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Meeting Transcript
June 23, 2006


COUNCIL MEMBERS PRESENT

Edmund Pellegrino,M.D.,Chairman
Georgetown University

Floyd E. Bloom,M.D.
Scripps Research Institute

Benjamin S. Carson, Sr., M.D.
Johns Hopkins Medical Institutions

Daniel W. Foster, M.D.
University of Texas, Southwestern Medical School

Michael S. Gazzaniga, Ph.D.
University of California, Santa Barbara

Alfonso Gómez-Lobo, Dr.phil.
Georgetown University

William B. Hurlbut, M.D.
Stanford University

Leon R. Kass, M.D.
American Enterprise Institute

Peter A. Lawler, Ph.D.
Berry College

Paul McHugh, M.D.
Johns Hopkins University School of Medicine

Gilbert C. Meilaender, Ph.D.
Valparaiso University

Janet D. Rowley, M.D., D.Sc.
University of Chicago

Diana J. Schaub, Ph.D.
LoyolaCollege

Carl E. Schneider, J.D.
University of Michigan

INDEX

SESSION 5: NEWBORN SCREENING FOR GENETIC DISORDERS

CHAIRMAN PELLEGRINO:  This morning we turn to a new topic, Newborn Screening for Genetic Disorders.  Our first speaker will be Dr. Duane Alexander, who is Director of the National Institute of Child Health and Human Development, National Institutes of Health.

Dr. Alexander, we usually do not go into a lengthy curriculum vitae, simply because it's so long and so impressive that we want to leave time for you to speak rather than spend it all on your biography.  So if you would be kind enough, we're delighted to have you address us.

DR. ALEXANDER:  Thank you very much.  That's the best kind of introduction, is a very brief one.

Thank you for the opportunity to speak with you today on a topic that's very dear to my heart, something that I've been involved in for a long time, something that I am not involved in as a geneticist or a professional genetics screener, but as a pediatrician who has had some experience in the ethics arena, but has been dealing throughout his career with the field of developmental disabilities and mental retardation and ways to alleviate those particular problems and disorders, by prevention when possible and by treatment to the fullest extent that we can.

I'm going to be talking with you about newborn screening, and I'm going to begin with a highly visible disclaimer.  These are usually in small print at an end, but the fact is that much of the factual information that I'm presenting is clear and referenced and well defined, but I will also be presenting to you some opinions that are quite clearly my own, not necessarily those of the Department or of the NIH or of the NICHD.

Some of these have been vetted and cleared for publication by the Department, an article by Dr. Van Dyck and myself that's I believe in your folders, but that has a disclaimer on it as well as representing our views and not necessarily those of the Department.  And it's very clear that that be understood.

Now, newborn screening has been around really as long as medicine has for particular defects or problems with the infant.  We look at the newborn infant, we count numbers of fingers and toes, we listen to the heart for heart murmurs or successions of heart disease, or look at the skin color.  We look at the genitalia for abnormalities and other parts of the anatomy as well. 

We even look at the baby with the idea of genetic disorders in mind, for Down's Syndrome, we look for ephocanthal folds, low-set ears, transverse Palmer crease .. this is something that's called a simian crease .. and we were diagnosing Down's Syndrome, a genetic disorder, long before we knew it was a genetic disorder, and far longer than we knew that it was caused by an extra chromosome 21.

So the idea of newborn screening itself is not new.  What is new is using laboratory studies to help with that process of screening the newborn infant for genetic disorders.  And it really begins with the story of phenylketonuria.  It's important that you understand that background, because it not only was the first but it's the model on which we learn about newborn screening for other disorders. 

And some of the problems we've had with it, some of the unexpected things that have occurred, and how we've dealt with them are all important for you to have as background for understanding what's going on with newborn screening today and presents to us some of the ethical issues and concerns.  So I'm going to spend a fair amount of time about .. talking about the PKU story. 

It really began in 1934 with a description of the condition for the first time by Foling, who observed several patients with phenylpyruvic acid in the urine in association with their severe mental retardation, and he called this condition phenylketonuria. 

It was clearly due to a deficiency of an enzyme that converts phenylalanine to tyrosine, so that phenylalanine accumulates in the blood, crosses into the brain, and the high levels of phenylalanine are toxic to the developing brain and caused the mental retardation and some of the other adverse symptoms of the condition.

No therapy was possible.  People started to question whether it might be possible to reduce the amount of phenylalanine in the diet and, therefore, reduce the phenylalanine levels in the blood.  There was no good way to do that at the time.  Phenylalanine is one of the essential amino acids.  It's part of protein, and it's essential because the body can't make it itself.  It has to be supplied to some degree in the diet.

But in persons with this condition, just the amount that they get in a diet is too much for their systems to handle, because they can't get rid of the phenylalanine by converting it to tyrosine, and so it accumulates and causes the damage.  It was very difficult with the knowledge from the '30s to the '50s to make a diet sufficiently reduced in phenylalanine to really do studies, but some people did this. 

They tried the treatment of people who already had full-blown PKU with all of the symptoms, and some people reported some suggested improvement, but for the most part there was no evidence of any benefit by this kind of late treatment of people who had already been damaged.

The only people who could benefit were the siblings of people who were born to some .. to parents who had already had a child with PKU and who could be identified in the newborn period and be treated with a low phenylalanine diet.  This was done, and there was enough evidence of benefit that people thought that they ought to try to do this in a better way.

This required two things .. first, a better source of dietary protein that was free of phenylalanine; and, second, a way to identify not just siblings of affected individuals who are very few contributing to the problem, but people who had no family history of the disorder and were born with hyperphenylalanine and were people who could potentially benefit from treatment if we had a low phenylalanine diet.

In 1958, the infant formula industry developed a product called Lofenalac, which was markedly reduced in phenylalanine.  It didn't taste very good, but it worked.  And people who were identified early .. sibs of affected individuals .. did show clear benefit from this reduced phenylalanine diet.

Then, the remarkable breakthrough occurred by a microbiologist, not a pediatrician, named Bob Guthrie.  Dr. Guthrie had a mentally retarded son, and he had a niece who had phenylketonuria, and he attacked this as a problem of trying to develop an early diagnostic test that would work in infants.  And what he came up with was something that was quite ingenious, that a microbiologist, not somebody else, might think of.

He identified a species of bacterium, a very common organism, called bacillus cedillas that was deficient in the ability to produce phenylalanine and required phenylalanine to be provided in order for it to grow.  Without phenylalanine, it didn't grow.  What he did then was plate agar plates about the size of a cookie sheet with cultures of bacillus cedillas, and held those in reserve and then would put onto that cookie sheet of agar the .. a sample of blood from newborn with or without phenylketonuria.

Without elevated phenylalanine in the blood the organism didn't grow, didn't have the substrate that it needed for it to grow.  But if there was elevated phenylalanine in that blood spot, the organism would grow and you get a growth ring around the spot of blood.  The blood was collected on little pieces of filter paper, just little dots about half an inch in diameter, and used in a project to test and see whether you could screen newborn infants this way.

And Guthrie's test worked.  You could clearly identify if you .. if the baby had been on milk formula for one or two days, those who had elevated levels of phenylalanine.  Guthrie announced this test in 1960, and there was a rush to apply it across the whole arena.  Even though it was very clear that phenylketonuria was not a very common cause of mental retardation, it was represented in institutions for individuals with MR (mental retardation), but it was a relatively small contributor.

When these individuals were picked up as newborns, and the dietary treatment with Lofenalac was instituted within the first couple weeks of life, these infants grew normally, they developed normally, and appeared to be spared the ravages of phenylketonuria.

There was not a study done immediately about this, but just a few anecdotal cases were sufficient to spark an interest in the whole mental retardation community and really helped to start a revolution in mental retardation research.  The picture of mental retardation research before 1960 when Guthrie's test became available was not a pretty one. 

It was mostly conducted in institutions for individuals with mental retardation.  It was not a topic that was either taught or researched very much in medical schools.  It was frowned on as a third rate field.  The people who were doing the research were pretty much limited to people who worked in state institutions for individuals with mental retardation, and you never saw a person with mental retardation on a medical school campus or in a hospital.

This was the sad state of affairs, and one of the reasons was the belief that this was a futile area for study.  There was nothing to be done for these individuals.  We could not improve their condition, we had no means of treatment, we had no means of intervention.

The PKU test changed that.  All of a sudden there was a means of detection and prevention of these terrible disabilities, and the idea was if there's PKU, there may be other PKUs out there.  Can we find them?  If we can find them and identify them,  particularly in newborns, we may be able to develop treatments akin to what we are able to do for PKU that will alleviate other disorders that cause mental retardation, and the search began.

People who previously had shunned the field of mental retardation entered it.  This was spurred in part by a stimulation of the Joseph P. Kennedy, Jr. Foundation, which the Kennedy family started, and they funded scholars in mental retardation, they funded centers in mental retardation, and this shifted and emphasis as well from places .. from these people working in institutions to working in academic centers .. again, the idea being, can we find and treat other PKU-like conditions?

The timing couldn't have been better, because President Kennedy .. John Kennedy was elected in 1960, the same time as the PKU test became available.  And he, as part of his transition team in Health Education and Welfare, included Dr. Robert Cooke, who had .. who was Chair of Pediatrics at Johns Hopkins and had two retarded .. mentally retarded children of his four children, and had a very profound interest in mental retardation.

 

He proposed establishing a new institute at the NIH to focus on mental retardation and development in general, to be called the National Institute of Child Health and Human Development, to provide a focus for research on mental retardation.  President Kennedy also appointed a President's Committee on Mental Retardation that still exists today.  

It has just changed its name to President's Committee on Intellectual Disabilities in keeping with the trend of the time, but that still exists.  And that committee made a number of recommendations, including efforts .. making efforts to try to reduce the prevalence of mental retardation by 50 percent by the year 2000.  This was the extent of the optimism that was triggered by the ability to screen for and treat and prevent PKU.

Legislation was also passed as part of President Kennedy's program to construct 12 mental retardation research centers at universities and academic health centers, not at the institutions, to bring this research into the mainstream of biomedical research in the country. 

They also established .. again, part of President Kennedy's legislative program .. university-affiliated facilities for mental retardation in a number of states, and now each state has at least one of these, for research on .. not medical treatment but behavioral treatment, educational treatment, social treatment, for individuals with mental retardation, and for training personnel to work in this field.

Also a part of this was a campaign begun by the Advertising Council spurred by the President's Committee on Mental Retardation, by the National Association for Retarded Children, to make PKU screening universal.  Their slogan was:  PKU tests should be a must for all babies everywhere.  This was done without real evidence of efficacy other than basically anecdotal case reports.  There had not been a combined study really looking at this in a scientific way.

So the Children's Bureau joined with NICHD in funding a study of efficacy.  This was based on a recommendation from a report from the American Academy of Pediatrics in 1965 that said a collaborative study to evaluate management of this disease would be valuable. 

They also pointed out that without any citation that there was evidence of some infants actually being harmed by unnecessary treatment for phenylketonuria when they really didn't have it, because they had some variant of the disorder that was relatively benign, and other infants who had suffered malnutrition because the restriction of phenylalanine from the diet was so severe.  You have to have some.  You can't eliminate it totally.  And some people in the zeal for this treatment eliminated it too much, more than was appropriate, and some babies did suffer malnutrition as a consequence.

So in 1967, this collaborative study was launched of children with PKU, and the data from this study showed clearly that early treatment led to normal growth of these kids, their IQ levels were comparable to those of their unaffected siblings, and that the diet should be maintained at least throughout childhood.

The best predictor of efficacy was the age at which the dietary treatment began, and second was the degree of dietary control that was maintained. 

So with this information, then, more and more states began to pick up and screen.  Massachusetts, New York, Louisiana, and Rhode Island led the way, and many other states joined.  By 1975, 43 states had mandated PKU screening.

We had learned that its prevalence was 1 in 14,000 births.  We had discovered variants, particularly a non-PKU hyperphenylalanine anemia, that did not require treatment.  We had also started to learn about what we knew was going to happen, the problems of false positives and false negatives.  At that time, in the early days, about 95 percent of the babies who screened positive were false positives.  Only 1 in 20 who tested positive actually had the condition, so there was a fairly high ratio.

False negatives, up to 10 percent in the early days were missed.  Most of these misses were people who were not appropriately .. who were not screened in the hospital.  Today our figures are a little better.  The prevalence is 1 in 14,000.  We identify in 14,000 about 10 kids who test positive by screening.  Only one of those has PKU, so we've lowered it from only 1 in 20 being positive to 1 in 10 being positive.

We still have a rare, rare false negative.  These are almost non-existent.  And if there are kids who were missed, they were not generally screened in the hospital.  It's not the lab test that fails; it's the fact that they were born at home or for some other reason didn't get screened in the hospital.

So we've made major efforts to improve these, and that's about where we are at the present time.  You can't totally eliminate your false positives, because of the way these levels are distributed in a population, and what you have to do is draw a line, your cutoff, of babies who are called back for a retesting for a confirmatory test, so that you can not miss kids who should be tested.  And that's a very tricky thing.  It has to be done differently for each disorder we screen for.  But, again, here's the lesson, the model from PKU.

Okay.  Other problems with PKU.  One was dietary management.  We didn't know at the beginning how low we had to keep phenylalanine in order to allow for normal growth but to avoid the adverse consequences of phenylalanine being too high.  Over the years we learned that the level should be about six milligrams per deciliter, and that has been the target for control.

We also didn't know how long to continue the diet.  The studies early on suggested that it probably should be continued through childhood.  Initially, people said age seven and then let up.  Now people believe I think it certainly should be continued throughout childhood. 

Adolescence is tough.  There's an awful lot of phenylalanine in a hamburger, and these kids have to stay on some dietary restriction that's hard to do and have a good bit of their protein intake coming still from Lofenalac in order to avoid still some consequences in their behavior, their intellectual functioning, their general sense of well being, as teenagers, and it looks like this carries over into adulthood as well.

Then, there's the problem of maternal PKU.  This really did take people pretty much by surprise.  What we did was create a population that had never existed before .. that is, a group of women who instead of being severely retarded and basically out of the reproductive pool, were now functioning normally, marrying, and having children.  They had high phenylalanine levels during their pregnancy, and it turned out that the phenylalanine crosses the placenta and is toxic to the development of the brain and other body parts in the fetus.

Even though the fetus does not have phenylketonuria itself, and it is an obligate carrier, but it does not have PKU, but it is adversely affected by the high levels of phenylalanine it is exposed to during the pregnancy, because of the mother's high levels.  And as a consequence, those babies are born microcephalic, many of them have heart disease, they stay small, and they are mentally retarded.

Generally, their mental retardation is not as severe as people with untreated PKU, but it is severe enough to be significantly problematic.  What the data showed, then, was that if each of these women had two children .. and all of them are affected, there was no escape .. we would have as much mental retardation due to PKU in a generation as we had before we started the screening program.  Something had to be done.

