Increased correlation between methylation sites in epigenome-wide replication studies: impact on analysis and results. (December 2017)

• Record Type: Journal Article
• Authors: Popovic, Maja; Fasanelli, Francesca; Fiano, Valentina; Biggeri, Annibale; Richiardi, Lorenzo
• Is Part Of: Epigenomics. Volume 9:Number 12(2017)
• Page Start: 1489
• Page End: 1502
• Publication Date: 2017-12
• Subjects: bias -- correlation -- discovery study -- epigenetics -- EWAS -- replication study; Epigenesis -- Periodicals; Genomics -- Periodicals; Chromatin -- Periodicals; DNA -- Periodicals; 572.87
• DOI: 10.2217/epi-2017-0073
• Languages: English
• ISSNs: 1750-1911

Abstract

Aim: To show that an increased correlation between CpGs after selection through an epigenome-wide association studies (EWAS) might translate into biased replication results.Methods: Pairwise correlation coefficients between CpGs selected in two published EWAS, the top hits replication, Bonferroni p-values, Benjamini–Hochberg (BH) false discovery rate (FDR) and directional FDR r-values were calculated in the NINFEA cohort data. Exposures' random permutations were performed to show the empirical p-value distributions.Results: The average pairwise correlation coefficients between CpGs were enhanced after selection for the replication (e.g., from 0.12 at genome-wide level to 0.26 among the selected CpGs), affecting the empirical p-value distributions and the usual multiple testing control.Conclusion: Bonferroni and Benjamini–Hochberg FDR are inappropriate for the EWAS replication phase, and methods that account for the underlying correlation need to be used.