3
MAJOR COHORT STUDIES

This chapter provides an overview of the major cohort studies of Gulf War veterans, and describes in detail the populations studied, the methods used to select those populations, and the approaches used to identify the health status of the veterans—including questionnaires, examinations, and laboratory tests. The findings from the studies described in this chapter are reviewed and evaluated in Chapter 4.

The major cohort studies are important for understanding the health of Gulf War veterans. Some of these cohorts were brought together in the first few years after the Gulf War; others were assembled more recently. The largest studies of Gulf War veterans have been conducted in countries that were members of the Gulf War coalition, including the United States, the United Kingdom (UK), Denmark, and Australia. Most of the studies compare sizable groups of deployed veterans with groups of nondeployed veterans or with veterans who were deployed to locations other than the Persian Gulf (for example, Bosnia or Germany).

Most major cohorts, once established, led to numerous studies that examined more detailed questions about Gulf War veterans’ health; the committee refers to those studies as derivatives. A derivative study is included and summarized under the original cohort from which the study population was drawn. This organization helped the committee identify populations that have been studied and understand which studies were independent of one another; establishing which studies rely on the same population sample is important because it helped the committee avoid double counting when weighing the evidence.

GENERAL LIMITATIONS OF GULF WAR COHORT STUDIES AND DERIVATIVE STUDIES

The cohort studies of Gulf War veterans and their derivative studies have contributed greatly to our understanding of veterans’ health, but they are beset by limitations that are commonly encountered in epidemiologic studies (see Chapter 2), including lack of representativeness, selection bias, lack of control for potential confounding factors, self-reports of exposures, lack of a diagnosis by a health professional for some health effects, and outcome misclassification.

The foremost limitation is lack of representativeness, which limits one’s ability to generalize results to the entire population of interest; for example, about half the cohorts focus on groups of veterans that are selected for study according to where they served in the military, that is, a military-unit-based study. Military-unit studies are not representative of all Gulf War



The National Academies | 500 Fifth St. N.W. | Washington, D.C. 20001
Copyright © National Academy of Sciences. All rights reserved.
Terms of Use and Privacy Statement



Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.
Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.

Do not use for reproduction, copying, pasting, or reading; exclusively for search engines.

OCR for page 39
3 MAJOR COHORT STUDIES This chapter provides an overview of the major cohort studies of Gulf War veterans, and describes in detail the populations studied, the methods used to select those populations, and the approaches used to identify the health status of the veterans—including questionnaires, examinations, and laboratory tests. The findings from the studies described in this chapter are reviewed and evaluated in Chapter 4. The major cohort studies are important for understanding the health of Gulf War veterans. Some of these cohorts were brought together in the first few years after the Gulf War; others were assembled more recently. The largest studies of Gulf War veterans have been conducted in countries that were members of the Gulf War coalition, including the United States, the United Kingdom (UK), Denmark, and Australia. Most of the studies compare sizable groups of deployed veterans with groups of nondeployed veterans or with veterans who were deployed to locations other than the Persian Gulf (for example, Bosnia or Germany). Most major cohorts, once established, led to numerous studies that examined more detailed questions about Gulf War veterans’ health; the committee refers to those studies as derivatives. A derivative study is included and summarized under the original cohort from which the study population was drawn. This organization helped the committee identify populations that have been studied and understand which studies were independent of one another; establishing which studies rely on the same population sample is important because it helped the committee avoid double counting when weighing the evidence. GENERAL LIMITATIONS OF GULF WAR COHORT STUDIES AND DERIVATIVE STUDIES The cohort studies of Gulf War veterans and their derivative studies have contributed greatly to our understanding of veterans’ health, but they are beset by limitations that are commonly encountered in epidemiologic studies (see Chapter 2), including lack of representativeness, selection bias, lack of control for potential confounding factors, self-reports of exposures, lack of a diagnosis by a health professional for some health effects, and outcome misclassification. The foremost limitation is lack of representativeness, which limits one’s ability to generalize results to the entire population of interest; for example, about half the cohorts focus on groups of veterans that are selected for study according to where they served in the military, that is, a military-unit-based study. Military-unit studies are not representative of all Gulf War 39

OCR for page 39
40 GULF WAR AND HEALTH veterans with respect to their duties and location during deployment, their military status during the war (active duty, reserves, or National Guard), their military status after the war (active duty, reserves, or discharged), their branch of service (Army, Navy, Air Force, or Marines), or ease of ascertainment (IOM, 1999). The most representative studies are population-based: the cohorts are selected on the basis of where their members reside. In population-based studies of Gulf War veterans, the cohort might be the entire deployed population, as in studies of Canadian and Australian veterans, or a random selection from the population of interest, as in several studies of US and UK veterans. The committee, in evaluating major cohort studies, gave greater weight to Gulf War studies that were population based. A study’s representativeness, even if it is population based, can be compromised by low participation rates. Low participation rates can introduce selection bias, such as when Gulf War veterans who are symptomatic choose to participate more frequently than those who are not symptomatic. Nondeployed veterans, who might be healthier, may be less inclined to participate. In some studies, researchers not only try to assess the potential for selection bias by comparing participants with nonparticipants from both deployed and nondeployed populations, but also implement strategies to reduce the impact of selection bias, such as by oversampling nondeployed populations as in the study by Eisen and colleagues (2005). Selection bias might also occur through the so-called healthy warrior effect. That form of bias has the potential to occur in most of the major cohorts that compare deployed veterans with nondeployed personnel. The healthy warrior effect is a form of selection bias insofar as chronically ill or less fit members of the armed forces might be less likely to have been deployed than more fit members. Some of the best studies attempt to measure the potential for selection bias and adjust for it in the analysis. Many cohort studies rely on self-reports of symptoms and medical conditions. This may introduce reporting bias, which occurs when the study population (in this case the deployed veterans) over- or underreports symptoms or medical conditions relative to a comparison group (in this case the nondeployed veterans). This over- or underreporting may be related to beliefs about the effect of deployment on health, especially among deployed veterans who, if they are experiencing health problems, may have already formed an opinion on the cause of their malady. Comparison groups, in contrast, may have little reason to conjecture possible links between past exposures and any current health conditions they may be experiencing. In most cases, reporting bias leads to an overestimation of the prevalence of symptoms or diagnoses in the deployed population. Self-reports of symptoms or medical conditions might sometimes introduce another type of bias known as outcome misclassification, in which there are errors in how symptoms or medical conditions are classified into outcomes and analyzed. One Gulf War study sought to document outcome misclassification by comparing veterans’ symptom reporting on questionnaires with clinical examination about 3 months later (McCauley et al., 1999a). The study found that the extent of misclassification depended on the type of symptom being reported; agreement between questionnaire and clinical examination ranged from 4% to 79%. The overall problem led the investigators to caution that questionnaire data, in the absence of clinical evaluation or adjustment, might lead to outcome misclassification (McCauley et al., 1999b). Another study also found poor reliability and validity of self-reported medical diagnoses when compared with medical records (Gray et al., 1999). In contrast, a study by the Department of Veterans Affairs (VA) (Kang et al., 2000), which verified a random subset of self-reported conditions (n = 4200) against medical records, found a strong correlation between the two (above

OCR for page 39
MAJOR COHORT STUDIES 41 93%). Those data, however, were available only for the 45.2% who signed consent forms that allowed researchers to verify records. The concerns relating to symptom self-reporting are best addressed through medical evaluations in which the veterans’ reports of symptoms can be further explored with a health professional. This was done by VA researchers (for example, Eisen et al., 2005) and by several other investigators with the resources to conduct medical evaluations (for example, Sim et al., 2003). The committee acknowledges that many medical conditions, such as chronic fatigue syndrome (CFS) and fibromyalgia, are diagnosed solely on the basis of symptom reports, but where possible these symptoms should be evaluated by a medical professional. Another limitation of most major cohort studies is self-reporting of exposures, often years after the exposure had occurred. Self-reporting of exposures, as with self-reporting of symptoms, introduces the possibility of recall bias, the tendency for participants who are symptomatic to overestimate (or underestimate) their exposures compared with those who are not symptomatic. Indeed, a major study from the United Kingdom found that Gulf War veterans with more symptoms were likely to report more exposures than those not deployed to the gulf (Unwin et al., 1999). Exposures often cannot be validated by objective means, may have occurred years earlier, and might have been perceived rather than actual (Fricker et al., 2000). For example, the high sensitivity of chemical-warfare monitors used in the Persian Gulf War to warn of impending attacks led to many false alarms, which might have been perceived by veterans as actual exposures. Enhanced recordkeeping and monitoring of environmental exposures during and after the Gulf War would have averted this exposure reporting problem. Indeed, many expert panels have recommended improved recordkeeping and environmental monitoring in future deployments (for example, IOM, 1999; NRC, 2000a,b,c). Other limitations of the body of evidence are that studies might be too narrow in their assessment of health status, the measurement instruments might have been too insensitive to detect health problems that affect deployed veterans, and the period of investigation has been too brief to detect health outcomes that have a long latency or require many years to progress to the point where disability, hospitalization, or death occurs. Virtually all US studies are cross- sectional, and this limits the opportunity to learn about symptom duration and chronicity, latency of onset (especially for health conditions with a long latency, such as cancer), and prognosis. ORGANIZATION OF THIS CHAPTER This chapter describes the major cohort studies and their derivative studies used by the Update committee to provide the evidence for the conclusions presented in Chapter 4. For each separately assembled cohort, the reference study is described first, followed by a summary of any derivative studies cited in Chapter 4 or Appendix A. The majority of the cohort studies are population-based, although some military-unit-based studies are described later in the chapter. Table 3-1 lists the reference and derivative studies of each cohort cited in this chapter and Chapter 4. The committee did not identify any new major cohort studies for this report. Furthermore, not all derivative studies for a particular cohort study are included in this chapter or in Chapter 4. In many cases, the derivative studies identified by the committee from the literature searches were highly specialized; for example, they reported on family issues, pathologic changes in a subgroup of veterans, or treatment outcomes. Such studies are not included in this chapter or in Chapter 4.

