MOTIVATION: Transcriptome-wide association study (TWAS) aims to identify trait-associated genes regulated by significant variants to explore the underlying biological mechanisms at a tissue-specific level. Despite the advancement of current TWAS methods to cover diverse traits, traditional approaches still face two main challenges: (i) the lack of methods that can guarantee finite-sample false discovery rate (FDR) control in identifying trait-associated genes; and (ii) the requirement for individual-level data, which is often inaccessible. RESULTS: To address this challenge, we propose a powerful knockoff inference method termed TWAS-GKF to identify candidate trait-associated genes with a guaranteed finite-sample FDR control. TWAS-GKF introduces the main idea of Ghostknockoff inference to generate knockoff variables using only summary statistics instead of individual-level data. In extensive studies, we demonstrate that TWAS-GKF successfully controls the finite-sample FDR under a pre-specified FDR level across all settings. We further apply TWAS-GKF to identify genes in brain cerebellum tissue from the Genotype-Tissue Expression (GTEx) v8 project associated with schizophrenia (SCZ) from the Psychiatric Genomics Consortium (PGC), and genes in liver tissue related to low-density lipoprotein cholesterol (LDL-C) from the UK Biobank, respectively. The results reveal that the majority of the identified genes are validated by Open Targets Validation Platform. AVAILABILITY AND IMPLEMENTATION: The R package TWAS.GKF is publicly available at https://github.com/AnqiWang2021/TWAS.GKF.

MOTIVATION: It is of scientific interest to identify DNA methylation CpG sites that might mediate the effect of an environmental exposure on a survival outcome in high-dimensional mediation analysis. However, there is a lack of powerful statistical methods that can provide a guarantee of false discovery rate (FDR) control in finite-sample settings. RESULTS: In this article, we propose a novel method called CoxMKF, which applies aggregation of multiple knockoffs to a Cox proportional hazards model for a survival outcome with high-dimensional mediators. The proposed CoxMKF can achieve FDR control even in finite-sample settings, which is particularly advantageous when the sample size is not large. Moreover, our proposed CoxMKF can overcome the randomness of the unstable model-X knockoffs. Our simulation results show that CoxMKF controls FDR well in finite samples. We further apply CoxMKF to a lung cancer dataset from The Cancer Genome Atlas (TCGA) project with 754 subjects and 365 306 DNA methylation CpG sites, and identify four DNA methylation CpG sites that might mediate the effect of smoking on the overall survival among lung cancer patients. AVAILABILITY AND IMPLEMENTATION: The R package CoxMKF is publicly available at https://github.com/MinhaoYaooo/CoxMKF. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

MOTIVATION: Variable selection is a common statistical approach to identifying genes associated with clinical outcomes of scientific interest. There are thousands of genes in genomic studies, while only a limited number of individual samples are available. Therefore, it is important to develop a method to identify genes associated with outcomes of interest that can control finite-sample false discovery rate (FDR) in high-dimensional data settings. RESULTS: This article proposes a novel method named Grace-AKO for graph-constrained estimation (Grace), which incorporates aggregation of multiple knockoffs (AKO) with the network-constrained penalty. Grace-AKO can control FDR in finite-sample settings and improve model stability simultaneously. Simulation studies show that Grace-AKO has better performance in finite-sample FDR control than the original Grace model. We apply Grace-AKO to the prostate cancer data in The Cancer Genome Atlas program by incorporating prostate-specific antigen (PSA) pathways in the Kyoto Encyclopedia of Genes and Genomes as the prior information. Grace-AKO finally identifies 47 candidate genes associated with PSA level, and more than 75% of the detected genes can be validated.