Rather than give up screening, we've looked for a way to try to deal with the problem of the high phenylalanine levels in pregnancy.  And the obvious approach was to try to reinstitute the diet during pregnancy, ideally before pregnancy, keep the mother's phenylalanine levels as low as possible, six was the target, and see if this would not reduce the likelihood of hyperphenylalanine anemia in the mom, crossing in the placenta into the baby and affecting its developing brain.

This was tried.  NICHD actually organized a collaborative study that started in 1984, went on for about 15 years, and that study demonstrated very clearly the benefits of this dietary approach.  It also showed how difficult it was.  Many of the women were off the diet before they got pregnant and had instituted it again during early pregnancy.  It was very difficult to do.  Some women just could not do it.

The ones who did the best and had the best outcomes, basically normal babies, were the ones who had instituted the diet before they got pregnant, kept their dietary control around six during the pregnancy, and the babies basically were minimally affected, although that was not 100 percent, and essentially were normal.

The moms who were not able to achieve this still had the problems with babies who were damaged by the phenylalanine exposure.  So NICHD held a consensus conference on this topic after the study was done trying to bring attention of the scientific community and the OB/GYN and pediatric communities to this as a problem .. the fact that there was a solution, it was a hard one, but there was a way to avoid this as an issue.

And today I think there is general knowledge in the OB/GYN and pediatric communities about this as a problem.  What we don't always know is that the women are phenylketonuric, because they appear normal in so many ways, unless the moms tell and unless we remember to ask.

The other thing that happened was the addition of new disorders to the screening.  With the success in PKU and the development of means to detect other conditions, it was pressed for these to be added to the conditions we screened for.  The most successful of these was congenital hypothyroidism.  This has a prevalence about four times as high as that of PKU, about 1,000 babies born in the United States each year with congenital hypothyroidism, compared to about 250 with PKU.

So if the problem with congenital hypothyroidism is that, again, these babies don't look any different than other kids at birth.  They are very hard to pick up, because the mother's thyroid has protected them during pregnancy.  But once they lose that maternal thyroid hormone, they start to develop symptoms. 

Thyroid hormone is necessary for normal growth and brain development.  Without it, the kid's growth slows, their appearance changes, and their intellectual development suffers irreparably.  If we don't pick these kids up by three to four months of age and institute thyroid hormone replacement therapy, they are marked for life. 

They do not improve their mental function.  They may change their physical appearance, but that brain development that is so critical in those early months has not taken place in the absence of thyroid hormone stimulation, and they permanently are mentally retarded.

Dr. Del Fisher, a pediatric endocrinologist at the University of California-San Francisco, in the 1970s said, "I think we can develop a test to screen for congenital hypothyroidism like we screen for PKU."  It's different, it's not genetic.  It's like a birth defect that is sporadic.  The thyroid gland basically doesn't grow.  There is a very small portion of this that is genetic that's based on an enzyme deficiency in making thyroid hormone, but that's a very small subset of the group.  Most of these kids do not have thyroid glands.

If we replace that absent thyroid gland with thyroid hormone, which is very cheap, very easy to do, these kids grow normally, their brain development is normal.  So he set out to develop a screening test using the same filter paper blood spots that we used to screen for PKU and was able to develop a micro-assay for thyroid hormone and thyroid-stimulating hormone, was able to pick up virtually every kid with congenital hypothyroidism.

The thyroid hormone is very low.  The thyroid-stimulating hormone, TSH, is very high, because it's responding to the lack of thyroid hormone and overworking, trying to make something make a hormone that isn't there.  So with the combination of these two assays, basically you've demonstrated you could pick up all the kids.  Dr. Dussault in Quebec demonstrated in a province-wide study that this screening system worked and states rushed to add it to their screening armamentarium.  And very quickly it became mandatory, along with PKU.

But in 1975, a National Research Council report on newborn screening, particularly for PKU, was issued and it was cautionary in several ways.  First, it said, "Do not rush to add too many new tests to screening, until you have systems in place for medical education to know how to deal with these, to counsel parents, to provide information so that misinformation is not there, and kids don't get treated inappropriately."

They also issued what sort of was practiced in the community but became dogma, which was a recommendation that you should not screen for anything that you don't have an effective treatment for.  And that dogma has persisted until just .. until recent years.

I'm going to skip now over the intervening years until today and look at where we are.  Here's where we stand today with newborn screening.  This is data as of June 1st.  You can see that there are nine states that screen for more than 50 disorders.  What has made this growth possible is the development of what we call tandem mass spectroscopy, where we are able to use a technique that looks at proteins, enzymes in the blood, as well as accumulated abnormal products, and detect those in a way that multiple things can be detected at once.  So you basically with tandem mass spec can detect as many as 50 disorders, and the number of those is growing. 

So there are nine states that are screening for 50 or .. for more than 50 disorders.  There are .. and you can see the other numbers right here.  There are only three states that screen for less than 10, so that this system of screening has grown markedly, and a lot of that growth has occurred in the last two or three years with the advent of tandem mass spectroscopy. 

With the report from the American College of Medical Genetics recommending the expanded use, and the adoption and endorsement of that report by the Secretary's Advisory Committee, this has markedly expanded.  So you can see the current picture of newborn screening.

How fast is this?  How quick can we get answers?  I can give you one example.  The State of Iowa screens for 53 disorders.  They pick out or they get samples sent to the state laboratory every day by 5:00 p.m.  All those samples are at the laboratory by midnight.  They work 24 hours a day, seven days a week.  They run those analyses.  The results are back to the hospital by 5:00 p.m. the next day, 24-hour turnaround.  That's very, very, very fast. 

So we are able to pick up these kids by really a day after the heel stick is done.  Not every state is that fast, but the rest are not far behind that kind of a record.

Now, we've learned, as I said, a lot of lessons along the way from PKU screening, from congenital hypothyroidism screening, from galactosemia screening, from screening for many of these other disorders.  And basically, we've learned from this process enough that I believe we can proceed with caution to avoid harm.  But we must proceed to take advantage of the preventive potential of this technique of newborn screening.

And if we apply the lessons we have learned as we have broken this new ground, we didn't do it perfect the first time around.  We learned along the way, but we have learned a lot and there is carryover applicability to virtually each of the other conditions that we would screen for.  And if we apply these lessons we learned as we broke this new ground, we can implement expanded screening responsibly.

Now, how do we proceed?  There are a number of guidelines here that I'm just going to run through very quickly, and then I'm going to spend some time on each of them in order.  First, I think we need to make the programs comparable across the states.  We need to improve the technology that we use in screening, emphasizing DNA-based approaches.

We need to aggressively pursue development and testing of therapies for disorders that currently we could screen for, but we don't have effective treatments for them.  We need to evaluate the tests to minimize the false positives and the negatives, and have a confirmatory test system in place that can operate very quickly to evaluate kids who screen positive and have a good system of parental counseling, especially for those with the false positives, so they don't continue to think "something is wrong with my kid."

We also need for the treatable conditions to have a science-based service delivery and a followup system in place, so that these children do get appropriate treatment, and expand our screening to include disorders that don't yet have proven preventive therapy available, and also provide a registry of these patients with parental approval, so that they will be available for future research participation if the parents agree to do that, because only in this way can we develop, test, and evaluate effective treatments for the conditions we don't have treatments for now.

Let's take a look at each of these now in order.  First, making newborn screening programs comparable across the states.  These programs vary from state to state.  Remember the map.  These are state programs; they're not Federal Government programs.  The Federal Government has provided assistance to the states through the Maternal and Child Health Bureau grants to develop and implement these screening programs.

But the government has not dictated what you screen for.  The states choose that.  They choose it in a variety of ways.  Sometimes the legislature itself dictates which conditions will be screened for.  Sometimes they set up a commission.  Sometimes they entrust the Health Department to do it.  But each state winds up with essentially a different group of conditions for which they screen, and, again, remember the map.

They decide this in a variety of ways.  It can be either based on legislation, on a payment system, what they'll pay for, what the costs of the individual tests may be.  Some are more expensive than others, and essentially you're paying for each test separately, except for tandem mass spec, and a variation in prevalence of the conditions by state.

North Dakota or Montana may not have very many people who would be even at risk for sickle cell disease, and they may not want to spend whatever additional it costs to screen for that condition.

So this is really what got me involved, I will confess to you, in newborn screening, was this problem of variability across the states.  And this is .. I got involved with this, I will tell you, by a letter that was referred to me by Hillary Clinton when she was First Lady. 

She had gotten a letter from a constituent.  She passed it on to me to respond to.  I'm going to read to you a piece of this letter, because it had such a profound effect on me, making me determined to try to do something about this if I ever got the chance, that I think you ought to .. because it sets the case forward so well.  And I'm going to just take a minute to read this.

The letter was from the mother of an infant with a very rare condition called glutaric acidosis.  The cause of that condition was first described in 1985 by Steve Goodman at the NICHD-supported University of Colorado, Mental Retardation Research Center.  It's a genetic disorder that causes an enzyme defect.

The affected children appear normal at birth with no suggestion of abnormality until enough brain injury occurs at around one year of age to cause poor muscle tone and movement problems.  Treatment by dietary restriction of lysine and tryptophan is at least partially successful if instituted before the brain injury occurs, again like PKU, but is useless once symptoms appear.

This mother's poignant story illustrates the problem of a policy of screening for a disease that is based on cost and rarity.  Here's her letter.  "There's a two-year old boy with golden curls, bright blue eyes, and an incredible will to walk and run, talk and play.  His story, however, is one of constant struggle and heartache.  He was born prematurely.  Although small for his age, he did all of the things that normal babies do. 

"On Christmas Eve, one month before his first birthday, the real tragedy began.  With the entire family at home ready to celebrate all the joys of the season, he was sick.  Held close in his father's arms, his limbs were limp.  His golden curls dangled as his head fell back.

"No one could possibly imagine the diagnosis.  In the local hospital he was subjected to a variety of tests.  The doctors were baffled; all tests were negative.  But his condition remained the same, even worse.  His motor skills had regressed to those of an infant.  After months of prodding and poking, he was diagnosed with a rare genetic disease .. glutaric acidosis Type I, a genetic disorder that could have been detected at birth with a $17 routine test.

"Instead, it is a disease that results in brain deterioration.  There are approximately only 70 cases known in the United States, less than double that figure worldwide.  Each story is equally heartbreaking.  The statistics are grim, and research minimal, due to the small number of children affected."

That's the end of the letter.  This letter goes on to talk about a foundation that parents set up to support research and education and provide support for other parents.  Resolving this screening dilemma is a major problem we face when we have a preventable disease that we can screen for, but the rarity and the expense mitigate against doing so.  So that's the situation we face. 

Equity across states, I believe, is an ethical imperative.  Mandating it is difficult.  Another approach would be to try to develop a test that tests for everything at once, with one cost, no difference between how many tests you test for.  If you test for five, it's the same cost as if you test for 50 or 100 or 200.  And that test could then be so attractive that every state would want to adopt it.

For a long time such an idea was only a dream, but with new genetic technology it now becomes possible to think about doing that and try to develop a single, unified test system.  Tandem mass spec comes close, but it is limited in the number of disorders it can screen for.  It is not a gene-based test.  It's not a DNA-based test.  It's a product .. a gene product-based test.  And so we're still trying to find this single DNA-based test. 

So the current system basically is a different test for everything you want to screen for.  Congenital hypothyroidism is different from the bacterial assay of PKU, which is different from the gene assay for something else, or a biochemical assay, or an endocrine assay, or whatever.

Tandem mass spec has changed this a lot, but it still doesn't go as far as we need it to go.  And so we're looking at potential DNA-based systems.  If we could have this, we could screen for basically anything we have the gene for.  We could screen for all of the genetic metabolic diseases that have mental retardation or neural degeneration associated with them. 

We could screen for all the immunodeficiencies, all the hemoglobinopathies like sickle cell disease or thalycemia, all the coagulopathies like hemophilia, all the muscular dystrophies, Dushen's, spinal muscular atrophy, for cystic fibrosis, for hereditary deafness syndromes, and others as well.  The numbers go into the hundreds.

And each time we discover a new gene or a new abnormality of a gene the number of conditions would go up.  The only exception that couldn't be done this way is congenital hypothyroidism, which as I said is not a genetic disorder.  We would still have to screen for that separately.

So NICHD almost a year ago put out a solicitation for contract proposals to develop and test new approaches to newborn screening focusing on DNA-based systems.  Now, we have received applications for those.  Those are in the review process and will be negotiated and hopefully funded early in the next fiscal year.

We are optimistic that these systems will work.  Now, there's two basic systems.  Excuse me for a minute.  I want to pick up one of these things.  This is a microchip, DNA microassay, microarray.  This one is for the mouse.  This chip has 45,000 genes on it, basically a whole genome of a mouse.  That's how fast this technology has come along.

Basically, there's a separate little dot, a well for each gene, and basically what we can do is digest the DNA, break up the DNA of the genome of a mouse or of an infant, newborn, and expose it to .. with a special technique to this chip, and any abnormalities that are detected will be .. can be detected by a color change of the little dot on this chip that's read by a computer.  I'm going to pass this around so you can see it.

Potentially, we could screen every newborn with this kind of a system.  If we put on a chip, just not 30,000 genes of the whole human genome, but the genes that we are interested in screening for, for conditions that we're interested in screening for, either the normal gene to make sure that what we see in the infant is normal or the abnormalities, the genetic .. specific gene abnormalities of the conditions. 

That gets a little complicated.  Some of these conditions only have one or two known gene abnormalities.  Some have several hundred, like cystic fibrosis.  So the technology for doing this still needs to be developed, but we're determined to proceed with trying to do this.

There's a second technology that has come along and is in early testing phases.  It's called Luminex microbeads, and it replaces this gene chip with a microbead system.  Each of the beads has annealed onto it oligonucleotides, small fragments of a gene of particular interest.  Here we can make a bead for a given gene of interest, and, again, expose the chopped up DNA of the infant to the beads in this case rather than to the microarray chip, and, again, with lasers and computers identify which .. whether there are any abnormalities of interest.

We don't, again, have to put the whole genome on it.  We put on genes of interest, ones that are associated with the abnormalities that we want to screen for.

This is another technology that's coming along.  It has some potential advantages over the microarray chip.  It's simpler to use, it's easier to change, it might even be cheaper.  So these are things that are coming along and that we are investing in, trying to develop an enhanced capability to screen, and to have a test that is so attractive, so simple, and not too expensive, so that every state will want to use this in their screening program, and no longer will there be this state-to-state variability, so that what you get screened for depends on the state in which you're born.

