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A Index of Scientific Opportunities The following index provides a summary of the many scientific opportunities that were identified by individual workshop speakers and participants. These ideas were not prioritized or debated at the workshop and are not adopted, endorsed, or verified as accurate by the National Academies and as such should not be attributed to the National Acad- emies or the Institute of Medicine. They do, however, represent a rich diversity of possible directions for future research. Each research priority is organized into one of five general categories (Scientific Opportunities for Human Subjects Research, Opportunities Identified to Improve and Enhance Epidemiological Studies, Opportunities to Improve the Under- standing of Autism’s Pathology, Tools and Infrastructure Needs, and Opportunities for Public–Private Partnerships). In addition, each research priority is referenced to the specific page(s) of the proceedings (Chapter 2) where the concept was discussed and attributed to the associated workshop speaker or participant. Concepts are not listed in order of pri- ority or importance. Scientific Opportunities for Human Subjects Research Update clinical diagnosic criteria for autism pp. 21, 249 (Swedo) spectrum disorder (ASD) p. 57 (Choi); p. 268 • Base clinical definition on (Singer) quantifiable measures rather than qualitative scores if needed pp. 50, 88 (Levitt); p. 89 • Establish clinical definitions that (Martinez) allow stratification of ASD subpopulations 283

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284 AUTISM AND THE ENVIRONMENT Identify and stratify biologically meaningful pp. 31, 88 (Levitt); pp. 38, subpopulations 234 (Pessah); p. 48 (Herbert); p. 89 (Martinez); pp. 191, 249 (Bernard); p. 240 (Redwood); p. 256 (Falk); p. 267 (Singer); p. 279 (participant) p. 32 (Levitt); p. 258 • Perform genetic sequencing to (Goldstein) identify functional variants p. 46 (Herbert); p. 57 • Analyze biological samples, (Choi); p. 144 (Redwood); including blood and urine (see also p. 279 (participant) “expand tissue repositories” below in Tools and Infrastructure Needs section) Perform metabolic profiling p. 44 (Herbert) p. 44 (Herbert); p. 281 • Establish metabolic profiles of (participant) vulnerability and treatability p. 37 (Pessah); p. 80 • Separate individuals with genetic (Martinez) etiology from those with a predominately environmental etiology (that may have some genetic susceptibility) to aid in epigenetic sampling p. 137 (Swedo) • Perform genetic analysis comparing distinct ASD subpopulations and similar disorders, for example, Asperger’s disorder, Fragile X Identify biomarkers to examine ASD onset, p. 82 (Lipkin); p. 141 progression, treatment efficacy, metabolic (Leshner); p. 191 (Wilcox); changes, and subpopulations (see also Tools p. 240 (Redwood); p. 242 and Infrastructure Needs section) (Pessah); p. 248 (Blaxill); pp. 268, 271 (Colamarino and Bono); p. 275 (Herbert) Perform scientifically rigorous analysis of novel pp. 12, 146, 234, 271 and purported treatments (Bono); pp. 13, 51, 141 (Leshner); pp. 19, 21 (Swedo); p. 90 (Herbert); p. 144 (Blaxill); p. 235 (participant); p. 239 (Noble); p. 269 (Bernard); p. 276 (Zimmerman)

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285 APPENDIX A p. 21 (Swedo); p. 243 • Use randomized clinical trials (Pessah) p. 53 (James); p. 148 • Investigate responses to medication (Swedo); p. 154 (Herbert); or other forms of treatment p. 235 (participant); p. 268 individuals are currently undergoing (Redwood); p. 271 (Bono); p. 277 (Zimmerman) Perform further analysis on “n of p. 21 (Swedo); p. 45 1” studies including serial (Herbert); p. 141 (Insel); analyses to capture which p. 256 (Falk); p. 275 biomarkers change with (Landrigan) treatment progression pp. 12, 271 (Bono); p. 238 • Examine individuals’ medical (Pessah); p. 263 records (Redwood) p. 90 (Herbert); pp. 91, • Establish metrics by which to 269 (Bernard); p. 234 measure onset and recovery (Bono); p. 249 (Swedo) p. 276 (Swedo) • Perform medical and genetic workups on all known and suspected cases of ASD p. 263 (Redwood) • Explore treatment strategies dependent on autism phenotype p. 268 (Bernard); p. 273 • Investigate comorbidities and cases (Beaudet) of abnormal onset, for example, de novo defects p. 223 (Insel); p. 249 • Examine ASD throughout an (Bernard); p. 251 (Wilcox); individual’s life span, including p. 270 (Hertz-Picciotto) adolescence and adulthood Opportunities to Improve and Enhance Epidemiological Studies Expand analysis of longitudinal studies utilizing pp. 73, 229 (Susser); birth cohorts p. 232 (Fombonne); p. 233 (Insel)

