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9. I think you're right, I think it is 40. Okay, all right.|
So where are we now? General Category Analyses. It's right at 4:30. Do we want to do the General Health data, and listen to any other general comments and then maybe call it quits? Yes.
` DR. FAVATA: I have actually a couple more points before the general health.
DR. HARRISON: Okay, go ahead.
DR. FAVATA: One is regarding Lab QC; I think that that's important to revisit. But can you explain this tri-level controls? And also when are the samples collected?
DR. MICHALEK: The patient samples or the control samples?
DR. FAVATA: The control samples. It says under 188.8.131.52.6, the contractor shall initially run sample of each tri-level control for 20 days prior to the first physical exam.
DR. MICHALEK: The purpose of that tri-level control is to establish by means of quality control charts that the laboratory methodology is in control; namely that the laboratory instruments are measuring what they're supposed to measure.
So that for example in the area of cholesterol there will be a manufactured control that they will get from the company that makes the lab kit for cholesterol that will provide a specimen with supposedly exactly 100 milligrams per deciliter of cholesterol, and that when they run that specimen through their instrument, they had better get something close to 100.
So they will see these repeated assays of these manufactured controls, and those will also be charted and will get that from Scripps, and we can watch the control of that instrument, low, medium, high. And we do that in many different lab panels. We do it in liver, we do it in lipids, we do it in urology and we do it in many different ways.
In this respect, this study is probably unprecedented in that as the men are walking through the clinic, we at Brooks Air Force Base are visually watching in real time the instrumental accuracy of the laboratory at Scripps that's measuring the specimens in the men.
DR. HARRISON: I don't understand how that differs from what the lab has to do anyway.
DR. MICHALEK: It isn't; it's over and above.
DR. HARRISON: It's not over and above. The lab is required --
DR. MICHALEK: They're required to do that, yes.
DR. HARRISON: Every day they have to run their controls and they've got to have values that are both above and below the expected values.
DR. MICHALEK: Exactly right. But we as the we want to see it, and we do see it, and we get deliveries periodically from the lab so that we can watch to assure ourselves that there's no trend out of bounds and there are no trends in the data, and there's nothing in the data to suggest that there may be a change in the instrumentation or a change in the batch that might cause --
DR. HARRISON: I'm just asking, this implies that they're running a separate QC when all you really should be asking them for is to fax you a copy of their QC.
DR. MICHALEK: In effect most--
DR. HARRISON: You're paying them.
DR. MICHALEK: Yes, we're paying them to do a research level quality laboratory job, and we are monitoring to the nth degree the output of that process. We're monitoring on a daily basis the values of these manufactured controls and the values from the men themselves.
We worry about changes in batch, we worry about trends with time, we worry about everything and we watch it on a daily basis.
DR. GRUBBS: I think more the point is, they want the lab to use the standard data; they want to see it. They want to see it every month or every three months.
DR. MICHALEK: Every day.
DR. GRUBBS: We had a real issue with alkaline phosphatases last time, we had to clarify it; but it was because it was Joel had seen the data and saw something that was foreign to him, and we went through and explained it. But it was mainly to see the data. It's important to do, but the added requirement is please provide us this data so we can look at it, too.
DR. MICHALEK: Sometimes it can happen, for example, that the batch will change on the lab kit, and that can cause a change in the response by a small percentage. We want to accommodate that in the analysis.
DR. HARRISON: that's one of the comments that I had; I can't find it now, but you said you were going to run 20 samples for each one, and I was wondering where you came up with that, it seemed like such a small number; it's 184.108.40.206.4.
DR. MICHALEK: The idea there is to establish the quality control chart parameters prior to the men walking into the clinic.
DR. HARRISON: This is where if you do have to change lots, I'm saying that if you do have to change lots, I'm not sure that 20 samples is enough. And I'm just asking, where did you come up with that number?
DR. MICHALEK: That number was prescribed a long time ago; probably 1984 and has been reviewed ever since by this committee. And if you think that number should be increased, say so.
DR. HARRISON: I don't know what the number should be, and I suspect that the number should be different for each test, depending on the coefficient of variation and inter-assay variation for the test. And I'm saying that if there's anyplace that you might put your statistical expertise to use, it would be there.
