3

STUDIES OF SYMPTOMS IN GULF WAR VETERANS

This chapter provides an overview of the cohorts that were assembled to study the symptoms of the 1990–1991 Gulf War veterans. It discusses the limitations of the studies and summarizes the finding of each. Some of the cohorts were brought together in the first few years after the Gulf War; others were assembled later. Most of the studies compare sizable groups of deployed veterans with groups of veterans who were not deployed during the period of the Gulf War (often referred to as era veterans) or who were deployed to locations other than the Persian Gulf (for example, Bosnia) during the period (referred to as deployed elsewhere). In addition, a number of volunteer registries were assembled by the US Department of Defense (DOD) and Department of Veterans Affairs (VA) and by other governments whose forces were included in the Gulf War coalition. All those groups constitute the major cohorts that are described in this chapter.

The chapter’s focus on symptom studies, rather than on studies of well-characterized diagnosed medical and psychiatric conditions, provides the foundation for the committee’s understanding of the symptomatology experienced by the Gulf War veterans. Some of the authors have conducted factor analyses or proposed case definitions, and those studies are discussed in Chapters 4 and 5.

The chapter begins with a discussion of the limitations seen throughout the studies, which is followed by a description of the cohorts assembled after the Gulf War. The studies detail the symptoms found in the Gulf War veterans. They are organized by a key feature of the studies’ design: how the study populations were defined. Three categories of studies were identified—population-based, military-unit–based, and registry-based. The discussion of each study includes a summary of its methods and its major findings pertaining to reported symptoms. Table 3.1, summarizing all the studies reviewed, is at the end of the chapter.

GENERAL LIMITATIONS OF GULF WAR STUDIES

The cohort studies of Gulf War veterans and their derivatives have contributed greatly to our understanding of veterans’ health but are subject to limitations that are commonly encountered in observational epidemiologic studies. They include selection biases that limit the studies’ representativeness and generalizability



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3 STUDIES OF SYMPTOMS IN GULF WAR VETERANS This chapter provides an overview of the cohorts that were assembled to study the symptoms of the 1990–1991 Gulf War veterans. It discusses the limitations of the studies and summarizes the finding of each. Some of the cohorts were brought together in the first few years after the Gulf War; others were assembled later. Most of the studies compare sizable groups of deployed veterans with groups of veterans who were not deployed during the period of the Gulf War (often referred to as era veterans) or who were deployed to locations other than the Persian Gulf (for example, Bosnia) during the period (referred to as deployed elsewhere). In addition, a number of volunteer registries were assembled by the US Department of Defense (DOD) and Department of Veterans Affairs (VA) and by other governments whose forces were included in the Gulf War coalition. All those groups constitute the major cohorts that are described in this chapter. The chapter’s focus on symptom studies, rather than on studies of well-characterized diagnosed medical and psychiatric conditions, provides the foundation for the committee’s understanding of the symptomatology experienced by the Gulf War veterans. Some of the authors have conducted factor analyses or proposed case definitions, and those studies are discussed in Chapters 4 and 5. The chapter begins with a discussion of the limitations seen throughout the studies, which is followed by a description of the cohorts assembled after the Gulf War. The studies detail the symptoms found in the Gulf War veterans. They are organized by a key feature of the studies’ design: how the study populations were defined. Three categories of studies were identified— population-based, military unit–based, and registry-based. The discussion of each study includes a summary of its methods and its major findings pertaining to reported symptoms. Table 3.1, summarizing all the studies reviewed, is at the end of the chapter. GENERAL LIMITATIONS OF GULF WAR STUDIES The cohort studies of Gulf War veterans and their derivatives have contributed greatly to our understanding of veterans’ health but are subject to limitations that are commonly encountered in observational epidemiologic studies. They include selection biases that limit the studies’ representativeness and generalizability to the larger veteran population; self-reporting of health outcomes and exposures, which is affected by recall bias; outcome misclassification; and 31

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32 CHRONIC MULTISYMPTOM ILLNESS IN GULF WAR VETERANS reporting bias.1 Box 3.1 briefly summarizes some of the general biases that affect this body of literature. Bias refers to the systematic, or nonrandom, tendency for an observed value to deviate from a true value because of flaws in study design and methods. A biased design may result in weakening an association, in strengthening an association, or in generating a spurious association. Because all studies are susceptible to bias, a primary goal of research design is to minimize bias or to adjust the observed value of an association by correcting for bias if its sources are known. There are two major types of bias: selection bias and information bias. Selection bias involves a systematic error—in how subjects are identified, recruited, included, or excluded or in how they participate in a study—that leads to a distortion of a true association. Information bias results from how data are collected and can result in measurement errors, imprecise measurement, and misclassification. Those biases may be uniform in an entire study population or may affect some subgroups of the population more than others. BOX 3.1 Common Medical-Research Biases That Affect Studies of Gulf War and Health Selection bias: Bias can result from selection of participants in such a way that they do not represent the target population or the probability of selection is related to exposure or disease status. This may be due to a poor definition of the eligible population or failure to obtain a random sample. Includes Nonresponse bias: Participants have a different exposure or disease status from nonparticipants. Volunteer bias: Participants who volunteer are more likely to have the exposure or disease of interest; this is a particular problem for registry studies that collect information on participants who enroll voluntarily. Healthy-warrior effect: Veterans or personnel who were deployed may be healthier than those who were not deployed or than civilians; selection of healthier people occurs at enlistment and separation (ill and injured personnel are more likely to leave the military). Information or measurement bias: Misclassification of participants’ exposure or disease status may be based on the information collected by various methods (such as a mailed questionnaire, a telephone interview, record review, or a medical examination). Includes Recall bias: The presence of disease influences participants’ reflection and perception of possible causes and can make them likely to report more exposures than or different exposures from nondiseased participants. Reporting bias: Participants are more likely to report responses that they perceive as favorable and to underreport undesirable responses. Temporal ambiguity: This occurs when it cannot be established that an exposure occurred before the onset of disease; it is common in cross-sectional assessments. Confounding: This occurs when a risk factor for the disease that is also related to the exposure creates a spurious exposure–disease association; in other words, a risk factor may cause the exposed and nonexposed participants to have different background disease risks. SOURCES: Delgado-Rodríguez and Llorca, 2004; Levenson et al., 1990; Pearce et al., 2006. 1 Biases previously described by the IOM (2006, 2010).

