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Thursday, June 26, 2008

Session 1: Ethical Challenges of Expanded Newborn Screening

Discussion of Staff Working Paper


CHAIRMAN PELLEGRINO: Good morning, especially to those of you who were right on time. Forgive me starting a minute or two late violating my own first premise. And welcome to those who are in the audience. We're delighted to have you with us.

One or two announcements before we start the formal program. We have two new members who are still in the process of being reviewed. And I think you're familiar with their names — Dr. Elshtain and Dr. Landry. I'm speaking to the Council members now who know about this. They're not here because they've not completed the entire process, which is rather complicated and takes a significant amount of time, more than we anticipate, usually.

I'd like to bring you up-to-date on the reports that we're working with so that you know there are coming very close to completion and we'll have several publications in the late summer or early fall and beyond that.

One is on newborn screening, and you'll be seeing a draft of that today or have seen it. The other one is on the definition of death, which is completed virtually except for one or two small items.

Also, we have completed the — the reason I'm having trouble, this is not one of those microphones you can turn on and leave it alone. You have to keep your finger on it, and —

PROF. SCHNEIDER: In order to shorten comments.

CHAIRMAN PELLEGRINO: I'm relaxing my finger from time to time, maybe when I have something I don't want you to hear. The organ transplant document, which is in a far advanced state but still needs reworking after you've made your comments on it. And we're very eager to hear from all of you, especially before we put it to bed. So we can look forward to at least three documents in the early fall.

And with the dignity volume and with others we're preparing before the end of the year, we will have completed our work we have in mind, and we'll have drafts for you on futility and on conscientious objection possibilities and problems in ethical issues and decisions by the professionals.

The two new appointments, as I said, we hope will be with us at the next meeting, but they will get all of the materials so that we'll have their input. And I think that's extremely important.

This morning we will pick up a discussion on the ethical challenges of expanded newborn screening, which has also been before us, and you have this document. And we're very much interested in having your comments, suggestions, so that we can put final touches on it, and this is an important document, I think, in the current situation. So I'm going to ask two of the members of the Council to open the discussion — Dr. Diana Schaub and Dr. Floyd Bloom. Diana, would you pick us up?

DR. SCHAUB: I want to thank Adam and Sam for another excellent staff working paper. They document just how dramatically the rationale for newborn screening has shifted. The 2005 ACMG report recommended a sizable increase in the number of diseases for which newborns should be screened.

And it strove to present that expansion as in line with the established principle that direct benefit to the newborn child should be the paramount and indispensable criterion for inclusion of a disease in a uniform screening panel. However, as the staff paper shows, the recommended expansion was not simply in number, but in kind.

We don't just have more newly eligible diseases being passed through the screen. We have an altogether new screen and a new justification for that screen. The old rule was screen only if you can treat. The new rule, although not yet so forthrightly expressed, is screen unless there is a compelling reason not to.

The adoption of this new rule seems to have been driven by a technological imperative and a research imperative, rather than, say, a strictly medical imperative. The paper details some of the ways in which the selection of disorders was skewed by the evaluative role given to the technology of tandem mass spectrometry.

So, for instance, 200 points were awarded to a condition just for being detectable using a multiplex platform. The privileging of the full profile mode, which will sooner or later be even more complete when DNA profiling replaces the existing platforms, is linked to the ACMG's redefinition of benefit. Benefit is no longer limited to direct treatment of the child, but includes notions of public benefit and, in particular, the progress of biomedical research.

The authors describe this transformation in strong terms, stating that hitherto for diseases that were poorly understood or for which no effective treatment was available, we as a nation have not been in the habit of subjecting individuals to mandatory screening merely for research purposes. Is this a habit we are now content to acquire?

It would seem so since the call for expanded screening has been answered by the states to such an extent that we are well on the way to a uniform system. According to the staff paper, the lone holdout is Washington State. Interestingly, not a state that I think of as backward. So why should this reputedly progressive state resist expanded screening?

The paper by the U.S. Preventive Services Task Force, included in our briefing book, points out that Washington and Massachusetts are two states that conducted structured reviews of scientific evidence as a result of which their state programs mandate screening for far fewer conditions. Thank goodness for that glimmer of independent-minded federalism.

I'm very much in favor of the Council moving forward with this report. Now, I think, may be one of the last useful moments in which to raise serious doubts about this incipient ethical shift in newborn screening.

My own preference would be for a return to the principle of “screen only if you can treat,” and I hoped that the final report would focus some attention on the downsides of screening, especially the effects of false positives, particularly when, as a number of experts have testified, the positive predictive value for any newborn screening test is less than 2 percent.

I wouldn't be opposed to providing an avenue for ongoing research on a wide array of disorders that don't meet the stringent criteria for mandatory screening, but if research is the aim, then in my view participation should be voluntary and informed consent of the parents should be required. Neither the technological nor the research imperative justifies state-ordered profiling of every newborn infant.

CHAIRMAN PELLEGRINO: Thank you very much, Diana. We'll hold comments until we've heard from Floyd Bloom and then open it up to the Council deliberation.

DR. BLOOM: This is going to test my eye/hand coordination to be able to do this. As they note in the preparatory paragraph, the expanded uniform screening panel proposed by the American College of Medical Genetics in 2005 and promptly endorsed by the Advisory Committee to the Secretary of HHS and thereafter by other groups has already been adopted in more or less identical fashion by virtually all of the 50 states.

