Craig J. Newschaffer, Ph.D. Director, A.J. Drexel Autism Institute

1. Novel (epidemiologic) perspectives on environmental contributions to autism risk Craig J. Newschaffer, Ph.D. Director, A.J. Drexel Autism Institute Professor, Epidemiology and Biostatistics Drexel University Philadelphia, Pennsylvania cjn32@drexel.edu

2. Outline • Background issues • Opportunistic research on ASD and the environment (secondary data) • Retrospective research on ASD and the environment (primary data) • Prospective research on ASD and the environment (primary data) • The “iceberg and the lamppost”… • Discovery approaches to ASD and the environment

3. Background issues

4. Autism twin studies Causal Mechanism PKU G E PAH Diet

5. ENVIRONMENTAL RISK FACTORS SECULAR TRENDS IN PREVALENCE

6. Dev Med Child Neurol, 1994 A prenatal critical period… Source: Amaral et al. Trends Nuerosci, 2008 Source: Courchesne et al. JAMA; 2003

7. Opportunistic research on ASD and the environment (secondary data)

8. Most common study type last five years • Rely on existing sources for data on environmental exposures

9. Pesticides Exposure 26-81 days after estimated date of conception Source: Roberts et al EHP 2007

10. Air pollution * Significant test for dose-response Sources: Windham et al EHP 2006 Kalkbrenner et al. Epidemiol 2010

11. Air pollution * Significant test for dose-response Sources: Windham et al EHP 2006 Kalkbrenner et al. Epidemiol 2010 Weiskopf ISEE presentation 2012

12. Maternal prenatal medication use Odds ratios adjusted for parental age, sex of the child, history of maternal asthma (matching: child birth month and year) Source: Gidaya et al IMFAR poster 2012

13. Retrospective research on ASD and the environment (primary data)

14. Most results over the next five years will come from studies with this design • Advantages: • Outcome: • Confirms and subtypes cases • Exposure: • Individual level information • Integration of biosampling (exposure biomarkers; genetic data to address GxE) • Major limitation: measuring exposure during critical periods

15. PBDE exposure Source: Hirtz-Picciotto et al Environ Hlth2011

16. Prenatal vitamin exposure (GxE) • Effect of periconception vitamin intake modified by maternalMTHFR genotype • Larger than expected risk seen for no vitamin use and TT (low enzyme activity) genotype Source: Schmidt et al Epidemiol2011

17. Prospective research on ASD and the environment (primary data)

18. Emergent results over the next five years – more findings over the following five years • Advantages: • Outcome: • Confirms and subtypes cases • Longitudinal outcomes • Quantitative outcomes • Exposure: • Individual level information • Real-time exposure data collection in critical windows • Integration of biosampling (exposure biomarkers; genetic data to address GxE) • Major limitation: time and cost

19. The EARLI study • Dad • Medical records • Self-report • Biological samples DELIVERY • Medical records • Biological samples Pre-pregnancy follow-up Sibling @ 36 mos PREGNANCY POST-PARTUM / EARLY CHILDHOOD Eligibility interview • Mom • Medical records • Self-report • Biological samples • Home • Environmental samples • Environmental surveys • Home • Environmental samples • Environmental surveys • Mom • Biological samples • Sibling • Medical records • Behavioral assessments • Physical examinations • Biological samples • Maternal report • Proband • Medical records • Behavioral assessments • Physical examinations • Biological samples

20. The “iceberg and the lamppost”

21. 8 identified developmental neurotoxicants 200 neurotoxic in humans 1,000 neurotoxic in animal models 3,000 high volume chemicals 80,000 new synthesized chemicals Sources: Landrigan and GrandjeanLancet 2006 Landrigan. CurrOpinPediat 2010 Landrigan and Goldman Health Aff2012

22. Exposomics “Adductomics” • Proof-of-principal work completed comparing smokers and non-smokers Source: Li et al Molec Cell Proteomics2008 Source: Rappaport and Smith Science2010

23. Genome-wide SNP and environment interaction Study to Explore Early Development • Identify SNPs whose effects on ASD risk are heterogeneous by particular prenatal exposures: • Infection • Medication use (B2AR and SSRIs) • Smoking • Alcohol use Source: Ladd-Acosta et al. IMFAR presentation 2012

24. Genotype * Active:Passive Smoking Genotype * Maternal prenatal infection Source: Ladd-Acosta et al. IMFAR presentation 2012

25. Genome-wide DNA methylation • No indication of differences in methylationover the course of pregnancy • Methylation pattern in some regions is different in pregnancy than post partum (post-partum patterns in pregnant women similar to controls) • Methylation patterns in some regions during pregnancy were found to differ by exposure status (alcohol) Source: Feinberg et al. IMFAR poster 2012

26. Recap • Strong rationale exists for investigating environmental risk factors and ASD • Transitioning from opportunistic research relying on secondary data to studies involving primary data collection • Prospective and retrospective approaches are now underway • -omics approaches being integrated into epidemiologic samples • Will provide a platform for discovery work on environmental risk factors • Will also support targeted, hypothesis driven work

27. Acknowledgements Funding • 5R01 ES016443 (NIEHS, NINDS, NICHD, NIMH) • 5R01 ES016443 S1 S2 (NIEHS) • 5938 (Autism Speaks) • 1R01 ES017646 (NIEHS, OD, NICHD) • R01 ES017646 (Fallin) Staff at EARLI and SEED field sites, DCC, and repositories All the EARLI and SEED participating families!!! Collaborators M. DaniFallin Christine Ladd-Acosta Jason Feinberg Nicole Gidaya EARLI and SEED investigators Colleagues William Funk Marc Weiskopff Eric Roberts