SSDEPARTMENT OF HEALTH AND HUMAN SERVICES

> FOOD AND DRUG ADMINISTRATION
>
> CENTER FOR TOXICOLOGICAL RESEARCH
>
> **RANCH HAND ADVISORY COMMITTEE**
>
> Thursday, March 13, 2003
>
> 8:00 a.m.
>
> San Diego Marriot La Jolla
>
> Newport-Irvine Room
>
> 4240 La Jolla Village Drive
>
> La Jolla, California
>
> PARTICIPANTS
>
> MEMBERS
>
> Robert Harrison, M.D., Chairman
>
> Leonard Schechtman, Ph.D., Executive Secretary
>
> Michael Stoto, Ph.D.
>
> Robert Sills, Ph.D.
>
> Paul Comacho, Ph.D.
>
> Ronald Trewyn, Ph.D.
>
> Kwame Osei, M.D.
>
> Ronald Varsaci
>
> OTHER ATTENDEES
>
> Richard Ogershok
>
> Jay Miner, Ph.D.
>
> Joel Michalek, Ph.D.
>
> Lt. Col Julie Robinson
>
> Maurice Owens, Ph.D.
>
> Monica Perlman
>
> Bill Grubbs
>
> [C O N T E N T S]{.underline}
>
> [PAGE]{.underline}
>
> Welcome 5
>
> Opening Remarks
>
> Request for Approval of Minutes From 11/14-15/01 Meeting
>
> Status of New Members
>
> Robert Harrison, M.D., Chair
>
> Personnel Changes and Contract Actions 22
>
> Cancer - Review/Discuss Manuscript 53
>
> Joel Michalek, Ph.D.
>
> Mortality - Review Findings from Latest Paper 111
>
> Joel Michalek, Ph.D.
>
> Diabetes - Summarize latest Analysis of the 129
>
> Insulin Sensitivity Study
>
> Joel Michalek, Ph.D.
>
> Public Oral Presentation \[None\] 146
>
> Hypertension - Summarize the Latest Analysis, 190
>
> Including Skin Exposure Index Results
>
> Joel Michalek, Ph.D.
>
> Thyroid - Review Results of the Latest Paper 230
>
> Joel Michalek, Ph.D.
>
> Statistics on Study Compliance to Cycle 6 238
>
> Joel Michalek, Ph.D.
>
> Latest Results of Consent for Future Use of 244
>
> The Data
>
> Joel Michalek, Ph.D.
>
> Update on Study Shut Down and Transfer of Data 249
>
> Joel Michalek, Ph.D.
>
> Publishing Strategies - Journal Choices Versus 276
>
> Time Remaining Before Shut Down
>
> Joel Michalek, Ph.D.
>
> [P]{.underline} [R]{.underline} [O]{.underline} [C]{.underline}
> [E]{.underline} [E]{.underline} [D]{.underline} [I]{.underline}
> [N]{.underline} [G]{.underline} [S]{.underline}
>
> **Welcome**
>
> DR. HARRISON: Shall we get started? With the permission of this August
> assemblage.
>
> I\'m Robert Harrison. And it\'s been my poor decision-making that has
> led me to chair this committee for the last several years. A much
> smarter man that I \--Mick Gough, sitting to my left\--somehow or
> another managed to weasel out of doing this job back in the early
> \'90s, and no one else has been silly enough to take it since then.
>
> \[Laughter.\]
>
> Before we start, can we go around the room and introduce ourselves.
> We\'ve got a few new people here. Again, I\'m Robert Harrison. I\'m no
> professor emeritus of medicine at the University of Rochester, and
> doing mostly consultant work and running and internet-based weight
> management program called \"Be Slender.\"
>
> Why don\'t we go this way.
>
> DR. GOUGH: I\'m mike Gough. I\'m retired. I guess I\'m a retired
> bureaucrat\--a retired Congressional bureaucrat. That says it. And as
> Bob said, I chaired the committee for five years, from \'85 to \'90.
> And then I came back four or five years ago. So I\'ve been here a long
> time.
>
> DR. STOTO: I\'m Mike Stoto. I\'m an epidemiologist, and also I
> \[inaudible\]\--the Rand Corporation \[inaudible\]\--use to be true.
> I\'m also on the faculty of Harvard School of Public Health
> \[inaudible\].
>
> DR. STILLS: I\'m Robert Stills. I\'m a Veterinary Pathologist in the
> National Institute of Environmental \[inaudible\] Sciences. And I\'m
> also \[inaudible\] at UNC \[inaudible\].
>
> LT. COL. ROBINSON: I\'m Julie Robinson, and I\'m Branch Chief for
> Biomechanisms and Modeling at Brooks City Base. And I\'m also the
> Director of the \[inaudible\], and just recently re-associated with
> \[inaudible\].
>
> DR. HARRISON: Let\'s continue on around.
>
> Ron?
>
> DR. TREWYN: Ron Trewyn, Kansas State University. I was on the
> committee for awhile, and then got thrown off for causing too much
> trouble\--
>
> \[Laughter.\]
>
> \--and I think they figured out that it was too quiet without me, so
> brought me back the last time. And so, you know\--
>
> DR. CAMACHO: I\'m Paul Camacho. I\'m at the William Joiner Center for
> the Study of Law and Social Consequences at the University of
> Massachusetts. It\'s a research institute\--one of several that are
> located in Boston.
>
> DR. HARRISON: Okay. And continuing in this\--I\'m sorry\--
>
> DR. SCHECHTMAN: I\'m Leonard Schechtman. I\'m the Executive Secretary
> of the Ranch Hands Committee. I\'m also the Associate Deputy Director
> of the FDA National Center for Toxicological Research.
>
> DR. HARRISON: Sounds important to me.
>
> DR. MICHALEK: I\'m Joel Michalek, Principal Investigator of the
> \[inaudible\] study, and adjunct faculty at the University of Texas
> School of Public Health, University of Texas, San Antonio.
>
> DR. BABYAK: I\'m Babyak \[inaudible\].
>
> DR. I\'m Manuel Bancas, the \[inaudible\] contractor working for
> program management \[inaudible\].
>
> DR. MINER: I\'m Jay Miner, formerly on the technical side of the
> house. I \[inaudible\] completed my active duty and came back to the
> dark side of the force, in program management.
>
> \[Laughter.\]
>
> DR. OGERSHOK: I\'m Richard Ogershok. I am the program manager of the
> Ogershok Study.
>
> DR. BROWN: Program monitor from Washington, D.C. \[inaudible\].
>
> DR. PERLMAN: I\'m Monica Perlman \[inaudible\].
>
> DR. OWENS: My name is Maurice Owens. I\'m the science applications
> \[\[inaudible\] for my program managers.
>
> DR. GRUBBS: I\'m Bill Grubbs \[inaudible\].
>
> DR. YEAGER: I\'m Meghan Yeager \[inaudible\].
>
> DR. KEIHL: Bill Keihl \[inaudible\].
>
> DR. LANGER: Walt Langer \[inaudible\].
>
> DR. FORNEY: Joseph Forney \[inaudible\].
>
> DR. HARRISON: Welcome, everybody.
>
> Some additional information for everyone. The Secretary\'s office has
> the Ranch Hand Advisory Committee nomination package. Two new members
> have been nominated: Sanford Leffingwell, M.D., M.P.H., and Isabel
> Hoverman, M.D. And it\'s also been requested that Dr. Stoto be
> reappointed.
>
> Dr. Leffingwell is an occupational and environmental medicine
> consultant, with HLM Consultants in \|Atlanta; served as a medical
> epidemiologist for the chemical de-militarization program with the
> CDC, a group providing Congressionally mandated oversight of the
> Army\'s chemical weapons disposal activities. Are those weapons of
> mass des\--nah.
>
> \[Laughter.\]
>
> Dr. Leffingwell also served as a member of the U.S. negotiating
> committee for a bilateral chemical weapons treaty, and was a member of
> the U.S. medical management of people injured in the 1995 subway
> nerve-gas incident\--I assume that\'s Japan?
>
> He serves on the NRC Standing Committee on Program and Technical
> Review of the U.S. Army Chemical and Biological Defense Command, and
> the Committee on Chronic Reference Doses for Selected Chemical Warfare
> Agents. It says \"welfare agents\" here.
>
> \[Laughter.\]
>
> Dr. Hoverman is a practicing physician in internal medicine in Austin,
> with extensive experience in the development of clinical practice
> guidelines, and has participated in the design of health outcome
> studies and measures for out-patient practice.
>
> Prior to entering private practice, she was an assistant professor of
> medicine at the University of Texas Medical Branch at Galveston. Dr.
> Hoverman has served on Previous Institute of Medicine committees, most
> recently on the Committee on a National Center for the Study of
> War-Related Illnesses and Post-Deployment Issues.
>
> Does this mean, Len, that you have some housekeeping items? Should we
> interrupt here for you? Okay. I\'ll finish the rest.
>
> One of the things that\'s come up that\'s been an issue\--I know, with
> me, and perhaps with others\--is that the FDA has instituted new
> guidelines for advisory committees, requiring that prior to every
> meeting the agency is to review members\' files for conflict of
> interest. This means at least once a year you\'re going to be
> requested to submit updated and signed OGE-450 forms; those are the
> confidential financial disclosure reports; and Form HHS-697, which is
> a foreign activities questionnaire.
>
> Those at present are the only requirements. In order for FDA, NCTR to
> be responsive to these requirements now in effect, and in order for
> members to attend and participate in Ranch Hand Advisory Committee
> meetings, and to qualify for reimbursement of committee-related
> expenses, it\'s essential that you have these things turned in in a
> timely fashion.
>
> Later on we\'ll be discussing the next meeting dates. As far as travel
> voucher expenses are concerned, please submit to Ron Varsaci who, I
> think somehow or another, managed to avoid introducing himself during
> the round of introductions.
>
> Hotel receipts; mileage if you used a vehicle; airport parking
> receipts, taxi costs; receipts are required for \$75 or more, and
> airline ticket receipts, where applicable.
>
> Now, Len has some other housekeeping stuff.
>
> DR. SCHECHTMAN: Just to reinforce the issue around these new FDA
> policies: it\'s critically important that everyone submit their
> conflict of interest forms, filled out and signed, as well as their
> foreign activities questionnaire.
>
> Unfortunately, because FDA is now under extremely tight scrutiny
> around these issues from the Department\--DHHS\--we have to comply, as
> a committee, with those new rules and regulations. And because of
> that, unfortunately, if those forms aren\'t\--if we don\'t get
> responses to those questionnaires, and those forms aren\'t filed out
> and signed in an appropriate manner, with complete identification of
> your financial holdings, we can\'t have you sit at the table, we
> can\'t have you participate in the meeting, we can\'t reimburse you
> for any of your expenses to get to the meeting. And we apologize for
> that, but this is how they\'re trying to enforce these new\--or
> tighter\--regulations that weren\'t, perhaps, as tightly adhered to
> before.
>
> So, FDA is being held to the task, and that\'s passed right down
> through all the committee and subcommittee activities that FDA leads.
>
> So, please, when the requests come\--and they come every October,
> while this committee is still operational, within two weeks of that
> request, please turn that information around to us. It will be
> scrutinized before every meeting that the committee holds. And if
> there are questions that arise, we need to have that all cleared up
> before we congregate and have our meeting. And then there will be no
> questions; we won\'t have to be making phone calls back and forth to
> FDA from whatever meeting location we\'re at to get last-minute
> approval. Because often they don\'t want to deal with it at that point
> in time.
>
> So, please\--thank you for your cooperation, and we look forward to
> hearing from you two weeks into October.
>
> DR. HARRISON: Okay.
>
> \[Discussion off mike.\]
>
> Can we have just a short break?
>
> \[Off the record.\]
>
> DR. HARRISON: Sorry for the interruption. I was concerned because one
> of the committee members, Kwame Osei, because of some of the business
> I just finished describing about financial reporting, is having
> difficulty being allowed to attend this meeting; or participate in
> this meeting.
>
> It\'s one of those trivial things, where you put down \"Vanguard
> Fund,\" and then you have to put down precisely which Vanguard Fund.
> And I\'m concerned, because Kwame is not just a clinician, but is an
> active and prolific researcher in the area of diabetes, which is one
> of the areas that we\'ve identified, and we\'ll be listening to a
> report later on. And I\'m basically tired of being the only person who
> is supposed to know anything about diabetes, being on this committee,
> listening to this report.
>
> So I\'ve Kwame\--talked to him and asked him to contact his broker,
> and see if the FDA staff can\'t get his approval expedited so that he
> can participate in this program by 10:00 a.m. this morning. If he
> cannot, then we\'ll have to stop. I\'m not going to participate.
>
> MR. VARSACI: Could I add one thing? There was some confusion as to
> whether the individual companies of the fund holds, and that\'s not
> that far. You have a family of funds, and they have sub-segment
> funds\--
>
> DR. HARRISON: I\'m not really interested in that. What I\'m interested
> in is being able to apply the scientific method to this advisory
> committee\'s actions. And to do that, we need certain people. And if
> we can\'t have them, then I\'m not sure that I want to be a
> participant. It\'s just that simple.
>
> DR. STOTO: Bob, if he can\'t get the information by 10:30 this
> morning, are we\--
>
> DR. HARRISON: I\'m\--we can rearrange the agenda. But I\'m just
> getting irritated. I\'m sorry. For some reason, the older I get, the
> less tolerant I become of this kind of stuff\--you know. And so we\'ll
> see what happens.
>
> So, until then, let\'s proceed. So I just wanted to\--a couple of
> people have asked me why I asked for the break and everything, and I
> just wanted to explain to everyone what had happened.
>
> Okay. Can we go ahead now and proceed with\--oh, wait a minute. We
> need to approve the minutes from the 11/14, 15 meeting. All of you
> have copies of the agenda in front of you. Are there any corrections
> to the\--I\'m sorry, not agenda\--minutes. Al of you have copies of
> the minutes? Do any of you have\--thank you, thank you, thank you. Try
> to keep them, you know.
>
> Okay. I\'m starting to come back down again. We\'re doing okay.
>
> DR. GOUGH: \[off mike.\]
>
> DR. HARRISON: No, no. Not at all. You could never rile me up.
>
> DR. GOUGH: I have some corrections to the structure of some of these
> sentences, which I\'ll just pass on. But I do have one significant
> thing, and that is on the second page, under \"Technical
> Presentations,\" the second bulleted item. That sentence, which says,
> \"Stated another way, after adjustment\--\"\--blah, blah, blah.
>
> I would like to have an insight to\--that\'s what Dr. Michalek said?
> Because I disagree with the statement. I mean, Ranch Hand veterans
> have not experienced a significant increase in the risk of diabetes.
>
> DR. HARRISON: Well, why don\'t we do this. At the beginning of the
> technical presentation section, it says, \"Dr. Michalek presented a
> series of slides on his statistical analysis on diabetes and other
> effects.\" These are Dr. Michalek\'s statements.
>
> DR. GOUGH: That\'s fine. That\'s fine.
>
> I think all of the\--in fact, I think every time it\--
>
> DR. HARRISON: You could almost assume that it was.
>
> DR. GOUGH: I know. But when you say, \"in other words,\" is as
> though\--
>
> DR. HARRISON: And then the last bullet in that section, then, should
> be pulled out and not made a bullet. We can leave the statement in. It
> just shouldn\'t be a bullet. Then it\'s obvious, then, that the Ranch
> Hand Advisory Committee complimented Dr. Michalek\--okay.
>
> Anything else?
>
> DR. CAMACHO: So, you wanted to pull that sentence.
>
> DR. HARRISON: Well, otherwise, if it\'s left as a bullet, Paul\--
>
> DR. CAMACHO: No, no, no, no. The sentence\--\"Ranch hand veterans have
> experienced significant increase in risk\--\"\--
>
> DR. GOUGH: No, just leave it in, because Dr. Michalek said that.
>
> DR. HARRISON: Yes. All of those\--everything that\'s in there that\'s
> bulleted stays in. It now is just preceded by a sentence that says,
> \"These are Dr. Michalek\'s statements.\"
>
> DR. CAMACHO: Okay.
>
> DR. HARRISON: And then the last bullet, which isn\'t Dr. Michalek\'s
> statement\--
>
> DR. CAMACHO: Gets the bullet pulled\--
>
> DR. HARRISON: Gets the bullet pulled out, but the statement stays in
> that we complimented him on his stuff.
>
> DR. CAMACHO: All right.
>
> DR. HARRISON: Is that fair enough, everybody? Okay.
>
> DR. GOUGH: Then can I ask for one other\--
>
> DR. HARRISON: Yes, sir?
>
> DR. GOUGH: If it\'s possible, on page 3, under dioxin and insulin
> sensitivity\--right within that paragraph, the penultimate sentence in
> that paragraph, it says, \"Dr. Michalek\'s slides presented
> preliminary data\--\"\--Joel, is it possible to summarize those data,
> and have them in the minutes? I don\'t know if that could work.
>
> DR. MICHALEK: I have not seen the minutes. \[Off mike.\]
>
> DR. HARRISON: That\'s reasonable enough. Anyone disagree with that? Or
> do you want to add to it in any way?
>
> DR. STOTO: Consistent with what we just did \[inaudible\].
>
> DR. HARRISON: Hmm?
>
> DR. STOTO: It\'s consistent with what we just did with the previous
> one, is to\--you know, have the summary be prepared by the person who
> was doing it.
>
> DR. HARRISON: Oh, yes. Yes. But, in this case, it\'s adding
> Michalek\'s rendition of the results to the paragraph.
>
> DR. MICHALEK: \[Off mike\]\--by e-mail?
>
> DR. HARRISON: By all means. By all means. At that point, what we can
> do then is we\'ll make the edit changes that have been suggested and
> we\'ll send it out\--we\'ll send the minutes out to the committee for
> final approval, through you. Can we do that?
>
> What we can do is approve it, with changes, subject to my review
> and\--
>
> DR. GOUGH: I so move.
>
> DR. CAMACHO: Second.
>
> DR. HARRISON: Moved and seconded. Any other questions or comments? Any
> other corrections to the minutes?
>
> DR. CAMACHO: Was Mr. Weidman ever sent the public section that he
> spoke\--
>
> DR. HARRISON: What page?
>
> DR. CAMACHO: It\'s page 4, bottom\--\"Public Session\--Mr.
> Weidman\--\". Does he have to be sent\--
>
> DR. HARRISON: I don\'t know. Maybe\--
>
> DR. STOTO: I don\'t think it\'s appropriate for him\--
>
> DR. HARRISON: Maybe I\'m\--I mean, Michalek\'s not a committee member
> either, but in this case, these are minutes of what we think happened,
> not minutes of what Weidman thinks he said.
>
> DR. CAMACHO: Okay.
>
> DR. HARRISON: That would be my thought.
>
> Okay. Anything else?
>
> Okay. Then I\--sir?
>
> DR. OGERSHOK: \[Off mike\].
>
> DR. HARRISON: Oh, yeah. No, we\'re almost there. So, there\'s a
> consensus that that\'s how these minutes will be handled? So we\'re
> almost exactly on time, and we\'ll proceed with personnel changes and
> contract actions.
>
> DR. OGERSHOK: \[Off mike\]. In the context of\--what the\--the website
> had certain data pulled off it, right? Remember, there was a big issue
> about privacy?
>
> DR. HARRISON: Yes.
>
> DR. OGERSHOK: Is that reflected in the\--I didn\'t see that reflected
> at all in this. Is that something we should be concerned about, or
> I\'m being\--
>
> DR. HARRISON: That was in the minutes.
>
> DR. OGERSHOK: It was.
>
> \[Discussion off mike.\]
>
> DR. HARRISON: It came off e-mail. I\'m sorry, we\'ve regressed\--just
> momentarily here.
>
> DR. STOTO: My recollection is that it was resolved. More happened
> after the meeting, but these are minutes of what happened at the
> meeting. And I think from that perspective, they\'re correct.
>
> DR. GOUGH: I thought that all the data was pulled off the website,
> because of the legal determination by \[\[inaudible\]. And that\'s not
> reflected in the minutes, but I think that happened after\--
>
> DR. HARRISON: So then shall we include it as a part of the discussion
> at this meeting? That as the minutes were being discussed, the
> question was being brought up about the display, or the availability
> of Ranch Hand data on the Air Force website. And it was suggested and
> agreed by Joel Michalek that the material was pulled from the website
> because of legal concerns by the Air Force.
>
> DR. SCHECHTMAN: Was that done advice of legal counsel at that time?
>
> DR. HARRISON: By the Air Force.
>
> DR. SCHECHTMAN: By the Air Force.
>
> DR. HARRISON: So that will now be a part of this meeting\'s minutes,
> in a\--as a display of the discussion.
>
> DR. TREWYN: Probably generally, just having a topic of \"Business
> Arising from the Minutes\" would be good so those sorts of
> issues\--because I think we generally wind up leaving something that
> needs to be handled afterwards, and if we could have those highlighted
> in the minutes, then that could be an update right after we\'ve dealt
> with those.
>
> DR. HARRISON: It looks like Len has agreed with that statement, and I
> expect that we see that sub-heading when we see the next set of
> minutes.
>
> DR. CAMACHO: Yes, I just brought it up because\--
>
> DR. HARRISON: That\'s a good point\--
>
> DR. CAMACHO: \--the veterans community\--causes a concern, among
> others.
>
> DR. HARRISON: Well, and I think there should be more discussion about
> that when we get to the section on the consent for further use of data
> that\'s in here. I certainly have some questions about how that was
> done to achieve a 99 percent compliance.
>
> Okay. Any other questions about the minutes? Are we finished with the
> minutes? Anyone who has any thought that we\'re not finished with
> the\--any glimmer of\--no? We\'re finished with the minutes now. All
> right.
>
> DR. GOUGH: Will you yield me three minutes?
>
> \[Laughter.\]
>
> DR. HARRISON: If you have something, let\'s deal with it now.
>
> DR. GOUGH: I don\'t have it now. No. I have to think about it. No, I
> had nothing, actually. I just want to keep it open.
>
> DR. HARRISON: Okay. Anybody got any Zantac?
>
> \[Laughter.\]
>
> Okay. The minutes are approved. Let\'s go on now to program management
> update.
>
> Thank you. Sorry to have kept you delayed, sir.
>
> **Personnel Changes and Contract Actions**
>
> DR. OGERSHOK: Since our last meeting I thought we\'d go over some of
> the events that transpired in the program since\--I think it was,
> what?\--November of \'01 or so?.
>
> DR. HARRISON: Sounds right.
>
> DR. OGERSHOK: All right. Next slide.
>
> \[Slide\]
>
> This is our program team. And as you see, we include the advisory
> committee as an integral part of the team. One change\--I believe it
> was changed about the time we last met, however we have our program
> element monitor was shifted from Air Force RD to the Surgeon General
> of the Air Force.
>
> Next.
>
> \[Slide.\]
>
> To get ready for the physical exams, we had different types of
> documents that had to be prepared, between October and March of 2002,
> which included the biomedical test plan, schedule and tracking plan
> and a QA plan.
>
> And then we had to do some testing of some of the components of the
> examination. We had a schedule and tracking system demonstration at
> the National Opinion Research Center in Chicago. We did a CAPI demo
> down at Brooks Air Force Base. And then we did a test of the
> examination itself, to see how the protocol was being adhered to by
> the examiners. And that was done here in Scripps in March of last
> year.
>
> Next.
>
> \[Slide.\]
>
> We started the exams in May of 2002. We planned on doing 81 groups,
> approximately\--hopefully\--2,100 participants. We\'re not going to
> achieve that. We\'ve scheduled about 1,969, I think it was, as of
> yesterday\--which probably changed by today. And we\'ve completed 75
> groups, with 1,831 participants.
>
> To give you an idea what it costs\--on the cost of doing the
> examinations, when you include the exam and the reimbursables
> associated with it, it\'s about \$6,350 per person.
>
> What we\'re planning on doing in the near term: SAIC has already
> submitted the stat plan to us. We plan to get back with them at the
> end of this month with out comments. Exams will be ending the first
> week in April. And, let\'s see the next one up there. Oh\--delivery
> and acceptance of the exam data will be taking place in June of this
> year.
>
> Next.
>
> \[Slide.\]
>
> What\'s going to happen in the following fiscal years, of course, is
> the stat analyses which take about\--what?\--13 months, I believe.
> Then we have the report-writing and chapter reviews, which you will
> all be an integral part of. And Dr. Miner\'s going to give you his
> layout of how that\'s to be accomplished. And then, of course, our
> final cycle report delivery.
>
> Now, after that\--after the data, the report\--obviously we can do
> peer reviewed articles. And Dr. Michalek will go into that. We
> obviously have to publish a final mortality report; any special
> studies\--depending on the findings and data that we get; and then
> digitize the rest of the exam data that we are getting right now; and,
> of course, complete the study according to the protocol.
>
> Next.
>
> \[Slide.\]
>
> Now, special interest items. I mentioned that we transferred our
> program element monitor to the Surgeon General of the Air Force.
> We\'re short money in 2003 because of some cuts that were taking
> place. However, we were fortunate to get a Congressional plus-up of a
> million dollars in 2002 that we were able to use this year.
> So\--we\'re copacetic.
>
> And, of course, our special interest item on the process for
> completion, disposition of data and specimens, which we have talked
> about in the past. And, again, we will discuss the process for review
> of the chapters.
>
> Dr. Miner will take over.
>
> DR. MINER: You all may remember these slides from before, but the Air
> Force is very concerned that they want the committee\'s involvement in
> chapter review. And just to kind of serve as a reminder, what we
> have\--April, the exams end. In about 60 days\--but that might be 30,
> it might be a little bit more than that\--we\'ll get our last data
> delivery. Air Force then has 30 days to accept the data, and then our
> prime contractor, Science Applications International, will begin the
> analysis.
>
> And that will be a 13-month effort, and the draft report is due in
> August of 2004. We have 90 days, then, to look at the draft report,
> provide comments back to them. Thirty days after that, a final report
> is due, and then in December of 2004, the final report will be
> delivered.
>
> It\'s this 13-month period that I would like to highlight;
> specifically, the involvement of the committee. As you may remember,
> the Air Force has an iterative chapter review with SAIC, and they send
> us draft chapters; we resolve comments. And you had requested that we
> then provide you those draft chapters with Air Force comments for
> review.
>
> So the committee review process\--I don\'t want to say here\'s
> what\--yes, sir?
>
> DR. HARRISON: Jay, can I interrupt you for a second?
>
> DR. MINER: Sure.
>
> DR. HARRISON: My question actually has to do with the selection of
> experts and writers for the draft chapters. How is that done? I assume
> that\'s done by the contractor, and the\--
>
> DR. MINER: We had a presentation on that yesterday with our management
> meeting; individuals here\--if you want to address that a little bit.
>
> DR. HARRISON: Because the concern I have is the quality of the authors
> and the fact that once the thing is written, you\'re basically reduced
> to editorial changes, as opposed to anything substantive.
>
> Can we have some comment on that? Is that\--
>
> DR. MINER: Yes. Dr. Owens is here, and he can address that.
>
> DR. OWENS: I\'ll just review our process and procedures for
> accomplishing this.
>
> The bulk of the material that\'s in a chapter\--a clinical chapter,
> say \"General Health,\" or \"Hematology,\"\--in the report is
> statistical analysis that is presented according to plan. And that\'s
> pretty straightforward procedure. I think our practice has been very
> factual and objective.
>
> There are two areas where we have people coming in\--expertise\--in
> terms of preparing the report. One is the review of the literature. We
> had, in the past, we had one person that did that, who was a
> cardiologist. This committee commented on that. The Air Force changed
> its requirements, and we have requirements to provide experts in
> medical literature. We have an epidemiology firm, experienced
> people\--Ph.Ds in epidemiology\--that will be doing those literature
> reviews. So that\'s one piece.
>
> The other piece is the clinical interpretations of the findings of the
> report, that hithertofore were written by one person. The Air Force
> has changed its requirements, given some of the committee\'s feedback
> on that, and we\'re required to provide an expert in the respective
> clinical area.
>
> So we have made arrangements with Scripps Clinic to handle the medical
> reviews for the individual chapters. Dr. Monica Perlman, here, will
> be\--she\'s going to be heading up that process, and will be working
> with physicians, board certified in their respective areas, for the
> interpretation for the chapters.
>
> So that is the process that we have in place, and are ready to go for
> the 2002 study report.
>
> DR. HARRISON: You could almost gather from\--so, out of all of that,
> the question that I\'m asking is specifically about those experts. And
> all that you\'ve said so far is that they\'re board certified.
>
> Dr. Perlman, George Dailey will tell you that I\'m a bit difficult at
> times\--
>
> DR. PERLMAN: That\'s okay.
>
> DR. HARRISON: I knew him when he was a young lad.
>
> DR. PERLMAN: It won\'t just be a board certified physician in that
> area. It will be an expert in that area who\'s done research in the
> area. George Dailey, as an example, would be for diabetes
> endocrinology.
>
> DR. HARRISON: So George is going to write the diabetes section?
>
> DR. PERLMAN: Well, he\'s the one I was going to go\--I have not
> specifically gone and asked anybody, but he\'s the one in our
> division\--our division of diabetes endocrinology\--that I would
> approach, unless\--you know, I mean we have two other choices that are
> excellent. And I haven\'t really done final selection at this point.
>
> DR. STOTO: I wonder if we could resolve this by just asking to see the
> list so people will have an opportunity to comment on the list.
>
> DR. HARRISON: That would be very reasonable. Is that logistically
> achievable?
>
> DR. PERLMAN: To give you a list of who\--yes, sure.
>
> DR. STOTO: I\'d ask the same with the epidemiologists.
>
> DR. PERLMAN: Yes.
>
> DR. HARRISON: Great.
>
> DR. MINER: We do try to pay attention.
>
> DR. STOTO: Not that we have any, you know, concerns in advance. But I
> just think that part of our oversight responsibilities, it would be
> appropriate.
>
> DR. HARRISON: Well, and that\'s a really critical process.
>
> DR. MINER: Right.
>
> DR. HARRISON: I mean, that puts the rubber on the road.
>
> DR. MINER: Yes, sir.
>
> And then again, back to the advisory committee review, there\'s about
> 20 chapters that will require reviewing in this 13-month period. And
> whatever process the committee decides on how they want to do
> that\--that\'s why I put a little star there that says that\'s your
> process, you decide, and we\'ll do our very best to expedite and help
> you do that.
>
> DR. STOTO: On those three meetings to review chapters, I think the
> first one should be November \'03.
>
> DR. MINER: Again, keep in mind that that little star says you decide
> how you want to do that.
>
> I just tossed some\--
>
> DR. STOTO: It\'s just a typo, though, I think. It says, \"November
> \'04.\" I think you\--
>
> DR. MINER: Oh\--a typo. I\'m sorry\--yes. Or you might work real fast
> and\--yes, that should be November \'03.
>
> Anyway, so by July of 2004, we will need to review and resolve
> comments. August would be the draft report for 13 months. And then, as
> the custom, we have an advisory committee meeting and review of that
> big, giant final thing. But if everybody\'s reviewed chapaties, that
> should not be nearly the trauma that it was the last time\--we hope.
>
> And then, again, we have 90 days from the draft report for Air Force
> comments, and the final report in December.
>
> DR. HARRISON: I\'m not sure I understand one thing\--and that is, the
> draft chapters\--the ones before\--that the Air Force is going to
> comment on, when do those chapters start to come out?
>
> DR. MINER: As soon as Air Force accepts the data, the statistical
> analysis will begin; some report-writing will have been done on the
> basic chapters at that time. And as quickly as they get chapters to
> us\--and that could be as early as\--do you want to comment on\--
>
> This is Dr. Bill Grubbs, our\--SAIS\'s statistician.
>
> DR. GRUBBS: Hi. It depends on the\--as Dr. Miner said, it depends on
> the approval of the final data. That kicks off the process.
>
> If the Air Force has comments on the data, need to be revised, it
> pushes the process back a little bit.
>
> DR. HARRISON: But according to the schedule, when should the
> draft\--not the ones after Air Force approval, the ones before Air
> Force approval.
>
> DR. GRUBBS: To give you an idea from last time, the approval from the
> Air Force happened on August 26 of 1998\--it happened near the end of
> August. The 13-month period then ended in September of\--late
> September of 1999. Just to review from last time.
>
> DR. HARRISON: But if the Air Force approves the data in August of
> 2003\--
>
> DR. GRUBBS: Right.
>
> DR. HARRISON: \--according to the schedule, when should the first
> drafts be back to the Air Force for Air Force\'s comments?
>
> DR. GRUBBS: the process is a rolling report. The first chapter of the
> 12 clinical chapters would be there approximately October or November
> of 2003.
>
> Then undergoes the process where they review it, give it comments, we
> resolve those comments. We get back the second draft to them, and then
> you get that.
>
> So, as an estimate, from when we submit the first draft of a chapter
> to the Air Force, it would be approximately two months before a second
> draft would be available for the committee to review, incorporating
> the Air Force comments.
>
> DR. MINER: I think you\'re asking when will the first chapter be in to
> the Air Force.
>
> DR. HARRISON: Well, and Bill is saying that that\'s approximately two
> months after the Air Force approves the data. And\--
>
> DR. GRUBBS: Not quite.
>
> DR. MINER: \[Off mike\].
>
> DR. GRUBBS: The clinical chapters\--once they approve the data, we
> need to do the analysis, and submit a draft chapter.
>
> DR. HARRISON: But you said August? You said the last time, it was
> approved in August, and the first chapter was out in October.
>
> DR. GRUBBS: Late October, early November \--correct. So that\'s two
> months. But then the review process will probably take\--
>
> DR. HARRISON: I\'m not asking about the review process.
>
> DR. GRUBBS: Okay.
>
> DR. HARRISON: I want to know when the first draft is ready.
>
> DR. GRUBBS: Probably\--the first draft of the first chapter, about two
> months after the approval of the final data.
>
> DR. HARRISON: Okay. And obviously the reason why I\'m asking when the
> first draft is ready is to ask whether the committee would like to
> discuss whether it\'s worth seeing the drafts before the Air Force\'s
> corrections, versus after.
>
> DR. MINER: Do not use the word \"corrections.\"
>
> \[Laughter.\]
>
> DR. MINER: We don\'t like that word.
>
> DR. HARRISON: After the Air Force\'s airbrushing\--
>
> \[Laughter.\]
>
> DR. MINER: That\'s worse.
>
> DR. HARRISON: After the Air Force review.
>
> DR. STOTO: So, in other words, that\'s three times, rather than
> two\--adding upon, rather than\--
>
> DR. CAMACHO: Well, already we\'re talking\--I mean, this plan has us
> looking at them twice\--chapter by chapter, and as a whole. And
> you\'re\--just clarifying what you have in mind.
>
> DR. HARRISON: I\'m not\--actually, I don\'t have a proposal in mind.
