Ranch hand advisory committee




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DR. OGERSHOK: They have a system that they use like that, and --

DR. HARRISON: That's fine. If that's done, that's fine. I'm just trying to   .

DR. OGERSHOK: They've had all kinds of problems that way, though, when people will say they'll come and don't show up.

DR. HARRISON: And I guess this wasn't quite in the General Health section; it was before that. The herbicide exposure question asks if they ever intentionally drank the herbicide, determine how many missions they were on; but they also used the herbicide as a degreaser, right? So you want to also know if they washed with the herbicide.

DR. MICHALEK: We have already questioned the enlisted in great detail about that. The questions that are there are primarily focused at the flyers, the officers.

The questions about using it as a hand cleaner have already been summarized and published.

DR. STOTO: I read in the paper yesterday that Colin Powell does his own plumbing.

DR. MICHALEK: Great.

DR. STOTO: So maybe officers used this stuff for things, too.

DR. HARRISON: Could have been. I don't understand what the term severity of diabetes means.

DR. MICHALEK: That is a label that may not be appropriate. The values of that variable are, no    diet control, medications--

DR. HARRISON: Well, there's severity of diabetes and there's current level of control.

DR. MICHALEK: Level of control might be a better name for it.

DR. HARRISON: Well, first of all, as I said, I don't understand what severity of diabetes really means. I don't think that insulin-requiring diabetes is more severe than diabetes that's treated with oral medication, and not intrinsically.

I don't know that    you have objective assessments of control in the endocrine chapter; I don't know that you want a very subjective measure, assessment of control as a part of a diabetic question.

So for the diabetic questions, I would    now, maybe you meant to ask the type of diabetes, just to get rid of the Type Is.

DR. MICHALEK: We already know only there's only one Type I in the whole study.

DR. HARRISON: So that's --

DR. MICHALEK: It was a question about level of control. Is that a better name for it?

DR. HARRISON: I don't especially   .

DR. STOTO: How is this used.

DR. MICHALEK: It is a variable that has four levels. 1 was called no control, 2 was called diet, 3 was called medication, 4 was called insulin. What you name that thing, I don't know, but what would you call that?

DR. HARRISON: I couldn't use it in terms assessing what kind of diabetes the person had.

DR. STOTO: How is it currently used?

DR. MICHALEK: Well, it's been published; it's in our paper on diabetes and dioxin --

DR. STOTO: As an outcome variable?

DR. MICHALEK:    as an outcome variable, and it trends with dioxin.

DR. STOTO: But you've got better measures of diabetes than that.

DR. HARRISON: If everyone was being taken care of by a uniform protocol in terms of treatment of the diabetes, then I would think that has some relevance. But some of us use oral medication for a long, long time. Others of us use insulin fairly quickly, others of us use insulin very poorly and not well, you know, we don't actually treat the diabetes even though we're giving them insulin.

DR. MICHALEK: So you're saying we shouldn't even measure this?

DR. HARRISON: I'm saying that the measure of control of diabetes, probably the best measure you have is the glycosylated hemoglobin.

DR. MICHALEK: And that's one of our laboratory outcomes.

DR. HARRISON: Yes, that's a direct measurement.

DR. MICHALEK: So we should drop this variable from the report?

DR. HARRISON: Yes, I would.

DR. STOTO: Is that a question that's filled out by the men or by their medical review, or?

DR. MICHALEK: That's a question, the answers are determined by us by reviewing medical records.

DR. HARRISON: I guess, Mike, the things I'm looking for are things that I think would not elicit an argument from other endocrinologists, and if they save a little bit of time here, then we can use it in other places.

DR. STOTO: But that's why question is relevant. They're not asking that of the men.

DR. MICHALEK: We're reviewing medical records.

DR. STOTO: Record reviewers are doing that.

DR. MICHALEK: Record reviewers are telling us.

DR. HARRISON: I'd like them reviewing something else. Wouldn't you?

DR. STOTO: I guess that they have to look at those --

DR. MICHALEK: They're looking at them anyway.

DR. STOTO: They have to look at that part of the record for other reasons, and it's just kind of a summary measure.

DR. GOUGH: But it's from very different sources with very different standards of care, what does it tell you? That's the question.

DR. STOTO: I think that there's a real question about whether it should be included in the analysis. I think that you can do a better job with the analysis.

But if the guys are reviewing the record and are getting a lot of information out, does it hurt to get one more little summary thing? I don't think it hurts to ask them to do it. It doesn't involve new records. I don't feel very strongly about that.

DR. HARRISON: I wouldn't ask something that I wasn't going to use, and I wouldn't ask something that I'd feel embarrassed to be using.

DR. STOTO: But you're asking the people who do the record review, not the men.

DR. HARRISON: What I'm saying is, I wouldn't    I'm making up a table; I wouldn't add something in the table that I wouldn't want my colleagues to think I was going to use in some way.

DR. STOTO: I don't think it should go in the publication. I guess the question is, does that help in just making sure the people are doing a complete review, or something like that    may help our quality control purposes.

Maybe not. I don't think it hurts too much.

DR. HARRISON: I agree that there's no great harm done either way with this. Either way.

