Study population and recruitment. This study had a case–control design involving a population-based sample of 304 veterans who served in the 1990–1991 Gulf War. In 2000, a random sample of Gulf War veterans, stratified by sex, was identified from among veterans residing in the greater Kansas City metropolitan area, including both Kansas and Missouri residents. The sampling pool for Kansas residents was drawn from a database of all Kansas Gulf War–era veterans maintained by the Kansas Commission on Veterans Affairs (Topeka, KS). Gulf War veteran residents of Missouri were sampled from among area veterans identified through the U.S. Department of Defense’s (DOD) Defense Manpower Data Center (Seaside, CA).
Potential study participants were contacted by telephone and invited to complete a brief screening interview to determine study eligibility. Eligible veterans were required to have deployed to the Gulf War theater of operations for any period between 1 August 1990 and 31 July 1991. To optimize the proportions of cases and controls enrolled, the screening interview queried veterans about 10 symptoms to determine if they screened positive or negative for multisymptom illness (sMSI+ or sMSI–), as defined by Fukuda et al. (1998)
. Briefly, sMSI+ veterans reported at least one symptom in two of the following symptom groups: a
) fatigue, b
) mood/cognition, and c
) musculoskeletal pain. sMSI– veterans reported fewer or no symptoms.
In accordance with the GWI case definition used for the study, potential participants were excluded if they reported being diagnosed by a physician with chronic medical conditions that might account for their symptoms (including diabetes, heart disease other than hypertension, stroke, lupus, multiple sclerosis, cancer other than nonmelanoma skin cancers, liver disease) or had persistent health problems due to chronic infection or serious injury. Veterans were also excluded if they reported being diagnosed with schizophrenia or bipolar disorder or if they had been hospitalized since the Gulf War for alcohol or drug dependence, depression, or posttraumatic stress disorder (PTSD).
Veterans determined to be eligible were invited to come to the study site to provide blood samples for genetic/enzyme activity testing and to complete a self-administered questionnaire providing information on their health, military, and deployment characteristics. Recruitment continued until a final sample of at least 300 veterans completed appointments at the study site, including similar numbers of sMSI+ and sMSI– veterans, with similar proportions of women in each group.
Among the 906 households initially contacted, informants indicated that 76 veterans could not participate (71 were deployed or no longer in the area, 5 were deceased); 86 (9%) refused to provide information or be interviewed. Of the remaining 744 veterans, 98 (13%) reported they had not deployed to the Persian Gulf region during the required period, and 646 completed the screening interview. Overall, 288 (45%) of the 646 veterans screened sMSI+ and 358 (55%) screened sMSI–. A total of 121 veterans were ineligible for the study based on health exclusions, 450 were eligible and were invited to participate, and 75 qualified but were not recruited based on their sMSI status or sex. Of the 450 recruited veterans, 385 (86%) agreed to participate, and 304 (68%) completed appointments at the study site.
Among the 121 veterans excluded for health reasons, 102 were excluded for one or more medical conditions, 12 were excluded based on self-reported psychiatric hospitalizations or diagnoses, and 7 were excluded for both medical and psychiatric reasons. Leading reasons for medical exclusions included chronic problems resulting from serious injury (n = 27), chronic infection (n = 25), heart disease (n = 21), cancer (n = 18), diabetes (n = 18), and liver disease (n = 12). Of the 74 veterans who reported physician-diagnosed psychiatric conditions, 19 were excluded for one or more of the following: diagnosed schizophrenia (n = 3) or bipolar disorder (n = 8), postwar hospitalization for PTSD (n = 2), drug or alcohol dependence (n = 8), or depression (n = 6). The remaining 56 veterans who reported being diagnosed, but not hospitalized, for psychiatric conditions were eligible for the study and remained in the sampling pool.
In conducting this research, investigators complied with all applicable U.S. regulations regarding the protection of human subjects. The study was approved by the U.S. Army Human Subjects Research Review Board and by the institutional review boards of Midwest Research Institute and the Kansas Department of Health and Environment. Veteran participants gave both oral and written informed consent before enrolling in the study. Data were collected from September through December 2000.
