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.
|Andrew, Angeline S; Gui, Jiang; Hu, Ting et al. (2015) Genetic polymorphisms modify bladder cancer recurrence and survival in a USA population-based prognostic study. BJU Int 115:238-47|
|Davis, Matthew A; Gilbert-Diamond, Diane; Karagas, Margaret R et al. (2014) A dietary-wide association study (DWAS) of environmental metal exposure in US children and adults. PLoS One 9:e104768|
|Pechenick, Dov A; Payne, Joshua L; Moore, Jason H (2014) Phenotypic robustness and the assortativity signature of human transcription factor networks. PLoS Comput Biol 10:e1003780|
|Yan, Jingwen; Du, Lei; Kim, Sungeun et al. (2014) Transcriptome-guided amyloid imaging genetic analysis via a novel structured sparse learning algorithm. Bioinformatics 30:i564-71|
|Penrod, Nadia M; Moore, Jason H (2014) Influence networks based on coexpression improve drug target discovery for the development of novel cancer therapeutics. BMC Syst Biol 8:12|
|Hu, Ting; Banzhaf, Wolfgang; Moore, Jason H (2014) The effects of recombination on phenotypic exploration and robustness in evolution. Artif Life 20:457-70|
|Gorlov, Ivan P; Moore, Jason H; Peng, Bo et al. (2014) SNP characteristics predict replication success in association studies. Hum Genet 133:1477-86|
|Darabos, Christian; Harmon, Samantha H; Moore, Jason H (2014) Using the bipartite human phenotype network to reveal pleiotropy and epistasis beyond the gene. Pac Symp Biocomput :188-99|
|Sheng, Jinhua; Kim, Sungeun; Yan, Jingwen et al. (2014) DATA SYNTHESIS AND METHOD EVALUATION FOR BRAIN IMAGING GENETICS. Proc IEEE Int Symp Biomed Imaging 2014:1202-1205|
|Cheng, Chao; Moore, Jason; Greene, Casey (2014) Applications of bioinformatics to non-coding RNAs in the era of next-generation sequencing. Pac Symp Biocomput :412-6|
Showing the most recent 10 out of 68 publications