Abstract
Infant sibling studies have been at the vanguard of autism spectrum disorders (ASD) research over the past decade, providing important new knowledge about the earliest emerging signs of ASD and expanding our understanding of the developmental course of this complex disorder. Studies focused on siblings of children with ASD also have unrealized potential for contributing to ASD etiologic research. Moving targeted time of enrollment back from infancy toward conception creates tremendous opportunities for optimally studying risk factors and risk biomarkers during the pre-, peri- and neonatal periods. By doing so, a traditional sibling study, which already incorporates close developmental follow-up of at-risk infants through the third year of life, is essentially reconfigured as an enriched-risk pregnancy cohort study. This review considers the enriched-risk pregnancy cohort approach of studying infant siblings in the context of current thinking on ASD etiologic mechanisms. It then discusses the key features of this approach and provides a description of the design and implementation strategy of one major ASD enriched-risk pregnancy cohort study: the Early Autism Risk Longitudinal Investigation (EARLI).
Highlights
In 1957, Pearson and Kley published a prescient paper asserting that neuropsychiatric research should capitalize on the “tendency of particular abnormalities of behavior to run in families” (p. 406) so that “subpopulations defined in terms of genetic relationship to index cases... might be studied longitudinally...” (p. 418) [1]
We consider the role that infant sibling designs can play in autism risk factor research in the context of the evolving understanding of autism etiology and describe the design and methods which are being employed by a major high-risk sibling cohort study focused on autism etiology: the Early Autism Risk Longitudinal Investigation (EARLI)
Infant sibling studies have already played a major role in autism research over the past decade, improving our understanding of the complex early developmental trajectory of autism, providing exciting leads on approaches for early detection and documenting recurrence risk under today’s diagnostic standards
Summary
In 1957, Pearson and Kley published a prescient paper asserting that neuropsychiatric research should capitalize on the “tendency of particular abnormalities of behavior to run in families” (p. 406) so that “subpopulations defined in terms of genetic relationship to index cases... might be studied longitudinally...” (p. 418) [1]. Certain findings that have begun to emerge regarding potential environmental risk factors for autism have limitations with respect to exposure measurement that could be obviated through prospective data collection in an expanded infant sibling study design. Etiologic heterogeneity in autism is likely, and identification of phenotypic correlates that mark distinct etiologies or, perhaps more realistically, can serve as useful endophenotypes for identifying certain causal components, is an active area of ongoing research Given this situation, the expansion of infant sibling study designs for etiologic research where exposure data are captured prospectively during potentially relevant critical windows, outcomes are prospectively characterized in detail, and event rates are higher than in population-based samples would appear to be one quite useful research approach. EARLI’s sample size is large in relation to other infant sibling studies, there will no doubt be challenges related to sample size, and, as mentioned previously, attention to designing analytic contrasts in ways that maximize efficiency and incorporation of dimensional as well as categorical outcomes will likely prove helpful in this regard
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