NOTE: UNEDITED DOCUMENT
UNITED STATES OF AMERICA
PRESIDENTIAL ADVISORY COMMITTEE
ON GULF WAR VETERANS' ILLNESSES
WEDNESDAY, NOVEMBER 8, 1995
EPIDEMIOLOGICAL RESEARCH ISSUES PANEL
The panel met in the Green Room, San Francisco War Memorial Building, 401 Van Ness Avenue, San Francisco, California at 8:30 a.m.,
JOYCE C. LASHOF, M.D., Committee Chair, presiding.
PANEL MEMBERS PRESENT:
JOYCE C. LASHOF, M.D., Committee Chair
JOHN BALDESCHWIELER, Ph.D., Committee
ANDREA KIDD TAYLOR, Dr.P.H., Committee Member
MARK BROWN, Committee Staff
HOLLY GWIN, Committee Staff
LOIS JOELLENBECK, Committee Staff
MICHAEL KOWALOK, Committee Staff
JOYCE C. LASHOF, M.D. 4
DEPARTMENT OF VETERANS AFFAIRS' EPIDEMIOLOGICAL
Mortality Follow-up Study of Persian Gulf
DR. HAN KANG
Environmental Epidemiology Service
Veterans Health Administration Department of Veterans Affairs
Principal Investigator 6
QUESTIONS FROM THE PANEL 15
The National Health Survey of Persian Gulf
Veterans and their Family Members
DR. HAN KANG 26
DR. HOWARD KIPEN
Robert Wood Johnson School of
MS. ALLISON EYDT
Office of Management and Budget 40
QUESTIONS FROM THE PANEL 51
DEPARTMENT OF DEFENSE EPIDEMIOLOGICAL STUDIES
Morbidity Among Gulf Veterans: A Search for Etiologic Agents and Risk Factors (studies
related to symptoms, hospitalization, and
Naval Health Research Center
DR. GREGORY GRAY 66
MR. KEVIN KAISER 75
DEPARTMENT OF DEFENSE EPIDEMIOLOGICAL STUDIES
Naval Health Research Center (continued)
MR. BRUCE COATE 83
DR. DAVID COWAN 92
Scientific Advisory Panel
DR. WARREN WINKELSTEIN 101
DR. HAL MORGENSTERN 105
DR. PHILIP CARTER 109
QUESTIONS FROM THE PANEL 113
PANEL DISCUSSION ON STRATEGY ON OUTSTANDING EPIDEMIOLOGICAL RESEARCH ISSUES 147
1 P R O C E E D I N G S
2 8:34 a.m.
3 COMMITTEE CHAIR LASHOF: Good morning.
4 I think we're ready to get started. Let me just
5 make a couple of opening remarks.
6 I appreciate all of you coming today.
7 Yesterday, we spent the morning hearing from a
8 number of concerned veterans who have serious
9 problems. In the afternoon, we began our discussion
10 of epidemiologic studies.
11 We all recognize, on the Committee, that
12 epidemiologic studies are difficult ones but they
13 certainly are our first method of attack at trying
14 to uncover what may be going on among the Gulf War
16 This morning, we are pleased that we are
17 going to be able to hear about the National Health
18 Survey of Persian Gulf Veterans and then also hear
19 from a series of studies being carried out by the
20 San Diego Research Group on the Seabees.
21 Before I call our first panel to the
22 podium, let me ask the members of our Committee and
23 Staff who are here to introduce themselves. I
24 should say that we are just a small subcommittee of
25 the whole Presidential Commission that is holding
1 this hearing around epidemiologic studies. We will
2 be reporting the results of these two days to the
3 full Committee at our meeting in December, assuming
4 that the debt ceiling is solved and the government
5 is functioning on December 3rd and 4th.
6 With that, let me ask Mark Brown to
7 introduce himself.
8 MR. BROWN: I'm one of those people paid
9 by the government so I'm particularly hopeful.
10 I'm Mark Brown; I'm with the Committee
12 DR. BALDESCHWIELER: I'm John
13 Baldeschwieler; I'm a member of the Committee and
14 I'm from the Chemistry Department at Cal Tech.
15 MS. JOELLENBECK: I'm Lois Joellenbeck
16 on the Committee Staff.
17 COMMITTEE CHAIR LASHOF: And I should
18 have said that I'm Joyce Lashof and I am Chair of
19 the Committee.
20 MS. GWIN: I'm Holly Gwin of Committee
22 DR. TAYLOR: I'm Andrea Taylor; I'm an
23 Industrial Hygienist with United Auto Workers Health
24 and Safety Department in Detroit and I'm a member of
25 the Advisory Committee.
1 MR. KOWALOK: And I'm Mike Kowalok with
2 the Committee Staff.
3 COMMITTEE CHAIR LASHOF: Let me ask Dr.
4 Han Kang, Dr. Howard Kipen, and Ms. Allison Eydt to
5 come to the table and do our first presentation.
6 DR. KANG: Good morning. This morning I
7 am going to describe two studies that VA is involved
8 with concerning Persian Gulf veterans' health.
9 The first study I'm going to describe to
10 the Committee this morning is the Persian Gulf
11 veterans mortality follow-up study of Persian Gulf
12 veterans. This study is initiated because of the
13 concerns expressed by Persian Gulf veterans soon
14 after they come home from the theater of operations.
15 We receive many inquiries from veterans, as well as
16 Congressional Staff and Congressmen themselves, how
17 many Persian Gulf veterans die of diseases or
19 There was numerous reports in the news
20 media that over 4,000 Persian Gulf veterans die of
21 Persian Gulf-related diseases of which about 1,500
22 veterans die of cancer. So we decided to conduct a
23 formal epidemiological study to compare the
24 mortality experience of those who served in the
25 Persian Gulf to the Persian Gulf era veteran.
1 (Slide change)
2 You may have already heard the
3 background information on the sequence of events in
4 the theater so I will not go into details, just to
5 let you know that, because of the different events
6 that occurred in the Persian Gulf, we may be able to
7 subgroup the study population into various exposure
8 categories. For example, those who were deployed in
9 the theater after the ground war is over, they may
10 not have been subject to anti-volatile chemical
11 agents, whereas those who were deployed at the time
12 of air war, they would have been subject to oil fire
14 So, based on the history of warfare, we
15 may be able to analyze the Persian Gulf veterans by
16 their potential exposure categories.
17 (Slide change)
18 These are a list of some of the risk
19 factors that have been measured in the literature or
20 in the news media; and I will not go into details.
21 (Slide change)
22 As I mentioned earlier, the objective
23 study is to compare the post-war mortality
24 experience; I need to emphasize that. It is not the
25 mortality experience of the entire Persian Gulf
1 veterans from the beginning of the war, it is after
2 the war, to compare the post-war mortality
3 experience of all Persian Gulf War veterans to that
4 of Persian Gulf War era veterans who did not serve
5 in the Persian Gulf theater.
6 (Slide change)
7 Design is the typical historical cohort
8 studies utilizing all Persian Gulf veterans,
9 approximately 700,000, to those sample 750,000;
10 that's about one-half of the all-era veterans at
11 that time.
12 (Slide change)
13 Definition of study subjects, all
14 military personnel who served in the Persian Gulf
15 theater of operation anytime between August, '90
16 through April, 1991. The control subjects are those
17 individuals who are in the military during the same
18 time period but who did not serve in the Persian
19 Gulf. And study subjects and control subjects are
20 frequency-matched by branch and the unit status;
21 that is, active, Reserve, and National Guard status.
22 (Slide change)
23 The vital status follow-up will begin
24 when Persian Gulf veteran return alive, and control
25 subject follow-up will begin on May 1, 1991. The
1 reason we don't want to bring that follow-up period
2 to the earlier period, that the experience of
3 Persian Gulf veterans and those who stayed stateside
4 will not be substantially different. The Persian
5 Gulf veterans are isolated, they are not driving on
6 the freeway. Our understanding is that the alcohol
7 usage was almost non-existent. So, comparing the
8 Persian Gulf and non-Persian Gulf veterans prior to
9 that period will not be appropriate.
10 (Slide change)
11 The vital status ascertainment will be
12 based on VA's own computer record as well as Social
13 Security Administration death benefits record and
14 also we will utilize National Death Index for
15 control purpose.
16 (Slide change)
17 Statistical analysis, we will compare
18 the experience of Persian Gulf veterans to non-
19 Persian Gulf veterans without adjustment, it will be
20 direct comparison based on their unit components.
21 So we will be comparing the active duty personnel
22 who served in Persian Gulf against active duty who
23 did not serve in Persian Gulf, and then Reserve
24 component against Reserve component who did not
1 And, after -- on adjusted ratio
2 comparison with adjustment based on their, of
3 course, age, sex, the length of time in the Persian
4 Gulf area, and other demographic and military
5 variables. And then finally, we will compare the
6 mortality experience of both Persian Gulf veterans
7 and non-Persian Gulf veterans against the national
8 experience, the United States population-based, the
9 mortality statistics.
10 (Slide change)
11 These are the results as of last month.
12 We have 695,516 individuals allied with the study as
13 Persian Gulf veterans and 746,000 as non-Persian
14 Gulf veterans. After vital status ascertaining
15 using VA and also SSA files, we found 1,765
16 individuals deceased among Persian Gulf, and 1,729
17 among non-Persian Gulf veterans.
18 We are still collecting death
19 certificates but, as of last month, we were able to
20 collect death certificates for 87 percent of Persian
21 Gulf veterans and 85 percent of non-Persian Gulf
22 veterans. So we know the cause of death for 87
23 percent of Persian Gulf and 85 percent of non-
24 Persian Gulf veterans.
25 (Slide change)
1 As I say, this is based on that 85
2 percent death certificate information.
3 When we compare those who served on
4 active duty, which of over 80 percent of all Persian
5 Gulf veterans, against non-Persian Gulf veterans who
6 served on active duty, the overall mortality rate
7 are about 15 percent higher among Persian Gulf War
8 veterans. The rate ratio is 1.15, which was
9 statistically significant for Persian Gulf veterans,
10 and most of those excess mortality rates came from
11 external causes, accidents, motors vehicle
12 accidents, and other accidental deaths.
13 And the other hand, the deaths to
14 illness or diseases are much lower among Persian
15 Gulf veterans compared to non-Persian Gulf veterans.
16 The rate ratio is generally less than one. The
17 infectious diseases are 0.17; all cancer, 0.57;
18 respiratory disease, .67; and digestive disease,
20 And I want to draw attention to
21 infectious diseases, there are only seven
22 individuals die of infectious diseases, in contrast
23 with a lot of concerns about the effects of
24 biological warfare agents and other endemic diseases
25 in Persian Gulf area, and we only see seven cases of
1 that from infectious disease among Persian Gulf
3 (Slide change)
4 Among the Reserve component, when we
5 compared Persian Gulf War veterans who came from
6 Reserve component against non-Persian Gulf veterans
7 from Reserve component who are activated and
8 deployed elsewhere, again we see similar result.
9 Their mortality due to external causes are elevated
10 although, because of the small number, that excess
11 mortality risk was not statistically significant.
12 (Slide change)
13 Unlike previous war, the Vietnam War, we
14 have approximately 50,000 women served in Persian
15 Gulf. And, when we compare them against non-Persian
16 Gulf War women veterans, their mortality experience
17 similar to the overall Persian Gulf War veterans.
18 The overall mortality risk is elevated about 50
19 percent and most of those elevated mortality risk
20 comes from external causes, accident, motor vehicle
22 (Slide change)
23 Finally, comparing against the U.S.
24 population, because of what we call the healthy-
25 veteran effect or healthy-worker effect, we expect
1 that their mortality experience will be much
2 favorable and here it is. Their mortality rate is
3 about half of what you expect from age, sex, race
4 adjusted national statistics. The all-cause of
5 deaths of Persian Gulf veterans SMR variable was .44
6 and, for non-Persian Gulf veterans, it's .38.
7 And it's understandable because, to be
8 in the military, you have to meet certain physical
9 criteria and also, to stay in the military, you have
10 to maintain certain physical criteria. And, when
11 they are separated, they have a better access to
12 medical care than average U.S. male or average U.S.
14 So all the studies of veteran population
15 show favorable mortality statistics; and this is no
16 different from the previous study.
17 (Slide change)
18 For women, they have a favorable
19 mortality experience compared to the national
20 statistics but their external cause of death for
21 Persian Gulf veterans are over 1.0. Compared to
22 U.S. general female population, the Persian Gulf
23 veterans, their mortality risk for accidents and
24 motor vehicle accidents and suicides are higher.
25 (Slide change)
1 The strengths of this study that I just
2 finished describing is that we do have a veteran
3 comparison group and, also, differential estimate of
4 the vital status is unlikely because both groups of
5 veteran population went through the same vital
6 status ascertainment procedure using VA's as well as
7 SSA's files.
8 And the statistical variation will be
9 small because we are taking all available study
10 subjects, all Persian Gulf veterans, 700,000, into
11 our study.
12 Limitations of cause of death is based
13 on death certificates. Sometimes death
14 certificates, the listing of cause of death may not
15 agree with actual -- the medical record itself so
16 there is some potential for misclassification if you
17 use the cause of death information only from death
19 And the most important thing is the
20 short follow-up period. Any disease that has a long
21 latent period, the follow-up period will be only two
22 and a half years, so we will not see any long-term
23 effects that originated from the Persian Gulf
24 experience and we do not have potential risk factor
25 information on both groups of veterans.
1 (Slide change)
2 In summary, since the war, Persian Gulf
3 veterans experienced a significant excess overall
4 mortality when compared to their military peers who
5 did not serve in the Operation Desert Shield/Desert
6 Storm, and that excess mortality occurred mainly due
7 to external causes, accidents and trauma, rather
8 than natural causes. And the mortality risk
9 experienced by Gulf War veterans was still less than
10 half of all expected from civilian counterpart for
11 overall causes as well as specific disease category.
12 That concludes my description of the
13 mortality study.
14 COMMITTEE CHAIR LASHOF: I think what we
15 should do now is take questions from the panel
16 concerning the mortality study, as I understand that
17 Dr. Kipen and Allison Eydt will be commenting on the
18 other study on the survey.
19 So, if the panel has any questions on
20 the mortality, let's do that now and then proceed to
21 the National Survey studies.
22 DR. TAYLOR: I want to go back to your
23 point about the death certificates.
24 How reliable is that information?
25 DR. KANG: The death certificate
1 information is very reliable, first of all, for
2 counting deaths. It is a legal document so it is
3 presumed to be a hundred percent reliable for --
4 DR. TAYLOR: But you said it was
5 different than what --
6 DR. KANG: But, for cause of death,
7 especially for cancer, there is, you know, several
8 studies comparing the cause of death information on
9 the death certificate against medical records.
10 For accidental death and external cause
11 of death, it is very reliable; but for natural
12 causes, especially for cancer, especially for
13 specific type of cancer, for example non-Hodgkin's
14 lymphoma, it is not as reliable as external cause of
16 DR. TAYLOR: Okay, so this is just
17 looking at the death certificate.
18 Were there any attempts made to look at
19 comparisons between what appeared on the medical
20 records versus what you had in the death
22 DR. KANG: Not at this point. The
23 driving force behind conducting this study is that,
24 in our experience dealing with the previous war
25 veterans, it tends to show elevated risk due to
1 external causes, the Vietnam veterans, World War II
2 veterans, Korean War veterans, the external cause of
3 death are elevated within a few years after they
4 come back from the war.
5 So the main focus -- hypotheses behind
6 this study was that we would expect to see elevated
7 mortality due to external causes. In fact, we did
8 find that from this study.
9 But, for disease with a long latent
10 period, we cannot use the death certificate to make
11 any accurate assessment of mortality risk for, for
12 example, the particular type of cancers.
13 DR. TAYLOR: Okay. So how useful would
14 this study be for delving into finding out whether
15 there was any relationship to Gulf War veterans or
16 any of the health symptoms that Gulf War veterans
17 are experiencing?
18 DR. KANG: Well, I think the conclusion,
19 at least based on preliminary data, is that their
20 mortality risk due to natural causes, that is due to
21 diseases, are lower than their counterpart who did
22 not serve in the military.
23 We have a lot of concern about the
24 illness and diseases that related to Persian Gulf
25 veterans but at least it hasn't shown yet from their
1 mortality experience.
2 DR. TAYLOR: And I don't know if you
3 would expect that it would be at this point, though.
4 DR. KANG: It will be too short.
5 DR. TAYLOR: Too short; okay.
6 COMMITTEE CHAIR LASHOF: Are there plans
7 to do -- to follow this group and --
8 DR. KANG: Yes.
9 COMMITTEE CHAIR LASHOF: -- and
10 periodically recheck? I don't know how often one
11 ought to but, several years downstream, taking
12 another look seems to be indicated.
13 DR. KANG: Since we already have a core
14 developed, the periodic follow-up updating the
15 mortality experience downstream will not be much
16 problem so we plan to do that in, say, every two or
17 three years.
18 COMMITTEE CHAIR LASHOF: The only
19 question I have is, as you point out, one of the
20 limitations was that you don't have specific risk
21 factors. Now, granted, since the overall mortality,
22 except for the excess external causes are not
23 different, still I wonder whether, once we get the
24 troop location information, which we expect to get
25 from the Department of Defense within the next month
1 or two, whether it will be worth going back and
2 looking at some of the specific locations where
3 we've had anecdotal presentations to this Committee
4 of high number of deaths in specific units, whether
5 we ought to take a look at those.
6 DR. KANG: We would like to do that.
7 When that information is available, we can quantify
8 the Persian Gulf veteran into the time and space in
9 the theater and see whether there is any difference
10 in the mortality experience based on their troop
11 movement and the time of performance.
12 COMMITTEE CHAIR LASHOF: Good, we will
13 look forward to that, too.