Imagine being the physician who had to tell a mom that .. who has an injured infant that, "If you had been born in the neighboring state, your child would have been screened for this disorder.  It would have been detected, we could have initiated treatment, and your child would be normal."  That's what we've got to get away from.  That's why we've got to push the development of this technology.

Okay.  So the next thing, if we're going to develop capabilities for screening like this, we also need to develop improved approaches to treatment. And what we need to do here is remember that part of the justification for screening for these disorders is to identify a population that is presymptomatic, so that they don't have damage before we have an opportunity to try therapies.

Once they've developed these .. the brain deterioration or lost the brain development, it's too late for any known potential therapy.  And so they have to be picked up as newborns.  Only newborn screening can do that.

So what screening has the potential to do is to make available populations of patients with these rare disorders .. there's not many of them .. for study of new treatments as we get ideas for these approaches and be able to use to .. approach the families of these children before they get symptomatic ideally, and roll them .. with their permission .. in trials of new therapy developments.

In companionship with our solicitation for new screening technology development by contracts, NICHD also put out a program announcement to the scientific community asking them to submit their ideas for new therapeutic approaches to conditions that we could screen for but don't have effective treatments for at the present time.

We have already received a number of proposals.  Some of these look very good and are all set to get funded.  This is an ongoing solicitation that runs over three years, and I hope that we will get many projects, many ideas from investigators for therapeutic interventions.

We also by doing this will have an opportunity to enter patients in a registry with the consent of parents, and I'm going to spend a little more detail on that in a minute.

We also need to evaluate tests to minimize false positives and negatives as they are entered into the screening system.  Clearly, as I indicated before, there's a balance in where you draw your cutoffs, particularly so that you don't have too many false positives, but you don't miss patients at the same time.  And this is tricky.

There's also some variability from lab to lab, and there's needs to try and make practices in labs as comparable as possible.  Again, with these new techniques this lab-to-lab variability should basically be eliminated.

There's concerns of the costs and the parental anxiety with these .. particularly by the false positives.  Each false positive requires a subsequent visit and a workup and evaluation.  They cost money.  They also worry parents.  You get a phone call, "Your child screened positive.  We need to do a followup.  It may not be anything, but we need to check."  And immediately the anxiety meter goes off the scale.  So we need to minimize those false positives to the extent we can to avoid both the cost and the anxiety. 

The Secretary's Advisory Committee on Inheritable Disorders and Genetic Diseases in Newborns and Children is evaluating each of these proposed new tests before recommending its addition to a treatment regimen, taking into account this issue of false positives and negatives.

There's also an ongoing monitoring and standardization needed, that the system of regional collaboratives .. there are seven .. each state is part of one of seven regional collaboratives network, and it's headed by a national coordinating center.  And this gives us the opportunity for monitoring and standardization across the state sites.

We have to have in place a confirmatory test system with parental counseling.  Again, the problem with the false positives, we have to have .. these are just part of a screening.  Remember, this is screening.  This is not diagnosis. 

The screening must be followed by diagnosis, often a second screen.  If the second screen is negative, then we just can kind of relax.  If the second screen is also positive, then we go on to a confirmatory test and make sure whether .. that the person in fact has the disorder and what the nature of it is and can institute therapy.

Again, we have the system of the regional collaboratives and the national coordinating center in place to make sure that patients who screen positive get referred for this confirmatory testing, and this has to be done very quickly in order to initiate therapy when it's needed, and the results have to get confirmed by experts, a system of referrals has to be in place, so that we get the best information for these, and this information has to be passed on to the families.

The treatment initiation has to be done.  There has to be a system in place, so that these kids don't fall through the cracks, so that there is an expert system of care for those who test positive and have a disorder that we can treat.  And, again, the regional collaboratives follow .. provide this, and we need to learn as we go, so we must have a system in place with these regional collaboratives as they begin treatment, particularly for disorders where we don't know what standard treatment should be, or we're testing new ones, to follow these, to gather data, so that we can evaluate these new treatment approaches.

Finally, we need to expand screening to diagnose .. include disorders without definitive treatment.  Now, this goes against the dogma, and this is probably the biggest challenge that we have.  Why do we want to do this?  Again, as I mentioned before, even though the standard belief has been don't screen for something you can't treat, we now have confronting us not just the definitive preventive or therapeutic treatment, but other ancillary treatments for these kids as well.

There are some things that you can do for these children that don't necessarily mean a curative treatment, but they improve their quality of life and their ability of parents to care for them, and their ability to get programs and services in the community.  So there is benefit to the child from having this diagnosis, even if there is not definitive therapy.

In addition to that, the only way we are going to develop therapies for these conditions is to be able to diagnose them before symptoms develop.  And the only way to do that is through newborn screening.  The requirements here I believe should be .. include consent.  Most of the state programs for newborn screening for conditions now do not have a consent.  A few states do, but they are part of standard treatment, and their parents do generally not sign a form to consent for these.

If you're going to screen for conditions that don't have a treatment, some parents might like not to know about that, and they should .. this is being done in part as research, and parents should have the opportunity to be informed that this is being done and have the opportunity to opt out if they wish to of this part of the screening, not for the mandatory parts where we have clear benefit to the child.  But if there's not evidence of clear benefit, this, again, is .. this is my belief, they should be asked for their consent to this screening.

There should also be counseling for the parents, and there should be supportive treatment available for those who have conditions that are diagnosed that we don't have effective treatment for.  I also believe that there should be an opportunity offered to the parents to have their child listed in a registry that would be maintained either by the regional collaboratives or by the Centers for Disease Control or some other possibility.

This, again, would be offered to the parents, an opportunity to list their child on this registry by disease and disorder with contact information for the parents, agreeing to be contacted by investigators if someone comes up with a potential trial for a therapy that .. for these disorders.

What drives this is that many of these disorders are so rare nobody can get enough of a population at their own academic health center to test.  And it requires not just a collaboration of 10 or 20 academic health centers, but the whole national network of screening to get a sufficient number of children presymptomatically to do the studies once they're ready for human testing of these therapeutic interventions.

So this would be kept confidential, and parents would just agree to be contacted, not necessarily to participate, but to weigh the study and decide on each study's basis whether they want their child to participate in this or not.  And the outcomes of these studies would also be maintained by the registry, so that we gain knowledge of what the effects of these interventions are.

Okay.  That brings us to my final slide, and this is what I call the legislative and ethical imperative.  And this is perhaps the key to the whole success of this operation of newborn screening.  Basically, it relates to a belief that nobody's DNA information should be used to discriminate against them in employment or insurance. 

And unless we assure by national legislation that such discrimination won't happen I think parents are going to be reluctant to have their newborns screened in a public program, particularly for conditions if we don't have a treatment for them.  What they will worry about is that this will disqualify their children for insurance, it will disqualify them later as adults for employment if they have a condition that, you know, may not develop until later on, and this proceeding with caution .. as we've talked about from the beginning, "proceed with caution" includes providing this protection as well as all of the medical and the laboratory procedures identified.

I think that if we have learned enough from the experience that we've had starting with PKU, and involving numerous other disorders as well, that if we apply what we've learned and we can have the necessary funding support and continue to learn as we go, that newborn screening can take its full place among the most significant and effective public health measures of all time.

Thank you for your attention.  This has been a long talk.  I'll be glad to answer any questions.

(Applause.)

CHAIRMAN PELLEGRINO:  Thank you very much, Dr. Alexander, for a very enlightening overview of a very complex problem.  We appreciate it very, very much.

I'm going to ask now a Council Member, Dr. Floyd Bloom, to open the discussion.  Would you, Dr. Bloom?

DR. BLOOM:   I enjoyed reading your paper and hearing your talk to spell out the details of your paper, but it brings up the fact that, while I don't think that anyone could argue with the concept that if we could prevent mental retardation due to a post-natal screening procedure that we'd want to do so, obvious as that is. 

The question is .. you've named the points .. the cutoffs, the need for evolving technology to improve the breadth and sensitivity and accuracy of the tests.  And when are we ready to implement such tests?  As you say, the Luminex technology looks as though it will displace DNA chip technology.

You raise a very radical concept of screening for things even if we can't treat them, because unless we can identify who has them we'll never be able to develop treatments for them.  I think those are all very laudable, but I foresee great difficulties in getting states, particularly poor states whose health budgets are already compromised, to invest in such testing, particularly with such rare disorders.

Maybe just to get your discussion aspects going, I'll take you to one aspect of your paper with Dr. Van Dyck in which you said perhaps the biggest set of discussions will involve deciding what not to include in the set of tests, and there you list Huntington's Disease as something not to include.  But it seems to me that fulfills all of the criteria by which you listed the tests that you want to include, even though we can't treat them. 

And Nancy Wexler has many poignant stories of people who grew up thinking they had the gene and lived their lives as though they were going to die and then found out they didn't, whose lives were then wasted, and people who grew up not knowing creating additional children with the genes and thereby perpetuating the problem. 

And one could contrast that with the prenatal testing for Gaucher's Disease where the community involved and vulnerable to the disease decided to have all their children tested, so that that recessive disease could be identified and to avoid matings among people in whom the recessive pairings would perpetuate that disease.  And that has been largely eliminated.

So my question is:  why did you put Huntington's Disease on the question of not to be tested for, and why do you not also focus intensively on prenatal testing as well as neonatal screening?

DR. ALEXANDER:  Okay.  Good and difficult questions.  Huntington's was thrown out as one example for discussion for consideration, and probably the one where there has been much .. most discussion and controversy about screening.  I think where people have come own on that is allowing individuals to decide when they have capabilities for decisionmaking, whether they want to be screened for that or not.

The consequences of that disease are so devastating, but they fail to appear until relatively late in life, after child-bearing is over, that parents knowing about that particular one where there really is nothing that we have to offer at the present time may well treat that child differently.  If that child is told what they have, and they may well not be, knowing .. just knowing that information may be extremely difficult in terms of the life choices it presents, and so forth.

I did not put that down as an absolute, just as an example of something that might be considered, maybe at the top of the list, as a prototype for conditions that you might exclude from this. 

So I think you're quite right in raising the question, and responding exactly as I hoped people would, and thinking about, are there conditions that we might not want to screen for, that we can't treat for, can't treat, and just use Huntington's as probably the most familiar example of something that might be in that category?

As far as, you know, the state decisions, and so forth, part of the drive here is to develop a technology that can screen for with basically one test instead of multiple tests, at one cost, many conditions, so that you don't have to look at the individual cost of adding/not adding each test.  And that's what we would hope the microarray or the beads might provide.

As for the issue of screening for conditions that we can't treat, again, there are benefits to and arguments for this above and beyond the issue of making available a population to test presymptomatically, to try interventions.  There are benefits to the child and the family, the benefits of knowing what a diagnosis is, the benefits of avoiding what's often called the diagnostic odyssey, when the child does start to develop some symptoms, as you well know .. the search that the parents undergo to try to come up with a diagnosis.

Many of these are such rare diseases that physicians have not seen or even heard of them, and that odyssey may go on for two or three years before they get to a point where the diagnosis is finally made.  During those three years, that child has been poked, prodded, radiated, everything you can imagine.  And having that diagnosis made as a newborn would avoid that diagnostic odyssey and what is done to the child in the course of such a diagnostic odyssey.

It also enables the parents to make decisions .. decisions about future child-bearing, decisions about care and treatment for that child, decisions as practical as if you have a child with muscular dystrophy, should I buy a one-story house or a two-story house?  Very practical things like that.

And you hear stories about families whose kids were not diagnosed with muscular dystrophy until they were three or four, and in the meantime they bought a two- or three-story house that they would not have done if they knew they were going to have a child with this kind of disability getting around.  They would have bought a one-story house.

So decisionmaking on practical things like that are added to benefits I believe of being able to give parents a diagnosis before the child shows any symptoms, and even for conditions that you don't have treatment for.  I have not done a large sample, but I have talked to a lot of parents of kids with a variety of conditions and asked them, many having completed the diagnostic odyssey, "Would you rather have had this diagnosis at one or two weeks of age, or gone through what you have gone?"  And to a person, there hasn't even been one who hesitated with an answer, "I would rather have known about it right from the beginning."

Now, that's not a big sample, but it's a diverse sample, and it's without even any hesitancy or any divergence of opinion.  So I think that parents, offered the choice, are likely to opt for having this screening available as to their newborn infant, even if we don't have a specific preventive, curative treatment to offer.

CHAIRMAN PELLEGRINO:  Dr. Rowley?

DR. ROWLEY:  Well, I think it's very common.  It has to do with the Guthrie blots.  And just as an aside, it's interesting that some states, and particularly countries in Europe, save the blots for quite a long time and they were used quite imaginatively by Mel Greaves in London to show that children who developed leukemia, sometimes even as adolescents, but initially he used them for children who developed leukemia in the first few years of life to show that they had leukemic cells circulating at the time of their birth, namely at the time that Guthrie's file was taken.  And for those of us in the arcane field of leukemia, and the etiology of leukemia, that came as a surprise. 

So that's .. unfortunately, in Illinois, because of financial reasons, they store blots only for about three months, so they're not useful.  Some states do store them longer.

Let me now get to my questions, and there are two.  It was my impression as a member of the American Society for Medical Genetics that at least the Senate had considered the question of making genetic information not available to insurance, or at least disallowing insurance discrimination based on genetic information, and that would go to one of the points or concerns that you raised.  And I could be incorrect, because this was just coming for a vote rather than having been for a vote.

And I know that isometrics chips at least at the University of Chicago cost a great deal of money, and so I'm interested about cost.  And can you give more insight as to why, when the Federal Government is willing to intervene on many different arenas, why the tests aren't either federally mandated or uniform across states?

Thank you.  And I should say I enjoyed your talk very, very much.

DR. ALEXANDER:  Thank you.  Excellent questions.  First, let me say something about the leukemia issue.  Clearly, the studies have shown this.  The problem is that they also find leukemic cells in individuals who never developed leukemia, and so they are not 100 percent predictive.  So you're not quite sure what to do with them.  And until we try to figure that out, I don't think we're ready to, you know, start screening and treating individuals with leukemia. 

We still have to figure out what the natural history of that phenomenon is.  But it's a very interesting observation, and it's something that could in fact lead to earlier treatment, if we can separate out those kids who are destined to go on and develop full-blown leukemia from those who for some reason lose these cells.

The Senate vote .. a year ago the Senate voted 99 to nothing to support this legislation to ban discrimination based on genetic discrimination in insurance or employability.  And it was just totally overwhelming .. 99 to nothing.  Legislation is now before the House, and the House has not taken action on it.  The reasons for that are not totally clear.

You would presume that there is objection to it from insurers, perhaps from employers, but, again, I don't have the information to really comment on that, other than to say the effort now must be with the House.  And we really need to push that agenda, if we are, I believe, going to be able to take full advantage of what the potential is for newborn screening into public health measure.

