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Minutes of the Interagency Autism Coordinating Committee (IACC) Subcommittee for Basic and Translational Research Conference Call and Webinar on November 26, 2012

The Interagency Autism Coordinating Committee (IACC) Subcommittee for Basic and Translational Research (also referred to as "the subcommittee") convened a conference call and webinar on Monday, November 26, 2012, from 12:00 p.m. to 3:39 p.m.

In accordance with Public Law 92-463, the meeting was open to the public. Thomas R. Insel, M.D., Director, National Institute of Mental Health (NIMH), Chair, IACC, and Co-Chair, Subcommittee for Basic and Translational Research, and Geraldine Dawson, Ph.D., Co-Chair, Subcommittee for Basic and Translational Research, chaired the meeting.

Participants:

Thomas R. Insel, M.D., Co-Chair, Subcommittee for Basic and Translational Research; Geraldine Dawson, Ph.D., Co-Chair, Subcommittee for Basic and Translational Research, Autism Speaks; Susan Daniels, Ph.D., Executive Secretary, Office of Autism Research Coordination (OARC),; Anshu Batra, M.D., Our Special Kids; Linda Birnbaum, Ph.D., National Institute of Environmental Health Sciences (NIEHS); Coleen Boyle, Ph.D., M.S., Centers for Disease Control and Prevention (CDC); Noah Britton, M.A., Bunker Hill Community College; Matthew J. Carey, Ph.D., Left Brain Right Brain and Other Autism Blogs; Tiffany R. Farchione, M.D., Food and Drug Administration (FDA); Alice Kau, Ph.D., Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (for Alan E. Guttmacher, M.D.); Donna M. Kimbark, Ph.D., U.S. Department of Defense (DoD); Walter J. Koroshetz, M.D., National Institute of Neurological Disorders and Stroke (NINDS); Cindy Lawler, Ph.D., National Institute of Environmental Health Sciences (NIEHS) (for Linda Birnbaum, Ph.D.); Lyn Redwood, R.N., M.S.N., Coalition for SafeMinds; John Elder Robison, Self-Advocate, Parent, and Author; Alison Tepper Singer, M.B.A., Autism Science Foundation

Roll Call and Opening Remarks

The IACC Subcommittee for Basic and Translational Research held a telephone conference and webinar on Monday, November 26, 2012, to discuss and vote on draft updates for Chapters 1, 2, 3, 4, and 7 of the 2012 IACC Strategic Plan, covering diagnosis, biology, risk factors, treatments and interventions, and infrastructure and surveillance needs. The updates describe recent progress in the autism field as well as research gaps that have emerged since the previously released 2011 Strategic Plan.

Dr. Susan Daniels opened the call and noted that Dr. Geraldine Dawson would help lead the meeting and that Dr. Insel would be joining the call soon. Dr. Dawson welcomed Dr. Daniels back and discussed the purpose of the call and webinar. She thanked participants for their work on the draft chapter updates (Chapters 1, 2, 3, 4, and 7) and discussed the meeting process, which would entail discussion opened by the lead(s) for each chapter, OARC tracking specific changes to the documents requested by subcommittee members, and a final subcommittee vote on the proposed changes for each chapter. She said that a roll call vote would be taken only for votes that are not unanimous in order to accurately record the votes. Dr. Dawson explained that the votes taken during the call would reflect the opinion of the subcommittee regarding the draft versions of these chapters, and that drafts approved by the subcommittee would then go forward to the full IACC during the December 18, 2012, phone conference for final approval. She reminded everyone that these are updates on research that has occurred over the last year and the new gaps that have emerged. She noted that overall strategy and any broader changes will be addressed in 2013. Dr. Daniels commented that a full IACC in-person meeting would be held January 29, 2013, in Bethesda, Maryland, at the Natcher Conference Center on NIH's main campus. Dr. Daniels conducted roll call.

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Discussion of Question 1 Update: Diagnosis

Mr. John Elder Robison, the Lead for the Question 1 Planning Group, led the discussion on Question 1, during which he noted that the first section on prevalence is in good shape. Regarding the early diagnosis section, there was a comment about citing the first of the Diagnostic and Statistical Manual of Mental Disorders (DSM) validation studies1; the subcommittee members agreed that this would be added to the question. For early screening and detection, Mr. Robison said there had been discussion regarding the Wolff study about detecting autism before behaviors emerge in the first year of life,2 which he thought should remain in Question 1, although the material also appears in Question 2. He also said that he thought that the Bosl study3 (in the last two paragraphs of that section) could also be cited in more than one place in the report. Ms. Alison Tepper Singer noted that in the second paragraph under prevalence (page 1), "The ADDM Network released their most recent data," should read "The ADDM Network released its most recent data."

