**3. Causes of death and comparative mortality for United States astronauts**

We focus here and throughout this chapter on underlying cause of death as reported in official NASA astronaut biographies and in the news media. In this way, astronaut and cosmonaut deaths are categorized according to a single underlying cause of death.

Though there are many ways to quantify the mortality experience of groups such as astro‑ nauts and cosmonauts, here, we will focus on the Standardized Mortality Ratio (SMR). SMR is a risk ratio; it is computed by dividing the observed number of deaths in a group by the number of deaths that would be counterfactually "expected" were the group subject to a set of death rates from a reference population. (By convention, the resulting ratio is multiplied by 100.) Thus, SMRs of 100 represent equal risk between the group under study and the reference population, SMRs above 100 represent increased risk for the group under study, and SMRs below 100 represent decreased risk for the same.

### **3.1. Numbers and causes of death**

(in person-years), and counts of deaths. Crude death rates, being in each case the ratio of total deaths to total person-years lived by a respective group, are also reported. Crude rates are highly dependent on the age structure of each cohort, and differences in crude rates may be due to differences in one or more cause-specific rates, or due to age differences in the cohorts, or both. To better understand whether and to what extent the rates in the various cohorts may

There have been 622 individuals selected and trained as astronauts or cosmonauts between April 1959 and October 2017. These men and women have contributed a total of 18462.8 per‑ son-years of observation time and 176 deaths, for an overall crude mortality rate of 9.53 deaths

The United States space programs account for 360 astronauts, contributing 10,291.8 personyears of follow-up and 80 deaths, yielding a crude mortality rate of 7.77 deaths per 1000

**Source Count Exposure\* Deaths Crude rate†** All astronauts and cosmonauts 622 18462.9 176 9.53 U.S. astronauts‑all sources 360 10291.8 80 7.77 NASA Astronaut Corps 338 9565.7 62 6.48 USAF programs 22 726.1 18 24.79 X-15 7 230.7 7 30.34 X-20 5 160.6 5 31.13 MOL 10 334.7 6 17.93 Cosmonauts-all sources 262 8171.1 96 11.75 Soviet (1960–1989) 194 7089.2 91 12.84 Russian (1990–2017) 68 1081.9 5 4.62

differ, a more careful examination of these issues is required.

**Event Astronauts Cosmonauts p > t**

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Selection 34.4 (3.6) 31.3 (5.4) <0.0001 Death 59.6 (17.8) 61.4 (14.2) 0.4762 End of study 64.0 (11.7) 63.2 (14.7) 0.5523 *Follow-up (year)* 28.6 (14.1) 31.2 (14.8) 0.0269

**Table 2.** Average ages and follow-up time for astronauts and cosmonauts, 1959–2017.

**Mean (sd) Mean (sd)**

\*Pooled observation time since selection, expressed as person-years.

**Table 3.** Actuarial characteristics of astronauts and cosmonauts, 1959–2017.

Crude death rate, expressed as deaths per 1000 person-years.

†

per 1000 person-years of observation.

*Age (year)*

**Figure 1** shows the distribution by cause of the 80 astronaut deaths recorded through 31 October 2017. More than half of all deaths (46/80) were due to natural causes. Among natu‑ ral causes, most deaths have been due to cancer (41.3%), followed by cardiovascular disease (CVD) (23.9%).

The 34 deaths from external (i.e., not natural) causes are dominated by 33 accidental deaths. Plane crashes and space craft accidents account for 29 of these deaths, with vehicular acci‑ dents accounting for the other 4. The only nonaccidental externally caused death was attrib‑ uted to suicide (**Figure 1**).

For comparisons, all-cause United States general population mortality rates were taken from the Human Mortality Database for years 1960 through 2015 [2] and cause-specific rates from the CDC WONDER database for 1970 to 2015 [3–5]. The 2015 rates were used as the compari‑ son rates for astronaut data from 2016 and 2017.

As it turned out, external causes-accidental deaths in particular-were the main drivers of the observed increased mortality risk in the early years, mainly due to deaths that occurred in the 1960s. A drop in the accidental death rate over time lowered SMRs from the year 1980 onward, though astronauts were still at a significantly higher risk of accidental death than the general population throughout the study period. Eventually, as the cohort of astronauts aged, the near absence of death by chronic diseases reduced astronaut all-cause mortality rates to

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**Figure 2** displays all-cause decade-specific SMRs for astronauts for 1960 to 2017, as well as a summary SMR for the entire 1960 to 2017 period, based on the latest available data. It is imme‑ diately apparent in **Figure 2** that 1960–1969 was a period of high risk for astronauts, as they were more than 8 times as likely to die during this period as were age- and gender-matched members of the United States general population. The pattern across the decades is consistent

levels significantly below those in the general population.