Therefore, the first point I raise for discussion is what practical utility would be gained by having the Council speak out on the issue and declare whether it is ethically defensible to transition from the position “screen only if you can intervene” to the position “screen unless there's some reason not to” since it's already in effect in 49 states.

Can we expect to mount an ethical argument sufficiently persuasive to have 50 state legislatures reverse their prior commitments to the screening process or are there some constructive, congratulatory suggestions we can offer to state legislators who bought the ACMG's arguments in full?

We considered this question with an earlier draft in March, and at that point you had five chapters — "Trends in Newborn Screening in the Age of Genetic Medicine," "The Debate over Expanded Newborn Screening at Present," "The Debate over Future Newborn Screening," "The Case for Expanded Screening," and lastly "The Case for Caution."

And in my view this was a better way to report our diverse topics — our diverse views of the topic and the trends in the technologies. That draft had a much more neutral tone to the narratives than does the current version. The critical analysis is emphasized from the two Hastings Center reports that you gave us to read.

If we look at their arguments, while I'm sure, as we just heard from Diana, our Council's views are quite mixed, Bailey and Murray base their concerns on a five-year Hastings Center project that ended last year. That project examined general requirements for an ethical newborn screening policy and the degree to which the current technological capabilities conform to those ethical requirements.

They listed four concerns, which are summarized in one sentence: A newborn screening policy is ethically acceptable when it is evidence-based, takes into account the opportunity cost of the newborn screening program, distributes the costs and benefits fairly, and respects human rights. But these arguments are mainly rhetorical and without any data to support them.

Their conclusion was that there should be evidence on the scientific validity, clinical utility, and research cost of the screening test requires that the test be implemented and its cost and accuracy determined.

They say there should be evidence on the effectiveness of the research cost and the availability of treatment and that the positive and negative effects of introducing screening must be measured, aggregated, and compared.

While all that is at some level valid logic, operationally it's difficult for me to understand how heritable diseases can be detected before the onset of symptoms and pathology without starting with multiplex screening platforms.

Those are the kind advocated by Duane Alexander when he reported to us. Tandem mass spec methods can indeed measure multiple metabolic variants indicative of abnormal protein, carbohydrate, or lipid metabolism, but the future of this testing in my view and the arguments about cost opportunity will be set aside by the future higher throughput, higher sensitivity assays for direct DNA sequence diagnoses of the rare metabolic disorders that are mainly featured in the current primary and secondary screening panels.

More importantly to me, DNA testing will inform a variety of genetic markers for enhanced vulnerability to future diseases ranging from obesity, hypertension, cardiac, and other organic diseases to depression, schizophrenia, Alzheimer's, and even to those non-disease states that we all aspire to, namely successful aging.

What we might be able to speak to effectively are to encourage the pilot studies that Bailey and Murray note under their policy goals on pages 30-31 of their very long paragraph on those pages. I certainly agree with their premise that if the benefit of the screening is to anyone other than the infant being screened or that benefit is as yet uncertain, that parental informed consent should be required, along with a pregnancy-long educational process to help the parents make fully informed decisions with the knowledge that any genetic results will remain confidential to the family.

Whether such parental participation in the lifelong health- and wellness-oriented child rearing program can be made part of our concerns with the flawed current state of our health care system can be a topic for our second discussion today.

The second critical paper by Moyer, et. al, I find even less persuasive, especially given that the screening against which they are the most critical is the one currently adopted by the states. They focus only on the screening technology and questions of the current era and not those that one sees evolving into operational status tomorrow.

Given the unquestioned evolution of genetics-based disease vulnerability, comprehensive health systems will need the screening data in order to develop and apply preventative strategies. I believe in the ultimate evidence-based benefits beyond the infant being screened to family and society when they are implemented in light of the constraints of the Genetic Information Non-Discrimination Act of 2007.

Today's untreatable heritable diseases will never be treated unless we can understand the etiology, environmental and cultural influences, and the pathophysiology of specific genotypes. In my view, that all begins with screening. Let the heel stick blood blot be replaced by a buccal swab and whole genomic analyses.

CHAIRMAN PELLEGRINO: Thank you very much, Floyd. Before opening up for discussion, I'd like to ask if Dr. Adam Schulman and Dr. Sam Crowe, who had the responsibility for pulling together most of the research here — if they would like to add anything at this point. But before I do so, Adam, Sam, I have to apply a necessary benediction on our meeting.

It is not an official governmental meeting until I recognize the presence among us of our executive director, and I know that Dan Davis goes along with the benediction. So we'll just take it for granted, but we are now official and go on the record. Thanks a lot, Dan, for your help.

Now, Adam and Sam, do you have something to add?

DR. SCHULMAN: Yes, I will add a couple of comments in response to some points raised by Dr. Bloom. One point of clarification: The papers that we presented in the last meeting are intended to form the core of the first and third chapters. So there's nothing in those that will not be included in the final White Paper as currently envisaged.

And it is our — I think it's our purpose to try to lay out as neutrally as possible the issues — that is to say, present the case for and against the expansion and really leave to the members in their personal statements the decision as to which seems more plausible. So we will certainly do our best, especially in response to comments from this meeting and the past meeting, to include all the arguments on both sides.

I also mention about the question of what practical utility there could be to the Council weighing in on this point given that the states have adopted most of the recommended screening panel. As we discovered as we studied the ACMG report in detail, there are 54 diseases recommended, but really all but five of them could be justified under the traditional criteria of either being — either fully meeting the Wilson-Jungner criteria or being screened for as part of the differential diagnosis of those.

