Design and validation of methods searching for risk factors in genotype case-control studies.

Accessibility of high-throughput genotyping technology allows genome-wide association studies for common complex diseases. This paper addresses two challenges commonly facing such studies: (i) searching an enormous amount of possible gene interactions and (ii) finding reproducible associations. These challenges have been traditionally addressed in statistics while here we apply computational approaches--optimization and cross-validation. A complex risk factor is modeled as a subset of single nucleotide polymorphisms (SNPs) with specified alleles and the optimization formulation asks for the one with the maximum odds ratio. To measure and compare ability of search methods to find reproducible risk factors, we propose to apply a cross-validation scheme usually used for prediction validation. We have applied and cross-validated known search methods with proposed enhancements on real case-control studies for several diseases (Crohn's disease, autoimmune disorder, tick-borne encephalitis, lung cancer, and rheumatoid arthritis). Proposed methods are compared favorably to the exhaustive search: they are faster, find more frequently statistically significant risk factors, and have significantly higher leave-half-out cross-validation rate.