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Day 2 April 19, 2007 WELCOME AND INTRODUCTIONS Dr. Alan Leshner Dr. Leshner: Yesterday was a terrific day, and therefore that puts great pressure on all of us to make sure today is an equally good day. One of the things it was characteristic of is a wide variety of people sharing their views, but also listening carefully to each other. That is what characterizes a good workshop, that it is actually a workshop and not a bunch of monologues where people tell you just how it is. One of the things, since I am somewhat outside this field, that I have been struck by is how many research opportunities and how many research challenges exist. That is both good news and bad news. The bad news is that I believe that we are way behind where we ought to be, that there is a tremendous need to have a focused research agenda, but also from my perspective the resources necessary to implement that research agenda as well. I have been very impressed by the number of NIH Institute directors, the Deputy Director of the National Science Foundation, and a variety of other people who have access to resources who have spent so much time with us, and I applaud that. I applaud their leadership in helping to move this field forward. Now, just to remind everybody of the ground rules, first, speakers, there is a little clock up here. The format for the discussions is that after the 15-minute talk, we will have hopefully 3 to 5 minutes for urgent questions of the speaker. We will restrict those to the participants at the table. At the end of each 165

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166 AUTISM AND THE ENVIRONMENT session, we will have an open discussion. Again, we will give priority to people at the table, then if we have time open it to the broader audience. Then at the end of the day, we have reserved a substantial amount of time for discussion by everybody in the room. Let me now introduce Henry Falk, who is the chair of this first session on environmental epidemiology, using population-based studies to isolate the environmental causes of autism. Dr. Falk is the director of the Coordinating Center for Environmental Health and Injury Prevention at CDC.

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Session V Environmental Epidemiology—Utilizing Population-Based Studies to Isolate the Environmental Causes of Autism Dr. Falk: Thank you very much, Alan. There was a lot of discussion yesterday about issues we will be talking about this morning, so I think there is a lot of interest in these sessions. We will start with Irva Hertz-Picciotto, who has a Ph.D. in epidemiology from the University of California–Berkeley. She was on the University of North Carolina–Chapel Hill faculty for 12 years, and is now at UC–Davis Department of Public Health Sciences. Her research interests are in environmental exposures, pregnancy outcomes, and epidemiological methods. She is on the editorial boards of the American Journal of Epidemiology, Environmental Health Perspectives, and Epidemiology, and was on the scientific advisory board for the U.S. EPA. Thank you very much, Irva. ENVIRONMENTAL EPIDEMIOLOGY STUDIES: NEW TECHNIQUES AND TECHNOLOGIES TO USE EPIDEMIOLOGY TO FIND ENVIRONMENTAL TRIGGERS15 Dr. Irva Hertz-Picciotto Dr. Hertz-Picciotto: Thank you. I am going to provide an overview of environmental epidemiology and epidemiology generally. I’ll talk about different study designs and what we have learned from them, and then make some recommendations. The first couple of study designs I am going to go through somewhat quickly, because I think most of the meat is really at the end, in terms of the future for the field. Starting with focused clinical studies, these are generally self- selected populations or a group of patients in a clinic. These studies are descriptive. They usually have small numbers of subjects in them. Sometimes the hypotheses are generated a posteriori. These are the 15 Throughout Dr. Hertz-Picciotto’s presentation, she may refer to slides that can be found online at http://www.iom.edu/?id=42469. 167

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168 AUTISM AND THE ENVIRONMENT studies that have taught us about sibling recurrence, about twin concordance, male–female ratio, the comorbidities, and the genetic syndromes that seem to also go sometimes with autism, as well as seizure disorders and gastrointestinal symptoms. They have taught us about the heterogeneity of onset, including the regression phenomenon that seems to happen in a lot of cases, and the data on anthropometrics, such as head size, have come from these studies as well. The second kind of study, described in the next slide, is based on administrative databases. These are large databases that are collected for administrative purposes. The diagnosis of autism is frequently done by whoever the clinician is who happens to see that child. We have learned about perinatal factors and about time trends from these studies. There are two ways in which these studies assess exposure. When exposures are not assessed in the individual and the outcomes are summarized at the group level, for instance, by area, it is called an ecologic study; in the other design, both exposure and outcomes are assessed at the individual level. This is an example of a time trend study conducted in Denmark using an administrative database of diagnoses. It was a study looking at the removal of thimerosal from vaccines and the rates of autism before and after. What you can see from this time line, which was not necessar- ily obvious from the original paper, was that before thimerosal was removed, there was a period of time when only inpatients were in the database, and during part of the “after-removal” period, which covered all the way out to 2000 in this study, there was an interval when both outpatients and inpatients were included. This study, therefore, is not a rigorous design, because as you can see, you can’t really compare the before and after periods because of artifacts in how the database was constructed, and specifically, in how that changed over time. The next slide shows another administrative database study, quite a good one done from the Swedish Birth Registry, which was linked to their inpatient register. It gave us some information about some of the aspects of the perinatal period that seemed to be associated with higher risk for autism. From these administrative database studies, we have learned about patterns: We have learned about the age effect of the parents, obstetric complications as risk factors, and aspects of the time trends in autism. Moving along to the genetic studies, these again, like the clinical studies, are volunteer samples. The largest such study right now is the