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286 AUTISM AND THE ENVIRONMENT pp. 64, 66, 73, 84, 90, 91, • The National Children’s Study 159, 172, 201, 202, 206, 227, 256 (Landrigan, Susser, Schwartz, Alexander, Hertz- Picciotto, Bernard, participant, Schendel, Needham, Pessah, Falk); p. 80 (Martinez); p. 90 (Hertz-Picciotto); p. 233 (Susser) p. 201 (Hertz-Picciotto) • MARBLES (Markers of Autism Risk in Babies Learning Early Signs) Review and assess on going and completed pp. 145, 200 (Schwartz); epidemiological studies for gaps and p. 202 (Falk); p. 231 opportunities (Schendel) Collect data and examine time trends to p. 21 (Swedo); p. 142 determine if the incidence of ASD has increased (Beaudet); p. 176 (Newschaffer); p. 250 (Susser); p. 267 (Singer); pp. 271, 273, 274, 278 (Bono, Blaxill, Susser, Insel) p. 192 (Wilcox); p. 230 • Examine incidence data from (Newschaffer) populations with distinct risk factors p. 247 (Blaxill); p. 270 • Read retrospective studies that may (Singer); p. 267 offer insightful information on time (Newschaffer) trends Improve pooling and sharing of data and pp. 182, 188, 202, 232, resources 270 (Schendel); pp. 189, 245 (Leshner); p. 197 (Bono); pp. 200, 270 (Hertz-Picciotto); p. 245 (Schwartz); p. 258 (Goldstein) p. 180 (Newschaffer); • Standardize criteria used to define p. 182 (Schendel); p. 276 cohorts (Swedo) p. 182 (Schendel); p. 236 • Improve and standardize screening (Martinez); p. 270 criteria (Newschaffer)

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287 APPENDIX A Perform epidemiological analysis using cohorts p. 73 (Susser); pp. 73, 75, established through “natural experiments” 80, 85, 228, 247, 248, 273 (Susser, Martinez, Schwartz, Fombonne, Blaxill); p. 229 (Fombonne); p. 239 (Swedo); p. 278 (Insel) p. 87 (participant); p. 91 • Examine potential similarities and (Bernard); pp. 181, 228 differences in specific ethnic groups, (Martinez) e.g., Hispanic versus non-Hispanic, The Amish p. 228 (Schendel) • Examine specific occupational exposures p. 229 (Fombonne) • Study populations that were exposed prenatally to infectious diseases, toxins from industrial disasters, etc. pp. 12, 198, 271 (Bono); • Compare vaccinated and p. 198 (Redwood) unvaccinated children p. 162 (participant) • Compare effect of RhoGAM exposure Examine potential increases of associated p. 234 (Pessah) comorbidities Consider adding genetic analysis to all p. 140 (Noble); p. 145 epidemiological studies examining (Falk) environmental risks Consider expansion of analysis of concordance p. 54 (Insel); p. 561 studies in monozygotic and dizygotic twins (Susser); p. 278 (Fombonne) Examine cohorts from international countries, p. 21 (Swedo); pp. 178, especially developing countries 179, 180, 270 (Newschaffer); p. 250 (Falk); p. 278 (Insel) p. 82 (Lipkin); p. 82 • Norwegian cohort (Schendel); pp. 116, 201 (Lipkin, Hertz-Picciotto); p. 194 (Wilcox)

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288 AUTISM AND THE ENVIRONMENT Examine cohorts with an elevated risk of autism, p. 91 (Bernard); p. 258 e.g., AGRE and Baby Sibs (Goldstein) Coordinate efforts with the toxicology field p. 172 (Hertz-Picciotto) Opportunities to Improve the Understanding of Autism’s Pathology and Etiology Examine potential impact of convergence of p. 44 (Herbert); p. 115 multiple types of stressors (Lipkin); p. 131 (Slotkin) Elucidate the potential role of immune system pp. 12, 271 (Bono); pp. and immunological susceptibilities 38, 242 (Pessah); pp. 259, 269 (Goldstein); p. 272 (Noble); p. 277 (Cohen) p. 118 (Lipkin); p. 278 • Expand current efforts in (Insel) microbiomics p. 251 (Bono) • Investigate the role of biopathogens on organ systems, including nervous and digestive Focus on toxicology Examine effects of subtoxic pp. 38, 276 (Pessah) • exposure levels on different organ systems p. 66 (Landrigan); p. 205 • Collect data on neurodevelopmental (Needham) toxicity of major priority pollutants, including toxokinetic study p. 12 (Bono); p. 87 • Examine the potential impact of (participant); p. 240 heavy metals and cosmetics (Hertz-Picciotto) Perform toxokinetic studies pp. 250, 271 (Bono), Develop distribution and p. 239 (Noble); p. 257 excretion profiles (Falk) p. 34 (Pessah); p. 244 • Examine potential effects of toxicant (Noble) synergies Examine the potential role of oxidative stress p. 237 (Needham) Investigate the potential role of metabolism and pp. 44, 128 (Herbert) metabolic responses/dysfunctions