14 Are there any other questions?
16 MS. JOELLENBECK: A comment and a
18 The comment was, it looks from the data
19 as though, between deployed and non-deployed, there
20 really is a healthy-worker effect, a healthy-soldier
21 effect, which brings us back to something we touched
22 on lightly yesterday which was, when we're using the
23 deployed-but-not-to-the-Persian Gulf as a comparison
24 group, how good a comparison group is it.
25 DR. KANG: Okay.
1 MS. JOELLENBECK: And this just might
2 make us aware that, in fact, the deployed-to-the-
3 Persian Gulf might be expected to be healthier.
4 DR. KANG: I don't know what kind of
5 screening there was to select individuals to be sent
6 to the Persian Gulf; I guess the DOD can answer
8 But this particular comparison that I
9 presented here, if you look at the control group,
10 you know, we can say non-Persian Gulf veterans. For
11 those who served in Reserve units, there are two
12 parts of control that we are utilizing for this
13 study as well as the survey that I'm going to
14 describe later, that there are Reservists who are
15 activated and deployed somewhere, either stateside
16 or overseas, but not Persian Gulf area. And there
17 are Reservists who are in Reserve but not called up.
18 So I like to compare the effects of the
19 activation, or deployment itself, by comparing the
20 Reservists who are activated and deployed versus the
21 Reservists who are not activated at all. And this
22 particular comparison that I presented is the
23 comparison between Reservists who are activated and
24 sent to Persian Gulf, and Reservists who are
25 activated and sent elsewhere.
1 And I don't know whether there is a
2 particular physical -- to send one person to Persian
3 Gulf and one person to Germany; I don't know that.
4 But at least that kind of comparison will minimize
5 that healthy-soldier effect.
6 MS. JOELLENBECK: My question was, at
7 the beginning of your talk, about how you could
8 analyze, maybe by different time periods, that
9 people were in the Gulf. Have you moved ahead to do
11 DR. KANG: We'll do that. We just
12 finished the preliminary analysis; we haven't done
13 any subgroup analysis based on the time period when
14 they are in the Gulf area or their military
15 occupation. And we'd like to compare those who have
16 combat MOSC, the Military Occupational Specialty
17 versus the support troops, compared to based on the
18 branch because their experience may not be the same,
19 either environmental or psychological experience.
20 We would like to do all that analysis in the future.
21 COMMITTEE CHAIR LASHOF: John?
22 DR. BALDESCHWIELER: In your comparisons
23 with the civilian non-military operation, are those
24 cohorts age-matched?
25 DR. KANG: Yes.
1 DR. BALDESCHWIELER: Because it seems to
2 me age is a critical factor.
3 DR. KANG: Oh, sure.
4 DR. BALDESCHWIELER: And are there
5 systematic differences in age when you compare the
6 Reserves versus the active duty troops that were --
7 DR. KANG: The Reservists are older; I
8 think they are two or three years older than active
9 duty troops.
10 DR. BALDESCHWIELER: And so, when you
11 compare the era veterans versus the Gulf War
12 veterans, is there a systematic age difference
13 between those total groups?
14 DR. KANG: Well, we try to account for
15 that by comparing Reservists against Reservists, the
16 age are about the same, almost identical. And, when
17 we do SMR, we are adjusting for age, sex, race, and
18 calendar year of death because some cause of deaths
19 are going up, for example, say lung cancer on women
20 in general are going up without knowing what causes
22 DR. BALDESCHWIELER: I can imagine that
23 there is a systematic selection of age among those
24 -- for example those Reservists who are called up to
25 serve and those who are not. I would expect the
1 younger people had a higher rate of call-up.
2 DR. KANG: That's why I'm just comparing
3 those who are called up. Both groups are called up,
4 one sent to Persian Gulf and one sent to somewhere
6 DR. BALDESCHWIELER: All right.
7 DR. KANG: And, when I look at the
8 demographic characteristics, they are identical in
9 terms of age and race.
10 DR. BALDESCHWIELER: One extraordinary
11 feature of your results is the difference in
12 infectious disease, the numbers are very small for
13 deaths in those particular categories. But I wonder
14 if that reflects the selection on the basis of
15 positive versus negative HIV?
16 DR. KANG: In the veteran population in
17 general or --
18 DR. BALDESCHWIELER: It was my
19 recollection that they were screened for HIV.
20 DR. KANG: Right. I think the Armed
21 Forces screen for HIV at the entrance and as well as
22 periodically while they're in the service. So they
23 are --
24 DR. BALDESCHWIELER: Wouldn't there be
25 HIV-positive soldiers in the era but-not-sent-over
2 DR. KANG: I don't have that
3 information; I can't find that out.
4 DR. BALDESCHWIELER: Is there
5 differential or is HIV-positive a cause of rejection
6 for military service or Reserve service altogether?
7 I simply don't know.
8 DR. KANG: I don't know either.
9 COMMITTEE CHAIR LASHOF: If you have the
10 answer to that, go ahead.
11 DR. GREGORY GRAY: It's very true we
12 have people who are infected with HIV who remain in
13 the service and there is a judgement call regarding
14 the progression of their disease. There is a period
15 where they actually leave the service and if so --
16 and depending on their status they are kept
17 stateside where they can obtain excellent health
19 So you're right in the sense that the
20 differential representation with respect to HIV
21 serology. But I want to remind you that the number
22 of people infected with HIV in the DOD is very very
23 small compared to the number of people in the
24 general population.
25 COMMITTEE CHAIR LASHOF: Thank you.
1 Anything else or can we move on.
2 MR. BROWN: May I ask one?
3 COMMITTEE CHAIR LASHOF: Sure.
4 MR. BROWN: Did I understand you, Dr.
5 Kang, to say that there is a precedent for observing
6 this effect of greater accident -- greater mortality
7 rates due to accidents in returning veterans from
8 previous wars? And are the effects that you saw
9 comparable to the -- in terms of their magnitude to
10 these other situations?
11 DR. KANG: I don't know where there is a
12 coincidence or not. CDC conducted the mortality
13 study of Vietnam veterans to compare Vietnam ground
14 troops against the non-Vietnam ground troops which
15 was published in 1986 and they show .7 percent
16 elevated overall mortality among Persian Gulf
17 veterans and their risk ratio is lower for natural
18 cause and then, of course, the risk ratio is higher
19 for external cause including --
20 MR. BROWN: It's similar.
21 DR. KANG: So it is not -- it is
22 consistent with the previous war veterans' mortality
24 COMMITTEE CHAIR LASHOF: Do we know
25 whether any of those external causes or accidents
1 were related to alcohol abuse and drug problems and
2 depression and psychological problems that followed
3 the war?
4 DR. KANG: Well, we didn't have access
5 to the medical records so we can't say anything
6 about that yet. But the CDC mortality study that I
7 just finished describing, they did go back and
8 collect the medical records of those accidental
9 deaths except for motor vehicle accidents. I think
10 they were able to add two or three additional cases
11 to suicide based on the record received.
12 So I don't think there would be many
13 hidden suicides among accidental deaths.
14 COMMITTEE CHAIR LASHOF: Thank you.
15 I think we need to move on to ask you
16 now to discuss the National Survey of Persian Gulf
17 War veterans, which is just getting under way.
18 DR. KANG: Yes.
19 COMMITTEE CHAIR LASHOF: I know you
20 don't have results, you are just going to tell us
21 about how it's playing and what we can hope to get
22 from it.
23 DR. KANG: Almost a year and a half ago,
24 there was a workshop at NIH in April. The panel
25 members of that group committee were asked to review
1 the relevant information and make a recommendation
2 what future research is needed.
3 (Slide change)
4 The NIH panel recommended that more
5 accurate estimate of the symptom prevalence be
6 established. They had been hearing a lot about, you
7 know, high proportion of returning persons
8 complaining of various symptoms. Our experience
9 dealing with Persian Gulf Registry, House Registry,
10 it is a self-elected group coming to the aid,
11 receiving medical examinations.
12 The proportion of individual with
13 fatigue is in the range of 20 percent, with the skin
14 problem, 20-some percent; and this all self-selected
15 group, there is no good estimate of symptom
16 prevalence as well as the medical conditions. Both
17 NIH panel recommend that we should do that, we
18 should either conduct a survey of entire 700,000
19 veterans or do representative samples and then
20 conduct a survey.
21 So that was NIH panel recommendations.
22 And the VA accepted recommendation and decide to do
23 National Survey.
24 And then the following November,
25 Congress passed a law, Public Law 103-446, actually
1 direct the Secretary of Veterans Affairs to conduct
2 the House survey. So those two instance are driving
3 force behind what we designed for the National
5 (Slide change)
6 We have three objectives of purpose, to
7 estimate and compare prevalence of symptoms and
8 health outcome among Persian Gulf veterans and non-
9 Persian Gulf veterans; and also to estimate and
10 compare prevalence of their reproductive health
11 among spouses and birth defects among children of
12 Persian Gulf veterans and non-Persian Gulf veterans;
13 and then finally, to the extent of -- and I need to
14 emphasize "to the extent possible" because most of
15 the exposure information we will collect will be
16 self-reported and non-verified.
17 So, to the extent possible, prevalent
18 relations between selected symptoms and health
19 outcome and then certain environment exposure in the
20 Gulf area.
21 (Slide change)
22 Study subjects, we sampled 15,000
23 Persian Gulf veterans from the cohort that we
24 developed and used for the mortality study and an
25 equal number of non-Persian Gulf veterans from the
1 population that we select for the mortality study.
2 (Slide change)
3 Study design, we will use questionnaire;
4 it will be mail questionnaire supplemented with a
5 telephone interview for the non-respondents and then
6 finally, physical examination on a sample of
7 veterans and their family members.
8 And also we will supplemental validate
9 the self-reported exposure and health outcome of
10 data against available military NDA records.
11 (Slide change)
12 For the mail survey, we will send out
13 the initial notification letter, followed up with
14 the questionnaire and then postcard reminder and
15 then replacement questionnaire and then another
16 replacement questionnaire.
17 Because of the expected low response
18 rate based on mail survey, we will do all we can to
19 increase response by sending out the reminders and
20 follow-up questionnaires and then also supplemental
21 telephone interview for a sample of non-respondents
22 to ascertain non-respondents bias and then physical
24 (Slide change)
25 The time table, the Phase I postal
1 survey will take us about a year, 12 months.
2 (Slide change)
3 The telephone interview will take some
4 other 18 months. During that time, we will validate
5 the medical records of random sample 1,000 from
6 Persian Gulf and 1,000 from non-Persian Gulf groups,
7 compare their medical records, both from civilian
8 facility as well as DOD and VA facility.
9 And then final physical examination from
10 the same 1,000 respondents from Persian Gulf group
11 and that non-Persian Gulf group, veterans groups,
12 will be conducted.
13 This table show this division of study
14 subjects and control by Persian Gulf service status,
15 as well as the unit component status. Our expert
16 panel recommend that we do over-sample -- we should
17 over-sample Reservists and the National Guard
18 servicemen and also women, for those three groups
19 are oversampled. Altogether, 15,000 Persian Gulf
20 veterans, 3,000 of those 15,000 will be women.
21 (Slide change)
22 The strength of this proposed National
23 Survey, based on postal questionnaire is -- it is
24 not a very expensive propagation compared to either
25 telephone survey of all 30,000 or in-person survey
1 of all 30,000. And because this postal survey will
2 be much shorter information collection time compared
3 to other methods, and we can have a very large
4 number of individuals for the study. And also wider
5 geographic area.
6 And respondent will have the time to
7 review and compare their -- pull out their medical
8 records or any records they need to answer the
10 So those are the strengths of the postal
11 questionnaire method.
12 The limitations are very obvious. We
13 expect lower response rate, 40 to 60 percent
14 compared, say a telephone survey which, if it is a
15 good telephone survey, range around 80, 90 percent.
16 The questionnaire has to be very short
17 because, you know, we don't expect many people to
18 spend hours and hours to filling out the
19 questionnaire, otherwise it will go down the
20 wastebasket. So there is a limited number of
21 questions that we can ask. And the question has to
22 be very simple and straightforward. And it doesn't
23 give a chance to ask follow-up questions.
24 So those are the limitations of the
25 methodology that we are proposing here.
1 (Slide change)
2 This is the table describing sample size
3 we require for certain statistical power given
4 background prevalence rate. For example, what you
5 are interested in is the symptom that has five
6 percent prevalence rate among your comparison
7 population, for example, say, slip disturbance.
8 To have a 90 percent statistical power
9 when, in fact, the difference is say over 50
10 percent, you will need 1,966 individuals in each
11 study. And we have 30,000 people in each study.
12 So we have adequate statistical power
13 for the prevalence, the symptom prevalence up to
14 five percent. But if your symptom prevalence is two
15 percent, for same statistical power with the same
16 relative risk, you will need 5,116 people for 90
17 percent statistical power.
18 So statistical power, for our study, is
19 fairly good because of the large sample size we are
21 (Slide change)
22 And, of course, if you have a higher
23 prevalence, like if 15 percent, which is what we
24 observe among the Persian Gulf veterans who come for
25 Registry examination for fatigue you will need a
1 very small number, only 567 people in the study.
2 (Slide change)
3 This is what transpired up to this
4 point. As I described earlier, after April 27 NIH
5 Technology Assessment Workshop, we proposed a study
6 to Persian Gulf Expert Scientific Committee in July
7 meeting. They accept that and asked us to develop a
8 full study protocol which we presented in November
10 And, because of the need for having
11 standing oversight committee and because of the
12 difficulty of establishing advisory committee
13 because there is a moratorium on federal advisory
14 committee, the advisory committee decided to have a
15 subcommittee overseeing the proposed National
16 Survey. So they established the oversight committee
17 as subcommittee of the parent VA Persian Gulf Expert
18 Scientific Committee.
19 So we had our first meeting in November
20 and, in January, the Secretary gave us approval to
21 go ahead with the Study. In March, we had another
22 meeting and then, in April, we received final
23 approval for protocol as well as the questionnaire
24 that we proposed.
25 In May, we applied for OMB approval for
1 the questionnaire and, on September 20, we received
2 the approval. On October 11th, we sent out pre-
3 notification letters and, today, the actual
4 questionnaire is being mailed out.
5 That's where we stand in terms of
7 (Slide change)
8 The individuals who serve on the
9 oversight committee, Dr. Stolley is the Chair, and
10 Dr. Bascom, Dr. Leon Gordis. Dr. Gordis is not a
11 member of the parent Expert Scientific panel but he
12 is a member of the subcommittee because of his
13 expertise in epidemiology. And Dr. Howard Kipen,
14 who is also a member of the full committee, serving
15 on the oversight committee, and Dr. Jim Melius.
16 Those five individuals are serving as oversight
17 committee members.
18 That concludes my --
19 COMMITTEE CHAIR LASHOF: Thank you very
20 much and we are very pleased that Dr. Kipen is here
21 to talk from the oversight committee and he will
22 comment at this point.
23 DR. KIPEN: I'd like to thank the
24 Committee very much for being here and I will
25 apologize in advance for the art work on my
1 overheads which, because of the timeline done on the
2 airplane, which was a smooth flight, fortunately.
3 (Slide change)
4 As Dr. Kang said, I am a member of the
5 oversight committee although, again, because of the
6 timeline, I have reviewed our minutes, I have not
7 consulted with any of the other committee members
8 prior to this presentation.
9 The aspects of the study that we
10 concentrated on in our two face-to-face meetings and
11 one conference call were a review of the goals of
12 the project and I will, for each of these things, I
13 will tell you what in particular we recommended in a
14 moment, and then also various aspects of the methods
15 which included the design and protocol, various
16 aspects of statistical analysis, considerations of
17 power, study recruitment -- meaning the invitation
18 letter -- the format of various questions, and then
19 finally the content of some questions.
20 If I could have the next overhead,
22 (Slide change)
23 What I have listed for you on this slide
24 are the areas in which I thought the study was
25 significantly modified by our input of where the VA
1 investigators were significantly responsive to
2 things that we talked about.
3 First of all was the idea that, in terms
4 of the goals, that the goal of doing etiologic
5 analyses in determinations be de-emphasized because
6 of the limited ability to capture information on
7 exposures of interest, or primarily because of that.
8 In fact, it has been de-emphasized, as Dr. Kang
10 We asked, in particular at the first
11 meeting, for some clarification and increased detail
12 on the statistical methods that he proposed to use
13 and that was provided and the committee was
14 satisfied with the robustness of those methods.
15 We were concerned that initially the
16 sample size for the Phase II follow-up telephone
17 interviews of 500 persons, that it would not provide
18 adequate power for assessing prevalence of
19 relatively rare or less than even five percent
20 outcomes in there. And, because of that, we
21 suggested to Dr. Kang that an attempt be made to
22 increase that number to 4,000.
23 He was reluctant at first, I think
24 because of concerns of the cost of the telephone
25 interviews. However, I believe that it has now been
1 increased to 4,000 and so we're glad that those
2 resources were recovered.
3 We suggested some revisions of the
4 recruitment letter to clarify for the recipients or
5 the potential subjects that confidentiality would be
6 protected and also to try to appeal to what we
7 thought would be some of their nobler instincts
8 rather than compliance with Public Law 103-446. And
9 we think the letter has made some improvement in
10 doing that.
11 We suggested some changes in order of
12 questions that we thought would be more well-
13 received by subjects, some changes in how -- one of
14 the characteristics of the questionnaire that I
15 particularly like is the way the -- for symptoms, we
16 ask when they began and we ask subjects to clarify
17 whether it was before the Gulf, during service in
18 the theater, or afterwards. And how that's
19 formatted was a little bit complex and I think it
20 kind of came out quite nicely.
21 We made a number of detailed suggestions
22 on the reproductive section having to do with
23 identification of partner or spouse for a given
24 child and just how this would be recorded in a
25 useful manner. We suggested some revisions in -- in
1 fact, a different version of the review of systems
2 questionnaire and that was incorporated.