You mentioned the cost of the chips.  This chip, if you try to .. if you buy them individually it's about $400.  If you buy them in bulk it's about $200.  Now, there's not four million of these sold and run a year.  What we are hoping and anticipating in our discussions with the companies that make these and the beads is that by bulk purchase and bulk use that cost would come down dramatically.  And what we have been talking about is trying to get these under $100.

Many of the states now that screen for this many disorders spend $100 a kid or more.  And if you could substitute this for many of these other tests, you would not be money behind.  You might come out ahead.  And, in fact, you could screen for so many more disorders with these that you might come out way ahead.

So what we're hoping is that if you have a purchase of 4.1 million of these a year that that cost will come down significantly.  Now, that's just the cost of the chip.  That's not the cost of running the assays and the personnel and the system, and so forth.

DR. ROWLEY:  Or the oligonucleotides that are used.

DR. ALEXANDER:  Yes.  So, but I think with the large numbers of these that we can get .. we should be able to get the cost down.  That's the goal.

Finally, about a federal mandate, one of the things that the Federal Government has generally tried to stay away from is directing health care policies in states.  And one of the things that they definitely have stayed away from is dictating what conditions states screen for.

States pretty much jealously guard their prerogatives in the medical arena, and the Federal Government has, to a large extent, not always, stayed away from dictating these kinds of policy.  So I don't see much likelihood of that changing.  That's why I think the carrot, rather than the stick approach, is the one that's likely to be the most successful.  And that carrot is a chip or a bead.

CHAIRMAN PELLEGRINO:  Dr. Meilaender?

DR. MEILAENDER:  This is just a small question that follows up, really, on something Janet just asked about.  But with respect to the worry that parents would not want to have children tested for non-treatable .. currently non-treatable disorders because of the possibility of not being able to get health insurance or something like that, and your answer to that is the need for legislation to prohibit that.

I'm just wondering .. and I don't know the answer to this exactly, but with .. and we don't know what the future direction of health insurance will be in this country, but with the proliferation of consumer-driven plans and cafeteria policies, and so forth, aren't there plenty of ingenious ways to get a select population that don't involve anything that would be called discrimination?  I mean, I'm just wondering if .. it's not so easy to get a solution to that problem, it seems to me, and I just wondered what you'd say about that.

DR. ALEXANDER:  Well, it was in the Senate.  You're right.  This is a changing field, a changing situation, and there are opportunities for things like you're talking about.  But they're not universal; people have to know about them, have to search for them, need to know what they have to look for something like this.

It won't take too many cases, if we start down this path, of families being denied insurance for their child who tested positive for something we can't treat to get publicized and scare people away very quickly.  That's what worries me.

And I think it is imminently solvable.  We have it half-solved, and we need to go the rest of the way.  That's my personal view.

CHAIRMAN PELLEGRINO:  Dr. Kass?

DR. KASS:  Thank you very much, and thank you for the very illuminating and clear presentation.

The Council has been given, and no doubt you have seen, this commentary from the May 5th .. May issue of Pediatrics by Dr. Botkin and colleagues, "Newborn Screening Technology:  Proceed with Caution."  And ..

DR. ALEXANDER:  You may have recognized some of those words in my talk.

DR. KASS:  No.  I recognized "proceed with caution," but they seem to be much less ready than you are to proceed along the lines you've suggested, and the particular offer for recommendations that ought to take place before, in fact, one institutes a plan for which you are so enthusiastic.  And I wonder what comments you might offer in response to this critique.

I mean, I could raise some of the issues, but let's .. Council has all read this, and I would just .. these are all people in the field.  I mean, these are not just outlying ethicists who ..

(Laughter.)

DR. ALEXANDER:  This field has been one of widely divergent opinions in some of these issues from the beginning.  PKU screening was characterized by many widely differing opinions about whether it should be done at all, whether it should be mandatory, etcetera.

Sam Besseman made a life work of critiquing PKU screening, and making many claims, some of which were true, many of which had no foundation in truth at all, about PKU screening.  It has persisted in spite of that.

I think that the concerns and the issues that are raised by Botkin and his colleagues are concerns that many people have thought about but come down differently in terms of our readiness for moving ahead.  I think that numbers of problems that have occurred and infants that have been affected by adverse consequences in the past are not documented, and probably are vastly exaggerated. 

If you really try to go to the literature, the courts, or anywhere, finding these is .. the numbers are very, very small, and we have learned from those frank mistakes how to try to avoid them, and things that we should avoid, not just with PKU but with other disorders as we move into those.

My contention is that we know where the minefields are, we know where the problems are, we know enough that we can proceed with caution if we put into place the things that I listed.  And those are pretty much not very different from Botkin's.  Where we differ I think is in the availability of this system to carry the stuff out.

And we need .. we have the beginnings of it.  We have the foundations for it.  Every state screens .. everybody.  Every state has a list of conditions they screen for.  Every state has a system of standards.  Every state is a member of one of the regional collaboratives .. the seven.  There is a national coordinating center for those regional collaboratives. 

We hope to build on that foundation to construct the things that I have listed here, so that we have in place that whole system, starting with obtaining the blood spots, doing the analyses, confirming the analyses, doing the counseling with the parents, initiating the treatment, following the treatment, that can make this go right.  That has not always been present in the past, and that has accounted for some of our failures and our problems.

I think that we are .. we now have the foundation to build on, and what we have to make is the commitment to do that building, to proceed with caution.  I don't disagree with that at all.  I fully agree.  I think we must proceed with caution.  We'll get in trouble if we don't, and I think we're only going to get one shot at this kind of expanded screening program, and we have to do it right.

And I think that the field knows what they have to do, there's a commitment to do it, and wise people who are in positions to try to make sure that that happens, and critics out there who are going to point out the problems as they develop, so that we can fix them.

CHAIRMAN PELLEGRINO:  Yes, go ahead, Leon.

DR. KASS:  May I just follow up?  Let me land on just one of the questions that I at least would have before one moved to any kind of mandatory screening.  And I grant you all the states have them, so this is not something new.  But the yield is very small.  The number of false positives .. the ratio of false positives to actual cases is very high.  I mean, if you looked at the total of the data that's pooled, 95 percent of the initial screens are false positives over all of the different diseases.

As you can say, you know, one should reassure those parents whose subsequent tests reveal that their child doesn't have a disease, but we all know that simply telling somebody once doesn't sort of settle the anxieties.  And the question is:  are there built-in programs before you make this thing mandatory and not requiring parental consent that one do the careful research to find out what the consequences are simply of having identified somebody as a positive incorrectly on the first screen?

Now, maybe we don't do enough of that already, but we are on the threshold, it seems to me, of screening not just for the 29 things here but with the new DNA arrays for potentially thousands of things, many of which will not have treatment.  So there's a kind of complication, and the question is whether one has built in enough research to make sure that one is not in those areas doing harm as opposed to the harm done by giving someone a treatment which is itself harmful. 

I mean, that wasn't well put, Duane, but perhaps you could address that.

DR. ALEXANDER:  Yes, that's a very good point, an extremely important consideration.  The issue of false positives has haunted this field from the very beginning, and major efforts have been directed to get that number down as low as possible, with PKU screenings now down to about 1 in 10, a little less.  But you still have nine families that you are going to subject to the anxiety at least of a repeat test.

The field is very aware of this.  One of the major topics of discussion in the Secretary's Advisory Committee is the issue of false positives, of laboratory standards, and of trying to draw the boundaries as precisely as possible.  It's not easy, and you're always going to have some number, some proportion of false positives.  You're going to have more false positives than true positives, and you just try to keep that number in balance as low as possible.

What we do need to learn .. and I think you're absolutely right here .. is better ways as we counsel families, as we deal with families, of conveying the information about false positives, what they mean, and then, when we go back and do the confirmatory tests and it's normal, your child has nothing.  This was a fluke, this was a temporary phenomenon, we don't have an explanation for it, but your child does not have this disorder.  And you can go home and not worry about it, treat them as normally.  There's no risk of this condition.

We need to be .. to learn how to do that better and more effectively than we're doing in the past, because the studies that have been done have in fact shown that even some years later parents still have some concern.  "Well, they said he was okay, but I'm not sure he really is." 

And that's a valid concern, and we do need to study that better and get better at our counseling techniques of conveying that information and that assurance that if you have been retested and the confirmatory test is negative, and even the screening test is now negative, you can stop worrying.

CHAIRMAN PELLEGRINO:  Professor Schneider?

PROFESSOR SCHNEIDER:   I just wanted to say a word about the confidentiality issue, which showed up in this conversation and which showed up in the paper we're going to be discussing later.  I'm aware that part of the confidentiality problem is not a problem about actual leaks of information or misuse of information.  It's apprehension about misuse of information.

I think for that reason it's especially important that bodies like this one and people who are supposed to be knowledgeable about the kinds of problems people are going to encounter speak accurately about what the actual behavior of insurance companies is. 

And there is a small literature that suggests that insurance companies in fact, in reality, do not discriminate on this basis, and that they have no good economic reasons for discriminating on this basis, partly because an awful lot of genetic risks never materialize, and it just .. and the numbers are so small that it isn't worth the insurance companies trying to take these things into account, partly of course a lot of .. an awful lot of American insurance is insurance acquired through employers and the companies essentially don't have an opportunity to discriminate on that basis.

In any event, since there is this empirical information suggesting that at least now insurance companies are not discriminating and have reasons not to discriminate, partly of course market reasons not wanting to be branded as companies that discriminate on this basis, I think it would be a good thing if we were able to tell people that even if Congress has not acted that no problems seem currently to be materializing. 

I'm also apprehensive about the idea of asking Congress to legislate to get rid of a problem that does not exist, because when Congress and the Department of Health and Human Services have tried to act to protect confidentiality, as through HIPAA, they have often done so in ways that have been damaging and clumsy and extremely burdensome without being remotely beneficial.  So I urge us to keep this empirical information in mind.  It may not be accurate, but it's the best information I've been able to locate.

CHAIRMAN PELLEGRINO:  I have ..

DR. ROWLEY:  On this point ..

CHAIRMAN PELLEGRINO:   I'm sorry.  On this point?

DR. ROWLEY:  On this point, concern for discrimination, while it's true that these newborn screening disorders have been on aspect of it, the other is the concern of patients who have genetic changes predisposing to cancer.  And this is particularly true of women with BRC-1 mutations, and there are many women who have a strong family history of breast cancer in young parents or other young female members of their family who have refused to have BRC-1 mutation analysis because of this.

Now, you're saying, as I gather the gist of your remarks, that they are either misinformed, that there is no discrimination, or they are concerned about a problem that doesn't exist, because that's another whole group that has refused diagnostic DNA analysis for fear of discrimination.

PROFESSOR SCHNEIDER:   Yes, that's quite right, and that was one of the reasons that the research that I'm describing was done, and it's quite clear that genetic counselors, for example, themselves often believe that any such testing ought to be done outside of your insurance program, so the insurance company won't find out.

But the fact that it is widely believed that insurance companies are going to discriminate on this basis doesn't make it true, and what alarms me is the extent to which it is apparently universally believed that this is a real problem currently going on at a serious level when there doesn't seem to be actually any information about it.  So I'd like to be able to calm people's apprehensions.

CHAIRMAN PELLEGRINO:  We're getting close to the end of the time for this session, so can I ask Dr. Carson and Dr. Hurlbut, who have asked to speak, to pose their questions, and Dr. Alexander to hold until they've both presented, and then you respond to both.  Thank you.

DR. McHUGH:  Am I not in the queue?  Can I join the three of them?

CHAIRMAN PELLEGRINO:  Yes, by all means, Paul.  I didn't see you.  Thank you.

DR. CARSON:  Okay.  Very interesting and well presented dialogue.  This is obviously a rapidly-moving train as we are able to diagnose more and more things.  And as you're working with various others to try to create, you know, legislation that will protect children in the long run, is there any interest on your behalf of looking at prenatal genetic diagnosis?

Because it seems to me like if we go through a great deal of trouble dealing with just post-natal, and then we .. while the prenatal diagnosis is moving along very rapidly, particularly with more and more older women involved in in vitro fertilization, and the possibilities of multiple types of screenings there, shouldn't there be some effort to try to couple these things, so that we don't have to go through the whole thing all over again?

CHAIRMAN PELLEGRINO:  Could you hold?  Dr. Hurlbut, and then Dr. McHugh.

DR. HURLBUT:   Well, my question/comment relates to that as well.  Obviously, it's a very exciting time, because we're getting at the molecular foundations of disease, and yet at the same time there is a troubling reductionistic foundation for .. a reductionistic kind of paradigm that is operating here, and that raises some questions I want to probe with you a little bit.

You spoke of the false positives and negatives.  Obviously, in some cases you're speaking not just of a missed detection of a presence of an indicator, but a lack of correlation between a real indicator and a phenotypic outcome.  In other words, you can have the presence of a gene, but balanced with other genes it will never express a disease.  Right?  That's a fair statement at this point?

DR. ALEXANDER:  In some rare instances, that could be the case.

DR. HURLBUT:   I mean, if we start with a one-to-one correlation between genotype and phenotype, that's one possibility, but there are many other possibilities .. variable penetrants and various even lack of manifestations of a phenotype.

DR. ALEXANDER:  Right.

DR. HURLBUT:   I mean, identical twins, for example, are largely thought to be on the popular level identical, when in fact their concordance of gene expression, at least at one study done at Stanford, was only 18 percent relative to fraternal twins, 18 percent higher. 

So the point is that what we're really looking at is not one-to-one correlations for many things.  Some traits will be one to one, but many will be just statistical probabilities.  And, therefore, you finally have to come down to what the gene tests really mean, and that means you have to do even further tests and maybe further tests of the further tests.  Isn't this fair to say?

And that finally you are going to enter into that strange zone of, what's the phenotype really?  The secondary question of that is:  wouldn't this logically translate out .. and here I'm not objecting, I'm just raising these concerns and questions.  Wouldn't this logically play out ultimately to much more complicated phenotypes, not just obvious genetic diseases, but finally even behavioral phenotypes?  And wouldn't this then carry us into the realm of racial implications and backwards into prenatal diagnoses that would also relate to potential treatments in the womb? 

And I'm just raising this because I think there are lots of issues here that we haven't yet introduced.  And a troubling implication I think we all ought to face is the idea that they're talking now about the $1,000 genome, where every gene is tested.  That would obviously, is you were doing a purely scientific approach to it, logically be correlated with phenotypes all the way through the history of the individual's life, not just at birth.  Maybe mandatory testing at two, five, and 10 years, and 22 years, and so forth. 

And a huge data bank of the relationship between genotype and phenotype, and then backwards into prenatal diagnosis, maybe even pre-implantation diagnosis.  I mean, you can see this opening up into a hugely positive but hugely dangerous thing.

