorbencies were measured at λ227 nm, using the solvent as the blank. Florescent, precoated plates were used for normal phase TLC, utilizing silica K6, and hexane: ethylacetate as mobile phase. Solutions of analytes were prepared and applied as follows: To 1 mg of the analyte, 2 drops of ethanol were added and mixed well (~1 %w/v solution). The plates used were 5 cm wide x 20 cm long. With a ruler and a pencil, a distance of 5 mm was measured from the bottom of the plate, and a line of origin was lightly drawn across the plate, without disturbing the adsorbent. The analyte was applied to the origin as a 1 μl droplet. The spot was allowed to dry. Subsequently, the plate was developed in a developing tank saturated with the vapour of the solvent system to be used as mobile phase. The level of the solvent in the tank was adjusted to a level 2 to 3 mm below the line of origin on the plate. The plate was considered developed when the solvent front reached a predetermined line, not less than 5 mm below the top of the plate. The air-dried plate was visualized using a viewing cabinet (Cammag) and a UV-lamp (Cammag – equipped to emit light at 254 or 366 nm). The resulting chromatogram was photographed and subsequently drawn to scale.

#### **2.7 Determinations of pH of preparations – herb and the dry extract**

Determination of pH values was with a Jenway pH Meter. Standard pH solutions: 4, 7 and 10; and freshly distilled water were used for the study.

#### **2.8 Determination of foaming indices of preparations – herb and the dry extract**

Decoctions of plant materials foam due to the presence of saponins. This ability is measured as foaming index, and is an important quality control parameter. The requirements for the test include: conical flasks (500-ml); volumetric flasks (100-ml); test tubes (16cm x 16mm); ruler; and stop-clock. The procedure was as follows: Exactly 1.0 g of powdered material was accurately transferred into a 500-ml conical flask containing 100 ml of boiling water, and maintained at moderate boiling for 30 minutes. The mixture was then cooled and filtered into a 100-ml volumetric flask. The volume was made up to 100 ml with water. Successive portions of 1 ml, 2 ml, 3 ml etc up to 10 ml of the filtrate was poured into ten stoppered tubes having the following dimensions: height, 16 cm; diameter, 16 mm. Subsequently, the volume of each tube was adjusted to 10 ml with water, stoppered and shaken in lengthwise motion for 15 seconds, at 2 shakes per second. The tubes were allowed to stand for 15 minutes, and the height of the foam in each tube was measured. The results were assessed as follows:

Foaming index is ≤ 100, if the height of foam in all the tubes is less than 1 cm.

If a height of 1 cm is obtained in any tube, the volume [V] of the decoction in that tube, is used to determine the foaming index, as = 1000/V.

But if the tube above is the first or the second in the series, prepare an intermediate dilution to obtain a more precise result.

If the height of the foam is > 1 cm in every tube, the foaming index is over 1000.

To obtain a more precise result, repeat the determination using a new series of dilutions of the decoction. Note the tube in which the height of foam is 1 cm, and the volume [V] of the decoction therein, and calculate the foaming index, as = 1000/V. Results are expressed as expressed as a quantity [Q] per ml or as [Q]ml-1.

Herbal Drug Regulation Illustrated with Niprifan® Antifungal Phytomedicine 375

**3.2 Results of physicochemical tests on the herb and extract of** *Mitracarpus scaber* Typical results of loss on drying (LOD as %w/w was 10.29 ± 1.81 for the herb; and 15.86 ± 0.72 for the extract) and total ash (TA as %w/w was 12.44 ± 2.95 for the herb; and 0.40 ± 0.09 for the extract) are shown in Table 5. The Table also shows that a 5%w/v mixture of the herb had pH of 5.7 ± 0.3, while that of the extract was 6.9 ± 0.3. The herb in water foamed slightly (that is: Foaming Index [FI] ≤ 100), but the extract did not foam at all (that is: FI = 0). Table 5 further shows that the herb in methanol/water (80/20: v/v) had an A1%1cm of 325.8 ± 15.6, while that of the extract was 349.5 ± 14.1. The Table also shows the extractabilities of the herb in various solvents. The extractability results expressed as (%w/w) were as follows: acetone, 6.89 ± 0.89; water, 28.37 ± 1.77; ethanol, 11.72 ± 0.81; ethylacetate, 14.02 ± 1.89; hexane, 4.11 ± 0.47; and methanol, 15.11 ± 1.07. The extractability of the air-dried weed was highest in water and least in hexane. Among the organic solvents, extractability was lowest in hexane, and highest in methanol, followed by ethylacetate,

**Parameter (Mean ± SD) Air-dried Herb Ethylacetate Extract**  Loss on drying (LOD: % w/w ) 10.29 ± 1.81 (n=12) 15.86 ± 0.72 (n=12) Total ash (TA: % w/w) 12.44 ± 2.95 (n=12) 0.40 ± 0.09 (n=11) pH of 5 % w/v in water 5.7 ± 0.3 (n=5) 6.9 ± 0.3 (n=5)

(MeOH/ H2O: 80/20 v/v) 325.8 ± 15.6 (n=5) 349.5 ± 14.1 (n=5)

Water 28.37 ± 1.77 >10³ Methanol 15.11 ± 1.07 25.0 ± 0.0 Ethylacetate 14.02 ± 1.89 25.0 ± 5.0 Ethanol 11.72 ± 0.81 25.0 ± 0.0 Acetone 6.89 ± 0.89 15.0 ± 0.0 Hexane 4.11 ± 0.47 55.0 ± 5.0 The LOD results were validated by concurrent determination of the LOD of copper sulphate, which result (mean ± SD) was 36.12 ± 0.19 %. The results prove that the extract was quite hygroscopic. The low TA results for the extract but not the herb probably suggests a high presence of high bio-minerals. The high water extractability result agrees with the high TA of the herb, and the fact that hexane, the least polar solvent, produced the lowest extractability result. Among the organic solvents the solubility of the extract was least in hexane (55 ml/g), but higher in ethanol, ethylacetate and methanol (15-25 ml/g). The extract was practically insoluble in water (>10³ml/g). The colour of the solution obtained from the herb using different organic solvents was clear and greenish-brown in each case, but that obtained with

Table 5. Various physicochemical parameters of herb and extract of *Mitracarpus scaber.*

**3.3 Results of thin layer chromatographic (TLC) studies on the herb and extracts of** 

Figure 1 is a normal phase TLC of the herb and extract developed with hexane-ethylacetate. The Figure indicates the following: The herb in acetone (A) or ethanol (C) yielded 5 identical

(n=5)

Extractive value (n=8-12) -

No foam. FI = 0 (n=5)


Foaming Index (FI: as ml-1) Slight foam. FI ≤<sup>100</sup>

water was yellowish brown, and slightly cloudy, with no tinge of green.

ethanol and acetone.

A 1%1cm at λ227 nm

*M. scaber* 

**Extractability** (% w/w) in: **Solubility** (ml/g) in:

## **3. Results**

## **3.1 Results of botanical examination / phytochemical tests on the herb and extract**

The key botanical and phytochemical characteristics of *Mitracarpus scaber* Zucc (Family: Rubiaceae) with Voucher specimen number: NIPRD/H/4208, preserved in the Institute's Herbarium are indicated in Table 4. The plant grows erect, up to 55 cm high, usually branched; the leaves are lanceolate, 2-4 cm long, with the upper surface bearing minute hairs. The plant manifests dense clusters of inflorescence, 6-14 mm across, with minute white flowers. The fruits are dehiscent capsules, about 0.5-1 mm long. Both the fresh plant and air-dried weed are practically odourless but possess a slight warm taste. Tannins, saponins and anthraquinones were detected in the weed. The extract also contained tannins and anthraquinones but not saponins. Tests for alkaloids were negative for the weed and extract.


The samples described above were obtained from the NIPRD Botanical Gardens at Idu Industrial Area, Idu, Abuja, Federal Capital Territory, Nigeria.

Table 4. Some key characteristics of *Mitracarpus scaber* and its aerial parts.

**3.1 Results of botanical examination / phytochemical tests on the herb and extract**  The key botanical and phytochemical characteristics of *Mitracarpus scaber* Zucc (Family: Rubiaceae) with Voucher specimen number: NIPRD/H/4208, preserved in the Institute's Herbarium are indicated in Table 4. The plant grows erect, up to 55 cm high, usually branched; the leaves are lanceolate, 2-4 cm long, with the upper surface bearing minute hairs. The plant manifests dense clusters of inflorescence, 6-14 mm across, with minute white flowers. The fruits are dehiscent capsules, about 0.5-1 mm long. Both the fresh plant and air-dried weed are practically odourless but possess a slight warm taste. Tannins, saponins and anthraquinones were detected in the weed. The extract also contained tannins and anthraquinones but not saponins. Tests for alkaloids were negative for the weed and

Characteristic Live Sample Air-dried Sample

M. scaber is an annual, with erect stems, up to 55 cm high, and often branched. The leaves are lanceolate, 3-5 cm long, with the upper surface scabrous. The inflorescence consists of clusters of small white flowers. The fruits are dehiscent capsules, up to 1 mm long. The plant is of the Family, Rubiaceae, reproduces by seeds, and is found in the tropics.

Odor Odourless Odourless

Tannins, saponins and anthraquinones were detected. The tests for alkaloids were negative.

Table 4. Some key characteristics of *Mitracarpus scaber* and its aerial parts.

Taste Very slightly warm Slightly warm

The samples described above were obtained from the NIPRD Botanical Gardens at Idu Industrial Area,

The air-dried sample consists of brownish green twigs and other parts that can readily be ground in a mortar or comminuting machine. The air-drying process takes about a week during the months of October to December, at NIPRD Herbarium, Abuja. The extracts obtained with various solvents yield a black, odorless and sticky mass.

Tannins and anthraquinones were detected. The tests for alkaloids and saponins were negative.

**3. Results** 

extract.

General appearance

Phytochemicals

Idu, Abuja, Federal Capital Territory, Nigeria.

## **3.2 Results of physicochemical tests on the herb and extract of** *Mitracarpus scaber*

Typical results of loss on drying (LOD as %w/w was 10.29 ± 1.81 for the herb; and 15.86 ± 0.72 for the extract) and total ash (TA as %w/w was 12.44 ± 2.95 for the herb; and 0.40 ± 0.09 for the extract) are shown in Table 5. The Table also shows that a 5%w/v mixture of the herb had pH of 5.7 ± 0.3, while that of the extract was 6.9 ± 0.3. The herb in water foamed slightly (that is: Foaming Index [FI] ≤ 100), but the extract did not foam at all (that is: FI = 0). Table 5 further shows that the herb in methanol/water (80/20: v/v) had an A1%1cm of 325.8 ± 15.6, while that of the extract was 349.5 ± 14.1. The Table also shows the extractabilities of the herb in various solvents. The extractability results expressed as (%w/w) were as follows: acetone, 6.89 ± 0.89; water, 28.37 ± 1.77; ethanol, 11.72 ± 0.81; ethylacetate, 14.02 ± 1.89; hexane, 4.11 ± 0.47; and methanol, 15.11 ± 1.07. The extractability of the air-dried weed was highest in water and least in hexane. Among the organic solvents, extractability was lowest in hexane, and highest in methanol, followed by ethylacetate, ethanol and acetone.


The LOD results were validated by concurrent determination of the LOD of copper sulphate, which result (mean ± SD) was 36.12 ± 0.19 %. The results prove that the extract was quite hygroscopic. The low TA results for the extract but not the herb probably suggests a high presence of high bio-minerals. The high water extractability result agrees with the high TA of the herb, and the fact that hexane, the least polar solvent, produced the lowest extractability result. Among the organic solvents the solubility of the extract was least in hexane (55 ml/g), but higher in ethanol, ethylacetate and methanol (15-25 ml/g). The extract was practically insoluble in water (>10³ml/g). The colour of the solution obtained from the herb using different organic solvents was clear and greenish-brown in each case, but that obtained with water was yellowish brown, and slightly cloudy, with no tinge of green.

Table 5. Various physicochemical parameters of herb and extract of *Mitracarpus scaber.*

#### **3.3 Results of thin layer chromatographic (TLC) studies on the herb and extracts of**  *M. scaber*

Figure 1 is a normal phase TLC of the herb and extract developed with hexane-ethylacetate. The Figure indicates the following: The herb in acetone (A) or ethanol (C) yielded 5 identical

Herbal Drug Regulation Illustrated with Niprifan® Antifungal Phytomedicine 377

Table 6. Effect of storage on herb and ethylacetate extract of *M. scaber* as evaluated by

appearance, extractability, solubility and loss on drying.

principal spots, while the herb in water (B) yielded only 2 principal spots – Rf1 and Rf4. The herb in ethylacetate (D) or hexane (E) yielded 3 spots, while the herb (F) in methanol yielded 4. The dry hexane extract (G) re-dissolved in hexane yielded 7 spots, while the ethylacetate extract (H) re-dissolved in ethylacetate yielded 10. Notably, Rf4 was present in all the chromatograms, while Rf2 and Rf3 were present only in the H chromatogram. On the other hand Rf1 was present only in the B, G and H chromatograms.


The above diagram is of a normal phase TLC (K5 Silica, using hexane: ethylacetate at 60:40 v/v as mobile phase) of samples of samples of herb and extracts in various solvents as follows. Types of samples/ solvents: A: Herb in Acetone, B: Herb in Water, C: Herb in Ethanol, D: Herb in Ethylacetate, E: Herb in Hexane, F: Herb in Methanol, G: Hexane extract in Hexane, H: Ethylacetate extract in Ethylacetate. The samples in G and H were dry extracts re-dissolved in hexane and ethylacetate respectively. Rf as detected at λ366nm: Rf1: 0.07, Rf2: 0.13, Rf3: 0.22, Rf4: 0.41, Rf5: 0.49, Rf6: 0.71, Rf7: 0.73, Rf8: 0.79, Rf9: 0.84, Rf10: 0.86. Descriptions/interpretations: The herb in acetone (A) or ethanol (C) yielded 5 identical principal spots, while the herb in water (B) yielded only 2 principal spots – Rf1 and Rf4. The herb in ethylacetate (D) or hexane (E) yielded 3 spots, while the herb (F) in methanol yielded 4. The dry hexane extract (G) re-dissolved in hexane yielded 7 spots, while the ethylacetate extract (H) redissolved in ethylacetate yielded 10. Notably, Rf4 was present in all the chromatograms, while Rf2 and Rf3 were present only in the H chromatogram. On the other hand Rf1 was present only in the B, G and H chromatograms.

Fig. 1. Diagrammatized normal phase TLC of *M. scaber* extracts showing up to ten principal spots.

principal spots, while the herb in water (B) yielded only 2 principal spots – Rf1 and Rf4. The herb in ethylacetate (D) or hexane (E) yielded 3 spots, while the herb (F) in methanol yielded 4. The dry hexane extract (G) re-dissolved in hexane yielded 7 spots, while the ethylacetate extract (H) re-dissolved in ethylacetate yielded 10. Notably, Rf4 was present in all the chromatograms, while Rf2 and Rf3 were present only in the H chromatogram. On the other

> A: *M. scaber* in Acetone B: *M. scaber* in Water C: *M. scaber* in Ethanol D: *M. scaber* in Ethylacetate E: M. scaber in Hexane F: *M. scaber* in Methanol G: Hexane extract in Hexane H: Ethylacetate extract in Ethylacetate

G and H were dry extracts re-dissolved in hexane and ethylacetate respectively

Rf as detected with light at λ366nm

Rf1: 0.07 Rf2: 0.13 Rf3: 0.22 **Rf4: 0.41** Rf5: 0.49 Rf6: 0.71 Rf7: 0.73 Rf8: 0.79 Rf9: 0.84 Rf10: 0.86

Rf1 Rf2

The above diagram is of a normal phase TLC (K5 Silica, using hexane: ethylacetate at 60:40 v/v as mobile phase) of samples of samples of herb and extracts in various solvents as follows. Types of samples/ solvents: A: Herb in Acetone, B: Herb in Water, C: Herb in Ethanol, D: Herb in Ethylacetate, E:

Fig. 1. Diagrammatized normal phase TLC of *M. scaber* extracts showing up to ten principal

Herb in Hexane, F: Herb in Methanol, G: Hexane extract in Hexane, H: Ethylacetate extract in Ethylacetate. The samples in G and H were dry extracts re-dissolved in hexane and ethylacetate respectively. Rf as detected at λ366nm: Rf1: 0.07, Rf2: 0.13, Rf3: 0.22, Rf4: 0.41, Rf5: 0.49, Rf6: 0.71, Rf7: 0.73, Rf8: 0.79, Rf9: 0.84, Rf10: 0.86. Descriptions/interpretations: The herb in acetone (A) or ethanol (C) yielded 5 identical principal spots, while the herb in water (B) yielded only 2 principal spots – Rf1 and Rf4. The herb in ethylacetate (D) or hexane (E) yielded 3 spots, while the herb (F) in methanol yielded 4. The dry hexane extract (G) re-dissolved in hexane yielded 7 spots, while the ethylacetate extract (H) redissolved in ethylacetate yielded 10. Notably, Rf4 was present in all the chromatograms, while Rf2 and Rf3 were present only in the H chromatogram. On the other hand Rf1 was present only in the B, G and

**Origin**

Rf3

**Rf4** Rf5

Rf6 Rf7 Rf8 Rf10 Rf9

**Solvent front**

hand Rf1 was present only in the B, G and H chromatograms.

A B C DE F G H

H chromatograms.

spots.


Table 6. Effect of storage on herb and ethylacetate extract of *M. scaber* as evaluated by appearance, extractability, solubility and loss on drying.

Herbal Drug Regulation Illustrated with Niprifan® Antifungal Phytomedicine 379

mixture of the fresh plant material in water did foam slightly; this property diminished rapidly, and was totally lost after the 3rd month of storage. By contrast, the ethylacetate

> Ethyl acetate extract in water

5.7 ± 0.3 (5) 6.9 ± 0.3 (5) Foam: Slight

0 5.9 ± 0.2 (6) 6.1 ± 0.3 (5) Foam: Slight

3 5.6 ± 0.2 (5) 6.2 ± 0.4 (6) Foam: Slight

9 5.4 ± 0.2 (5) 6.1 ± 0.3 (5) Foam: Nil

21 5.9 ± 0.3 (7) 6.7 ± 0.3 (5) Foam: Nil

39 5.9 ± 0.3 (5) 6.5 ± 0.3 (5) Foam: Nil

Both (a) and (b) indicate that the pH of the 5 %w/v aqueous mixtures at every stage fell within the mean values of 5.8 ± 0.2a and 6.4 ± 0.4b - they indicate that any deviations from these mean values were insignificant (P > 0.05). The freshly harvested samples foamed measurably, but the ability was totally lost after the 3rd month of dry storage. In all cases however, the dry ethylacetate extract was virtually

Table 8. Effect of storage on pH and foaming indices of the fresh plant material, the dry herb

The aim of this study was to apply official methods of WHO (1998) and BP (2004) to study the key quality attributes of the air-dried weed and the ethylacetate extract of *Mitracarpus scaber,* for the purpose of quality control, GMP production and registration of Niprifan by NAFDAC. WHO had defined "Herbal Substance" as "Material derived from the plant(s) by extraction, mechanical manipulation, or some other process" (WHO, 2005). Thus, either the ethylacetate extract, or even the comminuted, air-dried vegetable matter, may rightly be termed the "Herbal Substance" of Niprifan. Since the advent of the Alma-ata Declaration in 1978, many developing countries opted to adopt the WHO model in developing their National Traditional Medicine, especially phytotherapy (Ameh et al., 2010b). NIPRD's adherence to the WHO model had resulted in the sickle cell drug – Niprisan, developed from Yoruba Traditional Medicine (Wambebe et al., 2001). It is generally held that in most countries, especially in Africa, the populations depend greatly on herbal remedies, up to 90 % in some instances like Ethiopia (BBC, 2006). Such high dependence calls for a system or mechanism for harnessing and optimizing all or most of such plant resources. That means that every effort must be made to obtain maximum benefits from them. One way to do this is to standardize the raw materials used in producing the remedies, by studies such as this

pH of mixture (5% w/v) Foaming index

Herb in water

Ethylacetate extract in water

<sup>≤</sup> 100 (5) Foam: Nil (5)

< 100 (5) Foam: Nil (6)

< 100 (5) Foam: Nil (5)

(6) Foam: Nil (5)

(5) Foam: Nil (5)

(5) Foam: Nil (5)

extract never foamed at any stage of storage.

insoluble in water, and did not foam at all.

and the ethylacetate extract of *M. scaber.* 

**4. Discussions** 

Herb in water

Months of storage in capped glass bottles at RTH

Within 1st day of harvest or preparation

#### **3.4 Effect of storage on herb and ethylacetate extract of** *M. scaber* **as evaluated by appearance, extractability, solubility and loss on drying**

Table 6 shows that the general appearance of the herb as wrinkled, brownish green/ grey leaves and twigs remained essentially unchanged up to the 39th month of storage. However, the extractability of the herb in water fell slightly but significantly as from after the 3rd month of storage. Table 6 also shows that neither the solubility profile nor the appearance of the extract and the solutions made from them in different solvents changed with storage. The same Table 6 shows that storage of the herb and the extract in capped glass bottles at room temperature and humidity (RTH) for up to 39 months produced no consistent or statistically significant changes in moisture content.

## **3.5 Effect of storage on light absorption and TLC features of the herb and extract**

Table 7 presents the effect of storage on light absorption and TLC features of the herb and extract. It shows the following: that the difference in absorbance between 0th month and the 21st/ 39th months was insignificant for the herb (P > 0.05). By contrast, the corresponding difference for the extract was significant (P < 0.05). Table 7 also shows that the number of TLC spots observed for the herb and extract at every stage of storage was unchanged up to the 39th month.


For the herb, the difference in absorbance between 0th month and the 21st/ 39th months, denoted by (a), was insignificant (P > 0.05). By contrast, for the extract, the difference in absorbance between the 0th or 3rd month and the 21st or 39th month, denoted by (b), was significant (P < 0.05). Notably, the number of TLC spots observed for both the herb and extract remained unchanged up to the 39th month.

Table 7. Effect of storage on light absorption and TLC characteristics of herb and extract of *M. scaber.*

#### **3.6 Effect of storage on pH and foaming indices of herb and ethylacetate extract of**  *M. scaber*

Table 8 shows that the pH of a 5 %w/v mixture of the herb or extract in water did not change significantly with storage for up to 39 months. However, although the 5 %w/v mixture of the fresh plant material in water did foam slightly; this property diminished rapidly, and was totally lost after the 3rd month of storage. By contrast, the ethylacetate extract never foamed at any stage of storage.


Both (a) and (b) indicate that the pH of the 5 %w/v aqueous mixtures at every stage fell within the mean values of 5.8 ± 0.2a and 6.4 ± 0.4b - they indicate that any deviations from these mean values were insignificant (P > 0.05). The freshly harvested samples foamed measurably, but the ability was totally lost after the 3rd month of dry storage. In all cases however, the dry ethylacetate extract was virtually insoluble in water, and did not foam at all.

Table 8. Effect of storage on pH and foaming indices of the fresh plant material, the dry herb and the ethylacetate extract of *M. scaber.* 

## **4. Discussions**

378 Modern Approaches To Quality Control

Table 6 shows that the general appearance of the herb as wrinkled, brownish green/ grey leaves and twigs remained essentially unchanged up to the 39th month of storage. However, the extractability of the herb in water fell slightly but significantly as from after the 3rd month of storage. Table 6 also shows that neither the solubility profile nor the appearance of the extract and the solutions made from them in different solvents changed with storage. The same Table 6 shows that storage of the herb and the extract in capped glass bottles at room temperature and humidity (RTH) for up to 39 months produced no consistent or

**3.4 Effect of storage on herb and ethylacetate extract of** *M. scaber* **as evaluated by** 

**3.5 Effect of storage on light absorption and TLC features of the herb and extract**  Table 7 presents the effect of storage on light absorption and TLC features of the herb and extract. It shows the following: that the difference in absorbance between 0th month and the 21st/ 39th months was insignificant for the herb (P > 0.05). By contrast, the corresponding difference for the extract was significant (P < 0.05). Table 7 also shows that the number of TLC spots observed for the herb and extract at every stage of storage was unchanged up to

**Types of solvent/ number of TLC** 

0.104 (5) 5 2 5 3 3 4 2.330 ±

0.114 (6) 5 2 5 3 3 4 2.174 ±

0.098 (5) 5 2 5 3 3 4 2.104 ±

5 2 5 3 3 4

5 2 5 3 3 4

For the herb, the difference in absorbance between 0th month and the 21st/ 39th months, denoted by (a), was insignificant (P > 0.05). By contrast, for the extract, the difference in absorbance between the 0th or 3rd month and the 21st or 39th month, denoted by (b), was significant (P < 0.05). Notably, the number of TLC spots observed for both the herb and extract remained unchanged up to the 39th month. Table 7. Effect of storage on light absorption and TLC characteristics of herb and extract of

**3.6 Effect of storage on pH and foaming indices of herb and ethylacetate extract of** 

Table 8 shows that the pH of a 5 %w/v mixture of the herb or extract in water did not change significantly with storage for up to 39 months. However, although the 5 %w/v

**Herb Extract** 

**spots Abs. at** 

**A B C D E F G H** 

**λ227 nm** 

2.039 ± 0.104b (5)

2.084± 0.111b (6)

0.094 (5) 7 10

0.107 (5) 7 10

0.070 (5) 7 10

**TLC spots** 

7 10

7 10

**appearance, extractability, solubility and loss on drying** 

statistically significant changes in moisture content.

**Abs. at λ227 nm** 

2.322 ± 0.117a (5)

2.233 ± 0.114a (5)

<sup>0</sup>2.172 ±

<sup>3</sup>2.221 ±

<sup>9</sup>2.144 ±

the 39th month.

Months of storage in capped glass bottles at RTH

21

39

*M. scaber.*

*M. scaber*

The aim of this study was to apply official methods of WHO (1998) and BP (2004) to study the key quality attributes of the air-dried weed and the ethylacetate extract of *Mitracarpus scaber,* for the purpose of quality control, GMP production and registration of Niprifan by NAFDAC. WHO had defined "Herbal Substance" as "Material derived from the plant(s) by extraction, mechanical manipulation, or some other process" (WHO, 2005). Thus, either the ethylacetate extract, or even the comminuted, air-dried vegetable matter, may rightly be termed the "Herbal Substance" of Niprifan. Since the advent of the Alma-ata Declaration in 1978, many developing countries opted to adopt the WHO model in developing their National Traditional Medicine, especially phytotherapy (Ameh et al., 2010b). NIPRD's adherence to the WHO model had resulted in the sickle cell drug – Niprisan, developed from Yoruba Traditional Medicine (Wambebe et al., 2001). It is generally held that in most countries, especially in Africa, the populations depend greatly on herbal remedies, up to 90 % in some instances like Ethiopia (BBC, 2006). Such high dependence calls for a system or mechanism for harnessing and optimizing all or most of such plant resources. That means that every effort must be made to obtain maximum benefits from them. One way to do this is to standardize the raw materials used in producing the remedies, by studies such as this

Herbal Drug Regulation Illustrated with Niprifan® Antifungal Phytomedicine 381

Abere, T. A.; Onwukaeme, D. N. & Eboka, C. J. (2007b). Pharmacognostic evaluation of the

Ameh, S. J.; Obodozie, O. O.; Inyang, U. S.; Abubakar, M. S. & Garba, M. (2010a). Current

Ameh, S. J.; Obodozie, O. O.; Inyang, U. S.; Abubakar, M. S. & Garba, M. (2010b). Current

Ameh, S. J.; Tarfa, F. D.; Abdulkareem, T. M.; Ibe, M. C.; Onanuga, C. & Obodozie, O. O.

Medicinal Plants. *Tropical Journal of Pharmaceutical Research,* 9 (2): 119-125. Ameh, S. J.; Obodozie, O. O.; Inyang, U. S.; Abubakar, M. S. & Garba, M. (2010d). Quality

Ann Godsell Regulatory (2008). Pharmaceutical Good Manufacturing Practice for Herbal

BBC News (2006). Can herbal medicine combat Aids? Wednesday, 15 March, 13:10 GMT. http://newsvote.bbc.co.uk/mpapps/pagetools/print/news.bbc.co.uk/2/hi/Afric

Benjamin, T. V.; Anucha, T. C. & Hugbo, P. G. (1986). An approach to the study of medicinal

Bisignano, G.; Sanogo, R.; Marino, A.; Angelo, V.; Germano, M.; De Pasquale, R. & Pizza, C.

Cimanga, R. K.; Kambu, K.; Tona, L.; Bruyne, T.; Sandra, A.; Totte, J.; Pieters, L. & Vlietinck,

De Smet, P. N. (2005). Herbal medicine in Europe – relaxing regulatory standards. *New* 

DSHEA (1994). Dietary Supplements Health Education Act of 1994 [cited 2010 April 8]. Available at: http://fda/Food/DietarySupplements/ucm109764.htm Gbaguidi, F.; Accrombessi, G.; Moudachirou, M. & Quetin-Leclercq, J. (2005). HPLC

plants with antimicrobial activity with reference to *Mitracarpus scaber*. *In*: Sofowora, A. (Ed.) *The State of medicinal Plants Research in Nigeria*, pp. 243-245, Ibadan

(2000). Antimicrobial activity of Mitracarpus scaber extract and isolated constituents. *Letters in Applied Microbiology*, Vol. 30, pp. 105-108. doi:10.1046/j.1472-

A. J. (2004). Antibacterial and antifungal activities of some extracts and fractions of Mitracarpus scaber Zucc. (Rubiaceae). *Journal of Natural Remedies,* Vol. 4, No. 1, pp.

quantification of two isomeric triterpenic acids isolated from Mitracarpus scaber and antimicrobial activity on Dermatophilus congolensis. *Journal of Pharmaceutical* 

Drug Substances 2008 [cited 2010 April 8]. Available online at: http://www.pharmaceutical-int.com/article/category/treatment-herbal-

University Press, ISBN 978-30285-0-2, Ibadan, Nigeria.

*England Journal of Medicine,* Vol. 352, No. 12, pp. 1176-78.

*& Biomedical Analysis*, Vol. 39, No. 5, pp. 990-995.

*Journal of Medicinal Plants Research*; Vol. 4(2): 072-081.

*Research* Vol. 6, No. 4, pp. 849-853.

August, 2010.

No 4, pp. 387-394

medicines

a/4793106.stm .

765x.2000.00692.x.

17-25

leaves of *Mitracarpus scaber* Zucc (Rubiaceae). *Tropical Journal of Pharmaceutical* 

phytotherapy – an inter-regional perspective on policy, research and development of herbal medicine. *Journal of Medicinal Plants Research* Vol. 4(15), pp 1508-1516, 4

phytotherapy - A perspective on the science and regulation of herbal medicine.

(2010c). Physicochemical Analysis of the Aqueous Extracts of Six Nigerian

Control Tests on Andrographis paniculata Nees (Family: Acanthaceae) – an Indian 'Wonder' Plant Grown in Nigeria. *Tropical Journal of Pharmaceutical Research*, Vol. 9,

one. Such studies will at least help to minimize waste, and even lead ultimately to conservation of endangered plants. Indeed, efforts at conservation are more likely to succeed when the value of what is to be conserved is proven.

Our immediate interest however, is in the need to entrench the use of these resources by taking appropriate actions, which, in this case is - an application to NAFDAC to consider the registration of Niprifan, based on folkloric use evidence, pertinent literature, and the experimental data provided in this study. These three lines of evidence can be summarized as follows. At the peak of British colonialism in Africa considerable effort was made to harness the continent's wealth in herbal traditions. Thus at as far back as the 1930s a team of British scientists had combed the entire West Africa to research traditional herbal remedies. Thus, for *Mitracarpus scaber,* Hutchinson and Dalziel (1948) reported a number of findings that have subsequently been confirmed by work in NIPRD and elsewhere (Benjamin et al., 1986; Irobi and Daramola, 1994; Cimanga et al., 2004; Abere et al., 2007a, 2007b). These include the following: that *M. scaber* was widely distributed and used topically in all of West Africa for various skin infections; and orally for various internal conditions. Among the traditional indications mentioned, and which have since been confirmed by NIPRD's Ibrahim Muaazzam (ethnobotanist and consultant on TM) are: leprosy, lice, ringworm, eczema and craw-craw. Currently, the plant is used orally for sore throat, for which purpose it is wholly macerated in water.

Among the vernacular names of *M. scaber* are: Hausa (*goga masu*); Fulani (*gadudal*); Yoruba (*irawo-ile*); and Ibo (*obu obwa*). Professor Ogundiani (2005) in his inaugural address at the University in Ile-Ife commented on Niprifan,

stressing the antimicrobial potency of *M. scaber.* Ogundiani, as stated in the lecture, had been unaware of the NIPRD's work on Niprifan, until shortly before the inaugural, since that work, led by Professors Wambebe, Okogun and Nasipuri, had been unpublished. Therefore, in this paper we elect to present not only these historical antecedents, but also to furnish the results of our evaluation of the key quality variables of the herb and extract of *M. scaber,* with a view to advancing the registration of Niprifan (for skin infections) by NAFDAC. The results here presented probably suffice for quality control and GMP production, particularly if more emphasis is placed on technical requirements than on bureaucracy. It must be remarked at this juncture that NAFDAC only belatedly recognized the sickle cell drug, Niprisan, after the US-FDA and EMEA had granted it orphan status (Pandey, 2003). One may wonder - What a paradox! Why should the US and Europe that need herbal drugs far less than Nigeria be keener in their regulation? Therefore, from the foregoing, it seems that the key to this Nigerian enigma lies not in the technical but in the non-technical differences between NAFDAC and EMEA as depicted in Tables 1-3. The said differences which hinge on NAFDAC's extra requirements (Table 3) suggest that NAFDAC needs to re-strategize for efficient discharge of its Mandate. For example, despite the widespread use of herbal medicines in Nigeria and the Federal Policy on TM (2007), NAFDAC is not known to have "fully registered" a single herbal medicine since its creation in 1992/3, whereas it should. This is the puzzle this article had hoped to address.

### **5. References**

Abere , T. A.; Onyekweli, A. O. & Ukoh, G. C. (2007a). *In vitro* Antimicrobial Activity of the Extract of Mitracarpus scaber Leaves Formulated as Syrup. *Tropical Journal of Pharmaceutical Research* Vol. 6, No. 1, pp. 679-682.

one. Such studies will at least help to minimize waste, and even lead ultimately to conservation of endangered plants. Indeed, efforts at conservation are more likely to

Our immediate interest however, is in the need to entrench the use of these resources by taking appropriate actions, which, in this case is - an application to NAFDAC to consider the registration of Niprifan, based on folkloric use evidence, pertinent literature, and the experimental data provided in this study. These three lines of evidence can be summarized as follows. At the peak of British colonialism in Africa considerable effort was made to harness the continent's wealth in herbal traditions. Thus at as far back as the 1930s a team of British scientists had combed the entire West Africa to research traditional herbal remedies. Thus, for *Mitracarpus scaber,* Hutchinson and Dalziel (1948) reported a number of findings that have subsequently been confirmed by work in NIPRD and elsewhere (Benjamin et al., 1986; Irobi and Daramola, 1994; Cimanga et al., 2004; Abere et al., 2007a, 2007b). These include the following: that *M. scaber* was widely distributed and used topically in all of West Africa for various skin infections; and orally for various internal conditions. Among the traditional indications mentioned, and which have since been confirmed by NIPRD's Ibrahim Muaazzam (ethnobotanist and consultant on TM) are: leprosy, lice, ringworm, eczema and craw-craw. Currently, the plant is used orally for sore throat, for which purpose

Among the vernacular names of *M. scaber* are: Hausa (*goga masu*); Fulani (*gadudal*); Yoruba (*irawo-ile*); and Ibo (*obu obwa*). Professor Ogundiani (2005) in his inaugural address at the

stressing the antimicrobial potency of *M. scaber.* Ogundiani, as stated in the lecture, had been unaware of the NIPRD's work on Niprifan, until shortly before the inaugural, since that work, led by Professors Wambebe, Okogun and Nasipuri, had been unpublished. Therefore, in this paper we elect to present not only these historical antecedents, but also to furnish the results of our evaluation of the key quality variables of the herb and extract of *M. scaber,* with a view to advancing the registration of Niprifan (for skin infections) by NAFDAC. The results here presented probably suffice for quality control and GMP production, particularly if more emphasis is placed on technical requirements than on bureaucracy. It must be remarked at this juncture that NAFDAC only belatedly recognized the sickle cell drug, Niprisan, after the US-FDA and EMEA had granted it orphan status (Pandey, 2003). One may wonder - What a paradox! Why should the US and Europe that need herbal drugs far less than Nigeria be keener in their regulation? Therefore, from the foregoing, it seems that the key to this Nigerian enigma lies not in the technical but in the non-technical differences between NAFDAC and EMEA as depicted in Tables 1-3. The said differences which hinge on NAFDAC's extra requirements (Table 3) suggest that NAFDAC needs to re-strategize for efficient discharge of its Mandate. For example, despite the widespread use of herbal medicines in Nigeria and the Federal Policy on TM (2007), NAFDAC is not known to have "fully registered" a single herbal medicine since its creation in 1992/3, whereas it should. This is the puzzle this article had

Abere , T. A.; Onyekweli, A. O. & Ukoh, G. C. (2007a). *In vitro* Antimicrobial Activity of the

*Pharmaceutical Research* Vol. 6, No. 1, pp. 679-682.

Extract of Mitracarpus scaber Leaves Formulated as Syrup. *Tropical Journal of* 

succeed when the value of what is to be conserved is proven.

it is wholly macerated in water.

hoped to address.

**5. References** 

University in Ile-Ife commented on Niprifan,


**21** 

*Italy* 

**Procedures for Evaluation of Slice Thickness** 

The main goal of a medical imaging system is to produce images to provide more accurate and timely diagnoses (Torfeh et al., 2007). In particular, Computed Tomography (CT), Magnetic Resonance Imaging (MRI), and Ultrasound (US) are resourceful tools in medical practice, and in many cases a life saving resource when rapid decisions are needed in the emergency room (Rehani et al., 2000). The above diagnostic techniques are based on the evaluation of high resolution images from technologically sophisticated equipment. Individual images are obtained by using several different electronic components and considerable amounts of data processing, which affect the quality of images produced and,

In this context, to guarantee a consistent image quality over the lifetime of the diagnostic radiology equipment and to ensure safe and accurate operation of the process as a whole, it is necessary to establish and actively maintain regular and adequate Quality Assurance (QA) procedures. This is significant for computer-aided imaging systems, such as CT, MRI and US. The QA procedure should include periodic tests to ensure accurate target and critical structure localization (Mutic et al., 2003). Such tests are referred to as Quality Controls (QCs). They hold a key role within the QA procedure because they enable complete evaluation of system status and image quality (Chen et al., 2004; Vermiglio et al.,

Importantly, QCs permit the identification of image quality degradation before it affects patient scans, and of the source of possible equipment malfunction, pointing to preventive or immediate maintenance requirements. Thus, image QC is crucial to ensure a safe and efficient diagnosis and treatment of diseases (Rampado et al., 2006; Torfeh et al., 2007). For this reason, periodic QCs have been recommended by manufacturers and medical physicists' organizations to test the performance of medical imaging systems. Protocols for QCs and QA in medical imaging systems have been produced by several professional groups (AAPM – NEMA) (Goodsitt et al., 1998). This highlights the extensive role of QA programs, including QC testing, preventive maintenance, etc. (Rampado et al.,

In any clinical imaging study, it is important to have accurate confirmation of several physical characteristics of the medical imaging device. In particular, the slice thickness

consequently, make the diagnostic process more complicated (Torfeh et al., 2007).

**1. Introduction** 

2006).

2006).

**in Medical Imaging Systems** 

Federica Causa and Maria Giulia Tripepi

*University of Messina* 

*Environmental, Health, Social and Industrial Department –* 

Giuseppe Vermiglio, Giuseppe Acri, Barbara Testagrossa,


## **Procedures for Evaluation of Slice Thickness in Medical Imaging Systems**

Giuseppe Vermiglio, Giuseppe Acri, Barbara Testagrossa, Federica Causa and Maria Giulia Tripepi *Environmental, Health, Social and Industrial Department – University of Messina Italy* 

## **1. Introduction**

382 Modern Approaches To Quality Control

Germanò, M. P.; Sanogo, R; Costa, C; Fulco, R; D'Angelo, V.; Viscomi, E. G. & de Pasquale,

*Journal of Pharmacy & Pharmacology*, June 1999. Vol. 51, No. 6, pp. 729-734. Goldman, P. (2001). Herbal medicines today and the roots of modern pharmacology. *Annual* 

Gross, A. & Minot, J. (2007). Chinese Manufacturing: Scandals and Opportunities. Published

Houghton, P. J.; Ibewuike, J. C.; Mortimer, F.; Okeke, I. N. & Ogundaini, A. O. (2002).

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The main goal of a medical imaging system is to produce images to provide more accurate and timely diagnoses (Torfeh et al., 2007). In particular, Computed Tomography (CT), Magnetic Resonance Imaging (MRI), and Ultrasound (US) are resourceful tools in medical practice, and in many cases a life saving resource when rapid decisions are needed in the emergency room (Rehani et al., 2000). The above diagnostic techniques are based on the evaluation of high resolution images from technologically sophisticated equipment. Individual images are obtained by using several different electronic components and considerable amounts of data processing, which affect the quality of images produced and, consequently, make the diagnostic process more complicated (Torfeh et al., 2007).

In this context, to guarantee a consistent image quality over the lifetime of the diagnostic radiology equipment and to ensure safe and accurate operation of the process as a whole, it is necessary to establish and actively maintain regular and adequate Quality Assurance (QA) procedures. This is significant for computer-aided imaging systems, such as CT, MRI and US. The QA procedure should include periodic tests to ensure accurate target and critical structure localization (Mutic et al., 2003). Such tests are referred to as Quality Controls (QCs). They hold a key role within the QA procedure because they enable complete evaluation of system status and image quality (Chen et al., 2004; Vermiglio et al., 2006).

Importantly, QCs permit the identification of image quality degradation before it affects patient scans, and of the source of possible equipment malfunction, pointing to preventive or immediate maintenance requirements. Thus, image QC is crucial to ensure a safe and efficient diagnosis and treatment of diseases (Rampado et al., 2006; Torfeh et al., 2007). For this reason, periodic QCs have been recommended by manufacturers and medical physicists' organizations to test the performance of medical imaging systems. Protocols for QCs and QA in medical imaging systems have been produced by several professional groups (AAPM – NEMA) (Goodsitt et al., 1998). This highlights the extensive role of QA programs, including QC testing, preventive maintenance, etc. (Rampado et al., 2006).

In any clinical imaging study, it is important to have accurate confirmation of several physical characteristics of the medical imaging device. In particular, the slice thickness

Procedures for Evaluation of Slice Thickness in Medical Imaging Systems 385

dedicated phantom and the following image elaboration by employing LabView based

The slice thickness is evaluated by measuring the width (FWHM) of the image of one or more Aluminium ramps at the intersection of the ramp(s) with the scan plane (CEI, 1998), as illustrated schematically in Fig. 1. The sensitivity profile measures the system response to an attenuating impulse as a function of the z-axis position, through the slice plane. The sensitivity profile is a function of pre- and post-patient collimation, and appears as a blurred square wave. The FWHM of this blurred square is defined as the nominal slice width. The slice thickness of a CT scanner is determined by focal spot geometry as well as pre-patient

An customary method of monitoring equipment performance is to measure the parameters of interest using test objects. For example, Goodenough et al. proposed an approximate measure of beam width by using a series of small beads positioned across the beam width. However, this phantom is difficult to use for a precise quantitative measure because of the uncertainty on the alignment of the beads with respect to the beam. Indeed, the beam width can be measured directly from a beam profile plot only if care is taken to ensure that the Aluminium piece is oriented at 45 degrees across the width of beam (Judy et al., 1977, as

A typical performance phantom (Philips, 1997) uses Aluminium plates slanted 26.565 degrees and which are across each other, as shown in Fig. 2. With X-rays irradiated to the Aluminium plates, the axial length of each Aluminium can be measured in CT image. With this method, it is possible to obtain an accurate measurement even if the intersection of the Aluminium plates is not aligned with the X-ray beam, by averaging the two measurements

> tan 26.565 2 4

*L L a b L L a b <sup>L</sup>* (1)

software is also proposed.

and detector collimation and alignment.

cited in Goodenough et al., 1977).

Fig. 1. Principle of slice thickness measurement (Philips, 1997).

L*a* and L*b*. The slice thickness L is calculated as follows:

**2.1 CT scanners** 

accuracy represents an important parameter that should be estimated during QC procedures, not only because the signal to noise ratio varies linearly with the slice thickness, but also because clinical image resolution is strongly affected by partial volume effects, thus reducing clinical image quality with increasing slice thickness (Narayan et al., 2005). In addition, to determine the FWHM the AAPM procedure involves the evaluation of a line profile of the slice. So, during QC procedures many and different available test objects are used to assess different physical characteristics of the medical imaging device, including slice thickness, spatial resolution, dark noise, uniformity, etc. AAPM Reports No 1 and No 28 state that the slice thickness can be evaluated from the measure of the full width at half maximum (FWHM) of the response across the slice (Judy et al., 1977; Price et al., 1990). In particular, for a high-accuracy measurement of slice thickness, several test objects inserted in multipurpose phantoms can be used, most of which utilize inclined surfaces (plane, cone or spiral). A typical test object for the slice thickness evaluation is the crossed high signal ramps oriented at a fixed angle (Price et al., 1990).

Whereas in US equipment the slice thickness is typically not measured (Skolnick, 1991), most CT and MRI scanners adopt specific and automated procedures that require the use of dedicated phantoms, coupled with a dedicated imaging software that, however, does not always include line profile tools.

Standard slice thickness accuracy evaluation methods consist of scan explorations of phantoms that contain different specific patterns. These methods are based on manual scans with graphics tools or, alternatively, on automatic scans utilizing encoded masks to determine the Region Of Interest (ROI) for quantization (Torfeh et al., 2007). Therefore, a variety of different phantoms presently exists, but each requiring a specific QC protocol.

Further, even the newest medical imaging software do not allow a direct measurement of the slice thickness accuracy with CT and MRI scanners, but require a complicated procedure to be performed by specialized technicians authorized to enter in the SERVICE menu of medical devices.

To reduce complications and provide a versatile and unique QC procedure to estimate slice thickness accuracy, a novel dedicated phantom and associated procedure is proposed here that is easy to implement and that can be used on both CT and MRI scanners.

Such phantom can be used either with already existing dedicated software or with to this aim dedicated LabView-based tools, to readily measure the slice thickness in real time and/or post-processing operation. The reliability of the innovative technique proposed here has been evaluated with respect to previously validated procedures by conducting statistical analysis, as discussed in detail in the following sections.

Further, this novel technique is suitable also for the evaluation of the elevation resolution in US scanners, and easier to perform than standard techniques. This chapter is structured as follows: a review of the materials and methods commonly used in CT, MRI and US imaging systems, and the novel and versatile methodology proposed here for slice thickness measurements are presented in Section 2. The results obtained from the application of the proposed novel methodology to the three different imaging techniques are discussed in Section 3. The conclusions are drawn in Section 4.

#### **2. Materials and methods**

In this section the commonly used methods for determining the slice thickness accuracy in CT, MRI and US scanners are presented. In addition, a novel procedure that uses a dedicated phantom and the following image elaboration by employing LabView based software is also proposed.

#### **2.1 CT scanners**

384 Modern Approaches To Quality Control

accuracy represents an important parameter that should be estimated during QC procedures, not only because the signal to noise ratio varies linearly with the slice thickness, but also because clinical image resolution is strongly affected by partial volume effects, thus reducing clinical image quality with increasing slice thickness (Narayan et al., 2005). In addition, to determine the FWHM the AAPM procedure involves the evaluation of a line profile of the slice. So, during QC procedures many and different available test objects are used to assess different physical characteristics of the medical imaging device, including slice thickness, spatial resolution, dark noise, uniformity, etc. AAPM Reports No 1 and No 28 state that the slice thickness can be evaluated from the measure of the full width at half maximum (FWHM) of the response across the slice (Judy et al., 1977; Price et al., 1990). In particular, for a high-accuracy measurement of slice thickness, several test objects inserted in multipurpose phantoms can be used, most of which utilize inclined surfaces (plane, cone or spiral). A typical test object for the slice thickness evaluation is the crossed high signal

Whereas in US equipment the slice thickness is typically not measured (Skolnick, 1991), most CT and MRI scanners adopt specific and automated procedures that require the use of dedicated phantoms, coupled with a dedicated imaging software that, however, does not

Standard slice thickness accuracy evaluation methods consist of scan explorations of phantoms that contain different specific patterns. These methods are based on manual scans with graphics tools or, alternatively, on automatic scans utilizing encoded masks to determine the Region Of Interest (ROI) for quantization (Torfeh et al., 2007). Therefore, a variety of different phantoms presently exists, but each requiring a specific QC protocol. Further, even the newest medical imaging software do not allow a direct measurement of the slice thickness accuracy with CT and MRI scanners, but require a complicated procedure to be performed by specialized technicians authorized to enter in the SERVICE menu of

To reduce complications and provide a versatile and unique QC procedure to estimate slice thickness accuracy, a novel dedicated phantom and associated procedure is proposed here

Such phantom can be used either with already existing dedicated software or with to this aim dedicated LabView-based tools, to readily measure the slice thickness in real time and/or post-processing operation. The reliability of the innovative technique proposed here has been evaluated with respect to previously validated procedures by conducting statistical

Further, this novel technique is suitable also for the evaluation of the elevation resolution in US scanners, and easier to perform than standard techniques. This chapter is structured as follows: a review of the materials and methods commonly used in CT, MRI and US imaging systems, and the novel and versatile methodology proposed here for slice thickness measurements are presented in Section 2. The results obtained from the application of the proposed novel methodology to the three different imaging techniques are discussed in

In this section the commonly used methods for determining the slice thickness accuracy in CT, MRI and US scanners are presented. In addition, a novel procedure that uses a

that is easy to implement and that can be used on both CT and MRI scanners.

analysis, as discussed in detail in the following sections.

Section 3. The conclusions are drawn in Section 4.

**2. Materials and methods** 

ramps oriented at a fixed angle (Price et al., 1990).

always include line profile tools.

medical devices.

The slice thickness is evaluated by measuring the width (FWHM) of the image of one or more Aluminium ramps at the intersection of the ramp(s) with the scan plane (CEI, 1998), as illustrated schematically in Fig. 1. The sensitivity profile measures the system response to an attenuating impulse as a function of the z-axis position, through the slice plane. The sensitivity profile is a function of pre- and post-patient collimation, and appears as a blurred square wave. The FWHM of this blurred square is defined as the nominal slice width. The slice thickness of a CT scanner is determined by focal spot geometry as well as pre-patient and detector collimation and alignment.

An customary method of monitoring equipment performance is to measure the parameters of interest using test objects. For example, Goodenough et al. proposed an approximate measure of beam width by using a series of small beads positioned across the beam width. However, this phantom is difficult to use for a precise quantitative measure because of the uncertainty on the alignment of the beads with respect to the beam. Indeed, the beam width can be measured directly from a beam profile plot only if care is taken to ensure that the Aluminium piece is oriented at 45 degrees across the width of beam (Judy et al., 1977, as cited in Goodenough et al., 1977).

Fig. 1. Principle of slice thickness measurement (Philips, 1997).

A typical performance phantom (Philips, 1997) uses Aluminium plates slanted 26.565 degrees and which are across each other, as shown in Fig. 2. With X-rays irradiated to the Aluminium plates, the axial length of each Aluminium can be measured in CT image. With this method, it is possible to obtain an accurate measurement even if the intersection of the Aluminium plates is not aligned with the X-ray beam, by averaging the two measurements L*a* and L*b*. The slice thickness L is calculated as follows:

$$L = \left(\frac{L\_a + L\_b}{2}\right) \cdot \tan 26.565^\circ = \frac{L\_a + L\_b}{4} \tag{1}$$

Procedures for Evaluation of Slice Thickness in Medical Imaging Systems 387

Fig. 4. High signal ramp phantoms: (a) A typical slice-thickness phantom consisting of a set of crossed thin ramps. A ramp crossing angle of 90° yields an angle of 45° between the ramp and the image plane. The phantom length (L) should be greater than twice the maximum slice thickness. An alignment rod placed between the two ramps defines the point where the two ramps cross. When the slice is properly aligned through the intersection of the ramps the images of the ramps and of the rod will be aligned. (b) The slice sensitivity profile is directly proportional to the image intensity profiles if the image plane is perpendicular to

Since the signal obtained is directly proportional to the thickness of the slice, an inaccurate slice width can lead to a reduced Signal-to-Noise Ratio (SNR) (Lerski, 1992). Partial volume effects can significantly alter sensitivity and specificity. Quantitative measurements such as relaxation time T1 and T2 values, are also greatly influenced by slice thickness. Inaccuracies in slice thickness may result in inter-slice interference during multi-slice acquisitions, and invalid SNR measurements (Och et al., 1992). The slice profile, ideally rectangular, may contain side lobes which can produce very confusing effects (Lerski, 1992). In addition, gradient field nonuniformity, radio frequency field nonuniformity, nonuniform static magnetic field, noncoplanar slice selection pulses between excitation and readout, TR/T1 ratio (where TR represents the repetition time), and radio frequency pulse shape and

stimulated echoes can also affect the slice thickness accuracy (Price et al., 1990).

the alignment rod (Price et al., 1990).

Fig. 2. CT image of the section dedicated to the measurements of slice thickness of a typical performance phantom: (a) layout of the measurement methodology; (b) schematic of resulting image with the centres of the four bars appearing as black spots (Philips, 1997).

Another performance phantom used for CT scanners (Fig. 3) is a poli methyl methacrilate (PMMA) box presenting a pattern of air filled holes drilled 1 mm apart and aligned in the direction of the slice thickness (perpendicular to the scan plane). Each visible hole in the image represents 1 mm of beam thickness (General Electric [GE], 2000).

Fig. 3. Phantom with air-filled holes for slice thickness measurement in CT scanners: (a) schematic of the phantom, (b) schematic of the calibration image (General Electric [GE], 2000).

To determine the slice thickness, the image is displayed at the recommended window level and width. The number of visible holes (representing air-filled holes) is counted. Holes that appear black in the image represent a full millimetre slice thickness. Holes that appear grey count as fractions of a millimetre; two equally grey holes count as a single 1 mm slice thickness.

#### **2.2 MRI scanners**

The technique of MRI differs from X-ray CT in many ways, but one of the most interesting is perhaps that the slice is not determined primarily by the geometry of the scanning apparatus but rather by electronic factors, namely the spectrum of radio frequency pulse and the nature of the slice selection gradient (Mc Robbie et al., 1986). The slice profile and width of a 2D imaging technique such as MRI is a very important feature of its performance.

Fig. 2. CT image of the section dedicated to the measurements of slice thickness of a typical performance phantom: (a) layout of the measurement methodology; (b) schematic of resulting image with the centres of the four bars appearing as black spots (Philips, 1997).

Another performance phantom used for CT scanners (Fig. 3) is a poli methyl methacrilate (PMMA) box presenting a pattern of air filled holes drilled 1 mm apart and aligned in the direction of the slice thickness (perpendicular to the scan plane). Each visible hole in the

(a) (b) Fig. 3. Phantom with air-filled holes for slice thickness measurement in CT scanners: (a) schematic of the phantom, (b) schematic of the calibration image (General Electric [GE],

To determine the slice thickness, the image is displayed at the recommended window level and width. The number of visible holes (representing air-filled holes) is counted. Holes that appear black in the image represent a full millimetre slice thickness. Holes that appear grey count as fractions of a millimetre; two equally grey holes count as a single 1 mm slice

The technique of MRI differs from X-ray CT in many ways, but one of the most interesting is perhaps that the slice is not determined primarily by the geometry of the scanning apparatus but rather by electronic factors, namely the spectrum of radio frequency pulse and the nature of the slice selection gradient (Mc Robbie et al., 1986). The slice profile and width of a 2D imaging technique such as MRI is a very important feature of its performance.

(a) (b)

image represents 1 mm of beam thickness (General Electric [GE], 2000).

2000).

thickness.

**2.2 MRI scanners** 

Fig. 4. High signal ramp phantoms: (a) A typical slice-thickness phantom consisting of a set of crossed thin ramps. A ramp crossing angle of 90° yields an angle of 45° between the ramp and the image plane. The phantom length (L) should be greater than twice the maximum slice thickness. An alignment rod placed between the two ramps defines the point where the two ramps cross. When the slice is properly aligned through the intersection of the ramps the images of the ramps and of the rod will be aligned. (b) The slice sensitivity profile is directly proportional to the image intensity profiles if the image plane is perpendicular to the alignment rod (Price et al., 1990).

Since the signal obtained is directly proportional to the thickness of the slice, an inaccurate slice width can lead to a reduced Signal-to-Noise Ratio (SNR) (Lerski, 1992). Partial volume effects can significantly alter sensitivity and specificity. Quantitative measurements such as relaxation time T1 and T2 values, are also greatly influenced by slice thickness. Inaccuracies in slice thickness may result in inter-slice interference during multi-slice acquisitions, and invalid SNR measurements (Och et al., 1992). The slice profile, ideally rectangular, may contain side lobes which can produce very confusing effects (Lerski, 1992). In addition, gradient field nonuniformity, radio frequency field nonuniformity, nonuniform static magnetic field, noncoplanar slice selection pulses between excitation and readout, TR/T1 ratio (where TR represents the repetition time), and radio frequency pulse shape and stimulated echoes can also affect the slice thickness accuracy (Price et al., 1990).

Procedures for Evaluation of Slice Thickness in Medical Imaging Systems 389

beam depends on the focusing effect in the elevation direction, which is perpendicular to the scanning plane (Richard, 1999). In linear, curved linear and phased array sector probes, focus is controlled electronically, but in the elevation plane it is determined mechanically by the curvature of the crystals. The beam in the scan plane can be sharply focused only in a narrow focal range. Thus, beam profiles in the scan plane are not indicative of beam profiles in the elevation plane. As with lateral and axial resolution, elevational resolution can be measured indirectly with anechoic spherical objects or cylindrical plug phantoms. Slice thickness focusing can also be evaluated qualitatively by scanning the anechoic cylindrical objects in an ultrasound QC test phantom with the scan plane along the lengths of the cylinders (e.g., perpendicular to the usual scan direction). Quantitative assessment can be

The methodology used with the inclined plane phantom consists in obtaining the elevation beam profile, finding the depth where the image is narrowest. By focusing on that plane, the

(a) (b) Fig. 6. Phantom used for beam width measurement in the elevation plane: (a) schematic of the phantom; (b) schematic of the procedure to obtain the image at the beam waist (Goodsitt

This technique enables measurement of the elevation dimension of the beam only at a single depth. To determine the entire profile in the elevation plane, the probe must be moved horizontally along the surface of the phantom to make a series of measurements, with the

Slice thickness focal range, thickness and depth should be recorded on the US unit for each commonly used transducer. Any significant variation from those reference values may

A novel and versatile methodology is proposed here to determine the slice thickness accuracy using a novel phantom. The methodology can be applied to any image scanning technique, including CT, MRI and US scanning. The methodology consists of two steps: 1) acquisition of images of the phantom; 2) image elaboration by using the dedicated LabViewbased software. To test the proposed procedure and to obtain detailed information about the

beam intersecting the inclined plane at different depths (Skolnick, 1991).

indicate a detachment of the focusing lens.

**2.4 The novel procedure** 

achieved by using an "inclined plane" phantom (Fig. 6) (Goodsitt et al., 1998).

thickness of the image is measured at the focal plane.

et al., 1998).

A variety of phantoms have been designed to evaluate slice thickness. All are some variation of an inclined surface. These may include wedges, ramps, spirals, or steps. A typically used phantom is the crossed high signal ramps.

High signal ramp (HSR) phantoms generally consist of opposing ramp pairs oriented at a fixed angle (Fig. 4). The HSR's should be thin (ideally infinitesimally thin) to quantify the slice profile accurately. In general, the thickness of a (90°) HSR oriented at 45° respect to the image plane should be < 20% of the slice profile FWHM (i.e., for 5-mm slice it is necessary to use a l-mm ramp) to obtain a measurement with < 20% error.

The FWHM is the width of the slice profile (SP) at one-half of the maximum value. In this case, the SP should be obtained for each ramp. The FWHM then becomes

$$L = \text{FWHM} = \frac{(a+b)\cos\theta + \sqrt{(a+b)^2\cos^2\theta + 4ab\sin^2\theta}}{2\sin\theta} \tag{2}$$

where *a* and *b* refer to the FWHM of the intensity profiles measured for ramp 1 and ramp 2, respectively. Note that for =90° then Eq. 2 is simplified to:

$$L = \text{FV} \mathsf{V} \mathsf{H} \mathsf{M} = \mathsf{\check{\mathsf{A}}} \mathsf{a} \mathsf{b} \tag{3}$$

Fig. 5. Example of CT scanner image obtained from the assessment of the EUROSPIN phantom (Lerski, 1992).

The EUROSPIN test phantom contains two sets of structures that may be used for slice profile and width measurement. Pairs of angled plates are used to obtain a direct measurement. The additional pairs of wedges are used to calibrate especially thin slices. Typical examples of images obtained for slice width are presented in Fig. 5(a and b). The dark bands on the left hand side of Fig. 5a represent a projection of the slice profile from the angled plates; the shaded region on the right hand side of the Fig. 5b represents the projection of the profile at the wedge.

#### **2.3 US scanners**

Ultrasound image resolution depends on beam width in the scan and elevation (section thickness) planes (Skolnick, 1991). On US scanners slice thickness evaluation or elevational resolution is useful to understand some of the problems due to partial volume effect. Section thickness is significantly more complicated to check. This characteristic of the ultrasound

A variety of phantoms have been designed to evaluate slice thickness. All are some variation of an inclined surface. These may include wedges, ramps, spirals, or steps. A typically used

High signal ramp (HSR) phantoms generally consist of opposing ramp pairs oriented at a fixed angle (Fig. 4). The HSR's should be thin (ideally infinitesimally thin) to quantify the slice profile accurately. In general, the thickness of a (90°) HSR oriented at 45° respect to the image plane should be < 20% of the slice profile FWHM (i.e., for 5-mm slice it is necessary to

The FWHM is the width of the slice profile (SP) at one-half of the maximum value. In this

where *a* and *b* refer to the FWHM of the intensity profiles measured for ramp 1 and ramp 2,

(a) (b)

The EUROSPIN test phantom contains two sets of structures that may be used for slice profile and width measurement. Pairs of angled plates are used to obtain a direct measurement. The additional pairs of wedges are used to calibrate especially thin slices. Typical examples of images obtained for slice width are presented in Fig. 5(a and b). The dark bands on the left hand side of Fig. 5a represent a projection of the slice profile from the angled plates; the shaded region on the right hand side of the Fig. 5b represents the

Ultrasound image resolution depends on beam width in the scan and elevation (section thickness) planes (Skolnick, 1991). On US scanners slice thickness evaluation or elevational resolution is useful to understand some of the problems due to partial volume effect. Section thickness is significantly more complicated to check. This characteristic of the ultrasound

Fig. 5. Example of CT scanner image obtained from the assessment of the EUROSPIN

 <sup>2</sup> 2 2 cos cos 4 sin 2sin *a b a b ab*

(2)

*FWHML ab* (3)

 

phantom is the crossed high signal ramps.

use a l-mm ramp) to obtain a measurement with < 20% error.

respectively. Note that for =90° then Eq. 2 is simplified to:

*L FWHM*

phantom (Lerski, 1992).