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STUDIES OF SYMPTOMS IN GULF WAR VETERANS 33 An important limitation is selection bias, which results in a lack of representativeness and limits one’s ability to generalize results to the entire population of interest; this is related to what is known as external validity. For example, six of the cohorts are made up of veterans that were selected according to where they served in the military (a military unit–based study) (Fukuda et al., 1998; Gray et al., 1999; Haley et al., 1997; Pierce, 1997; Proctor et al., 1998; Stretch et al., 1995). Military-unit studies are not representative of all Gulf War veterans with respect to their duties and locations during deployment, possible exposures, military status during the war (active duty, reserves, or National Guard), military status after the war (active duty, reserves, or discharged), branch of service (Army, Navy, Air Force, or Marine Corps), or ease of ascertainment (IOM, 1999). In population-based cohort studies, a sample or the entire defined population is selected for longitudinal study. Ideally, a population-based study starts prospectively with a cohort that is convened before the exposure or onset of symptoms. The study of a cohort, that is representative of a defined population offers several advantages. For example, it allows the estimation of distributions and prevalences of relevant variables in the reference population; risk-factor distributions measured at baseline in a study involving periodic examinations of the cohort can be compared with distributions in future cross-sectional samples to assess risk-factor trends over time; and a representative sample is the ideal setting in which to carry out unbiased evaluations of relationships not only of confounders to exposures and outcomes but also among any other variables of interest (Szklo, 1998). Some population-based studies of Gulf War veterans sample a cohort of veterans by contacting them where they live as opposed to where they seek treatment or where they serve in the military (for example, a particular base or a particular branch, such as the Air Force). Studies of military units or other military groups are less representative of the broader Gulf War veteran population than are population-based studies. Military unit–based studies are generalizable only to members of that unit and not to the broader veteran or military population Large population- based studies of Gulf War veterans have been conducted in each of the three major countries that participated in the Gulf War coalition: the United States, Canada, and the United Kingdom (Cherry et al., 2001; Goss Gilroy Inc., 1998; Kang et al., 2000; Unwin et al., 1999). Representativeness is also compromised when some demographic groups are underrepresented in the study sample, such as women. Some studies used methods to increase a sample’s representativeness by oversampling specific groups. For example, Kang et al. (2000) oversampled women and those serving in the National Guard and reserves, and this resulted in a study sample that was about 20% women, 25% National Guard, and 33% reservists. The controls were stratified by sex, unit, and branch of service to mirror the population of deployed veterans. A study’s representativeness, even if it is population-based, can be compromised by low participation or response rates, which may result in nonresponse bias. For example, Gulf War veterans who are symptomatic may choose to participate more frequently than those who are not symptomatic. Response rates in the studies discussed in this chapter are highly variable; they range from 92% (Steele, 2000; Wolfe et al., 1998) to 28% (Salamon et al., 2006). In some studies, researchers not only try to measure nonresponse bias by comparing participants with nonparticipants from both deployed and nondeployed populations but make adjustments to overcome it, for example, by oversampling nondeployed populations.

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34 CHRONIC MULTISYMPTOM ILLNESS IN GULF WAR VETERANS Quite different from population-based studies are ones that rely on voluntary participants to identify themselves, such as those who volunteer to participate in a registry. Registry studies may be subject to volunteer bias. They should be interpreted with caution inasmuch as registry participants are self-selected (sicker people are more likely to join) and not representative of the entire Gulf War veteran population. In addition, they often do not include a control group for comparison. Selection bias might also occur through the so-called healthy-warrior effect. That 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 in that chronically ill or less fit members of the armed forces might be less likely to have been deployed than more fit members. That is, there might have been nonrandom assignment of those selected and not selected for deployment. Some studies attempt to measure the potential for selection bias and adjust for it in the analysis. Other studies compare Gulf War deployed veterans with two or more groups, such as veterans deployed to other locations or missions (Hotopf and Wessely, 2005). Many issues can contribute to information bias or measurement bias and result in the misclassification of people as sick or healthy when they are not. Symptom self-reporting might sometimes introduce outcome misclassification, in which there are errors in how symptoms are classified into outcomes and analyzed. One Gulf War study sought to document outcome misclassification by comparing veterans’ symptom reporting on questionnaires with results of clinical examination about 3 months later (McCauley et al., 1999). The authors 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. Another study also found poor reliability and validity of self-reported diagnoses compared with medical records (Gray et al., 1999). In contrast, a study by VA (Kang et al., 2000), which verified a random subset of self-reported conditions against medical records, found a strong correlation between the two (above 93%). Those data, however, were available only for the 45.2% who signed consent forms that allowed researchers to verify records. Another important limitation is that most cohort studies rely on self-reporting of symptoms on questionnaires. Most of the larger epidemiologic studies described here were conducted through mail or telephone surveys, and this precluded clinical examination and diagnosis. Studies based on self-reporting have inherent limitations because of potential inaccuracies in recalling past events and difficulty in verifying the reports. Symptom self- reporting potentially introduces reporting bias, which occurs when the group being studied (such as deployed veterans) overreports particular symptoms (such as symptoms that are more intense or more recently experienced), that is, reports the symptoms more frequently than a comparison group (such as nondeployed veterans). Reporting bias, in this example, would lead to an overestimation of the prevalence of symptoms or diagnoses in the deployed population. Similarly, self-reporting of exposures is problematic and subject to recall bias in that sick soldiers may be more likely to report that they were exposed. Issues arising as a result of symptom self-reporting are best addressed through clinical evaluations, as has been done by some researchers (Ishøy et al., 1999a; Kelsall et al., 2005; McCauley et al., 1999). Many

