capturing the spectrum of interaction effects in genetic association studies by simulated evaporative cooling network analysis捕获的交互作用在遗传关联研究模拟蒸发冷却网络分析.pdfVIP

Capturing the Spectrum of Interaction Effects in Genetic Association Studies by Simulated Evaporative Cooling Network Analysis 1 2 1 1 Brett A. McKinney *, James E. Crowe, Jr. , Jingyu Guo , Dehua Tian 1 Department of Genetics, University of Alabama School of Medicine, Birmingham, Alabama, United States of America, 2 Departments of Pediatrics, Microbiology and Immunology, Program in Vaccine Sciences, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America Abstract Evidence from human genetic studies of several disorders suggests that interactions between alleles at multiple genes play an important role in influencing phenotypic expression. Analytical methods for identifying Mendelian disease genes are not appropriate when applied to common multigenic diseases, because such methods investigate association with the phenotype only one genetic locus at a time. New strategies are needed that can capture the spectrum of genetic effects, from Mendelian to multifactorial epistasis. Random Forests (RF) and Relief-F are two powerful machine-learning methods that have been studied as filters for genetic case-control data due to their ability to account for the context of alleles at multiple genes when scoring the relevance of individual genetic variants to the phenotype. However, when variants interact strongly, the independence assumption of RF in the tree node-splitting criterion leads to diminished importance scores for relevant variants. Relief-F, on the other hand, was designed to detect strong interactions but is sensitive to large backgrounds of variants that are irrelevant to classification of the phenotype, which is an acute problem in genome-wide association studies. To overcome the w