an application of random forests to a genome-wide association dataset methodological considerations new findings应用随机森林全基因组关联数据集方法注意事项和新发现.pdfVIP

Goldstein et al. BMC Genetics 2010, 11:49 /1471-2156/11/49 R E S E A R C H A R T I C L E Open Access Research article An application of Random Forests to a genome-wide association dataset: Methodological considerations new findings 1,3 1 2 1 Benjamin A Goldstein* , Alan E Hubbard , Adele Cutler and Lisa F Barcellos* Abstract Background: As computational power improves, the application of more advanced machine learning techniques to the analysis of large genome-wide association (GWA) datasets becomes possible. While most traditional statistical methods can only elucidate main effects of genetic variants on risk for disease, certain machine learning approaches are particularly suited to discover higher order and non-linear effects. One such approach is the Random Forests (RF) algorithm. The use of RF for SNP discovery related to human disease has grown in recent years; however, most work has focused on small datasets or simulation studies which are limited. Results: Using a multiple sclerosis (MS) case-control dataset comprised of 300 K SNP genotypes across the genome, we outline an approach and some considerations for optimally tuning the RF algorithm based on the empirical dataset. Importantly, results show that typical default parameter values are not appropriate for large GWA datasets. Furthermore, gains can be made by sub-sampling the data, pruning based on linkage disequilibrium (LD), and removing strong effects from RF analyses. The new RF results are compared to findings from the original MS GWA study and demonstrate overlap. In addition, four new interesting candidate MS genes are identified, MPHOSPH9, CTNNA3, PHACTR2 and IL7, by RF analysis and warrant further follow-up in independent studies. Conclusions: This