OCR for page 39
42 GULF WAR AND HEALTH TABLE 3-1 Reference and Derivative Studies for the Major Gulf War Cohorts Cohort/Reference Study Derivatives Purpose/Outcome VA National Health Survey of Gulf War Veterans and Their Families/Kang et al., 2000 Volume 4 Davis et al., 2004 Presence of distal symmetric polyneuropathy Eisen et al., 2005 Numerous health outcomes and general health assessment Kang et al., 2001 Self-reported birth defects Kang et al., 2002 Association of symptom clusters with self-reported exposures Kang et al., 2003 Prevalence of PTSD and chronic fatigue syndrome Kang et al., 2005 Role of sexual assault and harassment on the risk of PTSD Karlinsky et al., 2004 Pulmonary function and self-reported respiratory symptoms New Kang et al., 2009 Self-reported general health status Page et al., 2005a,b Possible exposure at Khamisiyah and self-reported morbidity Blanchard et al., 2005 Prevalence of chronic multisymptom illness Toomey et al., 2007 Prevalence of psychiatric disorders, symptom self-report, and quality of life status Toomey et al., 2009 Neuropsychological functioning Iowa Veterans/Iowa Persian Gulf Study Group, 1997 Barrett et al., 2002 Association between PTSD and self-reported physical Volume 4 health status Black et al., 1999 Impact of multiple chemical sensitivity on quality of life and utilization of health services Black et al., 2000 Risk factors and prevalence of multiple chemical sensitivity Black et al., 2004a Prevalence of psychiatric disorders Black et al., 2004b Prevalence and risk factors for anxiety disorders Doebbling et al., 2000 Factor analysis of self-reported symptoms (Definition of Persian Gulf War Syndrome) Lange et al., 2002 Exposure to Kuwait oil fires and risk of asthma and bronchitis New Ang et al., 2006 Identification of predictors of chronic widespread pain Black et al., 2006 Prevalence of borderline personality disorder Forman-Hoffman et al., Prevalence of self-reports of symptoms of chronic 2007 widespread pain UK Veterans: University of London/Unwin et al., 1999 Volume 4 Hotopf et al., 2003a,b Neurologic assessments Macfarlane et al., 2000 Self-reported exposure and mortality Macfarlane et al., 2003 Incidence of cancer Reid et al., 2001 Self-reported exposure and multiple chemical sensitivity and chronic fatigue syndrome

OCR for page 39
MAJOR COHORT STUDIES 43 Cohort/Reference Study Derivatives Purpose/Outcome Rose et al., 2004 Neuromuscular symptoms evaluated through objective tests Sharief et al., 2002 Neuromuscular symptoms evaluated by objective tests Nisenbaum et al., 2004 Factor analysis of self-reported symptoms Macfarlane et al., 2005 Self-reported exposure and mortality New Stimpson et al., 2006 Self-report of chronic widespread pain Ismail et al., 2008 Prevalence of chronic fatigue and related disorders through assessment UK Veterans: University of Manchester/Cherry et al., 2001a,b Volume 4 None New None UK Veterans: London School of Hygiene and Tropical Medicine/Maconochie et al., 2003 Volume 4 Doyle et al., 2004 Prevalence of miscarriage, stillbirth, and congenital malformations Maconochie et al., 2004 Self-report of fertility problems Simmons et al., 2004 Self-report of medical symptoms or disease New None Danish Peacekeepers/Ishoy et al., 1999b Volume 4 Proctor et al., 2003 Prevalence of neuropsychologic symptoms and neurobehavioral performance Ishoy et al., 1999a Prevalence of gastrointestinal symptoms and diseases, skin disease, and respiratory symptoms and function Ishoy et al., 2001a,b Self-report of sexual dysfunction and birth defects New None Australian Veterans/Sim et al., 2003 Volume 4 Kelsall et al., 2004a Association between self-reported exposures with numerous symptoms and medical conditions Ikin et al., 2004 Prevalence of psychiatric disorders McKenzie et al., 2004 Psychological health and functioning Kelsall et al., 2004b Self-reported exposure and respiratory health status Kelsall et al., 2005 Self-report of exposures and neurological symptoms Forbes et al., 2004 Factor analysis of self-reported symptoms New Kelsall et al., 2006 Self-reported exposure and prevalence of chronic fatigue syndrome Kelsall et al., 2007 Self-reported birth defects and other pregnancy outcomes Oregon and Washington Veterans/McCauley et al., 1999a Volume 4 Bourdette et al., 2001 Prevalence of unexplained illness

OCR for page 39
44 GULF WAR AND HEALTH Cohort/Reference Study Derivatives Purpose/Outcome Spencer et al., 2001 Self-reported exposure and unexplained illness New None Canadian Veterans/Goss Gilroy, 1998 Volume 4 Statistics Canada, 2005 Mortality rate and cancer incidence New None Kansas Veterans Study/Steele et al., 2000 Volume 4 None New None Fort Devens and New Orleans Cohorts/Proctor et al., 1998 Volume 4 White et al., 2001 Self-reported exposure and neuropsychological functioning Proctor et al., 2001a Assessment of health-related quality of life Proctor et al., 2001b Overlap between symptoms of chronic fatigue and chemical sensitivity, and the case definition for chronic multisymptom illness New Proctor et al., 2006 Possible exposure at Khamisiyah and neuropsychological functioning Seabee Veterans/Haley et al., 1997b Haley and Kurt, 1997; Volume 4 Self-reported exposure to neurotoxicants and nervous Haley et al., 1997a system-based syndromes Haley et al., 1999 Genetic susceptibility and risk of neurologic damage New Haley et al., 2009 Gray et al., 1999 Volume 4 Gray et al., 2002 Self-report of symptoms and general health status Knoke et al., 2000 Self-report of symptoms New Phillips et al., 2009 Exposure to vaccines and chronic multisymptom illness Pennsylvania Air National Guard Veterans/Fukuda et al., 1998 Volume 4 Nisenbaum et al., 2000 Self-reported exposures and chronic multisymptom illness Nisenbaum et al., 2004 Factor analysis of self-reported symptoms New None Hawaii and Pennsylvania Active-Duty and Reserve/Stretch et al., 1995 Volume 4 Stretch et al., 1996a Prevalence of psychiatric disorders Stretch et al., 1996b Prevalence of PTSD

