**6. Conclusion**

314 Blood Cell – An Overview of Studies in Hematology

use in patient monitoring and management.

establish African toxicity tables.

**5. A case for African/ Region specific toxicity tables?** 

need to be screened in order to meet the required target [15].

In pregnancy, blood volume increases resulting in hemodilution. While the red cell mass increases during pregnancy, the plasma volume increases more resulting in a relative anemia. This leads to a lower Hb level, Hct and RBC. Hb is known to vary with gestational age with the highest values within the first and last trimesters and lowest during the second trimester. Similarly, the Hct and RBC decreases with gestational age. A stable higher upper reference limit for WBC count during pregnancy has been reported [65, 66]. WBC count is known to peak at delivery, thus limiting the use of this parameter as a marker for infection during delivery. This increase in WBC count results primarily from an increase in neutrophil counts and a slight increase in lymphocyte counts. Currently, there exists no African study designed to establish reference intervals during pregnancy and most laboratory information systems report reference values based on samples obtained from non–pregnant women which may not be useful for clinical decisions during pregnancy. Thus, there is an increased risk of overlooking important physiologic alterations resulting from pathological conditions and of misinterpreting normal changes as pathological events [64]. It is therefore important to develop reference intervals for women during pregnancy and the postpartum period for

Under a research-based approach, applying the US Massachusetts General Hospital derived reference intervals to our reference population from western Kenya during screening for a clinical trial (Table 4), over 58% of the volunteers would have been excluded from the trial despite having laboratory results consistent with the general population from which they were derived. This erroneous screening out of otherwise healthy volunteers would have important implications on study costs, work load and time, as more volunteers would be

Similarly, applying the DAIDS toxicity tables to our population, some of our calculated reference intervals fall between the normal, and grade 1–2 toxicity grading in the DAIDS system (Table 4). Using the clinic based approach, 40% of our otherwise healthy study participants would have erroneously been considered to have at least one laboratory-based grade 1–4 toxicity adverse event. The lower range for Hb, neutrophil counts, as well as the upper range for eosinophil counts and bilirubin would be considered as grade 2 adverse events, for example. Even though studies have documented these findings, this information is not widely known and as a result, DAIDS has issued only 1 set of "standard" toxicity tables without considering racial or ethnic differences [57]. Thus, during international clinical trials, these tables are used as guidelines in the conduct of such trials. This may result in a situation where the results of a clinical trial cannot be generalized to the population in question since a majority of otherwise healthy participants are screened out. Moreover, given that the investigational product is intended for use within the same population being sampled, this may complicate post-market analysis or application of the product for the general population. Unfortunately, there are no comparable tables from Africa on which such clinical decisions can be based. It is therefore important that African countries carry out large studies in different regions of Africa for such parameters to

While it is desirable to generate reference intervals for different populations, the procedure remains a challenge due to the prohibitive cost involved in performing these studies and the limitation in identifying suitable healthy reference individuals. Thus, the CLSI recommendation that all diagnostic laboratories should determine and maintain their own reference interval for each laboratory parameter is impractical. The revised CLSI guidelines have recommended that if it is not possible to establish detailed reference studies, then validation of published reference intervals can be performed using methodology tailored for the population served by the laboratory. As few as 20 specimens can be used to validate reference values within each laboratory by performing a formal outlier test.

Laboratory Reference Intervals in Africa 317

[4] TheGlobalFund, *The Global Fund to Fight AIDS, TB and Malaria;''Global* 

[5] Bakerman S, B.P., Stausbauch P *ABC's of Interpretive Laboratory Data*. 2002, Scottsdale.