In discussing what gaps have emerged over the past 18 months (page 3), Mr. Robison said that there is some question regarding whether the following paragraph belongs in Question 1, even if it repeats material that is in Question 5: "Some studies show that adults with autism continue to be socially disadvantaged and have significantly-lower academic and career attainments as compared to non-ASD adults…." Mr. Robison said he believed strongly that this material belongs in the first part of the report, where it is more likely to be seen by the public. He said this material represents a significant change in position because Question 1 in all previous iterations of this report focused exclusively on the diagnosis of young children. Some subcommittee members also thought the repetition of this material in both chapters would be helpful. There was discussion of some possible rewording and about whether the material should remain only in Chapter 5 or be located in both chapters. After additional discussion, subcommittee members agreed that a decision to include information about adults throughout the plan would represent a new decision for the IACC and that this would be more of an overall strategy decision/major restructuring that should be addressed in 2013 rather than in the current update. Subcommittee members reviewed the language in the third paragraph under gaps (page 3) concerning social communication disorder (SCD)—"There is a fear that it will be interpreted as 'mild ASD without supports,'" because "mild ASD" refers to diagnosis, and "without supports" refers to intervention. Different wording was discussed, with the idea that unlike autism spectrum disorder (ASD), this new condition (social communication disorder) does not have specific prescribed treatments, and there have never been any intervention studies or clinical guidelines about serving this population. Subcommittee members agreed that the new language should read "mild ASD without the need for supports" (with all quotation marks omitted).

Subcommittee members agreed that using actual numbers in addition to percentages throughout the report (1 in 91 children, for example) would make it more accessible to the average person. Dr. Dawson suggested that, in the third paragraph on page 1, because the data are 12 years old there should be a text change to indicate the current age of the children. Ms. Singer agreed to draft some language in this regard. Subcommittee members discussed whether the language in the last paragraph under prevalence should be modified, but after discussion it was agreed to leave the language as it is: "some but not all."

It was agreed that language is needed under gaps about the need to get prevalence data more rapidly. Dr. Coleen Boyle will draft this language. Also, in the second to the last paragraph on page 3, under gaps, the language would be changed to: "More emphasis must be placed on individuals of all ages."

Dr. Daniels summarized the proposed changes:

  • Under diagnosis, the first of the DSM validation studies would be cited.
  • In the second paragraph on page 1, "The ADDM Network released their most recent data" should read "The ADDM Network released its most recent data."
  • On page 3, the third paragraph under gaps would be changed to say "mild ASD without the need for supports," removing the quotation marks.
  • In the second paragraph on page 1 under prevalence, both the percentage and the number would be included.
  • In the third paragraph on page 1, for the South Korean study, both the percentage and the number would be included. (This will be done throughout the report.)
  • In the third paragraph on page 1, because the data are 12 years old, there should a text change to indicate the current age of the children. Ms. Singer agreed to draft some language in this regard.
  • In the gaps section, text would be included about the need to get prevalence data more rapidly (to be drafted by Dr. Boyle).
  • In the second to the last paragraph on page 3, the language would be changed to "more emphasis must be placed on individuals of all ages."

Dr. Thomas Insel said he agreed with all the proposed changes and wanted to emphasize that the prevalence numbers discussed above represent the 2000 cohort.

A vote was taken. The committee approved Question 1 with the agreed changes for submission to the full Committee, with one abstention. Ms. Lyn Redwood abstained because she had concerns about redundancy in the question.

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Discussion of Question 2 Update: Biology

Dr. Dawson said that there is a question about whether the paper in Pediatrics4 noting the lack of effect of gestational infection should be added. She then turned the discussion over to Dr. Walter Koroshetz, who served as the Lead for the Question 2 Planning Group, to review the material in Question 2. Dr. Koroshetz noted that it is still long, but not as long as it was when they began. He said certain areas were highlighted, the first of which was neuroimaging findings, with large growth in the use of high-technology imaging to study autism. He said that a few of these studies have opened doors to looking at neuropathways that differ between typically developed and autistic children. These are diffusion-weighted imaging studies that look at white matter tracts in a new way. One study claims to show differences in the brain in 6- to 24-month-olds,5 with the idea that it may at some point be possible to diagnose the changes in the brain even before symptoms become apparent. Other new studies look at the volume of the brain. Dr. David Amaral's group6 showed that the increased brain growth was primarily in boys with regressive autism—not in girls or in boys without regressive autism—which may indicate a marker of a phenotype. However, another study from Israel did not see macrocephaly as a common feature7; thus, some controversy remains.

A number of papers have been published claiming that using functional magnetic resonance imaging (fMRI), differences can be seen between children with autism and typically developing children involving the brain circuits used in social processing. In addition, some structural imaging studies are now starting to look at language areas and auditory processing in autism, with two studies finding differences in the white matter pathways that connect language areas in the brain. Neurophysiological studies look at how brain activation can be examined using measurements such as electroencephalography (EEG) or magnetoencephalography. One study using these techniques found atypical audiovisual speech integration in infants at risk for autism.8

Another area of interest is the molecular basis of phenotypic autism. In many of the phenotypic or syndromic autisms, often a gene has been identified, and this has aided in the study of the biology of autism. In many of the monogenic causes of autism, although the genes are different, there is a convergence in many of the studies on synaptic function. In addition, many of the abnormalities in the models of these monogenic disorders are reversible. This provides some hope that in autism, getting to the bottom of these synaptic abnormalities may lead to treatments that can help people who are already affected. Similarly, in many of the genome-wide association studies (GWAS), isoforms of genes have been identified associated with autism, but these have also often come down to synaptic function proteins. This is important because the monogenic and the large GWAS all seem to be pointing in the same direction.

