KEDDY: a knowledge-based statistical gene set test method to detect differential functional protein-protein interactions

Abstract

Motivation: Identifying differential patterns between conditions is a popular approach to understanding the discrepancy between different biological contexts. Although many statistical tests were proposed for identifying gene sets with differential patterns based on different definitions of differentiality, few methods were suggested to identify gene sets with differential functional protein networks due to computational complexity. Results: We propose a method of Knowledge-based Evaluation of Dependency DifferentialitY (KEDDY), which is a statistical test for differential functional protein networks of a set of genes between two conditions with utilizing known functional protein-protein interaction information. Unlike other approaches focused on differential expressions of individual genes or differentiality of individual interactions, KEDDY compares two conditions by evaluating the probability distributions of functional protein networks based on known functional protein-protein interactions. The method has been evaluated and compared with previous methods through simulation studies, where KEDDY achieves significantly improved performance in accuracy and speed than the previous method that does not use prior knowledge and better performance in identifying gene sets with differential interactions than other methods evaluating changes in gene expressions. Applications to cancer data sets show that KEDDY identifies alternative cancer subtype-related differential gene sets compared to other differential expression-based methods, and the results also provide detailed gene regulatory information that drives the differentiality of the gene sets.