PCBE: Transcripts (February 3, 2006)

Meeting Transcript
February 3, 2006

COUNCIL MEMBERS PRESENT

Edmund Pellegrino, M.D., Chairman
Georgetown University

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

Rebecca S. Dresser, J.D.
Washington University School of Law

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

Michael S. Gazzaniga, Ph.D.
University of California, San Diego

Robert P. George, D.Phil., J.D.
Princeton University

Alfonso Gómez-Lobo, Dr. phil.
Georgetown University

William B. Hurlbut, M.D.
Stanford University

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

Gilbert C. Meilaender, Ph.D.
Valparaiso University

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

Diana J. Schaub, Ph.D.
Loyola College

INDEX

SESSION 5: PSYCHOPHARMACOLOGY AND PSYCHIATRIC DISORDERS IN CHILDREN

CHAIRMAN PELLEGRINO: I think in deference to our speaker to allow him sufficient time for presentation and you sufficient time for interrogation in the best sense of that word -- this is not a hearing. I needed to modify that -- this morning we switch our attention to the field of

psychopharmacology in children, part of our overall attempt to look at some of the important ethical issues in childhood.

Dr. Biederman is the Professor of Psychiatry at Harvard Medical School and Chief of Pediatric Psychopharmacology at Massachusetts General Hospital. There are no extended introductions, and he understands that and knows that you're familiar with his curricula vitae.

Professor Biederman, I turn it over to you.

DR. BIEDERMAN: Well, first of all, the interrogation part is a very serious matter, and I was sure torture would not be included.

(Laughter.)

DR. BIEDERMAN: So it is a great pleasure to be with you. This subject that I'm going to cover is an area of enormous interest, enormous amount of media attention, and I'm glad that you are taking this on.

I am a practicing clinician and a scientist. So all of the issues that have interested me have been driven by clinical concerns.

In any event, I would like to share with you some general issues. Let me see. Where is my presentation?

First of all, as you know, the scope of mental disorders affecting children is extraordinarily large. It is maybe between 12 and 22 percent of children in this country and perhaps all over the world have major mental illnesses. This translates into seven and a half to 40 million children affected. About ten percent of those children are thought to have severe functional impairment. Those are children that are institutionalized in foster placement, require massive amounts of psychosocial and psychoeducational interventions.

However, less than 20 percent of these children receive any mental health services, and they never see a child or adolescent psychiatrist.

Many of these children, of course, would benefit from a treatment that may enhance their ability to be in a less restrictive environment, and so if you have a major psychiatric illness and the only intervention is institutionalization, it may not be the best service that the child can receive.

There is a serious problem in our field regarding manpower. There are less than 6,300 trained child and adolescent psychiatrists currently practicing in this country, and we estimate that probably by the amount of children that are affected with mental illness is that we may need at least 30,000 to meet current demand.

So I would like to say to you that of those 6,300 not all practice child psychology. Many just do psychotherapeutic interventions and do not take on the medical aspects of the profession. This need is projected to greatly increase over the years. So we probably will need something like 50,000. We probably are never going to get there.

So the next hope or the next best choice is to count on informed primary care physicians that will take on some of these responsibilities and help manage the many children in many parts of the country where there is not a single child psychologist to be found.

I would like to editorialize a little bit that the problem of manpower is extraordinarily severe. Remember that affects not only the number of child psychologists that we have, but the quality of our ability to train the next generation of child psychiatrists. So if we don't have a critical mass of high level child psychiatrists, we are not going to educate at the level that the new generation may need to be aware of the problems and the issues in front of the profession.

I suggested when I was invited to focus on one neurobiological problem like ADHD as the model of the problem of linking behaviors with the brain. In pediatric psychiatry we have very little approved medications beyond the treatment of ADHD. This has changed somewhat in the last few years, but not dramatically. In the last few years not only that we don't have approval for many drugs, but we have black boxes for all of them that create issues that I would like to make you aware of — what is the impact in our society and in the minds of the clinicians practicing out there.

So there is a vicious circle that immediately has created concerns about children, creates a bad climate to do research on children that is considered perhaps not ethical. So if we don't have evidence, what is more ethical, not to treat? We still have to treat. To treat in the absence of evidence or to do the studies that would allow us to have the evidence to treat ethically? So that's the dilemma.

There is also an enormous amount of prejudices and misconceptions in our society about psychopathology in children. There is some kind of naive belief that all children are angelical, and there is something wrong to the child. Somebody is doing something bad to the child. So there is no recognition of the fact that children, like adults, have bona fide psychopathology disorders that translate in aberrant behaviors, and the assumptions that it's just all psychosocial and if every child were to have loving parents and loving teachers, no child would be affected is really extraordinarily naive.

There is very poor public acceptance of the use of medications in children. There is an enormous amount of bad faith. I don't know. Probably you know more than me, but every week there is some kind of poisoning of the children, over-medicating, and so on and so forth. And periodically we are dealing with this alarming statistics about bad things, and some of these alarming statistics led to, I believe, all psychotropics having black boxes.

I would like to address two of those alarming statistics: This issue about suicidality and suicidal behaviors with the use of serotonergic antidepressants — as a context I would like to say that the serotonergic antidepressants provided the field of psychiatry in general and child psychiatry with very safe medicines, medically speaking. Before that we had tricyclic antidepressants and drugs like imipramine or amitriptyline or desipramine drugs that had very narrow margin of safety. Overdoses could be lethal. They require a high level of monitoring. These drugs could be arrhythmogenic. So the advent of the serotonergic drugs from the strictly speaking medical context provided a very safe environment.

As you know, these drugs over time became useful to treat an enormous chunk of psychopathology, not only the patient, but anxiety, obsessive-compulsive disease, social anxiety, post-traumatic stress disorders, eating disorders. So it provided a very safe environment to treat children.

So this data that started with paroxetine, then extended to venlafaxine, included all under the present, particularly as its rise led the British regulatory agency to proscribe altogether the use of SSRIs in the end.

The FDA took a less drastic position that has changed now over time and has been softened in light of evidence that has emerged. Part of the problem is that in clinical trials, two problems may have driven these statistics.

I would like to say this about the three percent versus about one and a half percent of placebo that we're talking about here: Part of the problem is that in the clinical trials with depression and all over the world there is a very high placebo response, and there is a little bit of a disconnect. I wish I had a placebo response when I have three depressed youngsters. I would like to make sure that you are aware that for reasons that have to do with the selection of subjects that participate in clinical trials, a child that may be in a deprived environment when participating in a clinical trial has an enormous amount of attention. People are taking care of the child and the family.

The child is immediately a very important person, and so on and so forth, and that has very impactful effects, even though it's not the treatment, on allowing people to feel better. So the placebo effect that has been so high did not permit the separation of the active ingredient from the placebo. It's not that the drug did not work, but it did not separate from placebo. The magnitude, the absolute magnitude of effect, was as high as in adult depression, but the placebo was higher.

So what I would speculate is many of the children that were entered in this clinical trial may have had some psychosocial type of adjustment difficulties with depressed features instead the melancholic problems that we face.

The concern that I would like to tell you is that in clinical practice treating depressed youngsters is a nightmare. I wish, again, I had the 60 percent of placebo that we have in clinical trials. That is not true to life in what I have to take care to do when I deal with depression in the young in my clinic.

So I would like to tell you the numbers, that out of 4,400 cases that participated in controlled clinical trials, largely adolescents, there were 78 that had some kind of [suicidal ideation]. Nobody died. I believe that nobody was even hospitalized. It was defined as ideation that the youngster reported to the treating clinician or the family reported. And that was larger than 3.8 versus 2.1 if you take all of these 4,400 kids.

What I would like to share with you is these numbers here, that if you take what is the rate of suicidality, including very serious, injurious suicide attempt in high school children in this country, look at these numbers. In the population, we're dealing with 20 or 30 percent, not three percent. So depression, as you know, increases this risk, does not decrease this risk.

So what we see in clinical trials is a small blip to the problem. These are not depressed. These are population rates. These are the Center for Disease Control statistics.

So suicidal ideations are extraordinarily common in our society. The data that we have regarding the life saving components of the antidepressants is in the opposite direction. In statistics available, and this is a paper published in a very reputable psychiatric journal, the Archive of General Psychology, your increased use of antidepressants in the '90s, largely SSRIs, led to a decrease in the rate of suicide, not an increase.

And there is a paper that I enclosed in the outline, this paper by Dr. Greg Simon that took a very large database to examine this issue that I just briefly would like to mention, and if you take the young children and adolescents, the risk for suicidality is much higher before you start medication than after you start medication.

These are months. If you look at weeks, so this is before and this is after. So in a large population, this is more true to life. We don't have any evidence that that's the case. However, a black box, the public and the treating community may not distinguish the potential remote risk from the tangible and present risk, and the results are that families may be handed by the pharmacy a handout that would say that this will make your child commit suicide. The primary care physicians that otherwise would have been able to prescribe these medications for the depressed youngster or somebody with severe anxiety or OCD will not do that anymore and will refer to psychiatrists.

As I said to you before, they are nowhere to be found. Okay? So the result is the children will not be treated with the drugs that can be lifesaving.

The other thing that I would like briefly to mention is the paper that was published in JAMA re Dr. Zito. Let me just go back.

In this paper, she looked at the trends in the last decade in prescribing medications to preschoolers, and what she was reporting in the paper is that less than two percent of preschoolers were receiving psychotropics. The way that the data were presented in that paper, instead of percentages were presented as per thousand. So for the uninformed reader, as you know, as you present data when you change your vertical and horizontal axis, anything can be one from 1.2, if you present it in particularly alarming ways, can be quite alarming.