OCR for page 39
MAJOR COHORT STUDIES 45 Cohort/Reference Study Derivatives Purpose/Outcome New None New Orleans Reservists/Sutker et al., 1995 Volume 4 Brailey et al., 1998 Prevalence of psychiatric disorders Sutker et al., 1995 Prevalence of psychologic disorders New None Department of Veterans Affairs Study Volume 4 described seven derivative studies of the National Health Survey of Gulf War Veterans and Their Families, conducted by the VA (Kang et al., 2000). The Update committee identified six additional derivative studies of this cohort that examine specific health outcomes or conducted a follow-up survey and analysis. Reference Study A major population-based study of US veterans was mandated by PL 103-446, with the purpose of estimating the prevalence of symptoms and other health outcomes (including reproductive outcomes in spouses and birth defects in children) in Gulf War deployed versus nondeployed veterans. This three-phase retrospective study, the National Health Survey of Gulf War Veterans and Their Families, was designed to be representative of the nearly 700,000 US veterans sent to the Persian Gulf and 800,680 veterans who were not deployed but who were in the military between September 1990 and May 1991. In the first phase, begun in 1995, the VA mailed questionnaires to a stratified random sample of 15,000 Gulf War and 15,000 veterans not deployed to the Gulf War identified by the Defense Manpower Data Center (DMDC) (Kang et al., 2000). Women and those serving in the National Guard and reserves were oversampled, resulting in a study population that was approximately 20% women, 25% National Guard, and 33% reservists. The controls were stratified by gender, unit, and branch of service to mirror the population of deployed veterans. The self-administered structured health questionnaire contained a 48-symptom inventory (somatic and psychological symptoms) and questions about chronic medical conditions, functional limitations, use of medical services, and environmental exposures (for example, immunizations, use of the prophylactic antinerve agent pyridostigmine bromide [PB], smoke from oil-well fires, pesticides, and insecticides). Phase II used telephone interview software in an attempt to capture those who did not respond to the mailed questionnaire. In addition, medical records were obtained for a random sample of 4200 respondents (either phase I or II) to validate self-reports of clinic visits or hospitalizations within the last year. Of the 2233 veterans with at least one clinic visit, 43.2% provided medical record release consent; of the 310 with at least one hospitalization, 45.2% provided medical record release consent. A total of 11,441 (75%) deployed and 9476 (64%) nondeployed veterans participated in the study; 15,817 veterans responded to phase I, and 5100 responded to the telephone portion of phase II (Kang and Bullman, 2001; Kang et al., 2000). Gulf War veterans reported significantly higher rates of functional impairment (27.8% vs 14.2%), limitations of employment (17.2% vs 11.6%), and health-care use as assessed by clinic visits (50.8% vs 40.5%) or hospitalizations (7.8% vs 6.4%) compared with nondeployed

OCR for page 39
46 GULF WAR AND HEALTH veterans. In a randomly selected subset of veterans, medical record reviews verified more than 90% of self-reported reasons for clinic visits or hospitalizations (Kang et al., 2000). Kang et al. (2000) did not assess exposure–symptom relationships but rather noted the percentage of veterans who reported each of 23 environmental exposures and nine vaccine or prophylactic exposures (such as to PB). The five most common environmental exposures reported by more than 60% of survey participants were to the following: diesel, kerosene, or other petrochemical fumes; local food other than that provided by the armed forces; chemical protective gear; smoke from oil-well fires; and burning trash or feces. Derivative Studies In Volume 4, seven derivative studies were identified: Davis et al. (2004), Eisen et al. (2005), Kang et al. (2001, 2002, 2003, 2005), and Karlinsky et al. (2004). Davis et al. (2004) studied the presence of distal symmetric polyneuropathy (DSP) determined by medical history, physical examination by a neurologist, blood tests, and standardized electrophysiologic assessment of motor and sensory nerves in the cohort of 1061 deployed veterans and 1128 nondeployed veterans from the National Health Survey of Gulf War Veterans and Their Families. Spouses of deployed (n = 484) and nondeployed (n = 533) veterans were studied to evaluate whether an infectious agent or environmental contaminant brought back from the gulf could be responsible for any adverse health outcomes. Evaluations of 244 Khamisiyah-exposed (data provided by the DoD) versus 817 nonexposed deployed veterans for the presence of DSP were conducted. See Chapter 4 for more details. In the third phase of the National Health Survey of Gulf War Veterans and Their Families, conducted 10 years after the Gulf War, Eisen and colleagues (2005) performed a cross- sectional study on numerous health outcomes of veterans 10 years after the Gulf War. The study population consisted of a stratified random sample of the 11,441 deployed and 9476 nondeployed veterans who participated in the above described phase I or II. This phase included a comprehensive medical examination and laboratory testing. Of the 1996 eligible deployed veterans, 1061 (53.1%) were examined; 680 (34.1%) declined and 255 (12.8%) were not located. Of the 2883 eligible nondeployed veterans, 1128 (39.1%) were examined; 1316 (45.7%) declined and 439 (15.2%) were not located. Despite three waves of recruitment into the study, the participation rate was low—60.9% of Gulf War deployed veterans and 46.2% of the nondeployed. Study participants were assigned a medical center closest to their residence where physicians and nurses performed medical, neurologic, psychiatric, and gynecologic histories and examinations; laboratory, nerve conduction, pulmonary function, and neuropsychological tests were also performed. Twelve primary health outcome measures and physical functioning on SF- 36 were examined.1 Outcome measures were chosen by the authors to cover the most common symptoms reported by veterans, such as musculoskeletal pain, fatigue, rashes, and neuropathy (Kang et al., 2000). Gulf War veterans reported worse physical health on the SF-36 (49.3 vs 50.8) but the magnitude of the difference, although statistically significant, was not clinically meaningful. Four of 12 conditions were more prevalent among Gulf War veterans: fibromyalgia (2.0% vs 1.2%), CFS (1.6% vs 0.1%), dermatologic conditions (34.6% vs 26.8 %), and dyspepsia (9.1% vs 6.0%). Further details are discussed in Chapter 4. 1 The SF-36 is a standardized instrument instrument to measure physical and mental health, physical and social functioning, and general well-being. It is the Medical Outcome Study’s 36-item questionnaire known as the Short Form-36, or SF-36.

OCR for page 39
MAJOR COHORT STUDIES 47 Kang and colleagues (2001) assessed the association between self-reported adverse pregnancy outcomes and deployment to the gulf using data from the phase I questionnaire. Results are based on the 3397 (2761 males, 636 females) deployed and 2645 (1951 males, 695 females) nondeployed veterans who reported their or their partner’s first pregnancy ending after June 30, 1991. See Chapter 4 for discussion of reproductive outcomes. A nested case-control analysis was performed on the 277 (2.4%) deployed veterans from Phases 1 and 2 who met the case definition for a possible neurological cluster of symptoms including blurred vision, loss of balance or dizziness, tremors or shaking, speech difficulty, concentration or memory problems, and irregular heartbeat, to determine which of 23 self- reported exposures were more common among cases than among the controls (6730 Gulf War veteran respondents who lacked symptoms) (Kang et al., 2002). Exposure to a variety of chemical agents were reported to be higher among cases than controls, specifically to chemical- agent-resistant compound paint, depleted uranium, nerve gas, food contaminated with oil or smoke, and bathing in or drinking water contaminated with oil or smoke. Further details on results from this study are found in Chapter 4 in the section on Multisymptom Illness. Kang et al. (2003) used the Kang et al. (2000) cohorts to assess the prevalence of PTSD and CFS in Gulf War veterans. The questionnaire administered to the veterans in Phases 1 and 2 described above included eight symptoms to be used to diagnose CFS, the PTSD Checklist was used to identify symptoms of PTSD. Assessment of CFS was based on the CDC case definition after exclusion of alternate medical causes of the symptoms. Further details on results from this study are found in Chapter 4 in the section on Mental and Behavioral Disorders. Kang and colleagues (2005) conducted a nested case-control study evaluating the role of sexual assault on the risk of PTSD from the 11,441 Gulf War veteran respondents of the 1995 questionnaire described above. A score of 50 or higher on the PTSD checklist (PCL) was necessary to have met the criteria for PTSD; 1381 (12.1%) Gulf War veterans (336 females and 1045 males) screened positive for PTSD, while 10,060 (1795 females and 8265 males) screened negative and were used as a comparison group. Adjustments for age, race, branch, combat, rank, and unit type, and self-report of sexual harassment and assault were made. Further details on results described above are found in Chapter 4 in the section on Female Veterans’ Health. Karlinsky and colleagues (2004) examined pulmonary function and self-reported respiratory symptoms in the deployed (n = 1036) versus nondeployed (n = 1103) veterans drawn from the National Health Survey of Gulf War Veterans and Their Families. Results of pulmonary function tests were classified into five categories: normal pulmonary function, nonreversible airway obstruction, reversible airway obstruction, restrictive lung physiology, and small-airway obstruction. The authors also reported on the pattern of pulmonary function test results in those exposed (n = 159) and those not exposed (n = 877) (according to DoD exposure estimates developed in 2002) to nerve agents from destruction of munitions at the storage site at Khamisiyah in 1991. See Chapter 4 for more details. The Update committee identified six studies (Blanchard et al., 2005; Kang et al., 2009; Page et al., 2005a,b; Toomey et al., 2007, 2009) published after Volume 4 that used data from the VA National Health Survey of Gulf War Veterans and Their Families. Findings from those studies are described in Chapter 4. Page and colleagues (2005a) assessed the possible health effects of Khamisiyah exposure (determined from models developed by the Department of Defense [DoD] and Central Intelligence Agency) in 5555 deployed army veterans drawn from the 11,441 deployed cohort who responded to either phase I or II (postal or telephone questionnaire). When the survey was