Another important research area involves studies that have been conducted in gene expression in postmortem brains with autism, which have shown that many of the gene expression changes in autism brains involve synaptic functional differences. The second part of one of the studies, however, showed that there is a whole range of gene expression changes that had never been seen before in GWAS. The changes all seemed to be linked to immune and glial gene expression in autism brains. Thus, some of this work suggests that the link to autism may be through abnormal immunity.

Regarding the section on immunity, a number of studies have demonstrated that immune abnormalities produced in animal models can result in behavioral abnormalities that are somewhat related to what is seen in autism. Also, the idea of maternal antibodies mediating autism through the placenta is one that has been studied in both humans and in animals, which again highlights the immune system. In fact, during the past year, although not directly related to autism, the immune system has been discovered to be a major sculptor of synaptic strength, indicating that immunity may be very closely related to synaptic function and that the immune system may be the mechanism through which the brain is eliminating redundant synapses, allowing the ones that are key to become stronger.

The section on co-occurring disorders includes studies showing that some genetic abnormalities lead to both epilepsy and autism. It also mentions a study on the link between autism and gastrointestinal (GI) disturbances that may not need to be included if it is also included in another section. It was noted that Dr. Beth Malow has provided some interesting information on recent studies on the biology of sleep and how it could affect behavior.9

The first gap involves the paucity of studies related to the cellular neuropathology of autism and the need for postmortem tissue in order to move this field forward, especially in light of the loss of brains that occurred after the difficulties at the Harvard-affiliated Brain Tissue Resource Center at McLean Hospital, Massachusetts. Another gap is in the area of induced pluripotent stem cells. Regarding gaps in imaging, longitudinal studies are needed to plot changes in brain structure and function over time. It is important to continue work on females with autism and, although progress has been made, more work is needed on the immune system and autism.

During the discussion, Dr. Insel talked about how over the past 18 to 24 months there has been an enormous set of breakthroughs, especially in understanding metabolic disease and certain forms of cancer, that are changing our approach to many other related developmental disorders. The efforts involved in these breakthroughs include the Human Microbiome Project and the ENCODE Project. For example, awareness has been increasing that the immune system is important for synaptic development and plasticity. Dr. Insel wondered if it would make sense under gaps to note that there has been an explosion of new tools and new insights that should be applied to autism in the way they are being applied to many other biomedical issues—which represents a striking gap that goes beyond a focus on the literature that already includes autism. Many new ways of thinking about neurodevelopmental disorders are available that have not been developed for the study of autism. Dr. Insel noted a pair of papers by Chris Walsh's group at Children's Hospital about the importance of looking at somatic mutations in postmortem material. The argument is that if one is looking for a genomic region, the actual region may not be apparent in blood and may only show up in the part of the brain that is affected.

Ms. Redwood mentioned that the need for work on the microbiome had been included in the 2011 Strategic Plan, and Dr. Insel pointed to the 17 papers that were published in June based on data from the Human Microbiome Project, as well as additional papers that have subsequently have become available. He indicated that this is an entirely new frontier of research, but that it has not yet been studied in terms of autism. Dr. Dawson mentioned that Autism Speaks is funding a major study on the microbiome and autism that is under way and agreed that more work is needed in this area. Dr. Insel emphasized that it is important to be thinking about not only what is new in autism, but what is not new in autism that is new in the rest of medicine that could be important as a gap area. Dr. Insel agreed to provide some introductory text for the gap section describing how over the past 18 months transformative breakthroughs have occurred in understanding human development and human biology. The text will stress the importance of bringing autism research into alignment with this exciting new biology research.

Dr. Birnbaum raised the issue of rewording material at the bottom of the page 2, in the molecular basis and phenotypical autism section, that reads as follows: "Surprisingly, the researchers also found a pattern of immune and glial gene expression in autism brains that has not been seen in the genetic studies, an observation that supports the view that brain immune system responses in autism are likely related to environmental events and not necessarily genetic influences." She said it is important to move from focusing on either genetics or environment and instead stress the intersection of the two by rewording to say "are likely related to environmental events as well as genetic influences." She noted that even genes that are highly penetrant still can be influenced environmentally. Dr. Insel said that the language should clarify that genetics and environmental influences work together. It was agreed to change on the last line of page 2 "and not necessarily genetic influences" to "as well as genetic influences."