> What I\'m asking is when the least\--huh?
>
> DR. CAMACHO: When the least work on the data. So you want to see
> closer to the raw\--
>
> DR. HARRISON: I\'m not saying I even want to see it. I\'m just saying
> that that\'s when the stuff first comes out, then there\'s an
> intermediate stage, after it\'s been\--any comments shave been
> incorporated, and then there\'s a stage after, say, some of us have
> seen it and made other comments.
>
> And the question is\--for two reasons\--number one, if I were asked if
> I knew\--how I knew that there was nothing contrary to the final
> report in the initial report, I\'d have to say I didn\'t know that in
> any way. You know.
>
> So if you have a segment of the population that is suspicious of the
> reports, and if the advisory committee is\--if a part of the advisory
> committee\'s function\--then can you validate a report that\'s already
> had comments incorporated?
>
> DR. STOTO: I\'m concerned about looking at it three times.
>
> DR. HARRISON: I understand that.
>
> DR. STOTO: So what I would propose is that when we see them for the
> first time, according to the schedule, that we be told what changes
> were made, beyond\--
>
> DR. HARRISON: Or could we simply ask for both copies?
>
> DR. STOTO: Well, I guess I\'d prefer to.
>
> DR. HARRISON: I understand. I understand. I\'m not opposed at all.
> I\'m just brining this up as we go along, that\'s all.
>
> DR. TREWYN: I think seeing the draft, when we see it, that has the
> changes highlighted or incorporated by the initial review\--I think
> that would be useful. Because then we\'ve seen what they have
> incorporated. So, presumably, what isn\'t highlighted\--
>
> DR. STOTO: And what they\'ve taken out, too.
>
> DR. TREWYN: What they\'ve taken out\--exactly. I think that\--
>
> DR. HARRISON: Okay. All right.
>
> Any other comments? Is that an official consensus-driven request by
> the committee?
>
> DR. TREWYN: I think that would address the issues that outside groups
> might have of, you know\--were we aware of what was there, you know.
>
> DR. HARRISON: Can we word it this way? Can we say that the advisory
> committee would like for its review, the revised draft, with
> indicators of deletions and changes that have been made. Or, if that
> is not possible\--it should be possible. But if that is not possible,
> then both the initial draft and the revised draft.
>
> Jay?
>
> DR. MINER: As part of the process, when we are resolving comments with
> SAIC, they usually prepare a table for us of comment resolution and
> recommendations. And perhaps we could just include that. Say \"Here\'s
> what it was, and here\'s what was suggested,\" and then a
> resolution\--Air Force resolution, which will be incorporated.
>
> That makes use of a document that we currently have.
>
> DR. HARRISON: Yeah. And we don\'t want to make any more work. I mean,
> that\'s not the objective. I understand.
>
> What\'s you all\'s feeling about this?
>
> Okay. So we\'ll revise the request, that when the revised draft is
> given to us for review, that it should be accompanied by the table
> referred to by Jay Miner, that includes the comments and actions taken
> on comments within the draft. And that\'s a comprehensive table. That
> includes any changes that are made?
>
> DR. MINER: Yes.
>
> DR. HARRISON: Okay.
>
> DR. MINER: Every single\--
>
> DR. TREWYN: We get the original draft, then we get all the changes\--
>
> DR. HARRISON: No. No. We get the changed draft\--
>
> DR. TREWYN: We get the changed draft.
>
> DR. HARRISON: \--plus the table that tells us what changes were made.
>
> DR. TREWYN: What was changed.
>
> DR. HARRISON: Yes.
>
> DR. STOTO: And I presume if there were something\--
>
> DR. MINER: \"We took out 10 pages here\--\"\--
>
> DR. STOTO: We might not, but if we though it was something, we could
> ask for it.
>
> DR. HARRISON: Well, that\'s a good question, though.
>
> \[Discussion, off mike.\]
>
> DR. MINER: Well, send the original draft, the table of changes, and
> the revised paper.
>
> DR. HARRISON: Okay. All right.
>
> DR. MINER: We will send it electronically, and you all can print it.
>
> DR. HARRISON: We can kill our own tree.
>
> DR. MINER: Right.
>
> DR. HARRISON: Everybody happy? Any dissent?
>
> Okay.
>
> DR. MINER: That\'s it, sir?
>
> DR. HARRISON: That\'s it. Thank you very much.
>
> So, next we have\--
>
> DR. GOUGH: When are these going to start coming in?
>
> DR. HARRISON: Next week, you get your first draft.
>
> \[Laughter.\]
>
> DR. STOTO: Probably November.
>
> DR. HARRISON: Yes, somewhere around October\--no, actually,
> November\--somewhere in that range.
>
> Now, can I\--before we get off of this, can I ask a non-agenda-driven
> question? And that is: how does this impact on when we meet next?
>
> \[Pause.\]
>
> DR. STOTO: Well, it sounds like the next business for us on this
> agenda is November\--right?
>
> DR. TREWYN: That\'s for reviewing\--we have to read it.
>
> \[Discussion off mike.\]
>
> DR. HARRISON: I\'m just raising the question. You know, we have a
> certain amount of work in front of us. We have a tentative schedule.
> How does this impact on when we meet the next time?
>
> Bill?
>
> DR. GRUBBS: \[Off mike\].
>
> DR. HARRISON: You need to get the microphone. Otherwise\--
>
> DR. GRUBBS: My best estimate, when you would see the second
> draft\--have the second draft available, of the first clinical chapter
> that comes out, would be approximately the start of the year\--start
> of January\--
>
> DR. HARRISON: Start of what?
>
> DR. GRUBBS: Start of January 2004. Because the first draft will come
> in November. There will be the resolution time\--the revision of the
> chapter to get to the second draft.
>
> So I would think you would have second drafts of chapters beginning
> January 2004, and going throughout the year until, I would guess, July
> or August.
>
> DR. STOTO: I thought the dates here on the chart we just looked at
> were for the second draft.
>
> DR. MINER: Those are just notional dates. As an example, you would
> have to have, perhaps, three meetings, with six or chapters each
> meeting. That\'s your process for deciding when you meet.
>
> \[Discussion off mike.\]
>
> DR. GRUBBS: Again, it\'s contingent on a final approval of the data by
> the Air Force. And any additional data that they would need to provide
> to us, such as medical records verification.
>
> So, it\'s contingent on a particular approval date by the Air Force.
>
> DR. MICHALEK: I\'d just like to remind you that we have been reviewing
> this data all along. As SAIC delivers the data to us from Scripps, we
> get it every quarter. And we\'ve been checking the data and reviewing
> it constantly. So this is not like in August of this year we\'re going
> to see the data for the first time. That\'s not true. We\'ve been
> seeing it since the beginning of the Scripps process.
>
> And so, in other words, I\'m telling you we\'re very highly confident
> that we\'ll provide an acceptance within a very short time of
> receiving the final data set from SAIC. We have a process in place to
> assure that that happens, so that we do not have a slip.
>
> Everything is checked and rechecked\--may times over. And that\'s part
> of our process. The same is true of the medical coding data, which is
> a necessary piece that isn\'t collected at Scripps, but which is
> derived from medical record review. We have a staff that does that
> full time, all the time, and keeps up with it, so that when the final
> Scripps physical exam is complete, we\'re nearly ready to deliver data
> as needed by SAIC to do the report.
>
> So, in other words, I\'m telling you we have very high confidence that
> when the deadline approaches in August that, yes, we will have an
> approval, and SAIC will launch their statistical analysis.
>
> DR. HARRISON: So\--okay. I\'m still trying to get my hands around this
> thing, though. All the chapters are going to be the chapters
> containing responses that are responsive to the Air Force\'s comments
> are going to be completed by November.
>
> DR. MICHALEK: There is a\--SAIC is working under a fixed-price
> contract. There are fixed timelines in place that Air Force must
> respond within, I think, 30 days. Is that true? Of every chapter? Yes?
> 30 days? As soon as they\--15 days\--15 days.
>
> As soon as SAIC delivers a draft chapter to us, we, the Air Force,
> have 15 days to review and comment, and send our markup back to them.
> And then they are free to agree or disagree with our changes\--our
> suggested changes. And they resolve\--we resolve together, as
> colleagues\--these issues, and they provide a document which lists
> every single issue and as to whether we yield or they yield on a
> point. And you will see all of that.
>
> DR. HARRISON: When?
>
> DR. MICHALEK: When. The first chapter should be delivered first week
> of November\--we think.
>
> DR. HARRISON: And the last chapter will be delivered\--
>
> DR. MICHALEK: The last chapter, first draft, would be delivered when?
> Roughly?
>
> DR. HARRISON: This is with the corrections, Mike.
>
> DR. GRUBBS: Roughly July of 2003.
>
> DR. STOTO: No, I thought he said the first draft.
>
> DR. MICHALEK: The first clinical chapter, roughly the first week of
> November of this year.
>
> DR. STOTO: First draft?
>
> DR. MICHALEK: First draft to us\--to the Air Force. We have 15 days to
> turn it around and get it back to SAIC. And how much time do you have
> to\--they have 15 days to revise. So we\'re talking about a one-month
> period before we have a second draft ready.
>
> DR. HARRISON: And the last chapter is not going to be done until
> the\--the first draft is not going to be done until July of 2004?
>
> DR. MICHALEK: Approximately July of 2004 would be the last first-draft
> clinical chapter that we will see.
>
> DR. HARRISON: Okay.
>
> DR. MICHALEK: We\'re talking about\--for those that don\'t
> know\--it\'s about a 4,000 page report.
>
> DR. HARRISON: Yes. Yes. But\--so we\'ve got a period, essentially,
> from December of 2003, through July 2004 when these babies are going
> to be rolling out.
>
> DR. MICHALEK: That\'s true.
>
> DR. HARRISON: And there\'s approximately 12 chapters. So that means
> that there\'s going to be, on average, two chapters per month.
>
> DR. MICHALEK: There are actually 20\--
>
> DR. HARRISON: Twelve clinical chapters.
>
> DR. MICHALEK: Twelve clinical chapters, and you should know that some
> of those other chapters are just as important to you as the clinical
> chapters, such as \"Methods\"\--
>
> DR. HARRISON: I agree. I agree.
>
> DR. MICHALEK: \--you need to see the \"Methods\" chapters\--and the
> concluding chapter. There\'s about 21 chapters.
>
> DR. HARRISON: Okay. All right.
>
> So\--
>
> DR. CAMACHO: We\'re getting first raw, and the changes\--
>
> DR. HARRISON: Well, yes.
>
> DR. CAMACHO: Which one?
>
> DR. HARRISON: Well, we\'re getting\--
>
> DR. CAMACHO: It\'s as if we\'re getting different versions.
>
> DR. HARRISON: Well, we\'re getting them in a stream.
>
> DR. CAMACHO: Yes.
>
> DR. HARRISON: And the point I\'m trying to get at is, that if the
> stream begins in December, we probably want to chop that into\--three
> parts you say? So we\'re talking about\--
>
> DR. TREWYN: Meeting a lot in 2004.
>
> DR. HARRISON: We\'re talking about February, April\--June. June would
> be too early.
>
> DR. MICHALEK: Plus, I want to emphasize that the most important
> chapters are, finally, the concluding chapter and the executive
> summary, which are extremely important.
>
> DR. HARRISON: I understand. And I didn\'t mean June in terms of
> cutting out before the end of it. That was my quick\--I\'m not good at
> this stuff.
>
> I\'m just trying to get a discussion right now about\--at least in
> terms of months, when we need to meet. It looks like we don\'t need to
> meet again in 2003. But we need to meet early in 2004\--which, for
> those of us coming from the northeast is always problematic. To quote
> a friend of mine in Rochester, New York, in February you can\'t always
> be sure of getting out, nor can you be sure of getting back.
>
> \[Laughter.\]
>
> DR. CAMACHO: So how many chapters do you think we\'ll be looking at
> in, say, January?
>
> DR. HARRISON: So, in January, we\'ll have four to six chapters
> ready\--they\'ll have four to six chapters ready.
>
> DR. CAMACHO: Ready for us to look at.
>
> DR. MINER: We think March would be a better guess as to when you would
> have enough work to discuss.
>
> DR. HARRISON: Okay. All right.
>
> DR. TREWYN: So if we don\'t get them before that time, or if we
> don\'t\--
>
> DR. HARRISON: We\'ll get them before that\--
>
> DR. MICHALEK: You\'ll have time to look at them.
>
> DR. HARRISON: If we\'re starting with two in\--two delivered
> with\--I\'m sorry\--the corrections in December, two delivered in
> January, two delivered in February, then that would be six for us to
> talk about in March\--with, you know, a couple weeks for whoever\--
>
> DR. MICHALEK: You\'re being a bit ambitious. We think that\'s an
> over-estimate, a little bit.
>
> DR. HARRISON: Well, even if we are\--
>
> DR. MICHALEK: Maybe five chapters.
>
> DR. HARRISON: Even if\--don\'t, you know, don\'t\--March. March.
>
> DR. MICHALEK: March is a good time.
>
> \[Discussion off mike.\]
>
> DR. GOUGH: If it\'s not six, and if it\'s five\--and then if it\'s not
> six and it\'s five, you\'re going to end up with four that aren\'t
> delivered by July.
>
> DR. HARRISON: Well, they\'ve already\--actually, the point that\'s
> already been made is the last meeting will have to be after July. The
> last meeting will have to be August or September.
>
> So we\'re talking about a March meeting, let\'s say a September
> meeting. So we\'re talking about 3, 9\--and 6 is really going to be
> the middle meeting.
>
> Now, I agree with Mike, though. What Mike wants is what I\'ve been
> trying to get for the last 15 minutes, and that is your best guess as
> to when these chapters are going to roll act\--written down. Okay?
>
> DR. MICHALEK: Can we put that as an action item, and we will deliver
> that by e-mail to Leonard?
>
> DR. HARRISON: Well, can you do that this morning?
>
> VOICE: I don\'t think we can do that on laptops.
>
> DR. HARRISON: No, not on laptops, just handwritten. Just\--roughly\--
>
> VOICE: So we can plan our meetings.
>
> DR. STILLS: So, Dr. Harrison, I really want to underscore that that\'s
> important, because a number of us have many\--have commitments already
> for next year. And so that will help us to plan.
>
> I think these reports are really critical, that we have the time to
> review them and do the best job that we could. And, like you\'re
> saying, if we have a heads up as to the time frame for next year, then
> we can put it in our calendars, and we\'ll be here to do the work.
>
> DR. HARRISON: Also, you know, I think that if we set March, June and
> September at the times that we\'re going to do this, then I would hope
> that you all would\--the Air Force and its consultants\--or
> contractors\--would make an effort to help us out a little bit, too,
> and not come back and say, \"Well, you know, we weren\'t able to get
> the stuff done in time\--\"\--you know, sort of thing.
>
> If we make a best guess as to when we\--because what\'s been said is
> correct, and that is that we need to plan these meetings, essentially,
> now for several of the members of the committee to be able to
> incorporate into their schedules.
>
> Yes, sir\--Jay?
>
> DR. MINER: Shown to us yesterday was what happened with chapters last
> cycle. And here is that outline right here. And perhaps during the
> break you can kind of look and see how many chapters you can expect,
> and so forth. Would that be helpful? There are dates on here.
>
> DR. HARRISON: So you\'re saying your best guess is that they\'re going
> to be the same dates this time as they were the last time? Same
> months? That\'s a reasonable assumption\--give or take a little?
>
> DR. MICHALEK: Yes.
>
> DR. HARRISON: And the delivery that we\'re talking about, of the
> chapters with the Air Force comments responded to are the \"X\'s,\"
> the \"S\'s,\" the \"AF\'s\" or the double-X\'s?
>
> LT. COL. ROBINSON: X\'s.
>
> DR. HARRISON: The X\'s.
>
> LT. COL. ROBINSON: \[Off mike\].
>
> DR. HARRISON: Okay. So, according to this, this is\--final data
> approval was in August. \"General Health\" was delivered in November,
> \"Dioxin Assay\" in December, \"Hematology\" in January, \"Pulmonary\"
> in February, \"Physical Examination\" in February\"\--so we\'ve
> got\--we can look at that\--work this out.
>
> DR. TREWYN: But you\'re not going to meet the projected timeline on
> here, then, to have the final report due at the date indicated.
>
> DR. STOTO: I think this would be beset worked out off-line here. I
> mean, I think that\--
>
> DR. HARRISON: Okay. All right.
>
> DR. STOTO: We have\--
>
> DR. HARRISON: Well, before the end of the meeting I want to have some
> months down, if not dates down.
>
> DR. STOTO: Let\'s ask them when they\'re reasonably confident that a
> third of the chapters will be done.
>
> DR. HARRISON: Well, that\'s what Jay\'s saying, is that\'s what\'s
> here. So it\'s just a matter of doing it without taking up too much
> more time here.
>
> Okay. Can I just\--do you want to make a copy of this for me?
>
> Next. Let\'s go on. As Mike is intimating, we\'re behind time now.
>
> So, Joel is going to discuss the cancer findings.
>
> **Cancer-Review/Discuss Manuscript**
>
> DR. MICHALEK: Well, good morning. I am Joel Michalek, Principal
> Investigator in the study. Dr. Fatema Akhtar is the statistician, and
> David Garebrant is an epidemiologist.
>
> This effort was begun shortly after the last committee meeting. It was
> motivated by committee comments on our previous publication of
> describing cancer and dioxin levels in Ranch Hand veterans.
>
> What\'s different about this cancer analysis is that we are now
> comparing the observed with the expected cancer incidence in both
> cohorts, relative to national rates. Yes sir?
>
> DR. HARRISON: No\--I\'m sorry.
>
> DR. MICHALEK: We are using the surveillance epidemiology end result
> rates of the National Cancer Institute as our standard\--the SEER
> rates\--as our standard. And we\'re referencing against\--in other
> words, the cancer experience in U.S. males. And we\'re also tabulating
> and analyzing the observed and expected mortality due to cancer, using
> national rates.
>
> And, finally, we\'re conducting our internal analysis against dioxin
> levels, stratifying and adjusting for when these veterans were in Viet
> Nam, and for how long, and what their exposure opportunity may have
> been. This is new, in other words.
>
> There are three levels of change in our cancer approach here, as
> opposed to previous reports. First, we\'re using SEER definitions of
> cancer categories, which we never did before. Secondly, we have the
> very latest cancer data, up through December 31, 1999, which has
> increased our prevalence, and increased our statistical power. And,
> finally, we\'re making adjustments for concepts that were given to us
> by the committee.
>
> \[Pause.\]
>
> Somehow the computer is not working. The machine just locked up.
>
> \[Pause.\]
>
> DR. HARRISON: Presentation equivalent of the smart bomb.
>
> \[Laughter.\]
>
> DR. MICHALEK: Okay. This summarizes what I just got through telling
> you.
>
> Slide, please.
>
> \[Slide.\]
>
> This was published in the American Journal of Epidemiology, 1998/99.
> These are the latest cancer results published in a peer reviewed
> scientific journal. They show now evidence of a dose-response pattern
> on dioxin versus cancer, on any site, in Ranch Hand veterans. I\'ve
> just put this up here to remind you that what you\'re going to see
> today is different from what\'s been published.
>
> Slide, please.
>
> \[Slide.\]
>
> The dioxin measurements remain, as by the Centers for Disease Control
> in Atlanta, the very first measurements were made for the study in
> 1987, and subsequently in 1992 and \'97, by the Center for
> Environmental Health Laboratory Sciences in CDC.
>
> We have made an adjustment for dioxin levels below the limit of
> detection, and below the limit of quantitation, using a published
> method by Kornon, to divide these limits of detection by the square
> root of 2 to provide an unbiased estimate of the true dioxin level at
> these very low levels.
>
> Slide, please.
>
> \[Slide.\]
>
> Again, following ideas given to us by the committee, we used published
> information in the National Academy books on veterans and Agent Orange
> to stratify the cohort in accordance with when they were in Viet Nam,
> focusing, most important to us, the period of 1966 to 70, which was
> the period of heaviest Agent Orange spraying, and taking account of
> periods prior to that, and subsequent to that, where no spraying
> occurred, for example between \'62 and \'72.
>
> Slide, please.
>
> \[Slide.\]
>
> And we have also stratified by military occupation, because we know
> from our own measurements in these study subjects that the enlisted
> ground crew, for example, have the highest dioxin levels.
>
> Slide, please.
>
> \[Slide.\]
>
> Following comments from the committee a year-and-a-half ago, we have
> devised some measures of exposures opportunity which are approximate.
> We attempted to isolate Ranch Hand veterans who spent the majority of
> their time in Viet Nam, as opposed to Southeast Asia, and for that
> we\'ve adopted a two-year cut point. And I have some graphics to show
> you where that two-year cut point came from.
>
> And, so trying to isolate comparisons who spent little or no time in
> Viet Nam. And to drive that point home further, we carried out another
> analysis, in addition to this one, where we pulled off only rand hand
> veterans who spent all of their time in Viet Ham, and only controls
> that spent absolutely none of their time in Viet Nam\--to address the
> concern that some controls, having been in Viet Nam, are disrupting
> our efforts to find a treatment effect, because they themselves were
> in Viet Nam, and possibly exposed to herbicides.
>
> Next slide, please.
>
> \[Slide.\]
>
> And so there\'s two rounds of analyses: external against national
> rates, adjust for age, calendar period and race, using SEER rates,
> which are available on the internet.
>
> Then we strategized those external analyses, again by the same factors
> that we were using in the internal analysis, by tour-date, military
> occupation, and exposure opportunity category, and using second order
> tabulations of tour date by military occupation, which I\'m not going
> to describe here.
>
> In the internal analysis, we\'re comparing Ranch Handers with high
> dioxin levels against comparisons, stratified by these exposure
> opportunity category strata.
>
> Slide, please.
>
> \[Slide.\]
>
> To give you an idea as to why we chose a two-year cut point, this is a
> plot of the percent of time that Ranch Hand veterans spent actually
> in-country, against he number of years spent in Southeast Asia. And
> you see there\'s a natural break point here of about two years. If you
> isolate those individuals that were in Southeast Asia less that two
> years, you predominantly pick up a lot of Ranch Handers who were there
> a hundred percent of their time. And so by cutting this at two years
> we\'re attempting to find a very simple dichotomy that would allow us
> to pull off Ranch Handers that may have had increased exposure
> opportunity.
>
> Slide, please.
>
> \[Slide.\]
>
> DR. HARRISON: Joel?
>
> DR. MICHALEK: Yes, sir.
>
> DR. HARRISON: I though Ranch Hand tours were one year\--I mean, not
> Ranch Hand\--Viet Nam tours were one year. Was that just army?
>
> DR. MICHALEK: I\'m not familiar with the Army. Most Ranch Hand tours
> were about 11 months, but many men came back for more than one tour.
> And some of the Ranch Hand veterans were in Southeast Asia for a long
> time\--if you back up that previous slide.
>
> DR. HARRISON: I\'ve read that one of the criticisms of how the war was
> conducted was that one-year tour. So that by the time you actually
> knew what you were doing, it was time for you to rotate out again.
>
> DR. MICHALEK: Many Ranch Handers were there one tour, which was about
> 11 months. Some of them re-upped\--re-enlisted and came back. But some
> of them were there a long time\--as you see\--many years in Southeast
> Asia, but only one year in Viet Nam.
>
> DR. HARRISON: Okay. Sorry.
>
> DR. CAMACHO: I didn\'t notice it the first time through, that line at
> 100 percent there\--how many people there are.
>
> DR. MICHALEK: Well, you\'ll see that in a minute, because we\'re going
> to isolate those people.
>
> Slide, please.
>
> \[Slide.\]
>
> And this is the pattern in the control group. You see a far different
> pattern here. With the two-year cut point we\'re basically just
> controlling the two-year period. Down here are a lot of veterans
> comparisons who were never in Viet Nam at all\--spent zero percent of
> their time in Viet Nam. There\'s about 300 comparisons like that.
>
> Slide, please.
>
> \[Slide.\]
>
> So, the external analysis is based on any study participant who was
> ever at Scripps Clinic, or even participated partially in the study
> and took only a questionnaire. If an individual participated at
> baseline, and took only a questionnaire, and never went to Scripps
> Clinic, or\--we followed that subject just like we do all the other
> with regard to disease and mortality.
>
> So this is the maximum possible sample size that could have been
> derived in the entire cohort: 2,981. We excluded individuals who we
> knew from medical records had cancer during or before their tour of
> duty in Southeast Asia, leaving a sample size of 2,965 for the entire
> cohort, against national rates.
>
> In the internal analysis, we excluded individuals with missing dioxin
> levels, and most of these individuals that were excluded were the
> partially complying from baseline. We never changed the subsequent
> cycles, and particularly the 1987 cycle, when we put our first dioxin
> measures, giving us a total sample size of 2,438\--in the internal
> analysis\--against dioxin levels.
>
> Slide, please.
>
> \[Slide.\]
>
> And here\'s an overall sample size table for our internal analysis,
> where we have broken out Ranch Hand veterans to three levels: high,
> low and background, depending on their dioxin level and their
> estimated initial dose in Viet Nam. Then the 10 parts per trillion is
> the 99^th^ percentile of the dioxin distribution in the comparison
> group, is the 40^th^ percentile of the dioxin distribution in the
> control group. Of those that are above 10 parts per trillion in the
> Ranch Hand group, the median dioxin level in Viet Nam was estimated to
> be 118.5 parts per trillion. So this cut point was used to separate
> those individuals with values above background into a low and high
> category. And it\'s a scheme that\'s been used in many of our
> publications.
>
> And this table\--all sample sizes, by the way, are for white
> individuals.
>
> Slide, please.
>
> \[Slide.\]
>
> And here are the sample sizes for the \"at most two years\" and SEA
> exposure opportunity strata, and there you see 580 comparisons and
> about 600 or so Ranch Handers who were in that category.
>
> Slide, please.
>
> \[Slide.\]
>
> And here are the \"100 percent\" versus \"zero percent.\" So there
> were 291 comparisons who had absolutely no time in Viet Nam and the
> rest of their time in Southeast Asia, which would have included the
> Philippines, Taiwan, perhaps Cambodia\--wherever they were\--and
> we\'re attempting to find out exactly where they were, just now, by
> reviewing military records.
>
> And here are the Ranch Handers who spent 100 percent of their time in
> Viet Nam.
>
> Slide, please.
>
> \[Slide.\]
>
> And this is just a table of person-years calculations. I want to
> emphasize that, as opposed to our previous reports and articles, we
> had to spend a lot of time very carefully reviewing race, because race
> is a factor in the SEER tabulations of national rates, and you must
> know who is white and who\'s black and who\'s neither. So this is
> unprecedented for us. We had never gone through this level of detail
> before, by reviewing records and photographs, and surnames to decide
> who\'s in any of these categories. It took a lot of time.
>
> Yes, sir?
>
> DR. HARRISON: Keep your hands under the table.
>
> \[Laughter.\]
>
> DR. MICHALEK: And here are the Ranch Hand cohort for the period 1966
> to 1970. You can see that\'s where the bulk of the activity was during
> the war, or the period of heaviest spraying. And that\'s where most of
> your person-years are.
>
> Slide, please.
>
> \[Slide.\]
>
> And the same is true in the comparison group.
>
> DR. STOTO: May I ask what other \[off mike.\]
>
> DR. MICHALEK: Want to say that again?
>
> DR. STOTO: What \"Other\" means? Does it mean Hispanic, or\--
>
> DR. MICHALEK: That would include Hispanic, primarily\--and Oriental.
>
> DR. STOTO: But would SEER\--
>
> DR. MICHALEK: We attempted, the best we could to match the SEER
> definition of race. I can amplify that later.
>
> DR. STOTO: In most federal statistical systems, \"Hispanic\" is not a
> race.
>
> DR. MICHALEK: Okay.
>
> DR. STOTO: And so I would be surprised as many \"others\" as Black.
>
> DR. MICHALEK: Well, we\'ll need to discuss that in detail, then.
> Because I have \[off mike.\]
>
> DR. STOTO: The key thing is that you are consistent with SEER.
>
> DR. MICHALEK: Yes.
>
> DR. HARRISON: Except this is not self-identified race, this is
> guessed-at race.
>
> DR. STOTO: Well, no, for SEER, it is\--
>
> DR. HARRISON: No, I\'m talking about for the Air Force.
>
> DR. STOTO: Yes.
>
> DR. HARRISON: Because that\'s not a part of the\--
>
> DR. MICHALEK: It is our best effort to determine race. It is not easy
> to determine race.
>
> DR. HARRISON: But what I\'m getting at is, that in the examinations\--
>
> DR. MICHALEK: They were asked to describe their race. Our exams do
> that during the exam, I believe. We have that on the questionnaire.
>
> DR. HARRISON: They are?
>
> DR. MICHALEK: Yes. They classify themselves.
>
> DR. HARRISON: So why did you go through this other process?
>
> DR. MICHALEK: Because an individual may call himself black or white,
> depending on his parentage, and he may\--I don\'t know, there are all
> kinds of complications here, when you\'re trying to classify an
> individual. It\'s not easy.
>
> DR. HARRISON: Well, but\--
>
> DR. MICHALEK: Individuals who call themselves white may not be white,
> they may be Hispanic. And if you\'re telling me that the \"other\"
> category in the SEER rates does not include Hispanics, then we need to
> rethink the racial characteristics.
>
> DR. STOTO: I think the key thing here is that your classifications are
> as similar as possible to what\'s done at SEER.
>
> DR. MICHALEK: We tried. Yes.
>
> DR. STOTO: And I suspect that SEER is based on self-report.
>
> DR. MICHALEK: All right. Then we went beyond self-report, because we
> looked at photographs.
>
> DR. STOTO: But that\'s not good.
>
> DR. HARRISON: Yeah\--that\'s actually.
>
> DR. MICHALEK: We looked at every single case\--one by one.
>
> DR. HARRISON: You\'d possibly classify me as an Eskimo.
>
> \[Laughter.\]
>
> No, I mean self-identification is\--I mean, one of the problems with
> race classification is that it depends on self-classification. And\--
>
> DR. MICHALEK: It does.
>
> DR. HARRISON: \--you don\'t have any objective way\--
>
> DR. MICHALEK: No, we don\'t.
>
> DR. HARRISON: \--of determining a person\'s race.
>
> DR. MICHALEK: That\'s right.
>
> DR. STOTO: So, consistency is what\'s important.
>
> DR. HARRISON: Yes.
>
> DR. MICHALEK: That\'s right.
>
> DR. STOTO: If they told you in their survey that they were green,
> then\--
>
> DR. MICHALEK: Then we\'ve got a problem.
>
> DR. STOTO: \--then they\'re \"other.\"
>
> DR. MICHALEK: I can tell you that it makes little difference as to how
> we classified the Ranch Handers.
>
> DR. HARRISON: Okay.
>
> DR. MICHALEK: Slide, please.
>
> \[Slide.\]
>
> Here is the bottom line. The national rates, in the Ranch Hand cohort,
> overall, there is no significant increase in the risk of cancer at any
> site, using the SEER definition against national rates. We have a
> standardized incidence ratio of 1.09, and that is not significantly
> different from 1.0
>
> I want to remind you that \"cancer at any site,\" following the SEER
> definition, is not the same as \"cancer at any site,\" following our
> published paper. In the SEER definition, \"cancer at any site\" does
> not include basal or squamous cell carcinoma, whereas in our previous
> publications, and all of SAIC reports, \"cancer at any cite includes
> all of those other skin cancers that the SEER does not. So you\'re
> going to find differences here between our published reports written
> by SAIC, and even our own published papers, because now we\'re using
> SEER definitions.
>
> VOICE: \[Off mike\]\--SEER\'s\--
>
> DR. MICHALEK: Yes. Yes. And I also want you to know that that is one
> of the reasons why we\'re seeing things now that we never saw
> before\--because we\'re using the SEER definitions. When we use our
> \"all cancer combined\" analysis, we see nothing. And yet we use the
> SEER definitions, we now see trends.
>
> DR. STOTO: Does the SEER definition classify melanoma as a \"site\" or
> does it\--\[off mike\]. I\'m just trying to get a better feel. Because
> melanoma is a tumor, and\--
>
> DR. MICHALEK: All right.
>
> DR. STOTO: You know\--
>
> DR. MICHALEK: Yes.
>
> DR. STOTO: So this \[off mike\]\--I was just trying to get your
> classification, versus SEER\'s classification.
>
> DR. MICHALEK: This slide is an attempt to put as few words and symbols
> on a PowerPoint slide as possible. You will find the full, detailed
> definition of melanoma in the document, which was all the ICD codes
> that went into the melanoma site definition. It\'s all taken directly
> from the SEER specifications that we received from the National Cancer
> Institute.
>
> So the actual nomenclature, as to whether the name that goes to this
> category is simply melanoma, or melanoma plus qualifiers is all in the
> article. And we have distributed the article to the committee.
>
> DR. STILLS: \[Off mike\] I read the article last night when I was
> going through\--and that was a question that I had. Because I
> never\--in the reports\--melanoma. It seems as though \[inaudible\].
>
> DR. MICHALEK: Yes, sir. And that\'s\--
>
> DR. STILLS: \[Off mike\] And as I looked through the article, I
> had\--the rate of melanomas were, you know\--some more description as
> to is it malignant or benign\--
>
> DR. MICHALEK: Those are all malignant.
>
> DR. STILLS: And that was my assumption. But I never could get at it in
> the paper.
>
> DR. MICHALEK: I\'ll show you where that is.
>
> We do see a significant increase in the risk of melanoma in the Ranch
> Hand cohort, as against national rates relative risk 2.33, the
> observed 17, we expected 7, and that\'s significant.
>
> You see a significant increase in the risk of malignancy of prostate.
> We observed 36, expected 23, relative risk 1.58, and that\'s
> significant.
>
> The category called \"genitalia\"\--it\'s almost entirely prostate. It
> was 38 genitalia, and 36 prostate\--36 of those 38 are cancer of the
> prostate.
>
> Yes?
>
> DR. GOUGH: You go from all sites, to systems, to specific
> sites\--prostate. How many comparisons did you make like that?
>
> DR. MICHALEK: The entire list is in the manuscript that was sent to
> the committee. This slide is a reduction of the entire list to reduce
> the number of slides down to 60.
>
> The document is 92 pages\--
>
> DR. GOUGH: I know that\--
>
> DR. MICHALEK: The entire list gives all the sites described by SEER
> are in the\--
>
> I cannot recite to you\--I can tell you that in one table we counted
> up the number of significant tests that were conducted\--we conducted
> a lot of significant tests\--a lot of statistical testing. The number
> of results that were statistically significant was, like 36 percent
> and the expected number was 5 percent.
>
> DR. GOUGH: That\'s what I wanted to know.