**2.3 US scanners** 

projection of the profile at the wedge.

case, the SP should be obtained for each ramp. The FWHM then becomes

beam depends on the focusing effect in the elevation direction, which is perpendicular to the scanning plane (Richard, 1999). In linear, curved linear and phased array sector probes, focus is controlled electronically, but in the elevation plane it is determined mechanically by the curvature of the crystals. The beam in the scan plane can be sharply focused only in a narrow focal range. Thus, beam profiles in the scan plane are not indicative of beam profiles in the elevation plane. As with lateral and axial resolution, elevational resolution can be measured indirectly with anechoic spherical objects or cylindrical plug phantoms. Slice thickness focusing can also be evaluated qualitatively by scanning the anechoic cylindrical objects in an ultrasound QC test phantom with the scan plane along the lengths of the cylinders (e.g., perpendicular to the usual scan direction). Quantitative assessment can be achieved by using an "inclined plane" phantom (Fig. 6) (Goodsitt et al., 1998).

The methodology used with the inclined plane phantom consists in obtaining the elevation beam profile, finding the depth where the image is narrowest. By focusing on that plane, the thickness of the image is measured at the focal plane.

Fig. 6. Phantom used for beam width measurement in the elevation plane: (a) schematic of the phantom; (b) schematic of the procedure to obtain the image at the beam waist (Goodsitt et al., 1998).

This technique enables measurement of the elevation dimension of the beam only at a single depth. To determine the entire profile in the elevation plane, the probe must be moved horizontally along the surface of the phantom to make a series of measurements, with the beam intersecting the inclined plane at different depths (Skolnick, 1991).

Slice thickness focal range, thickness and depth should be recorded on the US unit for each commonly used transducer. Any significant variation from those reference values may indicate a detachment of the focusing lens.

#### **2.4 The novel procedure**

A novel and versatile methodology is proposed here to determine the slice thickness accuracy using a novel phantom. The methodology can be applied to any image scanning technique, including CT, MRI and US scanning. The methodology consists of two steps: 1) acquisition of images of the phantom; 2) image elaboration by using the dedicated LabViewbased software. To test the proposed procedure and to obtain detailed information about the

Procedures for Evaluation of Slice Thickness in Medical Imaging Systems 391

Protocol

kV 120 120 mA 100 45 Scan Time (s) 3 1 Field of View (mm) 230 360 Reconstruction Matrix 512 512

Filter None None

Protocol

Coil type Head Body Scan mode SE SE Scan technique MS MS Slice orientation Transversal Transversal Numbers of echoes 2 3 Field of View (mm) 250 250 Repetition Time (ms) 1000 1000 Scan matrix 256 256 Water fat shift 1.3 Maximum

The methodology developed here for data elaboration, utilizes a purposely developed LabView-based slice thickness measurement software. LabView is a graphical programming language that uses icons instead of lines of text to create applications. In contrast to textbased programming languages, where instructions determine program execution, LabView uses data flow programming, where the flow of data determines execution (National Instruments [NI], 2003). The software is compatible with both non-standard and standard image formats (BMP, TIFF, JPEG, JPEG2000, PNG, and AIPD) (Vermiglio et al., 2008). To evaluate the slice width the FWHM of the wedge, expressed in pixels, is measured and calibrated with respect to the effective length of the PMMA box, expressed in mm. The result is displayed in real-time at the user interface, known as the software Front Panel (Fig. 8), with the advantage of providing a complete set of data with a user-friendly interface. By plotting the radiation profile obtained as a system response to an attenuating impulse, as a function of position (z axis), that is through the slice plane, it is possible to estimate the slice thickness accuracy of the acquired image utilising the developed software. This is referred to as the sensitivity profile. Gaussian smoothing is applied to smooth out the sensitivity profile and permit a clearer estimate of the desired FWHM. To evaluate the slice

To test the proposed procedure, results are compared with those obtained by elaborating the same phantom images using commercial software, in particular Image-Pro Plus software

Body Protocol

Body Protocol

*ST FWHM* 26tan (4)

Scan Parameters Head

Scan Parameters Head

Table 1. Standard Protocol for testing CT medical devices.

Table 2. Standard Protocol for testing MRI medical devices.

thickness , in real time, the software utilises the following equation:

from Media Cybernetics (Sansotta et al., 2002; Testagrossa et al., 2006).

quality of the obtained results, the acquired and processed images were compared with those obtained by elaborating the same phantom images using commercial software following already validated procedures (Testagrossa et al., 2006).

The novel proposed dedicated phantom consists of a poli-methyl-methacrilate (PMMA) empty box (14.0 cm x 7.5 cm x 7.0 cm) diagonally cut by a septum at 26 degrees (Fig. 7). The PMMA septum is 2.0 mm thick and it divides the box into two sections, thus reproducing both single and double wedges. The two sections can be filled with the same fluid or with fluids of different densities. In particular, to determine the slice thickness accuracy the PMMA box was filled with two different fluids (water and air) for assessment in a CT scanner. To perform the same assessment with an MRI scanner, water was replaced with a CuSO4 5H2O+H2SO4+1ml/l antialga (ARQUAD) liquid solution (T1=300 ms, T2=280ms). For US systems the upper wedge was filled with ultrasound gel, as conductive medium.

In addition, a spirit level is used to verify the planarity of the phantom with respect to the beam and the patient couch.

Fig. 7. The novel proposed PMMA phantom for the evaluation of the slice thickness accuracy: (a) proposed for the evaluation of the slice thickness accuracy. (b) the spirit level used to verify the planarity of the phantom with respect to the beam and the patient couch is also shown for completeness.

The test procedure followed for both CT and MRI devices consists of four steps:


The phantom images were acquired using standard Head and Body protocols, shown in Table 1 and Table 2 for CT and MRI medical devices, respectively. After, the phantom images were acquired, elaborated and analyzed, they were stored and/or transmitted to a printer. The stored ones were further transferred to a dedicated workstation, whereas the printed ones were acquired by the same workstation using a VIDAR Scanner, for the next elaboration.

quality of the obtained results, the acquired and processed images were compared with those obtained by elaborating the same phantom images using commercial software

The novel proposed dedicated phantom consists of a poli-methyl-methacrilate (PMMA) empty box (14.0 cm x 7.5 cm x 7.0 cm) diagonally cut by a septum at 26 degrees (Fig. 7). The PMMA septum is 2.0 mm thick and it divides the box into two sections, thus reproducing both single and double wedges. The two sections can be filled with the same fluid or with fluids of different densities. In particular, to determine the slice thickness accuracy the PMMA box was filled with two different fluids (water and air) for assessment in a CT scanner. To perform the same assessment with an MRI scanner, water was replaced with a CuSO4 5H2O+H2SO4+1ml/l antialga (ARQUAD) liquid solution (T1=300 ms, T2=280ms). For

US systems the upper wedge was filled with ultrasound gel, as conductive medium.

Fig. 7. The novel proposed PMMA phantom for the evaluation of the slice thickness accuracy: (a) proposed for the evaluation of the slice thickness accuracy. (b) the spirit level used to verify the planarity of the phantom with respect to the beam and the patient couch is

The test procedure followed for both CT and MRI devices consists of four steps: 1. Placing the slice thickness accuracy phantom in the scanner head holder.

4. Scanning the phantom with a single slice using the desired slice width available

The phantom images were acquired using standard Head and Body protocols, shown in Table 1 and Table 2 for CT and MRI medical devices, respectively. After, the phantom images were acquired, elaborated and analyzed, they were stored and/or transmitted to a printer. The stored ones were further transferred to a dedicated workstation, whereas the printed ones were acquired by the same workstation using a VIDAR Scanner, for the next

2. Adjusting level position of the phantom if necessary. 3. Moving/positioning the phantom in the gantry aperture.

a

b

In addition, a spirit level is used to verify the planarity of the phantom with respect to the

following already validated procedures (Testagrossa et al., 2006).

beam and the patient couch.

also shown for completeness.

elaboration.


Table 1. Standard Protocol for testing CT medical devices.


Table 2. Standard Protocol for testing MRI medical devices.

The methodology developed here for data elaboration, utilizes a purposely developed LabView-based slice thickness measurement software. LabView is a graphical programming language that uses icons instead of lines of text to create applications. In contrast to textbased programming languages, where instructions determine program execution, LabView uses data flow programming, where the flow of data determines execution (National Instruments [NI], 2003). The software is compatible with both non-standard and standard image formats (BMP, TIFF, JPEG, JPEG2000, PNG, and AIPD) (Vermiglio et al., 2008). To evaluate the slice width the FWHM of the wedge, expressed in pixels, is measured and calibrated with respect to the effective length of the PMMA box, expressed in mm. The result is displayed in real-time at the user interface, known as the software Front Panel (Fig. 8), with the advantage of providing a complete set of data with a user-friendly interface.

By plotting the radiation profile obtained as a system response to an attenuating impulse, as a function of position (z axis), that is through the slice plane, it is possible to estimate the slice thickness accuracy of the acquired image utilising the developed software. This is referred to as the sensitivity profile. Gaussian smoothing is applied to smooth out the sensitivity profile and permit a clearer estimate of the desired FWHM. To evaluate the slice thickness , in real time, the software utilises the following equation:

$$ST = FVWM \cdot \tan(26^\circ) \tag{4}$$

To test the proposed procedure, results are compared with those obtained by elaborating the same phantom images using commercial software, in particular Image-Pro Plus software from Media Cybernetics (Sansotta et al., 2002; Testagrossa et al., 2006).

Procedures for Evaluation of Slice Thickness in Medical Imaging Systems 393

Fig. 9. CT scanner in-built software results displaying the line profiles obtained for different

readings of the X-ray image of the dedicated phantom.

Fig. 8. Front Panel of the dedicated slice thickness LabView software showing (a) X-ray phantom section, (b) the detected line profile and corresponding Gaussian fit, and (c) the resulting slice thickness value. All steps are performed in real time.

The measurements presented here have been conducted on several CT and MRI devices in an extended study from 2006 to 2010. In addition, a statistical analysis was conducted on the resulting datasets to further validate the proposed methodology. The chosen statistical method is the variance analysis, through Fisher's exact test (F-test), to assess if a significant difference exists between datasets obtained following different procedures (C.A. Markowski & E.P. Markowski, 1990). The F-test is useful when the aim of the study is the evaluation of the precision of a measurements technique. In fact, the variance analysis consists in the factorisation of the total variance into a set of partial variances corresponding to different and estimated variations. The statistical analysis was conducted both on CT and MRI datasets.

For CT scanners three different datasets of slice thickness measurements were considered. The first dataset of 16 measurements was done on a reference (RF) value of 10 mm The second dataset of 14 measurements, on a RF value of 5 mm. The third dataset of 10 measurements, on a RF value of 2 mm. The data was obtained using two different procedures.

For MRI scanners slice thickness measurements were done on a RF value of 10 mm. In this case three different procedures were compared and 24 measurements in total were obtained on different MRI systems.

## **3. Results**

The slice thickness measurements results using the novel proposed methodology and the statistical data analysis are presented in this section for CT, MRI and US systems.

#### **3.1 CT medical devices**

A two-dimensional image of the wedge of the dedicated phantom of Fig. 7 was acquired using the Standard Head Protocol described in Table 1. The X-Ray image of the phantom is presented in Fig. 9. In this case the line profile tool was available and the related trend was shown in the same figure.

b a

Fig. 8. Front Panel of the dedicated slice thickness LabView software showing (a) X-ray phantom section, (b) the detected line profile and corresponding Gaussian fit, and (c) the

The measurements presented here have been conducted on several CT and MRI devices in an extended study from 2006 to 2010. In addition, a statistical analysis was conducted on the resulting datasets to further validate the proposed methodology. The chosen statistical method is the variance analysis, through Fisher's exact test (F-test), to assess if a significant difference exists between datasets obtained following different procedures (C.A. Markowski & E.P. Markowski, 1990). The F-test is useful when the aim of the study is the evaluation of the precision of a measurements technique. In fact, the variance analysis consists in the factorisation of the total variance into a set of partial variances corresponding to different and estimated variations. The statistical analysis was conducted both on CT and MRI

For CT scanners three different datasets of slice thickness measurements were considered. The first dataset of 16 measurements was done on a reference (RF) value of 10 mm The second dataset of 14 measurements, on a RF value of 5 mm. The third dataset of 10 measurements, on a RF value of 2 mm. The data was obtained using two different

For MRI scanners slice thickness measurements were done on a RF value of 10 mm. In this case three different procedures were compared and 24 measurements in total were obtained

The slice thickness measurements results using the novel proposed methodology and the

A two-dimensional image of the wedge of the dedicated phantom of Fig. 7 was acquired using the Standard Head Protocol described in Table 1. The X-Ray image of the phantom is presented in Fig. 9. In this case the line profile tool was available and the related trend was

statistical data analysis are presented in this section for CT, MRI and US systems.

resulting slice thickness value. All steps are performed in real time.

c

datasets.

procedures.

**3. Results** 

on different MRI systems.

**3.1 CT medical devices** 

shown in the same figure.

Fig. 9. CT scanner in-built software results displaying the line profiles obtained for different readings of the X-ray image of the dedicated phantom.

Procedures for Evaluation of Slice Thickness in Medical Imaging Systems 395

(b) Fig. 10. CT slice thickness accuracy obtained for a 10mm RF value: (a) data set (blue: IPP;

From the results presented in Table 3, it is observed that the mean values calculated for both the IPP and LV procedures, are comparable. However, the standard deviation obtained from the two different procedures is considerably different, with the LV procedure providing a narrower deviation, and hence more accurate results of the performed

In Table 4, the slice thickness accuracy results obtained with IPP and LV are compared with the corresponding 5 mm RF value. Also in this case, for the sake of completeness, the respective mean values and standard deviations obtained from the IPP and LV datasets are

IPP (mm)

4.03

IPP mean value and standard deviation (mm)

4.830.41

LV mean value and standard deviation (mm)

4.730.25

Also for the 5 mm RF value case, the mean values obtained from LV and IPP datasets are comparable, with a slightly better estimate for the IPP procedure. However, the standard deviations obtained from the two procedures are significantly different. As in the previous case, the LV procedure provides a narrower deviation, thus enabling a more accurate

4.75 4.82 4.80 4.83 4.36 5.36 4.89 4.85 4.71 4.80 5.13 5.13 Table 4. Slice thickness accuracy results obtained with LV and IPP for a 5mm RF value,

red: LV); (b) deviation from the RF value (blue: IPP; red: LV).

measurements.

RF Values

5

measurement.

(mm) LV (mm)

using different types of CT scanners.

4.50

reported.

The results obtained by measuring the slice thickness accuracy with different CT scanners and by employing the in-house developed LabView (LV) program and the commercial Image Pro Plus (IPP) software are compared with the corresponding 10 mm RF value in Table 3. In the same table mean values and standard deviations are also reported for both procedures.


Table 3. Slice thickness accuracy results obtained with LV and IPP for a 10 mm RF value, using different types of CT scanners.

The data of Table 3 are presented in graphical form in Fig. 10. The slice thickness accuracy results (blue: IPP; red: LV) and deviation from the RF value (blue: IPP; red: LV) obtained using the IPP and LV procedures are presented for the 10 mm RF value.

Fig. 10. (a)

The results obtained by measuring the slice thickness accuracy with different CT scanners and by employing the in-house developed LabView (LV) program and the commercial Image Pro Plus (IPP) software are compared with the corresponding 10 mm RF value in Table 3. In the same table mean values and standard deviations are also reported for both

> IPP (mm)

> > 8.07

IPP mean value and standard deviation (mm)

9.641.26

LV mean value and standard deviation (mm)

9.690.68

The data of Table 3 are presented in graphical form in Fig. 10. The slice thickness accuracy results (blue: IPP; red: LV) and deviation from the RF value (blue: IPP; red: LV) obtained

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

Fig. 10. (a)

using the IPP and LV procedures are presented for the 10 mm RF value.

 LV IPP RF

9.30 10.33 9.44 9.44 10.80 10.04 9.50 8.62 10.18 12.00 10.26 8.54 9.45 10.10 Table 3. Slice thickness accuracy results obtained with LV and IPP for a 10 mm RF value,

procedures.

RF Value (mm)

10

using different types of CT scanners.

0

2

4

6

8

Slice Thickness (mm)

10

12

LV (mm)

8.61

Fig. 10. CT slice thickness accuracy obtained for a 10mm RF value: (a) data set (blue: IPP; red: LV); (b) deviation from the RF value (blue: IPP; red: LV).

From the results presented in Table 3, it is observed that the mean values calculated for both the IPP and LV procedures, are comparable. However, the standard deviation obtained from the two different procedures is considerably different, with the LV procedure providing a narrower deviation, and hence more accurate results of the performed measurements.

In Table 4, the slice thickness accuracy results obtained with IPP and LV are compared with the corresponding 5 mm RF value. Also in this case, for the sake of completeness, the respective mean values and standard deviations obtained from the IPP and LV datasets are reported.


Table 4. Slice thickness accuracy results obtained with LV and IPP for a 5mm RF value, using different types of CT scanners.

Also for the 5 mm RF value case, the mean values obtained from LV and IPP datasets are comparable, with a slightly better estimate for the IPP procedure. However, the standard deviations obtained from the two procedures are significantly different. As in the previous case, the LV procedure provides a narrower deviation, thus enabling a more accurate measurement.

Procedures for Evaluation of Slice Thickness in Medical Imaging Systems 397

Finally, in Table 5, the results obtained by measuring the slice thickness accuracy by employing the IPP and the LV procedures are compared with the corresponding 2 mm RF value and mean values and standard deviation are also indicated. From the analysis of the data of Table 5, it can be observed that the mean value calculated by the LV dataset is significantly closer to the RF value than that calculated from the IPP dataset. This further

> LV mean value and standard deviation (mm)

> > 2.320.48

The data of Table 5 are represented in graphical form in Fig 12, where the slice thickness accuracy results obtained using IPP and LV (blue: IPP; red: LV) and their deviation from the

12345

Fig. 12. (a)

3.00 2.75 2.06 2.83 1.96 2.56 1.95 3.00 Table 5. Slice thickness accuracy results obtained with LV and IPP for a 2 mm RF value,

IPP (mm)

2.79

IPP mean value and standard deviation (mm)

2.790.16

supports the validity of the proposed technique.

2.66

2 mm RF value (blue: IPP; red: LV) are presented.

 LV IPP RF

(mm) LV (mm)

using different types of CT scanners.

0.0

0.5

1.0

1.5

2.0

Slice Thickness (mm)

2.5

3.0

3.5

4.0

RF Values

2

The data of Table 4 are reported in graphical form in Fig 11, where the slice thickness accuracy results obtained with the two procedures (blue: IPP; red: LV) and their deviation from the 5 mm RF value are presented.

Fig. 11. CT slice thickness accuracy obtained for a 5 mm RF value: (a) sample set (blue: IPP; red: LV); (b) deviation from the RF value (blue: IPP; red: LV).

The data of Table 4 are reported in graphical form in Fig 11, where the slice thickness accuracy results obtained with the two procedures (blue: IPP; red: LV) and their deviation

1234567

(a)

(b) Fig. 11. CT slice thickness accuracy obtained for a 5 mm RF value: (a) sample set (blue: IPP;

red: LV); (b) deviation from the RF value (blue: IPP; red: LV).

from the 5 mm RF value are presented.

0

1

2

3

Slice Thickness (mm)

4

5

6

 LV IPP RF

Finally, in Table 5, the results obtained by measuring the slice thickness accuracy by employing the IPP and the LV procedures are compared with the corresponding 2 mm RF value and mean values and standard deviation are also indicated. From the analysis of the data of Table 5, it can be observed that the mean value calculated by the LV dataset is significantly closer to the RF value than that calculated from the IPP dataset. This further supports the validity of the proposed technique.


Table 5. Slice thickness accuracy results obtained with LV and IPP for a 2 mm RF value, using different types of CT scanners.

The data of Table 5 are represented in graphical form in Fig 12, where the slice thickness accuracy results obtained using IPP and LV (blue: IPP; red: LV) and their deviation from the 2 mm RF value (blue: IPP; red: LV) are presented.

Procedures for Evaluation of Slice Thickness in Medical Imaging Systems 399

Fig. 13. MRI PMMA box image and corresponding line profile appearing on the MRI display. It is possible to notice the related line profile as obtained directly at the equipment

the RF value are presented for the three sets of data.

CS mean value and standard deviation (mm)

10.050.17

standard deviations for the three different procedures are also reported.

The slice thickness accuracy data of Table 7 are presented in graphical form in Fig. 14(a), where the slice thickness accuracy determined directly at the equipment console and that measured using the IPP and the LV procedures are compared. In Fig. 14(b) deviations from

> LV mean value and standard deviation (mm)

> > 10.050.15

IPP (mm)

9.80

IPP mean value and standard deviation (mm)

9.960.31

LV (mm)

10.3

9.90 9.92 9.85 10.3 10.2 9.80 9.80 10.0 10.5 10.1 9.94 10.1 10.2 10.17 10.3 9.90 9.95 9.60 10.1 9.90 9.90 Table 7. Comparison between the slice thickness accuracy obtained from the MRI in-built software (CS), the Image Pro Plus (IPP) procedure and the dedicated LabView (LV) software for a 10.0 mm Reference (RF) value. In the same table mean values and corresponding

console.

RF value (mm)

10

CS (mm)

10.1

Fig. 12. CT slice thickness accuracy obtained for a 2 mm RF value: (a) sample set (blue: IPP; red: LV); (b) deviation from the RF value (blue: IPP; red: LV).

Statistical analysis conducted on the datasets shown in Tables 3-5 yielded the F-values reported in Table 6. Such F-values indicate that there is no significant statistical variation between the two different procedures, thus validating the methodology.


Table 6. F values calculated for different RF values (FC). These F-values were compared to the tabulated ones (FT) for the P=0.05 confidence level.

#### **3.2 MRI medical devices**

Two-dimensional images of the wedge of the dedicated phantom were acquired using the Scan Head Protocol reported in Table 2. A typical MRI image of the PMMA box and the corresponding line profile calculated with the in-built MRI software are shown in Fig. 13. The preliminary results obtained using the IPP and LV procedures discussed above applied to MRI are reported in Table 7 for a RF value of 10 mm. In this case the slice thickness accuracy measured using an in-built MRI software (CS) is also included. The corresponding mean value and standard deviation of the three datasets are also reported.

Also in this case, the mean values calculated from the three different datasets of measurements are comparable between them. However, whereas the standard deviations obtained from CS and LV procedures are comparable, those obtained from IPP and LV are significantly different. The LV procedure provides a narrower deviation with respect to that obtained with IPP, which gives evidence for a more accurate measurement.

(b) Fig. 12. CT slice thickness accuracy obtained for a 2 mm RF value: (a) sample set (blue: IPP;

Statistical analysis conducted on the datasets shown in Tables 3-5 yielded the F-values reported in Table 6. Such F-values indicate that there is no significant statistical variation

Two-dimensional images of the wedge of the dedicated phantom were acquired using the Scan Head Protocol reported in Table 2. A typical MRI image of the PMMA box and the corresponding line profile calculated with the in-built MRI software are shown in Fig. 13. The preliminary results obtained using the IPP and LV procedures discussed above applied to MRI are reported in Table 7 for a RF value of 10 mm. In this case the slice thickness accuracy measured using an in-built MRI software (CS) is also included. The corresponding

Also in this case, the mean values calculated from the three different datasets of measurements are comparable between them. However, whereas the standard deviations obtained from CS and LV procedures are comparable, those obtained from IPP and LV are significantly different. The LV procedure provides a narrower deviation with respect to that

(mm) FC FT 10 0.011 4.54 5 0.332 4.67 2 4.18 5.12 Table 6. F values calculated for different RF values (FC). These F-values were compared to

red: LV); (b) deviation from the RF value (blue: IPP; red: LV).

RF Values

the tabulated ones (FT) for the P=0.05 confidence level.

**3.2 MRI medical devices** 

between the two different procedures, thus validating the methodology.

mean value and standard deviation of the three datasets are also reported.

obtained with IPP, which gives evidence for a more accurate measurement.

Fig. 13. MRI PMMA box image and corresponding line profile appearing on the MRI display. It is possible to notice the related line profile as obtained directly at the equipment console.

The slice thickness accuracy data of Table 7 are presented in graphical form in Fig. 14(a), where the slice thickness accuracy determined directly at the equipment console and that measured using the IPP and the LV procedures are compared. In Fig. 14(b) deviations from the RF value are presented for the three sets of data.


Table 7. Comparison between the slice thickness accuracy obtained from the MRI in-built software (CS), the Image Pro Plus (IPP) procedure and the dedicated LabView (LV) software for a 10.0 mm Reference (RF) value. In the same table mean values and corresponding standard deviations for the three different procedures are also reported.

Procedures for Evaluation of Slice Thickness in Medical Imaging Systems 401

The F-test is then used to verify that the three datasets are comparable (Table 8). As evident from the data of Table 8, the F values calculated for the three sets of data are significantly smaller than that tabulated (FT) for a P=0.05 confidence level in all cases. Therefore, there is no significant statistical difference between the three different procedures, thus validating

Datasets FC FT

values were compared to the tabulated ones (FT) for the P=0.05 confidence level.

degrees, the beam width in the elevation plane can be calculated as follows:

displayed on the screen of the dedicated PC.

CS-LV 0.00165 4.54

Table 8. Results of the F-test calculated comparing the CS, IPP and LV datasets (FC). These F-

The novel PMMA phantom proposed here (Fig. 7) was utilised also to test the elevation resolution in ultrasound systems. Preliminary measurements have been conducted on US probes to evaluate if it is possible to measure the beam width in the elevation plane. To correctly determine the elevation beam profile, it was necessary to slightly modify the phantom. In particular, the septum position was modified and, for the beam width evaluation, the inclined plane was oriented 28 degrees to the top and bottom surface, so the probe intersects the inclined plane at 28 degrees. The upper side of the inclined surface was filled with ultrasound gel, as conductive medium. The echoes reflected from the inclined plane are displayed as a horizontal band. Because the beam intersects the plane at 28

The above technique enables the measurement of the elevation dimension of the beam at a single depth only. To determine the entire profile in the elevation plane, the probe must be moved horizontally along the surface of the phantom to make a series of measurements, with the beam intersecting the inclined plane at different depths. With the use of the novel phantom described here, the resolution in the elevation plane is completely independent from the lateral resolution in the scanning plane. The new phantom proposed here is easy to use and does not require any additional equipment and the results are immediately

Slice thickness represents an important parameter to be monitored in CT, MRI an US. Partial volume effects can significantly alter sensitivity and specificity. Especially for MRI, quantitative measurements such as T1 and T2, are also greatly influenced by the accuracy of the slice thickness. Inaccuracies in the measurement of this parameter may result in interslice interference in multi-slice acquisitions, leading to invalid SNR measurements. In addition, for the US scanners, significant differences in image resolution can occur because of variations in the beam width of the elevation plane. So, it is important to know the profiles of the elevation planes of various probes to choose the probe that offers resolution

*ST FWHM* tan 28 (5)

the novel LV procedure proposed here also for MRI imaging.

CS-IPP 0.836

IPP-LV 0.513

**3.3 US scanners** 

**4. Conclusion** 

(a)

Fig. 14. MRI slice thickness accuracy obtained for a 10 mm RF value: (a) data obtained directly from the MRI scanner (CS) and measured using the IPP and the LV procedures (grey: CS; blue: IPP; red: LV); (b) deviation from the RF value (grey dots: CS; blue dots: IPP; red dots: LV).

The F-test is then used to verify that the three datasets are comparable (Table 8). As evident from the data of Table 8, the F values calculated for the three sets of data are significantly smaller than that tabulated (FT) for a P=0.05 confidence level in all cases. Therefore, there is no significant statistical difference between the three different procedures, thus validating the novel LV procedure proposed here also for MRI imaging.


Table 8. Results of the F-test calculated comparing the CS, IPP and LV datasets (FC). These Fvalues were compared to the tabulated ones (FT) for the P=0.05 confidence level.

#### **3.3 US scanners**

400 Modern Approaches To Quality Control

 CS IPP LV RF

12345678

(a)

(b)

Fig. 14. MRI slice thickness accuracy obtained for a 10 mm RF value: (a) data obtained directly from the MRI scanner (CS) and measured using the IPP and the LV procedures (grey: CS; blue: IPP; red: LV); (b) deviation from the RF value (grey dots: CS; blue dots: IPP;

0

red dots: LV).

2

4

6

Slice Thickness (mm)

8

10

12

The novel PMMA phantom proposed here (Fig. 7) was utilised also to test the elevation resolution in ultrasound systems. Preliminary measurements have been conducted on US probes to evaluate if it is possible to measure the beam width in the elevation plane. To correctly determine the elevation beam profile, it was necessary to slightly modify the phantom. In particular, the septum position was modified and, for the beam width evaluation, the inclined plane was oriented 28 degrees to the top and bottom surface, so the probe intersects the inclined plane at 28 degrees. The upper side of the inclined surface was filled with ultrasound gel, as conductive medium. The echoes reflected from the inclined plane are displayed as a horizontal band. Because the beam intersects the plane at 28 degrees, the beam width in the elevation plane can be calculated as follows:

$$ST = FVHM \cdot \tan\left(28^{\circ}\right) \tag{5}$$

The above technique enables the measurement of the elevation dimension of the beam at a single depth only. To determine the entire profile in the elevation plane, the probe must be moved horizontally along the surface of the phantom to make a series of measurements, with the beam intersecting the inclined plane at different depths. With the use of the novel phantom described here, the resolution in the elevation plane is completely independent from the lateral resolution in the scanning plane. The new phantom proposed here is easy to use and does not require any additional equipment and the results are immediately displayed on the screen of the dedicated PC.

## **4. Conclusion**

Slice thickness represents an important parameter to be monitored in CT, MRI an US. Partial volume effects can significantly alter sensitivity and specificity. Especially for MRI, quantitative measurements such as T1 and T2, are also greatly influenced by the accuracy of the slice thickness. Inaccuracies in the measurement of this parameter may result in interslice interference in multi-slice acquisitions, leading to invalid SNR measurements. In addition, for the US scanners, significant differences in image resolution can occur because of variations in the beam width of the elevation plane. So, it is important to know the profiles of the elevation planes of various probes to choose the probe that offers resolution

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Murakami, T. & Shrimpton, P. (2000). Managing patient dose in computed tomography. *Annals of ICRP*, Vol. 30, No. 4 (December 2000), pp. 7-45, ISSN 0146-

image quality and validation on radiographic films. *Proceedings of the 7th Internet* 

in the elevation plane that is most appropriate for the particular clinical application. Moreover, slice thickness accuracy is an important element also in the QC program for CT scanner, because quantitative CT analysis is heavily dependent on accuracy of slice thickness. Therefore, to provide an adaptable, reliable and robust procedure to evaluate the slice thickness accuracy a novel, dedicated phantom and corresponding LabView-based procedure have been proposed here, up to date applied to both CT and MRI devices. The new PMMA box proposed here to be associated with the dedicated software enables an innovative, accurate, easily applicable and automated determination of this parameter.

The carried on studies have utilised the 2 mm septum because the z axis dimensions for rotating anode x-ray tube foci are typically less than this value, but is our intention reduce the septum width, in order to evaluate the slice thickness also for the helicoidal CT scanners, that can reach slice widths smaller than 2 mm.

The accuracy (standard deviation) obtained with the novel procedure proposed here is significantly higher than that obtained with other procedures (e.g., in-built software, IPP).

This new slice thickness accuracy procedure is proposed as an alternative to the commonly adopted ones, which are typically complicated by the use of ad-hoc software and phantoms distributed by manufacturers and specific to the medical equipment. The proposed method employs a novel universal phantom, coupled with a dedicated LabView-based software that can be used on any CT and MRI scanner in a quick, simple and reproducible manner.

The readiness and applicability of the proposed procedure has been validated by quantitative tests using several different medical devices and procedures. In all cases the results obtained using the novel proposed procedure were statistically compatible with other commonly used procedures, but provided a very immediate determination of the slice thickness for both CT and MRI equipments, thus confirming the flexibility of the described method, its simplicity and reproducibility as an efficient tool for quick inspections.

The same procedure should be suitable also for determining elevation accuracy on US scanner: in fact, preliminary results confirmed that the novel phantom, opportunely modified, when coupled with the LabView dedicated software, allowed measurements of the section thickness

#### **5. References**


in the elevation plane that is most appropriate for the particular clinical application. Moreover, slice thickness accuracy is an important element also in the QC program for CT scanner, because quantitative CT analysis is heavily dependent on accuracy of slice thickness. Therefore, to provide an adaptable, reliable and robust procedure to evaluate the slice thickness accuracy a novel, dedicated phantom and corresponding LabView-based procedure have been proposed here, up to date applied to both CT and MRI devices. The new PMMA box proposed here to be associated with the dedicated software enables an innovative, accurate, easily applicable and automated determination of this parameter. The carried on studies have utilised the 2 mm septum because the z axis dimensions for rotating anode x-ray tube foci are typically less than this value, but is our intention reduce the septum width, in order to evaluate the slice thickness also for the helicoidal CT scanners,

The accuracy (standard deviation) obtained with the novel procedure proposed here is significantly higher than that obtained with other procedures (e.g., in-built software, IPP). This new slice thickness accuracy procedure is proposed as an alternative to the commonly adopted ones, which are typically complicated by the use of ad-hoc software and phantoms distributed by manufacturers and specific to the medical equipment. The proposed method employs a novel universal phantom, coupled with a dedicated LabView-based software that can be used on any CT and MRI scanner in a quick, simple and reproducible manner. The readiness and applicability of the proposed procedure has been validated by quantitative tests using several different medical devices and procedures. In all cases the results obtained using the novel proposed procedure were statistically compatible with other commonly used procedures, but provided a very immediate determination of the slice thickness for both CT and MRI equipments, thus confirming the flexibility of the described

method, its simplicity and reproducibility as an efficient tool for quick inspections.

The same procedure should be suitable also for determining elevation accuracy on US scanner: in fact, preliminary results confirmed that the novel phantom, opportunely modified, when coupled with the LabView dedicated software, allowed measurements of

CEI EN 61223-2-6. (1997). Evaluation and routine testing in medical imaging departments.

Chen, C.C.; Wan, Y.L.; Wai, Y.Y. & Liu, H.L. (2004). Quality assurance of clinical MRI

General Electric Medical System. (2000). Quality Assurance. In: *CT HiSpeed DX/i Operator* 

Goodsitt, M.M.; Carson, P.L.; Witt, S.; Hykes, D.L. & Kofler, J.M. (1998). Real-time B-mode

Judy, P.F.; Balter, S.; Bassano, D.; McCollough, E.C.; Payne, J.T. & Rothenberg, L. (1977).

Vol. 17, No. 4 (December 2004), pp. 279-284, ISSN 0897-1889

*manual Rev. 0*. General Electric Company (Ed.). Chapter 6, pp. 1-28

Part 2-6: Constancy tests – X-ray equipments for computed tomography. CEI, (Ed.),

scanners using ACR MRI phantom: preliminary results. *Journal of Digital Imaging,*

ultrasound quality control test procedures. Report of the AAPM ultrasound task group No. 1. *Medical Physics,* Vol. 25, No. 8 (August 1998), pp. 1385-1406, ISSN

Phantoms for performance evaluation and quality assurance of CT scanners.

that can reach slice widths smaller than 2 mm.

the section thickness

pp. 1-26

0094-2405

**5. References** 

AAPM Report No. 1 (American Association of Physicist in Medicine, Chicago, Illinois, 1977)


http://www.ni.com/pdf/manuals/320999d.pdf


**22** 

**Nursing Business Modeling with UML:** 

A nurse is an autonomous, decentralized worker who recognizes goals, his or her environment, the conditions and actions of patients and other staff members, and determines his or her own actions. Put another way, the nurse makes decisions flexibly in the midst of uncertainty. Because of this, nursing work differs from individual nurse to

Concerning nursing work analysis, research has been done on task load (time required for tasks). However, there has been scant academic research on work processes in nursing compared with research that has accumulated in other industrial fields, including research on structuralizing work, i.e., defining and visualizing work processes. To improve work processes, it is necessary to understand and clarify work as a chain of theoretically related

Thus in this study, using time and motion study techniques, a method used to measure jobs, we clarify the structure of the work of transporting patients by nurses. We also attempt to

Time and motion study is a method that actually measures the movements of a particular person. Its results can be applied not only to measuring the work load of nurses (Van de Werf et al., 2009; Were et al., 2008;Hendrich et al.,2008) and analyzing the workflow(Tang et al., 2007), they can also be used as basic data for task scheduling(Yokouchi et al., 2005) and efficient arrangement of personnel. In addition, the results are being used as indicators to evaluate changes in a hospital brought about by systems deployed (Yen et al., 2009), such as an electronic medical record (EMR) system. Thus many time and motion studies of hospitals

Specifically, a time and motion study is defined as a study that records the time of occurrences of tasks through continuous observation. A type of measuring technique similar

1Rie Tomizawa, Maya Iwasa, Satoko Kasahara, Tamami Suzuki, Fumiko Wako, Ichiroh Kanaya,

nurse, and understanding this process theoretically is considered to be difficult.

visualize it. We use objected-oriented modeling to express the operation visually.

**2. From time and motion study to business modeling** 

have been conducted both within Japan and without.

Kazuo Kawasaki, Atsue Ishii, Kenji Yamada and Yuko Ohno

**1. Introduction** 

activities.

*Osaka University, Japan* 

**From Time and Motion Study** 

**to Business Modeling** 

Sachiko Shimizu et al.1

*Osaka University* 

*Japan* 


http://www.colloquium.fr/06IRPA/CDROM/docs/P-121.pdf

Vermiglio, G.; Tripepi, M.G.; Testagrossa, B.; Acri, G.; Campanella, F. & Bramanti, P. (2008). LabView employment to determine dB/dt in Magnetic Resonance quality controls. *Proceedings of the 2nd NIDays,* pp. 223-224. Rome, Italy, February 27, 2008

## **Nursing Business Modeling with UML: From Time and Motion Study to Business Modeling**

Sachiko Shimizu et al.1 *Osaka University Japan* 

## **1. Introduction**

404 Modern Approaches To Quality Control

Skolnick, M.L. (1991). Estimation of Ultrasound beam width in the elevation (section

Testagrossa, B.; Novario, R.; Sansotta, C.; Tripepi, M.G.; Acri, G. & Vermiglio, G. (2006).

Vermiglio, G.; Testagrossa, B.; Sansotta, C. & Tripepi, M.G. (2006). Radiation protection of

Vermiglio, G.; Tripepi, M.G.; Testagrossa, B.; Acri, G.; Campanella, F. & Bramanti, P. (2008).

*Proceedings of the 2nd NIDays,* pp. 223-224. Rome, Italy, February 27, 2008

ISBN 88-88648-05-4, Turin, Italy, september 20-23, 2006

http://www.colloquium.fr/06IRPA/CDROM/docs/P-121.pdf

France, May 15-19, 2006, Available from

USA, March 6, 2007

thickness) plane. *Radiology,* Vol. 180, No. 1 (July 1991), pp. 286-288, ISSN 0033-8419 Torfeh, T.; Beaumont, S.; Guédon, J.P.; Normand, N. & Denis, E. (2007). Software tools

dedicated for an automatic analysis of the CT scanner Quality Control's Images, In: *Medical Imaging 2007: Physics of Medical Imaging. Proceedings of SPIE*, Vol. 6510, J. Hsien & M.J. Flynn (Eds.), 65104G*,* ISBN 978-081-9466-28-0, San Diego, California,

Fantocci multiuso per i controlli di qualità in diagnostica per immagini. *Proceedings of the XXXIIIth International Radio Protection Association (IRPA) Conference,* IRPA,

patients and quality controls in teleradiology. *Proceedings of the 2nd European Congress on Radiation Protection «Radiation protection: from knowledge to action».* Paris,

LabView employment to determine dB/dt in Magnetic Resonance quality controls.

A nurse is an autonomous, decentralized worker who recognizes goals, his or her environment, the conditions and actions of patients and other staff members, and determines his or her own actions. Put another way, the nurse makes decisions flexibly in the midst of uncertainty. Because of this, nursing work differs from individual nurse to nurse, and understanding this process theoretically is considered to be difficult.

Concerning nursing work analysis, research has been done on task load (time required for tasks). However, there has been scant academic research on work processes in nursing compared with research that has accumulated in other industrial fields, including research on structuralizing work, i.e., defining and visualizing work processes. To improve work processes, it is necessary to understand and clarify work as a chain of theoretically related activities.

Thus in this study, using time and motion study techniques, a method used to measure jobs, we clarify the structure of the work of transporting patients by nurses. We also attempt to visualize it. We use objected-oriented modeling to express the operation visually.

## **2. From time and motion study to business modeling**

Time and motion study is a method that actually measures the movements of a particular person. Its results can be applied not only to measuring the work load of nurses (Van de Werf et al., 2009; Were et al., 2008;Hendrich et al.,2008) and analyzing the workflow(Tang et al., 2007), they can also be used as basic data for task scheduling(Yokouchi et al., 2005) and efficient arrangement of personnel. In addition, the results are being used as indicators to evaluate changes in a hospital brought about by systems deployed (Yen et al., 2009), such as an electronic medical record (EMR) system. Thus many time and motion studies of hospitals have been conducted both within Japan and without.

Specifically, a time and motion study is defined as a study that records the time of occurrences of tasks through continuous observation. A type of measuring technique similar

Kazuo Kawasaki, Atsue Ishii, Kenji Yamada and Yuko Ohno

<sup>1</sup>Rie Tomizawa, Maya Iwasa, Satoko Kasahara, Tamami Suzuki, Fumiko Wako, Ichiroh Kanaya,

*Osaka University, Japan* 

Nursing Business Modeling with UML:

Fig. 1. Functional diagram-patient transports system.

studied.

**4. Results** 

from our analysis.

From Time and Motion Study to Business Modeling 407

however, its use for business modeling has been suggested (Eriksson and Penker, 2000). The reason is that the structure of a job can considered oriented-oriented in nature. The content of a job can be treated as exchanges of messages between objects, such as materials and users. Thus UML as a descriptive method can allow one to intuitively understand the job. In this study, we elucidated the functional aspect of the operation of transporting patients. We also used an activity diagram to visualize the work process of transporting patients. Finally, we discussed the work load and its time efficiency by adding time information to the activity diagram. This study was approved by the ethics committee of the hospital we

From the time and motion study, we observed and recorded 213 jobs of transferring patients. Overall, the number patient transfer assignments recorded was 3,775. Of these records, 387 records were not jobs related to transporting patients, so they were removed

A use case diagram extracted from the results of the time and motion study is shown in Figure 1. There were seven types of actors involving in transporting patients: nurses, head nurses, medical clerks, nursing assistants, the central medical examination department, the order entry system, and the hospital information system. The nurses were divided into two groups: head nurses, who had the responsibility of being in charge of nursing duties, and staff nurses, who received patients and provided care for them. The head nurse and the

to the time study is work sampling, which seeks to comprehend a job by sampling its conditions at predetermined time intervals. Work sampling cannot comprehend a job in its entirety, but it lessens the burden on the measurer. It also makes it possible for the worker himself or herself to record time. In contrast, a time and motion study comprehends the job in its entirety, but the burden on the measurer is great. The differences in results between the two methods have been observed to be large for jobs in which there were few events(Finkler et al., 1993). Currently, the results that come from measuring a job through continuous time and motion observation are said to be the gold standard.

While the breadth of research that utilize measurement results from time and motion studies encompasses all nursing work, individual studies have been limited to examining the amount of work for individual caring assignments, such as cleaning a patient, feeding a patient, and taking care of a patient's toilet needs. There have been especially few studies that evaluate the work amount of a job by focusing on the job and clarifying its work process. While not on concerned with nursing work, the only such study conducted so far in the medical field was visualizing and understanding the amount of work involved in the process of registering cancer patients by Shiki et al. (Shiki et al., 2009). They proposed the method of "time-process study," a method to visualize tasks by adding time information to the process. However, because both the process and amount of work were estimated through interviews, the results can be said to be lacking in objectivity. Thus our study uses the time and motion study method, which actually measures a task. We focus on the job of transporting patients and clarifying its process. We also study the possibility of a method to visualize the work process using the clarified process and time information.

Transporting patients is an operation that is often performed outside hospital wards. It is both physically and mentally demanding of nurses. This job should also be scrutinized because it reduces the number of nursing staff inside the wards, as nurses go outside the wards in order to safely transport patients.

## **3. Methods**

## **3.1 Study setting**

We carried out a time and motion study of nursing work related to transporting patients in four hospital wards of a cardiovascular treatment facility. We tracked our subjects, who were nurses, nursing assistants, and medical clerks, from the time of the start of a task until its end, and recorded the task actions. The record of a task action included the content of the action, the time of its start and end, the person who was the target of the action, and the location of the action. The four wards of the treatment facility consisted of the cardiac failure ward, arrhythmia ward, cardiomyopathy/pulmonary hypertension ward, and cerebral vascular and metabolism ward. The destinations of patient transport included exam rooms for CT, X-ray, MRI, echocardiography, respiratory function testing, cardiac rehabilitation, neurological rehabilitation, cardiac catheterization investigation, and dialysis.

#### **3.2 Business modeling with UML**

From the time and motion study records we obtained, we created a use case diagram and activity diagram. Use case diagrams and activity diagrams are types of diagrams created using Unified Modeling Language (UML). UML is the de facto standard objected-oriented modeling language, and was developed for software development. In recent years,

to the time study is work sampling, which seeks to comprehend a job by sampling its conditions at predetermined time intervals. Work sampling cannot comprehend a job in its entirety, but it lessens the burden on the measurer. It also makes it possible for the worker himself or herself to record time. In contrast, a time and motion study comprehends the job in its entirety, but the burden on the measurer is great. The differences in results between the two methods have been observed to be large for jobs in which there were few events(Finkler et al., 1993). Currently, the results that come from measuring a job through

While the breadth of research that utilize measurement results from time and motion studies encompasses all nursing work, individual studies have been limited to examining the amount of work for individual caring assignments, such as cleaning a patient, feeding a patient, and taking care of a patient's toilet needs. There have been especially few studies that evaluate the work amount of a job by focusing on the job and clarifying its work process. While not on concerned with nursing work, the only such study conducted so far in the medical field was visualizing and understanding the amount of work involved in the process of registering cancer patients by Shiki et al. (Shiki et al., 2009). They proposed the method of "time-process study," a method to visualize tasks by adding time information to the process. However, because both the process and amount of work were estimated through interviews, the results can be said to be lacking in objectivity. Thus our study uses the time and motion study method, which actually measures a task. We focus on the job of transporting patients and clarifying its process. We also study the possibility of a method to

Transporting patients is an operation that is often performed outside hospital wards. It is both physically and mentally demanding of nurses. This job should also be scrutinized because it reduces the number of nursing staff inside the wards, as nurses go outside the

We carried out a time and motion study of nursing work related to transporting patients in four hospital wards of a cardiovascular treatment facility. We tracked our subjects, who were nurses, nursing assistants, and medical clerks, from the time of the start of a task until its end, and recorded the task actions. The record of a task action included the content of the action, the time of its start and end, the person who was the target of the action, and the location of the action. The four wards of the treatment facility consisted of the cardiac failure ward, arrhythmia ward, cardiomyopathy/pulmonary hypertension ward, and cerebral vascular and metabolism ward. The destinations of patient transport included exam rooms for CT, X-ray, MRI, echocardiography, respiratory function testing, cardiac rehabilitation,

From the time and motion study records we obtained, we created a use case diagram and activity diagram. Use case diagrams and activity diagrams are types of diagrams created using Unified Modeling Language (UML). UML is the de facto standard objected-oriented modeling language, and was developed for software development. In recent years,

continuous time and motion observation are said to be the gold standard.

visualize the work process using the clarified process and time information.

neurological rehabilitation, cardiac catheterization investigation, and dialysis.

wards in order to safely transport patients.

**3.2 Business modeling with UML** 

**3. Methods** 

**3.1 Study setting** 

Fig. 1. Functional diagram-patient transports system.

however, its use for business modeling has been suggested (Eriksson and Penker, 2000). The reason is that the structure of a job can considered oriented-oriented in nature. The content of a job can be treated as exchanges of messages between objects, such as materials and users. Thus UML as a descriptive method can allow one to intuitively understand the job. In this study, we elucidated the functional aspect of the operation of transporting patients. We also used an activity diagram to visualize the work process of transporting patients. Finally, we discussed the work load and its time efficiency by adding time information to the activity diagram. This study was approved by the ethics committee of the hospital we studied.

## **4. Results**

From the time and motion study, we observed and recorded 213 jobs of transferring patients. Overall, the number patient transfer assignments recorded was 3,775. Of these records, 387 records were not jobs related to transporting patients, so they were removed from our analysis.

A use case diagram extracted from the results of the time and motion study is shown in Figure 1. There were seven types of actors involving in transporting patients: nurses, head nurses, medical clerks, nursing assistants, the central medical examination department, the order entry system, and the hospital information system. The nurses were divided into two groups: head nurses, who had the responsibility of being in charge of nursing duties, and staff nurses, who received patients and provided care for them. The head nurse and the

Nursing Business Modeling with UML:

Table 1. Identified tasks and their descriptive statistics.

TOT: time on task.

composed of 47 tasks.

From Time and Motion Study to Business Modeling 409

T38 Reattach ME devices 0:41:25 18 82 ( 6-766 ) T39 Reattach medical supplies 0:21:23 14 69 ( 2-396 ) T40 Secure consultation card 0:04:35 23 9 ( 1-44 ) T41 Secure patient record 0:23:02 30 19 ( 1-560 ) T42 Clear away film 0:00:28 4 5 ( 3-16 ) T43 Clear away transport care equipment 0:25:52 40 34 ( 2-115 ) T44 Clear away map 0:01:54 5 11 ( 1-78 ) T45 Finish clean up 0:13:24 15 33 ( 1-159 ) T46 Record the transfer 0:11:10 11 32 ( 3-247 ) M Move 4:36:03 119 95 ( 2-1068 )

The dynamic aspect of transporting patients is shown as an activity diagram (see Figure 2). The head nurse, who is in charge of communication in the hospital ward, and the medical clerk receive a call for a patient from the central medical examination department. They confirm the bed rest level of the patient from his or her chart. If the patient can walk outside the ward by himself or herself (self-reliant), the person in charge of communication prepares the chart, the patient's exam ticket, and the map to the exam room. He or she searches for the patient, relays the call for examination to the patient, and hands over necessary items. If the bed rest level is escort (transport in a wheelchair) or litter care (transport on a stretcher), the person in charge of communication searches for the transport personnel and hands over the exam call. The transport personnel prepare the patient's chart, the exam ticket, and the instrument for transport care such as a wheelchair or stretcher, and move to the patient's location. They relay the exam call to the patient, and assess the patient's conditions to determine if transport is possible. If the transport personnel determine that the patient can be transported, he/she/they prepare oxygen or transfusion devices for transport, and perform excrement care and assist the patient in changing clothes. Next, the transport personnel move the patient from the bed to the transport instrument, and transport the patient to the exam room. After the patient arrives in the examination room, the transport personnel notify the exam receptionist of the patient's arrival, hand over the patient, and hand over items brought along, such as the patient chart and the exam ticket. If the exam takes only a short time, e.g. in the case of an x-ray exam, the transport personnel wait in the exam room, assist with preparing the patient for examination, and assists in the examination. If the exam takes a longer period of time, the transport personnel return to the hospital ward and perform other tasks. When communication comes from the examination room, the transport personnel receive the message and move to the exam room. After the exam has completed, the transport personnel receive the call from the patient, transfer the patient to the transport instrument, transport him or her back to the ward, and again move him or her to the hospital bed. The transport personnel prepare medical electronic equipment and medical devices attached to the patient so that subsistence in bed is possible. After assessing the patient's conditions, the transport personnel puts away the items brought along, such as the exam ticket and the patient chart, and record the transport. As shown in the activity diagram, we clarified that the process of transporting a patient was

Task TOT Frequency Median Range

medical clerk received communication about the transport of a patient, and confirmed the predetermined method of transport care. In addition, the head nurse made adjustments such as changing the transport personnel and finding appropriate personnel. Of the tasks related to transport care, the nurse and nursing assistant handled tasks that had direct bearing on the patient. In the hospital of this study, patients undergoing oxygen therapy, patients being monitored by EKG, and patients undergoing transfusion were the responsibility of nurses, not nursing assistants.



Nursing Business Modeling with UML: From Time and Motion Study to Business Modeling 409

TOT: time on task.

408 Modern Approaches To Quality Control

medical clerk received communication about the transport of a patient, and confirmed the predetermined method of transport care. In addition, the head nurse made adjustments such as changing the transport personnel and finding appropriate personnel. Of the tasks related to transport care, the nurse and nursing assistant handled tasks that had direct bearing on the patient. In the hospital of this study, patients undergoing oxygen therapy, patients being monitored by EKG, and patients undergoing transfusion were the

T01 Coordinate time for examination 0:33:27 28 58 ( 5-273 ) T02 Confirm schedule of examination 0:05:24 10 29 ( 4-100 ) T03 Accept call for examination 0:31:30 45 34 ( 1-324 ) T04 Look for patient record 0:04:32 11 18 ( 2-64 ) T05 Check bed rest level 0:09:11 10 36 ( 6-186 ) T06 Identify care-giver 0:00:58 3 21 ( 4-32 ) T07 Prepare map 0:08:27 20 23 ( 3-70 ) T08 Prepare patient consultation card 0:14:37 31 18 ( 1-108 ) T09 Prepare patient record 0:28:41 42 31 ( 5-187 ) T10 Find care-giver 0:01:59 3 42 ( 16-60 ) T11 Find patient 0:07:33 11 17 ( 4-116 ) T12 Wait for care-giver 0:00:21 1 21 ( 21-21 ) T13 Relay examination information to patient 0:29:55 43 34 ( 1-144 ) T14 Hand necessary materials to patient 0:00:21 3 6 ( 2-13 ) T15 Change care-giver assignment 0:00:37 1 37 ( 36-36 ) T16 Relay exam information to nurse 0:26:48 38 21 ( 1-384 ) T17 Prepare film 0:00:44 2 22 ( 15-29 ) T18 Prepare materials to be brought 0:04:02 3 38 ( 6-198 ) T19 Prepare transport care equipment 0:22:38 46 20 ( 1-139 ) T20 Carry transport care equipment 0:21:27 40 26 ( 1-88 ) T21 Assess situation 0:24:48 17 26 ( 2-382 ) T22 Confirm patient name 0:02:45 10 16 ( 6-30 ) T23 Prepare to move ME devices 0:13:50 19 31 ( 7-237 ) T24 Prepare to move medical supplies 0:16:43 23 42 ( 2-117 ) T25 Assist in excretion 0:05:16 5 52 ( 10-152 ) T26 Assist in changing of clothes 0:12:35 19 25 ( 10-127 ) T27 Prepare for transfer 0:10:22 13 29 ( 5-199 ) T28 Carry patient 1:46:59 83 43 ( 3-707 ) T29 Transport patient 9:15:49 109 292 ( 1-866 ) T30 Go through reception procedures 0:08:56 34 9 ( 1-90 ) T31 Hand-over patient 0:01:55 8 13 ( 2-34 ) T32 Hand-over necessary supplies 0:10:31 30 15 ( 1-89 ) T33 Relay information 0:33:09 31 63 ( 3-156 ) T34 Prepare for examination 0:27:16 26 32 ( 1-370 ) T35 Assist in examination 0:42:01 41 28 ( 6-255 ) T36 Standby at destination 1:57:19 35 92 ( 1-1612 ) T37 Receive patient 0:06:37 7 20 ( 6-208 )

Task TOT Frequency Median Range

responsibility of nurses, not nursing assistants.

Table 1. Identified tasks and their descriptive statistics.

The dynamic aspect of transporting patients is shown as an activity diagram (see Figure 2). The head nurse, who is in charge of communication in the hospital ward, and the medical clerk receive a call for a patient from the central medical examination department. They confirm the bed rest level of the patient from his or her chart. If the patient can walk outside the ward by himself or herself (self-reliant), the person in charge of communication prepares the chart, the patient's exam ticket, and the map to the exam room. He or she searches for the patient, relays the call for examination to the patient, and hands over necessary items. If the bed rest level is escort (transport in a wheelchair) or litter care (transport on a stretcher), the person in charge of communication searches for the transport personnel and hands over the exam call. The transport personnel prepare the patient's chart, the exam ticket, and the instrument for transport care such as a wheelchair or stretcher, and move to the patient's location. They relay the exam call to the patient, and assess the patient's conditions to determine if transport is possible. If the transport personnel determine that the patient can be transported, he/she/they prepare oxygen or transfusion devices for transport, and perform excrement care and assist the patient in changing clothes. Next, the transport personnel move the patient from the bed to the transport instrument, and transport the patient to the exam room. After the patient arrives in the examination room, the transport personnel notify the exam receptionist of the patient's arrival, hand over the patient, and hand over items brought along, such as the patient chart and the exam ticket. If the exam takes only a short time, e.g. in the case of an x-ray exam, the transport personnel wait in the exam room, assist with preparing the patient for examination, and assists in the examination. If the exam takes a longer period of time, the transport personnel return to the hospital ward and perform other tasks. When communication comes from the examination room, the transport personnel receive the message and move to the exam room. After the exam has completed, the transport personnel receive the call from the patient, transfer the patient to the transport instrument, transport him or her back to the ward, and again move him or her to the hospital bed. The transport personnel prepare medical electronic equipment and medical devices attached to the patient so that subsistence in bed is possible. After assessing the patient's conditions, the transport personnel puts away the items brought along, such as the exam ticket and the patient chart, and record the transport. As shown in the activity diagram, we clarified that the process of transporting a patient was composed of 47 tasks.

Nursing Business Modeling with UML:

was relatively low.

made up 14 percent of all tasks.

Table 2. Time on task by each task category.

**5. Discussion** 

From Time and Motion Study to Business Modeling 411

Table 1 shows the total time on task during a day in the four wards for each of the 47 tasks shown in the activity diagram. Also shown are the number of occurrences of each task, the median value, and the range. The task that took up the most total time was "T29 Transporting patient" (9:15:49). It took about 5 minutes on average for the nurse(s) to transport a patient. Of the 213 patient transport jobs observed, 109 actually involved transporting the patient. Patient transport jobs that did not involve transport were only those to support self-reliant patients and to adjust the scheduled time of exams. After T29, the task that took the most time was "T36 Standing by at the destination" (1:57:19), followed by "T28 Transferring the patient" (1:46:59). On the other hand, there were few occurrences of tasks related to searching for or changing transport personnel, such as "T06 Identifying care provider," "T12 Waiting for care provider," and "T15 Changing care provider." Comparing the coefficient of variance, we found that the coefficient of variance for "T41 Putting patient chart away," "T16 Conveying exam information to nurse," "T36 Standing by at destination," and "T21 Assessing conditions" was high. On the other hand, the coefficient of variance of "T29 Transporting patient" and "T43 Putting instruments for transport care"

The time on task for each type of task is shown in Table 2. Direct tasks are those that deal directly with the patient. Indirect tasks are tasks carried out without direct contact with the patient, including preparatory tasks for direct tasks and cleaning tasks. Direct tasks, which involve transporting the patient, made up about 60 percent of all tasks, and indirect tasks

Task category No. of task Time on Task ( % )

Indirect care 21 3:56:23 (14.1)

Direct care 21 16:08:27 (58.0)

Communication 2 0:59:57 (3.5)

Waiting 1 1:57:19 (7.0)

Record 1 0:11:10 (0.6)

Move 1 4:36:03 (16.5)

Total 47 27:49:19 (100.0)

First, we clarified the location and roles of persons in charge of tasks by making use of time and motion study data to visualize the object-oriented work process. From a functional point of view, the main persons in charge of the job of transporting patients were nurses. However, we understood that medical clerks participated in coordinating communication and that nursing assistants participated in transporting patients who did not need custody

Fig. 2. Dynamic diagram-patient transports.

Fig. 2. Dynamic diagram-patient transports.

Table 1 shows the total time on task during a day in the four wards for each of the 47 tasks shown in the activity diagram. Also shown are the number of occurrences of each task, the median value, and the range. The task that took up the most total time was "T29 Transporting patient" (9:15:49). It took about 5 minutes on average for the nurse(s) to transport a patient. Of the 213 patient transport jobs observed, 109 actually involved transporting the patient. Patient transport jobs that did not involve transport were only those to support self-reliant patients and to adjust the scheduled time of exams. After T29, the task that took the most time was "T36 Standing by at the destination" (1:57:19), followed by "T28 Transferring the patient" (1:46:59). On the other hand, there were few occurrences of tasks related to searching for or changing transport personnel, such as "T06 Identifying care provider," "T12 Waiting for care provider," and "T15 Changing care provider." Comparing the coefficient of variance, we found that the coefficient of variance for "T41 Putting patient chart away," "T16 Conveying exam information to nurse," "T36 Standing by at destination," and "T21 Assessing conditions" was high. On the other hand, the coefficient of variance of "T29 Transporting patient" and "T43 Putting instruments for transport care" was relatively low.

The time on task for each type of task is shown in Table 2. Direct tasks are those that deal directly with the patient. Indirect tasks are tasks carried out without direct contact with the patient, including preparatory tasks for direct tasks and cleaning tasks. Direct tasks, which involve transporting the patient, made up about 60 percent of all tasks, and indirect tasks made up 14 percent of all tasks.



## **5. Discussion**

First, we clarified the location and roles of persons in charge of tasks by making use of time and motion study data to visualize the object-oriented work process. From a functional point of view, the main persons in charge of the job of transporting patients were nurses. However, we understood that medical clerks participated in coordinating communication and that nursing assistants participated in transporting patients who did not need custody

Nursing Business Modeling with UML:

jobs in several other facilities.

**7. Acknowledgment** 

gratitude to all involved.

1270.

2063, 0090-3493.

0954-0121.

9780471295518.

**8. References** 

**6. Future outlook** 

From Time and Motion Study to Business Modeling 413

In this study, the structure of the work of transporting patients was visualized. The study suggests that the work of transporting patients has great differences in the objects, the process, and time efficiency depending on the conditions of the patients, type of exam, and occurrence of the work. Also, because many work occurrences were irregular and required quick responses, we learned that nurses must make adjustments with other tasks while at

This study showed the usefulness of time and motion study for clarifying not only work load but also work structure and work processes. In the future, we seek to confirm the applicability of this study by conducting similar studies based on other jobs and records of

We wish to express our sincere gratitude to all the nurses, nursing assistants, and medical clerks who cooperated with us in this study. We also received assistance from research seminar students of the Osaka University Graduate School of Medicine, Division of Health Sciences. They conducted the time and motion study measurements. Once again, our deep

Eriksson , H.E., Penker, M. (2000). *Business modeling with UML*. Wiley, New Jersey,

Finkler, S.A., Knickman, J.R., Hendrickson, G. et al.(1993). A Comparison of work-sampling

Hendrich, A., Chow, M.P., Skierczynski, B. A. et al.(2008). A 36-Hospital Time and Motion

Shiki, N., Ohno, Y., Fujii, A. et al.(2009).Time process study with UML a new method for

Tang, Z., Weavind, L., Mazabob, J. et al.(2007).Workflow in intensive care unit remote

Van de Werf, E., Lievens, Y., Verstraete, J. et al.(2009).Time and motion study of

Were, M.C., Sutherland, J.M., Bwana, M. et al.(2008).Patterns of care in two HIV continuity

Yen, K., Shane, E.L., Pawar, S.S. et al.(2009).Time motion study in a pediatric emergency

*Service Research,* Vol.28, No.5, pp.577-597, 0017-9124.

