VA Issues Responses to RAC Recommendations on Planned National Follow-up Study of Gulf War Veterans

The VA’s Environmental Epidemiology Service (EES), Office of Public Health and Environmental Hazards (OPHEH), offers the following responses to the public comments offered by the Research Advisory Committee on Gulf War Veterans' Illnesses (RAC-GWVI) regarding the planned “Follow-Up Study of a National Cohort of Gulf War and Gulf War Era Veterans."

The public comments provided by the RAC-GWVI were provided as part of the Office of Management and Budget (OMB) 30 day public comment period, in response to an announcement of the proposed study published by the Department of Veterans Affairs (VA) in the Federal Register.

1.  First comment:

“The VA should "suspend current plans to field the Follow-Up Study of a National Cohort of Gulf War and Gulf Era Veterans, the large longitudinal survey under development by VA’s Office of Public Health and Environmental Hazards, pending extensive revisions of the survey instrument."

"The Committee continues to consider longitudinal assessment of the health of Gulf War veterans to be an essential element of the federal Gulf War research effort. Unfortunately, as currently designed, the proposed survey fails to collect data on the most pressing health issues related to Gulf War service, while collecting excessive information on more peripheral concerns.

Major examples include:
- No follow-up on essential elements of VA’s initial survey of Gulf War veterans
- Lack of systematic, comprehensive data on symptoms associated with Gulf War service
- Lack of systematic, comprehensive data on diagnosed medical conditions
- Lack of information on the health of veterans’ family members
- Lack of information on veterans’ use of health care services and treatments"

VA response: The EES appreciates the Committee's interest in this survey and is grateful to committee members for taking the time to provide comments. The panel of 30,000 Gulf War and Gulf Era Veterans who will be contacted as part of the planned survey were initially contacted as part of EES longitudinal studies in 1995-1997 (the National Health Survey of Persian Gulf Era Veterans), and many were resurveyed 10 years later in 2003-2005 (the Longitudinal Health Study of Persian Gulf War Era Veterans) (Kang et al., 2000; Kang et al., 2009). The planned survey represents the second time that the overall panel of surviving Gulf War and Gulf Era Veterans will be re-contacted for a follow-up survey. The Longitudinal Health Study of Persian Gulf War Era Veterans, which is an active IRB-approved protocol of this same panel of Veterans, includes linkages of survey data with VA medical records databases. The proposed survey includes questions about recent hospitalizations and outpatient clinic visits in the past 12 months (questions 5a, 5b, 6a, 6b). These questions are retained from previously administered studies and provide open text response fields. Thus, many of the Committee's concerns (for example, the need for comprehensive data on diagnosed medical conditions and information on Veteran's use of health care services and treatments) are actively being addressed by EES investigators.

In developing the survey instrument for the planned survey, EES researchers carefully considered existing questionnaires including the survey instruments used for the 1995-1997 and 2003-2005 surveys (OMB numbers 2900-0558 and 2900-0637). All questions pertaining to diagnosed medical conditions and symptoms associated with Gulf War service, which were successfully used in the 2003-2005 survey, were retained in the newly developed questionnaire.

These include 46 questions on physician-diagnosed medical conditions (questions 8a items 1-7, 8b, 8c Items 8-23, and 8d) and more than 47 questions on symptoms (questions 14a item 1-8, 14b items 1-8), question 19, and question 22 items a-p, and question 26 items a-g. Three additional symptoms (wheezing in your chest, problems with coughing, a fever or chills), which had been included in the 1995-1997 survey, were also included In the planned survey. In addition, EES researchers added a series of questions on amyotrophic lateral sclerosis (ALS), irritable bowel syndrome (IBS), and functional dyspepsia (Rome criteria) which were recommended by Cooperative Studies Program collaborators at VA Medical Centers in Durham, North Carolina, and Miami, Florida. The Rome questions on IBS (http://www.romecriteria.org/questionnaires/ have previously been used in surveys of Veterans by EES researchers. In developing the questionnaire, EES researchers have strived to retain questions that are needed to assess the persistence of symptoms over time, and the incidence and prevalence of major medical conditions in this panel of Veterans. Another important consideration was the need to collect updated information about potential confounding variables and effect modifiers about health risk factors (for example, cigarette smoking and alcohol consumption). Another goal was to enhance the questionnaire by including questions on the use of complementary and alternative medicine which were successfully used by EES researchers in the National Health Study of a New Generation of U.S. Veterans, and which were adapted from those used in the Department of Defense (DoD) Millennium Cohort Study. A further goal was to incorporate questions on important womens' health topics which were obtained from National Health and Nutrition Examination Survey (NHANES) questionnaires (http://www.cdc.gov/nchs/nhanes/nhanes_questionnaires.htm). The specific questions on womens' health added to the questionnaire were recommended by experts in the VA OPHEH Women Veterans Health Strategic Health Care Group.

