title: From comorbidities of chronic obstructive pulmonary disease to identification of shared molecular mechanisms by data integration.
abstract: BACKGROUND
  Deep mining of healthcare data has provided maps of comorbidity relationships between diseases. In parallel, integrative multi-omics investigations have generated high-resolution molecular maps of putative relevance for understanding disease initiation and progression. Yet, it is unclear how to advance an observation of comorbidity relations (one disease to others) to a molecular understanding of the driver processes and associated biomarkers.
  
  
  RESULTS
  Since Chronic Obstructive Pulmonary disease (COPD) has emerged as a central hub in temporal comorbidity networks, we developed a systematic integrative data-driven framework to identify shared disease-associated genes and pathways, as a proxy for the underlying generative mechanisms inducing comorbidity. We integrated records from approximately 13 M patients from the Medicare database with disease-gene maps that we derived from several resources including a semantic-derived knowledge-base. Using rank-based statistics we not only recovered known comorbidities but also discovered a novel association between COPD and digestive diseases. Furthermore, our analysis provides the first set of COPD co-morbidity candidate biomarkers, including IL15, TNF and JUP, and characterizes their association to aging and life-style conditions, such as smoking and physical activity.
  
  
  CONCLUSIONS
  The developed framework provides novel insights in COPD and especially COPD co-morbidity associated mechanisms. The methodology could be used to discover and decipher the molecular underpinning of other comorbidity relationships and furthermore, allow the identification of candidate co-morbidity biomarkers.
authors.affiliation: Department of Medicine, Karolinska Institutet, Unit of Computational Medicine, Stockholm, 171 77, Sweden. david.gomezcabrero@ki.se.|Karolinska Institutet, Center for Molecular Medicine, Stockholm, 171 77, Sweden. david.gomezcabrero@ki.se.|Department of Medicine, Unit of Clinical Epidemiology, Karolinska University Hospital, Solna, L8, 17176, Sweden. david.gomezcabrero@ki.se.|Science for Life Laboratory, Solna, 17121, Sweden. david.gomezcabrero@ki.se.|Mucosal and Salivary Biology Division, King's College London Dental Institute, London, UK. david.gomezcabrero@ki.se.
authors.forename: David
authors.initials: D
authors.lastname: Gomez-Cabrero
authors.affiliation: Center for Complex Networks Research and Department of Physics, Northeastern University, Boston, MA, USA.|Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.|Center for Network Science, Central European University, Budapest, Hungary.
authors.forename: Jörg
authors.initials: J
authors.lastname: Menche
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clinic de Barcelona, Universitat de Barcelona, Barcelona, Spain.|Center for Biomedical Network Research in Respiratory Diseases (CIBERES), Madrid, Spain.
authors.forename: Claudia
authors.initials: C
authors.lastname: Vargas
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clinic de Barcelona, Universitat de Barcelona, Barcelona, Spain.|Center for Biomedical Network Research in Respiratory Diseases (CIBERES), Madrid, Spain.
authors.forename: Isaac
authors.initials: I
authors.lastname: Cano
authors.affiliation: Biomax Informatics AG, Planegg, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Maier
authors.affiliation: Center for Complex Networks Research and Department of Physics, Northeastern University, Boston, MA, USA.|Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.|Center for Network Science, Central European University, Budapest, Hungary.|Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Albert-László
authors.initials: AL
authors.lastname: Barabási
authors.affiliation: Department of Medicine, Karolinska Institutet, Unit of Computational Medicine, Stockholm, 171 77, Sweden.|Karolinska Institutet, Center for Molecular Medicine, Stockholm, 171 77, Sweden.|Department of Medicine, Unit of Clinical Epidemiology, Karolinska University Hospital, Solna, L8, 17176, Sweden.|Science for Life Laboratory, Solna, 17121, Sweden.
authors.forename: Jesper
authors.initials: J
authors.lastname: Tegnér
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clinic de Barcelona, Universitat de Barcelona, Barcelona, Spain. jroca@clinic.ub.es.|Center for Biomedical Network Research in Respiratory Diseases (CIBERES), Madrid, Spain. jroca@clinic.ub.es.
authors.forename: Josep
authors.initials: J
authors.lastname: Roca
mesh_terms: D000375:Aging; D015415:Biomarkers / Q000378:metabolism; D002874:Chromosome Mapping; D016000:Cluster Analysis; D015897:Comorbidity; D016208:Databases, Factual; D018450:Disease Progression; D006801:Humans; D008019:Life Style; D025341:Principal Component Analysis; D029424:Pulmonary Disease, Chronic Obstructive / Q000453:epidemiology / Q000235:genetics / Q000473:pathology*; D012306:Risk; D012907:Smoking
chemical_list: D015415:Biomarkers