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STUDIES OF SYMPTOMS IN GULF WAR VETERANS 35 limitations of reporting and recall bias are present in Gulf War research (e.g., Murphy et al., 2006, 2008). Virtually all the studies cited in this chapter are cross-sectional—surveys, questionnaires, interviews, and the like were conducted at a single time—and can thus be subject to temporal ambiguity. Even though some studies conduct serial cross-sectional assessments over time (Kang et al., 2000, 2009), the timing of retrospective exposures and symptoms is difficult to ascertain, and this limits the opportunity to learn about symptom duration and chronicity, latency of onset, prognosis, and potential causal factors. Many other factors can affect the association between an exposure and an outcome, including lifestyle, hereditary factors, and additional exposures, which are known as confounding factors. Confounding occurs when a variable or characteristic otherwise known to be predictive of an outcome and associated with an exposure (and not on the causal pathway under consideration) can account for all or part of an apparent association. A confounding variable is an uncontrolled variable that influences the outcome of a study to an unknown extent and whose effects cannot be precisely evaluated. Carefully applied statistical adjustments can often control for or reduce the influence of a confounder (IOM, 2010). 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 abnormalities that affect deployed veterans, and the period of investigation might have been too brief to detect health outcomes that have a long latency or require many years to progress to disability, hospitalization, or death. Finally, research into the health effects of Gulf War deployment is limited by the interval between the war and when the studies were conducted. Many studies were conducted years after the war, and this limits the ability to determine when symptoms developed and the ability to detect causal associations—for example, the earliest assessments were conducted in 1993 by Pierce (1997) and Wolfe et al. (1998), in 1994 by Gray et al. (1999), and in 1995 by Fukuda et al. (1998). Followup of the cohorts is also limited because some active military separate each year. And the delay between the war and the studies allows the dissemination of speculation by the media and others that may have affected veterans’ recall (Hotopf and Wessely, 2005). POPULATION-BASED STUDIES The following are population-based studies of samples of veterans or military personnel. VA conducted a nationally representative study of Gulf War veterans (Kang et al., 2000, 2002, 2009). Several studies of selected population-based samples of veterans defined by state of residence were conducted (Bourdette et al., 2001; Iowa Persian Gulf Study Group, 1997; McCauley et al., 1999; Steele, 2000). Finally, several additional studies of populations of allied military personnel are described (Cherry et al., 2001; Goss Gilroy Inc., 1998; Hotopf and Wessely, 2005; Ishøy et al., 1999a; Kelsall et al., 2004; Simmons et al., 2004; Unwin et al., 1999). Department of Veterans Affairs Study VA conducted a study that used the National Health Survey of Gulf War Veterans and Their Families to estimate the prevalence of symptoms and other health outcomes (including reproductive outcomes in spouses and birth defects in children) in Gulf War veterans vs

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36 CHRONIC MULTISYMPTOM ILLNESS IN GULF WAR VETERANS nondeployed Gulf War–era veterans. The three-phase retrospective study was designed to be representative of nearly 700,000 US veterans who were deployed to the Persian Gulf and 800,680 veterans who were not deployed but were in the military during September 1990–May 1991. In the first phase, questionnaires were mailed to 30,000 veterans (15,000 Gulf War deployed and 15,000 era veterans) identified by the DOD Data Manpower Center as representing the various branches and units of the military. The questionnaire contained a list of 48 symptoms and questions about chronic medical conditions, functional limitations, and other items from the National Health Interview Survey and included questions about exposures. The overall response rate was about 70%. The second phase used telephone interview software in an attempt to capture those who did not respond to the mailed questionnaires. In addition, medical records were obtained for a random sample of 4,200 respondents to validate self-reports of clinic visits or hospitalizations within the preceding year. The third phase was a comprehensive medical examination, including laboratory testing, of a random sample of 2,000 veterans drawn from the Gulf War population and a comparison group (Kang et al., 2000). The investigation found that Gulf War veterans reported statistically significantly greater functional impairment in the preceding 2 weeks (27.8% vs 14.2%), limitation of employment (17.2% vs 11.6%), and health care use in the preceding year as assessed on the basis of clinic visits (50.8% vs 40.5%) and hospitalizations (7.8% vs 6.4%) than era veterans. Gulf War veterans reported higher prevalences of all 48 symptoms on the health inventory. The most frequently reported were runny nose, headache, unrefreshing sleep, anxiety, joint pain, back pain, fatigue, ringing in ears, heartburn, difficulty in sleeping, depression, and difficulty in concentrating (see Table 3.2) (Kang et al. 2000). Those 12 symptoms are similar in prevalence to the same symptoms in a UK cohort (Unwin et al., 1999). 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). A followup study of the same population (Kang et al., 2009) was conducted in 2005 to obtain survey-based health information from the 15,000 Gulf War–deployed and 15,000 Gulf War–era veterans originally surveyed in 1995. In phase I of the followup, VA and Social Security records through December 2002 were used to identify the 29,607 living participants and mail health questionnaires to them. Phase II consisted of telephone interviews with 2,000 participants who did not respond to the initial mailed questionnaire (nonrespondents) and a sample of 1,000 participants (respondents) who had indicated a clinic visit or hospitalization within the previous 12 months. In all, 6,111 (40%) deployed and 3,859 (27%) nondeployed veterans participated in both phases I and II, but the overall response rate was low (only 34%). However, there were no differences in deployment status between respondents and nonrespondents. The administered questionnaire was a modified version of the 1995 questionnaire and included the Patient Health Questionnaire, the 12-Item Short Form Health Survey (SF-12), and other items used to assess general health status. Unexplained multisymptom illness, in this study, was defined as having several symptoms that persisted for 6 months or longer and were not adequately explained by other diagnoses. Those symptoms included fatigue; muscle or joint pain; headache; memory, digestive, respiratory, or skin problems; or any other unexplained symptoms. Unexplained multisymptom illness was identified in 36.5% of the deployed and 11.7% of the era veterans, for a risk ratio of 3.05 (95% confidence interval [CI] 2.77–3.36), after adjustment for age, sex, race, body mass index, current cigarette smoking, rank, branch of service, and unit component (active duty, National Guard, or reserve). Multisymptom

