Towards integrative gene prioritization in Alzheimer's disease

Abstract

Many methods have been proposed for facilitating the uncovering of genes that underlie the pathology of different diseases. Some are purely statistical, resulting in a (mostly) undifferentiated set of genes that are differentially expressed (or co-expressed), while others seek to prioritize the resulting set of genes through comparison against specific known targets. Most of the recent approaches use either single data or knowledge sources, or combine the independent predictions from each source. However, given that multiple kinds of heterogeneous sources are potentially relevant for gene prioritization, each subject to different levels of noise and of varying reliability, each source bearing information not carried by another, we claim that an ideal prioritization method should provide ways to discern amongst them in a true integrative fashion that captures the subtleties of each, rather than using a simple combination of sources. Integration of multiple data for gene prioritization is thus more challenging than its single data type counterpart. What we propose is a novel, general, and flexible formulation that enables multi-source data integration for gene prioritization that maximizes the complementary nature of different data and knowledge sources in order to make the most use of the information content of aggregate data. Protein-protein interactions and Gene Ontology annotations were used as knowledge sources, together with assay-specific gene expression and genome-wide association data. Leave-one-out testing was performed using a known set of Alzheimer's Disease genes to validate our proposed method. We show that our proposed method performs better than the best multi-source gene prioritization systems currently published.