A minimum Wasserstein distance approach to Fisher's combination of independent discrete p-values

This paper introduces a comprehensive framework to adjust a discrete test statistic for improving its hypothesis testing procedure. The adjustment minimizes the Wasserstein distance to a null-approximating continuous distribution, tackling some fundamental challenges inherent in combining statistical significances derived from discrete distributions. The related theory justifies Lancaster's mid-p and mean-value chi-squared statistics for Fisher's combination as special cases. However, in order to counter the conservative nature of Lancaster's testing procedures, we propose an updated null-approximating distribution. It is achieved by further minimizing the Wasserstein distance to the adjusted statistics within a proper distribution family. Specifically, in the context of Fisher's combination, we propose an optimal gamma distribution as a substitute for the traditionally used chi-squared distribution. This new approach yields an asymptotically consistent test that significantly improves type I error control and enhances statistical power

Concussion classification via deep learning using whole-brain white matter fiber strains

Developing an accurate and reliable injury predictor is central to the biomechanical studies of traumatic brain injury. State-of-the-art efforts continue to rely on empirical, scalar metrics based on kinematics or model-estimated tissue responses explicitly pre-defined in a specific brain region of interest. They could suffer from loss of information. A single training dataset has also been used to evaluate performance but without cross-validation. In this study, we developed a deep learning approach for concussion classification using implicit features of the entire voxel-wise white matter fiber strains. Using reconstructed American National Football League (NFL) injury cases, leave-one-out cross-validation was employed to objectively compare injury prediction performances against two baseline machine learning classifiers (support vector machine (SVM) and random forest (RF)) and four scalar metrics via univariate logistic regression (Brain Injury Criterion (BrIC), cumulative strain damage measure of the whole brain (CSDM-WB) and the corpus callosum (CSDM-CC), and peak fiber strain in the CC). Feature-based deep learning and machine learning classifiers consistently outperformed all scalar injury metrics across all performance categories in cross-validation (e.g., average accuracy of 0.844 vs. 0.746, and average area under the receiver operating curve (AUC) of 0.873 vs. 0.769, respectively, based on the testing dataset). Nevertheless, deep learning achieved the best cross-validation accuracy, sensitivity, and AUC (e.g., accuracy of 0.862 vs. 0.828 and 0.842 for SVM and RF, respectively). These findings demonstrate the superior performances of deep learning in concussion prediction, and suggest its promise for future applications in biomechanical investigations of traumatic brain injury.Comment: 18 pages, 7 figures, and 4 table

Two-stage joint selection method to identify candidate markers from genome-wide association studies

The interaction among multiple genes and environmental factors can affect an individual's susceptibility to disease. Some genes may not show strong marginal associations when they affect disease risk through interactions with other genes. As a result, these genes may not be identified by single-marker methods that are widely used in genome-wide association studies. To explore this possibility in real data, we carried out a two-stage model selection procedure of joint single-nucleotide polymorphism (SNP) analysis to detect genes associated with rheumatoid arthritis (RA) using Genetic Analysis Workshop 16 genome-wide association study data. In the first stage, the genetic markers were screened through an exhaustive two-dimensional search, through which promising SNP and SNP pairs were identified. Then, LASSO was used to choose putative SNPs from the candidates identified in the first stage. We then use the RA data collected by the Wellcome Trust Case Control Consortium to validate the putative genetic factors. Balancing computational load and statistical power, this method detects joint effects that may fail to emerge from single-marker analysis. Based on our proposed approach, we not only replicated the identification of important RA risk genes, but also found novel genes and their epistatic effects on RA. To our knowledge, this is the first two-dimensional scan based analysis for a real genome-wide association study

Gene hunting of the Genetic Analysis Workshop 16 rheumatoid arthritis data using rough set theory

We propose to use the rough set theory to identify genes affecting rheumatoid arthritis risk from the data collected by the North American Rheumatoid Arthritis Consortium. For each gene, we employ generalized dynamic reducts in the rough set theory to select a subset of single-nucleotide polymorphisms (SNPs) to represent the genetic information from this gene. We then group the study subjects into different clusters based on their genotype similarity at the selected markers. Statistical association between disease status and cluster membership is then studied to identify genes associated with rheumatoid arthritis. Based on our proposed approach, we are able to identify a number of statistically significant genes associated with rheumatoid arthritis. Aside from genes on chromosome 6, our identified genes include known disease-associated genes such as PTPN22 and TRAF1. In addition, our list contains other biologically plausible genes, such as ADAM15 and AGPAT2. Our findings suggest that ADAM15 and AGPAT2 may contribute to a genetic predisposition through abnormal angiogenesis and adipose tissue