Susceptibility to sporadic forms of cancer is determined by numerous genetic factors that interact in a nonlinear manner in the context of an individual's age and environmental exposure. This complex genetic architecture has important implications for the use of genome-wide association studies for identifying susceptibility genes. The assumption of a simple architecture supports a strategy of testing each single-nucleotide polymorphism (SNP) individually using traditional univariate statistics followed by a correction for multiple tests. However, a complex genetic architecture that is characteristic of most types of cancer requires analytical methods that specifically model combinations of SNPs and environmental exposures. While new and novel methods are available for modeling interactions, exhaustive testing of all combinations of SNPs is not feasible on a genome- wide scale because the number of comparisons is effectively infinite. Thus, it is critical that we develop intelligent strategies for selecting subsets of SNPs prior to combinatorial modeling. The objective of this renewal application is to continue the development of a research strategy for the detection, characterization, and interpretation of gene-gene and gene-environment interactions in genome-wide association studies of bladder cancer susceptibility. To accomplish this objective, we will continue developing and evaluating modifications and extensions to the ReliefF family of algorithms for selecting or filtering subsets of single- nucleotide polymorphisms (SNPs) for multifactor dimensionality reduction (MDR) analysis of gene-gene and gene-environment interactions (AIM 1). We will continue developing and evaluating a stochastic wrapper or search strategy for MDR analysis of interactions that utilizes ReliefF values as a heuristic (AIM 2). We will continue to make available ReliefF algorithms as part of our open-source MDR software package (AIM 3). Finally, we will apply the best ReliefF-MDR analysis strategies to the detection, characterization, and interpretation of gene-gene and gene-environment interactions in large genome-wide association studies of bladder cancer susceptibility (AIM 4). We anticipate the proposed machine learning methods will provide powerful new approaches for identifying genetic variations that are predictive of cancer susceptibility.
The technology to measure information about the human genome is advancing at a rapid pace. Despite these advance, the computational methods for analyzing the data have not kept pace. We will develop new computer algorithms and software that can be used to identify genetic biomarkers of common human diseases. We will then apply these new computational methods to identifying genetic biomarkers of bladder cancer in an epidemiological study from New Hampshire.
|Piette, Elizabeth R; Moore, Jason H (2018) Identification of epistatic interactions between the human RNA demethylases FTO and ALKBH5 with gene set enrichment analysis informed by differential methylation. BMC Proc 12:59|
|Urbanowicz, Ryan J; Olson, Randal S; Schmitt, Peter et al. (2018) Benchmarking relief-based feature selection methods for bioinformatics data mining. J Biomed Inform 85:168-188|
|Urbanowicz, Ryan J; Meeker, Melissa; La Cava, William et al. (2018) Relief-based feature selection: Introduction and review. J Biomed Inform 85:189-203|
|Yao, Xiaohui; Yan, Jingwen; Kim, Sungeun et al. (2017) Two-dimensional enrichment analysis for mining high-level imaging genetic associations. Brain Inform 4:27-37|
|Ahmed, Musaddeque; Sallari, Richard C; Guo, Haiyang et al. (2017) Variant Set Enrichment: an R package to identify disease-associated functional genomic regions. BioData Min 10:9|
|Hall, Molly A; Wallace, John; Lucas, Anastasia et al. (2017) PLATO software provides analytic framework for investigating complexity beyond genome-wide association studies. Nat Commun 8:1167|
|Graham, Britney E; Darabos, Christian; Huang, Minjun et al. (2017) Evolutionarily derived networks to inform disease pathways. Genet Epidemiol 41:866-875|
|Huang, Jing; Liu, Yulun; Vitale, Steve et al. (2017) On meta- and mega-analyses for gene-environment interactions. Genet Epidemiol 41:876-886|
|Wang, Lu; Chen, Yong; Zhu, Hongjian (2017) Implementing Optimal Allocation in Clinical Trials with Multiple Endpoints. J Stat Plan Inference 182:88-99|
|Hong, Chuan; Ning, Yang; Wei, Peng et al. (2017) A semiparametric model for vQTL mapping. Biometrics 73:571-581|
Showing the most recent 10 out of 145 publications