3 We suggested some clarifications of the
4 definition of the term "severe" for quantifying or
5 assessing how severe symptoms were and those
6 suggestions were also incorporated, although I
7 understand, during subsequent negotiations with OMB,
8 some of that has been changed, or at least the
9 moderate category of symptom severity has been
11 We suggested, in particular, some
12 questions to be added to assess the prevalence of
13 chronic fatigue or chronic fatiguing illness among
14 recipients of the questionnaire. And many of those
15 were added. We suggested the deletion of some
16 questions on chemical sensitivity which had been
17 proposed in initial versions of the questionnaire
18 but which we did not think were among the most
19 robust questions available for assessing that
20 symptomatic phenomenon and did suggest a replacement
21 question about chemical sensitivity be substituted;
22 and that is on the questionnaire.
23 Could I have the next slide, please?
24 (Slide change)
25 In terms of the strengths, Dr. Kang went
1 over most of those. I, and I think the rest of the
2 committee, feel that this is the best thing that I'm
3 aware of that's going out there for generating
4 prevalence of -- estimates of prevalence of symptoms
5 in the deployed cohort relative to appropriate
6 control groups, the ability to divide the comparison
7 groups into those who were deployed to the Gulf and
8 those who were merely activated, we see as a big
9 strength. The record review validation, in terms of
10 looking at hospitalizations and perhaps some other
11 end points will be quite useful.
12 And finally, the estimates now of non-
13 respondent bias with their increased size should
14 also be a big strength of this compared to many
15 other efforts of a similar type.
16 The limitations are that we still don't
17 have all the power we would like for some of the
18 things that concern a lot of people, certainly
19 individual reproductive outcomes and things like
20 that. But I think that, for looking at the
21 symptomatic illnesses, which this is best designed
22 to take a look at, I think we're going to be doing
23 okay in terms of power.
24 Exposures continue to be self-reported
25 and I'm sure your Committee is very familiar with
1 the problems with that. We will, of course, have
2 problems with lapse of memory as well as recall bias
3 among symptomatic people or people who have
4 experienced adverse outcomes.
5 And then finally, limitation will be
6 that we will not really be able to estimate the
7 prevalence of symptoms characteristic of actual full
8 chronic fatigue syndrome or of chemical
9 sensitivities because we did not use as many
10 questions as some members of the committee thought
11 would be useful for pursuing those lines of
13 That concludes my prepared remarks.
14 COMMITTEE CHAIR LASHOF: Thank you very
15 much, Dr. Kipen.
16 I think we will move on and ask Ms.
17 Allison Eydt from the Office of Management and
18 Budget to comment and then we will open it up for
19 questions from the panel.
20 MS. EYDT: Good morning members of the
21 Presidential Advisory Committee and researchers.
22 It is a pleasure and an honor to discuss
23 today the Office of Management and Budget's role in
24 reviewing federally-sponsored surveys on Gulf War
25 veterans' illnesses.
1 In particular, your staff has requested
2 that I highlight OMB's review of the Department of
3 Veterans Affairs survey entitled "National Health
4 Survey of Persian Gulf Veterans and their Family
6 Before discussing Dr. Kang's survey, let
7 me begin by providing some brief background on OMB's
8 role in reviewing federally-sponsored surveys.
9 I am a Senior Desk Officer in OMB's
10 Office of Information and Regulatory Affairs and
11 have worked in health regulation and research for
12 the last ten years at OMB on programs that include
13 the VA, Department of Defense, CHAMPUS, Medicare,
14 and Public Health Service accounts such as the
15 Agency for Health Care Policy and Research and the
16 National Center for Health Certificates.
17 As an OMB Desk Officer, I carry out
18 OMB's responsibilities under the Paperwork Reduction
19 Act in concert with other OMB Desk Officers,
20 statisticians, economists, budget analysts, and
21 other analysts from sister agencies such as the
22 Office for Science and Technology Policy. I serve
23 as the public point person for review of agency
24 efforts to ensure compliance with the Act.
25 Certain provisions of the Act and its
1 regulations have special import for the surveys we
2 have discussed in this public hearing. For example,
3 fundamental objectives of the Act are: to
4 coordinate; integrate; and to the extent practicable
5 and appropriate, make uniform federal information
6 resources management policy and practices as a means
7 to improve the productivity, efficiency, and
8 effectiveness of government programs; and to improve
9 the quality and use of federal information to
10 strengthen decision-making, accountability, and
11 openness in government and society.
12 Further, the statute requires that the
13 Director of OMB maximize the practical utility of
14 and public benefit from information collected by or
15 for the federal government.
16 The PRA regulations define practical
17 utility as the actual, not merely the theoretical or
18 potentially usefulness of information to an agency,
19 taking into account its accuracy, validity,
20 adequacy, and reliability, and the agency's ability
21 to receive and process the information it collects.
22 The VA was submitted to OMB earlier this
23 summer. Initially, OMB reviewed the VA study in
24 isolation of other Gulf War studies and on its own
25 merit. OMB staff considered the primary objectives
1 of VA's research and whether they were consistent
2 with VA's unique statutory and regulatory missions,
3 the proposed sample size and methodology, VA's
4 expected response rate, and plans for data
5 validation and respondent follow-up, et cetera.
6 In its supporting statement, the VA was
7 frank as to the research challenges in this area and
8 outlined potential pitfalls. OMB appreciated VA's
9 foresight and directness in exploring these issues
10 and ultimately approved this survey with the
11 expectation that many of these limitations would be
12 caveat on any dissemination of research findings.
13 The issues that concerned OMB most were
14 related to research coordination. As a result of
15 its Paperwork Act mandate and oversight role of
16 numerous executive agencies, OMB staff became aware
17 that the VA National Study was one in a series of
18 agency efforts. To meet conditions for OMB approval
19 under the law, it was imperative that the VA study
20 be coordinated sufficiently with other studies. In
21 particular, during the course of our review, the
22 Centers for Disease Control Iowa Study was submitted
23 and we learned of a promising VA study that would
24 pursue exposures in more detail.
25 Because OMB staff knew of these studies
1 in the course of our formal review, under the PRA,
2 the Paperwork Reduction Act, we coordinated the VA
3 Study with these efforts and vice versa. Within our
4 time constraints, we did the best we could to move
5 the studies in this direction.
6 Because of its reasonable design, scope,
7 and national representativeness, we focused on the
8 VA National Study as a valuable benchmark study for
9 future prevalence studies. Under this premise, we
10 compared its core question modules identifying
11 symptoms, medical conditions, and exposures with the
12 other two studies and targeted areas of deviation.
13 We felt it was important to use this VA
14 review as an opportunity to develop a standard set
15 of symptoms and, to a lesser extent, medical
16 conditions and exposures that could be validated by
17 other agency regional and localized studies as well
18 as defining its research progressive.
19 When OMB shared copies of these draft
20 studies between CDC, HHS, and DOD, we were pleased
21 to learn that the agency researchers were familiar
22 with each other's work. The agencies justified any
23 differences in terms of commitment to more in-depth
24 pursuits of certain issues, preferences for
25 different survey modes or methodologies, and
1 different agency cultural perspectives.
2 OMB continues to recognize the
3 rationales underlying survey differences and the
4 importance of intellectual freedom and exploration.
5 However, OMB was concerned that, if certain
6 questions were not consistently asked in all major
7 surveys, it may be impossible to control for
8 differences in research findings that would arise
9 from intricate differences in instrument design.
10 To strike this delicate balance between
11 using studies for validation versus exploration of
12 new realms, OMB decided to work with the interested
13 agencies to create core sets of symptoms, and to a
14 lesser extent, medical conditions and exposures, by
15 proving these differences between the VA survey and
16 the CDC survey. The resulting core symptoms list
17 will be incorporated into the VA prevalence survey,
18 the Iowa Study, and hopefully future studies that
19 begin exploring exposure and causation with a
20 symptom screen.
21 Of course, future studies would be free
22 to explore other issues appropriate to their efforts
23 consistent with meeting the Paperwork Reduction Act
24 standards for approval.
25 In examining the differences between
1 surveys, OMB negotiated several amendments that OMB
2 hopes will facilitate its use as a benchmark
3 prevalence survey. For example, rather than focus
4 on symptoms identified in the last week, the VA
5 study now determines whether symptoms have been
6 experienced in the last month consistent with CDC
8 VA added or revised existing symptoms on
9 their list to be consistent with CDC's inventory.
10 VA added and amended several exposure categories
11 that have been of interest to veterans, including
12 exposure to dead animals, chemical gear protection,
13 and SCUD missile explosions within a mile.
14 It is important to note that, on a
15 separate trek, OMB worked with CDC to make similar
16 conforming changes to the Iowa Study.
17 So what does the VA review mean for
18 future survey efforts that must receive OMB
19 clearance before they can be fielded? First, to the
20 extent that agencies and other formal coordinating
21 bodies aggressively can address the issues of where
22 standardization and coordination are critical to
23 achieving refinement in research and valid results,
24 all these review process will be simpler.
25 OMB does not approve the coordinating
1 board's overall research strategy. But, to the
2 extent that this strategy does not reflect
3 coordination, it satisfies the growth of the
4 Paperwork Reduction Act. OMB must ensure that this
5 is done to the extent possible because OMB review
6 typically is at the end of the agency survey design,
7 procurement, and contracting and budgeting streams.
8 It would be sensible for maximum
9 coordination to occur earlier before agencies are
10 locked into their own instruments, methodologies,
11 and schedules. If this coordination is not apparent
12 to OMB in future reviews, however, it must continue
13 to perform this function as required by law.
14 An immediate example for consideration,
15 many of the studies that are intended to fulfill the
16 first and most basic research question pertaining to
17 symptoms prevalence. Studies that focus on
18 prevalence or have a foundation in measuring
19 prevalence should justify by deviation from the
20 symptoms categories in the VA study.
21 OMB is not saying that additional
22 categories or some minor changes will not be
23 allowed. But the agency must be able to justify how
24 responses to each category can be related to NEVA
25 national findings in a valid and reliable manner.
1 Agencies that desire to deviate from basic VA core
2 symptoms list items must explain how these
3 deviations will have utility and contribute to firm
4 research findings on the incidence and causation of
5 Gulf War illnesses.
6 To put it simply, OMB's concern that too
7 much research could lead to inconsistent research
8 findings that conveniently cannot be resolved
9 because we are left with comparing apples and
10 oranges. OMB discourages unnecessary redundancy but
11 encourages consistency that leads to valid and
12 reliable findings and the refinement of research
14 Several pragmatic lessons that the
15 agencies can learn from our VA review: First,
16 future studies that must receive OMB clearance
17 should adopt, to the maximum extent feasible, the VA
18 symptoms list and to allow, to lesser extent, the
19 medical conditions list and exposure list. Agencies
20 must be prepared to identify any such deviations up
21 front and explain the research justification for
22 such deviation.
23 For example, an agency may explain that
24 its more-detailed categories could be collapsed into
25 one of the VA symptoms categories. In particular,
1 regional or local studies relying on symptoms screen
2 and prevalence measurement should be designed to
3 ensure that comparisons can be made to the VA
4 study's national results.
5 CDC worked with OMB to accomplish this
6 with its Iowa Study. Future studies may want to
7 build off the VA study as a screener instrument and
8 even use it as a sample base.
9 Second, the OMB-supported statements
10 should explain in detail how the agency has
11 coordinated its studies with other efforts designed
12 to answer the same research, question for question.
13 This may prevent OMB from reinventing the wheel and
14 will help us provide a more expeditious review.
15 Third, if the study is one phase of
16 several research protocols, agencies should provide
17 OMB with as much detail as possible regarding the
18 substance and methodology of future phases. OMB
19 cannot evaluate the practical utility of the
20 screener instrument unless it understands the entire
21 project and how its components together will address
22 research objectives.
23 Agencies should know if this study is
24 subject to OMB review and plan for the review period
25 in their schedule. All federally-sponsored studies
1 asking standard questions of ten or more respondents
2 are subject to OMB clearance, the joint-agency OMB
3 review can be expected to take from 90 to 120 days,
4 and finally, if the agency has completed its design
5 and supporting materials, OMB recommends that it
6 shares these materials in draft with us while the
7 public 60-day comment period is in progress. Early
8 discourse on issues may facilitate early resolution
9 and more expeditious OMB review.
10 MR. LEIGHTON: Can you --
11 MS. EYDT: Conclusion --
12 COMMITTEE CHAIR LASHOF: Okay.
13 MS. EYDT: OMB must satisfy a broad
14 mandate for ensuring maximum usefulness and
15 coordination in federal research. In reviewing
16 individual surveys, OMB attempts to appreciate and
17 evaluate prior efforts to fit discreet surveys into
18 a meaningful, comprehensive federal research
19 strategy. To the extent that this work has been
20 accomplished, it makes OMB's job simpler.
21 But, if this coordination does not
22 appear to have been accomplished with appropriate
23 attention to detail, OMB may work with agencies to
24 amend individual surveys to facilitate such
25 coordination. OMB strove to meet its coordination
1 responsibilities in this manner in the context of
2 its review of the VA National Prevalence Survey.
3 OMB looks forward to working with all
4 interested parties in ensuring that future Gulf War
5 surveys produce valid and reliable data that serves
6 the public interest.
7 Thank you and I welcome your questions.
8 COMMITTEE CHAIR LASHOF: Thank you very
9 much. We will now open it up for questions to any
10 one of the members of the panel.
12 DR. TAYLOR: Thank you.
13 I'm pleased to see that OMB is actually
14 helping to coordinate efforts between, I guess, the
15 Iowa Study and the VA Study. And I'm familiar with
16 OMB from working with OSHA and how long it takes for
17 a standard to be passed and I know this was a little
19 However, I guess I'll go back to the
20 question of, in the process of reviewing research
21 that is going on and the proposals for research that
22 you are going to be doing as far as questionnaires
23 and other, the process you mention will take 90 to
24 120 days.
25 Now I've heard that before and I've
1 heard it extended far beyond that. So I'm just
2 trying to get a sense of what that actually means,
3 more long-term.
4 MS. EYDT: Right. Hopefully, I won't
5 sound too bureaucratic, so I'll try to simplify it a
6 little here.
7 But the process begins with a notice
8 that's published by the agency in the Federal
9 Register. That notice commences a 60-day review
10 that's managed by the agency, comments are sent to
11 the agency. After those 60 days, the agency reviews
12 the comments and decides whether amendment would be
13 preferable or necessary.
14 At that point, after they make those
15 changes, they put in another notice in the Federal
16 Register saying "we're sending it to OMB now" and,
17 at that point, we would commence our review. We
18 have to hold the instrument for a minimum of 30
19 days, so we have a minimum 30-day review of any
20 instruments. And that can be extended for up to 60
22 So that's where I get the 90 to 120
23 days; that's actually -- it's quite conservative
24 assuming -- that assumes there will be no changes
25 made by the agency after the 60-day comment period.
1 DR. TAYLOR: Going back to my previous
2 experience with OMB, I know that it takes usually
3 longer than that.
4 MS. EYDT: I can't speak to your
5 previous experience.
6 DR. TAYLOR: All right.
7 MS. EYDT: But we are compelled, under
8 our regulations, at 5 CFR 1320, to take no longer
9 than a certain period of time, the time frame that
10 I've laid out.
11 I think some of the frustration may
12 result, also, from the review period within agencies
13 before they even get to the first step and so it's
14 all -- because it -- they're doing that because of
15 us, it all gets added in together.
16 But we are compelled under our
17 regulations to take no more than the 120 days in the
18 whole process.
19 DR. TAYLOR: Okay. I have one other
20 question of Dr. Kipen and Dr. Kang, with the
22 You mentioned that questions related to
23 chronic fatigue syndrome and multiple chemical
24 sensitivity were either changed or reduced -- the
25 number of questions? I'm not certain.
1 Can you go back over what happened in
2 that case with chronic fatigue syndrome and the
3 questions related to multiple chemical sensitivity?
4 DR. KANG: Because the study is the
5 symptom prevalence survey, we didn't want to focus
6 on any particular syndrome and I alluded to earlier
7 that one of the limitations of the postal survey is
8 that the length of the -- the questionnaire has to
9 relatively short.
10 So we were struggling with, you know,
11 whether we should lengthen to capture more
12 information or shorten it and have a higher response
13 rate. It's a trade off between the two and there
14 were extensive discussion among the oversight
15 committee and I think the final recommendation is
16 that they will leave it up to the principal
17 investigator to make that judgment.
18 So we compromised and took, not the
19 entire questions dealing with the multi-chemical
20 sensitivity and chronic fatigue syndrome, but some
21 of the questions dealing with chronic fatigue and
22 multi-chemical sensitivities so that, in the future
23 -- in fact, there is a marked difference between two
24 groups and somebody can explore that with another
1 But we thought that this study cannot be
2 a study for all health outcomes or -- that's where
3 we stand.
4 DR. TAYLOR: Okay.
5 COMMITTEE CHAIR LASHOF: You indicated
6 that, obviously, the response rate in mail
7 questionnaires is a problem and you have increased
8 the number of phone interviews you will do to try to
9 deal with that.
10 But you also indicated that, from the
11 physical examination, you would be doing a -- and
12 I've forgotten the number that would be done -- but
13 those were all follow-ups on those who responded and
14 it would be a certain number of deployed and non-
16 DR. KANG: Right.
17 COMMITTEE CHAIR LASHOF: Do you think
18 there is any chance of getting those who don't
19 respond to the questionnaire that you might have
20 been able to reach by phone to convince them to come
21 in for a physical examination so that you have some
22 better control on the non-respondents and whether
23 you are getting too much of a bias group from those
24 who responded compared to the non-?