I would say 90 percent of the conditions that emerge in childhood emerge in the preschool years. So I said to you before that about at a minimum ten percent of children have serious mental illnesses. Most of these mental illnesses will emerge in the preschool years, and if we treat 1.5 percent of those, and most of these treatments have to do with enursis, doing imipramine for enursis, not that they were taking something more than that.

So I would make the argument that we are not doing a good job in treating proximally to the onset of the disease the conditions that we ought to treat.

As you know, when the paper was published, Ms. Clinton asked the field -- we had many committees that participated, also myself -- about treating preschoolers. I would like to tell you that in my clinic everybody has a structured interview, and we do not select patients by race, social class, and we do not ask them to declare a diagnosis. We consider the diagnostic responsibilities are clinical issues upon us.

So we have a sizable number of preschoolers representing about ten percent of our referral pool. These preschools have an enormous amount of psychopathology. There is an average age, a defined preschoolers, children six or younger. Okay? Average age, about four.

These children not only have single diagnosis, but frequently have multiple diagnoses, including serious mood disorders, serious anxieties or a combination of behavior disorders, ADHD, et cetera, et cetera. So, for example, a small percentage of them have four diagnoses. Think about an adult patient with metabolic syndrome, diabetes, hypertension, and a wide range of difficulties. So this is a very compromised child. Okay?

So they are coming to a clinic. We did not get them. They are coming to us, asking us for help with very serious psychopathological manifestations.

What I wanted to point out here even though these children have an average age of 5.2, okay, the onset of the symptoms were at least a year and a half to two years before they reached our shores. So even in the preschool setting, we have a big gap from the time of the symptoms onset to the time that somebody is referred.

That gap, of course, is much larger. The average duration, the distance from onset of symptoms for ADHD to onset of treatment is somewhere in the order of magnitude of seven to nine years. If you think about if that distance where to apply to the treatment of a cavity, for example, what that will do to the affected person in the sense of chronicity, the impact of a repeat of seven years, you have many opportunities to ruin your life.

Okay. Children have long memories. A child that is a pain in kindergarten, even if the child improves, will never be forgotten by his peers for many years to come.

So we have the larger issue that because as prejudice is concerned, the difficulties in conducting studies in children and so on and so forth, that very few drugs do not have FDA approval, and as a consequence we are in kind of a Never-Never Land regarding risk. We have to make sure that you are aware that we still have to prescribe with or without FDA approval. Okay?

The recent past legislation has mandated pharmaceutical companies to conduct research in children and adolescents. The recent experience with SSRIs certainly had produced a very chilling event in the minds of pharmaceutical manufacturers. So the state of affairs of not having approval creates the uncertainties that lead to not knowing how to use, what to use, what is safe, what is not safe, et cetera, et cetera. So it has greatly limited the possibilities of using psychotropics safely and effectively in the management of children with serious psychopathology.

So I would like to switch to ADHD as a prototype. It is one of the most common disorders that we have in child psychiatry. It's one of the most common problems that pediatricians that deal with; [it generates] emotional issues faced all over the world; it is a highly heterogeneous illness, like all medical and psychiatric conditions. We know that genes have a lot to do with this, and I will tell you a little bit in my talk. We know quite a bit about anatomy and neurochemistry.

So here we are, with a condition that is one of the most beleaguered conditions that we have in psychiatry. It's among the most well established neurobiologically speaking, and I hope I will be able to make that point as a product of this discussion.

We know that environmental factors are a contributor to the disease. I would like to mention that what I call environmental factors are in themselves like family conflict, poverty, maternal and paternal psychopathology. Those are not sociological factors of bad mothers and bad schools and bad teachers. Those are conditions that themselves are given by genes.

So a child that is living with a parent that has a serious mental illness has two problems: she has the genes that the parent transmits, plus the bad environment that the parent transmits. If CNS incidents, of course, closed head injuries, accidents of other types damage the same regions of the brain that genes damage, [they] will produce a syndrome that is known as ADHD.

So think about ADHD as a final common pathway of multiple interlocking process that could come from different origins. The most common one is this one. It's one of the most genetic conditions in psychology and in medicine as I'm going to tell you in a second.

You probably heard many times that the children are over-diagnosed, over-medicated. This is an American disease. Data coming from all over the world -- we actually published a paper in the World Psychiatry Journal -- document [worldwide prevalence]. This is just an example of what I'm showing.

But no matter what definition you use, five to ten percent of children all over the world, (including Asia and China a few months ago, the five to ten percent numbers are there, too). Very, very common condition.

As you know, this is a chronic illness, and the children of today are going to be the adults of tomorrow, and the adults of today have been children yesterday. So we're talking about a condition that is only temporary in pediatrics, but will be a condition in adults as the child matures.

How do we know that? There have been several follow-up studies. My follow-up studies into adulthood, my study of boys with ADHD was just published in a very prestigious journal that is called Psychological Medicine This Month. What I wanted to show you is that there are many studies, very few into adulthood though, using different definitions.

DSM-2 emphasize hyperactivity. This is my study, the previous published study. By age of 15, we had 85 percent of persistence. So if you average this, it is about 50 percent of the minimum.

In my recent analysis of how persistent it is, we calculated that 80 percent of our original sample that was ascertained in childhood, by the age of 30 continued to have some form or another of ADHD into adulthood, 80 percent.

So we always imputed that, estimated that adult ADHD based on these follow-up studies of persistence may be common. Okay? So we now know from this paper that we published recently, and there is another one by Dr. Kessler that has done the national co-morbidity survey that is responsible to provide us with the statistics for all mental illnesses in our society.

The data emerging today are about five percent, between three and five percent of adults in our society have this condition. Okay. Remember that we have many more adults than children and people spent longer time being adults. Not only there is five percent, but I would like to share with you some statistics on how morbid it is. This is an adult.

I also wanted to mention to you this is strictly defined. People that have lifelong problems, the average age of the sample is about 40. The vast majority of those people have never been diagnosed in childhood. The vast majority of these people, despite diagnosis, have never been treated. Okay? So we have here a very peculiar situation that these people received the diagnosis perhaps in their communities, but they're not treated. It's estimated that 20 percent of adults are actually treated.

But what I wanted also to mention to you is that variations of these syndromes are extraordinarily common. In our study people that have less than required symptoms, a few less or they had a different age of onset and it ended up being up to 16 percent in Dr. Kessler's study. He had another five percent of adults that had a lot of symptoms in adulthood, not so many symptoms in childhood, kind of the reverse of what we see in the traditional definition of ADHD, a disorder that starts in grade school and continues.

This is not a disorder, by the way, [such] that people have attacks. So you have it chronically all the time. The frustrating component of this condition is that it's a behavioral syndrome, and the symptoms, like in depression actually -- it's not very different -- overlap with symptoms that all of us have. All of us may be distracted, inattentive, impulsive, but not to the degree that produces the symptoms all the time, and not to the degree that produces morbidity, dysfunction, disability, suffering. Okay.

So the distinctive point is the number of symptoms. You have to have a lot. Okay? And you have to have symptoms that produce dysfunction. And "dysfunction" is a relative term. Okay? It's not absolute dysfunction that you cannot do any school work. The child with ADHD may not be able to use his or her intellectual ability to the fullest.

Just before I came yesterday we were calculating if you look at my follow-up, if you look at the ADHD children that completed college compared with those that don't have ADHD, the ADHD group had to have 30 points higher of IQ compared with the average IQ of the control that completed college was 110. The average IQ of the ADHDs that completed college was 130.

Well, that means that the intellectual abilities of the person, his or her endowment that would allow the person to succeed, are substantially diminished by the conditions. So you are functioning effectively at the lower level.

Remember there is a connection between what you accomplish in school and where you end up in life. So these are not minor issues.

We also know that the ADHD individuals -- that the level of education is not predictive of level of functioning of occupations. So they have under occupation relative to their education. So they get two hits. One is that they have under education because they cannot get as high as their intellectual abilities will allow them, and those that get it, they have under occupational consequences.

So the gap from where you could have been, from where you are in society is very large. Okay? And we recently estimated that the cost of under employment of ADHD may be in the order of magnitude of $70 to $100 billion a year just from under employment.

So the frustrating situation in the clinic with ADHD is that the symptoms are not in front of us. So the patient is not dysmorphic. The patient doesn't have any different colors. They're not blue, yellow... The patient is not in acute pain. So it's a very different environment in capturing this syndrome. The patient may look like you and me. Okay? And the clinician then has to elicit the symptoms outside the office. The symptoms occur, are situation sensitive. They occur in situations that you are not interested in.

So, for example, a child can play Nintendo for many hours or watch Saturday morning cartoons for many hours, but may not be able to do homework for two minutes. That always has been interpreted as volitional.

If you look at the history, the first description medically speaking of ADHD was done by Professor George Steele in 1905 in London, in the Royal Academy of Sciences, I believe, and he described the symptoms very well, and the conclusion is that it's a moral disease. Why is it a moral disease? Because of the situation that the child can do; it's not an absolute failure of attention, but it's fluctuating and context sensitive.

That, by the way, is not different than other psychiatric illnesses or medical conditions. The patient with chest pain does not have it all the time. The patient with seizures does not seize in front of the doctor to document that they have a seizure.