*Radiotherapy and Oncology* ,Vol.93, pp.137-140, 0167-8140 .

*medicine,* Vol.53, No.4, pp.462-468, 0196-0644.

Vol.12, No.3, pp.25-34, 1552-5767.

and time and motion techniques for studies in health services research. *Health* 

Study: How Do Medical-Surgical Nurses Spend Their Time? *The Permanente Journal*,

process analysis. *Methods of informatics in Medicine*, Vol.48, No.6, pp.582-588, 0026-

monitoring: a time and motion study. *Critical Care Medicine,* Vol.35, No.9, pp.2057-

radiotherapy deliverly: economic burden of increased quality assurance and IMRT.

Clinics in Uganda, Africa:a time motion study. *AIDS care*, Vol.20, No.6, pp.677-682,

Department before and after computer physician order entry. *Annals of emergency* 

the same time accomplishing the task of transporting patients.

or attachment of medical electronic or transfusion devices. We understood that while medical clerks received communication about exams and confirmed the method of transport care on the patient chart, they did not have privilege to change the transport personnel or delegate the task, so they turned the task over to lead nurses. Furthermore, in the case of self-reliant patients, the person in charge of communication in a ward had the responsibility of transmitting the exam information to the patient regardless of whether he or she was a medical clerk or nurse. Furthermore, in the case of patients who needed wheelchair or stretcher transport, the person in charge of communication had the responsibility of sending information about the exam call to the transport personnel after receiving the communication about the exam. Our study showed that if the person in charge of communication was a medical clerk, he or she turned the task over the head nurse, because he or she did not have the privilege to change the care provider. The task that took the most time in this process was "Conveying exam information to the patient," followed by "Preparing patient chart" and "Preparing exam ticket." Use of the exam ticket was limited to outpatient exams of hospitalized patients and during the medical exam, so the repositories of the tickets were fixed. In contrast, because patient charts were used for a variety of purposes by physicians, nurses, medical clerks, and many other hospital employees, search for the charts took place, and the time required to prepare the charts grew longer. After information was conveyed to the transport personnel by the person in charge of communication, the transport personnel handled all responsibilities, including the final task of recording the transport.

Second, we understood the divergence between the work process specified in the hospital procedures manual and the actual work process. The manual used in the hospital of our study did not specify tasks such as "Searching for the patient," "Searching for the transport personnel," "Changing the transport personnel," "Preparing the exam (in the exam room)," and "Assisting in the exam." This reason is that the work procedures manual contains standard procedures. Irregular events and redundant tasks that should be kept in mind were not included. Also, the procedures manual was written to describe work procedures for individual nurses, so the location and role of workers described above were not clarified.

Third, from the work process diagram based on actual work records collected by this study and by adding time information to the process, we understood the efficiency with which tasks were carried out. By understanding the time used for each task and the variability of time, we clarified the time element that makes up the care of transporting patients. In the future, we seek to understand in detail how time on task changes depending on constraints.

Fourth, our study suggests that the data can be used for risk analysis. Our study extracted 47 tasks that made up the transport of patients, and listed their sequential order from time study records. Through our study, we clarified the input and output of each task, as well as the frequency of irregular events. Irregular events such as "Searching for the patient" and "Searching for the nurse" can be considered risks recorded by this study that prevent the work goal from being achieved. Although not carried out in this study, each task can be scrutinized to clarify factors that hinder each of their output. Doing this can draw out the risks associated with the work of transporting the patient, and produce discussions about concentrating risks and avoiding risks.

## **6. Future outlook**

412 Modern Approaches To Quality Control

or attachment of medical electronic or transfusion devices. We understood that while medical clerks received communication about exams and confirmed the method of transport care on the patient chart, they did not have privilege to change the transport personnel or delegate the task, so they turned the task over to lead nurses. Furthermore, in the case of self-reliant patients, the person in charge of communication in a ward had the responsibility of transmitting the exam information to the patient regardless of whether he or she was a medical clerk or nurse. Furthermore, in the case of patients who needed wheelchair or stretcher transport, the person in charge of communication had the responsibility of sending information about the exam call to the transport personnel after receiving the communication about the exam. Our study showed that if the person in charge of communication was a medical clerk, he or she turned the task over the head nurse, because he or she did not have the privilege to change the care provider. The task that took the most time in this process was "Conveying exam information to the patient," followed by "Preparing patient chart" and "Preparing exam ticket." Use of the exam ticket was limited to outpatient exams of hospitalized patients and during the medical exam, so the repositories of the tickets were fixed. In contrast, because patient charts were used for a variety of purposes by physicians, nurses, medical clerks, and many other hospital employees, search for the charts took place, and the time required to prepare the charts grew longer. After information was conveyed to the transport personnel by the person in charge of communication, the transport personnel handled all responsibilities, including the final

Second, we understood the divergence between the work process specified in the hospital procedures manual and the actual work process. The manual used in the hospital of our study did not specify tasks such as "Searching for the patient," "Searching for the transport personnel," "Changing the transport personnel," "Preparing the exam (in the exam room)," and "Assisting in the exam." This reason is that the work procedures manual contains standard procedures. Irregular events and redundant tasks that should be kept in mind were not included. Also, the procedures manual was written to describe work procedures for individual nurses, so the location and role of workers described

Third, from the work process diagram based on actual work records collected by this study and by adding time information to the process, we understood the efficiency with which tasks were carried out. By understanding the time used for each task and the variability of time, we clarified the time element that makes up the care of transporting patients. In the future, we seek to understand in detail how time on task changes

Fourth, our study suggests that the data can be used for risk analysis. Our study extracted 47 tasks that made up the transport of patients, and listed their sequential order from time study records. Through our study, we clarified the input and output of each task, as well as the frequency of irregular events. Irregular events such as "Searching for the patient" and "Searching for the nurse" can be considered risks recorded by this study that prevent the work goal from being achieved. Although not carried out in this study, each task can be scrutinized to clarify factors that hinder each of their output. Doing this can draw out the risks associated with the work of transporting the patient, and produce discussions about

task of recording the transport.

above were not clarified.

depending on constraints.

concentrating risks and avoiding risks.

In this study, the structure of the work of transporting patients was visualized. The study suggests that the work of transporting patients has great differences in the objects, the process, and time efficiency depending on the conditions of the patients, type of exam, and occurrence of the work. Also, because many work occurrences were irregular and required quick responses, we learned that nurses must make adjustments with other tasks while at the same time accomplishing the task of transporting patients.

This study showed the usefulness of time and motion study for clarifying not only work load but also work structure and work processes. In the future, we seek to confirm the applicability of this study by conducting similar studies based on other jobs and records of jobs in several other facilities.

## **7. Acknowledgment**

We wish to express our sincere gratitude to all the nurses, nursing assistants, and medical clerks who cooperated with us in this study. We also received assistance from research seminar students of the Osaka University Graduate School of Medicine, Division of Health Sciences. They conducted the time and motion study measurements. Once again, our deep gratitude to all involved.

## **8. References**


**23** 

*Spain* 

**Practical Quality Control: the Experiences of a** 

In the 1930's W.A. Shewhart pioneered the application of statistical principles to the quality control (QC) of production processes, eventually publishing the landmark book "Economic Control of Quality of Manufactured Products" (Shewhart, 1931). In this book, he states that a phenomenon is *under control* if its future variation can be predicted (within limits) based on previous experience. This is precisely the idea behind the control charts used in measurement processes—specifically, for chemical analysis. The International Organization for Standardization (ISO), in its standard ISO 9000 (ISO, 2005a), defines *quality control* as "the part of quality management focused on fulfilling quality requirements". According to the standard, quality management also includes quality planning, quality assurance and quality improvement. The above definition is rather vague, because quality management systems based on the ISO 9000 family of standards can be applied to any kind of organization regardless of its field of activity, its size or whether it is from the public or private sectors. Testing laboratories typically distinguish between *internal* and *external* QC. In this context, the International Union of Pure and Applied Chemistry (IUPAC, 1998) gives a definition of internal QC that is well-suited to an analytical laboratory: "the set of procedures undertaken by laboratory staff for the continuous monitoring of operation and the results of measurements in order to decide whether results are reliable enough to be released". Although the aforementioned document does not formally define *external QC,* it does mention that *external control* may be done by submitting blind samples to the measuring laboratory. This activity can be organized in the form of a collaborative test. The aim of these QC activities is to verify that the quality parameters of an analytical method ascertained in the method validation are maintained during its operational lifetime. Thus, method validation or revalidation tasks are periodic activities that end with a validation report, whereas QC activities are recurrent activities implemented in routine work. Apart from the use of fully validated methods, QC assumes the use of properly maintained, verified and calibrated equipment, reagents and consumables with the proper specifications; standards with well-established traceability; and qualified technicians working in suitable environmental conditions. However, fulfilling all these requirements is not enough to ensure the delivery of appropriate quality results over time: a laboratory's capacity to produce technically correct results must be continuously monitored. Indeed, according to Thompson *et al.* (Thompson & Lowthian, 1993), QC is the only quality

**1. Introduction** 

**Public Health Laboratory** 

Francesc Centrich1, Teresa Subirana1,

*2Universitat de Barcelona* 

Mercè Granados2 and Ramon Companyó2 *1Laboratori de l'Agència de Salut Pública de Barcelona;* 

Yokouchi, M., Ohno, Y., Kasahara, S. et al.(2005). Development of Medical Task Classification for Job Scheduling. *Medical and Biological engineering*, Vol.43, No.4, pp.762-768, 1347-443X.

## **Practical Quality Control: the Experiences of a Public Health Laboratory**

Francesc Centrich1, Teresa Subirana1, Mercè Granados2 and Ramon Companyó2 *1Laboratori de l'Agència de Salut Pública de Barcelona; 2Universitat de Barcelona Spain* 

## **1. Introduction**

414 Modern Approaches To Quality Control

Yokouchi, M., Ohno, Y., Kasahara, S. et al.(2005). Development of Medical Task

pp.762-768, 1347-443X.

Classification for Job Scheduling. *Medical and Biological engineering*, Vol.43, No.4,

In the 1930's W.A. Shewhart pioneered the application of statistical principles to the quality control (QC) of production processes, eventually publishing the landmark book "Economic Control of Quality of Manufactured Products" (Shewhart, 1931). In this book, he states that a phenomenon is *under control* if its future variation can be predicted (within limits) based on previous experience. This is precisely the idea behind the control charts used in measurement processes—specifically, for chemical analysis. The International Organization for Standardization (ISO), in its standard ISO 9000 (ISO, 2005a), defines *quality control* as "the part of quality management focused on fulfilling quality requirements". According to the standard, quality management also includes quality planning, quality assurance and quality improvement. The above definition is rather vague, because quality management systems based on the ISO 9000 family of standards can be applied to any kind of organization regardless of its field of activity, its size or whether it is from the public or private sectors. Testing laboratories typically distinguish between *internal* and *external* QC. In this context, the International Union of Pure and Applied Chemistry (IUPAC, 1998) gives a definition of internal QC that is well-suited to an analytical laboratory: "the set of procedures undertaken by laboratory staff for the continuous monitoring of operation and the results of measurements in order to decide whether results are reliable enough to be released". Although the aforementioned document does not formally define *external QC,* it does mention that *external control* may be done by submitting blind samples to the measuring laboratory. This activity can be organized in the form of a collaborative test. The aim of these QC activities is to verify that the quality parameters of an analytical method ascertained in the method validation are maintained during its operational lifetime. Thus, method validation or revalidation tasks are periodic activities that end with a validation report, whereas QC activities are recurrent activities implemented in routine work. Apart from the use of fully validated methods, QC assumes the use of properly maintained, verified and calibrated equipment, reagents and consumables with the proper specifications; standards with well-established traceability; and qualified technicians working in suitable environmental conditions. However, fulfilling all these requirements is

not enough to ensure the delivery of appropriate quality results over time: a laboratory's capacity to produce technically correct results must be continuously monitored. Indeed, according to Thompson *et al.* (Thompson & Lowthian, 1993), QC is the only quality

Practical Quality Control: the Experiences of a Public Health Laboratory 417

areas: two dealing with applications (food analysis and environmental analysis) and two dealing with analytical techniques (spectroscopic analysis and chromatographic analysis).

> Maintained and calibrated equipment

> > Selection/Development

Suitable environmental conditions

Traceable standards

Validation

Implementation in routine work

Internal quality control External quality control

Implementation of preventive and corrective actions

Revalidation

Accreditation

Fig. 1. Activities that determine the reliability of test results.

management system (LIMS).

**SHELF LIFE OF AN ANALYTICAL METHOD** 

Qualified staff

The LPHAB features a broad array of state-of-the-art equipment: roughly 500 instruments, including those for sample treatment, chromatography and spectroscopy. These include various gas and liquid chromatographs coupled to tandem mass spectrometry plus two inductively coupled plasma spectrometers, one equipped with photometric detection, and the other, with mass spectrometry detection. The LPHAB also uses a laboratory information

To date, the CAS has implemented about 110 analytical methodologies included in the scope of accreditation according to the requirements of the ISO 17025 standard (ISO, 2005b). In 2010, the CAS portfolio included approximately 1,800 different determinations, 1,400 of

management measure that provides a high level of protection against the release of inaccurate data. The authors demonstrate a significant relationship between the efficacy of a laboratory's QC and its subsequent performance in proficiency tests. They also consider that the implementation of QC activities and the participation in proficiency tests are two sides of the same coin: a laboratory's commitment to quality.

Once a laboratory has implemented a method in its routine work, is performing adequate QC, has taken any appropriate corrective and/or preventive actions, and its staff has acquired sufficient expertise, it may consider including this method in its scope of accreditation. Figure 1 shows these activities in the context of the operational lifetime of an analytical method.

This chapter was written to explain, in practical terms, the QC activities and management at an analytical laboratory—namely, the Chemical Analysis Service at the Laboratory of the Public Health Agency of Barcelona (*Laboratori de l'Agència de Salut Pública de Barcelona*; hereafter*, LPHAB*).

## **2. History and present context of the LPHAB**

The LPHAB has its origin in the Municipal Laboratory of Barcelona, a microbiology laboratory created in 1886 to provide support to the sanitary authorities in their efforts to prevent rabies; since its inception, the Municipal Laboratory of Barcelona was a reference laboratory in Spain. In 1907, owing to its ever-increasing activities, it was given a new structure that led to creation of a section dedicated to chemical analysis of foods, with the then innovative objective of studying health problems attributable to the presence of hazardous chemicals in foods.

From the 1950's onwards, the section on chemical analysis of foods underwent major development. This stemmed from advances in knowledge on food chemistry and was catalyzed by various international food crises caused by chemical pollutants such as mercury and methanol. A case of widespread food poisoning in Spain in 1981, traced to denatured rapeseed oil, triggered the modernization of many Spanish public health laboratories, including the Municipal Laboratory of Barcelona. The Laboratory's equipment was soon updated, and its organization and management were overhauled. These changes enabled the Municipal Laboratory of Barcelona to face new analytical challenges. In addition to assessing the nutritional properties of food, it also focused on detection and determination of additives, residues and contaminants in food. The Municipal Laboratory of Barcelona began serving customers outside of the municipal administration; the challenge of providing these customers with the data they sought at specific analysis costs and response times proved highly stimulating. By the year 2000, it had analyzed 20,000 samples. In 2003 the Municipal Laboratory of Barcelona merged with the Public Health Laboratory of the Autonomous Government of Catalonia (*Generalitat de Catalunya)* in Barcelona to form the LPHAB. This union led to significant investments in instrumentation and to the recruitment of new staff; consequently, the newly formed LPHAB became one of the strongest laboratories in Spain for food analysis.

The LPHAB currently comprises four departments: two technical departments (the Chemical Analysis Service [CAS] and the Microbiological Analysis Service) and two management & support departments (the Quality Assurance Unit [QAU] and the Logistics & Services Unit). It presently employs 65 people, 31 of which work in the CAS (11 senior technicians and 20 mid-level technicians and support staff). The CAS encompasses four

management measure that provides a high level of protection against the release of inaccurate data. The authors demonstrate a significant relationship between the efficacy of a laboratory's QC and its subsequent performance in proficiency tests. They also consider that the implementation of QC activities and the participation in proficiency tests are two sides

Once a laboratory has implemented a method in its routine work, is performing adequate QC, has taken any appropriate corrective and/or preventive actions, and its staff has acquired sufficient expertise, it may consider including this method in its scope of accreditation. Figure 1 shows these activities in the context of the operational lifetime of an

This chapter was written to explain, in practical terms, the QC activities and management at an analytical laboratory—namely, the Chemical Analysis Service at the Laboratory of the Public Health Agency of Barcelona (*Laboratori de l'Agència de Salut Pública de Barcelona*;

The LPHAB has its origin in the Municipal Laboratory of Barcelona, a microbiology laboratory created in 1886 to provide support to the sanitary authorities in their efforts to prevent rabies; since its inception, the Municipal Laboratory of Barcelona was a reference laboratory in Spain. In 1907, owing to its ever-increasing activities, it was given a new structure that led to creation of a section dedicated to chemical analysis of foods, with the then innovative objective of studying health problems attributable to the presence of

From the 1950's onwards, the section on chemical analysis of foods underwent major development. This stemmed from advances in knowledge on food chemistry and was catalyzed by various international food crises caused by chemical pollutants such as mercury and methanol. A case of widespread food poisoning in Spain in 1981, traced to denatured rapeseed oil, triggered the modernization of many Spanish public health laboratories, including the Municipal Laboratory of Barcelona. The Laboratory's equipment was soon updated, and its organization and management were overhauled. These changes enabled the Municipal Laboratory of Barcelona to face new analytical challenges. In addition to assessing the nutritional properties of food, it also focused on detection and determination of additives, residues and contaminants in food. The Municipal Laboratory of Barcelona began serving customers outside of the municipal administration; the challenge of providing these customers with the data they sought at specific analysis costs and response times proved highly stimulating. By the year 2000, it had analyzed 20,000 samples. In 2003 the Municipal Laboratory of Barcelona merged with the Public Health Laboratory of the Autonomous Government of Catalonia (*Generalitat de Catalunya)* in Barcelona to form the LPHAB. This union led to significant investments in instrumentation and to the recruitment of new staff; consequently, the newly formed LPHAB became one of the strongest

The LPHAB currently comprises four departments: two technical departments (the Chemical Analysis Service [CAS] and the Microbiological Analysis Service) and two management & support departments (the Quality Assurance Unit [QAU] and the Logistics & Services Unit). It presently employs 65 people, 31 of which work in the CAS (11 senior technicians and 20 mid-level technicians and support staff). The CAS encompasses four

of the same coin: a laboratory's commitment to quality.

**2. History and present context of the LPHAB** 

analytical method.

hereafter*, LPHAB*).

hazardous chemicals in foods.

laboratories in Spain for food analysis.

areas: two dealing with applications (food analysis and environmental analysis) and two dealing with analytical techniques (spectroscopic analysis and chromatographic analysis).

Fig. 1. Activities that determine the reliability of test results.

The LPHAB features a broad array of state-of-the-art equipment: roughly 500 instruments, including those for sample treatment, chromatography and spectroscopy. These include various gas and liquid chromatographs coupled to tandem mass spectrometry plus two inductively coupled plasma spectrometers, one equipped with photometric detection, and the other, with mass spectrometry detection. The LPHAB also uses a laboratory information management system (LIMS).

To date, the CAS has implemented about 110 analytical methodologies included in the scope of accreditation according to the requirements of the ISO 17025 standard (ISO, 2005b). In 2010, the CAS portfolio included approximately 1,800 different determinations, 1,400 of

Practical Quality Control: the Experiences of a Public Health Laboratory 419

The LPHAB performs research on developing and improving analytical methodology, both on its own and in collaboration with various universities. Its staff members often participate as experts in training courses organized by universities or government bodies, and some of its senior technicians are regularly asked by the Spanish Accreditation Body to participate as technical experts in laboratory accreditation audits for the food sector. Lastly, the LPHAB

Since it was issued in 2005, the ISO/IEC 17025 standard (ISO, 2005b) has been the international reference for accreditation of the technical competence of testing and calibration laboratories. The requirements of ISO/IEC 17025 (ISO, 2005b) concerning QC are concisely set out in Section 5.9 of the Standard, entitled "Assuring the Quality of Test and Calibration Results". Briefly, the Standard states that QC activities are mandatory and dictates that their results must be recorded. It also mentions the most frequent internal QC

"The laboratory shall have QC procedures for monitoring the validity of tests and calibrations undertaken. The resulting data shall be recorded in such a way that trends are detectable and, where practicable, statistical techniques shall be applied to the reviewing of the results. This monitoring shall be planned and reviewed and may include, but not be

a) Regular use of certified reference materials and/or internal QC using secondary reference

The standard goes on to state that the results of the monitoring activities performed must be

regularly hosts university or vocational students for training stays and internships.

**3. QC within the framework of the ISO/IEC 17025 standard** 

and external QC activities, without excluding other possible activities:

b) Participation in proficiency test or proficiency-testing programs; c) Replicate tests or calibrations using the same or different methods;

e) Correlation of results for different characteristics of an item."

analyzed and that appropriate measures should be taken:

d) Retesting or recalibration of retained items;

Fig. 4. Breakdown of the LPHAB's customers

limited to, the following:

materials;

which correspond to its scope of accreditation. Moreover, the flexible scope includes some 55 analytical methods, grouped according to instrumental techniques, and numerous analytes.

In 2010 the LPHAB tested 32,225 samples, for which it performed some 550,000 determinations. Roughly half of these samples were food samples, and the other half, environmental samples (chiefly, potable water and filters for atmospheric control). The LPHAB's main customers are the Public Health Agency of Barcelona (which owns it), and the inspection bodies of the Catalonian and Spanish governments.

Fig. 2. Breakdown of analyses performed at the LPHAB in 2010, by sample type.

In 2010, the LPHAB's budget, excluding staff costs, was €1.2 million. This includes consumables, gases, reagents, culture media, equipment maintenance, participation in proficiency testing, and small investments. Its revenue contracts and invoices totaled €7 million.

Fig. 3. Breakdown of analyses performed at the LPHAB in 2010, by analytical technique

which correspond to its scope of accreditation. Moreover, the flexible scope includes some 55 analytical methods, grouped according to instrumental techniques, and numerous

In 2010 the LPHAB tested 32,225 samples, for which it performed some 550,000 determinations. Roughly half of these samples were food samples, and the other half, environmental samples (chiefly, potable water and filters for atmospheric control). The LPHAB's main customers are the Public Health Agency of Barcelona (which owns it), and

the inspection bodies of the Catalonian and Spanish governments.

Fig. 2. Breakdown of analyses performed at the LPHAB in 2010, by sample type.

small investments. Its revenue contracts and invoices totaled €7 million.

In 2010, the LPHAB's budget, excluding staff costs, was €1.2 million. This includes consumables, gases, reagents, culture media, equipment maintenance, participation in proficiency testing, and

Fig. 3. Breakdown of analyses performed at the LPHAB in 2010, by analytical technique

analytes.

Fig. 4. Breakdown of the LPHAB's customers

The LPHAB performs research on developing and improving analytical methodology, both on its own and in collaboration with various universities. Its staff members often participate as experts in training courses organized by universities or government bodies, and some of its senior technicians are regularly asked by the Spanish Accreditation Body to participate as technical experts in laboratory accreditation audits for the food sector. Lastly, the LPHAB regularly hosts university or vocational students for training stays and internships.

## **3. QC within the framework of the ISO/IEC 17025 standard**

Since it was issued in 2005, the ISO/IEC 17025 standard (ISO, 2005b) has been the international reference for accreditation of the technical competence of testing and calibration laboratories. The requirements of ISO/IEC 17025 (ISO, 2005b) concerning QC are concisely set out in Section 5.9 of the Standard, entitled "Assuring the Quality of Test and Calibration Results". Briefly, the Standard states that QC activities are mandatory and dictates that their results must be recorded. It also mentions the most frequent internal QC and external QC activities, without excluding other possible activities:

"The laboratory shall have QC procedures for monitoring the validity of tests and calibrations undertaken. The resulting data shall be recorded in such a way that trends are detectable and, where practicable, statistical techniques shall be applied to the reviewing of the results. This monitoring shall be planned and reviewed and may include, but not be limited to, the following:

a) Regular use of certified reference materials and/or internal QC using secondary reference materials;


The standard goes on to state that the results of the monitoring activities performed must be analyzed and that appropriate measures should be taken:

Practical Quality Control: the Experiences of a Public Health Laboratory 421

although methods are explicitly specified, laboratories are allowed to use alternative methods, providing they can demonstrate that the results are at least as reliable as those produced by the specified methods. Another approach is that of Decision 2002/657/EC, concerning analytical methods for the analysis of residues and contaminants in food products, which establishes the performance criteria for methods. Directives 2009/90/EC and 98/83/EC establish analogous analytical method criteria for monitoring water status, sediment and biota, as do Regulation (EC) 333/2007 (on sampling and analytical methods for the control of some contaminants in foodstuffs), to SANCO/10684/2009 (on method validation and quality control procedures for pesticide residues analysis in food and feed), or to Regulation (EC) 401/2006 (on methods of sampling and analysis for the control of mycotoxins in foodstuffs). Representative examples of performance criteria for methods

This flexible approach to method performance criteria allows laboratories to quickly incorporate advances in analytical techniques and to apply new methods to address new problems when required. The crucial issues here are that the required performance criteria

> Level (µg/kg) RSDr % (a) RSDR % (b) Recovery % < 20 ≤ 30 ≤ 40 50 to 120 20 to 50 ≤ 20 ≤ 30 70 to 105 < 50 ≤ 15 ≤ 25 75 to 105

Since its publication, Decision 2002/657/EC has been a key document for analytical laboratories involved in food analysis and has proven utile for laboratories in other fields, such as environmental analysis. It introduced a change of mindset, replacing reference methods with the criteria approach, and launched new definitions, such as *minimum required performance limit (MRPL)*, *decision limit (CCα)* and *detection capability (CCβ)*. Decision 2002/657/EC determines common criteria for the interpretation of test results, establishes the performance criteria requirements for screening and confirmatory methods, and presents the directives to validate the analytical methods. However, it is a complex document, and guidelines for its implementation have been published (SANCO/2004/2726-rev-4-December-2008). The most

Minimum required performance limit is defined as the minimum content of an analyte in a sample that has to be detected and confirmed. It is intended to harmonize the analytical performance of methods for banned substances. The minimum required performance level for a method of a banned substance should be lower than the MRPL; however, very few

The decision limit is the limit at and above which one can conclude, with an error probability of α, that a sample is non-compliant. For substances with no permitted limit α is 1%, whereas for all other substances α is 5%. Thus, the result of an analysis shall be considered non-compliant if the CCα of the confirmatory method for the analyte is

Table 1. Performance criteria for methods of analysis of patulin in foodstuffs, from Regulation 401/2006. (a: Relative standard deviation, calculated from results generated under repeatability conditions, b: Relative standard deviation, calculated from results

relevant aspects of Decision 2002/657/EC are further described below.

used to analyze patulin in foodstuffs are shown in Table 1.

are met and that the method has been properly validated.

generated under reproducibility conditions.)

MRPL values have been established to date.

exceeded.

"QC data shall be analyzed and, where they are found to be outside pre-defined criteria, planned action shall be taken to correct the problem and to prevent incorrect results from being reported."

## **4. Legislative requirements**

Food safety and environmental protection are top priorities in the EU, which has implemented widespread legislation to support its policies in these fields. Noteworthy examples include Regulation (EC) No 178/2002, which establishes a legal framework for food; Directive 2000/60/EC, which establishes a framework for actions in the EU's water policy; and Directive 2008/50/EC, which outlines measures on ambient air quality. Currently, there is also a proposal for a framework Directive to create common principles for soil protection across the EU.

The EU has high standards for food safety and environmental protection. For instance, Regulation (EC) No 1881/2006 defines maximum levels for certain contaminants (*e.g.* mycotoxins, dioxins, heavy metals, and nitrate) in foodstuffs; Regulations (EU) No 37/2010 and (EC) No 830/2008 stipulate maximum residue levels of pharmacologically active substances or pesticides, respectively, in foodstuffs; and Directive 98/83/EC defines values for several microbiological and chemical parameters for water intended for human consumption. Regarding the environment, Directive 2008/50/EC defines objectives for ambient air quality and establishes limits on the concentration levels of air pollutants; Water Framework Directive 2000/60/EC presents a list of 33 priority pollutants based on their substantial risk; and Directive 2008/105/EC establishes environmental quality standards for these 33 pollutants.

Laboratories in charge of official controls provide essential support for these policies, by proficiently monitoring environmental and food samples. These laboratories should be equipped with instrumentation that enables correct determination of maximum levels as stipulated by EU law. According to Regulation (EC) No 882/2004, the laboratories designated for official controls in feed and food samples must operate and be assessed and accredited in accordance with ISO/IEC 17025 (ISO, 2005b). Likewise, Directive 2009/90/EC establishes that laboratories that perform chemical monitoring under Water Framework Directive 2000/60/EC must apply quality management system practices in accordance with the ISO/IEC 17025 standard or an equivalent standard accepted at the international level. Moreover, the laboratories must demonstrate their competence in analyzing relevant physicochemical parameters or compounds by participating in proficiency testing programs and by analysis of available reference materials representatives of the monitored samples. In Spain, Royal Decree 140/2003 stipulates that laboratories designated for official controls of water intended for human consumption that analyze more than 5,000 samples per year must be accredited in accordance with ISO/IEC 17025 (ISO, 2005b), and that other laboratories, if they are not accredited as such, must be at least certified according to ISO 9001 (ISO, 2005a).

There has been a shift from using official analytical methods to a more open approach that allows the laboratories involved in official controls to use validated analytical methods that have been proven to meet established performance criteria. Thus, different scenarios are presently possible: in very few cases, such as Commission Regulation (EEC) 2676/90, on the analysis of lead in wine, the method is defined; more frequently, as in Directive 2008/50/EC on air quality or in Directive 98/83/EC on water intended for human consumption,

"QC data shall be analyzed and, where they are found to be outside pre-defined criteria, planned action shall be taken to correct the problem and to prevent incorrect results from

Food safety and environmental protection are top priorities in the EU, which has implemented widespread legislation to support its policies in these fields. Noteworthy examples include Regulation (EC) No 178/2002, which establishes a legal framework for food; Directive 2000/60/EC, which establishes a framework for actions in the EU's water policy; and Directive 2008/50/EC, which outlines measures on ambient air quality. Currently, there is also a proposal for a framework Directive to create common principles

The EU has high standards for food safety and environmental protection. For instance, Regulation (EC) No 1881/2006 defines maximum levels for certain contaminants (*e.g.* mycotoxins, dioxins, heavy metals, and nitrate) in foodstuffs; Regulations (EU) No 37/2010 and (EC) No 830/2008 stipulate maximum residue levels of pharmacologically active substances or pesticides, respectively, in foodstuffs; and Directive 98/83/EC defines values for several microbiological and chemical parameters for water intended for human consumption. Regarding the environment, Directive 2008/50/EC defines objectives for ambient air quality and establishes limits on the concentration levels of air pollutants; Water Framework Directive 2000/60/EC presents a list of 33 priority pollutants based on their substantial risk; and Directive 2008/105/EC establishes environmental quality standards for

Laboratories in charge of official controls provide essential support for these policies, by proficiently monitoring environmental and food samples. These laboratories should be equipped with instrumentation that enables correct determination of maximum levels as stipulated by EU law. According to Regulation (EC) No 882/2004, the laboratories designated for official controls in feed and food samples must operate and be assessed and accredited in accordance with ISO/IEC 17025 (ISO, 2005b). Likewise, Directive 2009/90/EC establishes that laboratories that perform chemical monitoring under Water Framework Directive 2000/60/EC must apply quality management system practices in accordance with the ISO/IEC 17025 standard or an equivalent standard accepted at the international level. Moreover, the laboratories must demonstrate their competence in analyzing relevant physicochemical parameters or compounds by participating in proficiency testing programs and by analysis of available reference materials representatives of the monitored samples. In Spain, Royal Decree 140/2003 stipulates that laboratories designated for official controls of water intended for human consumption that analyze more than 5,000 samples per year must be accredited in accordance with ISO/IEC 17025 (ISO, 2005b), and that other laboratories, if they are not accredited as such, must be at least certified according to ISO 9001 (ISO,

There has been a shift from using official analytical methods to a more open approach that allows the laboratories involved in official controls to use validated analytical methods that have been proven to meet established performance criteria. Thus, different scenarios are presently possible: in very few cases, such as Commission Regulation (EEC) 2676/90, on the analysis of lead in wine, the method is defined; more frequently, as in Directive 2008/50/EC on air quality or in Directive 98/83/EC on water intended for human consumption,

being reported."

**4. Legislative requirements** 

for soil protection across the EU.

these 33 pollutants.

2005a).

although methods are explicitly specified, laboratories are allowed to use alternative methods, providing they can demonstrate that the results are at least as reliable as those produced by the specified methods. Another approach is that of Decision 2002/657/EC, concerning analytical methods for the analysis of residues and contaminants in food products, which establishes the performance criteria for methods. Directives 2009/90/EC and 98/83/EC establish analogous analytical method criteria for monitoring water status, sediment and biota, as do Regulation (EC) 333/2007 (on sampling and analytical methods for the control of some contaminants in foodstuffs), to SANCO/10684/2009 (on method validation and quality control procedures for pesticide residues analysis in food and feed), or to Regulation (EC) 401/2006 (on methods of sampling and analysis for the control of mycotoxins in foodstuffs). Representative examples of performance criteria for methods used to analyze patulin in foodstuffs are shown in Table 1.

This flexible approach to method performance criteria allows laboratories to quickly incorporate advances in analytical techniques and to apply new methods to address new problems when required. The crucial issues here are that the required performance criteria are met and that the method has been properly validated.


Table 1. Performance criteria for methods of analysis of patulin in foodstuffs, from Regulation 401/2006. (a: Relative standard deviation, calculated from results generated under repeatability conditions, b: Relative standard deviation, calculated from results generated under reproducibility conditions.)

Since its publication, Decision 2002/657/EC has been a key document for analytical laboratories involved in food analysis and has proven utile for laboratories in other fields, such as environmental analysis. It introduced a change of mindset, replacing reference methods with the criteria approach, and launched new definitions, such as *minimum required performance limit (MRPL)*, *decision limit (CCα)* and *detection capability (CCβ)*. Decision 2002/657/EC determines common criteria for the interpretation of test results, establishes the performance criteria requirements for screening and confirmatory methods, and presents the directives to validate the analytical methods. However, it is a complex document, and guidelines for its implementation have been published (SANCO/2004/2726-rev-4-December-2008). The most relevant aspects of Decision 2002/657/EC are further described below.

Minimum required performance limit is defined as the minimum content of an analyte in a sample that has to be detected and confirmed. It is intended to harmonize the analytical performance of methods for banned substances. The minimum required performance level for a method of a banned substance should be lower than the MRPL; however, very few MRPL values have been established to date.

The decision limit is the limit at and above which one can conclude, with an error probability of α, that a sample is non-compliant. For substances with no permitted limit α is 1%, whereas for all other substances α is 5%. Thus, the result of an analysis shall be considered non-compliant if the CCα of the confirmatory method for the analyte is exceeded.

Practical Quality Control: the Experiences of a Public Health Laboratory 423

Defining corrective and preventive actions, supervising their implementation and

 Managing documentation (Quality Manual, general procedures and SOPs, etc.), distributing and maintaining documents, and preparing lists for flexible-scope

Moreover, the LPHAB's QC activities are described in several documents of its QMS. Table

Document Scope

Whole laboratory

CAS

Table 3. Major QC documents from the LPHAB's QMS (CAS: Chemical Analysis Service). One of the chapters in LPHAB's Quality Manual defines the basis of QC in accordance with the requirements of the ISO/IEC 17025 standard (ISO, 2005b). General procedures, which are applicable either to the whole laboratory, or to the Microbiology Analysis Service or the CAS, outline the LPHAB's general QC activities. Standard operating procedures provide detailed specifications on the CAS's QC activities (both internal and external QC). Internal QC activities are either performed within each analytical run or are scheduled. The withinrun activities are done in accordance with the specific SOP for regular samples received by the LPHAB; these encompass analysis of reagent blanks, blank samples, spiked samples and verification of instrument sensitivity. They are employed to prevent releasing of any erroneous results to customers. Scheduled activities are used to check the efficacy of withinrun controls. External QC (EQC) relies on the regular and frequent participation of the LPHAB in proficiency tests organized by competent bodies (whenever possible, accredited as Proficiency Test Providers). All these activities are agreed upon by the head of the CAS, the director of the QAU and the senior technicians and are reflected in the Annual QC Plan.

All of the QC activities are described in the SOP entitled "Application of General Quality Criteria to the Chemical Analysis Service", as are the procedures for handling of all scheduled internal and external QC samples (in terms of ordering, analysis and evaluation).

verifying their efficacy

Approving the auxiliary equipment program control

3 shows these documents in a hierarchical order.

General procedure: "Assessment of the

General procedure: "Management of Complaints, Non-conforming Work, and Corrective and Preventive actions"

General procedure "Management of

Standard Operating Procedure (SOP): "Application of the General Quality Criteria

SOP: "Management of Standards" CAS Annual QC Plan CAS Specific SOPs (per method) CAS Records CAS

Table 4 shows a sample page from the CAS's Annual QC Plan.

These activities are summarized in Table 8.

to the Chemical Analysis Service"

Advising technicians on method validation and QC activities

Quality Manual (Section 14) Whole laboratory

Quality of Analytical Results" Whole laboratory

Flexible-Scope Accreditation" Whole laboratory

accreditation

Managing the LIMS

The detection capability is the smallest content of the substance that may be detected, identified and/or quantified in a sample with an error probability of β (β is 5%). Procedures to determine the CCα and CCβ are given in Decision 2002/657/EC and its corresponding guidelines document (SANCO/2004/2726-rev-4-December-2008).

Decision 2002/657/EC also introduces the concept of *identification point (IP)*. A minimum of three IPs is required to confirm the identity of a compound that has a permitted limit, whereas at least four IPs are required for a banned compound. The number of IPs provided by the analytical method depends on the technique used. For instance, with low-resolution MS each ion earns 1 point, and with low-resolution MSn each precursor ion earns 1 point, and each transition product, 1.5 points. More details on IPs for the different techniques can be found in Decision 2002/657/EC. This IP system has made MS an essential technique for laboratories that analyze residues and contaminants in foodstuffs.

In addition to the performance criteria requirements for screening and confirmatory methods, Decision 2002/657/EC also provides guidelines for the validation of analytical methods. Validation should demonstrate that the method complies with its performance criteria. Therefore, depending on the method category (*e.g.* qualitative or quantitative; screening or confirmatory), different performance characteristics must be determined. Table 2 shows an overview of EU legislation on analytical methods for environmental and food samples


Table 2. Overview of EU legislation on analytical methods for environmental and food samples

## **5. QC management**

At the LPHAB QC activities are managed by the Quality Assurance Unit (QAU), in close cooperation with the head of the Chemical Analysis Service (CAS) and the senior technicians responsible for each analytical technique or methodology.

The QAU comprises two senior technicians and one mid-level technician. Its functions include:


The detection capability is the smallest content of the substance that may be detected, identified and/or quantified in a sample with an error probability of β (β is 5%). Procedures to determine the CCα and CCβ are given in Decision 2002/657/EC and its corresponding

Decision 2002/657/EC also introduces the concept of *identification point (IP)*. A minimum of three IPs is required to confirm the identity of a compound that has a permitted limit, whereas at least four IPs are required for a banned compound. The number of IPs provided by the analytical method depends on the technique used. For instance, with low-resolution MS each ion earns 1 point, and with low-resolution MSn each precursor ion earns 1 point, and each transition product, 1.5 points. More details on IPs for the different techniques can be found in Decision 2002/657/EC. This IP system has made MS an essential technique for

In addition to the performance criteria requirements for screening and confirmatory methods, Decision 2002/657/EC also provides guidelines for the validation of analytical methods. Validation should demonstrate that the method complies with its performance criteria. Therefore, depending on the method category (*e.g.* qualitative or quantitative; screening or confirmatory), different performance characteristics must be determined. Table 2 shows an overview of EU legislation on analytical methods for environmental and food

> Methods of sampling and analysis of lead, cadmium, mercury, inorganic tin, 3-MCPD and benzo(a)pyrene in

Directive 98/83/EC Quality of water intended for human consumption Directive 2008/50/EC Ambient air quality and cleaner air for Europe Directive 2009/90/EC Technical specifications for chemical analysis and monitoring of water status

Decision 2002/657/EC Performance of analytical methods and interpretation of

Regulation (EC) 401/2006 Methods of sampling and analysis of mycotoxins in

Table 2. Overview of EU legislation on analytical methods for environmental and food

At the LPHAB QC activities are managed by the Quality Assurance Unit (QAU), in close cooperation with the head of the Chemical Analysis Service (CAS) and the senior

The QAU comprises two senior technicians and one mid-level technician. Its functions

Coordinating implementation and maintenance of the Quality Management System

Cooperating with the LPHAB's top management in the annual system review and in

foodstuffs.

foodstuffs

technicians responsible for each analytical technique or methodology.

Managing any complaints received from customers or third parties

preparation of the annual staff training program Preparing and conducting an annual internal audit

results

guidelines document (SANCO/2004/2726-rev-4-December-2008).

laboratories that analyze residues and contaminants in foodstuffs.

samples

samples

include:

(QMS)

**5. QC management** 

Regulation (EC) 333/2007

Moreover, the LPHAB's QC activities are described in several documents of its QMS. Table 3 shows these documents in a hierarchical order.


Table 3. Major QC documents from the LPHAB's QMS (CAS: Chemical Analysis Service).

One of the chapters in LPHAB's Quality Manual defines the basis of QC in accordance with the requirements of the ISO/IEC 17025 standard (ISO, 2005b). General procedures, which are applicable either to the whole laboratory, or to the Microbiology Analysis Service or the CAS, outline the LPHAB's general QC activities. Standard operating procedures provide detailed specifications on the CAS's QC activities (both internal and external QC). Internal QC activities are either performed within each analytical run or are scheduled. The withinrun activities are done in accordance with the specific SOP for regular samples received by the LPHAB; these encompass analysis of reagent blanks, blank samples, spiked samples and verification of instrument sensitivity. They are employed to prevent releasing of any erroneous results to customers. Scheduled activities are used to check the efficacy of withinrun controls. External QC (EQC) relies on the regular and frequent participation of the LPHAB in proficiency tests organized by competent bodies (whenever possible, accredited as Proficiency Test Providers). All these activities are agreed upon by the head of the CAS, the director of the QAU and the senior technicians and are reflected in the Annual QC Plan. Table 4 shows a sample page from the CAS's Annual QC Plan.

All of the QC activities are described in the SOP entitled "Application of General Quality Criteria to the Chemical Analysis Service", as are the procedures for handling of all scheduled internal and external QC samples (in terms of ordering, analysis and evaluation). These activities are summarized in Table 8.


Table 4. Sample page from the CAS's Annual QC Plan.

Practical Quality Control: the Experiences of a Public Health Laboratory 425

External QC is managed through proficiency tests. Participation in each test is scheduled according to proposals by the technician responsible for each analytical procedure. Each procedure is to be tested in at least one exercise per year, if possible. In parallel, certain

The LPHAB tends to be extremely active in this area, since it considers external QC among the strongest point of its QC system. In the CAS, in 2010, 458 samples were analyzed in proficiency tests that encompassed 1,915 assays, 420 different analytes and 89 analytical

Given that the market lacks universal exercises for all types of matrices and assays, the CAS aims to assess all families of analytes and all instruments. Usually, matrices included in the accreditation scope are used. Importantly, for assays included in the flexible-scope accreditation, different matrices that represent the entire assay category should be employed whenever possible. To evaluate some of the procedures for which no exercises are currently

It is extremely important that any organization that aims to organize these types of evaluations be accredited according to ISO/IEC 17043 (ISO, 2010). For non-accredited

In accordance with the aforementioned principles, CAS actively participates in the programs FAPAS® (for food) and LEAP (for water), both of which are accredited by the United

For each exercise, a technician is assigned to handle and follow the sample, which must be analyzed using the typical procedures and which must not be treated differently because of its interlaboratory status. Once the organizer's report has been received, an internal evaluation report is written up, which includes the results found by CAS, the mean result

Upon receiving the report, each manager performs a complementary evaluation of the results obtained, considering all of the documentation referring to the analysis performed, in order to confirm that all of the QC criteria have been met. Another very important and highly utile aspect to consider is the information on the methods applied by different

If the evaluation is unsatisfactory, then a report on corrective actions is written up. The results of proficiency tests are generally evaluated based on the z-scores. Nonetheless, other criteria (*e.g.* compatibility index) may also be used; these are described in the final

One of the critical points for evaluating z-scores is the standard deviation used in the calculations. The standard deviation used is generally that which is documented by the organizer, which tends to the value obtained from the Horwitz equation. Nevertheless, another value can be used, as deemed necessary by the technician responsible for the evaluation, as long as it is justified in the internal evaluation report for the exercise. Fig. 5

The results obtained are introduced into a database, which enables tracking of any possible

The figure below illustrates moisture analysis results for various types of samples from the

FAPAS® exercises in which LPHAB has participated over the past few years.

available, the CAS, together with other laboratories, has organized specific activities.

samples are requested in duplicate for use in scheduled internal QC.

entities, the quality of their exercises will be assessed.

assigned by the organizer, and the calculated z-score for each analyte.

laboratories, which can help the CAS to improve its methods.

shows a sample evaluation form for external QC samples.

trends as well as confirmation of validation data over time.

Kingdom Accreditation Service (UKAS).

evaluation report for the exercise.

**5.1 Management of external QC** 

procedures (SOPs).

### **5.1 Management of external QC**

424 Modern Approaches To Quality Control

Table 4. Sample page from the CAS's Annual QC Plan.

External QC is managed through proficiency tests. Participation in each test is scheduled according to proposals by the technician responsible for each analytical procedure. Each procedure is to be tested in at least one exercise per year, if possible. In parallel, certain samples are requested in duplicate for use in scheduled internal QC.

The LPHAB tends to be extremely active in this area, since it considers external QC among the strongest point of its QC system. In the CAS, in 2010, 458 samples were analyzed in proficiency tests that encompassed 1,915 assays, 420 different analytes and 89 analytical procedures (SOPs).

Given that the market lacks universal exercises for all types of matrices and assays, the CAS aims to assess all families of analytes and all instruments. Usually, matrices included in the accreditation scope are used. Importantly, for assays included in the flexible-scope accreditation, different matrices that represent the entire assay category should be employed whenever possible. To evaluate some of the procedures for which no exercises are currently available, the CAS, together with other laboratories, has organized specific activities.

It is extremely important that any organization that aims to organize these types of evaluations be accredited according to ISO/IEC 17043 (ISO, 2010). For non-accredited entities, the quality of their exercises will be assessed.

In accordance with the aforementioned principles, CAS actively participates in the programs FAPAS® (for food) and LEAP (for water), both of which are accredited by the United Kingdom Accreditation Service (UKAS).

For each exercise, a technician is assigned to handle and follow the sample, which must be analyzed using the typical procedures and which must not be treated differently because of its interlaboratory status. Once the organizer's report has been received, an internal evaluation report is written up, which includes the results found by CAS, the mean result assigned by the organizer, and the calculated z-score for each analyte.

Upon receiving the report, each manager performs a complementary evaluation of the results obtained, considering all of the documentation referring to the analysis performed, in order to confirm that all of the QC criteria have been met. Another very important and highly utile aspect to consider is the information on the methods applied by different laboratories, which can help the CAS to improve its methods.

If the evaluation is unsatisfactory, then a report on corrective actions is written up. The results of proficiency tests are generally evaluated based on the z-scores. Nonetheless, other criteria (*e.g.* compatibility index) may also be used; these are described in the final evaluation report for the exercise.

One of the critical points for evaluating z-scores is the standard deviation used in the calculations. The standard deviation used is generally that which is documented by the organizer, which tends to the value obtained from the Horwitz equation. Nevertheless, another value can be used, as deemed necessary by the technician responsible for the evaluation, as long as it is justified in the internal evaluation report for the exercise. Fig. 5 shows a sample evaluation form for external QC samples.

The results obtained are introduced into a database, which enables tracking of any possible trends as well as confirmation of validation data over time.

The figure below illustrates moisture analysis results for various types of samples from the FAPAS® exercises in which LPHAB has participated over the past few years.

Practical Quality Control: the Experiences of a Public Health Laboratory 427

Fig. 6. Proficiency testing: results from moisture analysis of different samples performed for

Another important factor concerning the results obtained from proficiency tests is their utility for systematic expansion of validation data. The CAS has established a dynamic validation system in which the overall validity of the uncertainty of a procedure is checked

The scheduled internal QC samples generally correspond to duplicates of samples from proficiency tests (the duplicates are purchased annually at the time the test is performed). In 2010 the CAS analyzed 99 samples for internal QC, encompassing 371 assays, 209

Once the samples arrive at the LPHAB, their information is entered into the reference materials database, and they are carefully handled, taking their particular storage needs and expiration dates into account. The new sample is added to the sample registry in the LIMS according to the schedule. The results are analyzed using an internal evaluation form in which the z-score (accuracy) is re-calculated, and the reproducibility is calculated based on the results from the external QC and from the internal QC test. This approach enables evaluation of both accuracy and precision. Fig. 7 shows a sample evaluation form for

Results obtained in both internal and external QC activities are suitably recorded. Out of control situations can be categorized as incidences and deviations. Incidences are sporadic events that usually do not occur in subsequent applications of the analytical method. Contrariwise, deviations are non-conforming work that must be managed through corrective actions. Detection of these events, and subsequent causal analysis, sometimes leads to proposal of preventive actions. Fig. 8 shows a general schematic of QC

against the different sample types and different concentration levels analyzed.

**5.3 Handling of any inconsistencies detected in the QC activities** 

FAPAS® exercises.

analytes and 77 SOPs.

internal QC.

management.

**5.2 Management of internal QC** 






Fig. 5. Sample evaluation form for external QC samples (completed by CAS based on the organizer's report).

Fig. 5. Sample evaluation form for external QC samples (completed by CAS based on the

organizer's report).

Fig. 6. Proficiency testing: results from moisture analysis of different samples performed for FAPAS® exercises.

Another important factor concerning the results obtained from proficiency tests is their utility for systematic expansion of validation data. The CAS has established a dynamic validation system in which the overall validity of the uncertainty of a procedure is checked against the different sample types and different concentration levels analyzed.

#### **5.2 Management of internal QC**

The scheduled internal QC samples generally correspond to duplicates of samples from proficiency tests (the duplicates are purchased annually at the time the test is performed).

In 2010 the CAS analyzed 99 samples for internal QC, encompassing 371 assays, 209 analytes and 77 SOPs.

Once the samples arrive at the LPHAB, their information is entered into the reference materials database, and they are carefully handled, taking their particular storage needs and expiration dates into account. The new sample is added to the sample registry in the LIMS according to the schedule. The results are analyzed using an internal evaluation form in which the z-score (accuracy) is re-calculated, and the reproducibility is calculated based on the results from the external QC and from the internal QC test. This approach enables evaluation of both accuracy and precision. Fig. 7 shows a sample evaluation form for internal QC.

#### **5.3 Handling of any inconsistencies detected in the QC activities**

Results obtained in both internal and external QC activities are suitably recorded. Out of control situations can be categorized as incidences and deviations. Incidences are sporadic events that usually do not occur in subsequent applications of the analytical method. Contrariwise, deviations are non-conforming work that must be managed through corrective actions. Detection of these events, and subsequent causal analysis, sometimes leads to proposal of preventive actions. Fig. 8 shows a general schematic of QC management.

Practical Quality Control: the Experiences of a Public Health Laboratory 429

INTERNAL QUALITY CONTROL

EXTERNAL QUALITY CONTROL

The reliability of QC activities is greatly based on the suitability of the criteria applied. Depending on whether the limits established are too strict or too lax, α or β errors, respectively, may be committed. Over the past few recent years, the CAS has adapted the criteria applied in its internal QC to the values obtained during method validation. Improving the frequency and quality of internal QC has enabled improved detection of non-conforming results, and therefore, has enabled optimization of external QC

Accreditation of a laboratory is usually based on a concrete definition of the laboratory's scope. Thus, the technical annexes for accreditation certificates comprise detailed lists of the tests for which the laboratory has been accredited. The lists clearly specify matrices, analytes, ranges of concentration, and methods. This scheme is known as *fixed-scope* 

Fig. 8. General schematic of QC management.

**5.4 QC in the framework of flexible scope accreditation** 

activities.

*accreditation*.





Fig. 7. Sample evaluation form for internal QC samples.

Figures 9 and 10 show the number of scheduled internal QC and external QC samples in absolute values and as percentages of the total number of samples analyzed, respectively, in the CAS. These figures are testament to the LPHAB's major efforts to ensure the reliability of its results and demonstrate its commitment to quality. Moreover, this approach also implies sizeable financial investment: participation in proficiency testing costs the LPHAB roughly €60,000 per year.

Fig. 7. Sample evaluation form for internal QC samples.

€60,000 per year.

Figures 9 and 10 show the number of scheduled internal QC and external QC samples in absolute values and as percentages of the total number of samples analyzed, respectively, in the CAS. These figures are testament to the LPHAB's major efforts to ensure the reliability of its results and demonstrate its commitment to quality. Moreover, this approach also implies sizeable financial investment: participation in proficiency testing costs the LPHAB roughly

Fig. 8. General schematic of QC management.

The reliability of QC activities is greatly based on the suitability of the criteria applied. Depending on whether the limits established are too strict or too lax, α or β errors, respectively, may be committed. Over the past few recent years, the CAS has adapted the criteria applied in its internal QC to the values obtained during method validation. Improving the frequency and quality of internal QC has enabled improved detection of non-conforming results, and therefore, has enabled optimization of external QC activities.

#### **5.4 QC in the framework of flexible scope accreditation**

Accreditation of a laboratory is usually based on a concrete definition of the laboratory's scope. Thus, the technical annexes for accreditation certificates comprise detailed lists of the tests for which the laboratory has been accredited. The lists clearly specify matrices, analytes, ranges of concentration, and methods. This scheme is known as *fixed-scope accreditation*.

Practical Quality Control: the Experiences of a Public Health Laboratory 431

Yes

Inform the QAU

Issue the analytical report as accredited

Analyze the sample

Satisfactory results?

Yes Check method performance with

spiked samples at several levels

Fig. 11. Procedure for analysis of an established analyte in a new matrix.

unsatisfactory, then the report cannot be issued as being accredited.

bounds of a flexible scope, it must do the following:

Optimize and validate the method for the new matrix

> Satisfactory results?

> > No

Inform the QAU

Sample cannot be analyzed. Inform the

customer

Is the new matrix similar to one in the scope of accred.

No

accreditation are summarized in Table 5.

matrix).

In this context, once a laboratory receives a request for an analysis that falls within the

Yes

No

 Inform the customer that the analysis will be performed in the framework of a flexible scope, and therefore, prior validation studies will be required; this will involve some delay in the delivery of results; and, if the results of the validation studies are

 Perform validation studies. A scheme of this process for analysis of an established analyte in a new material is illustrated in Fig. 11. An analogous process would be employed for the opposite case (*i.e.* analysis of a new analyte in an established

Flexible-scope accreditation was initiated in 2004 for pesticide analysis and was later extended to other analyte families. The LPHAB defines these families according to the type of analyte studied and the analytical technique used. Therefore, these vary from very broad (organic compounds studied by chromatographic techniques) to rather narrow (ions studied by liquid chromatography). The CAS's current fixed-scope and flexible-scope of

However, in recent years, in order to meet the needs of customers, laboratories have had to quickly expand their accreditation scope without compromising their technical competence or altering definition of the scope. Thus, highly experienced laboratories with a long history of accreditation can now adopt a new scheme, known as *flexible-scope accreditation*, whereby they perform analyses using appropriate validated methods, and then report the results as being accredited, without prior evaluation by the accreditation body. This may entail incorporation of new matrices or analytes, or inclusion of new tests within a generic method. Thus, the flexibility of the accreditation scope implies sufficient technical competence and operational capacity, which places more of the responsibility on the laboratory. This in turn means that the laboratory must endeavor to increase its QC operations in order to guarantee the quality of the results of the expanded scope. In any case, the bounds within which a scope is flexible must be precisely stated.

Fig. 9. Scheduled internal and external QC samples (ICQ and ECQ, respectively), expressed as number of samples.

Fig. 10. Scheduled internal and external QC samples (ICQ and ECQ, respectively), expressed as percentage of total samples.

However, in recent years, in order to meet the needs of customers, laboratories have had to quickly expand their accreditation scope without compromising their technical competence or altering definition of the scope. Thus, highly experienced laboratories with a long history of accreditation can now adopt a new scheme, known as *flexible-scope accreditation*, whereby they perform analyses using appropriate validated methods, and then report the results as being accredited, without prior evaluation by the accreditation body. This may entail incorporation of new matrices or analytes, or inclusion of new tests within a generic method. Thus, the flexibility of the accreditation scope implies sufficient technical competence and operational capacity, which places more of the responsibility on the laboratory. This in turn means that the laboratory must endeavor to increase its QC operations in order to guarantee the quality of the results of the expanded scope. In any

Fig. 9. Scheduled internal and external QC samples (ICQ and ECQ, respectively), expressed

Fig. 10. Scheduled internal and external QC samples (ICQ and ECQ, respectively), expressed

as number of samples.

as percentage of total samples.

case, the bounds within which a scope is flexible must be precisely stated.

Fig. 11. Procedure for analysis of an established analyte in a new matrix.

In this context, once a laboratory receives a request for an analysis that falls within the bounds of a flexible scope, it must do the following:


Flexible-scope accreditation was initiated in 2004 for pesticide analysis and was later extended to other analyte families. The LPHAB defines these families according to the type of analyte studied and the analytical technique used. Therefore, these vary from very broad (organic compounds studied by chromatographic techniques) to rather narrow (ions studied by liquid chromatography). The CAS's current fixed-scope and flexible-scope of accreditation are summarized in Table 5.

Practical Quality Control: the Experiences of a Public Health Laboratory 433

each analytical procedure (SOP) features a section describing internal QC activities that are performed within each run and the corresponding criteria for accepting the results, which must be evaluated by the technician responsible for the procedure before they are

An example of control analysis of spiked samples is illustrated in Fig. 12, which shows a plot of arsenic analysis in food samples by inductively coupled plasma mass spectrometry (ICP-MS). The results are evaluated based on the recovery (% Rec) of samples spiked at different concentrations and with different matrices, such that the entire scope of the

Fig. 12. Plot of arsenic recovery levels from spiked samples of different food types, as

Table 6 shows an example of a QC records for a procedure in which 44 antibiotics are analyzed in samples of products of animal origin by LC-MS/MS. The following data are recorded for representative analytes (in the case of Table 6, two antibiotics): the area of the peak corresponding to the standard used for verifying the instrument; retention time (TR) and the ratio of transitions (ion ratio [IR]) at CC level, which are the data used for identifying and confirming the two compounds. The peak area value is checked against the minimum peak area that guarantees response at the lowest level of validation, which also verifies the confirmation. Lastly, the analytical sequence and the user's initials are also

**6.2 Use of QC records for an LC-MS/MS procedure (detection of antibiotics)** 

communicated to the customer. Several concrete examples are presented below.

**6.1 Spiked samples** 

determined by ICP-MS.

recorded.

flexible-scope accreditation can be addressed.


Table 5. The CAS's current fixed-scope and flexible-scope of accreditation.

Managing the flexible scope implies a significant amount of extra documentation that must be completely updated. Indeed, in 2010 alone six new analytical methods were added, together with numerous matrices and analytes. The flexible scope is currently in its 22nd edition (an average of three editions are created per year).

## **6. QC in the analytical method SOPs: examples of general and specific QC activities**

This section provides examples of the some of the QC activities summarized in Table 8, as well as the corresponding documentation for recording and evaluating the data. Generally, each analytical procedure (SOP) features a section describing internal QC activities that are performed within each run and the corresponding criteria for accepting the results, which must be evaluated by the technician responsible for the procedure before they are communicated to the customer. Several concrete examples are presented below.

#### **6.1 Spiked samples**

432 Modern Approaches To Quality Control

Table 5. The CAS's current fixed-scope and flexible-scope of accreditation.

edition (an average of three editions are created per year).

**activities** 

Managing the flexible scope implies a significant amount of extra documentation that must be completely updated. Indeed, in 2010 alone six new analytical methods were added, together with numerous matrices and analytes. The flexible scope is currently in its 22nd

**6. QC in the analytical method SOPs: examples of general and specific QC** 

This section provides examples of the some of the QC activities summarized in Table 8, as well as the corresponding documentation for recording and evaluating the data. Generally, An example of control analysis of spiked samples is illustrated in Fig. 12, which shows a plot of arsenic analysis in food samples by inductively coupled plasma mass spectrometry (ICP-MS). The results are evaluated based on the recovery (% Rec) of samples spiked at different concentrations and with different matrices, such that the entire scope of the flexible-scope accreditation can be addressed.

Fig. 12. Plot of arsenic recovery levels from spiked samples of different food types, as determined by ICP-MS.

#### **6.2 Use of QC records for an LC-MS/MS procedure (detection of antibiotics)**

Table 6 shows an example of a QC records for a procedure in which 44 antibiotics are analyzed in samples of products of animal origin by LC-MS/MS. The following data are recorded for representative analytes (in the case of Table 6, two antibiotics): the area of the peak corresponding to the standard used for verifying the instrument; retention time (TR) and the ratio of transitions (ion ratio [IR]) at CC level, which are the data used for identifying and confirming the two compounds. The peak area value is checked against the minimum peak area that guarantees response at the lowest level of validation, which also verifies the confirmation. Lastly, the analytical sequence and the user's initials are also recorded.

Practical Quality Control: the Experiences of a Public Health Laboratory 435

**General internal QC**

Enables monitoring for any contamination in materials, reagents, the

**Matrix blank** See Table 7

Enables monitoring of the reproducibility (R) relative to the standard deviation of the validation (sR)

Enables monitoring of the bias or the trueness based on the recovery (% Rec), and compared with the recovery (%Recval) and the standard deviation (s) obtained in the validation

Enables monitoring of the accuracy of the results based on the compatibility index (CI), which is calculated from the reference value (xref) and the obtained value (xlab)

Enables monitoring for any contamination, and confirmation that the matrix is not responsible for any interference

tolerance limits

Evaluation: Blank < LOD

*<sup>R</sup> R* 2 2 *s*

Evaluation: *x*<sup>1</sup> *x*<sup>2</sup> *R* x1 and x2 are the results of duplicate samples

 Re (%) <sup>100</sup> *spiked lab x <sup>x</sup> <sup>c</sup>*

Xlab: obtained value Xspiked: spiked value

Evaluation: *c c s val* Re (%) Re (%) 2

Uref: expanded uncertainty of reference material Ulab: expanded uncertainty laboratory Evaluation: CI≤1

2 ref

*CI*

(U U ) x - x

ref lab 

2 lab

environment, etc. LOD: limit of detection

Frequency at the LASPB

Within-run (the type of blank depends on the method)

Scheduled: usually, once per year, using a reference material (normally, a duplicate sample from a proficiency test)

> Within-run See Fig. 12

Scheduled

QC factor Action Objective Calculations and

The analytical procedure is performed using only the reagents.