25 DR. KANG: Perhaps we didn't really
1 explore that possibility but we thought that, if
2 individuals choose not to even respond to the simple
3 postal survey, it would be extremely difficult to
4 have them come in for physical examination.
5 So that was a pure assumption.
6 COMMITTEE CHAIR LASHOF: All right.
7 DR. KANG: So our current proposal to
8 not include physical examination of all those
9 individuals who refused to participate.
10 COMMITTEE CHAIR LASHOF: Well, I
11 suspect, when you get to look at your non-
12 respondents and how -- whether they differ
13 significantly from the others, it may be worth
14 thinking about whether you could convince people who
15 don't want to fill out a questionnaire but, if given
16 an opportunity to have a complete physical exam at
17 some place close to them and so forth, might well
18 avail themselves of it. And it might be another way
19 to get at it. I'm not sure, but --
20 DR. KANG: We don't have any reason not
21 to include, it was a practical decision that we
23 COMMITTEE CHAIR LASHOF: I don't know
24 whether Dr. Kipen has any thoughts on that either,
25 just one I asked --
1 DR. KIPEN: I guess I would have to echo
2 Dr. Kang's concern about the likelihood that they
3 would accept it. And then you have to wonder a
4 little bit about what you're going to get out of it
5 in terms of a physical exam.
6 I think how much you uncover from
7 somebody who is not really willing to go in, I
8 think, on a physical exam is somewhat limited. And
9 perhaps, depending on the questions that you
10 successfully ask them on the telephone interview,
11 you may be able to get a lot of the meat of what you
12 really want.
13 COMMITTEE CHAIR LASHOF: Well, I won't
14 pursue it very far, it's just a thought in terms of
15 trying to deal with the non-respondents and
16 respondents and how comparable they are.
17 I wanted to ask Ms. Eydt about the OMB,
18 whether you feel that OMB should be involved earlier
19 and proceed or whether this experience and your
20 words to the agencies is sufficient to make sure
21 that the coordinating board of the other mechanisms
22 are utilized so that you have less problem when it
23 gets to you?
24 MS. EYDT: Well, like I said in my
25 remarks, at a minimum, I think, we should be
1 involved within the 60-day period when the
2 instrument is out for public comment.
3 We have also, in the past, been involved
4 with coordinating groups, we've been involved in the
5 formulation of RFP and have provided conceptual
6 clearances on packages before we see instruments.
7 So it is possible that we could become
8 more involved and it might be a very good idea.
9 COMMITTEE CHAIR LASHOF: The other
10 question I have for Dr. Kang and for you, you made,
11 obviously, a very strong point about trying to get
12 consistency and using the CDC and the Iowa.
13 Yesterday, we did hear the case
14 definition that CDC has developed for the specific
15 Pennsylvania Study and I would like to know whether
16 the questions in your survey now will enable you to
17 apply that case definition to your survey instrument
18 when you get it?
19 DR. KANG: I don't have detail
20 information on their criteria for cases so I can't
21 comment on it. But what I heard, yes, the results
22 of our survey can be applied to define the cases.
23 MS. EYDT: I would say that he has a
24 relatively rich listing of symptoms so hopefully
25 that will help that type of comparison.
1 But I will admit we did not consider the
2 Pennsylvania clusters when we did our review and it
3 probably would have been of great interest. And I
4 will investigate whether, at OMB, we reviewed that
5 project and if it was appropriate for our review
6 earlier on.
7 COMMITTEE CHAIR LASHOF: I would suggest
8 we all need to take a good hard look at that case
9 definition that's come out of the Pennsylvania and
10 see whether our other studies will be able to come
11 up with maybe a phone questionnaire; if it's not
12 covered by the other, you might be able to take a
13 look at that again.
14 Okay, that's all I have.
15 MS. JOELLENBECK: I have a question for
16 Dr. Kang.
17 You had pointed out the strength of the
18 study being its providing, perhaps, the best
19 estimate of prevalence. But it is relying on self-
20 report. And you've built into it going back and
21 looking at medical records and having physical exams
22 for 2,000.
23 If that were done earlier in the study,
24 you might have a better sense of how reliable the
25 self-reports were, you might then not have to mail
1 out to 20,000 if you were to find that the self-
2 reports weren't as valuable as the information you
3 got from the exams and the record review.
4 DR. KANG: Uh-huh.
5 MS. JOELLENBECK: Is that something that
6 occurred to you in the planning process?
7 DR. KANG: I don't think I'm getting the
8 part of your question.
9 MS. JOELLENBECK: Well, doing the -- of
10 the 2,000 that you plan to review records and do
11 physical exams --
12 DR. KANG: Right.
13 MS. JOELLENBECK: -- and your reason for
14 doing that is to see how reliable the self-reports
15 are, is that --
16 DR. KANG: Yeah, okay.
17 MS. JOELLENBECK: So, if you were to do
18 that up-front and to find that, in fact, self-
19 reports were not as useful --
20 DR. KANG: But, see, the symptoms, we
21 don't have any core standard to compare against.
22 The only thing we can validate is the medical
23 conditions and the hospitalizations.
24 So for symptoms, we don't have anything
25 to compare.
1 MS. JOELLENBECK: So, no matter what,
2 you have rely on the self-report?
3 DR. KANG: Yes.
4 MS. JOELLENBECK: Were the power
5 estimates based upon a 70-percent response rate or a
6 40 to 60 response rate?
7 DR. KANG: Well, I just presented
8 numbers, the number of respondents that you need to
9 have for the statistical power if, in fact, the
10 difference is twofold or 50 percent. So it doesn't
11 really matter what your response rate is going to
12 be, that will be final number.
13 But we hope that the response rate will
14 be about 60 percent.
15 MS. JOELLENBECK: One final question.
16 Was there some kind of pilot testing of
17 the questionnaire with a veteran group or a group
18 that might be comparable.
19 DR. KANG: We did pilot testing using
20 less than ten people. We did pilot testing, yes.
21 COMMITTEE CHAIR LASHOF: You are shaking
22 your head, Dr. Kipen.
23 DR. KIPEN: I am. I find a pilot test
24 with less than ten people, while I recognize it
25 complies with regulations, to be of limited general
2 COMMITTEE CHAIR LASHOF: Do you think
3 there should have been further pilot testing before
4 it goes out?
5 DR. KIPEN: I didn't actually consider
6 it in this case, I was kind of shaking my head
7 generically there. But, in general, I am a big fan
8 of pilot testing.
9 MS. EYDT: I would like to add that we
10 also generate like -- we do always like good pilot
11 testing and there is no regulation that says you're
12 supposed to do pilot test of less than ten, it's
13 because they don't want to come to OMB, they do
14 pilot tests of less than ten.
15 COMMITTEE CHAIR LASHOF: Okay.
16 Bureaucracy does have its problems.
17 MS. EYDT: That's an unintended effect,
18 I'm afraid.
19 COMMITTEE CHAIR LASHOF: Yes, okay.
21 DR. BALDESCHWIELER: I'm curious as to
22 how you actually get information, for example, on
23 chemical sensitivity by asking questions.
24 Could you give me an example of the kind
25 of question that might appear on such a survey to
1 get information on chemical sensitivity? Either
2 Howard or Han?
3 DR. KANG: May I defer to Dr. Kipen?
4 DR. KIPEN: Well, there is one question
5 on it which is taken -- actually borrowed -- from a
6 survey that's been going on randomly in California
7 sponsored by the CDC for a number of years and it
8 simply asks, "Do you consider yourself unusually
9 sensitive to..." and it lists about four or five
10 things, perfumes, scented products, exhaust fumes,
11 and the like. And so that's one question that is on
12 the survey.
13 Our estimates from previous use of
14 questions like that would suggest that as many as 15
15 percent of randomly selected Californians will say
16 yes to that. And --
17 COMMITTEE CHAIR LASHOF: Are
18 Californians typical?
19 DR. KIPEN: No, they are just --
20 And work we did a few years ago in
21 preparing an application to the VA for a Persian
22 Gulf center suggested as many as 40 percent of
23 Registered veterans will say yes to that.
24 So that would tend to get -- and that
25 was one of the reasons that I, among others on the
1 committee, thought that it would be nice to have
2 some follow-up questions which might be a little
3 less sensitive and a little more specific. Those
4 are not on the questionnaire.
5 There is some debate in the -- well,
6 there's no consensus and there's no gold standard
7 for what one would ask. Among the proposed
8 questions would be to ask people if they've changed
9 their lifestyle because of perceived increase in
10 sensitivity. And many fewer people, many people who
11 say, "Yes, I think I'm unusually sensitive" will not
12 say, "I've changed my shopping habits" or my eating
13 habits or my dressing habits and the like.
14 And so that's one of the approaches that
15 can be taken.
16 COMMITTEE CHAIR LASHOF: Go ahead.
17 MR. BROWN: A question for Dr. Kang.
18 We heard yesterday from some, during
19 testimony, about the concern of some veterans or
20 people who are related to veterans that the health
21 effects -- that there seems to be little work
22 looking at health effects in family members other
23 than immediate spouse and children.
24 And I'm wondering, for the purposes of
25 your survey, when you're looking at health effects
1 in the National Survey -- well, you haven't gotten
2 to that -- when you're looking at health effects in
3 family members, how exactly do you define --
4 DR. KANG: It's limited to a spouse and
6 MR. BROWN: So it wouldn't look at
7 roommates, siblings? Okay.
8 COMMITTEE CHAIR LASHOF: Are there other
10 If not, I want to thank you very much.
11 We are running a little behind but we
12 will take a break now and, Dr. Kang, I understand
13 you took the red-eye to come and we do appreciate
14 that very much.
15 And thank you.
16 We will resume again at 10:10; we'll
17 take a 15-minute break.
18 (Whereupon, a brief recess was taken.)
19 COMMITTEE CHAIR LASHOF: Would everyone
20 please take their seats; we would like to get
21 started. We are a little behind schedule and we'd
22 like to move ahead as expeditiously as we can.
23 Thank you.
24 We will now move to a discussion of a
25 group of studies being carried out at the San Diego
1 Naval Research Center.
2 Dr. Gray -- well, I guess I don't know
3 everybody else, Kevin Kaiser, Bruce Coate, and David
4 Cowan, all from that unit. And, Dr. Gray, you're
5 going to kick it off and introduce your colleagues.
6 DR. GRAY: Thank you, Dr. Lashof.
7 Yes, I would like to introduce some of
8 my colleagues. To my left, are Dr. Kathy Araneta,
9 and Dr. Larry Dlugosz, who are leading some of the
10 follow-on studies from initial data studies which
11 you will hear about today.
12 We also have members of our Scientific
13 Advisory Panel. We have Dr. Warren Winkelstein, Dr.
14 Hal Morgenstern, and Dr. Phil Carter here today, as
16 COMMITTEE CHAIR LASHOF: I think our
17 methodology will be for you to proceed through all
18 of your discussion of all of the studies, then we
19 will ask Dr. Winkelstein, Dr. Morgenstern, and Dr.
20 Carter to come forward. And then we will open it to
21 the panel; okay?
22 DR. GRAY: Very good.
23 COMMITTEE CHAIR LASHOF: Right.
24 DR. GRAY: What I would like to do today
25 is basically give you an overview of our seven
1 epidemiologic studies and talk about some of the
2 methodological problems that we've encountered.
3 (Slide change)
4 These studies are designed by a number
5 of investigators at a number of institutions. Here,
6 you see some of the institutions. In addition to
7 these qualifications, a number of our investigators
8 are veterans of the Persian Gulf War and four of our
9 investigators designed "hot pursuit", as the NIH
10 have called them, studies of various morbidity risks
11 among the Gulf War veterans.
12 (Slide change)
13 Here you see one of our recent
14 investigator meetings, collaborator meetings, where
15 our Scientific Advisors met in San Diego. And we've
16 had several of these in addition to the Scientific
17 Advisory Panel review which you'll see detailed in
18 the handout that I passed to the Committee earlier
20 Additionally, our studies have been
21 reviewed by the Defense Science Board, the Institute
22 of Medicine, and the Armed Forces Epidemiological
24 (Slide change)
25 Our objectives in these studies are to
1 characterize the prevalence of illnesses, symptoms,
2 infertility, and adverse pregnancy outcomes among
3 military personnel before the Persian Gulf War.
4 Additionally, we wish to determine if military
5 service in the Persian Gulf War was associated with
7 (Slide change)
8 For the purposes of these studies, we
9 define military personnel as deployed to the Persian
10 Gulf War if they were in the geographical area
11 depicted here anytime from the 2nd of August, 1990,
12 when Iraq invaded Kuwait, until 31 July, 1991,
13 nearly a year later. This map and each stage
14 reflect data which were provided by the various U.S.
15 military services and recorded by the Defense
16 Management Data Center in Monterey, California.
17 This data base is the standard from which most
18 studies of veterans of the Persian Gulf War are
20 (Slide change)
21 In addition to telling us which persons
22 were veterans of the Persian Gulf War, the same
23 organization, Defense Data Management Center, also
24 provided data regarding which military personnel
25 were not so deployed. We distinguish these two
1 groups by the terms "deployed" to the Gulf War and
3 (Slide change)
4 In developing these studies, we
5 encountered a number of tough issues. It's
6 difficult to look for a disease which is not well-
7 defined. The fact that many of the former service
8 members have left the military has increased the
9 complexities of our research. Choosing appropriate
10 comparison groups has been difficult and, with the
11 many unusual exposures our military personnel
12 encounter, there is a chance that we will find
13 associations of exposure and disease which may not
14 be real. So we're concerned regarding how best to
15 validate our findings.
16 (Slide change)
17 The first of these issues involves
18 defining appropriate outcomes to study. And it's
19 been a problem for us from the beginning.
20 If a new condition has arisen with
21 numerous objective manifestations such as symptoms
22 of fatigue and joint pain and there are no
23 biological tests available to detect it, how do we
24 effectively screen for it?
25 In a similar fashion, if veterans of the
1 Persian Gulf War are sicker than their peers, and
2 the illnesses have not been defined, how will you
3 compare their hospitalization experiences?
4 (Slide change)
5 We decided to take a three-pronged
6 exploratory approach designing studies to gather
7 information regarding symptoms, hospitalizations,
8 and birth defects. Necessarily, these studies are
9 broad and we evaluate many outcomes. The reason
10 that, after examining these numerous outcomes, if we
11 find a pattern of certain veterans with certain
12 exposures are in higher risk, then we would target
13 these individuals with more comprehensive research.
14 (Slide change)
15 Regarding symptoms, we performed a
16 cross-sectional survey of Navy construction workers,
17 or Seabees, who were on active duty at the time of
18 the Gulf War and have remained on active duty.
19 Seabees were some of the first personnel
20 to report unusual symptoms which they attributed to
21 the Persian Gulf War. We've collected questionnaire
22 data, have performed physiological testing, and
23 collected clinical specimens from 1500 service
25 (Slide change)
1 Regarding hospitalizations, we performed
2 a retrospective cohort study of the Department of
3 Defense hospitalization experience of 1.2 million
4 service persons who were on active duty at the time
5 of the Gulf War. These analyses involve all
6 Department of Defense hospitals throughout the
7 world. Additionally, we've examined the birth
8 outcomes from these 1.2 million persons and their
10 These three studies are well underway
11 and you'll hear about some of their results this
13 (Slide change)
14 A limitation of these initial three
15 studies is that we were only capturing data from
16 service personnel who remained on active duty. We
17 began our first survey work in September, 1994 and
18 you can see that a significant portion of the
19 original 697,000 military persons who were deployed
20 to the Persian Gulf War were no longer on active
21 duty at that time. And, of course, this percentage
22 continues to increase so our studies might miss
23 important findings among former military personnel
24 who left the military service.
25 (Slide change)
1 Hence, we've designed four other studies
2 to examine former military personnel, as well as
3 those who remained on active duty. These new
4 studies are in their early stages of data
5 collection. They include a large mail survey of
6 17,000 Seabees, analyses of civilian hospitalization
7 experiences focusing on California, a study of birth
8 defect registries maintained by seven states, and a
9 large mail and telephone reproductive survey of
10 16,000 couples.
11 (Slide change)
12 Our third issue area involved selecting
13 appropriate comparison groups from the service
14 personnel deployed to the Persian Gulf War. We're
15 concerned that deployed personnel might be healthier
16 than personnel who were not selected for deployment.
17 Sometimes we may avoid this potential bias by
18 examining outcomes only among the deployed group.
19 In other studies, we adjust for potential population
21 (Slide change)
22 We're concerned that news reports may
23 influence the way deployed personnel respond to
24 questions. We realize that self-reported data, such
25 as symptoms, are more likely to be influenced by
1 such recall bias than would measurable or objective
2 outcomes like a serologic test.
3 (Slide change)
4 However, it may be useful to study
5 softer outcomes, such as symptom complexes, with
6 serologic tests in order to evaluate various
7 hypotheses. For instance, once a serologic
8 screening test for leishmaniasis has been developed,
9 this test might be used to compare the most
10 symptomatic Seabees with those who have fewer
12 While we're not altogether satisfied
13 that we have solved the issue of recall bias, we
14 have designed a number of checks in our studies and
15 we are aware of this important potential problem.
16 I think we can look at some of the -- at
17 least roughly -- the CDC's proposed case definitions
18 through some of our initial data.
19 A final issue area involves the
20 question: How good are our data? How do we know if
21 our findings for association or lack of association
22 are real?
23 (Slide change)
24 By performing a number of studies, some
25 of which overlap, we may compare one study against
1 another. We can do this among several Department of
2 Defense studies and also compare the Department of
3 Defense studies with studies from other federal and
4 civilian institutions.
5 Regarding the quality of our data, we've
6 learned about the reliability of our surveys by
7 administering them to a portion of volunteers more
8 than one time. We've also validated some
9 questionnaire responses by reviewing service and
10 health records.
