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Funding Information: The WHO World Mental Health Survey collaborators are Sergio Aguilar-Gaxiola, MD, PhD; Ali Al-Hamzawi, MD; Mohammed Salih Al-Kaisy, MD; Jordi Alonso, MD, PhD; Yasmin A. Altwaijri, PhD; Laura Helena Andrade, MD, PhD; Lukoye Atwoli, MD, PhD; Corina Benjet, PhD; Guilherme Borges, ScD; Evelyn J. Bromet, PhD; Ronny Bruffaerts, PhD; Brendan Bunting, PhD; Jose Miguel Caldas-de-Almeida, MD, PhD; Gra?a Cardoso, MD, PhD; Somnath Chatterji, MD; Alfredo H. Cia, MD; Louisa Degenhardt, PhD; Koen Demyttenaere, MD, PhD; Silvia Florescu, MD, PhD; Giovanni de Girolamo, MD; Oye Gureje, MD, DSc, FRCPsych; Josep Maria Haro, MD, PhD; Meredith G. Harris, PhD; Hristo Hinkov, MD, PhD; Chi-yi Hu, MD, PhD; Peter de Jonge, PhD; Aimee Nasser Karam, PhD; Elie G. Karam, MD; Norito Kawakami, MD, DMSc; Ronald C. Kessler, PhD; Andrzej Kiejna, MD, PhD; Viviane Kovess-Masfety, MD, PhD; Sing Lee, MBBS; Jean-Pierre Lepine, MD; John J. McGrath, MD, PhD; Maria Elena Medina-Mora, PhD; Zeina Mneimneh, PhD; Jacek Moskalewicz, PhD; Fernando Navarro-Mateu, MD, PhD; Marina Piazza, MPH, ScD; Jose Posada-Villa, MD; Kate M. Scott, PhD; Tim Slade, PhD; Juan Carlos Stagnaro, MD, PhD; Dan J. Stein, FRCPC, PhD; Margreet ten Have, PhD; Yolanda Torres, MPH, Dra.HC; Maria Carmen Viana, MD, PhD; Daniel V. Vigo, MD, DrPH; Harvey Whiteford, MBBS, PhD; David R. Williams, MPH, PhD; Bogdan Wojtyniak, ScD. Funding Information: The Argentina survey -- Estudio Argentino de Epidemiologia en Salud Mental (EASM) -- was supported by a grant from the Argentinian Ministry of Health (Ministerio de Salud de la Nacion) - (Grant Number 2002–17270/13–5). The 2007 Australian National Survey of Mental Health and Wellbeing is funded by the Australian Government Department of Health and Ageing. The Sao Paulo Megacity Mental Health Survey is supported by the State of Sao Paulo Research Foundation (FAPESP) Thematic Project Grant 03/00204–3. The Bulgarian Epidemiological Study of common mental disorders EPIBUL is supported by the Ministry of Health and the National Center for Public Health Protection. EPIBUL 2, conducted in 2016–17, is supported by the Ministry of Health and European Economic Area Grants. The Colombian National Study of Mental Health (NSMH) is supported by the Ministry of Social Protection. The Mental Health Study Medellin – Colombia was carried out and supported jointly by the Center for Excellence on Research in Mental Health (CES University) and the Secretary of Health of Medellin. The ESEMeD project is funded by the European Commission (Contracts QLG5–1999-01042; SANCO 2004123, and EAHC 20081308), (the Piedmont Region (Italy)), Fondo de Investigacion Sanitaria, Instituto de Salud Carlos III, Spain (FIS 00/0028), Ministerio de Ciencia y Tecnologia, Spain (SAF 2000–158-CE), Generalitat de Catalunya (2017 SGR 452; 2014 SGR 748), Instituto de Salud Carlos III (CIBER CB06/02/0046, RETICS RD06/0011 REM-TAP), and other local agencies and by an unrestricted educational grant from GlaxoSmithKline. Implementation of the Iraq Mental Health Survey (IMHS) and data entry were carried out by the staff of the Iraqi MOH and MOP with direct support from the Iraqi IMHS team with funding from both the Japanese and European Funds through United Nations Development Group Iraq Trust Fund (UNDG ITF). The Israel National Health Survey is funded by the Ministry of Health with support from the Israel National Institute for Health Policy and Health Services Research and the National Insurance Institute of Israel. The World Mental Health Japan (WMHJ) Survey is supported by the Grant for Research on Psychiatric and Neurological Diseases and Mental Health (H13-SHOGAI-023, H14-TOKUBETSU-026, H16-KOKORO-013, H25-SEISHIN-IPPAN-006) from the Japan Ministry of Health, Labour and Welfare. The Lebanese Evaluation of the Burden of Ailments and Needs Of the Nation (L.E.B.A.N.O.N.) is supported by the Lebanese Ministry of Public Health, the WHO (Lebanon), National Institute of Health/Fogarty International Center (R03 TW006481–01), anonymous private donations to IDRAAC, Lebanon, and unrestricted grants from, Algorithm, AstraZeneca, Benta, Bella Pharma, Eli Lilly, Glaxo Smith Kline, Lundbeck, Novartis, OmniPharma, Pfizer, Phenicia, Servier, UPO. The Mexican National Comorbidity Survey (MNCS) is