Revealing missing parts of the interactome

Abstract: Protein interaction networks (PINs) are often used to "learn" new biological function from their topology. Since current PINs are noisy, their computational de-noising via link prediction (LP) could improve the learning accuracy. LP uses the existing PIN topology to predict missing and spurious links. Many of existing LP methods rely on shared immediate neighborhoods of the nodes to be linked. As such, they have limitations. Thus, in order to comprehensively study what are the topological properties of nodes in PINs that dictate whether the nodes should be linked, we had to introduce novel sensitive LP measures that overcome the limitations of the existing methods. We systematically evaluate the new and existing LP measures by introducing "synthetic" noise to PINs and measuring how well the different measures reconstruct the original PINs. Our main findings are: 1) LP measures that favor nodes which are both "topologically similar" and have large shared extended neighborhoods are superior; 2) using more network topology often though not always improves LP accuracy; and 3) our new LP measures are superior to the existing measures. After evaluating the different methods, we use them to de-noise PINs. Importantly, we manage to improve biological correctness of the PINs by de-noising them, with respect to "enrichment" of the predicted interactions in Gene Ontology terms. Furthermore, we validate a statistically significant portion of the predicted interactions in independent, external PIN data sources. Software executables are freely available upon request.