So really it's a question at this point of five illnesses, not all of which have been adopted by all of the states, and the ACMG is continually reviewing its protocols for expanding or possibly even contracting the recommended panel. And I think they are very responsive to suggestions and criticisms about how future illnesses ought to be added to the panel and under which criteria.

CHAIRMAN PELLEGRINO: Thank you very much, Adam. Sam? No comment? Rebecca?

DR. DRESSER: Thank you. I, too, think this is a very well written paper. I guess I have about three comments. One is another benefit external to the child that is cited in the Hastings papers is this benefit to the parents of knowledge and their desire to avoid the diagnostic odyssey. I didn't see so much on that particular justification in your paper, and so I wondered if you planned to address it. It seems to me that that needs to be addressed.

And it's interesting to me, it seems a lot of this is motivated by the advocacy of the parent groups and that diffuse organization. So sort of the role of advocacy in health policy might be worth mentioning. I'm not sure what you want to do with it, but it seems to me it underlies a lot of this momentum.

And then, secondly, I think as Floyd mentioned, there's this whole movement toward broader genetic testing or screening for everybody with this thousand-dollar genome people are talking about and pretty soon everybody will have this done and it will just be a part of primary care.

So it seems to me that in a way, if I understand it correctly, newborn screening is kind of going in that direction, too. And so maybe this is not so much a newborn-focused phenomenon, but a broader U.S. phenomenon where the increased ability to test for lots and lots of genetic predispositions is seen as exciting and positive and something we should move forward with. So I think that that particular angle would be worth mentioning, that sort of what's going on with adults and older children in terms of this sort of massive genetic evaluation.

And then, finally, this whole research issue. Of course, if someone wants to do research with the samples, they have to go through an IRB and meet the HIPPA requirements and so forth. So the implication in here was, well, research will just go on and the parents won't know about it and people will be identifiable. And, you know, I don't think that would happen.

So I guess it would be worth having a discussion of — and I don't know much about this, but I know people have written on how these newborn spots are used in research and what procedures have to be done before that can go forward. I think if it's anonymized, then you don't have to get permission, but if there's any kind of identification, they will have to get permission. So that seems to be worth putting in the report.

CHAIRMAN PELLEGRINO: Thank you very much, Rebecca. Sam or Adam, any further comment?

DR. CROWE: Thanks for your comments, Dr. Dresser. The research focus — we didn't mean to mislead you at all to suggest that there wouldn't be any informed consent. The idea was we wanted to show that behind the ACMG's — or within the ACMG's new proposal — there's a research component that's been added to a certain extent. And we only — and this is because the technology in some way picks or can pick up other kinds of diseases that aren't part of the differential diagnosis of the primary conditions they're recommending.

The idea would be that if a child has one of these diseases that's not part of the differential diagnosis, the physicians or technicians would report on those diseases and then offer the parents the opportunity to enlist their children as research subjects.

What we wanted to focus on, though, is that during the Wilson/Junger sort of criteria days, prior to the ACMG's report, the focus really was to find diseases that we could treat and not find diseases that we can't do anything about really or we don't know exactly what we can do about them.

DR. DRESSER: No, and I think that's very important, so I encourage that, I just thought maybe a footnote or something about what would then have to happen if somebody did want to go forward with research.

CHAIRMAN PELLEGRINO: Carl? Professor Schneider?

PROF. SCHNEIDER: I'm sorry that everybody has said these nice things about your report, because I wanted to say them first. I thought that it was really an exceptionally lucid presentation of some very difficult things.

I did agree that it was — it seemed to be quite tendentious. Over and over we were told, you know, should we abandon the old rock on which we have always stood, the it -must-be-for-the-benefit-of-the-child test. And I inferred from that that that would be a pretty perilous step to take. So if it is intended to be truly neutral, I didn't — I was not able to appreciate that as well as I should have been, I think.

I wanted to follow up on some of the things that Rebecca said. I find it very hard to say, "Here is the principle that ought to be used to solve all of these problems for the foreseeable future."

I know of very few issues which have been very satisfactorily resolved using only one principle. Prior commissions have often been content to use only one principle, and the result you see is some of the serious flaws of bioethical policy that we're contending with.

I'm persuaded that as to each thing you might screen for, there could be quite a complicated set of considerations, including not just, as Rebecca says, the interest of the family in avoiding the diagnostic odyssey. I can't see a difference between the interests of the family and the interests of the children in that case in avoiding the diagnostic odyssey.

So I'm nervous about the idea of saying "Here's the great principle. Apply it. Keep other things out of it." But I was quite struck by the Bailey and Murray story that they began with because it seemed to me to exemplify a systematic problem with the way that we make choices about medical care.

That article, as you may remember, was the story of the very sympathetic father in Mississippi whose child could have been screened and wasn't screened and he goes to the Mississippi legislature and says, "For God's sake, we have to screen," and they passed one of these acts I believe named after the poor child.

And the trouble with this is that this is the way that we make all kinds of decisions about policy, from a very one-sided kind of perspective without looking at what the costs of what we're doing are.

And it happens in at least two kinds of ways. One of them is the way that Rebecca knows more about than I do. The amount that is spent on research depends in significant part on how successful the patient advocacy groups in that area are, leading to some very strange proportions in amounts spent on research.