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169 PROCEEDINGS Autism Genetic Resource Exchange (AGRE) database. It has over 1,000 families right now. They are all multiplex families with at least two members who are affected, and they are focusing on genetics. We have learned from these studies how highly concordant monozygotic twins are, but not entirely. We have learned that this is not a condition that follows simple Mendelian inheritance. We have also seen the slide show yesterday by Isaac Pessah and others depicting the large number of chromosomes that may be involved, indicating multiple genes. But at this point those studies have focused on genes in isolation, although Clara Lajonchere has been working with me to figure out how to collect more environmental data on the AGRE families. Just a few words about studying environmental factors in autism. I think there are some misconceptions, maybe not in this room, but certainly out in the field of science and the community at large. We know from the genetic studies that about 60 to 90 percent of cases have some genetic component. What can we conclude about environment? Let’s look at these two pies. This is the sufficient causes model from epidemiology. Each pie represents a set of sufficient causes that will cause autism in at least one individual out there. It might be that A is a genetic factor, that B is another gene, that C is an environmental factor in the prenatal period, and D might be something happening at birth or postnatally, just hypothetically. Looking at the lower pie, this is another set of sufficient causes, where A and C can be substituted with some other set of events. Each set, that is, each causal pie is sufficient. So what that means is, if you take away B from either one of those pies you don’t get autism. This is gene–environment interaction. Because of gene–environment interaction, environment plays a role in 10 to 40 percent at a minimum. But notice that in this individual, say someone corresponding to the upper pie, it takes both. Let’s suppose that this particular set of sufficient causes produces 30 percent of the autism cases. That means 30 percent require genes and 30 percent require environment. Suppose the other pie corresponds to the remaining 70 percent of autism cases: Under this scenario, 100 percent of the cases require genes and 100 percent require the environment. In other words, the contribution from genes plus the contribution from environment do not have to sum to 100 percent, and they will not sum to 100 if there is any gene–environment interaction.

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170 AUTISM AND THE ENVIRONMENT There are also several environmental factors that have been associated with autism with very high relative risk. The first is congenital rubella. In the mid-1960s, the United States experienced an epidemic of rubella. Mothers who had rubella during a pregnancy and passed it transplacentally gave birth to children at a much higher risk for autism, about 10-fold higher, and that figure is based on counting only the cases that did not seem to resolve over time. Thalidomide: also, a very high relative risk. Just looking at a few other factors such as maternal age or male sex, that are not necessarily causal, but might be proxies for some causal factors, there are also some large relative risks. The fourth type of study design I will talk about is the new genera- tion of case-control studies. These are population-based studies where the diagnosis is confirmed in all of the individuals. They cover a broad range of factors. Generally speaking the exposure has been assessed retrospectively, but that is not 100 percent true. If you go back to get medical records from these individuals, you are collecting essen-tially prospective data, data that were originally written down in a prospective manner. These studies also have been collecting specimens with linkage to laboratory scientists. I’ll give an example. There aren’t very many of these studies, but you have heard yesterday a little bit about the Norwegian study, not a case-control study, but they are doing nested case-control studies within it. This is a case-control study we are conducting in California. CHARGE stands for Childhood Autism Risk from Genetics and the Environment. We currently have about 800 participating families. They include children with autism, children with developmental delay but not autism, and children from the general population. Each child with a potential diagnosis for autism is assessed with the ADOS and the ADI and other assessments are done on all children, including cognitive and adaptive development, a physical exam, medical history, and a structured interview that takes about an hour and 40 minutes, covering 12 domains. Six of them are shown here, including information about the index pregnancy, household product use, metal exposures, and so forth. Then there are some self-administered forms about comorbidities and also about treatments and services that the child receives. We collect urine, blood, hair, and we ask the mother to bring in the baby hair lock if she saved it, and many of them have. They don’t have to give all the hair;

