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

Abstract

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.

Keywords::

• DNA methylation
• mediation analysis
• misclassification

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: www.tandfonline.com/doi/suppl/10.2217/3dp-2022-0019

Acknowledgements

The authors are grateful to all the participating families in Norway who take part in the MoBa study. The authors thank F Day of NIEHS and for expert computing assistance.

Financial & competing interests disclosure

This work was supported in part by the Intramural Research Program of NIH, National Institute of Environmental Health Sciences (NIEHS). The Norwegian Mother and Child Cohort Study is supported by the Norwegian Ministry of Health and the Ministry of Education and Research, NIH/NIEHS (contract number N01-ES-75558 and ZO1 ES-49019), NIH/NINDS (grant number 1 UO1 NS 047537-01)and the Norwegian Research Council/FUGE (grant number 151918/S10), and the present project by the Norwegian Research Council/BIOBANK (grant no 221097). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Additional information

Funding

This work was supported in part by the Intramural Research Program of NIH, National Institute of Environmental Health Sciences (NIEHS). The Norwegian Mother and Child Cohort Study is supported by the Norwegian Ministry of Health and the Ministry of Education and Research, NIH/NIEHS (contract number N01-ES-75558 and ZO1 ES-49019), NIH/NINDS (grant number 1 UO1 NS 047537-01)and the Norwegian Research Council/FUGE (grant number 151918/S10), and the present project by the Norwegian Research Council/BIOBANK (grant no 221097). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.