We agree with the Committee that additional information is needed about the health of Gulf War Veteran's family members. However, there is a limit to the number and scope of questions that can be included in a single survey. The literature on survey methodology indicates that response rates are lower when potential respondents are asked to complete an overly lengthy questionnaire. A series of detailed questions on pregnancy outcomes was included in the 1995-1997 questionnaire and those data have generated key findings published in the peer reviewed literature (Kang et al., 2001). A validation study of reported birth defects is ongoing. On average, the members of this panel of Veterans are now in their early 50's and many are likely to be beyond their reproductive years or have adult children. For these reasons, the Committee's recommendation to obtain additional data about the health of Gulf War Veteran's family members should ideally be addressed in a separate research study.

2.  Second comment:

"The Gulf War longitudinal study represents a major commitment of time and funding. It should be designed as an integral part of VA’s new Gulf War research program, and support the objectives of the program. Extensive revisions should be undertaken in conjunction with researchers outside VA who have specific expertise in assessing the health problems of Gulf War veterans, and should be reviewed and approved by the Gulf War Research Steering Committee."

VA response: We are pleased that the Committee has the vision of seeing this follow-up study as an integral part of VA's Gulf War research program. This study was specifically listed among the many research-focused recommendations in the Final Draft Report of the Gulf War Veterans' Illnesses Task Force to the Secretary of Veterans Affairs (March 2010). In developing the scientific protocol and questionnaire, EES researchers consulted with a number of outside experts, reviewed key articles published in the peer-reviewed scientific literature, and reviewed important reports on the health of Gulf War Veterans including the Institute of Medicine Committee on Gulf War and Health 2009 report on "Gulf War and Health: Volume 8: Update of Health Effects of Serving In the Gulf War" and the Research Advisory Committee on Gulf War Veterans' Illnesses 2008 report on "Gulf War Illness and the Health of Gulf War Veterans:  Scientific Findings and Recommendations." The objectives of the planned follow-up survey address many of the recommendations in these reports. For example, the Research Advisory Committee's 2008 report states on page 4 that "Although Gulf War illness is the most prominent and widespread issue related to the health of Gulf War veterans, it is not the only one. Additional issues of importance include diagnosed medical and psychiatric conditions affecting Gulf War veterans…"

The planned survey has been designed by EES investigators, with appropriate consultation with outside experts, on a tight time-table in order to successfully field the survey in conjunction with the 20th anniversary of the end of the 1991 Gulf War and in keeping with plans for follow-up surveys of this panel of Veterans at 10 year intervals. Accomplishments to date have included preparation of the contract acquisition package, scientific protocol, OMB package, draft questionnaire, and contingent approval by the Institutional Review Board (IRB) at the VA Medical Center in Washington, DC. A suspension of current plans to field the survey in early 2011, in order to allow for additional scientific review of the questionnaire by a very broad group of experts, would likely delay the survey by as much as a year and there would be no guarantee that funds would be available to resurrect the survey after such a prolonged and unexpected delay.

A further issue is that EES researchers are active members of a Planning Committee for a large-scale genomics study and biorepository for Gulf War Veterans which is being planned through the VA's Cooperative Studies Program. Lead members of the Planning Committee for the Cooperative Studies Program initiative have reached out to the principal investigators of all known epidemiologic studies of U.S. Gulf War Veterans (including Dr. Lea Steele who is a member of the Research Advisory Committee on Gulf War Veterans' Illnesses) in order to seek ways to re-contact members of the original cohorts. The planned approach is for the EES survey to be fielded beginning in early 2011 and then for the pilot study for the Cooperative Studies Program genomics study and biorepository to be initiated in Summer 2011. A suspension of current plans to field the EES survey in early 2011 would hinder plans for this multi-institutional collaborative initiative.

3.  \Third comment:

"The Committee became aware of the pending survey only through the chance observation by a veteran who noticed a Federal Register posting required by the Paperwork Reduction Act disclosing the existence of the survey. The posting did not include the survey itself. Committee staff then requested and were given a copy of the survey. The Research Advisory Committee and the Gulf War Research Steering Committee should each have been provided the opportunity to review the survey prior to posting."

VA response: We regret any misunderstanding about the process for posting notices about proposed data collection in the Federal Register. The VA publishes notices about planned surveys in the Federal Register in order to comply with OMB requirements and ensure the widest possible distribution. The VA Advisory Committee on Gulf War Veterans 2009 report on "Changing the Culture: Placing Care Before Process" recommends on page 14 that a longitudinal study be conducted" and notes on page 15 that the physical and mental conditions of these Veterans is likely to have evolved over the last 18 years and that there is a need to chart the course of their illnesses over time. These are exactly the types of studies that EES investigators have conducted and are planning to conduct.