supported by The National Institute of Psychiatry Ramon de la Fuente (INPRFMDIES 4280) and by the National Council on Science and Technology (CONACyT-G30544- H), with supplemental support from the Pan American Health Organization (PAHO). Te Rau Hinengaro: The New Zealand Mental Health Survey (NZMHS) is supported by the New Zealand Ministry of Health, Alcohol Advisory Council, and the Health Research Council. The Northern Ireland Study of Mental Health was funded by the Health & Social Care Research & Development Division of the Public Health Agency. The Peruvian World Mental Health Study was funded by the National Institute of Health of the Ministry of Health of Peru. The Polish project Epidemiology of Mental Health and Access to Care –EZOP Project (PL 0256) was carried out by the Institute of Psychiatry and Neurology in Warsaw in consortium with Department of Psychiatry - Medical University in Wroclaw and National Institute of Public Health-National Institute of Hygiene in Warsaw and in partnership with Psykiatrist Institut Vinderen–Universitet, Oslo. The project was funded by the European Economic Area Financial Mechanism and the Norwegian Financial Mechanism. EZOP project was co-financed by the Polish Ministry of Health. The Portuguese Mental Health Study was carried out by the Department of Mental Health, Faculty of Medical Sciences, NOVA University of Lisbon, with collaboration of the Portuguese Catholic University, and was funded by Champalimaud Foundation, Gulbenkian Foundation, Foundation for Science and Technology (FCT) and Ministry of Health. The Saudi National Mental Health Survey (SNMHS) is conducted by the King Salman Center for Disability Research. It is funded by Saudi Basic Industries Corporation (SABIC), King Abdulaziz City for Science and Technology (KACST), Ministry of Health (Saudi Arabia), and King Saud University. Funding in-kind was provided by King Faisal Specialist Hospital and Research Center, and the Ministry of Economy and Planning, General Authority for Statistics. The Psychiatric Enquiry to General Population in Southeast Spain – Murcia (PEGASUS-Murcia) Project has been financed by the Regional Health Authorities of Murcia (Servicio Murciano de Salud and Consejeria de Sanidad y Politica Social) and Fundacion para la Formacion e Investigacion Sanitarias (FFIS) of Murcia. The US National Comorbidity Survey Replication (NCS-R) is supported by the National Institute of Mental Health (NIMH; U01-MH60220) with supplemental support from the National Institute of Drug Abuse (NIDA), the Substance Abuse and Mental Health Services Administration (SAMHSA), the Robert Wood Johnson Foundation (RWJF; Grant 044708), and the John W. Alden Trust. Funding Information: The World Health Organization World Mental Health (WMH) Survey Initiative is supported by the United States National Institute of Mental Health (NIMH; R01 MH070884), the John D. and Catherine T. MacArthur Foundation, the Pfizer Foundation, the United States Public Health Service (R13-MH066849, R01-MH069864, and R01 DA016558), the Fogarty International Center (FIRCA R03-TW006481), the Pan American Health Organization, Eli Lilly and Company, Ortho-McNeil Pharmaceutical Inc., GlaxoSmithKline, and Bristol-Myers Squibb. We thank the staff of the WMH Data Collection and Data Analysis Coordination Centres for assistance with instrumentation, fieldwork, and consultation on data analysis. None of the funders had any role in the design, analysis, interpretation of results, or preparation of this paper. The views and opinions expressed in this report are those of the authors and should not be construed to represent the views of the World Health Organization, other sponsoring organizations, agencies, or governments. Funding Information: In the past 3 years, RCK reports being a consultant for Datastat, Inc., RallyPoint Networks, Inc., Sage Pharmaceuticals, and Takeda. FNM reports non-financial support from Otsuka outside and not related to the submitted work. In the past 3 years LD has received untied educational grant funding from Indivior and Seqirus, not related to the submitted work. DJS has received research grants and/or honoraria from Lundbeck, Johnson & Johnson, Servier and Takeda. The remaining authors declare that they have no competing interests. Publisher Copyright: © 2021, The Author(s).

