title: Misclassified exposure in epigenetic mediation analyses. Does DNA methylation mediate effects of smoking on birthweight?
abstract: Assessing whether epigenetic alterations mediate associations between environmental exposures and health outcomes is increasingly popular. We investigate the impact of exposure misclassification in such investigations.
  
  
  
  We quantify bias and false-positive rates due to exposure misclassification in mediation analysis and assess the performance of the simulation extrapolation method (SIMEX). We evaluate whether DNA-methylation mediates smoking-birth weight relationship in the Norwegian Mother and Child Study birth cohort.
  
  
  
  Ignoring exposure misclassification increases type I error in mediation analysis. The direct effect is underestimated and, when the mediator is a biomarker of the exposure, as is true for smoking, the indirect effect is overestimated.
  
  
  
  Misclassification correction plus cautious interpretation are recommended for mediation analyses in the presence of exposure misclassification.
authors.affiliation: Department of Psychiatry, Harvard Medical School, Boston, MA 02115, USA.|Psychiatric Biostatistics Laboratory, McLean Hospital, Belmont, MA 02478, USA.
authors.forename: Linda
authors.initials: L
authors.lastname: Valeri
authors.affiliation: National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health & Human Services, Research Triangle Park, NC, USA.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Reese
authors.affiliation: National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health & Human Services, Research Triangle Park, NC, USA.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Zhao
authors.affiliation: National Institute of Public Health, Oslo, Norway.
authors.forename: Christian M
authors.initials: CM
authors.lastname: Page
authors.affiliation: National Institute of Public Health, Oslo, Norway.
authors.forename: Wenche
authors.initials: W
authors.lastname: Nystad
authors.affiliation: Department of Biostatistics, Harvard T.H. Chan School of Public Health.
authors.forename: Brent A
authors.initials: BA
authors.lastname: Coull
authors.affiliation: National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health & Human Services, Research Triangle Park, NC, USA.
authors.forename: Stephanie J
authors.initials: SJ
authors.lastname: London
mesh_terms: D000328:Adult; D015982:Bias; D001724:Birth Weight / Q000235:genetics*; D019175:DNA Methylation; D057890:Epigenomics / Q000379:methods / Q000592:standards*; D005189:False Positive Reactions; D005260:Female; D005317:Fetal Growth Retardation / Q000453:epidemiology / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods / Q000592:standards*; D006801:Humans; D007231:Infant, Newborn; D012907:Smoking / Q000009:adverse effects / Q000453:epidemiology* / Q000235:genetics
keywords: DNA methylation; mediation analysis; misclassification