4. Fourth comment:

"Without having had the opportunity to undertake an exhaustive review, the Committee notes the following examples of deficiencies to be addressed:

The survey fails to collect the most important types of data required to assess priority health issues specific to Gulf War service, while collecting detailed information in areas that are less pressing. This is reflected, overall, by the relatively few questions that provide data on undiagnosed symptomatic illness and diagnosed medical conditions, compared to the many pages of questions devoted to psychological problems and digestive issues.

Undiagnosed symptoms and symptom complexes are the most prevalent health concern resulting from Gulf War service. The proposed survey collects only limited data on symptoms of selected types. Further, symptoms in different areas are not queried in a consistent way, and are not consistent with symptom data collected in VA’s initial Gulf War survey. As a result, survey data will not provide clear, systematic information either on veterans’ current symptoms or changes in their symptoms over time, and cannot be used to construct a representative case definition for Gulf War illness."

VA response: The Institute of Medicine Committee on Gulf War and Health 2009 report on "Gulf War and Health: Volume 8: Update of Health Effects of Serving In the Gulf War" highlighted the need for studies of irritable bowel syndrome (IBS) and functional dyspepsia in Gulf War Veterans including studies that use symptom-specific criteria (for example, the Rome criteria). IBS has often been considered to be a part of unexplained multi-symptom illness (Kang et al., 2009). As mentioned above, the Rome criteria questions on IBS and gastric dyspepsia were recommended to EES investigators by outside medical experts who are playing a key role in planning the Cooperative Studies Program genomics study and biorepository for Gulf War Veterans. As noted above, all questions pertaining to symptoms associated with Gulf War service, which were successfully used in the 2003-2005 survey, were retained in the newly developed questionnaire. These include 47 questions on symptoms (questions 14a. item 1-8, 14b. items 1-8), question 19, and question 22 items a.-p., and question 26 items a.-g. The Committee is correct that some changes were made in symptom-related questions between the 1995-1997 and 2003-2005 surveys (OMB numbers 2900-0558 and 2900-0637). These improvements in survey content were made by EES and VA experts because of changes in the scientific understanding of Gulf War Veteran illnesses during that time period.

5.  Fifth comment:

"Federal advisory panels and Congressional committees have called on VA to determine if Gulf War veterans have excess rates of neurological diseases such as multiple sclerosis and Parkinson’s disease, or increased rates of cancers and other diagnosed medical conditions. But 20 years after the Gulf War, we still know very little about the prevalence of diagnosed medical conditions in Gulf War veterans. It is extremely important that this survey obtain systematic data on physician-diagnosed medical conditions, as well as information on hospitalizations and surgeries since the Gulf War. Examples of the types of data required include information on specific \neurological diagnoses and difficult-to-diagnose neurological conditions, data on specific cancer types and noncancerous tumors, migraines, autoimmune conditions, chronic infectious diseases, respiratory conditions, dermatological conditions, gastrointestinal conditions, and cardiovascular conditions."

VA response: We agree with the Committee that additional studies of neurological outcomes are needed. EES researchers have a separate study, currently in the contract acquisition phase, which will examine neurological mortality in Gulf War Veterans in follow-up to an earlier report (Barth et al., 2010). The planned survey includes questions about an array of physician-diagnosed medical conditions, clinic or doctor visits during the past 12 months (including the reasons for visits or diagnosis), and hospitalizations during the past 12 months (including the reasons for hospitalizations or diagnosis). It is not practical to ask the respondents to report information about all "hospitalizations and surgeries since the Gulf War" since some respondents may have been hospitalized numerous times over the 20-year time period. However, self-reported information about hospitalizations will now be available from three time periods (1995-1997, 2003-2005, and 2011-2012); additional review of VA medical records databases is ongoing.

6.  Sixth comment:

"The survey currently includes an extensive number of questions related to psychological problems (e.g., depression, anxiety, PTSD, substance abuse). While problems of this nature are found in Gulf War veterans, they are less common than in other war veterans, and there is no reason they should constitute such a large proportion of the Gulf War survey instrument. Similarly, the current survey devotes nearly four pages to detailed questions on gastrointestinal function and symptoms, giving them much more emphasis than other problems of importance."

VA response: The planned questionnaire includes the 17-item PTSD Checklist (PCL-17) and the Patient Health Questionnaire (PHQ) to assess major depressive disorder and other mental disorders. The PHQ is a brief self-report assessment of common mental disorders developed specifically for primary care. PHQ allows brief provisional primary care diagnoses of certain disorders including major depressive disorder and probable alcohol abuse or dependence. The additional set of questions about anxiety or panic attacks can be omitted based upon the Committee’s recommendations.