>
> DR. MICHALEK: All studies of this kind are subject to the criticism
> that we did extensive multiple comparisons\--statistical multiple
> comparisons. And that is absolutely true, not only of this paper and
> this report, but all papers and all reports produced by the study. The
> study\--the report you\'re going to review will be approximately 4,000
> pages. SAIC will conduct thousands of statistical tests, looking for
> dose response of health against dioxin. This is just one example of
> multiple statistical\--
>
> DR. STOTO: Well, I can see what would make you want to do that, but it
> would help to acknowledge that.
>
> DR. MICHALEK: Yes. And that\'s acknowledged in the discussion section.
> We have a paragraph in there about multiple testing.
>
> DR. STOTO: Well, but you might be able to do a little more than that;
> say, give us that number, 36 percent versus 5 percent.
>
> DR. MICHALEK: It\'s in the discussion.
>
> DR. STOTO: Okay. I did read it, and didn\'t see that.
>
> DR. MICHALEK: It\'s there.
>
> DR. STOTO: Another alternative to consider, is to actually do a
> correction \[inaudible\] report both the uncorrected and the
> corrected\--maybe for some selected ones or something.
>
> DR. MICHALEK: One point to make about the issue of multiple testing is
> that this was\--the scenario as to so-called fishing expedition, where
> we\'re out there chasing a p-value, this is not the approach that was
> taken here. We developed a strategy based on comments from the
> committee and we followed it\--no matter where it led. And we
> developed two levels of dioxin or herbicide exposure opportunity that
> we tried our best to do, and we used known classifications, by
> occupation and tour date, taken from published sources. And we used
> national published rates. And we used the prescribed method for
> internal analyses that we had used in other papers.
>
> So, in other words, this was not a chasing of a result down a road.
>
> DR. STOTO: I\'m certainly not criticizing you for that.
>
> DR. MICHALEK: Okay.
>
> DR. STOTO: I\'m just saying that\--
>
> \[Laughter.\]
>
> \--it would help to add a little bit more information to\--about the
> comparison.
>
> DR. MICHALEK: Yes. I agree.
>
> DR. GOUGH: The fact that you did\--the 36 percent.
>
> Now then, the next question about that, were about half the
> statistically significant results increases and half decreases? Or\--
>
> DR. MICHALEK: I cannot answer that without studying the article.
>
> DR. HARRISON: Go ahead, Joel.
>
> DR. STILLS: Joel, the only question I had was\--there\'s genitalia and
> prostate. And so you\'re saying that prostate is a subset of the 38.
> So you only have two\--and what were the other two?
>
> DR. MICHALEK: I don\'t have those memorized. I know that one of them
> is a carcinoma of the penis. I don\'t know what the other one is.
>
> DR. STILLS: And it seems as though\--you know, I mean, like in the
> studies that we do, where we report cancer data, we tend to, rather
> than\--you know, obviously there are duplications here, and so we tend
> to try not to report duplications, especially when you\'re trying to
> summarize the data.
>
> And it seems as though the most important thing here is the prostate,
> because the prostate\--without the prostate being in the genitalia
> group, you would not have\--you may not have that significance.
>
> DR. MICHALEK: That\'s true.
>
> DR. STILLS: And so I think you really need to\--I mean, this is very
> impressive data, and you want to be able to report the most important
> things. And it seems as though it may be helpful to take out
> \"genitalia.\" You know\--I mean, and just have prostate. Because
> that\'s where the findings are. I mean, \"genitalia\" takes away
> from\--or confuses the reader, and so you really want to be careful
> with that.
>
> DR. MICHALEK: We are always in this dilemma, that we try to show
> everything, and by doing so, we confuse sometimes.
>
> DR. STILLS: Right. And so, I think in this case, I think it may be
> best to just show what is important. Because I was a little confused.
> And, you know, you helped in terms of\--
>
> DR. HARRISON: Before there are other comments made, let me make sure I
> understand something here, Joel.
>
> There\'s a paper, and this is basically a condensation of what\'s in
> the paper.
>
> DR. MICHALEK: Right.
>
> DR. HARRISON: So, as\--when we\'re criticizing these tables, we\'re
> criticizing\--we\'re not necessarily criticizing the paper, which is
> out being reviewed, or is ready\--potentially ready to go out and be
> reviewed by whatever journal. So keep in mind that we\'re not\--it
> seems to me we\'d be better off commenting on the process than
> worrying about some of the smaller details in some of these tables,
> otherwise\--Joel just has 40 more slides to go, and\--
>
> \[Laughter.\]
>
> \--and he\'s got five minutes to do it.
>
> So\--go ahead. I\'m sorry. You were next, Ron.
>
> DR. TREWYN: I was just going to say, I mean, obviously, what you\'re
> going to synthesize for the paper is different from what you\'re going
> to put into the final report, where you want everything, you know\--ad
> nauseam\--that\'s probably not the way to put that\--
>
> \[Laughter.\]
>
> \--but you want everything included there. For the paper, I mean you
> want to make it as showy\--to punch\--without leaving out critical
> components, but want to be able to punch it up as much as possible,
> and not confuse the readers out there.
>
> DR. MICHALEK: The paper currently is 6,000 words. The maximum any
> journal we\'ve ever experienced is 4,000 words. So it obviously has to
> be trimmed down.
>
> It\'s 92 pages. Most papers submitted to journals are about 35 pages.
> And I want to also tell you that the review we gave to you at the
> outset was held back from you on purpose. That was a review by David
> Garabrant, University of Michigan. All of the comments from him have
> been incorporated in the document we gave to you, except for one. He
> said delete table 15. We have included all of the tables.
>
> \[Conversation off mike.\]
>
> DR. MICHALEK: He is a co-author.
>
> DR. STOTO: First of all, I want to second Ron\'s point. The other
> point about genitalia and prostate, is that there\'s a reason for
> hypothesizing prostate cancer, and there\'s other evidence suggesting
> it. I\'m not aware of evidence suggesting other cancer of the
> genitalia.
>
> DR. MICHALEK: The choice of the SEER categories was driven by SEER,
> not by us. We used the SEER category definitions across the board,
> without making any pre-judgments as to which ones to show or not show.
>
> DR. STOTO: But you could have included melanoma and \"other skin.\"
>
> DR. MICHALEK: \"Other skin\" is shown later in the internal analysis.
>
> DR. STOTO: Yes.
>
> DR. MICHALEK: There are no national rates for \"other skin,\" only for
> melanoma.
>
> DR. STOTO: Okay. So you do include both respiratory and lung
> blockages.
>
> DR. MICHALEK: Because there are\--
>
> DR. STOTO: The 30 are nested in the 33.
>
> DR. MICHALEK: Probably. And the definitions are given in the article.
>
> DR. STOTO: Right.
>
> DR. MICHALEK: So a lot of them are nested, that\'s true. But that\'s
> the way the SEER data is presented.
>
> DR. STOTO: Well, I guess that for a summary table like this, I would
> go with prostate and lung, and drop off respiratory and genitalia.
>
> DR. MICHALEK: Okay. Thank you.
>
> DR. HARRISON: That having been said, am I understanding this slide
> correctly that these are just the White Ranch Handers?
>
> DR. MICHALEK: These are Whites only, yes. But the article shows
> everyone.
>
> DR. HARRISON: And what you\'re saying is\--the specific question I
> have is: was there an effect on prostate cancer in African Americans?
> And if it wasn\'t, do you think it was because of smaller number, or
> what?
>
> DR. MICHALEK: Five percent of the cohort is Black, so the number is
> extremely small. The numbers are in the paper.
>
> DR. HARRISON: Okay.
>
> DR. MICHALEK: Whenever possible, we broke it out by race. You\'d see a
> table of zeros\--many zeros\--if I gave you a table on Blacks, for
> example.
>
> DR. HARRISON: Okay. Got you.
>
> DR. MICHALEK: And here the same table for the comparison cohort
> against national race. And you see\--here you see an increase in
> melanoma not significant; and increase in prostate which is
> significant. Again, the genitalia is driven by the prostate, because
> four of the 54 of the 55 are prostate cancers in this cohort.
>
> Slide, please.
>
> \[Slide.\]
>
> And once again\--and now we\'re going back to the occupational strata
> derived from our own information snout exposures. And we see\--I\'m
> going to now highlight\--I\'m not going to show every result in the
> paper. In an effort to bring the number of slides under control, I\'m
> showing you only prostate and melanoma now in subsequent slides. I\'m
> not showing you second order effects, which would be cross
> stratifications of tour date by military occupation, for example. I\'m
> showing you only what are called \"main effects.\" I\'m concentrating
> only on prostate and melanoma.
>
> And here, for example, is the pattern in the Ranch Hand cohort. You
> see an increase in the enlisted flyers, of relative risk 2.27, and
> that reaches significance.
>
> Slide, please.
>
> \[Slide.\]
>
> In melanoma, we see increase in ranch-hand officers, a relative risk
> of 3.02.
>
> Slide.
>
> \[Slide.\]
>
> DR. HARRISON: Time at the golf course.
>
> \[Laughter.\]
>
> DR. MICHALEK: Except that we see a trend against dioxin levels against
> melanoma, which suggests that it\'s not simply a matter of sun
> exposure.
>
> Slide, please.
>
> \[Slide.\]
>
> This is the comparison prostate, which is elevated in both enlisted
> flyers and officers.
>
> Slide.
>
> \[Slide.\]
>
> Comparison, melanoma\--borderline significant increase in officers,
> but not in the other two occupational strata.
>
> The comparison cohort consisted of air and ground crew who serviced or
> flew C-130 aircraft in the Southeast Asia region but did not spray
> herbicides.
>
> And here\'s a breakout by the tour dates\--the period of 1966 to \'70
> is the period where we have the most Agent Orange spraying is where we
> have the most statistical power, and it is the period where we see the
> increase in risk of prostate cancer in the Ranch Hand cohort.
>
> And in melanoma, the same pattern: increased risk of melanoma in Ranch
> Hand veterans against national rates. Among those Ranch Handers who
> were in Viet Nam and\--and on the Ranch Handing between 1966 and 1977,
> the period of heaviest Agent Orange spraying.
>
> Slide, please.
>
> \[Slide.\]
>
> In the comparison cohort, the period \'66 to \'70 exhibits an
> increased risk of prostate cancer against national rates.
>
> Slide.
>
> \[Slide.\]
>
> DR. STILLS: Joel, did any of the Ranch Handers in the years 1966 to
> \'97 have multiple tumors\--some of them may have had melanoma and
> prostate cancer. Did you ever see multiple\--
>
> DR. MICHALEK: Yes, we have many veterans with multiple tumors, and all
> we\'re analyzing here is the occurrence of the first tumor. And all
> these tumors are malignant.
>
> We have not made an attempt to describe or tabulate multiple tumors,
> but we could do that.
>
> DR. STILLS: It would be interesting to look at these two and get a
> feel for the impact of exposure. I mean, it would strengthen, the no,
> that that\'s what happened in terms of cancer.
>
> DR. STOTO: I had another comment about this breakout by year.
>
> Obviously, most of the cancers are in \'66 to \'70, because those were
> most of the experiences.
>
> DR. MICHALEK: Yes, it is.
>
> DR. STOTO: It ended in \'72\--right?
>
> So one thought would be to look at that period versus all other years.
>
> DR. MICHALEK: True.
>
> DR. STOTO: First and last years\--prior to \'66 and after \'70.
>
> DR. MICHALEK: Right. You could do that.
>
> \[Comments off mike.\]
>
> DR. OSEI: Help me out.
>
> DR. MICHALEK: The comparison group\--flew or serviced C-130 aircraft
> in Southeast Asia but did not spray herbicides, about more than half
> the comparison group were actually in Viet Nam, but the were not in
> the Ranch Hand unit. It\'s been a criticism of the study that our
> comparisons are themselves Viet Nam veterans, and so we may have
> frustrated our own attempts to find a treatment effect by including
> Viet Nam veteran comparisons. This was designed into the study in
> 1978. Many veterans are frustrated that we don\'t have control
> cohorts: one that went to Viet Nam, and one that didn\'t.
>
> Well, we do have a Viet Nam veteran cohort. So the analyses that you
> see here today are an attempt to address those concerns.
>
> DR. STOTO: This has been a recurring question.
>
> DR. MICHALEK: Yes, it has.
>
> DR. STOTO: And, of course, it gets to what the hypothesis is.
>
> DR. MICHALEK: And what is the direct comparison group.
>
> DR. STOTO: Right. And we have had Ranch Hand versus non Ranch Hand. We
> have had Viet Nam versus not Viet Nam, and now you\--I think it\'s
> become now, Ranch Handers in Viet Nam versus\--
>
> DR. MICHALEK: Comparisons who didn\'t go to\--
>
> DR. STOTO: \--non Ranch Hand, non-Viet Nam.
>
> DR. MICHALEK: It\'s Ranch Handers who were in Viet Nam, versus
> comparisons who were not in Viet Nam in some of our analysis, that\'s
> true.
>
> We\'re going to attempt to address\--
>
> DR. STOTO: Which is an interesting question, but a different one.
>
> DR. MICHALEK: It\'s a different one.
>
> DR. STOTO: Than the two we have been focusing on in the past.
>
> DR. MICHALEK: That\'s true.
>
> DR. HARRISON: Well, the problem is that anything that we do is
> inferred. You know, this is the issue with surrogates.
>
> DR. MICHALEK: Right.
>
> DR. HARRISON: And we\'ve just\--so it\'s nor really different, it\'s
> just a different surrogate.
>
> You can argue that makes it different, but\--
>
> DR. STOTO: I think it does make a difference. I mean, in one case
> we\'re talking about the chemicals that were a part of the Ranch Hand
> experience. In another one we\'re talking about all sorts of things
> that happened in the country\--
>
> DR. MICHALEK: Yes.
>
> DR. STOTO: \--and now we\'re kind of putting both of those together.
>
> DR. MICHALEK: Yes, we are.
>
> DR. STOTO: We\'re putting both those together.
>
> DR. MICHALEK: We\'re attempting to do that. That\'s right.
>
> DR. STOTO: So if it turns out something turns up positive here, we
> still can\'t isolate whether it\'s Ranch Hand or Viet Nam. We can say
> it\'s one or the other.
>
> DR. MICHALEK: Yes. We need to study the responses\--
>
> DR. TREWYN: But for those who served, that\'s okay.
>
> DR. MICHALEK: I would suggest that we put that idea on the table\--
>
> DR. TREWYN: I mean, because you are\--if it was their service in Viet
> Nam that caused it\--whatever these adverse health effects\--that is
> useful information for them to have.
>
> DR. STOTO: But if that\'s the question, the primary comparison should
> be Viet Nam versus non-Viet Nam.
>
> DR. GOUGH: But you\'re attempting to do that right now.
>
> DR. MICHALEK: Yes, we are.
>
> DR. GOUGH: And with the data you have\--
>
> \[Multiple comments off mike.\]
>
> DR. HARRISON: Well, let\'s\--let me ask\--the point\'s been brought
> up, and that is what the objective of this entire study is. And the
> objective of the study\--I\'m asking this question. Let me rephrase
> this.
>
> Is the objective of the study the health effects of service Viet Nam,
> or is the objective of this study the health effects of Agent Orange?
>
> DR. MICHALEK: Are you asking me to tell you?
>
> DR. HARRISON: Ahh-no.
>
> \[Laughter.\]
>
> DR. GOUGH: Well, the original\--the title of the study is about
> herbicides.
>
> DR. MICHALEK: Yes, it is.
>
> DR. GOUGH: But I think that the legitimate concern has come up about
> men who served\--Ranch Handers who were exposed to the Viet Nam
> experience, whatever that may have encompassed, plus a more specific
> exposures of Agent Orange. And Joel\'s trying to divide it up now and
> say, \"This is my best attempt to separate out the effects of Agent
> Orange, and in order to do that, I also have to know what happens to
> the guys who were just in-country.\"
>
> DR. CAMACHO: What was in-country was where it was dropped. It got
> dropped\--if you\'ll look at the tables and where the stuff got
> dropped, and where troops go in, and when troops walked around and,
> Christ, people were walking and swimming in the stuff up on the DMZ or
> in certain\--
>
> DR. MICHALEK: That\'s hard to cover.
>
> DR. CAMACHO: No, it\'s just applied research, because you\'re going
> back to a huge fight that took place over three years.
>
> DR. STOTO: I think it\'s fair to do this analysis\--I think it\'s
> useful to do this analysis.
>
> I do think, though, that it should lead to an extensive discussion in
> the introduction to the paper and the discussion session. This is not
> just all we\'re doing is\--you\'re changing the hypotheses. Which is
> fine. But you need to be absolutely clear that that\'s what\'s going
> on.
>
> DR. MICHALEK: Thanks. I\'d appreciate further comments by e-mail from
> you or whatever you suggest.
>
> DR. OSEI: We may have a further\--the issue is dioxin. Do you by any
> chance have data on when, you know\--what industries that could use
> \[off mike.\]
>
> DR. MICHALEK: Yes, I do. And those data have been published. And they
> have found\--those other studies have found increased risk of cancer
> in the factory workers that made herbicides in the United States.
>
> DR. OSEI: Then how about a comparison there. Because that may\--some
> of the issues\--
>
> DR. MICHALEK: And many of the patterns seen in those studies parallel
> these\--yes.
>
> DR. TREWYN: Well, the charge was not \"dioxin,\" it was
> \"herbicides\"\--
>
> DR. HARRISON: Yes.
>
> DR. TREWYN: \--okay\--and all of those bases were saturated with
> herbicides. There wasn\'t a blade of grass growing at most of them,
> because they were hand spraying herbicides all over everything around
> them. And it may not have been Agent Orange in all those cases. So,
> again, the exposure to those on the bases could have been different.
> And just looking for dioxin may not help you sort that out. So, just
> a\--
>
> DR. STOTO: The industrial studies that you were asking about\--some of
> them focus on dioxin, and some of them do focus on herbicides more
> generally. In fact for prostate\--one thing I noticed here, not just
> those ones you cited there. There was a study in, I think it
> was\--maybe in farmers, with some strong results in there. And that
> was farmers exposed to herbicides, not just dioxin.
>
> DR. MICHALEK: That\'s right.
>
> DR. OSEI: The reason I\'m bringing this up, because I was reading your
> intro. It seems that the focus, the starting point, was dioxin in most
> of the instruction to your paper, instead of herbicides in general.
>
> So\--
>
> DR. MICHALEK: We are in a bit of a quandary, in that we measure
> dioxin. We don\'t have a biomarker for 2-4D, 2-45T or any of the
> components of the other herbicides. We have a biomarker for exposure
> to the noxi-herbicides, which are those that were contained in many of
> them.
>
> It is the only study in the world, by the way, with a biomarker like
> this.
>
> Yes?
>
> DR. HARRISON: I\'m sorry. Finish your sentence.
>
> DR. MICHALEK: It\'s the only Viet Nam veteran study with a measured
> biomarker. And, by the way, this is the only Viet Nam veteran study of
> cancer incidence against national rates. This is the only SIR analysis
> against national rates in any veteran study.
>
> Yes?
>
> DR. HARRISON: You guys that do this epidemi\--whatever it is stuff\--
>
> \[Laughter.\]
>
> \--isn\'t it\--do you think it would be helpful\--the difficulty with
> this surrogate is it\'s even more tenuous\--it is less\--it is more
> tenuously related to herbicide exposure than, say, dioxin
> measurements\--dioxin levels.
>
> DR. STOTO: No, I don\'t think that\'s true.
>
> DR. HARRISON: The method-time, or the year that you were in Viet Nam
> does not have a direct relationship to herbicide exposure that a
> dioxin level has.
>
> DR. STOTO: Well, they stopped using Agent Orange after\--
>
> DR. HARRISON: Let me rephrase this. If I had a high dioxin level in my
> blood, there\'s no doubt that I was exposed. If I was in Viet Nam when
> Viet Nam was dripping with Agent Orange, there is no assurance that I
> was exposed.
>
> DR. STOTO: Well, no. No. If you had a high exposure level, you could
> have come back in worked in the factory.
>
> DR. HARRISON: No, I\'m just saying the fact that I was there is no
> assurance that I was exposed. But if I have a positive dioxin level,
> there is assurance that I was exposed\--whether it was there or
> anywhere else, there is assurance.
>
> So the one\--even granted that the dioxin level is a more specific
> surrogate than the fact that I was in Viet Nam\--
>
> DR. CAMACHO: The fight behind all of the issue, you\'re taking at that
> level that there\'s an implied research-that this all came from way
> back in the \'70s.
>
> DR. HARRISON: I understand. But it seems to me that that is the point
> that needs to be made about this presentation.
>
> DR. STOTO: I agree with you.
>
> DR. HARRISON: That\'s all\--that it\'s a less direct surrogate.
>
> DR. STOTO: I would just say that it\'s different.
>
> DR. HARRISON: I think it\'s important that it\'s less direct. You
> know, it\'s\--it reminds me of how salmon calcitonin got approved for
> the treatment of osteoporosis based on an increase in total body
> calcium, measured by\--oh, some kind of ion displacement technique.
> And when the real surrogate is bone fractures, of which a more direct
> surrogate is bone calcium, of which a very indirect surrogate is total
> body calcium\--which turned out not to be related, when it turned out
> that shortly thereafter people treated with salmon calcitonin actually
> had an increase in fracture rates in certain locations.
>
> DR. STOTO: Well, this is common in epidemiology that since you don\'t
> control who\'s exposed to what, you have to kind of live with what\'s
> here. And I think that the point that needs to be made is there really
> are three different hypotheses here.
>
> One is that dioxin is a health risk\--is a cancer risk, and we can
> address that because we have these measures. The other one is that
> being part of Ranch Hand\--whatever that means\--is a risk, and we can
> look at that. And the third one is being in Ranch Hand in Viet Nam,
> versus being a comparison who didn\'t serve in Viet Nam\--that\'s an
> interesting question.
>
> DR. HARRISON: But, Mike, I\'ve never thought of the question about
> dioxin. To me, dioxin\--I\'ve never thought that the question was
> whether dioxin was a health risk.
>
> DR. STOTO: Well, that\'s what\--
>
> DR. HARRISON: The question is whether herbicides are a health risk,
> and dioxin is the surrogate. We\'re not testing dioxin directly.
>
> DR. STOTO: And, I think, the surrogate for one of the herbicides.
>
> DR. HARRISON: That\'s right. And so it\'s\--like all surrogates, it\'s
> imperfect. But it\'s a surrogate. We\'re not testing dioxin. That\'s
> not the objective of the study.
>
> DR. STOTO: I understand that wasn\'t the original objective, but that
> has become an important topic in science.
>
> DR. HARRISON: Well\--
>
> DR. STOTO: And this has some bearing on it.
>
> DR. TREWYN: Well, it\'s become a pertinent topic for the VA, because
> they want to use\--if you can\'t prove that dioxin caused it, then
> they don\'t have to pay benefits to anybody who has adverse health
> outcomes. And this gets\--this opens up more areas. If you take the
> dioxin away from that argument, well, all of a sudden, you\'ve got the
> potential that the VA has to pay a lot more health benefits, and they
> don\'t want to do that.
>
> DR. STOTO: So it\'s a valid scientific question that we have some
> evidence that relates to it.
>
> DR. CAMACHO: We\'re at this imperfect study level, in a sense, because
> of the fights of 30 years ago. When people went down to CDC and CDC
> was pressured not to do certain studies, and to view certain studies
> as everybody had\--was in the military, but didn\'t go to Viet Nam,
> went to Viet Nam. They could have had that\--they still could have
> done that, as Massachusetts. But we\'re not there. We\'re here.
>
> \[Comments off mike.\]
>
> DR. HARRISON: Wait a minute. Wait a minute. Wait a minute. Yes, we
> can.
>
> But Paul, let\'s stick with the science here. Okay? Mike, too.
>
> DR. CAMACHO: You\'re asking me not to say anything.
>
> DR. HARRISON: No, no. No. No, I\'m not. And I apologize if you feel
> that way. What I\'m saying is, I\'m still concerned about the
> science\--
>
> DR. CAMACHO: Make it clear about the three pieces. I can go along with
> that.
>
> DR. HARRISON: Maybe I can\'t make it clear about the three pieces.
> I\'m beginning to falter.
>
> Mike?
>
> DR. GOUGH: I want to echo what Paul just said. I think despite the
> fact that you\'ve got a paper that\'s three times longer than is going
> to get accepted, that it would be far better to truncate these
> tables\--as your other author suggests\--as much as possible, and to
> explain, in this paper, where you\'re shifting the weight; explain so
> that everybody in this room will understand that we\'re now doing
> something new, and we\'re doing it because if the results go this way
> we would\--this happened, and the results go that way. That\'s far
> more important, I think, than the exhaustive tables.
>
> And it\'s got to be done, because otherwise this fight\'s going to
> come up\--it\'s not a fight, but this confusion\'s going to arise in
> every person\'s mind who reads this paper.
>
> DR. MICHALEK: Yes, I agree.
>
> DR. TREWYN: \--goes into the final report.
>
> DR. STOTO: And Paul is right. This does reflect what happened 30 years
> ago. But we have what we have, and I think that what Mike said is
> exactly the way to handle it.
>
> DR. HARRISON: Any other comments? We still have another 30 or 40
> slides to look at.
>
> \[Laughter.\]
>
> There\'s plenty of opportunity.
>
> You\'re doing great, Joel.
>
> DR. MICHALEK: Next slide, please.
>
> \[Slide.\]
>
> And the comparison group\--melanoma, we see no significant increase in
> risk of melanoma.
>
> Slide, please.
>
> \[Slide.\]
>
> Here are the two so-called Viet Nam exposure index strata. In the
> first, we have the Ranch Hand veterans with less than two years in
> Southeast Asia\--which tends to isolate Ranch Handers with a lot of
> time in Viet Nam.
>
> Here are the Ranch Handers with a hundred percent of their Southeast
> Asia experience in Viet Nam. And in both strata we see a significant
> increase in the risk of prostate cancer against national rates.
>
> DR. HARRISON: But those are all in 17, right?
>
> DR. MICHALEK: Those are the same numbers you saw in previous slides.
> There were observed 17, expected 9.
>
> DR. HARRISON: Okay.
>
> DR. MICHALEK: Slide.
>
> \[Slide.\]
>
> And here\'s the corresponding slide for melanoma. We see in both
> strata increased risk against national rates of melanoma. In the Ranch
> Handers who were there 100 percent of their time, we observed 12,
> expected 4. The relative risk is 3.
>
> Slide, please.
>
> \[Slide.\]
>
> In the comparison cohort, looking at either strata, we see no
> significant increase in risk against national rates on the occurrence
> of prostate cancer. And the same is true in the comparison cohort on
> the risk of melanoma against national rates. In either of the two
> strata we see no significant increase against national rates.
>
> It\'s interesting to note that although we say significant increases
> in the risk of cancer incidence, we see incidence, we see no
> significant increase in the risk of cancer mortality against national
> rates in either cohort. Just an example: in the Ranch Hand cohort,
> these same SEER categories now are used to tabulate observed and
> expected deaths from cancer at any site, for example, and you\'ll see-
>
> DR. HARRISON: Joel, that shouldn\'t surprise you. People don\'t die
> from prostate cancer.
>
> DR. GOUGH: But what about melanoma?
>
> DR. MICHALEK: No, again I\'m trying to reduce the number of slides,
> and did not include everything. I only included data for which there
> were some counts. And many of these SEER categories there were no
> deaths, or the counts were zero or one, so I didn\'t include those.
> They are in the article. If you look at Table 12 or so in the paper,
> you\'ll see them.
>
> DR. GOUGH: But melanoma is a pretty fatal tumor.
>
> DR. MICHALEK: Again, the actual counts are in the paper I did not
> include all data in the slides. It was just an attempt to give you a
> thumbnail sketch of what\'s in the article.
>
> DR. HARRISON: Does anybody know if melanoma is more common in males
> versus females? Is there a sex-based difference in the incidence of
> melanoma? Does anybody know that?
>
> \[No response.\]
>
> Dang. Okay.
>
> DR. MICHALEK: There\'s an important reason why we don\'t. Because all
> the veterans in this study are male.
>
> DR. HARRISON: No, no, no.
>
> \[Laughter.\]
>
> DR. GOUGH: No, we\'re making comparisons with the male SEER data.
>
> DR. MICHALEK: Yes, sir, we are.
>
> DR. HARRISON: No, I\'m just asking in general. The reason I\'m asking
> is the two things that have popped up\--of the two things that have
> popped up, prostate cancer is certainly androgen dependent, and it
> would be nice\--not nice, but it would be comforting to\--as far as
> the data was concerned, if melanoma was more commonly found, and also
> because androgen levels have something to do with aggression and so
> on, it may be that those people who spent more time in Viet Nam, who
> voluntarily spent more time in Viet Nam might have been pumping a
> little more testosterone than those who were out.
>
> DR. MICHALEK: The issue of volunteerism has been raised many times
> over the beginning of the study. You know, the current physical
> examination, we are displaying the tours of duty for each veteran and
> asking him which, if any, of these tours did he actually volunteer or
> attempt to manipulate his career so he would actually end up in Viet
> Nam.
>
> So, for the first time, we\'re getting that data on volunteerism,
> although we haven\'t summarized it yet.
>
> DR. HARRISON: I assume, though, that those people who spent eight
> years in Viet Nam had to have volunteered at some point, no matter
> how\--
>
> DR. MICHALEK: That\'s an assumption. We\'ll find that out when we
> actually review that data.
>
> DR. HARRISON: Okay.
>
> DR. GOUGH: You\'re making a very interesting point. Because, I mean,
> it says a lot about the VA\--
>
> \[Laughter.\]
>
> \--it\'s available to them. If they go and they get good care, then
> we\'ve got\--with the rest of our cancers, and we have prostate
> cancers where there\'s a significant increase in one group compared to
> the national, and without a significant increase\--not made a
> significant\--but there\'s a decrease here.
>
> DR. MICHALEK: Well, you see, for example, in the Ranch Hand groups
> there were no deaths from cancer of the genitalia. Of course those
> include mostly prostate. So these Ranch Hand veterans are not dying
> from prostate cancer. They\'re dying from something else.
>
> DR. OGERSHOK: Don\'t forget, every five years they go through an exam
> here. I mean, we picked up a lot of this stuff there, and they get
> treated.
>
> DR. HARRISON: That\'s true. That\'s true.
>
> DR. MICHALEK: Well, we are comparing the mortality experience of those
> who attended Scripps exam, and we didn\'t see any significant
> difference at all.
>
> So, that\'s a very interesting hypothesis, but it doesn\'t seem to be
> held up by the data.
>
> Slide, please.
>
> \[Slide.\]
>
> In the comparison cohort, we see no significant in the risk of
> mortality from cancer at any site or any specific site.
>
> Slide.
>
> \[Slide.\]
>
> Now, I\'m going to display for you some of the internal analyses that
> we conducted using the actual dioxin measurements, rather than simply
> comparing against the national rates. We\'re now focusing on those
> individuals that actually have dioxin measurements. And we\'re now
> within that line strata of exposure opportunity: those that were there
> less than two years, and we see a significant increase in the risk of
> cancer at any site in the Ranch Hand low and high categories against
> the comparison in this analysis, with a relative risk and 2 and 2.2 in
> the low and high categories. We\'ve never had this before
>
> Slide.
>
> \[Slide.\]
>
> And looking at the Ranch Handers who were there a hundred percent of
> their time, and a comparison to \"never in Viet Nam\"\--there were 291
> of them\--we see a significant increase\--actually a stronger
> increase, in the risk of cancer at any site, using the SEER category
> definition in the Ranch Hand cohort, accommodating dioxin levels.
>
> Slide, please.
>
> \[Slide.\]
>
> In prostate cancer, we see a significant increase in the risk of
> prostate cancer in the high-dioxin category, with a relative risk of
> 7, against the comparison cohort. This is among those individuals that
> were there less than two years.
>
> Slide.
>
> \[Slide.\]
>
> And in melanoma we see significant increases in the risk in the low
> and high category, dioxin exposure against the comparison cohort.
>
> Slide.
>
> \[Slide.\]
>
> Among the Ranch Hand veterans who were there a hundred percent of
> their time, and the comparisons that were not there at all, we see a
> significant increase in the risk of prostate cancer in the high-dioxin
> category.
>
> Slide.
>
> \[Slide.\]
>
> And the same is true of\--well, not the same\--not quite true in
> melanoma; relative risk 5.5, which does not reach significance.
>
> Slide.
>
> \[Slide.\]
>
> DR. HARRISON: Joel, those relative risks are pretty high, and the
> p-values are pretty\--unimpressive. Are those because of small numbers
> again?
>
> DR. MICHALEK: Yes.
>
> DR. GOUGH: I had the same concern about this analysis I had about the
> diabetes analysis after I thought about it last time. You have
> stratified the Ranch Hands to be the highs and lows; you\'ve taken the
> comparisons to get them homogeneous.
>
> If you stratify the comparisons between low and high, do these\--
>
> DR. MICHALEK: On dioxin, you mean?
>
> DR. GOUGH: Yes, on dioxin\--what happens?
>
> DR. MICHALEK: We have stratified the comparison group and we see
> differences within the comparison group. I have not displayed those in
> this\--because that was not the thrust of these analyses.
>
> DR. CAMACHO: There\'s little\--there\'s not much variance in the
> comparison group\--
>
> DR. MICHALEK: The dioxin levels ranks\--
>
> DR. GOUGH: \--with low levels?
>
> DR. MICHALEK: Yes, dioxin levels in the comparison groups range from
> zero to 10. In the Ranch Hand group they range from zero to 600.
>
> All we\'re doing here is stratifying, not by dioxin level with the
> comparison group, but whether they were in Viet Nam or not.
>
> DR. HARRISON: But background and lowest dioxin levels?
>
> DR. MICHALEK: Background and low\--these are Ranch Hand veterans who
> were there in Viet Nam for a second time, and who had the background
> levels of dioxin.
>
> DR. GOUGH: Yes, that\'s what I\'m saying.
>
> DR. HARRISON: What you\'re saying, though, is that even at background
> levels, the relative risk is 4.
>
> DR. MICHALEK: Right. That doesn\'t reach significance.
>
> DR. GOUGH: But given what happened with\--given the
> relationship\--Paul, you\'re exactly right, because if you plot this
> out on a log-base 2 table, and the comparisons go from essentially
> zero up to 10, and the Ranch Hands go from zero to way over here. But
> then if you cut in the quintile which drove it the last time, diabetes
> goes up with increasing body level of dioxin in the comparison, it
> also goes up with increasing levels in\--I mean, it goes up with
> increasing dioxin levels in both the comparisons and the Ranch Hands,
> which is a puzzle. Because if it\'s dose response, you\'d expect it to
> be much, much higher in the Ranch Hands.