The analytical procedure is performed using a blank sample.

Full analysis of duplicate samples on different dates

The analytical procedure is performed on a sample that has been spiked with the analyte (whenever possible, previously analyzed samples containing the analyte at levels lower than the limit of detection).

The analytical procedure is performed on a sample which has been prepared under concrete specifications and which contains the analyte in question at a known value.

**Reagent blank** 

**Duplicate samples** (intermediate precision)

> **Spiked samples**

**Reference materials** 

Table 8. Part I


Table 6. QC records from analysis of antibiotics in products of animal origin by LC-MS/MS.

In similar QC records, the responses of the internal standards (which are typically deuterated or C13-labeled analogs of the test compounds) from analysis of various types of samples are recorded. This control step can also be used to broaden the validation data by incorporating new matrices (*i.e. online validation*). Based on the values of the responses of the internal standards, one can deduce the validity of the matrix-matched surrogate quantifications in the different sample types that can be incorporated into the analytical sequence.

#### **6.3 QC records for verification of the instrument, its calibration levels, and the blank in the turbidity analysis procedure**

The format of the QC records used for turbidity analysis of water samples is illustrated in Table 7 as a representative example of a physicochemical assay.

The upper and lower limits traceable to the values obtained in the validation are shown. In this case, the experimental readings obtained are recorded for each certified standard and are used to verify calibration of the instrument and to confirm the response of the blank (in this case, ASTM type I purified water).


Table 7. QC records from turbidity analysis of water samples.

Table 6. QC records from analysis of antibiotics in products of animal origin by LC-

In similar QC records, the responses of the internal standards (which are typically deuterated or C13-labeled analogs of the test compounds) from analysis of various types of samples are recorded. This control step can also be used to broaden the validation data by incorporating new matrices (*i.e. online validation*). Based on the values of the responses of the internal standards, one can deduce the validity of the matrix-matched surrogate quantifications in the different sample types that can be incorporated into the analytical

**6.3 QC records for verification of the instrument, its calibration levels, and the blank** 

The format of the QC records used for turbidity analysis of water samples is illustrated in

The upper and lower limits traceable to the values obtained in the validation are shown. In this case, the experimental readings obtained are recorded for each certified standard and are used to verify calibration of the instrument and to confirm the response of the blank (in

MS/MS.

sequence.

**in the turbidity analysis procedure** 

this case, ASTM type I purified water).

Table 7 as a representative example of a physicochemical assay.

Table 7. QC records from turbidity analysis of water samples.


Table 8. Part I

Practical Quality Control: the Experiences of a Public Health Laboratory 437

Specific internal QC procedures: chromatographic methods

Verification of the procedure for each sample: extraction, and performance of different matrices

Verification of the criteria described in the chromatographic method

criteria described in the chromatographic method

Part III

Shewhart (1931). *Economic Control of Quality of Manufactured Products,* Van Nostrand, New

ISO (2005a). *ISO 9000:2005 standard*. *Quality management systems. Fundamentals and* 

ISO (2005b). *ISO 17025:2005 standard. General requirements for the competence of testing and* 

ISO (2010). *ISO/IEC 17043:2010 standard. Conformity assessment. General requirements for* 

tolerance limits

Signal traceable to previous analyses Quantification based on internal standard

According to chromatographic system; TR ± % tolerance limit

Spectral match

According to analysis; generally ± 20%

According to regulations, analysis type, concentration, intensity of the transitions, etc.

Frequency at the LASPB

Within-run

Performed for each chromatographic peak identified that corresponds to a standard See Table 6

Performed for each chromatographic peak identified See Table 6

QC factor Action Objective Calculations and

spectra Verification of the

Table 8. QC activities at the LPHAB's Chemical Analysis Service (CAS).

Addition of the internal standard to all samples, spiked samples, and other standards (matrixmatched surrogate) at the beginning of the procedure

Retention time of each compound relative to that of the internal standard

DAD, FLD, etc.: The compound spectra are compared to the internal standard

> MS (SIM): Mass spectra ion ratios

MS/MS: Transition ratios

York, USA. ISBN 0-87389-076-0.

*vocabulary,* ISO, Geneva, Switzerland.

*calibration laboratories.* ISO, Geneva, Switzerland.

*proficiency testing.* ISO, Geneva, Switzerland.

Verification of the response of the internal standard

Identification of the chromatographic peak

Confirmation of the identified compounds

**7. References** 



Part III

Table 8. QC activities at the LPHAB's Chemical Analysis Service (CAS).

## **7. References**

436 Modern Approaches To Quality Control

**External QC**

Enables monitoring of the accuracy of the results based on the z-score (z), which is calculated from the assigned value, the obtained value (xlab) and the standard deviation of the participants (p).

**Internal QC to verify equipment or reagents**

Enables verification of proper instrument performance before the sequence is started, and at every *n* samples, based on confirmation that the response of the standard (A) falls within a preestablished range of acceptable values (x %) that guarantee the limit of quantification (LOQ)

Enables monitoring of the **quality of the fit of the calibration curve**, based on at least two different criteria: for example, the coefficient of correlation (r) and the residual error of the standard (Er %), which is the ratio of the value of the concentration of the standard in the curve (Vcurve) to the nominal concentration value (Vnominal)

Enables confirmation that a standard has been correctly prepared, based on verification that the ratio of the response of the new sample (A) to the response of the sample from a previously used lot (B) falls within a pre-established range of acceptable values (x %)

tolerance limits

*z*

*p*

<sup>a</sup> <sup>x</sup> lab <sup>x</sup> -

Evaluation: *z* 2 satisfactory result 2 < z ≤ 3 questionable result *z* 3 unsatisfactory result

*A* : response of the standard Evaluation: *A x*%

r ≥ (see specific SOP) (%) 100 min *no al*

Evaluation: Er %≤ r ≥ (see specific SOP)

*A* : response ratio Evaluation: *<sup>x</sup>*% *<sup>B</sup> A*

*curve <sup>r</sup> <sup>V</sup> <sup>V</sup> <sup>E</sup>*

*B*

Frequency at the LASPB

> Scheduled See Fig. 5

Within-run See Table 7

Upon generation of a new calibration curve

Upon preparation of new lots of standards

QC factor Action Objective Calculations and

**Proficiency test** 

**Verification of instrument**  at the beginning of the run and monitoring of instrument drift

**Calibration of the instruments** associated with the analytical method

**Verification of a new lot of standards** 

Table. 8. Part II

The analytical procedure is performed on a sample which has been part of an interlaboratory comparison scheme.

A standard is injected under the instrumental conditions established in the analytical procedure.

The standards used to generate the calibration curve are injected.

Two different samples of the same standard are injected: one from a regularly used lot, and one from a newly prepared lot.


**24** 

*Spain* 

**Laser Diffuse Lighting in a Visual Inspection** 

David Martin, Maria C. Garcia-Alegre and Domingo Guinea

*Spanish Council for Scientific Research (CSIC), Madrid,* 

**System for Defect Detection in Wood Laminates** 

Nowadays, wood companies are ever more interested in automatic vision systems (Li & Wu, 2009), (Åstrand & Åström, 1994), for an effective surface inspection that greatly increases the quality of the end product (Smith, 2001), (Armingol et al., 2006). The inspection process, in most visual inspection systems, pursues online defects identification, to reach optimum

The usual wood inspection systems are visual ones, based on standard cameras and lighting (Batchelor & Whelan, 1997), (Cognex, 2011), (Parsytec, 2011), (Pham & Alcock, 2003) to operate in highly structured environments (Silvén et al., 2003). The quality control in visual surface inspection systems must be robust to cope with wood variable reflectance and high

The surface inspection methods proposed in the literature for visual inspection aim at adhoc surface inspection systems to solve each specific problem (Pham & Alcock, 1999). Usual inspection systems are based on visible lighting and few of them use diffuse components to illuminate the rough and bright surfaces. A visual wood defect detection system proposed by (Estévez et al., 2003) is composed by a colour video camera, where the standard lighting components are a mixture of two frontal halogen and ceiling fluorescent lamps. The commercial light diffusers use a light source and different components to illuminate the surface in an irregular way to eliminate shadows, but present some problems such as, short

On the other hand, one of the major drawbacks in automated inspection systems for wood defect classification is the erroneous segmentation of defects on light wood regions, (Ruz et al., 2009). Moreover, the speed of wooden boards at the manufacturing industry is at about 1

Current work presents a surface inspection system that uses laser diffuse lighting to cope with different type of defects and wood laminated surfaces to improve defect detection

The work will not only highlight the specific requirements for a laser diffuse lighting in a visual inspection system but also those of unsupervised defect detection techniques to cope with the variability of wood laminated surfaces and defect types, leading to a heterogeneous and robust visual surface inspection system. The manuscript is organized as follows: section 2 displays images of different wood laminated surfaces, captured by a visual surface inspection system with standard lighting. In Section 3, an innovative surface inspection

m/s, which implies high computational costs (Hall & Aström, 1995).

performance (Malamas et al., 2003), (Spínola et al., 2008).

useful life, extreme sensitivity and high cost.

without any previous defect information.

**1. Introduction** 

speed requirements.


## **Laser Diffuse Lighting in a Visual Inspection System for Defect Detection in Wood Laminates**

David Martin, Maria C. Garcia-Alegre and Domingo Guinea *Spanish Council for Scientific Research (CSIC), Madrid, Spain* 

## **1. Introduction**

438 Modern Approaches To Quality Control

IUPAC (1998). *Compendium of analytical nomenclature: Definitive rules 1997,* 3rd ed. Blackwell

Thompson, M. & Lowthian, P. J. (1993). Effectiveness of Analytical Quality Control is

Related to the Subsequent Performance of Laboratories in Proficiency Tests.

Science, ISBN 978-84-7283-870-3, Oxford, United Kingdom.

*Analyst*, Vol.118, No.12, (December 1993), pp. 1495-1500.

Nowadays, wood companies are ever more interested in automatic vision systems (Li & Wu, 2009), (Åstrand & Åström, 1994), for an effective surface inspection that greatly increases the quality of the end product (Smith, 2001), (Armingol et al., 2006). The inspection process, in most visual inspection systems, pursues online defects identification, to reach optimum performance (Malamas et al., 2003), (Spínola et al., 2008).

The usual wood inspection systems are visual ones, based on standard cameras and lighting (Batchelor & Whelan, 1997), (Cognex, 2011), (Parsytec, 2011), (Pham & Alcock, 2003) to operate in highly structured environments (Silvén et al., 2003). The quality control in visual surface inspection systems must be robust to cope with wood variable reflectance and high speed requirements.

The surface inspection methods proposed in the literature for visual inspection aim at adhoc surface inspection systems to solve each specific problem (Pham & Alcock, 1999). Usual inspection systems are based on visible lighting and few of them use diffuse components to illuminate the rough and bright surfaces. A visual wood defect detection system proposed by (Estévez et al., 2003) is composed by a colour video camera, where the standard lighting components are a mixture of two frontal halogen and ceiling fluorescent lamps. The commercial light diffusers use a light source and different components to illuminate the surface in an irregular way to eliminate shadows, but present some problems such as, short useful life, extreme sensitivity and high cost.

On the other hand, one of the major drawbacks in automated inspection systems for wood defect classification is the erroneous segmentation of defects on light wood regions, (Ruz et al., 2009). Moreover, the speed of wooden boards at the manufacturing industry is at about 1 m/s, which implies high computational costs (Hall & Aström, 1995).

Current work presents a surface inspection system that uses laser diffuse lighting to cope with different type of defects and wood laminated surfaces to improve defect detection without any previous defect information.

The work will not only highlight the specific requirements for a laser diffuse lighting in a visual inspection system but also those of unsupervised defect detection techniques to cope with the variability of wood laminated surfaces and defect types, leading to a heterogeneous and robust visual surface inspection system. The manuscript is organized as follows: section 2 displays images of different wood laminated surfaces, captured by a visual surface inspection system with standard lighting. In Section 3, an innovative surface inspection

Laser Diffuse Lighting in a Visual Inspection System for Defect Detection in Wood Laminates 441

1. Inspection of different wood surfaces without any reconfiguration of the system 2. Detection of different types of wood defects with the same diffuse lighting

3. Inspection of defects with different areas, ranging from 10 to 100 mm², and shapes.

The inspection vision system can be configured to work in two lighting modes (Martin et al.,

The proposed design permits to reuse the laser-optical system (laser-lighting and optical components) in both configurations to tackle high-speed and small-defect industrial surface inspections over the whole inspection region. The laser diffuse lighting provides a high intensity beam but only on a small area, removing the image shadows generated by the

The wood samples are illuminated using a green diode-pumped solid-state (DPSS) laser, which provides highly uniform illumination in the region of interest (ROI). Coherent laser light is unusual for surface illumination in inspection vision systems due to the emergence of interference patterns. The two images displayed in Figure 2, are captured using only a laser-optical system without any wood surface sample, to exhibit the interference patterns

Fig. 2. Two interference patterns (yellow) caused by coherent green laser light on the surface

Another interference effect appears when the laser beam is reflected on rough wood surfaces. The result of this effect in images acquired by a standard CCD camera is a bright and dark spot pattern, namely "speckle pattern", which is specific for each type of surface. The pattern is distributed randomly in the whole space and is caused by constructive and

In spite of the interference patterns, the laser lighting source is robust for integration in an industrial environment due to its low-cost and durability in comparison with commercial light diffusers. The solution to the interference problem has been achieved by means of a dispersion technique to obtain laser diffuse lighting and remove the speckle interference

Main advantages of the proposed lighting system are:

 Diffuse Coaxial Lighting Diffuse Bright-Field Lighting

2010):

inspection lenses.

destructive interference effects.

4. Each CCD camera has its own laser diode diffuse lighting

surface roughness, and facing the surface variable reflectance.

caused by the optical components with coherent laser lighting.

pattern. The components proposed for laser beam scattering are:

system using laser diffuse lighting is presented, as well as the acquired images. Section 4 describes an unsupervised wood defect detection and segmentation algorithm to process images acquired with the two types of lighting. Section 5 displays the results, and the conclusions are presented in Section 6.

## **2. Standard lighting visual systems**

Most inspection systems are based on visible lighting (Guinea et al., 2000), (Montúfar-Chaveznava et al., 2001). These systems can adequately tackle defect detection, but presents some drawbacks:


Images acquired with a standard visual surface inspection system, composed of a CCD visual camera and fluorescent light, are displayed in Figure 1. The images show knots and splits and are manually classified by a human expert to validate the performance of the automated visual inspection system. Images show different background colour as they come from different wood laminates.

Fig. 1. Defects, knots and splits, on images acquired from a standard lighting visual surface inspection system.

## **3. Laser diode diffuse lighting in visual systems**

Main innovation of current work is a CCD sensor-based industrial inspection system for defect detection on wood laminates, where lighting is based on a laser technique that comprises two different illumination modes: Diffuse Coaxial Lighting and Diffuse Bright-Field Lighting. Few visual inspection systems use laser-lighting (Palviainen & Silvennoinen, 2001), (Yang et al., 2006), and even less laser diode diffuse components, to illuminate both rough and bright surfaces. The commercial light diffusers are composed of a light source and different optical components to illuminate correctly the surface in an irregular way. However, they present drawbacks such as, short useful life, extreme sensitivity and high cost, that can be overcome with the use of laser diode diffuse lighting to highlight the relevant features.

Main advantages of the proposed lighting system are:


The inspection vision system can be configured to work in two lighting modes (Martin et al., 2010):

Diffuse Coaxial Lighting

440 Modern Approaches To Quality Control

system using laser diffuse lighting is presented, as well as the acquired images. Section 4 describes an unsupervised wood defect detection and segmentation algorithm to process images acquired with the two types of lighting. Section 5 displays the results, and the

Most inspection systems are based on visible lighting (Guinea et al., 2000), (Montúfar-Chaveznava et al., 2001). These systems can adequately tackle defect detection, but presents

1. Inspection systems composed by multiple cameras and equal standard lighting for all cameras, make difficult the inspection of the whole wood boards in the production line

2. When fluorescent light is replaced by commercial light diffusers to improve lighting,

Images acquired with a standard visual surface inspection system, composed of a CCD visual camera and fluorescent light, are displayed in Figure 1. The images show knots and splits and are manually classified by a human expert to validate the performance of the automated visual inspection system. Images show different background colour as they come

Fig. 1. Defects, knots and splits, on images acquired from a standard lighting visual surface

Main innovation of current work is a CCD sensor-based industrial inspection system for defect detection on wood laminates, where lighting is based on a laser technique that comprises two different illumination modes: Diffuse Coaxial Lighting and Diffuse Bright-Field Lighting. Few visual inspection systems use laser-lighting (Palviainen & Silvennoinen, 2001), (Yang et al., 2006), and even less laser diode diffuse components, to illuminate both rough and bright surfaces. The commercial light diffusers are composed of a light source and different optical components to illuminate correctly the surface in an irregular way. However, they present drawbacks such as, short useful life, extreme sensitivity and high cost, that can be overcome

with the use of laser diode diffuse lighting to highlight the relevant features.

conclusions are presented in Section 6.

some drawbacks:

inspection system.

**2. Standard lighting visual systems** 

due to non-uniform illumination of the surface.

**3. Laser diode diffuse lighting in visual systems** 

the maintenance cost greatly increases.

from different wood laminates.

Diffuse Bright-Field Lighting

The proposed design permits to reuse the laser-optical system (laser-lighting and optical components) in both configurations to tackle high-speed and small-defect industrial surface inspections over the whole inspection region. The laser diffuse lighting provides a high intensity beam but only on a small area, removing the image shadows generated by the surface roughness, and facing the surface variable reflectance.

The wood samples are illuminated using a green diode-pumped solid-state (DPSS) laser, which provides highly uniform illumination in the region of interest (ROI). Coherent laser light is unusual for surface illumination in inspection vision systems due to the emergence of interference patterns. The two images displayed in Figure 2, are captured using only a laser-optical system without any wood surface sample, to exhibit the interference patterns caused by the optical components with coherent laser lighting.

Fig. 2. Two interference patterns (yellow) caused by coherent green laser light on the surface inspection lenses.

Another interference effect appears when the laser beam is reflected on rough wood surfaces. The result of this effect in images acquired by a standard CCD camera is a bright and dark spot pattern, namely "speckle pattern", which is specific for each type of surface. The pattern is distributed randomly in the whole space and is caused by constructive and destructive interference effects.

In spite of the interference patterns, the laser lighting source is robust for integration in an industrial environment due to its low-cost and durability in comparison with commercial light diffusers. The solution to the interference problem has been achieved by means of a dispersion technique to obtain laser diffuse lighting and remove the speckle interference pattern. The components proposed for laser beam scattering are:

Laser Diffuse Lighting in a Visual Inspection System for Defect Detection in Wood Laminates 443

The main characteristics of the proposed visual inspection system endowed of laser diffuse

v. Algorithms required for defect detection are simpler and thus shorter the computing

Unsupervised visual processing algorithms are proposed for both wood defect detection and image segmentation. The sooner the line inspector accurately detects the appearance of defects, the shorter the problem is fixed. The defect detection process is accomplished with an algorithm that searches for the seeds of the defects, characteristic pixels belonging to the defect, which determines the location of the defects in the image. Then the image segmentation algorithm uses a region growing method to calculate the size of the defect. The region growing method is based on Active Contours (Chan & Vese, 2001). The validation of the automatic visual inspection results is performed by a human expert. An unsupervised defect detection algorithm has been developed and tested, to cope with variations in the laminated material, such as defect type, pose, size, shape and colour, as well as with environment variations: surface illumination and speed of the laminated material in the production line. All these variables make automatic wood defect detection a challenging task. The flow chart of Figure 5 summarizes the operation of the unsupervised

i. High intensity in the inspection region and consequently short exposure time ii. High-speed and small-defect surface inspection on the whole inspection region

iii. Elimination of the image shadows generated by the surface roughness iv. Deals with the variability of laminated wood such as, colour or texture

time, as all images present the same background colour.

**4. Wood defect detection and image segmentation** 

The second set of images obtained with this configuration is shown in Figure 4.

Fig. 4. Wood images acquired with a laser diffuse lighting.

lighting are:

defect detection algorithm.


The wood defect inspection and 1 m/s wood board speed, require high intensity in the inspection region and short exposure time for suitable image acquisition. Former requirements are interrelated, as if intensity increases the exposure time, for real-time inspection, can be reduced. This high intensity allows a correct inspection as the laser diode diffuse lighting illuminates only a small inspection area, about 10-100 mm².

In current work, a second set of images have been acquired with diffuse bright-field lighting. The configuration is composed by the laser-optical components (laser, dispersion lens and spinning diffuser) and the imaging components (CCD sensor camera and focusing lens). The orientation of the imaging components related to the laser diffuse lighting is approximately 30º, Figure 3. A black box covers the imaging components so that the light reaching the CCD sensor only comes from the focusing lens.

Fig. 3. Laboratory benchmark: diffuse bright-field lighting with a 160 mm focal length lens and a green DPSS laser.

The second set of images obtained with this configuration is shown in Figure 4.

442 Modern Approaches To Quality Control

The wood defect inspection and 1 m/s wood board speed, require high intensity in the inspection region and short exposure time for suitable image acquisition. Former requirements are interrelated, as if intensity increases the exposure time, for real-time inspection, can be reduced. This high intensity allows a correct inspection as the laser diode

In current work, a second set of images have been acquired with diffuse bright-field lighting. The configuration is composed by the laser-optical components (laser, dispersion lens and spinning diffuser) and the imaging components (CCD sensor camera and focusing lens). The orientation of the imaging components related to the laser diffuse lighting is approximately 30º, Figure 3. A black box covers the imaging components so that the light

Fig. 3. Laboratory benchmark: diffuse bright-field lighting with a 160 mm focal length lens

and a green DPSS laser.

1. A convergent lens that increases the width of the collimated beam

diffuse lighting illuminates only a small inspection area, about 10-100 mm².

2. A spinning diffuser that disperses the collimated beam

reaching the CCD sensor only comes from the focusing lens.

Fig. 4. Wood images acquired with a laser diffuse lighting.

The main characteristics of the proposed visual inspection system endowed of laser diffuse lighting are:


## **4. Wood defect detection and image segmentation**

Unsupervised visual processing algorithms are proposed for both wood defect detection and image segmentation. The sooner the line inspector accurately detects the appearance of defects, the shorter the problem is fixed. The defect detection process is accomplished with an algorithm that searches for the seeds of the defects, characteristic pixels belonging to the defect, which determines the location of the defects in the image. Then the image segmentation algorithm uses a region growing method to calculate the size of the defect. The region growing method is based on Active Contours (Chan & Vese, 2001). The validation of the automatic visual inspection results is performed by a human expert.

An unsupervised defect detection algorithm has been developed and tested, to cope with variations in the laminated material, such as defect type, pose, size, shape and colour, as well as with environment variations: surface illumination and speed of the laminated material in the production line. All these variables make automatic wood defect detection a challenging task. The flow chart of Figure 5 summarizes the operation of the unsupervised defect detection algorithm.

Laser Diffuse Lighting in a Visual Inspection System for Defect Detection in Wood Laminates 445

active contours method only in the regions where defects are detected, thus reducing

The wood defect detection and image segmentation algorithms, here proposed, have been tested with the two set of images acquired with both standard and laser diffuse lighting

The results of the unsupervised wood defect detection algorithm applied to the first set of images, are displayed in Figure 6. The results show that the algorithm is capable of detecting the position of the defects in the images several times (red dots). This multi-detection implies an accurate detection process caused by applying the algorithm only to each fifth row, for fast defect detection. A gap of five rows is an appropriate value for wood defect detection, as defects usually intersect in more than five rows. Then, the larger the defects are the greater the number of the detected pixels is (red dots). Knots defects have been correctly detected except in the sixth image due to the fact that the background was extremely similar to the defect grey-level. The split appearing on the eighth image has been detected. Moreover, comparing the results of the automatic defect detection algorithm with those of the expert, in the first set of images, the groundwork of the algorithm succeeded in 87.5%. Longer term processing would be required to detect a higher percentage of defects in

Fig. 6. Results of wood defect detection in images (first set) acquired with standard lighting

The results obtained with the unsupervised wood defect detection algorithm on the second set of images, are displayed in Figure 7. The second set of images has been captured with

The multi-detection process enhances defect detection due to the large size of the defect in the analysed images. The different types of defects are easily perceived by the expert. In the last image, split defect was not completely detected as a consequence of the similarity between the grey-level of the defect and that of the background. The success in comparing automatic defect detection and expert visual defect detection, is 98%. This percentage is

the laser diffuse lighting visual system, and in that case all defects were detected.

better than the one obtained in the processing of the first set of images.

computing costs.

**5. Results** 

visual system.

images.

visual system.

Fig. 5. Flow chart of the wood defect detection algorithm.

The wood defect detection algorithm proceeds as follows:

	- "Minimum valley depth", determines the minimum depth as a greyscale value. The valley depth value here selected is 190. Then, only valleys that exceed this value are returned.
	- "Minimum valley separation", specifies the minimum distance between valleys as a positive integer (pixels). That is, the algorithm ignores small valleys that occur in the neighbourhood of a deeper valley. The selected value is 100 pixels.

3. The position of the local minimum is visualised on the greyscale image with a red dot.

On the other hand, image segmentation allows for the calculation of the area of the defect. This is of great aid for quality control analyses, as the greater the size of the defects is, the lower is the quality of the wood laminates. The region growing algorithm groups pixels together into regions of similarity, beginning from an initial set of pixels (red dots). The method works iteratively for increasing the initial pixels set, comparing its grey value with that of its neighbours for increasing the area of the defect to reach the borders. These seeds, previously calculated by the unsupervised defect detection algorithm, allow applying the active contours method only in the regions where defects are detected, thus reducing computing costs.

## **5. Results**

444 Modern Approaches To Quality Control

Fig. 5. Flow chart of the wood defect detection algorithm. The wood defect detection algorithm proceeds as follows:

value are returned.

1. RGB colour image is converted to greyscale to reduce computational time

parameters are set up to configure the algorithm restrictions:

2. The developed algorithm searches for local minimum at each fifth row of the image and uses expert knowledge to associate defects with lower grey-level image pixels. The grey value of each pixel in an image row is compared to its neighbours and if its value is lower than the values of each neighbours, the pixel is defined as a local minimum. Two

 "Minimum valley depth", determines the minimum depth as a greyscale value. The valley depth value here selected is 190. Then, only valleys that exceed this

 "Minimum valley separation", specifies the minimum distance between valleys as a positive integer (pixels). That is, the algorithm ignores small valleys that occur in

the neighbourhood of a deeper valley. The selected value is 100 pixels. 3. The position of the local minimum is visualised on the greyscale image with a red dot. On the other hand, image segmentation allows for the calculation of the area of the defect. This is of great aid for quality control analyses, as the greater the size of the defects is, the lower is the quality of the wood laminates. The region growing algorithm groups pixels together into regions of similarity, beginning from an initial set of pixels (red dots). The method works iteratively for increasing the initial pixels set, comparing its grey value with that of its neighbours for increasing the area of the defect to reach the borders. These seeds, previously calculated by the unsupervised defect detection algorithm, allow applying the The wood defect detection and image segmentation algorithms, here proposed, have been tested with the two set of images acquired with both standard and laser diffuse lighting visual system.

The results of the unsupervised wood defect detection algorithm applied to the first set of images, are displayed in Figure 6. The results show that the algorithm is capable of detecting the position of the defects in the images several times (red dots). This multi-detection implies an accurate detection process caused by applying the algorithm only to each fifth row, for fast defect detection. A gap of five rows is an appropriate value for wood defect detection, as defects usually intersect in more than five rows. Then, the larger the defects are the greater the number of the detected pixels is (red dots). Knots defects have been correctly detected except in the sixth image due to the fact that the background was extremely similar to the defect grey-level. The split appearing on the eighth image has been detected. Moreover, comparing the results of the automatic defect detection algorithm with those of the expert, in the first set of images, the groundwork of the algorithm succeeded in 87.5%. Longer term processing would be required to detect a higher percentage of defects in images.

Fig. 6. Results of wood defect detection in images (first set) acquired with standard lighting visual system.

The results obtained with the unsupervised wood defect detection algorithm on the second set of images, are displayed in Figure 7. The second set of images has been captured with the laser diffuse lighting visual system, and in that case all defects were detected.

The multi-detection process enhances defect detection due to the large size of the defect in the analysed images. The different types of defects are easily perceived by the expert. In the last image, split defect was not completely detected as a consequence of the similarity between the grey-level of the defect and that of the background. The success in comparing automatic defect detection and expert visual defect detection, is 98%. This percentage is better than the one obtained in the processing of the first set of images.

Laser Diffuse Lighting in a Visual Inspection System for Defect Detection in Wood Laminates 447

The result of the image segmentation of the second set of images is displayed in Figure 9, where the partial border of the defect is marked in green colour. After 200 iterations of the algorithm, departing from the initialization pixels (red dots), the complete area of the defects present in the images is not totally segmented. Defects can be more accurately segmented by increasing the seed pixels (red dots) and the number of iterations of the region growing

Fig. 9. Segmentation of the images acquired from the laser diffuse lighting surface inspection

Summarizing, results displayed in Figure 9, are better than those shown in Figure 8, but total segmentation of the defects is not achieved as a greater number of seed pixels would be

Thus, to increase the number of seed pixels, the "Minimum valley separation" variable has been set to 10 pixels. The results obtained with the set of images acquired with laser diffuse lighting are shown in Figure 10. In first, second, fourth, tenth and twelfth images, the seeds (red dots) partially cover the wood defects, but in the third, fifth, sixth, seventh, eighth, ninth and eleventh images the defects are totally covered by the seeds. Then, the image processing would only require the wood defect detection algorithm as the calculated seeds can detect the shape of the whole defects. This point is extremely relevant as implies lower

Next, region growing method is applied to obtain the complete segmentation of the defects (green borders), and the results are displayed in Figure 11. It can be remarked that segmentation results of the region growing method are close to those of Figure 10, obtained

algorithm, but this implies a greater computing time.

system (second set).

computing costs.

with the wood defect detection algorithm.

required.

Therefore, the use of a surface inspection system with laser diffuse lighting greatly improves the success of the automatic wood defect detection algorithm.

Fig. 7. Results of wood defect detection in images, second set, acquired with a laser diffuse lighting surface inspection system.

The result of the image segmentation algorithm on the first set of images is displayed in Figure 8. The image segmentation algorithm is based on a region growing method that uses Active Contours. The results are displayed in Figure 8, marking the complete border of the defect, in green colour. The defect detected pixels (red dots) grow until the border of the defect is reached, whenever the border of the defect is obtained before last iteration. Moreover, the border can be extra grown, as happens in the sixth and seventh images of Figure 8. However, the wood defects are well shaped, in spite of that present in the eighth image that would need some more iterations to complete the whole defect contour. Finally, the areas of the defects are calculated for further off-line quality control analysis.

Fig. 8. Segmentation of images acquired with standard lighting visual system (first set).

Therefore, the use of a surface inspection system with laser diffuse lighting greatly improves

Fig. 7. Results of wood defect detection in images, second set, acquired with a laser diffuse

The result of the image segmentation algorithm on the first set of images is displayed in Figure 8. The image segmentation algorithm is based on a region growing method that uses Active Contours. The results are displayed in Figure 8, marking the complete border of the defect, in green colour. The defect detected pixels (red dots) grow until the border of the defect is reached, whenever the border of the defect is obtained before last iteration. Moreover, the border can be extra grown, as happens in the sixth and seventh images of Figure 8. However, the wood defects are well shaped, in spite of that present in the eighth image that would need some more iterations to complete the whole defect contour. Finally,

the areas of the defects are calculated for further off-line quality control analysis.

Fig. 8. Segmentation of images acquired with standard lighting visual system (first set).

the success of the automatic wood defect detection algorithm.

lighting surface inspection system.

The result of the image segmentation of the second set of images is displayed in Figure 9, where the partial border of the defect is marked in green colour. After 200 iterations of the algorithm, departing from the initialization pixels (red dots), the complete area of the defects present in the images is not totally segmented. Defects can be more accurately segmented by increasing the seed pixels (red dots) and the number of iterations of the region growing algorithm, but this implies a greater computing time.

Fig. 9. Segmentation of the images acquired from the laser diffuse lighting surface inspection system (second set).

Summarizing, results displayed in Figure 9, are better than those shown in Figure 8, but total segmentation of the defects is not achieved as a greater number of seed pixels would be required.

Thus, to increase the number of seed pixels, the "Minimum valley separation" variable has been set to 10 pixels. The results obtained with the set of images acquired with laser diffuse lighting are shown in Figure 10. In first, second, fourth, tenth and twelfth images, the seeds (red dots) partially cover the wood defects, but in the third, fifth, sixth, seventh, eighth, ninth and eleventh images the defects are totally covered by the seeds. Then, the image processing would only require the wood defect detection algorithm as the calculated seeds can detect the shape of the whole defects. This point is extremely relevant as implies lower computing costs.

Next, region growing method is applied to obtain the complete segmentation of the defects (green borders), and the results are displayed in Figure 11. It can be remarked that segmentation results of the region growing method are close to those of Figure 10, obtained with the wood defect detection algorithm.

Laser Diffuse Lighting in a Visual Inspection System for Defect Detection in Wood Laminates 449

Finally, the computation time for the defect detection and segmentation algorithms is calculated for each image in Figure 10 and Figure 11, and displayed in Table 1. The second column corresponds to the computation time of the wood defect detection algorithm increasing the number of seed pixels (red dots). The third column is the computation time of

> Defect detection algorithm (seconds)

Image 1 0.51 10.03 Image 2 0.23 8.65 Image 3 0.37 9.17 Image 4 0.21 9.82 Image 5 0.21 10.34 Image 6 0.21 9.90 Image 7 0.23 9.17 Image 8 0.31 12.42 Image 9 0.21 9.21 Image 10 0.23 7.96 Image 11 0.20 8.18 Image 12 0.18 8.09

Table 1. Computation time, in seconds, for each of the processing algorithm and images

acquired from laser diffuse lighting.

Region growing algorithm (seconds)

the region growing algorithm for the image segmentation (green borders).

Images acquired from laser diffuse lighting surface inspection system

Fig. 10. Wood defect detection on images acquired with laser diffuse lighting and "Minimum valley separation" = 10 pixels.

Fig. 11. Image segmentation using a large number of seeds: "Minimum valley separation"=10 pixels.

Fig. 10. Wood defect detection on images acquired with laser diffuse lighting and

Fig. 11. Image segmentation using a large number of seeds: "Minimum valley

"Minimum valley separation" = 10 pixels.

separation"=10 pixels.

Finally, the computation time for the defect detection and segmentation algorithms is calculated for each image in Figure 10 and Figure 11, and displayed in Table 1. The second column corresponds to the computation time of the wood defect detection algorithm increasing the number of seed pixels (red dots). The third column is the computation time of the region growing algorithm for the image segmentation (green borders).


Table 1. Computation time, in seconds, for each of the processing algorithm and images acquired from laser diffuse lighting.

Laser Diffuse Lighting in a Visual Inspection System for Defect Detection in Wood Laminates 451

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## **6. Conclusions**

The global goal of current work is the defect detection on wood images for quality control with short computing time. To this aim, the work compares wood images captured with both: a standard and an innovative surface inspection system that uses laser diffuse lighting.

Images from wood laminates with knots and splits defects acquired from the innovative lighting visual system are the most suitable for defect detection. The main characteristics of the proposed system to be used in the wood manufacturing industry are:


A smart combination of algorithms for wood inspection has been proposed, based on an unsupervised method for defect detection and a region growing algorithm for defect segmentation. Results indicate that processing time for wood defect detection algorithm is better than for region growing algorithm. Moreover, first algorithm reaches both objectives: wood defect detection and segmentation.

Finally, it has been demonstrated that the use of the proposed wood defect detection algorithm with images acquired from visual surface inspection system using laser diffuse lighting, appears as the best choice for real-time wood inspection.

## **7. References**


The global goal of current work is the defect detection on wood images for quality control with short computing time. To this aim, the work compares wood images captured with both: a standard and an innovative surface inspection system that uses laser diffuse

Images from wood laminates with knots and splits defects acquired from the innovative lighting visual system are the most suitable for defect detection. The main characteristics of

ii. Independence from the variable reflectance of the wood laminates. Images present both a high background smoothness and high-contrast of the defects, independently of the

v. The laser diffuse light source is robust enough for integration in an industrial environment, due to its low cost and durability, in comparison with commercial light

A smart combination of algorithms for wood inspection has been proposed, based on an unsupervised method for defect detection and a region growing algorithm for defect segmentation. Results indicate that processing time for wood defect detection algorithm is better than for region growing algorithm. Moreover, first algorithm reaches both objectives:

Finally, it has been demonstrated that the use of the proposed wood defect detection algorithm with images acquired from visual surface inspection system using laser diffuse

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for Defect Classification of Radiata Pine Boards. *Forest Products Journal*, Vol. 53, pp.

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Intelligent Visual Inspection System for Statistical Quality Control of a Production Line. *Frontiers in Robotics Research*, Nova Publishers, Chapter 1, pp.

Inspection, *Proceedings of the 12th IAPR International Conference on Pattern* 

the proposed system to be used in the wood manufacturing industry are: i. Detection of small defects ranging from one to few millimetres

iv. Defect detection success is 98% on a sample of two hundred images

lighting, appears as the best choice for real-time wood inspection.

America. Available from http://www.cognex.com/

**6. Conclusions** 

diffusers

**7. References** 

1-33

Verlag

87–94.

*Processing*, Vol.10, pp. 266–277

colour of the wood laminates iii. Defect detection time in less than 0.5 s

wood defect detection and segmentation.

lighting.


**25** 

*Israel USA* 

**Between Failures** 

*2St' Johns University* 

*1Technion - Israel Institute of Technology* 

Yefim Haim Michlin1 and Genady Grabarnik2

**Comparison Sequential Test for Mean Times** 

The present study deals with the planning methodology of tests in which the parameters of two exponentially-distributed random variables are compared. The largest application field of such tests is reliability checking of electronics equipment. They are highly cost-intensive, and the requirements as to their resolution capability become stricter all the time. Hence the topicality and importance of an optimal plan permitting decisions at a given risk level on the

Such comparison tests are required for example in assessing the desirability of replacing a "basic" object whose reliability is unknown, by a "new" one; or when the influence of test

This is the case when an electronics manufacturing process is transferred to another site and

Recently, equipment and methods were developed for accelerated product testing through continuous observation of a population of copies and replacement of failed objects without interrupting the test. For such a procedure, the sequential approach is a feasible and efficacious solution with substantial shortening – on the average – of the test duration (see

In these circumstances there is high uncertainty in the acceleration factor, with the same effect on the estimated reliability parameters of the product. This drawback can be remedied by recourse to comparison testing. The latter serves also for reliability matching in objects of the same design and different origins, or a redesigned product versus its earlier counterpart, or different products with the same function (see e.g. Chien & Yang, 2007; Kececioglu, 2002). The exponential nature of the Time Between Failures (TBF) of repairable objects, or the time to failure of non-repairable ones – is noted in the extensive literature on the reliability of electronic equipment (Kececioglu, 2002; Chandramouli et al, 1998; Drenick, 1960; Sr-332, 2001; MIL-HDBK-781A, 1996). For brevity, the TBF acronym is used in the sequel for both

Mace (1974, Sec. 6.12) proposed, for this purpose, the so-called fixed sample size test with the number of failures of each object fixed in advance – which is highly inconvenient from the practical viewpoint. For example, when the "basic" object has "accumulated" the

**1. Introduction** 

these notations.

basis of a minimal sample size.

conditions on the results has to be eliminated.

e.g. Chandramouli et al. 1998; Chien et al. 2007).

the product undergoes accelerated testing.

Yang, D.; Jackson, M.R. & Parkin, R.M. (2006). Inspection of Wood Surface Waviness Defects Using the Light Sectioning Method. *Proceedings of the Institution of Mechanical Engineers, Part I: Journal of Systems and Control Engineering*, Professional Engineering Publishing, Vol.220, pp. 617-626

## **Comparison Sequential Test for Mean Times Between Failures**

Yefim Haim Michlin1 and Genady Grabarnik2

*1Technion - Israel Institute of Technology 2St' Johns University Israel USA* 

## **1. Introduction**

452 Modern Approaches To Quality Control

Yang, D.; Jackson, M.R. & Parkin, R.M. (2006). Inspection of Wood Surface Waviness Defects

Publishing, Vol.220, pp. 617-626

Using the Light Sectioning Method. *Proceedings of the Institution of Mechanical Engineers, Part I: Journal of Systems and Control Engineering*, Professional Engineering

> The present study deals with the planning methodology of tests in which the parameters of two exponentially-distributed random variables are compared. The largest application field of such tests is reliability checking of electronics equipment. They are highly cost-intensive, and the requirements as to their resolution capability become stricter all the time. Hence the topicality and importance of an optimal plan permitting decisions at a given risk level on the basis of a minimal sample size.

> Such comparison tests are required for example in assessing the desirability of replacing a "basic" object whose reliability is unknown, by a "new" one; or when the influence of test conditions on the results has to be eliminated.

> This is the case when an electronics manufacturing process is transferred to another site and the product undergoes accelerated testing.

> Recently, equipment and methods were developed for accelerated product testing through continuous observation of a population of copies and replacement of failed objects without interrupting the test. For such a procedure, the sequential approach is a feasible and efficacious solution with substantial shortening – on the average – of the test duration (see e.g. Chandramouli et al. 1998; Chien et al. 2007).

> In these circumstances there is high uncertainty in the acceleration factor, with the same effect on the estimated reliability parameters of the product. This drawback can be remedied by recourse to comparison testing. The latter serves also for reliability matching in objects of the same design and different origins, or a redesigned product versus its earlier counterpart, or different products with the same function (see e.g. Chien & Yang, 2007; Kececioglu, 2002). The exponential nature of the Time Between Failures (TBF) of repairable objects, or the time to failure of non-repairable ones – is noted in the extensive literature on the reliability of electronic equipment (Kececioglu, 2002; Chandramouli et al, 1998; Drenick, 1960; Sr-332, 2001; MIL-HDBK-781A, 1996). For brevity, the TBF acronym is used in the sequel for both these notations.

> Mace (1974, Sec. 6.12) proposed, for this purpose, the so-called fixed sample size test with the number of failures of each object fixed in advance – which is highly inconvenient from the practical viewpoint. For example, when the "basic" object has "accumulated" the

Comparison Sequential Test for Mean Times Between Failures 455

whole test, as against several failures in the other object. The total work times *T* are equal for

Fig. 1. Scheme of test course (Upward marks – failures of basic item; downward marks –

*fTBF* (*t)*=(1/*θ*)\*exp(-*t*/*θ*) where *θ* is the MTBF for the "new" (*θn*) and "basic" (*θb*) objects respectively. At each failure, a decision is taken – continuing the test versus stopping and accepting the null hypothesis, or rejecting it in favour of the alternative (Michlin & Migdali, 2002; Michlin & Grabarnik, 2007):

(1)

1 0 /*d* (3)

*r r b n* / (4)

(2)

*a a*

*P P*

those of new item; *T* – time, common to both systems) (Michlin et al., 2011).

H :

The probability density of the TBF for each of the compared objects has the form:

00 0 10 1

> *n b* /

denoted by the subscript "*tg*", and their actual values – by the subscript "*real*".

*α* and *β* are the probabilities of I- and II-type errors; in the sequel, their target values will be

*Pa*(Φ) is the probability of acceptance of H0, which is the Operating Characteristic (OC) of the

Mace (1974 , Sec. 6.12) presents the following estimate ˆ for Φ, obtained with the aid of the

( / )( / ) *Tr Tr nn bb*

Figure 2 shows an example of the test field. In the course of the test, it can reside at a point of this field characterised by an integer number of failures of each of the objects. When one of them fails, the test "jumps" to a neighbouring point located above (failure of "*n*") or to the right (failure of "*b*"). With the test course thus described, shifts from point to point occur only on failures in one of the objects, i.e. the time factor is eliminated from the analysis. When the Accept boundary is crossed, the test stops at the Accept Decision Point (ADT),

maximum likelihood function (for the proof, see Kapur & Lamberson 1977, Sec. 10.C):

where *rn* and *rb* – the accumulated number of failures over times *Tn* and *Tb*.

H : 1

both objects.

where

test;

*d*>1 being the discrimination ratio.

As in this test *Tn=Tb=T*, we have:

specified number of failures, one has to wait until the "new" one has done the same, and if the latter is substantially more reliable, the waiting time may be very long.

The international standard IEC 61650 (1997) deals with two constant failure rates, which is equivalent to the problem just described. However, this standard, which forms part of an international system of techniques for reliability data analysis, does not refer to the planning aspect of the tests.

A solution to our problem was outlined in (Michlin & Grabarnik, 2007), where it was converted into binomial form, for which Wald's sequential probability ratio test (SPRT) is suitable (Wald, 1947, chap. 5). Wald and Wolfowitz (1948) also proved that this test is the most efficacious at two points of its characteristic, but it has one drawback – the sample size up to a decision can be many times larger than the average. This is usually remedied by resorting to truncation (see e.g. Wald, 1947; Siegmund, 1985).

A methodology is available for exact determination of the characteristics of such a truncated test with known decision boundaries. It was proposed by Barnard (1946) and developed by Aroian (1968). It served as basis for an algorithm and computer programmes (Michlin et al. 2007, 2009) used in examining its properties.

Hare we consider the inverse problem – determination of the test boundaries from specified characteristics.

In the absence of analytical dependences between the boundary parameters and characteristics, the search is hampered by the following circumstances:


The theme of this chapter is the planning methodology for comparison truncated SPRT's. Formulae derived on its basis are presented for calculation of the test boundary parameters.

The rest of the chapter is organised as follows: In Section 2 is given a description of the test and its conversion to SPRT form. In Section 3 are described the quality indices for a truncated test and criteria for the optimal test search. In Section 4 are discussed the discrete nature of the test boundaries and its characteristics; a search algorithm is presented for the oblique boundaries. Section 5 describes the planning methodology, and approximative dependences are presented for calculation of the boundary parameters. Section 6 deals with planning of group tests. Section 7 presents a planning example and applications. Section 8 – the conclusion.

## **2. Description of test and its SPRT presentation**

#### **2.1 Description of test procedure in time domain. Checked hypothesis**

In the proposed test two objects are compared – one "basic" (subscript "*b*") and the other "new" (subscript "*n*"). In the course of such tests, the "null" hypothesis is checked, that the ratio of the mean TBF (MTBF) of these objects exceeds or equals a prescribed value Φ0, versus the alternative of it being smaller than the latter. The compared objects work concurrently (Figure 1). When one of them fails, it is immediately repaired or replaced. The unfailed object is not replaced but allowed to continue working until it fails in turn (in which case it is neither replaced nor repaired), or until the test terminates. A situation may occur in which there has been no failure in one object and it kept working throughout the whole test, as against several failures in the other object. The total work times *T* are equal for both objects.

Fig. 1. Scheme of test course (Upward marks – failures of basic item; downward marks – those of new item; *T* – time, common to both systems) (Michlin et al., 2011).

The probability density of the TBF for each of the compared objects has the form:

*fTBF* (*t)*=(1/*θ*)\*exp(-*t*/*θ*)

where *θ* is the MTBF for the "new" (*θn*) and "basic" (*θb*) objects respectively. At each failure, a decision is taken – continuing the test versus stopping and accepting the null hypothesis, or rejecting it in favour of the alternative (Michlin & Migdali, 2002; Michlin & Grabarnik, 2007):

$$\begin{aligned} \mathcal{H}\_0: \quad \Phi \ge \Phi\_0 \quad & \left( P\_a(\Phi\_0) = 1 - \alpha \right) \\ \mathcal{H}\_1: \quad \Phi < \Phi\_0 \quad & \left( P\_a(\Phi\_1) = \beta \right) \end{aligned} \tag{1}$$

where

454 Modern Approaches To Quality Control

specified number of failures, one has to wait until the "new" one has done the same, and if

The international standard IEC 61650 (1997) deals with two constant failure rates, which is equivalent to the problem just described. However, this standard, which forms part of an international system of techniques for reliability data analysis, does not refer to the planning

A solution to our problem was outlined in (Michlin & Grabarnik, 2007), where it was converted into binomial form, for which Wald's sequential probability ratio test (SPRT) is suitable (Wald, 1947, chap. 5). Wald and Wolfowitz (1948) also proved that this test is the most efficacious at two points of its characteristic, but it has one drawback – the sample size up to a decision can be many times larger than the average. This is usually remedied by

A methodology is available for exact determination of the characteristics of such a truncated test with known decision boundaries. It was proposed by Barnard (1946) and developed by Aroian (1968). It served as basis for an algorithm and computer programmes (Michlin et al.

Hare we consider the inverse problem – determination of the test boundaries from specified

In the absence of analytical dependences between the boundary parameters and

While shortening of the step makes for more combinations, it cannot be guaranteed that

The standard optimum-search programmes are unsuitable for some of the discrete data

The theme of this chapter is the planning methodology for comparison truncated SPRT's. Formulae derived on its basis are presented for calculation of the test boundary parameters. The rest of the chapter is organised as follows: In Section 2 is given a description of the test and its conversion to SPRT form. In Section 3 are described the quality indices for a truncated test and criteria for the optimal test search. In Section 4 are discussed the discrete nature of the test boundaries and its characteristics; a search algorithm is presented for the oblique boundaries. Section 5 describes the planning methodology, and approximative dependences are presented for calculation of the boundary parameters. Section 6 deals with planning of group tests. Section 7 presents a planning example and applications. Section 8 –

In the proposed test two objects are compared – one "basic" (subscript "*b*") and the other "new" (subscript "*n*"). In the course of such tests, the "null" hypothesis is checked, that the ratio of the mean TBF (MTBF) of these objects exceeds or equals a prescribed value Φ0, versus the alternative of it being smaller than the latter. The compared objects work concurrently (Figure 1). When one of them fails, it is immediately repaired or replaced. The unfailed object is not replaced but allowed to continue working until it fails in turn (in which case it is neither replaced nor repaired), or until the test terminates. A situation may occur in which there has been no failure in one object and it kept working throughout the

the latter is substantially more reliable, the waiting time may be very long.

resorting to truncation (see e.g. Wald, 1947; Siegmund, 1985).

characteristics, the search is hampered by the following circumstances: The number of parameter-value combinations may be very large.

combinations with optimal characteristics are not missed.

**2. Description of test and its SPRT presentation** 

**2.1 Description of test procedure in time domain. Checked hypothesis** 

2007, 2009) used in examining its properties.

of the type in question.

aspect of the tests.

characteristics.

the conclusion.

$$
\Phi = \theta\_n \;/\; \theta\_b \tag{2}
$$

*α* and *β* are the probabilities of I- and II-type errors; in the sequel, their target values will be denoted by the subscript "*tg*", and their actual values – by the subscript "*real*". *Pa*(Φ) is the probability of acceptance of H0, which is the Operating Characteristic (OC) of the test;

$$
\Phi\_1 = \Phi\_0 \,/\, d\tag{3}
$$

*d*>1 being the discrimination ratio.

Mace (1974 , Sec. 6.12) presents the following estimate ˆ for Φ, obtained with the aid of the maximum likelihood function (for the proof, see Kapur & Lamberson 1977, Sec. 10.C):

$$
\hat{\Phi} = (T\_n \; / \; r\_n) / (T\_b \; / \; r\_b)
$$

where *rn* and *rb* – the accumulated number of failures over times *Tn* and *Tb*. As in this test *Tn=Tb=T*, we have:

$$
\hat{\vec{\Phi}} = r\_b \;/\; r\_n \tag{4}
$$

Figure 2 shows an example of the test field. In the course of the test, it can reside at a point of this field characterised by an integer number of failures of each of the objects. When one of them fails, the test "jumps" to a neighbouring point located above (failure of "*n*") or to the right (failure of "*b*"). With the test course thus described, shifts from point to point occur only on failures in one of the objects, i.e. the time factor is eliminated from the analysis. When the Accept boundary is crossed, the test stops at the Accept Decision Point (ADT),

Comparison Sequential Test for Mean Times Between Failures 457

The expressions (10)-(12) have one drawback: the parameters *α*\* and *β\** are unknown. Their dependence on *α*0, *β*, Φ0, *d,* and on the TA coordinates is available only in the form of the limits between which the parameters lie (Michlin et al., 2009). Still, these limits suffice for

search methodology, within these limits, for exact values ensuring the target characteristics

The probability of hitting a given point of the test is given by (Barnard, 1946; Michlin &

*Pa*(Φ) is the sum of all the probabilities *P r ADP n* , of hitting all ADP, hence the actual

*TA TA ASN r r b nRDP b RDP b n bADP n ADP n r r rP r r r rP r* (17)

*real a* 1 *P* <sup>0</sup> ;

 0 0 () , () , *b n b n*

> *ATD ASN*

In this Section the optimality criteria for the test, on which the comparison- and selection

In (Michlin & Grabarnik, 2007) were presented three optimality criteria which can be

algorithm is based, are substantiated, and the problems of the study are clarified.

The Average Sample Number (ASN) of a truncated test is calculated as:

, () () , 1 1, ()1 *b n b n b n P P PP P rr rr R r r <sup>R</sup>* (13)

, 1 1, *Pr P P ADP n r r b n <sup>R</sup>* (14)

, , 1 *Pr P P RDP b r r b n <sup>R</sup>* (15)

*real a P* <sup>1</sup> (16)

*<sup>b</sup>* 1 1 (18)

ln ln *q d* (11)

*<sup>b</sup>* and *hn*. A

*h hs b a* / (12)

 

'

determining – from the above expressions – corresponding search limits for *h'*

\* \* *hn* ln 1

**2.3 Calculation of test characteristics acc. to given boundaries** 

– is, basically, the goal of this work.

while that of hitting the given ADP is:

values of *α* and *β*, namely *αreal* and *βreal* , are given by:

where ( ) *nRDP b r r* is the *rn*-coordinate of the RDP with given *rb*.

**3. Comparative characteristics and optimality of test** 

The Average Test Duration (ATD) for each object is:

calculated for the specified boundaries:

and that for the given RDP is:

Grabarnik, 2007):

and when its Reject counterpart is crossed – at the RDP. The boundaries consist of two parallel oblique straight lines (accept line (AL) and reject line (RL)) and the truncation lines parallel to the coordinate axes and intersecting at the Truncation Apex (TA).

Fig. 2. Truncated test field for Φ0=4.3, *d*=2, *αreal*=0.098, *βreal*=0.099, *RASN* =9.2%, (Michlin et al., 2011).

#### **2.2 Binomial presentation of test and SPRT solution**

For all points of the test field, the probability of the next failure occurring in the new object (i.e. of a step upwards) is constant and given by the following expression (for proof see Michlin & Grabarnik, 2007):

$$P\_R(\Phi) = 1/(1+\Phi)\tag{5}$$

A binomial SPRT is available for such a test (Wald, 1947, chap. 5), whose oblique boundaries are:

$$\text{Accept line (AL):} \qquad \qquad r\_b = r\_n/s + \mathbf{h}'\_b \tag{6}$$

$$\text{Reject line (RL):}\qquad r\_n = r\_{b'} \mathbf{s} + l\_n\tag{7}$$

where *s* is their slope, uniquely determined by the SPRT theory depending on *α, β,* Φ0, *d* (Wald,1947; Michlin & Grabarnik, 2007), and given by:

$$s = -\ln q / (\ln q + \ln d) \tag{8}$$

where

$$q = \left(1 + \Phi\_0\right) \Big/ \left(d + \Phi\_0\right) \tag{9}$$

The absolute terms of (6) and (7) are given by:

$$\mathcal{M}\_a = \ln \left( \beta^\* \Big/ \left( 1 - \alpha^\* \right) \right) \Big/ \left( \ln q + \ln d \right) \tag{10}$$

and when its Reject counterpart is crossed – at the RDP. The boundaries consist of two parallel oblique straight lines (accept line (AL) and reject line (RL)) and the truncation lines

> Accept Line ADP Reject Line RDP

Centerline Truncation Apex

*rnMax*

*rbMax*

*PR*() 11 (5)

Accept line (AL): *rb*= *rn*/*s*+*h'b* (6)

Reject line (RL): *rn*= *rb*·*s*+*hn* (7)

*s* ln ln ln *q q d* (8)

*q d* (10)

TA

0 10 20 30 40 50 60

Fig. 2. Truncated test field for Φ0=4.3, *d*=2, *αreal*=0.098, *βreal*=0.099, *RASN* =9.2%, (Michlin et al.,

For all points of the test field, the probability of the next failure occurring in the new object (i.e. of a step upwards) is constant and given by the following expression (for proof see

A binomial SPRT is available for such a test (Wald, 1947, chap. 5), whose oblique boundaries

where *s* is their slope, uniquely determined by the SPRT theory depending on *α, β,* Φ0, *d*

*q d* 1 0 0 (9)

\* \* *ha* ln 1 ln ln

 

**Basic item number of failures (***rb***)**

parallel to the coordinate axes and intersecting at the Truncation Apex (TA).

0

**2.2 Binomial presentation of test and SPRT solution** 

(Wald,1947; Michlin & Grabarnik, 2007), and given by:

The absolute terms of (6) and (7) are given by:

10

**New item number of failures (***rn***)**

2011).

are:

where

Michlin & Grabarnik, 2007):

20

$$h\_n = \ln\left(\left(1 - \boldsymbol{\beta}^\*\right) \left/\boldsymbol{\alpha}^\*\right)\right) \left(\ln \boldsymbol{q} + \ln \boldsymbol{d}\right) \tag{11}$$

$$
\hbar \stackrel{\cdot}{h} = -\hbar\_a \,/\,\text{s}\tag{12}
$$

The expressions (10)-(12) have one drawback: the parameters *α*\* and *β\** are unknown. Their dependence on *α*0, *β*, Φ0, *d,* and on the TA coordinates is available only in the form of the limits between which the parameters lie (Michlin et al., 2009). Still, these limits suffice for determining – from the above expressions – corresponding search limits for *h' <sup>b</sup>* and *hn*. A search methodology, within these limits, for exact values ensuring the target characteristics – is, basically, the goal of this work.

#### **2.3 Calculation of test characteristics acc. to given boundaries**

The probability of hitting a given point of the test is given by (Barnard, 1946; Michlin & Grabarnik, 2007):

$$P\_{r\_b, r\_n}(\Phi) = P\_{r\_b, r\_n - 1}(\Phi) \cdot P\_R\left(\Phi\right) + P\_{r\_b - 1, r\_n}(\Phi) \cdot \left[1 - P\_R\left(\Phi\right)\right] \tag{13}$$

while that of hitting the given ADP is:

$$P\_{ADP}\left(r\_{n'}\Phi\right) = P\_{\eta\_{\bar{\eta}}-1, r\_{\bar{n}}}\left(\Phi\right) \cdot \left[1 - P\_{\bar{\mathcal{R}}}\left(\Phi\right)\right] \tag{14}$$

and that for the given RDP is:

$$P\_{RDP}\left(r\_{b\prime},\Phi\right) = P\_{r\_b,r\_n-1}\left(\Phi\right)\cdot P\_R\left(\Phi\right) \tag{15}$$

*Pa*(Φ) is the sum of all the probabilities *P r ADP n* , of hitting all ADP, hence the actual values of *α* and *β*, namely *αreal* and *βreal* , are given by:

$$
\alpha\_{\text{real}} = 1 - P\_a \left( \Phi\_0 \right); \quad \mathcal{J}\_{\text{real}} = P\_a \left( \Phi\_1 \right) \tag{16}
$$

The Average Sample Number (ASN) of a truncated test is calculated as:

$$ASN\left(\Phi\right) = \sum\_{r\_b=0}^{TA\_b} \left[r\_b + r\_{nRDP}\left(r\_b\right)\right] P\_{RDP}\left(r\_b, \Phi\right) + \sum\_{r\_n=0}^{TA\_n} \left[r\_n + r\_{bADP}\left(r\_n\right)\right] P\_{ADP}\left(r\_n, \Phi\right) \tag{17}$$

where ( ) *nRDP b r r* is the *rn*-coordinate of the RDP with given *rb*. The Average Test Duration (ATD) for each object is:

$$ATD\left(\Phi\right) = \theta\_b \cdot ASN\left(\Phi\right) / \left(1 + 1/\Phi\right) \tag{18}$$

#### **3. Comparative characteristics and optimality of test**

In this Section the optimality criteria for the test, on which the comparison- and selection algorithm is based, are substantiated, and the problems of the study are clarified.

In (Michlin & Grabarnik, 2007) were presented three optimality criteria which can be calculated for the specified boundaries:

Comparison Sequential Test for Mean Times Between Failures 459

The TA of such a test called Optimal TA (OTA). Section 5 presents approximative formulae for determination of those OTA coordinates which permit reduction of the search field to 2 to 6 points. A particular problem in this context is: for a given TA, find *h'b* and *hn* (eqs. (6),

This Section deals with the interrelationships between the boundary parameters of the test on the one hand, and the characteristics of the test itself (namely, *αreal* and *βreal*) and those of its quality (introduced in the preceding Section, *Rd* and *RASN*) – on the other. These interrelationships lack analytical expression and are further complicated by the discreteness of the test. Thus one had to make do with typical examples of their behaviour in the vicinity of the optimum. With this behaviour clarified, an efficacious search algorithm could be developed for the optimum in the discrete space in question. Clarity of the picture is essential both for the developer of the planning methodology and for the practitioner

As the slope *s* of the oblique test boundaries, described by eqs. (6) and (7), is unrelated to *α* and *β* (see eq. (8)), the search for them under the min *Rd* stipulation reduced to finding the absolute terms in the describing equation, namely the intercepts *h'b* and *hn* on the coordinate

*rnMax* TA

0123456

Fig. 3. Test Plane (Michlin & Grabarnik, 2010). 1 – Example of interval of *h'b* values over

Continue zone

> **Basic system number of failures,** *rb*

AL RL ADP RDP Shifted AL Shifted RL

*rbMax*

**4. Discreteness of test boundaries and their search at given TA** 

where *Rd*0 and *RASN*0 – threshold values of *Rd* and *RASN*.

(7)) ensuring min *Rd*.

axes (Figure 3).

planning the binomial test in the field.

**4.1 Discreteness of test boundaries** 

*h*'*b*

which the test ADP's do not change. 2 – Ditto for *hn* and RDP.