OCR for page 39
48 GULF WAR AND HEALTH completed in 1995, veterans were not yet notified of possible chemical agent exposure in Khamisiyah. No difference in self-perception of health status was found between the exposed (n = 1898) and unexposed (n = 3336) groups. Page and colleagues (2005b) also examined the association between notification of possible exposure at Khamisiyah and self-reported morbidity. In 2000, a subsample of 1056 deployed army veterans was surveyed; of the 600 notified subjects, 438 (73%) responded, and of the 456 nonnotified subjects, 318 (70%) responded. Results indicate no significant difference in activity limitations, bed days, or number of clinic or hospital visits among the groups. Blanchard and colleagues (2005) assessed the prevalence and severity of chronic multisymptom illness (CMI) in the same cohort of deployed (n = 1061) and nondeployed (1128) veterans as described by Eisen and colleagues (2005). Combat exposure was significantly associated with CMI. The prevalence of CMI in the nondeployed population has remained relatively constant at 4, 7, and 10 years postwar. Among the deployed veterans, CMI prevalence has decreased from 44.7% at 4 years to 28.9% after 10 years (Fukuda et al., 1998; Steele, 2000). Blanchard et al. (2005) also assessed for the presence of CMI based on the possible exposure of deployed veterans to nerve agents as a result of the Khamisiyah demolition. Based on DoD modeling, 236 (22.2%) of the deployed veterans were exposed; 92 (39.0%) had CMI, and 144 (61.0%) did not. See Chapter 4 for more details. Toomey and colleagues (2007) examined the prevalence of mental health disorders, self- report of symptoms, and quality of life in the same cohort of 1061 Gulf War deployed versus 1128 nondeployed veterans 10 years postconflict as that of Eisen et al. (2005). Deployed veterans self-reported lower levels of life satisfaction and their SF-36 scores were significantly lower than the nondeployed veterans. See Chapter 4 for more details. Toomey and colleagues (2009) also evaluated neuropsychologic functioning 10 years postconflict in the same population as the study described above (Toomey et al., 2007). The measures assessed were based on those previously found to be different between the deployed and nondeployed groups in earlier studies of the same cohort; examples include measures of general intelligence, attention or executive functioning, motor ability, visuospatial processing, and verbal and visual memory. Further details can be found in Chapter 4. Kang and colleagues (2009) conducted a 10-year follow-up general health assessment using the population of the National Health Survey of Gulf War Veterans and Their Families (15,000 Gulf War deployed and 15,000 nondeployed). In phase I of the follow-up, VA and Social Security records through December 2002 were used to identify and mail health questionnaires to the 29,607 living participants. Phase II consisted of telephone interviews with 2000 nonresponsive participants and a sample of 1000 participants who had indicated a clinic visit or hospitalization within the previous 12 months in order to obtain permission for medical record retrieval. After phases I and II, 6111 (40%) deployed and 3859 (27%) nondeployed participants responded to the survey; overall response rate was low, only 34%. The administered questionnaire was a modified version of that used in the 1995 survey and included the Psychopathy Check List (PCL), the Patient Health Questionnaire (PHQ), and the SF-122 in addition to other items used to assess general health status. See Chapter 4 for more details. 2 “The 12-Item Short Form Health Survey (SF-12) was developed for the Medical Outcomes Study, a multiyear study of patients with chronic conditions. The instrument was designed to reduce respondent burden while achieving minimum standards of precision for purposes of group comparisons involving multiple health dimensions” (RAND Corporation, 2010).

OCR for page 39
MAJOR COHORT STUDIES 49 The Iowa Persian Gulf Study In Volume 4, the Iowa Persian Gulf Study was presented as the reference study with eight derivative studies. The Update committee identified three new studies derived from the original Iowa cohort. Reference Study The Iowa study was a cross-sectional survey of a representative sample of 4886 military personnel who listed Iowa as their home of record at the time of enlistment and served between August 2, 1990, and July 31, 1991 (Iowa Persian Gulf Study Group, 1997). The DMDC identified 29,010 potentially eligible military personnel; 42 records were not included for a variety of reasons including incomplete data or duplicate records, leaving a representative sample of 28,968. Study subjects were divided into four groups: Gulf War-deployed active duty, Gulf War- deployed National Guard or reserve, Gulf War nondeployed active duty, and Gulf War nondeployed National Guard or reserve; samples were evenly selected from each of the four domains. A total of 4886 study subjects were randomly selected from the four groups; of the study subjects who were contacted, 3695 (76%) completed a telephone interview. Trained examiners used standardized questionnaires, instruments, and scales to collect information from the subjects. Sources of questions included the National Health Interview Survey, the Behavioral Risk Factor Surveillance Survey, the National Medical Expenditures Survey, the Primary Care Evaluation of Mental Disorders, the Brief Symptom Inventory, the CAGE questionnaire (for alcoholism),3 the PTSD (Posttraumatic Stress Disorder) Checklist—Military, the Centers for Disease Control and Prevention Chronic Fatigue Syndrome Questionnaire, the Chalder Fatigue Scale, the American Thoracic Society questionnaire, and the Sickness Impact Profile. The conditions listed were not diagnosed, because no clinical examinations were performed. Rather, before conducting their telephone survey, researchers grouped sets of symptoms from their symptom checklists into a priori categories of diseases or disorders. After a veteran identified himself or herself as having the requisite set of symptoms, researchers analyzing responses considered the veteran as having symptoms “suggestive” of or consistent with a particular disorder but not as having a formal diagnosis of the disorder. Gulf War veterans scored significantly lower on all eight subscales for physical and mental health on the SF-36. The subscales for bodily pain, general health, and vitality showed the greatest absolute differences between deployed and nondeployed veterans. The Iowa study assessed exposure–symptom relationships by asking veterans to report on their deployment exposures including to solvents or petrochemicals, smoke or combustion products, lead from fuels, pesticides, ionizing or nonionizing radiation, chemical warfare agents, PB use, infectious agents, and physical trauma. The authors concluded that no exposure to any single agent was related to the medical conditions found to be more prevalent in Gulf War veterans (Iowa Persian Gulf Study Group, 1997). 3 The CAGE is a four-item scale to assess cutting down (C), feeling annoyed by people criticizing your drinking (A), feeling guilty about drinking (G), and using alcohol as an eye-opener in the morning (E).

OCR for page 39
60 GULF WAR AND HEALTH surveyed, and respondents were asked to rate each on a scale of 0-2, (0 = no exposure; 1 = exposed; 2 = exposed and felt sick at the time). Using standardized regression, the authors found the strongest associations between musculoskeletal, neurologic, neuropsychologic, and psychologic symptoms and several exposures⎯debris from Scuds and chemical and biologic warfare agents. Findings from this study are discussed in Chapter 4. The health-related quality of life among the Fort Devens cohort (n = 141) and the Germany deployed cohort (n = 46) was evaluated by Proctor et al. (2001a). The SF-36 was administered to a stratified, random sample of the original cohort, approximately 4 years after the war. Proctor et al. (2001b) assessed 180 deployed veterans from the Fort Devens cohort and 46 Germany deployed veterans for symptoms of chronic fatigue and chemical sensitivity to assess the prevalence of the symptoms and whether there was an overlap between these symptoms and the case definition of chronic multisymptom illness. The Update committee identified one new derivative study. Proctor et al. (2006) assessed neurobehavioral functioning in relationship to potential exposure to sarin and cyclosarin as a result of the demolition of the Khamisiyah munitions dump. Data had been collected in 1994 to 1996, before veterans had been notified about their potential exposure to the nerve agents. The neurobehavioral tests included those for attention, executive function, psychomotor function, visuospatial abilities, and short-term memory. See Chapter 4 for further details. Seabee Studies Numerous studies have been conducted on the Seabees, members of the reserve naval construction battalions. Two reference studies were included in Volume 4. Haley et al. (1997b) began a study on one cohort of Seabees and Gray et al. (1999a) surveyed a subset of the Haley cohort that excluded Gulf War veterans who were no longer in the service at the time of their study. Three derivative studies for Haley et al. (1997b) are presented in Volume 4 along with two derivative studies for Gray et al. (1999a). The Update committee identified one new derivative study of the Haley et al. (1997b) cohort; none were identified for the Gray et al. (1999a) cohort. Reference Study Haley et al. (1997b) studied members of the Twenty-Fourth Reserve Naval Construction Battalion living in five southern states who were called to active duty for the Gulf War. More than half the battalion had left the military by the time of the study. Participants were recruited from those that investigators had addresses for and from veterans’ meetings; 58.0% (n = 606) were located, and 41.1% (n = 249) agreed to participate in the study; there was no comparison cohort of nondeployed veterans. Of those participating, 70% reported having had a serious health problem since returning from the Gulf War. A telephone survey of a random sample of nonparticipants found that, while they were demographically similar to participants, 43% reported having serious health problems since the war. Eleven percent of participants and 3% of nonparticipants were unemployed. Derivative Studies The three syndromes identified by Haley and colleagues (1997a) were the focus of another case-control study that examined their relationship to self-reported exposures to neurotoxicants. The study tested the hypothesis that exposure to organophosphates and related