Background: decisive information on the parameters involved in cognitive impairment in patients with chronic heart failure is as yet lacking. Our aim was to determine the functional and psychosocial variables related with cognitive impairment using the mini-mental-state examination (MMSE) with age-and education-corrected scores. Methods: a cohort study of chronic heart failure patients included in an integrated multidisciplinary hospital/primary care program. The MMSE (corrected for age and education in the Spanish population) was administered at enrolment in the program. Analyses were performed in 525 patients. Demographic and clinical variables were collected. Comprehensive assessment included depression (Yesavage), family function (family APGAR), social network (Duke), dependence (Barthel Index), frailty (Barber), and comorbidities. Univariate and multivariate logistic regression were performed to determine the predictors of cognitive impairment. Results: cognitive impairment affected 145 patients (27.6 %). Explanatory factors were gender (OR: 2.77 (1.75-4.39) p 3.5 (OR: 0.59 (0.35-0.99) p = 0.048), and beta-blocker treatment (OR: 0.36 (0.17 to 0.76, p = 0.007)). No association was found between cognitive impairment and social support or family function. Conclusion: the observed prevalence of cognitive impairment using MMSE corrected scores was 27.6 %. A global approach in the management of these patients is needed, especially focusing on women and patients with frailty, low albumin levels, and ischemic aetiology heart failure.

BACKGROUND AND HYPOTHESIS: Chronic Obstructive Pulmonary Disease (COPD) patients are characterized by heterogeneous clinical manifestations and patterns of disease progression. Two major factors that can be used to identify COPD subtypes are muscle dysfunction/wasting and co-morbidity patterns. We hypothesized that COPD heterogeneity is in part the result of complex interactions between several genes and pathways. We explored the possibility of using a Systems Medicine approach to identify such pathways, as well as to generate predictive computational models that may be used in clinic practice. OBJECTIVE AND METHOD: Our overarching goal is to generate clinically applicable predictive models that characterize COPD heterogeneity through a Systems Medicine approach. To this end we have developed a general framework, consisting of three steps/objectives: (1) feature identification, (2) model generation and statistical validation, and (3) application and validation of the predictive models in the clinical scenario. We used muscle dysfunction and co-morbidity as test cases for this framework. RESULTS: In the study of muscle wasting we identified relevant features (genes) by a network analysis and generated predictive models that integrate mechanistic and probabilistic models. This allowed us to characterize muscle wasting as a general de-regulation of pathway interactions. In the co-morbidity analysis we identified relevant features (genes/pathways) by the integration of gene-disease and disease-disease associations. We further present a detailed characterization of co-morbidities in COPD patients that was implemented into a predictive model. In both use cases we were able to achieve predictive modeling but we also identified several key challenges, the most pressing being the validation and implementation into actual clinical practice. CONCLUSIONS: The results confirm the potential of the Systems Medicine approach to study complex diseases and generate clinically relevant predictive models. Our study also highlights important obstacles and bottlenecks for such approaches (e.g. data availability and normalization of frameworks among others) and suggests specific proposals to overcome them.

