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1. 2dGBH: Two-dimensional group Benjamini–Hochberg procedure for false discovery rate control in two-way multiple testing of genomic data

   https://doi.org/10.1093/bioinformatics/btae035  

   Yang, Lu ; Wang, Pei ; Chen, Jun ; Schwartz, ed., Russell ( January 2024 , Bioinformatics)

   Emerging omics technologies have introduced a two-way grouping structure in multiple testing, as seen in single-cell omics data, where the features can be grouped by either genes or cell types. Traditional multiple testing methods have limited ability to exploit such two-way grouping structure, leading to potential power loss.

   We propose a new 2D Group Benjamini–Hochberg (2dGBH) procedure to harness the two-way grouping structure in omics data, extending the traditional one-way adaptive GBH procedure. Using both simulated and real datasets, we show that 2dGBH effectively controls the false discovery rate across biologically relevant settings, and it is more powerful than the BH or q-value procedure and more robust than the one-way adaptive GBH procedure.

   2dGBH is available as an R package at: https://github.com/chloelulu/tdGBH. The analysis code and data are available at: https://github.com/chloelulu/tdGBH-paper.

    

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2. Leveraging biological and statistical covariates improves the detection power in epigenome-wide association testing

   https://doi.org/s13059-020-02001-7  

   Huang, J. ( April 2020 , Genome biology)

   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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3. A Two-Sample Distribution-Free Test for Functional Data with Application to a Diffusion Tensor Imaging Study of Multiple Sclerosis

   https://doi.org/10.1111/rssc.12130  

   Pomann, Gina-Maria ; Staicu, Ana-Maria ; Ghosh, Sujit ( January 2016 , Journal of the Royal Statistical Society Series C: Applied Statistics)

   Motivated by an imaging study, the paper develops a non-parametric testing procedure for testing the null hypothesis that two samples of curves observed at discrete grids and with noise have the same underlying distribution. The objective is to compare formally white matter tract profiles between healthy individuals and multiple-sclerosis patients, as assessed by conventional diffusion tensor imaging measures. We propose to decompose the curves by using functional principal component analysis of a mixture process, which we refer to as marginal functional principal component analysis. This approach reduces the dimension of the testing problem in a way that enables the use of traditional non-parametric univariate testing procedures. The procedure is computationally efficient and accommodates different sampling designs. Numerical studies are presented to validate the size and power properties of the test in many realistic scenarios. In these cases, the test proposed has been found to be more powerful than its primary competitor. Application to the diffusion tensor imaging data reveals that all the tracts studied are associated with multiple sclerosis and the choice of the diffusion tensor image measurement is important when assessing axonal disruption.

    

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4. Fine‐Mapping Additive and Dominant SNP Effects Using Group‐LASSO and Fractional Resample Model Averaging

   https://doi.org/10.1002/gepi.21869  

   Sabourin, Jeremy ; Nobel, Andrew B. ; Valdar, William ( November 2014 , Genetic Epidemiology)

   Genomewide association studies (GWAS) sometimes identify loci at which both the number and identities of the underlying causal variants are ambiguous. In such cases, statistical methods that model effects of multiple single‐nucleotide polymorphisms (SNPs) simultaneously can help disentangle the observed patterns of association and provide information about how those SNPs could be prioritized for follow‐up studies. Current multi‐SNP methods, however, tend to assume that SNP effects are well captured by additive genetics; yet when genetic dominance is present, this assumption translates to reduced power and faulty prioritizations. We describe a statistical procedure for prioritizing SNPs at GWAS loci that efficiently models both additive and dominance effects. Our method, LLARRMA‐dawg, combines a group LASSO procedure for sparse modeling of multiple SNP effects with a resampling procedure based on fractional observation weights. It estimates for each SNP the robustness of association with the phenotype both to sampling variation and to competing explanations from other SNPs. In producing an SNP prioritization that best identifies underlying true signals, we show the following: our method easily outperforms a single‐marker analysis; when additive‐only signals are present, our joint model for additive and dominance is equivalent to or only slightly less powerful than modeling additive‐only effects; and when dominance signals are present, even in combination with substantial additive effects, our joint model is unequivocally more powerful than a model assuming additivity. We also describe how performance can be improved through calibrated randomized penalization, and discuss how dominance in ungenotyped SNPs can be incorporated through either heterozygote dosage or multiple imputation.

    

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5. Covariate adaptive familywise error rate control for genome-wide association studies

   https://doi.org/10.1093/biomet/asaa098  

   Zhou, Huijuan ; Zhang, Xianyang ; Chen, Jun ( November 2020 , Biometrika)

   null (Ed.)

   Summary The familywise error rate has been widely used in genome-wide association studies. With the increasing availability of functional genomics data, it is possible to increase detection power by leveraging these genomic functional annotations. Previous efforts to accommodate covariates in multiple testing focused on false discovery rate control, while covariate-adaptive procedures controlling the familywise error rate remain underdeveloped. Here, we propose a novel covariate-adaptive procedure to control the familywise error rate that incorporates external covariates which are potentially informative of either the statistical power or the prior null probability. An efficient algorithm is developed to implement the proposed method. We prove its asymptotic validity and obtain the rate of convergence through a perturbation-type argument. Our numerical studies show that the new procedure is more powerful than competing methods and maintains robustness across different settings. We apply the proposed approach to the UK Biobank data and analyse 27 traits with 9 million single-nucleotide polymorphisms tested for associations. Seventy-five genomic annotations are used as covariates. Our approach detects more genome-wide significant loci than other methods in 21 out of the 27 traits. 

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