11 (Slide change)
12 These studies have led us to the
13 development of a bibliography of over 17,000
14 references which we've uploaded to the Gulf Link in
15 the Web sites listed here. Also, we benefit from
16 the input from various agencies including the DOD
17 Persian Gulf investigating team headed by Colonel
19 (Slide change)
20 In closing, I'd like to emphasize that
21 we're very concerned about the health of Persian
22 Gulf War veterans and their families. The
23 Department of Defense studies reflect multiple
24 research approaches which have received intensive
25 external scientific review. These studies, coupled
1 with studies from other federal and civilian
2 academic researchers will give us an excellent
3 picture of the morbidity of veterans of the Persian
4 Gulf War.
5 Dr. Kevin -- or Kevin Kaiser -- he's not
6 a doctor yet but he's working on it -- will talk a
7 little bit about our Seabee study.
8 MR. KAISER: Good morning everyone.
9 This study was initiated to examine the
10 possible associations between military service in
11 the Persian Gulf War and morbidity. Our emphases
12 were on symptoms and exposures that were not
13 captured by existing databases.
14 (Slide change)
15 We selected regular active duty Navy
16 construction workers, or Seabees, as our study
17 population for a number of reasons. Number one,
18 Reserve Seabees have reported a higher prevalence of
19 morbidity. Number two, regular active duty Seabees
20 have the same jobs and exposures as the Reserve
21 Seabees. Third, active duty Seabees are
22 concentrated in either California or Mississippi
23 when not deployed overseas and, each year, active
24 duty Seabees are deployed overseas for approximately
25 six months and, hence, experience frequent
1 deployment-related exposures.
2 Regular active duty Seabees are less
3 affected by civilian occupational experiences than
4 are Reserve Seabees who serve in the military on a
5 part-time basis and are exposed to other occupation-
6 related agents.
7 (Slide change)
8 During the period from September, 1994
9 through June of 1995, we made six trips to two
10 Seabee centers in California and Mississippi. We
11 enrolled Seabees who had remained on active duty
12 since the time of the Persian Gulf War. Both Seabee
13 military personnel who had been deployed to the
14 Persian Gulf War and other military personnel from
15 the same era who did not deploy to the Gulf War were
16 permitted to participate.
17 (Slide change)
18 Our cross-sectional survey collected
19 information regarding demographics, symptoms,
20 chronic diseases, hospitalizations, and birth
21 outcomes. This survey instrument was designed to
22 screen for chronic fatigue syndrome, post-traumatic
23 stress disorder, and five psychological symptom
24 dimensions from the Hopkins Psychological Symptom
25 Dimension Survey. This is an instrument to quantify
1 psychological status profiles.
2 And, for each Hopkins Psychological
3 Symptom Dimension, an average score for each
4 individual was calculated for the five dimensions.
5 And these dimensions are somatization, obsessive-
6 compulsive disorder, interpersonal sensitivity,
7 anxiety, and depression. Birth outcomes and
8 hospitalizations were assessed from July, 1990 and
9 blood and urine specimens were collected from each
10 study subject during our site visits for later
12 (Slide change)
13 We also tested the reliability of the
14 study instrument by retesting a random sample of 260
15 individuals who are known to be available for
16 retesting at the time of our next study visit.
17 Similarly, we randomly sampled another 150
18 individuals out of this initial 260 to perform
19 validated checks by comparing selected survey
20 responses to medical and service records.
21 Due to low participation by some
22 commands, we also looked at the potential selection
23 bias by comparing volunteers and non-volunteers with
24 regard to demographics and Gulf War status.
25 (Slide change)
1 Handgrip strength was assessed by
2 calculating an average of three successive efforts
3 using a hand-held dynamometer.
4 (Slide change)
5 Lung function was measured as the mean
6 of two efforts and quantified according to
7 percentage predicted of the forced expiratory volume
8 in one second over the forced vital capacity.
9 (Slide change)
10 We enrolled a total of 1497 subjects
11 with 527 deployed to the Gulf War and 970 non-
12 deployed. After adjusting for availability during
13 our site visits, we estimate the participation
14 ranged from 38.6 to 61.5 percent of eligible
16 The demographic characteristics of
17 participants and non-participants were very similar.
18 (Slide change)
19 Demographically, the two groups of
20 participating veterans was similar with respect to
21 race, marital status, height, and weight, but
22 differed in that deployed veterans were slightly
23 younger and more individuals whose highest degree of
24 attainment was a high school diploma.
25 (Slide change)
1 Veterans who had deployed to the Persian
2 Gulf War had higher scores on all five dimension
3 scales of the Hopkins Psychological Symptom Profile.
4 However, their mean scores were low compared to the
5 published mean scores of patients clinically
6 diagnosed with depression or anxiety disorders.
7 (Slide change)
8 Regarding their physical measurements,
9 individuals deployed to the Gulf War were no
10 different from the non-deployed for both handgrip
11 strength and spirometry.
12 (Slide change)
13 These are the eight most prevalent self-
14 reported symptoms in our study population.
15 Regarding these symptoms expressed for one month or
16 more since July, 1990, those deployed to the Gulf
17 War reported significantly higher prevalences for 35
18 of the 41 symptoms queried.
19 (Slide change)
20 However, a large portion of those
21 participating in this survey reported no symptoms at
22 all. This result is not surprising since the study
23 population consisted of active duty Seabees who are
24 expected to be in good physical condition in order
25 to accomplish the tasks required by their jobs.
1 (Slide change)
2 Additionally, it was noteworthy that,
3 among those deployed personnel who complained of
4 muscle weakness for one month or more since July,
5 1990, there were no major differences in handgrip
6 strength testing compared to deployed personnel who
7 did not report muscle weakness.
8 (Slide change)
9 Similarly, among those deployed
10 personnel reporting shortness of breath for one
11 month or more since July, 1990, there was no marked
12 difference in lung function by spirometry compared
13 to those who did not report shortness of breath.
14 (Slide change)
15 Subjects were asked about pregnancy
16 information on all of their partners and responses
17 were divided into two groups, those being live
18 births and other non-live birth outcomes, including
19 still birth, miscarriage, ectopic pregnancy, and
20 elective induced abortion. The results show no
21 difference between the groups regarding birth
22 outcomes with results derived from 590 birth events
23 in those deployed to the Gulf War and 1364 birth
24 events for those not deployed to the Gulf.
25 (Slide change)
1 Individuals were also asked about their
2 number of hospital visits since July, 1990.
3 However, unlike the results from birth outcomes, the
4 two groups were different with the deployed Gulf War
5 veterans reporting more hospitalizations than the
6 non-deployed group.
7 (Slide change)
8 Using several strategies, including
9 reviewing past investigations, multivariate logistic
10 regression, and univariate analyses, we designed
11 three diagnostic hypotheses each composed of a
12 unique symptom pattern. From our questionnaire, we
13 also derived similar screening tools for post-
14 traumatic stress disorder and chronic fatigue
16 Not one of the 1497 study subjects
17 screened for chronic fatigue syndrome; however, we
18 did find that personnel deployed to the Persian Gulf
19 War were more likely to screen for both post-
20 traumatic stress disorder and for the three
21 exploratory symptom patterns we designed.
22 (Slide change)
23 Gulf War veterans were more likely to
24 self-report exposures such as the eight most
25 prevalent shown here. However, examining various
1 exposures in a myriad of univariate and multivariate
2 models, more exposures were consistently associated
3 with the prior-mentioned study outcomes, which were
4 chronic fatigue, post-traumatic stress disorder, and
5 the three hypothesized symptom patterns.
6 (Slide change)
7 As with any study, there is some
8 limitations that may influence the results such as
9 recall bias involved in trying to answer questions
10 regarding symptom expression, health history, and
11 psychological status. Another factor was incomplete
12 participation in some commands which was influenced
13 by a multitude of factors.
14 However, we feel that selection bias was
15 not a significant factor in our analyses based on
16 the comparisons of those who participated and those
17 who did not.
18 Only currently active duty individuals
19 were studied so those Seabees who have separated
20 from the military since the Gulf War would be unable
21 to participate which possibly could influence the
23 (Slide change)
24 In summary, those deployed to the Gulf
25 War had higher self-reported prevalences for 35 of
1 the 41 symptoms. Although, when specific symptoms
2 were compared with physical measurements, there was
3 no difference. Those deployed to the Gulf War had
4 higher average scores than the non-deployed for all
5 five of the Hopkins Symptom Dimensions, however it
6 is not clear whether this is reflective a pre-Gulf
7 War or a post-Gulf War condition.
8 Third, we found no major difference in
9 physical performance or self-reported birth outcomes
10 between the groups. And fourth, no single exposure
11 was consistently associated with any of our study
13 (Slide change)
14 Future analyses will focus on possible
15 latent effects of Gulf War service by conducting a
16 more comprehensive survey of 17,000 Seabees
17 including both active duty and Reservist
18 individuals. This will also complement our study of
19 solely active duty military.
20 Our stored pre-Gulf War and post-Gulf
21 War sera will also be used to test hypotheses
22 regarding infectious agents as they emerge.
23 COMMITTEE CHAIR LASHOF: And now Mr.
24 Bruce Coate will express some of our hospital study
1 MR. COATE: I'm going to talk about the
2 results of our study on morbidity of regular active
3 duty Gulf War veterans as measured by
4 hospitalization discharges.
5 (Slide change)
6 The objectives of our study were to
7 describe the differences in hospitalization rates
8 between those who deployed to the Persian Gulf and
9 those who did not deploy.
10 Secondly, we were seeking to identify
11 specific disease categories which may warrant
12 further investigation so our analyses were mainly
13 exploratory in nature rather than testing any
14 specific hypothesis.
15 (Slide change)
16 Our study design is a retrospective
17 cohort study covering the period from August 1st,
18 1991 through September 30th of 1993. We chose these
19 dates because, as of August of 1991, over 95 percent
20 of the deployed personnel had returned from the Gulf
21 and September, 1993 is the latest date for which
22 hospitalization data were available.
23 (Slide change)
24 Our study population consisted of two
25 groups, the deployed and non-deployed, the deployed
1 being those regular active duty service members who
2 were in the Persian Gulf anytime between August 1st,
3 1990 and July 31st of 1991, while the non-deployed
4 were active duty service members who did not deploy
5 during this time and who were on active duty as of
6 September 30th of 1990.
7 So this sample includes personnel from
8 all branches of the military but does not include
9 Reservists or National Guard members, who accounted
10 for about 100,000 of the deployed troops.
11 (Slide change)
12 This is just a comparison of the two
13 groups that affected a few variables. We have about
14 99 percent of the deployed personnel in our sample.
15 And, with respect to the non-deployed, we have a 50
16 percent random sample stratified by branch of
17 service so we have obtained follow-up information on
18 700,000 of the 1.4 million non-deployed troops.
19 We can see that there is a larger
20 percentage of males among the deployed personnel and
21 the deployed personnel were somewhat younger than
22 the non-deployed.
23 (Slide change)
24 Our data was obtained from the
25 Department of Defense Manpower Data Center and
1 hospitalization files contained discharge records
2 covering the period from 1989 through 1993 and each
3 discharge could contain up to eight separate
4 diagnoses. The diagnoses were coded according to
5 the International Classification of Diseases and
6 Injuries, Ninth Revision.
7 (Slide change)
8 The outcome variable in each of our
9 analyses was essentially the same, mainly the
10 occurrence or non-occurrence of a hospital
11 discharge. We divided our follow-up period into
12 three eras, it would be the last five months of
13 1991, all 1992, and the first nine months of 1993.
14 Within these time frames, we examined an all-cause
15 hospitalization outcome as well as 14 category-
16 specific hospitalizations.
17 (Slide change)
18 This is a list of the broad disease
19 categories we examined, diseases associated with
20 pregnancies, congenital anomalies, and perinatal
21 conditions are not included in our list of outcomes,
22 as these were dealt with in Dr. Cowan's study.
23 (Slide change)
24 This is a graph of the crude all-cause
25 hospitalization rate from October, 1988 through
1 September of 1993 for the deployed and non-deployed.
2 The crude rate per 100,000 is on the vertical axis
3 and the month is on the horizontal axis. We divided
4 the time scale into three periods, a pre-War period,
5 the Gulf War era, and the post-War period.
6 During the pre-War era, the rate is
7 generally higher among the non-deployed with this
8 difference becoming accentuated in the months just
9 prior to deployment. These are not too surprising
10 since the personnel who have recently been
11 hospitalized are going to be less likely to be
12 eligible for deployment overseas.
13 During the second period when the troops
14 were in the Gulf, the difference in hospitalization
15 rates became even more pronounced reflecting, among
16 other factors, low battle casualty rates, absence of
17 serious disease outbreaks, and deferral of elective
19 During the post-War era, the rates were
20 still high among the non-deployed but the difference
21 is somewhat less pronounced than it was earlier.
22 (Slide change)
23 This slide shows the post-War crude
24 hospitalization rates per 1,000 -- between the two
25 groups for each of the 14 specific disease
1 categories we examined. The crude hospitalization
2 rates were generally higher for the non-deployed
3 with the exceptions of injury and poisoning, which
4 is C14 over there, and C5, which is mental
6 We used two basic statistical
7 methodologies to examine our data, standardized
8 rates and multivariate logistic regression.
9 (Slide change)
10 This table just shows the various models
11 which we fit for various time periods. And we were
12 only concerned with logistical regression results,
13 the other, the more exploratory time analyses, and
14 all the stuff I'm going to talk about today will
15 just be logistic regression results and rate ratios.
16 (Slide change)
17 Our directly standardized rates were
18 obtained by applying age- and sex-specific cohort
19 rates to the standard distribution which in this
20 case was the combined population of deployed and
21 non-deployed, and each subject could count for, at
22 most, one hospitalization per year per category.
23 (Slide change)
24 The standardized rate ratio of greater
25 than 1.0 would indicate that the deployed were at
1 increased risk for hospitalization relative to the
2 non-deployed. This occurred only for the 1992 time
3 period but the effect is still quite small; the rate
4 ratio of 1.02 was also a little bit higher in 1993
5 but that was not statistically significant.
6 (Slide change)
7 This is a list of the variables which we
8 included in our multivariate logistic regression
9 models, an indicator variable for deployment status
10 which was fixed in each model while the other
11 variables were kept in the model based on a
12 backwards elimination procedure. And we categorized
13 all our continuous variables into discrete levels.
14 And we also attempted to adjust for pre-War health
15 status by including a pre-War hospitalization rate.
16 But this was dropped from our final models because
17 it has little effect on our odds ratios.
18 (Slide change)
19 These are the adjusted odds ratios for
20 the all-cause hospitalization outcome adjusted for
21 the factors listed in the previous slide. The odds
22 ratios are all quite close to 1.0 indicating that
23 the deployed were not at increased risk for
24 hospitalization relative to the non-deployed.
25 In addition to these all-cause outcomes,
1 we also fit models for each of the category's
2 specific outcomes. Of these models, only two were
3 significant, and these are listed in the next slide.
4 (Slide change)
5 In both instances, there's only a
6 moderate risk increased hospitalization for the
7 deployed but, because of the multiple models which
8 we set, numbering about 42, this could have just
9 occurred by chance.
10 (Slide change)
11 But we looked at these categories in a
12 little more detail. These are the four most
13 prevalent diagnoses for the mental disorder category
14 in 1992, these accounted for approximately 75
15 percent of all hospitalizations in this category.
16 The largest difference in rates is found
17 in the alcohol dependence diagnoses, followed by
18 adjustment reaction.
19 (Slide change)
20 Among the genitourinary diseases, the
21 highest rates occurred among females with deployed
22 women having higher rates of hospitalization for
23 pain and other symptoms from inflammatory diseases.
24 (Slide change)
25 The limitations in our study are that --
1 the most serious one probably is the loss to follow
2 up. By the end of our study period approximately 40
3 percent of the population have left the military.
4 We have no information on potential compounders such
5 as diet, weight, and smoking.
6 And we have looked at hospitalizations
7 in the military facilities so, if non-military
8 hospital use is different among deployed, this may
9 bias our results. But we feel this is unlikely to
10 occur since it is difficult for a regular active
11 duty service member to seek in-patient care outside
12 of the military system. And also, as mentioned
13 earlier, we didn't include any Reservists or
14 National Guard in our sample.
15 (Slide change)
16 The strengths of our study are its
17 perspective design, the factoring of information on
18 the large number of individuals from all branches of
19 the military and that we were able to work with a
20 large number of outcomes.
21 (Slide change)
22 In conclusion, when hospitalizations
23 among broad categories were examined using logistic
24 regression and age- and sex-adjusted rates, deployed
25 personnel were found to generally not be at
1 increased risk for hospitalization.
2 Two exceptions were the mental disorders
3 and diseases of the genitourinary system but these
4 results were significant for only one time period
5 and were not consistent the length of the entire
6 study period. We are planning on doing further
7 descriptive analyses of these two categories in the
8 near future.
9 Thank you.
10 COMMITTEE CHAIR LASHOF: Our last
11 presentation involves a similar approach; Dr. David
12 Cowan will discuss birth defects as occurred in the
13 DOD hospitalization system.
14 DR. COWAN: Thank you.
15 Please let me know if this is not loud
17 We've all seen the Life magazine
18 article with these tragic stories and photographs,
19 yet individual case reports are not adequate to
20 establish if there is an association between Gulf
21 War service and the risk of birth defects.
22 (Slide change)
23 In order to assess risks, epidemiologic
24 studies utilizing appropriate comparison groups are
25 required. To that end, it is important that we do
1 our very best to measure the risk of events
2 occurring in these populations in determining if the
3 risk of defects occurring among children of Gulf War
4 veterans is actually higher than the risk among
5 military members who did not serve in the Gulf.