**1**

**New system number of failures***, rn*

2

*hn*

 Closeness of the test OC to the prescribed one. For given *d*, the measure of this closeness is *RD*:

$$R\_D = \sqrt{\left[\left(\alpha\_{real} - \alpha\_{tg}\right) \Big/ \alpha\_{tg}\right]^2 + \left[\left(\beta\_{real} - \beta\_{tg}\right) \Big/ \beta\_{tg}\right]^2} \tag{19}$$

with *αreal* and *βreal* as per (16).


$$R\_{\rm ANN} = \left\langle \sum\_{i=1}^{5} \left[ A \text{SN} \left( \Phi\_{i} \right) - A \text{SN}\_{\rm nTr} \left( \Phi\_{i} \right) \right] \right\rangle \left\langle \sum\_{i=1}^{5} A \text{SN}\_{\rm nTr} \left( \Phi\_{i} \right) \right\rangle \tag{20}$$

where Φ*i* - values of Φ in geometric progression:

$$\Phi\_0 \cdot \left(\sqrt{d}\right)^{i-4} \quad \text{for} \ i = 1...5 \tag{21}$$

*ASN*(Φ) – calculated as per the recursive formulae (17), (13…15) *ASNnTr*(Φ) – calculated by Wald's formulae (1947, chap. 3) obtained for a non-truncated test of the type in question:

$$ASN\_{nTr}\left(\Phi\right) = \frac{\left(1 + \Phi\left(\eta\right)\right)\left[P\_a\left(\eta\right)\ln B + \left(1 - P\_a\left(\eta\right)\right)\ln A\right]}{\left(1 + \Phi\left(\eta\right)\right)\ln\left[\left(1 + \Phi\_0\right)\left\{\left(d + \Phi\_0\right)\right\} + \ln d}\tag{22}$$

where

$$\Phi\left(\eta\right) = \frac{d^{\eta}\left(1 + \Phi\_{0}\right)^{\eta} - \left(d + \Phi\_{0}\right)^{\eta}}{\left(d + \Phi\_{0}\right)^{\eta} - \left(1 + \Phi\_{0}\right)^{\eta}}\tag{23}$$

$$P\_a\left(\eta\right) = \left(A^{\eta} - 1\right) \Big/ \left(A^{\eta} - B^{\eta}\right) \tag{24}$$

$$A = \left(1 - \beta\_{\text{real}}\right) / \alpha\_{\text{real}} \tag{25}$$

$$B = \mathcal{J}\_{rel} \Big/ \left(1 - \alpha\_{rel}\right) \tag{26}$$

*η*– an auxiliary parameter calculated by (23) for Φ values as per the progression (21). The choice criterion for the optimal test is:

$$\min(TA\_n + TA\_b) \tag{27}$$

subject to:

$$(\text{min}R\_d \text{ at given TA}) \& (R\_d \triangleleft R\_{d0}) \& (R\_{ASN} \triangleleft R\_{ASN0}) \tag{28}$$

Closeness of the test OC to the prescribed one. For given *d*, the measure of this closeness

 2 2 *RD real tg tg real tg tg*

The degree of truncation, which characterises the maximum test duration whose

 The efficacy of the test according to Wald (1947) and to Eisenberg & Ghosh (1991), as the measure of which *RASN* was adopted (Michlin et al., 2009) – the relative excess of the function *ASN*(Φ) of the truncated test over *ASNnTR*(Φ), its non-truncated counterpart

*ASN* 1 1 *<sup>i</sup> nTr i nTr i i i <sup>R</sup> ASN ASN ASN*

 

 (19)

(20)

for *i* = 1…5 (21)

*d d*

(22)

(23)

 

(24)

*real real* (25)

*real real* 1 (26)

*PBP A*

 

measure can be, for example, the sum of the TA coordinates.

where Φ*i* - values of Φ in geometric progression:

*nTr*

*B*

The choice criterion for the optimal test is:

<sup>4</sup>

*ASN*

 

5 5

*i <sup>d</sup>*

*ASN*(Φ) – calculated as per the recursive formulae (17), (13…15) *ASNnTr*(Φ) – calculated by Wald's formulae (1947, chap. 3) obtained for a non-truncated test of the type in question:

*d d*

*P A AB <sup>a</sup>* 1 

1

*d*

*A* 1

 0 0 1 ln 1 ln 1 ln 1 ln *a a*

0 0 0 0

1

 

 

 

*η*– an auxiliary parameter calculated by (23) for Φ values as per the progression (21).

min(*TAn+TAb*) (27)

(min*Rd* at given TA)&(*Rd*< *Rd*0)&(*RASN*< *RASN*0) (28)

 

0

is *RD*:

where

subject to:

with *αreal* and *βreal* as per (16).

which can be taken as ideal:

where *Rd*0 and *RASN*0 – threshold values of *Rd* and *RASN*.

The TA of such a test called Optimal TA (OTA). Section 5 presents approximative formulae for determination of those OTA coordinates which permit reduction of the search field to 2 to 6 points. A particular problem in this context is: for a given TA, find *h'b* and *hn* (eqs. (6), (7)) ensuring min *Rd*.

### **4. Discreteness of test boundaries and their search at given TA**

This Section deals with the interrelationships between the boundary parameters of the test on the one hand, and the characteristics of the test itself (namely, *αreal* and *βreal*) and those of its quality (introduced in the preceding Section, *Rd* and *RASN*) – on the other. These interrelationships lack analytical expression and are further complicated by the discreteness of the test. Thus one had to make do with typical examples of their behaviour in the vicinity of the optimum. With this behaviour clarified, an efficacious search algorithm could be developed for the optimum in the discrete space in question. Clarity of the picture is essential both for the developer of the planning methodology and for the practitioner planning the binomial test in the field.

#### **4.1 Discreteness of test boundaries**

As the slope *s* of the oblique test boundaries, described by eqs. (6) and (7), is unrelated to *α* and *β* (see eq. (8)), the search for them under the min *Rd* stipulation reduced to finding the absolute terms in the describing equation, namely the intercepts *h'b* and *hn* on the coordinate axes (Figure 3).

Fig. 3. Test Plane (Michlin & Grabarnik, 2010). 1 – Example of interval of *h'b* values over which the test ADP's do not change. 2 – Ditto for *hn* and RDP.

Comparison Sequential Test for Mean Times Between Failures 461

The figure also contains the contours (isopleths) of *Rd* (solid lines) and *RASN* (dashed lines), given as percentages. In macro the *Rd* contours can be described as oval-shaped, whereas in micro they are quite uneven, so that derivatives calculated from a small set of points would show large jumps, which would hamper the search for the minimum *Rd* . It is seen that in

Figure 5 shows two projections representing *αreal* and *βreal*, calculated according to the coordinates of Figure 4, so that to each point of the latter corresponds one of *αreal* and *βreal*. These points form intersecting almost-plane surfaces. In the upper figure the coordinate axes are oriented so that the intersection zone (*αreal* - *βreal*) is perpendicular to the page; in the lower figure. the orientation is such that the rows of *βreal* points reduce in projection to a

single point – in other words, they form parallel or almost-parallel lines.

the vicinity of that minimum, *RASN*≈11%.

Fig. 5. Two projections of

*real* and 

*real* "planes". (Michlin & Grabarnik, 2010).

Stopping of the test occurs not on the decision lines, but at points with integer coordinates, with ADP to the right of the AL and RDP above the RL. If the AL is shifted from an initial position (solid line in Figure 3) to the right, the test characteristics remain unchanged until it crosses an ADP, which in turn is then shifted in the same direction by one failure. The AL positions at these crossings are shown as dot-dashed lines, and its shifts are marked with arrows. Projecting the termini of these arrows, parallel to the AL, on the *rb* axis, we obtain the values of *h'b* at which the changes occur. An analogous process takes place when the RL is shifted upwards.

The intervals of *h'b* and *hn* over which the test characteristics remain unchanged are marked in Figure 3 by the circled numbers 1 and 2 respectively.

When the AL is shifted to the right (*h'b* increased) *Pa*(Φ) is reduced, i.e. *αreal* increases and *βreal* decreases. When the RL is shifted upwards, the effects are interchanged. These relationships are monotonic and stepwise, and differ in that change of *h'b* is reflected more strongly in *βreal* and more weakly in *αreal*. With *hn* the pattern is reversed.

#### **4.2 Basic dependences between oblique boundaries and test characteristics**

In (Michlin et al., 2009, 2011; Michlin & Kaplunov, 2007) were found the limits within which *α*\* and *β\** of the optimal tests should be sought. These limits can also serve for determining the search limits of *h'b* and *hn*, as per (10) – (12).

Figure 4 shows an example of the above, with the limits for *h'b* and *hn* calculated, according to the data of (Michlin et al., 2009), for *d*=2, Φ0=1, *αtg*=*βtg*=0.1*, TAb*=27, *TAn*=38, *RASN*≤12%. In the figure, the points mark the centres of rectangles within which the characteristics remain unchanged. The resulting picture is fairly regular, even though the spacings of the columns and rows are variable. In space, the *Rd* points form a cone-shaped surface.

Fig. 4. Contours of *RASN* (dashed lines) and *RD* (solid lines) vs. *h'b* and *hn*. (Michlin & Grabarnik, 2010). The dots mark the centres of rectangles within which the test characteristics do not change. 1 – 4 are the corner points at which the test characteristics are calculated in the search for the optimum (Subsection 4.3, stage ‹1.1›).

Stopping of the test occurs not on the decision lines, but at points with integer coordinates, with ADP to the right of the AL and RDP above the RL. If the AL is shifted from an initial position (solid line in Figure 3) to the right, the test characteristics remain unchanged until it crosses an ADP, which in turn is then shifted in the same direction by one failure. The AL positions at these crossings are shown as dot-dashed lines, and its shifts are marked with arrows. Projecting the termini of these arrows, parallel to the AL, on the *rb* axis, we obtain the values of *h'b* at which the changes occur. An analogous process takes place when the RL

The intervals of *h'b* and *hn* over which the test characteristics remain unchanged are marked

When the AL is shifted to the right (*h'b* increased) *Pa*(Φ) is reduced, i.e. *αreal* increases and *βreal* decreases. When the RL is shifted upwards, the effects are interchanged. These relationships are monotonic and stepwise, and differ in that change of *h'b* is reflected more strongly in *βreal*

In (Michlin et al., 2009, 2011; Michlin & Kaplunov, 2007) were found the limits within which *α*\* and *β\** of the optimal tests should be sought. These limits can also serve for determining

Figure 4 shows an example of the above, with the limits for *h'b* and *hn* calculated, according to the data of (Michlin et al., 2009), for *d*=2, Φ0=1, *αtg*=*βtg*=0.1*, TAb*=27, *TAn*=38, *RASN*≤12%. In the figure, the points mark the centres of rectangles within which the characteristics remain unchanged. The resulting picture is fairly regular, even though the spacings of the

**4.2 Basic dependences between oblique boundaries and test characteristics** 

columns and rows are variable. In space, the *Rd* points form a cone-shaped surface.

Fig. 4. Contours of *RASN* (dashed lines) and *RD* (solid lines) vs. *h'b* and *hn*. (Michlin & Grabarnik, 2010). The dots mark the centres of rectangles within which the test

calculated in the search for the optimum (Subsection 4.3, stage ‹1.1›).

characteristics do not change. 1 – 4 are the corner points at which the test characteristics are

is shifted upwards.

in Figure 3 by the circled numbers 1 and 2 respectively.

and more weakly in *αreal*. With *hn* the pattern is reversed.

the search limits of *h'b* and *hn*, as per (10) – (12).

The figure also contains the contours (isopleths) of *Rd* (solid lines) and *RASN* (dashed lines), given as percentages. In macro the *Rd* contours can be described as oval-shaped, whereas in micro they are quite uneven, so that derivatives calculated from a small set of points would show large jumps, which would hamper the search for the minimum *Rd* . It is seen that in the vicinity of that minimum, *RASN*≈11%.

Figure 5 shows two projections representing *αreal* and *βreal*, calculated according to the coordinates of Figure 4, so that to each point of the latter corresponds one of *αreal* and *βreal*. These points form intersecting almost-plane surfaces. In the upper figure the coordinate axes are oriented so that the intersection zone (*αreal* - *βreal*) is perpendicular to the page; in the lower figure. the orientation is such that the rows of *βreal* points reduce in projection to a single point – in other words, they form parallel or almost-parallel lines.

Fig. 5. Two projections of *real* and *real* "planes". (Michlin & Grabarnik, 2010).

Comparison Sequential Test for Mean Times Between Failures 463

‹1.1› Calculation of the test characteristics at the four vertices of a rectangle (Figure 4) whose

‹1.2› Approximation of *αreal*(*h'b*, *hn*) and *βreal*(*h'b*, *hn*) as planes, and determination of the first estimate *h'b1*, *hn1* yielding min *RD* (point 5, Figure 7). Checking for *RD* ≤ *RD*0. If satisfied,

Fig. 7. Example of search scheme for min(*RD*). (Michlin & Grabarnik, 2010). 5 – 11 are points

Determination of point 6 – from *αreal*5, *βreal*5 and the slopes of the *α*-, *β*-planes as per ‹1.2›.

Alternating advance parallel to the *h'b*- and *hn-*axes. In view of the discreteness and complexity of the *RD* function, the search for its minimum was reduced to one for the points

Δ*α= αreal – αtg;* Δ*β= βreal –βtg*

‹3.1› If at point 6 (‹2› above) Δ*α*6 > Δ*β*6, a path parallel to the *hn*-axis is taken in uniform steps Δ*hn*, until Δ*α* changes its sign (points 6,7,8 on Figure 7), Δ*hn*= Δ*α*6/*a3*, where *a3* is the

This problem is easier to solve, as both Δ*α* and Δ*β* are monotonic functions of *h'b* and *hn*.

 Stronger dependence of *αreal* on *hn* than on *h'b*; the reverse – for *βreal*. In expanded form, the search algorithm for min *Rd* consists in the following:

coordinates are obtained from the relationships presented in Subsection 5.3.

1st stage.

stopping of search.

of test characteristics calculation.

*h'b* and *hn* where Δ*α* and Δ*β* change sign:

The search can be stopped at every step, subject to *RD* ≤ *RD*0.

Re-checking for *RD* ≤ *RD*0.

2nd stage.

3rd stage.

Figure 6 shows analogous projections for *RASN*, and we again have an almost-plane surface, monotonic and uneven in micro.

The provided examples show that the described patterns characterise the dependences of *αreal*, *βreal* and *RASN* on *h'b* and *hn* within the limits determined in Subsection 5.3 (Michlin et al., 2009, 2011; Michlin & Kaplunov, 2007). Over small intervals these dependences are stepwise, and the lines through the step midpoints are uneven as well.

Fig. 6. Two projections of *RASN* "plane". (Michlin & Grabarnik, 2010).

#### **4.3 Search algorithm for oblique test boundaries**

Standard search programmes for minima (such as those in Matlab) operate poorly, or not at all, with discrete data of the type in question. Availability of known regularities in the behaviour of the functions *αreal*, *βreal*, *RASN*, *RD* makes it possible to construct a fast and efficacious algorithm.

These known regularities are:


Stronger dependence of *αreal* on *hn* than on *h'b*; the reverse – for *βreal*.

In expanded form, the search algorithm for min *Rd* consists in the following:

1st stage.

462 Modern Approaches To Quality Control

Figure 6 shows analogous projections for *RASN*, and we again have an almost-plane surface,

The provided examples show that the described patterns characterise the dependences of *αreal*, *βreal* and *RASN* on *h'b* and *hn* within the limits determined in Subsection 5.3 (Michlin et al., 2009, 2011; Michlin & Kaplunov, 2007). Over small intervals these dependences are

stepwise, and the lines through the step midpoints are uneven as well.

Fig. 6. Two projections of *RASN* "plane". (Michlin & Grabarnik, 2010).

 The values of *h'b* and *hn* at which the test characteristics change. The limits of *h'b* and *hn*, yielding tests with the specified characteristics.

stepwise and unstable but also monotonic in narrower intervals.

Standard search programmes for minima (such as those in Matlab) operate poorly, or not at all, with discrete data of the type in question. Availability of known regularities in the behaviour of the functions *αreal*, *βreal*, *RASN*, *RD* makes it possible to construct a fast and

Almost-plane monotonic dependences of *αreal*, *βreal* and *RASN* within the above limits,

**4.3 Search algorithm for oblique test boundaries** 

efficacious algorithm.

These known regularities are:

monotonic and uneven in micro.

‹1.1› Calculation of the test characteristics at the four vertices of a rectangle (Figure 4) whose coordinates are obtained from the relationships presented in Subsection 5.3.

‹1.2› Approximation of *αreal*(*h'b*, *hn*) and *βreal*(*h'b*, *hn*) as planes, and determination of the first estimate *h'b1*, *hn1* yielding min *RD* (point 5, Figure 7). Checking for *RD* ≤ *RD*0. If satisfied, stopping of search.

Fig. 7. Example of search scheme for min(*RD*). (Michlin & Grabarnik, 2010). 5 – 11 are points of test characteristics calculation.

2nd stage.

Determination of point 6 – from *αreal*5, *βreal*5 and the slopes of the *α*-, *β*-planes as per ‹1.2›. Re-checking for *RD* ≤ *RD*0.

3rd stage.

Alternating advance parallel to the *h'b*- and *hn-*axes. In view of the discreteness and complexity of the *RD* function, the search for its minimum was reduced to one for the points *h'b* and *hn* where Δ*α* and Δ*β* change sign:

$$
\Delta a = a\_{\rm real} - a\_{t\%}; \quad \Delta \beta = \beta\_{\rm real} - \beta\_{t\%}
$$

This problem is easier to solve, as both Δ*α* and Δ*β* are monotonic functions of *h'b* and *hn*. The search can be stopped at every step, subject to *RD* ≤ *RD*0.

‹3.1› If at point 6 (‹2› above) Δ*α*6 > Δ*β*6, a path parallel to the *hn*-axis is taken in uniform steps Δ*hn*, until Δ*α* changes its sign (points 6,7,8 on Figure 7), Δ*hn*= Δ*α*6/*a3*, where *a3* is the

Comparison Sequential Test for Mean Times Between Failures 465

The ordinate axis represents the "acceleration factor of calculation", which is the ratio of references to the WAS-function by fminsearch and the proposed algorithm respectively. The larger the ratio, the faster the algorithm compared with the standard Matlab function. The diagram shows that at low densities (short tests, zone A) fminsearch fails to find min *Rd*. In zone C (long tests) the command finds it or stops close to it, but with 3 to 6 times more references to WAS. In zone B (medium tests) the minimum is either not found, or found with 2.5 to 5 times more references to WAS. By contrast, the programme based on the

Accordingly, for the present task – searching for the optimum in a discrete space – the proposed algorithm accomplishes it much faster than the Matlab standard fminsearch command, thus saving computation time in long tests. Moreover, it guarantees a solution – a

In (Michlin & Grabarnik, 2007) it was established that for Φ0=1 and *α*=*β*, the OTA lie on the

This was checked for different Φ0. With given *αtg*=*βtg*, *d*, and *RD*≤1%, a search was conducted for three location zones of the TA – namely, with *RASN*≤5%, 5%<*RASN*≤10%, and *RASN*>10%, the last-named being restricted by the above requirement on *RD*, i.e. achievability of *αtg* and

A typical example of such zones for *αtg*=*βtg*=0.05, *d*=2, and Φ0=1, 2, 3 is shown in Figure 9. The fan-shaped zones have their apices on the corresponding centrelines. These apices are the OTA locations, as with the imposed limits satisfied they are closest to the origin (heaviest truncation). In these circumstances the search zone is narrowed, the location

To study the relationships between the sought boundary parameters (*TA*, *α*\*, *β*\*) and the specified test characteristics (Φ0, *d*, *αtg*=*βtg*, *RASN max*), a search was run over a large population

The dots in Figure 10a mark the OTA for *αtg*=*βtg*=0.05, *RASN*≈10%, and wide intervals of *d* and Φ0. Figure 10b is a zoom on the domain in 3a representing the "short" tests, namely those with small ASN and – correspondingly – low TA coordinates. It is seen that all curves smooth out as the distance from the origin increases (the tests become longer), the reason

Upper limit

*n b r sr* (29)

Number of levels

proposed algorithm found the minimum in all cases.

**5.1 Search methodology for optimal test boundaries** 

problem being converted from two- to one-dimensional.

Table 1. Regions of characteristics covered by search

**5.2 Search results for OTA and their curve fitting** 

of optimal tests with the characteristics given in the Table below.

Lower

limit

Φ0 0.3 5 9 *d* 1.5 5 12 *αtg*=*βtg* 0.05 0.25 5 *RASN max* 5% 10% 2

**5. Estimates for boundary parameters** 

*βtg*.

critical aspect in short tests, where fminsearch usually fails to find one.

centreline (which runs through the origin parallel to the AL/RL), so that

coefficient in the equation of the *α*-plane as per ‹1.2›. Beyond that point, the root Δ*α*(*hn*) is searched for by the modified Regula Falsi method (point 9). (The term "root" refers here to one of a pair of adjoining points at which the function changes its sign and has the smaller absolute value). The special feature of this procedure is accounting for the discreteness of the solution.

‹3.2› At the point of the root Δ*α*, a right-angled turn is executed and a path parallel to the *h*'*b*-axis is taken, searching for the Δ*β* root (point 10).

‹3.3› The alternating procedure is continued until a situation is reached where two consecutive turns involve only movement to an adjoining point. This point 10 corresponds to min(*RD*). If in ‹3.1› Δ*α*6 < Δ*β*6, we begin from ‹3.2›.

#### **4.4 Efficacy of algorithm**

With a view to assessing the efficacy of the proposed algorithm, a search for the *h'b* and *hn* values yielding min *Rd* was conducted with the aid of a Matlab programme which realised this algorithm, and alternatively with the Matlab fminsearch command, with the same function WAS (Michlin & Grabarnik, 2007) referred to in both cases. This function determines the test characteristics according to its specified boundaries. The run covered different tests with *RASN*0=5 and 10%.

The calculation results are shown in Figure 8.

Fig. 8. Comparative efficacy of proposed algorithm. (Michlin & Grabarnik, 2010).


In it, the abscissa axis represents the product *TAb*\**TAn*, which we term "density factor of test states". The higher the latter, the denser the disposition of the test points in the search zone (see Figure 4), the smaller the changes in the test characteristics from point to point, and the closer the search to one over a continuous smooth surface. A small value of the product is associated with a short test, due to be completed at small sample size and moderate computation times for the characteristics; a large value – with long tests, completed on the average at large sample sizes and long computation times.

coefficient in the equation of the *α*-plane as per ‹1.2›. Beyond that point, the root Δ*α*(*hn*) is searched for by the modified Regula Falsi method (point 9). (The term "root" refers here to one of a pair of adjoining points at which the function changes its sign and has the smaller absolute value). The special feature of this procedure is accounting for the discreteness of

‹3.2› At the point of the root Δ*α*, a right-angled turn is executed and a path parallel to the

‹3.3› The alternating procedure is continued until a situation is reached where two consecutive turns involve only movement to an adjoining point. This point 10 corresponds

With a view to assessing the efficacy of the proposed algorithm, a search for the *h'b* and *hn* values yielding min *Rd* was conducted with the aid of a Matlab programme which realised this algorithm, and alternatively with the Matlab fminsearch command, with the same function WAS (Michlin & Grabarnik, 2007) referred to in both cases. This function determines the test characteristics according to its specified boundaries. The run covered

Fig. 8. Comparative efficacy of proposed algorithm. (Michlin & Grabarnik, 2010).

In it, the abscissa axis represents the product *TAb*\**TAn*, which we term "density factor of test states". The higher the latter, the denser the disposition of the test points in the search zone (see Figure 4), the smaller the changes in the test characteristics from point to point, and the closer the search to one over a continuous smooth surface. A small value of the product is associated with a short test, due to be completed at small sample size and moderate computation times for the characteristics; a large value – with long tests, completed on the

1 – fminsearch (Matlab) found min *RD* or stopped close to it;

average at large sample sizes and long computation times.

A, B, C – short, medium and long tests, respectively.

the solution.

**4.4 Efficacy of algorithm** 

different tests with *RASN*0=5 and 10%.

2 – fminsearch failed to find *RD*;

The calculation results are shown in Figure 8.

*h*'*b*-axis is taken, searching for the Δ*β* root (point 10).

to min(*RD*). If in ‹3.1› Δ*α*6 < Δ*β*6, we begin from ‹3.2›.

The ordinate axis represents the "acceleration factor of calculation", which is the ratio of references to the WAS-function by fminsearch and the proposed algorithm respectively. The larger the ratio, the faster the algorithm compared with the standard Matlab function.

The diagram shows that at low densities (short tests, zone A) fminsearch fails to find min *Rd*. In zone C (long tests) the command finds it or stops close to it, but with 3 to 6 times more references to WAS. In zone B (medium tests) the minimum is either not found, or found with 2.5 to 5 times more references to WAS. By contrast, the programme based on the proposed algorithm found the minimum in all cases.

Accordingly, for the present task – searching for the optimum in a discrete space – the proposed algorithm accomplishes it much faster than the Matlab standard fminsearch command, thus saving computation time in long tests. Moreover, it guarantees a solution – a critical aspect in short tests, where fminsearch usually fails to find one.

### **5. Estimates for boundary parameters**

#### **5.1 Search methodology for optimal test boundaries**

In (Michlin & Grabarnik, 2007) it was established that for Φ0=1 and *α*=*β*, the OTA lie on the centreline (which runs through the origin parallel to the AL/RL), so that

$$r\_n = \mathbf{s} \cdot r\_b \tag{29}$$

This was checked for different Φ0. With given *αtg*=*βtg*, *d*, and *RD*≤1%, a search was conducted for three location zones of the TA – namely, with *RASN*≤5%, 5%<*RASN*≤10%, and *RASN*>10%, the last-named being restricted by the above requirement on *RD*, i.e. achievability of *αtg* and *βtg*.

A typical example of such zones for *αtg*=*βtg*=0.05, *d*=2, and Φ0=1, 2, 3 is shown in Figure 9. The fan-shaped zones have their apices on the corresponding centrelines. These apices are the OTA locations, as with the imposed limits satisfied they are closest to the origin (heaviest truncation). In these circumstances the search zone is narrowed, the location problem being converted from two- to one-dimensional.

To study the relationships between the sought boundary parameters (*TA*, *α*\*, *β*\*) and the specified test characteristics (Φ0, *d*, *αtg*=*βtg*, *RASN max*), a search was run over a large population of optimal tests with the characteristics given in the Table below.


Table 1. Regions of characteristics covered by search

#### **5.2 Search results for OTA and their curve fitting**

The dots in Figure 10a mark the OTA for *αtg*=*βtg*=0.05, *RASN*≈10%, and wide intervals of *d* and Φ0. Figure 10b is a zoom on the domain in 3a representing the "short" tests, namely those with small ASN and – correspondingly – low TA coordinates. It is seen that all curves smooth out as the distance from the origin increases (the tests become longer), the reason

Comparison Sequential Test for Mean Times Between Failures 467

The Φ0-isopleths in the figures are broken radial lines, whereas their *d*-counterparts are

<sup>1</sup> <sup>1</sup> <sup>1</sup> , *n b ASN b r r kd qxR r*

The formulae indicate that the approximate curves differ only in the scale factor *k*(*d*),

As the formulae do not contain Φ0, the OTA is searched for through its required adherence to the centreline, whose expression (29) is uniquely determined by *d* and Φ0. Accordingly, the sought OTA is the integer point closest to the intersection of the curve (30) and the

(30)

1 4 *k d* exp 5.58 1 1 *<sup>d</sup>* ; (31)

<sup>20</sup> *qxRASN xR Rx ASN ASN* (32)

20 40 60 80 100

**OTA**

Hyperbola by (30) Centerline by (29)

) of these parameters. These dependences, determined

**Basic system number of failures,** *rbMax*

The coefficients in (31) and (32) were found through the requirement of minimal root mean square error (*RMSE*) – the difference between the OTA's found as per eqs. (29) and (30). For the data in the Table, *RMSE*=0.88, indicating high estimation accuracy for such a broad

As already mentioned, the problem of finding the oblique boundaries reduces to that of finding *α*\* and *β*\*. This Subsection presents regressional dependences of the latter on the test characteristics Φ0, *d*, *x=αtg*=*βtg*, and *RASN max*, as well as their counterparts for the upper and

on the basis of the total data on optimal tests with the characteristics in the Table, were

symmetrical about the *rn*= *rb* line and approximate neatly to a hyperbola:

<sup>1</sup> , 1 1.10ln 0.41 1.03 ln

common to both axes – it remains the same for any pair (*x*, *RASN*).

*x* – common target value for *α* and *β*, *x*= *αtg*=*βtg*; *RASN* – in relative units rather than in percent.

0

Fig. 11. Determination of OTA. (Michlin et al., 2011).

20

40

centreline (29) (Figure 11).

**New system** 

**5.3 Estimates for** *α***\* and** *β***\*** 

*U* and *L , U* and *L*

domain.

lower limits (

sought in the form:

**number of failures,** 

*rnMax*

where

Fig. 9. TA zone boundaries for three 0 values and three *RASN* zones (Michlin et al., 2011): 1 = Boundary beyond which *RD*≤1% is unachievable at any *RASN*; 2 = Boundary for *RASN*≤10%; 3 = Boundary for *RASN*≤5%; 4 = Centreline. Remark 1. 0=1 subgraph: OTA for each *RASN* zone circled. Remark 2. For this figure: *d*=2, *αtg*=*βtg*=0.05, *RD* =1%.

being the weakening influence of discreteness of the test characteristics (Michlin et al., 2009).

Fig. 10. (a) OTA locations for different *d* and 0, and for *αtg*=*βtg*=0.05, *RASN*≈10%. (b) Zoom on short test zone. (Michlin et al., 2011).

The Φ0-isopleths in the figures are broken radial lines, whereas their *d*-counterparts are symmetrical about the *rn*= *rb* line and approximate neatly to a hyperbola:

$$r\_n(r\_b) = \left\{ \left[ k \left( d \right) \cdot q \left( \mathbf{x}\_\prime \mathcal{R}\_{ASN} \right) \right]^{-1} - r\_b^{-1} \right\}^{-1} \tag{30}$$

where

466 Modern Approaches To Quality Control

*Φ*<sup>0</sup> = 1

*Φ*<sup>0</sup> = 2

*Φ*<sup>0</sup> = 3

35 45 55 65 75 85 95

being the weakening influence of discreteness of the test characteristics (Michlin et al.,

**Truncation Apex** *rb* **coordinate ≡** *rbMax*

Fig. 9. TA zone boundaries for three 0 values and three *RASN* zones (Michlin et al., 2011): 1 = Boundary beyond which *RD*≤1% is unachievable at any *RASN*; 2 = Boundary for *RASN*≤10%; 3 = Boundary for *RASN*≤5%; 4 = Centreline. Remark 1. 0=1 subgraph: OTA for

each *RASN* zone circled. Remark 2. For this figure: *d*=2, *αtg*=*βtg*=0.05, *RD* =1%.

25

35

45

**Truncation Apex** *rn*

2009).

0

0

50

d=5

100

d=3 d=2

short test zone. (Michlin et al., 2011).

Φ0=0.3

Φ0=0.5

Φ0=0.7 Φ0=1

150

200

Φ0=1.5

d=1.65 d=1.77

**Basic system max number of failures,** *rbMax*

250

300

<sup>Φ</sup>0=2 <sup>Φ</sup>0=3 <sup>Φ</sup>0=4Φ0=5

**(a)**

350

**New system max number of failures,**

Fig. 10. (a) OTA locations for different *d* and 0, and for *αtg*=*βtg*=0.05, *RASN*≈10%. (b) Zoom on

 *rnMax*

0

5

10

15

d=5

20

25

30

**Basic system max number of failures,** *rbMax*

35

40

d=3.18

45

50

**(b)**

55

d=2.54

60

d=1.5 d=1.54

50

100

150

**New system max number of failures,**

200

250

300

 *rnMax* 350

55

**coordinate**

**≡**

*rnMax*

65

75

85

95

$$k\left(d\right) = \exp\left[5.58\left(d-1\right)^{-1/4}\right] - 1 \; ; \tag{31}$$

$$q(\mathbf{x}, R\_{\rm ANN}) = -\frac{1}{20} (\mathbf{1} + \mathbf{1}.10 \ln \mathbf{x} + 0.41 R\_{\rm ANN} - \mathbf{1}.03 R\_{\rm ANN} \ln \mathbf{x}) \tag{32}$$

*x* – common target value for *α* and *β*, *x*= *αtg*=*βtg*;

*RASN* – in relative units rather than in percent.

The formulae indicate that the approximate curves differ only in the scale factor *k*(*d*), common to both axes – it remains the same for any pair (*x*, *RASN*).

As the formulae do not contain Φ0, the OTA is searched for through its required adherence to the centreline, whose expression (29) is uniquely determined by *d* and Φ0. Accordingly, the sought OTA is the integer point closest to the intersection of the curve (30) and the centreline (29) (Figure 11).

Fig. 11. Determination of OTA. (Michlin et al., 2011).

The coefficients in (31) and (32) were found through the requirement of minimal root mean square error (*RMSE*) – the difference between the OTA's found as per eqs. (29) and (30). For the data in the Table, *RMSE*=0.88, indicating high estimation accuracy for such a broad domain.

#### **5.3 Estimates for** *α***\* and** *β***\***

As already mentioned, the problem of finding the oblique boundaries reduces to that of finding *α*\* and *β*\*. This Subsection presents regressional dependences of the latter on the test characteristics Φ0, *d*, *x=αtg*=*βtg*, and *RASN max*, as well as their counterparts for the upper and lower limits (*U* and *L , U* and *L* ) of these parameters. These dependences, determined on the basis of the total data on optimal tests with the characteristics in the Table, were sought in the form:

Comparison Sequential Test for Mean Times Between Failures 469

alStL alStU alStM Bisector

*\* \*L \*U \*M*

alSt for d=1.5

0.00 0.05 0.10 0.15 0.20 0.25

alSt for d=3

alStL alStU alStM Bisector

*\**

*\*L*

*\*U \*M*

0.00 0.05 0.10 0.15 0.20 0.25

Fig. 12. Actual *α*\*, regressional dependence, and upper and lower search limits. *RASN*=5%.

In this case the items are compared groupwise, which makes for economy in the time to a decision. The items of the respective subgroups, *Nb* and *Nn* in number, are drawn at random from their respective populations with exponential TBF's, and tested simultaneously. On failing, they are immediately replaced or repaired – just as in the two-item tests. The subgroup can be treated as a single item with an *N*-times shorter MTBF (Epstein & Sobel, 1955). The planning procedure remains the same, except that Φ in the calculations is

*αtg=βtg*

**(b)**

*αtg=βtg*

**(a)**

0.00

0.00

(a) *d*=1.5. (b) *d*=3. (Michlin et al., 2011).

**6. Group tests** 

replaced by Φ*g*:

0.05

0.10

0.15

0.20

*α\**

0.25

0.30

0.35

0.05

0.10

0.15

*α\**

0.20

0.25

$$\begin{aligned} \alpha\_M^\* &= \mathfrak{c}\_\alpha \cdot \mathfrak{x};\\ \beta\_M^\* &= \mathfrak{c}\_\beta \cdot \mathfrak{x}. \end{aligned} \tag{33}$$

The Matlab tool for stepwise regression yielded the coefficients for the above:

$$c\_a = 1.10 - 0.021 \left(\ln\text{x}\right)^2 - 0.0081 \Phi\_0^2 + 0.036 \Phi\_0 d + 1.07 R\_{A\text{SN}} \ln\text{x} \tag{34}$$

where *RMSE*=0.061 and *R*2=0.83, the latter being the coefficient of determination, and

$$c\_{\beta} = 1.09 + 0.096 \ln \text{x} + 0.14d - 0.018 \Phi\_0 d + 1.11 R\_{\text{ASD}} \ln \text{x} \tag{35}$$

with *RMSE*=0.069 and *R*2=0.80. The limit formulae read

$$
\begin{pmatrix} a\_{\ll}^\* \\ a\_{\ll}^\* \end{pmatrix} = \begin{pmatrix} \mathbf{1} \pm c\_{\alpha\theta} \end{pmatrix} a\_M^\* \tag{36}
$$

$$
\begin{pmatrix} \boldsymbol{\beta\_{L}^{\*}}\\\boldsymbol{\beta\_{L}^{\*}} \end{pmatrix} = \left(\mathbf{1} \pm c\_{\beta B}\right) \boldsymbol{\beta\_{M}^{\*}}\tag{37}
$$

where

$$
\mathcal{L}\_{\alpha\beta} = -0.045 + 0.14 \ln d - 0.031 \ln x \tag{38}
$$

$$
\sigma\_{\beta\beta} = -0.059 + 0.16 \ln d - 0.048 \ln \text{x} \tag{39}
$$

and such that all *α*\* and *β*\* obtained for the Table are included.

Figure 12 shows example dependences for the regressional value *M* and the upper and lower limits, versus *x*=*αtg* for Φ0=3 and *d*=1.5, 3. Also included are the actual values of *α*\*. (The graphs for *β*\* are analogues). The bounded zone becomes narrower as *d* and *αtg* decrease. It is seen that at low *d*, *M* and *M* can serve as the calculation values without undue deviation of *αreal* and *βreal* from their targets.

The search methodology for *α*\* and *β*\* of the optimal test, described in detail in Section 4, is based on knowledge of the limits (36), (37), which is one of the reasons for its high efficacy.

#### **5.4 Accuracy assessment of proposed planning**

The accuracy of the proposed planning, using eqs. (30) – (32) and (33) – (35) – was assessed by applying them in calculating the test boundaries for all characteristic values in the Table. This was followed by calculation of *αreal*, *βreal* and *RASN* for these tests and their deviation from the targets. The *RMSE*'s of *αreal* and *βreal* decrease with decreasing *d* and *RASN*. For *d*≤2 they do not exceed 3 to 4% of the target value and for large *d* they reach 8 and 10% at *RASN*=5 and 10% respectively. In the former case this is very satisfactory accuracy, while in the latter case it may become necessary to find more accurate values of the boundary parameters – for which the methodology outlined in Section 4 is recommended, using eqs. (30) – (32) and (34) – (39) for the search limits.

*M M*

where *RMSE*=0.061 and *R*2=0.83, the latter being the coefficient of determination, and

 

The Matlab tool for stepwise regression yielded the coefficients for the above:

0 0 *c*

0 *c xd dRx*

*L*

*L*

 

 

<sup>2</sup> <sup>2</sup>

1 *<sup>U</sup>*

1 *<sup>U</sup>*

 *c dx* 

and such that all *α*\* and *β*\* obtained for the Table are included. Figure 12 shows example dependences for the regressional value

> *M* and

with *RMSE*=0.069 and *R*2=0.80. The limit formulae read

decrease. It is seen that at low *d*,

– (39) for the search limits.

undue deviation of *αreal* and *βreal* from their targets.

**5.4 Accuracy assessment of proposed planning** 

where

; .

1.10 0.021 ln 0.0081 0.036 1.07 ln *x dRx ASN* (34)

1.09 0.096ln 0.14 0.018 1.11 ln *ASN* (35)

*B M*

*B M*

*<sup>B</sup>* 0.045 0.14ln 0.031ln (38)

*<sup>B</sup>* 0.059 0.16ln 0.048ln (39)

*M*

can serve as the calculation values without

and the upper and

*c*

*c*

*c dx*

lower limits, versus *x*=*αtg* for Φ0=3 and *d*=1.5, 3. Also included are the actual values of *α*\*. (The graphs for *β*\* are analogues). The bounded zone becomes narrower as *d* and *αtg*

The search methodology for *α*\* and *β*\* of the optimal test, described in detail in Section 4, is based on knowledge of the limits (36), (37), which is one of the reasons for its high efficacy.

The accuracy of the proposed planning, using eqs. (30) – (32) and (33) – (35) – was assessed by applying them in calculating the test boundaries for all characteristic values in the Table. This was followed by calculation of *αreal*, *βreal* and *RASN* for these tests and their deviation from the targets. The *RMSE*'s of *αreal* and *βreal* decrease with decreasing *d* and *RASN*. For *d*≤2 they do not exceed 3 to 4% of the target value and for large *d* they reach 8 and 10% at *RASN*=5 and 10% respectively. In the former case this is very satisfactory accuracy, while in the latter case it may become necessary to find more accurate values of the boundary parameters – for which the methodology outlined in Section 4 is recommended, using eqs. (30) – (32) and (34)

*M*

(33)

(36)

(37)

*c x c x* 

Fig. 12. Actual *α*\*, regressional dependence, and upper and lower search limits. *RASN*=5%. (a) *d*=1.5. (b) *d*=3. (Michlin et al., 2011).

#### **6. Group tests**

In this case the items are compared groupwise, which makes for economy in the time to a decision. The items of the respective subgroups, *Nb* and *Nn* in number, are drawn at random from their respective populations with exponential TBF's, and tested simultaneously. On failing, they are immediately replaced or repaired – just as in the two-item tests. The subgroup can be treated as a single item with an *N*-times shorter MTBF (Epstein & Sobel, 1955). The planning procedure remains the same, except that Φ in the calculations is replaced by Φ*g*:

Comparison Sequential Test for Mean Times Between Failures 471

b. Eqs. (41) and (18) yielded the approximate dependences of *ATDg*(Φ)/*θb* on *Nn* for different Φ, given *Nn*+ *Nb*=28. A minimum was found at *Nn*≈18. Figure 14 shows examples of these dependences at Φ= Φ0 and Φ= Φ1, which are seem to be almost flat over a wide interval around the minimum, and *Nn*=15 was chosen accordingly. With this choice, *ATDg*(Φ) only slightly exceeds the minimum, while the number of new items is lower, with the attendant saving in preparing the experimental batch. By (40)

 The values of *ASNg*(Φ) and *ATD*(Φ), obtained by (41) and (18) with allowance for (44) – confirmed the practicability of the test. c. Eq. (8) yielded *s*=0.330. Simultaneous solution of (29) and (30) yielded, after rounding-

Eqs. (33) through (35) yielded *α*\*=0.0909, *β*\*=0.074, which in turn, by (11) and (12),

The decision boundaries for a test planed on the basis of these parameters are shown in

Figure 13 shows the exact values of the functions *OC*(Φ) and *ASN*(Φ) as per eqs. (13) – (18), which in turn yield the test's real characteristics: Φ0=5, *d*=2, *αreal* =0.098, *βreal* =0.099, *RASN*=9.2%, in very close agreement with the given (42) and (43) – evidence of the high

Fig. 13. OC and ASN of truncated group test and of non-truncated theoretical (subscript *nTr*)

*<sup>b</sup>* for 0=5, 0*<sup>g</sup>*=41/3, *d*=2,

test; normalised expected duration of group test *ATDg*()/

*real*=0.099, *rbMax*=66, *rnMax*=22. (Michlin et al., 2011).

0 0 <sup>3</sup> 13 /15 4 *<sup>g</sup>* (44)

we have

yielded *h'*

accuracy of eqs. (30) – (35).

Figure 2.

*real*=0.098,

1

off, the TA coordinates: *rbMax*=66, *rnMax*=22.

*<sup>b</sup>*=4.804, *hn*=4.453.

$$
\Phi\_{\mathcal{g}} = \Phi \cdot \mathcal{N}\_b / \mathcal{N}\_n \tag{40}
$$

Thus when *Nb*=*Nn*= *N*, the test boundaries remain as in the two-item case, except that the test duration is also *N* times shorter (see (18)). When *Nb*≠*Nn*, it is recommended to check the efficacy of larger groups, e.g. in terms of a shorter average test duration *ATDg*(*Φ*). By (18) and (40) we obtain:

$$\mathrm{ATD}\_{\mathcal{g}}\left(\Phi\_{\mathcal{g}}\right) = \left(\theta\_{\mathcal{b}}/N\_{\mathcal{b}}\right) \cdot \mathrm{ASN}\_{\mathcal{g}}\left(\Phi\_{\mathcal{g}}\right) \Big/ \left(1 + 1/\Phi\_{\mathcal{g}}\right) \tag{41}$$

where *ASNg*(Φ*g*) is the ASN of the group test as per (17) or (22), except for Φ*g* replacing Φ of (40).

The planning example covers also the problem of choice of *Nb* and *Nn*, while ensuring min *ATDg* and satisfying additional essential test-planning conditions.

#### **7. Example of test planning**

A large organisation operates a correspondingly large body of mobile electronic apparatus whose MTBF is substantially shortened under the stressful exploitation conditions. The manufacturer offers to modify this equipment, thereby significantly improving its resistance to external impacts, albeit at increased weight and cost.

In a fast laboratory test the modified (hereinafter "new") apparatus exhibits high reliability, but so does the original ("basic") one. Accordingly, it is decided to check the MTBF increase under field conditions on an experimental batch.

The requirements regarding the test OC are established as follows. If the MTBF of the new product is 5 times that of the basic (Φ=5), replacement is beneficial; at Φ=2.5 it does no harm; but at Φ=1.5 it is unacceptable. These findings follow from the *OCnTr* of a non-truncated SPRT with *α*==0.1, *d*=2, Φ0=5 (Figure 13), constructed as per (23) – (24).

The apparatus are operated in sets of 28 items, so that conditions within a set are practically uniform. Each set comprises both new and basic items, so as to offset the influence of fluctuating conditions.

A "failure" in this context is defined as any event that necessitates repair or re-tuning of the item, with enforced idleness for more than 20 seconds. The failed item is either treated in situ – or replaced by a spare, repaired and stored with the spares. Thus the size of the operative set remains 28.

The assignment is – planning a truncated test with the proportions of new and basic items in the test group chosen so as to ensure a minimal ATD. Below is the planning procedure:

a. As the OC's are practically the same for truncated and non-truncated tests when their Φ0, *d*, *αreal* and *βreal* coincide (Michlin & Grabarnik, 2007) – we chose the initial parameters given above:

$$\spadesuit\_0 = \sf{5}, \; d = \sf{2}, \; a\_{\wr} = \beta\_{\wr} = 0.1 \tag{42}$$

and specified

$$R\_{\text{ASN\\_max}} = 10\% \tag{43}$$

Thus the test has an ASN and ATD close to that of the non-truncated SPRT, and at the same time its maximal duration is heavily restricted, a fact of practical importance for the organisation.

Thus when *Nb*=*Nn*= *N*, the test boundaries remain as in the two-item case, except that the test duration is also *N* times shorter (see (18)). When *Nb*≠*Nn*, it is recommended to check the efficacy of larger groups, e.g. in terms of a shorter average test duration *ATDg*(*Φ*). By (18)

where *ASNg*(Φ*g*) is the ASN of the group test as per (17) or (22), except for Φ*g* replacing Φ

The planning example covers also the problem of choice of *Nb* and *Nn*, while ensuring min

A large organisation operates a correspondingly large body of mobile electronic apparatus whose MTBF is substantially shortened under the stressful exploitation conditions. The manufacturer offers to modify this equipment, thereby significantly improving its resistance

In a fast laboratory test the modified (hereinafter "new") apparatus exhibits high reliability, but so does the original ("basic") one. Accordingly, it is decided to check the MTBF increase

The requirements regarding the test OC are established as follows. If the MTBF of the new product is 5 times that of the basic (Φ=5), replacement is beneficial; at Φ=2.5 it does no harm; but at Φ=1.5 it is unacceptable. These findings follow from the *OCnTr* of a non-truncated

A "failure" in this context is defined as any event that necessitates repair or re-tuning of the item, with enforced idleness for more than 20 seconds. The failed item is either treated in situ – or replaced by a spare, repaired and stored with the spares. Thus the size of the

The assignment is – planning a truncated test with the proportions of new and basic items in the test group chosen so as to ensure a minimal ATD. Below is the planning procedure: a. As the OC's are practically the same for truncated and non-truncated tests when their Φ0, *d*, *αreal* and *βreal* coincide (Michlin & Grabarnik, 2007) – we chose the initial

Thus the test has an ASN and ATD close to that of the non-truncated SPRT, and at the same time its maximal duration is heavily restricted, a fact of practical importance for

*tg*=0.1 (42)

*RASN max* =10% (43)

=0.1, *d*=2, Φ0=5 (Figure 13), constructed as per (23) – (24). The apparatus are operated in sets of 28 items, so that conditions within a set are practically uniform. Each set comprises both new and basic items, so as to offset the influence of

*ATDg g*

*ATDg* and satisfying additional essential test-planning conditions.

to external impacts, albeit at increased weight and cost.

under field conditions on an experimental batch.

and (40) we obtain:

**7. Example of test planning** 

of (40).

SPRT with *α*=

fluctuating conditions.

operative set remains 28.

and specified

the organisation.

parameters given above:

Φ0=5, *d*=2, *αtg*=

*<sup>g</sup> N Nb n* (40)

*b b N ASNgg g* 1 1 (41)

b. Eqs. (41) and (18) yielded the approximate dependences of *ATDg*(Φ)/*θb* on *Nn* for different Φ, given *Nn*+ *Nb*=28. A minimum was found at *Nn*≈18. Figure 14 shows examples of these dependences at Φ= Φ0 and Φ= Φ1, which are seem to be almost flat over a wide interval around the minimum, and *Nn*=15 was chosen accordingly. With this choice, *ATDg*(Φ) only slightly exceeds the minimum, while the number of new items is lower, with the attendant saving in preparing the experimental batch. By (40) we have

$$
\Phi\_{0g} = \Phi\_0 \cdot 1\Im / \, 1\Im = 4\,\text{\AA}\,\text{\AA}\tag{44}
$$

 The values of *ASNg*(Φ) and *ATD*(Φ), obtained by (41) and (18) with allowance for (44) – confirmed the practicability of the test.

c. Eq. (8) yielded *s*=0.330. Simultaneous solution of (29) and (30) yielded, after roundingoff, the TA coordinates: *rbMax*=66, *rnMax*=22.

Eqs. (33) through (35) yielded *α*\*=0.0909, *β*\*=0.074, which in turn, by (11) and (12), yielded *h' <sup>b</sup>*=4.804, *hn*=4.453.

The decision boundaries for a test planed on the basis of these parameters are shown in Figure 2.

Figure 13 shows the exact values of the functions *OC*(Φ) and *ASN*(Φ) as per eqs. (13) – (18), which in turn yield the test's real characteristics: Φ0=5, *d*=2, *αreal* =0.098, *βreal* =0.099, *RASN*=9.2%, in very close agreement with the given (42) and (43) – evidence of the high accuracy of eqs. (30) – (35).

Fig. 13. OC and ASN of truncated group test and of non-truncated theoretical (subscript *nTr*) test; normalised expected duration of group test *ATDg*()/*<sup>b</sup>* for 0=5, 0*<sup>g</sup>*=41/3, *d*=2, *real*=0.098, *real*=0.099, *rbMax*=66, *rnMax*=22. (Michlin et al., 2011).

Comparison Sequential Test for Mean Times Between Failures 473

It was established that the basic test characteristics *αreal*, *βreal*, *RASN* depend monotonically

At the search limits for these absolute terms, determined in Section 5, these

 *αreal* and *βreal* change stepwise with the smooth changes in the absolute terms of the oblique boundaries; expressions are derived for the minimal intervals of these terms,

These and other established regularities yielded an efficacious algorithm and

 The found links between the input and output characteristics of the test, and the fastworking algorithm for its planning, permit improvement of the planning methodology

 On the basis of the above body of information, regressional relationships were derived for determining the TA coordinates and oblique-boundary parameters of the optimal tests. Also derived were formulae for the limits of the latter parameters. These are very close at low *d* and *RASN* and draw apart as the characteristics increase; the reason being increasing influence of the test's discreteness. The regressional relationships and boundary-parameter limits permit quick determination of these boundaries for the

The methodology is also applicable in group tests, with the attendant time economy;

The authors are indebted to Mr. E. Goldberg for editorial assistance, and to MSc students of the "Quality Assurance and Reliability" Division of the Technion: Mrs. E. Leshchenko, and Messrs. Y. Dayan, D. Grinberg, Y. Shai and V. Kaplunov, who participated in different

The project was supported by the Israel Ministry of Absorption and the Planning and

moreover, it permits optimisation of the respective group sizes. A planning and implementation example of this test is presented.

Budgeting Committee of the Israel Council for Higher Education.

on the absolute terms in the equations of the oblique test boundaries.

programme for determining the optimal location of the test boundaries.

dependences are almost plane.

over which *αreal* and *βreal* remain unchanged.

and its extension to all binomial truncated SPRT.

optimal test with specified characteristics.

**9. Acknowledgements** 

stages of this project.

**10. Acronyms** 

ADP accept decision point

ASN average sample number ATD average test duration

OC≡ *Pa*() operating characteristic

RMSE root mean square error

RDP reject decision point

OTA truncation apex of the optimal test

SPRT sequential probability ratio test

AL accept line

MTBF mean TBF

RL reject line

The *OC*(Φ) of the planned test (Figure 13) practically coincides with that of the nontruncated test *OCnTr*(Φ) with the same *αreal* and *βreal*. The ASN of the former is higher than that of the latter, in accordance with *RASN*=9.2%. The diagram also shows the estimate for the normalised ATD, i.e. the ratio *ATDg*(Φ)/*θb*. Assuming ˆ 10 hr *<sup>b</sup>* , the time requirement of the test should be reasonable. In practice, it ended with acceptance of the null hypothesis in 16 hr, following the twenty-first failure in the basic subgroup, by which time a total of 2 failures in the new subgroup had been observed.

Fig. 14. Normalised expected group test duration vs. number of new devices, for =0, and =1. (Michlin et al., 2011).

## **8. Conclusion**

The example in Section 7 demonstrated the potential of the proposed planning methodology for a truncated discrete SPRT. An innovative feature in it are the test-quality characteristics *RASN* and *RD* – which represent, respectively, increase of the ASN on truncation and closeness of the test OC to the non-truncated one. This innovation permitted comparison of different SPRT and automatisation of the optimum-choice process. It was found that over a large domain about the solution, the *RASN* and boundary parameters are linked monotonically and almost linearly. This implies sound choice of this characteristic and simplifies the planning. An efficacious search algorithm was developed for the optimal test boundaries, incorporating the obtained interrelationships.

The findings can be summed up as follows:

 A truncated SPRT was studied with a view to checking the hypothesis on the ratio of the MTBF of two objects with exponential distribution of TBF.

The *OC*(Φ) of the planned test (Figure 13) practically coincides with that of the nontruncated test *OCnTr*(Φ) with the same *αreal* and *βreal*. The ASN of the former is higher than that of the latter, in accordance with *RASN*=9.2%. The diagram also shows the estimate for the

the test should be reasonable. In practice, it ended with acceptance of the null hypothesis in 16 hr, following the twenty-first failure in the basic subgroup, by which time a total of 2

1 3 5 7 9 11 13 15 17 19 21 23 25 27

**New devices number,** *Nn*

Fig. 14. Normalised expected group test duration vs. number of new devices, for =0, and

The example in Section 7 demonstrated the potential of the proposed planning methodology for a truncated discrete SPRT. An innovative feature in it are the test-quality characteristics *RASN* and *RD* – which represent, respectively, increase of the ASN on truncation and closeness of the test OC to the non-truncated one. This innovation permitted comparison of different SPRT and automatisation of the optimum-choice process. It was found that over a large domain about the solution, the *RASN* and boundary parameters are linked monotonically and almost linearly. This implies sound choice of this characteristic and simplifies the planning. An efficacious search algorithm was developed for the optimal test

A truncated SPRT was studied with a view to checking the hypothesis on the ratio of

boundaries, incorporating the obtained interrelationships.

the MTBF of two objects with exponential distribution of TBF.

The findings can be summed up as follows:

ATDg(F0)

*ATDg*(*Φ*0)

ATDg(F1)

*ATDg*(*Φ*1)

*<sup>b</sup>* , the time requirement of

normalised ATD, i.e. the ratio *ATDg*(Φ)/*θb*. Assuming ˆ 10 hr

failures in the new subgroup had been observed.

0

=1. (Michlin et al., 2011).

**8. Conclusion** 

1

2

*ATDg***()/**

 *b*

3

4

5

6


## **9. Acknowledgements**

The authors are indebted to Mr. E. Goldberg for editorial assistance, and to MSc students of the "Quality Assurance and Reliability" Division of the Technion: Mrs. E. Leshchenko, and Messrs. Y. Dayan, D. Grinberg, Y. Shai and V. Kaplunov, who participated in different stages of this project.

The project was supported by the Israel Ministry of Absorption and the Planning and Budgeting Committee of the Israel Council for Higher Education.

## **10. Acronyms**


Comparison Sequential Test for Mean Times Between Failures 475

Barnard, G. A. (1946). Sequential test in industrial statistics, *Journal of the Royal Statistical* 

Chandramouli, R.; Vijaykrishnan N. & Ranganathan, N. (1998). Sequential Tests for

Chien, W. T. K. & Yang, S. F. (2007). A New Method to Determine the Reliability

Drenick, R. F. (1960). The failure law of complex equipment. *The Journal of the Society for* 

Eisenberg, B., & Ghosh, B. K. (1991). The sequential probability ratio test. In: *Handbook of* 

Epstein, B. & Sobel, M. (1955). Sequential life test in the exponential case. *The Annals of* 

IEC 61650 (1997) *Reliability Data Analysis Techniques* – *Procedures for Comparison of Two* 

Kapur, K. C. & Lamberson, L. R. (1977). *Reliability in Engineering Design*. Wiley, NY, pp. 342-

Kececioglu, D. (1993). *Reliability & Life Testing: Handbook.* Vol. 1, Prentice Hall, NJ, pp. 133-

Mace, A. E. (1974). *Sample Size Determination*. Robert E. Krieger Pub. Co., NY, pp. 110-

Michlin, Y. H. & Grabarnik, G. (2007). Sequential testing for comparison of the mean time

Michlin, Y. H.; Grabarnik, G., & Leshchenko, L. (2009). Comparison of the mean time

Michlin, Y. H. & Grabarnik, G. (2010). Search boundaries of truncated discrete sequential

Michlin, Y. H.; Ingman, D. & Dayan, Y. (2011). Sequential test for arbitrary ratio of mean

Michlin, Y. H. & Kaplunov, V. (2007). Optimal truncation of comparison reliability tests

Michlin, Y. H. & Migdali, R. (2004). Test duration in choice of helicopter maintenance policy.

MIL-HDBK-781A (1996). *Reliability test methods, plans, and environments for engineering,* 

Siegmund, D. (1985). *Sequential Analysis: Tests and Confidence Intervals,* Springer, NY,

*Reliability Engineering & System Safety*, Vol. 86, No. 3, pp. 317-321.

*development, qualification, and production*. US DOD, pp. 32-42.

test. *Journal of Applied Statistics*. Vol. 37, No. 05, pp. 707-724.

*Israel Society for Quality*, Tel-Aviv, Nov. 2007, 6 pp.

between failures for two systems. *IEEE Transactions on Reliability*, Vol. 56, No. 2, pp.

between failures for two systems under short tests. *IEEE Transactions on Reliability*,

times between failures. *Int. J. of Operations Research and Information Systems*, Vol. 2,

under unequal types I and II error probabilities, *Proceedings of the 9th Conference of* 

*Industrial Applications of Mathematics*, Vol. 8, No. 4, pp. 680-689.

*Constant Failure Rates and Two Constant Failure (Event) Intensities.*

*Transactions on Reliability*, Vol. 56, No. 1, pp. 69–76.

*Mathematical Statistics*, Vol. 26, pp. 82-93.

Integrated-Circuit Failures, *IEEE Transactions on Reliability*. Vol. 47, No. 4, pp. 463–

Comparability for Products, Components, and Systems in Reliability Testing. *IEEE* 

*Sequential Analysis*, B. K. Ghosh, Sen P.K (Ed.), pp. 47-66, Marcel Dekker,

*Society*. Suppl., Vol. 8, pp. 1-21.

471.

NY.

363.

156.

114.

321-331.

Vol. 58, No. 4, pp. 589-596.

No. 1, pp. 66-81.

pp. 34-63.

## **11. Notations**


## **12. References**

Aroian L. A. (1968). Sequential analysis-direct method. *Technometrics*. Vol. 10, pp. 125- 132.

*c* with the appropriate subscripts, coefficients in the approximative

*RASN* relative excess of the ASN of the truncated test over its non-truncated

computed for prescribed stopping boundaries

*h'b*, *hn* absolute terms of Accept, and Reject oblique boundaries, respectively

*Nb*, *Nn* item numbers of "basic" and "new" subgroups in group test

*PR*() probability of new system failing next during test *rb, rn* system number of failures observed up to time T

*RD* relative deviation *αreal* and *βreal* from their targets

 and 

*α\*, β\** parameters determining the constant terms of initial boundary lines

Φ0 Φ value for which the null hypothesis is rejected with probability *α* Φ1 Φ value for which the null hypothesis is rejected with probability 1-*β*

 regressional value, upper and lower search limits of *α\** and *β\* θ, θb, θn* MTBF, same for the basic system *θb*, and for the new system *θn* respectively

Aroian L. A. (1968). Sequential analysis-direct method. *Technometrics*. Vol. 10, pp. 125-

*TAb*, *TAn rb*- and *rn*-coordinates of TA, respectively *x* common target value for *α* and *β*, *x*= *αtg*=*βtg α, β* probabilities of I- and II-type errors in test

*PADP*(*rn*,), *PRDP*(*rb*,) probabilities of reaching the given points ADP, RDP

*ASN*() exact value of ASN for a truncated test, obtained recursively (17) *ASNnTr*() ASN calculated via an analytical formula (22) for a non-truncated test

TA truncation apex

WAS program name

 equations *d*= Φ0/ Φ1 discrimination ratio

*ATD*() ATD function for given

**11. Notations** 

TBF time between failures or time to failure

*Pa*()≡OC acceptance probability of H0 at given Φ

( ) *bADP n r r* rb-coordinates of ADP for given rn ( ) *nRDP b r r rn*-coordinates of RDP for given *rb R*2 coefficient of determination

*Rd*0 and *RASN*0 threshold values of *Rd* and *RASN s* slope of oblique boundaries

counterpart

*T* current test time

*αreal, βreal* exact real values of

*αtg, βtg* target values of *α, β*

 

true MTBF ratio

*U LMUL*

Φ*<sup>g</sup>* Φ for group test

*<sup>M</sup>* , , , , ,

**12. References** 

132.

 *n b* /

 


**26** 

**Dependence of Determination Quality on** 

**Technique, Exemplified by the Electron Probe** 

*Vinogradov Institute of Geochemistry, Siberian Branch of Russian Academy of Sciences,* 

The quality of results obtained by any analytical method depends on every stage of data acquisition: representativeness of study object; appropriate sample preparation; optimum conditions for analytical signal excitation and registration; availability of reference materials for comparison; procedure to process acquired values referred to the content to be determined. These characteristics vary in different analytical methods. In some cases, the sample preparation represents the major source for analytical errors, in some others, the complexities arise from the incorrect selection of calibrating plot, and thus availability of reference materials for comparison is essential. The technique specifications pose the

The problem of quality has ever been critical in analytical work, and every time it depends

Quality has emerged and remained the dominant theme in management thinking since the

The electron probe X-ray microanalysis is a fairly young technique. The first papers describing the basics of electron probe microanalysis (EPMA) (Castaing, 1951; Borovskii, 1953) and original designs and constructions of microanalyzers (Castaing & Guinier, 1953; Borovskii & Il'in, 1956) were published in 1951-1956 in France and the USSR. The technique was rapidly progressing. In 1973 Borovskii (Borovskii, 1973), the founder of EPMA in Russia, admitted that one could hardly identify the fields of science and engineering, where the EPMA had not been successfully used. The instruments and theory were developing

At present it is difficult to overestimate the significance and application of the method. It is one of the leading methods in mineralogy, and similarly in metallurgy and biology. The investigations of the micro-level are required at approbation of technological processes in all

on the level of progress in the theory and application of selected technique.

**2. Quality of the electron probe X-ray microanalysis at each stage** 

**1. Introduction** 

simultaneously.

fields of science and engineering.

requirements to every stage of analysis.

mid-twentieth century (Beckford, 2010).