The other way in which we systematically distort decision-making is that we appoint agencies to be responsible for worrying about some aspect of health care. So you have HHS, which has an agency which cares only about health care privacy, and they issue regulations intended to maximize health care privacy in ways that seem quite uninterested in the costs of the operation. We have another agency, OHRP, which is responsible for, as they see it, protecting subjects of human subject research and only doing that, whatever harm that may do to useful research.

So I agree with Rebecca that this looks in many ways like a small part of a much larger irrationality in the way that we make health care decisions in areas related to the kind of things that the Council is worried about.

CHAIRMAN PELLEGRINO: Thank you, Carl. Ben? Dr. Carson?

DR. CARSON: Well, you know, I think obviously we're only in the infancy when it comes to these screening techniques and the things that we can screen for. So this is certainly not something that's going to go away in the future no matter what we say.

You know, I like to think in terms of analogies, to put things in clear perspective. And, you know, within five years there's a very strong chance that one or more of us sitting at this table will be dead. Now, would you like to know if it's you and when you're going to die? You know, how would that change your life?

Now, some people would say, "Yes, I'd like to know exactly when that's going to be, because, you know, it would certainly change the way that I did things." Some people would say, "That's the last thing I want to know." So I'm not sure that that's a moral or ethical issue, because it's going to affect different people in different ways.

And I guess the real issue is how can or whether we can actually regulate the way that the information is used, because the information is going to be out there no matter what we say.

CHAIRMAN PELLEGRINO: Thank you, Ben. Bill? Dr. Hurlbut?

DR. HURLBUT: Floyd, I agreed with quite a bit of what you said in a broad sense, but did I understand that you feel as though eventually we should have a uniform national policy of sequencing the whole genome for each newborn?

DR. BLOOM: Well, that's what I was implying and I think that's where the future is taking us, but it doesn't necessarily have to be a federally or a state supported system that will do that, because as this month's issue of Nature Medicine indicates there are already three very thriving firms offering to do that for individuals at any age.

But I think ultimately if we consider what's wrong with our current health care system and try to implement something along the lines of prevention rather than waiting until the disease happens, we're going to need to have that information as early in the life course as possible in order to understand how best to go about the possibilities of prevention.

DR. HURLBUT: Well, that's a good answer, and it's your latter sentence that I think is something we should pay attention to, because why would it be a newborn. If it's early in the life cycle as possible, why would it not be prenatal. And you actually mentioned in your opening comments a pregnancy-long education process. How about one that's informed with early testing?

And as probably all of you know there are advances being made in taking the peripheral blood from the mother and detecting either DNA fragments or even fetal cells. So this may not be invasive and not carry any risks.

There are some troubling dimensions to this, however, and I think they could be included properly in our report. I agree that the thousand-dollar genome is imminent and I think sooner than most people are — even professional publications are stating. And maybe then it would go down to the — who knows, maybe the hundred-dollar genome eventually.

And if I understand it right, the tests currently cost about $70. Is that what was implied in our report, Adam? The mandatory screening that's currently in place in 49 states, roughly $70, $100?

DR. SCHULMAN: I think that's the right ballpark, but I'm not certain.

DR. HURLBUT: Okay, first statement — you must have this somewhere in your report already, but you should remember that's a huge amount of money — I mean, if, what are there, 4 or 5 million births a year in America. If it's a thousand-dollar genome, as you suggested, that would be 4 or 5 billion dollars a year. That's a significant amount of money to work toward cures and who knows what information we'd get from it.

But there are several things I'd like to say over the course of the discussion, but so that I get right to the heart if it is, do you think, Floyd, that it should be a mandatory — ideally you'd have that a mandatory approach?

DR. BLOOM: What I said was that I agreed with Bailey 's statement that if it was beyond the benefit of the child being screened that parental consent should be required and that the results should be kept confidential. And that would be along the lines of the IRB currently allowing for research on blood blots in an anonymized fashion.

DR. HURLBUT: And benefits to the child being a direct medical treatment or knowledge that the parents would have which would be preventive or some statistical possibility of the emergence of the disease? I mean, you know as well I do, knowing the science, that this kind of information that you'll get from a thousand-dollar genome, especially in the early decades, will be framed in statistical terms.

Some of the statistics will be hard for even the most informed scientists and physicians to understand and that's going to put an enormous burden on the average person in terms of what has been called toxic knowledge, information they simply don't know how to process no matter how much education you give them. Maybe we should just speak to those issues a little bit.

It seems to me this is what we're supposed to do as a Council is to talk about it no matter how we feel about it, but since you think this is a good idea, maybe you should address some of those questions.

DR. BLOOM: Well, calling it toxic knowledge already sets it up in a context that I'm not sure I agree with. We've have that kind of knowledge that — right now people with the Huntington's disease gene may or may not pose the same question that Ben raised earlier. Nancy Wexler, who talked to us three or four meetings ago, has a wonderful story that she often talks about of children who refused to be tested because they were sure they were going to get it and led their lives in a way that they later regretted because they didn't have the gene and mothers who have the gene aborting early fetuses and then deciding they didn't care anymore. So that toxic knowledge has been with us for a long time.

The Tay-Sachs disease gene in the Ashkenazi community was seen as toxic in the beginning, but the community rose to the occasion and now Tay-Sachs disease amongst Jews is extremely low in incidence. So I think the community has to be brought along.

We're not going to be able to deny the knowledge exists. And complex genetic disorders are going to be the mainstay of the kinds of diseases that Paul and I have been concerned with for our entire careers. And I don't see a better way to get at that knowledge than having the genetic sequence information as early as possible in the disease course. That doesn't mean it's going to be implemented in time to help my grandchildren, but my grandchildren's grandchildren will benefit from that.