**Figure 2.** SMRs for all causes of death among United States astronauts, 1960–2017.

**Figure 1.** Causes of death among United States astronauts, 1960–2017.

#### **3.2. All-cause mortality**

In perhaps the first systematic analysis of astronaut mortality, based on data from 15 April 1959 to 30 September 1991, a nearly two-fold increased risk of death was reported compared to age- and gender-matched general population rates (SMR = 181, 95% CI = 110–279) [6]. The result was surprising, as it was expected that astronauts might experience lower all‑cause mortality rates than the general population, thanks to their high levels of physical fitness, socio-economic status, and free access to presumably top-quality healthcare (a phenomenon often referred to as the healthy worker effect (HWE)) [7]. Another analysis of the same data compared astronauts with ground-based employees of the Johnson Space Center (JSC) in Houston, TX and found astronauts to be at more than 5 times the risk of death from all causes (hazard ratio = 5.07; 95% CI = 2.46–10.41), adjusting for sex, education, marital status at selec‑ tion, and smoking history [8]. Comparing astronauts to a similar occupational cohort seemed to suggest that astronauts really were at greater risk of death by virtue of their status as space travelers. But if so, why?

By 2009, the picture had become clearer. After 1980, all-cause SMRs began declining: from a statistically insignificant 115 (95% CI = 53–219) in the 1980s, to 61 (95% CI = 29–112) in the 1990s, to finally a statistically significant 43 (95% CI = 23–74) in the first decade of the 2000s [9]. The overall SMR for 1980–2009 was also significant, at 59 (95% CI = 40–83) [9]. It appeared, then, that astronauts were at lower overall risk of death than the general population as a whole.

As it turned out, external causes-accidental deaths in particular-were the main drivers of the observed increased mortality risk in the early years, mainly due to deaths that occurred in the 1960s. A drop in the accidental death rate over time lowered SMRs from the year 1980 onward, though astronauts were still at a significantly higher risk of accidental death than the general population throughout the study period. Eventually, as the cohort of astronauts aged, the near absence of death by chronic diseases reduced astronaut all-cause mortality rates to levels significantly below those in the general population.

**Figure 2** displays all-cause decade-specific SMRs for astronauts for 1960 to 2017, as well as a summary SMR for the entire 1960 to 2017 period, based on the latest available data. It is imme‑ diately apparent in **Figure 2** that 1960–1969 was a period of high risk for astronauts, as they were more than 8 times as likely to die during this period as were age- and gender-matched members of the United States general population. The pattern across the decades is consistent

**Figure 2.** SMRs for all causes of death among United States astronauts, 1960–2017.

**3.2. All-cause mortality**

**Figure 1.** Causes of death among United States astronauts, 1960–2017.

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travelers. But if so, why?

In perhaps the first systematic analysis of astronaut mortality, based on data from 15 April 1959 to 30 September 1991, a nearly two-fold increased risk of death was reported compared to age- and gender-matched general population rates (SMR = 181, 95% CI = 110–279) [6]. The result was surprising, as it was expected that astronauts might experience lower all‑cause mortality rates than the general population, thanks to their high levels of physical fitness, socio-economic status, and free access to presumably top-quality healthcare (a phenomenon often referred to as the healthy worker effect (HWE)) [7]. Another analysis of the same data compared astronauts with ground-based employees of the Johnson Space Center (JSC) in Houston, TX and found astronauts to be at more than 5 times the risk of death from all causes (hazard ratio = 5.07; 95% CI = 2.46–10.41), adjusting for sex, education, marital status at selec‑ tion, and smoking history [8]. Comparing astronauts to a similar occupational cohort seemed to suggest that astronauts really were at greater risk of death by virtue of their status as space

By 2009, the picture had become clearer. After 1980, all-cause SMRs began declining: from a statistically insignificant 115 (95% CI = 53–219) in the 1980s, to 61 (95% CI = 29–112) in the 1990s, to finally a statistically significant 43 (95% CI = 23–74) in the first decade of the 2000s [9]. The overall SMR for 1980–2009 was also significant, at 59 (95% CI = 40–83) [9]. It appeared, then, that astronauts were at lower overall risk of death than the general population as a whole.

with previously published results, with higher astronaut mortality in the 1960s, then falling rates up to the current decade, and an overall lower than expected rate of mortality for astro‑ nauts from 1960 to 2017.

SMR of 53 (95% CI = 34–80) for 2010–2017 is reported here for the first time, based on all cur‑ rently available data. This is broadly consistent with SMR from 2000 to 2009, suggesting a sustained reduction in risk for astronauts and a possible plateauing of the protective effect. If trends in specific causes of death continue as they have, this trend in all-cause SMR will continue as well.

#### **3.3. External causes**

Causes of death are subdivided at the most basic level into internal and external causes. Examples of external causes include drowning, electrocution, poisoning, burns, and trauma. For purposes of analysis, we consider external causes to be any death with primary cause code of E800–E899 in the International Classification of Diseases code set, Eighth Edition (ICD-8), E800–E899 in the ICD-9 code set, and V01–Y89 in the ICD-10 code set.

#### *3.3.1. All external causes of death*

As we have noted, accidental deaths accounted for all external deaths in the astronaut cohort for many years, and no published study bothered to report on nonaccidental external causes for this reason. Current data include a fair number of deaths due to external causes other than accidents, and we present in **Figure 3**, for the first time, SMRs for all external causes com‑ bined, as well as SMRs for accidental causes.

Across all decades, United States astronauts have been at approximately 250% risk of the gen‑ eral population of death due to external causes. This excess risk continues to be driven almost entirely by accidental deaths, some of which occurred in catastrophic accidents that many readers will recall, which took the lives of multiple astronauts in single events.