OCR for page 39
MAJOR COHORT STUDIES 61 chemicals that inhibit cholinesterase are responsible for the three nervous system-based syndromes (Haley and Kurt, 1997). Results of this study are discussed in Appendix A. Another study by Haley and collaborators (1999) examined whether genetic susceptibility could play a role in placing some veterans at risk for neurologic damage by organophosphate chemicals. The investigators studied 45 veterans: 25 with chronic neurologic symptoms identified through their earlier factor analysis study and 20 healthy controls from the same battalion. Investigators measured blood butyrylcholinesterase and two types, or allozymes, of paraoxonase/arylesterase-1 (PON1). The genotypes encoding the allozymes were also studied. Results of this study are also discussed in Appendix A. The Update committee identified one new study by Haley et al. (2009) that looked at abnormal brain response to cholinergic challenge in a small group of Gulf War veterans. Twenty-one Gulf War veterans with symptom complexes used by Haley to define three forms of Gulf War illness and 17 age-, sex- and education-matched controls, underwent a 99mTc- HMPAO-SPECT brain scan with and without an infusion of PB. Reference Study The first in a series of studies by Gray et al. (1999) surveyed Seabees who remained on active duty for at least 3 years after the Gulf War. The Seabees were from 14 commands at two locations (Port Hueneme, California, and Gulfport, Mississippi). Those who were deployed to the Gulf War were in mobile construction battalions serving in the same tasks and at the same sites as did the reserve Seabee battalion studied by Haley et al. (1997b), Gray et al. (1999) excluded Gulf War veterans who were no longer on active duty at the time of study. In 1994, 1497 study subjects were enrolled: 527 Gulf War veterans and 970 nondeployed veterans. The participation rate of eligible Seabees was 53%. The following were administered to the study participants: eight-page questionnaire regarding medical history, Gulf War exposures, postwar symptoms, hospitalization, and pregnancy outcomes; questions regarding the presence of chronic fatigue syndrome and PTSD; laboratory testing—sera, blood, urine; and pulmonary function and handgrip strength tests. Findings of this study can be found in Chapter 4. Derivative Studies Beginning in May 1997, Gray et al. (2002) distributed a postal questionnaire to all regular and reserve navy personnel (n = 18,945) who served on active-duty Seabee command during the Gulf War period. The questionnaire collected information regarding medical history, current health status, symptoms, and environmental exposures (for example, PB). Of the 17,559 located participants, 11,868 completed and returned the survey: 3831 Gulf War deployed, 4933 deployed elsewhere, and 4933 nondeployed. Compared with the two control groups, the deployed were more likely to report having more symptoms and being in fair or poor health. Outcome specific results are found in Chapter 4. Knoke et al. (2000) used the same Seabee cohort to conduct a factor analysis of the symptoms reported by the veterans on the Hopkins Symptom Checklist to determine whether there was a unique Gulf War syndrome.

OCR for page 39
62 GULF WAR AND HEALTH Pennsylvania Air National Guard Study Reference Study In response to requests from the DoD, the VA, and the Commonwealth of Pennsylvania, Fukuda and colleagues (1998) conducted a factor analysis study in 1995 to assess health status and prevalence and causes of an unexplained illness in Gulf War deployed and nondeployed members of a currently active Air National Guard unit (n = 667). Three demographically similar air force units were used as comparison groups (n = 538, 838, and 1680). Questionnaires regarding military characteristics, demographics, health status, and 35 specific symptoms previously identified to be of concern were distributed and completed by 3723 participants (1163 Gulf War deployed, 2560 nondeployed). Participation rates were as follows: 62% index unit; 35% unit A; 73% unit B; and 70% unit C. To assess symptom prevalence, investigators combined the four units and compared questionnaire responses of deployed and nondeployed. The authors further studied health outcomes in a subset of participants from the index unit of the Pennsylvania Air Force National Guard. Of the 490 (45%) deployed members of this unit, 173 (35%) volunteered to participate in the clinical evaluation and completed a mailed clinical questionnaire and the SF-36. This study is discussed in Chapter 4. Derivative Studies A nested case-control study of the same cohort (n = 1002) sought to identify self-reported exposures associated with cases of chronic multisymptom illness (Nisenbaum et al., 2000). Results indicate that meeting the case definition of severe and mild-to-moderate illness was associated with use of PB, use of insect repellent, and belief in a threat from biologic or chemical weapons. Having an injury requiring medical attention was also associated with having a severe case of chronic multisymptom illness. Nisenbaum et al. (2004) conducted a factor analysis of the symptoms reported by the UK Gulf War veterans combined with those reported by the Pennsylvania Air Force veterans. Further details from these studies are discussed in Chapter 4. Hawaii and Pennsylvania Active Duty and Reserve Study Reference Study One of the first epidemiologic studies of US Gulf War veterans was a congressionally mandated study evaluating the psychologic and physical health of active-duty and reserve army, navy, air force, and marine personnel from bases in Pennsylvania and Hawaii (Stretch et al., 1995). Self-reported questionnaires were mailed to 16,167 potential study participants and inquired about the following: demographics; physical, psychological, and psychosocial symptoms; deployment type; and perceived sources of stress prior to, during, and after combat or deployment. A total of 4334 veterans returned the questionnaires for a response rate of 31%. Of those, 715 active duty and 766 reserves were deployed to the Gulf War; 1576 active duty and 948 reserves were not deployed. Findings are discussed in Chapter 4. Derivative Studies Two derivative studies of Stretch et al. (1995) were identified. In response to a questionnaire, deployed veterans commonly reported significant levels of stress during deployment, including operating in desert climates, long duty days, extended periods in

OCR for page 39
MAJOR COHORT STUDIES 63 chemical-protective clothing, lack of sleep, crowding, lack of private time, physical workload, and boredom. Significant levels of stress continued postdeployment (Stretch et al., 1996a). Another publication examined PTSD in this cohort (Stretch et al., 1996b). The prevalence of PTSD symptoms was measured by the Impact of Event Scale and the Brief Symptom Inventory. New Orleans Reservist Studies Reference Study A study by Sutker et al. (1995) and colleagues analyzed psychologic outcomes in a cohort of New Orleans reservists (n = 1520). The cohort consisted of Louisiana National Guard and reservists from the army, air force, and navy who had been deployed to combat. Of the 1272 who responded (overall response rate of 83.7%), 876 had been deployed and 396 had not been deployed. A discriminant function model was used to assess the relationship between personal and environmental resources and psychological outcomes. Low personality hardiness, high avoidance coping, and low perceived family cohesion were the personality and coping factors found to increase the likelihood of PTSD (Sutker et al., 1995). Derivative Studies One derivative study of Sutker et al. (1995) was identified. Assessed by survey at an average of 9 months (time 1) after the war, veterans completed the Beck Depression Inventory, the Brief Symptom Inventory for Anxiety and Depression, the PTSD checklist, and the Mississippi Scale for PTSD (Brailey et al., 1998). See Chapter 4 for more detail. REFERENCES Ang, D. C., P. M. Peloso, R. F. Woolson, K. Kroenke, and B. N. Doebbeling. 2006. Predictors of incident chronic widespread pain among veterans following the first Gulf War. Clinical Journal of Pain 22(6):554-563. Barrett, D. H., C. C. Doebbeling, D. A. Schwartz, M. D. Voelker, K. H. Falter, R. F. Woolson, and B. N. Doebbeling. 2002. Posttraumatic stress disorder and self-reported physical health status among U.S. Military personnel serving during the gulf war period: A population-based study. Psychosomatics 43(3):195-205. Black, D. W., B. N. Doebbeling, M. D. Voelker, W. R. Clarke, R. F. Woolson, D. H. Barrett, and D. A. Schwartz. 1999. Quality of life and health-services utilization in a population-based sample of military personnel reporting multiple chemical sensitivities. Journal of Occupational and Environmental Medicine 41(10):928-933. Black, D. W., B. N. Doebbeling, M. D. Voelker, W. R. Clarke, R. F. Woolson, D. H. Barrett, and D. A. Schwartz. 2000. Multiple chemical sensitivity syndrome: Symptom prevalence and risk factors in a military population. Archives of Internal Medicine 160(8):1169-1176. Black, D. W., C. P. Carney, V. L. Forman-Hoffman, E. Letuchy, P. Peloso, R. F. Woolson, and B. N. Doebbeling. 2004a. Depression in veterans of the first Gulf War and comparable military controls. Annals of Clinical Psychiatry 16(2):53-61.

