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1. APIR: Aggregating Universal Proteomics Database Search Algorithms for Peptide Identification with FDR Control

   https://doi.org/10.1093/gpbjnl/qzae042  

   Chen, Yiling Elaine; Ge, Xinzhou; Woyshner, Kyla; McDermott, MeiLu; Manousopoulou, Antigoni; Ficarro, Scott B; Marto, Jarrod A; Li, Kexin; Wang, Leo David; Li, Jingyi Jessica (April 2024, Genomics, Proteomics & Bioinformatics)

   Fu, Yan (Ed.)

   Abstract Advances in mass spectrometry (MS) have enabled high-throughput analysis of proteomes in biological systems. The state-of-the-art MS data analysis relies on database search algorithms to quantify proteins by identifying peptide–spectrum matches (PSMs), which convert mass spectra to peptide sequences. Different database search algorithms use distinct search strategies and thus may identify unique PSMs. However, no existing approaches can aggregate all user-specified database search algorithms with a guaranteed increase in the number of identified peptides and a control on the false discovery rate (FDR). To fill in this gap, we proposed a statistical framework, Aggregation of Peptide Identification Results (APIR), that is universally compatible with all database search algorithms. Notably, under an FDR threshold, APIR is guaranteed to identify at least as many, if not more, peptides as individual database search algorithms do. Evaluation of APIR on a complex proteomics standard dataset showed that APIR outpowers individual database search algorithms and empirically controls the FDR. Real data studies showed that APIR can identify disease-related proteins and post-translational modifications missed by some individual database search algorithms. The APIR framework is easily extendable to aggregating discoveries made by multiple algorithms in other high-throughput biomedical data analysis, e.g., differential gene expression analysis on RNA sequencing data. The APIR R package is available at https://github.com/yiling0210/APIR. 

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2. Multi-omics Integrative Analysis for Incomplete Data Using Weighted p-Value Adjustment Approaches

   https://doi.org/10.1007/s13253-024-00603-3  

   Zhang, Wenda; Ma, Zichen; Ho, Yen-Yi; Yang, Shuyi; Habiger, Joshua; Huang, Hsin-Hsiung; Huang, Yufei (February 2024, Journal of Agricultural, Biological and Environmental Statistics)

   Abstract The advancements in high-throughput technologies provide exciting opportunities to obtain multi-omics data from the same individuals in a biomedical study, and joint analyses of data from multiple sources offer many benefits. However, the occurrence of missing values is an inevitable issue in multi-omics data because measurements such as mRNA gene expression levels often require invasive tissue sampling from patients. Common approaches for addressing missing measurements include analyses based on observations with complete data or multiple imputation methods. In this paper, we propose a novel integrative multi-omics analytical framework based onp-value weight adjustment in order to incorporate observations with incomplete data into the analysis. By splitting the data into a complete set with full information and an incomplete set with missing measurements, we introduce mechanisms to derive weights and weight-adjustedp-values from the two sets. Through simulation analyses, we demonstrate that the proposed framework achieves considerable statistical power gains compared to a complete case analysis or multiple imputation approaches. We illustrate the implementation of our proposed framework in a study of preterm infant birth weights by a joint analysis of DNA methylation, mRNA, and the phenotypic outcome. Supplementary materials accompanying this paper appear online. 

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3. Exaggerated false positives by popular differential expression methods when analyzing human population samples

   https://doi.org/10.1186/s13059-022-02648-4  

   Li, Yumei; Ge, Xinzhou; Peng, Fanglue; Li, Wei; Li, Jingyi_Jessica (March 2022, Genome Biology)

   Abstract When identifying differentially expressed genes between two conditions using human population RNA-seq samples, we found a phenomenon by permutation analysis: two popular bioinformatics methods, DESeq2 and edgeR, have unexpectedly high false discovery rates. Expanding the analysis to limma-voom, NOISeq, dearseq, and Wilcoxon rank-sum test, we found that FDR control is often failed except for the Wilcoxon rank-sum test. Particularly, the actual FDRs of DESeq2 and edgeR sometimes exceed 20% when the target FDR is 5%. Based on these results, for population-level RNA-seq studies with large sample sizes, we recommend the Wilcoxon rank-sum test. 

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4. A generalized knockoff procedure for FDR control in structural change detection

   https://doi.org/10.1016/j.jeconom.2022.07.008  

   Liu, Jingyuan; Sun, Ao; Ke, Yuan (February 2024, Journal of Econometrics)

   Controlling false discovery rate (FDR) is crucial for variable selection, multiple testing, among other signal detection problems. In literature, there is certainly no shortage of FDR control strategies when selecting individual features, but the relevant works for structural change detection, such as profile analysis for piecewise constant coefficients and integration analysis with multiple data sources, are limited. In this paper, we propose a generalized knockoff procedure (GKnockoff) for FDR control under such problem settings. We prove that the GKnockoff possesses pairwise exchangeability, and is capable of controlling the exact FDR under finite sample sizes. We further explore GKnockoff under high dimensionality, by first introducing a new screening method to filter the high-dimensional potential structural changes. We adopt a data splitting technique to first reduce the dimensionality via screening and then conduct GKnockoff on the refined selection set. Furthermore, the powers of proposed methods are systematically studied. Numerical comparisons with other methods show the superior performance of GKnockoff, in terms of both FDR control and power. We also implement the proposed methods to analyze a macroeconomic dataset for detecting changes of driven effects of economic development on the secondary industry. 

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5. A new p-value based multiple testing procedure for generalized linear models

   https://doi.org/10.1007/s11222-025-10600-2  

   Rilling, Joseph; Tang, Cheng_Yong (March 2025, Statistics and Computing)

   Abstract This study introduces a novelp-value-based multiple testing approach tailored for generalized linear models. Despite the crucial role of generalized linear models in statistics, existing methodologies face obstacles arising from the heterogeneous variance of response variables and complex dependencies among estimated parameters. Our aim is to address the challenge of controlling the false discovery rate (FDR) amidst arbitrarily dependent test statistics. Through the development of efficient computational algorithms, we present a versatile statistical framework for multiple testing. The proposed framework accommodates a range of tools developed for constructing a new model matrix in regression-type analysis, including random row permutations and Model-X knockoffs. We devise efficient computing techniques to solve the encountered non-trivial quadratic matrix equations, enabling the construction of pairedp-values suitable for the two-step multiple testing procedure proposed by Sarkar and Tang (Biometrika 109(4): 1149–1155, 2022). Theoretical analysis affirms the properties of our approach, demonstrating its capability to control the FDR at a given level. Empirical evaluations further substantiate its promising performance across diverse simulation settings. 

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