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STUDIES OF SYMPTOMS IN GULF WAR VETERANS 37 TABLE 3.2 Results of Department of Veterans Affairs Studya Most Common Self-Reported Prevalence in Gulf War Prevalence in Non–Gulf War Symptoms Veterans (%) Veterans (%) Runny nose 56 43 Headache 54 37 Unrefreshing sleep 47 24 Anxiety 45 28 Joint pain 45 27 Back pain 44 30 Fatigue 38 15 Ringing in ears 37 23 Heartburn 37 25 Difficulty in sleeping 37 21 Depression 36 22 Difficulty in concentrating 35 13 5 Most Common Self- Reported Chronic Medical Conditions Sinusitis 38.6 28.1 Gastritis 25.2 11.7 Dermatitis 25.1 12.0 Arthritis 22.5 16.7 Frequent diarrhea 21.2 5.9 a Subjects were asked whether symptoms were recurring or persistent during previous year. Differences in prevalence are all statistically significant (p < 0.05). SOURCE: Kang et al., 2000. Adapted with permission from Lippincott Williams and Wilkins/Wolters Kluwer Health: Journal of Occupational and Environmental Medicine (2000). illness was the most widely reported medical condition in Gulf War veterans except for arthritis. Gulf War veterans also had higher rates of functional impairment, of limitations of activities, of at least one clinic or doctor visit, and of hospitalization. The Iowa Study The Iowa study was a cross-sectional survey of a sample of 4,886 military personnel who listed Iowa as their home of record at the time of enlistment (Iowa Persian Gulf Study Group, 1997). The study examined the health of military personnel in all branches of service who were still serving or had left service. The sample was randomly selected from the 28,968 military personnel who listed Iowa as their home of record. Of the study subjects who were contacted, 3,695 (90.7%) completed a telephone interview in 1995–1996. Study subjects were divided into four groups: Gulf War–deployed regular military, Gulf War–deployed National Guard or reserve, non–Gulf War–deployed regular military, and non–Gulf War–deployed National Guard or reserve. Trained examiners used standardized questions, instruments, and scales in

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38 CHRONIC MULTISYMPTOM ILLNESS IN GULF WAR VETERANS interviewing the subjects.2 The study found that Gulf War veterans had significantly higher prevalences of symptoms of depression (17.0% vs 10.9%, p < 0.001), posttraumatic stress disorder (PTSD; 1.9% vs 0.8%, p = 0.007), chronic fatigue (1.3% vs 0.3%, p < 0.001), cognitive dysfunction (18.7% vs 7.6%, p < 0.001), bronchitis (3.7% vs 2.7%, p < 0.001), asthma (7.2% vs 4.1%, p = 0.004), fibromyalgia (19.2% vs 9.6%, p < 0.001), alcohol abuse (17.2% vs 4.1%, p = 0.02), and anxiety (4.0% vs 1.8%, p < 0.001). Gulf War veterans scored significantly lower on all eight subscales for physical and mental health on the 36-item Short Form Health Survey (SF- 36); this indicated lower quality of life than that of nondeployed personnel. The subscales for bodily pain, general health, and vitality showed the greatest differences between deployed and nondeployed veterans (Iowa Persian Gulf Study Group, 1997). In short, this large, well- controlled study demonstrated that some sets of symptoms were more frequent in Gulf War veterans than in nondeployed military controls. Oregon and Washington Veteran Studies Veterans from Oregon and Washington were studied in a series of analyses by investigators of the Portland Environmental Hazards Research Center (McCauley et al., 1999). A mailed questionnaire, to assess general health through symptom self-reports, was sent to a random sample of 2,343 of the total of 8,603 Gulf War veterans who listed Oregon or Washington as their home state of record at the time of deployment. The study did not include a nondeployed comparison group. The response rate was 48.4%. The study found high rates (21– 60%) of self-reported symptoms, including cognitive–psychologic symptoms, unexplained fatigue, musculoskeletal pain, gastrointestinal complaints, and rashes. The 225 veterans who participated in the clinical examinations displayed differences between the symptoms that they reported on questionnaires and the symptoms that they reported at clinical examination. The difference might suggest high rates of outcome misclassification based on either the questionnaire or the examination. Kansas Veteran Study Kansas established the Kansas Persian Gulf War Veterans Health Initiative to determine the patterns of veterans’ health problems. Using lists of eligible veterans from DOD, Steele (2000) conducted a population-based survey of veterans who listed Kansas as their home state of record. A stratified random sample of 3,138 was selected, of whom 2,396 were located with in- state contact information. The survey, mailed out in 1998, asked about 16 specific medical or psychiatric conditions, 37 symptoms, service branch, locations during the Gulf War (including whether the veterans were notified about the Khamisiyah demolitions; see Chapter 2), and vaccinations. Kansas Gulf War veterans reported greater prevalences of 10 physician-diagnosed conditions than Kansas nondeployed veterans: skin conditions, stomach or intestinal conditions, depression, arthritis, migraine headaches, chronic fatigue syndrome (CFS), bronchitis, PTSD, asthma, and thyroid conditions. The investigators used their own definition of Gulf War illness, which was similar to that used by the Centers for Disease Control and Prevention (CDC) (Fukuda et al., 1998) and which required having at least one moderately severe or two or more 2 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), 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.