In the 1980s and 2000s, astronauts were at significantly increased risk of death from exter‑ nal causes, and this is unsurprising. These two decades each saw the destruction of a space shuttle, with the death of multiple astronauts in each: the space shuttle Challenger explosion in January 1986, which claimed the lives of five astronauts, and the Space Shuttle Columbia reentry disintegration in February 2003, which killed 6 astronauts.<sup>1</sup> These deaths pushed SMRs significantly high, even as deaths from other external causes-particularly other acciden‑ tal sources-were on the decline. These deaths are largely responsible for the overall 2.5-fold increased risk of death due to external causes for the entire follow‑up period. Indeed, with‑ out these deaths, overall SMR in the 1980s would be approximately 160, and not statistically significant. Likewise, SMR for the 2000s would be approximately 115, and not statistically significant.

*3.3.2. Accidental death*

from the general population.

The high risk of accidental death was anticipated from the beginning of the United States space program, when then U.S. President Dwight Eisenhower called for astronauts to be selected from the ranks of military test pilots, because, among other reasons, they were accus‑ tomed to high-risk vocational activities [10]. This proved to be prescient: by the end of 1991, 16 of the 20 recorded astronaut deaths were accidental, with half due to space craft accidents, and several of which were duty-related plane crashes. As we have noted, the rate of accidental deaths for this cohort is significantly greater than expected in an age- and sex-matched cohort

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**Figure 3.** SMRs for all external causes and accidental causes of death among United States astronauts, 1970–2017.

Accidental death SMRs for all astronauts based on data through 2017 are also given in **Figure 3** as the orange points and lines. The progression of risk for accidental death is the main driver

<sup>1</sup> Three additional people were killed in these two disasters, all of were whom Payload Specialists, i.e., civilians trained for single missions only. As they are not considered a part of the NASA Astronaut Corps, those individuals were not included in either prior research or the updated analyses presented here.

**Figure 3.** SMRs for all external causes and accidental causes of death among United States astronauts, 1970–2017.

#### *3.3.2. Accidental death*

with previously published results, with higher astronaut mortality in the 1960s, then falling rates up to the current decade, and an overall lower than expected rate of mortality for astro‑

SMR of 53 (95% CI = 34–80) for 2010–2017 is reported here for the first time, based on all cur‑ rently available data. This is broadly consistent with SMR from 2000 to 2009, suggesting a sustained reduction in risk for astronauts and a possible plateauing of the protective effect. If trends in specific causes of death continue as they have, this trend in all-cause SMR will

Causes of death are subdivided at the most basic level into internal and external causes. Examples of external causes include drowning, electrocution, poisoning, burns, and trauma. For purposes of analysis, we consider external causes to be any death with primary cause code of E800–E899 in the International Classification of Diseases code set, Eighth Edition

As we have noted, accidental deaths accounted for all external deaths in the astronaut cohort for many years, and no published study bothered to report on nonaccidental external causes for this reason. Current data include a fair number of deaths due to external causes other than accidents, and we present in **Figure 3**, for the first time, SMRs for all external causes com‑

Across all decades, United States astronauts have been at approximately 250% risk of the gen‑ eral population of death due to external causes. This excess risk continues to be driven almost entirely by accidental deaths, some of which occurred in catastrophic accidents that many

In the 1980s and 2000s, astronauts were at significantly increased risk of death from exter‑ nal causes, and this is unsurprising. These two decades each saw the destruction of a space shuttle, with the death of multiple astronauts in each: the space shuttle Challenger explosion in January 1986, which claimed the lives of five astronauts, and the Space Shuttle Columbia

SMRs significantly high, even as deaths from other external causes-particularly other acciden‑ tal sources-were on the decline. These deaths are largely responsible for the overall 2.5-fold increased risk of death due to external causes for the entire follow‑up period. Indeed, with‑ out these deaths, overall SMR in the 1980s would be approximately 160, and not statistically significant. Likewise, SMR for the 2000s would be approximately 115, and not statistically

Three additional people were killed in these two disasters, all of were whom Payload Specialists, i.e., civilians trained for single missions only. As they are not considered a part of the NASA Astronaut Corps, those individuals were not

These deaths pushed

(ICD-8), E800–E899 in the ICD-9 code set, and V01–Y89 in the ICD-10 code set.

readers will recall, which took the lives of multiple astronauts in single events.

reentry disintegration in February 2003, which killed 6 astronauts.<sup>1</sup>

included in either prior research or the updated analyses presented here.

nauts from 1960 to 2017.

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continue as well.

significant.

1

**3.3. External causes**

*3.3.1. All external causes of death*

bined, as well as SMRs for accidental causes.

The high risk of accidental death was anticipated from the beginning of the United States space program, when then U.S. President Dwight Eisenhower called for astronauts to be selected from the ranks of military test pilots, because, among other reasons, they were accus‑ tomed to high-risk vocational activities [10]. This proved to be prescient: by the end of 1991, 16 of the 20 recorded astronaut deaths were accidental, with half due to space craft accidents, and several of which were duty-related plane crashes. As we have noted, the rate of accidental deaths for this cohort is significantly greater than expected in an age- and sex-matched cohort from the general population.

Accidental death SMRs for all astronauts based on data through 2017 are also given in **Figure 3** as the orange points and lines. The progression of risk for accidental death is the main driver of the risk for death by all external causes. As such, SMRs follow much the same pattern as those from all external causes. The main difference is that SMRs for accidental death are higher than those for all external causes due to the smaller number of expected deaths in the general population from this causal subset.