Dr. Dawson said that new papers are constantly being published, including one last week from Paul Ashwood's group that looked at immune markers in blood and found that the increased frequency of myeloid dendritic cells was associated specifically with GI problems, enlarged amygdala volume, and severity of repetitive behaviors—and was also more pronounced in children with regression.10 This is an interesting combination of highly correlated factors that might suggest a particular subtype. Also, today three papers are coming off embargo (Archives of General Psychiatry/JAMA Psychiatry), one of which is the first in vivo study to show microglia activation in the brains of adults with autism (by Robert Amos) 11; previous studies had used postmortem tissue, raising all kinds of caveats. Another is a study that looked in detail at using MRI to determine what accounts for enlarged brain. It found that the differences in brain volume are due to differences in surface area, not cortical thickness, which suggests that different developmental and genetic mechanisms are involved.12 The third study is on air pollution and links high levels of exposure to traffic pollution during the prenatal period with a threefold increase in autism risk.13 Dr. Dawson suggested including the two studies that involve immune function in the chapter.

Subcommittee members agreed that these articles should be included (Breece et al., 2012 and Suzuki et al., 2013).

Dr. Birnbaum suggested moving the text about Ashwood's study involving the overlap between ASD and GI disturbances into the section on new findings involving the immune system. It was agreed to also include the microglia paper in this section.

There was discussion about the effort to determine the best placement for material about co-occurring issues and about using the term "co-occurring disorders" in a clear way and whether some disorders are co-occurring or actually part of a subtype of ASD. Subcommittee members discussed the question of whether the term "co-occurring disorders" should be replaced with "associated disorders" to indicate that they can be co-occurring or inherent. It was noted that although we may be talking about a form of ASD for which the GI symptoms are a manifestation, because we do not know enough yet to say this, using the word "associated" may be preferred. Dr. Daniels said that the previous committee had chosen to use the wording "co-occurring conditions" throughout various iterations of the Strategic Plan, and Dr. Insel remarked that this may be an issue to address in 2013.

Dr. Daniels reviewed the proposed changes:

  • Dr. Insel would provide a few sentences of introductory material on page 4 (the gap section) that focus on the transformative breakthroughs that have occurred over the past 18 months.
  • On page 2, material on the last line would be changed from "and not necessarily genetic influences" to "as well as genetic influences."
  • Dr. Dawson and Dr. Koroshetz would work together to add/move the various studies/references and the related text as discussed throughout this section, including the Ashwood study and three papers that recently came off embargo (Archives of General Psychiatry/JAMA Psychiatry).
  • On page 3, the use of the phrase "co-occurring disorders" or "associated disorders" would be discussed at a future meeting.

A vote was taken. The subcommittee voted unanimously to finalize Question 2 with these changes for submission to the full Committee.

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Discussion of Question 3 Update: Risk Factors

Ms. Redwood stated that the material for this question came mainly from the external experts and that many queries to these experts remain outstanding, especially some regarding the references. Dr. Insel said that many of the comments were his and that he was concerned about how accessible this material would be to the general reader. He thought that rather than listing genes, it might be better to provide an overview for readers about how to understand this enormous volume of literature. Dr. Birnbaum suggested that providing a table might be useful. Dr. Insel noted that the problem is that more than 100 genes have been implicated, mostly over the last 9 months, and it is difficult to summarize this material. What might be needed, he suggested, is an overview/perspective on what the information is saying about risk and resilience. He said he would rework the material to make it more accessible and provide concise take-home messages.

There was also a question about whether or not the subcommittee agreed with the conclusion on page 1, third paragraph, that "New research has emphasized the substantial work supporting environmental causes (potentially as large or larger than genetic heritability) in the etiology of autism." Subcommittee members

discussed reference 17, the Hallmayer study, in regard to that conclusion—the only data paper included in references 17, 18, and 19. Dr. Insel pointed out that the Hallmayer paper did not look at non-twin siblings.14 Rather, it looked at monozygotic (MZ) and dizygotic (DZ) twins and accepted the previous literature that said that the recurrence rate was 8 percent in siblings, which is much lower than the 21 percent rate that was found in the DZ twins. Therefore, one could conclude that shared prenatal environment is a very significant factor. The problem is that once one knows what the actual recurrence rate is from the Ozonoff paper,15 the Hallmayer conclusion does not hold up. Although it could be stated that the rate in MZ twins was lower than previously described, there was concern about the conclusion that the high rate in the DZ twins relative to the recurrence rates can be taken to mean that shared prenatal environment is a major factor.

Dr. Koroshetz said that the conclusions in this paper16 are based on the data in that paper alone, but it is only when the data are compared to the data in another study of non-twins that problems in interpretation arise. After discussion, it was agreed that to clarify this issue, a detailed description of the concordance rates for autism and ASD for the two samples would be provided and there would be no attempt to try to use the Hallmayer paper as evidence to support shared prenatal influences. A general statement also will be added at the end of the paragraph that talks about the need to continue to explore both genetic and shared environmental risk factors in the prenatal environment. Dr. Insel agreed to craft some language, working with Ms. Redwood and Dr. Dawson. Also, after discussion, it was agreed to delete the last sentence at the bottom of page 1 about cortical gene expression.

Dr. Insel observed that, on page 2, the text indicates that identifying environmental chemicals that affect particular patterns of gene expression or particular pathways of gene involvement may be a better way forward. He said that this may not be realistic, given the large number of genes and gene pathways implicated and the difficulties involved in linking environmental chemicals to any of the known signaling pathways. Dr. Birnbaum said that the effects on pathways or patterns will be important rather than effects on any one specific gene.

