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Background Epigenome-wide association studies (EWAS), which seek the association between epigenetic marks and an outcome or exposure, involve multiple hypothesis testing. False discovery rate (FDR) control has been widely used for multiple testing correction. However, traditional FDR control methods do not use auxiliary covariates, and they could be less powerful if the covariates could inform the likelihood of the null hypothesis. Recently, many covariate-adaptive FDR control methods have been developed, but application of these methods to EWAS data has not yet been explored. It is not clear whether these methods can significantly improve detection power, and if so, which covariates are more relevant for EWAS data. Results In this study, we evaluate the performance of five covariate-adaptive FDR control methods with EWAS-related covariates using simulated as well as real EWAS datasets. We develop an omnibus test to assess the informativeness of the covariates. We find that statistical covariates are generally more informative than biological covariates, and the covariates of methylation mean and variance are almost universally informative. In contrast, the informativeness of biological covariates depends on specific datasets. We show that the independent hypothesis weighting (IHW) and covariate adaptive multiple testing (CAMT) method are overall more powerful, especially for sparse signals, and could improve the detection power by a median of 25% and 68% on real datasets, compared to the ST procedure. We further validate the findings in various biological contexts. Conclusions Covariate-adaptive FDR control methods with informative covariates can significantly increase the detection power for EWAS. For sparse signals, IHW and CAMT are recommended.
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ZAP: Z -Value Adaptive Procedures for False Discovery Rate Control with Side Information
Abstract Adaptive multiple testing with covariates is an important research direction that has gained major attention in recent years. It has been widely recognised that leveraging side information provided by auxiliary covariates can improve the power of false discovery rate (FDR) procedures. Currently, most such procedures are devised with p-values as their main statistics. However, for two-sided hypotheses, the usual data processing step that transforms the primary statistics, known as p-values, into p-values not only leads to a loss of information carried by the main statistics, but can also undermine the ability of the covariates to assist with the FDR inference. We develop a p-value based covariate-adaptive (ZAP) methodology that operates on the intact structural information encoded jointly by the p-values and covariates. It seeks to emulate the oracle p-value procedure via a working model, and its rejection regions significantly depart from those of the p-value adaptive testing approaches. The key strength of ZAP is that the FDR control is guaranteed with minimal assumptions, even when the working model is misspecified. We demonstrate the state-of-the-art performance of ZAP using both simulated and real data, which shows that the efficiency gain can be substantial in comparison with p-value-based methods. Our methodology is implemented in the R package zap.
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- Award ID(s):
- 2015339
- PAR ID:
- 10468549
- Publisher / Repository:
- Oxford University Press
- Date Published:
- Journal Name:
- Journal of the Royal Statistical Society Series B: Statistical Methodology
- Volume:
- 84
- Issue:
- 5
- ISSN:
- 1369-7412
- Page Range / eLocation ID:
- 1886 to 1946
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1111/rssb.12557