>
> DR. MICHALEK: We did not analyze dioxin versus cancer in the
> comparison group in this study\--in this particular manuscript.
>
> DR. HARRISON: We\'re going to need to conclude this discussion in
> about five minutes.
>
> Do your best, Joel.
>
> DR. MICHALEK: Slide, please.
>
> \[Slide.\]
>
> So here are the conclusions of\--
>
> \[Laughter.\]
>
> \--all of which I already stated, and you already know what they are.
>
> This study was not designed to do this, and we tried our best to do
> it, following comments from the committee.
>
> Slide.
>
> \[Slide.\]
>
> Increased risks against cancer rate an site, not increased against the
> national rates. I\'m not going to say these words. You know what they
> are. We just got through talking.
>
> Slide.
>
> \[Slide.\]
>
> Again, this is summarizing the same slides you just saw.
>
> Slide.
>
> \[Slide.\]
>
> We saw no evidence of a healthy-worker effect, as regards incidence.
> Healthy-worker effect would be expressed if the incidence, for
> example, were much less than the national rates, and we are seeing
> increases against national rates in the incidence of prostate and
> melanoma in the Ranch Hand cohort. However we\'re not seeing any
> increase in cancer mortality in either cohort, which suggests they\'re
> getting better than average health care.
>
> Slide.
>
> \[Slide.\]
>
> And here are the limitations that you all know about. And these are
> the results you already mentioned, Mike, about the multiple testing.
> In one particular table we have nine significant results out of 34
> tests. And I didn\'t make an attempt to break those out as to whether
> they\'re adverse or not adverse, but we can certainly do that in our
> revision.
>
> Slide.
>
> \[Slide.\]
>
> And those same caveats apply to all of our work. We don\'t know the
> initial dose. There was no dosimetry in Viet Nam. We\'re using a first
> order kinetic model to estimate the initial dose to estimate the
> initial dose that they had while they were in Viet Nam.
>
> Slide.
>
> \[Slide.\]
>
> The strengths are that we think we have full ascertainment: every
> single study subject is followed up with our own staff by telephone to
> make sure they see their doctor as following Scripps physical exams,
> and we have record review to back up every single case that\'s been
> shown in every table. And we\'ve had good compliance.
>
> And this is the only Viet Nam veteran study with dioxin measurements
> in both cohorts.
>
> Slide.
>
> \[Slide.\]
>
> And these are the same bullets we just talked about.
>
> Thank you very much.
>
> DR. HARRISON: Okay. Any other questions?
>
> DR. STOTO: I have a suggestion\--to deal with the length, and that is
> to break it up into two papers, for the internal and the external.
>
> DR. MICHALEK: Yes, that\'s on the table as an option.
>
> DR. STOTO: Get\'s two publications instead of one.
>
> \[Laughter.\]
>
> DR. HARRISON: Okay. So what we\'ve managed to do is not do the
> mortality paper before the 10:15 break.
>
> Let\'s see if we can\'t make up a little bit of the time as we go
> through, so we have a break now at 10:15. Let\'s try to get back
> here\--why don\'t we try to do this: why don\'t we try to get back
> here in 10 minutes, get started promptly on the mortality paper; see
> if we can\'t finish the mortality paper a little early, and squeeze
> the diabetes paper in and let the public presentation run over into
> lunch a little bit. Okay?
>
> So\--10 minutes.
>
> \[Recess.\]
>
> DR. HARRISON: Let\'s go.
>
> **Mortality-Review Findings from Latest Paper**
>
> DR. MICHALEK: I have a statistician with me from Brooks Air Force
> Base.
>
> This is summary slide of a paper on post-service mortality in the
> Ranch Hand cohort, which was submitted and rejected by the [American
> Journal of Epidemiology]{.underline}. And I want to go through the
> results and the referee comments.
>
> In this analysis we are comparing the mortality experience in the
> Ranch Hand cohort against all 19,000 comparisons in the comparison
> population\--which is different than what you just saw in the previous
> talk.
>
> In the previous talk we had isolated comparisons who had attended the
> Scripps exams, or the Kelsey-Sebold exams, questionnaires. This
> involves all 19,000 comparisons. And so we have a lot of numbers, but
> we have fewer co-variants. we are unable to adjust for known risk
> factors for certain kinds of death; for example, in these analyses we
> can only adjust for age, race and military occupation.
>
> We\'re looking at the same standard of causes and cause-specific
> assessments of mortality we have done in previous reports. The
> cut-point for mortality was 31 December 1999, which was the same
> cut-point we used in the previous talk.
>
> And this updates a published paper in 1999 in the [American Journal of
> Epidemiology]{.underline}. And it was recently submitted and rejected
> by the same journal.
>
> Slide.
>
> \[Slide.\]
>
> So here is risk. As I said, it was from the start of service in Viet
> Nam to 31 December 1999, all outcomes verified by record review,
> following ICD rules. Twenty-two Ranch Hand were killed in action, and
> they\'re not included in this report or any of our reports, actually.
>
> Slide, please.
>
> \[Slide.\]
>
> We are breaking out by military occupation, which we already know
> correlates with dioxin body-burden in Ranch Hand veterans.
>
> Slide.
>
> \[Slide.\]
>
> The statistical analysis, now, is an internal comparison of Ranch Hand
> mortality against comparison mortality, using something called
> \"proportional hazards model,\" adjusted for birth date and military
> occupation.
>
> The summary statistics are relative risks.
>
> Slide.
>
> \[Slide.\]
>
> At the time\--by December 31, 1999, of the 1,262 Ranch Hand veterans
> who ever existed\--that\'s minus the 22 killed in action\--there were
> 440\--I\'m sorry\--this doesn\'t give me a total number\--this is
> numbers at risk. Of the 1,262 Ranch Handers who ever existed, to the
> 19,078 of the comparison population, and there it is broken out by
> military occupation.
>
> Slide.
>
> \[Slide.\]
>
> And these demographics will show you that the groups are approximately
> comparable on dates of birth and military occupation and race.
>
> Slide.
>
> \[Slide.\]
>
> And so here are the mortality analyses. We have approximately\--we
> have 14.7 percent of the Ranch Hand veterans have died as of 31
> December 1999, versus 12 percent in the comparison cohort. And that
> relative risk is borderline significantly increased. And that\'s a
> first in our study. Prior reports, the relative risk was a lot closer
> to 1.0.
>
> There are reasons for that increase, which I\'m going to bring out in
> the subsequent slides. This is not a comprehensive of all the causes.
> Once again I\'m trying to reduce the number of PowerPoint slides. The
> document shows all causes. I\'m only showing those for which there are
> some counts to show.
>
> Cancer risk, for example\--cancer mortality, there is no significant
> increase in the risk of cancer mortality. Previously reported in the
> published article in the [American Journal of
> Epidemiology]{.underline}\--again, 118 deaths, and there we used a
> similar methodology instead of a Cox model, we had an expected of 120,
> a relative risk of 1.0. So you see, in the last couple years there\'s
> been a change in the mortality experience, relative to the comparison
> cohort in the adverse direction.
>
> Slide.
>
> \[Slide.\]
>
> And here you see one of the reasons why we have an increased
> risk\--borderline significant increase in all-cause mortality, is
> being driven by circulatory deaths in the Ranch Hand cohort; relative
> risk 1.3, also borderline significant. And there\'s a reason for that,
> which you\'ll see in subsequent slides.
>
> In previous analyses we had a significant increase in the deaths due
> to digestive diseases, which no longer reaches significance.
>
> And on asterisk on the 66 means that in the previous publication we
> have 39 deaths from circulatory diseases, whereas now we have 66 in
> the Ranch Hand cohort.
>
> Slide, please.
>
> \[Slide.\]
>
> DR. STILLS: Joel, what sort of circulatory diseases do you mean here?
>
> DR. MICHALEK: Primarily heart disease. And I have another slide
> breaking that out by specific type of heart disease.
>
> DR. STILLS: Thank you.
>
> DR. HARRISON: Joel, in your discussion of this, do you relate that at
> all to the increased risk of diabetes?
>
> DR. MICHALEK: We don\'t have diabetes as a cause of death on death
> certificates.
>
> DR. HARRISON: Diabetes doesn\'t cause death. Diabetes causes
> circulatory disease.
>
> DR. MICHALEK: Yes. And we\'re attempting to explore that now. We\'re
> trying to relate these deaths\--obverse of what we see at Scripps, and
> that would include diabetes. I\'m not ready to show that.
>
> DR. HARRISON: Maybe let me ask the question another way: of those
> people who died with circulatory illnesses, were a disproportionate
> number of them diabetic?
>
> DR. MICHALEK: That analysis is in the works. I\'m not ready to show
> that.
>
> DR. HARRISON: Okay. So that\'s the answer. Okay. Thank you.
>
> DR. MICHALEK: Slide.
>
> \[Slide.\]
>
> And here are the three external causes: accidents, homicides and
> suicides. And you see no significant increase in the Ranch Hand cohort
> on those three causes.
>
> And now we start to see what\'s really driving this increased
> mortality in the Ranch Hand cohort. It\'s coming from the enlisted
> ground crew. And you\'ll see soon that what\'s happening in the
> enlisted ground crew is that those\--the overall mortality in that
> cohort is being driven by circulatory-disease deaths.
>
> However, we do have also a significant increase\--although small
> numbers\--in Ranch Hand administrative officers. There are Ranch Hand
> officers who did not fly airplanes but\--and certainly did not handle
> herbicides, but are experiencing increased mortality. And I\'ve listed
> them all down here. There are seven deaths, and there are certainly no
> apparent pattern there: one accident, one suicide, one cancer, and so
> on.
>
> Slide.
>
> \[Slide.\]
>
> Cancer mortality by occupation\--cancer and heart disease are the two
> causes of death that have enough numbers so we can actually break them
> out by military occupation, which is our best surrogate for herbicide
> exposure. And you see here, with regard to cancer mortality, there is
> no apparent pattern here that would suggest an adverse relation
> between dioxin or herbicide exposure and cancer mortality.
>
> Slide.
>
> \[Slide.\]
>
> However, when we look at circulatory disease mortality, now we see the
> reasons for these increases are driven by 40 enlisted ground
> individuals who have died of diseases of the circulatory system; 6.8
> percent, against 3.7 percent enlisted group comparisons, which is a
> relative risk of 1.7, and that reaches a significance.
>
> In our previous article, we had 24 enlisted ground who had died from
> diseases of the circulatory system, and expected 16, a relative risk
> of 1.5. And so what\'s happened is that the result becomes stronger
> since we published our last paper.
>
> DR. STILLS: Are they included in the 40?
>
> DR. MICHALEK: Those 24 are included in the 40. Yes, this is
> cumulative.
>
> DR. STILLS: Is there any co-that you could identify?
>
> DR. MICHALEK: Yes. That\'s coming in a subsequent slide.
>
> DR. HARRISON: What was the question?
>
> DR. MICHALEK: Any particular kind of heart disease that would explain
> these\--and the answer is yes, and that\'s coming in another slide.
>
> And here is\--the analysis that we do, driven by referee request that
> we break out cancer deaths as to those that occurred within 20 years
> of service in Viet Nam, versus those that occurred subsequent to 20
> years, looking for a latency effect. And we see no increase in risk
> among veterans who had cancer within 20 years. However\--
>
> Next slide, please.
>
> \[Slide.\]
>
> \--after 20 years, there is a suggestion of increased risk, but
> certainly nothing statistically significant.
>
> Slide.
>
> \[Slide.\]
>
> Among those enlisted ground personnel who died from disease of the
> circulatory system, the majority of those deaths were cause by
> atherosclerotic heart disease. There you see 28 of the 40 were caused
> by atherosclerotic heart disease among Ranch Hand, or 4.8 percent
> versus 2.6 percent in the comparison cohort; p-value of 009.
>
> DR. HARRISON: Joel, atherosclerotic heart disease produces
> cardiomyopathy\--atherosclerotic disease\--I\'m sorry\--when applied
> to the heart can result in cardiomyopathy; in terms of the
> cerebrovascular system can produce strokes. So how was
> atherosclerotic\--\"atherosclerotic\" doesn\'t kill you.
>
> DR. MICHALEK: I\'m reporting to you the underlying cause of death as
> recorded on the death certificates from these men. We have not yet
> finished an analysis comparing these results with what we see at
> Scripps clinic. We have the health records on many of these men from
> their repeated physical exams at Scripps. They are not reflected in
> these numbers. And that is coming in a separate paper to be presented
> to the committee at the next meeting, if they\--
>
> DR. HARRISON: So you\'re saying on the death certificate it was just
> the single word \"atherosclerotic?\"
>
> DR. MICHALEK: This is an abbreviation of a specification that was
> given to us from the underlying cause of death on death certificates.
> I can provide a more detailed description of that if you would like
> it.
>
> DR. HARRISON: So it may well have been \"atherosclerotic XX,\"
> \"atherosclerotic XY,\" \"atherosclerotic XYZ.\"
>
> DR. MICHALEK: Yes. There is an ICD code associated with that word, and
> I can tell you the exact specification on those codes if you would
> like to have that.
>
> DR. STOTO: The underlying cause, rather than\--
>
> DR. MICHALEK: Yes, they\'re underlying causes\--underlying cause of
> death.
>
> DR. HARRISON: Only in terms of whether it adds credulity to the
> statistical findings\--
>
> DR. MICHALEK: I believe those codes are in the article.
>
> DR. HARRISON: \--it would be nice to be able\--
>
> DR. MICHALEK: Yes.
>
> DR. HARRISON: \--to related things up.
>
> DR. MICHALEK: Those are in the article.
>
> DR. HARRISON: Question a little bit off\--does anybody happen to
> remember if there is a significant difference in proteinuria between
> the Ranch Handers and the comparisons?
>
> DR. MICHALEK: Proteinuria would be in the renal functioning?
>
> DR. HARRISON: Yes.
>
> DR. MICHALEK: As I recall, there were no significant findings in
> renal. We\'ve never seen significant findings in renal in the entire
> study. However that doesn\'t mean they\'re not there, and we can look
> at that again.
>
> DR. HARRISON: It may be that you just didn\'t have enough people. But
> you know if you had a group with more diabetes than another group,
> you\'d expect there to be some diabetic nephropathy. And you know, if
> they had enough you\'d expect to see some renal failure, and you\'d
> expect to see deaths from renal failure\--which might be in that
> \"other\" category that you\'ve got down there.
>
> DR. MICHALEK: Okay.
>
> Slide.
>
> \[Slide.\]
>
> So\--and the bottom line is what you just heard: that there\'s a
> significant increase in risk of death from circulatory diseases among
> enlisted Ranch Hand ground crew, which is increased over the last
> analysis published in the [American Journal of
> Epidemiology]{.underline}; and no evidence of an increased risk of
> death from cancer, matching reference. And the risk of death from
> digestive diseases is no longer significant.
>
> I need to underline once again that these analyses are unadjusted for
> known risk factors for these diseases: for example, in heart disease
> we can\'t adjust against the 19,000 comparisons for smoking or family
> history of disease, like we can in the analysis of data from Scripps.
>
> Slide, please.
>
> \[Slide.\]
>
> And these are same strengths that we\'ve seen before.
>
> Slide.
>
> \[Slide.\]
>
> The limitations, I just said: the lack of adjustment, and the fact
> that the information from death certificates is limited, as compared
> to what we see from the extensive Scrips physicals.
>
> Now, this paper was rejected within the last two months by the
> [American Journal of Epidemiology]{.underline}. I want to just go
> through the referee comments.
>
> Slide.
>
> \[Slide.\]
>
> The first reviewer was concerned that these results are already
> published, and why are we trying to publish this again? Well, the
> results are worse; I mean, they\'re adverse. They\'re getting worse
> than they were two years ago, and that\'s important to us.
>
> And the second part of that is that the protocol prescribes a series
> of mortality analyses coming out of the study. In previous years we
> would write an Air Force Technical report summarizing mortality, and
> that would get a blue cover and put on our shelf. It doesn\'t receive
> as much attention as a published article does. It\'s not peer
> reviewed. So we\'re attempting to peer review all of our work, rather
> than write blue-covered Air Force tech reports. And so that was why we
> submit to journals.
>
> Small sample size, exposure period and so on\--all of these critiques
> were on the table in 1977 when the study was conceived. We knew we had
> a fixed sample size, and therefore a limited ability and limited power
> of Viet Nam veterans comparisons. And here the referee is saying
> exactly the reason why we did the analyses I just showed you on
> cancer, where we attempt to break out exposure opportunity and limit
> the comparison cohort.
>
> And some of these techniques I showed you on cancer incidence could be
> applied here, although we haven\'t done so yet.
>
> And he\'s making some of the statements that you just said at the
> table just a few minutes ago.
>
> Slide.
>
> \[Slide.\]
>
> He\'s saying the Ranch Hand cohort is not the best group to study for
> health effects of dioxin or health consequences of service in Viet
> Nam. And here, I think, the reviewer is revealing his own bias towards
> industrial cohort studies: namely the NIOSH industrial cohort studies,
> where we think he\'s been basing his experience.
>
> \"Not representative of Viet Nam veterans,\" sample size is too
> small.\"
>
> Slide, please.
>
> \[Slide.\]
>
> And in here he\'s arguing that the industrial cohort studies have
> experienced exposures 10 to 20 times greater than Ranch Hand veterans.
> And all of that is true. However, Ranch Hand veterans is the only
> identifiable cohort of Viet Nam veterans that has demonstrably
> increased dioxin levels. And it does have this order of exposure
> period relative to industrial cohort members who worked in the
> factories for up to 20 or 30 years. All of that is true.
>
> Slide, please.
>
> \[Slide.\]
>
> DR. STOTO: I think that this reviewer says that you did the wrong
> study.
>
> DR. MICHALEK: Yes. He\'s saying the veterans should be happy with the
> industrial cohort studies, and you shouldn\'t even be doing the Ranch
> Hand study.
>
> DR. STOTO: Right\--and that\--you know, those are their comments if
> this were a review group that\--whether or not the study should be
> funded or not. But it\'s irrelevant.
>
> DR. MICHALEK: That\'s right.
>
> DR. HARRISON: Can we, instead of going through all the reviewers\'
> comments, can we just stop here and discuss\--in terms of time, unless
> someone protests vociferously? Comments?
>
> DR. GOUGH: Well, Joel, since we\'re almost to the end of the
> study\--when was the last collection of mortality data?
>
> DR. MICHALEK: We will continue mortality assessment up until the last
> day.
>
> DR. GOUGH: So wouldn\'t it be reasonable, then\--I mean, I think it\'s
> legitimate. They\'re saying they\'re coming too fast. But that final
> mortality report I think would be published almost anywhere.
>
> DR. MICHALEK: Probably. Except that, in the worst scenario, the
> program would be ended and the village would be shut down, and all of
> our computers archived, and we wouldn\'t be around to receive comments
> from the referees to get the thing published. I would be working
> somewhere else.
>
> So, in other words, there has to be an end-game worked out for this
> project.
>
> DR. HARRISON: Well, first of all\--as, Mike, you and I discussed this
> morning\--Joel, you\'re to be commended on doing something that was
> brought up to you several years ago, and that is the desirability of
> publishing this material in peer-reviewed publications where there\'s
> some assurance of quality because of the nature of peer-reviewed
> publications.
>
> I also thought that this was kind of like a locomotive that finally
> got going\--
>
> \[Laughter.\]
>
> \--you know, the juggernaut kind of theory. I mean, papers flying all
> over the place.
>
> The other way that you might be able to add interest to this paper
> would be if you tried to relate it to your other major finding. If
> there\'s a lot of cardiovascular death in this study, and there\'s a
> lot of diabetes in another study, those two are actually related\--
>
> DR. MICHALEK: Yes.
>
> DR. HARRISON: \--and add interest because of their relationship. So
> that might actually add relevance that would help you in terms of the
> review route.
>
> DR. TREWYN: Yes, and I think you don\'t want to just package these the
> same way each time. You can use the learnings from the other things,
> but there are also\--as we all know in the scientific area there are
> multiple journals. And so you can utilize reviewer comments\--even if
> you can\'t go back to that particular journal, but you utilize the
> good points, ignore the dumb stuff that they said\--and they always
> have some of those\--and you try to improve the paper and submit it
> somewhere else.
>
> And I think another point here is: is this the right time, or do you
> wait until you\'ve got\--you see where the trends are going, and
> so\--but I think doing a different collection, and focusing it
> differently using your other positive findings is one way. And they
> looking towards the end of targeting, \"Okay, at such-and-such a time
> we try to say, all right, we\'re going to cut off now,\" so we\'ve got
> enough time to package this all and get it published somewhere while
> we\'re all still\--
>
> But I think looking at that\--again, I commend you on pushing these
> things out the door. It helps everyone.
>
> DR. HARRISON: Speaking of other findings, shall we go on to the
> insulin sensitivity?
>
> DR. MICHALEK: Yes. Then we\'ll skip Reviewer 2?
>
> DR. HARRISON: Reviewer No. 2 always has the same comments.
>
> **Diabetes- Summarize Latest Analysis of the Insulin**
>
> **Sensitivity** **Study**
>
> DR. MICHALEK: All right\--insulin sensitivity.
>
> Diabetes has been an issue in the study since 1992, when we found a
> significant trend in the Ranch Hand cohort, of diabetic risk against
> dioxin category. That paper was published in 1996, in
> [Epidemiology]{.underline}, and since then we\'ve continued to see
> increased risk. The pattern is complicated by confounding, and the
> results require careful analysis to display.
>
> We have since then made two efforts to try to understand the diabetic
> finding at a biological level. One is to conduct a matched-pair
> insulin sensitivity analysis, using the glucose clamp method at the
> Little Rock VA medical center. The other was to extract adipose tissue
> specimens from 313 study subjects and have those assayed by the
> Department of Toxicology, University of California-Davis.
>
> This is a series of slides summarizing preliminary results from the
> Little Rock study on 29 matched pairs who received the glucose-clamp
> measurement of insulin sensitivity. The first officer was Dr. Philip
> Kern. And I\'m sorry Dr. Kern is not here\--emphasizing, once again, I
> am a statistician. Dr. Kern is an M.D., and he is a specialist in this
> area and can describe the methodology that I cannot.
>
> Sensitivity index was derived by the euglycemic clamp in 29 matched
> pairs. We have 29 Ranch Hand veterans matched to 29 comparisons, all
> non-diabetic and matched in great detailed, and will be described to
> you in coming slides.
>
> We also have a quick index of insulin sensitivity derived from data
> collected currently at Scripps clinic, using fasting glucose and
> fasting insulin, and the reference for that calculation is a paper by
> Katz, et al., which is given on the last PowerPoint slide.
>
> The dioxin measurements were made by the Centers for Disease Control
> using the same dioxin data you\'ve seen represented in other slides.
>
> Slide, please.
>
> \[Slide.\]
>
> Inclusion criteria was these veterans had to have participated in the
> 1997 physical examination at Scripps. They had to have all been
> non-diabetic, and the proscription for non-diabetic\--in absence of a
> doctor\'s diagnosis are these specifications for fasting glucose and
> two hour postprandial.
>
> The comparison had to have a dioxin level less than 10 parts per
> trillion, and the Ranch Hand had to have four repeated dioxin
> measurements all greater than 10. So all of these Ranch Hand veterans
> that qualified for inclusion in this study are in our half-life study,
> and they all have demonstrably high levels made four times over a 15
> year period.
>
> Exclusion criteria\--following a protocol written by Dr. Kern, we
> excluded individuals who had large weight gains or losses, or acute
> illnesses or medications that would have affected the measurement, or
> any other condition that would have affected the measurement.
>
> Slide.
>
> \[Slide.\]
>
> The matching criteria were more stringent than the matching that\'s
> used in the global study. They\'re matched on age within five years,
> body mass index within two units, perfectly on race, and imperfectly
> on reported family history of diabetes in first order relatives.
>
> DR. HARRISON: Joel, was that race self-reported?
>
> DR. MICHALEK: Self-reported.
>
> Slide.
>
> \[Slide.\]
>
> This is a matched-pair study, so that the first statistic that people
> like to see is the pair t-test. And that is the first analysis that
> you will see. Subsequent to that we\'re going to reveal significant
> adverse trends in both cohorts relative to dioxin and insulin
> sensitivity. And for that we\'re going to use a number of different
> regression models. In one we\'re going to combine all 58 subjects
> together and display a single regression line of insulin sensitivity
> versus dioxin, using a single intersect and a single slope.
>
> In another analysis we\'re going to realize that we\'ve got dose
> response patterns going on within both cohorts: within the 29
> comparisons and within the 29 Ranch Handers, and so we\'re going to
> fit separate regression lines within each of those two cohorts of 29
> veterans\--with this for the common slope, because the slopes are
> parallel.
>
> And, finally, in other analyses we\'re going to introduce a separate
> regression line in each cohort, because we see differing patterns
> sometimes in the comparisons as compared to the 29 Ranch Hand
> veterans.
>
> This is the sample reduction, which gets us from the 567 Ranch Hands
> and 815 comparisons down to the actual 29 that were actually
> used\--driving home the point that this is a very stringent sampling
> criterion. Not only did you have to have them matched, if a Ranch
> Hander volunteered to go to Little Rock and his matched comparison
> didn\'t, that Ranch Hander can\'t go, because we had to have 29
> matched pairs. And that\'s a very stringent criteria which led us to
> the absolute\--if we actually had more funding, we could not have
> exceeded 29 matched pairs. We have used up all available resources, in
> other words, to do this little study in Little Rock.
>
> Slide, please.
>
> \[Slide.\]
>
> The sensitivity index was measured in a fasting state. These
> individuals were invited to Little Rock and arrived the night before,
> and had a special hospital room set up for them where they slept the
> night and approached the examination room in a fasting state in the
> morning. And these details here describe the actual clinical procedure
> to do the glucose clamp.
>
> DR. OSEI: Joel, you\'ve got to be very careful if you\'re actually say
> this is euglycemic clamp. This is not euglycemic clamp. This is a
> MINMOD model, the FSIGT. So you cannot equate them. And so you
> really\--what did he do? Did you guys do MINMOD model? This one, or
> you did a clamp.
>
> DR. MICHALEK: We did a MINMOD model, and that\'s described in the
> methods section. So I\'ll make sure that the words are correct, as
> you\'re describing.
>
> DR. OSEI: Because you\'ve got to, you know, get rid of the euglycemic
> clamp, because that\'s not what you did.
>
> Slide.
>
> \[Slide.\]
>
> More detail on the measurement. This was done over a four-hour period,
> with frequently sampled insulin and glucose measurements made, both
> arms; insulin measured by radio-amino assay at the endocrinology
> laboratory at the university.
>
> Slide.
>
> \[Slide.\]
>
> And there\'s the MINMOD software that was used. There are the units.
> And we also measured something called \"acute insulin response to
> glucose,\" which is not shown in these talks. I mean, I\'m only going
> to concentrate on the sensitivity index in this talk. Although we have
> this data available, we have not analyzed it yet.
>
> Slide.
>
> \[Slide.\]
>
> We also have measured cytokines, which are also not available yet, or
> haven\'t been statistically analyzed. They\'re available, but not
> analyzed, so we\'re not going to talk about that in this presentation.
>
> Slide.
>
> \[Slide.\]
>
> Using the Scripps data and data from Little Rock, we computed a
> so-called \"quick Index\" of insulin sensitivity, which is based
> solely on fasting glucose and fasting insulin, which is published in a
> recent issue of the [Journal of Clinical Endocrinology]{.underline},
> first author Katz. We were able to compute this index using data
> collected in Little Rock, and the data collected at Scripps. And
> you\'re going to see that data in this talk.
>
> And the Scripps data, you\'re going to see, is cumulative as of
> January of this year. So as this paper evolves and we get our final
> data sets from SARC and Scripps, we\'re going to update these analyses
> to include everyone that went to Scripps and satisfies the inclusion
> criteria. We\'re restricting to non-diabetic participants.
>
> DR. GOUGH: Joel, I hate to interrupt, but I have a really basic
> question, because I don\'t understand. The measurement is in levels of
> insulin. You did a glucose bolt to the subject, then that sample is
> taken and insulin is measured in blood, over a period.
>
> DR. MICHALEK: Dr. Harrison is a better person to describe the actual
> method than I am.
>
> DR. HARRISON: I defer to Dr. Osei. I know how it\'s done, but I\'m
> just not going to tell you.
>
> DR. OSEI: The way you do it, you take at zero time, it has to be a
> basal sample, the first sample that he did. Then you give IV glucose,
> which\--what\'s that 3.3 \[inaudible\] as a bolus. Then in 20 minutes,
> you give IV \[inaudible\], like you\'ve got to read the insulin now.
> And we have a computer derived computer model that calculates the
> relationship of the insulin and glucose assay you can pull down. And
> that\'s how you derive the sensitivity index. Okay? And this was
> described by Bergman. It\'s called Bergman MINMOD model. So the
> relationship is actually the \[inaudible\] disappearance of glucose
> into the tissue, and that is a reflection of sensitivity.
>
> DR. GOUGH: If a person is diabetic what way does it go compared to a
> normal person?
>
> DR. OSEI: The normal individual will have a high level. If you have
> impaired glucose you will be little, and if you\'re diabetic very,
> very low. So the higher the number, the more sensitive you are.
>
> DR. GOUGH: And that\'s good.
>
> DR. OSEI: That\'s good.
>
> DR. MICHALEK: That\'s important, because the slides you\'re going to
> see will be precisely in that direction. With higher dioxin levels you
> have reduced insulin sensitivity.
>
> DR. STOTO: I\'d like to ask a different question about the design. I
> mean, you\'ve take out the people who have diabetes.
>
> DR. MICHALEK: Yes, we did.
>
> DR. STOTO: And so you\'re looking at people\--you\'re
> comparing\--you\'re looking for insulin sensitivity in people who
> don\'t have diagnosed\--or even symptomatic\--
>
> DR. MICHALEK: That\'s right.
>
> DR. STOTO: \--diabetes.
>
> DR. MICHALEK: There\'s a reason for that.
>
> DR. STOTO: That\'s what I want to know.
>
> DR. MICHALEK: The reason for that\--
>
> DR. OSEI: The best study you can think of to look at, you know, this
> issue. If you have diabetes already, that per se can impact on insulin
> sensitivity, just the hyperglycemia on the cell function. So that\'s
> not the right study to do. This is actually the best study to do\--to
> really take healthy individuals and try to look at one variable, and
> that is exposure to dioxin. So if you can isolate that, you have a
> case to make.
>
> DR. STOTO: So it\'s that these people who have decreased sensitivity
> to insulin will\--are at risk for getting diabetes eventually?
>
> DR. OSEI: Exactly. Actually, if you go to families who don\'t have
> diabetes like he\'s doing, you just have the genetic predisposition to
> diabetes, they will have insulin resistance\--so they have lower
> sensitivity. And these are individuals who are predisposed to becoming
> diabetic in the future.
>
> So having insulin resistance is bad for you; or having lower insulin
> sensitivity is dangerous, actually. So I think it\'s critical.
>
> DR. CAMACHO: Moving into the tissue faster, that\'s better?
>
> DR. OSEI: Yes. Actually, the disposal\--the reason you\'re blood sugar
> goes up, because the blood sugar cannot get into your tissue. So you
> build up almost as a black of transported glucose from the circulation
> into the cells. And that\'s called insulin resistance. So if that
> herbicide causes insulin resistance, they are more prone to become
> diabetic.
>
> DR. STOTO: So we\'re trying to understand the mechanism by which
> dioxin could be a cause of diabetes?
>
> DR. OSEI: Right. One way you can say the mechanism\--this is not at a
> molecular level. This is the global physiologic level. But if you
> really wanted to do.
>
> DR. STOTO: But it could mediate between whether or not they develop or
> not. It\'s why\--it\'s how does this\--
>
> DR. OSEI: Right. Actually, to really know whether this is\--dioxin is
> the way to\--you have a tissue you can really look at the transport of
> glucose in vitro, outside the body, and as the question: does dioxin
> impair the ability to transport glucose, which is something I think
> global about this as you state.
>
> DR. HARRISON: Now that you\'ve got them on the ropes, Kwame, tell them
> about syndrome-X.
>
> \[Laughter.\]
>
> DR. OSEI: Give me time.
>
> DR. HARRISON: No, I\'m serious. Because it\'s relevant.
>
> DR. OSEI: One of the issues that have come up, you know, over the
> years is that the insulin resistance that you have\--whatever the
> cause is, genetic or acquired\--that is associated with other
> cardiovascular risk, such as hyperlipidemia, lipid disorders\--all
> these things\--obesity, and trunk obesity, and more fat can develop.
> And these are what everybody\'s looking at in terms of what we call
> metabolic syndrome, or syndrome X, which are risk factors for
> cardiovascular death.
>
> So these individuals who can demonstrate, that have insulin resistance
> earlier, that may be relevant to the mortality data you showed, in
> terms of atherosclerosis and death.
>
> DR. STOTO: So it makes the whole thing consistent.
>
> DR. OSEI: Exactly. And I think the point that you made, Ron, about
> taking hypertension, taking the diabetes into the cardiovascular
> mortality is relevant, it\'s very critical, because you may be able to
> tease out what is driving the horse at this point.
>
> DR. STILLS: And I think you answered my question, when you were
> talking about atherosclerosis, and one of my question was, you
> know\--in terms of the Ranch Hand population\--you know, people with
> cardiovascular disease, do they have hyperlipidemia, and all the other
> factors\--you know, diabetes.
>
> And so I think that\'s the critical aspect, in terms of writing these
> papers and making an impact, is pull in all the clues together that
> really tell the story.
>
> And I think, you know\--
>
> DR. OSEI: And I hope Joel will take advantage of this because you
> have, you know, well characterized sub-groups to be able to look the
> importance of lipids in relationship to what Bob was talking about in
> insulin resistance.
>
> So you can have lipid disorder, which would predispose them to
> atherosclerosis in the future. Yes.
>
> DR. STILLS: I just want to ask one other question of the committee. Is
> there not an example where people are exposed to like herbicides or
> chemicals where we know that there\'s a link to cardiovascular
> disease? Or this would be the first study that really shows that?
>
> DR. HARRISON: I don\'t know the answer to that.
>
> DR. OSEI: What I know that\--I don\'t really trust about environmental
> factors as a cause of atherosclerosis, by pointing\--by asking what
> specific environmental factor, what are you talking about. It\'s very
> difficult to actually pinpoint exactly what factor in the environment
> that leads to all these things.
>
> And I think this will be one of the best studies to link an
> environmental factor to this. But the variables here, the variable
> that you\'re dealing with is the whole experience of the Ranch
> Hand\--the military itself, or the Air Force itself. That experience
> may be another variable that we need to look into.