DR. HURLBUT: I certainly didn't mean to imply that I thought this all was toxic knowledge. I just meant that that dimension for which the average person can't assimilate, that becomes to that person a burden, that we should address the issue of that, I think, because beyond the difficulty of dealing with false positives or statistical probabilities that are hard to explain — and, by the way, how far would you take it? Would you do not just the genome, but the epigenome also?

DR. BLOOM: It's not a slope on which I'm willing to put my feet.


DR. SCHAUB: Yeah, just a question for Floyd. I initially thought that we were pretty far apart on the spectrum on this one, but I'm not actually so sure that we are, because you spoke quite favorably of this notion of having pilot programs and parental consent.

So, I mean, would you be in favor of the mandatory program, the state-run program, operating according to the original principle of screen only if you can treat and then having a sort of second tier program that could operate according to a different principle and screen for everything, but that would require parental consent and all of the sort of educational framework that would have to go with that?

So, Carl, you suggested that there had been, you know, a suggestion floated that we just operate according to some monolithic principle. In fact, I think that's not at all what I was suggesting, but that you could have a kind of two-tiered program that would take proper account of when consent should be sought.

DR. BLOOM: I'm in favor of two tiers, but I'm also in favor of looking beyond where we are now to a much more complete, comprehensive, accurate, and sensitive profiling when DNA testing becomes the mainstream, rather than tandem mass spec or other direct measurements of abnormal metabolites.

And I would assume that the ACMG will continue to evaluate the state of the testing arts and the opportunities for the future so that the current panel, even though it has things that may not benefit the person being screened, will inform medical research. And that's the angle that I would like to see. I am not in favor of screen only if you can treat, because what I really want to get at are the ones that we can't treat today.

DR. SCHAUB: But do you think that when you go beyond that screen-only-if-you-can-treat, you must secure parental consent or not?

DR. BLOOM: I agreed with the Bailey position on informed consent if it goes beyond the benefit of the child being screened.

CHAIRMAN PELLEGRINO: Dr. Meilaender. Excuse me. Diana, finished? Dr. Gil Meilaender.

PROF. MEILAENDER: As I listen to our discussion, it strikes me that in certain ways a more interesting question has emerged than just the question of this newborn screening policy. I think this is significant, though I do take Floyd's point that if 49 states have done this, we might be thought to be sort of arriving a little late on the scene.

That doesn't mean that it's not worth rethinking. It may well be worth rethinking, but there is a concern there. But the larger point — and maybe somehow — I mean, it doesn't mean that we can't do this, but we need to set this focused discussion into the context of a larger point that has to do with the purposes for which one seeks knowledge.

If I'm a researcher — which I'm not, of course — I suppose the more knowledge, the better. Even if I see absolutely no possible use for that knowledge right now, it's useful to have, who knows what may come of it.

If I'm a patient or even just a potential patient or the parent of a very little patient, the more knowledge is not necessarily always the better. This is a problem. There may be a lot of things I'd just as soon not know along the way because I can't process them or I've got nothing to do with them and so forth.

And if this problem is buried in the newborn screening issue here, the various comments people have made suggest that it's a problem that is only going to grow enormously over the next few decades, and so we might not be coming on the scene too late at all if we couch this in a way that not only deals with this focused issue of newborn screening, but tries to say something — I mean, we have to think about what exactly there is useful to say, but tries to say something about a certain kind of tension between what patients or potential patients want and need as knowledge and what research needs and how one sorts that out. I mean, I think if we do something with that larger issue, we might be able to set this in a context that would be quite useful.

CHAIRMAN PELLEGRINO: Thank you, Gil. Dr. Dresser?

DR. DRESSER: Carl, I don't mean to put you on the spot, but I remember you did some work on prostate cancer screening and about the attitude that patients had toward it when sort of perhaps from a more objective viewpoint the value of the knowledge was questionable, but the way that the patients felt about it was different. So maybe that would be useful to share with us.


PROF. SCHNEIDER: It at least speaks, I think, to the idea that in some circumstances getting the informed consent of the parents for this kind of screening would be a useful thing. It strikes me as very unlikely that you will actually be getting informed consent from parents if you present them with the form and ask them to sign it or even if you try to explain it.

The study that Rebecca was talking about was 40 men in Ann Arbor, and we spent — a doctor and I spent as long as needed to give them the information that they needed to decide whether to be screened using the PSA test for prostate cancer. And we worked in a way that no physician would ever be able to work with a patient, and then we would ask them, do you want to be screened.

And either answer, of course, was perfectly correct. Nobody could agree on whether the screening was a good thing. That's why the official guidelines always have punted this to the patient and to the doctor. The answers we got revealed that the hour and a half or so that we would sometimes spend had been time wasted, because they responded to the question by consulting assumptions in what I called folk wisdom that they had, like, “it is always better to prevent a disease than to have to treat it,” which is no doubt true, but screening doesn't prevent diseases.

The thing that came easily to their minds was this principle of the American Cancer Society that they applied in ways that we didn't anticipate and understand. More broadly — and there were lots of these pieces of folk wisdom that they used, like, "Well, the PSA test may not be really good, but it's the most recent thing and you should always use the most recent thing."

The literature on informed consent is massive, and it repeatedly, invariably suggests that if the goal is really to give patients information so that they can make a well based medical decision, the success you have in communicating the facts runs somewhere between about a third and a half if the answer is correct.