6 In order to contribute to the
7 understanding of this situation, we have initiated
8 this epidemiologic study of the risk of birth
9 defects among children of Gulf War veterans and
10 other military personnel.
11 (Slide change)
12 Hundreds of thousands of men and women,
13 soldiers, sailors, airmen, and marines serve in our
14 armed forces each year. Many of them have children
15 while they or their spouses are on active duty and
16 these children are often delivered in a military
18 For our study population, we identified
19 all the active duty Gulf War veterans and a sample
20 of active duty non-Gulf War veterans.
21 (Slide change)
22 We conducted a historical cohort study
23 in which the individuals were identified based on
24 their deployment status and were followed over time
25 to identify live births and then defects occurring
1 in military hospitals. This is a graphic
2 representation of our study.
3 (Slide change)
4 In this study, we are not evaluating any
5 specific environmental exposures. Rather, we are
6 comparing the risks of defects between those who
7 served in the theater of operations and those who
8 did not. In addition, we are examining the data to
9 see if there is an association between duration of
10 time in the theater and the risk of birth defects.
11 The data are stratified and separate
12 analyses presented for active duty women and wives
13 of active duty men.
14 (Slide change)
15 We accessed an existing administrative
16 database to identify live births to active duty
17 personnel occurring in military hospitals. Children
18 with estimated dates of conception after the return
19 of the sponsor from the Gulf or after the 1st of
20 January, 1991 for non-deployed members and with
21 dates of birth before the 1st of October, 1992 were
22 eligible for study inclusion.
23 (Slide change)
24 This is the number of births occurring
25 to our study subjects. Note that, in the early
1 months, the non-deployed military personnel had
2 higher numbers of babies but that, as they re-
3 deployed back to the United States, the Gulf War
4 veterans rapidly caught up.
5 (Slide change)
6 Medical diagnostic data were acquired
7 from an administrative database which is routinely
8 created for each in-patient in military hospitals.
9 Note that these diagnoses are from the birth
10 hospitalization only. ICD-9 codes are used with up
11 to eight different diagnoses captured and the
12 diagnoses are up to five digits in length.
13 (Slide change)
14 We looked at two non-birth-defect
15 outcomes, live birth rates and the sex ratio of
16 newborns. For definitions of the birth defects, we
17 used the coding manual from the Metropolitan Atlanta
18 Congenital Defects Program.
19 (Slide change)
20 The MACDP had been in existence for
21 several years and was developed for the Centers for
22 Disease Control. We utilized their diagnostic codes
23 in order to have an externally validated coding
24 scheme. The MACDP uses the ICD-9 codes which gave
25 compatibility with the military coding system.
1 There are some important points I'd like
2 to make. The MACDP includes other codes besides
3 just the malformation codes such as neoplasms and
4 hereditary diseases. In the Atlanta Program, some
5 minor cases of certain defects are excluded based on
6 medical records review. Because our study did not
7 include a medical records review, minor cases of
8 certain defects were retained in our data set.
9 (Slide change)
10 For our statistical analyses, we used
11 Chi square to assess linear trend, relative risks to
12 assess univariate associations, Mantel-Haenzel
13 Summary relative risks to assess potential
14 confounders, and logistic regression to develop
15 adjusted odds ratios.
16 Note that all comparisons I will present
17 are statistically significant unless otherwise
19 (Slide change)
20 Here we see our study population broken
21 out by Gulf War service and sex. These are active
22 duty men, Gulf War veterans and non-Gulf War
23 veterans, active duty women, veterans and non-Gulf
24 War veterans.
25 We ascertained attrition by identifying
1 those in the original cohort that were still
2 participating on active duty at the close of the
3 study period. Note that the attrition rate is quite
4 similar for both comparison groups.
5 Excuse me -- this is the survival rate,
6 the percent remaining on active duty.
7 (Slide change)
8 Now we move to the next step of the
9 results, the numbers of live births occurring in
10 each cohort.
11 (Slide change)
12 On this slide we see the total number of
13 births by cohorts and the accrued live birth rate.
14 Note that this is not a time-based rate, but numbers
15 only, a proportion.
16 Even though there are significant
17 differences between the cohorts and the live birth
18 rate, the numbers are -- the proportions are very
19 similar. The male to female ratio of the newborns
20 is shown and there are no significant differences
21 between these ratios for the comparison groups for
22 either men or women.
23 (Slide change)
24 Here we see the numbers of children with
25 birth defects born to each cohort.
1 (Slide change)
2 This slide shows the percent of live
3 births with the coded defect for each of the
4 comparison groups. At the bottom of the slide is
5 the crude relative risk for Gulf War veterans
6 compared to non-veterans, 1.02 for active duty men
7 and 1.13 for active duty women. Please note that
8 there are no statistically significant differences
9 in these comparisons.
10 (Slide change)
11 On this slide, we examine the data for
12 an association between duration of time in the Gulf
13 theater of operations for men and women. None of
14 the individual time periods are significantly
15 associated with increased risk. The competence
16 intervals for all of the odds ratios include the
17 value of 1.0.
18 Furthermore, there was no significant
19 linear trend for increasing risk with increasing
20 duration of time in the theater.
21 (Slide change)
22 Finally, we conducted multivariate
23 analyses controlling for several potential
24 confounding factors. The final model for both men
25 and women controlled the race, ethnicity of the
1 sponsor, age of the mother at time of birth, the
2 branch of service, and the rank of the sponsor. We
3 found no significant association between Gulf War
4 service, yes or no, for men or for women.
5 None of the individual time periods was
6 significantly associated with an increased risk of
7 birth defect. And, when the duration of time spent
8 in the theater was entered as a continuous variable,
9 it was not a significant predictor.
10 (Slide change)
11 There are limitations to this study
12 which restrict the interpretation. We assessed only
13 live births of active duty personnel occurring in
14 military hospitals and we only captured data from
15 routinely-generated administrative sources. Because
16 our coding system is based on that used by an active
17 case-finding program, there is limited
18 generalizability beyond our comparison groups.
19 For all of these reasons, comparisons
20 with published rates of birth defects from civilian
21 populations may not be appropriate.
22 (Slide change)
23 This study also has important strengths
24 including a large number of observations so that we
25 had good statistical power to detect differences
1 that may have existed. We had the exposure and
2 birth outcome data for both men and women service
3 members. All births occurred shortly after the war,
4 presumably when any affects of wartime exposures
5 would have been most pronounced.
6 Our multivariate analyses controlled for
7 potential confounders including surrogate measures
8 of socioeconomic status. Our attrition rates are
9 similar between groups and we utilized the same
10 exposure and outcome data sources for deployed and
11 non-deployed members.
12 (Slide change)
13 Finally, our conclusions are that we
14 found no significant association between Gulf War
15 service and the overall risk of birth defects for
16 children of women or men in our cohorts and we found
17 no significant dose response relationship between
18 duration of Gulf War service and the overall risk of
19 birth defects for children for men or women in our
21 Thank you.
22 COMMITTEE CHAIR LASHOF: Okay, Commander
23 Gray, does that complete the studies that are
24 ongoing at this time?
25 DR. GRAY: Yes, Dr. Lashof.
1 COMMITTEE CHAIR LASHOF: Okay. Then I
2 think what I'd like to do at this point, advance Dr.
3 Winkelstein, Dr. Morgenstern, Dr. Carter to come
4 forward and if you'll just take seats in the front
5 and then we will have you all. So we will figure
6 out how we will arrange the seating when we get to
7 the question and answers.
8 Commander Gray and your group would take
9 seats in the front row and let Dr. Carter,
10 Morgenstern, and Winkelstein take the podium there
11 where they have the mikes. Then we will try to
12 rearrange things after the three of you finish so
13 that we can get everybody together in a way that at
14 least we can ask questions.
15 Thank you very much for coming and we'd
16 like you -- all of you have been involved in the
17 scientific review of the cases done at the Naval
18 Research unit, the San Diego unit, and we'd like to
19 hear your comments at this time.
20 Dr. Winkelstein, do you want to start?
21 DR. WINKELSTEIN: Thank you, madam
22 Chairman -- Chairperson.
23 My role was to act as a sort of advisor
24 at a meeting at which the protocols were presented
25 last February in San Diego. And the committee of
1 three, Dr. Baird, Dr. Morgenstern, and myself
2 produced a report as a result of that meeting and of
3 our examination of the protocols.
4 And I know you have copies of that
5 report in your briefing book.
6 Since that time, I was at San Diego for
7 sort of a review session in August and wrote a brief
8 memorandum as a result of the August meeting; and
9 that, too, you have in your briefing book.
10 I did not attend the APHA meeting at
11 which the results of the studies were presented so
12 that the first chance of seeing the results was
13 today. And I was pleased to see that some of the
14 suggestions that we had made in our report had been
15 implemented in the report of the findings.
16 I'd like to address very briefly some of
17 the issues of the Seabee study which was of
18 particular interest to me. I missed the statement
19 of the participation rate but I want to address that
20 problem first.
21 The Seabee study of symptoms is based on
22 a sample, a volunteer sample, obtained many years
23 after the actual exposure period and, at the time we
24 reviewed the work last February, the participation
25 rate was 50 percent. And I believe it ended up a
1 little bit better than 50 percent, although I'm not
2 sure what it was.
3 Could you tell me that?
4 MR. KAISER: (Inaudible comment from an
5 unmic'ed location.)
6 DR. WINKELSTEIN: So the final -- what
7 do you mean by the range?
8 MR. KAISER: (Inaudible from an unmic'ed
10 DR. WINKELSTEIN: So the final
11 participation rate was somewhere in the neighborhood
12 of 50 percent, as just reported between 38 and 65
13 percent, so roughly 50 percent.
14 And I think that is what is the major
15 problem with interpreting the findings. The
16 findings were, in general -- showed that there were
17 excess symptoms among deployed personnel but it's
18 difficult to interpret that when you're faced with a
19 50 percent participation rate and the 50 percent
20 were all volunteers.
21 So I don't really know how to interpret
22 that. As I said yesterday, in connection with the
23 Pennsylvania study, if deployment status and symptom
24 status is related to participation, then you have
25 the potential for bias and you can get either -- any
1 result that you get is always subject to question.
2 So that's really my main problem with
3 the Seabee study. I think that the fact that they
4 did a retest and that they did a record survey to
5 validate what they found, and even if they have
6 compared the characteristics of participants,
7 general characteristics of participants with non-
8 participants, we're still left with a problem of
10 Now the second Seabee study, which was
11 only mentioned today, I think we have a new protocol
12 in the briefing book and I was able to look at it
13 briefly yesterday and today. It's a revision of the
14 protocol that was presented in August.
15 And originally, in February, the mail
16 survey proposal was designed to deal with some of
17 the problems of the original Seabee survey. The new
18 protocol is not clear to me exactly what the long-
19 term objectives are but it includes at least mention
20 of the possibility of a follow-up, as long as 15
21 years. And that presents, it seems to me, immense
22 problems in terms of selection, follow-up, biases,
23 and costs.
24 And that's not very clearly described in
25 the protocol. So I would just draw your attention
1 to those problems.
2 That's all I have to say at this point.
3 COMMITTEE CHAIR LASHOF: Okay, thank
5 I think we will ask you to give the
6 comments and then we will have the questions.
7 Dr. Morgenstern?
8 DR. MORGENSTERN: I'm Hal Morgenstern,
9 Professor of Epidemiology at UCLA School of Public
10 Health and I was asked to participate as a member of
11 the Scientific Advisory Committee for the Naval
12 Health Research Center some time in January and
13 agreed to do so.
14 The idea was that we would review the
15 seven studies that were being conducted by the Naval
16 Health Research Center, as well as a few that were
17 being planned in different phases. And we met for a
18 two-day site visit in San Diego in February and, as
19 you know, we assembled a report over the next month
20 to month and a half which was issued to the
21 appropriate Defense Department -- Office of the
22 Defense Department in late March.
23 During the two-day site visit, we were
24 asked if we were interested in participating in
25 future ongoing efforts by the study team and, as I
1 recall, all three of us agreed, and I did, too; we
2 were planning to actually be there in August for
3 another meeting.
4 During the next couple of weeks,
5 sometime after the report was issued, I was sent a
6 message, I think it was a FAX, by Commander Gray
7 asking if I would be interested in participating
8 again in August, even though there were no funds to
9 support our time but there was opportunity to pay
10 for our expenses. And there was also a comment
11 about not wanting us to distribute our share of the
12 report that we wrote with anyone.
13 And so I was, of course, still
14 interested in participating and left a message with
15 Commander Gray, which he never answered. So I have
16 no knowledge of actually what was done after
17 February or March on any of these projects except
18 what I heard here this morning.
19 So it's difficult for me to comment on
20 the progress that's been made and how I would view
21 the studies in terms of opportunity for drawing
22 conclusions that were relevant to the mandate of
23 those studies.
24 We made a number of recommendations; I
25 was actually responsible for reviewing and writing
1 about the hospitalization studies. And one of the
2 things that concerned us -- two of the things that
3 concerned us at the two-day site visit, is first
4 that the protocols that were laid out to do those
5 studies were rather incomplete and were very
6 difficult for us to sort out what the members of the
7 team were trying to accomplish. But much of that
8 was supplemented at the site visit itself, when we
9 found out what the team was doing.
10 It appeared to me that the studies were
11 designed rather hastily initially, possibly in
12 response to some funding that came about very
13 quickly. I don't know the history of it too well, I
14 just know that this funding started in 1994.
15 It appeared that the first three studies
16 that you heard reported here today were initiated
17 and then the investigators apparently realized that
18 there were some potential problems, sources of bias
19 that would impede the ability to make causal
20 inferences from those studies.
21 So they initiated three other studies to
22 supplement those findings and make up for the bias,
23 so to speak.
24 I remember that my reaction to that, and
25 I believe it was the position of the entire advisory
1 panel of three, was that, rather than trying to do
2 three studies that were obviously limited for
3 drawing important inferences about this very
4 important topic, rather they should try to integrate
5 the concerns that they were doing in the
6 supplementary studies and do one study of each of
7 these topics and try to do it appropriately with
8 minimal bias by trying to study as properly as they
9 could the population at risk of interest.
10 My impression this morning is that that
11 may not have been done. It still appears that the
12 major limitations of all of the studies that we
13 pointed out are still major limitations. That's not
14 to suggest that the group, the study team, hasn't
15 advanced their ideas of how to do the studies and
16 doing them well; I suspect they've done quite a bit.
17 And certainly, by virtue of seeing the results here,
18 I can see that a great deal of work was done since I
19 was involved.
20 But nevertheless, I still think that
21 there will be a number of important questions that
22 will remain about the validity of the results that
23 we just saw and the conclusions that were drawn.
24 But again, it's hard for me to comment
25 on the specifics right now since all I've heard
1 since February were the results that you just saw.
2 COMMITTEE CHAIR LASHOF: Thank you very
4 Dr. Carter?
5 DR. CARTER: Thank you, madam Chairman.
6 The Committee has my biography but, for
7 clarification and the benefit of the audience, I'd
8 like to take a minute to tell you why I'm here.
9 My expertise is not in epidemiology so I
10 shan't comment on the studies that you heard
12 I'm a full professor since 1982 of
13 microbiology and immunology at the College of
14 Veterinary Medicine in North Carolina State
15 University. In the State of North Carolina, we have
16 two major military installations, Fort Bragg in
17 Fayetteville and Camp Lejune in Jacksonville.
18 Personnel from those sites frequently are deployed
19 first to areas of conflict.
20 And I think the civilians in our state,
21 perhaps more than in other areas of the country, are
22 well aware of the necessity to properly protect our
23 troops against the ravages of war. For that reason,
24 we have a particular interest in such things as
25 toxic warfare and biological warfare agents.
1 My own background is pathogenic
2 bacteriology and mycology and the immune responses
3 to those. I taught at North Carolina State
4 University, to veterinary students since 1982 and,
5 prior to that, at the Veterinary College at the
6 University of Illinois and, in the '70's, to medical
7 students at the University of Alabama in Birmingham.
8 My area of expertise is infectious
9 agents. In the -- factors, I've worked with
10 potential BW agents such as Listeria Salmonella,
11 plague bacillus, anthrax, and I've also worked with
12 mycoplasms that aren't known to be BW agents but
13 certainly cause disease in armed forces personnel.
14 I've served on VA committees and
15 committees for the DOD, as you know from my
17 I've been Director of Biotechnology at
18 North Carolina State University, which is an
19 extremely fine program. Ten percent of our faculty
20 in that program that I directed are members of the
21 National Academy of Sciences.
22 The potential for BW agents, using --
23 microorganisms was evident to us in the middle '80's
24 and, for that reason, we've been more involved,
25 perhaps, in those places in studying the potential
1 for that to be used as a weapon against our troops.
2 Because of my knowledge of BW agents,
3 actually beginning in 1965 when we worked with the
4 Navy on Neisseria meningitidis outbreak in
5 Alexandria, Egypt, Commander Gray asked me to serve
6 as an advisor to him.
7 I was interacted with the Veterinary
8 Corps, which is one aspect of my background that I
9 think Commander Gray wanted to take advantage of.
10 I'm familiar, for instance, with the potential cause
11 of piles of animals, which was mentioned in
12 yesterday's testimony, found in the Gulf War site,
13 and also where action was being taken by the
14 Veterinary Corps to study the potential untoward
15 effects of environmental exposure using dogs that
16 were deployed in the Gulf. Those dogs are now,
17 rather than being euthanized, are being maintained
18 for their natural life near San Antonio, Texas.
19 I might just add that canines are an
20 appropriate sentinel animal for potential oncogenous
21 or cancer-causing agents in humans. Unlike cats,
22 tumors in dogs are particular similar to those of
23 humans and have no known bio-etiology.