OCR for page 39
64 GULF WAR AND HEALTH Black, D. W., C. P. Carney, P. M. Peloso, R. F. Woolson, D. A. Schwartz, M. D. Voelker, D. H. Barrett, and B. N. Doebbeling. 2004b. Gulf War veterans with anxiety: Prevalence, comorbidity, and risk factors. Epidemiology 15(2):135-142. Black, D. W., N. Blum, E. Letuchy, C. Carney Doebbeling, V. L. Forman-Hoffman, and B. N. Doebbeling. 2006. Borderline personality disorder and traits in veterans: Psychiatric comorbidity, healthcare utilization, and quality of life along a continuum of severity. CNS Spectrums 11(9):680-689; quiz 719. Blanchard, M. S., S. A. Eisen, R. Alpern, J. Karlinsky, R. Toomey, D. J. Reda, F. M. Murphy, L. W. Jackson, and H. K. Kang. 2005. Chronic multisymptom illness complex in Gulf War I veterans 10 years later. American Journal of Epidemiology 163(1):66-75. Bourdette, D. N., L. A. McCauley, A. Barkhuizen, W. Johnston, M. Wynn, S. K. Joos, D. Storzbach, T. Shuell, and D. Sticker. 2001. Symptom factor analysis, clinical findings, and functional status in a population-based case control study of Gulf War unexplained illness. Journal of Occupational and Environmental Medicine 43(12):1026-1040. Brailey, K., J. J. Vasterling, and P. B. Sutker. 1998. Psychological aftermath of participation in the Persian Gulf War. In The Environment and Mental Health: A Guide for Clinicians, edited by A. Lundberg. London, UK: Lawrence Erlbaum Associates. Pp. 83-101. Cherry, N., F. Creed, A. Silman, G. Dunn, D. Baxter, J. Smedley, S. Taylor, and G. J. Macfarlane. 2001a. Health and exposures of United Kingdom Gulf War veterans. Part I: The pattern and extent of ill health. Occupational and Environmental Medicine 58(5):291-298. Cherry, N., F. Creed, A. Silman, G. Dunn, D. Baxter, J. Smedley, S. Taylor, and G. J. Macfarlane. 2001b. Health and exposures of United Kingdom Gulf War veterans. Part II: The relation of health to exposure. Occupational and Environmental Medicine 58(5):299-306. Davis, L. E., S. A. Eisen, F. M. Murphy, R. Alpern, B. J. Parks, M. Blanchard, D. J. Reda, M. K. King, F. A. Mithen, and H. K. Kang. 2004. Clinical and laboratory assessment of distal peripheral nerves in Gulf War veterans and spouses. Neurology 63(6):1070-1077. Doebbeling, B. N., W. R. Clarke, D. Watson, J. C. Torner, R. F. Woolson, M. D. Voelker, D. H. Barrett, and D. A. Schwartz. 2000. Is there a Persian Gulf War syndrome? Evidence from a large population-based survey of veterans and nondeployed controls. American Journal of Medicine 108(9):695-704. Doyle, P., N. Maconochie, G. Davies, I. Maconochie, M. Pelerin, S. Prior, and S. Lewis. 2004. Miscarriage, stillbirth and congenital malformation in the offspring of UK veterans of the first Gulf War. International Journal of Epidemiology 33(1):74-86. Eisen, S. A., H. K. Kang, F. M. Murphy, M. S. Blanchard, D. J. Reda, W. G. Henderson, R. Toomey, L. W. Jackson, R. Alpern, B. J. Parks, N. Klimas, C. Hall, H. S. Pak, J. Hunter, J. Karlinsky, M. J. Battistone, M. J. Lyons, and Gulf War Study Participating Investigators. 2005. Gulf War veterans' health: Medical evaluation of a U.S. cohort. Annals of Internal Medicine 142(11):881-890. Forbes, A. B., D. P. McKenzie, A. J. Mackinnon, H. L. Kelsall, A. C. McFarlane, J. F. Ikin, D. C. Glass, and M. R. Sim. 2004. The health of Australian veterans of the 1991 Gulf War: Factor analysis of self-reported symptoms. Occupational and Environmental Medicine 61(12):1014-1020.

OCR for page 39
MAJOR COHORT STUDIES 65 Forman-Hoffman, V. L., P. M. Peloso, D. W. Black, R. F. Woolson, E. M. Letuchy, and B. N. Doebbeling. 2007. Chronic widespread pain in veterans of the first Gulf War: Impact of deployment status and associated health effects. Journal of Pain 8(12):954-961. Fricker, R. D., E. Reardon, D. M. Spektor, S. K. Cotton, J. Hawes-Dawson, J. E. Pace, and S. D. Hosek. 2000. Pesticide Use During the Gulf War: A Survey of Gulf War Veterans. Santa Monica, CA: RAND Corporation. Fukuda, K., R. Nisenbaum, G. Stewart, W. W. Thompson, L. Robin, R. M. Washko, D. L. Noah, D. H. Barrett, B. Randall, B. L. Herwaldt, A. C. Mawle, and W. C. Reeves. 1998. Chronic multisymptom illness affecting Air Force veterans of the Gulf War. JAMA 280(11):981-988. Goss Gilroy Inc. 1998. Health study of Canadian forces personnel involved in the 1991 conflict in the Persian Gulf. Ottawa, Canada: Goss Gilroy Inc. and Department of National Defence. Gray, G. C., K. S. Kaiser, A. W. Hawksworth, F. W. Hall, and E. Barrett-Connor. 1999. Increased postwar symptoms and psychological morbidity among U.S. Navy Gulf War veterans. American Journal of Tropical Medicine and Hygiene 60(5):758-766. Gray, G. C., R. J. Reed, K. S. Kaiser, T. C. Smith, and V. M. Gastanaga. 2002. Self-reported symptoms and medical conditions among 11,868 Gulf War-era veterans: The Seabee Health Study. American Journal of Epidemiology 155(11):1033-1044. Haley, R. W., and T. L. Kurt. 1997. Self-reported exposure to neurotoxic chemical combinations in the Gulf War: A cross-sectional epidemiologic study. JAMA 277(3):231-237. Haley, R. W., J. Hom, P. S. Roland, W. W. Bryan, P. C. Van Ness, F. J. Bonte, M. D. S. Devous, D. Mathews, J. L. Fleckenstein, F. H. J. Wians, G. I. Wolfe, and T. L. Kurt. 1997a. Evaluation of neurologic function in Gulf War veterans. A blinded case-control study. JAMA 277(3):223-230. Haley, R. W., T. L. Kurt, and J. Hom. 1997b. Is there a Gulf War syndrome? Searching for syndromes by factor analysis of symptoms. JAMA 277(3):215-222. Haley, R. W., S. Billecke, and B. N. La Du. 1999. Association of low PON1 type Q (type A) arylesterase activity with neurologic symptom complexes in Gulf War veterans. Toxicology and Applied Pharmacology 157(3):227-233. Haley, R. W., J. S. Spence, P. S. Carmack, R. F. Gunst, W. R. Schucany, F. Petty, M. D. Devous, Sr., F. J. Bonte, and M. H. Trivedi. 2009. Abnormal brain response to cholinergic challenge in chronic encephalopathy from the 1991 Gulf War. Psychiatry Research: Neuroimaging 171(3):207-220. Hotopf, M., A. S. David, L. Hull, V. Nikalaou, C. Unwin, and S. Wessely. 2003a. Gulf War illness—Better, worse, or just the same? A cohort study. British Medical Journal 327(7428):1370-1372. Hotopf, M., M. I. Mackness, V. Nikolaou, D. A. Collier, C. Curtis, A. David, P. Durrington, L. Hull, K. Ismail, M. Peakman, C. Unwin, S. Wessely, and B. Mackness. 2003b. Paraoxonase in Persian Gulf War veterans. Journal of Occupational and Environmental Medicine 45(7):668-675. Ikin, J. F., M. R. Sim, M. C. Creamer, A. B. Forbes, D. P. McKenzie, H. L. Kelsall, D. C. Glass, A. C. McFarlane, M. J. Abramson, P. Ittak, T. Dwyer, L. Blizzard, K. R. Delaney, K. W. A. Horsley, W. K. Harrex, and H. Schwarz. 2004. War-related psychological stressors and risk of psychological disorders in Australian veterans of the 1991 Gulf War. British Journal of Psychiatry 185(2):116-126.