And here you have parents, very recent parents, and what you're presumably trying to do medically is to help them deal with their child as well as possible. And I think a decision needs to be made about how much of that — of the scarce educational energy that you have for dealing with these people you want to spend on pretending to inform them about the screening choice and how much time it would be better to spend on things that would probably do a whole lot more good for a whole lot more children a whole lot more quickly.

CHAIRMAN PELLEGRINO: Thank you. Peter? Peter Lawler.

DR. LAWLER: Right. This has been a fascinating conversation going well beyond the scope of the report, but I just think from the point of view of the parent because, like you all, I can't think from the point of view of the researcher, particularly — that, of course, a parent would want to know about specific diseases that your kid has that could be treated. This doesn't seem controversial.

But when you talk about the more comprehensive knowledge that will soon be available that Floyd was talking about, a parent would be presented with a whole bunch of statistical probabilities or risk factors. And this might, in fact, as has been said, be way too much knowledge, turning preventative medicine into indiscriminate paranoia, like "You don't get dessert because you have a slightly better than average chance of getting hypertension."

And so preventative medicine is good, but this explosion of information presented as statistical probabilities a parent might not, in fact, want because prevention could turn into paranoia. But, in fact, how could you turn this down if it were available. It would seem irresponsible.

So that leads to all the things Carl was talking about in terms of informed consent. It would be very hard, in fact, to say no, and it would be very hard, in fact, to know enough to know whether you should say no.

So, in fact, the question of informed consent is a big issue, the issue of the explosion of information and kind of — which will seem like quasi-deterministic information that, you know, you'll know what's going to happen in advance.

And even though it's not really that, as was pointed out, it will seem like that to the parent, that, in fact, I tend to agree that we will not prevent people — be able to prevent people from being burdened with this information if it's available at a relative low cost.

And so there are all kinds of interesting psychological issues there about whether it's better to know all that much. And is there really an ethical and public policy issue — will we be able to withhold this information effectively from people; will the very idea of consent really mean anything given that it will seem irresponsible to turn it down. And then I can go on, as Bill wants to, to talk about how all these issues are enhanced or inflamed once you get into the prenatal area, but I won't.

CHAIRMAN PELLEGRINO: Thank you, Gil. Peter, further comments? Janet?

DR. ROWLEY: I don't know that I have anything very profound to say. I can speak from somebody who's been involved in genetics, at least as related to cancer and as somebody who does research, that I think that one of the points that Floyd made in terms of being able to advance our knowledge and ultimately to benefit patients is an important consideration.

And it is true that in mass spec analysis you can do whole genome-wide mass spec. So you're looking at all the proteins, whether they're the ones you're interested in or not. And if you find an unusual pattern that keeps repeating — which, of course, is difficult in rare diseases. It could just be a polymorphism.

But if enough of them are pooled together, you then can both find diseases, presumably many of them of genetic origin, but you also can have individuals who are knowledgeable and interested in that particular metabolic pathway involved in trying to figure out both what the errors are, but also then what the possible treatment is.

So you can say, well, this is knowledge for knowledge's sake or research for research's sake, but I think that's how much of — many of our discoveries have been made just by following that particular pathway. So I think that only screening for treatable diseases is too narrow a focus because what's treatable today or what's not treatable today may well be treatable tomorrow.

And particularly with the recent discussion here on informed consent, is doing a mass spec twice on a sample and only looking for defined things that you know about in the first sample and then looking at everything the second time. Firstly, you may not have enough sample. Secondly, it's at least twice as expensive as it would be otherwise.

And I think we're all brought up to say, yes, we're all in favor of informed consent, but as a practical matter, I'm not so sure that it's really the critical issue. I think, not to misuse any genetic information that is obtained is the critical issue and one hopes that the legislation that has recently been passed will deal at least with some aspects of that.

But just think logistically. If you say you're only going to screen for diseases that are treatable and in five-years ' time that number is doubled, are you going back to the legislature and say, "Well, now we can treat this, so now it should be mandatory, not voluntary."

I think that we have to put some reasonableness in the kinds of recommendations that we make. And I do think that we have something to say as a Council, if as Gil has been suggesting, it is expanded or at least in, say, the last chapter it's pointed out that many of the considerations are applicable to a far wider population, then that would be a sensible thing to do.

CHAIRMAN PELLEGRINO: Thank you, Janet. I have Paul McHugh and then Bill Hurlbut.

DR. HURLBUT: Could I ask a question of Janet?

CHAIRMAN PELLEGRINO: Relevant? Yes, go ahead.

DR. HURLBUT: As a point of clarification, Janet, and for information for our Council record, would it be more meaningful in terms of the value of information to have a test of all the proteins and can you, in fact, with mass spectrometry actually look at a whole view, essentially like the equivalent of a genome-wide expression? Can you look at, what is it, ten thousand proteins or so forth. And, if so, is that information reliable or does it sequence through cycles that make it less information-rich and how much would it cost and when would you do this in the newborn period?

DR. ROWLEY: Well, my understanding is that the tests currently are using mass spec, and I don't know how many proteins are analyzed. I know that for our research purposes in leukemia, we're proposing to do genome-wide screening, which — of proteins. So it's whole cell protein analysis.

And it's extremely expensive, but it's also new, and there are very few companies that you can get to do this. And if you really did it on a larger scale, then the efficiencies and the economy of scale would come in.