After discussion, it was agreed to delete the parenthetical phrase "specific congeners" on page 2, because it would be confusing. It was also agreed to write, "Specific PCBs have been shown...." and then provide an example about PCBs or some other environment factor in that sentence. Dr. Birnbaum and Dr. Lawler will work with Ms. Redwood to do this. Also, the references will be carefully reviewed in this section. Dr. Insel said he would withdraw his previous comment about environmental factors and genetics.

Ms. Redwood and Dr. Lawler will work on some rewording in the second paragraph on page 2 and add a specific reference to the folate paper.17

Regarding the discussion about advancing maternal and paternal age and the strength of the findings, in the third paragraph on page 2, Dr. Insel said that the biggest recent study was the Kong paper in Nature, which did, in fact, find a maternal effect.18 However, after regression against paternal age, it turned out that the paternal age effect was the driving factor. Only Peter Bearman's study has reported a maternal age effect, and that study used a very different approach and a different kind of dataset than did Kong, Richenberg, and others. Subcommittee members discussed the effects different kinds of studies tend to find regarding maternal and paternal age. It was agreed to leave the reference to the maternal age as is.

Ms. Redwood suggested changing the beginning of the first paragraph under gaps on page 2,"…new investigations have emphasized the absence of a role for environmental factors in etiology," referring to the traction that has been gained in genetic studies and the much greater need at this time to investigate environmental factors—because we still lack the ability to pinpoint high-impact environmental signals. She noted that this is the most serious gap in the studies of risk factors, and more detail is needed in this area. Subcommittee members discussed some of the difficulties involving in finding possible environment "smoking guns" and emphasized the need to try to understand the range of environmental impacts on autism. Dr. Insel said that he believed it would be important to open the paragraph by saying that there is a real need to study environmental factors without listing those specific factors at this time. Dr. Boyle and Dr. Dawson mentioned that, to elaborate on the beginning of this paragraph, they could provide text that would emphasize a number of studies involving environmental factors that are coming to fruition fairly soon, as well as some studies that have now been replicated. Ms. Redwood will also help revise the introductory sentence. Ms. Redwood said that there have been several public comments indicating that parents are asking for this research, and this continues to be an area that is not being studied in terms of cumulative effects.

Dr. Daniels reviewed the proposed changes:

  • At the beginning of the chapter, Dr. Insel would provide some updated information about new papers and take-home messages and will rework chapter material as necessary to improve accessibility.
  • Dr. Insel, Ms. Redwood, and Dr. Dawson would develop some descriptive language about the concordance rates and the role of prenatal environment on page 1. The Hallmayer paper would not be used as evidence to support shared prenatal influences. A general statement would be added at the end of the paragraph that talks about the need to continue to explore both genetic and shared environmental risk factors in the prenatal environment.
  • The last sentence at the bottom of page 1 about cortical gene expression would be deleted.
  • It was agreed to delete the phrase "specific congeners" on page 2.
  • Dr. Birnbaum and Dr. Lawler will work with Ms. Redwood (page 2) to give an example about PCBs or some other environmental factors. It was also agreed to write, "Specific PCBs have been shown...." and then provide an example about PCBs or some other environment factor. The references in this section will be carefully reviewed.
  • In the second paragraph, page 2, Ms. Redwood and Dr. Lawler would do some rewording and add a specific reference to the folate paper.
  • In the third paragraph on page 2, the reference to the maternal age would be left in its current form.
  • Dr. Boyle, Dr. Dawson, and Ms. Redwood would revise the beginning of the first paragraph under gaps on page 2,"…new investigations have emphasized the absence of a role for environmental factors in etiology," to refer to the traction that has been gained on genetic studies and the much greater need at this time to investigate environmental factors. It would be noted that a number of studies involving environmental factors would be coming to fruition fairly soon, and some studies have now been replicated.

A vote was taken. The committee voted unanimously to finalize Question 3 with these changes for submission to the full Committee.

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Discussion of Question 4 Update: Treatments and Interventions

Dr. Batra remarked that this question summarizes the various treatment options and interventions supported by research that have been conducted over the past 18 months. It covers interventions based on different developmental stages or ages, including early behavioral intervention—for which there is resounding evidence supporting the benefits—and interventions for school-age and adult individuals. Also covered are medications as interventions and pharmacogenetics. Dr. Insel commented, regarding the second full paragraph on page 2, that pharmacogenetics in this area is in its relatively early stages; it was agreed to move this material to the gap section. Subcommittee members also agreed that on page 2, in the first sentence of the third full paragraph "(Phase 1-Phase 4)" will be deleted, and "In addition," will be added before the last sentence, so that it is clear that the 10 studies are in addition to the 12.