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171 PROCEEDINGS we can do with a few strands. We also collect specimens from siblings and parents, and then we go back to get medical records. We have them sign medical record release forms. It’s a very labor-intensive process, and we try to obtain as many of the types of medical records shown on the slide as possible. In addition, in California there is a banking of newborn blood spots on every newborn. Currently we have about 480 dried blood spots and we are applying to get more. Overall, this is the scheme that we are working with. On the left side is a panel of broad classes of exposures that we drafted as priority exposures to take a look at, and on the right side are the methods for collecting data about those exposures. Just a few examples: From blood, we can measure pesticides, and we can ask about what pesticides were used in the home. We can also link the residential information the mother provides with some databases that are also available in California, which have a record of every commercial application of a pesticide anywhere in the state. The database has geographic locations of applications, which we then can link to the residence of the mother at the time of birth, or at any other time because we collect those residential data. Measurement of metals can be conducted in blood, hair, the baby lock, the newborn blood spot. We ask about fish consumption and other household product use for metals. Another example, data on infections can be abstracted from the medical records and is collected by interview from the medical history. You get the picture. The CHARGE study is in progress. With regard to other case-control studies of this type, there is also an autism phenome project, which Sue Swedo talked about yesterday; it involves NIMH and the M.I.N.D. Institute. The CADDRE study we will be hearing about later in the session from Diana Schendel. Just briefly, some of the things that we are starting to see: In CHARGE, we are finding very different immunologic profiles in the children with autism as compared to the control groups. A wide range of immune markers appear different in the children with autism. We have also examined gene expression, and have observed a set of genes that seem to be differentially expressed in the children with autism, especially in cells from the immune system called the natural killer cells. There are also some hints now that there are perinatal factors, potentially avoidable ones, that might be linked to autism. We have looked at the metals and last year reported at the IMFAR meeting those

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172 AUTISM AND THE ENVIRONMENT results. This year I will be reporting on PBDEs; that work was funded by Cure Autism Now, which is now in the process of merging with Autism Speaks. The CHARGE study, by the way, is funded by the National Institute for Environmental Health Sciences as part of one of the children’s centers. It began in 2001, and we are now in our second 5-year period. The last study design I wanted to talk about is the prospective cohort studies. These are studies where we start with a pregnant woman, and follow her and the child forward. We have already heard a little bit about the National Children’s Study. A couple of other studies are now looking at high-risk cohorts. In particular, the pregnant women are ones who already have a child with autism and are carrying another child. Because of the high sibling recurrence rate, these are high-risk pregnancies. One of these studies, which is also part of our Children’s Center, is called MARBLES; we are also collaborating with the EARLI network, which is scheduled to be funded beginning in 2008, for which Craig Newschaffer will be the PI (principal investigator). What we are focusing on is trying to find out how early we can see biological signs of autism. Several baby sib studies to date have been focused on the early behavioral, but not biological, indicators, and have started postnatally. Our aim is to determine what are the critical time windows for environmental exposures, and what are the biomarkers that we might use to identify pregnancies and children at high risk. However, any marker is only useful if we can additionally identify what are the target issues or receptors or enzymes on which we might intervene in order to interrupt the development of autism. In conclusion then, we have had a couple of decades in which we have learned a lot about autism from psychologists and psychiatrists. We have learned how to diagnose reliably, and even some early behavioral markers. We have learned from neuroscientists about aspects of the brain and brain growth, and now is the time for the environmental epidemiol- ogy and toxicology to work together. This is an area that has not received a lot of attention. What you see in this room is what is out there, pretty much. We have in this room about 80 percent of the environmental epidemiologists and toxicologists, who are looking at autism from this perspective. And only half the scientists in this room are currently doing autism research. So this is an area that has been understudied. There are very few studies of environ- mental factors in the causation of autism. What I have shown you is

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173 PROCEEDINGS basically about what there is. These large epidemiologic studies can be linked to all the mechanis- tic questions that were raised yesterday. We are doing genomics and there is a potential to do metabolomics and proteomics to figure out biologically, physiologically, molecularly what is different in these children. With the prospective studies we can take the hypotheses that we are getting from the case-control studies, such as the finding from the CHARGE study of differences in expression of certain genes, and ask: Do those same genes differ, and how early on do they differ? Does it start at 18 months, 12 months, 6 months, or what about in the cord blood? In other words, let’s go back to the very early stages of life and brain development. That is the state of the art and that is where we should be going. Thank you. Dr. Falk: Thank you very much, Irva. There is time maybe for one or two very quick questions. Dr. Fombonne: Your design includes data that looks at a range of exposures, but you do not include in your model any timing of expo- sures. A lot of data suggest that early exposure is important. Therefore, my question relates to how you can modify your study design to look for common exposures at early time points. Dr. Hertz-Picciotto: In the case-control studies, obviously that is the deficiency in the design of the case-control study, is that you are measuring things now, and you really want to know what happened before the diagnosis, perhaps in the prenatal or perinatal period. As I said, the medical records do provide us with early information. We have been looking at even preconception, looking at things like in vitro fertilization, medications that the mother took during pregnancy, what kind of induction or augmentation of labor happened. So there is that component. We looked at the metals so far in the concurrent blood samples, and now we are going back and taking the baby lots. We started measuring the metals in the baby lots, which represent exposures in usually the first year of life, and then the newborn blood spot, which will tell us something about right before the time of delivery. So yes, it is a problem. In the questionnaire we also asked whether we can get valid information. It is subject to how well people can remember what happened, and do cases remember better than parents who have a child who is developing quite typically, if you ask them what