>
> DR. STILLS: And I just want to underscore\--the importance of this
> study, Joel, is at NIHS, that\'s one of the questions we\'re asking,
> because we\'re an environmental institute, because we\'re really
> working hard to find examples where you could pull\--you have this
> story to tell. And I think your study is one, you know, if you pull
> out aspects it would be a nice example. And, you know, what type of
> models we use for asking that question: environmental exposure, how
> does it play a role in terms of cardiovascular disease.
>
> So, I mean, I think it\'s a very impressive study, and it\'s something
> that at a Congressional level and at the intergovernmental level, that
> these questions have been asked. So packaged correctly, like the
> committee is recommending, I think, you know, you have a highly
> visible paper.
>
> DR. OSEI: And just to finish on that, you\'re not going to look at
> ARR, which is a mistake at this point. Either you don\'t have the data
> or\--but it\'s so critical\--
>
> DR. MICHALEK: We have the data, if somebody wants to do it.
>
> DR. OSEI: Okay. All right. Because that is an issue.
>
> DR. MICHALEK: To answer your question, the reason why we restricted to
> non-diabetics is that that is the cohort where we found the dose
> response on dioxin. It was among the non-diabetics that we saw
> increased insulin levels.
>
> And so once you look at diabetics, you see no pattern whatsoever
> against dioxin.
>
> DR. STOTO: Because it\'s the diabetes itself.
>
> DR. MICHALEK: Apparently\--it\'s disrupted, yes.
>
> DR. HARRISON: Yes, as Kwame was pointing out, there\'s a good reason
> why you don\'t see a pattern in diabetics.
>
> DR. OSEI: Yes, you know, it\'s a mistake. We used to do this a
> lot\--for 20 years that\'s what we\'ve been doing, looking at
> diabetics. At the end of the day, it\'s very difficult to look at
> secretions and ask specific question what your study\'s about. And
> this particular one, since you want to know why that one agent is
> involved in this. You cannot study a diabetic, because at the end of
> the day you can\'t interpret your data.
>
> DR. HARRISON: Joel?
>
> DR. STOTO: That was very instructive. Thank you, Kwame.
>
> DR. HARRISON: There\'s been such a long, long interruption here of
> your presentation, I wonder if we could pause for a moment and ask if
> there\'s anyone here\--because public statements were scheduled for 11
> o\'clock. I wonder if we could pause for just a moment and ask if
> there is anyone that has a public statement that they would like to
> make and, if so, they would be welcome to do so now. And then we could
> finish with the\--because we\'re not to the results section yet. So
> you\'ve introduced us. We\'re all primed and everything. This is a
> nice place to make a cut, and have the public statements on time,
> which will satisfy lots of people.
>
> **Call for Public Oral Presentations**
>
> DR. HARRISON: Public statements. Public statements. Public statements.
>
> \[No response.\]
>
> Going once.
>
> Be it known that public statements were scheduled for 11:00. We\'ve
> requested public statements at five minutes after 11:00. There\'s no
> one present to make one. If it turns out that someone shows up at an
> odd time, if it\'s possible to make provision for that we\'ll do so.
> But, otherwise\--carry on, Joel.
>
> DR. MICHALEK: I\'ll just back up a few slides. I missed the point that
> I want to show you\--that these measurements were made between
> December 199 and March 2001\--at Little Rock.
>
> Demographic summary of the 29 matched pairs\--you see a very good
> concordance, of course, because of the matching, on everything except
> dioxin. And there you see the 45 parts per trillion in the Ranch Hand
> cohort, among those 29, versus 3.6 median in the 29 comparisons. We
> have Ranch Handers with a lot of dioxin in their bodies are being
> matched to comparisons.
>
> Slide, please.
>
> \[Slide.\]
>
> And this is the corresponding contrast of demographics on the
> individuals that were available to us from the Scripps data as of
> January of this year to be used in our Quick Index.
>
> And we see comparability across the board on these measurements,
> except dioxin, of course, where the Ranch Hand\'s are increased.
>
> Next slide, please.
>
> \[Slide.\]
>
> And here is the first cut analysis, where we found a mean sensitivity
> index among the 29 Ranch Handers is decreased\--in other words, in the
> adverse direction\--relative to the 29 comparisons, but did not reach
> statistical significance, either in original units or in log units.
> But in both analyses, the Ranch Hand experience is in the detrimental
> direction.
>
> Slide.
>
> \[Slide.\]
>
> Now, we\'re going to march through a series of analyses to describe to
> you the patterns within each cohort which are statistically
> significant.
>
> In the Model 2 analysis, we\'re simply taking all 58 individuals and
> lumping them all together, and asking: is there a relation between
> dioxin and insulin sensitivity, and does it reach significance? And
> the answer is no. It\'s in the detrimental direction\--insulin
> sensitivity decreases with dioxin. It\'s a negative slope, but did not
> reach significance.
>
> And the numbers on this slide are unadjusted for covariance. The
> numbers in the footnotes are\--the point being that whether we adjust
> or don\'t adjust, we find the same results.
>
> Over here we have what we call Model 3, where we accommodate a
> regression line within each cohort, but with different intercepts, and
> we find a common slope, which is the detrimental direction, and it
> does reach significance within each cohort. But we have significantly
> different intercepts. So what I have to say is that when we do the
> pair t-test, we find no significance. However, when we look within
> each of the 29 components of the matched pairs, we see significant and
> detrimental results relative to dioxin.
>
> Slide, please.
>
> \[Slide.\]
>
> Parallel to that, using the Scripps data derived from very current
> information from right here at Scripps clinic, we see the same pattern
> with an overall decrease in insulin sensitivity among non-diabetics
> who were at the Scripps clinic. Using the Quick Index, in all
> non-diabetics combined, and yet also within each cohort, within the
> comparisons and he Ranch Hands, we see an even stronger detrimental
> slope of dioxin versus the Quick Index, with differing intercepts.
>
> Slide.
>
> \[Slide.\]
>
> And all of that\--those words and those slides were unadjusted, and
> the footnotes show that the results remain the same\--with adjustment
> for covariance.
>
> Here is the picture\--and to back out the number and p-values I just
> described on the 29 matched pairs. This is the Model 2 where we lump
> all of the 58 individuals together and ask is there a relation between
> dioxin level and insulin sensitivity in log units, and we see that
> lack of significance on the slope. It\'s in the negative direction,
> but it\'s not significant. And yet when we look within the 29
> comparisons, and within the 29 Ranch Handers, we see significant
> decrease in insulin sensitivity within increased dioxin within both
> cohorts.
>
> And this vertical line here is used to remind you that of the 29
> pairs, we had comparisons less than 10 ppt, and 29 Ranch Handers
> greater than 10 ppt. And so we have this built in dichotomy to the
> Little Rock study where we had comparisons with low levels, and Ranch
> Hand veterans with high levels.
>
> DR. STOTO: Do I understand this correctly when I say that this
> suggests that dioxin alone does not explain the difference in insulin
> sensitivity? There actually is a difference between\--
>
> DR. MICHALEK: To accommodate the cohorts, yes. Within each cohort you
> see a significant detrimental association between dioxin in insulin
> sensitivity.
>
> DR. STOTO: Well, our focus is on the difference between the cohorts.
>
> DR. MICHALEK: There was also a difference\--well, there was no
> difference between the cohorts\--significant difference between mean
> insulin sensitivity and log units. That\'s the paired t-test. And yet,
> when you look within the cohorts, you see these significant dynamics
> going on within each cohort.
>
> DR. STOTO: And why would that be\--what does that mean?
>
> DR. MICHALEK: I have reasons for that. It comes in the subsequent
> slides.
>
> \[Laughter.\]
>
> DR. HARRISON: Nice save.
>
> DR. MICHALEK: You think just like me. That\'s the problem.
>
> Let\'s back up one more slide. I want to just emphasize a point here.
>
> DR. HARRISON: Joel, I have a question.
>
> DR. MICHALEK: Yes.
>
> DR. HARRISON: It may be Mike\'s question, but I\'ve never understood
> Mike\'s questions, so\--
>
> \[Laughter.\]
>
> If you look at the comparisons at a level of 10, the slope give an
> insulin\--whatever the vertical axis is\--
>
> DR. MICHALEK: The vertical is log insensitivity.
>
> DR. HARRISON: \--is like .5.
>
> DR. MICHALEK: Yes.
>
> DR. HARRISON: And then you go over to the Ranch Handers, and at 20,
> their insulin sensitivity\--
>
> DR. MICHALEK: Is increased.
>
> DR. HARRISON: Right. Is that what you\'re\--is that\--was that Mike\'s
> question?
>
> DR. MICHALEK: Yes.
>
> DR. HARRISON: Okay. And you\'ve got a reason for that.
>
> DR. MICHALEK: We think we understand that.
>
> DR. HARRISON: Okay.
>
> DR. MICHALEK: Want to hear the bottom line? The punch line? I can tell
> you now.
>
> DR. HARRISON: Okay.
>
> DR. MICHALEK: It goes like this. Even though we have matched, to the
> bet of our ability, based on all those factors that we though and know
> are important, such as family history, we cannot match for other
> things.
>
> As you\'ll see in other slides\--not just in this talk, but on the
> hypertension talk\--what\'s happening is that comparison veterans with
> high dioxin, for a comparison the high dioxin is somewhere between 5
> and 10 ppt. Those individuals are older and heavier than their
> comparisons with low dioxin levels. What\'s happening is that these
> comparisons are getting dioxin from the same sources in the United
> States that we get it from: from out diet, from pollution, from air
> pollution, from smoke from burning trash, from Styrofoam cups\--from
> all kinds of sources, we get dioxin. And they\'re building up a body
> burden as they get older. These individuals in the higher range of
> dioxin in the comparison group, between 5 and 10, are heavier, and
> therefore they are\--because they\'re heavier, they have higher BMIs
> and higher body fats, they are at risk of having less insulin
> sensitivity than the individuals who are younger and have low body
> fats, because BMI is adversely related to insulin sensitivity in both
> cohorts.
>
> DR. HARRISON: But you matched for BMI.
>
> DR. MICHALEK: I know we did. Our statistical models are failing us.
> Our statistical models most of the time work for us. But this is an
> example where our statistical modeling has reached the limit\--
>
> DR. GOUGH: A far more trivial recommendation\--which\--and I\'ll
> express it trivially, because I can\'t\--but, we have to send the
> comparisons\--the comparisons and the Ranch Hands both have the same
> background exposure. They live in the United States. I mean, that\'s
> what Joel is talking about right now. And it seems to me that what
> these data say is that a person who is likely to get diabetes, or
> likely to become insulin insensitive, for some reason is more likely
> to retain dioxin in his body than the other person. And I don\'t know
> how to explain that.
>
> DR. HARRISON: But the mechanism of that should be BMI, because dioxin
> is retained in the fatty tissue.
>
> DR. STOTO: Yes\--and they don\'t.
>
> DR. HARRISON: No\--and it\'s not. Because Joel is putting the
> comparison\--is saying that the comparisons have higher BMIs than the
> Ranch Handers.
>
> DR. GOUGH: No, he\'s not.
>
> DR. HARRISON: That\'s what he\'s just saying.
>
> DR. MICHALEK: There are many factors going on at the same time.
>
> DR. GOUGH: Let me get this straight, Joel. Didn\'t you say that the
> comparisons who have the decreased sensitivities\--
>
> DR. MICHALEK: Right.
>
> DR. GOUGH: \--are heavier and older than the comparisons, who don\'t
> have it. Isn\'t that also true of the Ranch Hands?
>
> DR. OSEI: But the BMI is only one index. It doesn\'t give you how much
> fat you have in your body. So as you get older, and you accumulate
> more fat, dioxin accumulates in fat. You can have the same BMI, but
> your total\--
>
> DR. HARRISON: Higher percent\--
>
> DR. OSEI: \--you have higher dioxin, because you\'re accumulating that
> in the fat.
>
> But the point that is missing here is the fat distribution. The BMI
> just gives you the overall. If you have more fat in your belly, you
> have trunk obesity, you are more likely going to have more insulin
> resistence.
>
> But do the numbers show\--we can do this in so many ways, you can
> measure the total body fat content, which would give you some of the
> answers that you\'re talking about.
>
> DR. MICHALEK: We have measured all the BMI.
>
> DR. OSEI: Yes, one you measure the BMI, or you can actually, in a real
> substance kind of way, do the CAT scan of their belly, measure how
> much fat is in the belly. So if you\'re on the match, which you did,
> the difference is coming from what you\'re talking about\--that is
> this more distribution of fat content in the body. And you need to
> have another way of looking at that. And it can be done in so many
> ways.
>
> DR. GOUGH: But to return to my comment\--but the same argument you
> make to explain the decreased sensitivity in comparisons could be made
> for the Ranch Hands.
>
> DR. MICHALEK: Yes, sir. I\'m not finished with my argument.
>
> DR. GOUGH: So it\'s not an explanation.
>
> DR. MICHALEK: I\'m not finished yet.
>
> DR. GOUGH: Sorry.
>
> DR. MICHALEK: There\'s more to show.
>
> DR. HARRISON: Let\'s wait until Joel is fully committed before we jump
> on him again.
>
> We\'re having fun, though, Joel.
>
> DR. MICHALEK: All right.
>
> Next slide.
>
> \[Slide.\]
>
> In this, we are looking simply, just to slow you how the log of the SI
> relates to the QUICKI index. We have strong correlations between the
> SI, as measured by Dr. Kern, and the QUICKI measurement derived from
> the Katz formula. Here\'s the\--among the\--there\'s 58 individuals in
> the matched pair study. Among those 58, using measurements made at
> Little Rock, and correlation between the log SI and the QUICKI\'s is
> very high. It\'s .71.
>
> If you ask what is the relation between low SI measured at Little Rock
> and the QUICKI measured among those who went to Scripps clinic, of the
> 58, 37 were non-diabetic and available and had measurements from
> Scripps clinic at the time this was written, the correlation was .51.
> Remember that the measurements at Little Rock were made between
> December 1999 and March 2001, and the measurements at Scripps were
> made more recently, and so there\'s a time factor involved here.
>
> DR. OSEI: And what you did was the same insulin assay\--
>
> DR. MICHALEK: Yes.
>
> DR. OSEI: \--because if it was different you\'re going to have
> different results.
>
> DR. MICHALEK: Yes. Here are the measurements of fasting glucose and
> insulin that were made at Scripps, and over here they were made on
> site at Little Rock.
>
> DR. OSEI: That\'s a problem.
>
> DR. MICHALEK: That\'s right.
>
> DR. OSEI: Okay.
>
> DR. MICHALEK: That would explain\--
>
> DR. OSEI: Okay. So it was a different assay\--
>
> DR. MICHALEK: Correct\--different time points, yes. But they\'re in
> the same direction and highly significant.
>
> And here is the BMI when they were in Viet Nam is adversely related to
> the insulin sensitivity, as you would expect, in heavier individuals.
> But it doesn\'t reach significance.
>
> Among the 37 who showed up at Scripps, using measurements made here at
> Scripps clinic measuring BMI, there is a negative and adverse relation
> between BMI and the log of the DR. STILLS: measured at Little
> Rock\--which is all in the direction of adversity. Increased body mass
> index\--
>
> DR. OSEI: When was the BMI\--when they went in?
>
> DR. MICHALEK: BMI measured in 2-R was calculated from the height and
> weight that they had when they were in Viet Nam during the war.
>
> DR. OSEI: And they were much younger.
>
> DR. MICHALEK: Yes, they were.
>
> DR. OSEI: Okay. So the variable\--
>
> DR. MICHALEK: That\'s measured\--yeah\--
>
> DR. OSEI: \--as you get older you put on more weight\--
>
> DR. MICHALEK: Right.
>
> DR. OSEI: \--you are more sedentary. They\'re back home. So what
> you\'re looking out, maybe you\'re fleshing out not only BMI but the
> lifestyle\--
>
> DR. MICHALEK: Yes.
>
> DR. OSEI: \--for coming back.
>
> DR. MICHALEK: All kinds of intervening variables.
>
> That BMI was made in 1967. This BMI was made in the year 2002.
>
> DR. HARRISON: Another way of saying that is that the variation between
> the low BMI\--the distance between the low BMI and the high BMI in
> Viet Nam would have been shorter than the distance between the low BMI
> and high BMI now\--
>
> DR. MICHALEK: Yes.
>
> DR. HARRISON: \--because you had to meet certain physical fitness
> standards.
>
> DR. MICHALEK: Yes. All of that\'s true.
>
> DR. HARRISON: And accordingly, you\'d have more difficulty making a
> correlation.
>
> DR. MICHALEK: And in all of our statistical models we accommodate not
> just the BMI in Viet Nam but the change in BMI from Viet Nam to the
> present, as well as the BMI in the present. The change itself is
> important\--and detrimental. People who gained weight are at increased
> risk of insulin resistance and diabetes.
>
> DR. HARRISON: Kwame, would you have been happy with a waist
> measurement as an assessment of visceral fat?
>
> DR. OSEI: Yes. You know, if you don\'t have the money, you can do it
> in a very cheap way by just looking at\--taking tape and measure the
> waist circumference. And that\'s very easy to do. You can do the waist
> hip ratio or so, and try to help you at. But if you have the money,
> you have to do a CAT scan or MRI.
>
> DR. MICHALEK: We did the waist. Waist measurements were done as a
> current physical, but not an MRI.
>
> DR. OSEI: Did you have a waist circumference?
>
> DR. MICHALEK: Yes there were. They were done. It\'s not been used yet,
> but could be used.
>
> DR. OSEI: It will help you out, you know, to really resolve some of
> the issues.
>
> DR. MICHALEK: Okay.
>
> And here is the corresponding pattern, as I showed you in previous
> slides\--there\'s a parallel pattern of the QUICKI using Scripps data
> that we saw in the log insulin sensitivity data measurement at
> Scripps. We have a weak detrimental trend overall, but stronger trends
> within both groups in the detrimental direction of dioxin versus the
> insulin sensitivity measured using the QUICKI index.
>
> Here, again is the definition of the QUICKI index. In this so-called
> statistical Model 4, we have simply fit a separate regression line
> within each cohort. And here I isolated comparisons with less than 10
> ppt and Ranch Handers with greater than 10 ppt who went to Scripps and
> were non-diabetic and satisfied all the conditions of this particular
> study. I\'m trying to imitate, in other words, the Little Rock
> experience, using the Scripps experience. In other words, these are
> not all comparisons, only those less than 10. These are not all Ranch
> Handers, only those Ranch Handers greater than 10. So I, the best I
> can, imitate Little Rock using Scripps data. And we see a parallel
> pattern.
>
> Slide.
>
> \[Slide.\]
>
> DR. STOTO: So the fact that there\'s a greater slope on the left in
> the comparison\--
>
> DR. MICHALEK: Yes.
>
> DR. STOTO: \--could that be because they\'re more sensitive\--
>
> DR. MICHALEK: To dioxin.
>
> DR. STOTO: \--dioxin being retained because of their fat.
>
> DR. MICHALEK: Possibly.
>
> DR. STOTO: The guy\'s in the Ranch Hand group are really even\--direct
> affect. That\'s the hypothesis\--
>
> DR. MICHALEK: That is a hypothesis, yes.
>
> Another hypothesis that we\'ve entertained is that these Ranch Handers
> down here who are at the low end of the Ranch Hand scale are lucky
> guys. They were able to eliminate dioxin more rapidly than other Ranch
> Handers, therefore they\'re healthier. They could eliminate not just
> dioxins, but PCBs and feurans and other organic pollutants from their
> bodies. And so that would maybe accommodate some of the differences we
> see in intercepts.
>
> DR. OSEI: But you are using serum levels, and you may have an
> opportunity to look at tissue levels, which would be actually the key.
> So the comparisons on the left side, you may have a lower
> level\--serum level\--but it\'s all in the fat. If it\'s already there
> you\'re going to see the same result. So the opportunity\--you have an
> opportunity to look at the tissue levels, and that may actually tell
> you the difference.
>
> DR. MICHALEK: Yes. That\'s been done already. That was done by CDC.
>
> DR. OSEI: The tissue levels?
>
> DR. MICHALEK: Yes.
>
> DR. HARRISON: I\'d argue that the dioxin that\'s in the fat is
> biologically inactive.
>
> DR. OSEI: I don\'t know that.
>
> DR. HARRISON: That the dioxin that\'s in the circulation, that\'s able
> to go to other tissues and interact with dioxin receptor would be the
> biologically relevant measurement.
>
> DR. OSEI: But maybe\--
>
> DR. HARRISON: That the fat may retain the dioxin longer, and hence
> give you a longer dioxin effect, but it\'s still mediated through
> plasma dioxin levels.
>
> DR. OSEI: Yes, but, you know, separation of a hormone would have no
> meaning unless it acts on the tissue at some receptor enzymatic
> pathway.
>
> DR. HARRISON: Exactly.
>
> DR. OSEI: So that if you are accumulating that longer, you\'re more
> likely going to have the tissue fat at the muscle or the fat longer
> for it to have more biologically negative effect than just the
> circulation.
>
> So it may not be a direct relationship between the serum and the
> tissue. And I think you maybe hit on something interesting if you have
> the numbers.
>
> DR. HARRISON: Well, but unless you\'re arguing that fat is a dioxin
> target tissue\--
>
> DR. OSEI: Or muscle.
>
> DR. HARRISON: You take another hormone, do an injection with
> cortisone, and what you\'ll find very shortly is that a certain amount
> of cortisone may be retained in fat, but that\'s not\--the cortisol
> effects on the liver and all the rest are mediated through the
> cortisol that\'s circulating and able to enter muscle and liver cells.
>
> DR. STOTO: Have you been showing a strong correlation between dioxin
> and fat\--
>
> DR. HARRISON: What?
>
> DR. STOTO: A strong correlation between dioxin and fat\--in the serum.
> So that it could be a reservoir of the stuff comes and goes.
>
> DR. HARRISON: Well, that\'s my point though, is that Kwame\'s arguing
> that a low serum level is not\--may not be the right thing to look at
> because it may all be in fat. And I\'m saying that the only reason
> that fat matters\--yes, I\'m saying the only reason that fat matters
> is because it provides dioxin to the circulation to go to other
> tissues and cause a dioxin effect.
>
> DR. OSEI: It may be that the same scenario, the dioxin also goes to
> the muscle. And this \[off mike\] muscle mass.
>
> So, if it\'s a poison used for whatever reason used in Viet
> Nam\--dioxin they could have a low insulin sensitivity, even though
> your levels may not be very dramatic.
>
> DR. MICHALEK: Well, relevant to your point, the CDC did the study of
> 50 individuals and measured dioxin in serum and in adipose tissue, and
> their best estimate on the partitioning coefficient was 1.0. In other
> words, there is no difference between the method in adipose as opposed
> to the method and the basis in serum in 50 individuals from Missouri.
> And that was published in 1989 or 1990, I believe.
>
> DR. STOTO: The thing that strikes me here is that you\'ve left off the
> comparisons with dioxin greater than 10.
>
> DR. MICHALEK: Which number only about 10 people.
>
> DR. STOTO: Oh, is that right?
>
> DR. MICHALEK: Yes.
>
> DR. STOTO: Okay, and then similarly, the Ranch Handers with less than
> 10.
>
> DR. MICHALEK: I lopped off Ranch Handers with less than 10. However,
> in the footnotes, if you include all Ranch Handers, including those
> less than 10, you see the same pattern. You see a negative and
> detrimental slope. I only did this to try to imitate Little Rock.
>
> Slide.
>
> \[Slide.\]
>
> Here I\'m looking at correlations between the QUICKI and these
> covariates at the Scripps examination. And you see negative and
> detrimental associations between insulin sensitivity, various measures
> of BMI and age\--and BMI but not age. Actually the correlation is
> positive with age, but negative with BMI.
>
> These are the non-diabetes who were extracted from the Scripps data to
> try to imitate Little Rock.
>
> Slide.
>
> \[Slide.\]
>
> However, we see a different pattern when we relate dioxin to BMI,
> using that same dichotomy of comparisons less than 10, Ranch Hands
> greater than 10. We see a positive and significant slope among
> comparisons\--there it is right there. But in the Ranch Hand cohort we
> see nothing. We see a relatively attenuated slope. However these are
> Ranch Handers greater than 10, but when we include all the Ranch
> Handers, then the slope becomes positive.
>
> So we see this as kind of an interference of the exposures in Viet Nam
> that are sort of disrupting the natural relation between dioxin and
> BMI that we see in the comparison group is being disrupted by what
> happened to the Ranch Hand veterans in Viet Nam.
>
> The Ranch Hand veterans in Viet Nam experienced a slug of dioxin over
> a one-year period. The comparisons received their body burden over
> many years in the United States and during their tours in Southeast
> Asia. So there\'s a different exposure experience in the two cohorts.
>
> Slide.
>
> \[Slide.\]
>
> Well, there are many caveats associated with the dioxin measurement,
> as you\'ve already pointed out. The dioxin half-life is associated
> with BMI. Heavier individuals have a longer half-life. Heavier
> individuals have higher dioxin levels for that reason. They retain it
> longer than thin individuals do. There\'s perhaps\--and we suspect
> very strongly\--that there are differences between individuals and how
> they eliminate dioxin. And so to avoid and to address those caveats,
> we re-analyzed using another measure which is free of many of those
> caveats.
>
> We interviewed all enlisted Ranch Hand veterans by questionnaire in
> 1989, after having received the first dioxin levels from Scripps, we
> sent them a questionnaire asking them what they did on the job in Viet
> Nam. Did you get in the tanks? Did you ever use herbicide as a hand
> cleaner? Did you get it on your skin, did you get it on your clothing?
>
> We asked them all of this before we had told them their dioxin levels,
> so they were blinded to their dioxin levels when they responded to our
> questionnaire. And we simply counted up the number of days of reported
> skin exposure, and this published later showed a significant and
> detrimental association between skin exposure on the questionnaire and
> subsequent dioxin measurements made by CDC. This was the first direct
> validation of the dioxin measurement in a Viet Nam veteran study. That
> was published in the [Journal of Exposure Analysis and Environmental
> Epidemiology]{.underline}
>
> So we have this exposure index, and we\'re now going to apply the
> exposure index, based on this so-called enlisted questionnaire, to ask
> whether that index is related to any of the things we see in this
> study. And we asked, in particular, does dioxin relate to the index
> and body mass index, for separate intercepts for enlisted flyers and
> enlisted ground crew. And we\'re going to propose an argument that may
> explain some of the patterns we see in these data.
>
> Slide.
>
> \[Slide.\]
>
> DR. HARRISON: Joel, the questioner also did not know the dioxin level,
> right?
>
> DR. MICHALEK: The questioner was me. I wrote the questionnaire. And,
> of course, I wasn\'t study individual dioxin levels as I wrote the
> questionnaire to distribute to the veterans.
>
> DR. HARRISON: You said the veteran didn\'t know what his dioxin level
> was. Did the person questioning the veteran\--
>
> DR. MICHALEK: These were not in-person questionnaires. They were
> mailed out to the individuals.
>
> DR. HARRISON: Okay. \|Okay.
>
> DR. MICHALEK: What we\'ve got here, based on the previous quadratic
> model that you just saw shown in the previous slide, we\'re able
> to\--all of the coefficients of which are statistically
> significant\--we were able to predict a curve of constant dioxin as a
> function of body mass index and skin exposure as derived from that
> mail-out questionnaire.
>
> The point here is an individual\--this is a curve of constant dioxin.
> Everyone on this curve has 28 ppt. A person could have 28 ppt because
> he had a lot of skin exposure but a low BMI, or he can have 28 ppt
> because he had very little exposure and a high BMI, which is
> consistent with the idea that individuals can absorb more dioxin if
> they have more body fat\--even though they had less skin exposure. And
> individual with high skin exposure can have an elevated ppt for
> dioxin, even though they have reduced body mass index.
>
> Slide.
>
> \[Slide.\]
>
> That slide, together with the patterns you saw in previous slides, and
> together with known differences of comparisons in Ranch Hands by
> dioxin level on body mass index may explain why we have the parallel
> lines but different intercepts for comparisons with values near the
> high end of their distribution have more insulin resistance than the
> Ranch Hand veterans with low dioxin levels, because the Ranch Handers
> with low dioxin levels consistent with the slide I just showed you are
> going to have lower BMI than the comparisons with high dioxin levels.
> And BMI relates adversely to insulin sensitivity.
>
> DR. STOTO: That\'s comparing models 2 and 3.
>
> DR. MICHALEK: Yes.
>
> DR. STOTO: Was 4 demonstrably better than 3?
>
> DR. MICHALEK: Only with regard to BMI, where we had different slopes;
> when the thing became cockeyed. But the other\--against the
> sensitivity we have parallel slopes. So that was why\--the only reason
> we introduced model 4 was to accommodate the different patterns on BMI
> versus dioxin, as sort of a second- or third-order effect.
>
> We don\'t have a manuscript ready for use today at this meeting, but
> we will have one to be distributed to the committee very soon. We gave
> you our manuscript on cancer, and this manuscript isn\'t ready yet for
> you to see, but it\'s very close.
>
> Yes?
>
> DR. GOUGH: Joel, could you go\--I\'m not\--this is a question about my
> understanding.
>
> Why does this plot\--the plot of the 28 ppt\--the ones\--could you\--
>
> DR. MICHALEK: The point here is that there\'s a concept going on here
> that this plot is approximating. And that is there\'s two ways you
> could have a high dioxin. You could have high dioxin because you had a
> lot of exposure but low BMI. Or you could have high dioxin because you
> had a relatively low exposure but a high BMI. That\'s what the plot is
> telling us.
>
> DR. GOUGH: Okay.
>
> DR. MICHALEK: And that would explain, perhaps, the difference in the
> intercepts on those two plots.
>
> DR. GOUGH: Okay. What was the correlation between the reported skin
> exposures and the measured dioxin levels.
>
> DR. MICHALEK: That reached statistical significance, and it\'s
> published\--
>
> DR. GOUGH: It was statistically significant? Okay.
>
> DR. STOTO: Why is it that the curve has that shape? I mean, I would
> guess that a straight line would fit equally as well.
>
> DR. MICHALEK: Well, because\--back up a slide.
>
> DR. HARRISON: I would, too.
>
> DR. MICHALEK: We had a significant quadratic contribution to the model
> here.\\
>
> DR. STOTO: Oh, okay. So you tested it, and\--
>
> DR. MICHALEK: Yes. It\'s more than linear\--perhaps hyperbolic.
>
> DR. OSEI: \[Off mike.\]
>
> DR. MICHALEK: Let\'s back up a slide. This is on BMI. BMI is already
> normally distributed. On the dependant variable\--sorry, I did not put
> that in the slide, whether that\'s log dioxin or dioxin.
>
> DR. HARRISON: You said BMI is normally distributed?
>
> DR. MICHALEK: The histogram of BMI is relatively bell-shaped relative
> to dioxin, for example, which is highly skewed and has a logmoral
> distribution\--yes.
>
> DR. HARRISON: But it doesn\'t go to zero.
>
> DR. MICHALEK: No, it\'s bell-shaped, though, and the minimum is about
> 17, or maybe 12. And the maximum\'s about 50.
>
> DR. HARRISON: You just made me think of something. You said that the
> CDC did a study of tissue and serum\--
>
> DR. MICHALEK: Yes, I did.
>
> DR. HARRISON: And found that the partition coefficient was 1.
>
> DR. MICHALEK: 1.0\--yes.
>
> DR. HARRISON: Which means that you would expect, if you did a
> partition coefficient using liquid\--you know, a typical chemistry
> experiment, that dioxin is as soluble in water as it is in lipid.
>
> DR. MICHALEK: In this case it\'s as soluble in lipid as it is in
> adipose.
>
> DR. HARRISON: And the lipid fraction of the blood\--that\'s what it\'s
> measured in.
>
> DR. MICHALEK: That\'s right.
>
> DR. HARRISON: Lipid fraction of the blood.
>
> DR. MICHALEK: Fraction of the blood, as opposed to adipose itself.
> They measured it in adipose tissue and they measured it in the lipid
> blood.
>
> DR. HARRISON: What I\'m trying to figure out is if the partition was
> 1, and dioxin is excreted by the kidney or metabolized by liver\--more
> likely\--why it has such a prolonged half life? Because it sounds like
> it doesn\'t have any trouble getting out of fat. And once it\'s in the
> circulation, then why isn\'t it metabolized.
>
> It doesn\'t say it\'s in fat\--it\'s in the fat fraction. It\'s in the
> fat fraction the same way as cholesterol, the same way that steroid
> hormones are in the fat fraction. It doesn\'t say that it\'s bound to
> fat any more than cortisol is bound to fat when it\'s in the
> circulation.
>
> DR. MICHALEK: I think you\'ll find the explanation in the first
> National Academy book.
>
> DR. HARRISON: First what?
>
> DR. MICHALEK: The first NAS book explains in great detail\--I
> think\--the concept you\'re trying to describe.
>
> DR. HARRISON: Okay.
>
> DR. MICHALEK: Why the half-life is so long.
>
> DR. HARRISON: I didn\'t mean to prolong this discussion.
>
> DR. OSEI: The problem is it\'s accumulated in the fat, just like
> vitamin D, so that you have to leak it out over a long-term period.
> So\--it\'s lipophilic, therefore it doesn\'t come out. So it just
> leaks out over a long-term period.
>
> DR. MICHALEK:
>
> Slide. Slide. Slide.
>
> \[Slide.\]
>
> Okay. So as you\'ll see\--it\'s not as graphically displayed here as
> I\'d like\--but in the hypertension talk you\'ll see that comparisons
> with high dioxin levels are older and heavier than the Ranch Handers
> with low dioxin levels. And that could explain the difference in the
> intercept. I guess what we\'d like to see is a single line coming down
> in the adverse direction, where the comparisons are here and the Ranch
> Handers are here, and you have this nice clean dose response. We
> don\'t have that. We have this. And there are many intervening reasons
> why that could be the case. And we\'ve tried to touch on some of those
> here today.
>
> One would be differences in BMI and age and maybe the rate at which
> people eliminate dioxins from their body.
>
> Slide, please.
>
> \[Slide.\]
>
> DR. OSEI: Or you may have a\--it may be a, you know, threshold effect
> that at some point, some dose, it doesn\'t matter. What you need is
> just a small amount of dioxin in your body to do what it\'s supposed
> to do on insulin sensitivity. If you go beyond that, you\'re flat
> because you already maxed out on what dioxin can do. So you will have
> to transform your curves again to see where the threshold\--what is
> the critical dioxin level that gives you the maximum effect of the
> EP-50 that can help you separate that.
>
> DR. MICHALEK: I made a note of your remarks, and we\'ll attempt to do
> that.
>
> And the concepts I just described are described by the plots we\'ve
> just shown.
>
> Slide.
