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Neil Holtzman, M.D., M.P.H.

The following is an excerpt from an interview with Neil Holtzman that took place at the "Winding Your Way through DNA" symposium at the University of California San Francisco in 1992. Neil Holtzman is the author of Proceed With Caution. Baltimore: Johns Hopkins University Press, 1989 and co-author of Assessing genetic risks: implications for health and social policy. National Academy Press. 1994.

Excerpted from the symposium transcripts with permission of the University of California, San Francisco.

Q. What's the major goal of your work? What are you trying accomplish?

NH. We're trying to determine how people will respond to some of the new technologies in genetics. By 'people' I mean physicians as health care providers--whether they're ready to cope with this, to present this to patients and how patients or how the public in general will respond to being offered genetic tests. That is, I think, the major technology we're confronted with now. Now those questions raise many interesting issues and the answers are fascinating to me and I think they're also important to inform public policy: Who should be providing genetic tests? What does the public need to know? What do they know right now about genetic testing?

Q. What's the fundamental issue for you when you look at genetic testing? How would you phrase it in terms of the forces that are at work and do you think of it in that way?

NH. The forces that are at work are tremendous advances in science and probably the applications. We have a genome project that has as its goal to identify all of the 50 or 100 thousand human genes within the next 15 years or so. When we have that information it will be relatively easy to develop tests for a number of those diseases and that, I think, is driving my concern, my interests about what people will do with that.

For instance, insurance companies and employers are interested for the following reason. If a person is going to develop a genetic disease or a disease to which genes contribute and where that contribution can be detected by a test, it's likely--in the absence of a definitive treatment--that when those people get sick they're going to need a lot of supportive care that may go on for years and years and that's expensive. An insurance company does not want to pay for those tests. And if an employer who is paying health benefits for workers has a way of finding out in advance of hiring whether or not a worker is going to develop a disease, then that employer is going to be less likely to want to hire that worker since the employer is paying health care benefits. So this is an area where tremendous discrimination based on one's genes is possible both in employment and in directly getting health care insurance.

Q. Do you blame an insurance company? Don't they want information about risk?

NH. That's a very good question because, you're right, the principle on which private insurance is based in this country is called by some insurance underwriters "Equal Payments for Equal Risks." And, consequently, when you have someone at high risk you wouldn't expect that person to pay in as little as somebody who is at lower risk.

Now, what happened, classically, as private insurance developed was, the insurance underwriter had no way of identifying people who were at higher risk than other people, so you could put them all in one risk pool and say we don't know whether this person is going to get disease at the age of 30 or at the age of 80. We'll throw them all into one pool and charge them the same premium and the amount of the premium was determined actuarially by what the predicted life span would be for all the people in the pool. Now what has happened over the last 20 or 30 years, not only in genetics but as a result of the collection of more detailed actuarial information about occupation, is that you can't throw so many people into that common risk pool. We now know who is at risk; there are some occupations that are more dangerous than others, are predisposed to disease or early death.

It's pretty evident that there are genetic diseases which will shorten the life span and lead to high costs of care since there is no treatment and for which tests will be available. So, an insurance company cannot afford to pay to have everybody pay the same rate and continue to make a profit. Now, that's fine for the insurance company but what it means is this: as you're identifying many more people because their risks are higher than others you're excluding more people from health insurance. And that's the crisis that we've got ourselves in today, along with the mounting costs that make the premium even for the people who are low risk very high. Because it's no longer possible to put everyone, or a large portion of the population into one risk pool, the whole concept on which private insurance is based is out the window.

Q. Doesn't it impact a bit also on our old notion in society of what's normal? What is average? And is that something we want to do?

NH. Well, certainly what the Human Genome Project and what studies and genetics have already taught us is that there is an enormous range of variation from one person to another. The reason none of us look alike is to a large part, not completely, but to a large part, based on genetic differences that we have. And, while we can pretty much talk about normality or, rather, in terms of health, that is, somebody who is not sick, the variations will play a greater role in the immediate future in terms of how we characterize illness.

Let's take people who have heart disease. The time that one person will develop coronary artery disease may be much earlier than another person. The severity of that disease or certain other diseases may vary. Somebody may just have some pain and still live to 70 or 80 while others may die of a heart attack at the age of 40. So what I'm getting at is, even as we discover genetic differences, that not only is there normal variation but some of these genetic differences also influence the severity of genetic disease.

Now one of the problems about genetic tests, even for the very clear, sharp genetic diseases like cystic fibrosis, is that using a genetic test to predict whether or not a disease will occur is often not going to predict the severity of that disease. So that confronted with a choice, for instance of terminating a pregnancy, a couple cannot know in advance how severely affected their child is going to be. And that makes it very difficult how to explain genetics tests to people and to make sure that they understand that this enormous variation, not only between normals but even when one confronts illness, makes some of these choices pretty difficult.

Q. You didn't start off being involved in health policy. Why did you decide to get involved in that?

NH. Well, it's interesting. I actually did the basic biochemical work when I was still a medical student and was very interested in that when I took my residency in pediatrics and actually did a fellowship in biophysics that prepared me in those days to begin to look at some of the problems of genetic disease. At the same time, of course, since I became a pediatrician, I had clinical responsibilities and many of those were in the area of caring for children with genetic disease. Now, about the time that I was finishing my training and doing this, there was a large collaborative project organized in the United States in which our University, Johns Hopkins, was asked to participate to look at the effectiveness of therapy for genetic disease.

The genetic disease was phenylketonuria (PKU) for which at that time all newborns essentially were being screened in the United States. And a very puzzling thing had come out of the early findings of that project. This is a disease that you would expect to find equal numbers of males and females, but in the first 90 children who were identified through population-based screening, for PKU, there were twice as many males as females. And this was very puzzling and as a participant in this collaborative project I volunteered to look into this further and did this by a survey of the laboratories that were providing genetic testing.