And let me just close with one comment here.  There was a public .. it wasn't .. it was a public forum at a major hospital in the United States recently in which somebody stood up and said to the physicians, "Well, what are you doing in this university about Down's Syndrome?"  And a physician told me that the physician who answered this question stood up and said, "The cure for Down's Syndrome is abortion."

And that .. regardless of how you feel about the status of the fetus at the stage in which these tests are done, it struck me as a strange transformation of the historical attitude in medicine that we are a healing profession.  And I find there is troubling dimensions to all of this, and I also find very positive things in what you said, certainly the poignancy of the letter you read.  It's powerful.

Could you just give us some general comments on how we need to frame this to make sure that the positives come out and not the negatives?

CHAIRMAN PELLEGRINO:  Dr. McHugh?

DR. McHUGH:  Dr. Alexander, I want to thank you very much for that splendid presentation, and the demonstration of how lucky in America we are to have public servants like yourself.  I particularly appreciate this, of course, as a neuropsychiatrist who has looked over and has lived in this field for over 60 years and have turned to the PKU achievements and the achievements that have followed after it as one of the few advances that have really occurred in the field, and to see it described and developed the way you have and show how carefully our people are .. doctors and public servants are working to make all the messages of that achievement clear and the advances go further from it.

It was a great drink of water in the desert, so ..

(Laughter.)

But I wanted also to ask you, and I'm sure you are thinking in these terms, but they come up for someone like myself in the neuropsychiatric domain.  And that is that as biology and particularly neurobiology advances, the issues illuminated by mental retardation and the issues of mental retardation will blur with the .. will blur the seemingly and obviously biologically inappropriate sharp division between the cognitive disorders that turn up in childhood, and the cognitive disorders that turn up in adulthood.

And those are the matters that are little touched upon by what Floyd Bloom said to you about Huntington's Disease, another condition that I am very .. have been very interested in, and the two .. the two issues that come up, and I wonder whether your group is thinking about them .. in deciding about what to study for and what to recognize early on, the first one is that other matters besides the cognitive problems of patients with these genetic disorders are accessible to treatment, after all, if they are early identified.

In the MR group, of course, it's the autistic features and other kinds of things that go along with the cognitive problems, some of which can be treated with medications today.  And particularly in Huntington's Disease there are two aspects of that that are appropriate to identify. 

One of them is the great vulnerability of these patients to show classical bipolar disorder before the onset of either the motor or other cognitive disorder, and in that time the suicide rate amongst Huntington's patients, whether they know or not about the presence of their genetic thing, is extremely high, not only suicide but homicide.  You probably know that.

But it does make it clear that in the discussion of the biology of these matters, from MR until now, people like yourself can champion a spread of these identified .. I understand all that we .. at Hopkins we know a lot about the problems of counseling and the issues of identification, particularly in Huntington's Disease.  So I know it's a fraught area, but on the other hand there are things to be said other than just that we can cure the disorder now to make it identified.

And the other thing is that, you know, one of the great messages of PKU and congenital hypothyroidism is that the preventive treatment post-natally is the action.  You work because the disorder isn't symptomatic at this point, and you can prevent it by treating now.  Well, it .. if I'm correct that there will be a blurring of the boundaries, then conditions like Huntington's Disease that don't show up until you're in your late thirties or early forties .. by the way, there are some Huntington's patients, as you know, that turn up at age 12, 13, or 14, very difficult problems.

But if Huntington's Disease or Alzheimer's Disease or things of that sort take from conception until 40 or 50 years later to produce their effect, presumably there are things that are going on that we may be able to interfere with and interrupt, again, given the model of PKU and congenital hypothyroidism.  And, once again, I wondered whether those issues are considered in terms of the scientific advances, the state programs, and, to some extent, very much the ethical principles that we have as a caring society.

CHAIRMAN PELLEGRINO:  Thank you very much, Dr. McHugh.

Dr. Alexander, we have presented you with three very complex questions, so we're going to extend the time so you have a chance to give justice to those questions and to yourself.  I hope all of you will permit this.  Thank you.

DR. ALEXANDER:  Well, they are terrific questions.  It's hard to do justice to them.  Let me just try to respond without too .. not too extensively.  The question of using comparable technologies for prenatal diagnosis is obviously one that people have thought of and talked about. 

Basically, what you need is cells, cells of the fetus and those are obtainable by either amniocentesis or chorionic villi sampling.  That's basically what we use now. 

We're not developing it for that purpose.  We're dealing .. we're working on this for newborn screening.  Whether people will take it and apply it in prenatal diagnosis, it's likely that that will be done.  But I have no way of predicting that for sure, and the applications that we're working on right now are focused very precisely on prenatal .. on newborn screening, and all of the technologies that are associated with that, where you're screening essentially everybody in the population.

So that's a short answer to a question.

With regard to the issues of gene variability and behavioral phenotypes, and so forth, clearly this is a problem and a concern.  The classic example here is cystic fibrosis.  There is hundreds of gene variants in cystic fibrosis.  There's an extremely variable phenotype of people who are affected severely in infancy and early childhood to people who show no symptoms at all even until late adulthood.  And it would be nice if this would correlate with the particular gene variant, but it doesn't seem to precisely.

So one of the issues that we have to deal with in this .. and, believe me, we have our eyes open, it's not like we're doing this for the first time, like we were with PKU.  We know the issue of gene variability, and the .. how the .. not only the genes vary, but the phenotype varies as well.  And to take this into account as we make our diagnoses.

This is a problem much more for some conditions than it is for others.  For others there is very little gene variability, and the clinical course and the phenotype show very little variability.  But for others it's enormous, and, again, we've learned a lot about that.  We know for many of these conditions what that variability is. 

We know the different gene variants that are associated with the disorders, and at least we are aware of the issue and the problem and the concern, and it is humbling, believe me, to people who are working in this, trying to deal with it, and to know that there is no 100 percent predictability for most of this, because not only is there variation in the gene, there is variation, as you say, in what other genes may be present and what environmental stimuli may be, etcetera.

So it's a very good question, a very important point to raise.  I should have included it.  I didn't.  I appreciate your raising the issue.

Dr. McHugh, the issues that you raise about more than just the newborn in terms of the expression of these issues, clearly there are some of these conditions that don't have expression until later on.  We know most about the ones that express early, and we are just in the process of learning about some of these others that have perhaps some suggestive signs but not the expected phenotype earlier in life.  Your Huntington's example is a perfect one.

So this is in the category of things we still have to learn about, and why we have to proceed with caution as we go about this screening process, and implement it in a way that we learn about the conditions as we go.  We don't assume that we know everything, and that we don't start screening for some of these things where there is so much variability that we can't predict until we know more.

So people are making decisions about what should be in the test regimen, and part of that is based on how much predictability there is about phenotype from genotype, and when these things are likely to occur.

Another issue with the Huntington's is that the whole picture of Huntington's may change within the .. before the disease might be expressed.  Hopefully, it's going to.  I've got my fingers crossed and my hopes up.  And so I hope that .. another reason for maybe not screening for that condition that isn't manifest in most people until later is that the picture may change. 

And why worry people unnecessarily for 30 years if we are going to have a much better treatment prognosis outlook for them?  So that, again, is part of the thinking.

DR. McHUGH:  Just to follow up on that, given that you have been saying that we need to have these registries and things to go forward to know these treatments, and that's about the kids that show their disorders in childhood ..

DR. ALEXANDER:  That's right.

DR. McHUGH:  .. how much more is it necessary to do the same thing for things which are slower in onset but still have the causal factors present at conception?

DR. ALEXANDER:  That's a very good point.

CHAIRMAN PELLEGRINO:  Again, on behalf of the Council members, let me thank you for a superb presentation.  We are going to have our break until 10:30, and then pick up the next session. 

Again, thank you very much, Dr. Alexander.

DR. ALEXANDER:  Thank you.

(Applause.)

(Whereupon, the proceedings in the foregoing matter went off the record at 10:14 a.m. and went back on the record at 10:33 a.m.)

SESSION 6: NEWBORN SCREENING FOR GENETIC DISORDERS

CHAIRMAN PELLEGRINO:  Thank you for reassembling.  My apologies.  Our next session will be devoted to discussion around a staff paper prepared by Richard Roblin, Dr. Daniel Davis' predecessor as Executive Director of the President's Council.  The discussion will be opened by Dr. Leon Kass.  Leon, you're on.

DR. KASS:  Thank you.  First of all, I want to say that I think that Dick has done an admirable job of laying out some of the questions that should come before this Council as a prelude to thinking about what I think is the question we ought to be discussing in this session, namely is there work for the Council to do on this subject.  That's where he gets us at the end and my comments are with a couple of preliminaries. I'm going to put my foot in the water on that last question. 

I do think that one should not  underestimate the seriousness and importance of this move to increase mandatory screening.  These 29 metabolites are just the tip of the iceberg and when genomic knowledge is added and the DNA screening can be done, we will see a massive increase in screening and it, therefore, behooves somebody, a body like this to at least consider whether there are ethical questions beyond saying proceed with caution and to see whether there is some kind of positive intellectual contribution that one could make just sorting out those questions.  So I don't think there's any question about the importance of this subject, even if at the moment we're talking about identifying 8,000 babies — screening 4 million children to identify 8,000 patients with disease.  This is a big subject and coming fast.

Second, without in any way casting any doubts on the motives, intentions, goodwill of the people who are bringing us these questions, there is a certain kind of logic which goes something like this and this is a caricature but have test, can screen, will find, may treat, must screen.  And for certain kinds of conditions where there really is clear treatment, where the ratio of false positives to true positives is small, much less worrisome, but if you look at the table that Dick has provided for us, we are talking really about false positive to true positive ratio in the neighborhood of 15 to one over all of these diseases and I think it's very important to raise the question that he does about the absence of information about what the effect of this false positive diagnosis is and whether or not it's enough to say, "You're baby is in the clear" when you've got some empirical studies that suggest that there are deleterious consequences to children and their families going long beyond and the need to study that before speaking with confidence that this is really a marginal problem, I think is evident.

By the way, it's going to be hard to get that data thanks to HIPAA because we're not going to be able easily to do the findings, to do the studies on these families that have been given false positive diagnosis at first and then find out what those effects were.  So this is an area in which research will be needed.  It's going to be hard to do. 

Should the Council take this up and what could we contribute?  There are people who like clean ethical problems.  Is the embryo one of us or not, that's hard to answer but it's at least formulable.  Here when Dick poses the question about how do I analyze the risks and benefits which are incommensurable, the goods and the harms are sort of incommensurable where you're dealing with statistical matters at best.  I think that this will not appeal to the people who like neat and clean but it seems to me that increasingly in sort of risk management medicine, more and more of our ethical problems are going to be formulated in these terms.  And while I'm not sure I know how to proceed with that analysis and I know it's going to be a mess, it does seem to me that it would be given the importance of screening, given the difficulties in fact of doing proper sort of assessment of goods and harms, I think it would be worth a try to see if we can't make some progress, maybe ahead of the curve, to begin to lay down certain kinds of notions of how to begin to think about this before one rushes ahead, especially, and this is — well, let me just stop with that.  I think that's really enough to open — I hope to open a conversation.

CHAIRMAN PELLEGRINO:  Thank you very much, Leon.  Dr. Roblin?

DR. ROBLIN:  I'm much in agreement, I think, with Leon's analysis of where this issue is, vis-a-vis, the Council.  Certainly if you read the working paper and if you followed the discussions in the Council meetings over the last several months, this is now I think the third or fourth meeting where the Council has had some presentations and some discussion on newborn screening programs.  And so I think it is timely to move to a discussion of whether the Council sees something here as Leon was pointing out, that is worth further time and attention, and if so, some guidance to the staff sort of in what directions those things might lie.

CHAIRMAN PELLEGRINO: Dr. McHugh.

PROFESSOR McHUGH:  I think it's imperative that we go on and do this and follow up with what Dick has already done.  And again, in my preamble to my questions to Dr. Alexander, you can't — unless you were there, I suppose, realize what it was like to try to stimulate an interest in young psychiatrists in mental retarded patients and the like.  They really thought it was a waste of time, futile, all that kind of stuff, and yes, it's true that PKU has huge false positives, and yes, it's all of these things but the opening, the dynamic opening of interest in mental retardation that is now so common that when somebody says a psychiatrist is interested in it, they wonder whether it really belongs in psychiatry, but that's a problem for psychiatry.

And one of the things psychiatrists realize is that you know, if you look at medicine and the like, we don't have anything like the achievements of germ theory, even anesthesiology or the experimental method, almost, so this comes as a tremendous opening in the arena of neuro-biology.  I do appreciate exactly what is being said in both of these papers about the dangers of false positives and the issues of what false positives present to the world but by the way, if we were going to go out and attack conditions or tests that are now uniformly used in America, that turn out to have huge false positives.  The one test that we should be attacking vigorously as an ethical problem is the triple test for Down's syndrome given to mothers during early pregnancy which has a false positive rate that's so high that — and then when it's recognized to be false, becloud not only that pregnancy but every other pregnancy that a young woman goes through.  So when it comes to the false positives there, they are just as vicious and perhaps, more vicious than these issues which ultimately can be resolved with work-ups and identify the issues of what screening is about.  So I would very much like to see and the Council engage in a discussion about the matters of policy, the matters of ethics, the matters of issues of life that turn up and are trying to understand and develop screenings for the neuro-psychiatric disorders of which mental retardation is but one and given that we've already devoted a good bit of our attention to the study of Alzheimers disease in the past, I would have thought given that biology is biology, that this would be an appropriate thing for us to discuss and talk about its meanings even as it continues to be a developing arena.

CHAIRMAN PELLEGRINO:  Thank you.  Dr. Meilaender?

PROFESSOR MEILAENDER:  This won't really be a clarifying remark.  It's just to add a puzzle but I don't think Leon mentioned this, though despite the Chairman's insistence, I was a minute late getting in here, so maybe I missed something.  But the question that — I don't know what I think about it and I would be happy to hear what anybody said with respect to it, is whether uniformity is really that desirable or not here with respect to the newborn screening tests. 

I mean, I understand the difficulty one might have in the scenario Dr. Alexander painted for us of saying to parents, "If you child had been born in the adjoining state this would have — you know, we would have caught this very rare disease."  On the other hand, they are very rare.  Uniformity multiplies mistakes, if mistakes are — wrong directions are taken.  Non-uniformity allows for sort of experimentally different approaches to doing things and so forth. 

Is uniformity really desirable or not here?  I honestly, I don't — that's what I said, this is not a clarifying remark.  I don't know what I think.  I'd be glad to be persuaded one way or the other by anything anybody else had to say but I think that's also a part of the issue that would be worth pondering a bit.

CHAIRMAN PELLEGRINO:  Thank you.  Dick, any response?