#### **3.4. Natural causes**

Natural causes of death are causes originating within the body (albeit possibly as a result of an unseen and perhaps unfelt external force, such as cancer precipitated by radiation expo‑ sure), rather than a cause related to an obvious external force or object. In the universe of all possible causes, natural causes are the complement of external causes, and thus, in terms of ICD-8, −9, and −10 codes, these would include all codes other than those noted above for external causes in Section 3.3. Natural causes are also a major concern for astronauts in rela‑ tion to space travel: does time in space equate to a higher mortality risk due to disease?

Natural causes of death include cancer, cardiovascular disease (CVD), and myriad other less common diseases. Testing hypotheses related to large numbers of potential causes as a group can boost statistical power, which can be helpful when analyzing rare events that may have long latency periods (e.g., cancers related to radiation exposure). However, studying natural causes as a single group has its drawbacks, too. The rigorous physical fitness requirements, high-quality health care and careful follow-up of health, and relative high socio-economic status of astronauts may all be protective of some diseases. Thus, there may be two forces at work, each of which may mask the effects of the other relative to all natural-cause mortality: exposure to space on the one hand, which may elevate the risk of death due to some causes, and a healthy lifestyle on the other hand, which may mitigate the risk of other (or even some of the same) causes. We will explore these issues in some depth now.

#### *3.4.1. Any natural cause of death*

As far as we are aware, analysis of natural-cause mortality of astronauts has only previously been reported in the context of a dissertation project [11]. In that project, the authors fit a Poisson regression model to explore possible differences in natural-cause mortality rates of astronauts above and below the median in estimated space radiation exposure. Unfortunately, the risk of misclassification of exposure and demonstrably low statistical power made the results inconclusive [11]. We present SMRs for death by natural causes, CVD, and cancer in **Figure 4**.

*3.4.2. Cardiovascular disease*

I00–I99.

Cardiovascular disease includes ischemic heart disease, heart failure, stroke, and any other circulatory disease captured by ICD-8 codes 390–458, ICD-9 codes 390–459, and ICD-10 codes

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**Figure 4.** SMRs for natural-cause, CVD, and cancer mortality among United States astronauts, 1970–2017.

Death from CVD is an outcome that has been tracked since the first published research on astronaut mortality in 1993. Even though CVD has been one of the most common causes of death for astronauts, SMR for CVD through 1991 was reported to be a statistically insignifi‑ cant 47 (95% CI = 5–168), suggesting (inconclusively) that astronauts may be at less than half the risk of death from CVD in the general population [6]. An analysis comparing the same astronaut mortality rates to those of ground-based controls from the JSC found astronauts to have an insignificant elevation in risk (HR = 1.20; 95% CI = 0.27–5.28) [8]. Considering the

The darker blue points in **Figure 4** suggest that astronauts have been at a consistently reduced mortality risk due to natural causes and significantly so since the year 2000. For the entire 1970 to 2017 period, astronauts were at less than half the risk of death from natural causes as the general population. As with SMRs for external causes, SMRs in **Figure 4** are based on only a few deaths through the end of the 1990s and thus do not reach statistical significance. From the year 2000 onward, the aging astronaut cohort resulted in dramatic increases in the number of expected deaths, and observed astronaut deaths did not keep up, resulting in SMRs statisti‑ cally significantly less than 100 for the latest two periods.

**Figure 4.** SMRs for natural-cause, CVD, and cancer mortality among United States astronauts, 1970–2017.

#### *3.4.2. Cardiovascular disease*

of the risk for death by all external causes. As such, SMRs follow much the same pattern as those from all external causes. The main difference is that SMRs for accidental death are higher than those for all external causes due to the smaller number of expected deaths in the

Natural causes of death are causes originating within the body (albeit possibly as a result of an unseen and perhaps unfelt external force, such as cancer precipitated by radiation expo‑ sure), rather than a cause related to an obvious external force or object. In the universe of all possible causes, natural causes are the complement of external causes, and thus, in terms of ICD-8, −9, and −10 codes, these would include all codes other than those noted above for external causes in Section 3.3. Natural causes are also a major concern for astronauts in rela‑ tion to space travel: does time in space equate to a higher mortality risk due to disease?

Natural causes of death include cancer, cardiovascular disease (CVD), and myriad other less common diseases. Testing hypotheses related to large numbers of potential causes as a group can boost statistical power, which can be helpful when analyzing rare events that may have long latency periods (e.g., cancers related to radiation exposure). However, studying natural causes as a single group has its drawbacks, too. The rigorous physical fitness requirements, high-quality health care and careful follow-up of health, and relative high socio-economic status of astronauts may all be protective of some diseases. Thus, there may be two forces at work, each of which may mask the effects of the other relative to all natural-cause mortality: exposure to space on the one hand, which may elevate the risk of death due to some causes, and a healthy lifestyle on the other hand, which may mitigate the risk of other (or even some

As far as we are aware, analysis of natural-cause mortality of astronauts has only previously been reported in the context of a dissertation project [11]. In that project, the authors fit a Poisson regression model to explore possible differences in natural-cause mortality rates of astronauts above and below the median in estimated space radiation exposure. Unfortunately, the risk of misclassification of exposure and demonstrably low statistical power made the results inconclusive [11]. We present SMRs for death by natural causes, CVD, and cancer in