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289 APPENDIX A p. 281 (participant) • Explore impact on modulating brain function and vice versa Generate gene expression profiles, both time p. 32 (Levitt); p. 258 and topology (Goldstein) Examine the potential impact of genetic pp. 29, 32 (Levitt); p. 41 mutations and environmental toxicants on the (Herbert); p. 98 (Beaudet); development and maintenance of neuronal p. 241 (Insel); p. 275 circuitry (Pessah) Examine autism pathology p. 41 (Herbert); p. 258 (Goldstein) p. 21 (Swedo) • Explore changes over time in nervous system function, neurotransmitter profiles, and neuronal circuitry p. 278 (Fombonne) • Examine impact on germ-line cells Expand development and use of imaging as a pp. 41, 45 (Herbert); mechanism to examine progression of autism p. 276 (Spence); p. 277 pathology (Cohen) Develop chelators p. 271 (Hertz-Picciotto) p. 12 (Bono) • Formulate chelators that can cross the blood–brain barrier p. 87 (participant) • Examine efficacy of glutathione as a chelator p. 271 (Bono) • Investigate impact of detoxification of organ systems and its possible impact on inflammation and gastrointestinal problems Expand efforts to perform epigenetic analysis p. 80 (Martinez); pp. 98, 273 (Beaudet); p. 241 (Insel); p. 250 (Bono) Expand development and use of models to pp. 30, 32 (Levitt); p. 243 study ASD (Pessah); p. 252 (Martinez); p. 272 (Noble) p. 112 (Slotkin) • Develop high-throughput models, e.g., cell culture methods

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290 AUTISM AND THE ENVIRONMENT p. 243 (Pessah) • Create animal models that reflect pathology in specific organ systems p. 276 (Pessah) • Establish primary cell lines from autistic individuals p. 237 (Swedo); p. 277 • Study related disorders, e.g., cystic (Coetzee) fibrosis and Fragile X Tools and Infrastructure Needs Expand tissue repositories p. 150 (Insel); pp. 150, 250, 265, (Schwartz); pp. 171, 224 (Hertz- Picciotto, Falk, Schendel); p. 268 (Needham); p. 271 (James); p. 279 (participant) p. 215 (Walt); p. 227 • Require standardized sample (Pessah); p. 269 procurement and storage (Goldstein) Establish programs to expand the number of p. 66 (Landrigan); pp. 221, investigators trained in environmental biology 265 (Schwartz); p. 221 (Goldstein) Establish incentive programs to attract p. 270 (Newschaffer) individuals from other fields to study ASD Develop biomarkers of exposure, susceptibility, p. 82 (Lipkin); p. 134 state, outcome; biomarkers studies that are (Insel); p. 172 (Hertz- replicable; biomarkers to spot the effects of Picciotto); p. 240 environmental neurotoxicants (Redwood); p. 247 (Blaxill); p. 250 (Newschaffer) Invest in the development of improved tools to p. 216 (Walt) analyze and multiplex data, including environmental sampling, biological samples, and potential metabolic changes Develop a large clinical trial network p. 265 (Schwartz); p. 276 (Swedo) p. 54 (Insel); p. 73 (Susser); • Expand autism patient and family pp. 235, 236 (participants); registries p. 237 (Beaudet); p. 269 (Goldstein); p. 276 (Swedo)

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291 APPENDIX A Establish and expand autism centers of p. 66 (Landrigan) excellence to study children’s environmental health Expand resources to identify potential p. 82 (Lipkin); p. 208 environmental factors (Needham); pp. 215, 221 (Walt); p. 238 (Pessah); p. 241 (Hertz-Picciotto); p. 252 (Martinez) • Develop and implement environmental sensor and biosensor technology Take advantage of continuous p. 211 (Walt) sampling p. 207 (Needham); p. 215 • Use strategies that prioritize (Walt); pp. 268, 271 potential environmental stressors or (Singer) use an unbiased strategy p. 205 (Slotkin) • Expand use of technologies that allow high-throughput analysis For example, HPLC, mass p. 207 (Needham); spectroscopy, two-dimensional pp. 213, 214 (Walt) gas chromatography, “lab-on-a- chip”/microfluidics Opportunities for Public–Private Partnerships Increase coordination and integration of each p. 246 (Blaxill); p. 269 stakeholder’s ongoing and planned efforts (Redwood) Establish enhanced methods of coordination p. 188 (Schendel); p. 259 and data-sharing policies for public–private (Goldstein); p. 269 partnerships (Schwartz) Establish collaborations with small, p. 221 (Walt); p. 277 • innovative biotech companies (Coetzee) Improve public engagement in the development p. 260 (Insel); pp. 262, 269 of research priorities (Redwood); p. 267 (Leshner)

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