Background: There is evidence that social anxiety disorder (SAD) is a prevalent and disabling disorder. However, most of the available data on the epidemiology of this condition originate from high income countries in the West. The World Mental Health (WMH) Survey Initiative provides an opportunity to investigate the prevalence, course, impairment, socio-demographic correlates, comorbidity, and treatment of this condition across a range of high, middle, and low income countries in different geographic regions of the world, and to address the question of whether differences in SAD merely reflect differences in threshold for diagnosis. Methods: Data from 28 community surveys in the WMH Survey Initiative, with 142,405 respondents, were analyzed. We assessed the 30-day, 12-month, and lifetime prevalence of SAD, age of onset, and severity of role impairment associated with SAD, across countries. In addition, we investigated socio-demographic correlates of SAD, comorbidity of SAD with other mental disorders, and treatment of SAD in the combined sample. Cross-tabulations were used to calculate prevalence, impairment, comorbidity, and treatment. Survival analysis was used to estimate age of onset, and logistic regression and survival analyses were used to examine socio-demographic correlates. Results: SAD 30-day, 12-month, and lifetime prevalence estimates are 1.3, 2.4, and 4.0% across all countries. SAD prevalence rates are lowest in low/lower-middle income countries and in the African and Eastern Mediterranean regions, and highest in high income countries and in the Americas and the Western Pacific regions. Age of onset is early across the globe, and persistence is highest in upper-middle income countries, Africa, and the Eastern Mediterranean. There are some differences in domains of severe role impairment by country income level and geographic region, but there are no significant differences across different income level and geographic region in the proportion of respondents with any severe role impairment. Also, across countries SAD is associated with specific socio-demographic features (younger age, female gender, unmarried status, lower education, and lower income) and with similar patterns of comorbidity. Treatment rates for those with any impairment are lowest in low/lower-middle income countries and highest in high income countries. Conclusions: While differences in SAD prevalence across countries are apparent, we found a number of consistent patterns across the globe, including early age of onset, persistence, impairment in multiple domains, as well as characteristic socio-demographic correlates and associated psychiatric comorbidities. In addition, while there are some differences in the patterns of impairment associated with SAD across the globe, key similarities suggest that the threshold for diagnosis is similar regardless of country income levels or geographic location. Taken together, these cross-national data emphasize the international clinical and public health significance of SAD. This work was carried out in conjunction with the World Health Organization World Mental Health (WMH) Survey Initiative which is supported by the National Institute of Mental Health (NIMH; R01 MH070884), the John D. and Catherine T. MacArthur Foundation, the Pfizer Foundation, the US Public Health Service (R13-MH066849, R01-MH069864, and R01 DA016558), the Fogarty International Center (FIRCA R03-TW006481), the Pan American Health Organization, Eli Lilly and Company, Ortho-McNeil Pharmaceutical, GlaxoSmithKline, and Bristol-Myers Squibb. The 2007 Australian National Survey of Mental Health and Wellbeing is funded by the Australian Government Department of Health and Ageing. The São Paulo Megacity Mental Health Survey is supported by the State of São Paulo Research Foundation (FAPESP) Thematic Project Grant 03/00204-3. The Bulgarian Epidemiological Study of common mental disorders EPIBUL is supported by the Ministry of Health and the National Center for Public Health Protection. The Chinese World Mental Health Survey Initiative is supported by the Pfizer Foundation. The Shenzhen Mental Health Survey is supported by the Shenzhen Bureau of Health and the Shenzhen Bureau of Science, Technology, and Information. The Colombian National Study of Mental Health (NSMH) is supported by the Ministry of Social Protection. The Mental Health Study Medellin-Colombia was carried out and supported jointly by the Center for Excellence on Research in Mental Health (CES University) and the Secretary of Health of Medellin. The ESEMeD project is funded by the European Commission (Contracts QLG5-1999-01042; SANCO 2004123, and EAHC 20081308), (the Piedmont Region, Italy), Fondo de Investigación Sanitaria, Instituto