%0 Journal Article %A Sarah A. Gagliano %A Reena Ravji %A Michael R. Barnes %A Michael E. Weale %A Jo Knight %T Circumstantial Evidence? Comparison of Statistical Learning Methods using Functional Annotations for Prioritizing Risk Variants %D 2014 %R 10.1101/011445 %J bioRxiv %P 011445 %X Although technology has triumphed in facilitating routine genome re-sequencing, new challenges have been created for the data analyst. Genome scale surveys of human disease variation generate volumes of data that far exceed capabilities for laboratory characterization, and importantly also create a substantial burden of type I error. By incorporating a variety of functional annotations as predictors, such as regulatory and protein coding elements, statistical learning has been widely investigated as a mechanism for the prioritization of genetic variants that are more likely to be associated with complex disease. These methods offer a hope of identification of sufficiently large numbers of truly associated variants, to make cost-effective the large-scale functional characterization necessary to progress genome scale experiments. We compared the results from three published prioritization procedures which use different statistical learning algorithms and different predictors with regard to the quantity, type and coding of the functional annotations. In this paper we also explore different combinations of algorithm and annotation set. We train the models in 60% of the data and reserve the remainder for testing the accuracy. As an application, we tested which methodology performed the best for prioritizing sub-genome-wide-significant variants (5×10-8<p<1×10-6) using data from the first and second rounds of a large schizophrenia meta-analysis by the Psychiatric Genomics Consortium. Results suggest that all methods have considerable (and similar) predictive accuracies (AUCs 0.64-0.71). However, predictive accuracy results obtained from the test set do not always reflect results obtained from the application to the schizophrenia meta-analysis. In conclusion, a variety of algorithms and annotations seem to have a similar potential to effectively enrich true risk variants in genome scale datasets, however none offer more than incremental improvement in prediction. We discuss how methods might be evolved towards the step change in the risk variant prediction required to address the impending bottleneck of the new generation of genome re-sequencing studies. %U https://www.biorxiv.org/content/biorxiv/early/2014/11/14/011445.full.pdf