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174 AUTISM AND THE ENVIRONMENT pesticides did you use around the home when you were pregnant or in the first year of the child’s life. Obviously that is a problem, and that is partly why we are moving now to also doing prospective studies, where all the information will be collected prior to the diagnosis. Dr. Fombonne: May I ask another question? There are also techniques to look at clustering around different environmental exposures. There is currently a study in California looking at increased risk of autism to exposure to different pesticides at early periods of development and gestation. They have found really interesting findings that you can look at one particular exposure and map that to autism rates. Dr. Hertz-Picciotto: Yes, that is quite a lovely analysis. That is using administrative databases and then linking them to exposure databases. Where those databases exist, I think that is a really excellent approach. One of my graduate students has been doing—it is not looking to exposures, but she is looking at spatial clustering in California, and breaking it down. But yes, those exposure databases are quite useful, and the pesticide use report one is a very interesting database. Dr. Falk: Thank you very much. The second speaker is Craig Newschaffer. He will speak on environmental exposures in autism international studies. Craig is professor and chairman of the Department of Epidemiology and Biostatistics at Drexel University School of Public Health. He had founded and directed the surgical office in development, disabilities, and epidemiology at Johns Hopkins previously. ENVIRONMENTAL EXPOSURES IN AUTISM: INTERNATIONAL STUDIES16 Dr. Craig Newschaffer Dr. Newschaffer: Thank you. I have been tasked to talk a little bit about the promise and potential of international studies and international epidemiologic studies that shed some light on environmental exposures and autism. This framework of looking at frequency by person, place, and time predates the formulation of epidemiology as a discipline. It guides us still 16 Throughout Dr. Newschaffer’s presentation, he may refer to slides that can be found online at http://www.iom.edu/?id=42470.

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175 PROCEEDINGS in doing basic descriptive work on disease frequency. What we find, however, is just describing frequency of disease is important for assessing pharmacology burden, but very quickly we transition from just a pure description to wanting to make some inferences about risk factors or causal mechanisms. In person, place, and time, the variation of disease across those three domains is very important to analytic epidemiology. The dimension of place plays a prominent role in this, and there are a few ways that place factors into this type of thinking. For the rest of my talk—place—I am going to be focusing on national variations. As Eric brought up, we can also talk about studies of place looking at smaller geographic units, but again, for the rest of my talk I am going to be focusing on cross-national variation. The way we bring these data on place into our thinking is, there is a classical application that I will be talking about in a little bit greater detail that in theory can help us shed light on whether or not environ- mental or genetic factors may be prominent in etiology for the particular disease under study. Then there are also location-specific opportunities. We heard a lot about these yesterday, studies taking place in specific locations because there are higher or lower exposures in those particular locales. I will talk about those a little bit, too. Then lastly, the notion of place in analytic epidemiology in terms of multilevel analyses. These are the sorts of analyses where we look at variables at the individual level and also at the contextual level or level of place. A variable like socioeconomic status (SES) in modern studies of epidemiology is often looked at from a multilevel perspective. My personal socioeconomic status might influence my risk for a particular outcome, but also the SES in the area that I live might have a separate and independent effect on outcome. I think that at this point, where we are with autism epidemiology is probably not to the point where multilevel analyses are going to be prominent, but I think the first two approaches are worth talking about in greater detail. What about this classic application? The first thing that we want to do when we want to think about variation in place or variation cross- nationally in terms of helping us think about environmental versus genetic causes, we need to rule out bias. We need to make sure that variation in measures of disease frequency in one country and another country reflect underlying risk and aren’t related to other factors.

