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
PAGE
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 R
O C E E D I N G S
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 99th
percentile of the dioxin distribution in the comparison group, is the 40th
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. 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. 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--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; 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. 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,
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, 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
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
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.
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
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. 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, 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 20th 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 20th, 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. Our paper on psychology took five years, after submission to a
number of journals. It is now in press in Military Medicine.
Slide, please.
[Slide.]
And
hematology took four years, with the Archives of Environmental Health. 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.]
- - -