Regarding the first full paragraph on page 2, where it is stated that "there is moderate evidence to support efficacy of antipsychotic medication for treating irritability, but there is also strong evidence of its adverse side effects, including sedation and weight gain," it was noted that this sounds like the evidence for the side effects is stronger than the events for efficacy, which is not true. Subcommittee members discussed including text to emphasize that this is an FDA-approved drug that has side effects. There was also discussion that the language currently being used may minimize the benefit and confuse or mislead the public. It was agreed to reword this material to say that there is concern about adverse side effects and their prevalence. However, the rewording should not make it appear as though the evidence for the side effects is much larger than the evidence for efficacy.

Subcommittee members discussed possible confusion in the use of the words "moderate" and "systematic." Dr. Dawson noted that the language refers to the systematic review conducted by the Agency for Healthcare Research and Quality, which concluded that there was insufficient evidence to support even early intervention and also a dearth of research on treatment.19 Ms. Redwood said that it is important to include in the language that there is strong evidence for adverse effects, because this is important to the parent community. Dr. Farchione agreed to reword the first sentence of the first full paragraph on page 2 about systematic review, side effects, and FDA approval to make it more understandable

Dr. Batra said that in the paragraph about co-occurring medical conditions on page 2, the material regarding sleep and use of melatonin and efficacy is also included in Question 2. After discussion, it was agreed to remove the material from Question 2.

Before Mr. Britton began the review of the gaps section, Ms. Singer mentioned that over the past 18 months, they have learned that imaging (fMRI, EEG) can be used to validate treatment response not only of medication but also of behavioral interventions. Dr. Dawson noted that one of the studies that Ms. Singer is referring to is one published this year on early intervention and electrophysiology.20 Ms. Singer said there is also a study by Dr. Kevin Pelphrey looking at pivotal response training that demonstrated the presence of a biological signature in response to a behavioral intervention.21 Dr. Insel said that the Pelphrey paper represents a breakthrough—the first study to find change in brainwave activity—and is a major finding as well as an example of the kind of work that is needed going forward. He suggested that the Pelphrey paper be mentioned under gaps, in the fourth paragraph on page 3, which talks about outcome measures that can monitor changes in brain connectivity and/or activity and correlate those changes with behavioral and social therapies.

To address concerns about language involving neural responses not being sufficiently specific, Dr. Dawson suggested adding a sentence on page 1 along the lines of "This is the first study to show that a behavioral intervention can result in a measured change in brainwave activity and brain connectivity." It was also agreed to delete, at the very bottom of page 1, the sentence "In an exciting example of this approach, which could serve as a model for ASD, in 2012 the FDA approved Ivacaftor for cystic fibrosis, a breakthrough medication specifically for the 4% of cystic fibrosis with a G551D mutation."

Mr. Britton described the material in the gaps section, which begins by summarizing the contributions of the four experts. The next paragraph is a large section on the impact of phenotypical differentiation among co-occurring conditions. A clarification was requested in the final sentence of the second paragraph under gaps that reads "Treatments for co-occurring conditions may be less effective or result in paradoxical effects in some individuals with ASD" to indicate that there are no peer-reviewed studies supporting this. Subcommittee members discussed whether to remove the sentence or modify it. Ms. Singer suggested keeping the sentence because of concerns among many parents and clinicians, while at the same time pointing out that there is no evidence about this one way or the other. Dr. Dawson said that she thought that the need for treatment to be tailored to the biology of a person's autism is important. Dr. Koroshetz suggested changing the sentence to read as follows: "It is important to understand whether the standard treatments for co-occurring conditions are as effective in individuals with autism as in typically developed individuals." Subcommittee members agreed on this wording.

Mr. Britton described the next several paragraphs in gaps, noting that the final paragraph covers an important if controversial subject—the side effects of behavioral interventions, which are not being sufficiently studied. He said that there is a need to weigh the negatives and the positives of these interventions and identify their net effects.

Ms. Redwood said that regarding the phrasing in the first sentence of the first full paragraph on page 4, "Interventions that are commonly used yet have little evidence need to be rigorously evaluated so they can be disregarded if found ineffective," it is important to also say that interventions need to be used more universally if they are found to be effective. She noted that because there are so few effective drugs and interventions available, parents often make decisions without sufficient evidence (for example, using treatments such as high-dose nonsteroidal anti-inflammatories). However, children with different co-occurring conditions may not respond to a drug or intervention in the same way, and this deserves more study. Helping parents make these types of decisions by providing sufficient information to aid them in determining whether treatments are effective is a gap.

Subcommittee members engaged in extensive discussion of various possible changes in language in this section and the implications of those changes. Mr. Britton emphasized the importance of considering the unintended negative consequences of behavioral interventions, such as loss of strengths or unique interests. Ms. Singer countered that if the unintended side effects were going to be discussed, that it was equally important to point out that there are some children for whom the critical nature of these interventions is such that without them they would not be able to participate in the community or go to school and that behavioral interventions that help decrease negative behaviors are extremely valuable—even critical—for many children.

Dr. Daniels commented that everyone seemed to be in agreement that although interventions are being used to help individuals with ASD, it is important to keep in mind and be respectful of individual differences and individual strengths, as well as the potential benefits and side effects of the intervention. She noted that both of these ideas could be fit into the same sentence by stressing the importance of having interventions to minimize the negative behaviors and symptoms and balancing that by noting the importance of looking at the various side effects, both positive and negative.