In that regard, I'm also not clear how you came up with the acceptable coefficient of variations for the lab values that you have listed here. You don't list all of the lab values, but the total testosterone for instance, levels in men should be something from 300-something to 1200 and something. The free testosterone, on the other hand, goes from something like .5 to 2.5; yet you've got a coefficient of variation of 10 in both cases here.
DR. MICHALEK: Well, we can revisit the c.v.s. Those most likely came from a textbook. We can check those.
DR. HARRISON: You have the same coefficient of variation for ACTH as you have for insulin. That's got to be crazy. ACTH has a half life of five minutes in blood. I'll bet you a jelly donut that 90 percent of the ACTHs that you're getting aren't worth nothing and serum insulin, on the other hand, is extremely stable. Nowadays you can sniff it.
So again, I think those coefficients of variation don't seem to have the correct relationships with each other. I'd expect ACTHs to be higher.
DR. GRUBBS: Again, we had talked about this issue a couple years ago and our agreement was that this should be in a biomedical plan, should be specified by the lab according to current methodologies and procedures as to what their c.v. is, and then approved or disapproved by the Air Force.
DR. HARRISON: Okay.
` DR. GRUBBS: So yes, that section should be revised.
DR. HARRISON: All right, so that section should be revised.
DR. STOTO: I was just noting, now that this has been called to my attention, that in one section you talk about 20 specimens, in another place you talk about 20 days. Another place you talk about 20 sampling days.
VOICE: Somebody likes 20.
DR. STOTO: I mean, are these things all supposed to be the same? Probably not.
DR. MICHALEK: I suspect, a long time ago, this was taken from a textbook, but we'll have to revisit that issue, as well as the c.v.s. And we will.
DR. FAVATA: I'll leave my diabetic question, but I have a question regarding 3.5.3, out of range variable review. And B in that section notes that B. My question is, who was carrying out this review; specifically the assessment of whether a value is compatible with the patient's clinical status, and what clinical information is available to them if, say if medical records are not supplied or they're incomplete.
So who does this, to decide whether it's clinically compatible?
DR. MICHALEK: that was a medical doctor at SAIC, I forgot the name.
Dr. John Whiteman.
And the answer is, doesn't he have available the entire patient folder?
DR. HARRISON: He's the person that you refer to in another place as the diagnostician or something?
DR. MICHALEK: The diagnostician is a physician at Scripps Clinic. Dr. Whiteman is the physician at SAIC.
DR. CAMACHO: The out of range variable review.
DR. HARRISON: Yes. So you just need to make explicit who's doing that?
DR. MICHALEK: Is that your recommendation?
DR. HARRISON: Well, apparently, you know who's doing it.
DR. MICHALEK: Right.
DR. HARRISON: It just would be nice if it were in the Statement of Work. Not nice, it would be desirable for it to be within the Statement of Work.
DR. MINER: The scope of work, though, we put things in there often that says: "Contractor, we want you to do this" and they come back to us with a biomedical test plan specifically on how they're going to do it.
DR. OGERSHOK: Right. A lot of this would be in their approach.
DR. MICHALEK: It's actually the bid, what we call the proposal from the company that the government buys. Is that a good way to put it? So that's the document you ultimately want to see, too. This is what we're asking for, then you're going to see what it is they bid and what they propose.
MS. YEAGER: And that's where we propose Dr. Whiteman.
DR. MINER: But your comments are very valid; that when they come back with our
DR. OGERSHOK: Wait a minute. The proposal, a proposal has got to be compliant with the Statement of Work. Otherwise it is unacceptable. There is a provision, in at least a couple points, to refine or to fill in the details of the Statement of Work. We have a biomedical test plan which has been mentioned, which takes us through the biomedical procedures; everything that goes on in the laboratory, the urine collection, the analytical methods, certifications of personnel, all kinds of stuff like that.
There's also, to harken back to a previous discussion, we have a statistical analysis plan that refines what's in the Statement of Work.
The proposal, I think, is kind of intermediate to this process. The real key documents are the Statement of Work and the plans to implement that Statement of Work.
