Statistical Learning Methods Applicable to Genome-Wide Association Studies on Unbalanced Case-Control Disease Data

Abstract

Despite the fact that imbalance between case and control groups is prevalent in genome-wide association studies (GWAS), it is often overlooked. This imbalance is getting more significant and urgent as the rapid growth of biobanks and electronic health records have enabled the collection of thousands of phenotypes from large cohorts, in particular for diseases with low prevalence. The unbalanced binary traits pose serious challenges to traditional statistical methods in terms of both genomic selection and disease prediction. For example, the well-established linear mixed models (LMM) yield inflated type I error rates in the presence of unbalanced case-control ratios. In this article, we review multiple statistical approaches that have been developed to overcome the inaccuracy caused by the unbalanced case-control ratio, with the advantages and limitations of each approach commented. In addition, we also explore the potential for applying several powerful and popular state-of-the-art machine-learning approaches, which have not been applied to the GWAS field yet. This review paves the way for better analysis and understanding of the unbalanced case-control disease data in GWAS.