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STUDIES OF SYMPTOMS IN GULF WAR VETERANS 39 chronic symptoms in at least three of six domains: fatigue and sleep problems; pain symptoms; neurologic, cognitive, and mood symptoms; gastrointestinal symptoms; respiratory symptoms; and skin symptoms. The symptoms had to persist or recur in the year before the study interview and had to have been a problem for the study participants in 1990 or later. Using their case definition, the researchers found that 34.2% of Gulf War veterans and 8.3% of nondeployed veterans met criteria for Gulf War illness (odds ratio [OR] = 4.68, 95% CI 3.25–6.75). On the basis of the CDC case criteria, the study found that 47.2% of Gulf War veterans and 19.8% of nondeployed veterans had chonic multisymptom illness (OR = 3.26, 95% CI 2.48–4.28). The prevalence of Kansas-defined Gulf War illness was lowest in Gulf War veterans who served on ships and highest in those who served in Iraq or Kuwait. Canadian Veteran Study A 1997 survey mailed to the entire cohort of Canadian Gulf War veterans found high prevalences of several chronic conditions (Goss Gilroy Inc., 1998).3 Some 3,113 respondents from Canada who had been deployed to the Gulf War were compared with 3,439 respondents who had been deployed elsewhere during the same period. The Gulf War veterans who responded reported symptoms of cognitive dysfunction, multiple chemical sensitivity (MCS), major depression, PTSD, chronic dysphoria, anxiety, and respiratory diseases at higher rates than the controls. The greatest differences between Gulf War–deployed forces and those deployed elsewhwere were in symptoms of cognitive dysfunction, MCS, and major depression. Symptoms of cognitive dysfunction had the highest overall prevalence: in 34–40% of Gulf War veterans and 10–15% of veterans deployed elsewhere. Gulf War veterans also reported significantly more visits to health care practitioners, greater dissatisfaction with their health status, and greater health-related reductions in recent activity. United Kingdom Veteran Studies The United Kingdom sent 53,000 personnel to the Gulf War. Two teams of researchers each studied a separate, nonoverlapping, stratified random sample of those Gulf War veterans. The first team was from the University of London (Guy’s, King’s, and St. Thomas’s Medical Schools), the second team from the University of Manchester. A third team of researchers from the London School of Hygiene and Tropical Medicine surveyed the entire cohort of 53,000 veterans for a focused study of birth defects and other reproductive outcomes. University of London Veteran Studies Unwin et al. (1999) at the University of London investigated the health of UK servicemen in a population-based study. The study used a random sample of the entire UK contingent deployed to the Gulf War and two comparison groups. One of the comparison groups (n = 2,620) was deployed to the conflict in Bosnia; this is the only study that used a comparison population that had combat experience during the time of the Gulf War. The second comparison group of era veterans (n = 2,614) was deployed to noncombat locations outside the United Kingdom in the same period. As opposed to what was done in some studies, the nondeployed control group was recruited from among the subset of nondeployed service members who were 3 In January 1997, Goss Gilroy Inc. was contracted by the Canadian Department of National Defence to carry out an epidemiologic survey of Canadians who served in the Gulf War to establish the overall health status of Gulf War personnel.

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40 CHRONIC MULTISYMPTOM ILLNESS IN GULF WAR VETERANS fit for combat duty, and this avoided selection bias related to the healthy-warrior effect. A mailed questionnaire queried symptoms (50 items), medical disorders (39 items), exposure history (29 items), and functional capacity. The authors compared ORs for each symptom after controlling for potential confounding factors (including sociodemographic and lifestyle factors), using logistic regression analysis. Only results on male veterans were analyzed, because female veterans’ roles and symptoms were distinct enough to warrant separate consideration. Responses to the questionnaire were received from 70% of the 53,462 Gulf War–deployed, 61.9% of the 39,217 in the Bosnia cohort, and 62.9% of the 250,000 era cohort members. Bosnia-deployed veterans were more likely to be in service, unmarried, younger, and drank more alcohol than Gulf War–deployed veterans. The era veterans were similar to Gulf War–deployed veterans but included more non-smokers. The Gulf War–deployed veterans (n = 2,961) reported higher prevalences of symptoms and diminished functioning than did either comparison group. Gulf War veterans were 2–3 times more likely than comparison subjects to have met symptom-based criteria for chronic fatigue, posttraumatic stress reaction, and CDC-defined chronic multisymptom illness (CMI; Fukuda et al., 1998). More specifically, 25.3% of Gulf War veterans met CDC case criteria for CMI compared with 11.8% of Bosnia and 12.2% of Gulf War–era veterans. The most frequently reported symptoms were feeling unrefreshed after sleep, irritability or outbursts of anger, headache, fatigue, sleeping difficulties, forgetfulness, joint stiffness, loss of concentration, flatulence or burping, pain without swelling, and redness in several joints. Gulf War veterans were 2–3 times more likely to report those symptoms, but results were not statistically significant. On the SF-36, Gulf War veterans reported significantly worse health perception but not worse physical functioning. It should be noted that the members of the Bosnia cohort, who also had been deployed to a combat setting, reported fewer symptoms than the Gulf War cohort, and this suggests that combat deployment itself does not necessarily account for higher symptom reporting (Unwin et al., 1999). In a followup study, a postal survey was sent 11 years after the war to a random sample of 3,305 participants (1,472 Gulf War–deployed, 909 Bosnia-deployed, and 924 era veterans) from the total who completed the first study described above. The response rates were as follows: 74.0% Gulf War–deployed, 70.2% Bosnia-deployed, and 69.7% era veterans. Respondents completed the Chalder fatigue scale, the General Health Questionnaire (GHQ), SF- 36, and the count of physical symptoms (Hotopf et al., 2003). Compared with the first survey (time 1), respondents reported a modest reduction in fatigue, modest reduction in psychologic distress on the GHQ, and slight worsening on SF-36. Compared with the two groups of non–Gulf War–deployed veterans surveyed at time 2, deployed veterans performed worse on all measures. Deployed veterans reported a mean of 10.7 symptoms vs 7.9 and 6.4 in the two non–Gulf War– deployed veteran groups. They had no higher incidence of new illnesses. University of Manchester Veteran Study The University of Manchester study used a random sample of UK veterans 7 years after the Gulf War (Cherry et al., 2001). The cohort was deliberately separate from that studied by Unwin et al. (1999). The 9,505 eligible deployed veterans were divided into two groups—4,755 in the main cohort and 4,750 in a validation cohort to permit replication of analysis and to assess consistency. The control population of 4,749 consisted of nondeployed veterans who were in good general health. Veterans were sent a questionnaire about the extent to which they were