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272 AUTISM AND THE ENVIRONMENT biomarkers, we have got to have something to compare it to, and they are very hard to come by. I don’t know how to approach that, whether we can have a control repository at the same time. The other practical problem with the repository, especially metabolic biomarkers, is that they degrade over time. They have to be stored properly in the same way. So I would just make a plea for standardized protocol for collection. It will take a small working group to establish those criteria. Dr. Noble: Three things that haven’t been said. On the immune system, I think Gary Goldstein is right. I think one can make the prediction that these individuals are in TH-2 imbalance. They will have low glutathione levels. It is easily studied in T-cell populations. They will have memory cell defects. There are a lot of data from the AIDS literature on the effects of glutathione decreases on those areas. It might be useful surrogates, if not functional. Isaac Pessah said we can’t get access to the nervous system. I have been thinking about that. What we can get access to is neural crest stem cells. They are very easily grown from skin biopsies. That has been very well worked out. That may be something for us to look at. Lastly, I made the statement earlier that this is unlike any other neurological disorder that I have been interested in in terms of these recovery stories. That was a misstatement. This sounds like a biochemi- cal disorder. That is where we get those kinds of turnarounds. When we get the right drugs into an individual who has a biochemical disorder, we have these effects. So I am starting to now go in that direction in my thinking for awhile. Dr. Goldstein: In terms of neural tissue, we do nasal biopsies in Rett syndrome, and can get growing neurons from nasal biopsies. Dr. Noble: So you and I should talk about what would be the best to look at. Dr. Beaudet: I guess I am the genetic representative. There seems to be a certain sense that maybe genetics is somehow competing for resources with the environment considerations. I would just make a couple of points about the genetic situation. There are dramatic advances going on at this moment. They are not at all the outcome of the money that was invested. They do with discovery of de novo defects, and all this big investment has been in inherited kinds of abnormalities. I think this group that have de novo defects are by and large mentally

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273 PROCEEDINGS retarded and dysmorphic, and they can be identified to a great extent and moved apart from some of the other studies, because I think they will make any other study more complicated and contaminated if it is not done. Another thing which I haven’t pushed particularly is epigenetic sampling, which is very difficult because of the tissue specificity. I have a sense there is probably a group of patients where the etiology is mostly genetic, and another group where it is mostly environmental with some genetic susceptibility component. I think it would be helpful to separate these. Then an area where I don’t really have any expertise, I still feel like we need to know whether the incidence has changed between 1970 and 2000. Even if it is stable now, we need to know if it changed. Mr. Blaxill: I want to talk a little bit about the burden of proof on time trends. I would make the suggestion that given the increases that we have seen, the notion that the reported increases are an artifact is a hypothesis, and it is a testable hypothesis. I’ll just take California as an example, because there is a pretty good surveillance system there, better than other parts of the country. A child born in California in the early 1980s had less than a 5 in 10,000 chance of becoming autistic. By the late 1990s, that rate was closer to 40 for 10,000, so that is roughly a 10-fold increase in about 15 years. The notion of that increase being artifactual has been tested in a lot of natural experiments. There is a hypothesis of diagnostic substitution that has been tested and falsified. There is the hypothesis of diagnostic expansion, that somehow we are changing the quality of the diagnoses. The interesting thing about California is that the registry is for a full syndrome, it doesn’t include the broader spectrum, so that theory of expansion doesn’t hold. The M.I.N.D. Institute has done a quality control check across decades. There are problems with those kinds of studies, but they didn’t uncover any different diagnostic quality in birth cohorts from the 1980s or the 1990s. And the surveillance system has been in place. It has changed, any administrative system changes, but it has been in place since the 1970s, unlike some of the educational records in the 1990s. So the notion of diagnostic expansion is not supported. The only remaining hypothesis, or what I like to call the hidden horde hypothesis, that somehow hundreds if not thousands of children escaped the service systems, and if we looked for 25-year-old Califor- nian young men and women with autism, we would find them in large

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274 AUTISM AND THE ENVIRONMENT numbers somewhere. That is an interesting hypothesis. I would suggest people ought to prove it before we start accepting the notion that the increases are artifactual. So all you can say from that is that there is a lot of evidence that suggests that in California the increases are real. California, when you compare other databases to the rest of the country, they don’t look that different, so again that is inductive reasoning, but you could argue that is a pretty useful database for the United States. Then I would ask the question in terms of studies, I think we should pursue studies to clarify uncertainties, but I would urge us to consider changing the burden of proof. Rather than saying the burden of proof is to demonstrate that all this is real, I would say the burden of proof is to demonstrate that it is artifactual. If that is the case, we ought to think about changing our official narrative, because the expression of doubt about the increases creates the sense that we have a mystery and a puzzle, and no sense of urgency. The recognition of the reality changes the entire dynamic. I think a lot of us are saying we need to treat autism as an emergency, and that is what all the data points to. Dr. Susser: I agree that we should really tackle the time trends problem, and that we should trace the course of autism over an individ- ual’s life span, not just over the first few years. So I second those two points that have already been made. The only point that I would like to add is that I would like to extend what Art Beaudet said, but in a different way. I think one thing that we have learned from all these genetic studies is that there is a sizeable proportion of kids with autism that do have de novo genetic defects. That is really important, and that is new knowledge. I think what that should lead us to do is to look for the causes of those de novo defects. They are probably going to be environmental. I think we should focus there when we are thinking about environmental studies of autism. Dr. Landrigan: On the first day of science class, we are generally taught to beware of the study with the n of 1, and for good reason. But to summarize from yesterday, I think we heard several instances where the n of 1 study, to the extent that it is a hypothesis-generating process, can be extraordinarily valuable, especially in the face of a disease of this complexity. But also, it would be a way of ensuring that the engagement of the

