June 23, 2006
COUNCIL MEMBERS PRESENT
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.
William B. Hurlbut, M.D.
Leon R. Kass, M.D.
American Enterprise Institute
Peter A. Lawler, Ph.D.
Paul McHugh, M.D.
Johns Hopkins University School of Medicine
Gilbert C. Meilaender, Ph.D.
Janet D. Rowley, M.D., D.Sc.
University of Chicago
Diana J. Schaub, Ph.D.
Carl E. Schneider, J.D.
University of Michigan
SESSION 5: NEWBORN SCREENING FOR
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
"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
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
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
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
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
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
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
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
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
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
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
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.
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
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
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
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
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
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
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 ..
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
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
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
I mean, that wasn't well put, Duane, but perhaps you could address
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
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
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
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
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
DR. McHUGH: Am I not in the queue? Can I join the three of
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.
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 was a great drink of water in the desert, so ..
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
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
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
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
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
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
Again, thank you very much, Dr. Alexander.
DR. ALEXANDER: Thank you.
(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
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
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
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.
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,
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
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
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
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.
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
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.
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
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
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
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
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
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
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
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
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
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
"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
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
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
Thank you, Jana Monaco, Board of Directors, Organic Acidemia Association,
3175 Ironhorse Drive, Woodbridge, Virginia, 22192, phone number
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
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