So the symptoms occur in situations that they're uninterested. So a child will have symptoms in school in some classes, not in all, depending on interest or capabilities or how fascinating the teacher is in teaching. The adult may have difficulties in paper work. Physicians, for example, with these conditions do well when they are in one-to-one with their patients. They tend to have a lot of difficulties when they are called to administer clinics or to organize something, and then they have no idea what they are doing.

The symptoms of impassivity and hyperactivity are very age sensitive. They tend to decline early on in life, and that has been the reason that this condition has been assumed to be a childhood adolescent diagnosis. Not to worry; things will disappear.

We know very well that things do not disappear. The most covert symptoms, those of inattention, those that we don't see, are persistent.

The other problem that we have is that the symptoms are very variable. They vary in the frequency in which they occur, and they vary in the degree that they impair the individual, and that also creates a lot of confusion. There is an expectation that I don't think applies to any other medical condition, that you have to be near death to qualify for a psychiatric diagnosis.

We don't have that standard for hypertension or for strep throat, by the way. So here the idea is if you have -- as I said to you before, a child who is very bright will not fail school, will do okay in school. The distance of doing okay in school for a bright student is the same distance as somebody that is not so bright that fails. It is exactly the same distance.

So there is no expectation that we need to demand that a child be failing school or the adult being incarcerated to consider a diagnosis. So the issue of impairment is a matter of judgment and is relative, not absolute.

As I said before, I treat a lot of adults, and many of them are in the high professions. So you can say, well, if you made it to medical school, law school, architectural school, how can you have ADHD?

Well, many of these people are really brilliant and they're able to pass their exams, but they're not able to practice. They have a lot of problems in life. They have difficulties in their marriages. They have difficulties with their children. There are difficulties in managing their household chores, and so on and so forth. So life is not a picnic for many of these people.

As I said before, the symptoms of hyperactivity tend to decline around the age of 12, those of impulsivity. It's not that they disappear. They go below radar. They are less prominent. So you no longer see a child in my waiting room at the age of 15 that is running on my furniture.

That does not mean that the child is out of the woods. What they will tell me is that they have this horrendous inner sense of restlessness. Many of these adults are always doing something. There's a different flavor than being hyperactive. They cannot sit still. Many of these adults, for example, do not know how to relax. So these are the Blackberry people, people that are at the beach, have five computers and a telephone. So they are workaholics.

Many people go to the office because they do not know what to do with unstructured time. This is not a condition that is adult- or marriage-friendly. It is not a condition in pediatrics that is family-friendly. It is highly impactful.

I would like to go a little bit to the brain because contrary to accusations by the Church of Scientology that this is all kind of an invented disease, as you know, the Church of Scientology has several class action suits against American Psychiatric Association, the American Academy of Child Psychiatry, claiming that they are in cahoots with pharmaceutical companies to invest the disease to sell medications.

The literature from MRIs in pediatrics [is based on] small studies... To my knowledge, we have now more than 30 studies. To my knowledge, there is not a single MRI study that has been negative in ADHD. The findings are different, but in areas of the brain that are clearly associated with the disease, [one finds] asymmetry of the caudate nucleus; differences in size and shape of the corpus callosum; smaller right frontal area, and the frontal lobe is a key region for cognition, as you know; smaller right basal ganglia; and the cerebellum is increasing recognized as particularly vermis -- the cerebellum is important in cognition, attention and ADHD.

These studies were criticized because many of the children had been medicated. So you can then argue that what you see in the MRIs are the consequences of the treatment, not the consequences of the disease.

This study that was published in JAMA in 2002 by our colleagues at the National Institute of Mental Health, (Dr. Castellanos was the lead author). It's a very large study. The previous study had ten, 12 subjects, maybe 20. This has 152 children and adolescents, boys and girls, and a sizable number of controls.

The study's objectives were to assess volumetric changes over time and to address directly the issue of medication, and therefore, they have medicated and unmedicated youngsters.

What this study found is that the cerebral and cerebella volumes were significantly reduced in the order of magnitude of three percent in children with ADHD. This volumetric abnormality, with the exception of the called weight, persisted with age. This was not a neurodegenerative condition that things went progressively worse over time. There were no degenerative instances, and there was some evidence that these volumetric changes were correlated with the severity of ADHD.

So the visual of this is this. So in girls we have data up to 15 and boys up to 20. This is brain volume. This is age. So these are the males, and these are the females. You see that in both genders you have the same magnitude of smaller cerebral volumes. Okay?

The conclusion of this paper is that either genetic or early environmental influences in brain development in ADHD are fixed, nonprogressive and unrelated to stimulant treatment. It's a very important finding for the field in reassuring that what we see is not just the toxic effects of medication.

So if you look at some of the key regions of the brain in all of us, not in people with ADHD, there are regions that we know are involved in key cognitive processes. The anterior cingulate, the dorsal anterior cingulate, and the cognitive division are associated with executive control -- the ability to inhibit thought and behavior, the ability to direct attention to things that were not interested. The dorsal (unintelligible) prefrontal cortex, right frontal lobe, and these are, of course, highly interconnected areas of the brain.

We can use imaging. So what I'm going to show you is imaging of this region. Okay? This is really very exciting data. We just completed this study. So this is not yet published. I promise you that it will be published, but I would like to share it with you nonetheless. So this is the anterior cingulate gyrus here which I am depicting. Okay?

You can measure with MRI volume, of course, but you can also use the latest technology to measure cortical thickness. How thick or thin is the cortex?

So in this paper that we were able to document, I believe, for the first time, that in an adult with ADHD unmedicated, what I'm showing here is the statistical comparison of the average brains of adults with ADHD compared with adults without ADHD looking specifically at cortical thickness.

So you see here this is the dorsal anterior cingulate, the same area of the brain that I showed you before that we know is involved in cognition. It's not a diffuse, encephalopathic process, and we also have thinness here. This is significantly thinner in the dorsal and the frontal cortex, also a key area of the brain involved in the processes that can lead to the symptoms that we know as ADHD.

These findings are remarkably congruent with what neuropsychologists conceptualize as ADHD from a neuropsychological perspective. In a very interesting and special issue in Biological Psychiatry on ADHD, on the neuroscience of ADHD, there is a group of extraordinary review articles on the genetics neuroimaging. Dr. Sonuga-Barke did the review in the neuropsychology of ADHD, and he argues that the process of ADH and the circuits of attention was called directed attention, essentially paying attention to things that we're not interested.

So the person with ADHD cannot put his or her brain in four wheel drive when confronted with the task that the person is not interested in, and equally important is their disturbances in the reward circuit. The person with ADHD will not be able to not do something that may be pleasurable.

And as you know, if you go for things that are rewarding and pleasurable without some kind of scrutiny, you are going to engage in a wide range of difficulties in our society. The issue of difficulties with delay aversion, so many people with ADHD will very rapidly approach something, drugs, alcohol, sex, in a manner that may lead them to a wide range of difficulties.

Going back a little bit to the dorsal-anterior cingulate, the cingulate gyrus, this area here in red, is tightly organized into a cognitive and an emotional division. This is the general here. The blue is the emotional division. Well, what is remarkable is these are different studies that can activate this area of the anterior cingulate using functional MRI and a very simple cognitive load.

You can consistently activate this area of the brain using imaging techniques, particularly functional MRI.

In a study that we did, Dr.Bush, this is a neuroscientist in in our group, who is called George Bush. Now, what a name, no? But it's not the one in the White House.

This is a coronal view of the brain, and in normal controls if the person is
asked to do a simple cognitive task, you will activate the anterior cingulate.
If you put adults with ADHD in the scanner, the same region is blank, does not activate. Instead they activate the insula. So the adult with ADHD can do this task, but it's recruiting areas of the brain that are not particularly designed to do the task. Therefore, they are going to do the task more slowly and less efficiently.

We have emerging data that you can correct that with treatment. So when you prescribe treatments like stimulants, methylphenidate, that normalizes. Distal imaging data that I just showed you has to be seen as interesting, linking the disease or the condition, the syndrome, with the brain, but not useful for diagnostic purposes because we are not yet like we are in chest X-rays, that it's always the same. These are group data. There's very large inter-patient variability.

Another very important component of ADHD is that ADHD is a genetic illness. How do we know it's a genetic illness? The first signal comes from family studies. Familiality, of course, is not evidence for genetics, but if there is no familiality, there is very little impetus to pursue a genetic hypothesis.

Twin studies are very important in pursuing a genetic hypothesis because twins come in two varieties, monozygotic and dizygotic, and in genetic illnesses we expect that the concordance will be higher in dizygotic twins.

Also, twin studies are important because they allow us to compute coefficients of variability that tells us how much of the variance of the disease can be accounted for by genes.

Adoption studies, if you find a genetic illness, you expect biological relatives to be more affected than adopting relative.

And finally, you look for genes. So as a final product, this is a polygenic disease. So looking for genes is not a minor undertaking, as you know.

This condition has been documented for three decades to be highly familiar. There is a five to seven-fold increased risk in relatives of children with ADHD, irrespective of what criteria we use. This is my study. I did probably the most on documenting familiality. This is DSM-III. We documented with DSM-IIIR. We documented with DSM-IV. That is very familiar. We documented in Caucasian samples, in African American samples, in boys and in girls. Clearly, highly familial.

But even in the '70s, before my time, Dr. Kant with Morrison and Stewart documented the same. So if you started with the child, it is much more prevalent in relatives, first degree relatives of children with ADHD than in relatives of controls.

Coefficients of variability, briefly, they are based on twin studies. There's first a lot of twin studies. These twin studies are remarkably heterogeneous. They use questionnaires, teacher report, parent report. It does not matter. I'll show you the results in a second.