**Performance Capacity of Researching** 

**X-Ray Microanalysis** 

Liudmila Pavlova

*Irkutsk Russia* 


## **Dependence of Determination Quality on Performance Capacity of Researching Technique, Exemplified by the Electron Probe X-Ray Microanalysis**

Liudmila Pavlova

*Vinogradov Institute of Geochemistry, Siberian Branch of Russian Academy of Sciences, Irkutsk Russia* 

## **1. Introduction**

476 Modern Approaches To Quality Control

Sr-332. (2001). *Reliability prediction procedure for electronic equipment*., Telcordia Technologies

Wald, A. & Wolfowitz, J. (1948). Optimum character of the sequential probability ratio test.

*The Annals of Mathematical Statistics*, Vol. 19, No. 3, pp. 326-339.

Inc.,. Red Bank, NJ, Section 2.4.

Wald, A. (1947). *Sequential Analysis*, John Wiley & Sons, NY.

The quality of results obtained by any analytical method depends on every stage of data acquisition: representativeness of study object; appropriate sample preparation; optimum conditions for analytical signal excitation and registration; availability of reference materials for comparison; procedure to process acquired values referred to the content to be determined. These characteristics vary in different analytical methods. In some cases, the sample preparation represents the major source for analytical errors, in some others, the complexities arise from the incorrect selection of calibrating plot, and thus availability of reference materials for comparison is essential. The technique specifications pose the requirements to every stage of analysis.

The problem of quality has ever been critical in analytical work, and every time it depends on the level of progress in the theory and application of selected technique.

Quality has emerged and remained the dominant theme in management thinking since the mid-twentieth century (Beckford, 2010).

## **2. Quality of the electron probe X-ray microanalysis at each stage**

The electron probe X-ray microanalysis is a fairly young technique. The first papers describing the basics of electron probe microanalysis (EPMA) (Castaing, 1951; Borovskii, 1953) and original designs and constructions of microanalyzers (Castaing & Guinier, 1953; Borovskii & Il'in, 1956) were published in 1951-1956 in France and the USSR. The technique was rapidly progressing. In 1973 Borovskii (Borovskii, 1973), the founder of EPMA in Russia, admitted that one could hardly identify the fields of science and engineering, where the EPMA had not been successfully used. The instruments and theory were developing simultaneously.

At present it is difficult to overestimate the significance and application of the method. It is one of the leading methods in mineralogy, and similarly in metallurgy and biology. The investigations of the micro-level are required at approbation of technological processes in all fields of science and engineering.

Dependence of Determination Quality on Performance

pastes.

layer.

**2.2.1 Particle preparation** 

Capacity of Researching Technique, Exemplified by the Electron Probe X-Ray Microanalysis 479

**a b** c **d** 

**e f g h** 

Fig. 1. The gold inclusion found in the mineral only after the third try of surface polishing. for the electron probe microanalysis is in many ways still as much of an art as a science (Goldstein et al., 1992). Different procedures are applied in EPMA for sample preparation. The solid samples for EPMA may be thin sections, thick micro sections, briquette sections and isolated particles. The preparation of polished thin sections and thick micro sections consists in selecting sized solid material, its cutting, polishing selected surface with diamond

When examining the grinded substance the particles should be fixed so that they are not scattered in air and retain the representativity of material when investigated in the vacuum microanalyzer. Various preparation procedures are used to analyse different solid particles (Pavlova et al., 2001): (1) fixing particles on substrate with colloid; (2) pasting particles on the carbon double-faced adhesive tape; (3) preparing briquette sections. In the first case particles are fixed on the polished surface of the substrate with collodion. The particles are distributed as a thin layer on the surface of the substrate, which is preliminarily covered by a thin layer of the liquid collodion. While drying the collodion fixes the particles on the surface. Gluing particles on the carbonic adhesive tape is commonly applied when studying conductive materials. In this case the glued particles cannot be covered by the conductive

Two techniques to prepare briquette thin sections: 1) Particles of any solid material are mixed with epoxy resin, and after the surface is hardened it is polished. 2) Grains of any solid material are glued on the adhesive tape and coated with epoxy resin. After the resin is hardened, the sample is removed from the adhesive tape and the surface with particles is polished to make it mirror-smooth. Due to this procedure plenty of grains are included in the same puck. The briquette thin sections with particles are often used for quantitative determinations of particle composition using the wave spectrometers applied for studying horizontal well polished surfaces. Table 1 presents the data on the comparison of two garnet

particles composition processed by different methods of sample preparation.

The quality of results is of prime importance for researchers in all fields of science. The specifics of the method related to obtaining information suggest it to be the research technique, thus intensifying the problem of determination quality, rather than the analytical method. The studies on developing the theoretical foundation of the method and upgrading the instruments, reported in numerous publications, and partly mentioned in the articles reviewed by authors of articles (Szaloki et al., 2004; Pavlova et al., 2000), allow the way of improving quality of the electron probe X-ray microanalysis to be observed. The topical studies undertaken by the author are included into this chapter.

#### **2.1 Representativeness of materials**

The representativeness of the sample substance is initially defined when posing problem, and it depends on the requirements of particular analytical technique. These requirements imply the subsample weight, homogeneity of components, and particle size in the subsample, solubility and miscibility of subsample substance with a binding substance or a solvent, and others.

In case of EPMA the representativeness of determinant, namely the quantity of samples and size of the surface, prepared for examination, depend on the frequency of component occurrence in material, probability of their occurrence on the prepared surface and their phase distribution over the investigated surface. In electron probe microanalysis, when we study the inclusions rarely occurring in the groundmass, it is essential to have a sufficient amount of the geological substance to be examined.

In EPMA a correct solution of the problem posed is dependent on the frequency of determinant occurrence within the observation zone. With EPMA, an absence on the studied surface of the element to be defined is not suggestive of its complete lack in the sample. It might be assumed, that the sought element has skipped from the study zone.

It can be exemplified by searching for the invisible gold in lithochemical stream sediments of the Dukat gold-silver deposit in northeastern Russia. Initially, the studies of rock in thin and polished sections did not provide wanted results - fine gold inclusions have not been detected. The probability of gold inclusion occurrence on the studied surface was negligibly small. Only having extracted the heavy fraction and prepared the briquette thin sections and after locating grains on the surface and polishing thin sections and thoroughly studied numerous grains in the thin section we managed to obtain positive results.

If the sought inclusion had not been found on the surface, a thin layer of substance was removed, and researched through entire sample. The process was being repeated until the sought inclusion was found (Fig. 1). If the grains of heavy fraction were completely polished down a new briquette thin section of the same sample was prepared and searching was continued. Figure 1 presents the gold inclusion found in the mineral only after the third try of surface polishing. The size of the inclusions is 10 µm, while the area of thin section is about 25mm2. In such cases the quality of investigations and conclusion correctness result from both correctly selected and prepared material and thorough search.

#### **2.2 Sample preparation**

In any technique sample preparation is truly important, that is decisive for analytical procedures. In different analytical methods the laboriousness of sample preparation varies. Because the EPMA, in effect, is the analysis of a surface, the sample surface is required to be flat, well polished, smooth and clean and to have a good conductivity. Sample preparation

Fig. 1. The gold inclusion found in the mineral only after the third try of surface polishing.

for the electron probe microanalysis is in many ways still as much of an art as a science (Goldstein et al., 1992). Different procedures are applied in EPMA for sample preparation. The solid samples for EPMA may be thin sections, thick micro sections, briquette sections and isolated particles. The preparation of polished thin sections and thick micro sections consists in selecting sized solid material, its cutting, polishing selected surface with diamond pastes.

## **2.2.1 Particle preparation**

478 Modern Approaches To Quality Control

The quality of results is of prime importance for researchers in all fields of science. The specifics of the method related to obtaining information suggest it to be the research technique, thus intensifying the problem of determination quality, rather than the analytical method. The studies on developing the theoretical foundation of the method and upgrading the instruments, reported in numerous publications, and partly mentioned in the articles reviewed by authors of articles (Szaloki et al., 2004; Pavlova et al., 2000), allow the way of improving quality of the electron probe X-ray microanalysis to be observed. The topical

The representativeness of the sample substance is initially defined when posing problem, and it depends on the requirements of particular analytical technique. These requirements imply the subsample weight, homogeneity of components, and particle size in the subsample, solubility and miscibility of subsample substance with a binding substance or a

In case of EPMA the representativeness of determinant, namely the quantity of samples and size of the surface, prepared for examination, depend on the frequency of component occurrence in material, probability of their occurrence on the prepared surface and their phase distribution over the investigated surface. In electron probe microanalysis, when we study the inclusions rarely occurring in the groundmass, it is essential to have a sufficient

In EPMA a correct solution of the problem posed is dependent on the frequency of determinant occurrence within the observation zone. With EPMA, an absence on the studied surface of the element to be defined is not suggestive of its complete lack in the sample. It

It can be exemplified by searching for the invisible gold in lithochemical stream sediments of the Dukat gold-silver deposit in northeastern Russia. Initially, the studies of rock in thin and polished sections did not provide wanted results - fine gold inclusions have not been detected. The probability of gold inclusion occurrence on the studied surface was negligibly small. Only having extracted the heavy fraction and prepared the briquette thin sections and after locating grains on the surface and polishing thin sections and thoroughly studied

If the sought inclusion had not been found on the surface, a thin layer of substance was removed, and researched through entire sample. The process was being repeated until the sought inclusion was found (Fig. 1). If the grains of heavy fraction were completely polished down a new briquette thin section of the same sample was prepared and searching was continued. Figure 1 presents the gold inclusion found in the mineral only after the third try of surface polishing. The size of the inclusions is 10 µm, while the area of thin section is about 25mm2. In such cases the quality of investigations and conclusion correctness result

In any technique sample preparation is truly important, that is decisive for analytical procedures. In different analytical methods the laboriousness of sample preparation varies. Because the EPMA, in effect, is the analysis of a surface, the sample surface is required to be flat, well polished, smooth and clean and to have a good conductivity. Sample preparation

might be assumed, that the sought element has skipped from the study zone.

numerous grains in the thin section we managed to obtain positive results.

from both correctly selected and prepared material and thorough search.

studies undertaken by the author are included into this chapter.

**2.1 Representativeness of materials** 

amount of the geological substance to be examined.

solvent, and others.

**2.2 Sample preparation** 

When examining the grinded substance the particles should be fixed so that they are not scattered in air and retain the representativity of material when investigated in the vacuum microanalyzer. Various preparation procedures are used to analyse different solid particles (Pavlova et al., 2001): (1) fixing particles on substrate with colloid; (2) pasting particles on the carbon double-faced adhesive tape; (3) preparing briquette sections. In the first case particles are fixed on the polished surface of the substrate with collodion. The particles are distributed as a thin layer on the surface of the substrate, which is preliminarily covered by a thin layer of the liquid collodion. While drying the collodion fixes the particles on the surface. Gluing particles on the carbonic adhesive tape is commonly applied when studying conductive materials. In this case the glued particles cannot be covered by the conductive layer.

Two techniques to prepare briquette thin sections: 1) Particles of any solid material are mixed with epoxy resin, and after the surface is hardened it is polished. 2) Grains of any solid material are glued on the adhesive tape and coated with epoxy resin. After the resin is hardened, the sample is removed from the adhesive tape and the surface with particles is polished to make it mirror-smooth. Due to this procedure plenty of grains are included in the same puck. The briquette thin sections with particles are often used for quantitative determinations of particle composition using the wave spectrometers applied for studying horizontal well polished surfaces. Table 1 presents the data on the comparison of two garnet particles composition processed by different methods of sample preparation.

Dependence of Determination Quality on Performance

*AuL*

simultaneously produced.

to remove the accumulative charge.

**e** 

**2.2.3 The influence of surface on the quality of results** 

surface is either not flat or not horizontal the analytical signal is distorted.

**a b** 

**c d** 

Capacity of Researching Technique, Exemplified by the Electron Probe X-Ray Microanalysis 481

The distortion of horizontal position of surface (effect of absence of flat horizontal surface) is the cause of false conclusions and considerable deterioration of analytical results. If the

Figure 3 presents the pattern of x-ray radiation distribution of manganese in Mn-pure (a) and gold in Au-pure (b). Samples of pure Mn and Au have flat polished, even if not horizontal surfaces, displaying the x-ray intensity distortion. Manganese shows decrease in intensity to the right and to the left of center (Fig. 3a), because the sample surface is tilted relative to the center: the right part is higher, and the left one is lower. In Fig. 3b the gold particle bottom is in focus, but the top part is elevated toward horizon, therefore

 intensity is deformed in the top markedly lower, though the sample is homogeneous, but some inclusions. The gold image in backscattered electrons does not exhibit the surface inclination (Fig. 3c). Both gold images in Fig. 3b and Fig. 3c were

Because the grains of majority of natural samples are dielectrics, a layer of carbon (20-30 nm thick) is vacuum-sprayed onto the polished surface of all tablets to make it conductive and

Fig. 2. The sponge surface prepared for EPMA studies. The image is given in back- scattered electrons. Section of whole sponge in epoxy resin (a). Section of sponge part (b). Sections

**f** 

several separate sponge spicules (c, d). Cross-sections of sponge spicules (e, f).


Table 1. Compared compositions of two garnet particles processed by different methods of sample preparation. Relative error=100\*(C-Ccer)/Ccer; C- is concentration; Ccer – is certified concentration.

The composition of non-polished particles is not determined with wave spectrometers splitting the X-ray spectrum by the wave length. The quality of determinations is low and the error can reach as high as tens percent. When the particles are glued on the substratum and adhesive tape it is feasible to study the shape and size of particles; when using the energy-dispersive spectrometer it is possible to identify (i) what elements compose grains, (ii) how elements are distributed over the surface, (iii) element contents.

### **2.2.2 Preparation of biological samples**

The surface suitable for the analysis is hard to receive in examining porous samples, which are often biological samples. Preparation of biological materials is differently approached. For example, sponges are first rinsed in distilled water, then dehydrated in alcohol, freed from alcohol with acetone and impregnated with epoxy resin (Pavlova et al., 2004). The samples obtained are fit in one or some briquette sections. The briquette sections with specimens are polished with diamond paste to get the surface flat and mirror-smooth. The Figure 1 displays the sponge image. The solid part of the sponge, its skeleton consists of spicules. This kind of preparation of fragile biological specimens ensures intact solid part of sponge. It avoids distortions due to destructions when polishing. With this procedure we determine silicon concentration in the center of spicule cross-section and on its margins: they are higher in the center than in the margins.

## **2.2.3 The influence of surface on the quality of results**

480 Modern Approaches To Quality Control

Preparation Non-polished particles Polished particles Analytical method EDS WDS EDS WDS

ion, wt. % Relative error, % Concentrat

*MgO* 20 20,59 *2,95* 21,325 6,63 20,91 *4,55* 19,93 *-0,35 Al*2*O*<sup>3</sup> 23,4 23,62 *0,94* 21,286 -9,03 23,19 *-0,90* 23,36 *-0,17*  <sup>2</sup> *SiO* 42,3 42,55 *0,59* 43,527 2,9 42,07 *-0,54* 42,56 *0,61 CaO* 4,03 4,14 *2,73* 3,06 -24,02 4,34 *7,69* 4,03 *0,00 MnO* 0,17 0,07 *-58,82* 0,12 -29,41 0,16 *-5,88* 0,16 *-5,88 FeO* 10,1 9,3 *-7,92* 9,63 -4,65 9,36 *-7,33* 10,04 *-0,59* 

*MgO* 21,09 22,61 *7,21* 23,46 11,24 21,25 *0,76* 20,93 *-0,76 Al*2*O*<sup>3</sup> 18,09 17,73 *-1,99* 19,97 10,39 18,86 *4,26* 17,84 *-1,38*  <sup>2</sup> *SiO* 41,52 42,24 *1,73* 42,98 3,52 42,27 *1,81* 41,94 *1,01 CaO* 3,4 3,7 *8,82* 3,94 15,88 3,62 *6,47* 3,38 *-0,59 Cr*2*O*<sup>3</sup> 7,41 6,59 *-11,07* 6,89 -7,02 7,09 *-4,32* 7,3 *-1,48 MnO* 0,32 0,21 *-34,38* 0,27 -15,63 0,534 *66,88* 0,34 *6,25 FeO* 7,59 6,85 *-9,75* 6,57 -13,44 6,163 *-18,8* 7,41 *-2,37* 

Table 1. Compared compositions of two garnet particles processed by different methods of sample preparation. Relative error=100\*(C-Ccer)/Ccer; C- is concentration; Ccer – is

The composition of non-polished particles is not determined with wave spectrometers splitting the X-ray spectrum by the wave length. The quality of determinations is low and the error can reach as high as tens percent. When the particles are glued on the substratum and adhesive tape it is feasible to study the shape and size of particles; when using the energy-dispersive spectrometer it is possible to identify (i) what elements compose grains, (ii) how elements are distributed over the surface, (iii)

The surface suitable for the analysis is hard to receive in examining porous samples, which are often biological samples. Preparation of biological materials is differently approached. For example, sponges are first rinsed in distilled water, then dehydrated in alcohol, freed from alcohol with acetone and impregnated with epoxy resin (Pavlova et al., 2004). The samples obtained are fit in one or some briquette sections. The briquette sections with specimens are polished with diamond paste to get the surface flat and mirror-smooth. The Figure 1 displays the sponge image. The solid part of the sponge, its skeleton consists of spicules. This kind of preparation of fragile biological specimens ensures intact solid part of sponge. It avoids distortions due to destructions when polishing. With this procedure we determine silicon concentration in the center of spicule cross-section and on its margins:

ion, wt. % Relative error, % Concentrat

ion, wt. % Relative

error, %

Sample Oxide Certified concent-

Garnet O-145

Garnet C-153

certified concentration.

element contents.

**2.2.2 Preparation of biological samples** 

they are higher in the center than in the margins.

ration, wt. % Concentrat

ion, wt. % Relative error, % Concentrat

The distortion of horizontal position of surface (effect of absence of flat horizontal surface) is the cause of false conclusions and considerable deterioration of analytical results. If the surface is either not flat or not horizontal the analytical signal is distorted.

Figure 3 presents the pattern of x-ray radiation distribution of manganese in Mn-pure (a) and gold in Au-pure (b). Samples of pure Mn and Au have flat polished, even if not horizontal surfaces, displaying the x-ray intensity distortion. Manganese shows decrease in intensity to the right and to the left of center (Fig. 3a), because the sample surface is tilted relative to the center: the right part is higher, and the left one is lower. In Fig. 3b the gold particle bottom is in focus, but the top part is elevated toward horizon, therefore *AuL* intensity is deformed in the top markedly lower, though the sample is homogeneous, but some inclusions. The gold image in backscattered electrons does not exhibit the surface inclination (Fig. 3c). Both gold images in Fig. 3b and Fig. 3c were simultaneously produced.

Because the grains of majority of natural samples are dielectrics, a layer of carbon (20-30 nm thick) is vacuum-sprayed onto the polished surface of all tablets to make it conductive and to remove the accumulative charge.

Fig. 2. The sponge surface prepared for EPMA studies. The image is given in back- scattered electrons. Section of whole sponge in epoxy resin (a). Section of sponge part (b). Sections several separate sponge spicules (c, d). Cross-sections of sponge spicules (e, f).

Dependence of Determination Quality on Performance

Henke\*, 1967

determination depends on choice of absorption coefficients.

should be the same not to deteriorate the quality of results.

conditions for any method of analytical chemistry.

**2.3.1 The criterion of minimum detection limit** 

measurement conditions (Paradina @ Pavlova, 1999).


**2.3 Optimum conditions to excite and register analytical signals** 

Emitter *CK*

1986)

Authors (Heinrich,

Carbon

Athor-Heinrich, 1986

Athor – Henke\*, 1967

Athor – Henke, 1993

comparison data.

1969).

Radiation of *SrL*

 -, *BaL*

Relative deviation, %

Capacity of Researching Technique, Exemplified by the Electron Probe X-Ray Microanalysis 483

absorber 2147 2292 1960 23585 21784 25000 11575 9079 12100

Table 3. X-ray absorption coefficients (centimeter2/g) in the carbon and relative deviations in the data of different authors. **\***Henke's data from work of Saloman (Saloman et al., 1988). Relative deviation=(Author-Comp)/Author\*100%. Author - is data of author; Comp – is

It might be assumed how the quality light elements (carbon, nitrogen and oxigen)

The thickness of carbonic film on the studied surface and on the sample for comparison

Ensuring a high quality of results depends on uniformity of analytical signal through the time of observation. The conditions of exciting and registering analytical signal are to provide such uniformity. Selection of optimum conditions to excite and register analytical signals is the major condition to obtain correct information on a sample. It is one of the main

With EPMA applied the surface of different samples: glassy materials, sponges, bones, argentiferous samples and others can be destroyed during excitation with x-radiation, when electron probe falls on the sample surface, and as this takes place, the analytical signals become heavily contorted. Selection of optimum conditions of measurement can be based on the criteria of (a) minimum detection limit of sought elements, (b) uniformity of analytical signal during measurement, (c) variations of element intensity depending on the electron beam density or (d) sample stability while performing measurements (Buseck @ Goldstein,

The detection limit variations depending on measurement conditions were identified for scandium, strontium and barium in basalt glasses. Figure 4 illustrates the plotted variations of detection limits for scandium, strontium and barium in basalt glasses depending on

accelerating voltages, counting times and probe currents. The curves show that the optimum conditions for electron probe microanalysis with wavelength spectrometers (WD EPMA) of


Henke\*, 1967



8,7 14,5 - -6,0 -14,8 - -4,5 -33,3 -

*OK*

(Heinrich, 1986)

(Henke, 1993)

(Henke, 1993)

Henke\*, 1967

*NK*

(Heinrich, 1986)

(Henke, 1993)

Fig. 3. Patterns of x-ray radiation distribution of manganese (a) and gold (b) in Mn- and Aupure samples. The samples have flat polished but not horizontal surfaces.

The mass absorption coefficients are basic quantities used in calculations of the penetration and the energy deposition by photons of x-ray in biological, shielding and other materials. The different authors offer special absorption coefficients of x-ray radiation in the same element, specifically in carbon. Varying mass absorption coefficients defined in about twenty articles are discussed in the work (Hubbell et al., 2011). In Table 2 the x-ray absorption cross sections, determined by different authors for energy 0,277 keV in carbon have been compared with the experimental data contained in the National Bureau of Standards collection of measured x-ray attenuation data (Saloman et al., 1988)

The x-ray attenuation coefficients have been approximated by Finkelshtein and Farkov (Finkelshtein & Farkov, 2002). The article by Farkov with co-autors (Farkov et al., 2005) reports the data on compared absorption coefficients of nitrogen and oxygen radiation in carbon from different literature sources (Table 2). Table 3 presents the absorption coefficients of carbon, nitrogen and oxygen radiation in carbon, as well as relative deviations in the data of different authors.


Table 2. X-ray absorption cross sections, determinated by different authors (Saloman et al., 1988). XACS - is X-ray absorption cross sections of authors; Relative error= -EXPS - XACS)/ EXPS)\*100; EXPS - is experimental data contained in the National Bureau of Standards collection of measured x-ray attenuation data.

Fig. 3. Patterns of x-ray radiation distribution of manganese (a) and gold (b) in Mn- and Au-

The mass absorption coefficients are basic quantities used in calculations of the penetration and the energy deposition by photons of x-ray in biological, shielding and other materials. The different authors offer special absorption coefficients of x-ray radiation in the same element, specifically in carbon. Varying mass absorption coefficients defined in about twenty articles are discussed in the work (Hubbell et al., 2011). In Table 2 the x-ray absorption cross sections, determined by different authors for energy 0,277 keV in carbon have been compared with the experimental data contained in the National Bureau of

The x-ray attenuation coefficients have been approximated by Finkelshtein and Farkov (Finkelshtein & Farkov, 2002). The article by Farkov with co-autors (Farkov et al., 2005) reports the data on compared absorption coefficients of nitrogen and oxygen radiation in carbon from different literature sources (Table 2). Table 3 presents the absorption coefficients of carbon, nitrogen and oxygen radiation in carbon, as well as relative deviations

pure samples. The samples have flat polished but not horizontal surfaces.

**a b c** 

Standards collection of measured x-ray attenuation data (Saloman et al., 1988)

Denne D.R.

(70DE2)

Denne D.R.

(70DE1)

Weiswe-iler

% 3,7 -17 -40 -31,8 -6,6 -57,2 -17,5 -28,4 -22,5

Table 2. X-ray absorption cross sections, determinated by different authors (Saloman et al., 1988). XACS - is X-ray absorption cross sections of authors; Relative error= -EXPS - XACS)/ EXPS)\*100; EXPS - is experimental data contained in the National Bureau of Standards

W.

(68WE1)

5,600 4,569 3,850 4,09 5,056 3,43 4,587 4,200 4,400

Messner

R.H.

(33ME1)

Duncumb P.

& Melford

D.A.

(65DU1)

Kurtz H.

(28KU1)

Dershem, E.

& Schein, M.

(31DE1)

in the data of different authors.

Authors (Reference from the article of Saloman et al., 1988) Fomichev V.A. & Zhukova I.I. (68FO1) Henke et al. (67HE1)

collection of measured x-ray attenuation data.

XACS, barns/atom \* <sup>4</sup> 10

Relative error,


Table 3. X-ray absorption coefficients (centimeter2/g) in the carbon and relative deviations in the data of different authors. **\***Henke's data from work of Saloman (Saloman et al., 1988). Relative deviation=(Author-Comp)/Author\*100%. Author - is data of author; Comp – is comparison data.

It might be assumed how the quality light elements (carbon, nitrogen and oxigen) determination depends on choice of absorption coefficients.

The thickness of carbonic film on the studied surface and on the sample for comparison should be the same not to deteriorate the quality of results.

## **2.3 Optimum conditions to excite and register analytical signals**

Ensuring a high quality of results depends on uniformity of analytical signal through the time of observation. The conditions of exciting and registering analytical signal are to provide such uniformity. Selection of optimum conditions to excite and register analytical signals is the major condition to obtain correct information on a sample. It is one of the main conditions for any method of analytical chemistry.

With EPMA applied the surface of different samples: glassy materials, sponges, bones, argentiferous samples and others can be destroyed during excitation with x-radiation, when electron probe falls on the sample surface, and as this takes place, the analytical signals become heavily contorted. Selection of optimum conditions of measurement can be based on the criteria of (a) minimum detection limit of sought elements, (b) uniformity of analytical signal during measurement, (c) variations of element intensity depending on the electron beam density or (d) sample stability while performing measurements (Buseck @ Goldstein, 1969).

## **2.3.1 The criterion of minimum detection limit**

The detection limit variations depending on measurement conditions were identified for scandium, strontium and barium in basalt glasses. Figure 4 illustrates the plotted variations of detection limits for scandium, strontium and barium in basalt glasses depending on measurement conditions (Paradina @ Pavlova, 1999).

Radiation of *SrL* -, *BaL* - and *ScK* - lines is measured with the PET crystal for different accelerating voltages, counting times and probe currents. The curves show that the optimum conditions for electron probe microanalysis with wavelength spectrometers (WD EPMA) of

Dependence of Determination Quality on Performance

0,950

 

**2.3.3 Criterion of sample stability while performing measurements** 

(analytical signal is constant for counting time), if it obeys the relationship

*W m* / ): 1 – 191,00; 2 – 3,82; 3 – 2,54; 4 – 2,86; 5 – 3,06.

The X-ray intensity of calcium versus counting time (Fig. 6) with varying electron beam power density assessed for omul fish otoliths (Pavlova et al., 2003). This change of *CaK*

line intensity versus the electron beam power densities has been chosen as the criterion for selecting optimum conditions for analyzing the elements in omul fish otoliths. As seen on

The stability of argentiferous samples can be studied quantitatively by Buseck's technique (Buseck @ Goldstein, 1969), and it can also be used as the criterion for selecting optimum conditions for EPMA and thereby refinement of substance test (Pavlova @ Kravtsova, 2006). According to the recommendations (Buseck and Goldstein, 1969) the sample is stable

> *Sc c*

where the repeatability of standard deviation of the measured x-ray counts for the major

where *Ni* is the number of x-ray counts in each measurement *i* and *n* is the number of

1

individual measurements, and average number of x-ray counts is

*S NN n* 

*n c i i*

2

( ) /( 1)

Fig. 6. The change of *CaK*

 

power density is below 2.8 <sup>2</sup>

distortion and deterioration of result quality.

densities ( <sup>2</sup> 

the plot the *CaK*

elements Sc is given by:

1,000

1,050

1,100

Относит. интенсивность

Relative intensity

1,150

1,200

1,250

Capacity of Researching Technique, Exemplified by the Electron Probe X-Ray Microanalysis 485

0 2 0 4 0 6 0 8 0 100 120 140 Время , с

Counting time, second


intensity of otoliths remains constant during twenty seconds, if the beam

*W m* / . The increase of measuring time causes signal

(1)

(2)

> -

*Ba* , *Sc* and *Sr* are accelerating voltage 25 kV, sample current 80-100 nA and counting time 20 s. With the other measurement conditions the detection limits of above-indicated elements are higher, thus the determination quality of these elements in glasses is worse.

Fig. 4. Detection limits for *SrL* - (1), *BaL* - (2), and *ScK* - (3) as the functions of: (a) accelerating voltage (sample current 15 nA, counting time 10 s); (b) sample current (accelerating voltage 25 kV, counting time 10 s); (c) counting time (probe current 15 nA, accelerating voltage 25 kV). Measurements were made by Camebax-micro and Camebax SX-50 microprobes (Paradina @ Pavlova, 1999).

#### **2.3.2 Variations of x-ray intensity versus counting time**

Intensity variations of the elements present in the bones versus counting time are examined by microprobe Superprobe-733 (Pavlova et al., 2001). Intensity variations of elements present in bone tissue are shown in the fig. 5.

Fig. 5. Intensity variations of elements present in bone tissue versus counting time: (a) *NaK* (curves 1–3 correspond to accelerating voltage 10, 15 and 20 kV, respectively, and probe current 15 nA) and *MgK* (curves 4–6 correspond to accelerating voltage 10, 15 and 20 kV, respectively, and probe current 15 nA); (b) *NaK* (curves 1–4 correspond to sample current 10, 15, 20 and 25 nA, respectively, and accelerating voltage 15 kV) and *MgK* (curves 5–8 correspond to sample current 10, 15, 20 and 25 nA, respectively, and accelerating voltage 15 kV). Measurements were made by Superprobe-733 microprobe (Pavlova et al., 2001).

*Ba* , *Sc* and *Sr* are accelerating voltage 25 kV, sample current 80-100 nA and counting time 20 s. With the other measurement conditions the detection limits of above-indicated elements are higher, thus the determination quality of these elements in glasses is worse.

c a b

Fig. 4. Detection limits for *SrL*

10 15 20 25 30 35 Accelerating voltage, kB

0

0,01

0,02

Detection limit, % m/m

0,03

0,04

*NaK*

2001).

probe current 15 nA) and *MgK*

Relative intensit

y

50 microprobes (Paradina @ Pavlova, 1999).

present in bone tissue are shown in the fig. 5.

**1 2 3**

**2.3.2 Variations of x-ray intensity versus counting time** 


0

0,01

0,02

Detection limit, % m/m

0,03

accelerating voltage (sample current 15 nA, counting time 10 s); (b) sample current (accelerating voltage 25 kV, counting time 10 s); (c) counting time (probe current 15 nA, accelerating voltage 25 kV). Measurements were made by Camebax-micro and Camebax SX-


0 20 40 60 80 100 Sample current, nA

Intensity variations of the elements present in the bones versus counting time are examined by microprobe Superprobe-733 (Pavlova et al., 2001). Intensity variations of elements

a b

Fig. 5. Intensity variations of elements present in bone tissue versus counting time: (a)

current 10, 15, 20 and 25 nA, respectively, and accelerating voltage 15 kV) and *MgK*

20 kV, respectively, and probe current 15 nA); (b) *NaK*

(curves 1–3 correspond to accelerating voltage 10, 15 and 20 kV, respectively, and

Counting time, sec Counting time, sec

(curves 5–8 correspond to sample current 10, 15, 20 and 25 nA, respectively, and accelerating voltage 15 kV). Measurements were made by Superprobe-733 microprobe (Pavlova et al.,

(curves 4–6 correspond to accelerating voltage 10, 15 and

(curves 1–4 correspond to sample

Relative

 intensity

**1 2 3** Detection limit, % m/m


0 5 10 15 20 25 Counting time, second

**1 2 3**

0 0,01 0,02 0,03 0,04

Fig. 6. The change of *CaK* - line intensity in accordance with the electron beam power densities ( <sup>2</sup> *W m* / ): 1 – 191,00; 2 – 3,82; 3 – 2,54; 4 – 2,86; 5 – 3,06.

The X-ray intensity of calcium versus counting time (Fig. 6) with varying electron beam power density assessed for omul fish otoliths (Pavlova et al., 2003). This change of *CaK* line intensity versus the electron beam power densities has been chosen as the criterion for selecting optimum conditions for analyzing the elements in omul fish otoliths. As seen on the plot the *CaK* intensity of otoliths remains constant during twenty seconds, if the beam power density is below 2.8 <sup>2</sup> *W m* / . The increase of measuring time causes signal distortion and deterioration of result quality.

#### **2.3.3 Criterion of sample stability while performing measurements**

The stability of argentiferous samples can be studied quantitatively by Buseck's technique (Buseck @ Goldstein, 1969), and it can also be used as the criterion for selecting optimum conditions for EPMA and thereby refinement of substance test (Pavlova @ Kravtsova, 2006). According to the recommendations (Buseck and Goldstein, 1969) the sample is stable (analytical signal is constant for counting time), if it obeys the relationship

$$S\_{\mathfrak{c}} < \sigma\_{\mathfrak{c}} \tag{1}$$

where the repeatability of standard deviation of the measured x-ray counts for the major elements Sc is given by:

$$S\_c = \sqrt{\sum\_{i=1}^{n} (N\_i - \overline{N})^2 \;/\; (n-1)}\tag{2}$$

where *Ni* is the number of x-ray counts in each measurement *i* and *n* is the number of individual measurements, and average number of x-ray counts is

Dependence of Determination Quality on Performance

Capacity of Researching Technique, Exemplified by the Electron Probe X-Ray Microanalysis 487

A specific feature of electron probe X-ray microanalysis is its locality, which is 10-13 g of the substance, causing toughening the requirements for standard and reference materials claimed for EPMA. In the case of EPMA, reference and connrol samples should correspond with the following requirements simultaneously: (1) have known chemical composition; (2) be uniform at macro and micro levels of spatial resolution; (3) remain stable under action of electron probe; (4) do not decay in vacuum (up to 10-16 mm Hg); (5) must be well polished. Evidently, only the samples being standard samples of structure and properties at the same time may become standard and reference samples for EPMA. The standard samples widely utilized in the other analytical techniques are often inapplicable in the case of EPMA,

The homogeneity (at macro- and micro-level) of space resolution and substance stability resulting from the effect of electron beam is of particular interest for the EPMA. There are different approaches to assess the substance homogeneity (Borkhodoev, 2010; Buseck @ Goldstein, 1969; MI, 1988). Two methods to test the homogeneity of elements distribution at macro and micro levels (Buseck @ Goldstein, 1969; MI, 1988) are described for the copper-

According to the recommendations of Buseck and Goldstein (Buseck @ Goldstein, 1969) the

/2 1 *Sc c* 

1 /2 2 *Sc c* 

> 2 /2 *Sc c*

The macro homogeneity at the micrometer to millimeter scale was evaluated by recording

The beam diameter ranged from 1 to 10 m, the profile length was about 1000 μm, the point

that at micron-mm level in alloys CA-2 and CA-6 all elements are distributed irregularly

According to the National Standard for homogeneity assessment (MI, 1988) the material is

*<sup>i</sup> <sup>b</sup> <sup>l</sup> RSD* <sup>2</sup> <sup>2</sup>

 (5)

, (6)

, (7)

, (8)

values in Table 5 demonstrate

**2.4 Reference samples and standard materials for electron probe microanalysis**  The accuracy of results of any analytical technique depends on the application of a sufficient number of required reference and control samples of top quality. An important condition to acquire appropriate analytical results of required quality is the application of a sufficient number of required reference samples meeting all requirements of analytical method

employed. It is desirable to use certified standards as control and reference samples.

because they are not homogeneous both at macro and micro levels.

sample is homogeneous on micrometer- to millimeter scale if

*<sup>c</sup>* values are determined from (2)-(4) formulae.

EPMA profiles across a few different profile lines of sample.

spacing was 10 μm and the line spacing was 20 μm. *<sup>c</sup> <sup>c</sup> S* / 2

and the tin homogeneity in CA-4 alloy is doubtful.

**2.4.1 Homogeneity and stability of samples** 

rich alloys and basaltic glass.

the homogeneity is doubtful if

the sample is inhomogeneous if

uniform on a micrometer scale, if

*Sc* and

$$\overline{N} = \sum\_{i=1}^{n} (N\_i \;/\; n) \tag{3}$$

the population standard deviation stipulated by the Poisson counting statistics *<sup>c</sup>* is:

$$
\sigma\_c = \sqrt{N} \ . \tag{4}
$$

The stability characteristics of argentiferous sample were determined according to the recommendations (Buseck and Goldstein, 1969). Table 4 provides stability characteristics of argentiferous samples.

It was found that the response from argentiferous sample was stable through period from 1 to 1.5 min depending on the beam power densities.

The beam power density <2.55 <sup>2</sup> *W m* / is admissible for the analysis of argentiferous samples. The best compromise conditions for exciting the x-ray radiation and recording analytical signal for WD EPMA of argentiferous samples are: accelerating voltage of 15-20 kV, beam current of 10 nA, probe diameter of 10 μm and counting time of 10 s. Hence, so as to obtain the correct results of analysis it is necessary to select optimum conditions for exciting and registering analytical signals.


Table 4. The stability characteristics of argentiferous sample. *<sup>b</sup> d* – beam diameter; *E*0 – accelerating voltage; *i* – probe current; *P* – beam power densities; *Sc* is repeatability standard deviation of the measured X-ray counts; *<sup>c</sup>* is population standard deviation, stipulated by Poisson counting statistics.

#### **2.4 Reference samples and standard materials for electron probe microanalysis**

The accuracy of results of any analytical technique depends on the application of a sufficient number of required reference and control samples of top quality. An important condition to acquire appropriate analytical results of required quality is the application of a sufficient number of required reference samples meeting all requirements of analytical method employed. It is desirable to use certified standards as control and reference samples.

A specific feature of electron probe X-ray microanalysis is its locality, which is 10-13 g of the substance, causing toughening the requirements for standard and reference materials claimed for EPMA. In the case of EPMA, reference and connrol samples should correspond with the following requirements simultaneously: (1) have known chemical composition; (2) be uniform at macro and micro levels of spatial resolution; (3) remain stable under action of electron probe; (4) do not decay in vacuum (up to 10-16 mm Hg); (5) must be well polished. Evidently, only the samples being standard samples of structure and properties at the same time may become standard and reference samples for EPMA. The standard samples widely utilized in the other analytical techniques are often inapplicable in the case of EPMA, because they are not homogeneous both at macro and micro levels.

#### **2.4.1 Homogeneity and stability of samples**

The homogeneity (at macro- and micro-level) of space resolution and substance stability resulting from the effect of electron beam is of particular interest for the EPMA. There are different approaches to assess the substance homogeneity (Borkhodoev, 2010; Buseck @ Goldstein, 1969; MI, 1988). Two methods to test the homogeneity of elements distribution at macro and micro levels (Buseck @ Goldstein, 1969; MI, 1988) are described for the copperrich alloys and basaltic glass.

According to the recommendations of Buseck and Goldstein (Buseck @ Goldstein, 1969) the sample is homogeneous on micrometer- to millimeter scale if

$$S\_c \,/\, 2\sigma\_c < 1\tag{5}$$

the homogeneity is doubtful if

486 Modern Approaches To Quality Control

( /)

(3)

*<sup>c</sup> N* . (4)

*W m* / is admissible for the analysis of argentiferous

*<sup>c</sup> Sc*

*<sup>c</sup>* is population standard deviation,

*<sup>c</sup> Sc*

*c*

*<sup>c</sup>* is:

*i*

1

The stability characteristics of argentiferous sample were determined according to the recommendations (Buseck and Goldstein, 1969). Table 4 provides stability characteristics of

It was found that the response from argentiferous sample was stable through period from 1

samples. The best compromise conditions for exciting the x-ray radiation and recording analytical signal for WD EPMA of argentiferous samples are: accelerating voltage of 15-20 kV, beam current of 10 nA, probe diameter of 10 μm and counting time of 10 s. Hence, so as to obtain the correct results of analysis it is necessary to select optimum conditions for

second 10 20 30 40 50 60

 0,64 15 33, 16, 33, 15, 34, 16, 33, 16, 34, 15, 33, 0,96 16 35, 15, 35, 16, 35, 16, 35, 16, 35, 16, 34, 1,27 15 37, 16, 37, 16, 37, 15, 37, 15, 37, 42, 38, 5 1 1,27 16 37, 16, 37, 16, 37, 16, 37, 16, 37, 42, 38, 8 1 2,04 15 39, 16, 39, 16, 38, 18, 39, 50, 39, 49, 39, 2,55 16 40, 16, 40, 16, 39, 49, 41, 52, 41, 62, 42, 3,06 16 41, 48, 41, 51, 42, 53, 42, 59, 43, 63, 43, 3,82 47 45, 69, 44, 69, 43, 59, 44, 63, 44, 65, 44, 5 1 127, 49 48, 96, 48, 98, 49, 97, 50, 98, 56, 99, 49,

Table 4. The stability characteristics of argentiferous sample. *<sup>b</sup> d* – beam diameter; *E*0 – accelerating voltage; *i* – probe current; *P* – beam power densities; *Sc* is repeatability

*<sup>c</sup> Sc*

*i N Nn* 

the population standard deviation stipulated by the Poisson counting statistics

argentiferous samples.

Counting time,

Conditions of measurements

*kV*

*i nA*

*Sc <sup>E</sup>*<sup>0</sup>

*P W* /

*b d m*

to 1.5 min depending on the beam power densities.

*<sup>c</sup> Sc*

standard deviation of the measured X-ray counts;

stipulated by Poisson counting statistics.

 

> *<sup>c</sup> Sc*

The beam power density <2.55 <sup>2</sup>

exciting and registering analytical signals.

*n*

1 /2 2 *Sc c* , (6)

the sample is inhomogeneous if

$$2 < S\_c \mid 2\sigma\_c \,, \tag{7}$$

*Sc* and *<sup>c</sup>* values are determined from (2)-(4) formulae.

The macro homogeneity at the micrometer to millimeter scale was evaluated by recording EPMA profiles across a few different profile lines of sample.

The beam diameter ranged from 1 to 10 m, the profile length was about 1000 μm, the point spacing was 10 μm and the line spacing was 20 μm. *<sup>c</sup> <sup>c</sup> S* / 2 values in Table 5 demonstrate that at micron-mm level in alloys CA-2 and CA-6 all elements are distributed irregularly and the tin homogeneity in CA-4 alloy is doubtful.

According to the National Standard for homogeneity assessment (MI, 1988) the material is uniform on a micrometer scale, if

$$
\sigma\_l = \sqrt{\sigma\_b^2 + \sigma\_l^2} < RSD \,\,\,\tag{8}
$$

Dependence of Determination Quality on Performance

detect possible micro heterogeneity at 1–10

**2.4.2 Valuation of laboratory reference samples** 

fulfilled and these materials assessed (Wilson & Taggart, 2000).

where 

and CA-4.

minutes.

of the specimen;

(Thompson et al., 1997).

Capacity of Researching Technique, Exemplified by the Electron Probe X-Ray Microanalysis 489

the analytical areas; *RSD* is the relative standard deviation used for certification

The total X-ray counts were recorded at each point of the sample by the static beam to

lines were measured from 20 to 30 points of a sample. The pattern of these points was chosen from the table of random numbers. At each point two measurements were made using the optimum conditions. The homogeneity of the material in the surface layers was estimated by repeating measurements after the repeated polishing. The results for each element were processed by a dispersion analysis with a three-step grouping of material. Evidently the samples are homogeneous on micrometer scale excepting alloys CA-2, CA-6

At EPMA the stability of reference samples and standards under the microprobe is significant both during measuring the analytical signal and using the sample for studies. The data on stability of alloys and glasses, given in Table 5, are obtained by the following method (Pavlova et al., 2001). The X-ray radiation of the most intensive lines was excited by the electron beam at 5 arbitrary points of the selected sample. This was the x-ray radiation of copper Kα-line for alloys and calcium Kα-line for basalt glass recorded by the WD EPMA technique. The measurements were made 30 times and lasted for 5 minutes per point. Relationship (1) was applicable for some elements of all copper alloys and basalt glass. Table 5 indicates that all copper alloys and basalt glass are resistant to electron action during 2

The necessity to have certified standard samples is obvious; they help to achieve the requisite quality of results. But in some cases the certified standard samples are absent and researchers are forced to apply laboratory reference materials after having the control study

One of the techniques to assess quality of the EPMA results obtained using laboratory reference samples instead of standards is described below for the silicate mineral analysis (Pavlova et al., 2003). Measurements were performed on the Jeol Superprobe-733 electron microprobe using accelerating voltage of 15 kV and probe current of 20 nA with an electron beam diameter of 1 and 10 m. Assessment was done by analyzing 26 control samples (glass K-412, garnet IGEM, *Ti* - glass, Mn-glass, Cr –glass, basalt glasses BHVO-2G, BCR-2G, BIR-1G, diopside, ilmenite, garnet O-145, olivine, spinel, garnet C-153, albite, garnet UD-92, orthoclase, chromite UV-126, oxides *MgO* , *MnO* , *Fe O*2 3 , *Cr O*2 3 , *A* 2 3 *l O* , *TiO*<sup>2</sup> , *SiO*2 and *CaSiO*<sup>3</sup> ). The glass K-412 was supplied by the National Institute of Standards and Technology of the USA (NIST, 1990). Garnet IGEM, *Ti* - glass, Mn-glass and Cr -glass were prepared as laboratory reference samples at the Institute of Geology and Mineralogy, Moscow, Russia. Three basalt glasses BHVO-2G, BCR-2G andBIR-1G were produced by the US Geological Survey (Denver Federal Center) (Wilson & Taggart, 2000). The diopside, ilmenite, olivine, spinel, garnets C-153 and UD-92, albite and orthoclase were certified as the laboratory reference samples at the Institute of Geology and Geophysics, Novosibirsk,

*<sup>b</sup>* is the root mean square deviation of random components of error for some parts

*<sup>l</sup>* is the root mean square deviation of random components of error for

*m* scale. The X-ray intensities of analytical


Table 5. Characteristics of stability and uniformity of copper alloys and basalt glass. n.d. means that the value was not determined. CA stands for coppery alloys; *Sc* is repeatability standard deviation of the measured X-ray counts; *<sup>c</sup>* is population standard deviation, stipulated by Poisson counting statistics; *<sup>i</sup>* is total root mean square deviation; *<sup>b</sup>* is the root mean square deviation of random components of error for some parts of the specimen; *<sup>l</sup>* is the root mean square deviation of random components of error for the analytical areas; *RSD* is the relative standard deviation (Thompson et al., 1997).

where *<sup>b</sup>* is the root mean square deviation of random components of error for some parts of the specimen; *<sup>l</sup>* is the root mean square deviation of random components of error for the analytical areas; *RSD* is the relative standard deviation used for certification (Thompson et al., 1997).

The total X-ray counts were recorded at each point of the sample by the static beam to detect possible micro heterogeneity at 1–10 *m* scale. The X-ray intensities of analytical lines were measured from 20 to 30 points of a sample. The pattern of these points was chosen from the table of random numbers. At each point two measurements were made using the optimum conditions. The homogeneity of the material in the surface layers was estimated by repeating measurements after the repeated polishing. The results for each element were processed by a dispersion analysis with a three-step grouping of material. Evidently the samples are homogeneous on micrometer scale excepting alloys CA-2, CA-6 and CA-4.

At EPMA the stability of reference samples and standards under the microprobe is significant both during measuring the analytical signal and using the sample for studies. The data on stability of alloys and glasses, given in Table 5, are obtained by the following method (Pavlova et al., 2001). The X-ray radiation of the most intensive lines was excited by the electron beam at 5 arbitrary points of the selected sample. This was the x-ray radiation of copper Kα-line for alloys and calcium Kα-line for basalt glass recorded by the WD EPMA technique. The measurements were made 30 times and lasted for 5 minutes per point. Relationship (1) was applicable for some elements of all copper alloys and basalt glass. Table 5 indicates that all copper alloys and basalt glass are resistant to electron action during 2 minutes.

#### **2.4.2 Valuation of laboratory reference samples**

488 Modern Approaches To Quality Control

(for 2 min) homogeneity

*Sn* 1,62 1,38 0,77 0,03 0,71 0,71 0,71 *Ni* 0,10 n.d 0,76 0,08 1,94 1,94 2,10 *Fe* 0,05 n.d 0,88 0,09 2,05 2,05 2,50

*Cu* 68,74 1,48 2,96 n.d n.d n.d n.d *Sn* 0,97 1,75 2,95 n.d n.d n.d n.d *Zn* 30,00 1,13 2,27 n.d n.d n.d n.d

*Zn* 0,71 n.d 0,80 0,12 1,12 1,12 0,26 *Cu* 98,53 1,49 0,98 0,14 1,12 1,13 0,31 *Sn* 0,19 n.d 0,79 0,00 1,55 1,55 1,56 *Ni* 0,26 n.d 0,79 0,07 1,13 1,13 1,20 *Fe* 0,30 n.d 0,76 0,06 1,16 1,16 0,81

*Zn* 1,56 1,36 0,73 0,04 0,68 0,68 0,85 *Sn* 0,09 n.d 1,48 n.d n.d n.d n.d

*Zn* 1,00 1,46 0,92 0,11 1,12 1,12 1,13 *Sn* 0,12 n.d 0,83 0,00 1,55 1,55 1,56 *Ni* 0,51 n.d 0,89 0,07 1,13 1,13 1,20 *Fe* 3,63 1,45 0,87 0,14 0,79 0,80 0,81

*Cu* 63,00 1,23 2,46 n.d n.d n.d 0,31 *Zn* 33,80 1,43 2,87 n.d n.d n.d n.d

*Ba* 2,30 1.94 0,47 0,00 1,73 1,73 3,80 *Sr* 2,01 1.75 0,375 0,00 1,56 1,56 2,80 *Si* 21,84 1.84 0,42 0,02 0,13 0,13 0,13 *Al* 9,50 1.72 0,36 0,20 0,34 0,40 0,44 *Ca* 7,34 1.68 0,34 0,13 0,38 0,40 0,40 *Mg* 3,49 1.88 0,44 0,17 0,49 0,52 0,58 *Fe* 8,94 1.66 0,33 0,12 0,32 0,35 0,35 *Na* 2,02 1.58 0,29 0,02 0,96 0,96 1,00 *Ti* 0,87 n.d 0,39 0,17 0,81 0,83 0,88

*<sup>c</sup>* is population standard deviation,

*<sup>b</sup>* is the

*<sup>i</sup>* is total root mean square deviation;

Table 5. Characteristics of stability and uniformity of copper alloys and basalt glass. n.d. means that the value was not determined. CA stands for coppery alloys; *Sc* is repeatability

root mean square deviation of random components of error for some parts of the specimen;

areas; *RSD* is the relative standard deviation (Thompson et al., 1997).

*<sup>l</sup>* is the root mean square deviation of random components of error for the analytical

standard deviation of the measured X-ray counts;

stipulated by Poisson counting statistics;

*b* *l* *i* /8

Characteristics Stability

*c c* /*<sup>S</sup>* / 2 *Sc*

Sample Eleme

CA-1

CA -2

CA -3

CA -4

CA -5

CA -6

Basalt glass

Coppery alloys

nt

*Ccer* , wt. %

The necessity to have certified standard samples is obvious; they help to achieve the requisite quality of results. But in some cases the certified standard samples are absent and researchers are forced to apply laboratory reference materials after having the control study fulfilled and these materials assessed (Wilson & Taggart, 2000).

One of the techniques to assess quality of the EPMA results obtained using laboratory reference samples instead of standards is described below for the silicate mineral analysis (Pavlova et al., 2003). Measurements were performed on the Jeol Superprobe-733 electron microprobe using accelerating voltage of 15 kV and probe current of 20 nA with an electron beam diameter of 1 and 10 m. Assessment was done by analyzing 26 control samples (glass K-412, garnet IGEM, *Ti* - glass, Mn-glass, Cr –glass, basalt glasses BHVO-2G, BCR-2G, BIR-1G, diopside, ilmenite, garnet O-145, olivine, spinel, garnet C-153, albite, garnet UD-92, orthoclase, chromite UV-126, oxides *MgO* , *MnO* , *Fe O*2 3 , *Cr O*2 3 , *A* 2 3 *l O* , *TiO*<sup>2</sup> , *SiO*2 and *CaSiO*<sup>3</sup> ). The glass K-412 was supplied by the National Institute of Standards and Technology of the USA (NIST, 1990). Garnet IGEM, *Ti* - glass, Mn-glass and Cr -glass were prepared as laboratory reference samples at the Institute of Geology and Mineralogy, Moscow, Russia. Three basalt glasses BHVO-2G, BCR-2G andBIR-1G were produced by the US Geological Survey (Denver Federal Center) (Wilson & Taggart, 2000). The diopside, ilmenite, olivine, spinel, garnets C-153 and UD-92, albite and orthoclase were certified as the laboratory reference samples at the Institute of Geology and Geophysics, Novosibirsk,

Dependence of Determination Quality on Performance

Capacity of Researching Technique, Exemplified by the Electron Probe X-Ray Microanalysis 491

Table 6. Analytical results for USGS TB-1 glass measured by EPMA with the calibrations obtained from three separate groups of reference materials for each of samples: *Ccer* is the

*<sup>r</sup>* 100 \* 0.02 \* / *C C* is acceptable standard deviation (Thompson et al., 1997),

1 1

*i i s n C C nn* 

*n n i i*

{[ ( ) ( )]/[ ( 1)]}

is *z* -scores (Thompson et al.,

;

certified concentration; *n* is number of measurements; *C ts n* \* / is confidence

intervals; *s sC r av* / is standard deviations, where 2 2

is average concentrations; ( )/ *av cer r zC C*

where *C* is the concentration expressed as fraction.

1

1997); 0.8495

1 *<sup>n</sup> av i i C C n*

Russia. The oxides *MgO* , *MnO* , *Fe O*2 3 , *Cr O*2 3 , *Al O*2 3 , *TiO*<sup>2</sup> , *SiO*2 and *CaSiO*3 were supplied by JEOL Ltd., Tokyo, Japan. Each reference sample producer has reported that all samples meet the requirements needed for the samples for comparison at EPMA.

These control samples comprised the following. (I) Seven glasses, in which the contents of the elements analyzed varied over the following ranges (wt.%): *SiO*<sup>2</sup> , 45.35–54.11; *MgO* , 3.48–19.33; *Al O*2 3 , 1.40–16.68; *FeO* , 8.46–12.04; *CaO* , 6.87–23.38; *TiO*<sup>2</sup> , 0.81–9.11; *MnO* , 0.17–8.48; and *Cr O*2 3 , 10.20. (II) Eight oxides: *MgO* , *SiO*<sup>2</sup> , *Al O*2 3 , *TiO*<sup>2</sup> , *Fe O*2 3 , *MnO* , *Cr O*2 3 and *CaSiO*<sup>3</sup> . (III) Twelve minerals with concentrations varying as follows (wt.%): *MgO* , 1.02–49.20; *Al O*2 3 , 0.50–26.10; *SiO*<sup>2</sup> , 0.30–55.50; *CaO* , 2.24–53.80; *TiO*<sup>2</sup> , 0.33–50.00; *Cr O*2 3 , 0.08–44.80; *MnO* , 0.17–30.76; and *FeO* , 0.05–62.40.

All samples were at first used as control samples before being accepted as reference samples. The available reference samples were divided into three groups (Table 6). Group I comprised the basic components ( *Si* , *Al* , *Fe*, *Mg* and *Ca* ) which were defined using glass K-412, while *Ti* , Mn and Cr were defined from *Ti* -glass, Mn-glass and Cr-glass. The second complete set (II) consisted of simple minerals: diopside (for *Si* and *Ca* ); ilmenite GF-55 (for *Ti* ); olivine (for *Mg* ); spinel *MnFe O*2 4 (for *Fe*); garnets C-153 (for *Al* ), UD-92 (for Cr) and IGEM (for Mn). Simple oxides *MgO* , *MnO* , *Fe O*2 3 , *Cr O*2 3 , *Al O*2 3 , *TiO*<sup>2</sup> , *SiO*2 and *CaSiO*3 (*Ca* ) represent the third complete set of reference samples (III). In all three cases the sodium content was determined from albite and that of potassium from the orthoclase standard sample. The analyzed values were corrected for matrix effects using the PAP method (Pouchou @ Pichoir, 1984) through the MARCHELL program (Kanakin @ Karmanov, 2006) adapted for the Superprobe-733 operating system. When applying three complete sets of calibration samples the three series of concentration data (*CI* , *CII* and *CIII* ) have been received. Table 6 shows the analytical results for USGS TB-1 glass measured by EPMA. The same analytical results have been acquired for every control sample.

The results obtained in this study (Table 6) showed that deviations from the recommended/certified value varied in value and sign, however, they did not depend on the group of the reference samples selected for calibration. The largest deviations were observed in the elements with concentrations close to the detection limit. The relative standard deviations do not exceed the target precision ( *<sup>r</sup>* ) in all cases. The values of *z*scores for all elements determined lie within permissible limits (-2<*z*<2) for the elements ranging in concentration from 0.1 to 100%. The relative standard deviation for each element assessed in all control samples depends on the concentration and varies as (%): *Na*2*O* , 0.30– 2.89; *MgO* , 0.42–1.76; *Al*2*O*<sup>3</sup> , 0.29–2.4; <sup>2</sup> *SiO* , 0.11–2.32; *K*2*O* , 0.43–2.00; *CaO* , 0.37–1.91; *TiO*<sup>2</sup> , 0.84–2.16; *Cr*2*O*<sup>3</sup> , 0.71–2.25; *MnO* , 0.72–2.59; and *FeO* , 0.45–2.80. The relative standard deviations for each element in all control samples were not higher than the admissible relative standard deviations ( *<sup>r</sup>* ), defined for 'applied geochemistry' category of analysis (category 2) in the GeoPT proficiency testing program (Thompson et al., 1997). Fig. 7 shows the correlation of concentrations for *MgO* and *Cr*2*O*3 analyzed using the different sets of reference samples vs. their recommended or certified values.

Each trend of data plotted in Figure 7 is well described as a straight line. In all cases the correlation coefficients (*R2*), describing the reliability of the linear dependence, is close or equal to 1 (Table 7). This confirms the absence of systematic differences and confirms the reliability of each set of reference samples in the calibration of the EPMA instrument.

Russia. The oxides *MgO* , *MnO* , *Fe O*2 3 , *Cr O*2 3 , *Al O*2 3 , *TiO*<sup>2</sup> , *SiO*2 and *CaSiO*3 were supplied by JEOL Ltd., Tokyo, Japan. Each reference sample producer has reported that all

These control samples comprised the following. (I) Seven glasses, in which the contents of the elements analyzed varied over the following ranges (wt.%): *SiO*<sup>2</sup> , 45.35–54.11; *MgO* , 3.48–19.33; *Al O*2 3 , 1.40–16.68; *FeO* , 8.46–12.04; *CaO* , 6.87–23.38; *TiO*<sup>2</sup> , 0.81–9.11; *MnO* , 0.17–8.48; and *Cr O*2 3 , 10.20. (II) Eight oxides: *MgO* , *SiO*<sup>2</sup> , *Al O*2 3 , *TiO*<sup>2</sup> , *Fe O*2 3 , *MnO* , *Cr O*2 3 and *CaSiO*<sup>3</sup> . (III) Twelve minerals with concentrations varying as follows (wt.%): *MgO* , 1.02–49.20; *Al O*2 3 , 0.50–26.10; *SiO*<sup>2</sup> , 0.30–55.50; *CaO* , 2.24–53.80; *TiO*<sup>2</sup> , 0.33–50.00;

All samples were at first used as control samples before being accepted as reference samples. The available reference samples were divided into three groups (Table 6). Group I comprised the basic components ( *Si* , *Al* , *Fe*, *Mg* and *Ca* ) which were defined using glass K-412, while *Ti* , Mn and Cr were defined from *Ti* -glass, Mn-glass and Cr-glass. The second complete set (II) consisted of simple minerals: diopside (for *Si* and *Ca* ); ilmenite GF-55 (for *Ti* ); olivine (for *Mg* ); spinel *MnFe O*2 4 (for *Fe*); garnets C-153 (for *Al* ), UD-92 (for Cr) and IGEM (for Mn). Simple oxides *MgO* , *MnO* , *Fe O*2 3 , *Cr O*2 3 , *Al O*2 3 , *TiO*<sup>2</sup> , *SiO*2 and *CaSiO*3 (*Ca* ) represent the third complete set of reference samples (III). In all three cases the sodium content was determined from albite and that of potassium from the orthoclase standard sample. The analyzed values were corrected for matrix effects using the PAP method (Pouchou @ Pichoir, 1984) through the MARCHELL program (Kanakin @ Karmanov, 2006) adapted for the Superprobe-733 operating system. When applying three complete sets of calibration samples the three series of concentration data (*CI* , *CII* and *CIII* ) have been received. Table 6 shows the analytical results for USGS TB-1 glass measured by EPMA. The

The results obtained in this study (Table 6) showed that deviations from the recommended/certified value varied in value and sign, however, they did not depend on the group of the reference samples selected for calibration. The largest deviations were observed in the elements with concentrations close to the detection limit. The relative

scores for all elements determined lie within permissible limits (-2<*z*<2) for the elements ranging in concentration from 0.1 to 100%. The relative standard deviation for each element assessed in all control samples depends on the concentration and varies as (%): *Na*2*O* , 0.30– 2.89; *MgO* , 0.42–1.76; *Al*2*O*<sup>3</sup> , 0.29–2.4; <sup>2</sup> *SiO* , 0.11–2.32; *K*2*O* , 0.43–2.00; *CaO* , 0.37–1.91; *TiO*<sup>2</sup> , 0.84–2.16; *Cr*2*O*<sup>3</sup> , 0.71–2.25; *MnO* , 0.72–2.59; and *FeO* , 0.45–2.80. The relative standard deviations for each element in all control samples were not higher than the

analysis (category 2) in the GeoPT proficiency testing program (Thompson et al., 1997). Fig. 7 shows the correlation of concentrations for *MgO* and *Cr*2*O*3 analyzed using the different

Each trend of data plotted in Figure 7 is well described as a straight line. In all cases the correlation coefficients (*R2*), describing the reliability of the linear dependence, is close or equal to 1 (Table 7). This confirms the absence of systematic differences and confirms the

reliability of each set of reference samples in the calibration of the EPMA instrument.

*<sup>r</sup>* ), defined for 'applied geochemistry' category of

*<sup>r</sup>* ) in all cases. The values of *z*-

samples meet the requirements needed for the samples for comparison at EPMA.

