Roca, JosepVargas, ClaudiaCano, IsaacSelivanov, VitalyBarreiro Portela, EstherMaier, DieterFalciani, FrancescoWagner, PeterCascante Serratosa, MartaGarcía Aymerich, JudithKalko, Susana G.Marin de Mas, IgorTegnér, JesperEscarrabill, JoanAgustí García-Navarro, ÀlvarGomez Cabrero, DavidSynergy-COPD consortium2015-03-252015-03-252014Roca J, Vargas C, Cano I, Selivanov V, Barreiro E, Maier D et al. Chronic Obstructive Pulmonary Disease heterogeneity: challenges for health risk assessment, stratification and management. Journal of Translational Medicine. 2014; 12(S2): S3. DOI 10.1186/1479-5876-12-S2-S31479-5876http://hdl.handle.net/10230/23271Background and hypothesis: Heterogeneity in clinical manifestations and disease progression in Chronic Obstructive Pulmonary Disease (COPD) lead to consequences for patient health risk assessment, stratification and management. Implicit with the classical "spill over" hypothesis is that COPD heterogeneity is driven by the pulmonary events of the disease. Alternatively, we hypothesized that COPD heterogeneities result from the interplay of mechanisms governing three conceptually different phenomena: 1) pulmonary disease, 2) systemic effects of COPD and 3) co-morbidity clustering, each of them with their own dynamics. Objective and method: To explore the potential of a systems analysis of COPD heterogeneity focused on skeletal muscle dysfunction and on co-morbidity clustering aiming at generating predictive modeling with impact on patient management. To this end, strategies combining deterministic modeling and network medicine analyses of the Biobridge dataset were used to investigate the mechanisms of skeletal muscle dysfunction. An independent data driven analysis of co-morbidity clustering examining associated genes and pathways was performed using a large dataset (ICD9-CM data from Medicare, 13 million people). Finally, a targeted network analysis using the outcomes of the two approaches (skeletal muscle dysfunction and co-morbidity clustering) explored shared pathways between these phenomena. Results: (1) Evidence of abnormal regulation of skeletal muscle bioenergetics and skeletal muscle remodeling showing a significant association with nitroso-redox disequilibrium was observed in COPD; (2) COPD patients presented higher risk for co-morbidity clustering than non-COPD patients increasing with ageing; and, (3) the on-going targeted network analyses suggests shared pathways between skeletal muscle dysfunction and co-morbidity clustering. Conclusions: The results indicate the high potential of a systems approach to address COPD heterogeneity. Significant knowledge gaps were identified that are relevant to shape strategies aiming at fostering 4P Medicine for patients with COPD.application/pdfeng© 2014 Roca et al.; licensee BioMed Central Ltd.This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Pulmons -- Malalties obstructives -- TractamentMedicina preventivainfo:eu-repo/semantics/articlehttp://dx.doi.org/10.1186/1479-5876-12-S2-S3Chronic diseasesCOPDDisease heterogeneityIntegrated CarePredictive MedicineRedox disequilibriumSystems MedicineVO2maxinfo:eu-repo/semantics/openAccess