The coefficients of variability range from zero percent of the volumes accounted for by genes to one, 100 percent of the variance accounted for by genes. So look how consistent these studies are. The average coefficient of variability of ADHD is close to 80 percent. Comparison of high to highly inheritable trait, about 90 percent. Schizophrenia, bipolar illness, about 80 percent. In the genome issue of Science, in the part that was written on psychiatry, they had three conditions likely to be genetic: schizophrenia, bipolar, and of course, ADHD was the third one.

Panic disorder and major depression are genetic illness, but not as genetic as bipolar and schizophrenia; about 50 percent genetics. Breast cancer is about 30 percent or so.

So this is a very genetic condition, 80 percent chances to be genetic.

And the first genes that we have looked at in ADHD were candidate genes that had to do with polymorphism on the dopaminergic system, a polymorphism on the dopamine transporter gene, and a polymorphism in the dopamine receptor default genes.

The reason that we focused first on dopamine genes is because the drugs that are effective in ADHD are highly dopaminergic like the stimulants.

So ADHD is conceptualized as a hypodopaminergic disease. So you can get to be hypodopaminergic by not having an adequate production. This is presynaptic/post synaptic. You can have hypodopaminergic situation if the presynoptic vesicles do not release dopamine. You can have a hypodopaminergic state if the transporters take too much dopamine back to the dopamine presynaptic neuron or if you have receptors that couple with dopamine, but do not transmit the signal.

So what I'm going to show you in a second are the data. Consistent data are emerging, and perhaps as consistent or more consistent as other major psychiatric illnesses linking polymorphism in the dopamine transporter gene. The polymorphism that has been identified in ADHD over expresses dopamine transporter in animal studies. So if you have too many dopamine transporters, there's a lot of dopamine going back to the presynaptic neuron.

The genes that have been associated with ADHD are some receptor genes, dopamine receptor IV and V that are localized in the prefrontal cortex and are this polymorphism produced, some kind of a defective receptor.

I would like to remind you that the stimulus in general, and methylphenidate, in particular, block the dopamine transporter. So if you block the dopamine transporter, you can compensate for deficiencies over expressed transporter or defective genes.

So the odds ratios on several genes, I don't want to bother you, but this includes the dopamine transporter gene. There is a gene that is called SNAP25 that is involved in the encapsulation of dopamine. So if this gene produces a difficulty in releasing dopamine, you will have a hypodopaminergic ZDBH. This is the .1 or .10 polymorphism in dopamine transporter gene. There are receptor genes D4 and D5. One particular one, these are the alterations today at close to two with this gene. This polymorphism here is called a seven repeat allele, and has been identified in the personality trait that is called sensation seeker.

So these are vulnerability genes, not disease genes. Having those genes increases the odds of having the disease. So if you're going back to the DRD4, again, localized dopamine receptor genes, heavily localized in the prefrontal cortex, anterior cingulate, if these genes produce faulty receptors, you may have inadequate risk of dopamine, inadequate transporter, but signal is not, the transmitter is not propagated.

If the transporter is overactive, as I said, too much dopamine goes out. Not enough dopamine remains at the synaptic cleft to activate the receptors, and if you prescribe treatment for that, you're correct.

Briefly, another known risk factor that we have identified that has been confirmed by many other groups is maternal smoking during pregnancy. This is a significant risk factor for ADHD even after controlling for genetics, social class and IQ in both parents. We still have a significant independent effect of maternal smoking in contrast to genes. Maternal smoking is a preventable problem.

ADHD is heavily co-morbid with a wide range of other psychiatric disorders. That's the reason that I selected this one from ADHD. You see a wide range of problems, oppositional defiance disorder, enuresis. Measure a patient's anxiety disorders, conduct disorders, and mood disorders, bipolar disorders. Okay. It's a very serious, morbid illness that can profoundly impact the life of the children.

One of the co-morbidities that emerges in adolescents and adult years is addiction, and it's a major concern. It was the most feared complications of ADHD. In the untreated state, we estimate that about half of the people with ADHD will have significant problems with alcohol abuse or dependence or drug abuse or dependence, twice as much as the population.

Another issue that has been controversial in the treatment of ADHD is that there is a similarity of mechanism of action between cocaine and methylphenidate. Both block the dopamine transporter and improve the signal. Okay? They both act here in a transporter.

The work done by Dr. Nora Volkow, now the director of NIDA, attempted to clarify that the mechanism of action is not the entire story. If you inject IV, this is work done with SPECT. If you inject IV cocaine, you have a very rapid uptake into the brain and a very rapid decoupling. It is this very rapid ascension to the brain that you can attain with IV cocaine, similarly with IV methylphenidate. This is what produces the high. Okay?

Remember that we administer medications orally. If you give oral methylphenidate, there is a slow uptake into the brain and no euphorism effects. So that's the reason that many of the children or individuals that use inappropriately our medicines, insufflate them, snort them, because that's the way that you get the high. The addict is not looking for oral administration. The new generation of slow acting compounds, are in some ways protective because you cannot extract easily the methylphenidate. You can crush the pill and snort it, but you cannot take the methylphenidate out... and you cannot snort the pebbles of those that have microbead technology.

We published perhaps the first evidence against the argument that treating children with drugs like stimulants will enhance the risk for drug abuse. In the paper that we published, we first presented it in the NIH consensus conference and then in Pediatrics in 1999, we were able to show that children who were medicated in childhood and when we looked at substance abuse, abuse or dependence on alcohol or drugs in adolescents, had an indistinguishable risk, whereas those that were unmedicated had a threefold increased risk.

Since then, a colleague of mine, Dr. Williams, published a meta-analysis that incorporated four other studies showing the same, that the treatment of a child with ADHD protects the child against emergence of abuse or dependency in those areas.

ADHD is associated with car accidents and car accidents are a leading cause of mortality in the young. So this is not only a problem of school. People with ADHD frequently are unemployed or under employed when there are 15 hour statistics in the community and a thousand subjects, 500 with ADHD, 500 without. Fifty percent were unemployed. Okay? Adults with ADHD frequently have multiple jobs and about 50 percent had to leave a job directly as a consequence of ADHD.

And as I said before, the estimated cost to society of all of these job related problems is about 70 to $100 billion.

ADHD is a highly impairing condition in terms of parental stress, family conflict, accidents and injuries, substance abuse, legal difficulties, problems with relationships, marital difficulties, school failure and heavy dose of psychiatric co-morbidity, including addictions.

So if you look at the treatments that we have, I would like to briefly say to you that medications are considered as the fundamental part of the treatment. This study that was funded by the National Institute of Mental Health and the Department of Education is the largest effort to show that behavioral treatment is more effective or equally effective as medication.

This study randomized about 600 children in five sites in the country to medication, stimulants in good doses across the day. A behavioral treatment, very comprehensive, very expensive, both of them, medication and behavior management and treatment as usual.

What this study found is that medication was as effective as medication plus a very sophisticated treatment, and I would like to point out that this is considered the ideal treatment, the massive behavioral treatment and very aggressive medication, up to 60 percent, not more, not 100 percent. So herein we have a very common illness leaving 40 percent of our subjects not responding to our best treatments.

Behavioral treatment was less effective, was less effective as management in the community most with medication. Most of the data on treatment that we have are on children six to 12 years old, but data from preschoolers, adolescents and adults document that the treatments work across the life cycle.

And from the treatments that we have..., stimulants in particular, treat these, the core symptoms, but there was a variety of other situations like oppositionalism, like aggressivity, social interactions, academic deficiency, and academic accuracy, areas that if not attended to can produce serious morbidity in the child.

And the medicines that we have have what's called moderate to large effect sizes. So they're not little treatments. So we know, for example, that approved medications like the stimulants, long acting and short acting, have very large effect sizes, close to one. Although the non-stimulants have moderate effect sizes, they're potent treatments to treat people with ADHD.

So we are dealing with a very serious neurobehavioral disorder largely beleaguered... in our society, [with a] complex etiology, neurobiological basis, strong genetic components, affects millions of people all over the world, boys and girls, men and women, highly persistent, at least 50 percent, and has a very large impact in multiple areas of function.

Thank you very much.

(Applause.)

CHAIRMAN PELLEGRINO: Thank you very much, Dr. Biederman, for a very, very clear and orderly and stimulating discussion.

We'll turn now to questions from the Council. I'd like to just put forward a question I do not wish you'll answer right now because you may want to think about it more. But what are some of the ethical issues that derive from these data which you present to us and what recommendations could a body like this make to deal with some of those issues?

But I would hold those for the time being and turn to the members of the Council. I saw Dr. Dresser's hand first, and Dan.

DR. DRESSER: Thank you.

That was a really good overview, and we've heard a lot about issues with overtreatment with drugs in this population, and I think you've emphasized the problems with under treatment. Do you see any problems with overtreatment yourself?

And second, given limited resources, what approach do you think would be best to minimize overtreatment and minimize under treatment?

DR. BIEDERMAN: I don't think that there is evidence for overtreatment. It's only in the hands and minds and eyes and ears of the people that want to see that. The evidence is in the opposite direction.

The majority of children with ADHD are not treated. Okay? So the statistics that are frequently used is if you see an increase in treatment, you can conclude there is overtreatment. But the rate of treatment does not catch up with the rate of the disease. So I would say that's under treatment.

Most parents are on the fence, but most of my struggles every day when I go to the office is to encourage the families to tolerate adverse effects. No, I don't have anybody that is looking forward for the next prescription.