*Cr O*2 3 , 0.08–44.80; *MnO* , 0.17–30.76; and *FeO* , 0.05–62.40.

same analytical results have been acquired for every control sample.

sets of reference samples vs. their recommended or certified values.

standard deviations do not exceed the target precision (

admissible relative standard deviations (


Table 6. Analytical results for USGS TB-1 glass measured by EPMA with the calibrations obtained from three separate groups of reference materials for each of samples: *Ccer* is the certified concentration; *n* is number of measurements; *C ts n* \* / is confidence

$$\text{intervals: } s\_r = s \nmid \mathbb{C}\_{uv} \text{ is standard deviations, where } s = \sqrt{\left[ \left( n \sum\_{i=1}^{n} (\mathbb{C}\_i)^2 - \left( \sum\_{i=1}^{n} \mathbb{C}\_i^2 \right) \right) / \left[ n(n-1) \right] \right]}:$$

1 1 *<sup>n</sup> av i i C C n* is average concentrations; ( )/ *av cer r zC C* is *z* -scores (Thompson et al., 1997); 0.8495 *<sup>r</sup>* 100 \* 0.02 \* / *C C* is acceptable standard deviation (Thompson et al., 1997), where *C* is the concentration expressed as fraction.

Dependence of Determination Quality on Performance

Capacity of Researching Technique, Exemplified by the Electron Probe X-Ray Microanalysis 493

Table 7. Evaluation of the linear function and correlation coefficients ( <sup>2</sup> *R* ) between determinations made against the three sets of calibration samples (*CI* , *CII* , *CIII* ) and the certified concentrations of control samples (*Ccer* ) as well as between *CII* , *CIII* and *CI* . Concentrations *CI* , *CII* , *CIII* are determined using the respective sets of reference samples: (I) – glass K-412, *Ti* -glass, Mn-glass, Cr-glass, albite and orthoclase; (II) – diopside, ilmenite GF-55, olivine, spinel, garnets C-153, UD-92, IGEM, albite and orthoclase; (III) – *MgO* ,

Figure 7 includes the data for elements in which the maximum differences were observed between the results. It is evident that in all cases there are no essential systematic differences between the data sets. This confirms the absence of systematic differences and confirms the

Table 8 gives the results of calculations designed to check the hypothesis that there are no differences between sets of results obtained from any of these three sets of calibration

The series of concentrations determined using calibrations established using three sets of reference samples have been compared with certified values using a two-tailed selective Student's *t*-test. Numerical values of probabilities for each pair of the series are significant, showing that the populations of results from all three series are statistically

The closeness in value of the significance data listed in Table 8 demonstrates the absence of systematic differences between the certified concentrations and the analyzed data for every series. Thus, the sets of reference samples tested in such a way can be successfully applied in

reliability of each set of reference samples in the calibration of the EPMA instrument.

*MnO* , *Fe O*2 3 , *Cr O*2 3 , *Al O*2 3 , *TiO*<sup>2</sup> , *SiO*<sup>2</sup> , *CaSiO*<sup>3</sup> , albite and orthoclase.

samples.

indistinguishable certified values.

EPMA for obtaining high-quality results.

Fig. 7. The graphic correlation of concentrations for MgO and Cr2O3. a, b – the graphic correlation of concentrations (C) received according to three different reference sample sets (I, II, III), to their certified values (Ccer). Graphic representation of the ratio between the concentrations determined using laboratory reference samples II (CII) and III (CIII) and CI determined using standard sample glasses I. Graphs correspond to the concentrations, determined using: fist set of reference samples (I) – glass K-412, Ti-glass, Mn-glass, Cr-glass, albite and orthoclase; the second set (II) – diopside, ilmenite GF-55, olivine, spinel, garnets C-153, UD-92, IGEM albite and orthoclase; for the third set (III) – MgO, MnO, Fe2O3, Cr2O3, Al2O3, TiO2, SiO2, CaSiO3, albite and orthoclase.


Fig. 7. The graphic correlation of concentrations for MgO and Cr2O3. a, b – the graphic correlation of concentrations (C) received according to three different reference sample sets (I, II, III), to their certified values (Ccer). Graphic representation of the ratio between the concentrations determined using laboratory reference samples II (CII) and III (CIII) and CI determined using standard sample glasses I. Graphs correspond to the concentrations, determined using: fist set of reference samples (I) – glass K-412, Ti-glass, Mn-glass, Cr-glass, albite and orthoclase; the second set (II) – diopside, ilmenite GF-55, olivine, spinel, garnets C-153, UD-92, IGEM albite and orthoclase; for the third set (III) – MgO, MnO, Fe2O3, Cr2O3,

Al2O3, TiO2, SiO2, CaSiO3, albite and orthoclase.


Table 7. Evaluation of the linear function and correlation coefficients ( <sup>2</sup> *R* ) between determinations made against the three sets of calibration samples (*CI* , *CII* , *CIII* ) and the certified concentrations of control samples (*Ccer* ) as well as between *CII* , *CIII* and *CI* . Concentrations *CI* , *CII* , *CIII* are determined using the respective sets of reference samples: (I) – glass K-412, *Ti* -glass, Mn-glass, Cr-glass, albite and orthoclase; (II) – diopside, ilmenite GF-55, olivine, spinel, garnets C-153, UD-92, IGEM, albite and orthoclase; (III) – *MgO* , *MnO* , *Fe O*2 3 , *Cr O*2 3 , *Al O*2 3 , *TiO*<sup>2</sup> , *SiO*<sup>2</sup> , *CaSiO*<sup>3</sup> , albite and orthoclase.

Figure 7 includes the data for elements in which the maximum differences were observed between the results. It is evident that in all cases there are no essential systematic differences between the data sets. This confirms the absence of systematic differences and confirms the reliability of each set of reference samples in the calibration of the EPMA instrument.

Table 8 gives the results of calculations designed to check the hypothesis that there are no differences between sets of results obtained from any of these three sets of calibration samples.

The series of concentrations determined using calibrations established using three sets of reference samples have been compared with certified values using a two-tailed selective Student's *t*-test. Numerical values of probabilities for each pair of the series are significant, showing that the populations of results from all three series are statistically indistinguishable certified values.

The closeness in value of the significance data listed in Table 8 demonstrates the absence of systematic differences between the certified concentrations and the analyzed data for every series. Thus, the sets of reference samples tested in such a way can be successfully applied in EPMA for obtaining high-quality results.

Dependence of Determination Quality on Performance

Metrological

where 2 2

1997); 0.8495

1 1

*i i s n C C nn* 

*n n i i*

{[ ( ) ( )]/[ ( 1)]}

*C ts n* \* / is confidence intervals; ( )/ *av cer r zC C*

;

where *C* is the concentration expressed as fraction.

Group of reference samples

1

2

3

Capacity of Researching Technique, Exemplified by the Electron Probe X-Ray Microanalysis 495

*n* 14

*n* 17

*n* 12

Table 9. Analytical results for copper alloys measured by EPMA using calibrations obtained from three separate groups (1, 2 and 3) of reference materials for each of samples: *Ccer* is the certified concentration; *n* is number of measurements; *s sC r av* / is standard deviations,

*<sup>r</sup>* 100 \* 0.02 \* / *C C* is acceptable standard deviation (Thompson et al., 1997),

check the hypothesis that there are no differences between the series of data obtained from any of the three groups of reference samples. We can see, the numerical values of probabilities in columns II, III and VI are not significant, thus indicating that the population of results from series *C2* is statistically different from the recommended values (column II),

performance *Zn Cu Sn Ni Fe*

*Ccer* , wt. % 1,96 88,8 4,89 1,09 2,46

*Cav* , wt.% 1,94 88,5 4,85 1,11 2,48 *s* 0,07 1,78 0,14 0,04 0,08 *rs* , % 3,56 2,01 2,98 3,89 3,41

 *<sup>r</sup>* , % 3,61 2,04 3,15 3,95 3,49 *C* , wt. % 0,04 1,05 0,09 0,03 0,05 *z* -0,3 -0,2 -0,3 0,46 0,24

*Cav* , wt.% 1,75 85,7 4,56 1,34 2,95 *s* 0,07 2,25 0,16 0,06 0,11 *rs* , % 3,78 2,63 3,45 4,22 3,76

 *<sup>r</sup>* , % 3,61 2,04 3,15 3,95 3,49 *C* , wt. % 0,05 1,67 0,12 0,04 0,08 *z* -3,2 -1,4 -2,1 4,42 4,34

*Cav* , wt.% 1,98 89,3 4,92 1,08 2,45 *s* 0,07 1,81 0,15 0,04 0,08 *rs* , % 3,54 2,03 3,12 3,92 3,46

 *<sup>r</sup>* , % 3,61 2,04 3,15 3,95 3,49 *C* , wt. % 0,04 1,03 0,09 0,02 0,05 *z* 0,29 0,26 0,2 -0,2 -0,1

1

is average concentrations;

is *z* -scores (Thompson et al.,

1 *<sup>n</sup> av i i C C n*


Table 8. Results from checking the hypothesis that there is no significant difference between determinations made by any of the three sets of calibration and certified/recommended values using a 2-pair selective Students t-test. Ccer – certified concentrations of control samples; CI, CII, CIII – concentrations, determined using the following sets of reference samples: (I) – glass K-412, Ti-glass, Mn-glass, Cr-glass, albite and orthoclase; (II) – diopside, ilmenite GF-55, olivine, spinel, garnets C-153, UD-92, IGEM, albite and orthclase; (III) – MgO, MnO, Fe2O3, Cr2O3, Al2O3, TiO2, SiO2, CaSiO3, albite and orthoclase.

#### **2.5 The dependence of EPMA quality on homogeneity of reference samples**

The influence of inhomogeneity of reference samples on the EPMA quality has been exemplified by copper-containing alloys (Pavlova, 2009). Ten copper-rich alloys, the standards for chemical, optical and x-ray fluorescence analysis have been quantitatively evaluated as the reference materials to be employed in the electron probe microanalysis.

The optimum conditions for measurements were selected considering the dependence of intensity and detection limit on conditions of the x-ray radiation excitation and analytical signal recording.

The reference samples were divided into the three groups: the control group 1 consisted of the certified glass ( *Fe*), simple minerals ( *Zn* , *Sn* ), metals (*Cu* , *Ni* ); two groups of samples for comparison included the assessed alloys: group 2 comprised the alloys МС76 ( *Fe*), МС44 ( *Sn* ,*Cu* ), МС104 ( *Ni* ), МС153 ( *Zn* ); and group 3 included МС71 ( *Zn* ), МС74 ( *Fe*, *Ni* ), МС42 ( *Sn* ) and metallic copper (*Cu* ).

Three data sets (1, 2 and 3 - in agreement with the groups of reference samples) comprising the average concentrations, standard deviations, relative standard deviations, confidence interval and the z-score of data quality were calculated for 10 copper-rich alloys.

The average concentrations for all elements of every control sample were being defined from 8 to 18 times. The measured values were corrected for matrix effects using the PAP method (Pouchou and Pichoir, 1984) and applying the MARCHELL program (Kanakin & Karmanov, 2006) adapted for the microanalyzer Superprobe-733 operating system. Table 9 presents the data for one alloy.

The relative standard deviations obtained for each element were lower than the target values for all determinations in all cases except for set 2, where group 2 of reference samples was used. In two sets of data the z-score values for all elements determined lie within acceptable limits (-2<z<2) for concentrations ranging from 0.1 to 100%.

Figure 8 shows the graphic dependence of certified *Ni* , *Fe*, *Sn* , *Zn* concentrations and values obtained from different (1, 2 and 3) groups of reference samples. Obtained sets of concentrations were compared between each other and with the certificated/recommended values using 2-pair selective Student's t-test. The table 9 gives the results of calculations to

Oxides Ccer – CI Ccer – CII Ccer – CIII CI – CII CI – CIII MgO 0.312 0.355 0.299 0.359 0.268 AL2O3 0.244 0.237 0.215 0.251 0.267 SiO2 0.310 0.363 0.328 0.265 0.368 CaO 0.455 0.444 - 0.292 - MnO - 0.503 0.490 - - FeO 0.359 0.390 0.346 0.374 0.328 Table 8. Results from checking the hypothesis that there is no significant difference between determinations made by any of the three sets of calibration and certified/recommended values using a 2-pair selective Students t-test. Ccer – certified concentrations of control samples; CI, CII, CIII – concentrations, determined using the following sets of reference samples: (I) – glass K-412, Ti-glass, Mn-glass, Cr-glass, albite and orthoclase; (II) – diopside, ilmenite GF-55, olivine, spinel, garnets C-153, UD-92, IGEM, albite and orthclase; (III) –

MgO, MnO, Fe2O3, Cr2O3, Al2O3, TiO2, SiO2, CaSiO3, albite and orthoclase.

signal recording.

( *Fe*, *Ni* ), МС42 ( *Sn* ) and metallic copper (*Cu* ).

presents the data for one alloy.

**2.5 The dependence of EPMA quality on homogeneity of reference samples** 

The influence of inhomogeneity of reference samples on the EPMA quality has been exemplified by copper-containing alloys (Pavlova, 2009). Ten copper-rich alloys, the standards for chemical, optical and x-ray fluorescence analysis have been quantitatively evaluated as the reference materials to be employed in the electron probe microanalysis. The optimum conditions for measurements were selected considering the dependence of intensity and detection limit on conditions of the x-ray radiation excitation and analytical

The reference samples were divided into the three groups: the control group 1 consisted of the certified glass ( *Fe*), simple minerals ( *Zn* , *Sn* ), metals (*Cu* , *Ni* ); two groups of samples for comparison included the assessed alloys: group 2 comprised the alloys МС76 ( *Fe*), МС44 ( *Sn* ,*Cu* ), МС104 ( *Ni* ), МС153 ( *Zn* ); and group 3 included МС71 ( *Zn* ), МС74

Three data sets (1, 2 and 3 - in agreement with the groups of reference samples) comprising the average concentrations, standard deviations, relative standard deviations, confidence

The average concentrations for all elements of every control sample were being defined from 8 to 18 times. The measured values were corrected for matrix effects using the PAP method (Pouchou and Pichoir, 1984) and applying the MARCHELL program (Kanakin & Karmanov, 2006) adapted for the microanalyzer Superprobe-733 operating system. Table 9

The relative standard deviations obtained for each element were lower than the target values for all determinations in all cases except for set 2, where group 2 of reference samples was used. In two sets of data the z-score values for all elements determined lie within

Figure 8 shows the graphic dependence of certified *Ni* , *Fe*, *Sn* , *Zn* concentrations and values obtained from different (1, 2 and 3) groups of reference samples. Obtained sets of concentrations were compared between each other and with the certificated/recommended values using 2-pair selective Student's t-test. The table 9 gives the results of calculations to

interval and the z-score of data quality were calculated for 10 copper-rich alloys.

acceptable limits (-2<z<2) for concentrations ranging from 0.1 to 100%.


Table 9. Analytical results for copper alloys measured by EPMA using calibrations obtained from three separate groups (1, 2 and 3) of reference materials for each of samples: *Ccer* is the certified concentration; *n* is number of measurements; *s sC r av* / is standard deviations,


1997); 0.8495 *<sup>r</sup>* 100 \* 0.02 \* / *C C* is acceptable standard deviation (Thompson et al., 1997), where *C* is the concentration expressed as fraction.

check the hypothesis that there are no differences between the series of data obtained from any of the three groups of reference samples. We can see, the numerical values of probabilities in columns II, III and VI are not significant, thus indicating that the population of results from series *C2* is statistically different from the recommended values (column II),

Dependence of Determination Quality on Performance

different (1, 2 and 3) groups of reference samples.

of microprobe JXA8200 (Japan).

Capacity of Researching Technique, Exemplified by the Electron Probe X-Ray Microanalysis 497

Fig. 8. Dependence of certified *Ni* , *Fe* , *Sn* , *Zn* concentrations and values obtained from

program MARshell (Kanakin & Karmanov, 2006) adapted for JCXA-733 microprobe.

One can observe how available results differ in various methods of calculating matrix effects and how the quality of results depends on the correct calculation of absorption coefficients. It is evident, that the best results are gained by the PAP method (Pouchou & Pichoir, 1984), when the Marenkov's absorption coefficients are applied (Marenkov, 1982), as well as program of JXA8200 Unix platform by PPX method (Pouchou & Pichoir, 1991) from software

When applying EPMA, the recalculation of x-ray radiation intensity in the concentration of silver group elements depends on the correct choice of x-ray radiation absorption coefficients and ability to consider the matrix effects. The determination of the composition of silver-containing compounds can exemplify how the counting procedure influences the quality of composition determination. The results on the composition of silver minerals, differently obtained by calculating absorption coefficients, are compared in Table 10 (Pavlova @ Kravtsova, 2006). The measured intensities, acquired by microprobes JXA8200 and JCXA-733 (Japan), were corrected for matrix effects using programs of JXA8200 Unix platform and the PAP method (Pouchou & Pichoir, 1984) applying the original controlling computer

and the values *C1* and *C3* obtained with groups 1 and 3 of reference samples (columns III and VI).

No systematic divergence was the case between the concentrations obtained from set 1 and set 2, when analyzed results were compared with the certified compositions. The set (2) of reference samples for copper-rich alloys yields erratic data because this set contained the inhomogeneous reference samples.

Lack of close values of probabilities (columns II, III and VI) demonstrates the presence of systematic differences between the concentration series *C*2 and recommended concentrations (column II) as well as between the results of the second series *C*2 and the data on the series *C*<sup>1</sup> and *C*3 (columns III and VI). This confirms incorrectness of reference samples in group 2. It was previously shown that alloys CA-6 and CA-2 are not homogeneous (table 5).

The numerical values of probabilities are significant in columns I, IV, V and exhibit that the concentrations from selected sets are statistically indistinguishable. Similar values of probabilities listed in these columns for alloys demonstrate the absence of systematic differences of the first and third concentration series both between each other and the recommended concentrations.


Table 10. Comparison of concentrations using a coupled selective Student's t-test; Ccer is the certified concentration; *C*<sup>1</sup> , *C*<sup>2</sup> , *C*3 are three series of concentration data obtained for each of copper-rich alloys using three groups of reference samples.

As a result, the systematic error is very small in the case when the compositions of control samples are calculated using groups 1 and 3 of reference samples. These experiments show that the quality of data obtained from alloy reference samples of group 3 is not inferior to that from the certified reference samples. The quality of results obtained from group 3 of reference samples corresponds to the 'applied geochemistry' type of analysis (category 2) as defined in the GeoPT proficiency testing program (Thompson et al., 1997)

#### **2.6 Method to recalculate experimental values into concentrations**

The choice of method of processing experimental values, when the concentration to be determined is concerned, influences determination of a true composition and thus the quality of analysis. Almost every analytical method of recalculating of experimental values into concentrations is developed for certain samples and conditions. Different methods of analytical chemistry have several ways of recalculating experimentally measured values in the concentration. Every way has its own advantages and disadvantages.

and the values *C1* and *C3* obtained with groups 1 and 3 of reference samples (columns III

No systematic divergence was the case between the concentrations obtained from set 1 and set 2, when analyzed results were compared with the certified compositions. The set (2) of reference samples for copper-rich alloys yields erratic data because this set contained the

Lack of close values of probabilities (columns II, III and VI) demonstrates the presence of systematic differences between the concentration series *C*2 and recommended concentrations (column II) as well as between the results of the second series *C*2 and the data on the series *C*<sup>1</sup> and *C*3 (columns III and VI). This confirms incorrectness of reference samples in group 2. It was previously shown that alloys CA-6 and CA-2 are not

The numerical values of probabilities are significant in columns I, IV, V and exhibit that the concentrations from selected sets are statistically indistinguishable. Similar values of probabilities listed in these columns for alloys demonstrate the absence of systematic differences of the first and third concentration series both between each other and the

Table 10. Comparison of concentrations using a coupled selective Student's t-test; Ccer is the certified concentration; *C*<sup>1</sup> , *C*<sup>2</sup> , *C*3 are three series of concentration data obtained for each

As a result, the systematic error is very small in the case when the compositions of control samples are calculated using groups 1 and 3 of reference samples. These experiments show that the quality of data obtained from alloy reference samples of group 3 is not inferior to that from the certified reference samples. The quality of results obtained from group 3 of reference samples corresponds to the 'applied geochemistry' type of analysis (category 2) as

The choice of method of processing experimental values, when the concentration to be determined is concerned, influences determination of a true composition and thus the quality of analysis. Almost every analytical method of recalculating of experimental values into concentrations is developed for certain samples and conditions. Different methods of analytical chemistry have several ways of recalculating experimentally measured values in

of copper-rich alloys using three groups of reference samples.

defined in the GeoPT proficiency testing program (Thompson et al., 1997)

**2.6 Method to recalculate experimental values into concentrations** 

the concentration. Every way has its own advantages and disadvantages.

Numerical values of probabilities for each pair of the series I II III IV V VI *Ccer* &*C*<sup>1</sup> *Ccer* &*C*<sup>2</sup> *C*<sup>1</sup> &*C*<sup>2</sup> *Ccer* &*C*<sup>3</sup> *C*<sup>1</sup> &*C*<sup>3</sup> *C*<sup>2</sup> &*C*<sup>3</sup>

*Fe* 0.341 0.031 0.013 0.421 0.296 0.021 *Ni* 0.324 0.012 0.009 0.367 0.311 0.008 *Cu* 0.336 0.003 0.026 0.383 0.382 0.017 *Sn* 0.445 0.0154 0.0142 0.435 0.278 0.007 *Zn* 0.425 0.009 0.001 0.398 0.318 0.011

and VI).

inhomogeneous reference samples.

homogeneous (table 5).

Samples Elements

Alloys

recommended concentrations.

Fig. 8. Dependence of certified *Ni* , *Fe* , *Sn* , *Zn* concentrations and values obtained from different (1, 2 and 3) groups of reference samples.

When applying EPMA, the recalculation of x-ray radiation intensity in the concentration of silver group elements depends on the correct choice of x-ray radiation absorption coefficients and ability to consider the matrix effects. The determination of the composition of silver-containing compounds can exemplify how the counting procedure influences the quality of composition determination. The results on the composition of silver minerals, differently obtained by calculating absorption coefficients, are compared in Table 10 (Pavlova @ Kravtsova, 2006). The measured intensities, acquired by microprobes JXA8200 and JCXA-733 (Japan), were corrected for matrix effects using programs of JXA8200 Unix platform and the PAP method (Pouchou & Pichoir, 1984) applying the original controlling computer program MARshell (Kanakin & Karmanov, 2006) adapted for JCXA-733 microprobe.

One can observe how available results differ in various methods of calculating matrix effects and how the quality of results depends on the correct calculation of absorption coefficients. It is evident, that the best results are gained by the PAP method (Pouchou & Pichoir, 1984), when the Marenkov's absorption coefficients are applied (Marenkov, 1982), as well as program of JXA8200 Unix platform by PPX method (Pouchou & Pichoir, 1991) from software of microprobe JXA8200 (Japan).

Dependence of Determination Quality on Performance

Capacity of Researching Technique, Exemplified by the Electron Probe X-Ray Microanalysis 499

Table 12. Particle composition versus the method of calculation of their size. *Ci* is obtained

concentration; R. er. 100(Cs *C C i s* ) / %.

The change of the subject under study often requires the change in the method of recalculating of experimental intensities into concentrations. Thus, a correct determination of the composition of particles comparable in size with the area of generation of x-ray radiation is dependent on the particle size. The quality of obtained results for such particles depends on a correct consideration of size factor (Table 12). The dependence of quality of particle composition versus the method of calculation of their size is exemplified in the article (Belozerova, 2003). Here it is seen that the results obtained for particles with size 3–5 m are closer to the stoichiometrical composition than those obtained for particles sized 1–2 m size. One of the best commonly used methods of calculating element content in bulk samples (PAP-method) provides a relative error of determining the composition of one micron particles ranging from 0.5 to 45 %. Using the exponent model of particle composition calculation lowers this inaccuracy.


Table 11. Comparison of methods to compute matrix effects and coefficients of absorption to measure silver by EPMA.

The change of the subject under study often requires the change in the method of recalculating of experimental intensities into concentrations. Thus, a correct determination of the composition of particles comparable in size with the area of generation of x-ray radiation is dependent on the particle size. The quality of obtained results for such particles depends on a correct consideration of size factor (Table 12). The dependence of quality of particle composition versus the method of calculation of their size is exemplified in the article (Belozerova, 2003). Here it is seen that the results obtained for particles with size 3–5 m are closer to the stoichiometrical composition than those obtained for particles sized 1–2 m size. One of the best commonly used methods of calculating element content in bulk samples (PAP-method) provides a relative error of determining the composition of one micron particles ranging from 0.5 to 45 %. Using the exponent model of particle composition

Table 11. Comparison of methods to compute matrix effects and coefficients of absorption to

calculation lowers this inaccuracy.

measure silver by EPMA.


Table 12. Particle composition versus the method of calculation of their size. *Ci* is obtained concentration; R. er. 100(Cs *C C i s* ) / %.

Dependence of Determination Quality on Performance

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The EPMA technique (Belozerova, 2003) for calculating composition developed for approximately spherical particles, comparable in size to the X-ray generation volume, takes into account the particle-size factor. The size factor correction significantly improves the results in spite of a simple analytical function of average atomic number and particle size.

Taking into account the particle-size factor reduces the error of composition determination from 0.5–45 to 0.2–22% relative percent, for particles sized as 1–3 m.

The relative error increases with decreasing the element concentration from 0.02% for bulk sample to 22.2% for 1 m particle. The size-factor introduction markedly improves the quality of determinations of particles comparable in size with the area of x-ray radiation excitation.

## **3. Conclusion**

This chapter shows the quality dependence of EPMA on every analysis stage, beginning from the representativeness of the material, sample preparation and conditions for analytical signal excitation and registration to the availability of reference samples and the calculation methods.

We have shown how important it is to correctly select the study area and to have properly prepared samples.

It has been found that the quality of study performance is dependent on the optimum conditions of measuring and processing analytical signal.

The comparison of different methods of taking into account the processes occurring in substance in the electron-excited x-ray radiation proves the necessity to correctly select the methods of their consideration in every study.

The method of assessing the selected set of reference samples and defining their appropriateness for EPMA is described.

The urgency to develop and certify new control samples is critical for the methods of analytical chemistry and especially EPMA.

We have shown the influence of inhomogeneity of samples for comparison on the quality of EPMA results.

Thus, the example of EPMA for the case study of determination content quality suggests, that every aspect of analytical technique is responsible for the quality of element tests.

## **4. Acknowledgment**

The author is grateful to Mrs. T. Bunaeva and Mrs. M. Khomutova for editing the English version of this.

## **5. References**

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The EPMA technique (Belozerova, 2003) for calculating composition developed for approximately spherical particles, comparable in size to the X-ray generation volume, takes into account the particle-size factor. The size factor correction significantly improves the results in spite of a simple analytical function of average atomic number and particle size. Taking into account the particle-size factor reduces the error of composition determination

The relative error increases with decreasing the element concentration from 0.02% for bulk sample to 22.2% for 1 m particle. The size-factor introduction markedly improves the quality of determinations of particles comparable in size with the area of x-ray radiation

This chapter shows the quality dependence of EPMA on every analysis stage, beginning from the representativeness of the material, sample preparation and conditions for analytical signal excitation and registration to the availability of reference samples and the

We have shown how important it is to correctly select the study area and to have properly

It has been found that the quality of study performance is dependent on the optimum

The comparison of different methods of taking into account the processes occurring in substance in the electron-excited x-ray radiation proves the necessity to correctly select the

The method of assessing the selected set of reference samples and defining their

The urgency to develop and certify new control samples is critical for the methods of

We have shown the influence of inhomogeneity of samples for comparison on the quality of

Thus, the example of EPMA for the case study of determination content quality suggests, that every aspect of analytical technique is responsible for the quality of element tests.

The author is grateful to Mrs. T. Bunaeva and Mrs. M. Khomutova for editing the English

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Belozerova, O.Y., Afonin, V.P. & Finkelshtein, A.L. (1998). Modified biexponential model

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from 0.5–45 to 0.2–22% relative percent, for particles sized as 1–3 m.

conditions of measuring and processing analytical signal.

methods of their consideration in every study.

appropriateness for EPMA is described.

analytical chemistry and especially EPMA.

excitation.

**3. Conclusion** 

calculation methods.

prepared samples.

EPMA results.

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**5. References** 

**4. Acknowledgment** 

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**27** 

*Colombia* 

**Nose System** 

and Edilson Delgado-Trejos

*Metropolitano (ITM), Medellín* 

*MIRP, Research Center, Instituto Tecnológico* 

**Quality Control Through Electronic** 

Juan C. Rodríguez-Gamboa, E. Susana Albarracín-Estrada

Quality control is defined as: "a process selected to guarantee a certain level of quality in a product, service or process. It may include whatever actions a business considers as essential to provide for the control and verification of certain characteristics of its activity. The basic objective of quality control is to ensure that the products, services or processes provided meet particular requirements and are secure, sufficient, and fiscally sound"1 In order to apply Quality Control through the Electronic Nose System, all the stages involved in the process must be taken into account, this case refers to the use of electronic nose systems as a tool for quality control tasks. Therefore best practices must be implemented that will lead to obtaining good quality measures, which will later become good results

Section 2 of this chapter presents an overview of the parts or subsystems involved in an

Section 3 deals with the issue of food quality control using electronic nose systems. This section discusses how to use the electronic nose system for these types of applications, and also presents some issues for consideration when analyzing products such as coffee, fruits

Section 4 covers other applications of electronic nose systems, especially applications in the medical field for detection and diagnosis of diseases. This section focuses more on viable

It is important to note that quality control is mainly used to find errors in processes, so the deductions presented here have gone through a series of tests and experiments to obtain the desired results and thus facilitate further research and shed light on the question of how

Existing systems for electronic olfaction (EOS), also commonly known as electronic noses, are basically arrays of chemical sensors, connected to a computer or processing systems

<sup>1</sup> Applications and experiences of Quality Control. Preface. www.intechweb.org Copyright 2011 Intech.

alternatives for the detection of diseases, rather than on quality control.

**1. Introduction** 

(Badrick, 2008; Duran, 2005)

and alcoholic beverages.

electronic nose system and the operating principle.

these types of applications should be addressed.

**2. A look at the electronic nose systems** 


## **Quality Control Through Electronic Nose System**

Juan C. Rodríguez-Gamboa, E. Susana Albarracín-Estrada and Edilson Delgado-Trejos *MIRP, Research Center, Instituto Tecnológico Metropolitano (ITM), Medellín Colombia* 

## **1. Introduction**

504 Modern Approaches To Quality Control

Thompson, M., Potts, P.J. & Webb, P.C. (1997). GeoPT1. International proficiency test for

Wilson, S.A. & Taggart, J.E. (2000). Development of USGS microbeam reference materials for

0150-5505.

2000.

analytical geochemistry laboratories — report on round 1 (July 1996). *Geostandard Newsletter: the Journal of Geostandard and Geoanalysis*, Vol. 21, No. 1, pp. 51–58, ISSN:

geochemical analysis, *Proceedings of the 4th International Conference on the Analysis of Geological and Environmental Materials*, Pont a Mousson, France, 29th Aug.-1st Sep.,

> Quality control is defined as: "a process selected to guarantee a certain level of quality in a product, service or process. It may include whatever actions a business considers as essential to provide for the control and verification of certain characteristics of its activity. The basic objective of quality control is to ensure that the products, services or processes provided meet particular requirements and are secure, sufficient, and fiscally sound"1 In order to apply Quality Control through the Electronic Nose System, all the stages involved in the process must be taken into account, this case refers to the use of electronic nose systems as a tool for quality control tasks. Therefore best practices must be implemented that will lead to obtaining good quality measures, which will later become good results (Badrick, 2008; Duran, 2005)

> Section 2 of this chapter presents an overview of the parts or subsystems involved in an electronic nose system and the operating principle.

> Section 3 deals with the issue of food quality control using electronic nose systems. This section discusses how to use the electronic nose system for these types of applications, and also presents some issues for consideration when analyzing products such as coffee, fruits and alcoholic beverages.

> Section 4 covers other applications of electronic nose systems, especially applications in the medical field for detection and diagnosis of diseases. This section focuses more on viable alternatives for the detection of diseases, rather than on quality control.

> It is important to note that quality control is mainly used to find errors in processes, so the deductions presented here have gone through a series of tests and experiments to obtain the desired results and thus facilitate further research and shed light on the question of how these types of applications should be addressed.

### **2. A look at the electronic nose systems**

Existing systems for electronic olfaction (EOS), also commonly known as electronic noses, are basically arrays of chemical sensors, connected to a computer or processing systems

<sup>1</sup> Applications and experiences of Quality Control. Preface. www.intechweb.org Copyright 2011 Intech.

Quality Control Through Electronic Nose System 507

Fig. 2. Commercial gas sensors manufactured by Figaro and FIS, with different sizes and pin

The majority of gas sensors are general purpose and usually have high sensitivity, detecting very low concentrations of volatile, but have disadvantages when trying to determine concentrations of a single component, because the output signal cannot be unambiguously

Due to the fact that all EOS have a gas sensor array, it is desirable that the array be located in a special chamber or compartment in which the right conditions can be ensured for the proper operation. Mainly adequate insulation must be ensured to prevent pollutants from entering and the appropriate temperature and pressure must be maintained, these parameters are important or critical depending on the type of sensor used (Duran, 2005). Another advantage of using a chamber of sensors is that it facilitates the measurement process, because the volatiles will be in a higher concentration and they will have more contact with the active element of the sensor, which enables better and faster response from the sensors. It has also been experimentally determined that if the chamber of sensors is more hermetic, it can further exploit these advantages. Figure 3 shows a photograph of a chamber of sensors used in one of our projects with EOS (Velásquez et

Basically it is a system that is responsible for transporting volatiles emitted by the samples or elements to be scanned into the chamber of sensor. Sometimes the sample is manually injected into the chamber of sensors, which results in error and delays; other times an automated system is responsible for transporting the volatile odorous molecules to the

chamber of sensors, with the injection of a gas or air (Duran 2005, 2009).

<sup>2</sup> Images of sensors were taken from different Internet pages.

assigned to the component by its generality (Duran, 2005, 2009).

configuration.2

al., 2009).

**2.1.2 Volatile delivery system** 

which apply advanced techniques of digital signal processing and statistical pattern recognition. Their main objective is to enable the qualification of odours through classification tasks, discrimination, prediction, and even quantification of products, elements or components according to their organoleptic characteristics (Duran & Baldovino, 2009; Wilson & Baietto, 2009; Zhou et al., 2006).

## **2.1 Elements of an Electronic Nose System (EOS)**

An electronic nose system can be seen as an instrument or measuring equipment of artificial olfaction, consisting of a series of modules that work together, which analyzes gas samples, vapours and odours. An instrument or equipment of this type has at least 4 parts, each with specific functions which are detailed below (Duran & Baldovino, 2009; Tian et al., 2005).

## **2.1.1 Matrix or array of gas sensors**

In general, the gas sensors are devices that consist of two main parts, the first is an active element which changes its physical or chemical properties in the presence of that which it detects and the second part is a transducer, which converts the changes in the properties of the active element into an electrical signal. These sensors typically have a selective membrane, preventing passage of particles or unwanted material, acting as a first noise filter. In Figure 1 shows a simplified diagram of a device of this type, in which the main parts of a gas sensor and the nature of the inputs and outputs can be seen. (Grupo E-Nose, 2011, Tian et al., 2005).

Fig. 1. Simplified schematic diagram of a gas sensor.

There are different types of gas sensors for use in EOS, the most common are: MOX (Metal Oxide Semiconductor), QCM (Quartz Crystal microbalance), SAW (Surface Acoustic Waves), MOSFET (Metal Oxide Semiconductor Field Effect Transistor), CP (Conducting Polymers), and FO (Fiber Optics). This chapter deals specifically with MOX sensors built with semiconductor materials such as Tin oxide (SnO2), Zinc oxide (ZnO), Titanium oxide (TiO2), among others. Their operating principle is based on the change of conductivity of a sensitive material when it absorbs or reacts with the gases in the environment, Figure 2 shows several commercial sensors of this type (Berna, 2010).

which apply advanced techniques of digital signal processing and statistical pattern recognition. Their main objective is to enable the qualification of odours through classification tasks, discrimination, prediction, and even quantification of products, elements or components according to their organoleptic characteristics (Duran & Baldovino, 2009;

An electronic nose system can be seen as an instrument or measuring equipment of artificial olfaction, consisting of a series of modules that work together, which analyzes gas samples, vapours and odours. An instrument or equipment of this type has at least 4 parts, each with specific functions which are detailed below (Duran & Baldovino, 2009; Tian et al., 2005).

In general, the gas sensors are devices that consist of two main parts, the first is an active element which changes its physical or chemical properties in the presence of that which it detects and the second part is a transducer, which converts the changes in the properties of the active element into an electrical signal. These sensors typically have a selective membrane, preventing passage of particles or unwanted material, acting as a first noise filter. In Figure 1 shows a simplified diagram of a device of this type, in which the main parts of a gas sensor and the nature of the inputs and outputs can be seen. (Grupo E-Nose,

There are different types of gas sensors for use in EOS, the most common are: MOX (Metal Oxide Semiconductor), QCM (Quartz Crystal microbalance), SAW (Surface Acoustic Waves), MOSFET (Metal Oxide Semiconductor Field Effect Transistor), CP (Conducting Polymers), and FO (Fiber Optics). This chapter deals specifically with MOX sensors built with semiconductor materials such as Tin oxide (SnO2), Zinc oxide (ZnO), Titanium oxide (TiO2), among others. Their operating principle is based on the change of conductivity of a sensitive material when it absorbs or reacts with the gases in the environment, Figure 2

Wilson & Baietto, 2009; Zhou et al., 2006).

**2.1.1 Matrix or array of gas sensors** 

2011, Tian et al., 2005).

**2.1 Elements of an Electronic Nose System (EOS)** 

Fig. 1. Simplified schematic diagram of a gas sensor.

shows several commercial sensors of this type (Berna, 2010).

Fig. 2. Commercial gas sensors manufactured by Figaro and FIS, with different sizes and pin configuration.2

The majority of gas sensors are general purpose and usually have high sensitivity, detecting very low concentrations of volatile, but have disadvantages when trying to determine concentrations of a single component, because the output signal cannot be unambiguously assigned to the component by its generality (Duran, 2005, 2009).

Due to the fact that all EOS have a gas sensor array, it is desirable that the array be located in a special chamber or compartment in which the right conditions can be ensured for the proper operation. Mainly adequate insulation must be ensured to prevent pollutants from entering and the appropriate temperature and pressure must be maintained, these parameters are important or critical depending on the type of sensor used (Duran, 2005). Another advantage of using a chamber of sensors is that it facilitates the measurement process, because the volatiles will be in a higher concentration and they will have more contact with the active element of the sensor, which enables better and faster response from the sensors. It has also been experimentally determined that if the chamber of sensors is more hermetic, it can further exploit these advantages. Figure 3 shows a photograph of a chamber of sensors used in one of our projects with EOS (Velásquez et al., 2009).

#### **2.1.2 Volatile delivery system**

Basically it is a system that is responsible for transporting volatiles emitted by the samples or elements to be scanned into the chamber of sensor. Sometimes the sample is manually injected into the chamber of sensors, which results in error and delays; other times an automated system is responsible for transporting the volatile odorous molecules to the chamber of sensors, with the injection of a gas or air (Duran 2005, 2009).

<sup>2</sup> Images of sensors were taken from different Internet pages.

Quality Control Through Electronic Nose System 509

The control system takes care of proper handling of the Volatiles Transport System, for example: valves, air pump and other devices that are part of this system. It is also in charge of controlling additional subsystems or variables that the electronic nose system may have,

The data acquisition system is responsible for capturing the signals provided by the gas sensors and then delivering them to the process processing or computing system that has the appropriate software for processing such information (Rodriguez & Duran, 2008). The control and data acquisition systems can be integrated into a single device, which can be a data acquisition card, a microcontroller, a DSP (Digital Signal Processor) or a computer; it must also have adequate power stage to handle the elements that consume more power and must have the proper memory settings to store large amounts of data obtained from the

We recommend working with a data acquisition card connected to a computer, to achieve good storage capacity, correct handling of information processing and graphical representation. Although in some cases when portability is required, a DSP or

A significant part of the control system is the power source, which must be of a few amps, depending on the number of gas sensors and additional elements used; a source of 3 Amps

The processing system in most cases consists of a computer with an appropriate software for manipulating the data obtained by the sensors. Pre-processing techniques are applied to the data in order to extract the static parameters of the measures and reduce the amount of information to be analyzed. Subsequently multivariate analysis techniques and pattern recognition can be applied, such as PCA (Principal Component Analysis) and ANN (Artificial Neural Networks) to perform tasks such as: classification, discrimination, prediction, quantification of samples according to their organoleptic characteristics (Wilson

The operation of an electronic nose system depends on the component parts and the features of the equipment. In order to obtain measurements with a EOS the first step is to adjust the adequacy of the sample to be examined, this depends on the type of element to be analyzed, which sometimes must be heated, cut, mixed with other elements and simply placed near the sensors array or in the chamber of concentration ready to be analyzed.

The concentration process begins when the sample is placed in the chamber of concentration. After this a few minutes should be given to allow the sample to release enough volatile particles, only then can the measurement process begin, for which the volatiles must be deposited or transported from then chamber of concentration to the chamber of sensors. During the measurement process, the data acquisition system records all the changes in the output signal of each of the gas sensors. When the measurement process is finished the cleaning process of chamber of sensors begins and the stored data can be processed and analyzed immediately (off-line processing), using the pre-processing software and signal processing, in order to obtain an olfactory footprint that represents the

is enough when working with an EOS that contains an array of 8 gas sensors.

such as temperature and humidity control, among others (Duran, 2005).

**2.1.3 Control system and data acquisition** 

sensors.

microcontroller can be used.

**2.1.4 Processing system** 

& Baietto, 2009; Berna, 2010).

(Duran & Baldovino, 2009).

**2.2 Operation of an electronic nose system** 

Fig. 3. The chamber of sensors provides hermetic isolation and guarantees reliable measurements.

Fig. 4. Block diagram representing the electronic nose system.

Additionally most EOS have some kind of cleaning mechanism for the chamber of sensors, so that subsequent measures are made based on the same initial conditions and thus reproducibility of results is ensured. We recommend a different camera or hermetic compartment be used, called the "Chamber of Concentration", for containing the sample to be analyzed provided the environmental and physical conditions of the system allow it. Figure 4 shows the representation of an electronic nose system; note that the volatiles transport system is fundamental because it affects the operation of the EOS in the 3 different processes that can be carried out: concentration of volatiles, measurement and cleanup. (Rodriguez & Duran, 2008).

Fig. 3. The chamber of sensors provides hermetic isolation and guarantees reliable

Fig. 4. Block diagram representing the electronic nose system.

(Rodriguez & Duran, 2008).

Additionally most EOS have some kind of cleaning mechanism for the chamber of sensors, so that subsequent measures are made based on the same initial conditions and thus reproducibility of results is ensured. We recommend a different camera or hermetic compartment be used, called the "Chamber of Concentration", for containing the sample to be analyzed provided the environmental and physical conditions of the system allow it. Figure 4 shows the representation of an electronic nose system; note that the volatiles transport system is fundamental because it affects the operation of the EOS in the 3 different processes that can be carried out: concentration of volatiles, measurement and cleanup.

measurements.

## **2.1.3 Control system and data acquisition**

The control system takes care of proper handling of the Volatiles Transport System, for example: valves, air pump and other devices that are part of this system. It is also in charge of controlling additional subsystems or variables that the electronic nose system may have, such as temperature and humidity control, among others (Duran, 2005).

The data acquisition system is responsible for capturing the signals provided by the gas sensors and then delivering them to the process processing or computing system that has the appropriate software for processing such information (Rodriguez & Duran, 2008).

The control and data acquisition systems can be integrated into a single device, which can be a data acquisition card, a microcontroller, a DSP (Digital Signal Processor) or a computer; it must also have adequate power stage to handle the elements that consume more power and must have the proper memory settings to store large amounts of data obtained from the sensors.

We recommend working with a data acquisition card connected to a computer, to achieve good storage capacity, correct handling of information processing and graphical representation. Although in some cases when portability is required, a DSP or microcontroller can be used.

A significant part of the control system is the power source, which must be of a few amps, depending on the number of gas sensors and additional elements used; a source of 3 Amps is enough when working with an EOS that contains an array of 8 gas sensors.

## **2.1.4 Processing system**

The processing system in most cases consists of a computer with an appropriate software for manipulating the data obtained by the sensors. Pre-processing techniques are applied to the data in order to extract the static parameters of the measures and reduce the amount of information to be analyzed. Subsequently multivariate analysis techniques and pattern recognition can be applied, such as PCA (Principal Component Analysis) and ANN (Artificial Neural Networks) to perform tasks such as: classification, discrimination, prediction, quantification of samples according to their organoleptic characteristics (Wilson & Baietto, 2009; Berna, 2010).

#### **2.2 Operation of an electronic nose system**

The operation of an electronic nose system depends on the component parts and the features of the equipment. In order to obtain measurements with a EOS the first step is to adjust the adequacy of the sample to be examined, this depends on the type of element to be analyzed, which sometimes must be heated, cut, mixed with other elements and simply placed near the sensors array or in the chamber of concentration ready to be analyzed. (Duran & Baldovino, 2009).

The concentration process begins when the sample is placed in the chamber of concentration. After this a few minutes should be given to allow the sample to release enough volatile particles, only then can the measurement process begin, for which the volatiles must be deposited or transported from then chamber of concentration to the chamber of sensors. During the measurement process, the data acquisition system records all the changes in the output signal of each of the gas sensors. When the measurement process is finished the cleaning process of chamber of sensors begins and the stored data can be processed and analyzed immediately (off-line processing), using the pre-processing software and signal processing, in order to obtain an olfactory footprint that represents the

Quality Control Through Electronic Nose System 511

hillsides between 1000 m and 2000 m above sea level, with temperatures between 17ºC (290ºK) and 23ºC (296ºK) and relative humidities between 70% and 85%. The Table 1, show other data associated with optimal climatic conditions for growing coffee ([CENICAFE],

> Between 1800 and 2800 mm annually.

Humidity

Between 70 and 85%

Daily

Between 3 to 4 mm.

evaporation Winds

Below 5 km/h.

Brightness Temperature Rainfall Relative

Table 1. Average Climatic conditions in coffee growing regions ([CENICAFE], 2011).

The CENICAFE web page (2011) states that: "The soils of the Colombian coffee region are relatively young, e.g. they are still under development and the nature of the material which is derived from petrographic material is grouped into the following classes: Metamorphic, igneous and sedimentary, which occur on different levels and patterns of coverage with volcanic ash. These soils are highly variable in their characteristics and their distribution throughout the coffee zone, its location in reliefs from flat or gently undulating to steep with 75% slope, and the variety of their physical (from rocky and sandy to loam and clay) and

**3.1.1 What should be taken into account when considering a product such as coffee?**  Coffee is a product that is collected manually and subjected at certain processes before obtaining the green coffee beans (Fig. 5. b. ), in this condition it is more difficult to make an organoleptic analysis of coffee; therefore the best way to analyze coffee is the same way as tasters do, who perform tests on toasted and ground coffee, therefore the coffee must be subjected to a process of roasting and grinding in order to obtain a powder which is mixed with water at an average temperature of 60ºC (333ºK), which enables the emission of volatile particles. This mixture is introduced into the chamber of concentration (Fig. 6) in order to cluster the volatile particles which are then carried to the chamber of sensors for the measurement process. Figure 7 shows in detail the procedure used for the preparation of the

Fig. 6. Chamber of concentration, container for the different samples to be analyzed.

Between 17 and 23 ° C or 290ºK and 296ºK

chemical conditions (low to high content of organic matter and minerals)".

mixture before the measurements (Falasconi et al., 2005).

2011).

Average Solar Radiation

Between 300 and 450 cal/cm ² per day.

Solar

Between 4 to 5 hours daily.

sample, to perform the tasks of classification, discrimination and other (Berna, 2010; Wilson & Baietto, 2009).

## **3. Quality control of food using electronic nose systems**

A great part of electronic nose system applications are used in the food industry, where studies can be found with meat, milk and dairy products, eggs, different grains, fruits, oils, alcoholic and non alcoholic beverages, among others (Berna, 2010).

Fig. 5. a) Growing Coffee.3. b) Image of green coffee beans.4

Food quality control is one of the many applications that can benefit from the use of electronic nose (EOS). E.g., it can determine the type of product that is being analyzed, it can be classified by region, quality, time of ripening or storage, the food life span can be determined or predicted, as well as the level of deterioration or decomposition, the food life span can be determined or predicted and can determine flavors (Berna, 2010; El Barbri et al., 2008).

This chapter discusses the use of EOS in the quality control of foodstuffs such as coffee, fruits and alcoholic beverages.

## **3.1 Quality control of coffee with an electronic nose system**

In the quality control of coffee, the organoleptic characteristics are a determinant of its quality and therefore, they are significant to locating the predominant defects of coffee beans, as they negatively affect its flavor and odor (Rodriguez et al., 2010; Pardo et al., 2000). It is important to keep in mind that coffee production (Fig. 5. a.) is such an artisan process, that its control is somewhat complex and highly dependent on the historical traditions and cultural knowledge of those involved in the process, the lack of modernization of coffee farms, the incidence of fungal and other diseases in the crops and the need for chemicals sometimes influences the product quality (Rodriguez et al., 2010).

Another important factor to take into consideration in the quality of coffee is the climatic and edaphological conditions or nature of the soil. The Colombian coffee zone is located on

<sup>4</sup> Taken from the website of Herbolario Esencia.

<sup>3</sup> Photo owned by FNC, by Patricia Rincon Mautner. http://www.colombia.travel/es/turista-

internacional/actividad/590-clima-y-ubicacion-geografica-del-cafe

http://herboesencia.es/a-e/cafe-verde-coffea-arabica/

sample, to perform the tasks of classification, discrimination and other (Berna, 2010; Wilson

A great part of electronic nose system applications are used in the food industry, where studies can be found with meat, milk and dairy products, eggs, different grains, fruits, oils,

a) b)

Food quality control is one of the many applications that can benefit from the use of electronic nose (EOS). E.g., it can determine the type of product that is being analyzed, it can be classified by region, quality, time of ripening or storage, the food life span can be determined or predicted, as well as the level of deterioration or decomposition, the food life span can be determined or predicted and can determine flavors (Berna, 2010; El Barbri et al.,

This chapter discusses the use of EOS in the quality control of foodstuffs such as coffee,

In the quality control of coffee, the organoleptic characteristics are a determinant of its quality and therefore, they are significant to locating the predominant defects of coffee beans, as they negatively affect its flavor and odor (Rodriguez et al., 2010; Pardo et al., 2000). It is important to keep in mind that coffee production (Fig. 5. a.) is such an artisan process, that its control is somewhat complex and highly dependent on the historical traditions and cultural knowledge of those involved in the process, the lack of modernization of coffee farms, the incidence of fungal and other diseases in the crops and the need for chemicals

Another important factor to take into consideration in the quality of coffee is the climatic and edaphological conditions or nature of the soil. The Colombian coffee zone is located on

<sup>3</sup> Photo owned by FNC, by Patricia Rincon Mautner. http://www.colombia.travel/es/turista-

**3. Quality control of food using electronic nose systems** 

alcoholic and non alcoholic beverages, among others (Berna, 2010).

Fig. 5. a) Growing Coffee.3. b) Image of green coffee beans.4

**3.1 Quality control of coffee with an electronic nose system** 

sometimes influences the product quality (Rodriguez et al., 2010).

internacional/actividad/590-clima-y-ubicacion-geografica-del-cafe

<sup>4</sup> Taken from the website of Herbolario Esencia. http://herboesencia.es/a-e/cafe-verde-coffea-arabica/

& Baietto, 2009).

2008).

fruits and alcoholic beverages.

hillsides between 1000 m and 2000 m above sea level, with temperatures between 17ºC (290ºK) and 23ºC (296ºK) and relative humidities between 70% and 85%. The Table 1, show other data associated with optimal climatic conditions for growing coffee ([CENICAFE], 2011).


Table 1. Average Climatic conditions in coffee growing regions ([CENICAFE], 2011).

The CENICAFE web page (2011) states that: "The soils of the Colombian coffee region are relatively young, e.g. they are still under development and the nature of the material which is derived from petrographic material is grouped into the following classes: Metamorphic, igneous and sedimentary, which occur on different levels and patterns of coverage with volcanic ash. These soils are highly variable in their characteristics and their distribution throughout the coffee zone, its location in reliefs from flat or gently undulating to steep with 75% slope, and the variety of their physical (from rocky and sandy to loam and clay) and chemical conditions (low to high content of organic matter and minerals)".

## **3.1.1 What should be taken into account when considering a product such as coffee?**

Coffee is a product that is collected manually and subjected at certain processes before obtaining the green coffee beans (Fig. 5. b. ), in this condition it is more difficult to make an organoleptic analysis of coffee; therefore the best way to analyze coffee is the same way as tasters do, who perform tests on toasted and ground coffee, therefore the coffee must be subjected to a process of roasting and grinding in order to obtain a powder which is mixed with water at an average temperature of 60ºC (333ºK), which enables the emission of volatile particles. This mixture is introduced into the chamber of concentration (Fig. 6) in order to cluster the volatile particles which are then carried to the chamber of sensors for the measurement process. Figure 7 shows in detail the procedure used for the preparation of the mixture before the measurements (Falasconi et al., 2005).

Fig. 6. Chamber of concentration, container for the different samples to be analyzed.

Quality Control Through Electronic Nose System 513

Figure 8 shows the analysis of these measurements, using the technique PCA (Principal Component Analysis). The different measurement groups can be seen, clearly differentiated in samples of regular and export type coffee. The measurements taken from export quality coffee are highlighted in green circles, while the measurements taken from regular coffee are

Fig. 8. Results of PCA analysis between measures of good quality coffee (green circles) and

Fig. 9. Classification results of the measurements with a radial basis neural network, between good quality coffee (green circles) and coffee with defects (red circles).

in red circles.

coffee with defects (red circles).

#### **3.1.2 Some results obtained with the coffee**

There have been several tests of different varieties of export quality "Excelso" coffee, with "regular" coffee and coffee with marked defects in the grains. Tests have been accompanied by personnel trained in coffee tasting, who issued their concept based on their personal perception of each coffee sample, helping in the designation of various patterns for facilitating subsequent classification tasks with different measures (Rodriguez et al., 2010). In one of the tests measures were taken from samples of export quality coffee of two different varieties, Excelso Europe and Excelso UGQ-10%, which are classified as good quality cafes. These measurements were compared to those of regular coffee (for domestic consumption, commonly known as "Pasillas"), in which the experts detected some defects such as traces of fermentation, chemical contamination and signs of "Repose" (caused by prolonged storage or storage in unfavorable conditions). It is noteworthy that the defects mentioned are those most commonly found in coffee, influenced by poor product handling techniques (Rodriguez et al., 2010).

Fig. 7. Procedure used for preparing samples of coffee before starting the measurement process.

There have been several tests of different varieties of export quality "Excelso" coffee, with "regular" coffee and coffee with marked defects in the grains. Tests have been accompanied by personnel trained in coffee tasting, who issued their concept based on their personal perception of each coffee sample, helping in the designation of various patterns for facilitating subsequent classification tasks with different measures (Rodriguez et al., 2010). In one of the tests measures were taken from samples of export quality coffee of two different varieties, Excelso Europe and Excelso UGQ-10%, which are classified as good quality cafes. These measurements were compared to those of regular coffee (for domestic consumption, commonly known as "Pasillas"), in which the experts detected some defects such as traces of fermentation, chemical contamination and signs of "Repose" (caused by prolonged storage or storage in unfavorable conditions). It is noteworthy that the defects mentioned are those most commonly found in coffee, influenced by poor product handling

Notes:





taken for each measurement.

60ºC (333ºK) approximately.

mixture should be prepared.

approximately 10 g.

Fig. 7. Procedure used for preparing samples of coffee before starting the measurement

**3.1.2 Some results obtained with the coffee** 

techniques (Rodriguez et al., 2010).

Choose a sample of coffee (green beans).

Toast coffee.

Grind coffee.

Weigh 5 g of coffee.

Add water at 60ºC or 333ºK.

Place this mixture in the Chamber of Concentration.

Start the Measurement Process.

process.

Figure 8 shows the analysis of these measurements, using the technique PCA (Principal Component Analysis). The different measurement groups can be seen, clearly differentiated in samples of regular and export type coffee. The measurements taken from export quality coffee are highlighted in green circles, while the measurements taken from regular coffee are in red circles.

Fig. 8. Results of PCA analysis between measures of good quality coffee (green circles) and coffee with defects (red circles).

Fig. 9. Classification results of the measurements with a radial basis neural network, between good quality coffee (green circles) and coffee with defects (red circles).

Quality Control Through Electronic Nose System 515

Fig. 11. Validation Results of measurements with passion fruit (yellow circle), peaches (red circle) and apples (blue circle) using a neural network Feed Forward Back Propagation.

Electronic nose systems have been widely used for classification, discrimination of characteristics and detection of different elements or compounds considering the organoleptic characteristics, but its application in quantification tasks has not been widely explored. In some of these studies the least square regression method is used to consider the gas concentration (Khalaf et al., 2009) and for the quantification of mixed contaminants in the air (Zhou et al., 2006), also the new technologies have been used as systems based on micro-electromechanical sensors for the quantification of components in vapor mixtures

Below is a study with an electronic nose system, where a digital signal processor DSP was adapted and artificial neural network "Feed-forward back propagation" was implemented, which was trained with the aim of identifying and quantifying levels of Ethanol and Methanol in different samples. As result the percentage of Ethanol and Methanol of the samples were obtained, and the electronic nose system was improved, called "A-NOSE" (Rodriguez et al., 2010), when the processing software was implemented in a different

The artificial neural network that was used to perform the identification and quantification of Ethanol and Methanol was Multi Layer Perceptron (MLP) Feed-forward back propagation network, which was trained and tried in R2006a Matlab software; as a result of training of the artificial neuronal network the weight matrices and bias vectors were obtained, that were used to codify the artificial neural network program in C++ language with software CodeWarrior and subsequently downloaded this program in the digital signal

The initial samples were 95% Ethanol and 95% Methanol, which were diluted with distilled water to obtain 50%, 25% and 10% concentrations. Different measurements with the Ethanol and Methanol were realized in their different concentrations to realize the training of the

**3.3 Quality control of alcoholic beverages** 

(Zhao et al, 2007).

device from the personal computer.

processor DSP56F801 of Motorola.

This group of measurements was classified using a radial basis neural network (Figure 9). It can be seen how the various measurements of the same type are located within a horizontal axis, forming 5 different subgroups, which belong to two major groups of export type coffee (green circles) and regular coffee (red circles).

#### **3.2 Quality control of fruits**

For the analysis of fruits invasive and noninvasive techniques can be used. Invasive techniques involve damaging the fruit to take a sample, in order to perform various tests with the same fruit at the same moment and also facilitate extraction of volatile particles, as manipulation helps to release more volatile particles, which facilitates the measurement process. A drawback of this technique is that once the product is handled it can only serve in the measurement process, because handling accelerates the decomposition process. Meanwhile, the noninvasive techniques, just take the fruit for testing without inflicting damage therefore the same fruit can be used for further testing in order to analyze maturity stages and study the processes of decomposition. (Rodriguez & Duran, 2008; Duran & Baldovino, 2009; Berna, 2010).

Figure 10 shows the results of the analysis of some measurements made on samples of passion fruit, peaches and apples, using the PCA technique. The 2 measurement groups can be seen, which can be clearly differentiated in samples of passion fruit and peaches, in addition 2 measurements of apple were introduced as a test (Creole apple and Chilean apple), in order to test the classification accuracy of the system and the similarity that may exist between different varieties of a fruit. Also Figure 11 shows the validation of the measurements using an Artificial Neural Network Feed Forward Back Propagation, applying the technique "Leave one out", it can be seen how the system responds to the eventual absence of a measure in the training of neural network, the most significant result occurs with measurements of apples which are classified successfully despite having so few measures.

Fig. 10. Results of PCA analysis between passion fruit (yellow circle), peaches (red circle) and apples (blue circle).

This group of measurements was classified using a radial basis neural network (Figure 9). It can be seen how the various measurements of the same type are located within a horizontal axis, forming 5 different subgroups, which belong to two major groups of export type coffee

For the analysis of fruits invasive and noninvasive techniques can be used. Invasive techniques involve damaging the fruit to take a sample, in order to perform various tests with the same fruit at the same moment and also facilitate extraction of volatile particles, as manipulation helps to release more volatile particles, which facilitates the measurement process. A drawback of this technique is that once the product is handled it can only serve in the measurement process, because handling accelerates the decomposition process. Meanwhile, the noninvasive techniques, just take the fruit for testing without inflicting damage therefore the same fruit can be used for further testing in order to analyze maturity stages and study the processes of decomposition. (Rodriguez & Duran, 2008; Duran &

Figure 10 shows the results of the analysis of some measurements made on samples of passion fruit, peaches and apples, using the PCA technique. The 2 measurement groups can be seen, which can be clearly differentiated in samples of passion fruit and peaches, in addition 2 measurements of apple were introduced as a test (Creole apple and Chilean apple), in order to test the classification accuracy of the system and the similarity that may exist between different varieties of a fruit. Also Figure 11 shows the validation of the measurements using an Artificial Neural Network Feed Forward Back Propagation, applying the technique "Leave one out", it can be seen how the system responds to the eventual absence of a measure in the training of neural network, the most significant result occurs with measurements of apples which are classified successfully despite having so few

Fig. 10. Results of PCA analysis between passion fruit (yellow circle), peaches (red circle)

(green circles) and regular coffee (red circles).

**3.2 Quality control of fruits** 

Baldovino, 2009; Berna, 2010).

measures.

and apples (blue circle).

Fig. 11. Validation Results of measurements with passion fruit (yellow circle), peaches (red circle) and apples (blue circle) using a neural network Feed Forward Back Propagation.

#### **3.3 Quality control of alcoholic beverages**

Electronic nose systems have been widely used for classification, discrimination of characteristics and detection of different elements or compounds considering the organoleptic characteristics, but its application in quantification tasks has not been widely explored. In some of these studies the least square regression method is used to consider the gas concentration (Khalaf et al., 2009) and for the quantification of mixed contaminants in the air (Zhou et al., 2006), also the new technologies have been used as systems based on micro-electromechanical sensors for the quantification of components in vapor mixtures (Zhao et al, 2007).

Below is a study with an electronic nose system, where a digital signal processor DSP was adapted and artificial neural network "Feed-forward back propagation" was implemented, which was trained with the aim of identifying and quantifying levels of Ethanol and Methanol in different samples. As result the percentage of Ethanol and Methanol of the samples were obtained, and the electronic nose system was improved, called "A-NOSE" (Rodriguez et al., 2010), when the processing software was implemented in a different device from the personal computer.

The artificial neural network that was used to perform the identification and quantification of Ethanol and Methanol was Multi Layer Perceptron (MLP) Feed-forward back propagation network, which was trained and tried in R2006a Matlab software; as a result of training of the artificial neuronal network the weight matrices and bias vectors were obtained, that were used to codify the artificial neural network program in C++ language with software CodeWarrior and subsequently downloaded this program in the digital signal processor DSP56F801 of Motorola.

