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Epigenomics. 2017 Dec;9(12):1489-1502. doi: 10.2217/epi-2017-0073. Epub 2017 Nov 6.

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

Author information

1
Department of Medical Sciences, University of Turin & CPO Piemonte, Turin, Italy.
2
Department of Statistics, Computer Science, Applications «G. Parenti», University of Florence, Florence, Italy.

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.

KEYWORDS:

EWAS; bias; correlation; discovery study; epigenetics; replication study

PMID:
29106300
DOI:
10.2217/epi-2017-0073
[Indexed for MEDLINE]

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