From Systems Understanding to Personalized Medicine: Lessons and Recommendations Based on a Multidisciplinary and Translational Analysis of COPD.

Systems medicine, using and adapting methods and approaches as developed within systems biology, promises to be essential in ongoing efforts of realizing and implementing personalized medicine in clinical practice and research. Here we review and critically assess these opportunities and challenges using our work on COPD as a case study. We find that there are significant unresolved biomedical challenges in how to unravel complex multifactorial components in disease initiation and progression producing different clinical phenotypes. Yet, while such a systems understanding of COPD is necessary, there are other auxiliary challenges that need to be addressed in concert with a systems analysis of COPD. These include information and communication technology (ICT)-related issues such as data harmonization, systematic handling of knowledge, computational modeling, and importantly their translation and support of clinical practice. For example, clinical decision-support systems need a seamless integration with new models and knowledge as systems analysis of COPD continues to develop. Our experience with clinical implementation of systems medicine targeting COPD highlights the need for a change of management including design of appropriate business models and adoption of ICT providing and supporting organizational interoperability among professional teams across healthcare tiers, working around the patient. In conclusion, in our hands the scope and efforts of systems medicine need to concurrently consider these aspects of clinical implementation, which inherently drives the selection of the most relevant and urgent issues and methods that need further development in a systems analysis of disease.

[1]  Eric J Topol,et al.  Individualized Medicine from Prewomb to Tomb , 2014, Cell.

[2]  Josep Roca,et al.  A systems biology approach reveals a link between systemic cytokines and skeletal muscle energy metabolism in a rodent smoking model and human COPD , 2014, Genome Medicine.

[3]  Amanda H. Salanitro,et al.  Risk prediction models for hospital readmission: a systematic review. , 2011, JAMA.

[4]  B. Celli,et al.  Comorbidities and risk of mortality in patients with chronic obstructive pulmonary disease. , 2012, American journal of respiratory and critical care medicine.

[5]  David Gomez-Cabrero,et al.  The COPD Knowledge Base: enabling data analysis and computational simulation in translational COPD research , 2014, Journal of Translational Medicine.

[6]  D. Poole,et al.  Muscle oxygen transport and utilization in heart failure: implications for exercise (in)tolerance. , 2012, American journal of physiology. Heart and circulatory physiology.

[7]  R. Thomas,et al.  Multistationarity, the basis of cell differentiation and memory. I. Structural conditions of multistationarity and other nontrivial behavior. , 2001, Chaos.

[8]  L. Hood,et al.  Systems medicine and integrated care to combat chronic noncommunicable diseases , 2011, Genome Medicine.

[9]  S. Rennard,et al.  COPD Heterogeneity: What This Will Mean in Practice , 2011, Respiratory Care.

[10]  Lew McCreary,et al.  Kaiser Permanente's innovation on the front lines. , 2010, Harvard business review.

[11]  Andrew J. Bulpitt,et al.  A Primer on Learning in Bayesian Networks for Computational Biology , 2007, PLoS Comput. Biol..

[12]  Josep Roca,et al.  Telemedicine enhances quality of forced spirometry in primary care , 2011, European Respiratory Journal.

[13]  Tom Doel,et al.  Computational modeling of the obstructive lung diseases asthma and COPD , 2014, Journal of Translational Medicine.

[14]  Judy A. Shea,et al.  Open Access in the Patient-Centered Medical Home: Lessons from the Veterans Health Administration , 2013, Journal of General Internal Medicine.

[15]  A. Barabasi,et al.  Uncovering disease-disease relationships through the incomplete interactome , 2015, Science.

[16]  Edwin K Silverman,et al.  Characterisation of COPD heterogeneity in the ECLIPSE cohort , 2010, Respiratory research.

[17]  Jesper Tegnér,et al.  Systems Medicine: from molecular features and models to the clinic in COPD , 2014, Journal of Translational Medicine.

[18]  Kumiko Hattori,et al.  A comparison of three multidimensional indices of COPD severity as predictors of future exacerbations , 2013, International journal of chronic obstructive pulmonary disease.

[19]  Tudor I. Oprea,et al.  Temporal disease trajectories condensed from population-wide registry data covering 6.2 million patients , 2014, Nature Communications.

[20]  J Frank Wharam,et al.  The promise and peril of healthcare forecasting. , 2012, The American journal of managed care.

[21]  Luigi Ceccaroni,et al.  Clinical Decision Support Systems (CDSS) for preventive management of COPD patients , 2014, Journal of Translational Medicine.

[22]  A. Barabasi,et al.  Systems biology and the future of medicine , 2011, Wiley interdisciplinary reviews. Systems biology and medicine.

[23]  Judith Garcia-Aymerich,et al.  Phenotypic Characterization and Course of Chronic Obstructive Pulmonary Disease in the PAC-COPD Study: Design and Methods , 2009 .

[24]  Ulrike Held,et al.  Expansion of the prognostic assessment of patients with chronic obstructive pulmonary disease: the updated BODE index and the ADO index , 2009, The Lancet.

[25]  Gilles Clermont,et al.  Computational disease modeling – fact or fiction? , 2009, BMC Systems Biology.

[26]  Martin J. Aryee,et al.  Epigenome-wide association data implicate DNA methylation as an intermediary of genetic risk in Rheumatoid Arthritis , 2013, Nature Biotechnology.

[27]  Albert Alonso,et al.  Integrated care services: lessons learned from the deployment of the NEXES project , 2015, International journal of integrated care.

