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?