These are just kinds of things I saw as I was reading through, Joel. In the medical authorization request, that's 3.3.3.2, it just says that: Participant can't recall the addresses of the doctors, and the contractor shall question the participant as to whether this information can be obtained after his departure from the examination site    ya-da, ya-da, ya-da.

Wouldn't it be simpler, because most guys know the names of their doctor, and they know what town the doctor's in. Wouldn't it be simpler to have a clerk call information and get the name and address right then rather than going back and forth?

DR. MICHALEK: I don't think so, because this is a two and a half hour interview, and they're asked about

the different medical conditions. There's a great volume of material that has to be received for that to be done, for that to work.

DR. HARRISON: If you don't think it can be done, that's fine.

DR. MINER: We actually ask them to bring the names of their physicians with them.

DR. HARRISON: I am just saying, a guy says, "Well, you know, he's Dr. Winthrop in Edwards, but I don't know his address or phone number."

DR. STOTO: Are there directories that they might have on    matched analysis

DR. HARRISON: Well, we have directories that could be used for that.

I don't consider this to be anything to really    I'm just reading through the terms, and   .

Okay, I'm up to page 26 now.

So, Neoplasia Data.

DR. GOUGH: That's me. I just have a couple of questions.

Besides PSA, is there any other routine test or standard test for prostate?

DR. HARRISON: There's no standard test.

DR. FAVATA: And that's not even without flaw.

DR. GOUGH: Oh, I know that. I know that. But it's a concern    because dioxin is also a concern in older men, and I just wonder if there's something else that should be done for prostate.

DR. HARRISON: Well, you could always look at the repeat element in the first exon.

You know, the molecular basis for the race-based difference in prostate cancer incidence and incidence of BPH is thought to be an expansion of a repeat element in the first exon of the androgen receptor.

DR. GOUGH: I did not know that.

DR. HARRISON: And what happens is, if you get a very long repeat element, you get a neuromuscular disorder called Kennedy Syndrome. If you get a little bit shorter element than that, you get a normal person who's Asian; and if you get a shorter element, you get a normal person who's white and an even shorter one gives you a normal person who's black but who has the most    who gets the most bang from his testosterone buck.

In other words, the receptor translocates more readily. What this expansion effects is receptor translocation into the nucleus after exposure to androgens.

So if you actually wanted to look at a propensity for prostate enlargement in cancer in this large group, then very simple; you'd take some white cells, extract the DNA, do a PCR across this region, run it on a gel and measure its length. And guys at the NIH and U of R do that all the time. But it's not a standard --

DR. GOUGH: Well, it is?

DR. HARRISON: It's not predictive; it's correlative.

DR. MICHALEK: Is it expensive?

DR. HARRISON: No. Actually, it's pretty cheap. I mean, PCR is very cheap.

DR. MICHALEK: Can you give us a methods paper on that?

DR. HARRISON: I will. Be happy to.

DR. MICHALEK: Mail a citation to me.

DR. GOUGH: From the standpoint of what you just described, it would also provide a database, with 2000 men.

DR. HARRISON: Oh, this has been done. I don't think 2000 men would be   .

DR. GOUGH: Then my nice question for the clinicians, both of you, is are there other cancers    I mean, I know all cancer incidence goes up with increasing age, but are there any in 60-year old men that we should    I mean, prostate comes to my mind as one that we should really look at carefully. Are there others that we should at this stage?

DR. MICHALEK: Other what?

DR. GOUGH: Other cancers.

DR. FAVATA: You need to --

DR. HARRISON: In other words, should something be appearing now that    is there something we should be alert to?

DR. GOUGH: Yes. I mean, I just know everything's going to go up.

DR. FAVATA: Colorectal, we were looking to that already; but I don't think there's anything that we're not looking for.

DR. GOUGH: I had a couple editorial questions.

On these long tables, 3.6.4.2.!!, is there a difference between    are malignant skin neoplasms different from malignant neoplasms, the eye, face, head and neck    head and neck? The cancers they had that are different than the skin cancers.

Okay, that's fine. I didn't want there to be a redundancy. Then on paragraph 3.6.4.2.1, are you really doing this thing about skin reaction at this stage? Covariants were adjusted out for skin neoplasm?

DR. MICHALEK: Good point. Those are strong covariates, by the way, for skin cancer.

DR. GOUGH: Oh, I know that. But the skin reaction after two hours of Sunday after first --

DR. MICHALEK: They are questioned about that, as I understand it, on the questionnaire, and use those responses here as covariates.

DR. GOUGH: That should    if that's a question, that's fine. No, if it's a question, I guess it's fine, but I just didn't imagine you had time built in to have a guy sit under a heat    for two hours.

DR. MICHALEK: No

DR. GOUGH: And it looks very specific, and it's not very specific.

DR. MICHALEK: What do you mean.

DR. GOUGH: Well, it looks like this is part of the clinical exam, and it's not; it's a matter of    questioning people.

DR. MICHALEK: Well, the only piece that's specific is the hair color. Actually we have some different samples of hair, and they hold it up next to --

DR. GOUGH: But Joel, your hair's going to    it will have changed over the last twenty years.

DR. MICHALEK: Yes, it's changing already.

DR. HARRISON: Or even front to back.

DR. MICHALEK: Less brown and more and more gray.

DR. STOTO: What do they say, what the hair used to be, or what it is now?