Subcommittee members agreed to use the language Dr. Koroshetz offered for the first sentence in the first full paragraph on page 4 about evidence for these commonly used interventions. Dr. Dawson and Ms. Redwood agreed to work with other subcommittee members to revise the middle part of this paragraph, talking about interventions and increasing and supporting positive effects without creating unintentional negative effects. Dr. Dawson and Dr. Insel agreed to draft a general statement about how when conducting interventions, it is important to ensure that the broad impact of interventions (taking into consideration the unique characteristics of individuals) are considered and that happiness and quality of life are included as outcome measures, among other kinds of measures. Mr. Britton suggested that the chapter address observations that he had made in his own research that autistic individuals benefit from being in groups of peers with similar characteristics. Dr. Dawson said that other research has suggested the opposite—that spending time with typically developing peers was more beneficial for overall social skills development. She noted that in a major longitudinal study conducted by Dr. Marian Sigman, it was found that the best predictor of a positive long-term outcome is time spent early on with typically developing peers. Dr. Insel suggested that due to the conflicting data, perhaps there is a research gap in understanding whether spending time in groups with other autistic individuals or interacting with typically-developing peers is more beneficial.

Ms. Redwood raised a concern that although abnormalities such as immune dysregulation and inflammation, oxidative stress, microglial activation, GI problems, and seizures have been documented in children with autism, researchers have not looked at targeted treatments for these issues or gained an understanding of whether they can or should be treated. She suggested that this should be addressed as a gap. Subcommittee members agreed this material could be included in the gaps section.

Dr. Daniels reviewed the proposed changes:

  • Dr. Insel commented, regarding the second full paragraph on page 2, that pharmacogenetics in this area in is in its relatively early stages; it was agreed to move this material to the gap section.
  • On page 2, third full paragraph, in the first sentence, "(Phase 1-Phase 4)" would be deleted and "In addition," would be added before the last sentence so that it would be clear that the 10 studies are in addition to the 12.
  • Dr. Farchione agreed to reword the first sentence of the first full paragraph on page 2 about systematic reviews, side effects, and FDA approval to make it more understandable.
  • In the paragraph about co-occurring medical conditions on page 2, the material regarding sleep and use of melatonin and efficacy would be removed from Question 2.
  • The Pelphrey paper would be mentioned under gaps, in the fourth paragraph on page 3.
  • To address concerns about language involving neural responses not being sufficiently specific, a sentence would be added on page 1 along the lines of "This is the first study to show that a behavioral intervention can result in a measured change in brainwave activity and brain connectivity."
  • It was agreed to delete, at the bottom of page 1, the sentence "In an exciting example of this approach, which could serve as a model for ASD, in 2012 the FDA approved Ivacaftor for cystic fibrosis, a breakthrough medication specifically for the 4% of cystic fibrosis with a G551D mutation."
  • The last sentence of the second paragraph under gaps would be changed to read as follows: "It is important to understand whether the standard treatments for co-occurring conditions are as effective in individuals with autism as in typically developed individuals."
  • Regarding the first full paragraph on page 4 about evidence for commonly used interventions, subcommittee members agreed to use the language Dr. Koroshetz offered for the first sentence in that paragraph. Dr. Dawson and Ms. Redwood agreed to work with other Subcommittee members to revise the middle part of this paragraph, talking about interventions and increasing and supporting positive effects without creating unintentional negative effects. Dr. Dawson and Dr. Insel agreed to draft some text for review to make the last sentence of that paragraph more general. This text would talk about the importance of measuring how these interventions are impacting quality of life and ensuring that we are looking broadly at the impact of interventions (taking into consideration the unique characteristics of individuals) and including happiness and quality of life as outcome measures.
  • It was agreed that in the second paragraph under gaps text would be added to address the concern that although radiological abnormalities and immune dysregulation and inflammation, oxidative stress, microglial activation, and GI problems and seizures have been documented in children with autism, researchers have not looked at targeted treatments for these issues or gained an understanding of whether they can or should be treated.

A vote was taken. The subcommittee voted unanimously to finalize Question 4 with these changes for submission to the full Committee.

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Discussion of Question 7 Update: Infrastructure and Surveillance

Dr. Kimbark said that most of the discussion points focused on the biobanking and genetics sections of this question. The first comment was about current brain banks and the loss of 50 brains from a freezer malfunction in June, which was a tragic blow to the ASD biobank effort. She said that needed here is a clear statement about how many brains are in brain banks, and this information might be best obtained from the experts. Dr. Kau offered to supply to Dr. Kimbark the relevant information, including information about the NICHD brain and tissue bank with the University of Maryland. Ms. Singer noted that we have regressed in brain banking and that this could be a gap area that would help us to institute fail proof measures to prevent such a loss from happening again.

