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The complexity of neurodevelopment, the rapidity of early neurogenesis, and over 100 years of research identifying environmental influences on neurodevelopment serve as backdrop to understanding factors that influence risk and severity of autism spectrum disorder (ASD). This Keynote Lecture, delivered at the May 2016 annual meeting of the International Society for Autism Research, describes concepts of causation, outlines the trajectory of research on nongenetic factors beginning in the 1960s, and briefly reviews the current state of this science. Causal concepts are introduced, including root causes; pitfalls in interpreting time trends as clues to etiologic factors; susceptible time windows for exposure; and implications of a multi-factorial model of ASD. An historical background presents early research into the origins of ASD. The epidemiologic literature from the last fifteen years is briefly but critically reviewed for potential roles of, for example, air pollution, pesticides, plastics, prenatal vitamins, lifestyle and family factors, and maternal obstetric and metabolic conditions during her pregnancy. Three examples from the case-control CHildhood Autism Risks from Genes and the Environment Study are probed to illustrate methodological approaches to central challenges in observational studies: capturing environmental exposure; causal inference when a randomized controlled clinical trial is either unethical or infeasible; and the integration of genetic, epigenetic, and environmental influences on development. We conclude with reflections on future directions, including exposomics, new technologies, the microbiome, gene-by-environment interaction in the era of -omics, and epigenetics as the interface of those two. As the environment is malleable, this research advances the goal of a productive and fulfilling life for all children, teen-agers and adults. Autism Res 2018, 11: 554-586. © 2018 International Society for Autism Research, Wiley Periodicals, Inc.

LAY SUMMARY

This Keynote Lecture, delivered at the 2016 meeting of the International Society for Autism Research, discusses evidence from human epidemiologic studies of prenatal factors contributing to autism, such as pesticides, maternal nutrition and her health. There is no single cause for autism. Examples highlight the features of a high-quality epidemiology study, and what comprises a compelling case for causation. Emergent research directions hold promise for identifying potential interventions to reduce disabilities, enhance giftedness, and improve lives of those with ASD.