With the development of high-throughput single-nucleotide polymorphism (SNP) technologies, the vast number of SNPs in smaller samples poses a challenge to the application of classical statistical procedures. A possible solution is to use a two-stage approach for case-control data in which, in the first stage, a screening test selects a small number of SNPs for further analysis. The second stage then estimates the effects of the selected variables using logistic regression (logReg). Here, we introduce a novel approach in which the selection of SNPs is based on the permutation importance estimated by random forests (RFs). For this, we used the simulated data provided for the Genetic Analysis Workshop 15 without knowledge of the true model.
The data set was randomly split into a first and a second data set. In the first stage, RFs were grown to pre-select the 37 most important variables, and these were reduced to 32 variables by haplotype tagging. In the second stage, we estimated parameters using logReg.
The highest effect estimates were obtained for five simulated loci. We detected smoking, gender, and the parental DR alleles as covariates. After correction for multiple testing, we identified two out of four genes simulated with a direct effect on rheumatoid arthritis risk and all covariates without any false positive.
We showed that a two-staged approach with a screening of SNPs by RFs is suitable to detect candidate SNPs in genome-wide association studies for complex diseases.