And you're not looking at proteins. You're looking at peptides. And at least this is — I'm so far out of my field that I shouldn't be saying this, but it's my impression that you look at the peptides and then you know which peptides you expect to be in which proteins and which amounts and with the controls, you can see what appears to be aberrant.


DR. McHUGH: Well, I also want to begin by thanking the office for the report. It was wonderful and very informative. And it spoke a bit to my conflicts, and I'm deeply conflicted in this arena in two ways.

First of all, I believe that the conditions that I study, in particular, the ones that emerge in early adulthood and challenge the rest of the life of those people will need us to understand them earlier in order for us to develop appropriate work for them and to understand what the mechanisms of their conditions are and the things which prevent and enhance it. So I'm in that area.

I also, of course, am a person who informs people of them carrying a particular gene, and if you work in a Huntington 's center like I do and have the problem of telling somebody this kind of bad news, you really know in the hardest kind of way what effects it will have on them.

So when it comes, therefore, to this area of infant information, I want the information as an investigator and very much worry about the information as a doctor and as a person caring for these people.

And what I liked particularly about the report was that it was emphasizing for everyone that there's a transformation of moral custom here if this new method comes into play. That's all I think we have to do for the public is to say, something has been transformed and it's important for you to know about it.

Then I was delighted with what Floyd said about, "Gosh, we're playing catch-up here a little bit. After all 49 states have done this." But I wouldn't worry too much about that. Forty-nine states are a lot of states, but I think it was 32 states that agreed that there should be involuntary sterilization of people who they believed at that time could be, as Oliver Wendell Holmes was saying, "Three generations of imbeciles is enough."

So the states do these things prompted not by careful thought about the moral transformations, but they do it in relationship to the bits and pieces of information they get from so-called experts — or true experts and the like — who become focused on what they do like I could be.

So I'm very pleased with the report and I'm looking forward to having an ongoing conversation like this from different perspectives as it needs to be when moral issues conflict as they do for me, personally.

CHAIRMAN PELLEGRINO: Thank you very much, Paul. Carl Schneider.

PROF. SCHNEIDER: I would be helped if the report could — and if anybody here could help me understand what kinds of costs we're talking about here. I can easily be persuaded that it is useful in terms of research to collect this kind of information, even if it doesn't go to parents. None of that bothers me very much.

But we happen to be talking about this area. We happen to be able to learn something by studying this area, but is this actually a good expenditure of our resources? Is the margin — if you start mandatory screening for a few things where you really believe that it's cost effective, is the marginal cost of screening for everything else so low that it simply doesn't matter, or do the kinds of cost the report does talk about eventually become so great that you'd really have to get quite a large return on your investment in order to make it worthwhile. So I'm interested in the cost/benefit question here and quite confused about it at the moment.

CHAIRMAN PELLEGRINO: Thank you, Carl. I think Dr. Davis would like to pose a question.

DR. DAVIS: I'll only do so after the Council is concluded. Has everyone commented?

PROF. MEILAENDER: I just wanted to add to Carl something that I'm not entirely clear about. You said — you referred to the use of "our resources." And I'm not sure whose resources. I mean, my understanding is some of this is publicly funded and some is not. That might make a difference to me, sort of, in what I think about it. So a little more clarity on that would be good, too.

CHAIRMAN PELLEGRINO: I have Professor Gómez-Lobo and then I have Rebecca Dresser. Did I see your hand flick up here, Floyd? Okay.

DR. GÓMEZ-LOBO: This is sort of a comment from someone looking at the earth from the moon roughly, because, of course, I'm not in this field, but it seems to me that if I try to reflect on the bioethical issues involved, I see that there's screening in three different situations — screenings for conditions that we can do something about; screening for conditions that we cannot do anything yet; and then general scientific knowledge, which, of course, at some point may become useful or not.

And I see the drawbacks or the negatives in a limited fashion. Maybe I'm mistaken on this. I see that with informed consent a lot of these things could be done. And I'm not so sure about the toxic knowledge argument. I think that I'm inclined to say most knowledge is good, and it becomes toxic in very particular circumstances. And I'm not sure it should be a very weighty consideration in public policy whether some people might — or for some people the knowledge might be toxic.

So my last question would be to Diana, but I think we're very close to each other now, is under what conditions would you accept a shift to the new principle? And in a way it seems to me that you have already accepted this by speaking of the two-tier approach. But that would be my view. I think that from a bioethical point of view most of the arguments should be taken to really favor massive newborn screening.

CHAIRMAN PELLEGRINO: Diana, did you want to comment? Dr. Dresser is next.

DR. DRESSER: I wanted to talk about if we have a two-tier system in the mandatory part where it sounds as though we're going to say there should be benefit to the child or — I don't know if we're going to say it should be, but that that's traditionally been the goal — how do things like — and they'll have to make decisions about what to look for in the future. So what about late onset diseases — APOE4, Huntington 's.

As these things become easy to find, is this something that should be included in the panel and how — if it's pretty much done without parental consent, what are you going to say to parents about this kind of thing?

There is today this therapeutic gap they talk about where we can know about a predisposition, but really not do anything about it or in some cases — say, a predisposition to obesity or addictive behavior — alcoholism, abuse of something — okay, well, what effect is that going to have on people to know about that.

You know, we already know we shouldn't smoke and drink too much and all that. So this discussion of if — even if we do rest mandatory screening on the notion of benefit to the child, how should that be interpreted in the future. What kind of evidence of benefit, what kind of benefit, would be justified as a sort of a tipping point before — you know, to have it included in the screening.