The darker blue points in **Figure 4** suggest that astronauts have been at a consistently reduced mortality risk due to natural causes and significantly so since the year 2000. For the entire 1970 to 2017 period, astronauts were at less than half the risk of death from natural causes as the general population. As with SMRs for external causes, SMRs in **Figure 4** are based on only a few deaths through the end of the 1990s and thus do not reach statistical significance. From the year 2000 onward, the aging astronaut cohort resulted in dramatic increases in the number of expected deaths, and observed astronaut deaths did not keep up, resulting in SMRs statisti‑

of the same) causes. We will explore these issues in some depth now.

cally significantly less than 100 for the latest two periods.

general population from this causal subset.

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**3.4. Natural causes**

*3.4.1. Any natural cause of death*

**Figure 4**.

Cardiovascular disease includes ischemic heart disease, heart failure, stroke, and any other circulatory disease captured by ICD-8 codes 390–458, ICD-9 codes 390–459, and ICD-10 codes I00–I99.

Death from CVD is an outcome that has been tracked since the first published research on astronaut mortality in 1993. Even though CVD has been one of the most common causes of death for astronauts, SMR for CVD through 1991 was reported to be a statistically insignifi‑ cant 47 (95% CI = 5–168), suggesting (inconclusively) that astronauts may be at less than half the risk of death from CVD in the general population [6]. An analysis comparing the same astronaut mortality rates to those of ground-based controls from the JSC found astronauts to have an insignificant elevation in risk (HR = 1.20; 95% CI = 0.27–5.28) [8]. Considering the wide range of possible effect sizes those two studies suggested were possible (and the lack of statistical significance in both of them), no solid conclusions could be drawn about CVD mortality from the 1991 data set.

A reanalysis of the astronaut data set used by Delp et al. [14] revealed that lunar astronauts were significantly older than the nonflight and LEO-only astronauts at the start and end of the study, making the potential for age confounding in the PMR high [17]. Using SMRs instead of PMRs demonstrated that when the age structure was taken into account (and all the available information, including follow-up time, used), there were no significant differences between

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In comparison to nonflight astronauts, lunar astronauts had no significant increase in risk, with an SMR of 117 (95% CI = 24–343) for the 1968–2015 period. In comparison to LEO astro‑ nauts in the same period, SMR was 67 (95% CI = 14–197), and, in comparison to the combined group of LEO and nonflight astronauts (nonlunar astronauts) in the same period, the SMR was 77 (95% CI = 17–237) [17]. These results offered no plausible evidence of an increase in risk of death from CVD for Apollo lunar astronauts and showed that prior research on the topic was still entirely tenable: there is simply no evidence to support the hypothesis that lunar astronauts are at elevated risk of CVD mortality compared to nonlunar astronauts [17].

Since the beginning of the space program in the United States, there has been concern that radiation exposure in space may lead to greater mortality from cancer, particularly from the unique radiation sources found in outer space [18, 19]. Because of this, cancer incidence has been under regular surveillance by NASA, and cancer mortality has been reported on repeat‑

Cancer deaths are those with a primary cause ICD-8 code of 140–239, ICD-9 code of 140–239, or ICD-10 code of C00–D48. The first study of astronaut mortality from 1993 did not report any mortality measures related to cancer and for good reason: at that point in time, there had only been one death due to cancer among astronauts. The first reported analysis of can‑ cer mortality among astronauts was from the 1998 Longitudinal Study of Astronaut Health (LSAH) [12]. The study compared the three observed astronaut deaths from cancer to the number expected in two comparison groups: the general population of Public Health Region 6 of Texas and ground-based controls from Johnson Space Center (JSC) [12]. In comparison to the general population, astronauts were found to be at less than half the risk of dying from cancer (SMR = 47; 95% CI = 10–105). In comparison to the LSAH controls, however, astronauts were at almost three and a half times the risk of death from cancer (SMR = 345; 95% CI = 66–756) [12]. These results suggested three possibilities for astronauts: (1) they are at greater risk of cancer due to exposure to space travel, (2) the JSC ground-based con‑ trols are healthier than astronauts in ways that protect against cancer, or (3) these results represent a statistical anomaly of this relatively small sample of data. In any case, the small number of observed deaths provides for low statistical power, making results inconclusive. The LSAH reexamined cancer mortality in a study published in 2000 [8]. In a proportional hazards model, again comparing astronauts to the LSAH controls, astronauts were found to have a hazard ratio of 3.19 (95% CI = 0.93–21.85), adjusted for sex, education, marital status at selection, and smoking history [8]. This similar result is not surprising, as the analysis was based on essentially the same data set as the prior study: there had been only one additional

any of the astronaut groups in risk of death from CVD [17].

*3.4.4. Cancer mortality among astronauts*

edly over the years [6, 8, 12].

The 2010 study of astronaut mortality by Reynolds and Day [9] reexamined CVD mortality and found that, in comparison to the general population for the 1980 to 2009 period, CVD SMR was a statistically significant 27 (95% CI = 9–63), validating the findings from Peterson et al. [6].

