title: Chronic Obstructive Pulmonary Disease heterogeneity: challenges for health risk assessment, stratification and management.
abstract: OBJECTIVE
  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
  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.
authors.forename: Josep
authors.initials: J
authors.lastname: Roca
authors.forename: Claudia
authors.initials: C
authors.lastname: Vargas
authors.forename: Isaac
authors.initials: I
authors.lastname: Cano
authors.forename: Vitaly
authors.initials: V
authors.lastname: Selivanov
authors.forename: Esther
authors.initials: E
authors.lastname: Barreiro
authors.forename: Dieter
authors.initials: D
authors.lastname: Maier
authors.forename: Francesco
authors.initials: F
authors.lastname: Falciani
authors.forename: Peter
authors.initials: P
authors.lastname: Wagner
authors.forename: Marta
authors.initials: M
authors.lastname: Cascante
authors.forename: Judith
authors.initials: J
authors.lastname: Garcia-Aymerich
authors.forename: Susana
authors.initials: S
authors.lastname: Kalko
authors.forename: Igor
authors.initials: I
authors.lastname: De Mas
authors.forename: Jesper
authors.initials: J
authors.lastname: Tegnér
authors.forename: Joan
authors.initials: J
authors.lastname: Escarrabill
authors.forename: Alvar
authors.initials: A
authors.lastname: Agustí
authors.forename: David
authors.initials: D
authors.lastname: Gomez-Cabrero
mesh_terms: D016000:Cluster Analysis; D015897:Comorbidity; D016207:Cytokines / Q000097:blood; D020000:Decision Support Systems, Clinical; D020869:Gene Expression Profiling; D006801:Humans; D008171:Lung Diseases / Q000503:physiopathology; D055370:Lung Injury / Q000503:physiopathology; D018482:Muscle, Skeletal / Q000503:physiopathology; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010100:Oxygen / Q000737:chemistry; D010101:Oxygen Consumption; D029424:Pulmonary Disease, Chronic Obstructive / Q000175:diagnosis* / Q000503:physiopathology*; D018570:Risk Assessment; D016896:Treatment Outcome
chemical_list: D016207:Cytokines; D010100:Oxygen