Ultimately, we found the answer to that question which was that phenylalanine probably increases earlier in newborn males than it does in newborn females so that if you're testing them for PKU in the first couple of days of life you're more likely to pick up males than females and that was supported by the finding that when we looked for infants that were missed by screening there were more females than there were males.

Now, all of that was sort of a long prelude to tell you that when we did this survey and collected information one of the appalling things was the quality of laboratories that were performing newborn screening tests around the country and this has been confirmed by many other people since then. And I began to be worried as to whether these advances that were just beginning at that time and that offered hope that there would be other diseases that could be as effectively treated as PKU that as we moved from the laboratory into the clinical part of practice that these applications would not be handled appropriately, that there would be a poor quality of labs which means that some infants who could benefit from a treatment would be missed by a test and that other infants who didn't have the disease that they were tested for would be mislabeled as having the disease. And it's actually that experience that made me aware that in the practice of medicine there were a number of problems that were going to interfere with the appropriate use of new science, new technology and I continued from there and I found many other problems just in the area of genetics that indicate that we need to pay careful attention to the clinical application of advances in science.

Q. I've been asking a lot of the other speakers, "Why is biology different from physics or astronomy?"

NH. ...We're dealing with people and we're providing them a service. We have to make sure that it really is a service to people and not something that we're inflicting on them, imposing on them, particularly in the area of genetics, that they don't want or that may harm them.

Q. Who should be making policy about the uses of genetic information? Is that (information) mine? If I get a test should BWIB (a governmental agency) get that or should I be able to hold onto that?

NH. Well, I operate on a very simple fundamental principle and that is the one of autonomy: that the person who is being offered the test--and it should always be an offering--is the one to make the decision as to whether he or she wants the test and that decision has to be a fully informed decision so that the person offering the test, either directly or through videotape or brochures or group counseling, has to be at great pains to deliver the information that people need and want in order to make an informed, autonomous decision.

Q. But there are some insurance companies that are basically saying, "If you haven't taken the test, then we're going to drop you anyway because then you're too much of an unknown risk." How do you protect against that?

NH. Well, we've talked already of the necessity that private insurers or employers have for genetic information and so far as I'm concerned we need a new type of health insurance to deal with that. Because even if we pass laws saying they shall not use genetic information, there's a real problem as to how well and how inexpensively they'll be able to provide insurance under those circumstances. They could do it because, for instance, the people who were getting disease could now be identified were getting genetic disease before there were tests available, but I think it will be difficult to turn the clock back. I think insurance companies will lobby very hard for tests that are important, that is, that identify large numbers of people and that really do influence what an insurance company can charge and what an insurance company's profit is.

Now, one of the saving factors: we may have exaggerated the opportunities that understanding our genes will provide. Genetic disease is fairly complex. Particularly if you're looking for the more common diseases that affect a lot of people (and therefore will be of greater interest to the insurance companies), the tests may not be very highly predictive.

We're talking here about diseases for which there are genetic predispositions. So let's say you have a test and only 20% of people who have a positive test result are going to go on and develop that disease. If an insurance company should use that test it means that it's going to deny insurance to five people out of six who are never going to develop the disease. The insurance company is losing money there and it will have to weigh very carefully whether the cost of providing insurance to that sixth person is going to be greater than denying it to the other five.

So, it's not so clear that we're going to have a large number of tests that are going to be of critical importance to insurers but it's clear that the insurance industry has been interested in genetic testing and has generally opposed the notion that they should not be allowed to test or not have access to information. You have to remember that in addition to testing, insurance companies right now and for many years have used family history, genetic history, to make these decisions and they have also very clearly excluded people who have already had the clinical manifestations of genetic diseases, things like sickle cell or Huntington's disease.

(These examples) are what we call single gene diseases--where a problem in a single mutation in a single gene will cause disease and do it almost invariably if that mutation is present, either inherited from one parent in some types of diseases or inherited from both parents in other types of diseases. But, by virtue of where we stand with the technology now, we have the opportunity to develop tests well in advance of having a therapy treatment for those diseases. So we have a gap where we are able to predict disease. That might be a disease that's going to develop in the person being tested; it might be a disease that will develop in the unborn children of the people being tested, and will have that opportunity (to detect) without treatment.

Now, what do you do in a situation like that? Why should someone want to be tested? Well, they may want to be tested to know and to prepare to alter their life plans. Some of them may know they're at risk and would like to know with certainty whether they are going to develop a disease or not develop a disease. In the case of predicting disease in one's offspring in the absence of treatment, one can either decide to go ahead with the pregnancy and this will be influenced by the type of disease it is, or one can decide to terminate the pregnancy, to have an abortion. Now there are concerns about pressures compelling people to have tests and to take certain actions. So, we have tests that can predict the occurrence of disease, and to turn the clock back will be extraordinarily difficult to do.

Q. When did you get started in science? What got you started in becoming a pediatrician?

NH. Well, it's interesting, I actually was a history major in college but pretty early on decided I wanted to be a doctor and actually thought I would go into public health. It's interesting that what I'm dealing with now is much closer to public health than (my work) shortly after I started out. In medical school in the late Fifties early Sixties I was sort of smitten with the new genetics advances that were being made in protein synthesis at that time. I decided that I was interested in hard science and spent all of my elective time in medical school and then afterwards in basic science laboratories. As I became concerned with the applications of this basic science, I sort of came full circle back to what my original interests were with a background in history and political science, and now again for many years I've had this interest in health policy, public policy.

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