DR. MINER: As we evaluate your biomedical test plan, then our comments are very appropriate about who's doing what.
DR. STOTO: I have a different question about that paragraph. It says the contractor shall record out of range variables. Does that mean that it just notes them and doesn't fix them, or?
DR. MICHALEK: We don't change any data. If an individual has --
DR. HARRISON: What you're saying is there's nothing there saying that you're going to act on it; it's just saying you're going to record it.
DR. MINER: We wanted a separate, out-of-range report that addresses every single out-of-range variable and whether that's clinically feasible or not.
DR. HARRISON: This is to make sure that your data is correct. This has nothing to do with taking care of the patient.
DR. OGERSHOK: That exercise is a two-step procedure. The first, out-of-range, is a statistical procedure to go through and just sift out unusually high values. The medical adjudicator reviews that information and the patient folder to say could this be a real measurement? Is this thing too big to be believable, or could it be this big?
DR. STOTO: So this relates to the data cleaning, but it's not clear from this document how it does.
DR. HARRISON: Well, now that you say it, it's pretty clear. A doctor looks at this and says: "Wait a minute, this guy's bilirubin is reported as 20, but he's not jaundiced." So the bilirubin is wrong.
DR. STOTO: And what do they do? Do they go back and look at the folder and see if they made a mistake transcribing it, or?
MR. OWENS: We haven't had any material number any number of variables that come out of that, measurements that comes out of that process as being that "this is just unacceptable." But if that happened, that's what we would recommend to the Air Force.
Is that not --?
DR. MICHALEK: I think, Maurice, to back up a step further. Isn't it true that at Scripps Clinic, if they see a value of beyond a certain range, don't they automatically do a retest?
MR. OWENS: Yes.
DR. MICHALEK: So the answer to your question is that actually, they have emergency values.
DR. MINER: I was going to say, panic values.
DR. MICHALEK: Panic values, at Scripps Clinic, that they act on.
DR. MINER: This is a statistical thing; there's also the patient consideration, that if a high value of something is found, very high blood glucose, out of sight. They are emergency values, they are attended to right then. Values that are diagnostically either too high or too low in the outbriefing, the diagnostic outbriefing that the individual gets.
Those are documented and a letter sent from Scripps for follow up, so the individual gets care. It's not just a statistical thing.
DR. STOTO: But I'm concerned about the statistical aspect of it.
DR. MINER: I know, but these are--
DR. STOTO: These guys deserve care, I won't deny that.
But I'm trying to understand the relationship between this, 3.5.3, and the data cleaning which is simply --
DR. MICHALEK: It's part of the data cleaning.
MR. OWENS: It's part of the data cleaning.
DR. OGERSHOK: There's another paragraph later .
DR. STOTO: I thought the data cleaning was earlier.
DR. HARRISON: No, data cleaning is right up there at Cumulative Data. Look right up above it, 220.127.116.11.
So it's all in the same general area.
DR. CAMACHO: Can I insert something?
DR. HARRISON: Insert away.
DR. CAMACHO: By the way, the one just above 18.104.22.168, the size of that data dictionary for the nonresponse; these are tailored to each question and I surmise when you get a new answer that you didn't think about, you're going to add a code?
DR. MICHALEK: Yes.
DR. HARRISON: Yes.
You don't like that?
DR. CAMACHO: Well, it's nice to go through and think of all the kinds of codes, possibilities beforehand. I mean -- for that matter, I never thought of asking this: Is there any kind of a little pretest in this questionnaire?
DR. MICHALEK: Yes.
DR. STOTO: Well, they haven't been doing it for 15 years.
DR. MICHALEK: Prior to the start of physical, there were ten individuals who are given the questionnaire and the physical in a pretest, or actually in a test. And I'm one of them. Some of them are in this room. The investigators, the contractors, and some military.
DR. CAMACHO: Very well.
MR. WEIDMAN: I have two questions. One is, Joel, did you pass every time?
MR. WEIDMAN: The second question is, part of the purpose of doing this is to complete the sixth round with some reliable evidence and conclusions that can't be drawn and hopefully published by the folks that are working on it currently from the Air Force. That's one goal.