The data that we have parenthetically on continuation of treatment is very dismal. It's worse than any other therapeutic entity. Over a bit of a year 80 percent of patients prescribed medicine no longer will take it. People with ADHD do not follow through. So they initiate treatment. Maybe every often the child has a mother or father with ADHD who will initiate treatment and will get tired. It's too inconvenient, et cetera, et cetera.

So the issue of therapeutics, the burden is in the other direction, that we are not treating a condition that is treatable. So the tragedy here is that this is a very morbid condition that will produce a wide range of impairments, functional life as we know from the adult data. What you see in the adults, this is the untreated state.

I do not have time to tell you that the rate, everything is disturbed, the rate of divorce and separation, the number of automobile accidents, the use of tobacco, alcohol, drugs, bad health habits. There's not a single area from loving to friendship to working to studying that they're not worse. Okay? Economically worse off.

So this gives you a flavor of what the children of today will reach tomorrow and the cost to society. So I would argue that we have a very difficult task ahead of us with who is going to prescribe. There is under treatment, under monitoring, under prescribing, and I see that as an ethical problem in my mind where I sit, okay, because I know from our follow-up studies what awaits my patients tomorrow, and it's not going to be a kind, soft landing at the end of the road.

DR. DRESSER: I was just wondering. Do you have any recommendations for addressing the situation? I mean obviously --

DR. BIEDERMAN: Yeah.

DR. DRESSER: -- it's problematic if people are refusing to continue treatment. How do you feel about that?

DR. BIEDERMAN: I don't. Unfortunately, you have a difficult task. The problem is extraordinarily complicated. The bad media lets parents be on the offense for years. So parents are heavily tortured when they come to the doctor's after hearing the same music year after year from the teachers. The child is clearly at risk. He's beginning to do serious academic work and obviously has massive holes in his or her knowledge, and at that point, seven, eight years later when the child has been compromised, self-esteem is in the basement, the child is not doing well, the parents come to the doctor's office, and at that point we start the process of treatment that may not be necessarily simple. The child may not respond to Drug A. It may take months or at that point remember we have a child in school. This is a year that's in progress, whatever we do. So the child may miss another year of education after we find our way around it. The media approach to this problem is consistently negative.

So I do not know what to do. There is a lot of charlatanism in this profession. In a free society, anybody, everybody is entitled to say whatever they want, but there is no way to distinguish opinions, prejudices from facts. So I try to present at least what we know, and I tortured you with the charts for a reason because if I were just to extemporaneously tell you all of these things, it's not an opinion. I mean, it's as good as somebody that just had that thought yesterday and will tell you that this is what they believe, and if there is enough pathos in the voice, you will believe it.

There is another complication that what I do is very boring in the sense of there's not a track to capture the attention of the talk shows and things like that. When people write anything in a book that could be totally unsubstantiated, the likelihood of being an Oprah on a "Today Show" is very high, and this is what the public will listen. They will not know that the brain is affected. My genetic word is a little too technical. What does it really mean, et cetera, et cetera?

So those prejudices are the ones that are largely propagated. So I do not know how to combat them. I wish I had the solution, how to combat prejudices, misinformation, dissemination of the wrong information. I have no idea.

The Web offers incredible possibilities only if you know where to look. So you can be bombarded with nonsense and how will you know what is nonsense from facts?

In the NIH conference, I don't remember the name of the person that sat at the conference. He said to all of us, "Remember that anecdotes are not the plural of datum." Okay?

CHAIRMAN PELLEGRINO: Dr. Carson.

DR. CARSON: Yes, I have a number of questions about your presentation.

In the situations where you say the brain volumes were decreased in children who were affected with this disease, were those studies controlled for body weight and body size?

DR. BIEDERMAN: Yes.

DR. CARSON: Is it possible that early environmental factors can affect the development of the brain? In other words, is there something else going on that may cause certain areas of the brain to be smaller rather than that being the primary problem?

And in children of parents with ADHD, you indicated that they have a significant, fivefold increase incidence of developing the problem themselves. Has anyone looked at a situation in which those children were raised in an environment that was "normal"? Did they still have that high incidence?

And -- well, I'll let you answer those ones first.

DR. BIEDERMAN: So you're counting on my working memory.

The data on the brain study controlled for social class. So, yes, I think that you need to make the argument. You need to take a sample of children that came from very unprivileged environment and look at their brains. Usually not the cognitive area are selectively affected. Many of the children, they work the closest, and they can tell you in extreme cases where people that were traumatized different areas of the brain light up in those children. Usually they had composed, say, with high levels of cortisone.

What I just showed you, in our work these were adults that were not traumatized. These are adults that had high IQ, very well matched with controls. All of these studies are well controlled.

Our adults in the selective findings on the cortex of attention, these adults did not have any particular history of having been traumatized from coming from unprivileged backgrounds, and so on and so forth.

Your second question has to do with -- what was the second part?

DR. CARSON: In children who grow up in normal environments who have had children who are parents.

DR. BIEDERMAN: Yes. I think that the rate of ADHD is not due to social class. We included in our studies and other class status. Well, all social class set, and I'm not sure what you call normal because --

DR. CARSON: That's why I said, "Quote, normal."

DR. BIEDERMAN: Yes. We corrected by social class using Holligshead-
Redlich social class (SES) stratification. The rate of ADHD was high in all
social class strata. It was not driven by socioeconomic differences in samples.

DR. CARSON: Okay, and then lastly, is the incidence of ADHD increasing or was it simply that two or three decades ago people didn't recognize it?

DR. BIEDERMAN: Correct. I think that this is one of the most commonly asked questions. The answer in my mind is no. This is a similar issue. You may face or not with the autism-PDD dilemma. I think that the main reason that children were not diagnosed is because if the diagnosis leads to a particular treatment that you do not want to deploy, the best way to avoid the treatment is to avoid the diagnosis. So you don't have anything. Boys are boys. This is what has happened a lot in Europe.

Today with the availability of non-stimulant treatments and so on and so forth, people are more willing to make the diagnosis. Also, diagnosis is sensitive to how you define it. So if you use a broad umbrella, you have more people. If you demand very strict criteria, you have small numbers.

Let me give you an example. If you define alcoholism only by those people that need to go to a detox center, you have very different numbers than if you define it just by misusing or having total dependence on alcohol. So our definition leads to the prevalence of the condition, but there is no epidemic of ADHD. We're just more clinicians willing to make the diagnosis, more awareness that this is a brain disorder, not just bad manners, more aware that the treatments that we have despite controversy are safe and effective.

CHAIRMAN PELLEGRINO: Dr. Meilaender.

PROF. MEILAENDER: Yes, I feel as if I ought to apologize at the start because I think I'm about to ask the kind of question that drives you crazy. So --

DR. BIEDERMAN: As long as torture is not involved, it's fine.

PROF. MEILAENDER: No, no, no. Well, there may be some mental torture, but --

(Laughter.)

PROF. MEILAENDER: Somebody has to speak on behalf of all those people who were never interested in school, and I certainly wasn't. I don't know how to frame the question exactly, but I mean, I don't doubt that there are some people who are genuinely ill. Okay? But what I'm struck by is the fact that, on the one hand, the narrowing imaging techniques are not useful for diagnosis, you said, at least not now and, therefore, other methods sort of in the clinical interaction you have to make judgments about diagnosis, and then you say in describing those interactions that, you know, you have to sort of elicit the symptoms. Symptoms occur in circumstances where they're not interested, and it turns out that some of these studies depend on teachers' reports and things like that.

And you know, there may be a lot of misinformation and charlatans out there, and I may be one of them. I don't know, but there's an awful lot that goes on in school that you shouldn't be interested in. You know, I'd tell my children they had to more or less behave, but I wouldn't for a moment pretend they should be interested in it. It's not interesting.

And I'd worry if, even thinking back to my own teachers, if I were to be judged primarily on their reports. So you know, I think I understand your appeal to expertise, and I understand your worry about misinformation and so forth, and I'm not trying to exacerbate those problems for you, but it seems to me that has to be addressed somehow.

If this is the way diagnosis takes place and inattentiveness when confronted with things that are inherently boring is part of the diagnosis, I mean, then we do have to worry a little bit. Somehow you have to address that, it seems to me.

Now, I may just be off base, and that's a simple minded question, but could you speak to it?

DR. BIEDERMAN: Yes, sure. I certainly can. I think that you're right that you are kind of representing the kind of misconceptions and prejudices of our --

(Laughter.)

DR. BIEDERMAN: I will give you that. I think that you need to distinguish. I have no doubts that there are boring things in school. I have no doubts that there are boring schools in our everyday lives also.

So if you are a physician and when you practice you cannot attend to the latest regulations of Medicaid Part D or you cannot go to the very interesting meeting about how HIPAA should be discussed with your patients and you sleep and daydream and you have no idea what are you doing, you can be a very gifted physician when you examine your patient and have made a diagnosis, but you have a lot of troubles in real life deployment.

So what I'm talking about is not the teachers expecting the children to be lobotomized and quiet in the classroom. Remember one more time that there is a seven-year gap that occurs and the demands for diagnosis are not just a little bit of not liking the math teachers well. Those are children that have a part of the symptoms. The symptoms are very well operationalized, and I will not banalize.

You have to have a lot of symptoms. That distinguishes you or the affected person from the nonaffected person. The symptoms have to be associated with impairment. They have to be associated with disability. So it's not just the presence of the symptoms that define the diagnosis, but the associated impairment. The child is not able to make academic progress.