Dr. Kimbark also reviewed text about the relationship with the NIH Neurobiobank and the work Autism Speaks and the Simons Foundation are doing in brain banking. Dr. Insel said that information about how all of the efforts are being coordinated would be useful and that if this information was included in an earlier version of the document, it could be reinserted. It was agreed that Dr. Kimbark will consult with Dr. Dawson regarding a statement about coordination.

Dr. Kimbark moved to the next comment—about pluripotent stem cells—which was discussed to some extent in Question 2. Dr. Insel said that if the number is anything under 5,000 fibroblast lines (collected from people with ASD for induced pluripotent stem cells [iPSC]) the material should be moved to the gaps section. It was agreed to place this material under gaps.

Regarding the genetics section, the main comments focused on the tables and whether they should be kept in the document. Subcommittee members discussed this issue, and Dr. Insel said that for both brains and DNA, a status report is what is needed. Because this is an update on infrastructure, very specific numbers should be provided regarding how many brains are available, but in summary and not table form. It was agreed that the tables are confusing because it is not clear what the differences are between the studies. Dr. Kimbark said she would remove the tables and write some summary sentences to incorporate that information. She said that this text also will provide a broader view of what is happening in the area of DNA collection. Dr. Insel suggested separating DNA collection into multiplex and simplex and then clarifying what is material from probands and what is material from other family members. He also said that it would be important to know what is available currently and what is expected to be available in the future.

The other question is whether or not the subjects mentioned in the sentence "The NIMH-funded Center for Collaborative Genomics Studies on Mental Disorders (CCGSMD) at Rutgers University currently distributes samples from almost 11,500 subjects" are all ASD subjects (bottom of page 2). It was agreed that Dr. Kimbark will get information from the experts to answer this question.

Dr. Boyle said that one important topic that has arisen at the IACC is why ASD prevalence has changed so dramatically over time; since the last report, there has been considerable work that needs to be incorporated. She noted that CDC and Autism Speaks held a workshop to try to guide research on factors contributing to the increase and that since then (2011), there have been two studies that have highlighted the role of changes in identification and a third that has highlighted the limited importance of some perinatal risk factors on changes in ASD prevalence. Dr. Boyle said she would draft a few sentences to include within the context of the surveillance piece on why prevalence has changed.

Dr. Kimbark noted that regarding gaps, from previous discussions it was clear that information is needed about how to create a back-up/protection system for the brain biobank. Mr. Dan Hall is the expert in this area, and it would be valuable to find out from him what kind of backup the National Database for Autism Research (NDAR) uses and how to ensure that there are redundancies in the system. If the appropriate redundancies are not present, this would be considered a gap. Dr. Kimbark agreed to add some information about redundancy in the systems for NDAR and brain and tissue banking.

Dr. Daniels reviewed the proposed changes:

  • Regarding material on page 1 in the biobanking section, Dr. Kau would send Dr. Kimbark relevant material.
  • Dr. Kimbark would consult with Dr. Dawson regarding a statement about coordination (the next paragraph on page 1).
  • It was agreed to place the material on pluripotent stem cells (the first full sentence at the beginning of page 2) under gaps.
  • In the section on genetics, the tables would be removed and replaced with some summary sentences written by Dr. Kimbark.
  • Dr. Kimbark would obtain information from experts regarding question of whether or not the subjects mentioned in the sentence "The NIMH-funded Center for Collaborative Genomics Studies on Mental Disorders (CCGSMD) at Rutgers University currently distributes samples from almost 11,500 subjects" are all ASD subjects.
  • Dr. Boyle would provide Dr. Kimbark with some language in the surveillance section to discuss why prevalence has changed.
  • Dr. Kimbark would add some information about redundancy in the systems for NDAR and brain and tissue banking, after consulting with experts, NDAR, and Dr. Zielke.

A vote was taken. The subcommittee voted unanimously to finalize Question 7 with these changes for submission to the full Committee.

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Wrap-up and Next Steps

Dr. Insel thanked everyone for the hard work on the updates and said that there would be one more pass with these revisions, and then on December 18th the document will be finalized with the full IACC.

Dr. Daniels reviewed next steps. The chapter leads would collect the information that needs to be integrated for their chapters and would receive chapter copies with annotation for the changes that resulted from this meeting. The entire subcommittee would also receive these chapter copies. Drafts should be returned by November 30 so that there is time to integrate the changes. OARC would harmonize the language to ensure a uniform document. On December 18, the chapters would be available—formatted for consideration and voting by the full committee. The December 18 full Committee meeting would be a phone conference and webinar, but the public comment period would be held in-person in a meeting room at NIH, and those comments will be webcast. Written public comments will also be accepted.

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Adjournment

Dr. Insel adjourned the meeting at 3:39 p.m.

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Certification

These minutes of the IACC Subcommittee for Basic and Translational Research were approved by the Subcommittee on March 6, 2013.

I hereby certify that this meeting summary is accurate and complete.

/Thomas Insel/
Thomas Insel, M.D.
Basic and Translational Research Subcommittee Co-Chair
/Geraldine Dawson/
Geraldine Dawson, Ph.D.
Basic and Translational Research Subcommittee Co-Chair
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