Again, it has been speculated that HWE is responsible for the reduction in risk of CVD mortal‑ ity even in the face of potentially heavy smoking by the earliest groups of (mostly military) astronauts [9, 12]. Prior reports of astronaut biometric measurements have shown astronauts to be at or below suggested normal limits for blood pressure, cholesterol, and body mass index, all important risk factors for cardiovascular disease [8, 13].

**Figure 4** shows updated SMRs for CVD among astronauts (orange points and lines), once again adding in the USAF astronauts and extending follow-up to the end of 2017. Thin data in the early decades give statistically insignificant SMRs through 1999. However, in the last two periods, SMRs show significant reductions in CVD mortality rates for astronauts, as does the overall 1970–2017 SMR. For the overall period, astronauts are at less than one third the risk of death from CVD as is the general population of the United States (SMR = 30; 95% CI = 15–54).

In total, the evidence thus far suggests that astronauts are at a greatly reduced risk of death from CVD in comparison to the general population.

#### *3.4.3. Lunar astronaut mortality from CVD*

In 2016, a published study investigated the risk of CVD mortality for astronauts who had either walked on the moon or who completed circumlunar flights as part of the Apollo mis‑ sions (so-called lunar astronauts) [14]. The study compared lunar astronauts to astronauts who only completed missions on low Earth orbit (LEO), or to astronauts who had not flown to space at all ("nonflight" astronauts). Dividing the lunar astronaut percentage by the per‑ centage of deaths from CVD in the comparison groups (up to the end of 2015), the authors computed proportionate mortality ratios (PMRs). PMRs attempt to look for differences in the proportion of deaths by a specific cause between two groups. In this case, PMRs demon‑ strated that a higher proportion of lunar astronauts died of CVD than either of the compari‑ son groups, leading the authors to conclude that lunar astronauts were at greater risk of death by CVD than astronauts who had never left low Earth orbit or never flown into space at all. Conflating these findings with a model of how radiation may damage vascular endothelial tissue in rats, the authors proposed a potential biological mechanism to match their purported epidemiologic findings [14].

Other authors were quick to point out flaws in the study. Questions arose regarding the data set used, the analytic method, and the potential imprecision of the disease outcome definition [15]. Several comments on the online version of the paper pointed to methodological flaws in the PMR analysis, particularly the potential biases related to competing risks or confounding by age when the age structure is markedly different between groups [16]. As it turns out, these two issues were, in fact, driving the PMRs to be misleading.

A reanalysis of the astronaut data set used by Delp et al. [14] revealed that lunar astronauts were significantly older than the nonflight and LEO-only astronauts at the start and end of the study, making the potential for age confounding in the PMR high [17]. Using SMRs instead of PMRs demonstrated that when the age structure was taken into account (and all the available information, including follow-up time, used), there were no significant differences between any of the astronaut groups in risk of death from CVD [17].

In comparison to nonflight astronauts, lunar astronauts had no significant increase in risk, with an SMR of 117 (95% CI = 24–343) for the 1968–2015 period. In comparison to LEO astro‑ nauts in the same period, SMR was 67 (95% CI = 14–197), and, in comparison to the combined group of LEO and nonflight astronauts (nonlunar astronauts) in the same period, the SMR was 77 (95% CI = 17–237) [17]. These results offered no plausible evidence of an increase in risk of death from CVD for Apollo lunar astronauts and showed that prior research on the topic was still entirely tenable: there is simply no evidence to support the hypothesis that lunar astronauts are at elevated risk of CVD mortality compared to nonlunar astronauts [17].

#### *3.4.4. Cancer mortality among astronauts*

wide range of possible effect sizes those two studies suggested were possible (and the lack of statistical significance in both of them), no solid conclusions could be drawn about CVD

The 2010 study of astronaut mortality by Reynolds and Day [9] reexamined CVD mortality and found that, in comparison to the general population for the 1980 to 2009 period, CVD SMR was a statistically significant 27 (95% CI = 9–63), validating the findings from Peterson et al. [6]. Again, it has been speculated that HWE is responsible for the reduction in risk of CVD mortal‑ ity even in the face of potentially heavy smoking by the earliest groups of (mostly military) astronauts [9, 12]. Prior reports of astronaut biometric measurements have shown astronauts to be at or below suggested normal limits for blood pressure, cholesterol, and body mass

**Figure 4** shows updated SMRs for CVD among astronauts (orange points and lines), once again adding in the USAF astronauts and extending follow-up to the end of 2017. Thin data in the early decades give statistically insignificant SMRs through 1999. However, in the last two periods, SMRs show significant reductions in CVD mortality rates for astronauts, as does the overall 1970–2017 SMR. For the overall period, astronauts are at less than one third the risk of death from CVD as is the general population of the United States (SMR = 30; 95% CI = 15–54). In total, the evidence thus far suggests that astronauts are at a greatly reduced risk of death

In 2016, a published study investigated the risk of CVD mortality for astronauts who had either walked on the moon or who completed circumlunar flights as part of the Apollo mis‑ sions (so-called lunar astronauts) [14]. The study compared lunar astronauts to astronauts who only completed missions on low Earth orbit (LEO), or to astronauts who had not flown to space at all ("nonflight" astronauts). Dividing the lunar astronaut percentage by the per‑ centage of deaths from CVD in the comparison groups (up to the end of 2015), the authors computed proportionate mortality ratios (PMRs). PMRs attempt to look for differences in the proportion of deaths by a specific cause between two groups. In this case, PMRs demon‑ strated that a higher proportion of lunar astronauts died of CVD than either of the compari‑ son groups, leading the authors to conclude that lunar astronauts were at greater risk of death by CVD than astronauts who had never left low Earth orbit or never flown into space at all. Conflating these findings with a model of how radiation may damage vascular endothelial tissue in rats, the authors proposed a potential biological mechanism to match their purported