And then for the research consent, if it's just a matter of saying, well, it's okay with me to have my child's blood sample used in research for the future benefit of kids in the future and there's no coming back to me or my child with information and no linking of identity, I'm not so worried about how well informed they are about that choice. I think that that could be a pretty simple choice.

Then if it's something where they're going to want to come back and find the child and look at medical records, well, that's a different level, so maybe there should be more informed consent there or that people should understand that this could mean information about your child's health status and could have an effect on employment and so forth, confidentiality is important and all that. So I guess those are just some nuances about a two-tier system that I think should be at least mentioned.

CHAIRMAN PELLEGRINO: Dr. Davis, your comment.

DR. LAWLER: Very quickly, after listening to Rebecca, I think there is a non-trivial argument for no mandatory screening, in fact, that informed consent should govern it all. Parents should have the option of opting out precisely because of the slippery slope from prevention to predisposition and so forth.

So is there anyone out there defending that now, that there should be no mandatory screening at all. I mean, parents should be encouraged and so forth, but they should be able to opt out in a free country.


DR. DAVIS: Okay, just looking ahead very concretely to next steps, we do have one proposal on the table from Professor Meilaender about a more substantive and that is looking at the broader question of knowledge. Is there general agreement within the Council to do that?

We did have an earlier version that did that and so it would not take much to resuscitate that and bring that forward into this new plan, but just for the staff's benefit, is there general agreement that we should make that kind of revision? Okay. There have been a number of smaller suggestions I think that we can incorporate, but that will require a bit of rewriting.


DR. BLOOM: Well, if we did that, which I would favor, there is now a growing body of experience and data from the Icelandic DeCODE Study where the general population all volunteered to have their genomes analyzed. And the results of that analysis could be informative as to what we would do.

CHAIRMAN PELLEGRINO: And that's been in process for several years, hasn't it, Floyd?

Any other comments? We have some time. Do you want to respond, Adam?

DR. SCHULMAN: We did do some research on the experience of other countries with large-scale biobanking, including the Iceland case. And it's an interesting and complicated case, which is largely defunct at the moment because the Iceland Supreme Court decided that there were too many invasions of privacy involved.

And so it's a complicated situation where the country seemed very enthusiastic at first about compiling this information, but there were reservations expressed afterward. But we have a project ongoing that will be featured in this report about biobanking and the challenges of preserving privacy and consent while making maximum use of the data gathered.

CHAIRMAN PELLEGRINO: Bill Hurlbut and then Carl, and those will be the last — and Diana. Sorry.

DR. HURLBUT: I favor the expansion of the scope of the report as mentioned, and I think what we ought to do is center it around the question of the principle that governs the testing, which, whether or not direct therapeutic impact is the principle. I think you've done that in your staff paper today.

But I also think we should take seriously the troubling criticisms in the Moyer article. Did you guys follow up with those criticisms directly with anybody from the group that issued the study? What was it called? The College of —

DR. ROWLEY: The American College of Medical Genetics.

DR. HURLBUT: The American College of Medical Genetics. I mean, the Moyer article raises some troubling criticisms, and as Floyd says, they were themselves not exactly evidence-based in the article, although they may very well be. They may not have had space for what they intended.

But a secondary thing I think we should address besides the principle is the effect. And there I think we should take seriously the fact of when patients, the general population, hears a scientific statement, they don't necessarily have an easy time digesting it.

And we tend to hear things, and there are a lot of psychological studies that would confirm this. We hear things not as objective data-receiving machines, but as human beings with a weighted sense of significance.

And in the Moyer article they mention the effect of information concerning sickle cell anemia and the failure of large numbers of people to act on even very obvious information. So I know personally of cases where people have received prenatal diagnosis information where they've completely misunderstood it, and these were reasonably educated people.

And the burden of worry — converting pregnancy into nine months of worry is really something we should take seriously. Of course, we're talking about postnatal, newborn screening, but I think it's very likely this will extend itself, and therefore I agree with Gil, we should address the whole spectrum of this, as well as the practical impact on patients and the practical meanings of cost and follow-up, and the seriousness of this issue is quite deep, I think; whereas I want to also reaffirm that I agree with Floyd completely, that this will yield really wonderful, valuable information.


PROF. SCHNEIDER: I just have a quick question. You said that there was going to be a discussion somewhere of biobanks and privacy and is that to be in this report or in another one?

DR. SCHULMANOF: Biobanks come up in the third chapter, which looks largely to the future, in part, just because in this country they're really only being done on a limited basis, but there is discussion of nationwide large population studies and we will be going into that in the third chapter.


DR. SCHAUB: Bill 's comment took care of what I wanted to bring up. Thanks.

CHAIRMAN PELLEGRINO: Thank you. Well, let me thank all of the Council members. Each and every one of you participated in this discussion. You revealed the complexity of the issue. I think we all know that this movement is going ahead, and I think it's important that Council provide a systematic and orderly look at some of the issues.

It's clear that there isn't entire agreement on how we should go, but I think it's appropriate at this time, and as you all know, that you have the opportunity to provide an individual assessment, a personal contribution, to the issue and I would like to invite you to do that. As you look at this again, if you feel it should be added.

We're not going to achieve a consensus on every item — we all know that — but I think it's important for the Council at this point to say, "This is the state of the question" that the public can look at and can reflect upon and we know that things are going to change, but this is the present state. And I thank you all again very, very much, and especially Adam and Sam. We now have a break until 10:30.

  - The President's Council on Bioethics -  
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