The second goal, that's a larger goal, is that this is the only longitudinal study that we know of, of Vietnam veterans who were exposed in Vietnam. And therefore it carries on beyond as a public trust and record that can be mined by researchers all over the country and will be, for years to come.
DR. CAMACHO: Now we're getting into that "what happens after the study closes in 2006" problem?
MR. WEIDMAN: Well, no, I'm getting at something that's happening right now, because you mention that the only time that everybody who has not had a blood serum dioxin screen somewhere upwards or less than 40 people are going to have it now, and no one's going to be retested on the dioxin screen at this point.
There is no more, to the public and I can assure you to the Congress and to the organized veterans community, no more important variable to have a good lock on and to compare with to previous samplings than the blood dioxin serum as you go through the sixth cycle.
So I guess what we would urge you to think about and the committee to think about is to do a universal screening, because this is the last shot in the barrel you're going to get with this group of people.
And to not do it at this point will raise question after question after question, not only in 2006, but up to 2016, and in the future "Why the heck when they had them all there didn't they test them for the most important variable, which was the level of dioxin of the body burden at least at the time that they went through it to be able compare to the earlier cycles."
So that's both a question and a very strong recommendation.
DR. HARRISON: I think Joel's got a good answer to that.
DR. MICHALEK: Well, I agree.
DR. HARRISON: Joel.
DR. MICHALEK: Not only that, you can develop a good case that you should be measuring all the other congeners of dioxin, PCBs, and there's a full panel I think of 35 chemical congeners that should be measured, and a summary measure called the TEQ, computed for each individual. We're not budgeted to do that. I think it's important scientifically, personally, but we're not budgeted to do that. And if you are able to address the budget issue, then I think I agree with you.
DR. HARRISON: Let me ask I thought you were going to say something else.
DR. GOUGH: Me, too.
MR. WEIDMAN: That's an important issue. What would it cost?
DR. GOUGH: A thousand dollars a person.
DR. MICHALEK: I think to do the full panel, the estimate from CDC is roughly $700-$800 times 2300 people. So it's going to be about $2 million.
MR. WEIDMAN: So if that $2 million was available to you, you believe it would be scientifically valid.
DR. MICHALEK: I do, personally; but you'd have ask the committee.
DR. HARRISON: The answer that I thought, is that I thought that you had first of all, you've pretty firmly established the half life of dioxin.
DR. MICHALEK: Yes.
DR. HARRISON: You have two data points on the majority of the patients participating in the study, or at least a substantial number of them.
DR. MICHALEK: We have up to four data points on 343 Ranch Hand veterans. We have one data point on everybody else.
DR. HARRISON: So I thought the judgment that you had made, and I guess I should ask now, is knowing the half life and having the data points, do you feel that you can confidently assess their so now you have a batch of people who are down at baseline so you can't really extrapolate the baseline value back. You've got everybody else who is at above baseline, you can extrapolate them back. Measuring again doesn't help you, because they're going to be either lower or at background.
So in terms of estimating initial exposure, it seems to me your work is done.
DR. MICHALEK: If your goal is to estimate the decay rate, there's very little to be gained from a fifth measurement in that cohort of 300 men. But that's not the issue here.
DR. STOTO: I think the issue is the ones where you have only one measurement. If you believe that there are important differences from man to man in terms of the decay rate that may be related to BMI and obviously it would have related to the risk for diabetes and so on, you may want to do more sophisticated analyses, and you'd be better off having a second measure on as many people as possible.
So one to think about is, of the people who currently have only one --
DR. HARRISON: That's above baseline.
DR. MICHALEK: No, regardless of its value.
DR. STOTO: I was going to say that that's the fall-back position; but I'd prefer to do it for everybody.
DR. HARRISON: Okay.
DR. STOTO: Who only has measure.
DR. HARRISON: So you'd like to have two measurements on everyone?
DR. STOTO: I'd like to have two measurements on everybody.
DR. HARRISON: I think that's very reasonable.
DR. MICHALEK: Well, 99 percent of them have at least one.