And I would like to remind you one more time that academic progress is a fundamental passport for a good life. Okay? Under any circumstance. So the data that the child that has the ability to complete school and go to college, the child with ADHD may not be able to do just that. They will get four scores on their standardized test. They may have four scores in their grades. The doors rapidly close on you, okay, and that's it.

So I think that the idea that this is just a little problem that you don't like a particular class and not everything is interesting at school, I'm not talking about that.

CHAIRMAN PELLEGRINO: Dr. Foster.

DR. FOSTER: I just want to make a comment. In non-psychiatric medicine, we have many powerful drugs, and what's striking about the data that you showed is the great percentage changes between treatment and nontreatment, whereas in these very powerful drugs that we use, the conclusions if you look at hundreds of thousands of patients, for example, we have a very good study that says that estrogen protects against heart disease and then another that says, well, it doesn't, or we look at cancer or chemotherapy drugs and so forth. We're talking about usually a few percentage of differences. You know, you'll live two months longer if you use this new, powerful drug.

So what I'm having a little bit of trouble with -- I very much appreciate your showing the data, much of which I did not know -- was the very giant changes in drugs that nonpsychiatric medicine would not necessarily consider to be in the same order of power as the drugs that you're going to use to treat hypertension with, and yet with terrific drugs in terms of hypertension, the differences -- we still get people to take them and so forth -- are small, and so it's one of the most -- I read a lot, a lot in Science and so forth and have edited journals -- but I think the thing that was most astonishing, that there was not a single negative view about, you know, the treatment and these things were so large, and that seems to me to be very unusual for just science itself, and scientific medicine, and I just wondered. I don't doubt the data. I don't mean that what you are saying is not true, but one has to have sort of a -- I have a little bit of suspicion when everything that I deal with is so small changes that these are universal and nobody except the press, you know, seems to have a negative view about it.

That's the only comment I want to make. I don't know that you can answer that, and I don't know of any --

DR. BIEDERMAN: Well, I think that the meta-analytic data of enormous amount of studies that have been done and double blind conditions are extraordinary... just as you said, that this is a condition that responds very well to treatment. Those are the facts.

The effect size is... what is analyzed there. The critical mind just hit another one. Again, the issue is how much stimulant and non-stimulant is produced. But even the non-stimulants that have an effect size of close to .7, those are very good effect sizes for general medical standard. Those are based on double blind randomized studies. Some are very large. So we have probably now somewhere in the order of magnitude of 15,000 people if you put the meta analytic efforts all together.

So it's very robust evidence supporting the effectiveness of these treatments. I'm not saying that these are ideal treatments. They have side effects and so on and so forth, but so do any other medical interventions that I know of.

And so the expectation that taking children with psychotropics should be safer than crossing the street may be high order expectation.

CHAIRMAN PELLEGRINO: Dr. Hurlbut.

PROF. HURLBUT: Yesterday one of our speakers talked about the fast pace of input that children experience, telephone, rapid sequence events, and video games. This isn't my real question, but do you think that has any impact on this disease?

DR. BIEDERMAN: No. No, I don't.

PROF. HURLBUT: Okay. What I really want to ask you is about the placebo effect. Is that what you said at the beginning of your talk? I think it was related to --

DR. BIEDERMAN: In depression. ADHD has low placebo effect. The depression studies did not separate from placebo because it was a gigantic placebo effect.

PROF. HURLBUT: Yeah, but not in ADHD.

DR. BIEDERMAN: Not in ADHD effects. The placebo effects are in the order of magnitude of 30 percent. In the depression study they were more than 60 percent.

PROF. HURLBUT: Okay. Since the placebo effect is real in any case, I just wanted to know have there been any studies on the genetics of the placebo effect itself.

DR. BIEDERMAN: No, but we are actually -- most of the neuroimaging, fascinating neuroimaging studies on Parkinson's disease and in pain with the placebo, it's really telling that it's a real effect, that the same changes in the Science paper and Parkinson's disease, the same changes were documented on people that improved on placebo as they improved on the dopaminergic, anti-Parkinsonian agent.

We collect DNA in all our studies. So we are poised. The effort, of course, is to identify genes that moderate efficacy, but we can equally examine genes that enhance the likelihood of response to placebo.

PROF. HURLBUT: But it isn't been done?

DR. BIEDERMAN: It has not been done.

PROF. HURLBUT: Is it enduring as an effect?

DR. BIEDERMAN: The placebo? No.

PROF. HURLBUT: No. It's fast.

DR. BIEDERMAN: Yeah. Remember the studies that we conduct, we can now conduct studies for five years.

PROF. HURLBUT: Yeah.

DR. BIEDERMAN: So the studies are usually a few weeks long. For example, in the study that we did that carried the treatment for six months blindly, there was a very precipitous decline in the placebo patients that were months ensuing the acute trial.

PROF. HURLBUT: Finally I wanted to ask you. You said school is the passport for a good life, and my immediate response was as successful life within a social context.

DR. BIEDERMAN: Yes.

PROF. HURLBUT: But not necessarily a good life.

DR. BIEDERMAN: Pardon my use of an incorrect or confusing word. I'm not making a moral judgment. I'm not in any capacity trying to define what good life is.

PROF. HURLBUT: Right.

DR. BIEDERMAN: Okay? I only meant that it is a direct relationship between the job that you can get and your education. This is all what I meant, not that if you are making millions that you're happier than if you are not making millions. That's not what I'm talking about.

PROF. HURLBUT: Well, I didn't mean to put you under any criticism on that. I just wanted to play on that to ask you. It seems to me that in some context we're not emphasizing the right core values in our civilization. We had speakers yesterday that said this essentially, that we're putting children under a lot of pressure. Performance is so much talk in our society about the economic value of various things, and I think, I mean, I don't know. You hear different people say different things about this, but it does seem true to me that there is a decreased emphasis on what people used to call character qualities or spiritual qualities or fundamental values in children.

And when you look at what children want by self-report, it isn't necessarily noble or virtuous. It usually has to do with social standing, and I wonder what effect you think that might be having. I mean, after all, finally what the brain relates to the mind and the mind relates to images and values and goals in life, ideals, aspirations, can you say a little something about that?

DR. BIEDERMAN: Yes, absolutely. I never intended to say that. I was not talking about economical impact of what will be your paycheck at the end of the day. Let me give you an example.

Let's say that somebody has a true passion to take care of animals, to be a veterinarian. Okay? Veterinarians are not making -- I'm just using this as an example -- so that's what you would like to pursue. You'd like to become a nurse or a teacher. Okay? That also are not millionaires at the end of the day.

In order for you to become a teacher, you have to pursue a path of some academic competence. If you cannot graduate from high school, you're never going to pursue a teaching career, a nursing career, a veterinarian career. I'm not talking about being a master of the universe in the Bonfire of the Vanities lingo. I'm actually very saddened when I routinely ask children that come to care, "So what would you like to do or what would you like to be?"

So the model answer is to be a millionaire. So I say, "If being a millionaire if a profession, like in a bagel store, you take a number. In college you take Millionaire 101 and Millionaire 102.

(Laughter.)

DR. BIEDERMAN: So it's really amazing, but I agree with you that I'm a physician and not a moralist, and I don't pretend to have solutions for society's ills. So the kind of desires, the examples of millionaires in our sports arena and now with the Super Bowl this weekend, that somebody that knows how to throw a ball is discussing 50 or $100 million. That's not available to most human beings, but besides that, I think what I alluded to is when you have a dream that you'd like to pursue, okay, there are very little things in our society that you could do from being a social activist to being a religious leader that does not require some academic foundation.

If you have the vocation to be a religious leader and you cannot learn anything in school or you are thrown out of school or you became a drug addict, at some point in your life those dreams are shattered. Okay?

So I'm not talking about or I'm not measuring success by the amount of money that you bring at the end of the day; that if you don't make seven figure salaries, then you're a loser.

But none of your dreams, even if you have other vocations, may be accomplishable if you in your past, you have serious complications as the one that these conditions can bring in the untreated state.

PROF. HURLBUT: You know, this is a two-way arrow though. That's my point.

DR. BIEDERMAN: A two-way?

PROF. HURLBUT: I mean, you know, you see children, and it's like with Parkinson's disease and attention tremor. The closer you get to the goal, the more your hand shakes, you know?

When a child is put under pressure, if their whole construction of what makes a meaningful life relates to doing well on a test, that test is going to put them under anxiety in a way it wouldn't if it was just a stepping stone to, you know, one of many things in life.

My point is: is the reality of ADHD or other psychiatric disorders in childhood exasperated by the value system that children are growing up in?

DR. BIEDERMAN: I really don't think so. I'd like to distinguish what you do. The test is a final product of your knowledge. So if you're not doing well in the test, it does not matter. Of course, if you have a test you're going to be anxious, you should be anxious.

The tests measure what you know. Okay? So incremental learning in mathematics, if you did not learn Chapter 3, you will not be able to understand Chapter 4 or 7 or 8 or whatever comes after. So I think that the issue that you need to distinguish and what I'm trying to say is that a people that struggle, it's not that they're anxious about the next test. It's that they're not acquiring knowledge. They have holes in their information systems that you can drive a truck through. So they really are ignorant.

They grab it from high school. They may not have the information that they need to do anything. So I think that they are not talking about somebody who is aspiring to get A's in every class. Okay? But you still need to be competent in whatever your education is to be able to move to the next step and have some basic knowledge to be able to confront the multiple demands if you're illiterate or you have no ability to do the most basic calculations. You cannot work as a cashier in a local supermarket here.