DR. MICHALEK: Good. This is a problem. Here you have 70-year old men and you're trying assess susceptibility to skin cancer.

DR. GOUGH: If they're blonds, they probably had skin cancer, so.

DR. MINER: We have skin color charts.

DR. MICHALEK: That's true; we have skin color charts.

DR. GOUGH: I just want    because I couldn't imagine you doing a two-hour exposure to sun.

DR. MICHALEK: No.

DR. GOUGH: Then on 36424, the black

participants, you don't need the first only in that sentence.

DR. MICHALEK: good point.

DR. HARRISON: In fact, I think the sentence sort of bordered on silly. It's saying it's zero we're not going to do the analysis.

DR. MICHALEK: Well, that's just another attempt to do it the best we can, to exclude those 4 percent who are black to increase our ability to detect an effect in the remainder, and so on.

DR. GOUGH: No, I understand.

DR. HARRISON: So you're trying to exclude black people, huh?

DR. MICHALEK: Only, if they behave as they should, they won't have skin cancer, fortunately for them. And we hope that's the case. And that's all. Just another little attempt to tighten up the statistical analysis; that's all.

DR. STOTO: Suppose they're half black or a quarter black?

DR. GOUGH: Well, there's no question in this country.

DR. MICHALEK: Exactly right.

DR. HARRISON: In this country, you're black.

DR. STOTO: But you may be a bigger risk for skin cancer if you are   

DR. GOUGH: If you're lighter, of course.

I have a    I have one more question.

DR. HARRISON: Go ahead. Yes, sir.

DR. GOUGH: You clinicians, you just --

DR. HARRISON: We're overly aggressive; that's true.

DR. GOUGH: And domineering.

DR. HARRISON: I was once told I had the personality of a surgeon but none of the ability.

(Laughter)

DR. GOUGH: Back to 36421, the last sentence, a strategy for categorizing listed covariates will be provided by the offeror.

DR. MICHALEK: Right.

DR. GOUGH: Who is the offeror?

DR. MICHALEK: That will be SAIC and Bill Grubbs and company.

DR. HARRISON: Who's also called the contractor in other places.

DR. MICHALEK: Well, good point. We can do a search and replace on that.

DR. MICHALEK: Some of this language goes way back to 1982. It's carried along.

DR. GOUGH: Okay and    oh, I would like to    maybe not in the blue book, but sometime I would like to see a table for each exam of the hypotheses that came out about possible relationships or associations with dioxin, for everything. Because like the pulses, the abnormal pulses --

DR. MICHALEK: Across all cycles?

DR. GOUGH: Yes. Just so we can see what has remained consistent, what's drifted away.

LTC BURNHAM: You want a chart of each year, and then the abnormalities   

DR. MICHALEK: For every endpoint.

DR. GOUGH: No --

DR. MICHALEK: Actually, we have that.

DR. GOUGH: That would be really interesting to see.

DR. MICHALEK: Those are called longitudinal analyses.

DR. HARRISON: Tell me again what it is you're asking for?

DR. GOUGH: The pulses, the abnormal leg pulses; they came up in the very first examination. I think they weren't there in the second examination; isn't that right?

DR. MICHALEK: Yes. Back then we didn't have dioxin then. We measured them by physician's palpation, and then we    I can't remember whether they went away.

DR. MINER: They went away.

DR. MICHALEK: Then we went back to a doppler method for testing, and then they came back again.

DR. STOTO: So when you say they were there and went away, it means they were significant.

DR. MICHALEK: Yes.

DR. GOUGH: They were abnormal.

DR. MICHALEK: There was a significant difference in the groups.

DR. GOUGH: Then there wasn't, then they came back.

DR. HARRISON: But you're asking for the hypotheses.

DR. GOUGH: I think from that first examination our hypothesis would be that Ranch Hands are more likely to have abnormal pulses.

DR. HARRISON: So you want to know every hypothesis that was generated --

DR. GOUGH: Yes, I do.

DR. HARRISON:    in which cycle it was generated --

DR. GOUGH: Yes.

DR. HARRISON:    and what the final disposition or what the most recent disposition was.

DR. GOUGH: Yes.

DR. STOTO: That sounds like it would be good as a kind of summary of the whole process, not necessarily the blue book for --

DR. GOUGH: No, I don't think it belongs in the blue book, but I think at the end we'd like to see it.

DR. HARRISON: Well, you know   

LTC BURNHAM: I think it would be good in the blue book, a final blue book.

DR. GOUGH: One big, fat blue book.

DR. HARRISON: Wouldn't you also, though, if you were looking at something like that and you saw that pulses had had some significance, lost some significance, you might look more closely at the pulse question and ask whether there's anything that should be sharpened there to --

DR. STOTO: That's true. Or could be sharpened.

DR. HARRISON: Yes. So that's still not a blue book issue, but it says that it would be nice to --

DR. STOTO: Come to think of it, the blue books do say "in the past we found so-and-so." That's part of the introduction.

DR. GOUGH: You generally make a comparison between this exam and the previous one.

DR. HARRISON: Basically what you're saying is, everything that ever got flagged, like in a flow sheet, saying this was flagged and disproven, this was flagged and disproven, this is flagged and still bumping along.

That's not a bad planning tool.