Dr. Roblin: This was certainly raised in the working paper and I'm probably as uncertain in my own mind as Dr. Meilaender is, about what the right answer.  I mean, certainly you can note a number of things and one is the rare but tragic stories of people who learn that their affected child might have been helped if they had lived in another state where they do screen for this rare condition that the child has.

I can understand how devastating that would be to the parents on a number of levels.  However, we're — a certain structural feature of the screening system is the reliance on each individual state to make its own judgment, using the inputs that Dr. Alexander sketched as to what particular panel of tests they will mandate.  It's done somewhat differently in different states.  The paper makes reference to the program in New England.  There's a regional cooperative program where they mandate testing for a certain number of conditions and the subsequent, I think 19 conditions or so are made part of a research study approach. 

Parents are informed that this is available.  They have an opportunity to take advantages of those tests and have those tests done if they wish.  I think in those circumstances where the diseases are very rare and much is unknown about the efficacy of treatment, the research approach has much to recommend it.  I'm much more comfortable, I guess with a framework where parents are frankly told in a discussion what the level of understanding of their particular infant's condition is and what really is available at the moment in terms of treatment.

CHAIRMAN PELLEGRINO:  Thank you.  Professor Gómez-Lobo?

DR. GÓMEZ-LOBO:  I think Dick's paper is just wonderful.  I think it's very clear and it sorts out the main ethical issues and Leon being one of those people who like the black and white and clear-cut ethical dilemmas.  I just wanted to suggest a friendly amendment to Dick's paper which, I think, may be of use to us and it's this; that on page 7, the argument for the present practice is described as being conceived in a utilitarian framework.  Now, I would argue that it's also an argument perfectly acceptable for a non-utilitarian and the sense that it's not so much a matter of balancing goods but rather of saying, well, here there is a common good to be protected, to be pursued and nothing untoward is being done to pursue that.  And I suspect this is similar to the bioethical argument for vaccination, where you know, some families, some children, may have to suffer some negative effects, but the public health good is so clear that, I mean, it — I just can't see an ethical argument in that regard. 

So I would say that if, indeed, the screening practice is so important for all of these reasons that we were given, I think I, at least, would have no ethical qualms about it, even though we have problems such as false positives, et cetera.

CHAIRMAN PELLEGRINO:  Thank you.  Leon?

DR. KASS:  May I just a brief comment to you, Alfonso, I've puzzled in reading the discussion of this under the heading of public health.  That this is an instance of preventive medicine is clear, early diagnosis, intervention, no disease.  But — and I can also understand why if the state winds up paying the costs of the care of the people who have this disease untreated, it is a public problem.  But unlike an epidemic of smallpox, these things are not public health menaces in that sense. 

It's very hard, it seems to me, to make a common good argument unless you want to say by common good, the health of every citizen is somehow a piece of the common good.  But I would, I think, myself be more inclined to a more narrow view of those things which are genuinely public and I'm sort of puzzled by the treatment of this under the general heading of public health even though the health of each of us contributes to the health of the whole.  It's a different paradigm and maybe the field is moved in that direction but I find it puzzling.

CHAIRMAN PELLEGRINO:  Go ahead, yes, please.

DR. GÓMEZ-LOBO:  Yeah, I think I stand corrected on the apparent equation of public health and common good, but I think an argument can be made to the effect that although this may not be a public health issue in the way an epidemic is, if we conceive of the public good not just as the aggregate of pleasure experienced by the majority but really as providing the conditions for every single member of the community to flourish as best he or she can.  I would say there is an issue of public good. 

It's just like the expropriation of the house to build road, I mean, there is a sense in which there is a protection of the common good of our fellow citizens, in that case.  It's just under that rubric that I would put it in those terms.

PROFESSOR McHUGH:  Can I jump in on that issue and just —

CHAIRMAN PELLEGRINO:  Yes, surely.

PROFESSOR McHUGH:  — make it more clear on what Leon feels about issues of public health, since I belong to both the School of Medicine and the School of Public Health and across the street, back and forth, and describe what I'm doing when I do that. When I'm in the School of Medicine, for the most part, what I'm talking about the conditions in individuals and when I go across the street, I'm talking about conditions in the population. 

That's the only difference, that you're looking at the population and how the population is affected by anything, whether those things be accidents, whether those things be genes, whether those things be infectious diseases and the like on nutritional issues.  It seems to me that what we're trying to do here is to try to prevent this certain number of children, certain number of people from having to be treated as individuals by being recognized early on by policies that are public policies that prevent and organize for them programs that keep them healthy.

So I got lost when you said that you didn't think that was public health but maybe I've got the wrong idea.  Tell me, Leon.

CHAIRMAN PELLEGRINO:  Leon?

DR. KASS:  Well, the point is well taken and if each of us is — each of us is part of the public.  Our health is, in that sense, a matter of the public health, but if you want to take this subject up under the question of the health of the public as a whole, then you get into considerations of well, how big a public health problem is this compared to other sorts of things, and then you have questions of resource allocation and we heard in the last session that we're talking close to a billion dollars just for the arrays, for the detection of 4,000, 8,000 cases.    I don't want to trivialize the human suffering that's here, but if we're going to put this in terms of public health then you get into questions which Dick didn't raise here, could have about questions of resource allocation, especially with respect to treatment, efficacy, for loss of these things, and we might want to take that up, but —

PROFESSOR McHUGH:  Well, I think we're talking about the public health for mental retardation which is a big problem.  Mental retardation is a big problem.  It's not a trivial problem and if we're able to find more cases earlier that are treatable, it will be a reduced problem.  So hence, mental retardation is a population problem.

After all, it's a bel-shaped curve even with the look at it and so 2.3 percent of people are two standard deviations below the mean, hence, they're mentally retarded.  And some of them have these conditions and some of them don't.  We need to know the differences amongst those things.

CHAIRMAN PELLEGRINO:  Dr. Lawler?

PROFESSOR LAWLER: In terms of the alternatives Dick has laid out for us, I would want to investigate this matter of newborn screening as part of the broader concerns about the acquisition and uses of genetic information, that is to link it with prenatal uses of genetic screening as Ben said and as Bill said and as Paul said because one irony among many is newborn screening provides us with the opportunity of dealing with issues concerning — there's a more politically correct term than mental retardation — but mental retardation, more effectively than ever before, but it's easy to see how the prenatal screening could eliminate these people before they were dealt with as newborns all together, they become a kind of negative eugenics and so I would like to treat the big picture in terms of acquisition uses of genetic information.

I think this newborn thing, this newborn thing has problems that Leon outlined but the prenatal screening has monstrous possibilities if not properly regulated. 

CHAIRMAN PELLEGRINO:  Dr. Hurlbut?  Dr. Rowley?

DR. ROWLEY:  Well, I have several comments.  One, and I specifically stopped to ask Dr. Alexander about this, he thinks with the movement toward the DNA analysis that the problem of false positives is going to disappear.  And so a lot of what Dick had in his paper are comments regarding Norman Fost's analysis of early PKU screening which even Dr. Alexander says with the metabolic tests have gone from 95 percent false positives to I suppose it's 90 percent false positives, which is still a lot and he thinks with DNA screening that that's going to disappear. 

So I think that if — and this is a big if, if either chips or the microbeads turns out to be the technology used in the future, this is going to be an issue that will disappear and so for that reason, I think that the Council would be well-advised as has been brought up in the issue of newborn screening to proceed with caution.  So my vote would be more to watch this field and wait a bit before the Council weighs in.

Now, Paul McHugh, in his support of the Council's doing this also brought up other issues, not related to newborn screening, such as Alzheimers disease and if one — I don't know how it would be framed but if one wanted to consider larger issues of which newborn screening is one, you know, I would want to consider how that's assessed and analyzed and incorporated into a larger concern, but I think the people involved in newborn screening are well-aware of the hazards and the problems that have been created by the ability to screen for some of these very rare, fortunately very rare metabolic disorders and I think we should just watch what's going to happen in the future and hope that it will reduce some of the problems that have concerned us here.

CHAIRMAN PELLEGRINO:  Dick, would you kindly respond?

DR. ROBLIN:  I think DNA chip testing is a powerful technology and it's likely to be applied in this area when it's developed.  I guess I don't entirely agree with what Dr. Rowley said in the sense that I still don't think that once you can identify all the mutations, for example, that surround a particular condition that you can necessarily with 100 percent accuracy decide what the phenotype of any given individual is going to be.

I know there was some discussion back and forth about that earlier and I guess I have a particular paper in mind that dealt with a genetic disease where screening was newly implemented and so a number of newborns were picked up by that screen and that led to an examination of some of their siblings.  It turned out that in this particular case, some — several of the siblings had the same gene mutation that the affected newborns had but they're phenotypically normal.  And so even the able to screen using DNA is not always going to enable us to predict 100 percent who's going to be subject to disease.

CHAIRMAN PELLEGRINO:  Dr. Rowley?

DR. ROWLEY:  Well, I certainly agree with that because there isn't a one-to-one correlation genotype to phenotype.  But it's not going to be 90 percent false positives.  And so I think — I stand by my statement that with DNA analysis, the number of false positives is going to be reduced.  I agree with you, it's not going to be reduced to zero.

CHAIRMAN PELLEGRINO:  Anyone?  Dr. Schneider.

PROFESSOR SCHNEIDER: Well, if nobody else wants to say anything, I would like to respond to what Professor Meilaender said.  I think that when I encountered this, I was a little taken aback at the idea of the inequity because states were doing different things because I'm a lawyer and read the constitution and understood the way that we organized our country was to allow states to make these kinds of decisions and exactly for the kinds of reasons Professor Meilaender was suggesting.  That as Brandeis put it, the states are laboratories of democracy and the states are also different and it's open to states to conclude that their public health dollars are better spent, they will get more benefit from their public dollars doing things other than genetic testing.

So the idea that we are obliged to have everybody in the United States treated medically the same way seems to me not the usual understanding of the way we've organized our government and it also seems to me to be looking at the problem of genetic screening in isolation from other kinds of problems.  It is true that it's painful to say "If you had been giving birth in another state, this problem would have been caught."  But presumably, the state that didn't have that kind of genetic testing may be able to say to other people, "Because you live in this state, we are catching other problems that people in other states are not catching".

CHAIRMAN PELLEGRINO:  Dr. Schaub?

PROFESSOR SCHAUB:  Yeah, I don't know that my comment is necessary now.  I mean, my only contribution to the discussion has already been brought forward by Gil and by Carl, this question of federalism versus uniformity and centralization.  I don't know whether we should take this up or not, but if we do, I really think we should examine that implication of Dr. Alexander's that federalism is somehow unethical.  And you know, the point that you just made, I mean, it would be awful to tell a mother that yeah, "If you lived in a neighboring state that had more extensive screening, the child's disease would have been caught and treated", but the obverse is also true.  I mean, to tell a mother that, "If you had not screened your child would not have been subjected to unnecessary and harmful treatment", like those children seriously harmed by the PKU dietary restrictions.   I mean actually my reaction to the PKU story was a little different from Paul's.  I know Paul was there.  He was there at the start of everything.  And so he —

PROFESSOR McHUGH:  Since so little has happened in psychiatry you can be there at the beginning. 

(Laughter)

PROFESSOR SCHAUB:  You know more about this than I do but I just found that devastating.  The thought that a woman who, you know, this disease was caught and she was spared this mental retardation but then went on to pass this onto her children, you know — or not pass it on but, you know, have the ramifications that her child ended up mentally retarded, I mean, I understand now that we are able to catch that and address it but it just seems that progress, you know, comes at these terrible prices.  So I think that is an argument, given our ignorance and because of the possibility of mistakes, that's an argument for the advantages of state variability.  At least you can find and limit the scope of those mistakes.  So I would only want to see us move toward uniformity of legislation when we really have a firm sense of the common good and so we should take advantage of this, you know, natural testing ground of the states. 

CHAIRMAN PELLEGRINO:  Thank you. Dick?

DR. ROBLIN:  As the working paper points out, vis-a-vis federal responsibilities and state responsibilities, there is variety and variation among the state programs and I think you could hear from the way Dr. Alexander presented things that for him at least this is a — the non-uniformity is a driver in a couple of different directions.  It drove him, he said, in the direction of technology development that would reduce the cost and make it possible for state programs to be comparable all the way across the board.

And I think people who tend to promote screening and I think Dr. Alexander wasn't quite fair in terms of the Federal Government's role in this.  I think when he was asked about this, he said, "Well, this is really a matter for the states", but as the working paper points out, the Federal Government has nudged the states pretty hard and pretty directly in the direction of expanded testing and there's both an anecdote from the State of Texas and I think a more general description of the way in which Federal Government paid for studies recommending a common 29 test panel for the states certainly has had an influence in encouraging states to develop and expand their testing menus.

CHAIRMAN PELLEGRINO:  Dr. Foster?

DR. FOSTER:  I want to ask a question and make one comment.  Leon, is the clarification of your worry and the concern, how much of that is an economic concern, there are only 8,000 or whatever and it's going to cost a billion dollars for, you know, whatever to test and so forth.  I mean, is this basically a concern about the use of resources so that orphan diseases — we have a lot of orphan diseases, as you know, and sometimes they get solved.  Narcolepsy is now solved.  We know what is involved with that and so forth.

Is it an economic argument about that, and then I want to make one other comment.

DR. KASS:  Not only.  That — the economic argument was brought up in the context of if we do treat this as a public health matter, then it ought to be, I think, deliberated in the general argument of what's in the public health.  I guess if you ask me what am I personally concerned about here, it would come under the sort of funny heading of not only toxic knowledge and where you might have certain kind of knowledge that you can't put to any good use.  You have knowledge that there is some impending disease for which there is no treatment but toxic misinformation or toxic opinion based upon misunderstanding, say in the false positives, especially when, and this is a thing I didn't mention before but I think it's very important, doing the testing however sophisticated, that's easy relative to actually communicating with these poor parents what the meaning of all of this is. 

And it's very easy to say, "Well, we have to develop the resources to make sure that this knowledge is put to good use and that there are people there — and I don't know enough to know whether we have that.  I doubt very much if you're going to multiply the number of things for which you're providing information that you've got the infrastructure necessary to do that right and to do it without producing the harm based upon this toxic misunderstanding and the — so it's more that than the economic thing that leads me to say — there's something — in a way we've got some precedent but the precedent — how we manage the precedent, I don't think we know well enough how well we've done with the screening that we've had so far to be confident about expanding this, leaving alone the question of whether this is as public health calculation the best expenditure of resources. 

DR. FOSTER:  Let me just finish — I just want to make one other point.  There is an advantage, there is an additional advantage that doesn't apply immediately to the children that we're talking about here and that is what one may learn for the larger community that might be involved in public health.  One of the rarest of the genetic diseases is progeria.  You'll remember this as a disease in which these children look like they're 95 years old when they're five and most of them die by the age of 13 and they have a mutation which causes the appearance of a protein which is called progeria and there's a splice — I don't want to get too much into what the problem is but they're missing a splice that allows this molecule to move away from the membrane of the nucleus so it's stuck on the nucleus and the nucleus gets very blebbed [forms blister-like changes] and destructive and that's what causes it.