de Salud Carlos III, Spain (FIS 00/0028), Ministerio de Ciencia y Tecnología, Spain (SAF 2000-158-CE), Departament de Salut, Generalitat de Catalunya, Spain, Instituto de Salud Carlos III (CIBER CB06/02/0046, RETICS RD06/0011 REM-TAP), and other local agencies and by an unrestricted educational grant from GlaxoSmithKline. Implementation of the Iraq Mental Health Survey (IMHS) and data entry were carried out by the staff of the Iraqi MOH and MOP with direct support from the Iraqi IMHS team with funding from both the Japanese and European Funds through the United Nations Development Group Iraq Trust Fund (UNDG ITF). The World Mental Health Japan (WMHJ) Survey is supported by the Grant for Research on Psychiatric and Neurological Diseases and Mental Health (H13-SHOGAI-023, H14-TOKUBETSU-026, H16-KOKORO-013) from the Japan Ministry of Health, Labour and Welfare. The Lebanese Evaluation of the Burden of Ailments and Needs Of the Nation (L.E.B.A.N.O.N.) is supported by the Lebanese Ministry of Public Health, the WHO (Lebanon), National Institute of Health/Fogarty International Center (R03 TW006481-01), anonymous private donations to IDRAAC, Lebanon, and unrestricted grants from Algorithm, AstraZeneca, Benta, Bella Pharma, Eli Lilly, GlaxoSmithKline, Lundbeck, Novartis, OmniPharma, Pfizer, Phenicia, Servier, and UPO. The Mexican National Comorbidity Survey (MNCS) is supported by The National Institute of Psychiatry Ramon de la Fuente (INPRFMDIES 4280) and by the National Council on Science and Technology (CONACyT-G30544- H), with supplemental support from the Pan American Health Organization (PAHO). Corina Benjet has received funding from the (Mexican) National Council of Science and Technology (grant CB-2010-01-155221). Te Rau Hinengaro: The New Zealand Mental Health Survey (NZMHS) is supported by the New Zealand Ministry of Health, Alcohol Advisory Council, and the Health Research Council. The Nigerian Survey of Mental Health and Wellbeing (NSMHW) is supported by the WHO (Geneva), the WHO (Nigeria), and the Federal Ministry of Health, Abuja, Nigeria. The Northern Ireland Study of Mental Health was funded by the Health & Social Care Research & Development Division of the Public Health Agency. The Peruvian World Mental Health Study was funded by the National Institute of Health of the Ministry of Health of Peru. The Polish project Epidemiology of Mental Health and Access to Care - EZOP Project (PL 0256) was supported by Iceland, Liechtenstein, and Norway through funding from the EEA Financial Mechanism and the Norwegian Financial Mechanism. The EZOP project was co-financed by the Polish Ministry of Health. The Portuguese Mental Health Study was carried out by the Department of Mental Health, Faculty of Medical Sciences, NOVA University of Lisbon, with collaboration of the Portuguese Catholic University, and was funded by the Champalimaud Foundation, the Gulbenkian Foundation, the Foundation for Science and Technology (FCT), and the Ministry of Health. The Romania WMH study projects “Policies in Mental Health Area” and “National Study regarding Mental Health and Services Use” were carried out by National School of Public Health & Health Services Management (former National Institute for Research & Development in Health), with technical support of Metro Media Transilvania, the National Institute of Statistics-National Centre for Training in Statistics, SC. Cheyenne Services SRL, Statistics Netherlands and were funded by the Ministry of Public Health (former Ministry of Health) with supplemental support from Eli Lilly Romania SRL. The South Africa Stress and Health Study (SASH) is supported by the US National Institute of Mental Health (R01-MH059575) and the National Institute of Drug Abuse with supplemental funding from the South African Department of Health and the University of Michigan. DJS is supported by the South African Medical Research Council (MRC). The Psychiatric Enquiry to General Population in Southeast Spain - Murcia (PEGASUS-Murcia) Project has been financed by the Regional Health Authorities of Murcia (Servicio Murciano de Salud and Consejería de Sanidad y Política Social) and Fundación para la Formación e Investigación Sanitarias (FFIS) of Murcia. The Ukraine Comorbid Mental Disorders during Periods of Social Disruption (CMDPSD) study is funded by the US National Institute of Mental Health (RO1-MH61905). The US National Comorbidity Survey Replication (NCS-R) is supported by the National Institute of Mental Health (NIMH; U01-MH60220) with supplemental support from the National Institute of Drug Abuse (NIDA), the Substance Abuse and Mental Health Services Administration (SAMHSA), the Robert Wood Johnson Foundation (RWJF; Grant 044708), and the John W. Alden Trust.