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STUDIES OF SYMPTOMS IN GULF WAR VETERANS 41 burdened by 95 symptoms in the previous month. By asking them to mark their answers on a visual analogue scale, investigators sought to determine the degree of symptom severity. Investigators also sought to determine areas of peripheral neuropathy by asking veterans to shade on two pictures of mannequins the body areas where they were experiencing pain or numbness and tingling. Deployed veterans reported greater severity of almost all 95 symptoms. The overall mean severity scores of the two Gulf War cohorts were similar and significantly greater than the score of the non–Gulf War cohort. Deployed veterans’ severity scores for 14 symptoms— including memory, concentration, and mood problems—were at least twice those of the nondeployed veterans. Numbness and tingling were reported by about 13% of deployed and about 7% of nondeployed. Widespread pain was also reported more frequently (12.2% vs 6.5%). London School of Hygiene and Tropical Medicine Veteran Study The third British study was a large mail survey conducted by researchers at the London School of Hygiene and Tropical Medicine (Maconochie et al., 2003; Simmons et al., 2004). It was designed largely to assess reproductive outcomes in Gulf War veterans, but it contained open-ended questions about their general health. The exposed cohort consisted of all UK Gulf War veterans, and the unexposed cohort consisted of a random sample of nondeployed UK military personnel from the same period. Although the number of surveys returned in the study was large (25,084 by Gulf War veterans and 19,003 by non–Gulf War veterans), the participation rates were low (47.3% and 37.5% of male and female Gulf War veterans, respectively, and 57.3% and 45.6% of male and female nondeployed veterans, respectively). Simmons et al. (2004) reported that 61% of responding Gulf War veterans and 37% of responding nondeployed veterans reported at least one new medical symptom or disease since 1990. Some 85% of symptoms and diseases were reported more frequently by Gulf War veterans. The strongest associations were for mood swings (OR = 20.9, 95% CI 16.2–27.0), memory loss or lack of concentration (OR = 19.6, 95% CI 15.5–24.8), night sweats (OR = 9.9, 95% CI 6.5–15.2), general fatigue (OR = 9.6, 95% CI 8.3–11.1), and sexual dysfunction (OR = 4.6, 95% CI 3.2– 6.6). Adjustments were made for age, service, rank, serving status, alcohol consumption, and smoking. Veterans’ belief that they had “Gulf War syndrome” was associated with the greater reporting of symptoms or disease, but only 6% of Gulf War veterans believed that they had the syndrome. Danish Peacekeeper Studies Military personnel from Denmark were involved in peacekeeping or humanitarian missions that occurred predominantly after the Gulf War ceasefire but were in the same areas as other coalition forces that served in Gulf War combat (Ishøy et al., 1999). A total of 821 Danes, deployed from August 1990 to December 1997, were eligible for inclusion in this population- based cohort, and 686 (83.6%) agreed to participate in the study. The deployed veterans were matched by age, sex, and profession to 400 members of the Danish armed forces who were not deployed to the Gulf War; 231 (57.8%) agreed to participate. Participants completed a detailed questionnaire, including 22 neuropsychologic symptoms, and then received detailed clinical health and laboratory examinations (height, weight, blood pressure, a battery of urinary and blood work, and a battery of neuropsychologic tests) and participated in physician interviews about their medical history and symptoms. The examinations were conducted in 1997–1998.

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56 Reference Design Population Outcome Measures Results Adjustments Comments 2002–2004 (68.8%), backache (62.9%), and 1,008 GWVs memory difficulties (56.0%). completed the clinical exam. Hawaii and Pennsylvania Active-Duty and Reserve Study Stretch et al., Cross-sectional 16,167 active-duty Health questionnaire. GWVs were significantly more Age, rank, Response rate: 1995 survey of service and reserve likely than NDVs to report 12 education, 31%. members from personnel assigned symptoms: head cold, sinus marital status, No formal Hawaii and to all Army, Navy, trouble, sore throat, difficulty branch of assessment of Pennsylvania Air Force and swallowing, headache, back military selection bias Marine Corps units problems, stomach upset, muscle (speculated on in Hawaii and aches, aching joints, cough, reasons for Pennsylvania. chills/fever, other problems (all nonresponses). Enrolled 1,481 p < 0.001). GWVs and 2,524 NDVs. Ft. Devens and New Orleans Cohort Studies Proctor et Cross-sectional Stratified random 52-item symptom GWVs report higher prevalence Age, sex, Germany group al., 1998 study of samples of two questionnaire. of all but one of 52 symptoms. education only studied at 3 cohorts Gulf War–deployed Ft. Devens group reported time 2. followed groups: Ft. Devens significantly higher prevalences 300 completed longitudinally; and New Orleans than Germany group. New Ft. Devens dates of compared with Orleans group reported questionnaires enrollment: Ft. nondeployed group significantly higher prevalences were analyzed. Devens 1991, (Germany). of 24 of 52 symptoms. Among Response rates: 1992–1993, Ft. Devens: US musculoskeletal symptoms 53% Ft. Devens, 1994–1996; New Army active, reported more frequently by Ft. 34% New Orleans, Orleans 1991, reserve, and Devens–deployed veterans were 49% Germany. 1994–1995; National Guard joint pains (OR = 2.6) and neck Assessed selection Germany veterans; New ache or stiffness (OR = 2.7); bias. 1995 Orleans: active, among neurologic symptoms Oversampled reserve, and with greater prevalences in both women. National Guard US cohorts of deployed veterans Army, Navy, was headache (OR = 4.2); all

