Jia Guo1,2, Kylie W Riley1,3, Teresa Durham1,3, Amy E Margolis1,4, Shuang Wang1,2, Frederica Perera1,3, Julie B Herbstman1,3. 1. Columbia Center for Children's Environmental Health, Mailman School of Public Health, Columbia University, New York, NY, United States. 2. Department of Biostatistics, Mailman School of Public Health, Columbia University, New York, NY, United States. 3. Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY, United States. 4. Division of Child and Adolescent Psychiatry, Columbia University Irving Medical Center, New York, NY, United States.
Abstract
Introduction: Prenatal environmental exposures have been associated with children's cognitive, behavioral, and mental health problems, and alterations in DNA methylation have been hypothesized as an underlying biological mechanism. However, when testing this hypothesis, it is often difficult to overcome the problem of multiple comparisons in statistical testing when evaluating a large number of developmental outcomes and DNA methylation sites as potential mediators. The objective of this study is to implement a 'meet-in-the-middle' approach with a sequential roadmap to address this concern. Methods: In the Columbia Center for Children's Environmental Health birth cohort study, we implemented a 5-step sequential process for identifying CpG sites that mediate associations between prenatal environmental exposures and cognitive, behavioral, and mental health problems as measured by the Wechsler Intelligence Scale for Children-Fourth Edition (WISC-IV) and the Child Behavior Checklist (CBCL). These steps include 1) the identification of biological pathways that are relevant to each outcome of interest; 2) selection of a set of genes and CpGs on genes that are significantly associated with the outcomes; 3) identification of exposures that are significantly associated with selected CpGs; 4) examination of exposure-outcome relationships among those where significant CpGs were identified; and 5) mediation analysis of the selected exposures and corresponding outcomes. In this study, we considered a spectrum of environmental exposure classes including environmental phenols, pesticides, phthalates, flame retardants and air pollutants. Results: Among all considered exposures and outcomes, we found one CpG site (cg27510182) on gene (DAB1) that potentially mediates the effect of exposure to PAH on CBCL social problems at children aged 7. Conclusion: This 'meet-in-the-middle' approach attenuates concerns regarding multiple comparisons by focusing on genes and pathways that are biologically relevant for the hypothesis.
Introduction: Prenatal environmental exposures have been associated with children's cognitive, behavioral, and mental health problems, and alterations in DNA methylation have been hypothesized as an underlying biological mechanism. However, when testing this hypothesis, it is often difficult to overcome the problem of multiple comparisons in statistical testing when evaluating a large number of developmental outcomes and DNA methylation sites as potential mediators. The objective of this study is to implement a 'meet-in-the-middle' approach with a sequential roadmap to address this concern. Methods: In the Columbia Center for Children's Environmental Health birth cohort study, we implemented a 5-step sequential process for identifying CpG sites that mediate associations between prenatal environmental exposures and cognitive, behavioral, and mental health problems as measured by the Wechsler Intelligence Scale for Children-Fourth Edition (WISC-IV) and the Child Behavior Checklist (CBCL). These steps include 1) the identification of biological pathways that are relevant to each outcome of interest; 2) selection of a set of genes and CpGs on genes that are significantly associated with the outcomes; 3) identification of exposures that are significantly associated with selected CpGs; 4) examination of exposure-outcome relationships among those where significant CpGs were identified; and 5) mediation analysis of the selected exposures and corresponding outcomes. In this study, we considered a spectrum of environmental exposure classes including environmental phenols, pesticides, phthalates, flame retardants and air pollutants. Results: Among all considered exposures and outcomes, we found one CpG site (cg27510182) on gene (DAB1) that potentially mediates the effect of exposure to PAH on CBCL social problems at children aged 7. Conclusion: This 'meet-in-the-middle' approach attenuates concerns regarding multiple comparisons by focusing on genes and pathways that are biologically relevant for the hypothesis.
Authors: Sandra M Sánchez-Sánchez; Juliana Magdalon; Karina Griesi-Oliveira; Guilherme L Yamamoto; Carolina Santacruz-Perez; Mariana Fogo; Maria Rita Passos-Bueno; Andrea L Sertié Journal: Hum Mutat Date: 2018-07-26 Impact factor: 4.878
Authors: Virginia Rauh; Srikesh Arunajadai; Megan Horton; Frederica Perera; Lori Hoepner; Dana B Barr; Robin Whyatt Journal: Environ Health Perspect Date: 2011-04-21 Impact factor: 9.031
Authors: Robin M Whyatt; David E Camann; Patrick L Kinney; Andria Reyes; Judy Ramirez; Jessica Dietrich; Diurka Diaz; Darrell Holmes; Frederica P Perera Journal: Environ Health Perspect Date: 2002-05 Impact factor: 9.031
Authors: Amy E Margolis; Bruce Ramphal; David Pagliaccio; Sarah Banker; Ena Selmanovic; Lauren V Thomas; Pam Factor-Litvak; Frederica Perera; Bradley S Peterson; Andrew Rundle; Julie B Herbstman; Jeff Goldsmith; Virginia Rauh Journal: Environ Res Date: 2021-06-25 Impact factor: 6.498