And so those are things that could be profoundly interfered, not just core values. I'm not talking about those issues, and I am fully supportive of the fact that we need to do a much better job in promulgating dose than just the media will magnify the amount of income that an actor or singer makes and this is glorified to a sports figure. Those are the role models of our young, not somebody that is helping the world in Africa and dealing with poverty to the right and to the left.

DR. SCHAUB: Could I have just a very quick follow-up to Bill's question?

CHAIRMAN PELLEGRINO: Okay.

DR. SCHAUB: Just one sentence.

CHAIRMAN PELLEGRINO: All right.

DR. SCHAUB: Would ADHD have had an effect on life performance two centuries ago?

DR. BIEDERMAN: Yeah, absolutely. Some people talk about the hunters-gatherers, the idea that the hunters-gatherers' inattention and distractibility would be good for them. I think it's a true mistake to think that in the primitive society of hunters-gatherers, the person with ADHD would be carried by the group, but would not be an asset to the group. Okay?

This is not a condition that is associated with decreased fertility. So the genes for this disease are more extensively promulgated, if you want, because people with ADHD tend to be more disinhibited in that way than schizophrenics, for example, that will have fertility issues and will not date, but the people with ADHD have no problems dating and impregnating or being impregnated.

So I don't think that it has ever been adaptive. Why some conditions that are not adaptive are maintained in the genetic pool, we have a steady rate of schizophrenia from Biblical times. It's not an adaptive trait, or autism and so on, or mental retardation, et cetera, et cetera.

So I don't think that at any point in evolution even before the Nintendo and before our high tech society, being inattentive is a disability. I always try to use as an example when I was a few years ago in a photograph safari in Africa. I had an opportunity to follow a cheetah hunting. The cheetah is looking at the pray moving an inch an hour. The inattentive cheetah does not eat. Okay?

(Laughter.)

DR. BIEDERMAN: I will tell you that.

CHAIRMAN PELLEGRINO: I have requests from three speakers, and a response. I'd like to ask

Dr. Biederman if you'd be good enough to hold off your response to the three and summarize it and caution you that there is less than ten minutes left, and I would like to stay to the time requirement if at all possible.

Thank you.

Our first request is from Dr. McHugh.

DR. MCHUGH: Dr. Biederman, this was an impressive presentation, and I'm sure there's gold in here.

Let me though begin by saying that the suspicions that you're receiving from this group by other groups come not in relationship simply to your data, but through the history of Americans' relationships to psychiatry over the last 50 or so years when the characteristic of psychiatry has been to pathologize people and to increase the numbers out of proportion to the number of ill people that there are out there.

It began with the Manhattan study, and I have to go over these things with you, but the Manhattan study and several others right up till now so that these numbers begin to make anyone who has any skepticism begin to wonder about what is being described.

The phenotype that you're describing here and persuading us to use this powerful general stimulant that affects everybody if they take it is as you say, something that you'd call a final common pathway from a number of different things.

There's another way of describing a final common pathway of this sort, and that's called a waste basket, and yesterday we heard from the Eides that the patients that are sent to them from all over the country for assessment with diagnoses like ADHD or artistic spectrum disorder, that with those diagnoses they don't know what they're going to see, and they see all kinds of different children with very different disorders more specifically related to aspects of their social situation, aspects of their neuropsychological dysfunctions of particular sorts, each one of which can be differentiated from one another, all of which though are affected by the stimulants.

And when you show us the brain material that you have, it also is very general. It is not at all -- you can tie it together, but it's scattered and not diagnostic.

So I think you're in a tough spot really more than anything else, that I think this term ADHD, along with several other terms that have become current in psychiatry, in particular in child psychiatry, are just that. They need to be broken down much more specifically and have to be differentiated in relationship to more specific treatments depending upon the specific pathology there.

What would you say to that? That really we are still groping. What I believe -- I spoke about it yesterday -- is a very large amount of science in psychiatry is being done in relationship to checklist assessments; that they do not rest like medical diagnoses and developments do on full psychiatric assessments, external informants, developmental histories, psychological testings, all combined together to determine what the case really is both before and after.

So with a generic diagnosis and a generic treatment, a treatment that you admit has problems of side effects to it, we're still skeptical. That's all. We certainly want to do the best we can by children, but at the same time, we don't want to presume that everybody who is skeptical about it has some kind of other ax to grind other than the experience with psychiatry over the last 50 years.

CHAIRMAN PELLEGRINO: Dr. Rowley.

DR. ROWLEY: Well, my question is a follow-on to reports and work of the Council last year and the year before on Beyond Therapy, and there was a whole segment in that admitting that for properly diagnosed patients with ADHD, that various stimulants seem to be effective.

But that the same stimulants, ritalin, for example, is being used and the council's concern was misused in situations where children don't have that particular diagnosis or disorder, but often by parents who would like to have the child be particularly up for exams or other sorts of things.

So I guess my question is really: in your experience or as you view the scene, how much of these stimulants are being misused, if you will, for things other than what in your view would be their proper use?

CHAIRMAN PELLEGRINO: And the last question from Dr. Carson.

DR. CARSON: You indicated that children with ADHD can have selective manifestations, that is, you know, there are some times when they appear to be affected and other times when they are not. I'm very intimately familiar with a young man who gets into a lot of trouble in school, doesn't seem to pay much attention, but is a whiz at anything he's interested in, games and things of that nature.

Is that person likely to be suffering from the disease or is he just bored at school?

CHAIRMAN PELLEGRINO: Dr. Biederman.

DR. BIEDERMAN: Let me see. Just for working memory issues, I will start with your question and then we'll go backwards.

All of these things are empirical questions. We did an analysis in our sample in children that had IQs about 120 with and without ADHD to address the boredom hypothesis. Okay? Unfortunately they had the same level of familiality, the same level of co-morbidity, the same level of neuropsychological deficits that are the fingerprints of ADHD compared with children with the same IQ that did not have ADHD.

As I said to you before, you have to have many more IQ points to do the same if you have ADHD. Remember that life, as I said before, has a wide range of non-exciting things in front of us every day. So if you can only attend to the things that you like, you will be seriously handicapped in your job. It is no different for a child. For child, school is their job.

So the fact that you can build engines very well because that's your hobby and you cannot do anything else and you're a wizard with your engines does not mean that you can forego all the other things that you may be required to know to be an informed citizen of our society, and a very complicated society that you're going to navigate.

DR. CARSON: Just to follow up, that child was me.

(Laughter.)

DR. BIEDERMAN: But remember that you should be very careful. There are people that are survivors, people that go through greata trials and come out reasonably well. Okay? I certainly had my own history of misfortunes, but you cannot use that to generalize.

When I look at these things, I look from the broader panorama, not the few that will be able to navigate the waters very well and come out, but the majority may not be as successful as you are. Okay?

But in any event, the other question about misuse, as I said before, under medication and misusage, there is very little evidence that that is true. Okay? In medicine if a pediatrician prescribes an antibiotic to a child that has a viral infection because of parental pressure or something like that, well, that's not a good, necessarily medical disposition, but we should be very careful in my opinion not to throw the baby with the bath water.

And bad medicine in psychiatry or in outside psychiatry is bad medicine. So somebody that does not have a fever will not benefit from an antipyretic.

Dr. McHugh was saying about nonspecific treatments. Well, steroids are very nonspecific. They still help a wide range of medical conditions, and without steroid treatments, people will die.

So we have to be careful in equating absence of specificity with the fact that this is a waste basket kind of condition. You know, many of the treatments that we do in medicines are not curative. If we give antihypertensive to people that have hypertension secondary to a wide range of medical problems, they are not ecological treatments, but can save lives, can allow people to make the progress that they need to have to maintain a decent existence.

So I would like to caution you that this is not just a waste basket. The fact that this is heterogeneous, again, you can conclude that it's a waste basket. All medical conditions are heterogeneous. There are syndromes, genetic syndromes, that are produced by different genes that produce a very similar phenotype.

So it does not mean that it's a waste basket. If you get the flu, you cannot look at a patient and way that you know which pathogen, which type of virus hits you because they all look physically the same.

So the fact that it's a conglomerate of diseases with similar phenotype should not necessarily lead to banalization. The patients that we assess over the last 20 years, and we are now doing our 15 years follow-up, were very comprehensively assessed. These children had not only questionnaires. They have questionnaires with the parents. Each questionnaire, each structured interview takes two or three hours to administer.

We have similar information from the parents. We have neuropsychological testing. We have blood for genes. So there is a convergence here from neuroimaging, two cores, neurological testing, serious co-morbid psychiatric conditions that these people have.

So I think it's not just that you did a questionnaire and they had something that we call disease.

I would also like to stress that no clinician treats people. I don't recruit patients in the streets. "Come and see me because I have this wonderful stimulants to give you."

People wait a year to see me, and as I told you before, I never close my clinic. I always see patients, but you have to wait.

The idea is that the treatment that you can -- people are tortured with the notion that they will have -- the childhood medications. They're not looking forward to what was described, that parents want to advance the children's interest. It's not necessarily something that I contend. Most of the families that I deal with are tortured. They waited seven, eight years, and only if the child is unbelievably unfair, is not able to make the progress that the child could be expected to make, is failing school, is having difficulty socially, is having difficulty with his family, has no self-esteem.

At that point, the child can benefit from treatment. So it's not cosmetic... pharmacology.

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

We will have a very short break. Be back at 10:15 so we can stay on schedule.

Thank you very much.

(Whereupon, the foregoing matter went off the record at 10:07 a.m. and went back on the record at 10:16 a.m.)