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Reference Design Population Outcome Measures Results Adjustments Comments Marine Corps, and confidence intervals excluded Air Force troops; 1.0. About 30% of Gulf War Germany: Maine veterans and 11% of Germany National Guard air group reported inability to fall ambulance unit. asleep (OR = 3.4–3.6, 95% CI Final participation excludes 1.0). 252 GWVs (Ft. Devens and New Orleans) and 48 NDVs (Germany). Wolfe et al., Longitudinal Population included 20-item health- Most frequent symptoms were Age, Response rate: 1998 study, cross- Proctor et al. symptom checklist. general aches and pains, educational 92%. sectional survey (1998) sample. overtiredness or lack of energy, level, marital No NDVs. conducted in 1993 GWVs from Ft. headache, trouble sleeping, status, race Devens. nervous or tense, depressed Eligible 2,949; mood, difficulty concentrating; enrolled 2,119. 30% of sample indicated that their physical health had become either “worse” or “much worse” since their return. Seabee Studies Haley et al., Cross-sectional Active and retired Self-reported Survey results indicated 6 No assessment of 1997 survey, members of exposure to symptom factors (called selection bias. factor-analysis 24th Reserve Naval neurotoxic chemical syndromes by the authors): Small cohort, no survey conducted Mobile combinations and impaired cognition, confusion– control group. individually in Construction association with ataxia, arthromyoneuropathy, Response rate: supervised, in- Battalion, called factor analysis– phobia–apraxia, fever– 41%. person, group to active duty in defined syndrome. adenopathy, and weakness– Used cumulative sessions in 1995 GW, residents of incontinence. They accounted factor weights to Alabama, Georgia, for 71% of observed variance. assign veterans to North Carolina, 63 (25%) veterans had one of the “syndromes” with South Carolina, and 6 “syndromes,” authors noted. 1.5 cutoff. Tennessee in 70% had serious health problems 57

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58 Reference Design Population Outcome Measures Results Adjustments Comments November 1994. since returning from the Gulf Eligible 606; War. enrolled 249. Gray et al., Cross-sectional Active-duty Questionnaire on 55.8% of GWVs and 31.7% of Assessed selection 1999 survey conducted Seabees in Navy postwar symptoms; NGVs reported postwar bias. in 1994 in 1994 and serving screening for chronic symptoms lasting ≥1 month. Response rate: at Port Hueneme, fatigue and PTSD; GWVs reported significantly varied by unit, California, or Hopkins Symptom (p < 0.05) higher prevalences of 26–71%. Gulfport, Checklist for 35 out of 41 symptoms than Mississippi. psychologic NDVs. Both groups had similar Eligible 1,497; symptoms. Clinical clinical evaluations except enrolled 527 evaluation: serum GWVs had reduced hand grip GWVs and 970 collection, handgrip strength and were more likely to NDVs. strength, pulmonary- have PTSD (15% vs 9%) than function testing. NDVs. Gray et al., Cross-sectional All regular US Health questionnaire, GWVs reported poor general Age, sex, Study limited by 2002 survey conducted Navy Seabees. working case health, higher prevalences of 33 active-duty or recall bias. in 1997–1999 Eligible 18,945; definition. medical problems, and higher reserve status, Response rate: enrolled 3,831 prevalences of CFS, PTSD, race or 68.6%. GWVs, 4,933 MCS, and IBS. 22% met criteria ethnicity, Large sample. veterans deployed for Gulf War illness. current Assessed selection elsewhere, and smoking, bias with telephone 3,104 NDVs. current alcohol survey. drinking Pennsylvania Air National Guard Study Fukuda et Cross-sectional Everyone on base Survey of 35 GWV vs NDV: mild to moderate Rank, sex, age, Response rates: al., 1998 survey conducted when survey was symptoms, in-person cases 39% vs 14%, severe cases smoking status 61.6% index unit, in 1995 conducted was interview. Clinical 6% vs 0.7%. Veterans who met 35.4% Unit A, eligible. Index evaluations of index case definition had significantly 73.4% Unit B, population 667 in unit only. diminished functioning and well- 69.8% Unit C. ANG unit in being. Deployed to Gulf: Lebanon, 47% index unit,

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Reference Design Population Outcome Measures Results Adjustments Comments Pennsylvania. 22% Unit A, 32% Three comparison Unit B, populations: 28% Unit C. Unit A, 538 in Started as cluster ANG unit from investigation in Pennsylvania with Lebanon, different mission; Pennsylvania. Unit B, 838 in US No assessment of Air Force Reserve; selection bias. Unit C, 1,680 active-duty Air Force from Florida with missions similar to those of index. Women in the Air Force Pierce, 1997 Cross-sectional Stratified random Health survey At time 1, symptoms more Age Response rates: survey conducted sample of women sex-specific health frequent in GWVs vs NDVs 82% at time 1, in 1993 (Time 1) in Air Force. concerns. were rash, cough, depression, 92% at time 2. and 1995 (Time Eligible 638; unintentional weight loss, 88,415 women in 2) enrolled 525. insomnia, and memory Air Force at the problems. At time 2 symptoms time. more frequent in GWVs vs Sample NDVs were rash, cough, and composition: 47% memory problems. At time 1, no active duty, 25.5% major difference between GWVs reserve, 27.4% and NDVs in sex-specific Guard. symptoms. At time 2, most common symptoms in GWVs were lumps or cysts in breasts, abnormal PAP results, headache, and genital herpes. 59

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60 Reference Design Population Outcome Measures Results Adjustments Comments Registry Studies Joseph et al., Case series Veterans seen by Physical examination, 17.8% of GWVs had diagnoses Registry study. 1997 conducted in DOD for CCEP. medical and family of SSID, including primarily Self-selected 1994–1996 Enrolled 20,000 history. fatigue, headache, memory sample, no control GWVs. problems, and sleep disturbances group. Kroenke et Case series Veterans seen by Provider-administered Most common symptoms were Registry study. al., 1998 conducted in DOD for CCEP symptom joint pain (50%), fatigue Self-selected 1994–1996 Registry. questionnaire. (46.9%), headache (39.7%), sample, no control Enrolled 18,495 memory or concentration group. GWVs. difficulties (34%), sleep disturbance (33%), and rash (30.2%). 66% of symptoms did not appear until after Gulf War, and 40% of symptoms had a latency >1 year. Increased symptom counts were associated with loss of work. Roy et al., Case series Veterans seen by Health questionnaire, 17.2% of veterans had primary Registry study. 1998 conducted in DOD for physical examination, diagnosis of SSID. 41.8% had Self-selected 1994–1997 Comprehensive medical history, primary or secondary SSID sample, no control Clinical Evaluation laboratory studies. diagnosis. Most common group. Program Registry. symptoms were fatigue, Enrolled 21,579 headache, sleep disturbance, and GWVs. memory loss. Escalante Case series of GWVs enrolled in Symptoms, self- Pain was present in almost all None Registry study. and rheumatologic Persian Gulf reported pain, and SF- patients and was widely Self-selected Fischbach, referrals Registry from 36 for health-related distributed. Widespread pain sample, no control 1998 South Texas quality of life. was reported in 65.1% of group. Veterans Health GWVs. Most frequent painful Dates of Care System. areas were knees (65%), low examinations not Enrolled 145. back (>60%), shoulders (50%), reported. Registry