Within the last month or six weeks, don't hold me to the exact time, there's now an observation from human cells that are aging that shows that they randomly develop the same cleavage defect that is in progeria and as a consequence with aging cells, the progerine is now present in normal human persons.  So there — there's not a whole lot you're going to be able to do for these — it was thought that there was not anything that you could do for this but it turns out — I'm going to get too technical.

There's a molecule in cholesterol called farnesene and many proteins are farnesylated, meaning that farnesene sticks to them and alters what they do.  For example, the Ras oncogene [a gene that causes cancer] is activated by farnesylation.  It turns out that in the progeria, if you use inhibitors of farnesyl transferase, that is the enzyme that puts the farnesene on progerin, you prevent the syndrome of progeria in the animals.  Trials in humans are under way or will soon be undertaken.

Now, the implications here are astonishing because it might well be that a simple drug that's already approved might have something to do with aging or premature aging.  The point I'm making is that there may be benefits from screening and study along the science within what we're talking here that may, in fact, have public health issues beyond the 4,000 or the 8,000 which are here.  I mean, this is really an astonishing finding that with farnesyl transferase inhibitors that this syndrome — it's in clinical trials.  Francis Collins' lab is one of the ones that would be really involved in this and they're going into — you know, this is such a rare disease, to do it in humans is really going to be a problem.

So the point is that maybe the costs might benefit some things, but we learn so much from abnormalities, we learn a great deal in science about what's normal from what's abnormal and so I just wanted to throw that point out.

CHAIRMAN PELLEGRINO:  Dr. Hurlbut.

DR. HURLBUT: To add to that point, not only are diseases provide unique probes into basic molecular mechanisms, but there is something to be said on this issue of screening newborns and other phases of life for genes for conditions we can't treat because at this stage, we could follow their phenotypes in a way that once there starts to be some kind of suggested treatment, we can never do it again.    And that's not to say we want that condition to prevail but it gives us a unique chance to follow it.  I was thinking of this in relationship to the PKU description earlier.  Once detected, all those children were treated.  If they had sensitively probed the findings without treatment, they could have seen another layer of discernment as to what would happen if they weren't treated.  Is that clear?  Do you see what I'm saying? 

In other words, there really is some value to following conditions that we can't treat already.  There — this whole moment we're in, in the unfolding of genetics is providing us with a — just a fantastic opportunity to get to the bottom of our molecular mechanisms and one contribution we could make as a council perhaps a lot of people are working on this field, it's not like — we would have to do something that was drawing together a lot of streams of inquiry and already accumulated knowledge, but one thing we might be able to do is distill it down and fulfill our role as a council to engage and educate the public.

One of the things we might be able to do is to explain the value of this new phase of science and medicine and also to raise some clear cautions about over-interpreting the determinism of genetics.        

DR. ROWLEY:  Well, I initially was going to respond to them but let me begin by responding to Bill.  There's no guarantee what PKU is like because before 1973, there really wasn't a treatment, so you have years and years of experience, though it was rare.  We do know what untreated PKU was like and of course, the other rare metabolic diseases.  We also have some sense of what they were like, but going on to Leon's questions, it's interesting in Dr. Alexander's talk that he gave us a map and looking at the number or newborn screening conditions required as of June 1st, 2006, if you look at the map that he passed out in his — in the handout for his talk, there are 24 states that already test for 40 or more disorders and there are 13 that test for 19 or fewer.

So in a sense, we have the basis for trying to gather some data on how much harm is done in the states that test for more as compared with how much harm is done in the states that test for fewer.  And so we already have in the United Sates, if you will, the ability to collect the data based on the number of states and the number of disorders that they test for to gather some data to see whether being enamored if you will, of more diseases being tested for is a good thing or a bad thing.  So somehow we should be able to gather those data and the data, of course, would — and the kind of data one would like depends in part on the questions one wants to answer.  But I just want to point out that we already have some resources to go back to, to answer the question whether more is really better.

CHAIRMAN PELLEGRINO:   Thank you.  Dr. Carson. 

DR. CARSON:  Thank you, Janet, for making that point because that's what I was thinking about.  But, also I guess the question has come up what have we historically done with data that we've acquired on newborns or prenatal individuals?  And an example I think of specifically deals with the fact that almost all women in this nation now receive ultrasounds during the course of their pregnancy and you know, a number of things can be picked up on those ultrasounds, one of which is hydrocephalus.  And almost uniformly, when there is an indication of hydrocephalus a recommendation for termination is made.

I, as a pediatric neurosurgeon, have an opportunity to see many such patients as they're in the decision making process.  I have an opportunity to explain the implications of hydrocephalus but a significant number of those patients who decide not to go the abortion route it turns out end up with children who are normal, who never required a shunt, never required anything and yet had come to see me for a recommendation for abortion.

So, I just want us to throw into this mix that you know, we do have substantial data about what people have done when they have gathered the data and what they've done with it and maybe we should be trying to think of better ways to use the information.

CHAIRMAN PELLEGRINO:  Other questions or comments?  Dr. Meilaender?

PROFESSOR MEILAENDER:  As I listen, I find myself thinking that one way to sort of organize, at least in my mind the number of things that have been said, does turn on the — on making up your mind about the uniformity issue because there have been a number of questions that it's not quite clear what one ought to think or it may be that, you know, there's a reasonable argument to think different things about the wisdom of screening for conditions that one can't  yet treat, about the connection between the use of this kind of knowledge for newborn screening and the use of this knowledge in prenatal screening, about the degree to which the problem of false positives may have a sort of bad effect in terms of creating parental anxiety and can't really be fully relieved and so forth.  So there are a whole range of questions that reasonable people might think differently about.     Why should everybody have to think the same about them?  Why shouldn't different states, perhaps quite reasonably think quite differently about them?  That's — I mean, that's the direction that I find myself thinking with respect to that.  There are some other possibilities, too.  The thing that Dick mentioned that even if you fold some portion of this under the rubric of research rather than public health, that doesn't rule out the possibility of cooperative arrangements like the New England one that he mentions to share knowledge and make progress.

So that I guess as I try to organize what's being said, it just seems to me that where I find myself balking is on the notion that there's a persuasive argument for some single uniform policy because on a lot of these things reasonable people might well think differently and I can't figure out exactly, you know, why there should be a knock down, drag out argument for thinking only one way, at least that's the way it seems to me at the moment.

CHAIRMAN PELLEGRINO:  Thank you.  Dr. Bloom?

DR. BLOOM: Let me offer an alternate approach.  It seems what I heard from the last several rounds of discussion was that the uses and — the acquisition and uses of genetic information encompasses a lot of the concerns that were expressed and around that, I feel more urgency than I do about the newborn screening issue because there the technology is going to evolve and the possibility of broad sensitive accurate tests in the future may well provide some of the answers both to uniformity and to the ability of the poorer states to apply these rules, but the uses — collection and uses of genetic information is a situation that we're going to have increasingly before us and the implications of having a gene that in some cases sensitizes you to develop a  cancer and in other cases does not and what makes the difference is going to apply not only to pediatric illnesses but to diseases across the age spectrum.  It seems to me there's a lot more issues there.  The HIPAA issue, the ability to have registries where clinicians can go and find the patients who can stratify in these ways, those are issues that we run up against laws that don't necessarily help individuals.  If we could clarify the issues that Professor Schneider raised with regard to the employment and insurability of people who have had genetic tests done, I think that would help the public understand that they ought to embrace the genetic testing rather than be afraid of it.

CHAIRMAN PELLEGRINO:  Dr. Schneider.

PROFESSOR SCHNEIDER: I want to supplement, I think, what Dr. Bloom said.  There is an increasing amount of ethical and legal discussion about the — about how you can use medical information that has been accumulated in the past.  And there is a lot of suggestion in the ethical literature that you cannot use those data without getting fresh permission from all of the people who contributed to the data, which essentially makes the data collection impossible.  And there are also some legal questions about things like who owns that information, does the physician who acquired the data in the first place own it to the extent of being able to move to Northwestern University and to take the data with him?  Do the patients who gave the information in the first place have the ability to give him permission to take the data with him?  Does it belong to the university that hired him when the data were first collected and so on. 

But the presence of a large, truly huge amounts of useful medical information that cannot be accessed under these kinds of proposals I think is certainly the kind of topic that we would be well advised to be paying attention to.

CHAIRMAN PELLEGRINO:  Thank you.  Dr. Carson.

DR. CARSON:  Just a little addendum for that; there is precedence, of course, for the government feeling that they have ownership of the information because there are certain diseases that we are required to report on people who come to the emergency room and various places.  It's mandatory that they have to be reported.

PROFESSOR SCHNEIDER: There are many kinds of —

CHAIRMAN PELLEGRINO:  Dr. Kass.

DR. KASS:  This is a question for Dick or Janet or anyone else who might know.  This is to come back to the limited topic on which Dick has prepared this paper and he's given us three possible further steps for the Council.  I guess it would be relevant to ask if any other groups who are closer to this subject are doing anything at all on the ethical dimensions and of the concerns that are, in fact, expressed in your paper.  I meant there are individuals we know and they appear to be for us and they even write papers on this, but does anybody know whether if we were to tackle this we would be duplicating efforts that are now proceeding elsewhere?

CHAIRMAN PELLEGRINO:  Dick?

DR. ROBLIN:  I am not aware of any specific efforts that we'd be duplicating.  I think it is really important for the Council to find an approach to this area that makes sense and that you all are comfortable with.  I guess there's one suggestion in the last section of the working paper that came out of my reading of some previous papers that had attempted to figure out what kind of criteria ought to apply to newborn screening programs.  And the closest thing they could come up with influenced, I believe in part by the public health framework in which these programs are embedded were these 1968 WHO criteria, which really, if you read them carefully, and think about the current size and dimensions of the total US newborn screening program, I think are not very applicable.

So one concrete suggestion or idea that I had was to sort of take that framework but try to apply it in a sensitive and knowledgeable way to the dimensions and scope of the current US newborn screening program.

CHAIRMAN PELLEGRINO:  Thank you, Dick.  Questions or comments on this paper?  On any other subject?  I would put some limits on that, but as an opener.  Dr. Rowley?

DR. ROWLEY:  Well, I just want to endorse the idea that newborn screening is one aspect of DNA analysis and whether we want to get into the larger problem, again, you know, this is such a rapidly moving field, both in terms of technology — especially in terms of technology because what one can do with regard to people is really driven by the technology and chips have changed everything and new technology that's coming forward that may replace the chips. 

So I come back to what I said earlier, this is an area, I think the Council should move with caution.  Not that we should ignore it, but we have to make sure that we can add something that's going to be important.

CHAIRMAN PELLEGRINO:  Make haste slowly. Any other comments?  Oh, I'm sorry, Leon.

DR. KASS:  This is really a response to Janet.  Granting that the technology moves rapidly and in some ways defines the problem, that itself seems to me to invite a counter-thought, namely somebody ought to be thinking about the things that Dick puts in his last sentence, "The goals, the guidelines and the criteria", what it is we're actually trying to do here rather than to let the entire thing simply be driven by the technique. 

The technique will, of course, force certain questions but unless one wants to simply follow the logic of the technological imperative into this area without some kind of view of what the human purposes are, I think we could make a lot of mistakes.  So —

CHAIRMAN PELLEGRINO:  Thank you. 

DR. ROWLEY:  Some of the concerns are going to disappear with improved technology and so you'd spend a lot of time on something that's going to take care of itself and I guess that's my major concern.

SESSION 7: PUBLIC COMMENTS

CHAIRMAN PELLEGRINO:  Other questions, comments?  If there are none, with your permission, we'll move to the last item on the agenda which is the time we allow for public comments.  I have one, two, three, four requests.  I want to inform those who will be speaking that we have a rule that limits those presentations to five minutes.  And simply to advise a little in a friendly way that the most effective messages are the ones which are brief, crisp, to the point, premeditated and I think you'll find that that's the best way to make an impress rhetorically in a short time. 

I'll first call on Troy Zimmerman from the National Kidney Foundation and Dr. Davis will keep close — you may go to the microphone, please.  I was just going to say, Dr. Davis will be advising me on the time elapse.  Unfortunately, I am the chronoscopist by designation.

MR. ZIMMERMAN:  Good morning, I'm Troy Zimmerman.  I'm the Director of Government Relations for the National Kidney Foundation and I would like to comment today on your deliberations from yesterday's discussions.  The National Kidney Foundation is active in all aspects of organ donation and transplantation of all solid organs.  We are committed to increasing the number of organ donors, however, economic incentives constitute payment for organs and are inconsistent with our values as a society. 

We endorse the recommendations and findings in the Institute of Medicine's May 2006 Organ Donation Report that financial incentives, whether direct payment, funeral expenses or expression of gratitude should not be used to increase organ donation.  As the IOM panel stated, even on a trial basis, this would be easy to start but very difficult to stop. 

The sale of body parts would undermine the fundamental values of our society, diminish human dignity and exploit the most vulnerable members of our society.  Financial incentives could impact altruistic donation, closure for donor families and society at large.  As the Council heard yesterday morning, many Americans are not inclined to be organ donors because of their distrust of the organ donation process or of the health care system in general.  Financial incentives would intensify this distrust.

Proponents of financial incentives for non-living organ donation assert that demonstration projects should be conducted to determine whether it will increase the organ supply.  As the IOM panel stated, it is not feasible to design a pilot project on financial incentives.  The National Kidney Foundation suggests that emphasis should be in other areas, including the following; building on success of the organ donation break-through collaborative and best practices, providing additional support through the congressional appropriations process to fund the organ donation recovery and improvement act of 2004, Public Law 108-216, providing reimbursement for travel and subsistence expenses for living donors as authorize in Public Law 108-216, enactment of S-2306 introduced in this Congress by Senator Levin to clarify that kidney paired and kidney list donations do not constitute valuable consideration in the transfer of a human organ.  Some transplant experts estimate that a national registry, a national data base of medically incompatible couples could result in as many as 2,000 additional transplants annually. 

Encouraging employers to provide paid leave to living organ donors, an expansion of state legislation to reduce barriers to living organ donations such as paid leave for state employees, which many states have done already, business tax deductions to offset the expense of paid leave and state income tax deductions to assist living donors with unpaid expenses.  Thank you for the opportunity to present our views.

CHAIRMAN PELLEGRINO:  Thank you very much.  Dr. Rowley.

DR. ROWLEY:  Can I ask you a question?  How certain are you that financial inducement will increase distrust amongst particularly minority populations?