DR. GOUGH: The bad planning part of it, though, as Joel just mentioned, is that the criteria for assigning abnormalities changes.

DR. HARRISON: But that's okay.

DR. STOTO: Put it in the story you're telling them.

DR. HARRISON: Yes. I wouldn't try to go back and normalize everything --

DR. GOUGH: Oh, no, no. Absolutely no.

DR. HARRISON:    I would just take it as it is.

DR. FAVATA: Have the physician- examiners changed throughout this entire study?

MR. OWENS: Somewhat.

[Simultaneous discussion]

DR. FAVATA: Each time there's been a different   

MR. OWENS: Some are the same, but in general --

DR. FAVATA: That may be a problem, lack of standardization.

DR. HARRISON: So we have a recommendation that will be pending until Paul gets here to do --

DR. MICHALEK: Personality type.

DR. HARRISON: No, no, I got the personality test down, but this is to prepare a chart of all hypotheses   .

DR. MICHALEK: You want a longitudinal summary of the entire study?

DR. GOUGH: Yes.

DR. STOTO: I wouldn't use longitudinal, because that suggests following individual through.

DR. HARRISON: Well, and I wouldn't want the entire study. I'm just saying, I think you're saying, what are the things after the first cycle that you thought you found.

DR. GOUGH: Yes. That stirred some interest.

DR. HARRISON: And keep them, then for the rest of the time. What are the things in the second study that you thought you found, and keep them until the end, along with whatever dispositions occurred at each subsequent study?

DR. MICHALEK: Well, we have done that, and we can summarize all that for you.

DR. HARRISON: Yes.

DR. GOUGH: That would be good.

DR. HARRISON: I think that would be very nice.

DR. GOUGH: Those are all my comments.

@ DR. HARRISON: Okay. Neoplasia Data.

DR. STOTO: I think neurological is next.

DR. GOUGH: Wait, one other thing. I had this as a general question: Is there any attempt to verify smoking and alcohol history?

DR. MICHALEK: Smoking and alcohol are elicited by a detailed questionnaire; "tell me about your smoking during the past five years." Well, from year 1997 to '98 I was smoking a pack a day, and then I changed from, to two packs a day" and they tell us the time intervals, and tell us how much. We're taking their opinion for it, of course. We're not--

DR. GOUGH: Well, it's not    I don't think it's really an issue between the Comparisons and Ranch Hands, which would be the same kid of bias. But I just wondered    so there's no effort.

But what if you have a guy who says "I don't drink" and he has cirrhosis? Does that pop up?

DR. HARRISON: But that's possible.

DR. MICHALEK: A guy that has alcohol-liver cirrhosis?

Yes, that's possible. We're just taking their opinion.

DR. HARRISON: Could have even been taking testosterone, get peliotic hepatitis with that if you take an oral testosterone.

DR. MICHALEK: We do have the entire record of medications, of prescription meds. I don't believe we're making full use of that. We've not made full use of that. We've used it, but there's not been a full blown attempt to study that data.

DR. GOUGH: Well, it comes up because in the mortality part, which is very early on, there's an excess of digestive disease, mortality among ranch hand enlisted, and you say they're related to alcohol.

DR. MICHALEK: Well, we looked at those, and many of those were alcoholic-related liver conditions. So we presumed that they were alcohol-related conditions.

@ DR. HARRISON: Okay, neurological.

DR. FAVATA: One quick question just back to general. Were there only two races throughout the study? It just says: Race shall be dichotomized as black and non-black. Are there any other races?

DR. MICHALEK: Yes, if you study the data, you'll see there are some men with Hispanic surnames, for example. We did a detailed questionnaire on ethnicity, a couple of cycles back.

DR. HARRISON: Is Hispanic surname an ethnic group or a race?

DR. MICHALEK: I don't know. But we asked about the ethnicity of the father and the mother and the religion and all of that, and what you get yourself into is a very complicated mess.

DR. STOTO: Officially Hispanic is not a race.

DR. HARRISON: Not only that, but there are white Hispanics and there are Indian Hispanics for sure; there are even black Hispanics for that matter. But Asians.

DR. MICHALEK: I don't know if we have any Asians or not.

DR. HARRISON: Neurological.

DR. FAVATA: Neuro. Number one, relates to 3.6.4.3.b, Physical Examination.

DR. HARRISON: You're not going to bring this up, are you?

DR. FAVATA: Yes, I am. Because this is important. I had reviewed this section before and had made this point before, and I think it is important that we are testing appropriately, and it was in regard to the neck range of motion. That is not a cranial nerve. That does not relate to cranial nerve function.

If we are testing for the accessory nerve, it is not forward extension and flexion of the neck; and I went to the Neurologic chapter and that is what was tested. So that really should be stricken from    it should not be included by any means in the tests for cranial nerve functioning.

DR. MICHALEK: Should it be in this chapter at all?

DR. FAVATA: Neck range of motion.

DR. GRUBBS: Based on your recommendation at the October '99 meeting, what you suggest was done. It was taken out of the analysis, neck range of motion. It was not part of the cranial nerve function, and the appropriate cranial nerve was looked for, so.

DR. FAVATA: It was reported in the chapter, though. It talked about the flexion and extension of the head under the section of cranial nerve functioning.