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275 PROCEEDINGS parents and the treating clinicians and the scientific community come together. The problem is that peer review will be deaf on most of those kinds of studies seen one at a time. But if we could create an infrastruc- ture, direct the peer review to the mental level in terms of something that fosters those opportunities, and then make it easier somehow, a lower energy barrier, whereby opportunistic examinations of that sort, testing a variety of the hypotheses we had here, I think it could be seminal in terms of shaping the more deliberate and longer term research protocol. Dr. Herbert: That is really great, thanks. I want to mention three quick points. I think there needs to be support at the infrastructure level. Sallie Bernard talked about makeup funding for environment. I think there needs to be makeup funding for parents and integrative practitioners to come together and figure out what it is that they need to convey about the disease phenomenology and the methods of measurement that should be fed into the biomarker development and study design development process. The second thing is, there has been a lot of talk about having some kind of a biomarker consensus meeting or think tank to come up with standard operating procedures and standardized measurement. I think that should be fast tracked. Finally, with regard to interesting existing scientists and companies in studying autism, which is not a huge population, there are a variety of conditions which have overlapping biochemistry and pathophysiology with regard to inflammation and oxidative stress, various neurodegenera- tive diseases across the life span, obesity, diabetes, and work has been done in those domains. People who have been working in those domains, that could be recruited to this effort so that it wouldn’t have to start from scratch in autism. Dr. Pessah: A major gap in our knowledge is the neurodevelopmen- tal toxicity of some major priority pollutants that fall below the radar screen of the EPA. These are non-dioxin-like. They have tremendous potency toward certain signaling systems that may be very relevant to autism and other neurodevelopmental disorders. I think we need to promote applications that address low-level exposures that try to understand specific mechanisms that are relevant to autism. I think we can also use cell samples from autistic kids, preferably primary cells, to try to validate or further understand how these mechanisms are hypersensitive or insensitive to certain mechanisms.

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276 AUTISM AND THE ENVIRONMENT Dr. Spence: I have nothing new. Everything that everybody else said, and one other thing I stole from the father of one of my patients. He said, we ought to be able to look at the brain and decide if there are toxic elements. He said, can you look at the brain and see if there is mercury in them? I said, not with the technology that I know about. But I think the imaging technology is getting better, so maybe there are ways of development of technology to look at toxic exposures directly in the nervous system or in other systems. Dr. Swedo: This is the advantage of being at the end of the table; we can go fast. I would like to suggest that medical and genetic workups be done on every child who is suspected of having autism. Typically they are sent off to the waiting list for the developmental clinics without having had an EEG done, or other very basic workup. If the child wasn’t able to walk, we wouldn’t be sending them off for a psychologist to evaluate them. We need hypothesis-generating research. We heard about the NM-1 studies, but there are some case series that have been ignored. I would like to see genetics added to all of the epidemiologic studies that we have heard about this morning. If they aren’t already being collected, genetic samples should be, and would certainly get at that question of genetic susceptibility to environmental risk. Common measures across the patient population to allow compari- sons. Common measures of assessment, of recovery, of response, but also as we have heard, of biologic measures. I would like to propose a plan that we have follow-up evaluations for the IAN database. I know that Paul Law and the folks at Autism Speaks are working on ways that those individuals who can’t currently participate in research rapidly could. I will finish by echoing Gary Goldstein’s plea that we move very quickly to a cystic fibrosis or cancer-line treatment network. I know that the Autism Treatment Network and others have that as a goal, so they would need additional support to make that happen. Dr. Zimmerman: I would like to make two strategy points. First, I think there is a base for both a theoretical approach to this, but also an empirical approach. The theoretical approach is, all the scientists are here, and finding a neurobiological answer to why we have this problem. Second, I think the empirical approach would be a meta-analysis of all the treatment paradigms that have been tried to date, including biomedical, dietary, nutritional, home-based, or relationship-based