Other authors were quick to point out flaws in the study. Questions arose regarding the data set used, the analytic method, and the potential imprecision of the disease outcome definition [15]. Several comments on the online version of the paper pointed to methodological flaws in the PMR analysis, particularly the potential biases related to competing risks or confounding by age when the age structure is markedly different between groups [16]. As it turns out, these

index, all important risk factors for cardiovascular disease [8, 13].

from CVD in comparison to the general population.

two issues were, in fact, driving the PMRs to be misleading.

*3.4.3. Lunar astronaut mortality from CVD*

epidemiologic findings [14].

mortality from the 1991 data set.

264 Into Space - A Journey of How Humans Adapt and Live in Microgravity

Since the beginning of the space program in the United States, there has been concern that radiation exposure in space may lead to greater mortality from cancer, particularly from the unique radiation sources found in outer space [18, 19]. Because of this, cancer incidence has been under regular surveillance by NASA, and cancer mortality has been reported on repeat‑ edly over the years [6, 8, 12].

Cancer deaths are those with a primary cause ICD-8 code of 140–239, ICD-9 code of 140–239, or ICD-10 code of C00–D48. The first study of astronaut mortality from 1993 did not report any mortality measures related to cancer and for good reason: at that point in time, there had only been one death due to cancer among astronauts. The first reported analysis of can‑ cer mortality among astronauts was from the 1998 Longitudinal Study of Astronaut Health (LSAH) [12]. The study compared the three observed astronaut deaths from cancer to the number expected in two comparison groups: the general population of Public Health Region 6 of Texas and ground-based controls from Johnson Space Center (JSC) [12]. In comparison to the general population, astronauts were found to be at less than half the risk of dying from cancer (SMR = 47; 95% CI = 10–105). In comparison to the LSAH controls, however, astronauts were at almost three and a half times the risk of death from cancer (SMR = 345; 95% CI = 66–756) [12]. These results suggested three possibilities for astronauts: (1) they are at greater risk of cancer due to exposure to space travel, (2) the JSC ground-based con‑ trols are healthier than astronauts in ways that protect against cancer, or (3) these results represent a statistical anomaly of this relatively small sample of data. In any case, the small number of observed deaths provides for low statistical power, making results inconclusive.

The LSAH reexamined cancer mortality in a study published in 2000 [8]. In a proportional hazards model, again comparing astronauts to the LSAH controls, astronauts were found to have a hazard ratio of 3.19 (95% CI = 0.93–21.85), adjusted for sex, education, marital status at selection, and smoking history [8]. This similar result is not surprising, as the analysis was based on essentially the same data set as the prior study: there had been only one additional cancer death among astronauts since the 1998 study. Once again, the small number of deaths plus lingering doubt about the suitability of the controls yielded an underpowered and, ulti‑ mately, inconclusive analysis.

leads to all darker blue point estimates being higher than their corresponding orange point estimates. The true (unbiased) estimates, and estimates for all other potential scenarios, must be somewhere in between. Thus, the light blue zone surrounding these sets of SMRs show the

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http://dx.doi.org/10.5772/intechopen.73603

In the observed SMRs for natural causes (**Figure 5**), no SMRs are statistically significant until the 2000–2009 period. However, SMRs in the optimistic scenario (**Figure 5**) reach statistical significance in the 1980s and remain significant through the end of the observation period. This suggests that early deaths due to external causes may in fact be biasing SMRs for natural causes upward. Had those astronauts lived, SMRs for natural causes could be even lower than

total range of possibility for the true SMR (with 95% CI) in each period.

**Figure 5.** Alternative SMRs for natural-cause mortality among United States astronauts, 1970–2017.

observed.

In the 2010 study of astronaut mortality, cancer mortality was analyzed by decades between 1980 and 2009 [9]. By the end of 2009, the number of astronaut deaths from cancer had risen to a total of seven. For the three decades 1980–2009, SMRs for cancer in comparison to the general population were consistently below 100, but still, small numbers of cases made SMRs nonsignificant. Pooling the data from the entire 30 years led to SMR of 47 (95% CI = 19–97) [9]. This was the first time that the observed reduction in cancer mortality among astronauts reached statistical significance and was consistent with prior general population comparisons.

Updated findings through 2017 are displayed as the lighter blue points and lines in **Figure 4**. With the additional follow-up time and incorporation of USAF astronauts, we can see that astronauts are still estimated to be at about half the risk of cancer mortality as the general population between 2010 and 2017, though the results are again not significant (**Figure 4**). SMR for the period 1970 to 2017 is significant, however, with SMR of 62 (95% CI = 37–97).

#### *3.4.5. The effect of competing risks on rates of death by natural causes*

As we have seen, astronauts have at times been at elevated risk of death due to external causes (primarily accidents) and have been and continue to be at reduced risk of death due to natural causes. External and internal (or natural) causes are mutually exclusive, competing causes of death (at least in terms of an underlying cause of death). That this may explain the low natural-cause SMRs that have been observed has been suggested in recent literature [17, 20]. Given that a significant number of astronauts have died (some quite young) of external causes, this could alter natural-cause mortality rates at older ages.