DR. GRUBBS: What version?

DR. HARRISON: You're saying that it's still in the exam, but it's not being    it's not being analyzed.

DR. GRUBBS: It's not being analyzed as    the cranial nerve function.

DR. HARRISON: Dr. Favata is saying it shouldn't even be in the exam, under Neurological, because it indicates that we don't know what neurological is.

DR. FAVATA: And are you certain that it isn't, because why would it be noted in this    Joel, I'm not sure who sent this; if it was Ron's office or you.

DR. MICHALEK: I did.

DR. FAVATA: But this was the chapter on neurologic assessment.

DR. MICHALEK: From the '97 study.

DR. FAVATA: Right.

DR. MICHALEK: And is neck range of motion there in that chapter?

DR. FAVATA: It's noted in that section on cranial nerves.

DR. MINER: That was current I think through June, and this happened --

DR. MICHALEK: But I copied that from the web page.

LTC BURNHAM: I thought we sent them most current report.

DR. HARRISON: Well, let's put it like this: it seems like everybody agrees that this should go.

DR. MICHALEK: You want to remove it from the chapter.

DR. HARRISON: So let's just --

DR. MICHALEK: Drop it.

DR. HARRISON: Assure that we'll --

DR. STOTO: You want the chapter removed from the exam, or both?

DR. HARRISON: Both.

DR. OGERSHOK: Both.

LTC BURNHAM: Well, there may be a function for something other --

DR. HARRISON: I was going to ask. Now, it is nice to be able to note somewhere in the physical examination that the range of motion is appropriate.

Is there anyplace    and what we don't have here    it doesn't say anywhere in here it's neuromuscular or neuromuscular-skeletal.

DR. STOTO: Has there ever been any suspicion that this is --

DR. FAVATA: Well, it notes muscle status. So I think that's the point where they're testing muscle strength.

DR. HARRISON: I guess the question to ask them is, the question was being asked "Should range of motion of the neck be thrown out completely from the exam?" And I was saying "Well, range of motion is something that's noted in most physical exams, at least physical exams that I do, and one of the problems    the problem with it here is that there's not an appropriate place    maybe it could be noted under General Health Data?

DR. FAVATA: I think it should be a part of this exam, of the neuro section.

DR. HARRISON: You do?

DR. FAVATA: Yes.

VOICE: It's just not a measure of accessory nerve.

VOICE: Yes, it's just out of the cranial nerve.

DR. HARRISON: So you want it to be -- where do you want it to be?

DR. FAVATA: It should probably be under muscle status. Motor function.

DR. MICHALEK: So move it down to the next place, under Muscle Status?

DR. FAVATA: Uh-huh.

LTC BURNHAM: Do we need another test?

DR. FAVATA: Do you disagree? Because I don't see any better place to put it.

DR. HARRISON: No, actually I was just having trouble finding muscle status.

DR. FAVATA: I also want to note that we should clearly be testing for the 11th cranial nerve in the appropriate way.

DR. HARRISON: Which is?

DR. FAVATA: Well, basically you're testing for the motor function of the trapezius and sternocleidal mastoid muscles. So you're opposing someone's head as they're laterally rotating and you're palpating the muscle as you're doing that and shrugging the shoulders and palpating the trapezius; it's standard.

The other is, how is hearing, the cochlear nerve assessed? It's not included in the list of cranial nerve function tests.

DR. MICHALEK: I know.

DR. FAVATA: We have balance for vestibular but we don't have cochlear nerve. So hearing should be assessed.

DR. MINER: As I remember, we used a tuning fork.

DR. FAVATA: Yes. Weber and Renie. Lateralization, put it on and see if it lateralizes to either ear, and the Renie, and then you take it off and you see if they hear it.

DR. HARRISON: So that's not included in the physical exam; it should be listed.

DR. FAVATA: It should be. We're not covering the 8th cranial nerve.

DR. MICHALEK: The 8th cranial nerve.

DR. FAVATA: Yes. Fully. There are two components; vestibular and cochlear, and we're not covering the cochlear nerve.

DR. MICHALEK: Okay.

DR. FAVATA: This regards the    and this is another point I think that we've talked about before. Physical exam as noted in the ''97 neuro assessment, peripheral nerve status; there's a concern in that the patellar, Achilles and biceps reflexes are being coded as normal even if very active or sluggish. And that's inappropriate, that should be    it should be graded, actually, of None, and that relates, zero relates to your peripheral neuropathy. Sluggish may relate to your peripheral neuropathy, too, so there's a concern that that's seen as normal. 2+ should be normal and 3 to 4+ should be very active.

So it should be coded differently, and it does bear out in prediction of disease.

DR. MICHALEK: So that, summarize for me, which of these variables are we talking about?

DR. FAVATA: This is reflexes, under peripheral nerve status; patellar Achilles biceps.

DR. MICHALEK: So you're saying.

DR. FAVATA: Should not be listed as normal. It should be a graded scale.

DR. HARRISON: Should not be a dichotomous scale.

DR. FAVATA: Correct.

DR. MICHALEK: Is there some language here under the text that says otherwise?

DR. GRUBBS: 3 6 4 3 1, second paragraph.

DR. MICHALEK: So that sentence needs to be revised.

