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FWER and FDR control when testing multiple mediators.

ABSTRACT: Motivation:The biological pathways linking exposures and disease risk are often poorly understood. To gain insight into these pathways, studies may try to identify biomarkers that mediate the exposure/disease relationship. Such studies often simultaneously test hundreds or thousands of biomarkers. Results:We consider a set of m biomarkers and a corresponding set of null hypotheses, where the jth null hypothesis states that biomarker j does not mediate the exposure/disease relationship. We propose a Multiple Comparison Procedure (MCP) that rejects a set of null hypotheses or, equivalently, identifies a set of mediators, while asymptotically controlling the Family-Wise Error Rate (FWER) or False Discovery Rate (FDR). We use simulations to show that, compared to currently available methods, our proposed method has higher statistical power to detect true mediators. We then apply our method to a breast cancer study and identify nine metabolites that may mediate the known relationship between an increased BMI and an increased risk of breast cancer. Availability and implementation:R package MultiMed on https://github.com/SiminaB/MultiMed. Supplementary information:Supplementary data are available at Bioinformatics online.

SUBMITTER: Sampson JN

PROVIDER: S-EPMC6355102 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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FWER and FDR control when testing multiple mediators.

Sampson Joshua N JN Boca Simina M SM Moore Steven C SC Heller Ruth R

Bioinformatics (Oxford, England) 20180701 14

<h4>Motivation</h4>The biological pathways linking exposures and disease risk are often poorly understood. To gain insight into these pathways, studies may try to identify biomarkers that mediate the exposure/disease relationship. Such studies often simultaneously test hundreds or thousands of biomarkers.<h4>Results</h4>We consider a set of m biomarkers and a corresponding set of null hypotheses, where the jth null hypothesis states that biomarker j does not mediate the exposure/disease relation ...[more]

PMID: 29420693

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Project description:BackgroundIn microbiome studies, it is important to detect taxa which are associated with pathological outcomes at the lowest definable taxonomic rank, such as genus or species. Traditionally, taxa at the target rank are tested for individual association, followed by the Benjamini-Hochberg (BH) procedure to control for false discovery rate (FDR). However, this approach neglects the dependence structure among taxa and may lead to conservative results. The taxonomic tree of microbiome data represents alignment from phylum to species rank and characterizes evolutionary relationships across microbial taxa. Taxa that are closer on the tree usually have similar responses to the exposure (environment). The statistical power in microbial association tests can be enhanced by efficiently employing the prior evolutionary information via the taxonomic tree.MethodsWe propose a two-stage microbial association mapping framework (massMap) which uses grouping information from the taxonomic tree to strengthen statistical power in association tests at the target rank. massMap first screens the association of taxonomic groups at a pre-selected higher taxonomic rank using a powerful microbial group test OMiAT. The method then proceeds to test the association for each candidate taxon at the target rank within the significant taxonomic groups identified in the first stage. Hierarchical BH (HBH) and selected subset testing (SST) procedures are evaluated to control the FDR for the two-stage structured tests.ResultsOur simulations show that massMap incorporating OMiAT and the advanced FDR controlling methodologies largely alleviates the multiplicity issue. It is statistically more powerful than the traditional association mapping directly at the target rank while controlling the FDR at desired levels under most scenarios. In our real data analyses, massMap detects more or the same amount of associated species with smaller adjusted p values compared to the traditional method, which further illustrates the efficiency of the proposed framework. The R package of massMap is publicly available at https://sites.google.com/site/huilinli09/software and https://github.com/JiyuanHu/ .ConclusionsmassMap is a novel microbial association mapping framework and achieves additional efficiency by utilizing the intrinsic taxonomic structure of microbiome data.

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FWER and FDR control when testing multiple mediators.

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FWER and FDR control when testing multiple mediators.

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