DR. HARRISON: Yes, but we want two.
DR. MICHALEK: Right, I want two also. I mean, as a scientist I can always tell you that additional data will never hurt. It can only help. Plus there's the issue of the TEQ, which is considered in toxicological circles as the measure of exposure that we should have measured anyway.
DR. GOUGH: No, but with the dioxin in 2,4,5 T was largely 2378 TCDD. The others are inconsequential. So in terms of measuring what the dioxin exposure was in Vietnam, I think 2378 TCDD is fine. I know what EPA says, of course.
DR. STOTO: I agree, this is a study about the kind of dioxin that was in Agent Orange.
DR. HARRISON: So if we want you to do it, are you going to be able to can you do a second measurement on those what would that be, 1600 individuals?
DR. MICHALEK: 2,300.
DR. GOUGH: No, no --
DR. HARRISON: You've got 300 that you've already got four or five measurements on.
DR. MICHALEK: Well, it depends on what your goal is. If your goal is to measure another dioxin level, fine. You can probably get by with 1600. But if your goal is to measure TEQ --
DR. HARRISON: No. What we're saying is, for those individuals who have a single dioxin measurement there should be a second one.
DR. MICHALEK: Okay, that would mean all of the controls and about 500 of the Ranch Handers. There's about 1500-1600 people. Times about $1,000 apiece. $1.6 million.
DR. HARRISON: So that's Does everybody agree?
DR. STOTO: Well, it's not a thousand. You said $700-$800, and that was for the full TEQ. So it would be more like $500.
DR. MICHALEK: No, that's not true.
DR. HARRISON: Don't get evasive --
DR. MICHALEK: Let's be more realistic.
MR. WEIDMAN: Would the $700 or $800 include both the dioxin and the TEQ?
DR. HARRISON: No, that's just
MR. WEIDMAN: Joel, would that $700 to $800 per pop out of CDC, would that include both the dioxin and the TEQ?
DR. MICHALEK: Yes.
MR. WEIDMAN: So it would be the whole shooting match? So you could separate out the dioxin --
DR. MICHALEK: Exactly.
MR. WEIDMAN: And have the markers for 2,45T.
DR. MICHALEK: Dioxin plus all the others.
DR. GRUBBS: My biggest question is, on comparisons also? That's where I think you get the least amount of benefit for that.
DR. MICHALEK: Well, that's just the opposite of some opinion from my people.
DR. HARRISON: What Mike is saying, and I'm embarrassed to agree, is that it would be desirable, to draw a line you need two points. So if you're going to draw it flat or whatever, it's still two points. So everybody needs to have two points. That's not a bad idea at all.
Now if it turns out that there's really incredible budget problems, then I think no one would criticize you for saying "Well, everyone below X cutoff won't get repeated." That's a fall-back position.
DR. STOTO: Particularly if you're going to analyze the data by the way that you suggested here anyway.
LTC BURNHAM: Getting everybody would handle the geography question, also, if they're getting other sources of dioxin.
DR. STOTO: You already have one measure on everybody; the issue is the change over time.
DR. FAVATA: How many more people are there?
DR. MICHALEK: About 2200, 2300 total that will come to the next physical.
DR. FAVATA: So is it worth it to pursue having the entire group done again?
DR. MICHALEK: I think so.
DR. FAVATA: So that down the line is there a pop?
DR. MICHALEK: First of all, this is your last chance, supposedly. If you decide to do only 1600 of the 2300 and if you find a trend within those 1600, you're going to be awfully sorry you didn't do the rest of them.
DR. FAVATA: Right.
DR. GOUGH: Hopefully you won't find a trend on two points when you've got four and five points on everybody else.
DR. MICHALEK: I said 'if.'
DR. GOUGH: Well, I know.
DR. HARRISON: Okay.
DR. MICHALEK: But this is a major point, and I feel glad it's on the table. Should we do the TEQ? To do that, I think scientifically the answer is yes, and we need to do everyone, and I'm telling you we don't have the money to do it. If we did have the money, then I would vote in favor of doing it.