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Reference Design Population Outcome Measures Results Adjustments Comments and hands and wrists (35%). enrollment began Average values on SF-36 were in 1993. below 25th percentile of published national norms, with pain and nonarticular rheumatic symptoms explaining most of decrease in health-related quality of life. Hallman et Cross-sectional GWVs residents of Mailed survey. 84.5% attributed their medical Registry study. al., 2003 assessment, Delaware, Illinois, problems to service in the gulf. Self-selected conducted in 1995 New Jersey, New Participants endorsed average of sample, no control York, North 25.5 symptoms: 9.9 mild, group. Carolina, Ohio, and 9.5 moderate, and 6.1 severe. Response rate: Pennsylvania 60%. randomly sampled Registry contained from VA Gulf War more than 70,000 Health Registry. veterans at time of Enrolled 1,161. study. Ozakinci et Cross-sectional Derivative of Mailed survey and Compared with time 1, there was Sex, rank, race, Response rate: al., 2006 assessment, Hallman et al. telephone interview. no significant change in number marital status, 62%. 5-year followup (2003). Enrolled of symptoms reported or their education, of Hallman et al. 390. severity. Subjects who were branch of (2003) conducted more symptomatic in 1995 service, duty in 2000 showed some improvement but remained much more highly symptomatic than those who were less symptomatic. 61

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62 Reference Design Population Outcome Measures Results Adjustments Comments Coker et al., Cross-sectional, First 3,000 British Medical and 75% of first 3,000 GVMAP None Registry study. 1999; Lee et case series veterans attending psychiatric diagnoses registrants assessed were well Self-selected al., 2002, conducted in GVMAP. (ICD-10) and and symptom-free; 21% were sample, no control 2001 1993–2001 nonspecific health well with symptoms but no group. symptoms. disease. Most common symptom groups reported were affective (45%), joint and muscle aches and pains (39%), and fatigue (38%). Of registrants assessed as unwell, 11% had psychiatric conditions, 5% organic medical conditions, and 9% both. NOTE: ANG = Air National Guard; CCEP = Comprehensive Clinical Evaluation Program; CDC = Centers for Disease Control and Prevention; CFS = chronic fatigue syndrome; CI = confidence interval; CMI = chronic multisymptom illness; DOD = Department of Defense; GHQ = Global Health Questionnaire; GI = gastrointestinal; GVMAP = Gulf Veterans Medical Assessment Programme; GWS = Gulf War syndrome; GWV = Gulf War veteran; IBS = irritable bowel syndrome; ICD-10 = International Statistical Classification of Diseases and Related Health Problems, 10th Revision; MCS = multiple chemical sensitivity; NDV = nondeployed veteran; OR = odds ratio; PTSD = posttraumatic stress disorder; RR = relative risk; SSID = signs, symptoms, and ill-defined conditions; VA = Department of Veterans Affairs.

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STUDIES OF SYMPTOMS IN GULF WAR VETERANS 65 Murphy, D., R. Hooper, C. French, M. Jones, R. Rona, and S. Wessely. 2006. Is the increased reporting of symptomatic ill health in Gulf War veterans related to how one asks the question? Journal of Psychosomatic Research 61(2):181-186. Murphy, D., M. Hotopf, and S. Wessely. 2008. Multiple vaccinations, health, and recall bias within UK armed forces deployed to Iraq: Cohort study. British Medical Journal 337:a220. Ozakinci, G., W. K. Hallman, and H. M. Kipen. 2006. Persistence of symptoms in veterans of the first Gulf War: 5-year follow-up. Environmental Health Perspectives 114(10):1553-1557. Pearce, N., H. Checkoway, and Kriebel D. 2007. Bias in occupational epidemiology studies. Journal of Occupational and Environmental Medicine 64:562-568. Pierce, P. F. 1997. Physical and emotional health of Gulf War veteran women. Aviation Space and Environmental Medicine 68(4):317-321. 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. Roy, M. J., P. A. Koslowe, K. Kroenke, and C. Magruder. 1998. Signs, symptoms, and ill-defined conditions in Persian Gulf War veterans: Findings from the comprehensive clinical evaluation program. Psychosomatic Medicine 60(6):663-668. Salamon, R., C. Verret, M. A. Jutand, M. Begassat, F. Laoudj, F. Conso, and P. Brochard. 2006. Health consequences of the first Persian Gulf War on French troops. International Journal of Epidemiology 35(2):479-487. 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 4:1-10. 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. 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. Szklo, M. 1998. Population-based cohort studies. Epidemiologic Reviews 20(1):81-90. 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. Unwin, C., M. Hotopf, L. Hull, K. Ismail, A. David, and S. Wessely. 2002. Women in the Persian Gulf: Lack of gender differences in long-term health effects of service in United Kingdom Armed Forces in the 1991 Persian Gulf War. Military Medicine 167(5):406-413. Wolfe, J., S. P. Proctor, J. D. Davis, M. S. Borgos, and M. J. Friedman. 1998. Health symptoms reported by Persian Gulf War veterans two years after return. American Journal of Industrial Medicine 33(2):104-113.

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