24 One recommendation I'll make, and I'll
25 make that in writing to your Committee, is, having
1 served on the first committee, which was asked by
2 Secretary of Defense Cheney to be the first group to
3 review a service-wide -- that is, Department of
4 Defense medical RNB command research program, I can
5 say that I would recommend to your committee that
6 greater emphasis be given to the support of
7 appropriate research by the military.
8 And by that I mean, if I can suggest,
9 that the NIH, for instance, is far better equipped
10 to study breast cancer than is the military.
11 However, the military is far better equipped to
12 study vaccine development for potential BW agents
13 and the potential for recombinant bacteria, or
14 fungi, or viruses, for that matter, as potential
15 agents of war in the future.
16 Clearly, as we recognized in the middle
17 '80's, and now I think the general population of the
18 country recognizes, BW agents and chemical agents
19 certainly are the poor countries' atomic bomb and
20 this is an area where I think we've been deficient
21 in pursuing because of concerns in the civilian
22 population of the potential for offensive warfare.
23 COMMITTEE CHAIR LASHOF: Thank you very
24 much, Dr. Carter.
25 I think what we'll try to do at this
1 point is we'll ask the panel to direct questions to
2 either Dr. Gray and his team or to the panel. And
3 I'm not sure how you want to handle mikes.
4 MS. GWIN: We have a walk-around mike
5 sitting on the corner of the table there.
6 COMMITTEE CHAIR LASHOF: Okay, so that
7 can be passed; and, if it's directed to someone who
8 is not at the table, they can come forward and use
9 the walk-around mike.
11 DR. TAYLOR: I have a couple of
12 questions, and I guess I'll start with Dr. Gray,
13 regarding -- well, I understand the limitations are
14 that these are all active duty personnel versus
15 anyone who has left the service, there are no
16 surveys conducted among those?
17 DR. GRAY: Our first three studies
18 involved only active duty personnel. They were
19 exploratory in nature. The next generation of
20 studies include all personnel that were involved in
21 the Gulf, as well as control populations which were
22 not involved but on active duty.
23 DR. TAYLOR: So the information that
24 will be collected, will that be medical information
25 or will it just be self-reported questionnaires on
1 the second group?
2 DR. GRAY: Well, we didn't go into much
3 detail regarding the second studies but Study IV is
4 a survey where we will get some self-reported data
5 there, a mail survey, followed up by telephone
6 interview, following a model which was recommended
7 to us by Dr. Donna Baird, one of our Scientific
8 Advisors, Chicago Health Study. That is an
9 infertility study.
10 We have yet to finalize the second and
11 third phase of that study. We've contemplated
12 actually having a physical exam portion in Phase III
13 should funding continue and we find some interesting
14 things via the telephone interview regarding
15 infertility and pregnancy outcomes.
16 Study V is a survey of the 17,000
17 Seabees and that involves largely a questionnaire
18 and a follow-up with telephone interview of a
19 subsegment. We haven't yet decided if we will look
20 at medical records. The difficulty with medical
21 records review is, of course, they are spread out
22 all over the world in the DOD and again in the non-
23 federal system.
24 Then we have two other studies, Study VI
25 and VII, which involve -- Study VI is looking at
1 California non-federal hospitalization database; and
2 so that's medically oriented -- and data captured
3 for other purposes. And Study VII is a review of
4 the seven actively surveilled birth defect
6 So some of the studies will involve
7 medical records review and some will not, in a
9 DR. TAYLOR: I'll come back to that,
10 I'll let somebody ask another question. But I have
11 another question to ask before, it's regarding the
12 serologic tests that were conducted, the blood and
13 urine samples that were collected.
14 You mentioned that tests for
15 leishmaniasis will be done at some point?
16 DR. GRAY: Well, that's an example; and,
17 as yet, there is no good rapid serologic test such
18 as -- for leishmaniasis. Should one become
19 available, we would very much entertain examining
20 our pre- and post-War for serologic evidence of
22 DR. TAYLOR: So right as of now, most --
23 those sample have just been collected and they are
24 being stored; right?
25 DR. GRAY: Right, they are stored in
1 five aliquots. And the concept is, as hypotheses
2 arise, we decide through advisors whether or not to
3 expand some of our sera to test those infectious
4 disease relating hypotheses.
5 DR. TAYLOR: One other question
6 regarding the hospitalization data. I'm trying to
7 figure out what would be the purpose of looking at
8 this data and what are you planning to achieve?
9 Because many of the persons who served in the Gulf
10 may not end up in the hospital with chronic fatigue
11 syndrome, that's usually not where that would be
12 reported. They wouldn't be hospitalized for that or
13 for headaches or some of the other.
14 So what are you planning to achieve to
15 get at what the cause of the symptoms, of health
16 symptoms that are currently being felt by Gulf War
18 DR. GRAY: The concept is largely an
19 exploratory one and a rule-out one. The initial
20 study was to see if there were any differences
21 because we didn't really have good case data. If
22 there was a temporally-related unique exposure that
23 affected a lot of people in the Gulf, we might see
24 increased hospitalizations among the Gulf War
25 veterans. So it was sort of exploratory.
1 Study VI review is -- sort of continues
2 along the same vein. So we're basically looking for
3 hypotheses to test.
4 I think one of the unique things about
5 the available databases are, we could rapidly check
6 certain hypotheses. There was an article, I think
7 in New England Journal regarding aplastic anemias,
8 we were to quickly review that outcome, ICD-9 code,
9 and see if there was an increased risk. And we're
10 looking at other specific categories.
11 Dr. Winkelstein has suggested some
12 approaches for respiratory illnesses and we're
13 pursuing that. And some of the findings that we
14 presented today regarding mental illness and
15 genitourinary outcomes we're examining further.
16 Whether or not we will do case-
17 controlled studies and interviews or bring in people
18 for exams remains yet to be determined.
19 DR. TAYLOR: I still have another
21 COMMITTEE CHAIR LASHOF: Sure.
22 DR. TAYLOR: And I'm not trying to be
23 sarcastic but, do you have to follow OMB, the same
24 processes the other researchers --
25 DR. GRAY: Yes, we do and we've
1 submitted our package for both studies, the Seabee
2 mail survey and the infertility, to OMB. We think
3 we're in advance -- we received an approval
4 contingent upon making some changes, so we
5 anticipate approval soon.
6 COMMITTEE CHAIR LASHOF: I'd like to get
7 back to the three studies, really, that all have the
8 same problems you presented, the limitation that
9 anyone had to be on active duty. And I just don't
10 know what that tells us about the problem we're
11 trying to explore.
12 If we have sick people, they're probably
13 not on active duty. So I don't know what the
14 conclusions you presented in any of the three
15 studies really mean and what we're to do about that.
16 Could you tell me the justification for
17 doing any studies that are limited to only active
18 duty and also that have a response rate as low as
20 DR. GRAY: Well, you must know that we
21 captured, in Studies II and III, the general
22 hospitalization study and the birth rate, we
23 captured all data so, if you're looking at similar
24 participation, we have a hundred percent of those
1 And the concept was --
2 COMMITTEE CHAIR LASHOF: Let me --
3 DR. GRAY: Yes.
4 COMMITTEE CHAIR LASHOF: Maybe I
5 misunderstood. I thought in the hospitalization, it
6 was only in military hospitals.
7 DR. GRAY: That's correct.
8 COMMITTEE CHAIR LASHOF: So that
9 wouldn't be -- all people who have been separated
10 wouldn't have been hospitalized in military
12 DR. GRAY: I didn't mean to infer that.
13 What I meant is, among the people that
14 have remained on active duty, we would capture a
15 hundred percent --
16 COMMITTEE CHAIR LASHOF: Oh, yeah. My
17 question is, that as long as your studies are only
18 of those on active duty, what does it tell us about
19 the general problem we're trying to get at? How
20 does it elucidate the issue of whether we have Gulf
21 War veterans who are ill different than Gulf War --
22 than non-Gulf War?
23 DR. GRAY: I think I agree with what
24 you're inferring, that we cannot extrapolate these
25 data to people who have left the service; we
1 certainly understand that.
2 But, among the populations that remained
3 on active duty, we can examine some potential
5 COMMITTEE CHAIR LASHOF: I guess my
6 concern is, of what value is it to know that those
7 on active duty don't have any difference; what does
8 it tell us about the problem we're trying to
10 DR. GRAY: I think if we found a marked
11 difference for a causalry it might lead to further
12 illustrative studies.
13 COMMITTEE CHAIR LASHOF: Okay. So a
14 positive finding would have meant something and
15 negative is probably meaningless at this point?
16 DR. GRAY: I wouldn't say it's
17 meaningless but I'd say it would be hard to infer to
18 the population who left the active service.
19 COMMITTEE CHAIR LASHOF: And that would
20 apply to the birth defect data, as well; would it
22 DR. COWAN: Yes, it would apply to the
23 birth defect data. I took some comfort in that the
24 rates of attrition were very similar among Gulf War
25 veterans to non-Gulf War veterans, and indeed were a
1 little higher for female Gulf War veterans.
2 However, it may be possible that those
3 people that have a problem, differentially, leave
4 the military and, if they are in small-enough
5 numbers, then we would not be able to detect that
6 with our survival -- our attrition rates.
7 So I agree with you that we cannot
8 extrapolate to them although the evidence wasn't
9 there that they were leaving in disproportionately
10 high numbers.
11 COMMITTEE CHAIR LASHOF: The other
12 question about the birth defects, at this point, you
13 have not broken those down to look at the
14 differences in the diagnoses of the birth defects
15 between the deployed and non-deployed; is that
17 DR. GRAY: The specific categories?
18 COMMITTEE CHAIR LASHOF: Yes.
19 DR. GRAY: Yes, we haven't.
20 COMMITTEE CHAIR LASHOF: You have not.
21 You will be doing that and looking to
22 see were there any differences?
23 DR. GRAY: Actually, our Scientific
24 Advisors recommended that that would not be a good
25 use of these data. We have that capability. But
1 they thought that using the actively-surveilled
2 seven-state birth defect registries where they have
3 data beyond just birth, actually out to a year, and
4 good follow-up, good interview data would be much
5 more appropriate.
6 So we are a little hesitant to look at
7 specific ICD-9 codes in those studies.
8 COMMITTEE CHAIR LASHOF: If I follow,
9 then, that the birth defects data that we have,
10 again, doesn't tell us a great deal but you are
11 planning another study which I do believe, from the
12 protocol I've reviewed, does appear to be one that
13 should give us information. And that's being pilot-
14 tested in Hawaii at the present time; is that
16 DR. ARANETA: We returned from Honolulu
17 eight days ago and the purpose of the pilot study
18 was, first of all, to determine if our ability to
19 match our records of military personnel who could
20 have been deployed or resided or were residents of
21 Hawaii before they joined the military between 1989
22 and through 1993 actually live births in the State
23 of Hawaii.
24 We looked at several matching algorithms
25 to try to maximize identification of the number of
1 births. We are still analyzing the results of that
2 match and the birth defects monitoring program of
3 Honolulu will then identify which of the children
4 born to Persian Gulf War veterans and era veterans
5 were diagnosed with the congenital anomaly.
6 The advantage of Study VII is that,
7 first of all, since there is no national birth
8 defect surveillance system, there are, however,
9 seven states which participate in active
10 surveillance for birth defects -- for major birth
11 defects. And these seven states represent 18
12 percent of all the births in the United States so we
13 will be able to capture one-fifth of all the births
14 in the U.S.
15 We will also be -- and since these birth
16 defects registries ascertain birth defects through
17 the first year of infancy, we will be able to
18 identify births which are missed at birth. Only
19 about 60 to 70 percent of all birth defects are
20 diagnosed at birth. The remaining 30 to 40 percent
21 are diagnosed during -- anywhere between the first
22 month through the 12 months of infancy. So it will
23 enhance case ascertainment.
24 Secondly, since they are population-
25 based, it will enable comparisons of the prevalence
1 and the rates of birth defects among military
2 personnel who are still on active duty, those who
3 had separated, and those in the general non-military
5 COMMITTEE CHAIR LASHOF: Thank you very
6 much; I think that is helpful. And, from the
7 material we received before and the reviews, it does
8 appear that that study will be a meaningful study if
9 the pilot works out and you're able to do what you
10 hope to be able to do. And we'll be interested in
11 following that.
12 And, Dr. Cowan, did you have --
13 DR. COWAN: Yes, Dr. Lashof.
14 I don't think the Committee should be
15 left with the impression that the birth defect study
16 suffers from the same limitations that the other
17 study does. Dr. Donna Baird, who is an Advisor also
18 from North Carolina International Institute of
19 Environmental Health Science, who couldn't be here
20 today, would probably support this -- Dr.
21 Winkelstein can make comments.
22 But I think we should point out that
23 most of the people being evaluated, and I see this
24 in my newspaper every day with Fort Bragg being the
25 largest active army based in the United States, of
1 the continuing concern about birth defects. But the
2 birth defects that one's looking at are in the --
3 predominantly in the wives of military and those men
4 are still in the military.
5 So I don't think the concern you
6 initially voiced applies to the same extent in the
7 birth defect study.
8 Warren, did you have --
9 COMMITTEE CHAIR LASHOF: The only way it
10 might -- I mean, it's hard to know and, I think,
11 until we get the other study it's hard to be sure.
12 And the reason I have that concern is that, if the
13 men who have separated have separated because of
14 illness and were exposed more heavily to
15 environmental agents over there, then they may
16 indeed be having more problems with -- and so on.
17 So that's the only reason I question
18 whether we can make any flat-footed statements when
19 it's all based on active duty people.
20 DR. COWAN: People who have problems,
21 and I'm speaking specifically to the birth defect
22 problems, would have an incentive to stay in the
23 military because they would continue to receive
24 high-quality medical care for their families.
25 So I don't think that we can, without
1 further evaluation of it, speculate that people that
2 have problems, speaking only of birth defect
3 problems, are differentially leaving the military.
4 I think that there is a disincentive for them to
6 COMMITTEE CHAIR LASHOF: Well, it's
7 certainly true once they have a child with a birth
8 defect, but whether they are sick -- husbands have
9 left before they've had the baby, before it has a
10 birth defect, is the issue, that we just don't know.
11 And, until we have more data on troop location and
12 can compare troop location exposure data to look at
13 some of this, it's going to be very difficult to
14 know whether those who remained in versus those who
15 left have had the same experience in the Gulf; that
16 is really my point.
17 But let me now ask you about this
18 additional survey you're planning of 17,000. What
19 is the goal of that study and what will it add to
20 either the Iowa Study or the National Study being
21 carried out of the 15,000 that we heard this morning
22 that is being done by Dr. Kang and his group?
23 DR. DLUGOSZ: The goal of the Seabee
24 health study is to expand and extend upon the
25 original Seabee study and to correct the
1 deficiencies in the original study. The objective
2 is to determine whether Gulf War veterans have a
3 higher rate of symptoms and illness than non-Gulf
4 War veterans.
5 The original study, we've learned a
6 great deal from that. That study's limitation has
7 been well-discussed here, is that it only deals with
8 active duty people, the people that remained on
9 active duty, and does not include Reservists and
10 people who have separated from active duty.
11 Another limitation of that study is,
12 it's cross-sectional in nature and information on
13 exposures is limited to what people have told us.
14 The new Seabee study is a non-concurrent historical
15 prospective study and can take advantage of
16 information from the Registry of Unit Locations,
17 which the Army will provide, I believe next month.
18 And it has a greater size, which can be
19 used -- we are setting up a cohort which can be used
20 to evaluate new hypotheses as they might arise in
21 the future, collect baseline information at this
22 time before we get too far away from the Gulf War.
23 So that answers your question.
24 COMMITTEE CHAIR LASHOF: Well, could you
25 comment further, and then I'd like Dr. Winkelstein
1 and Dr. Morgenstern to comment further, as to what
2 it adds to, and how it relates to the two other
3 studies that are similar that we've heard about
4 yesterday and today, one being the Iowa Study and
5 the one you heard this morning on the National
6 Survey that's being carried out by the VA, which
7 covers 30,000, 15,000 deployed and 15,000 non-
9 DR. DLUGOSZ: It's somewhat similar in
10 design to the Iowa Study but the Iowa Study, of
11 course, is limited to Iowa. The Seabee health study
12 is limited -- is not limited, it covers personnel
13 all over the world and in the United States. And
14 it's much larger in nature.
15 As compared to the study from the
16 Veterans Administration, the Seabee health study is
17 -- it's a little bit different in that it covers
18 only one cohort, an occupational group of naval
19 construction workers.
20 And the concerns we hear over and over
21 again about Persian Gulf illness, that these
22 illnesses might relate to some environmental
23 exposures or to some things that are not routine
24 parts of battle, as the routine latent effects of
25 war, post-traumatic stress disorder and things.
1 Using the Seabees -- using this entire
2 cohort, I think, is advantageous in that we can look
3 at a group of workers that are highly mobile, that
4 are in many different locations in the Persian Gulf,
5 and are not intensely -- were not intensely exposed
6 to combat and the affects of combat, but they were
7 exposed to the medications, the prophylactic
8 medications, they were exposed to vaccinations, they
9 were exposed to the environmental affects of the
10 Gulf. And that's how I can relate to those other
12 COMMITTEE CHAIR LASHOF: Then going to
13 Dr. Winkelstein?
14 DR. WINKELSTEIN: If I understood the
15 protocol, the plan is to do a survey of the entire
16 Seabee roster, if you will, at some point in time,
17 which would include Reserves as well as active duty,
18 and then to do a mail survey, and then, in some way,
19 to follow these people for a period of time.
20 A look in the protocol, it's a little
21 bit unclear to me exactly how long they plan to
22 follow them. In the introduction it talks about the
23 protocol applying only for two years but, if you
24 examine their estimates of sample size and so forth,
25 they are based on the 15-year follow-up.
1 The first major problem that I have with
2 this particular study is the basic survey, which is
3 planned to be a mail survey. And we've heard mail
4 surveys discussed yesterday and today and I think
5 that everyone that's been involved in such surveys
6 realizes that the response rates are not very good.