Then 3 6 4 3 1, second paragraph, first sentence should be revised. Is that true?

DR. FAVATA: Is that all binary variables? Okay, shall be recorded as normal or abnormal.

DR. HARRISON: The sentence starts: Patellar, biceps and Achilles.

DR. FAVATA: Okay, that's what needs to be revised, yes.

DR. MICHALEK: And how would you revise that sentence?

DR. GOUGH: Graded?

DR. FAVATA: Shall be presented --

DR. HARRISON: 4+ is clonus, isn't it?

DR. FAVATA: 3 to 4 people say is very active; I don't know. I think people usually say clonus when it is.

DR. HARRISON: Okay.

DR. FAVATA: Shall be presented in an ordinal fashion with    absent equalling zero, sluggish equalling one, normal equalling two. And very active, it's usually three to four. And if you're dealing with clinicians, that's the way they usually write it.

DR. MICHALEK: Okay. It might already be that way on the exam form. But if it's not, we can take care of it.

DR. FAVATA: Okay. The other issue is regarding diabetics and diabetic questions. I didn't note it yesterday, but    and Bob, I look to you for this information. I think we should include the duration of diabetes in order to further evaluate the relationship between diabetes and peripheral neuropathy.

Isn't it usually decades before you see some peripheral neuropathy?

DR. HARRISON: It could be a lot sooner.

DR. FAVATA: Really?

DR. HARRISON: Yes. But certainly years. I wouldn't    to say decades is to say that you expect to see it after 20 years. I'm not surprised to see neuropathy after 10 years.

DR. FAVATA: However, wouldn't that be a helpful question in sorting out   

DR. HARRISON: Duration would be helpful.

DR. FAVATA:    this issue of attributing your peripheral neuropathy potentially to your diabetes? So that should be included. Actually, that pertains to 3.3.2.3, the diabetic questions. Note in there the date of diagnosis.

DR. HARRISON: Also, though, you've got that in this section under Covariates. So you probably want to add it or consider it as a covariate.

DR. FAVATA: Also my question is, the criteria that are defined here, that have just been inserted, I'm not quibbling with them, but what is the source for that criteria?

DR. MICHALEK: Dr. James Albers, University of Michigan, Department of Neurology. He's the coauthor of our paper in submission on this subject. So I want to repeat the analyses using the same criteria we used in our published paper, which    these are the criteria.

And based on those criteria, I think I sent you all a copy of that paper. We found a significant trend; risk with increased dioxin, with or without adjustment for diabetes.

DR. FAVATA: Okay.

DR. HARRISON: So this is the vibrator guy?

DR. MICHALEK: No, that's Alezo at Albert Einstein College of Medicine. He's the vibrator guy. Albers is the electrophysiological guy. He wants us to measure nerve conductions.

DR. FAVATA: I like the inclusion of the, or the use of the electrodiagnostic testing and the assessment of vibrotactile responses. I think that that would really help us with defining peripheral neuropathy.

Just another comment on the covariates; I think that they're comprehensive, particularly with the '97 additional questions regarding metals, vibrating tools.

DR. MICHALEK: Which reminds me   .

DR. HARRISON: What was that?

DR. FAVATA: I'm not sure if I read it in here    yes, it's 3.6.4.3.4. Can we expand insecticide to pesticide?

DR. MICHALEK: Uh-huh.

DR. FAVATA: And can we annotate that and the questioning so it would be helpful    as you noted yesterday, an individual may not know what a degreaser is. Can we say "such as toluene, acetone, and benzene"?

DR. MICHALEK: Yes; we have something for you on that. For example, we ask about heavy metals: Any other heavy metals, such as chromium, nickel or copper? So the interviewer does provide prompts.

DR. FAVATA: Okay.

DR. MICHALEK: So, yes. The same with pesticides and solvents. Yes.

We'll make sure that takes place.

DR. FAVATA: I don't have anything else.

DR. MICHALEK: Okay.

Dr. Stoto?

DR. STOTO: All those things occurred to me, but I   

(Laughter)

DR. STOTO:    I don't have anything beyond that.

DR. HARRISON: I'm sitting here in awe, you know. Where does she get all this stuff from?

DR. STOTO: I really don't have much to add to this whole section here.

DR. HARRISON: That reminds me, no one here would know my mentor, Grant Little, who established the dexamethasone suppression test, the mateer-pone {ph} stimulation test, and was the chairman of medicine and head of the Endocrine Division at Vanderbilt.

And one day we were talking and he said that well, he was a Mormon from American Fork, Utah. And he said "Well, I've never really aspired to be the first person to publish in a field. I've always aspired to be the last."

(Laughter)

So every now and then, there's someone who, when they finish their review, there's really nothing left to say and we just move on to psychological data.

DR. GOUGH: Paul.

DR. HARRISON: Paul's a psychology person?

DR. GOUGH: I am, too. Paul certainly knows a lot more than I do.

DR. HARRISON: You want to wait for Paul?

DR. GOUGH: No, because I have very little to say.

There is an association between either being a Ranch Hander with dioxin exposure and short-term memory.

DR. MICHALEK: Yes.

DR. GOUGH: And on the list of things you're going to do here, is there any follow up for that? Is there any investigation of that?