>
> \[Slide.\]
>
> So, finally, we have a relation between BMI\--not finally\--we also
> have a relation to BMI and dioxin that may have been disrupted by
> exposures in Viet Nam, which is a statement I already made, which is
> supported by the plot.
>
> Slide.
>
> \[Slide.\]
>
> So, in conclusion, we have no overall significant mean difference on
> the 29 Ranch Hand versus the comparisons, however we see adverse
> trends within both cohorts, supported by data from Scripps, that
> suggests that dioxin is adversely related to insulin sensitivity in
> both cohorts among non-diabetics.
>
> Slide.
>
> \[Slide.\]
>
> And there is the Katz reference that will give you the QUICK Index,
> published in 2000.
>
> Thank you very much.
>
> DR. STOTO: So, let\'s see\--I think this may be consistent with what
> Kwame was saying\--is that you had a negative slope in both groups.
>
> DR. MICHALEK: Yes.
>
> DR. STOTO: In the Ranch Hand group the slope is primarily due to
> dioxin affecting the insulin sensitivity.
>
> DR. MICHALEK: Yes.
>
> DR. STOTO: In the other group, you had that\--you may not have that
> going on because you\'re below the threshold, but you have the
> opposite causal relationship going on, in that the\--
>
> DR. MICHALEK: BMI.
>
> DR. STOTO: \--that the BMI is affecting how much dioxin is measured.
>
> DR. MICHALEK: It could be that there\'s a reverse causation going on.
>
> DR. STOTO: In the lower\--in the comparison group.
>
> DR. MICHALEK: Yes. The hypothesis there is that people who have
> dioxins in their bodies have triggered a mechanism to put on fat to
> thin it out. For example, if I gave you a hydrophilic poison, you tend
> to end up drinking a lot of water to try to thin it out, and urinate
> it out. Individuals with a chronic body burden\--this is the
> hypothesis.
>
> DR. STOTO: But that\'s not what I\'m\--
>
> DR. MICHALEK: But that is a hypothesis that\'s been proposed by
> referees\--tat individuals who have a chronic body burden of dioxin
> tend to put on weight because their body\'s trying to compensate for
> it, it\'s trying to thin it out.
>
> DR. STOTO: Well, I don\'t think you have to go that far.
>
> DR. MICHALEK: Okay.
>
> DR. STOTO: I\'m not saying it\'s not true. But it\'s just that
> the\--we don\'t know how much dioxin people were exposed to when they
> were in Viet Nam.
>
> DR. MICHALEK: Who? The comparisons or the Ranch Hands?
>
> DR. STOTO: Either one.
>
> DR. MICHALEK: Either one\--we don\'t. That\'s right.
>
> DR. STOTO: We only know that they were exposed and how much we
> measured 10 years ago.
>
> DR. MICHALEK: That\'s right\--\'87.
>
> DR. STOTO: And if, in fact, the fat guys would retain more of it\--
>
> DR. MICHALEK: Yes.
>
> DR. STOTO: \--so we expect to see a relationship between BMIs and
> dioxin, just because of the fact that the more fat you are the more
> you retain. And also the heavier guys\--do they have a higher
> insulin\--
>
> DR. MICHALEK: Yes.
>
> DR. STOTO: Lower insulin sensitivity.
>
> DR. MICHALEK: More insulin resistance.
>
> DR. STOTO: Right. So in the left half of the graph you had two things
> going on.
>
> DR. MICHALEK: That\'s right.
>
> DR. STOTO: In the right half of the graph you only have one thing
> going on.
>
> DR. MICHALEK: Primarily dioxin.
>
> DR. STOTO: Right.
>
> DR. MICHALEK: Those are higher levels.
>
> DR. STOTO: And therefore\--
>
> DR. MICHALEK: Somehow, after adjusting for BMI, we still have those
> parallel slopes.
>
> DR. STOTO: But just adjusting for them in a linear way isn\'t enough.
>
> DR. MICHALEK: Right.
>
> DR. STOTO: And this is the same\--
>
> DR. MICHALEK: Perhaps some other model\--
>
> DR. STOTO: And this is the same as a check markers\--people often say
> about check-
>
> DR. MICHALEK: There might be some other statistical model we haven\'t
> considered. And if you could help me with that, I\'d love it. I\'ve
> used all available modeling that we could think of; all available
> covariates.
>
> DR. CAMACHO: Isn\'t what he said that it may be that the dioxin, all
> the evil effects of the dioxin only requires so much. If you get more
> dioxin beyond that, you\'re not going to get that much more of an
> effect. The damage has already been done.
>
> DR. MICHALEK: That\'s called the saturation effect, and that\'s\--
>
> DR. OSEI: Saturation effect\--so you need to do\--if you can look at
> what that saturation point is, because that will help you to go back
> and maybe for insulin sensitivity you may get this to do the work.
>
> DR. MICHALEK: To do an ED-50 you need a binary response, dead or
> alive, all or none. And here we have a continuous insulin response
> among non-diabetics. All of these people are healthy
>
> DR. HARRISON: Those responses max out, Joel.
>
> DR. MICHALEK: That\'s true. They do.
>
> DR. HARRISON: In fact, there are two assumptions that may b e a
> problem here. The first assumption is that there\'s no lower limit to
> dioxin action.
>
> DR. MICHALEK: There might be.
>
> DR. HARRISON: And, in effect, if it\'s a receptor mediated mechanism,
> the way it seems to be\--there\'s a dioxin receptor and all this sort
> of business\--then there is a concentration of dioxin under which the
> organism doesn\'t see anything. There\'s no effect.
>
> And the same thing that Kwame is saying is true at the upper end; and
> that is that there is a concentration of dioxin that is 10 times the
> disassociation constant for dioxin receptor interactions, where
> you\'re at the end of this asyntopic curve, and there\'s no more
> measurable effect\--in fact, there\'s no more measurable effect way
> before then for a biological system like this.
>
> So it may be that there\'s two problems. One is the assumption of
> action all the way down to the very lowest dioxin levels. That\'s not
> true.
>
> DR. MICHALEK: At the highest end, too.
>
> DR. HARRISON: And the other is that it just keeps going on and on.
> That\'s not true either.
>
> DR. MICHALEK: Right. We agree. And some of those words are already in
> the discussion of the paper.
>
> DR. HARRISON: Okay. So rectilinear hyperbola.
>
> DR. OSEI: The dioxin that we talking about with insulin sensitivity,
> insulin sensitivity is also a function of\--okay, you can\'t just look
> at the SI alone. And you say\--trying to isolate SI. How your body
> responds to insulin sensitivity on organism function because of a high
> insulin sensitivity log. So you have to really look at that
> combination. And what we have done, just to look at the insulin
> sensitivity\--for you take the insulin\--by pancreatic function and
> sensitivity, just like we did in the QUICKI, and do a model of that,
> which would really help you to define, is this person really insulin
> sensitive, or is not insulin sensitive. What we need is insulin levels
> in this. The data you showed us is just the SI. We need an insulin
> level\--the true insulin level in order to make any decision about SI.
>
> DR. HARRISON: Okay. Any other comments?
>
> Mike?
>
> DR. STOTO: Regarding these models, 1, 2, 3 and 4\--there\'s another
> alternative, one that it would make sense to think about. And that is
> to fit two straight lines that are constrained to meet\--
>
> DR. MICHALEK: Intercept.
>
> DR. STOTO: \--at\--not the same intercept, but at the dioxin level at
> 10\--
>
> DR. HARRISON: Constrain the continuum from low to high?
>
> DR. STOTO: Yes. You could have different slopes, but they\'d be
> constrained to be continuous.
>
> Or quadratic, or something like that.
>
> DR. MICHALEK: But non-linear.
>
> DR. STOTO: Yes.
>
> DR. MICHALEK: Sure. We could try that.
>
> DR. STOTO: It seems like that\'s a little bit easier to think about
> conceptually than having these two lines.
>
> DR. MICHALEK: Okay.
>
> DR. HARRISON: Okay. Anything else?
>
> Thank you, sir.
>
> DR. MICHALEK: Thank you.
>
> DR. HARRISON: A couple of things. How long is it going to take us from
> the time we walk out the front door to the time we walk into wherever
> we\'re supposed to be at Scripps\--how long is that going to take?
>
> LT. COL. ROBINSON: Five, 10 minutes. Very close.
>
> DR. HARRISON: So if we allowed 15 minutes, that would be plenty of
> time?
>
> LT. COL. ROBINSON: Yes.
>
> DR. HARRISON: Okay. So, we\'re supposed to be there at one o\'clock
> for the closed session. So if we could present ourselves outside at
> 12:45, we should be in good shape.
>
> LT. COL. ROBINSON: 12:45\--\[off mike.\]
>
> DR. HARRISON: What?
>
> LT. COL. ROBINSON: If you tell the participants if they\'re not there
> on time we\'ll start calling rooms.
>
> DR. HARRISON: So we\'re at 11:40 now, so we\'ve got almost an hour to
> do whatever we do and call it lunch.
>
> The other comment that I wanted to make\--that last one before we
> leave\--is that both Len and the Air Force agree that the months for
> our meetings, according to the schedules of chapters, should be April,
> August and October of 2004. And my suggestion to Len and the Air Force
> is going to be that we actually put some days on there very quickly so
> that we can try and capture as many members of the committee as
> possible.
>
> April, August and October. That will take us through 19 chapters, plus
> future directions and the draft final report. That will leave the
> final report and journal articles, which will probably require yet
> another gathering of the eagles.
>
> DR. STOTO: August is a very bad month for many people, and for me in
> particular.
>
> DR. GOUGH: Nothing wrong with vacation.
>
> DR. STOTO: Well, I teach every day in August\--the first three weeks
> of August.
>
> DR. CAMACHO: Has this committee judged\--also worth considering, not
> just the report, but the closing down of the study in any way?
>
> DR. STOTO: We don\'t really want to go there right now.
>
> DR. HARRISON: But that\'s been a topic of discussion, and that\'s a
> topic of one of the presentations yet to come. Sure. \"Update on Study
> Shut Down and Transfer of Data\"\--that\'s what that really implies,
> Paul, is more\--I mean.
>
> So August is already meeting with protest. So\--
>
> LT. COL. ROBINSON: End of July?
>
> DR. HARRISON: Well, I think the other thing that\'s true for many
> academic people is that July and August are just not good months
> period. Those are the months when everybody\'s kind of buck naked and
> running free.
>
> So we may be better off looking into early September rather than
> August.
>
> DR. TREWYN: Not everybody, though\--except for Rochester. We
> have\--they do those things.
>
> DR. HARRISON: Okay. Anything else before we break?
>
> DR. SCHECHTMAN: A proposal was made for the members who will be
> involved in the closed session not to leave the hotel. I mean, you can
> do your walk. But we want to be able to gather promptly, as was
> pointed out, at 12:45. Julie has a van, Ron has a van. So we could
> probably accommodate the members of the committee, in terms of
> transportation.
>
> So we\'re just asking you not to wander off to the malls and all that,
> because we really have to\--12:45.
>
> LT. COL. ROBINSON: Front of the hotel.
>
> DR. SCHECHTMAN: In front of the hotel\--right.
>
> DR. HARRISON: 12:45 we load up.
>
> DR. SCHECHTMAN: We\'ll be returning to this meeting room by 3:00 p.m.,
> using the same means of transportation so that we can continue with
> Joel\'s presentation beginning at 3:15, and further committee
> discussion. Thank you.
>
> DR. HARRISON: Okay.
>
> \[Luncheon recess.\]
>
> [A F T E R N O O N P R O C E E D I N G S]{.underline}
>
> DR. HARRISON: Joel now has a five minute presentation.
>
> Shall we?
>
> **Hypertension\--Summarize the Latest Analysis,**
>
> **Including the Skin Exposure Index Results**
>
> DR. MICHALEK: All right. This is a summary of a paper on hypertension
> and dioxin that we have been working on for a number of years. It was
> recently rejected by the [American Journal of
> Epidemiology]{.underline}. It as part of an invited talk at Canada\'s
> Center for Inland Waters earlier this year in Toronto, and it was
> presented, an earlier version, in Barcelona, Spain, in 2002. It is an
> important paper because it illustrates the complexities of the study.
>
> Slide.
>
> \[Slide.\]
>
> The end point is diagnosed history of hypertension after service in
> Viet Nam. We did not analyze blood pressures, the reason being that
> once an individual is diagnosed with hypertension he\'s generally on
> anti-hypertensive medication, and so that the blood pressures are
> artificially maintained in the normal range, making blood pressures
> themselves not very informative. It is the diagnosis and the date of
> onset that is most important.
>
> Slide.
>
> \[Slide.\]
>
> So the methods are, as before, repeated physicals and questionnaires
> and record review. We have 100 percent ascertainment, and more than
> 100 percent quality control. And the study includes\--this paper
> includes any veteran who\'s compliant to at least one physical
> exam\--a total sample size of 2,682.
>
> Slide.
>
> \[Slide.\]
>
> We\'re using a Cox model, a proportional hazards model. Because we
> found strong trends in both groups\--as we saw in the earlier study on
> insulin\--we\'ve done both between and within-group analyses using a
> variety of models: dioxin quintiles, dioxin on a continuous scale.
>
> The dioxin quintile analyses are there to imitate the Plestagianes
> study of an industrial cohort in Germany, co-authored with James
> Dwyer, who is the first author on this paper. We were trying to
> imitate the German study because the Germans found a significant dose
> response in dioxin quintiles.
>
> Slide, please.
>
> \[Slide.\]
>
> We have a long list of covariates, which
>
> is unique to this study: drinking history, and smoking, and BMI and
> age and military occupation.
>
> Slide, please.
>
> \[Slide.\]
>
> The cholesterol\--the lipids that were measured by CDC, and the
> specimen that was used to measure the dioxin are in the model, along
> with family history of hypertension and stroke.
>
> Slide.
>
> \[Slide.\]
>
> Here\'s the study reduction. From the 2,682 down to the 2,417 that
> were actually included in the analyses by throwing out individuals
> with missing dioxins or hypertension prior to service in Viet Nam or
> Southeast Asia.
>
> Slide.
>
> \[Slide.\]
>
> Groups are comparable, as before, with respect to these covariates,
> except for dioxin.
>
> Slide.
>
> \[Slide.\]
>
> Actually, across the board they\'re fairly comparable.
>
> Slide.
>
> \[Slide.\]
>
> Overall\--and this is the puzzle of this data\--overall, there is no
> difference on prevalence of hypertension between groups. About 41
> percent of the Ranch Hand group and 40 percent\--sorry, 40 percent of
> the Ranch Handers and 41 percent of comparisons have a documented
> history of hypertension; relative risk 1.0.
>
> Slide.
>
> \[Slide.\]
>
> However\--same however as in the insulin study\--if you break out the
> comparison by quintile, within the comparison group, and Ranch Hand by
> quintile of dioxin within their cohort\--there are the sample sizes\--
>
> Slide.
>
> \[Slide.\]
>
> \--and consider the prevalence of hypertension by quintile of dioxin
> in the comparison group and within the Ranch Hand group, you see
> trends of increased risk of hypertension\--these are unadjusted, of
> course\--hypertension with increased dioxin level.
>
> Slide.
>
> \[Slide.\]
>
> And here\'s a plot showing the trends within both groups. Everything
> on that plot is significant. The trends are significant, the
> within-quintile contrasts are significant\--
>
> Slide, please.
>
> \[Slide.\]
>
> \--and here are the quintile contrasts, using the first quintile in
> the comparison group as the referent, and contrasting all the other
> quintiles with that first quintile, fully adjusted for all those
> covariates you saw on the earlier slides, we find significant
> increases in risk in the higher quintiles in both cohorts relative to
> the first quintile in the comparison group.
>
> Slide, please.
>
> \[Slide.\]
>
> If you combine the entire cohort together\--all 2,400, and then ask
> whether there is a relation between log dioxin on a continuous scale,
> and diagnoses of hypertension, you find a significant dose response,
> with about 8 percent increase in risk for every doubling of the dioxin
> concentration in the lipid in the serum
>
> DR. STOTO: Is there a dummy variable in there for Ranch Hands versus
> comparison?
>
> DR. MICHALEK: Yes. And there\'s no interaction.
>
> Slide.
>
> \[Slide.\]
>
> And here it is represented for the entire 2,400, broken out now into
> deciles of dioxin, with the hypertension prevalence on the vertical.
> And we\'ve got a log base 2 transformation of dioxin so that a unit
> change on the horizontal represents a doubling of the dioxin level.
> And there\'s a significant trend there, in value 001.
>
> Slide.
>
> \[Slide.\]
>
> Now, the idea here was to further examine this to looking for
> inconsistencies, in other words, and to further examine those patterns
> by the skin-exposure index you saw in the previous talk. And what
> we\'re headed for here is\--we\'re headed for a final bottom line that
> there is going to be a trend in both groups that we can\'t make
> disappear. And this was the paper we submitted to the
> [Journal]{.underline} and the journal rejected. And there are many
> reasons for the rejection which I\'ll show you in the referee
> comments.
>
> Slide.
>
> \[Slide.\]
>
> So what we did now was take the entire cohort, and rather do it in
> quintiles within each cohort, we took the entire cohort and broke it
> out into quintiles, and then compared comparisons in the first
> quintile with the Ranch Handers in the first quintile.
>
> Now these quintiles are in the entire spread of dioxins over all 2,400
> people.
>
> Back up one slide, please.
>
> Slide.
>
> \[Slide.\]
>
> So in the first quintile we have a range of dioxins from .3 to 2.9
> ppt, and in that first quintile there\'s 431 comparisons and 53 Ranch
> Hand. And as you see in moving up to, let\'s say, the fourth quintile,
> between 6.3 and 13.1 ppt, it\'s about equally balanced\--more Ranch
> Handers than comparisons. And finally, from 13 to 600, of course, that
> that\'s where most of the Ranch Hand\--or many Ranch Handers are,
> because they have higher levels.
>
> So what we\'re doing now is we\'re just taking the entire distribution
> and breaking them up into quintiles; again, trying to imitate the
> Germans. And we\'re considering the prevalence of hypertension within
> each cohort by quintile of dioxin. And we\'re comparing across
> quintiles.
>
> So we see here in the fourth quintile, for example, we have a higher
> prevalence of hypertension in the comparison group than in the dioxin
> group.
>
> Slide, please.
>
> \[Slide.\]
>
> And here\'s a graphic representation of that, where we have the
> comparisons dominating the Ranch Hands by quintile of dioxin in the
> combined cohort\--a pattern that was certainly not contemplated in
> 1977 when we wrote the protocol.
>
> \[Laughter.\]
>
> DR. STOTO: This is quintiles for the whole group.
>
> DR. MICHALEK: Yes.
>
> So the first quintile here\--take the lowest 20 percent in the entire
> cohort.
>
> DR. STOTO: Well, could this be that, like for the other studies, just
> swing BMI into the equation\--doesn\'t control?
>
> DR. MICHALEK: No, the BMI adjustment, using standard statistical
> methods doesn\'t make this go away. If you look at the next slide\--
>
> \[Slide.\]
>
> \--here is BMI on the vertical and dioxin on the horizontal. And so
> what we\'ve got here is a picture of what I said in the earlier talk,
> that the comparisons at the high dioxin levels within the comparison
> group are at higher BMI than the Ranch Hander do, because we think
> that they are just older and heavier, and they got their dioxins over
> many years in the States, whereas the Ranch Handers got it in a
> heavier dose in Viet Nam as young men. And so that\'s part of our
> problem.
>
> Yes?
>
> DR. HARRISON: Joel, I would expect the relationship to be cleaner
> between hypertension and insulin sensitivity.
>
> DR. MICHALEK: Because we\'re a little bit closer to the mechanism
> there.
>
> DR. HARRISON: Well, because of syndrome X.
>
> DR. MICHALEK: Because of syndrome X\--yes.
>
> We have\--syndrome X involves heart disease, hypertension and
> diabetes. And\--
>
> DR. HARRISON: Well.
>
> DR. MICHALEK: \--40 percent of the cohort has a diagnosed history of
> hypertension. About 23 percent have a diagnosed history of diabetes.
>
> DR. HARRISON: Well\--
>
> DR. MICHALEK: And about 65 percent\--
>
> DR. HARRISON: \--you wouldn\'t want to\--I don\'t think you\'d want to
> include the people with diabetes. But if you were to look for a
> relationship between\--and you\'ve got those data now. You\'ve got the
> QUICKI data, and then in the smaller group you\'ve got the comparison
> in between the 29 versus 29, out of one of those I would expect you to
> be able to show that the loss of insulin sensitivity was related to
> the prevalence of hypertension.
>
> And if that were the case\--see, the BMI in this case is\--I hate to
> keep using this word\--but the BMI is really a surrogate for insulin
> resistance. And you already have a better measurement of insulin
> resistance now. You have a direct measurement of insulin resistance
> now.
>
> DR. MICHALEK: Thank you. That\'s our way out of the box on this. I\'ll
> make a note, and\--
>
> DR. HARRISON: I\'m very familiar with boxes, and ways out of them.
>
> DR. MICHALEK: Way out\--that\'s right.
>
> Slide.
>
> \[Slide.\]
>
> DR. HARRISON: I learned it from Dr. Osei.
>
> DR. OSEI: Going back to your last study on insulin sensitivity, do you
> have blood pressure and lipid profile in those?
>
> DR. MICHALEK: Yes\--at Little Rock.
>
> DR. OSEI: That will help you.
>
> DR. MICHALEK: We also have history of medication use, so we know
> who\'s on anti-hypertensive medications.
>
> DR. OSEI: Do you have info on anti-hypertensives\--
>
> DR. MICHALEK: Yes.
>
> DR. OSEI: In that study?
>
> DR. MICHALEK: Yes.
>
> DR. HARRISON: The\--
>
> DR. MICHALEK: Because 40 percent of the group are hypertensive, or a
> history of, and many of those are on medications.
>
> DR. OSEI: But, see, that\'s the very serious problem for you.
>
> DR. MICHALEK: Yes, it is.
>
> DR. OSEI: Because somewhat\--
>
> DR. MICHALEK: It\'s almost half the cohort.
>
> DR. OSEI: That half of the anti-hypertensive may either go either way.
>
> DR. MICHALEK: So it\'s possible that by adjusting for our
> anti-hypertensive medication, we can clarify\--
>
> DR. OSEI: Exactly.
>
> DR. MICHALEK: -picture on insulin.
>
> DR. OSEI: Exactly. Because you have \[off mike\] by insulin
> sensitivity \[off mike\], neutral, so you may have to really look at
> that and tease out, and it may give you more answers.
>
> DR. MICHALEK: Thank you.
>
> DR. HARRISON: I didn\'t hear everything you said, Kwame, but one of
> the things that I would be concerned about, if you used blood pressure
> measurements, versus a history of hypertension, is that it\'s really
> difficult to get accurate blood pressure measurements. And unless you
> standardized on something like a mercury manometer, and unless you
> standardize on three measurements over a certain period of\--you know,
> it\'s very difficult to get reproducible, useful data out of blood
> pressure.
>
> DR. OSEI: Well, also trying to\--the effect of anti-hypertensive
> medications on glucose regulation.
>
> DR. HARRISON: Ahh. Okay.
>
> DR. OSEI: And half of his population, the last study, which apparently
> were on some anti-hypertensives. So this is a serious confounding
> variable, in terms of interpretation of this data. And part of his
> methodology demonstrates, you know, differences could be the effect of
> these drugs. Somebody\--one group will take and ACE inhibitor which we
> know will put insulin sensitivity\--that it can ameliorate the
> differences. So we need to go back and re-look at, you know\--you
> don\'t have a\--the n is not large enough to take 50 percent out, and
> just look at just those people on low medications and ask that
> question: is there any difference in terms of the total dioxin on
> insulin sensitivity.
>
> DR. HARRISON: Well, you could do that with the QUICKI group, right?
>
> DR. MICHALEK: Yes.
>
> DR. HARRISON: He can\'t do that with the rapid sampling group.
>
> DR. OSEI: Yes, the\--I think the same problem, because the\--you know,
> the drugs themselves can induce insulin resistance, regardless whether
> you measure fasting glucose or fasting insulin. So the farther that
> we\'re taking the medications, you know, throw you off because of any
> reasonable deductions you can make.
>
> DR. HARRISON: What I\'m saying, though, is they\'ve got 2,000 QUICKI
> measurements\--
>
> DR. OSEI: Mm-hmm.
>
> DR. HARRISON: So if they get rid of 40 percent of those\--
>
> DR. OSEI: Oh, yes, sure.
>
> DR. HARRISON: \--they still have enough to make the correlation.
>
> DR. OSEI: Mm-hmm.
>
> DR. HARRISON: But for the rapid sampling study, they only have 58
> total patients there, so they might not have enough numbers when they
> finish.
>
> But you don\'t know how many of those were hypertensive.
>
> DR. MICHALEK: Not offhand, no. But I would suspect at least 30
> percent.
>
> DR. HARRISON: Yes. And\--yeah. Okay.
>
> DR. MICHALEK: Well, thank you. That\'s why we\'re here.
>
> Slide, please.
>
> \[Slide.\]
>
> And here is the concept we had earlier, that there\'s two ways to get
> exposure of dioxin: one through skin and one through BMI, and that
> Ranch Handers, because they had more\--a Ranch Hand comparison with
> the same dioxin level are going to be at different points on this
> curve\--we think. A Ranch Hand with, say 28 parts per trillion will
> have to be here, as compared to a comparison with 28 parts per
> trillion. And we think there\'s support for this idea, which may
> explain some of the anomalies we see in this data set.
>
> Slide.
>
> \[Slide.\]
>
> Well, we have these complications with dioxin and hypertension that
> you\'ve just seen. Now we ask\--giving up the dioxin assay
> measurement, do these trends hold together if we look at what they
> told us on their questionnaire about what they did on the job in Viet
> Nam?
>
> So we took the individuals who had responded to the questionnaire, and
> we broke them out into quintiles by their skin-exposure index. And
> here are the sample sizes, and there are the dioxin levels. We see
> they\'re increasing\--age\--the point here being that individuals who
> report high skin exposure were generally younger than those who
> didn\'t, reflecting the senior master sergeant who gave the orders,
> versus the one and two-stripe or the guy on the tanks. You know,
> there\'s a definite demographic difference going on here.
>
> BMI\--and there\'s the percent hypertensive, and the pattern is
> certainly not clear by looking at that, certainly on these raw
> percents whether there\'s going to be a trend.
>
> Slide.
>
> \[Slide.\]
>
> And certainly when you do the adjusted relative risks, you don\'t see
> much going on here against the first quintile, and the entire cohort.
>
> Slide.
>
> \[Slide.\]
>
> However, if you look carefully at that you\'ll find that a good
> percentage of the people in the first cohort were those senior
> enlisted, and they were administrators in other words. So, start
> again\--
>
> Slide.
>
> \[Slide.\]
>
> \--we started over again and excluded the administrators and only look
> at the non-administrative enlisted Ranch Hand veterans who responded
> to the questionnaire, broke them out into quintiles by skin
> exposure\--and there are the sample sizes. And now we begin to see a
> trend. And it\'s obscured by changes in age here. These individuals in
> the fifth quintile are a lot younger than the ones in the lower
> quintiles\--still. And so after you adjust for age, you see a
> significant increase in the risk of hypertension in the highest
> quintile of skin exposure in the Ranch Hand enlisted, which is
> consistent with the idea that there really is a relation between
> dioxin exposure, or herbicide exposure, and hypertension.
>
> DR. GOUGH: Unless you\'re not exposed at all. I mean it seems to me if
> you have an essentially non-exposed group, like quintile one, then
> everything should be different from it, if you\'re going to have a
> difference between quintile two and quintile five.
>
> DR. MICHALEK: Are you objecting to the use of the first quintile as
> the referent?
>
> DR. GOUGH: No. I\'m saying\--
>
> DR. HARRISON: He\'s objecting to the exclusion of the administrators.
>
> DR. GOUGH: I mean, the exclusion of the lowest exposed groups. And
> actually the basis of the comparison\--that\'s brutal. When he does
> that\--I mean, with them as a comparison, he doesn\'t find a
> difference. He doesn\'t find a trend.
>
> DR. STOTO: But there the reference group. The lowest quintile is a
> reference group.
>
> DR. HARRISON: But the administrators are out of that group.
>
> DR. GOUGH: The administrators are out of that.
>
> DR. MICHALEK: These are non-administrative enlisted.
>
> DR. GOUGH: It just puzzles me that you would do that.
>
> DR. HARRISON: What, again, was your rationale for excluding the
> administrators?
>
> DR. MICHALEK: Administrators? They\'re older, heavier and they make a
> good referent for the younger, heavily exposed enlisted.
>
> DR. STOTO: I agree with this. I mean, you want the people to be as
> similar as possible\--
>
> DR. MICHALEK: Thank you.
>
> DR. STOTO: \--in every respect except their exposure.
>
> DR. MICHALEK: Yes.
>
> DR. GOUGH: Well, the big difference in exposure is one group has none,
> or very little, and the other groups\--
>
> DR. MICHALEK: Right.
>
> DR. HARRISON: Well\--
>
> DR. GOUGH: I mean that is really cutting.
>
> DR. HARRISON: Mike, it is possible, though, to make the argument\--
>
> DR. GOUGH: Yes, I can understand the argument.
>
> DR. HARRISON: \--that hypertension increases with age\--
>
> DR. GOUGH: And weight.
>
> DR. HARRISON: \--and with weight, and weight increases with age, and
> hypertension increases with weight and age. So, you might have a
> higher incidence of hypertension in the first group.
>
> I just think that the other problem that you\'re looking at here is
> that the stuff is far removed from a direct relationship, and that\'s
> why you\'re having to go through all these maneuvers to see anything.
>
> DR. OSEI: The other thing, Joel\--I keep on trying to look at the
> numbers you\'re showing us: the 51 percent, the 29 percent. I don\'t
> really know of any group that has that high rate of hypertension.
>
> DR. MICHALEK: You\'re looking at one right now.
>
> DR. OSEI: So, there has to be something that\--you need to explain the
> higher rate of hypertension in this group here. I mean, the general
> population has a rate of about, maybe 22 percent; the highest in
> African Americans, 28 percent.
>
> You have people with half of the population have hypertension. So
> their background may be different before even they go\--
>
> DR. MICHALEK: As the principle in statistics, if you\'re trying to
> look for a treatment effect, is to produce a group as homogeneous as
> possible\--except on the variable of interest which, in this case, is
> skin exposure.
>
> These guys are all non-administrative, enlisted Ranch Hand veterans
> who were either on the ground loading tanks or sat in the back of the
> plan, operating spray equipment. Forty-nine percent of the
> individuals\--
>
> DR. HARRISON: But Joel, it\'s like saying that you\'re relating height
> to skin exposure, and the average height in the first quintile is
> six-foot-five, and the average height in the fifth quintile is
> seven-foot-two. And we know that the general population has an average
> height of whatever.
>
> DR. MICHALEK: We\'re not asking about the general population. We want
> to know\--
>
> DR. HARRISON: The general Air Force population.
>
> DR. MICHALEK: We want to know of these enlisted Ranch Hand veterans,
> is there a trend? And the answer is, yes, there is.
>
> DR. STOTO: Now, we know that these are older guys, and it\'s not
> surprising that what is it some\--
>
> DR. MICHALEK: 49 percent.
>
> DR. HARRISON: I agree with Kwame. It is surprising.
>
> DR. MICHALEK: Well, at least to emphasize the point, that every single
> case here has been verified by record review. Every case\--all of
> those 49\--have a doctor\'s diagnosis of hypertension.
>
> DR. HARRISON: The disagreement is not over the diagnosis. The problem
> is\--the problem is that, you know, that the average height in the
> first group is six-five. I mean, that\'s\--
>
> DR. MICHALEK: The average what?
>
> DR. HARRISON: \--totally\--it\'s\--
>
> DR. MICHALEK: Say again?
>
> DR. HARRISON: It\'s\--what you\'re saying is, statistically, I\'m sure
> is correct.
>
> DR. MICHALEK: Yes.
>
> DR. HARRISON: It\'s just that what you\'re saying biologically is
> biologically implausible.
>
> DR. MICHALEK: I understood the purpose of this study was to determine
> whether exposure to herbicides is detrimental to your health. Is that
> true?
>
> There\'s a hierarchy here of exposure to herbicides, as measured by
> the skin exposure index, which was given to the men, blinded to their
> dioxin levels, in 1989. We ranked the men according to their skin
> exposure. We tabulated the percent hypertensive. The raw percentages
> are a bit misleading, because these are unadjusted for age. The
> individuals in the high category are younger. That\'s why this
> relative risk is 2.6, even though the raw percent down here is 51 and
> that\'s 49.
>
> DR. HARRISON: When you\'re saying \"younger,\" though, you\'re still
> saying that they\'re in their forties or fifties now.
>
> DR. MICHALEK: They\'re at least five years younger than those
> individuals in the first quintile.
>
> DR. HARRISON: But they\'re still in their forties and fifties. And\--
>
> DR. MICHALEK: This is the entire prevalence from Viet Nam to the
> present. Currently, the average age is about 62.
>
> DR. GOUGH: This is a diagnosis\--
>
> DR. MICHALEK: Are you telling me that this analysis should not be
> done?
>
> DR. HARRISON: Well, let me ask you this\--are you saying that you have
> participants in this group who were diagnosed as being hypertensive in
> the \'50s, who do not have a diagnosis of hypertension now?
>
> DR. MICHALEK: No. All these diagnoses were after service in Viet Nam,
> which meant since 1975.
>
> DR. HARRISON: Well, let me rephrase the question. Do all of the people
> in this group\--are all of the people in each of those groups
> presently hypertensive? Do they presently have the diagnosis of
> hypertension.
>
> DR. MICHALEK: Well, if an individual is hypertensive in 1982, and is
> put on anti-hypertensive medication, and holds his blood pressure
> steady\--
>
> DR. HARRISON: But is not on a an anti-hypertensive medication now.
>
> DR. MICHALEK: Well, I don\'t know if they\'re on or off hypertension.
>
> DR. HARRISON: That\'s right. You don\'t know that.
>
> DR. MICHALEK: I didn\'t include it in this analysis. All I included
> was date of onset, according to the diagnosis.
>
> DR. HARRISON: So, Kwame, that\'s why he\'s coming up with such high
> numbers.
>
> DR. MICHALEK: Yes.
>
> DR. HARRISON: Because you\'re talking about a cumulative\--
>
> DR. MICHALEK: Cumulative\--
>
> DR. HARRISON: \--diagnosis\--
>
> DR. MICHALEK: \--over the entire\--
>
> DR. HARRISON: \--where it may well be that half of the people that
> you\'ve got in this group are not presently hypertensive, nor are they
> on anti-hypertensives.
>
> DR. MICHALEK: But they had a history of\--they were diagnosed, they
> had a date of onset. It could have been anywhere between 1969 and the
> year 2002.