7 You've got a response rate somewhere in the
8 neighborhood of 50 to 65 percent. Generally
9 speaking, as I've said several times in the last 24
10 hours, that leaves you open for all kinds of
11 problems right there to begin with.
12 Now the protocol, from my point of view,
13 doesn't really deal with the complexities of the
14 follow-up. Now I think the Veterans' study of
15 mortality is reasonably rigorous. I mean, they have
16 the entire population, they have a good way of
17 getting the end points which are death. I mean, you
18 have a national death registry and deaths are
19 generally certified; you can't get buried without a
20 death certificate.
21 So that aspect of a mortality study and
22 mortality follow-up is relatively easy.
23 But I think that the end points that are
24 being proposed to study in the Seabee study are not
25 thank kind of end points. Generally speaking, they
1 are much softer end points. And, also, there's some
2 question as to whether it's appropriate to follow-up
3 on coronary heart disease, which is a major
4 component of the proposal.
5 So I have a lot of problems with the
6 protocol as I've seen it and I would like to be able
7 to study it in more detail and discuss with the
8 investigators at greater length before I made any
9 more comments about it.
10 COMMITTEE CHAIR LASHOF: Thank you.
11 Dr. Morgenstern?
12 DR. MORGENSTERN: I agree with Dr.
13 Winkelstein's comments about that study.
14 Let me return to your original question
15 to Commander Gray about the value of these other
16 studies that will be done to include inactive former
17 military personnel in the original three that we saw
18 this morning, which is the active military
20 The response, I believe, was that these
21 are exploratory studies and, therefore, if we see
22 some positive results it's indicative that we have
23 to do more work and pursue the reasons for that;
24 but, if the results are negative, that probably
25 means that there's nothing to it and I guess that
1 means we don't have to do any more work.
2 I disagree with that very strongly and
3 for a whole bunch of reasons that probably would
4 require some elaboration.
5 But one reason is that the problem here
6 is, first, it's not generalizability; that's not the
7 issue of studying active personnel. Can we
8 generalize to inactive personnel; that's not the
9 question. The question is one of bias, how you
10 select the subjects in such a way as to distort some
11 estimate of a causal relationship, presumed causal
13 And to the extent that we select
14 subjects for the study in ways, on variables that
15 might themselves have been influenced by Gulf War
16 participation, then we introduce a potential bias,
17 particularly if those variables are also related to
18 the outcome of the study.
19 Now it seems to me that that concern is
20 a major one here because it deals with all three of
21 the studies we discussed. I suspect intuitively
22 that it's much more of a problem with the study of
23 symptoms in the Seabees and in the hospitalization
24 than it is in the birth defects. Nevertheless, it's
25 a problem for all.
1 Now I don't think that a positive
2 finding means that we should go further and a
3 negative finding means that we should stop and say
4 there's no effect, it's nothing significant. The
5 fact is that there are many alternative explanations
6 for the negative findings that are consistent with
7 real effects.
8 In any study of occupational or
9 environmental exposures, for example, a major
10 concern, a major source of bias, is
11 misclassification and measurement of key variables,
12 outcome in particular in this case. And, to the
13 extent that there is such measurement error and
14 misclassification, the likely direction of the bias
15 resulting is towards the no, make it appear that
16 there are really no effects when there really could
18 There are other concerns, too. So the
19 bias can go in either direction. As a matter of
20 fact, with respect to the hospitalization, it
21 appears that likely bias might have been toward the
22 no because of differences in pre-War health status.
23 The one thing we saw this morning that
24 might indicate that, one of the findings on
25 hospitalization, was how different the deployed and
1 non-deployed were prior to the deployments of the
2 War. There was much more hospitalization in the
3 non-deployed group than in the deployed group. It
4 was a tremendous difference. Did you see how wide
5 apart those curves were?
6 Now, why were they so wide apart? Well,
7 clearly, those who were deployed were healthier in
8 some way. Now we can't ignore that. And, to say
9 that attempting to control for some surrogate proxy
10 confounder didn't correct the problem doesn't mean
11 that we solved the problem, it means that we have to
12 deal with it more thoroughly.
13 To draw conclusions from these studies
14 is going to be very tenuous. And the problem with
15 bias isn't that you know the direction and the
16 magnitude of the bias, the problem is that you don't
17 know. And that means that you have no confidence in
18 drawing conclusions from the results.
19 COMMITTEE CHAIR LASHOF: Thank you.
21 DR. BALDESCHWIELER: If there were a
22 specific -- this is directed at Dr. Gray.
23 If there were specific pathogen or an
24 environmental factor that were unique to service in
25 the Gulf, then a study of active duty personnel, in
1 fact, should have some chance of revealing a
2 difference between the Gulf and non-Gulf groups. In
3 the absence of a positive effect, that still should
4 allow you to place some limits on the occurrence of
6 Can you give us some feeling for the
7 numbers? That is, in your hospitalization study,
8 for example, if you see no positive effect within,
9 say, confidence limits of 90 percent, what are the
10 numbers of occurrences that would be below the limit
11 of statistical significance?
12 DR. GRAY: Well, I think we've listed
13 some of the confidence intervals around the rates.
14 I think your question about the statistical
15 significance requires a couple more elements to
16 figure out exactly what you're at.
17 DR. BALDESCHWIELER: I would like
18 something -- if you could give me just a general
19 feeling for what kinds of limits could you place on
20 the non-occurrence.
21 DR. GRAY: Yeah. If you figure that we
22 had approximately 1.2 million people who were in the
23 cohorts of interest initially, we do have -- I mean,
24 compared to studies that are published every day --
25 a heck of a lot of power for some of the outcomes,
1 particularly those that had a significant frequency.
2 I mean, there's over a thousand ICD-9 codes.
3 So it's a little bit difficult to answer
4 your question --
5 DR. BALDESCHWIELER: Could you, for
6 example, detect the occurrence of a thousand events
7 at a confidence level of 95 percent with the sample
9 DR. GRAY: Could we detect the
11 DR. BALDESCHWIELER: Yes, the occurrence
12 of some difference between Gulf and non-Gulf service
13 that involved, say, a thousand events.
14 DR. GRAY: So you're saying, if we have
15 2,000 cases in the Gulf War veterans and a thousand
16 in the non-veterans, could we detect that -- could
17 we infer some power? Yes, we can.
18 DR. BALDESCHWIELER: But at a 95 percent
19 confidence level?
20 DR. GRAY: I'm sure we can for that
21 example, that it would detect the difference.
22 DR. BALDESCHWIELER: Could you detect
23 the difference of 500?
24 DR. GRAY: Well, again, it depends on
25 the -- you know, it depends on the number of
1 outcomes in each of the two categories.
2 DR. BALDESCHWIELER: Yes.
3 DR. GRAY: I think -- it's just
4 difficult for me to answer that. We'd be happy to
5 respond to more specific questions at a later date
6 to the Committee. And we could send you power
7 calculations regarding some of the rate differences.
8 But, beyond that, I can't help you really too much
10 DR. BALDESCHWIELER: Well, I think first
11 thing, some upper bounds or limits what would be
12 detectable is a potentially useful --
13 DR. GRAY: We would agree with you.
14 I don't think the focus of the
15 hospitalization study is -- say that there was no
16 obvious hospitalization differences between these
17 two groups, hence, let's don't study this any more.
18 Our focus was to see where a quick look
19 at data that were already available, inexpensive,
20 and easy to access to try to answer some of the
21 important questions that our veterans who are
22 concerned about what they showed. And we know that
23 we have -- they are very much limited in what we can
24 say about those data.
25 So I think one of things we'll try to do
1 is qualify that as best we can with respect to the
2 conclusions we do make.
3 DR. BALDESCHWIELER: Well, I think I'm
4 really referring to a different way of presenting
5 the outcomes and, rather than saying that, for
6 example, there's no indication of a positive
7 correlation with service in the Gulf under various
8 categories of diseases, it might be useful to say --
9 I mean, within a 95 percent confidence level, that
10 we can report that there must have been a number
11 fewer than "x", that is less than a certain upper-
13 COMMITTEE CHAIR LASHOF: Warren, do you
14 want to comment?
15 DR. WINKELSTEIN: Well, I'm not a bias
16 statistician so I'm hesitant.
17 But I think one thing that strikes me
18 out of these data are that you have huge numbers and
19 so you can have very, very small relative risks that
20 are statistically significant because of the vast
21 numbers of observations. And that may be
23 And, if you have very small amount of
24 bias, the statistical test, of course, doesn't
25 realize that there's bias there so, let's say you
1 had a very tiny bias that produced, let's say,
2 relative risk of 1.2 or 1.3 -- we've seen some of
3 those kinds of relative risks -- those can be
4 statistically significant, meaningless, or biased.
5 So I think we ought to be very cautious
6 in the use of statistical significance with studies
7 like this with such large numbers in the
9 Maybe Hal is more sophisticated than I
10 am on this subject.
11 COMMITTEE CHAIR LASHOF: Hal?
12 DR. MORGENSTERN: I think I've warned
13 the Committee about treating the results of the
14 studies, boiling it down to statistical
16 You hear a lot about this, you see it in
17 the press, you see it in journals, you see it in
18 clinical papers; and it's true, this is a widely-
19 regarded concept. Somehow it's become almost
20 concrete in research findings.
21 Nevertheless, there isn't absolutely a
22 shred of scientific nature to the notion of
23 statistically significant. I truly wish it were
24 struck from the vocabulary of medical/clinical
1 It is completely arbitrary to say that
2 there is something significant about a finding when
3 the p-value, which is a rather arcane summary
4 statistic, is less than .05 versus when it's greater
5 than .05.
6 And one gets in trouble if one thinks
7 that you can boil down the conclusions of a study by
8 sort of taking this simple statistic and
9 dichotomizing it as significant or not significant.
10 A lot of people do it and it gets done quite a bit
11 and it makes things seem easy but, in fact, it's
12 covering up a lot.
13 For example, this morning I believe we
14 saw -- well, we saw the best estimate of an excess
15 mortality and hospitalization of, what, 13 percent
16 for the Gulf War participants versus the comparison
17 group; am I right? Was that the rate ratio, 1.13
19 MR. COATE: The mortality or the
21 DR. MORGENSTERN: In the
22 hospitalization, overall hospitalization? The rate
23 ratio for the Gulf War participation versus non-
24 participation was a rate ratio 1.13 and confidence
25 interval that just barely crossed the null-value and
1 the p-value is .06?
2 I warn you not to say, not to conclude
3 on the basis of this, that there is no significant
4 relationship. That is a conclusion that, I think,
5 belies the true nature of what statistics are
6 telling us and we have to go further than that.
7 I'm not suggesting that the researchers
8 would not go further than that, nevertheless, that's
9 what going to get reported, very often that's what
10 is going to make the newspapers, and that's what
11 people are going to believe.
12 Now why was there a 13-percent excess
13 hospitalization in Gulf War participants when, in
14 fact, it was much less before the war? Doesn't that
15 strike you as something going on there? Why?
16 And what makes these analyses
17 exploratory is that they often generate more
18 questions than they answer, and that's the question
19 being generated here, and that's the question that
20 we should now pursue: Why was there more
21 hospitalization among Gulf War participants after
22 the Gulf War even though there was considerably less
23 in the same groups before the Gulf War? And,
24 particularly, shortly before the Gulf War.
25 Now I think we have to address that
1 question and, to boil it down to a p-value of less
2 than .05 is entirely misleading.
3 COMMITTEE CHAIR LASHOF: John, do you
4 care to ask further questions concerning p-value?
5 DR. BALDESCHWIELER: This is probably
6 not the right forum.
7 But confidence is much better; isn't
8 this true. I mean, it looks like a difference but
10 DR. MORGENSTERN: Yes, in defense of the
11 research team -- I mean, they did present 95 percent
12 confidence intervals for virtually everything they
13 showed us, most of the things I remember. And the
14 result I even quoted, there was a 95 percent
15 confidence interval so they were basically telling
16 you what the likelihood -- you know, what the band
17 of effects that you would expect, you know, within
18 95 percent probability.
19 Nevertheless, as Dr. Winkelstein pointed
20 out, that assumes no bias. And those confidence
21 intervals basically pretend that there is absolutely
22 no bias and that what you got was perfectly valid.
23 And, of course, that addresses the question that we
24 were talking about before, source of bias.
25 COMMITTEE CHAIR LASHOF: Yeah. I mean,
1 basically, if the sample isn't a good sample, it
2 doesn't matter what statistics you apply to it.
3 DR. MORGENSTERN: Right, right.
4 And, you know, even though this is a
5 huge sample size in many of these studies initially,
6 if one starts weeding it down to subgroups or
7 looking at very rare outcomes like certain kinds of
8 birth defects, you will have a lot less power than
9 you might think.
10 So I agree with you in a sense of there
11 should be power calculations.
12 Now, in our March report we actually
13 called for that and, as I recall, in the response
14 that the research team gave in writing, the written
15 response which occurred a few days later, they
16 agreed with all that and they said they would do it.
17 COMMITTEE CHAIR LASHOF: Further
18 questions? Any further questions?
19 Dr. Ascher, did you want to make a final
20 comment on this aspect from the point of view of the
21 Epidemiological Board or --
22 DR. ASCHER: I would like to speak to
23 the AFEB issue.
24 I'm a representative of the AFEB; I
25 spoke yesterday. I'll try not to repeat myself.
1 But one of the aspects, observing this
2 overall process, to me is, this resembles a military
3 operation like we did in taking over Grenada, which
4 is, it was a free-for-all. All the forces went in
5 at once, they didn't talk to each other, their
6 radios wouldn't talk to each other, they shot each
7 other; and we didn't really have much of an overall
9 And, in this case, it's a similar thing,
10 that the VA has their studies, the Navy has their
11 studies, the Army has their studies, everybody has
12 their studies but there's no command and control at
13 the top.
14 Now who would be ostensibly responsible
15 for that? Well, that would be a role for the AFEB.
16 Well, up to this point, there has been
17 no official process by which this has occurred but
18 we have had unofficial input. And one of our
19 frustrations, reflected in Dr. Kuller's letter, is,
20 in the previous review of the protocols we've heard
21 today and others, we have made exactly the same
22 comments that were made by the outside advisory
23 panel that was commissioned sitting beside me, by
24 you today, by other people. So we're repeating
1 And one of the questions is, unless
2 anybody pulls all of this stuff together into
3 coherent approach of command and control of this,
4 it's going to go on and on.
5 For example, we made a very strong
6 statement that a birth defects monitoring program
7 was not worthwhile at the present time. And we
8 reviewed this and other things that should be done
9 including getting the Reservists in early, getting
10 social factors into the analysis. And apparently
11 there was absolutely no response to those comments.
12 That is our frustration. Dr. Kuller's letter
13 reflects the same thing.
14 In spite of that, they commissioned an
15 outside panel in addition to our review. So, at
16 some point after the free-for-all, let's find out
17 what's good among it, pull it all together, and get
18 it up at the top and make some hard decisions as to
19 what's worth doing.
20 I don't think OMB is where this should
21 meet. OMB is great and they do have a lot of
22 validity in their role, but I don't think they want
23 to get involved in these kinds of things, the big
25 I hope that's the forest, not the trees.
1 COMMITTEE CHAIR LASHOF: Thank you very
3 Are there any closing comments Commander
4 Gray would like to make, or his team, on any of
5 these studies and questions and critiques? It was
6 giving you a tough time.
7 DR. GRAY: We very much appreciate your
8 comments and we try to employ particularly our
9 Scientific Advisory Panel's comments as much as we
10 could. There are certain limitations with respect
11 to questions that we must answer, and finances.
12 But, anyway, we're actually trying to do
13 the very best job we can. We are very concerned
14 because we have, among us -- a number of us are Gulf
15 War veterans and we want to know if there is
16 something out there.
17 We appreciate anything the Committee can
18 do to help clarify things, streamline whatever
19 direction we should go next, and -- well, anyway, we
20 just thank you.
21 COMMITTEE CHAIR LASHOF: Thank you very
22 much. Any other closing comments?
23 If not, I thank all the panels; I
24 appreciate your input this morning and appreciate
25 your all coming.
1 We, on our panel, the next item on our
2 agenda is to talk about our strategy and where do we
3 go from here.
4 I think, from everything we've heard,
5 it's clear that will be asking staff to follow-up on
6 all the studies we've heard, keep us posted on the
7 progress of those studies. I think we will want to
8 look at some of the smaller studies.
9 I think, in these two days, we have
10 covered the big, major studies; there are a number
11 of others that are in the research plan that bear on
12 epidemiology. There are other studies in the
13 research plan that are more experimental and
14 environmental in the series that we will have to
15 also tackle at some time downstream.
16 I think the next big charge to us to try
17 to put all this together in a way to make some
18 recommendations for our interim report, which is due
19 in February.
20 So my suggestion is that we want to ask
21 staff to follow-up on what we've done today, take a
22 look and prepare for us brief summaries on the
23 additional studies that deal in epidemiology that we
24 didn't get to in the last two days, and that we
25 consider for our December meeting a further
1 discussion of the recommendations concerning the
2 whole series of issues that we've explored over the
3 last several meetings which include the
4 implementation, the outreach issues, and where we
5 stand on the epidemiology studies at this point.
6 I'm open to other suggestions, ideas, or
7 concerns that the subcommittee has.
8 Of course, our next meeting will be of
9 the full Committee and this subcommittee will be
10 reporting to the full Committee on what we came away
12 John, do you have any other thoughts or
14 DR. BALDESCHWIELER: I think not.
15 COMMITTEE CHAIR LASHOF: Andrea? No? If
16 not, again I thank you all and we will stand
18 (Whereupon, at 11:58 a.m., the meeting was