SESSION 6: NEWBORN SCREENING FOR GENETIC DISORDERS/DISEASES

CHAIRMAN PELLEGRINO: Let's begin the session.

Members of the Council, please be seated, and speakers as well. Members of the Council, please be seated. We need to send our border collie out and nip at the heels.

This is our last session for this particular meeting, and we'll be turning to the subject of newborn screening for genetic disorders. Our first speaker will be Dr. Jeffrey Botkin, Associate Vice President for Research Integrity and Professor of Pediatrics at the University of Utah in Salt Lake City.

The speakers have promised to be clear and brief, and I hope that will be a sample of what we would expect also from the interrogators.

Thank you very much.

Dr. Botkin, if you don't mind beginning, Id' very much appreciate it.

DR. BOTKIN: All right. Thank you, Dr. Pellegrino.

It's certainly an honor to be here for the Council today. This is a smaller core set of issues, I suspect, from what you've been discussing at least over the last two days, although I'm aware that Dr. Fost was here a month or two ago and did have some information to provide you about newborn screening.

Nevertheless, my plan was to go through a number of talking points. What I'd like to do is touch on a brief description of the program, talk a little bit about what the contemporary controversies are with some specific focus on some of the ethical issues, and then end with a couple of brief points about at least where I would like to see these programs go over the next 20 or 30 years.

These are issues that I think have been or were sleeper issues for a number of years. As a practicing pediatrician in my younger days, we were aware of the programs, but they weren't particularly controversial. They were really occurring below the radar.

I think to a large extent that's no longer true, and that's true both because of some technical innovations that have changed the nature of the programs, and I think some social dynamics that have been brought to bear that have changed how people, parents look at these programs.

Certainly the largest application of genetic testing in the U.S., four million infants per year being screened with these technologies, and it is most frequently described these days as a system. So I want to emphasize that concept. I think too often it's thought of more strictly in terms of a test, but should be thought more broadly in terms of a system, because I think it's the system issues that raise a number of the difficulties.

Parent education may or may not be a component of the system. Theoretically it is, but oftentimes quite limited, and this would be education that occurs in the perinatal period, most typically after the birth of the child.

A test is done, and what I've done is put on the table here what's known as the Guthrie cards. Heel sticks are done in the infants; blood spots are provided or put on these circles and then sent to the state lab. And in fact, this is an example of a relatively simple technology, but a technology nonetheless, and it's these cards that I think were a significant invention of Dr. Guthrie to enable mass screening to be conducted in an efficient manner with babies. If you had to send two or three cc's to the lab on every baby, it wouldn't happen.

So the system involves in the blood test or the blood spot that then goes to the laboratory. The results typically go back to the primary care physician. The primary care physician, if there's a difficulty that needs to be followed up with the family, contacts the family. There is an established mechanism by which the diagnosis is confirmed. There's short-term intervention for kids who need to have interventions and then long-term interventions to maintain the treatment for the affected child.

Now, any one of these components, of course, can be limited or weak and, therefore, undermine the efficacy of the system in general, and I would say that the test itself -- well, of course, highly technical is the easy part. The tougher parts, the more expensive parts are those other system components that involve the parents, the primary care providers, and the subspecialists who are all part of the larger system that helps support these kids.

Now, one of the aspects of the program that is strongly historically based is that they're state based. It's state health departments that take responsibility for these, and I think probably one of the few large health programs that are narrowly focused within state control, and as a result there's some substantial variability from state to state, and that has become a focus of significant dialogue in recent years.

And this has to do with the tests that are performed, as well as the nature of the tests, the specific technologies that might be employed, and other program components, like who it is that follows up on the test, et cetera.

All but three of the programs are mandated [meaning the informed permission of the parents is not required to conduct screening]. Maryland, Wyoming, and the District of Columbia are the exceptions, meaning the informed permission of the parents is not required to conduct screening. And I would have to say that this, within the nursery environment, this certainly is consistent with my experience. This is just not a high priority item for care providers.

Frequently, in this day and age, babies go home less than 24 hours of age. Particularly for new parents, there's just an enormous amount of material that needs to be covered. People need to rest. People need basic education about baby care, and they want screening as simply not a high priority item, given the a priori risk for many of these infants is quite low.

So it is an issue that does not end up having a significant amount of information related to parents about the nature of these programs.

Now, all but two states permit parental refusal for religious or philosophic reasons. However, parents are not routinely informed of their option to refuse, and in those states that do have an informed consent process, like Maryland, the number of parents who actually refuse screening is literally a handful per year.

Now, residual blood spots that I won't at least in my comments stress at all is another interesting domain here. Virtually all cards will have residual blood left after the mandatory screening programs have been conducted. So states will store these for various periods of time, various lengths of time. Utah, for three months and then destroys them. Some states at this point for 21 years or indefinitely, and an interesting potential source of DNA on the population.

Somewhat unclear how long the analytes for a variety of the other tests stayed good on those cards, but the DNA appears to stay good for quite a long period of time. So if many states were to retain these resources for decades, you would essentially have a DNA sample on a large segment of the population that would be potentially quite useful for a variety of applications.

Now, I will say that these programs really have been remarkably successful. To the extent that I've been critical of some issues, I don't think there's any question that the programs in general really have been extraordinarily beneficial, and particularly for conditions like PKU and hypothyroidism. These are conditions that will cause devastation, neurologic impairment in children by the time that they are detected clinically. So a screening approach is essential to pick up these kids prior to that damage, and the treatments are relatively straightforward. Although sometimes the treatment for PKU is underestimated in terms of the burden that that can provide to the child and the family, nevertheless, these are paradigm conditions for this approach, and I think this has worked remarkably well.

Part of the question is whether other conditions mirror the characteristics of PKU and hyperthyroidism and our ability to adequately intervene and protect children, as has been the case with these conditions.

All right. So what are the contemporary issues? Wide variability from state to state without clear justification for why that is. Local political pressures, local lay pressures, local expertise, different looks at the data at the state level. There's a wide variability, and I think there has been a concerted effort in recent years to say that this is not a rational system. We ought to have more uniformity across states with the types of tests that are being offered, and perhaps with the technology that is being used for the test.

Rapid increase in the number of conditions on the screening panels, and that's the majority of my slides here to illustrate for you. These are from Brad Therell, 2000. I mostly just want to point your attention to the purple, more than eight disorders, again, 2000, largely East Coast, north East Coast that had more than eight; 2001, 2003, 2004, October 2005. My home State of Utah is now purple having implemented tandem mass this past month.

So we now have quite a few states. Thirty-six states, I believe, have more than eight disorders on their panels now, whereas in 2000 there were eight states with more than eight disorders, and this expansion is really due to new technology, and specifically tandem mass spectroscopy and do a test simultaneously on 30 or more conditions from a single blood spot, and I think this is central to the ethical issues that are part of the newborn screening debate at this point.

And I think folks are anticipating the prospects of DNA based testing in the not too distant future, and so the number of tests that conceivably could be done on newborn screening spots is really quite large in number.

So part of the challenge that I'll mention here in a few minutes really is that. How do we draw appropriate lines around the types of test that ought to be implemented with this type of system.

I think this expansion is due to a variety of things, the technology, of course, and also lay advocacy in an emerging commercial market for newborn screening. Here's a screen shot of the Pediatrix Web site, a company that provides commercial newborn screening. Some states contract with this company to provide their screening. I believe they're up to about 50 conditions now on their panel, and these are marketed through women's magazines, et cetera, to parents directly as a way of providing care for their children.

So I think this commercial market has helped foster and encourage states to look pretty hard at a competitively large panel. I'd be interested in Mike's comments on that.

From my perspective, I think data on the efficacy of population screening for many of the conditions that are now part of these large panels is limited. It's very difficult to do research on rare conditions. Some 12 of the 29 conditions that are on the ACMG panel have an incidence of less than about one in 100,000. Much of the information to support screening for these rare disorders comes from small, uncontrolled observational studies, and given the rare nature of these conditions, if you're a clinician who has seen three or four kids with any one condition, then you are the world expert.

So oftentimes it's historical controls, I think, that are used to try to determine whether newer interventions are effective or not.

Again, from my perspective I think population screening has proven to be rarely an effective intervention for very many things in medicine. We have enthusiasm over the years for a variety of different approaches, and once the data is collected, we're disappointed.

I'm old enough to remember when a chest X-ray was done on every kid, every person admitted to the hospital. It seemed like a great idea. Once people collected the data on it, it's not that it never worked. You know, the argument is that you never found anything of value on those films. The argument is the benefits, the occasional good information that was provided was swamped by the false positives, the expense and the complexity of the program.

And I think we see that today. Mammography is recommended for women 50 and older. It's not recommended for women under 40. Is that because breast cancer doesn't occur at that age or that mammography is not useful at that age? You know, no. You could pick up cases at the younger age. It's just that the value of the screening program, given the low incidence and the high number of false positives overwhelms the benefits that are achieved by those detections.

So I think the questions are still out there with respect to many of these conditions about whether that will be the case for this population screening.

Now, of course, these are conditions that are not curable in any sort of quick infectious disease type sense. They're manageable or partially manageable through oftentimes fairly complicated and burdensome interventions over time, and the question then is is that part of the system. How well does our system support kids and families who have to maintain these complicated support services for kids over time, and if they're unable to do so, then the value of the screening program is substantially reduced.

Now, negative impacts of screening. I alluded to them a little bit, but I'll enumerate them a little bit more explicitly here. The positive predictive value from