[28]  Krin A. Kay,et al.  The implications of human metabolic network topology for disease comorbidity , 2008, Proceedings of the National Academy of Sciences.

[29]  Ciro Casanova,et al.  The progression of chronic obstructive pulmonary disease is heterogeneous: the experience of the BODE cohort. , 2011, American journal of respiratory and critical care medicine.

[30]  Jesper Tegnér,et al.  Chronic Obstructive Pulmonary Disease heterogeneity: challenges for health risk assessment, stratification and management , 2014, Journal of Translational Medicine.

[31]  Josep Roca,et al.  A Systems Biology Approach Identifies Molecular Networks Defining Skeletal Muscle Abnormalities in Chronic Obstructive Pulmonary Disease , 2011, PLoS Comput. Biol..

[32]  Josep Roca,et al.  Comparison of predictive risk modeling among 5 European regions in the ACT project , 2015 .

[33]  A. Barabasi,et al.  Network medicine : a network-based approach to human disease , 2010 .

[34]  J. Tegnér,et al.  Synergy-COPD: a systems approach for understanding and managing chronic diseases , 2014, Journal of Translational Medicine.

[35]  Josep Roca,et al.  Identification and prospective validation of clinically relevant chronic obstructive pulmonary disease (COPD) subtypes , 2010, Thorax.

[36]  T. Mikkelsen,et al.  The NIH Roadmap Epigenomics Mapping Consortium , 2010, Nature Biotechnology.

[37]  Xu Chen,et al.  Heterogeneity of chronic obstructive pulmonary disease: from phenotype to genotype , 2013, Frontiers of Medicine.

[38]  Alan D. Lopez,et al.  Measuring the global burden of disease. , 2013, The New England journal of medicine.

[39]  S. Coughlin Toward a road map for global -omics: a primer on -omic technologies. , 2014, American journal of epidemiology.

[40]  Jesper Tegnér,et al.  Accelerating Translational Research by Clinically Driven Development of an Informatics Platform–A Case Study , 2014, PloS one.

[41]  Hiroaki Kitano,et al.  The systems biology markup language (SBML): a medium for representation and exchange of biochemical network models , 2003, Bioinform..

[42]  Peter J. Barnes,et al.  Mechanisms of development of multimorbidity in the elderly , 2015, European Respiratory Journal.

[43]  Thierry Troosters,et al.  An official American Thoracic Society/European Respiratory Society statement: update on limb muscle dysfunction in chronic obstructive pulmonary disease. , 2014, American journal of respiratory and critical care medicine.

[44]  P. J. Barnes,et al.  Systemic manifestations and comorbidities of COPD , 2009, European Respiratory Journal.

[45]  Charles Auffray,et al.  Predictive, preventive, personalized and participatory medicine: back to the future , 2010, Genome Medicine.

[46]  J. Roca,et al.  Effects and barriers to deployment of telehealth wellness programs for chronic patients across 3 European countries. , 2014, Respiratory medicine.

[47]  K VanHentenryck Health Level Seven. Shedding light on HL7's Version 2.3 Standard. , 1997 .

[48]  P. Calverley,et al.  The ABCD of GOLD made clear , 2013, European Respiratory Journal.

[49]  Charles Auffray,et al.  Participatory medicine: a driving force for revolutionizing healthcare , 2013, Genome Medicine.

[50]  Klasien Horstman,et al.  European practices of genetic information and insurance: lessons for the Genetic Information Nondiscrimination Act. , 2008, JAMA.

[51]  Albert Alonso,et al.  An adaptive case management system to support integrated care services: Lessons learned from the NEXES project , 2015, J. Biomed. Informatics.

[52]  Niels H Chavannes,et al.  Derivation and validation of a composite index of severity in chronic obstructive pulmonary disease: the DOSE Index. , 2009, American journal of respiratory and critical care medicine.

[53]  Gj Ger Maas,et al.  The construction sector as strategic contributor to the European Innovation Partnership on Active and Healthy Ageing (EIP-AHA) , 2014 .

[54]  Edwin K Silverman,et al.  Network medicine approaches to the genetics of complex diseases. , 2012, Discovery medicine.

[55]  Courtney Crim,et al.  Should we view chronic obstructive pulmonary disease differently after ECLIPSE? A clinical perspective from the study team. , 2014, American journal of respiratory and critical care medicine.

[56]  F. Martinez,et al.  Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. , 2007, American journal of respiratory and critical care medicine.

[57]  Jesper Tegnér,et al.  Biomedical research in a Digital Health Framework , 2014, Journal of Translational Medicine.

[58]  Thierry Troosters,et al.  An official American Thoracic Society/European Respiratory Society statement: research questions in COPD , 2015, European Respiratory Review.

[59]  David Atkins,et al.  The Veterans Affairs experience: comparative effectiveness research in a large health system. , 2010, Health affairs.

[60]  Pere Caminal,et al.  Clinical Decision Support System to Enhance Quality Control of Spirometry Using Information and Communication Technologies , 2014, JMIR medical informatics.

[61]  M. Ashburner,et al.  Gene Ontology: tool for the unification of biology , 2000, Nature Genetics.

[62]  J. Epping-Jordan,et al.  Innovative care for chronic conditions: building blocks for action , 2002 .

[63]  Paul Enright,et al.  Large-scale international validation of the ADO index in subjects with COPD: an individual subject data analysis of 10 cohorts , 2012, BMJ Open.