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.