MR. ZIMMERMAN:  I think it would particularly be a problem in the minority populations given that —

DR. ROWLEY:  You think, but I'm asking for data.

MR. ZIMMERMAN:  I don't have data.

DR. ROWLEY:  Okay.  So that's one point that I want to make.  And the other is in a pluralistic society, should there be multiple ways of solving a problem?

MR. ZIMMERMAN:  I believe so.

DR. ROWLEY:  But then you're asking for the continued prohibition of financial reimbursement for a organ.

MR. ZIMMERMAN:  I believe we've laid out some alternatives, and we think there's certainly more than one way to address a shortage but we stand opposed to financial incentives even on a trial basis.  I think it could be counter-productive in terms of the impact on altruistic donations.  Many of the things that were stated in the Institute of Medicine report we support those findings.

DR. ROWLEY:  Well, I'm a member of the Institute of Medicine and I'm — you know, I certainly support some parts of that but I come back to my notion, in a pluralistic society, I'm not sure the prohibitions are appropriate.  I should say all prohibitions are appropriate.

CHAIRMAN PELLEGRINO:  Thank you very much.  Further — no? 

MR. ZIMMERMAN:  Thank you.

CHAIRMAN PELLEGRINO:  Next, I would like to call on Dr. Paul Billings of Lab Corp.

DR. BILLINGS: Thank you very much for letting me listen to this very interesting discussion this morning and for making a comment.  I'm a Fellow of the American College of Physicians, founding Fellow of the American College of Medical Genetics, a Professor at Cal but I'm here as — in my day job as the Senior Vice President and Senior Geneticist of Laboratory Corporation of America.  Of the more than 300 million tests that we provide the American health care system every year, a significant number of those are genetic tests and they've improved the lives of many Americans over the years.

In general, the state Public Health Agencies have done an excellent job of assuring equitable and universal access to reliable screening for restricted and somewhat regional variable set of disorders.  It is essential that these programs be of high quality and fairly distributed since they are provided generally without informed affirmative consent by the parents.  Most families have no idea that testing has occurred and often know little about the disorders or the risk of having them before the screening results are available.

The provision of screening, as we've heard already this morning, has provided some key lessons.  I'm just going to touch upon a couple and then add one.  The screening tests and their normal and abnormal reference ranges require stringent validation prior to the inclusion and broadly applied panels.  The experience of labeling benign fetal al — anemia  as PKU and then subjecting these normal children to treatment that harm them should never be forgotten.  While the provision of early detection for any disorder may offer significant benefits, it also brings responsibilities to the health care system.  Abnormal screening results require confirmation and then often life-long services to insure a salubrious result.  Vigilance to the remaining risk associated with false negative result also must be emphasized.  In some cases there are very few individuals in a country who know how to properly treat individuals with rare or orphan disorders.

Many state based public health care systems are not designed nor funded to deliver follow-up or long-term care and private sector resources may also be not available.  System failures in the absence of needed programs undermine the benefits of broad-based screening.  This is not a particularly profound point.  Rapid advances in knowledge and laboratory methods have created new tests to confirm current screening results accurately and in a cost-effective manner and have also offered very significant opposition to expansive screening and a much larger universal risk.

Some conditions proposed for new screening efforts represent rare and morbid disorders in pediatric patients much like the current panels, but others may be chronic disorders of childhood or adulthood that can be prevented or delayed or where recognition of risk can allow for adverse events to be avoided; take for instance, Type 1 diabetes and the presentation of Type 1 diabetes.  Some have suggested that purely developmental disorders of childhood, for instance, Fragile X syndrome and autism, should also be identified at birth so that planning and supplemental care can be promptly undertaken. 

The establishment of a public health consensus approach to the expansion of newborn testing will be difficult.  Expectations about medicine and choice are changing.  The provision of new screening tests in the absence of very significant involvement by the private sector will be impossible.  In response to market demands the private sector will work to deliver cost effective tests for all current and contemplated newborn conditions.  Luminex and Affymetrix, by the way, are private sector enterprises.  These may be quality controlled and distributed in collaboration with state public health establishments, but I strongly believe that consumer and technology demands will require the involvement of commercial laboratory and biotechnology sectors to best serve society's needs.

Increasing capability to accurately identify and successfully treat disease or prevent illness when significant risks exist requires both public and professional education reform and aggressive supplementation.  If these programs are created and provided, they may significantly alter how we care for a variety of conditions beginning at conception.

So in conclusion, the demonstrated success of newborn screening programs and the rapid evolution of knowledge and testing capability suggests the need to rethink how we will equitably make available proven technologies.  We must consider a variation of family need, individual choice and traditional manners for consent before applying medical technologies.  Stimulating market innovation and enterprise while fostering new types of public/private collaborations for universal provision and long-term follow-up will likely be needed.  As a major national provider of high quality innovative clinical laboratory services, LabCorp stands ready to work with other parties in the health care system to provide all newborns with appropriate screening and testing.  Thank you.

CHAIRMAN PELLEGRINO:  Thank you very much.  Dr. Rowley?

DR. ROWLEY:  In part my question, it's a follow-on of something I just had to ask Dr. Alexander in private and that relates to are you currently using DNA testing amongst the modalities that you use in your laboratory, and secondly, if you're not, how soon do you think you're going to incorporate or do you anticipate incorporating DNA analysis into your test modalities?  And if you've already used it, do you have any preliminary data on whether Dr. Alexander's notions of false positives are going to be diminished?

DR. BILLINGS: Well, so are you asking about the universe of genetic disorders, are you asking about newborn screening, Dr. Rowley?  What exactly are you asking about?

DR. ROWLEY:  Well, since the focus of this morning's session has been newborn screening, I suppose that that has to be an important component but I'm curious because Dr. Bloom has suggested that we expand from DNA analysis of newborns to other genetic disorders, a broader response would be appropriate if the Chairman thinks we have time.

DR. BILLINGS: Sure.  So as you well know, for pediatric disorders of which the concern has been this morning, chromosomal analysis and proteomic biochemical based testing has been the norm, the tradition.  For some follow-up, obviously, of certain screened results, DNA testing is now part of the confirmatory panel that we apply.  We are generally not a provider of newborn screening but we are a provider of the confirmatory testing that's involved in follow-up, false negative, false positive and so forth work, that's done in some states.

The answer to your question about the accuracy, fundamentally, we've found, of course, primarily driven by infectious disease molecular testing, but also by some rare genetics that, in fact, the cost and accuracy of DNA based testing is improved over sometimes rare, variable but proteomic or biochemical testing, but this, of course, requires that we have the data base to know what — how to interpret genetic variance and as you also know, when one looks carefully at any particular gene, one finds variance often that didn't — aren't expected, we don't understand the phenotypic implications.

So that's a lot of the long-winded answer saying I think what Dr. Alexander was saying is, in fact, true.  I think the cost will come down with molecular platforms with DNA platforms, but they require databases and phenotype, genotype correlation, information databases to be broadly available to the laboratories who are providing it.

CHAIRMAN PELLEGRINO:  Thank you very much.  Next, I would like to call on Thomas — Dr. Thomas McCome of the American Foundation for Donation and Transplantation.

DR. McCOME:  Thank you for the opportunity. My name is Thomas McCome.  I'm a Transplant Nephrologist from Norfolk, Virginia.  I'm here for the American Foundation for Donation and Transplantation.  I'm here to discuss the Living Organ Donor Network, which is a program that is a registry of living organ donors, primarily kidney donors.  We began in October of 2000.  This is a voluntary participation by the organ donor. 

Since October 2000 we have a registry that is currently covering about 1,000 kidney donors, 1,063.  Considering that every year we do about 6,000 living kidney donations a year, that's a drop in the bucket.  We have 19 centers who are participating voluntarily in this registry.  That's 19 out of 257, again, a very small number.  Donors like this, they fill out their questionnaires, they send their information back.  This information then goes back to the transplant programs to help them improve their technique, their care of the donor.

Additionally, that information, complications, time back to work, is all being tracked.  We're going to use that.  We've published it once.  We're going to continue to publish that data so that donor programs can say, "Well, donors report they would go back to work at this time.  Donors report they're driving at this point".   Additionally, it's a way for us to track complications.  Donors report complications differently than the transplant programs report complications.  Frequently, complications occur after the donor has left their transplant center and gone back home. 

The most intriguing part of this registry is an insurance policy.  There's an insurance policy that costs a one-time charge to the transplant center of $550.00.  This covers the life of the donor from the time they're admitted to the hospital for their donation surgery up to a year.  It covers accidental death due to complications from the transplant donation.  It covers disability insurance for up to five years and — from complications and it provides for medical coverage for costs that are not necessarily covered by the recipient's insurance.

Frequently the recipient's insurance will not cover outpatient charges and that continues to be a real problem.  So far since we've initiated this program, we've covered 257 lives, only 257 lives over this five-year period, six-year period, excuse me.  That's four centers are enrolling all of their patients and two individuals have actually purchased this insurance independently on their own.

Donation is dangerous.  Donors have died.  Donors will continue to die.  If you compare organ donation to say laparoscopic cholecystectomy, there's a risk of that.  One in about 6,000, one in about 10,000 of those individuals will die in surgery.  We do 6,000 kidney transplants a year.  We're overdue.  When I talk to programs, they're not willing to accept that this is an intrinsically dangerous procedure.  They say, "Well, we don't have complications".  Well, I'd much rather be lucky than good, but you can't always be lucky.  Our program has begun this as well.

What I ask from you is that you recognize the risk that donors willingly accept to donate and encourage all transplant programs to work to protect the lives and the well-being of the donor and their family from this donation procedure.  I encourage kidney donation.  We're one of the biggest programs in the state right now and this is something that we agree with.

CHAIRMAN PELLEGRINO:  Thank you very much.  If there are no comments, next we have a request for a statement by Jana Monaco of the Organic Acidemia Association.  I understand I'm to read this.

"Good morning.  I am a parent of two children with an inborn error of metabolism called isovaleric acidemia that is detectible at birth.  My son Steven, now eight and a half years old, was diagnosed five years ago after going into a metabolic crisis.  His late diagnosis resulted in severe brain damage.  He is now a severely disabled child with complex medical issues including G-tube feeding and uncontrollable seizures".  I'm reading this as is.

"He does not walk or talk nor can he sit up on his own and his medical care costs continue to soar.  He is far from the happy-go-lucky and healthy little boy that he once was.  Our daughter, Caroline, is three and a half and was fortunate to be diagnosed with prenatal testing enabling immediate treatment and management of her disorder.  Today, she is a bright and healthy child with a promising future.  She is always the reminder of what Steven was and could be had — could had he been screened at birth.  His family suffers every day from the consequences of inadequate newborn screening at the time of Steven's birth. 

I have dedicated my time to his care and that of my other three children and advocacy for expanded newborn screening.  We have been successful at the state level by getting legislation passed to expand Virginia's detectible disorders and I have also been immensely involved on the federal level.  I am on the Laboratory and Procedures Subcommittee of the Advisory Committee for Heritable Disorders and Genetic Diseases in Newborns and Children. 

Having witnessed the incredible amount of time and work involved in the ACMG recommendation of disorders to be screened to the Secretary of HRSA, I find it quite daunting to continue to listen to individuals question the ethics of newborn screening.  Every possible concern and issue related to the topic is and has been addressed by the committee and is being handled.  Many individuals claim to be knowledgeable on the subject yet I have never seen them present at any of the advisory committee meetings. 

I have been to every one of them.  I attend these meetings because I want to insure that children are protected from experiencing the same tragedy like my Steven.  I ask this Council how ethical is it to allow babies to be denied screening that could detect one of these deadly disorders?  We live in a country whose constitutional rights guarantee us equality.  Our son's equality was denied because he did not receive the same comprehensive screening that our neighboring state of North Carolina provided like others at the time of this birth. 

Is that ethical?  Is it unfortunate that some people have the opportunity to interpret ethics to suit their own beliefs, yet have the potential to have a tremendous impact on the lives of others?  I question the moral standards of these individuals that would prefer to interfere in a process implemented to save lives.  As I witness my son's daily seizures, though he takes three different medications and feed him his formula through his gastrostomy tube, change his positions and conduct his therapy sessions, I remind myself that this is a result of someone's so-called ethics and I am determined to insure that those ethics do not continue to influence people's lives.

Thank you, Jana Monaco, Board of Directors, Organic Acidemia Association, 3175 Ironhorse Drive, Woodbridge, Virginia, 22192, phone number 703-497-1216". 

Do I have someone to comment?  Someone in the audience?  We have one more person who has asked to speak.  Dr. Debra Budiani, I hope I have that correct, from the University of Pennsylvania, Center for Bioethics and the Coalition for Organ Failure Solutions.

DR. BUDIANI:  Thank you for this opportunity.  I've worked in an advocacy position with organ sellers and related donors in the developing world since 1999.  I'm conducting follow-up and outreach services.  The data is still preliminary but our findings have been very consistent with other reports of significant adverse outcomes.  I'm concerned then primarily with the exploitation of vulnerable individuals of kidney donorship and other organ donorship and I have a question, comment for Dr. Hippen's proposal.  I'm not sure if he's here still but I'd like to raise the question.

In addition to protecting potential exploitation of vulnerable potential donors from — via market forces, a strength of the current organ procurement and distribution system in the United States is its aim to develop equitable organ distribution policies that maximize the limited supply of organs.  Equitable distribution making organs available to the poor has also been a commitment of the Iranian system via government subsidized organ purchases.  Dr. Hippen's policy proposal appears to further enable those patients who could provide financial incentives to obtain an organ but I'd like to understand if it actually addresses the concerns of those who could not afford to do so.  Thank you.

CHAIRMAN PELLEGRINO:  Thank you very much.  A word of explanation for all of you who do not know the procedure here, if anything is to be gotten into the record by a non-member of the Council, the Chairman is expected to read it, that is why I read that statement, so it will get into the regular meeting account and be a part of the record.  I apologize if I've in any way not put the proper emphasis in the proper places but it was the first time I saw this statement. 

I think we are that point where I can thank the members of the Council for their participation, all who addressed us.  I wish all of you on the Council and all of you in the audience a very happy summer.  We will be, during the summer, we and the staff are looking at the report of this particular meeting and the other meetings and trying to arrive at the questions you raised properly, Dr. Rowley, earlier and which many of the Council members have expanded on and we're grateful for that on how we focus and what we do next.  And I hope I can promise on behalf of the staff that we will have a set of suggestions or directions to go in and particularly how to deal with this last question which, I agree thoroughly with all of you is a very complex one and certainly Dr. Kass, a question of either completing what was started or whether there is a place for a statement, will be looked at as critically as planned and we'll be back to you with a suggestion. 

Thank you very much, and have a good summer.

(Whereupon, at 11:58 a.m. the above-entitled matter concluded.)


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