DR. HARRISON: I was very convinced by what Mike said. He seemed to be pretty this Mike, the older Mike
DR. HARRISON: He seemed to be pretty convinced that the TCDD contaminant was clear, and there wouldn't be additional information to be gotten from doing the panel.
DR. GOUGH: The only thing you would learn, I think, if you did the panel, is that if somebody had been exposed, somebody outside of the Ranch Hand experience, in some mixed chemical environment where he's exposed to the pentas and the octas and so forth, you'd know that. But I don't think it makes any difference.
MR. WEIDMAN: I want to harken back, if I could, speaking from the point of view of somebody in my organization that worked hard for that ' 91 law. The issue is, something happened in Vietnam --
DR. GOUGH: No, the question is, did something happen in Vietnam?
MR. WEIDMAN: Well, all right. Did something happen in Vietnam. Not just due to 2,45T but in terms of total toxin exposure --
DR. GOUGH: No. This is a herbicide study.
DR. HARRISON: No, actually, you can't do that. You missed this earlier when we were talking about it, because the comparisons also come from Vietnam. So if something globally happened in Vietnam, there's nothing to compare to, it should have happened to both groups.
So the only real comparison that's being made is between exposure to Agent Orange and lack of exposure to Agent Orange; and even that's screwed up because --
MR. WEIDMAN: Because everybody was exposed in Vietnam.
DR. HARRISON: Everybody was exposed either to Agent Orange or agent whatever, some of the other herbicides were as well; Agent Orange was used in Army compounds, so it's still unclean. But you can't make it a Vietnam study without having a control group that wasn't in Vietnam.
LTC BURNHAM: But for another $2 million, we could just kidding.
MR. WEIDMAN: But if you had the data there with the TEQ, you can take this data and match it up with a cohort group that did not serve in Vietnam but who did serve in military service during the Vietnam era, and essential have the same, you know, be able to do those kinds of groups --
DR. STOTO: That's a whole another study.
MR. WEIDMAN: I'm not saying it's this study. I'm saying your responsibility does not end when this study ends in 2006 with this dataset.
DR. HARRISON: And on that note, I think that's going to be an excellent part of the discussion that I'm looking forward to hearing tomorrow. But I think our work should be done for the day.
DR. HARRISON: Wait a minute now. Tomorrow we start at 8:30, we're going to go from 8:30 to roughly 11:30 continuing our review of the SOW; at 11:30 we're going to have public session number two.
Is that acceptable?
DR. GOUGH: Sure.
DR. HARRISON: Paul?
DR. CAMACHO: Yes.
DR. HARRISON: Thanks a lot.
DR. CAMACHO: All right.
DR. HARRISON: Are you going to try to come up tonight, or are we going to call you again tomorrow?
DR. CAMACHO: I wouldn't is it more important to be there, do you think, or do you lose some quality is obviously lost. What would you like me to do?
DR. HARRISON: I would much rather have you here, if you can be here without if you can get permission from your physician, it would be nice for you to be here. But I don't want you killing yourself.
DR. CAMACHO: Let me check some planes and stuff, and if I can make it I might try to do it.
DR. HARRISON: It's up to you, and to get you and Dr. Favata in the same meeting at the same time is going to be the capstone of my career.
DR. HARRISON: We'll talk to you tomorrow. One way or the other.
DR. CAMACHO: One way or the other.
[Whereupon at 4:53 p.m., the meeting recessed, to reconvene at 8:30 a.m., the following day.]
|Advisory committee on immunization practices||Medical Devices Advisory Committee|
|Veterinary medicine advisory committee||National Vaccine Advisory Committee (nvac)|
|External Advisory Committee on Cities and Communities||Wildlife Diversity Policy Advisory Committee|
|Peer reviewed by the Arizona Department of Commerce Economic Research Advisory Committee||Food and drug administration national institutes of health advisory Committee on: transmissible spongiform|
|Advisory Committee, Cuyahoga Valley School-to-Career Consortium, Broadview Heights, Ohio 1996-2002||Jane D. Siegel, md; Emily Rhinehart, rn mph cic; Marguerite Jackson, PhD; Linda Chiarello, rn ms; the Healthcare Infection Control Practices Advisory Committee|