DR. MICHALEK: That's the new text on the page in the second part of the variable list there. It says Wexler Memory Scale.

DR. GOUGH: Yes.

DR. MICHALEK: That's the same instrument we gave at baseline in 1982. So we're going to give it again at 2002 so we'll have paired measurements on about 2,000 people.

DR. GOUGH: Well, is that it? Is there anything else that should be done? Again, this is a very specific hypothesis come out of this.

DR. MICHALEK: Well, the advise we got from CDC was to give exactly the same version of the Wexler that we gave at Cycle 1, because there had been many other Wexlers out there since then.

DR. GOUGH: I can understand that.

DR. MICHALEK: And not to use any of the other versions. That's the extent of the advice we got at this point.

Now if we see a continued, if this finding holds up, there's going to be a lot of interest in pursuing this.

DR. GOUGH: I'm asking, is there anything besides a Wexler that --

DR. HARRISON: That measures short-term memory.

DR. GOUGH: Yes, but    sort of another test for it.

DR. MICHALEK: We've asked the question, and the advice we're getting is to do this, and confirm what we've seen already before we launch into something else.

DR. GOUGH: But you won't be able to launch into anything else.

DR. MICHALEK: Well, someone else will, maybe.

DR. HARRISON: That sounds like a very limited answer. That answer sounds like the kind of answer I've heard before from psychologists that you know, every test is    I forget the word now, but it's verified. So you're using it against --

DR. MICHALEK: Take one step at a time, yes.

DR. HARRISON: But what we've been talking about is that this is the one last throw of the dice here.

DR. MICHALEK: Right.

DR. HARRISON: And I think what Mike is asking is, is this the only role that you've got?

DR. MICHALEK: Well, I think that's a great idea. This is an area where --

DR. HARRISON: Let's table that and ask Paul when he gets here. I think that's an excellent question.

DR. MICHALEK: Which opens up the whole SEL90R. You know, we're in a position with psych    the first part of this, the first 16 variables there come from the SEL90. I think the whole area of psychology needs a new look. In other words, we keep doing the SEL90R because we know what else to do. We gave it last time, we gave it the time before; if you could provide a fresh look at psych, I think we'd all benefit from that.

DR. HARRISON: Well, it certainly would be additive, though. Because you wouldn't want to drop out anything unless you could just show that it really wasn't working.

DR. MICHALEK: If you had a good reason for doing that.

DR. GOUGH: Would somebody at the National Institute of Mental Health, could you approach somebody there about it?

DR. MICHALEK: I'd need a name, I'd need a contact. I need somebody who    to talk to.

DR. GOUGH: Would you trust talking to a psychologist who will talk to me?

DR. MICHALEK: Sure.

(Laughter)

DR. STOTO: Have you looked into something like the SF36?

DR. STOTO: Well, it's the short form, it's a questionnaire developed at Rand, and now by a group at Tufts. John Ware is the key guy. It's a general health status questionnaire; it includes a mental functioning and a social role functioning and so on. It's used quite widely now, and it seems to be a pretty good measure in terms of limiting reliability.

DR. MICHALEK: Of psychological things?

DR. STOTO: Of general health status, and it has I think it's eight different scales, subscales.

DR. MICHALEK: That seems to be a different subject. I'm not opposed to it, but I though we were talking psych.

DR. STOTO: Well, no; part of it is psych, is mental health, but it also covers some other things as well. So it might fit into the general health better than here, but I didn't think about it at that point, though; it just occurred to me now.

DR. HARRISON: If you had a very specific question about short-term memory.

What would you --

DR. STOTO: This doesn't deal with the memory question; but this is a more general thing. I'm not saying the memory isn't important. But I think it's worth thinking about.

DR. MICHALEK: This has been mentioned before, the SF36.

DR. STOTO: They've got a web site.

DR. MICHALEK: Oh, they do?

DR. STOTO: www.sf-36.org.

DR. HARRISON: Well, we're now at --

DR. GOUGH: I have one other thing. This is just a comment. 3 6 4 4 3, covariants. That's such a jumble of outcome measurements and propensities and --

DR. MICHALEK: That, too, needs a fresh look. The whole idea of covariate adjustments, the whole section I think needs new eyes to look at it.

DR. GOUGH: I don't know what that means.

DR. STOTO: Have we been finding things in the psychology area generally?

DR. MICHALEK: Yes. Actually, having a child under thea gentlemen of 18 in the house seems to be correlated with depression.

(Laughter)

DR. HARRISON: And anxiety in the parents.

LTC BURNHAM: Yes, there's a test for anxiety.

DR. HARRISON: And low intelligence.

DR. MICHALEK: Many of these covariates are, I believe. I'll have to check that. We have the report right here, so during our break I can answer that.

DR. STOTO: But have we been finding differences between the Ranch Hands and the controls --

DR. MICHALEK: Probably not.

DR. STOTO:    in psychological things.

DR. HARRISON: Let me --

DR. STOTO: Maybe because the right questions haven't been asked.

DR. GOUGH: Except for the short-term memory.

DR. HARRISON: Let me make following observation: We are now an hour and a half into our second day and we are now just finishing the first chapter that we were supposed to have started this morning at 8:30. And I think we need to demonstrate a little more efficiency.

DR. STOTO: Why don't we wait until Paul gets here to continue this one?