OCR for page 39
66 GULF WAR AND HEALTH Ikin, J. F., D. P. McKenzie, M. C. Creamer, A. C. McFarlane, H. L. Kelsall, D. C. Glass, A. B. Forbes, K. W. A. Horsley, W. K. Harrex, and M. R. Sim. 2005. War zone stress without direct combat: The Australian naval experience of the Gulf War. Journal of Traumatic Stress 18(3):193-204. IOM (Institute of Medicine). 1999. Strategies to Protect the Health of Deployed US Forces: Medical Surveillance, Record Keeping, and Risk Reduction. Washington, DC: National Academy Press. Iowa Persian Gulf Study Group. 1997. Self-reported illness and health status among Gulf War veterans: A population-based study. JAMA 277(3):238-245. Ishoy, T., P. Suadicani, B. Guldager, M. Appleyard, and F. Gyntelberg. 1999a. Risk factors for gastrointestinal symptoms. The Danish Gulf War Study. Danish Medical Bulletin 46(5):420- 423. Ishoy, T., P. Suadicani, B. Guldager, M. Appleyard, H. O. Hein, and F. Gyntelberg. 1999b. State of health after deployment in the Persian Gulf. The Danish Gulf War Study. Danish Medical Bulletin 46(5):416-419. Ishoy, T., A. M. Andersson, P. Suadicani, B. Guldager, M. Appleyard, F. Gyntelberg, and N. E. Skakkebaek. 2001a. Major reproductive health characteristics in male Gulf War veterans. The Danish Gulf War Study. Danish Medical Bulletin 48(1):29-32. Ishoy, T., P. Suadicani, A.-M. Andersson, B. Guldager, M. Appleyard, N. Skakkebaek, and F. Gyntelberg. 2001b. Prevalence of male sexual problems in the Danish Gulf War Study. Scandinavian Journal of Sexology 4(1):43-55. Ismail, K., K. Kent, R. Sherwood, L. Hull, P. Seed, A. S. David, and S. Wessely. 2008. Chronic fatigue syndrome and related disorders in UK veterans of the Gulf War 1990-1991: Results from a two-phase cohort study. Psychological Medicine 38(7):953-961. Kang, H. K., and T. A. Bullman. 2001. Mortality among US veterans of the Persian Gulf War: 7- year follow-up. American Journal of Epidemiology 154(5):399-405. Kang, H. K., C. M. Mahan, K. Y. Lee, C. A. Magee, and F. M. Murphy. 2000. Illnesses among United States veterans of the Gulf War: A population-based survey of 30,000 veterans. Journal of Occupational and Environmental Medicine 42(5):491-501. Kang, H., C. Magee, C. Mahan, K. Lee, F. Murphy, L. Jackson, and G. Matanoski. 2001. Pregnancy outcomes among U.S. Gulf War veterans: A population-based survey of 30,000 veterans. Annals of Epidemiology. 11(7):504-511. Kang, H. K., C. M. Mahan, K. Y. Lee, F. M. Murphy, S. J. Simmens, H. A. Young, and P. H. Levine. 2002. Evidence for a deployment-related Gulf War syndrome by factor analysis. Archives of Environmental Health 57(1):61-68. Kang, H. K., B. H. Natelson, C. M. Mahan, K. Y. Lee, and F. M. Murphy. 2003. Post-traumatic stress disorder and chronic fatigue syndrome-like illness among Gulf War veterans: A population-based survey of 30,000 veterans. American Journal of Epidemiology 157(2):141- 148. Kang, H., N. Dalager, C. Mahan, and E. Ishii. 2005. The role of sexual assault on the risk of PTSD among Gulf War veterans. Annals of Epidemiology 15(3):191-195.

OCR for page 39
MAJOR COHORT STUDIES 67 Kang, H. K., B. Li, C. M. Mahan, S. A. Eisen, and C. C. Engel. 2009. Health of U.S. veterans of 1991 Gulf War: A follow-up survey in 10 years. Journal of Occupational and Environmental Medicine 51(4):401-410. Karlinsky, J. B., M. Blanchard, R. Alpern, S. A. Eisen, H. Kang, F. M. Murphy, and D. J. Reda. 2004. Late prevalence of respiratory symptoms and pulmonary function abnormalities in Gulf War I veterans. Archives of Internal Medicine 164(22):2488-2491. Kelsall, H. L., M. R. Sim, A. B. Forbes, D. C. Glass, D. P. McKenzie, J. F. Ikin, M. J. Abramson, L. Blizzard, and P. Ittak. 2004a. Symptoms and medical conditions in Australian veterans of the 1991 Gulf War: Relation to immunisations and other Gulf War exposures. Occupational and Environmental Medicine 61(12):1006-1013. Kelsall, H. L., M. R. Sim, A. B. Forbes, D. P. McKenzie, D. C. Glass, J. F. Ikin, P. Ittak, and M. J. Abramson. 2004b. Respiratory health status of Australian veterans of the 1991 Gulf War and the effects of exposure to oil fire smoke and dust storms. Thorax 59(10):897-903. Kelsall, H., R. Macdonell, M. Sim, A. Forbes, D. McKenzie, D. Glass, J. Ikin, and P. Ittak. 2005. Neurological status of Australian veterans of the 1991 Gulf War and the effect of medical and chemical exposures. International Journal of Epidemiology 34(4):810-819. Kelsall, H., M. Sim, D. McKenzie, A. Forbes, K. Leder, D. Glass, J. Ikin, and A. McFarlane. 2006. Medically evaluated psychological and physical health of Australian Gulf War veterans with chronic fatigue. Journal of Psychosomatic Research 60(6):575-584. Kelsall, H. L., M. R. Sim, J. F. Ikin, A. B. Forbes, D. P. McKenzie, D. C. Glass, and P. Ittak. 2007. Reproductive health of male Australian veterans of the 1991 Gulf War. BMC Public Health 7:79. Knoke, J. D., T. C. Smith, G. C. Gray, K. S. Kaiser, and A. W. Hawksworth. 2000. Factor analysis of self-reported symptoms: Does it identify a Gulf War syndrome? American Journal of Epidemiology 152(4):379-388. Lange, J. L., D. A. Schwartz, B. N. Doebbeling, J. M. Heller, and P. S. Thorne. 2002. Exposures to the Kuwait oil fires and their association with asthma and bronchitis among gulf war veterans. Environmental Health Perspectives 110(11):1141-1146. Macfarlane, G. J., E. Thomas, and N. Cherry. 2000. Mortality among UK Gulf War veterans. Lancet 356(9223):17-21. Macfarlane, G. J., A.-M. Biggs, N. Maconochie, M. Hotopf, P. Doyle, and M. Lunt. 2003. Incidence of cancer among UK Gulf War veterans: Cohort study. British Medical Journal 327(7428):1373-1375. Macfarlane, G. J., M. Hotopf, N. Maconochie, N. Blatchley, A. Richards, and M. Lunt. 2005. Long-term mortality amongst Gulf War Veterans: Is there a relationship with experiences during deployment and subsequent morbidity? International Journal of Epidemiology 34(6):1403-1408. Maconochie, N., P. Doyle, G. Davies, S. Lewis, M. Pelerin, S. Prior, and P. Sampson. 2003. The study of reproductive outcome and the health of offspring of UK veterans of the Gulf War: Methods and description of the study population. BMC Public Health 3(1):4. Maconochie, N., P. Doyle, and C. Carson. 2004. Infertility among male UK veterans of the 1990-1 Gulf War: Reproductive cohort study. British Medical Journal 329(7459):196-201.