>
> DR. HARRISON: Yep.
>
> DR. MICHALEK: That could explain the high percentages relative to the
> rates you\'re quoting. That\'s true, I guess.
>
> DR. STOTO: Well, the other thing is that they\'re old.
>
> DR. MICHALEK: That\'s right. The earliest birth year is 1908.
>
> DR. HARRISON: Yeah, I think I met him.
>
> \[Laughter.\]
>
> DR. CAMACHO: We\'re just seeing the confounding variables.
>
> DR. HARRISON: It doesn\'t surprise me\--
>
> DR. CAMACHO: \--confounding variable on these guys?
>
> DR. HARRISON: I\'m not saying age is a confounding variable. Mike is
> saying it\'s just they\'re old, it\'s okay for half of them to be
> hypertensive. I don\'t know\--
>
> \[Simultaneous multiple comments.\]
>
> DR. OSEI: I\'m very confused, actually, on what you did. I have no
> idea what you did.
>
> If you took them when they came in and you measured their blood
> pressure from day one, then just every so often. So you\'re getting a
> cumulative data over 20 years. What are you giving us? What is that?
>
> DR. MICHALEK: That is the risk of diagnosis of hypertension by a
> doctor.
>
> DR. STOTO: Of ever having been diagnosed.
>
> DR. MICHALEK: Diagnosed. By a doctor.
>
> DR. HARRISON: This is a chart review. This a chart review, Kwame.
> It\'s not a direct measurement of blood pressure.
>
> DR. CAMACHO: So what\'s the objection here? The age is a confounding
> variable?
>
> DR. HARRISON: I don\'t have any\--no. I think\--the majority of these
> people are white, so\--the incidence of hypertension is different in
> African Americans\--Kwame and I will differ a little bit on this\--but
> I expect a third of adult African Americans to be hypertensive, and
> that can slide up a little bit.
>
> But for White Americans\--20, 22 percent is probably a much more
> reasonable\--
>
> DR. STOTO: These are not White Americans, these are White Americans
> over 50.
>
> DR. OSEI: Even still, you are now talking half of the White Americans
> are hypertensive. Is that what you\'re saying?
>
> DR. STOTO: It\'s not half, either. It\'s\--
>
> DR. HARRISON: 49 percent.
>
> DR. STOTO: Well, that\'s 49 percent in one quintile, but that\'s 35
> percent of the quintiles overall. So it\'s about 40 percent.
>
> DR. MICHALEK: Overall, it\'s 40 percent.
>
> DR. STOTO: Yes.
>
> DR. MICHALEK: If I could enumerate every single case, I would.
>
> DR. HARRISON: But if you take into account that some of these are
> people who got a little bit overweight, got hypertensive, got put on a
> hypertensive medication\--or simply got told to lose weight and did
> so. And then you\'ve got some other people, you know, who may
> have\--you\'re not even distinguishing between systolic and diastolic
> hypertension here. So you\'ve got a few people in there that are\--I
> mean, that\'s a mixed bag, as well.
>
> DR. CAMACHO: But all this data was taken at a point in time in the
> past.
>
> DR. HARRISON: No. No. All this\--this is cumulative. So if you were
> diagnosed as hypertensive in 1971, and no mention was made of it since
> then, you\'re in this group.
>
> DR. MICHALEK: That\'s right.
>
> DR. HARRISON: And that\'s why the numbers, I think, are higher. And
> that\'s why I think they\'re inaccurate.
>
> DR. MICHALEK: Why would they be inaccurate?
>
> DR. HARRISON: Because you have no way of judging whether, for the
> different quintiles, that the occurrence of hypertension was
> distributed the same between the quintiles. You know, you\'re looking
> at a phenomenon, but you\'re not\--it\'s\--
>
> DR. STOTO: That\'s the nature of this kind of work, because you have
> to look at something. And then there\'s often not a perfect measure.
> But the key thing is that it\'s consistent.
>
> DR. HARRISON: No, it\'s not.
>
> DR. STOTO: It\'s consistently defined between the people in the five
> different groups.
>
> DR. HARRISON: It\'s like extracting and saying that the fifth quintile
> has two noses. I mean, it could be consistent statistically, but it
> just wouldn\'t make sense.
>
> Just because it\'s consistent statistically, doesn\'t make
> it\--doesn\'t mean that you should.
>
> DR. STOTO: It makes it the proper epidemiological study.
>
> DR. HARRISON: It means that you can only to your mother about stuff
> like that.
>
> DR. CAMACHO: But what\'s the statement? These people experienced
> hypertension at some point\--at least once. As long as that\'s said,
> what\'s the\--
>
> DR. OSEI: I will tell you the major\--\[off mike\] you said it\--these
> are some of the issues. I don\'t have enough breadth, the reviewer on
> one or two comments. These are some of the things\--if I had read your
> paper, this is what I\'m going to ask. Unless you really think through
> that, it\'s going to be rejected again, because at the end of the day,
> I have not read this paper very well\--I can\'t even tell how this
> study\--how you got this focus? And \[off mike\]. And that\'s the
> point that Paul makes. The fact that I went to a doctor and one day
> had hypertension, my blood pressure is high, doesn\'t give me a
> diagnosis of hypertension.
>
> DR. MICHALEK: No, no. These are all diagnosed by physician. We have a
> record\--a medical record proof of that. We have a signed statement by
> a doctor, \"He was hypertensive,\" at a certain point in time.
>
> DR. OSEI: Okay.
>
> DR. STOTO: So how about if we asked\--can you think of a better way to
> define hypertension for a study of this sort?
>
> DR. MICHALEK: How else would you define hypertension?
>
> DR. OSEI: I can\'t tell you.
>
> DR. STOTO: All right. If you can\'t come up with something better, you
> can\'t criticize this.
>
> DR. GOUGH: But if it\'s a meaningless measure, you don\'t want to do
> the study.
>
> DR. STOTO: Well, it\'s not a meaningless measure.
>
> DR. HARRISON: One of the first cuts that you could make it at is you
> could ask these people\--
>
> all right, I\'ll try this on for size.
>
> I would make the definition of hypertension those people who are
> presently on hypertensive medication; not have a history of having
> taken it in the past, not a history of it having been diagnosed in the
> past, but those people who presently are on anti-hypertensive
> medication.
>
> DR. STOTO: What about the people who have been diagnosed, really have
> high blood pressure now, but can\'t stand the medication?
>
> DR. HARRISON: All right. I\'ll add that group in: those people that,
> on this physical examination had an elevated blood pressure\--or
> elevated diastolic blood pressure. Let\'s get rid of some of the
> white-coat hypertension.
>
> DR. OSEI: If you have\--you said that the doctor\'s specification
> that\--nobody measured blood pressure.
>
> DR. MICHALEK: Yes.
>
> DR. OSEI: From where?
>
> DR. MICHALEK: That probably led to a diagnosis.
>
> DR. OSEI: All right. So, if you are going back through the charts, you
> should be able to find out when\--
>
> DR. MICHALEK: Mm-hmm.
>
> DR. OSEI: \--and what was the blood pressure?
>
> DR. MICHALEK: Yes.
>
> DR. OSEI: So you can assess change in that.
>
> DR. MICHALEK: Yes.
>
> DR. OSEI: That would strengthen this, because just the fact that
> somebody tells you that\--
>
> DR. MICHALEK: Right.
>
> DR. OSEI: \--it\'s not good enough.
>
> DR. MICHALEK: No, no. It\'s not a self-report.
>
> DR. OSEI: Maybe define what hypertension is.
>
> DR. MICHALEK: It\'s been verified.
>
> DR. OSEI: We have GNC-6 numbers. You can actually\--this is standard
> definition of hypertension.
>
> DR. MICHALEK: Yes. For every single case, we have document of the date
> and the doctor\'s signature that they\'re hypertensive.
>
> So we know the date, we know the\--
>
> DR. OSEI: And what was the blood pressure\--
>
> DR. MICHALEK: We know the blood pressures\--yes. It would probably be
> on the same document.
>
> DR. OSEI: Would it be grouped by date?
>
> DR. MICHALEK: That\'s what this does. This is the Cox model analysis,
> the same model we used to track the diabetes.
>
> DR. CAMACHO: So this is grouping by dates\--
>
> DR. MICHALEK: Yes.
>
> DR. CAMACHO: \--of when they were reported hypertension.
>
> DR. MICHALEK: Yes.
>
> DR. HARRISON: Okay. Okay.
>
> You know, I\'d like to take another tack on this. It may be\--I\'d
> like to return to my earlier comment.
>
> It may be that the problem here is that it\'s kind of a bloodless
> statistical observation, without\--it doesn\'t point you towards any
> mechanistic explanation for what\'s going on. And if it were possible
> to go back and do some sort of an analysis that tried to relate the
> occurrence of hypertension to the present\--frankly, I think I would
> much prefer those people who were presently hypertensive and relate
> that to their insulin sensitivity. It that turned out to show a
> relationship, I think then you\'d have a paper that would excite a lot
> of interest, and you wouldn\'t have much trouble selling it.
>
> The problem here is that it\'s a\--I\'ll take Mike\'s word for it,
> I\'ll take your word for it\--it\'s a valid statistical analysis of
> phenomena, that doesn\'t point to any mechanism.
>
> DR. CAMACHO: Is that skin exposure\--
>
> DR. HARRISON: It\'s not a mechanism. That\'s just a phenomenon. You
> know, you\'re saying this phenomenon and this phenomenon have a
> statistical relationship.
>
> DR. CAMACHO: Are correlated. Yes.
>
> DR. HARRISON: And I suspect the reviewers are saying, \"Well, yeah,
> okay.\" It doesn\'t light my fire.
>
> DR. MICHALEK: I think that\'s helpful. And I think we can do something
> along those lines. Thank you.
>
> Yes?
>
> DR. GOUGH: I\'m unclear\--if there\'s a good correlation between the
> skin exposure index and current ppt, then why do these results turn
> out so different?
>
> DR. MICHALEK: Why are they different?
>
> DR. GOUGH: Well, when you do it by current ppt, you don\'t get this
> trend. It\'s only when you do the skin\--
>
> DR. MICHALEK: Well, you saw a trend with current ppt also.
>
> DR. GOUGH: Here?
>
> DR. MICHALEK: Yes. We did the deciles\--back up a few slides.
>
> \[Slide.\]
>
> DR. GOUGH: Okay. But then what do we get different when you do
> the\--all right. But they go up together.
>
> DR. MICHALEK: Hypertensive risk increases with dioxin.
>
> DR. GOUGH: Yes. Okay. But then, didn\'t you do a comparison between
> the first through fifth quintiles, based on ppt\'s?
>
> DR. MICHALEK: Yes.
>
> DR. GOUGH: And wasn\'t the result from that different from doing it
> based on skin exposure index?
>
> DR. MICHALEK: No. We saw a trend with increased risk in the increased
> quintile.
>
> DR. GOUGH: That\'s the one I\'d like to see. Because I missed it when
> you went through.
>
> \[Slide.\]
>
> DR. MICHALEK: Right there. It\'s increasing in both groups. Take a
> quintile dioxin in each group.
>
> DR. GOUGH: Okay. Then why is it necessary to do this skin exposure
> index?
>
> DR. MICHALEK: Only because some people object to the dioxin measure
> because of all the caveats that are associated with it, such as
> differential elimination, such as confounding with body fat, such as
> it\'s being measured in 1987, and the exposure that occurred in 1967.
>
> DR. GOUGH: Okay. All right.
>
> DR. MICHALEK: And the advantage of\--
>
> DR. GOUGH: Okay. Okay. Well, if the results are the same\--fine.
>
> DR. MICHALEK: Yes.
>
> DR. GOUGH: You said the results are correlated. All right.
>
> DR. MICHALEK: But I think the comments we\'ve heard so far will help
> us strengthen the paper. Thank you very much.
>
> DR. HARRISON: Okey doke.
>
> DR. MICHALEK: So, that\'s just about the end. Let\'s continue on and
> finish this.
>
> So-slide, please.
>
> \[Slide.\]
>
> This is the same slide you saw before.
>
> Slide.
>
> \[Slide.\]
>
> And so we have this puzzle of no great difference on a history of
> diagnosed hypertension, and yet we see significant trends within each
> group.
>
> Some of the same mechanisms would apply here that we thought applied
> in insulin; that is, the comparisons at high levels could be older and
> heavier, and our statistical modeling has failed to accommodate
> that\--to adjustment on the Ranch Hands with low levels who just
> happened to be lucky, and they\'re able to eliminate dioxin quicker,
> and that\'s why they\'re low. And that would make them healthier, and
> that would confound our dose response patterns.
>
> Slide.
>
> \[Slide.\]
>
> And these are all the comments that we\'ve taken into account:
> possible uncontrolled confounding, and dioxin level may depend on a
> lot of things, including\--as well as exposure and body fat and
> uptake. Uptake may correlate with BMI, and it may correlate
> differently in the two groups. These are all speculations.
>
> Slide.
>
> \[Slide.\]
>
> Strengths, we already know about.
>
> Slide.
>
> \[Slide.\]
>
> Limitations, we know.
>
> Now, it was rejected recently by the [American Journal of
> Epidemiology]{.underline}. One of the reviewers said this report will
> have a major impact on public policy regarding the regulation of
> dioxin use. He liked the paper, basically, and his comments were
> fairly trivial.
>
> Slide.
>
> \[Slide.\]
>
> And he thought we should focus on the within-group analyses, and not
> at the size of the between-group\--similarity between the cohorts, and
> he was fascinated by the dose response within the Ranch Hands and
> controls. And he mentioned the EPA.
>
> However the second referee was far more critical, telling us we
> shouldn\'t have used the Cox model. We should have used logistic
> regression, which is a point we\'ve raised many times, and both
> methods give the same result, basically.
>
> Slide.
>
> \[Slide.\]
>
> \"Maybe due to confounding or some other variable that operates at the
> low end;\" \"This is all speculation,\" but we\'ve tried all available
> covariates and cannot make these patterns go away.
>
> Slide.
>
> \[Slide.\]
>
> You know, he doesn\'t like the fact that we used the change in BMI,
> but overlooked the fact that we used the absolute BMI. He thinks we
> used the change only, and we didn\'t. We used both the change and the
> current BMI, and a tour BMI.
>
> And he thought we should be using current alcohol consumption and
> smoking. But we didn\'t. We used the measures made in 1982, because we
> thought that however much he drank or smoked today should have no
> bearing whatsoever on a diagnosis that occurred 10 years ago. And so
> we tried to use an earlier measurement of the covariate to avoid the
> problems associated with time-dependent covariates.
>
> Slide, please.
>
> \[Slide.\]
>
> And he was just trying to discount the findings, saying the trends are
> not strong, and that there are insufficient data to support a causal
> relation. Well, that\'s not our job anyway. We\'re here to demonstrate
> an association or not.
>
> Slide.
>
> \[Slide.\]
>
> \"Discussion of possible mechanisms was vague.\" Well, after you
> present the findings, in a discussion section the idea is to
> speculate, and that\'s what we did. And he didn\'t like our
> speculations.
>
> So I think your ideas would help us revise the paper.
>
> DR. HARRISON: Okay. Any last comments on this paper?
>
> DR. TREWYN: Okay. Since one reviewer liked it and one didn\'t, but the
> editor just rejected the paper.
>
> DR. MICHALEK: Yes.
>
> DR. TREWYN: You did not re-contact, explaining how you could refute
> Reviewer #2?
>
> DR. MICHALEK: The editor\'s letter was clear. He didn\'t want to hear
> rebuttal. We need to start over with a different journal.
>
> DR. TREWYN: And\--yes. And that\'s always an option anyway.
>
> DR. HARRISON: Was it a definitive letter?
>
> DR. STOTO: Just had kind of a saturation effect\--there are just so
> many epidemiology journals, that\--
>
> DR. MICHALEK: One referee said we publish too much.
>
> \[Laughter.\]
>
> DR. HARRISON: Blame us. Shame, shame, shame.
>
> Any other comments before we go on to the next paper? We\'re only 15
> minutes late now.
>
> \[No response.\]
>
> Okay.
>
> **Thyroid - Review Results of the Latest Paper**
>
> DR. HARRISON: Thyroid. Thyroid. Basically, this paper says there
> wasn\'t any thyroid\--weren\'t any thyroid changes, right?
>
> DR. MICHALEK: There was no association between thyroid disease and
> dioxin, but there were associations between thyroid hormones and
> dioxin.
>
> DR. HARRISON: But you didn\'t measure TSH.
>
> DR. MICHALEK: We did measure TSH. TSH changed with dioxin. T4 and T3
> did not.
>
> DR. HARRISON: Okay.
>
> DR. MICHALEK: This paper was accepted by the [Annals of
> Epidemiology]{.underline}, and is in press. It was presented in
> Barcelona. I just show it here, because you may not have seen this
> before. This is a summary of all of our thyroid data over the entire
> study, from 1982 through 1997, written under contract with Drs.
> Schecter and Pavuk at the University of Texas at Dallas.
>
> Slide, please.
>
> \[Slide.\]
>
> We all know the background.
>
> Slide.
>
> \[Slide.\]
>
> You know the goals.
>
> Slide.
>
> \[Slide.\]
>
> Okay. We\'re talking about any veteran who participated in any of the
> five physical examinations from the baseline to cycle five. And here
> is the same dioxin category analysis that we\'ve been using in all of
> our published papers where we have broken out comparisons in Ranch
> Hand into these four categories. And this slide is simply showing that
> three is some heterogeneity across these categories that the Ranch
> Hands in the high category are far more likely to be enlisted ground
> crew than those in the background category, and they\'re far more
> likely to be officers.
>
> Slide.
>
> \[Slide.\]
>
> And here are the dioxin levels across categories, in case you didn\'t
> know these.
>
> In the high category, the median dioxin is 46 parts per trillion, and
> in the background category on the Ranch Hand side it\'s 6 parts per
> trillion, and in the comparison group it\'s 4 parts per trillion. And
> the maximum dose in Viet Nam is about 3,500 ppt.
>
> Slide.
>
> \[Slide.\]
>
> And here is a graphic showing the dioxin levels in the background, low
> and high categories, compared to the comparisons.
>
> Slide.
>
> \[Slide.\]
>
> And here is the finding of the paper. If you look at log transformed
> TSH means by dioxin category, by physical exam year, you\'ll see a
> significant trend in many of the exam years with higher TSH means in
> the high dioxin category. In spite of the fact there\'s been a change
> in the laboratory method for measuring TSH\--here is the Kelsey
> Siebold data, it was obviously on a different scale form the
> measurements made at Scripps in 1985 through 1987. And those were all
> accommodated in the statistical analysis.
>
> Slide.
>
> \[Slide.\]
>
> In a repeated measures analysis that accommodates all data over all
> cycles in all participates we see a significant increase in the mean
> TSH, using a repeated measures linear model. Accommodating all data,
> we see this significant increase, whereas the other analyses were
> cross-sectional in every single physical exam year.
>
> Slide.
>
> \[Slide.\]
>
> And, however, we saw a mean shift. We didn\'t see a significant
> increase in abnormally high TSH levels. The odds ratios are all
> increased, but none of them reach significance in any of the
> examination years in the high Ranch Hand category.
>
> Slide.
>
> \[Slide.\]
>
> And we saw now corresponding pattern with T4\--
>
> Slide.
>
> \[Slide.\]
>
> \--or T3, which is not shown. And when we considered diagnosis of
> hypo- or hyperthyroidism, we saw no significant increase in risk in
> the Ranch Hand high category.
>
> So this is the conclusion. We found a significant dose response
> between dioxin and TSH, but not between dioxin and T4 or T3, and no
> significant increase in the risk of thyroid disease with increased
> dioxin level.
>
> Thank you very much.
>
> DR. HARRISON: Whew. Neat. Or fast.
>
> DR. STILLS: \[Off mike.\] What is the thought behind the increases in
> TSH? The link between dioxin exposure and TSH? Is it\--
>
> DR. MICHALEK: There are only two thoughts I have. First, the results
> are consistent with animal studies that show an increase in TSH with
> dioxin body burden, perhaps in mice, and that whatever effect is going
> on is sub-clinical.
>
> The same is true in our analysis of liver data. We found increases in
> liver enzymes, but no increase in liver disease with increased
> dioxin\--the interpretation being that perhaps a dose is at such a
> range that no adverse disease endpoint could be detected, yet
> measurements on enzymes did detect a mean shift.
>
> DR. OSEI: \[Off mike.\] Do you have antibodies\--
>
> DR. MICHALEK: We measured what are called microsomal antibodies and we
> found no dose response.
>
> DR. OSEI: \[Off mike\] Okay. How about\--antibodies?
>
> DR. MICHALEK: That data was not available. I\'m not sure whether
> we\'re measuring that in cycle six or not. I think the answer is no.
>
> DR. OSEI: \[Off mike\] And these are\--in T4, what are you looking at?
> The number shift between free T4, and just the total T4?
>
> DR. MICHALEK: I think we measured both\--free and bound. And that\'s
> described in the paper.
>
> DR. OSEI: Okay.
>
> DR. HARRISON: Didn\'t you measure what\'s called T-3 uptake?
>
> DR. MICHALEK: Yes.
>
> DR. HARRISON: Okay. So and what you then calculated, using the T4 and
> the T3 uptake was a free thyroxin index\--
>
> DR. MICHALEK: Yes.
>
> DR. HARRISON: \--but you didn\'t measure free T4.
>
> DR. MICHALEK: No. We measured the free thyroxin index.
>
> DR. HARRISON: Okay.
>
> DR. MICHALEK: And found no dose response in free thyroxin.
>
> DR. HARRISON: This is subtle enough. I\'m not sure that that matters a
> whole lot anyway.
>
> Okay. And it\'s accepted. Hey. Whoo.
>
> DR. MICHALEK: Yes.
>
> DR. HARRISON: Go, man, go.
>
> \[Laughter.\]
>
> Before we go on to the next topic\--just in case we lose anyone along
> the way\--there was some comment earlier that August would be a bad
> month to plan a meeting next year. And the idea was to shift forward
> to September. And the only thing else that I wanted to raise was that
> if we shift from August to September for our second meeting, then
> we\--as Len pointed out\--we should switch from October to November
> for our third meeting, otherwise we\'ll be killing ourselves.
>
> So, does it sound reasonable to everyone to plan now on April,
> September and November for next year, and we should try and come up
> with some actual dates\--proposed dates\--pretty soon, and circulate
> those. Hopefully, they\'ll be far enough in advance of everyone\'s
> schedule that we can make a meeting date and you all can adjust your
> schedule for those? Does that sound?
>
> Huh?
>
> DR. CAMACHO: \[Off mike\] April I know I\'ve got one commitment on 12,
> 13, 14\--is not good.
>
> DR. HARRISON: Does anybody else have commitments in April so far?
>
> DR. CAMACHO: Well, you\'re talking about April \'04.
>
> Same date always on hold. It\'s going to be that same time\--12, 13,
> 14.
>
> DR. STILLS: \[Off mike\] I\'ll have to check my\--it may be around
> that time, too. So I\'ll let you know.
>
> DR. HARRISON: So we may be looking at late April. Either that, or
> we\'ll have two new members then. We might not need them.
>
> \[Laughter.\]
>
> Okay. All right. But we\'re in general agreement that those months are
> okay. April, September and November. Okay.
>
> So let\'s go on into the next show.
>
> **Statistics on Study Compliance to Cycle**
>
> DR. MICHALEK: Just to give you a little summary of how we stand
> currently on the physical exam at Scripps\--and I may need some help
> here from Bill Grubbs\--here\'s the total number of when this slide
> was made, which was up through\--we have 81 groups that are going
> through Scripps. There\'s two groups a week. This slide was made as of
> group 52, which passed through the clinic on the 20^th^ of November
> last year.
>
> At that time, we had 1,932 scheduled their exam, and the entire total
> from last cycle was 2,204 at this time, at group 52. So you see we\'re
> running behind what we did in 1997.
>
> Currently, 45\--or at the time this slide was made\--45 were in
> process, 7 were being located. These numbers change every day.
>
> A number of were excluded right up front because we had realized that
> they\'re not friendly, they\'re not comfortable, they don\'t want to
> be talked to, and we called them \"hostile,\" or \"can\'t
> locate\"\--and 216 were called hostile.
>
> And so I think our current best estimate is that we\'re going to
> arrive at about 1,960 individuals physically examined at Scripps this
> cycle, as compared to\--what was the total last time?
>
> \--2,121. So it\'s running around 200 less than what we had in
> 1997\--for a variety of reasons. There\'s apparently no single
> dominant reason\--is there?\--for this. It\'s sort of an
> across-the-board spread of reasons. And we\'re looking at those very
> closely now\--or we will\--specific group differences.
>
> DR. HARRISON: Joel, were the hostile\--what you call the hostile
> people, were they always hostile? Or did any of them become hostile?
>
> DR. OGERSHOK: Most of them\--I think the vast majority of that number
> have always been hostile. There have been a few that may have gotten
> that way after a written exam or two, for one reason or another; or
> people that showed up with basically problems\--weapons\--
>
> \[Laughter.\]
>
> \--and we didn\'t invite them back.
>
> DR. CAMACHO: Sounds hostile to me.
>
> DR. OGERSHOK: There was one gentleman that threatened to\--he had an
> Uzi and he was going to use it on everybody. So we didn\'t invite him
> back either.
>
> DR. HARRISON: Was he told anything about the identity of the advisory
> committee?
>
> \[Laughter.\]
>
> DR. TREWYN: Or does he want to be a member of the advisory committee?
>
> \[Laughter.\]
>
> DR. MICHALEK: We never analyzed the hostiles.
>
> DR. HARRISON: Okay.
>
> Well, you know, obviously the question, Joel, is: is there any
> increase in the hostility with time. It sounds like you\'re saying no,
> there isn\'t. But it also brings to mind an interesting difference
> between the attitude of the people that we talked to, who obviously
> aren\'t hostile and who are here participating, and they\'re all, you
> know, very enthusiastic about it. And then you\'ve got a
> smaller\--much, much smaller group that, you know, feels differently.
> And I\--if they were like that way from the beginning, then you can
> absolve yourself of any responsibility for it. But if they developed
> this with time, then\--
>
> DR. MICHALEK: Well, you raise a good point. Do we have the data that
> leads to when we declared them hostile, so we could analyze that?
>
> DR. TREWYN: It may have to do with that original Holiday Inn versus
> the Marriott.
>
> DR. HARRISON: Okay.
>
> DR. OSEI: \[Off mike.\] The get tired. It\'s very fatiguing. It\'s not
> uncommon to these this\--and this is a long-term study, before they
> come here \--they want to contribute to whatever\--same boat\--give
> up. It\'s not that they\'re even hostile, but that they\'re just
> fatigued.
>
> DR. MICHALEK: Some of these men are genuinely hostile. \"Don\'t call
> me again.\" You don\'t want to mess with some of these people.
>
> Thank you.
>
> Next slide, please.
>
> \[Slide.\]
>
> At every physical exam, the participants fill out a questionnaire
> rating us, rating the clinic, rating the investigators. And you see
> the very high scores we get on the different components of the study.
> And these are all real numbers. These are the men telling us what they
> think.
>
> And so the current study is very similar to the last study in many
> components, but you\'ll see a few differences.
>
> Slide, please.
>
> \[Slide.\]
>
> DR. HARRISON: What range of choice to they have, Joel?
>
> DR. MICHALEK: It\'s a scale.
>
> DR. HARRISON: Is this a five-scale?
>
> DR. MICHALEK: \"Good, excellent, fair, poor,\" and this is the percent
> that scored us excellent or good.
>
> DR. HARRISON: Good, excellent\--
>
> DR. MICHALEK: Fair or poor\--something like that.
>
> DR. HARRISON: You don\'t have\--
>
> DR. MICHALEK: Do you remember the choices?
>
> DR. GRUBBS: I think it\'s excellent, good, fair or poor.
>
> DR. MICHALEK: Okay. And not applicable.
>
> I guess the only one I want to point out is\--somewhere in here. Maybe
> it\'s in the next slide\--
>
> Slide.
>
> \[Slide.\]
>
> \--psychological testing, we\'re doing better this time. What\'s
> different this time is we actually had a psychological test being
> administered by a psychologist, works with memory scales, whereas in
> previous cycles it was all self-administered testing which, I guess,
> can get kind of dull. So we seem to be having a favorable response to
> our psych testing, and we seem to be doing better with the cafeteria
> meals this time\--
>
> \[Laughter.\]
>
> \--as opposed to last time.
>
> DR. HARRISON: Okay. Questions?
>
> They like the psychological evaluator better than themselves\--right?
> That\'s the\--
>
> \[Laughter.\]
>
> Okay. Moving right along. Roll on, Joel.
>
> He who hesitates is lost.
>
> **Latest Results on Consent for Future Use of the**
>
> **Data**
>
> DR. MICHALEK: Okay. The whole idea of\--the end result, the
> disposition of the study after 2006 has been on the table now for a
> while, and we have given options to Congress, and to the Surgeon
> General about, you know, what are the options regarding new study.
>
> The whole concept of continuing the study is tied up with informed
> consent. If the study is to continue in any way whatsoever, study
> subjects must provide their consent. And so at the current physical,
> in addition to the consent forms that they have to sign for the
> procedures that Scripps is administering to them, they have another
> consent form that says something to the effect, \"You have my
> permission to use my data for continuing Agent Orange Research,\" or
> \"for continued study of other health endpoints,\" or you can\'t use
> my data at all.
>
> So they have something like\--they have three questions\--in fact, the
> next slide shows that right here. These are the three options. This is
> copied right from the consent form.
>
> \"After September 30, 2006, your data may be used for Agent Orange
> research and other military health issues.\" That was a choice. The
> threw a box next to each one of these, and they would check off what
> they wanted to do.
>
> The second choice was \"May be used for Agent Orange research only.\"
> And finally, \"May not be used for any purpose\" at all.
>
> Three boxes, and they were to check one of them and sign it. And this
> was one of the many consent forms they were presented with at Scripps
> on their first morning there.
>
> Is there a question about the consent form before I continue?
>
> DR. HARRISON: There\'s another one about samples?
>
> LT. COL. ROBINSON: There\'s three consent forms all together. A
> general, HIV, and then the future use.
>
> DR. HARRISON: Just to cut to the chase, I was curious about the high
> percentage\--very high percentage that agreed to allow\--
>
> DR. MICHALEK: Yes. We were really elated\--
>
> DR. HARRISON: \--to be used, and I made that, for sure, one of the
> objectives of my\--
>
> DR. MICHALEK: Yes. We didn\'t expect high numbers like that.
>
> DR. HARRISON: \--asking the participants\--
>
> DR. MICHALEK: Yeah.
>
> DR. HARRISON: \--and can say that of the several people that I talked
> to, and asked specifically how these numbers came to be so high, their
> basic response was that they were surprised that the numbers were so
> low. One of the guys looked around and said, \"Should have been 100
> percent.\" It was like, \"Who the hell\--?\"
>
> \[Laughter.\]
>
> Am I right, Mike? I mean\--
>
> DR. STOTO: Yes. Absolutely.
>
> DR. HARRISON: \--Mike was there. So\--
>
> DR. MICHALEK: Well, good, I\'m glad you went over there today and
> talked with them.
>
> DR. HARRISON: So\--well, that was something that I was specifically
> interested in, in terms of the continuation of the study, and ethical
> continuation of the study. So I wanted to make sure that we looked and
> asked about that.
>
> DR. STOTO: Bob said, it was exactly right. It\'s rare that you see
> anything that\--
>
> DR. HARRISON: But, you know, it\'s very interesting. These are very
> thoughtful me. And\--I forget his name, but the guy I was talking to
> was from Tucson\--kind of short, was a mechanic, I guess, in\--back
> during Nam. You know, he said, \"Well, you have to realize that this
> is a different bunch of people. These are people who volunteered for
> service in Viet Nam, and who have this military approach, where they
> are willing to do the things that are asked of them. And they want to
> do those things.\" I\'m almost quoting. He almost made me want to
> volunteer.
>
> \[Laughter.\]
>
> So, put in that context, that this is\--that what we have here are,
> you know, a few thousand\--essentially we have a few thousand warriors
> here who have been asked if they want to continue and said, \"Well,
> sure\"\--you know, when\'s the next meeting.
>
> Some of them expressed an interest in having the entire study
> continue, and my response to that was that I thought that was very
> unlikely, because the conditions that established it in the first
> place were political conditions with a lot of pressure on the Air
> Force, and I haven\'t heard that that was occurring. But, you know,
> maybe I overspoke. But that was my opinion. And I made sure that they
> knew that was just my opinion and no one else\'s. But for most of them
> there, that\'s\--they would just as soon the thing just kept on going.
> But if it doesn\'t, then they\'re happy to have their data and
> materials used for other studies.
>
> DR. MICHALEK: So of the 1,499 respondents at the time this slide was
> made, all but 21 said yes to Agent Orange or other health conditions.
> So these are the numbers. And it\'s pretty constant across groups. The
> comparisons are saying yes to the first option more than the Ranch
> Handers, but I doubt if that\'s a significant difference.
>
> Slide, please.
>
> \[Slide.\]
>
> So what I did then was I simply combined the first two options to a
> \"yes,\" meaning Agent Orange or other military health issues, or
> Agent Orange only,\" and a nil otherwise\--
>
> Slide, please.
>
> \[Slide.\]
>
> \--and I simply looked at the simple binary \"yes/no,\" against group.
> And you see 99 percent of the comparisons said yes, to 98 percent of
> the Ranch Handers.
>
> Slide, please.
>
> \[Slide.\]
>
> And here it is broken out by military occupation, and within the
> comparisons it\'s pretty much 99 percent across the board: officer,
> enlisted, flyers and ground.
>
> Ranch Hand, please.
>
> \[Slide.\]
>
> And there you see the same thing in the Ranch Hand cohort.
>
> DR. HARRISON: Enlisted flyers were 100 percent?
>
> DR. MICHALEK: Yes, 100 percent of the Ranch Hand enlisted flyers said
> yes.
>
> Back up a slide. There. Forward a slide.
>
> \[Slide.\]
>
> 100 percent. So this was as of a few weeks ago\--1,499. We\'re
> expecting about 1,960 total.
>
> **Update on Study Shut Down and Transfer of Data**
>
> DR. MICHALEK: Slide.
>
> \[Slide.\]
>
> We wrote a talking paper recently and submitted that to SG, listing
> various options from top-of-the-line, which would be full-blown
> continuation, to the bottom option which was to stop and destroy
> everything. And so we gave the options to SG, which I think was
> transmitted to Congress, for these various kinds of options\--all of
> which involve transfer to another agency, because the Air Force has
> considered itself has having fulfilled its obligation to this cohort
> as of October 1, 2006.
