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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 Autismâs Pathology, Tools and Infrastructure Needs, and Opportunities for PublicâPrivate 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) ⢠Base clinical definition on p. 57 (Choi); p. 268 quantifiable measures rather than (Singer) qualitative scores if needed ⢠Establish clinical definitions that pp. 50, 88 (Levitt); p. 89 allow stratification of ASD (Martinez) subpopulations 283
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) ⢠Perform genetic sequencing to p. 32 (Levitt); p. 258 identify functional variants (Goldstein) ⢠Analyze biological samples, p. 46 (Herbert); p. 57 including blood and urine (see also (Choi); p. 144 (Redwood); âexpand tissue repositoriesâ below in p. 279 (participant) Tools and Infrastructure Needs section)  Perform metabolic profiling p. 44 (Herbert) ⢠Establish metabolic profiles of p. 44 (Herbert); p. 281 vulnerability and treatability (participant) ⢠Separate individuals with genetic p. 37 (Pessah); p. 80 etiology from those with a (Martinez) predominately environmental etiology (that may have some genetic susceptibility) to aid in epigenetic sampling ⢠Perform genetic analysis comparing p. 137 (Swedo) distinct ASD subpopulations and similar disorders, for example, Aspergerâs 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)
APPENDIX A 285 ⢠Use randomized clinical trials p. 21 (Swedo); p. 243 (Pessah) ⢠Investigate responses to medication p. 53 (James); p. 148 or other forms of treatment (Swedo); p. 154 (Herbert); individuals are currently undergoing p. 235 (participant); p. 268 (Redwood); p. 271 (Bono); p. 277 (Zimmerman)  Perform further analysis on ân of p. 21 (Swedo); p. 45 1â studies including serial (Herbert); p. 141 (Insel); analyses to capture which p. 256 (Falk); p. 275 biomarkers change with (Landrigan) treatment progression ⢠Examine individualsâ medical pp. 12, 271 (Bono); p. 238 records (Pessah); p. 263 (Redwood) ⢠Establish metrics by which to p. 90 (Herbert); pp. 91, measure onset and recovery 269 (Bernard); p. 234 (Bono); p. 249 (Swedo) ⢠Perform medical and genetic p. 276 (Swedo) workups on all known and suspected cases of ASD ⢠Explore treatment strategies p. 263 (Redwood) dependent on autism phenotype ⢠Investigate comorbidities and cases p. 268 (Bernard); p. 273 of abnormal onset, for example, de (Beaudet) novo defects ⢠Examine ASD throughout an p. 223 (Insel); p. 249 individualâs life span, including (Bernard); p. 251 (Wilcox); adolescence and adulthood p. 270 (Hertz-Picciotto) 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)
286 AUTISM AND THE ENVIRONMENT ⢠The National Childrenâs Study pp. 64, 66, 73, 84, 90, 91, 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) ⢠MARBLES (Markers of Autism Risk p. 201 (Hertz-Picciotto) 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) ⢠Examine incidence data from p. 192 (Wilcox); p. 230 populations with distinct risk factors (Newschaffer) ⢠Read retrospective studies that may p. 247 (Blaxill); p. 270 offer insightful information on time (Singer); p. 267 trends (Newschaffer) 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) ⢠Standardize criteria used to define p. 180 (Newschaffer); cohorts p. 182 (Schendel); p. 276 (Swedo) ⢠Improve and standardize screening p. 182 (Schendel); p. 236 criteria (Martinez); p. 270 (Newschaffer)