[6] Kratz A, F.M., Sluss PM, Lewandrowski KB, *Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Laboratory reference values.* New England

[7] DAIDS, *Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse* 

[8] CLSI, *Defining, Establishing, and Verifying Reference Intervals in the Clinical Laboratory; Approved Guideline*. 2008, Wayne, PA: Clinical and Laboratory Standards Institute. [9] Zeh C, A.P., Inzaule S, Ondoa P, Oyaro B, Mwaengo DM, Vandenhoudt H, Gichangi A, Williamson J, Thomas T, DeCock KM, Hart C, Nkengasong J, Laserson K, *Populationbased biochemistry, immunologic and hematological reference values for adolescents and young* 

[10] Ritchie RF, P.G., *Selecting clinically relevant populations for reference intervals.* Clin Chem

[11] O'Brien WA, H.P., Daar ES, Simberkoff MS, Hamilton JD, *Changes in plasma HIV RNA levels and CD4+ lymphocyte counts predict both response to antiretroviral therapy and* 

[12] Cengiz C, P.J., Saraf N, Dieterich DT, *HIV and liver diseases: recent clinical advances.*

[13] Phillips AN, S.S., Weber R, Kirk O, Francioli P, Miller V, Vernazza P, Lundgren JD, Ledergerber B, *HIV viral load response to antiretroviral therapy according to the baseline CD4* 

[14] Boyd, J.C., *Defining laboratory reference values and decision limits: populations, intervals, and* 

[15] Eller LA, E.M., Ouma B, Kataaha P, Kyabaggu D, Tumusiime R, Wandege J, Sanya R, Sateren WB, Wabwire-Mangen F, Kibuuka H, Robb ML, Michael NL, de Souza MS, *Reference intervals in healthy adult Ugandan blood donors and their impact on conducting* 

[16] Kibaya RS, B.C., Sawe FK, Shaffer DN, Sateren WB, Scott PT, Michael NL, Robb ML, Birx DL, de Souza MS, *Reference ranges for the clinical laboratory derived from a rural* 

[17] Omosa-Manyonyi GS, J.W., Anzala O, Ogutu H, Wakasiaka S, Malogo R, Nyange J, Njuguna P, Ndinya-Achola J, Bhatt K, Farah B, Oyaro M, Schmidt C, Priddy F, Fast P, *Reasons for ineligibility in in phase 1 and 2A HIV vaccine clinical trials at Kenya AIDS vaccine* 

[18] Chou VB, O.S., Hussain H, Mugasha C, Musisi M, Mmiro F, Musoke P, Jackson JB, Guay LA, *The costs associated with adverse event procedures for an International HIV Clinical Trial determined by activity-based costing.* Journal of Acquired Immune Deficiency

[19] Lubega IR, F.M., Musoke PM, Elbireer A, Bagenda D, Kafulafula G, Ko J, Mipando L, Mubiru M, Kumwenda N, Taha T Jackson, JB, Guay L, *Considerations in using US-based* 

*FundARVFactSheet*. 2009.

Lab Med, 2004. 42(7): p. 702-709.

AZ, USA: Interpretive Laboratory Data, Inc.

Journal of Medicine, 2004. 351(15): p. 1548-1563.

*Events*, DAIDS, Editor. 2004: Bethseda, MD, USA.

*adults in a rural population in Western Kenya.* PLoS One, 2011. 6(6).

*therapeutic failure.* Ann Intern Med, 1997. 126: p. 939–945.

*cell count and viral load.* JAMA, 2001. 286: p. 2560–2567.

*international vaccine trials.* PLoS ONE, 2008. 3(12).

*population in Kericho, Kenya.* PLoS One, 2008. 3(10).

*initiative (KAVI), Kenya.* PLoS One, 2011. 6(1).

Syndrome, 2007. 46: p. 426–432.

*interpretations.* Asian Journal of Andrology, 2010. 12: p. 83-90.

Clinics in Liver Disease, 2005. 9: p. 647–666.

Given the number of clinical trials and persons receiving clinical services is expected to increase substantially in sub-Saharan Africa, there is a need for the establishment of locally derived clinical laboratory reference values to ensure appropriate general health assessment, treatment monitoring, and efficient implementation of clinical trials. Even more important is the need for the establishment of toxicity grading tables for application in clinical care among Africans based on the documented differences between laboratory reference values from African populations and Caucasians or Western populations of mixed ethnic origin.