In the absence of a standard instrument used in studies of Gulf War veterans, we developed a questionnaire based on health and exposure questions representative of those used in several large population-based surveys of Gulf War veterans (Fukuda et al. 1998
; Iowa Persian Gulf Study Group 1997
; Kang et al. 2000
; Steele 2000
). The questionnaire asked veterans to report information related to their military and demographic characteristics, their health and medical histories, and the time periods and locations in which they served during the war. Deployment locations were identified using a map of the Gulf War theater of operations on which geographic regions were identified. Veterans were asked if they had been in each of the areas during deployment and, if so, for how long. Veterans were also asked if they had 19 specific experiences or exposures of interest during deployment. These questions emphasized veterans’ experiences rather than their impressions of their exposures. For example, veterans were not asked simply if they had been exposed to depleted uranium (which many were unlikely to have known) but if they had contact with destroyed enemy vehicles, an experience required for nearly all personnel directly exposed to spent depleted uranium. Symptom questions included those used to assess case status based on the Kansas GWI case definition, described below, as well as MSI defined by Fukuda et al. (1998)
, commonly referred to as the Centers for Disease Control and Prevention (CDC) case definition. The questionnaire was pretested in a group of Kansas Gulf War veterans who lived outside the sampling area.
GWI case status was determined using a previously described case definition developed in a large epidemiologic study of Kansas Gulf War era veterans (Steele 2000
). This case definition is based on an empirically identified pattern of symptoms found to significantly distinguish Gulf War veterans from veterans who had served during the same time period but did not deploy to the Persian Gulf theater. Briefly, the definition requires GWI cases to have multiple and/or moderate-to-severe chronic symptoms in at least three of six defined symptom domains. Qualifying symptoms must have first been a problem during or after the Gulf War and persisted over the 6-month period preceding the study. Symptom domains include a
) fatigue/sleep problems, b
) somatic pain, c
) neurologic/cognitive/mood symptoms, d
) gastrointestinal symptoms, e
) respiratory symptoms, and f
) skin abnormalities. Kansas GWI case criteria also exclude veterans who report being diagnosed with medical or psychiatric conditions that could explain their symptoms or interfere with their ability to report them, as detailed above in the exclusionary criteria for this study. Controls had insufficient symptoms to meet GWI case criteria and also reported no exclusionary diagnoses.
The Fukuda/CDC MSI criteria, described above (Fukuda et al. 1998
), provided the basis for our initial screening of veterans for the study sample. Overall, these criteria are less restrictive (i.e., they identify a broader range of cases) than the Kansas GWI criteria. This is because of the lesser number and severity of chronic symptoms required for CDC cases and because the CDC definition does not exclude veterans with medical or psychiatric diagnoses that potentially account for their symptoms.
Data analyses. We compared demographic and general health characteristics of GWI cases and controls using chi-square statistics. Bivariate (unadjusted) associations between case status and deployment and military characteristics were determined by calculating crude prevalence odds ratios (ORs) and 95% confidence intervals (CIs).
Preliminary analyses indicated that GWI case status was strongly associated with veterans’ reports of having been in Iraq, Kuwait, or both during deployment, regardless of the duration of time spent in those areas. To further evaluate associations between location in theater and deployment characteristics, four mutually exclusive veteran subgroups were defined: a) veterans who reported ever being in Iraq or Kuwait; or veterans who had not been in Iraq or Kuwait who were b) primarily at sea while in theater, c) primarily in eastern Saudi Arabia, or d) primarily on land in other support areas. The distribution of deployment experiences and exposures reported by veterans in each location subgroup was assessed using chi-square analyses.
Because the number of veterans in some location subgroups did not accommodate multivariable modeling of exposures in relation to case status, veterans who had not entered Iraq or Kuwait were combined into a single subgroup. We used a two-step process to identify independent associations between exposures and GWI for all veterans combined and for the two location subgroups of interest. First, ORs and 95% CIs were calculated to determine bivariate associations between case status and each exposure. All exposure variables that were significantly associated (at p < 0.05) with GWI in bivariate analyses were entered into a single logistic regression model to identify independent associations between these variables and GWI. Variables that had the weakest association with GWI (i.e., those with the smallest ORs) were dropped from the model sequentially until only those significantly associated with GWI remained. In the second step of the process, logistic regression analyses were used to determine multivariable associations for each individual exposure queried, controlling only for effects of the variables that were significantly associated with GWI in the backward elimination process.
Because very few veterans in the sample reported being directly involved in air combat or using flea collars during deployment, those two variables were not included in the modeling analyses. In addition, all “don’t know,” “refuse,” and unclear responses were coded as missing values for purposes of analysis. For most variables, this included only a small number of responses (≤ 3). However, the number was considerably higher for several variables: exposure to chemical agent resistant coating (CARC) paint (27 missing values), receipt of shots (injections) in the buttocks (19 missing) or arm (17 missing), and proximity to an exploded SCUD missile (12 missing). All analyses were conducted using SAS statistical software (version 9.2; SAS Institute Inc., Cary, NC).