Misclassified Exposure in Epigenetic Mediation Analyses. Does DNA Methylation Mediate Effects of Smoking on Birthweight?

AIMS: 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. MATERIALS & METHODS: 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. RESULTS: 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. CONCLUSION: Misclassification correction plus cautious interpretation are recommended for mediation analyses in the presence of exposure misclassification.