In general, we have tried to cover both general medical conditions and selected psychological conditions that are common in the general population and Veteran populations (major depression, PTSD, and other anxiety disorders) (Kang et al., 2009; Toomey et al., 2007). In planning the study, we have not drawn a sharp distinction between psychological conditions such as PTSD and medical conditions that have a biological basis since there is substantial evidence from neurological and genetics research that PTSD and other common psychological disorders are likely to have genetic, biological, and environmental determinants. In order to examine symptom-based conditions such as fibromyalgia, chronic fatigue syndrome-like illness, and unexplained multi-symptom illnesses in large-scale epidemiologic studies, it can be useful from a scientific or statistical perspective to be able to control for potential confounding factors or effect modifiers (for example, major depression). The Institute of Medicine Committee on Gulf War and Health 2009 report on "Gulf War and Health: Volume 8: Update of Health Effects of Serving In the Gulf War" highlighted the need for follow-up studies of neurologic and psychiatric outcomes.

The questions that were included from the Rome criteria for IBS and functional dyspepsia include several skip patterns. With the use of web-based survey techniques and built-in skip patterns, respondents who do not report discomfort or pain in their abdomen or chest (unrelated to heart problems) will not see the majority of the questions on IBS and functional dyspepsia. Respondents completing paper versions of the survey will see these items, but will be directed to bypass them.

7.  Seventh comment:

"The survey does not include questions related to the health of veterans’ family members, although this remains a concern for Gulf War veterans. Important areas for which systematic data are needed include information on children’s health —both congenital abnormalities and problems that develop later in life (e.g. childhood cancers, developmental disorders of learning and attention), and information on birth outcomes and fertility."

VA response: We agree with the Committee that additional information is needed about the health of Gulf War Veteran's family members. However, as noted above, there is a limit to the number and scope of questions that can be included in a single survey. A series of detailed questions on pregnancy outcomes was included in the 1995-1997 questionnaire and those data have generated key findings published in the peer review literature. Additional data about the health of Gulf War Veteran's family members (such as childhood cancer and developmental disorders of learning and attention) should ideally be collected as part of a separate study.

8.  Eighth comment:

"Although the last section of the survey includes questions on veterans’ use of several complementary and alternative medical (CAM) therapies, there is no systematic information collected on veterans’ use of healthcare services at VA and elsewhere, or their use of more conventional treatments at VA and elsewhere. There have been some indicators that most veterans with Gulf War illness do not use VA healthcare services, but that some may use services more intensively than veterans of other eras. It is not known if veterans with Gulf War illness have benefited from care provided by VA and outside sources, or from any specific treatments. It is also not known what proportion of veterans with Gulf War illness and other medical conditions have applied for and received disability benefits. Current data in these areas would be extremely useful."

VA response: We agree with the Committee about the value of collecting additional data about health care services utilized by Gulf War Veterans at VA and non-VA facilities. As mentioned above, the Longitudinal Health Study of Persian Gulf War Era Veterans, which is an active IRB-approved protocol of this same panel of Veterans, includes linkages of survey data with VA medical records databases.

9. Ninth comment:

"Several sections of the survey should include an “other” category to allow veterans to provide information that would otherwise be lost when the respondent is limited by choices provided in the questionnaire."

VA response: We agree with this Committee recommendation and can easily insert and "other" category to capture more information.

10.  Tenth comment:

“With the planned expansion of the Gulf War brain bank/tissue repository, the survey presents an opportunity to provide information on tissue and organ donation to the large group of Gulf War-era veteran survey participants. A brief introduction to the program could be provided, along with contact information for those interested in learning more. "

VA response: We appreciate this suggestion. All materials mailed to the participants as part of the survey have to be reviewed and approved by the IRB. Including materials about the brain bank, tissue repository, or organ donation in the same package as the survey may impact survey participation or create misperceptions among the study participants. A follow-up mailing to participants to introduce other opportunities to participate would have the support of EES.

Cited References
Kang HK, Mahan CM, Kee KY, et al. Illnesses among United States Veterans of the Gulf War: a population-based survey of 30,000 veterans. JOEM 2000;42:491-501.
Kang HK, Li B, Mahan CM, et al. Health of US veterans of 1991 Gulf War: a follow-up Survey In 10 years. JOEM 2009;51:401-10.
Kang H, Magee C, Mahan C, et al. Pregnancy outcomes among U.S. Gulf War veterans: a population-based survey of 30,000 veterans. Ann Epidemiol 2001;11:504-11.
Barth SK, Kang HK, Bullman TA, Wallin MT. Neurological mortality among U.S. veterans of the Persian Gulf War: 13-year follow-up. Am J Ind Med 2009;52:663-70.
Toomey R, Kang HK, Karlinsky J, et al. Mental health of US Gulf War veterans 10 years after the war. Br J Psychiatry 2007;190:385-93.