title: From molecular signatures to predictive biomarkers: modeling disease pathophysiology and drug mechanism of action.
abstract: Omics profiling significantly expanded the molecular landscape describing clinical phenotypes. Association analysis resulted in first diagnostic and prognostic biomarker signatures entering clinical utility. However, utilizing Omics for deepening our understanding of disease pathophysiology, and further including specific interference with drug mechanism of action on a molecular process level still sees limited added value in the clinical setting. We exemplify a computational workflow for expanding from statistics-based association analysis toward deriving molecular pathway and process models for characterizing phenotypes and drug mechanism of action. Interference analysis on the molecular model level allows identification of predictive biomarker candidates for testing drug response. We discuss this strategy on diabetic nephropathy (DN), a complex clinical phenotype triggered by diabetes and presenting with renal as well as cardiovascular endpoints. A molecular pathway map indicates involvement of multiple molecular mechanisms, and selected biomarker candidates reported as associated with disease progression are identified for specific molecular processes. Selective interference of drug mechanism of action and disease-associated processes is identified for drug classes in clinical use, in turn providing precision medicine hypotheses utilizing predictive biomarkers.
authors.affiliation: emergentec biodevelopment GmbH Vienna, Austria.
authors.forename: Andreas
authors.initials: A
authors.lastname: Heinzel
authors.affiliation: emergentec biodevelopment GmbH Vienna, Austria.
authors.forename: Paul
authors.initials: P
authors.lastname: Perco
authors.affiliation: Department of Internal Medicine IV, Medical University of Innsbruck Innsbruck, Austria.
authors.forename: Gert
authors.initials: G
authors.lastname: Mayer
authors.affiliation: Department of Internal Medicine III, KH Elisabethinen Linz and Medical University of Vienna Vienna, Austria.
authors.forename: Rainer
authors.initials: R
authors.lastname: Oberbauer
authors.affiliation: emergentec biodevelopment GmbH Vienna, Austria.
authors.forename: Arno
authors.initials: A
authors.lastname: Lukas
authors.affiliation: emergentec biodevelopment GmbH Vienna, Austria.
authors.forename: Bernd
authors.initials: B
authors.lastname: Mayer
keywords: biomarker; integration; molecular model; omics; precision medicine; systems biology; systems pharmacology; target