Such altered natural-cause mortality rates would in turn affect SMRs for natural causes, and this could explain the low natural-cause SMRs that have been observed for astronauts. We can attempt to quantify the potential effect of this via sensitivity analyses, whereby we com‑ pute SMRs under extreme hypothetical alternative scenarios regarding the reassignment of observed deaths due to external causes. These alternative SMRs are shown in lighter blue (left-most SMR in each cluster) and darker blue (right-most SMR in each cluster) in **Figure 5**, along with the observed natural-cause SMRs in orange.

Specifically, the lighter blue and darker blue point estimates in each period form an upper and lower bound to our natural-cause SMRs under two differing counterfactual assumptions regarding the occurrence of deaths due to external causes: (1) assuming the external deaths did not happen at all and the astronauts are still alive as of the end of the follow‑up period (lighter blue); (2) assuming all external deaths occurred at the observed times, but were due to natural causes instead (darker blue). The former is the most optimistic, biasing SMRs down‑ ward by inflating only the denominator of the natural-cause SMR. As a result, all of these point estimates are lower than their corresponding observed (orange) point estimates. The lat‑ ter scenario is the most pessimistic possible scenario, biasing SMRs for natural causes upward by inflating the number of natural-cause deaths without changing the observation time. This leads to all darker blue point estimates being higher than their corresponding orange point estimates. The true (unbiased) estimates, and estimates for all other potential scenarios, must be somewhere in between. Thus, the light blue zone surrounding these sets of SMRs show the total range of possibility for the true SMR (with 95% CI) in each period.

cancer death among astronauts since the 1998 study. Once again, the small number of deaths plus lingering doubt about the suitability of the controls yielded an underpowered and, ulti‑

In the 2010 study of astronaut mortality, cancer mortality was analyzed by decades between 1980 and 2009 [9]. By the end of 2009, the number of astronaut deaths from cancer had risen to a total of seven. For the three decades 1980–2009, SMRs for cancer in comparison to the general population were consistently below 100, but still, small numbers of cases made SMRs nonsignificant. Pooling the data from the entire 30 years led to SMR of 47 (95% CI = 19–97) [9]. This was the first time that the observed reduction in cancer mortality among astronauts reached statistical significance and was consistent with prior general population comparisons. Updated findings through 2017 are displayed as the lighter blue points and lines in **Figure 4**. With the additional follow-up time and incorporation of USAF astronauts, we can see that astronauts are still estimated to be at about half the risk of cancer mortality as the general population between 2010 and 2017, though the results are again not significant (**Figure 4**). SMR for the period 1970 to 2017 is significant, however, with SMR of 62 (95% CI = 37–97).

As we have seen, astronauts have at times been at elevated risk of death due to external causes (primarily accidents) and have been and continue to be at reduced risk of death due to natural causes. External and internal (or natural) causes are mutually exclusive, competing causes of death (at least in terms of an underlying cause of death). That this may explain the low natural-cause SMRs that have been observed has been suggested in recent literature [17, 20]. Given that a significant number of astronauts have died (some quite young) of external

Such altered natural-cause mortality rates would in turn affect SMRs for natural causes, and this could explain the low natural-cause SMRs that have been observed for astronauts. We can attempt to quantify the potential effect of this via sensitivity analyses, whereby we com‑ pute SMRs under extreme hypothetical alternative scenarios regarding the reassignment of observed deaths due to external causes. These alternative SMRs are shown in lighter blue (left-most SMR in each cluster) and darker blue (right-most SMR in each cluster) in **Figure 5**,

Specifically, the lighter blue and darker blue point estimates in each period form an upper and lower bound to our natural-cause SMRs under two differing counterfactual assumptions regarding the occurrence of deaths due to external causes: (1) assuming the external deaths did not happen at all and the astronauts are still alive as of the end of the follow‑up period (lighter blue); (2) assuming all external deaths occurred at the observed times, but were due to natural causes instead (darker blue). The former is the most optimistic, biasing SMRs down‑ ward by inflating only the denominator of the natural-cause SMR. As a result, all of these point estimates are lower than their corresponding observed (orange) point estimates. The lat‑ ter scenario is the most pessimistic possible scenario, biasing SMRs for natural causes upward by inflating the number of natural-cause deaths without changing the observation time. This

*3.4.5. The effect of competing risks on rates of death by natural causes*

causes, this could alter natural-cause mortality rates at older ages.

along with the observed natural-cause SMRs in orange.

mately, inconclusive analysis.

266 Into Space - A Journey of How Humans Adapt and Live in Microgravity

In the observed SMRs for natural causes (**Figure 5**), no SMRs are statistically significant until the 2000–2009 period. However, SMRs in the optimistic scenario (**Figure 5**) reach statistical significance in the 1980s and remain significant through the end of the observation period. This suggests that early deaths due to external causes may in fact be biasing SMRs for natural causes upward. Had those astronauts lived, SMRs for natural causes could be even lower than observed.

**Figure 5.** Alternative SMRs for natural-cause mortality among United States astronauts, 1970–2017.