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277 PROCEEDINGS treatments, because I think there is a probabilistic and causal relationship there. Dr. Coetzee: I am like Alan, I don’t have a particular stake in this disease. I come from the multiple sclerosis world. In thinking about what I have observed in the last couple of days, there are two areas. One is, I think the cystic fibrosis model is particu- larly powerful for another area, and that is the foundation’s approach to companies, in terms of contracting with them to do research on a population of 30,000. There is not a big market for cystic fibrosis drugs, but they have managed to invest $200 million over the last 6 years in company research. So I think that is a powerful model for the private sector to stimulate pharmaceutical companies to be engaged in this process. It is not the usual big players, but it is the small innovator companies that will come out of the young people who get recruited to be researchers in autism research and other areas. I would also suggest that we think about looking at other diseases that may have an adult onset, but that have complex genetics that have environmental triggers and environmental factors for which we don’t yet know causes. I think we don’t want to necessarily reinvent wheels that may have already been invented elsewhere. Dr. Cohen: I come here as a member of the Forum. This has all been very new to me. I would like to thank you all for an extraordinary 2-day education. From that admittedly uninformed perspective, two things struck me. One was the absence of imaging in the discussion. I was going to say fMRI, except Martha Herbert last night advised me that there were other directions to go. The second thing I missed was a deeper discussion of viral patho- gens. Like many of you who have been struck by a lot of the anecdotal conversations, that struck me as well, some of the conversa- tions about the kids with severe GI distress that responds to antivirals, just around the table, the very late onset with possible viral etiology. While I wouldn’t necessarily say that that is my lead hypothesis, it certainly strikes me as a significant element that has to be considered. Dr. Fombonne: Two ideas. One is to go back to the idea of setting up a study of discordant twins. I think the rates of twins are going up, and that would be an opportunity to look at not only environmental risk factors, but also maybe product risk factors, what makes the outcome

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278 AUTISM AND THE ENVIRONMENT different in that case. Second, it follows up on the last point. I think we should probably look at environmental exposure which might increase the rate of mutations in germ cell lines of fathers in particular. That would be something which would also be to follow up. Dr. Insel: There is not a lot left at the end of the row here, but let me give you one from Ian Lipkin which hasn’t been mentioned today, although David Schwartz started to get there, using microbiomics approaches, that is, this new way that Ian Lipkin described of looking at all the potential microbes through sequencing, not through culture. I think intuitively that is a great opportunity in this area for a lot of reasons. It fits in with the immune story, it fits in with potential time trends. There is just a whole range of things that would help you understand what is going on, and it is completely untapped. It is now doable. It wasn’t doable 6 months ago. But this is a place one might go. Two others. Mentioned yesterday, not today so much, Sue Swedo started by saying there are plenty of genetic diseases, Mendelian diseases, that have autism as part of the story. If you had anything else that increased the risk as much as Fragile X, you would want to know why. It seems to me that is also an opportunity. The last thing. Several people have mentioned international efforts. I do think, besides finding these natural experiments and special cohorts, there are a lot of things going on in other countries that we need to be more aware of. I was recently at a national autism meeting in The Netherlands. Someone came up to me and said, I have been collecting CSF on several hundred people who now have autism. Would that be of any interest to anybody? So there are opportunities out there that we need to be looking beyond our own borders to try to exploit. Dr. Leshner: That was pretty spectacular. I’m not quite sure what to do now other than to open it up to the broader floor with the same rule. You get one minute, no more, from the audience. Line up at the microphones. You have got to yell, we are collecting all of this. Name, where you are from, and no speech. A one- minute opportunity.

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Session IX Discussion with Meeting Participants and Audience Participant: I am from George Washington University. One of the things that has been maybe just hinted at here but hasn’t really been addressed is the possibility—and also, this would involve parents and clinicians as well, is the use of response to medications, to phenotype individuals for further study. As the parent of a child with Asperger’s syndrome, he has been thrown bucketloads of drugs, most of which have absolutely no positive effects, lots of negative effects. But if we can tap that database and sort out those kids that may respond well to antidepressants or antipsychotics, those are probably good biological phenotypes that can be useful in genetic or genomic or other studies as well as metabolomic studies. Participant: Dr. Nancy O’Hara. Two points I would like to follow up on from the panel. One, the University of Maryland has just partnered with Autism Research Institute to start to collect and bank tissue samples, not just brain samples, from children and adults with autism. I think that is very important when you look at environmental factors. Second, Dr. Sidney Baker, who I think is one of the most brilliant clinical minds in this research, is launching a beta trial of metagenesis, which is a collaborative technological tool to collect data from parents. Ten thousand parents will be receiving letters next Friday. I offer that to the board to look at that as a means, not of scientific rigor, but as a means of data collection, to start to look at what bio- markers, lab data, treatment protocols might be out there. If you don’t receive a letter as a parent or members of the board, you may go to http://autism.com/ to look at that. I think that is something we can use to start collecting some of these data. Participant: Richard Deth from Northeastern. There is a meeting at the same time as we are meeting here of the think tank from DAN and the Autism Research Institute. I want to bring greetings from them, because there has been some back and forth and there will continue to be back and forth. They represent an organization of resources for cooperation in these kinds of relationships, especially parent based as opposed to fundraising. Different organizations have different foci and so forth. 279

