Uncovering influence links in molecular knowledge networks to streamline personalized medicine

Objectives: We developed Resource Description Framework (RDF)-induced InfluGrams (RIIG) - an informatics formalism to uncover complex relationships among biomarker proteins and biological pathways using the biomedical knowledge bases. We demonstrate an application of RUG in morphoproteomics, a theranostic technique aimed at comprehensive analysis of protein circuitries to design effective therapeutic strategies in personalized medicine setting. Methods: RIIG uses an RDF mashup knowledge base that integrates publicly available pathway and protein data with ontologies. To mine for RDF-induced Influence Links, RIIG introduces notions of RDF relevancy and RDF collider, which mimic conditional independence and explaining away mechanism in probabilistic systems. Using these notions and constraint-based structure learning algorithms, the formalism generates the morphoproteomic diagrams, which we call InfluGrams, for further analysis by experts. Results: RIIG was able to recover up to 90% of predefined influence links in a simulated environment using synthetic data and outperformed a na ve Monte Carlo sampling of random links. In clinical cases of Acute Lymphoblastic Leukemia (ALL) and Mesenchymal Chondrosarcoma, a significant level of concordance between the RIIG-generated and expert-built morphoproteomic diagrams was observed. In a clinical case of Squamous Cell Carcinoma, RIIG allowed selection of alternative therapeutic targets, the validity of which was supported by a systematic literature review. We have also illustrated an ability of RUG to discover novel influence links in the general case of the ALL. Conclusions: Applications of the RIIG formalism demonstrated its potential to uncover patient-specific complex relationships among biological entities to find effective drug targets in a personalized medicine setting. We conclude that RIIG provides an effective means not only to streamline morphoproteomic studies, but also to bridge curated biomedical knowledge and causal reasoning with the clinical data in general. (C) 2014 The Authors. Published by Elsevier Inc.