LTC BURNHAM: Be efficient.

DR. HARRISON: My suggestion exactly.

So we'll revisit psych when Paul gets here.

GI Data.

I only had two questions in the whole GI section. One question, which I think we probably talked about before; and that is the use of laboratory normals versus using the comparisons as the normals. And Mike keeps telling me why we don't need to do that.

It seems to me with a big control group like this, your normals would be the control group, not a bunch of teenagers that Scripps gets to come in and donate blood.

DR. STOTO: I'm trying to remember what the issue is about there. These are dichotomous variables; either it's above normal or not.

DR. MICHALEK: We've already noted, Mike, that we can be misled by using the Scripps abnormal range. Many times I think the Scripps normal range will be taken from a package insert from a lab kit.

Sometimes those normal ranges are so -- they don't produce a very sensitive test for abnormality, a good example being insulin. We used the Scripps normal cut point for insulin last time in our big report, and we totally missed an effect. By using the upper 2-1/2 percentile of the comparison group we revealed an effect, an adverse effect on nondiabetic Ranch Handers.

DR. STOTO: So you are doing that now?

DR. MICHALEK: Yes, we are using the normal-abnormal cut points as the upper and lower 2-1/2 percentiles of the comparison group. Not always, but we need to reconsider every single one of these variables from that point of view.

DR. HARRISON: You're starting to sound like that guy yesterday.

DR. GOUGH: Gary Kayajanian.

DR. HARRISON: Yes. I mean, you change your analysis to --

DR. MICHALEK: No, actually we messed up. In all prior reports we had been using the upper and lower 2-1/2 percentiles. But in the Cycle 5 report, for some reason --

DR. GRUBBS: We've been using Scripps throughout.

DR. MICHALEK: We used Scripps. Well what happened was, Scripps changed their cut point.

DR. HARRISON: Now the way a lab usually does this is the lab gets a kit and a range is published in that kit. The lab then has to run a certain number of samples, depending on certain criteria, to confirm that its range is the same as the range presented in the kit. If it can't confirm that, it's supposed to change it.

DR. MICHALEK: Well, sometimes    getting back to the study    it can happen that by using the laboratory cut point you can find that 40 percent of the men in the comparison group are abnormal, using that particular cut point.

DR. HARRISON: What I'm saying is that if you take the package insert and you compare that range to the comparison group --

DR. MICHALEK: That has to be done, yes.

DR. HARRISON:    and it doesn't match, then you certainly have to change it.

DR. MICHALEK: Right. That has to be done.

DR. STOTO: Do these things have continuous values?

DR. MICHALEK: Yes. They're all analyzed both as continuous and discrete.

DR. STOTO: To me, that's the way to handle, is to analyze them as continuous variables. There's more information there.

DR. HARRISON: Okay, is that what you mean when you say, I've got it highlighted here: Continuous variables shall be transformed to normality as appropriate?

DR. MICHALEK: Yes, because some of them are highly skewed; they have exponential distributions rather than normal and so it's not appropriate to test on the mean.

DR. HARRISON: As someone who is naive about this, I --

DR. STOTO: I think that's part of it, but I think that the general part is that rather than them fuss about the cut point and decide whether the guy's normal or abnormal, you basically say "Let's look at the average between the control and   "

DR. HARRISON: Well, the reason I brought it up here is it says: All laboratory variables except bilirubin, et cetera.

3.6.4.5.1. All laboratory except certain laboratory data shall be analyzed twice, once with the dependent variable maintained as continuously distributed and again as a dependent variable dichotomized as normal or abnormal.

And it was the dichotomization that I was querying, how that would be accomplished.

DR. STOTO: Right. I understand. I guess my point is that if they can do it as continuous, I don't care so much about how they do dichotomous. I think it's a better analysis.

DR. HARRISON: Okay. Second paragraph, 3.6.4.5.2, participants whose blood contained hepatitis-B antigen shall be excluded from analysis of current hepatomegaly.

Does that mean that if they were positive at any point? Because I think sometimes you can be positive and then negative, can you not? In other words, someone who was hepatitis-B positive in 1987 may not be hepatitis-B positive today. Is that?

DR. GRUBBS: It's based on the measurement for the last report at the '97 exam. Nothing has gone back from '92 or '87.

LTC BURNHAM: Is this surface antigen?

DR. GRUBBS: Surface antigen is, correct me if I'm wrong, it's current hepatitis, where say antibodies or a history of?

DR. HARRISON: All right, so this is surface antigen, okay. Or hepatitis-C antibodies.

Okay. I understand now.

I did not have anything else on the GI system.

DR. FAVATA: I had one question regarding covariates. Why was that changed, regarding alcohol use? Was the data too cumbersome, asking it the way it was previously asked?

DR. MICHALEK: Where are you referring to?

DR. FAVATA: This is .5.3. Covariates for adjusted analysis.

DR. MICHALEK: Which sentence?

DR. FAVATA: You were excluding current alcohol use, average number of drinks per day during the two weeks prior to the physical exam.

DR. MICHALEK: You mean I crossed it out?

DR. FAVATA: Yes. And then you changed that to 'current drinking.'

DR. MICHALEK: Yes. What we're trying to do there is imitate what will be published in the
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