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280 AUTISM AND THE ENVIRONMENT That group is really anxious—you will probably receive something official from them, offering some cooperation in whatever way possible from that group. The other thing is, Dr. Insel, you pointed out the importance of private funding because the R01 process is fraught with problems. I, for example, had an R21 where the primary reviewer just cut and pasted the thimerosal statement from the FDA Web site instead of reviewing my grant. So this is really important for the environmental factors that other people step up and never get through the NIH peer review system. Participant: Mary McKenna, University of Maryland. We are talking here about environmental and inflammatory factors and how they impact on metabolism in the developing brain. I just wanted to point out, related to what he just said, that brain metabolism studies have difficulty already in study sections. There is no home for them. They get bounced from study section to study section. I think that is an issue that needs to be dealt with. Participant: Alaina Fournier, Department of Health and Human Services. I have been working with Dr. Raub for the last 3 months in preparation on this topic for this meeting and future work with this topic, but now I am on a different detail at the NCI (National Cancer Institute) Office of Liaison Activities. I would like to suggest using the NCI model of getting consumer advocates involved in the scientific process. They have several different programs that have been long, positive, and successful in getting the consumer advocates involved in speaking with the director about the research agenda as well as the peer review process, and just keeping open lines of communication between the two groups. Participant: I didn’t know she was going to talk, but this falls perfectly with what I was going to mention. I have had this conversation with Dr. Raub as well. I think it is very important to remember that just as our kids have varying—display different aspects that are all different, it is also the way our community is. We have a lot of different viewpoints. It is a wide spectrum. The point I would like to make about the partnership is, I hope that— and it sounds like from what she just said that the partnership isn’t going to be—the determining factor isn’t going to be that we have millions of dollars to bring to the table to be able to have our voices heard at the table.

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281 PROCEEDINGS So I think that it would be very important to remember that—to bring all the different advocacy groups to the table so that we all have a place and a voice, because these are all our kids. So I think that is very important to remember. Participant: Hi, I’m Beth Roy with Social and Scientific Systems. I have been the director of the Pediatric AIDS Clinical Trial Group Operations Center, and I was very interested in hearing about the possibility of looking at a model like that, that I think was successful in bringing together public–private partnerships, the involvement of consumers, and dealing with a very complex disease that was very multidisciplinary. So I just think it would be a good model to look at. Participant: Jim Moody with SafeMinds. To paraphrase a famous quote, money is the mother’s milk of science. When this country has faced a crisis in the past, the Manhattan Project in World War II, the opportunity to land a man on the moon in the 1960s with NASA, and more recently responding to crises like bird flu, SARS, even the recent pet food crisis, there has been a political response which helped drive the scientific response. So one thing that would I think help would be if this panel of distinguished scientists could urge upon national government the same kind of commitment that has called forth the sense of national urgency at the political level, and that begins at the presidential level, to declare a national emergency, to marshal all of the resources that we can bring to bear on this crisis. At the present rate of increase, which I think Mark Blaxill said was 10-fold since 1990, in two or three generations every child will be born with autism or related neurological deficit or some sort. These kids now are the canaries in the mine, and there needs to be the strongest possible social response to that. America is full of the top scientists in the world. We can solve any problem if we put our hearts and minds to it. The cost alone of the epidemic would justify that, if not the moral imperative. Thank you. Participant: A quick question to all of you here from NIH and the Institutes. How is the so-called funding from the Combat Autism Act recently passed by Congress supposed to be directed or targeted? Dr. Leshner: I can answer that. It has to be appropriated. It has not been appropriated. It was just authorized. Participant: A quick comment. I am with the Environmental Protection Agency. My name is Mark Corrales. I just wanted to offer

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282 AUTISM AND THE ENVIRONMENT myself as an unofficial contact. I am in the Administrator’s office. I am familiar with the various datasets and offices. EPA is a big place. It is sometimes hard to find the right information or people. So I just wanted to offer myself as a contact, if I can help, in the spirit of partnerships, data sharing, and so on. Dr. Leshner: I think we have gotten to the moment. It feels like I don’t want it to end. One thing that I would like everybody to do, because I think it has been really terrific, and we have been so well behaved and not applauded anyone, we need to take a moment. I think this has been spectacular, and I hope I am right. I would repeat the comment I made fairly glibly before, that is, this is a very important start, and if we don’t do some- thing, then shame on us. Thank you very much.