Background 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. The research described in this paper is partly supported by the Synergy-COPD European project (FP7-ICT-270086). Publication of this article has been funded by the Synergy-COPD European project (FP7-ICT-270086)

Background: Co-morbidity between Type 1 Diabetes Mellitus (T1DM) and eating disorders (ED) has been previously described; however the effect of this illness on the outcomes for conventional ED treatments has not been previously investigated. This study aims to compare clinical, psychopathological and personality features between two samples of ED individuals: those with comorbid T1DM and those without (No-DM); and to identify differences in treatment outcomes between the groups. Methods: This study compares treatment outcome, dropouts, ED psychopathology and personality characteristics for 20 individuals with ED and T1DM and 20 ED patients without diabetes, matched for diagnostic and treatment type. Results: The study found higher dropout rates from therapy in individuals with T1DM and worse treatment outcome in spite of having no significant differences in eating disorder psychopathology, although individuals with T1DM report misusing insulin. Conclusions: The low levels of motivation to change, and insulin abuse in T1DM patients, may suggest that treatment for patients with ED and T1DM should consider the individual's personality and role of insulin abuse when determining the appropriate intervention.

Producción Científica, Background: A relatively large percentage of patients with chronic obstructive pulmonary disease (COPD) develop systemic co-morbidities that affect prognosis, among which muscle wasting is particularly debilitating. Despite significant research effort, the pathophysiology of this important extrapulmonary manifestation is still unclear. A key question that remains unanswered is to what extent systemic inflammatory mediators might play a role in this pathology. Cigarette smoke (CS) is the main risk factor for developing COPD and therefore animal models chronically exposed to CS have been proposed for mechanistic studies and biomarker discovery. Although mice have been successfully used as a pre-clinical in vivo model to study the pulmonary effects of acute and chronic CS exposure, data suggest that they may be inadequate models for studying the effects of CS on peripheral muscle function. In contrast, recent findings indicate that the guinea pig model (Cavia porcellus) may better mimic muscle wasting. Methods: We have used a systems biology approach to compare the transcriptional profile of hindlimb skeletal muscles from a Guinea pig rodent model exposed to CS and/or chronic hypoxia to COPD patients with muscle wasting. Results: We show that guinea pigs exposed to long-term CS accurately reflect most of the transcriptional changes observed in dysfunctional limb muscle of severe COPD patients when compared to matched controls. Using network inference, we could then show that the expression profile in whole lung of genes encoding for soluble inflammatory mediators is informative of the molecular state of skeletal muscles in the guinea pig smoking model. Finally, we show that CXCL10 and CXCL9, two of the candidate systemic cytokines identified using this pre-clinical model, are indeed detected at significantly higher levels in serum of COPD patients, and that their serum protein level is inversely correlated with the expression of aerobic energy metabolism genes in skeletal muscle. Conclusions: We conclude that CXCL10 and CXCL9 are promising candidate inflammatory signals linked to the regulation of central metabolism genes in skeletal muscles. On a methodological level, our work also shows that a system level analysis of animal models of diseases can be very effective to generate clinically relevant hypothesis.

Chronic diseases (CD) are generating a dramatic societal burden worldwide that is expected to persist over the next decades. The challenges posed by the epidemics of CD have triggered a novel health paradigm with major consequences on the traditional concept of disease and with a profound impact on key aspects of healthcare systems. We hypothesized that the development of a systems approach to understand CD together with the generation of an ecosystem to transfer the acquired knowledge into the novel healthcare scenario may contribute to a cost-effective enhancement of health outcomes. To this end, we designed the Synergy-COPD project wherein the heterogeneity of chronic obstructive pulmonary disease (COPD) was addressed as a use case representative of CD. The current manuscript describes main features of the project design and the strategies put in place for its development, as well the expected outcomes during the project life-span. Moreover, the manuscript serves as introductory and unifying chapter of the different papers associated to the Supplement describing the characteristics, tools and the objectives of Synergy-COPD