The initial samples were 95% Ethanol and 95% Methanol, which were diluted with distilled water to obtain 50%, 25% and 10% concentrations. Different measurements with the Ethanol and Methanol were realized in their different concentrations to realize the training of the

Quality Control Through Electronic Nose System 517

Fig. 13. Results of PCA analysis for the classification of wines and Aguardiente, according to

Fig. 14. Results of PCA analysis for the classification of wines and Aguardiente, according to

the concentration of Ethanol.

the concentration of Ethanol and Methanol.

artificial neuronal network and additionally other measures with wines (red, white, fruity, orange wine) and Aguardiente (national drink) were performed. The percentages of wine were close to 10% Ethanol and 0% Methanol and Aguardiente was close to 30% Ethanol and 0% Methanol, values in accordance to the values specified on the product labels.

Fig. 12. Results of PCA analysis between Ethanol measurements (blue circles) and Methanol measurements (red circles).

Figure 12 the results of PCA analysis can be seen applied to measurements of different ethanol and methanol concentrations. It can be inferred that the measurements follow a trend, which yield a characteristic equation that models the behavior for different concentrations of Ethanol and Methanol. It can also be seen that as the concentration of Ethanol and Methanol is lower measurements tend to find a common point, this may be because they have are both alcohol.

Another test analyzed samples of different kinds of wines (e.g.: red wine, white wine, orange wine) and Aguardiente (national drink), the results are shown in Figures 13 and 14. It can be seen that wine measurements are close to 10% Ethanol, the results obtained by the neural network (feed-forward back propagation) that was trained for this purpose showed results very close to 10% and 0% Ethanol Methanol. It should be clarified that the neural network was trained with data from measurements of different ethanol and methanol concentrations and were then tested with data from measurements of different drinks.

## **4. Other applications of electronic nose systems**

The applications of electronic nose systems are very diverse. The previous sections have covered some of the possible applications in the agro-food industry, but there are many other still to be mentioned, for example: The identification and diagnosis of respiratory

artificial neuronal network and additionally other measures with wines (red, white, fruity, orange wine) and Aguardiente (national drink) were performed. The percentages of wine were close to 10% Ethanol and 0% Methanol and Aguardiente was close to 30% Ethanol and

Fig. 12. Results of PCA analysis between Ethanol measurements (blue circles) and Methanol

Figure 12 the results of PCA analysis can be seen applied to measurements of different ethanol and methanol concentrations. It can be inferred that the measurements follow a trend, which yield a characteristic equation that models the behavior for different concentrations of Ethanol and Methanol. It can also be seen that as the concentration of Ethanol and Methanol is lower measurements tend to find a common point, this may be

Another test analyzed samples of different kinds of wines (e.g.: red wine, white wine, orange wine) and Aguardiente (national drink), the results are shown in Figures 13 and 14. It can be seen that wine measurements are close to 10% Ethanol, the results obtained by the neural network (feed-forward back propagation) that was trained for this purpose showed results very close to 10% and 0% Ethanol Methanol. It should be clarified that the neural network was trained with data from measurements of different ethanol and methanol concentrations and were then tested with data from measurements of different drinks.

The applications of electronic nose systems are very diverse. The previous sections have covered some of the possible applications in the agro-food industry, but there are many other still to be mentioned, for example: The identification and diagnosis of respiratory

measurements (red circles).

because they have are both alcohol.

**4. Other applications of electronic nose systems** 

0% Methanol, values in accordance to the values specified on the product labels.

Fig. 13. Results of PCA analysis for the classification of wines and Aguardiente, according to the concentration of Ethanol.

Fig. 14. Results of PCA analysis for the classification of wines and Aguardiente, according to the concentration of Ethanol and Methanol.

Quality Control Through Electronic Nose System 519

flow control unit, a temperature control unit and a sorbent tube. The theoretical analysis and experimental results indicate that gas condensation, together with the medical electronic nose system can significantly reduce the detection limit of the nose system and increase the

Fig. 15. Results of PCA analysis for the classification of COPD patients and non-smokers.

Fig. 16. Results of PCA analysis with emphasis on measurements of patients with COPD.

Using DGN (Center), displaying the first 2 components.

system's ability to distinguish low concentration gas samples.

diseases (Xu et al., 2008, Velasquez et al ., 2009), the detection of narcotics and explosive substances (Oakes, L.; Dobrokhotov, V., 2010), determination of air quality and the environment (Zhou et al., 2006), among others, although there are still many possible applications to be explored.

## **4.1 Detection of diseases using electronic nose systems**

There are a variety of respiratory diseases, which in some cases are caused by smoking and exposure to contaminated environments. This is the case of Chronic Obstructive Pulmonary Disease COPD, which has a mortality rate exceeding 15.9% (Velásquez et al., 2009; Velásquez, 2008).

COPD is a chronic lung disease characterized by airflow limitation that is not fully reversible, with progressive deterioration and is associated with abnormal lung inflammatory response to noxious particles or gases (Velásquez et al., 2009; Velásquez, 2008). The main cause of COPD is prolonged consumption of cigarettes, it is said that up to 20% of smokers have COPD.

This disease is more common in:


## **4.1.1 Analysis of measurements taken from people with COPD and healthy controls**

Below are some results of the analysis of measurements taken from healthy controls, nonsmokers and patients diagnosed with COPD. All patients diagnosed with COPD were long time smokers from 16 years up to even 50 years and most of them have already quit smoking, due to the fact that many receive medical treatment. (Velásquez et al., 2009; Velásquez, 2008).

Figure 15 shows the results of PCA analysis of samples of healthy controls and patients with COPD. The low dispersion of measurements of healthy controls and high dispersion of measurements of patients with COPD can be seen; due the fact that to not all patients have the disease at the same level.

Figure 16 has separated the samples from different patients with COPD, from these results it can be inferred that according to the health of the person the different patients can be classified. Future research should conduct more measurements on patients at different stages of the disease and could also be extended to other respiratory diseases and even gastric related diseases.

A study that deserves attention is (Xu et al., 2008) who developed a solid trap/thermal desorption-based odorant gas condensation system designed and implemented for measuring low concentration odorant gas. The results showed that the technique was successfully applied to a medical electronic nose system. The developed system consists of a

diseases (Xu et al., 2008, Velasquez et al ., 2009), the detection of narcotics and explosive substances (Oakes, L.; Dobrokhotov, V., 2010), determination of air quality and the environment (Zhou et al., 2006), among others, although there are still many possible

There are a variety of respiratory diseases, which in some cases are caused by smoking and exposure to contaminated environments. This is the case of Chronic Obstructive Pulmonary Disease COPD, which has a mortality rate exceeding 15.9% (Velásquez et al., 2009;

COPD is a chronic lung disease characterized by airflow limitation that is not fully reversible, with progressive deterioration and is associated with abnormal lung inflammatory response to noxious particles or gases (Velásquez et al., 2009; Velásquez, 2008). The main cause of COPD is prolonged consumption of cigarettes, it is said that up to


**4.1.1 Analysis of measurements taken from people with COPD and healthy controls**  Below are some results of the analysis of measurements taken from healthy controls, nonsmokers and patients diagnosed with COPD. All patients diagnosed with COPD were long time smokers from 16 years up to even 50 years and most of them have already quit smoking, due to the fact that many receive medical treatment. (Velásquez et al., 2009;

Figure 15 shows the results of PCA analysis of samples of healthy controls and patients with COPD. The low dispersion of measurements of healthy controls and high dispersion of measurements of patients with COPD can be seen; due the fact that to not all patients have

Figure 16 has separated the samples from different patients with COPD, from these results it can be inferred that according to the health of the person the different patients can be classified. Future research should conduct more measurements on patients at different stages of the disease and could also be extended to other respiratory diseases and even

A study that deserves attention is (Xu et al., 2008) who developed a solid trap/thermal desorption-based odorant gas condensation system designed and implemented for measuring low concentration odorant gas. The results showed that the technique was successfully applied to a medical electronic nose system. The developed system consists of a

applications to be explored.

20% of smokers have COPD. This disease is more common in:


can damage the lungs.

Other COPD risk factors include:



Velásquez, 2008).



Velásquez, 2008).

the disease at the same level.

gastric related diseases.

**4.1 Detection of diseases using electronic nose systems** 

flow control unit, a temperature control unit and a sorbent tube. The theoretical analysis and experimental results indicate that gas condensation, together with the medical electronic nose system can significantly reduce the detection limit of the nose system and increase the system's ability to distinguish low concentration gas samples.

Fig. 15. Results of PCA analysis for the classification of COPD patients and non-smokers.

Fig. 16. Results of PCA analysis with emphasis on measurements of patients with COPD. Using DGN (Center), displaying the first 2 components.

Quality Control Through Electronic Nose System 521

To identify measurement patterns or to carry out the training applications using computational intelligence it is very important to have expert staff on hand, as in the case of coffee quality control which had the support of trained coffee tasters, who issued their concept based on personal perception of each coffee sample, helping in the designation of the various patterns to facilitate subsequent classification tasks with different

Electronic nose systems have been widely used for classification, discrimination of characteristics and detection of different elements or compounds considering the organoleptic characteristics, and even for quantification tasks. This can be carried out with tools like multivariate analysis techniques and pattern recognition, such as PCA (Principal

The processing software of electronic nose system can be implemented on a digital signal processor DSP using an artificial neural network like the alcohol research case presented in section 3 which used a Feed-forward back propagation network, which was trained with the aim of identifying and quantifying Ethanol and Methanol of different samples. As result the

The artificial neural network that was used for the identification and quantification of Ethanol and Methanol was trained and tried using R2006a Matlab software; the training results were used to codify the the artificial neural network program in C++ language and subsequently downloaded this program in the digital signal processor DSP56F801 of

The results of PCA analysis for samples of healthy controls and patients with COPD showed differences in the low dispersion of the measurements taken of healthy controls and high dispersion of the measurements taken of patients with COPD; due to the fact that not all

This study was supported by the P09225 grant and carried out within the MIRP Research Group, Research Center, Instituto Tecnológico Metropolitano ITM, Medellín–Colombia.

Badrick, T. (2008). The Quality Control System. The Clinical Biochemist – Reviews,

Berna, A. (2010). Metal Oxide Sensors for Electronic Noses and Their Application to Food Analysis. Sensors, Vol.10, (April 2010), pp. 3882-3910, ISSN 1424-8220. [CENICAFE] Centro Nacional de Investigaciones del Café Colombia (March 2011). Sistemas

industrial Products Through of an Electronic Nose. Revista Colombiana de Tecnologías de Avanzada*,* Vol.1, No.13, (December 2009), pp. 1-8, ISSN 1692-7257. Duran, C. (2005). Diseño y optimización de los subsistemas de un sistema de olfato

electrónico para aplicaciones agroalimentarias e industriales. Universitat Rovira i

Based on Metal Oxide Semiconductor Sensors as an Alternative Technique for the

El Barbri, N.; Llobet, E.; El Bari, N.; Correig, X. & Bouchikhi, B. (2008). Electronic Nose

 http://cenicafe.org/modules.php?name=Sistemas\_Produccion&file=condclim Duran, C. & Baldovino, D. (2009). Monitoring System to Detect the Maturity of Agro-

Component Analysis) and ANN (Artificial Neural Networks).

percentage of Ethanol and Methanol of the samples were obtained.

(August,2008), p.p. 67-70, ISSN 0159 – 8090.

de Producción, 25.03.2011, Available from

Virgili. Tarragona, España.

patients have the disease at the same level.

**6. Acknowledgements** 

**7. References** 

measurements.

Motorola.

## **4.2 Determination of air quality using electronic nose systems**

Such applications have a bright future in the industry, because the environment is very susceptible to leakage and contamination by gases, which in many cases can be harmful and even lethal to humans.

NASA has done some work on this issue, for example (Ryan et al., 2009), Whom Developed an Electronic Nose to be used in Environmental Monitoring in the International Space Station, the Electronic Nose (Enose) is an array of 32 polymer sensors, the pattern of response may identify contaminants in the environment. An engineering test model of the ENose was used to monitor the air of the Early Human Test experiment at Johnson Space Center for 49 days. Examination of the data recorded by the ENose shows that major excursions in the resistance recorded in the sensor array may be correlated with events recorded in the Test Logs of the Test Chamber. The ability to monitor the constituents of breathing air in a closed chamber in which air is recycled is important to NASA for use in closed environments such as the space shuttle and the space station.

In the same way an electronic nose system could be developed for places such as airports or customs, in order to detect narcotics or prohibited hallucinogenic substances and in hostile or war environment to detect explosives or mines planted in the soil.

## **5. Conclusions**

The operation of the electronic nose system depends on the component parts and the features of the equipment. Inside we find the gas sensor array, the volatile particle delivery system, control system, data acquisition and data processing system.

We recommend a different chamber or hermetic compartment be used for containing the sample to be analyzed, called "Chamber of Concentration", provided the environmental and physical conditions of the system allow it.

The volatile particle transport system is fundamental because it affects the operation of the electronic nose system in the 3 different processes: concentration of volatile particles, measurement and cleanup.

Measurements with electronic nose systems begin by ensuring the adequacy of the sample to be examined, this depends on the type of element to be analyzed, which sometimes must be heated, cut, mixed with other elements or simply placed near the sensor array or in the chamber of concentration.

During the measurement process, the data acquisition system records all the changes in the output signal of each of the gas sensors. When the measurement process is finished the cleaning of the chamber of sensors begins, which is very important to restore the initial conditions of the system and to ensure the reproducibility of the measurements.

Once the measurement process is finished the stored data is processed and analyzed using the pre-processing software which allows to extraction of static parameters from the measurements and reduces the amount of information to be analyzed. Subsequently the processing software is applied, in order to obtain an olfactory footprint that represents the sample, to perform classification, discrimination and other tasks.

Coffee is preferably analyzed in the same way as by tasters, who perform tests on toasted and ground coffee, therefore the coffee must be roasted and ground in order to obtain a powder which is mixed with hot water, to facilitate the emission of volatile particles and this mixture is introduced into the chamber of concentration for the measurement process. This procedure for the preparation of the mixture can be applied similarly to other elements before the start of the measurements.

Such applications have a bright future in the industry, because the environment is very susceptible to leakage and contamination by gases, which in many cases can be harmful and

NASA has done some work on this issue, for example (Ryan et al., 2009), Whom Developed an Electronic Nose to be used in Environmental Monitoring in the International Space Station, the Electronic Nose (Enose) is an array of 32 polymer sensors, the pattern of response may identify contaminants in the environment. An engineering test model of the ENose was used to monitor the air of the Early Human Test experiment at Johnson Space Center for 49 days. Examination of the data recorded by the ENose shows that major excursions in the resistance recorded in the sensor array may be correlated with events recorded in the Test Logs of the Test Chamber. The ability to monitor the constituents of breathing air in a closed chamber in which air is recycled is important to NASA for use in

In the same way an electronic nose system could be developed for places such as airports or customs, in order to detect narcotics or prohibited hallucinogenic substances and in hostile

The operation of the electronic nose system depends on the component parts and the features of the equipment. Inside we find the gas sensor array, the volatile particle delivery

We recommend a different chamber or hermetic compartment be used for containing the sample to be analyzed, called "Chamber of Concentration", provided the environmental and

The volatile particle transport system is fundamental because it affects the operation of the electronic nose system in the 3 different processes: concentration of volatile particles,

Measurements with electronic nose systems begin by ensuring the adequacy of the sample to be examined, this depends on the type of element to be analyzed, which sometimes must be heated, cut, mixed with other elements or simply placed near the sensor array or in the

During the measurement process, the data acquisition system records all the changes in the output signal of each of the gas sensors. When the measurement process is finished the cleaning of the chamber of sensors begins, which is very important to restore the initial

Once the measurement process is finished the stored data is processed and analyzed using the pre-processing software which allows to extraction of static parameters from the measurements and reduces the amount of information to be analyzed. Subsequently the processing software is applied, in order to obtain an olfactory footprint that represents the

Coffee is preferably analyzed in the same way as by tasters, who perform tests on toasted and ground coffee, therefore the coffee must be roasted and ground in order to obtain a powder which is mixed with hot water, to facilitate the emission of volatile particles and this mixture is introduced into the chamber of concentration for the measurement process. This procedure for the preparation of the mixture can be applied similarly to other elements

conditions of the system and to ensure the reproducibility of the measurements.

sample, to perform classification, discrimination and other tasks.

**4.2 Determination of air quality using electronic nose systems** 

closed environments such as the space shuttle and the space station.

or war environment to detect explosives or mines planted in the soil.

system, control system, data acquisition and data processing system.

physical conditions of the system allow it.

measurement and cleanup.

chamber of concentration.

before the start of the measurements.

even lethal to humans.

**5. Conclusions** 

To identify measurement patterns or to carry out the training applications using computational intelligence it is very important to have expert staff on hand, as in the case of coffee quality control which had the support of trained coffee tasters, who issued their concept based on personal perception of each coffee sample, helping in the designation of the various patterns to facilitate subsequent classification tasks with different measurements.

Electronic nose systems have been widely used for classification, discrimination of characteristics and detection of different elements or compounds considering the organoleptic characteristics, and even for quantification tasks. This can be carried out with tools like multivariate analysis techniques and pattern recognition, such as PCA (Principal Component Analysis) and ANN (Artificial Neural Networks).

The processing software of electronic nose system can be implemented on a digital signal processor DSP using an artificial neural network like the alcohol research case presented in section 3 which used a Feed-forward back propagation network, which was trained with the aim of identifying and quantifying Ethanol and Methanol of different samples. As result the percentage of Ethanol and Methanol of the samples were obtained.

The artificial neural network that was used for the identification and quantification of Ethanol and Methanol was trained and tried using R2006a Matlab software; the training results were used to codify the the artificial neural network program in C++ language and subsequently downloaded this program in the digital signal processor DSP56F801 of Motorola.

The results of PCA analysis for samples of healthy controls and patients with COPD showed differences in the low dispersion of the measurements taken of healthy controls and high dispersion of the measurements taken of patients with COPD; due to the fact that not all patients have the disease at the same level.

## **6. Acknowledgements**

This study was supported by the P09225 grant and carried out within the MIRP Research Group, Research Center, Instituto Tecnológico Metropolitano ITM, Medellín–Colombia.

## **7. References**


http://cenicafe.org/modules.php?name=Sistemas\_Produccion&file=condclim


**28** 

*France* 

**Mammographic Quality Control Using Digital** 

Breast cancer is the leading cause of cancer mortality among middle aged women. Survival and recovery depend on early diagnosis. At present mammography is one of the most reliable methods for early breast cancer detection. However relevance of diagnosis is highly correlated to image quality of the mammographic system. Hence periodic controls in mammographic facilities are necessary in order to make sure they work properly. In particular global image quality is evaluated from a mammographic phantom film. A phantom is an object with the same anatomic shape and radiological response as an average dense fleshed breast and in which are embedded structures that mimic clinically relevant features such as microcalcifications, nodules and fibrils. For each category of features, the targets have progressively smaller sizes and contrast so that the largest one is the most readily visible and the next is less visible and so on. Using a phantom makes it possible to free from the variable of differences in breast tissue positioning and level of compression from patient to patient. The process is as follows: the mammographic phantom film is analysed independently by several readers and a score is obtained by each of them depending on the number of objects they see. The independent object visibility scores are

Automating this score by using computer image processing of digitized phantom films should make the evaluation of mammographic facilities easier and less subjective. In addition image processing should enable us to take into account other parameters such as, for instance, noise, texture and shape of the targets that a reader eye cannot estimate quantitatively, and so to perform a more elaborate analysis. In collaboration with ARCADES (Association pour la Recherche et le Dépistage des Cancers du Sein et du col de l'utérus) which set, since 1989, a breast cancer screening program in South of France, a project aimed at automating phantom film evaluation is in progress. Such a project consists first in digitizing phantom films with the adequate spatial resolution and then in processing the obtained images in order to detect,

Little work has been done to automate quality control in mammographic facilities. Fast Fourier transform is used (Brooks et al., 1997) to establish some visibility criteria for the phantom test object. (Chakraborty et al., 1997) compares phantom images with a pattern image to obtain relations between some of the image parameters and the physical conditions

then averaged and the resulting score is assigned to the phantom film.

segment and characterize the objects contained in the phantom.

**1. Introduction** 

**Image Processing Techniques** 

*Université Paul Cézanne, Institut Fresnel, UMR-CNRS 6133* 

Mouloud Adel and Monique Rasigni

*Domaine Universitaire de Saint Jérôme,* 

Spoilage Classification of Red Meat. Sensors, Vol.8, (January 2008), pp. 142-156, ISSN 1424-8220.


## **Mammographic Quality Control Using Digital Image Processing Techniques**

Mouloud Adel and Monique Rasigni *Université Paul Cézanne, Institut Fresnel, UMR-CNRS 6133 Domaine Universitaire de Saint Jérôme, France* 

### **1. Introduction**

522 Modern Approaches To Quality Control

Falasconi, M.; Pardo, M.; Sberveglieri, G.; Ricco, I. & Bresciani, A. (2005). The novel EOS835

Grupo E-Nose, (March 2011) ¿Qué es una Nariz Electrónica?, 15.04.2011, Available from

Khalaf, W.; Pace, C. & Gaudioso, M. (2009). Least Square Regression Method for estimating

Oakes, L.; Dobrokhotov, V. (2010). Electronic Nose for Detection of Explosives. American

Pardo, M.; Niederjaufner, G.; Benussi, G.; Comini, E.; Faglia, G.; Sberveglieri, G.; Holmberg,

Institute of Technology. Johnson Space Center, NASA, Houston TX 77058. Rodríguez, J.; Durán, C.; Reyes, A. (2010). Electronic Nose for Quality Control of

Rodriguez, J. & Duran, C. (2008). Electronic odor system to detect volatile compounds.

Tian, F.; Yang, S. & Dong, K. (2005). Circuit and Noise Analysis of Odorant Gas Sensors in an E-Nose. Sensors, Vol.5, (February 2005), pp. 85-96, ISSN 1424-8220. Velásquez, A.; Durán, C.; Gualdron, O.; Rodríguez, J. & Manjarres, L. (2009). Electronic

Velásquez, A. (2008). Sistema Multisensorial Electrónico No Invasivo Para La Detección De

Wilson, A. & Baietto, M. (2009). Applications and Advances in Electronic-Nose Technologies. Sensors, Vol.9, (June 2009), pp. 5099-5148, ISSN 1424-8220. Xu, X.; Tian, F.; Yang, S.; Jia, Q. & Ma, J. (2008). A Solid Trap and Thermal Desorption

Zhao, W.; Pinnaduwagel, L.; Leis, J.W.; Gehl, A.C.; Allman, S.L.; Shepp,A. & Mahmud, K.K.

based electronic nose. Applied Physics Letters, 91 (4). ISSN 0003-6951. Zhou, H.; Homer, M.; Shevade, A. & Ryan, M. (2006). Nonlinear Least-Squares Based

http://www.e-nose.com.ar/paginas/funcionamiento.htm

ISSN 1424-8220.

ISSN 1424-8220.

1692-7257.

April 15-17, 2009.

Santander, Colombia.

2008), pp. 6885-6898, ISSN 1424-8220.

Physical Society. (March 2010).

(December 2009), pp. 36-46, ISSN 1424-8220.

0925-4005.

Spoilage Classification of Red Meat. Sensors, Vol.8, (January 2008), pp. 142-156,

electronic nose and data analysis for evaluating coffee ripening, Sensors and Actuators B: Chemical, Volume 110, Issue 1, (September 2005), p.p 73-80, ISSN

gas concentration in an Electronic Nose System. Sensors, Vol. 9, pp. 1678-1691,

M. & Lundstrom, I. (2000). Data preprocessing enhances the classification of different brands of Espresso coffee with an electronic nose, Sensors and Actuators B: Chemical, Volume 69, Issue 3, (October 2000), p.p 397-403, ISSN 0925-4005. Ryan, M.; Homer, M.; Buehler, M.; Manatt, K. & Zee, F. (2009). Monitoring the Air Quality in a

Closed Chamber Using an Electronic Nose. Jet Propulsion Laboratory, California

Colombian Coffee through the Detection of Defects in "Cup Tests". Sensors, Vol.10,

Revista Colombiana de Tecnologías de Avanzada*,* Vol.2, No.12, pp. 20-26, ISSN

Nose to Detect Patients with COPD From Exhaled Breath. Proceedings of the 13th International Symposium on Olfaction and Electronic Nose. AIP Conference Proceedings, Volume 1137, pp. 452-454, ISBN: 978-0-7354-0674-2, Brescia, Italy,

La Patología Respiratoria Epoc. Universidad de Pamplona. Pamplona, Norte de

System with Application to a Medical Electronic Nose. Sensors, Vol.8, (November

(2007) Quantitative analysis of ternary vapor mixtures using a microcantilever-

Method for Identifying and Quantifying Single and Mixed Contaminants in Air with an Electronic Nose. Sensors, Vol.6, (December 2005), pp. 1-18, ISSN 1424-8220.

Breast cancer is the leading cause of cancer mortality among middle aged women. Survival and recovery depend on early diagnosis. At present mammography is one of the most reliable methods for early breast cancer detection. However relevance of diagnosis is highly correlated to image quality of the mammographic system. Hence periodic controls in mammographic facilities are necessary in order to make sure they work properly. In particular global image quality is evaluated from a mammographic phantom film. A phantom is an object with the same anatomic shape and radiological response as an average dense fleshed breast and in which are embedded structures that mimic clinically relevant features such as microcalcifications, nodules and fibrils. For each category of features, the targets have progressively smaller sizes and contrast so that the largest one is the most readily visible and the next is less visible and so on. Using a phantom makes it possible to free from the variable of differences in breast tissue positioning and level of compression from patient to patient. The process is as follows: the mammographic phantom film is analysed independently by several readers and a score is obtained by each of them depending on the number of objects they see. The independent object visibility scores are then averaged and the resulting score is assigned to the phantom film.

Automating this score by using computer image processing of digitized phantom films should make the evaluation of mammographic facilities easier and less subjective. In addition image processing should enable us to take into account other parameters such as, for instance, noise, texture and shape of the targets that a reader eye cannot estimate quantitatively, and so to perform a more elaborate analysis. In collaboration with ARCADES (Association pour la Recherche et le Dépistage des Cancers du Sein et du col de l'utérus) which set, since 1989, a breast cancer screening program in South of France, a project aimed at automating phantom film evaluation is in progress. Such a project consists first in digitizing phantom films with the adequate spatial resolution and then in processing the obtained images in order to detect, segment and characterize the objects contained in the phantom.

Little work has been done to automate quality control in mammographic facilities. Fast Fourier transform is used (Brooks et al., 1997) to establish some visibility criteria for the phantom test object. (Chakraborty et al., 1997) compares phantom images with a pattern image to obtain relations between some of the image parameters and the physical conditions

Mammographic Quality Control Using Digital Image Processing Techniques 525

*M1*

relative size of features.

(b) : mass; (c) : fibre

**3.1 General description** 

last image segmentation is done.

*M5*

*M7*

*Basis*

*M6 N2*

*N1*

**3. Image processing of digitized phantom films** 

**3.2 Local contrast modification method description** 

*N5*

*B B D DD*

Fig. 1. Schematic diagram of the phantom MTM 100/R showing the locations and the

Fig. 2. Subimages extracted from a digitized phantom film. (a) : group of microcalcifications

Two pre-processing steps are applied to each extracted subimage before the segmentation step as shown in Fig. 3. Because of the noisy nature of these subimages, a noise reduction method is used as a first processing step. A contrast enhancement step is then applied. At

In classical image processing techniques, a fixed shape and a fixed size window around each pixel is used in order to convolve it with a defined filter. In order to take the local features

*N6*

*F1*

*F2*

*F4 F3*

*Envelope*

*F5*

*F6*

*F7*

*V*

*N7*

*C1 C2*

*H*

*Z*

*N3*

*N4*

*M2*

*M3*

*M4*

in which the images have been obtained. His work concerned only microcalcifications. (Dougherty, 1998) studies the most prominent microcalcification group and the most prominent mass using a manual threshold and some mathematical morphology operators. (Castellano et al., 1998) used binary masks to locate microcalcifications and they studied image resolution scales contained in the phantom. (Blot et al., 2003) used grey level cooccurrence matrices to score structures embedded in the phantom. (Mayo et al., 2004) used region growing and morphological operators to segment and characterize microcalcifications. They also studied horizontal resolution areas using morphological operators. This chapter presents a feasibility study aiming at automating phantom scoring using image processing techniques on digitized phantom films.

In the following sections, we describe the phantom used, the mammographic phantom image acquisition and digitization, the noise reduction and the contrast enhancement schemes used for processing phantom images, the segmentation step for each object (microcalcifications, masses and fibres) and the results obtained on nine phantoms films.

## **2. Description, acquisition and digitization of phantom films**

#### **2.1 Phantom description**

The phantom used in this study is the MTM 100/R (Computerized Imaging Reference Systems, Inc., 2428 Almeda Avenue Suite 212, Norfolk, VA 23513, U.S.A., Phantom Serial Number: 2788). The MTM 100/R is used in France for Mammography Accreditation. It is made of tissue equivalent material in which are embedded objects simulating 7 pentagonalshaped groups of microcalcifications (M1 to M7), 7 masses (N1 to N7) and 7 fibres (F1 to F7). For each category of features, the targets have progressively smaller size and contrast so that the largest one is the most readily visible, the next is less visible and so on. For convenience M1 stands for the microcalcification group containing the largest specks and M7, the smallest ones, with a similar convention for the other target structures. Inside are also present vertical (V) and horizontal (H) spatial resolution scales (line pair target : 20 lp/mm), a delimited zone (Z) for measuring a reference optical density, two different optical density contiguous areas (C1 and C2) for defining contrast, three cavities (D) for x-ray dose measurement and at last small balls (B) for x-ray alignment control. Figure 1 shows a schematic diagram of the MTM 100/R phantom.

## **2.2 Acquisition and digitization of phantom films**

Phantom films are digitized with an ultra high resolution drum scanner (Scanmate 11000- ScanView A/S.Meterbuen 6. DK-2740 Skovlunde. Denmark) which may digitize from 50 to 11000 dpi (dots per inch) and code images on 256 (8bits /pixel) or 16384 (14bits /pixel) grey levels. Spatial scanning resolution was chosen so that it approximately corresponds to the resolving power of a viewer (with a standard resolving power ~ 4.10-3rd) using a twice magnifying lens (such lenses are often used by radiologists for reading clinical mammograms). So phantom films were digitized with a resolution of 50 μm per pixel (or 508 dpi) and were coded on 256 grey levels.

For each category of structures (microcalcifications, masses and fibers) a sub-image was extracted from the digitized phantom image so that each sub-image contained one target and was roughly centered on it. Subimages sizes were 256256-pixels for microcalcification groups and masses and 412412-pixels for fibres. Fig. 2 shows an example of subimages extracted from a digitized phantom film.

in which the images have been obtained. His work concerned only microcalcifications. (Dougherty, 1998) studies the most prominent microcalcification group and the most prominent mass using a manual threshold and some mathematical morphology operators. (Castellano et al., 1998) used binary masks to locate microcalcifications and they studied image resolution scales contained in the phantom. (Blot et al., 2003) used grey level cooccurrence matrices to score structures embedded in the phantom. (Mayo et al., 2004) used region growing and morphological operators to segment and characterize microcalcifications. They also studied horizontal resolution areas using morphological operators. This chapter presents a feasibility study aiming at automating phantom scoring

In the following sections, we describe the phantom used, the mammographic phantom image acquisition and digitization, the noise reduction and the contrast enhancement schemes used for processing phantom images, the segmentation step for each object (microcalcifications, masses and fibres) and the results obtained on nine phantoms films.

The phantom used in this study is the MTM 100/R (Computerized Imaging Reference Systems, Inc., 2428 Almeda Avenue Suite 212, Norfolk, VA 23513, U.S.A., Phantom Serial Number: 2788). The MTM 100/R is used in France for Mammography Accreditation. It is made of tissue equivalent material in which are embedded objects simulating 7 pentagonalshaped groups of microcalcifications (M1 to M7), 7 masses (N1 to N7) and 7 fibres (F1 to F7). For each category of features, the targets have progressively smaller size and contrast so that the largest one is the most readily visible, the next is less visible and so on. For convenience M1 stands for the microcalcification group containing the largest specks and M7, the smallest ones, with a similar convention for the other target structures. Inside are also present vertical (V) and horizontal (H) spatial resolution scales (line pair target : 20 lp/mm), a delimited zone (Z) for measuring a reference optical density, two different optical density contiguous areas (C1 and C2) for defining contrast, three cavities (D) for x-ray dose measurement and at last small balls (B) for x-ray alignment control. Figure 1 shows a

Phantom films are digitized with an ultra high resolution drum scanner (Scanmate 11000- ScanView A/S.Meterbuen 6. DK-2740 Skovlunde. Denmark) which may digitize from 50 to 11000 dpi (dots per inch) and code images on 256 (8bits /pixel) or 16384 (14bits /pixel) grey levels. Spatial scanning resolution was chosen so that it approximately corresponds to the resolving power of a viewer (with a standard resolving power ~ 4.10-3rd) using a twice magnifying lens (such lenses are often used by radiologists for reading clinical mammograms). So phantom films were digitized with a resolution of 50 μm per pixel (or

For each category of structures (microcalcifications, masses and fibers) a sub-image was extracted from the digitized phantom image so that each sub-image contained one target and was roughly centered on it. Subimages sizes were 256256-pixels for microcalcification groups and masses and 412412-pixels for fibres. Fig. 2 shows an example of subimages

using image processing techniques on digitized phantom films.

**2.1 Phantom description** 

schematic diagram of the MTM 100/R phantom.

508 dpi) and were coded on 256 grey levels.

extracted from a digitized phantom film.

**2.2 Acquisition and digitization of phantom films** 

**2. Description, acquisition and digitization of phantom films** 

Fig. 1. Schematic diagram of the phantom MTM 100/R showing the locations and the relative size of features.

Fig. 2. Subimages extracted from a digitized phantom film. (a) : group of microcalcifications (b) : mass; (c) : fibre

## **3. Image processing of digitized phantom films**

## **3.1 General description**

Two pre-processing steps are applied to each extracted subimage before the segmentation step as shown in Fig. 3. Because of the noisy nature of these subimages, a noise reduction method is used as a first processing step. A contrast enhancement step is then applied. At last image segmentation is done.

## **3.2 Local contrast modification method description**

In classical image processing techniques, a fixed shape and a fixed size window around each pixel is used in order to convolve it with a defined filter. In order to take the local features

Mammographic Quality Control Using Digital Image Processing Techniques 527

terms of grey levels is no longer satisfactory. Let c0 be the upper c value beyond which the percentage P0 is greater than 60%. The pixel (i,j) is assigned the window W=(c0+2)(c0+2). In the window W such as WWmax we finally define the "center" as the set of pixels having the mask value "1", and the "background" as the set of pixels having both the mask value "0" and which are 8-neighbourhood connected at least to a pixel "1". Pixels "0" which do not verify the previous constraint belong neither to the "center" nor to the "background" and are not taken into account later on. Fig. 4 gives an example the way the "center" and the

1 1 0 0 0 0 0

1 1 1 1 0 1 1

1 1 1 1 0 0 1 1 1 0 0

(a) (b) (c)

1 0 0 1 1 1 0

0 0 0 1 1 1 0

0 0 1

1 1 0 0

0

0

0 0

0 0

0 0

0 0

1 0

0 0

1 1 0

1 0 0

1 1 0

Fig. 4. Adaptive neighbourhood selection with a threshold value T=5; (a) Wmax window around bold-faced pixel value 15, Nmax=4; (b) Mask values associated to test pattern in (a); (c) The "center" (light grey)and the "background" (dark grey) areas around the bold-faced

After determining the "center" and the "background" regions around each pixel (i,j), a local

(, ) (, ) (, ) max ( , ), ( , ) *c b c b*

where Mc(i,j) and Mb(i,j) are the mean values, in image I, of pixels labelled as the "center" and as the "background" regions around pixel (i,j) respectively. Note that C(i,j) is within the

The local contrast image C obtained in the previous step is transformed into a new image C' such as C'(i,j)=(C(i,j)), where is a contrast modification function depending on features to

In image C' each pixel value is a contrast value. In order to obtain the corresponding image in the grey level domain, an inverse contrast transform of the process used to obtain image

*E i* , ( , )(1 '( , )) *<sup>b</sup> j M i j C i j* if Mb(i,j) Mc(i,j)

be detected. This function meets some requirements in the interval [0,1] :

*M ij M ij Ci j <sup>M</sup> ij M ij*

(1)

pixel. White cells correspond to pixels belonging neither to the "center" nor to the

1 1 1 1 1 0 1 0

1 1 1 1 0 1 1 1

1 1 1 1 1 0 0 0

1 1 1 1 0 0 1 1

"background" areas are determined.

9 8 13

13 13 10 8

7 7

5

6

9 8

8 8

8 8

8 6

16 9

16 17 10

17 16 7

15 16 10

contrast image C is computed from :


C from I (Eq. 1) is used as follows:

"background".

1 1 1 1 13 10 15 10

1 1 1 1 8 5 15 14

1 1 1 1 11 15 14 15

1 1 1 1 13 21 22 21

13 14 10 9 8 10 11

12 15 14 14 9 14 15

1 1 1 1 10 9 15 14 15 <sup>16</sup> <sup>4</sup>

13 20 19 14 16 15 10

7 6 20 15 **1** 16 10

range [0,1].


around each pixel into account, a variable shape and size neighbourhood is defined (Dhawan et al., 1986; Dhawan & Le Royer, 1988) using local statistics.

Noise reduction step consist in filtering two kinds of noise. The non uniform background considered as a ''low frequency noise'' and the radiographic noise (high frequency noise): film granularity and quantum mottle. Shadow correction of the background is adapted to each object (microcalcifications, masse and fibre), whereas the radiographic noise filter and the contrast enhancement steps are based on the same method, described in the next section. This method consists in computing a local contrast around each pixel using a variable neighbourhood whose size and shape depend on the statistical properties around the given pixel. The obtained image is then transformed into a new contrast image using various contrast modification functions. At last an inverse contrast transform is applied on the new contrast image to yield an enhanced version of the original image. Contrast enhancement step consists in enhancing image features while preserving details for the segmentation step. Image Segmentation is adapted to the objects to be detected and is presented in the following sections.

Fig. 3. Flowchart of the image processing steps applied to phantom images.

Each pixel (i,j) is assigned an upper window Wmax centered on it, whose size is (2Nmax+1)(2Nmax+1). We also define an inner area around the pixel (i,j) whose size is (cc) and an external area whose size is (c+2) (c+2), where c is an odd number. Let I(i,j) be the grey level of pixel (i,j) in image I, and T a given threshold. Pixel (k,l) within Wmax is assigned a binary mask value "0" if |I(k,l) –I(i,j)| > T, else it is assigned a binary mask value "1". Then the percentage P0 of zeros is computed over the region between the external (c+2)(c+2) and the inner (cc) areas, for each c in the range [1, 3, 5, … ,2Nmax – 1]. The process stops if this percentage is greater than 60% or if the upper window Wmax is reached. The value of 60% has been chosen because beyond this limit, we may consider too many pixels "0" are surrounding the inner area and so the notion of neighbourhood with the central pixel (i,j) in

around each pixel into account, a variable shape and size neighbourhood is defined

Noise reduction step consist in filtering two kinds of noise. The non uniform background considered as a ''low frequency noise'' and the radiographic noise (high frequency noise): film granularity and quantum mottle. Shadow correction of the background is adapted to each object (microcalcifications, masse and fibre), whereas the radiographic noise filter and the contrast enhancement steps are based on the same method, described in the next section. This method consists in computing a local contrast around each pixel using a variable neighbourhood whose size and shape depend on the statistical properties around the given pixel. The obtained image is then transformed into a new contrast image using various contrast modification functions. At last an inverse contrast transform is applied on the new contrast image to yield an enhanced version of the original image. Contrast enhancement step consists in enhancing image features while preserving details for the segmentation step. Image Segmentation is adapted to the objects to be detected and is presented in the

> Extracted subimage

> Noise reduction

Contrast enhancement

(Dhawan et al., 1986; Dhawan & Le Royer, 1988) using local statistics.

Fig. 3. Flowchart of the image processing steps applied to phantom images.

Each pixel (i,j) is assigned an upper window Wmax centered on it, whose size is (2Nmax+1)(2Nmax+1). We also define an inner area around the pixel (i,j) whose size is (cc) and an external area whose size is (c+2) (c+2), where c is an odd number. Let I(i,j) be the grey level of pixel (i,j) in image I, and T a given threshold. Pixel (k,l) within Wmax is assigned a binary mask value "0" if |I(k,l) –I(i,j)| > T, else it is assigned a binary mask value "1". Then the percentage P0 of zeros is computed over the region between the external (c+2)(c+2) and the inner (cc) areas, for each c in the range [1, 3, 5, … ,2Nmax – 1]. The process stops if this percentage is greater than 60% or if the upper window Wmax is reached. The value of 60% has been chosen because beyond this limit, we may consider too many pixels "0" are surrounding the inner area and so the notion of neighbourhood with the central pixel (i,j) in

Image Segmentation

following sections.

terms of grey levels is no longer satisfactory. Let c0 be the upper c value beyond which the percentage P0 is greater than 60%. The pixel (i,j) is assigned the window W=(c0+2)(c0+2). In the window W such as WWmax we finally define the "center" as the set of pixels having the mask value "1", and the "background" as the set of pixels having both the mask value "0" and which are 8-neighbourhood connected at least to a pixel "1". Pixels "0" which do not verify the previous constraint belong neither to the "center" nor to the "background" and are not taken into account later on. Fig. 4 gives an example the way the "center" and the "background" areas are determined.


Fig. 4. Adaptive neighbourhood selection with a threshold value T=5; (a) Wmax window around bold-faced pixel value 15, Nmax=4; (b) Mask values associated to test pattern in (a); (c) The "center" (light grey)and the "background" (dark grey) areas around the bold-faced pixel. White cells correspond to pixels belonging neither to the "center" nor to the "background".

After determining the "center" and the "background" regions around each pixel (i,j), a local contrast image C is computed from :

$$\mathbf{C}(i,j) = \frac{\left| M\_c(i,j) - M\_b(i,j) \right|}{\max\left( M\_c(i,j), M\_b(i,j) \right)} \tag{1}$$

where Mc(i,j) and Mb(i,j) are the mean values, in image I, of pixels labelled as the "center" and as the "background" regions around pixel (i,j) respectively. Note that C(i,j) is within the range [0,1].

The local contrast image C obtained in the previous step is transformed into a new image C' such as C'(i,j)=(C(i,j)), where is a contrast modification function depending on features to be detected. This function meets some requirements in the interval [0,1] :

$$-\,\psi(0) = 0 \text{ and } \psi(1) = 1.$$



In image C' each pixel value is a contrast value. In order to obtain the corresponding image in the grey level domain, an inverse contrast transform of the process used to obtain image C from I (Eq. 1) is used as follows:

$$E(i,j) = M\_b(i,j)(1 - C'(i,j)) \text{ if } M\_b(i,j) \ge M\_c(i,j)$$

Mammographic Quality Control Using Digital Image Processing Techniques 529

(a) (b) (c)

(d) (e) (f)

(g) (h) (i)

Before applying noise reduction and contrast enhancement steps, inhomogeneous background of subimages containing microcalcification is extracted using the classical multiresolution Burt decomposition into level 3 (level 0 is the original image). A linear interpolation is then applied to obtain background image. The same method was not suitable to correct background for subimages containing masses and fibres, due to the object to image size ratio. Using the local contrast modification method described above with a big window size for Wmax, enabled us to obtain background image. At last corrected image for the whole objects is obtained by subtracting the background image from the original image

Applying the noise reduction and contrast enhancement steps described in the previous

Fig. 5. Correction of Background inhomogeneity on extracted subimages. (a), (d) and (g) : original extracted subimages; (b), (e) and (h) background images; (c), (f) and (i) corrected

images.

as shown in Fig. 5.

**3.2.2 Preprocessing of real phantom images** 

section, yield the images shown in Fig. 6.

$$E(i,j) = \frac{M\_b(i,j)}{(1 - C'(i,j))}\quad\text{if }M\_b(i,j) \le M\_c(i,j)$$

This transform gives a new image E which is an enhanced version of image I. It is then possible to evaluate the efficiency of the method from comparison between images E and I.

#### **3.2.1 Performance evaluation on simulated images**

Several functions including square root, exponential, polynomial and trigonometric were tested (Guis et al., 2003). Actually functions which are over the line y=x increase the contrast but enhance the noise too. In the other hand, functions which are under the line y=x yield noise reduction. Because of the noisy nature of real images of phantom, the second kind of functions was chosen for enhancing the objects contained in these images. To choose suitable function , computer simulated images containing objects similar to those observed in the phantom film were generated with various contrast and noise levels. The aim of this simulation was to perform a quantitative evaluation of the noise reduction method described in previous sections. For each target, 6 noise-free images were generated each of them with a different contrast level. Three noise levels were then assigned to each contrast level image. Contrast level is defined as the difference between the mean grey level of the object and the mean grey level of the background divided by the mean grey level of the background. According to studies on radiographic noise, two types of noise sources, namely film granularity and quantum mottle, are present in an X-ray image. Spatially correlated Poisson noise model has to be considered in the case of mammographic films. In our simulations, a signal-dependent spatially uncorrelated Gaussian noise is used as a firstorder approximation of the Poisson noise model (Quian et al., 1994; Aghadasi et al., 1992; Kuan et al., 1985) namely: n(i,j) f(i, j)u(i,j), where f is the noise free image and where u is a zero-mean Gaussian noise with standard deviation . The computer simulated image or noisy image g is then given by g(i,j) f(i, j) n(i, j) .

Contrast levels of noise free images were in the range [10%; 60%] with a step size of 10%. Background grey-level was set to 128. Concerning noisy images, standard deviation of the zero-mean Gaussian noise u was adjusted so that the signal to noise ratio (SNR) takes the values 21dB, 15dB and 9dB which simulate a low, an intermediate and a high noise level respectively. Computer simulated images consist of 256256-pixels for microcalcification groups and nodules, and 336336-pixels for fibres. The whole computer simulated images were coded on 256 grey levels.

Two criteria are used to test the effectiveness of the algorithm on computer simulated images. The first one, namely output to input Signal to Noise Ratio (SNR) , quantifies noise suppression, and the second one, namely the mean-squared error (MSE), in addition to quantify noise removal gives also an information on structure distortion and therefore better interprets the first criterion. One can notice that parameter is all the more higher as the method removes much more noise, whereas MSE parameter is all the smaller as the method denoises and preserves structures in the image.

Results obtained on simulated images show that the trigonometric function ( ) tan <sup>4</sup> *x x* 

gives the best balance between noise reduction and edge sharpness preservation and that( ) *x x* is suitable for contrast enhancement.

*Mb <sup>i</sup> <sup>j</sup> Eij C i <sup>j</sup>* if Mb(i,j) < Mc(i,j)

This transform gives a new image E which is an enhanced version of image I. It is then possible to evaluate the efficiency of the method from comparison between images E and I.

Several functions including square root, exponential, polynomial and trigonometric were tested (Guis et al., 2003). Actually functions which are over the line y=x increase the contrast but enhance the noise too. In the other hand, functions which are under the line y=x yield noise reduction. Because of the noisy nature of real images of phantom, the second kind of functions was chosen for enhancing the objects contained in these images. To choose suitable function , computer simulated images containing objects similar to those observed in the phantom film were generated with various contrast and noise levels. The aim of this simulation was to perform a quantitative evaluation of the noise reduction method described in previous sections. For each target, 6 noise-free images were generated each of them with a different contrast level. Three noise levels were then assigned to each contrast level image. Contrast level is defined as the difference between the mean grey level of the object and the mean grey level of the background divided by the mean grey level of the background. According to studies on radiographic noise, two types of noise sources, namely film granularity and quantum mottle, are present in an X-ray image. Spatially correlated Poisson noise model has to be considered in the case of mammographic films. In our simulations, a signal-dependent spatially uncorrelated Gaussian noise is used as a firstorder approximation of the Poisson noise model (Quian et al., 1994; Aghadasi et al., 1992; Kuan et al., 1985) namely: n(i,j) f(i, j)u(i,j), where f is the noise free image and where u is a zero-mean Gaussian noise with standard deviation . The computer simulated image or

Contrast levels of noise free images were in the range [10%; 60%] with a step size of 10%. Background grey-level was set to 128. Concerning noisy images, standard deviation of the zero-mean Gaussian noise u was adjusted so that the signal to noise ratio (SNR) takes the values 21dB, 15dB and 9dB which simulate a low, an intermediate and a high noise level respectively. Computer simulated images consist of 256256-pixels for microcalcification groups and nodules, and 336336-pixels for fibres. The whole computer simulated images

Two criteria are used to test the effectiveness of the algorithm on computer simulated images. The first one, namely output to input Signal to Noise Ratio (SNR) , quantifies noise suppression, and the second one, namely the mean-squared error (MSE), in addition to quantify noise removal gives also an information on structure distortion and therefore better interprets the first criterion. One can notice that parameter is all the more higher as the method removes much more noise, whereas MSE parameter is all the smaller as the method

Results obtained on simulated images show that the trigonometric function ( ) tan <sup>4</sup>

gives the best balance between noise reduction and edge sharpness preservation and

*x x* 

 

(, ) , (1 '( , ))

**3.2.1 Performance evaluation on simulated images** 

noisy image g is then given by g(i,j) f(i, j) n(i, j) .

denoises and preserves structures in the image.

( ) *x x* is suitable for contrast enhancement.

were coded on 256 grey levels.

that

Fig. 5. Correction of Background inhomogeneity on extracted subimages. (a), (d) and (g) : original extracted subimages; (b), (e) and (h) background images; (c), (f) and (i) corrected images.

#### **3.2.2 Preprocessing of real phantom images**

Before applying noise reduction and contrast enhancement steps, inhomogeneous background of subimages containing microcalcification is extracted using the classical multiresolution Burt decomposition into level 3 (level 0 is the original image). A linear interpolation is then applied to obtain background image. The same method was not suitable to correct background for subimages containing masses and fibres, due to the object to image size ratio. Using the local contrast modification method described above with a big window size for Wmax, enabled us to obtain background image. At last corrected image for the whole objects is obtained by subtracting the background image from the original image as shown in Fig. 5.

Applying the noise reduction and contrast enhancement steps described in the previous section, yield the images shown in Fig. 6.

Mammographic Quality Control Using Digital Image Processing Techniques 531

consisted in defining around each detected object, a window centered on it and using a threshold based on the computation of the mean and standard deviation of pixels within

cross-correlation

global thresholding

connected component Labelling

 microcalcifications extraction

Fig. 7. General scheme of microcalcification group segmentation. (1) Mmic : template image, (2) Inet : resulting image after noise reduction and contrast enhancement, (3) Ic : resulting image after cross-correlation,(4) Iseuil : thresholded cross-correlated image, (5) Ietiq : connected component labelled image, (6) Ifin : resulting image with detected microcalcifications.

this window. Fig 8 shows an example of microcalcifications group segmentation.

(2) Inet

(3) Ic

(4) Iseuil

(5) Ietiq

(6) Ifin

(1) Mmic

Fig. 6. Noise reduction and contrast enhancement steps on extracted subimages (a), (d) and (g): original extracted subimages; (b), (e) and (h) denoised images; (c), (f) and (i) contrast enhanced images.

#### **4. Segmentation of extracted subimages**

#### **4.1 Microcalcification segmentation case**

Microcalcifications segmentation was based on the computation of a cross-correlation between a template image Mmic and the preprocessed resulting image after noise reduction and contrast enhancement Inet. The different steps of microcalcification groups are summerized in figure 7. The template image was built after a supervised learning on real phantom images. A global thresholding was then applied on the thresholded image for extracting microcacifications. The connected component labelling step is done to determine the number of detected objects in Iseuil image. The microcalcification extraction step

(a) (b) (c)

(d) (e) (f)

(g) (h) (i)

Fig. 6. Noise reduction and contrast enhancement steps on extracted subimages (a), (d) and (g): original extracted subimages; (b), (e) and (h) denoised images; (c), (f) and (i) contrast

Microcalcifications segmentation was based on the computation of a cross-correlation between a template image Mmic and the preprocessed resulting image after noise reduction and contrast enhancement Inet. The different steps of microcalcification groups are summerized in figure 7. The template image was built after a supervised learning on real phantom images. A global thresholding was then applied on the thresholded image for extracting microcacifications. The connected component labelling step is done to determine the number of detected objects in Iseuil image. The microcalcification extraction step

enhanced images.

**4. Segmentation of extracted subimages** 

**4.1 Microcalcification segmentation case** 

consisted in defining around each detected object, a window centered on it and using a threshold based on the computation of the mean and standard deviation of pixels within this window. Fig 8 shows an example of microcalcifications group segmentation.

Fig. 7. General scheme of microcalcification group segmentation. (1) Mmic : template image, (2) Inet : resulting image after noise reduction and contrast enhancement, (3) Ic : resulting image after cross-correlation,(4) Iseuil : thresholded cross-correlated image, (5) Ietiq : connected component labelled image, (6) Ifin : resulting image with detected microcalcifications.

Mammographic Quality Control Using Digital Image Processing Techniques 533

Fig. 9. Segmentation of a mass subimage (a): extracted subimage after noise reduction and contrast enhancement; (b): Thresholded image. (c): Initialization of active contour. (d) First iteration of the active contour. (e): Second iteration of active contour. (f): final segmentation.

2

(d) (e) (f)

(a) (b) (c)

(a) (b)

<sup>1</sup>

Fig. 10. Template images for fibre segmentation.

Fig. 8. Segmentation of microcalcifications. (a): extracted subimage after noise reduction and contrast enhancement Inet ; (b): result of template matching Ic; (c): connected component labelled image Ietiq ; (d): resulting image Ifin.

#### **4.2 Mass segmentation case**

Mass segmentation was done by using an active contour. First a square was set as an initial contour and the energy used depended only on image gradient. The algorithm used for that purpose is described as follows:

Step 1: Each point i of the active contour evolved along the normal of segment (i-1,i+1) until it met a mass edge.

Step 2: When the four initial points reached the mass edges, other points were added between each couple of points (i and i+1).

Step 3: Each added point in the previous step evolved as initials points in step 1.

The algorithm stopped when a fixed but great number of iterations was reached. Fig. 9 shows an example of a mass segmentation.

#### **4.3 Fibre segmentation case**

As for microcalcifications, fibre segmentation used a template matching between two template images (see Fig. 10) and the preprocessed resulting fibre image after applying noise reduction and contrast enhancement steps. An automatic global thresholding is then used, followed by a logical filter OR and a connected component labelling step. Figs. 11 and 12 show the general scheme of a fibre segmentation and an example of fibre segmentation respectively.

(a) (b)

(c) (d)

Fig. 8. Segmentation of microcalcifications. (a): extracted subimage after noise reduction and contrast enhancement Inet ; (b): result of template matching Ic; (c): connected component

Mass segmentation was done by using an active contour. First a square was set as an initial contour and the energy used depended only on image gradient. The algorithm used for that

Step 1: Each point i of the active contour evolved along the normal of segment (i-1,i+1) until

Step 2: When the four initial points reached the mass edges, other points were added

The algorithm stopped when a fixed but great number of iterations was reached. Fig. 9

As for microcalcifications, fibre segmentation used a template matching between two template images (see Fig. 10) and the preprocessed resulting fibre image after applying noise reduction and contrast enhancement steps. An automatic global thresholding is then used, followed by a logical filter OR and a connected component labelling step. Figs. 11 and 12 show the general scheme of a fibre segmentation and an example of fibre segmentation

Step 3: Each added point in the previous step evolved as initials points in step 1.

labelled image Ietiq ; (d): resulting image Ifin.

between each couple of points (i and i+1).

shows an example of a mass segmentation.

**4.2 Mass segmentation case** 

purpose is described as follows:

**4.3 Fibre segmentation case** 

it met a mass edge.

respectively.

Fig. 9. Segmentation of a mass subimage (a): extracted subimage after noise reduction and contrast enhancement; (b): Thresholded image. (c): Initialization of active contour. (d) First iteration of the active contour. (e): Second iteration of active contour. (f): final segmentation.

Fig. 10. Template images for fibre segmentation.

Mammographic Quality Control Using Digital Image Processing Techniques 535

(a) (b)

(c) (d)

(e) (f)

(g) (h)

Fig. 12. Segmentation of a fibre subimage. (a): extracted subimage after noise reduction and contrast enhancement; (b): Thresholded image (c): Result of template matching with template image in Fig. 10(a); (d): Result of template matching with template image in Fig.

thresholding image (d); (g): Resulting image after applying OR logic filter on images (e) and

10(b); (e): Resulting image after thresholding image (c); (f): Resulting image after

(f); (h): Connect component labelled image.

Fig. 11. General scheme of fibre segmentation. (1) Inet : resulting image after noise reduction and contrast enhancement , (2) Iseuil : image Inet thresholded , (3) Mfib1 : template image 1, (4) Mfib2 : template image 2, (5) Ic,1 : obtained image after cross correlation between Mfib1 and Iseuil , (6) Ic,2 : obtained image after cross correlation between Mfib2 and Iseuil (7) Ic,1,s : image Ic,1 thresholded , (8) Ic,2,s : image Ic,2 thresholded , (9) Iadd : resulting image after logical filter OR between Ic,1,s and Ic,2,s (10) Ietiq : connected component labelled image.

global thresholding on histogram

**Images processing** 

cross-correlation

(2) Iseuil

(1) Inet

(3) Mfib1

(5) Ic,1

(7) Ic,1,s

(9) Iadd

(10) Ietiq

Fig. 11. General scheme of fibre segmentation. (1) Inet : resulting image after noise reduction and contrast enhancement , (2) Iseuil : image Inet thresholded , (3) Mfib1 : template image 1, (4) Mfib2 : template image 2, (5) Ic,1 : obtained image after cross correlation between Mfib1 and Iseuil , (6) Ic,2 : obtained image after cross correlation between Mfib2 and Iseuil (7) Ic,1,s : image Ic,1 thresholded , (8) Ic,2,s : image Ic,2 thresholded , (9) Iadd : resulting image after logical filter OR

connected component labelling

global thresholding

OR logical filter

(4) Mfib2

**Images** 

(6) Ic,2

(8) Ic,2,s

between Ic,1,s and Ic,2,s (10) Ietiq : connected component labelled image.

(e) (f)

Fig. 12. Segmentation of a fibre subimage. (a): extracted subimage after noise reduction and contrast enhancement; (b): Thresholded image (c): Result of template matching with template image in Fig. 10(a); (d): Result of template matching with template image in Fig. 10(b); (e): Resulting image after thresholding image (c); (f): Resulting image after thresholding image (d); (g): Resulting image after applying OR logic filter on images (e) and (f); (h): Connect component labelled image.

Mammographic Quality Control Using Digital Image Processing Techniques 537

This chapter presents a feasibility study of automating breast phantom scoring using image processing techniques. The main contribution in this project is noise reduction and contrast enhancement of noisy images extracted from digitized phantom films. The segmentation step which uses known methods shows that quality control in mammographic facilities could be done using image processing techniques. Next step in this project is to adapt image processing techniques used for digitized film to digital phantom images acquired directly from Full-Filed Digital Mammograms. In this case it will be possible to control the quality of digital mammographic systems using software

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**6. Conclusion** 

**7. References** 

similar to the one described in this study.

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## **5. Results and discussion**

Nine phantom images from different mammographic facilities were tested. For each phantom image, only 4 subimages of each target were extracted. Two main reasons leaded us to do this choice: first, readers could not detect more than 4 objects on the phantoms used in our study, and second, a mammographic facility is considered to have good quality phantom films if at least 4 objects are detected from each embedded target.

216 microcalcifications (36 microcalcification groups) were studied. The most prominent microcalcification group M1 and M2 were almost all detected. Microcalcifications that were not detected were those with poor contrast. False detections were due to film emulsion tearing and appeared on M3 and M4 groups. Table 1 summarizes results obtained on these nine phantom films.

Thirty six masses and 36 fibres were studied. Three masses among 36 were not detected because of the non convergence of the iterative active contour algorithm. This appeared on masses containing holes when being preprocessed. When better initialising the active contour, it was possible to detect the whole masses.

The whole fibres were detected but as seen in Fig 12 some other objects appeared on the final segmentation image. These small objects will be removed in a further processing.



## **6. Conclusion**

536 Modern Approaches To Quality Control

Nine phantom images from different mammographic facilities were tested. For each phantom image, only 4 subimages of each target were extracted. Two main reasons leaded us to do this choice: first, readers could not detect more than 4 objects on the phantoms used in our study, and second, a mammographic facility is considered to have good quality

216 microcalcifications (36 microcalcification groups) were studied. The most prominent microcalcification group M1 and M2 were almost all detected. Microcalcifications that were not detected were those with poor contrast. False detections were due to film emulsion tearing and appeared on M3 and M4 groups. Table 1 summarizes results obtained on these

Thirty six masses and 36 fibres were studied. Three masses among 36 were not detected because of the non convergence of the iterative active contour algorithm. This appeared on masses containing holes when being preprocessed. When better initialising the active

The whole fibres were detected but as seen in Fig 12 some other objects appeared on the final segmentation image. These small objects will be removed in a further processing.

*1 2 3 4 5 6 7 8 9* 

*number* **6 6 6 6 6 6 6 6 6** 

*number* **6 6 6 6 6 6 6 6 6** 

*number* **6 6 6 6 5 6 5 6 5** 

*number* **6 6 6 6 3 6 5 4 6** 

*False detection* **3 3 2 1 1** 

*False detection* **1 1 3** 

*False detection* **5 4 1 3 2** 

phantom films if at least 4 objects are detected from each embedded target.

contour, it was possible to detect the whole masses.

*Detected microcalcifications* 

*False detection* 

*Detected microcalcifications* 

*Detected microcalcifications* 

*Detected microcalcifications* 

Table 1. Detection results on microcalcification groups.

**5. Results and discussion** 

nine phantom films.

M1 group

M2 group

M3 group

M4 group

This chapter presents a feasibility study of automating breast phantom scoring using image processing techniques. The main contribution in this project is noise reduction and contrast enhancement of noisy images extracted from digitized phantom films. The segmentation step which uses known methods shows that quality control in mammographic facilities could be done using image processing techniques. Next step in this project is to adapt image processing techniques used for digitized film to digital phantom images acquired directly from Full-Filed Digital Mammograms. In this case it will be possible to control the quality of digital mammographic systems using software similar to the one described in this study.

## **7. References**


D. T. Kuan, A. A. Shawchuk, T. C. Strand, P. Chavel, "Adaptive noise smoothing filter for images with signal-dependent noise". IEEE Trans. Patt. Anal. Mach. Intell*.* 7(2), 165- 177, 1985.

D. T. Kuan, A. A. Shawchuk, T. C. Strand, P. Chavel, "Adaptive noise smoothing filter for

177, 1985.

images with signal-dependent noise". IEEE Trans. Patt. Anal. Mach. Intell*.* 7(2), 165-

## *Edited by Ahmed Badr Eldin*

Rapid advance have been made in the last decade in the quality control procedures and techniques, most of the existing books try to cover specific techniques with all of their details. The aim of this book is to demonstrate quality control processes in a variety of areas, ranging from pharmaceutical and medical fields to construction engineering and data quality. A wide range of techniques and procedures have been covered.

Photo by olm26250 / iStock

Modern Approaches To Quality Control

Modern Approaches To

Quality Control

*Edited by Ahmed Badr Eldin*