APPENDIX A 287 Perform epidemiological analysis using cohorts p. 73 (Susser); pp. 73, 75, established through ânatural experimentsâ 80, 85, 228, 247, 248, 273 (Susser, Martinez, Schwartz, Fombonne, Blaxill); p. 229 (Fombonne); p. 239 (Swedo); p. 278 (Insel) ⢠Examine potential similarities and p. 87 (participant); p. 91 differences in specific ethnic groups, (Bernard); pp. 181, 228 e.g., Hispanic versus non-Hispanic, (Martinez) The Amish ⢠Examine specific occupational p. 228 (Schendel) exposures ⢠Study populations that were exposed p. 229 (Fombonne) prenatally to infectious diseases, toxins from industrial disasters, etc. ⢠Compare vaccinated and pp. 12, 198, 271 (Bono); unvaccinated children p. 198 (Redwood) ⢠Compare effect of RhoGAM p. 162 (participant) 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) ⢠Norwegian cohort p. 82 (Lipkin); p. 82 (Schendel); pp. 116, 201 (Lipkin, Hertz-Picciotto); p. 194 (Wilcox)
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 Autismâs 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) ⢠Expand current efforts in p. 118 (Lipkin); p. 278 microbiomics (Insel) ⢠Investigate the role of biopathogens p. 251 (Bono) on organ systems, including nervous and digestive Focus on toxicology ⢠Examine effects of subtoxic pp. 38, 276 (Pessah) exposure levels on different organ systems ⢠Collect data on neurodevelopmental p. 66 (Landrigan); p. 205 toxicity of major priority pollutants, (Needham) including toxokinetic study ⢠Examine the potential impact of p. 12 (Bono); p. 87 heavy metals and cosmetics (participant); p. 240 (Hertz-Picciotto)  Perform toxokinetic studies pp. 250, 271 (Bono),  Develop distribution and p. 239 (Noble); p. 257 excretion profiles (Falk) ⢠Examine potential effects of toxicant p. 34 (Pessah); p. 244 synergies (Noble) Examine the potential role of oxidative stress p. 237 (Needham) Investigate the potential role of metabolism and pp. 44, 128 (Herbert) metabolic responses/dysfunctions
APPENDIX A 289 ⢠Explore impact on modulating brain p. 281 (participant) 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) ⢠Explore changes over time in p. 21 (Swedo) nervous system function, neurotransmitter profiles, and neuronal circuitry ⢠Examine impact on germ-line cells p. 278 (Fombonne) 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) ⢠Formulate chelators that can cross p. 12 (Bono) the bloodâbrain barrier ⢠Examine efficacy of glutathione as a p. 87 (participant) chelator ⢠Investigate impact of detoxification of p. 271 (Bono) 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) ⢠Develop high-throughput models, p. 112 (Slotkin) e.g., cell culture methods
290 AUTISM AND THE ENVIRONMENT ⢠Create animal models that reflect p. 243 (Pessah) pathology in specific organ systems ⢠Establish primary cell lines from p. 276 (Pessah) autistic individuals ⢠Study related disorders, e.g., cystic p. 237 (Swedo); p. 277 fibrosis and Fragile X (Coetzee) 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) ⢠Require standardized sample p. 215 (Walt); p. 227 procurement and storage (Pessah); p. 269 (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) ⢠Expand autism patient and family p. 54 (Insel); p. 73 (Susser); registries pp. 235, 236 (participants); p. 237 (Beaudet); p. 269 (Goldstein); p. 276 (Swedo)
APPENDIX A 291 Establish and expand autism centers of p. 66 (Landrigan) excellence to study childrenâs 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 ⢠Use strategies that prioritize p. 207 (Needham); p. 215 potential environmental stressors or (Walt); pp. 268, 271 use an unbiased strategy (Singer) ⢠Expand use of technologies that p. 205 (Slotkin) allow high-throughput analysis  For example, HPLC, mass p. 207 (Needham); spectroscopy, two-dimensional pp. 213, 214 (Walt) gas chromatography, âlab-on-a- chipâ/microfluidics Opportunities for PublicâPrivate Partnerships Increase coordination and integration of each p. 246 (Blaxill); p. 269 stakeholderâs ongoing and planned efforts (Redwood) Establish enhanced methods of coordination p. 188 (Schendel); p. 259 and data-sharing policies for publicâprivate (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)