>
> And so the idea is that if it were to continue, another agency would
> have to take over operations\--such as the VA, or CDC, or HHS, or
> whatever.
>
> So we have just laid out this first-cut list of options for
> decision-makers to think about, as to what to do. And later on we
> would provide budget estimates. We haven\'t done that yet. Manny
> Blankus was to give us some estimates of cost.
>
> DR. CAMACHO: Who were these alternatives laid out to? Just the
> Congressional staff, or\--
>
> DR. HARRISON: Surgeon General of the Air Force. He said \"SG.\"
>
> DR. CAMACHO: Does it have to go through a chain of command? Is that
> what you\'re telling me?
>
> DR. MICHALEK: I\'m sorry\--please repeat the question.
>
> DR. CAMACHO: This has been laid out to\--the Surgeon General you said?
>
> LT. COL. ROBINSON: \[Off mike\] Fields.
>
> DR. CAMACHO: Has any of this drifted down to the Veterans Affairs
> Committee, or any interested stakeholders in the veterans community?
>
> DR. MICHALEK: I don\'t know to whom these have been given. I suspect
> they were given to the House and Senate Veterans Affairs Committee
> staff, but I don\'t know.
>
> DR. HARRISON: These were\--to the staffers.
>
> DR. MICHALEK: That\'s true.
>
> \[Comments off mike.\]
>
> DR. MICHALEK: I agree. It\'s the House and Senate Veterans Affairs
> staff in November\--on November 20^th^, I believe, last year. And the
> slides were these options.
>
> DR. CAMACHO: Is it appropriate\--can I ask\--there\'s somebody from
> the VFW here. I just wanted to ask\--do staff people ever contact
> National, and tell them about these options? Do you know?
>
> MR. LANGER: They\'re aware of them.
>
> DR. CAMACHO: So National\'s aware of these options that are laid out.
> \[Off mike.\]VA may also, and possibly the Legion?
>
> DR. MICHALEK: Tied up with these options are the current\--of
> conducting the study. There are three integral pieces to the study
> that make all of this work. There are the computer data bases, the
> software; there are the 65,000 specimens in the freezers; and there
> are 6 million documents on our shelves, which has all been scanned
> into a Windows-driven system that we can bring up any document on any
> subject.
>
> We have staff at Brooks, including myself, that have been working with
> the data since 1980, and we know where everything is. The data is not
> totally pretty. Some of it clean and ready to go, and the rest of
> it\--we have hundreds of data sets, and thousands of SAS programs that
> are not fully documented. They are themselves self-documenting and you
> could read any program and figure out what it\'s doing, but it may not
> be the latest version. There may have been revisions later. There may
> be subsets or exclusions or conditions on data that came later. And so
> there\'s many years of experience here that would be lost if the
> program were simply terminated and handed over to someone else. It
> would create, we think, unacceptable delay in producing new work,
> without the benefit of the current staff.
>
> And so, from the bench level, we all know\--as anyone who would work
> on the study, perhaps including Bill Grubbs\--that the most efficient
> way to continue the study would be to include at least some of the
> people on the current staff.
>
> Slide, please.
>
> \[Slide.\]
>
> And there\'s the last of the options, down to: just store it all away
> somewhere in a warehouse, finally to destroy it. And that option is
> there because even in the worst case, where no interest is expressed,
> we do have materials that require a chain of custody in lock-and-key.
> We have the biological specimens that include DNA. We have the
> millions of documents, photographs and signatures and medical records
> on the men, their wives and their children. And all of that would have
> to be kept guarded, or else totally destroyed\--one or the
> other\--because of the threat of loss of privacy.
>
> So it costs money even to do nothing, in other words, with this data.
> And all of these issues about what to do with the data are tied up
> with IRB rules and the current laws regarding human studies\--which
> have driven the withdrawal of our data from our web page on the
> current\--
>
> DR. CAMACHO: Some of those issues are at least beginning to be
> addressed when you\'ve asked the question about continuation.
>
> DR. MICHALEK: Yes. That was why we gave the consent form.
>
> By the way, regarding data release, as you recall we released the data
> on the web page and then we were told to pull it back by our
> lawyers\--which we did. The lawyers have advised us to provide yet
> another consent form to the study subjects, asking them about their
> willingness to let us put their data on the web page, that we have not
> yet administered that consent form. We did not want to confuse them
> with that issue, as opposed to the future-use issue.
>
> And so we will consider the possibility of such a consent form after
> everyone is through at Scripps.
>
> That\'s it. Thank you very much.
>
> DR. STOTO: Is that a HIPPA consent?
>
> DR. MICHALEK: Yes.
>
> DR. GOUGH: Joel, I have a question about something we haven\'t talked
> about in a long time. And maybe it just fell by the wayside\--but,
> five or six years ago it seems, you guys were going to collaborate
> with the National Institute of Dental Health, or National Dental
> Institute, to do a study of mercury in amalgams, and blah, blah, blah,
> blah.
>
> What happened?
>
> DR. MICHALEK: What happened is that the NIDR\--or NIDCR, now\--did
> participate in the \'97 physical, had dentists on site at Scripps, and
> they examined the mouth, or the teeth, of nearly all of our study
> subjects. But they\'re now analyzing mercury exposures through dental
> amalgam against neurological endpoints\--the same data we used in our
> dioxin analysis.
>
> DR. GOUGH: So it\'s just\--it\'s ongoing. It\'s not done.
>
> DR. MICHALEK: It\'s ongoing. They\'re also analyzing this immunology
> data and cognitive function. They\'re using our health endpoints to
> ask the questions about mercury.
>
> DR. GOUGH: Okay.
>
> DR. STOTO: That\'s important, because I think that could be 500 of
> those things\--that had nothing to do with Agent Orange.
>
> DR. MICHALEK: Yes.
>
> DR. GOUGH: This is the example of it.
>
> DR. MICHALEK: And that\'s why this consent is so important.
>
> DR. STOTO: Even with the existing data.
>
> DR. MICHALEK: That\'s right.
>
> DR. TREWYN: A couple of things\--I think one, because DOD, subsequent
> to Viet Nam, did essentially the same thing with Persian Gulf, of
> ignoring health issues of those coming back from there, and Congress
> has had to, you know, go through all sorts of issues and whatnot
> dealing with that situation\--and, has essentially mandated that in
> the future, tracking and analysis and everything has to be done, I
> think a critical issue here is because of the lessons learned along
> the way with this study, and of the wealth of data that\'s already in
> hand\--I mean, clearly, I think this group needs to try to ensure that
> these samples are not just\--and the data isn\'t just all trashed.
>
> I think that could be a very important reference group for future
> sorts of things, and especially if specimens are saved, the samples
> and whatnot, who knows what other things one can go back then and
> analyze and determine.
>
> So I would just\--I\'m throwing in my vote that I think, before this
> is all wrapped up, that somehow the exercise that has occurred here,
> it needs to set the stage for maybe doing better in the future; that
> when we ship people off, that maybe there is a responsibility to be
> looking at them.
>
> DR. CAMACHO: We did touch upon this. And we talked about\--we\'re
> going to write a letter. The Chairman was going to write a letter.
>
> I know a lot about these people because it\'s part of what I do. I
> know some of these committee\--
>
> DR. HARRISON: Well, wait a minute\--
>
> DR. CAMACHO: \--Veterans Affairs, I know. If you\'re talking about how
> aware is the members of the Veterans Affairs Committee and so on, is
> it in their face? That\'s\--there\'s a lot of things. You\'ve got to
> keep it up on them.
>
> In other words, if I had a commitment to say I wanted this study to
> get level three preservation\--whatever\--I would be on the Committee
> now, talking about it, in a letter form and so on. And I\'d be working
> it.
>
> Is that our job as a committee, I\'m not sure. That\'s another
> question.
>
> DR. HARRISON: Well, I\'m not sure that\'s our job as a committee, but
> let me try\--see if Len agrees with me, with my answer to you about
> your vague recollection of a letter that was supposed to be done.
>
> We actually drafted a letter at one of our meetings to the Secretary
> of HHS. And my understanding of the way these things occur\--and it
> was a good letter. I mean, it had all kinds of juicy stuff in it, and
> we sent it off. And my understanding of the way those things are
> handled, is those letters actually come back through the channel to
> the FDA office, which is charged with preparing the response to the
> letter that \[inaudible\] sent, which then gets returned to Tommy
> Thompson, who then\--whose staff then does whatever they do.
>
> And my recollection was that the letter never came back\--that either
> the letter never came back through the chain, or it came back through
> the chain, but was never dealt with because of some communication
> problems within the FDA.
>
> DR. SCHECHTMAN: Well, in general, there have been communication gaps
> now with the DHHS. There has been a failure on the Department to
> return phone calls, respond to e-mail messages, and so on.
>
> So we no longer know who to contact. We\'ve tried\--we\'ve worked our
> way up through the chain of command, and nobody\--
>
> DR. STOTO: There\'s just a big void there.
>
> DR. SCHECHTMAN: Yes. No, it has nothing to do with FDA. FDA is doing
> its job to try and reach these people, and these people are not
> responding. We don\'t know what\'s going on.
>
> DR. CAMACHO: But you would say it\'s not our responsibility as a
> committee to bring this to a political level\--
>
> DR. STOTO: I think that it was appropriate for us to do what we did.
> We put that it was a scientific issue with respect to\--
>
> DR. HARRISON: And, in fact, I think we shared copies of those letters
> with interested\--I hate to use the word\--\"stakeholders.\"
>
> DR. STOTO: Yes. But I think it\'s not appropriate for us to go beyond
> that and lobby what they do with it. We could remind them that we sent
> that letter.
>
> DR. HARRISON: Right. I think it depends on the reason that you\'re on
> this committee, too. Some of us are on the committee in the guise of
> being scientists. And we\'re supposed to act like scientists and not
> know what the hell we\'re doing.
>
> Other people are on this committee in the guise of being advocates.
>
> DR. STOTO: Well I think that we all\--
>
> DR. HARRISON: \--and\--
>
> DR. STOTO: \--as scientists. But some people have other jobs in life.
>
> DR. TREWYN: But also if there\'s use for the data, whether it\'s for
> this purpose or not, I think even the non-advocate scientists who are
> on the committee should perhaps feel that because there may be more
> that can be done with it, that losing valuable data is not a good
> thing.
>
> DR. HARRISON: Well, I certainly think there\'s a consensus on this
> committee that these are important samples, this is important data.
> And we have no idea if there will ever be another study like this. We
> have no\--you can criticize it for having \"small numbers,\" and all
> this business. But we have no idea\--
>
> DR. STOTO: Let me suggest two things. One is that, given that we just
> got the report that the letter we sent was never responded to, let\'s
> send it again\--same letter. \"Dear Secretary Thompson, I think you
> missed our letter. If you could please respond.\"
>
> DR. HARRISON: And sign it \"Usama.\"
>
> DR. GOUGH: \"Dear Tommy. What have I done? You never call, you never
> write.\"
>
> \[Laughter.\]
>
> DR. MINER: As far as background package, when we\--the Senate and
> House Veterans Affairs Committee, we provided them a copy of that
> letter.
>
> DR. HARRISON: So that\'s probably the most widely distributed,
> non-responded to letter\--
>
> \[Multiple simultaneous comments.\]
>
> DR. HARRISON: Okay. One at time, or\--Ms\--oh, Lord, I\'ve forgotten
> your name.
>
> COURT REPORTER: It doesn\'t matter.
>
> DR. HARRISON: Yes, it does, if you go ballistic.
>
> DR. STOTO: The VA\--the Department of Veterans Affairs is another
> potentially interested party. And the question is how to get it to
> them?
>
> DR. HARRISON: Well\--
>
> DR. STOTO: I mean\--
>
> \[Multiple simultaneous comments.\]
>
> DR. HARRISON: Okay. So\--
>
> DR. CAMACHO: But you never got feedback from Tod or Michael Doritian?
>
> DR. STOTO: No. I mean, the people in the Air Force and FDA can\'t do
> that. But the service organizations can do that.
>
> DR. CAMACHO: Can I do it? I can do it as an individual\--anything I
> want.
>
> DR. STOTO: Right. You bet.
>
> DR. CAMACHO: I shouldn\'t\--
>
> DR. HARRISON: Well, you can\'t write a letter under the\--you know, as
> a\--
>
> DR. CAMACHO: I could write a letter and say it just so happens that
> I\'m a member of this committee\--
>
> DR. TREWYN: And that you may have not seen this letter.
>
> DR. HARRISON: Well, what are you\--
>
> DR. TREWYN: It would be good if we could all get a copy of that. I may
> have gotten it before, but I don\'t recall it.
>
> What I find is, if you really want, you know, some level of
> continuation, you\'ve got to find a conduit that\'s legal,
> ethical\--you\'re not supposed to talk across and all that other
> stuff.
>
> DR. HARRISON: I\'m having trouble remembering a lot of the letter, but
> let me bring up, I think another point that is in this letter. And
> that is, it\'s not enough simply to preserve the materials; that there
> needs to be a process that makes the presence of the materials known
> to the scientific world, and that provides a process for evaluation of
> requests to use the materials. Otherwise\--
>
> DR. CAMACHO: The census model\--it\'s almost like you apply to be sort
> of\--for lack of a better\--you can apply and you get sanctioned as a
> sort of census fellow, and you propose to them what you want to do.
>
> DR. HARRISON: Well, Paul, what I remember is the reason for Thompson
> as the object of the letter was that HHS\--oh\--
>
> DR. SCHECHTMAN: Here\'s the letter.
>
> DR. HARRISON: \--was that HHS had the requisite review facilities.
>
> But\--\"Dear Secretary Thompson: As Secretary of the DHHS Advisory
> Committee on the Air Force Health (Ranch Hand) Study, I am pleased to
> write you on behalf of the committee to apprise you of an important,
> time-sensitive opportunity for research on the health of Viet Nam
> veterans, environmental health, and aging and a critical need for your
> action.\"
>
> \"The purpose of this letter is to make you aware of this issue, and
> to request a meeting to discuss the disposition of this irreplaceable
> material.\"
>
> \"The Air Force Health Study was started in the 1980\'s at the
> direction of the White House, and with the support of Congress, to
> study the health of Viet Nam veterans and the health effects of Agent
> Orange and other herbicides used in Viet Nam. Approximately 1000 men
> who were involved in spraying these herbicides in Viet Nam, and
> thousands of carefully selected comparisons, have been followed for 20
> years in an epidemiologic study. More than 2,000 of these men have
> volunteered to participate in a thorough clinic examination every five
> years.\"
>
> \"The results of the study have been very helpful in showing the
> likelihood that diabetes and other conditions are associated with
> exposure to the herbicides, or to a chemical contaminant called
> dioxin. The study, therefore, has been influential in determining
> Federal policy for veterans\' compensation.\"
>
> \"During the course of this study the air Force has developed a very
> extensive data base of health information on thousands of men. The
> data includes information on a wide range of health outcomes,
> generated from medical records and vital statistics, as well as the
> study\'s clinical examinations and associated interviews. In addition,
> the study scientists have gathered extensive and detailed information
> on environmental and occupational exposures and behavioral risk
> factors, based on military service records, occupational records, and
> subject interviews.\"
>
> \"These exposures include not only herbicides and dioxin, but also a
> wide range of other chemicals and environmental risks. The Air Force
> has made the data used in published analyses available to the public,
> but even more data that are potentially useful to future investigators
> are available in the Air Force archives.\"
>
> \"The study has also generated an extensive amount of biological
> samples from the men in the study. This includes blood and other
> tissue samples taken at clinical examinations over a 20 year period.
> Based on these samples, for instance, the study\'s scientists were
> able to measure the concentration of dioxin in the subject\'s blood at
> one or more clinical examinations, and investigate possible
> relationships between higher dioxin exposures and health effects.\"
>
> \"At the Advisory Committee\'s meeting on April 2, 2001, we discussed
> the Air Force\'s plan to close down the study after the data from the
> final examination are analyzed in 2006. This closure would include the
> destruction of all the data and biological samples that have been
> gathered over two decades. The expertise of the project staff, who
> understand how the data were generated and stored, would also be lost.
> These are irreplaceable data that, if destroyed, will be a grave loss
> to the nation.\"
>
> I didn\'t realize it was this long.
>
> \"The data and biological samples are a precious scientific resource.
> Scientists can use them for further health studies of Viet Nam
> veterans and service members and veterans of other and future
> conflicts. Because such extensive data has been gathered on several
> thousand men, the data and samples can also be extremely useful in
> scientific research on other environmental and occupational health
> issues.\"
>
> \"Additionally, because of the detailed longitudinal information on
> risk as well as the health outcomes, the data could be very valuable
> to scientists studying normal aging processes. Because new assays are
> likely to be developed in the future, the biological samples
> potentially can contribute far more to scientific understanding than
> the existing statistical data.\"
>
> \"The Agent Orange Act of 1991 calls on the Secretary of Veterans
> Affairs to establish a system for collation and storage of biological
> samples to facilitate future research studies and, in consultation
> with the National Academy of Sciences, to conduct feasibility studies
> from additional research.\"
>
> \"Archiving the Ranch Hand data and samples could help to meet these
> Congressional mandates. In order to capitalize on the rich scientific
> information that currently exists, as well as the contributions of
> thousands of Viet Nam veterans who participated voluntarily in the
> study, the Committee urges you to encourage appropriate scientists
> from NIH, CDC and ATSDR to meet with representatives of the Air Force
> and the Department of Veterans Affairs to consider opportunities to
> archive and preserve the Air Force Health Study and biological
> samples, and to make the scientific community aware of this resource.
> If such an archive were available and made known to scientists, it
> could provide an opportunity for scientists to propose research
> projects that would be funded through existing NIH and other Federal
> programs.\"
>
> \"We recognize that there are complex confidentiality and other human
> subjects issues with response to our proposal\--\"\--yada, yada, yada.
>
> \"As mentioned\--\"\--\"would like to meet with you soon to initiate a
> discussion of how these activities might proceed.\"
>
> DR. STOTO: I think the opening is that we\'ve got this data that the
> participants wanted to\--that they\--be archived. So one thing we
> might do is to say, \"Dear Mr. Secretary, we sent you this letter.
> Since then, we\'ve learned\--\"\--
>
> DR. TREWYN: Tommy still hasn\'t finished reading the letter yet, is
> the problem.
>
> \[Laughter.\]
>
> DR. HARRISON: This kind of read like a letter written by a committee.
> Well, it\'s easy to say, and it\'s easy to do.
>
> Are you saying that there should be a second letter sent?
>
> DR. TREWYN: Yes. Because we\'ve now a huge number\--these 96 percent
> or whatever the total is\--close to 99\--who want this material
> utilized.
>
> DR. HARRISON: And you\'re saying that we should send the original
> letter, with a cover letter\--
>
> DR. TREWYN: Yes.
>
> DR. HARRISON: \--simply saying that since your previous non-answer\--
>
> \[Laughter.\]
>
> DR. TREWYN: \"I was pleased\--\" to do it before. I\'m less pleased
> now, but I still want you to do it.
>
> DR. GOUGH: You know, I think also that this would involve another
> paragraph\--but I think that given the health care crisis in this
> country, which is really related to the fact that we\'re all getting
> old, that we should focus on the fact that this\--longitudinal studies
> are just never, ever, ever done, and this is one.
>
> And we\'re up into the fifties and sixties and early seventies, now,
> with these guys. And it should be finished.
>
> DR. HARRISON: I would have thought nineties.
>
> DR. GOUGH: Well, only one man\'s in his nineties, isn\'t he?
>
> DR. TREWYN: I mentioned aging in that letter, but it was just sort of
> a throwaway. But now it\'s becoming\--
>
> DR. GOUGH: But, see, I think\--related to that, which is a major
> crisis, it might help.
>
> DR. CAMACHO: Well, I think you should cc the Committee on Veterans
> Affairs.
>
> DR. HARRISON: What I think we did the last time was we did not\--yes
> it was: Secretary of Veterans Affairs and Secretary of the Air Force
> were cc\'d.
>
> DR. CAMACHO: But not the Secretary\--I\'m talking about Congressional.
>
> DR. HARRISON: I think that others had received copies of the letter,
> although they were not cc\'d. And I think that\'s probably the way it
> should be done.
>
> \[Comments off mike.\]
>
> DR. HARRISON: You\'re misunderstanding me, Paul. I think they did
> receive letters. And I know, for instance, that\--the woman up at
> Yale\--
>
> DR. CAMACHO: Ohh\--Linda.
>
> DR. HARRISON: Yes. Yes. I know she got a copy of it.
>
> DR. STILLS: Do we need to give these people a call, like the lady who
> were talking about. You know, a letter and then follow-up with a call
> from you, Bob or Len, so you could make sure that we keep the
> momentum.
>
> But the one thing I want to underscore is that in talking to the Viet
> Nam vets today, the general consensus from them\--and I think you said
> the same thing, Bob\--was that they wanted this study to continue.
> They\'re willing to come back and do\--they\'re available for
> additional tests to be done. They want to make sure that the tissues
> are preserved, and they\'re available not only in terms of
> understanding the health effects in Viet Nam veterans, but also use
> this study in terms of understanding the health effects of the aging
> American population.
>
> DR. HARRISON: Yes.
>
> DR. STILLS: And I think\--you know, but the power of the survey that
> you guys are doing, where you have numbers\--
>
> DR. HARRISON: That\'s not a survey. Those are people\--
>
> DR. STILLS: But a consent\--
>
> DR. HARRISON: \--that signed consent forms allowing their data to be
> kept.
>
> DR. STILLS: So let me say that differently. So with power of the
> consent that we\'re going to get back from the consent forms-I mean,
> that\'s powerful. And, you know, we could make the letter a little
> more personal, that we the Committee had an opportunity to meet with
> the veterans\--underscoring that, you know, they were a hundred
> percent supportive; get a follow-up letter and attach the original
> letter.
>
> DR. CAMACHO: Well, send a second letter to the Secretary and see if we
> get another non-response.
>
> DR. HARRISON: Let me make the following comment.
>
> I think as an Advisory Committee, I think it\'s not only appropriate
> but sensible of us to write a letter to the Secretary of HHS,
> apprising him of an opportunity and the potential for a lost
> opportunity.
>
> I think it\'s acceptable for us to make sure that interested other
> parties, such as that guy over there, and other people like them, are
> aware of the letters that we\'ve sent, and are aware\--because this is
> a public meeting\--of the discussions that we\'ve had, and the reasons
> that we think these are important.
>
> But I think it\'s not appropriate for us to lobby for this change. I
> think that\'s somebody else\'s job to do. We set the table, we provide
> the scientific overview, but somebody else has to go to Congress and
> all the other places that people go to.
>
> DR. TREWYN: But by this being available they\'ll be able to do that.
> And I agree. And I would think within NIESH that, you know, some of
> the relevance of this, that that would be in your agency\'s best
> interest that this material be available; this data be available\--as
> it would with others.
>
> So I think it\'s\--you know\--
>
> DR. HARRISON: I was just asking Len if he could pull up the letter I
> wrote to Ken Olden.
>
> I think the other reality, of course, is that every agency is saying,
> \"Oh, boy. That\'s a great idea. And I think so-and-so agency would be
> a really great agency to handle this.\" Because, you know,
> everybody\'s short on cash.
>
> But we\'re in agreement then that there\'s going to be a second
> letter./ We\'re in agreement that the second letter is mainly going to
> point out that since our first letter, the Ranch Handers themselves
> have overwhelmingly opted to have their data maintained and would
> continue to participate if asked to do so.
>
> DR. GOUGH: And are wiling for it to be used in other health studies.
>
> DR. HARRISON: And are wiling for it to be used in other health
> studies.
>
> Yes, Joel?
>
> DR. MICHALEK: I wanted to remind you that the entire and complete
> consent data base will be ready by the middle of April.
>
> DR. HARRISON: Yes.
>
> DR. MICHALEK: So you\'ll have these numbers on all 1,900 if you want
> to wait.
>
> DR. HARRISON: Okay. But, you know, whether it\'s 98 percent, or 99
> percent, or 97 percent\--it doesn\'t make a damn bit of difference.
>
> DR. STOTO: It can only get worse, Joel.
>
> \[Laughter.\]
>
> DR. HARRISON: Okay.
>
> DR. TREWYN: It\'ll take you \'til April to write it. So\--
>
> DR. HARRISON: Is it the sense of the committee that within those
> general constraints, I can write a letter on behalf of the committee
> without having to go back and, you know\--
>
> VOICES: Yes.
>
> DR. CAMACHO: Talk about both\--and talk to the\--
>
> DR. HARRISON: Or do you want, say for instance\--does anyone want to
> work\--
>
> \[Simultaneous comments.\]
>
> DR. STOTO: I\'ll volunteer, if you want to e-mail it to me, or
> something like that.
>
> DR. HARRISON: If you want to do that\--I wasn\'t thinking about an
> approval process. I was just thinking that if there was anyone else
> that wanted to see it and wanted to, you know, perhaps make comments
> on it, that would be fine with me. And if you want to do that I\'ll
> make sure I have your e-mail address, or whatever, and we can do that.
>
> Okay?
>
> Well, everyone in favor of listening to Joel talk about publishing
> strategies\--okay. I\'m sorry, Joel. Go ahead.
>
> **Publishing Strategies**
>
> DR. MICHALEK: This is just an abbreviated version of our research
> plan, showing you what\'s in progress right now.
>
> Interesting\--that you might find interesting\--is a paper by
> Tennenbaum, reporting\--showing a connection between dioxin and
> osteoporosis, and we\'ve launched a study, based on a trend we found
> of increased risk of osteoporosis with increased dioxin level in Ranch
> Hand veterans.
>
> I visited Tennenbaum recently in Canada, and we are taking his new
> case definitions and applying that to the data base. That\'s just an
> example of evolving\--of science that has been used in the study to
> answer questions from veterans. This analysis was prompted by e-mail
> from veterans who asked me: \"My bones are breaking easy, and so are
> those of my buddies. What\'s going on with osteoporosis.\" I did a
> literature search, I found a mechanism, and I contacted the author,
> and we\'ve launched a study on osteoporosis and dioxin.
>
> Slide, please.
>
> \[Slide.\]
>
> These other points here are that we have the review-of-systems data
> that\'s never been analyzed. At every physical exam these individuals
> respond to an extensive questionnaire about symptoms, including aches
> and pains, and headaches, and tingling of the feet and so on. And
> that\'s never been looked at. And we have launched a study with CDC to
> analyze that data against dioxin.
>
> And the cancer SEER paper you saw today. The mortality you saw today.
> There is a paper out of Germany showing a relation to color vision and
> dioxin in animals. We are the only study in the world with repeated
> color vision data, taken in 1987 and in 1992 at Scripps on 2,000 men
> with dioxin levels.
>
> So we\'re collaborating with Dr. Lyn Frame at Texas Tech University to
> consider a relation, if any, between dioxin and color vision. And Dr.
> Frame will also re-analyze our data in combination with sleep disorder
> information and dioxin to explore a relation there.
>
> I spent the first day of this trip with investigators at the
> University of California-Berkeley, asking us to collaborate in a
> pharmakinetic study combining the Ceveso information with the Ranch
> Hand data on repeated measures of dioxin levels.
>
> We have a paper with Dr. James Dwyer, University of Southern
> California, who measured the carotid wall thickness\--the intima
> thickness data in 1992 and \'97, I believe, which is under way but not
> complete. And we have a paper, collaborated with Drs. Pavuk and
> Schecter at the University of Texas at Dallas on prostate conditions,
> including all conditions related to the prostate, not just prostate
> cancer.
>
> We want to summarize everything that we\'ve learned about skin
> exposure, BMI and dioxin in a separate paper. And, finally, we have an
> unpublished document relating cardiovascular disease and dioxin that
> we\'re still working on.
>
> Slide.
>
> \[Slide.\]
>
> Publication is a long process. For example, our paper on dermatology
> took us six years to get published. That was in the [Archives of
> Environmental Health]{.underline}. Our paper on psychology took five
> years, after submission to a number of journals. It is now in press in
> [Military Medicine]{.underline}.
>
> Slide, please.
>
> \[Slide.\]
>
> And hematology took four years, with the [Archives of Environmental
> Health]{.underline}. There are three years left to the study. Many
> times a paper will be submitted to a journal and we wait a year to get
> the first referee report back.
>
> So we are interested to know your ideas regarding publication.
>
> Slide, please.
>
> \[Slide.\]
>
> There are three ideas come to mind, of course. We need to find
> committed collaborators who are willing to drop what they\'re doing,
> to revise their own research agenda, and work with us, without any
> inhibition. And that\'s not easy to find.
>
> We\'re going to try to better work networking our papers before
> submission to a journal to send to our colleagues at CDC, NIEHS and
> EPA, to get feedback before we send to a journal. We have not done
> enough of that.
>
> And, finally, we\'re going to try to do a better job of tailoring the
> paper to the journal. And, certainly we\'re going to use everything
> you\'ve said today at this meeting to help us revise the hypertension
> paper. The hypertension paper has been in progress for four
> years\--just an example of how long it takes to get material
> published.
>
> The emphasis is on publication because the National Academy of
> Sciences ranks papers according to their publication status. And
> technical reports are at the bottom of the list, in terms of their
> influence. Papers published in scientific journals have most influence
> on public health policy.
>
> Slide, please.
>
> \[Slide.\]
>
> That\'s it. Thank you very much.
>
> DR. STOTO: Joel, when you have a collaborator, I presume you don\'t
> have any funding with it.
>
> DR. MICHALEK: No.
>
> DR. STOTO: It\'s just the data.
>
> DR. MICHALEK: We\'ve collaborated with individuals around the world.
> Tennenbaum\'s a good example. Dwyer at USC. Chack at the University of
> Illinois. Garabrant, the University of Michigan. All these people are
> working with us for free, without funding\--except for UT Dallas and
> Schecter. That\'s one of the few contracts we have let. And UC-Davis.
>
> UC-Davis is a good example of the depth t which we\'re studying
> diabetes. We\'ve extracted the adipose tissue and Dr. Natsimura is
> analyzing glucose transporters at the cellular level to ask questions
> about diabetes and dioxin.
>
> Separately, we are under contract\--SCIC\'s under contract with us to
> do a longitudinal analysis of all data in the study as a follow on to
> the last report\--to do a longitudinal analysis of the entire study.
>
> DR. HARRISON: Ron?
>
> DR. TREWYN: I feel compelled, at least once every meeting, to say, you
> know, that the original focus was not really dioxin. I know that this
> dioxin is going to show some things. I hope, in this whole variety of
> other areas, that the sort of analysis that has been done on cancer
> will at least be applied, to see if there are other areas where that
> is relevant beyond just cancer. So maybe it\'s beyond just dioxin
> effect.
>
> DR. MICHALEK: It\'s interesting that in these new analyses you saw
> this morning on cancer, as soon as we saw those patterns we ran to
> diabetes and heart disease and hypertension and birth defects to
> determine whether there\'s similar patterns there. And the patterns
> are restricted to cancer\--that we see the increases in cancer risk.
>
> Yes?
>
> DR. TREWYN: But you won\'t ignore it.
>
> DR. MICHALEK: No, we will not. No, that\'s on the table from now on.
>
> DR. TREWYN: Okay.
>
> DR. MICHALEK: Right.
>
> DR. HARRISON: Joel, I think we\'ve said this before, but papers are
> mother\'s milk to an academician. If you have somebody that you\'re
> paying to do the work, they shouldn\'t be on the paper. If you
> have\--in other words, if you\'ve contracted with someone to perform a
> certain job, you\'ve contracted them to perform the job, they give you
> the data back, they have no ownership over it.
>
> If they\--
>
> DR. STOTO: It\'s work for hire, versus a research collaboration.
>
> DR. HARRISON: Exactly.
>
> DR. MICHALEK: We funded two professors.
>
> DR. HARRISON: I\'m not\--look, I\'m not telling you that you should
> reverse anything that you\'ve already done. But I\'m sure you know
> this\--
>
> DR. STOTO: \[Off mike.\]If that were the case\--
>
> DR. HARRISON: Huh?
>
> DR. STOTO: If that were the case, I would never publish anything with
> the kind of job that I have.
>
> DR. HARRISON: Well, under certain circumstances, you should no longer
> publish. I mean, the\--but you\'re in a different\--you\'re in an
> entirely different area. I\'m talking about academic medicine. And in
> academic medicine, if you want to survive then you must publish. And
> if you can get on a paper with someone who\'s already generated the
> data, and all you\'ve got to do is write a little something in the
> introduction and the discussion, that\'s a fair exchange. And you
> shouldn\'t expect, nor should you expect to give them, any more
> inducement than that.
>
> DR. MICHALEK: That\'s the relationship we\'ve had for the last 15
> years.
>
> DR. HARRISON: Okay.
>
> Anything else before we declare victory.
>
> DR. STOTO: \[Off mike.\] At the National Academy of Sciences has
> exactly the opposite. They, in fact, do have funds they
> share\--they\'ve got the data. They set up an arrangement\--I think
> it\'s a contract-with academics who analyze the data. The put together
> a paper that\'s showing the authors\--by the academics.
>
> DR. HARRISON: Well, if you have raw data that you need analyzed and
> someone to draw to conclusions from it, that is a different situation.
> Because then the person has to have put intellectual content into it.
> But if you already know that you want to make a correlation between
> pro-insulin levels and BMI, and you\'ve already measured the BMI in
> your subjects; you\'ve already drawn the pro-insulin levels and have
> them frozen away, and you want to send them off to a lab to have
> pro-insulin levels done\--
>
> DR. STOTO: But that\'s not what we\'re talking about. We\'re talking
> about people\--Joel going out and finding experts in the field.
>
> DR. HARRISON: Well, Joel and I have\--I disagree with that, for some
> of these people who are publishing. But Joel\'s doing the best he can,
> without a lot of input from the Advisory Committee on collaborators
> that he can use.
>
> Any other comments?
>
> \[No response.\]
>
> Well, I declare a victory. And we\'re going to go home.
>
> DR. GOUGH: No, no. On the contrary. I really think that today\'s
> meeting was almost exemplary\--despite the fact that all four of
> us\--or six of us talk at one time.
>
> And Joel was on his feet most of the day. Most of the time you were
> talking about very concrete data. We\'d look at the numbers, we\'d
> look at the tables and try to figure out what the hell you were doing.
> And we could make comments. And I think he did really well. And Bob
> kept us to the schedule. It was a real good deal. And I think, you
> know.
>
> DR. HARRISON: Well, thank you. Unfortunately the transcriptionist has
> stopped transcribing, so we won\'t have\--
>
> \[Laughter.\]
>
> VOICE: Okay. So we\'re finished?
>
> DR. HARRISON: Well done. Well done.
>
> \[Applause.\]
>
> \[Whereupon, at 5:06 p.m., the meeting adjourned.\]
>
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