A DIseAse MOdule Detection (DIAMOnD) Algorithm Derived from a Systematic Analysis of Connectivity Patterns of Disease Proteins in the Human Interactome

The observation that disease associated proteins often interact with each other has fueled the development of network-based approaches to elucidate the molecular mechanisms of human disease. Such approaches build on the assumption that protein interaction networks can be viewed as maps in which diseases can be identified with localized perturbation within a certain neighborhood. The identification of these neighborhoods, or disease modules, is therefore a prerequisite of a detailed investigation of a particular pathophenotype. While numerous heuristic methods exist that successfully pinpoint disease associated modules, the basic underlying connectivity patterns remain largely unexplored. In this work we aim to fill this gap by analyzing the network properties of a comprehensive corpus of 70 complex diseases. We find that disease associated proteins do not reside within locally dense communities and instead identify connectivity significance as the most predictive quantity. This quantity inspires the design of a novel Disease Module Detection (DIAMOnD) algorithm to identify the full disease module around a set of known disease proteins. We study the performance of the algorithm using well-controlled synthetic data and systematically validate the identified neighborhoods for a large corpus of diseases.Author Summary: Diseases are rarely the result of an abnormality in a single gene, but involve a whole cascade of interactions between several cellular processes. To disentangle these complex interactions it is necessary to study genotype-phenotype relationships in the context of protein-protein interaction networks. Our analysis of 70 diseases shows that disease proteins are not randomly scattered within these networks, but agglomerate in specific regions, suggesting the existence of specific disease modules for each disease. The identification of these modules is the first step towards elucidating the biological mechanisms of a disease or for a targeted search of drug targets. We present a systematic analysis of the connectivity patterns of disease proteins and determine the most predictive topological property for their identification. This allows us to rationally design a reliable and efficient Disease Module Detection algorithm (DIAMOnD).