Beyond guilty by association at scale: searching for causal variants on the basis of genome-wide summary statistics.

Understanding the causal genetic architecture of complex phenotypes is essential for future research into disease mechanisms and potential therapies. Here, we present a novel framework for genome-wide detection of sets of variants that carry non-redundant information on the phenotypes and are therefore more likely to be causal in a biological sense. Crucially, our framework requires only summary statistics obtained from standard genome-wide marginal association testing. The described approach, implemented in open-source software, is also computationally efficient, requiring less than 15 minutes on a single CPU to perform genome-wide analysis. Through extensive genome-wide simulation studies, we show that the method can substantially outperform usual two-stage marginal association testing and fine-mapping procedures in precision and recall. In applications to a meta-analysis of ten large-scale genetic studies of Alzheimer's disease (AD), we identified 82 loci associated with AD, including 37 additional loci missed by conventional GWAS pipeline. The identified putative causal variants achieve state-of-the-art agreement with massively parallel reporter assays and CRISPR-Cas9 experiments. Additionally, we applied the method to a retrospective analysis of 67 large-scale GWAS summary statistics since 2013 for a variety of phenotypes. Results reveal the method's capacity to robustly discover additional loci for polygenic traits and pinpoint potential causal variants underpinning each locus beyond conventional GWAS pipeline, contributing to a deeper understanding of complex genetic architectures in post-GWAS analyses.

Second-order group knockoffs with applications to GWAS.

Conditional testing via the knockoff framework allows one to identify -- among large number of possible explanatory variables -- those that carry unique information about an outcome of interest, and also provides a false discovery rate guarantee on the selection. This approach is particularly well suited to the analysis of genome wide association studies (GWAS), which have the goal of identifying genetic variants which influence traits of medical relevance. While conditional testing can be both more powerful and precise than traditional GWAS analysis methods, its vanilla implementation encounters a difficulty common to all multivariate analysis methods: it is challenging to distinguish among multiple, highly correlated regressors. This impasse can be overcome by shifting the object of inference from single variables to groups of correlated variables. To achieve this, it is necessary to construct "group knockoffs." While successful examples are already documented in the literature, this paper substantially expands the set of algorithms and software for group knockoffs. We focus in particular on second-order knockoffs, for which we describe correlation matrix approximations that are appropriate for GWAS data and that result in considerable computational savings. We illustrate the effectiveness of the proposed methods with simulations and with the analysis of albuminuria data from the UK Biobank. The described algorithms are implemented in an open-source Julia package Knockoffs.jl, for which both R and Python wrappers are available.

Controlled Variable Selection from Summary Statistics Only? A Solution via GhostKnockoffs and Penalized Regression.

Identifying which variables do influence a response while controlling false positives pervades statistics and data science. In this paper, we consider a scenario in which we only have access to summary statistics, such as the values of marginal empirical correlations between each dependent variable of potential interest and the response. This situation may arise due to privacy concerns, e.g., to avoid the release of sensitive genetic information. We extend GhostKnockoffs He et al. [2022] and introduce variable selection methods based on penalized regression achieving false discovery rate (FDR) control. We report empirical results in extensive simulation studies, demonstrating enhanced performance over previous work. We also apply our methods to genome-wide association studies of Alzheimer's disease, and evidence a significant improvement in power.

Design and Modeling of a Test Bench for Dual-Motor Electric Drive Tracked Vehicles Based on a Dynamic Load Emulation Method.

Dual-motor Electric Drive Tracked Vehicles (DDTVs) have attracted increasing attention due to their high transmission efficiency and economical fuel consumption. A test bench for the development and validation of new DDTV technologies is necessary and urgent. How to load the vehicle on a DDTV test bench exactly the same as on a real road is a crucial issue when designing the bench. This paper proposes a novel dynamic load emulation method to address this problem. The method adopts dual dynamometers to simulate both the road load and the inertia load that are imposed on the dual independent drive systems. The vehicle’s total inertia equivalent to the drive wheels is calculated with separate consideration of vehicle body, tracks and road wheels to obtain a more accurate inertia load. A speed tracking control strategy with feedforward compensation is implemented to control the dual dynamometers, so as to make the real-time dynamic load emulation possible. Additionally, a MATLAB/Simulink model of the test bench is built based on a dynamics analysis of the platform. Experiments are finally carried out on this test bench under different test conditions. The outcomes show that the proposed load emulation method is effective, and has good robustness and adaptability to complex driving conditions. Besides, the accuracy of the established test bench model is also demonstrated by comparing the results obtained from the simulation model and experiments.