OCR for page 39
68 GULF WAR AND HEALTH McCauley, L. A., S. K. Joos, M. R. Lasarev, D. Storzbach, and D. N. Bourdette. 1999a. Gulf War unexplained illnesses: Persistence and unexplained nature of self-reported symptoms. Environmental Research 81(3):215-223. McCauley, L. A., S. K. Joos, P. S. Spencer, M. Lasarev, and T. Shuell. 1999b. Strategies to assess validity of self-reported exposures during the Persian Gulf War. Environmental Research 81(3):195-205. McKenzie, D. P., J. F. Ikin, A. C. McFarlane, M. Creamer, A. B. Forbes, H. L. Kelsall, D. C. Glass, P. Ittak, and M. R. Sim. 2004. Psychological health of Australian veterans of the 1991 Gulf War: An assessment using the SF-12, GHQ-12 and PCL-S. Psychological Medicine 34(8):1419-1430. Nisenbaum, R., D. H. Barrett, M. Reyes, and W. C. Reeves. 2000. Deployment stressors and a chronic multisymptom illness among Gulf War veterans. Journal of Nervous and Mental Disease 188(5):259-266. Nisenbaum, R., K. Ismail, S., Wessely, C. Unwin, L. Hull, and W. C. Reeves. 2004. Dichotomous factor analysis of symptoms reported by UK and US veterans of the 1991 Gulf War. Population Health Metrics 2(1):8. NRC (National Research Council). 2000a. Strategies to Protect the Health of Deployed US Forces: Analytical Framework for Assessing Risks. Washington, DC: National Academy Press. NRC. 2000b. Strategies to Protect the Health of Deployed US Forces: Detecting, Characterizing, and Documenting Exposures. Washington, DC: National Academy Press. NRC. 2000c. Strategies to Protect the Health of Deployed US Forces: Force Protection and Decontamination. Washington, DC: National Academy Press. Page, W. F., C. M. Mahan, T. A. Bullman, and H. K. Kang. 2005a. Health effects in Army Gulf War veterans possibly exposed to chemical munitions destruction at Khamisiyah, Iraq: Part I. Morbidity associated with potential exposure. Military Medicine 170(11):935-944. Page, W. F., C. M. Mahan, H. K. Kang, and T. A. Bullman. 2005b. Health effects in Army Gulf War veterans possibly exposed to chemical munitions destruction at Khamisiyah, Iraq: Part II. Morbidity associated with notification of potential exposure. Military Medicine 170(11):945-951. Phillips, C. J., G. R. Matyas, C. J. Hansen, C. R. Alving, T. C. Smith, and M. A. K. Ryan. 2009. Antibodies to squalene in US Navy Persian Gulf War veterans with chronic multisymptom illness. Vaccine 27(29):3921-3926. Proctor, S. P., T. Heeren, R. F. White, J. Wolfe, M. S. Borgos, J. D. Davis, L. Pepper, R. Clapp, P. B. Sutker, J. J. Vasterling, and D. Ozonoff. 1998. Health status of Persian Gulf War veterans: Self-reported symptoms, environmental exposures and the effect of stress. International Journal of Epidemiology 27(6):1000-1010. Proctor, S. P., R. Harley, J. Wolfe, T. Heeren, and R. F. White. 2001a. Health-related quality of life in Persian Gulf War veterans. Military Medicine 166(6):510-519. Proctor, S. P., K. J. Heaton, R. F. White, and J. Wolfe. 2001b. Chemical sensitivity and chronic fatigue in Gulf War veterans: A brief report. Journal of Occupational and Environmental Medicine 43(3):259-264.

OCR for page 39
MAJOR COHORT STUDIES 69 Proctor, S. P., R. F. White, T. Heeren, F. Debes, B. Gloerfelt-Tarp, M. Appleyard, T. Ishoy, B. Guldager, P. Suadicani, F. Gyntelberg, and D. M. Ozonoff. 2003. Neuropsychological functioning in Danish Gulf War veterans. Journal of Psychopathology and Behavioral Assessment 25(2):85-93. Proctor, S. P., K. J. Heaton, T. Heeren, and R. F. White. 2006. Effects of sarin and cyclosarin exposure during the 1991 Gulf War on neurobehavioral functioning in US Army veterans. Neurotoxicology 27(6):931-939. RAND Corporation. 2010. 12-Item Short Form Health Survey (SF-12). http://www.rand.org/health/surveys_tools/mos/mos_core_12item.html (accessed January 5, 2010). Reid, S., M. Hotopf, L. Hull, K. Ismail, C. Unwin, and S. Wessely. 2001. Multiple chemical sensitivity and chronic fatigue syndrome in British Gulf War veterans. American Journal of Epidemiology 153(6):604-609. Rose, M. R., M. K. Sharief, J. Priddin, V. Nikolaou, L. Hull, C. Unwin, R. Ajmal-Ali, R. A. Sherwood, A. Spellman, A. David, and S. Wessely. 2004. Evaluation of neuromuscular symptoms in UK Gulf War veterans: A controlled study. Neurology 63(9):1681-1687. Sharief, M. K., J. Priddin, R. S. Delamont, C. Unwin, M. R. Rose, A. David, and S. Wessely. 2002. Neurophysiologic analysis of neuromuscular symptoms in UK Gulf War veterans: A controlled study. Neurology 59(10):1518-1525. Sim, M., M. Abramson, P. A. Forbes, D. Glass, J. Ikin, P. Ittak, H. Kelsall, K. Leder, D. McKenzie, and J. McNeil. 2003. Australian Gulf War Veterans' Health Study. Canberra, Australia: Department of Veterans’ Affairs. Simmons, R., N. Maconochie, and P. Doyle. 2004. Self-reported ill health in male UK Gulf War veterans: A retrospective cohort study. BMC Public Health 4(1):27. Spencer, P. S., L. A. McCauley, J. A. Lapidus, M. Lasarev, S. K. Joos, and D. Storzbach. 2001. Self-reported exposures and their association with unexplained illness in a population-based case-control study of Gulf War veterans. Journal of Occupational and Environmental Medicine 43(12):1041-1056. Statistics Canada. 2005. The Canadian Persian Gulf Cohort Study: Detailed Report. Ottawa, Ontario: Minister of Industry. Steele, L. 2000. Prevalence and patterns of Gulf War illness in Kansas veterans: Association of symptoms with characteristics of person, place, and time of military service. American Journal of Epidemiology 152(10):992-1002. Stimpson, N. J., C. Unwin, L. Hull, T. David, S. Wessely, and G. Lewis. 2006. Prevalence of reported pain, widespread pain, and pain symmetry in veterans of the Persian Gulf War (1990-1991): The use of pain manikins in Persian Gulf War health research. Military Medicine 171(12):1181-1186. Stretch, R. H., P. D. Bliese, D. H. Marlowe, K. M. Wright, K. H. Knudson, and C. H. Hoover. 1995. Physical health symptomatology of Gulf War-era service personnel from the states of Pennsylvania and Hawaii. Military Medicine 160(3):131-136. Stretch, R. H., P. D. Bliese, D. H. Marlowe, K. M. Wright, K. H. Knudson, and C. H. Hoover. 1996a. Psychological health of Gulf War-era military personnel. Military Medicine 161(5):257-261.

OCR for page 39
70 GULF WAR AND HEALTH Stretch, R. H., D. H. Marlowe, K. M. Wright, P. D. Bliese, K. H. Knudson, and C. H. Hoover. 1996b. Post-traumatic stress disorder symptoms among Gulf War veterans. Military Medicine 161(7):407-410. Suadicani, P., T. Ishoy, B. Guldager, M. Appleyard, and F. Gyntelberg. 1999. Determinants of long-term neuropsychological symptoms. Danish Medical Bulletin 46(5):423-427. Sutker, P. B., J. M. Davis, M. Uddo, and S. R. Ditta. 1995. War zone stress, personal resources, and PTSD in Persian Gulf War returnees. Journal of Abnormal Psychology 104(3):444-452. Toomey, R., H. K. Kang, J. Karlinsky, D. G. Baker, J. J. Vasterling, R. Alpern, D. J. Reda, W. G. Henderson, F. M. Murphy, and S. A. Eisen. 2007. Mental health of US Gulf War veterans 10 years after the war. British Journal of Psychiatry 190:385-393. Toomey, R., R. Alpern, J. J. Vasterling, D. G. Baker, D. J. Reda, M. J. Lyons, W. G. Henderson, H. K. Kang, S. A. Eisen, and F. M. Murphy. 2009. Neuropsychological functioning of US Gulf War veterans 10 years after the war. Journal of the International Neuropsychological Society 15(5):717-729. United Kingdom Ministry of Defence. 2000. Background to the Use of Medical Countermeasures to Protect British Forces During the Gulf War (Operation Granby). http://www.mod.uk/issues/gulfwar/info/medical/ukchemical.htm (accessed September 26, 2003). Unwin, C., N. Blatchley, W. Coker, S. Ferry, M. Hotopf, L. Hull, K. Ismail, I. Palmer, A. David, and S. Wessely. 1999. Health of UK servicemen who served in Persian Gulf War. Lancet 353(9148):169-178. White, R. F., S. P. Proctor, T. Heeren, J. Wolfe, M. Krengel, J. Vasterling, K. Lindem, K. J. Heaton, P. Sutker, and D. M. Ozonoff. 2001. Neuropsychological function in Gulf War veterans: Relationships to self-reported toxicant exposures. American Journal of Industrial Medicine 40(1):42-54.