DATA REPORT published: 15 July 2021 doi: 10.3389/fpubh.2021.666844 A Map of the Initiatives That Harmonize Patient Cohorts Across the World Ángel Rodríguez-Laso 1 , Laura Alejandra Rico-Uribe 2 , Christine Kubiak 3 , Josep Maria Haro 4 , Leocadio Rodríguez-Mañas 1,5,6 and José Luis Ayuso 2,7,8* 1 Thematic Area for Frailty and Healthy Ageing of the Network of Biomedical Research Centers (CIBERFES), Instituto de Salud Carlos III, Madrid, Spain, 2 Centro de Investigación Biomédica en Red de Salud Mental, Instituto de Salud Carlos III, Madrid, Spain, 3 European Clinical Research Infrastructure Network (ECRIN-ERIC), Paris, France, 4 Parc Sanitari Sant Joan de Déu, Barcelona, Spain, 5 Biomedical Research Foundation, Hospital Universitario de Getafe, Madrid, Spain, 6 Geriatric Department, Hospital Universitario de Getafe, Madrid, Spain, 7 Department of Psychiatry, Universidad Autónoma de Madrid, Madrid, Spain, 8 Instituto de Investigación Sanitaria Princesa, Hospital Universitario de La Princesa, Madrid, Spain Keywords: clinical cohort, patient cohort, harmonization, integration, repository INTRODUCTION Integration of cohort studies allows taking advantage of already collected information to increase Edited by: Laura Beane Freeman, the sample size to study uncommon exposures, rare diseases, less strong associations, or very National Cancer Institute (NCI), restricted populations (personalized medicine). It also allows to carry out standardized analyses United States and avoid publication bias compared to the analysis of published data (1–5). Nevertheless, the Reviewed by: growing energy spent in conducting cohort studies across the world in the last decades has not Yutong Samuel Cai, been paralleled by an effort to make them accessible to the scientific community and harmonize University of Oxford, United Kingdom their data. This last limitation moved the European Commission to fund the SYNergies for Cohorts Milagros Ruiz, in Health: integrating the ROle of all Stakeholders (SYNCHROS) coordination and support action, University College London, endowed with almost e2 million1 from 2019 to 2021. It aims “to establish a sustainable European United Kingdom strategy for the development of the next generation of integrated cohorts, thereby contributing to *Correspondence: an international strategic agenda for enhanced coordination of cohorts globally, in order to address José Luis Ayuso the practical, ethical, legal, and methodological challenge of optimizing the exploitation of current joseluis.ayuso@uam.es and future cohort data, toward the development of stratified and personalized medicine as well as facilitating health policy.” Specialty section: In order to achieve its objectives, the first activity proposed in SYNCHROS was to map the This article was submitted to Life-Course Epidemiology and Social population, patient, and clinical trial cohort integration landscape. That would allow the project Inequalities in Health, to have a first look at the challenges and tried solutions adopted by different groups, and, more a section of the journal importantly, it would provide a list of principal investigators of these initiatives who could be Frontiers in Public Health contacted for the process of developing the common strategy. This study reports the result of the Received: 11 February 2021 mapping of the initiatives that integrate patient cohorts. The mapping of population cohorts will Accepted: 14 June 2021 be reported elsewhere. The aim of the study was to obtain a non-exhaustive, but representative, Published: 15 July 2021 list of these initiatives carried out in recent times in the world. To our knowledge, there is no other Citation: repository of integration initiatives of patient cohorts. Although excellent single cohort repositories Rodríguez-Laso Á, Rico-Uribe LA, exist, like the Maelstrom catalog, repositories of initiatives that integrate several patient cohorts Kubiak C, Haro JM, could not be found. Rodríguez-Mañas L and Ayuso JL This mapping will provide researchers with a useful tool to find initiatives on their areas of (2021) A Map of the Initiatives That interest with whom they can share or analyze harmonized data. Harmonize Patient Cohorts Across the World. Front. Public Health 9:666844. doi: 10.3389/fpubh.2021.666844 1 https://cordis.europa.eu/project/id/825884/es. Frontiers in Public Health | www.frontiersin.org 1 July 2021 | Volume 9 | Article 666844 Rodríguez-Laso et al. A Map of the Initiatives That Harmonize Patient Cohorts Across the World METHODS AND (“2000/01/01”[Date - Publication]: “2019/07/31”[Date The initiatives included in the mapping were obtained from three - Publication]) different sources: AND 1. Systematic searches, carried out in MEDLINE and the English[Language] Maelstrom catalog.2 AND 2. Suggestions of potential initiatives to be included in the Humans[MeSH] mapping provided by partners of the SYNCHROS consortium. 3. References and links provided by the initiatives detected in the Maelstrom Catalog two previous sources. The Maelstrom research catalog, supported by the Research Institute of the McGill University Health Centre, “contains The inclusion criteria were as follows: comprehensive information about epidemiological research a) initiatives that integrated patient, clinical, or disease cohorts; networks and studies, and the data they have collected. It also b) individual patient meta-analysis and mega-analyses; and provides information about harmonized data generated by these c) at least one cohort included in the initiative having research networks.” information about the sample at two or more points of time We looked for initiatives included in the “Networks” section (at least two waves). of the catalog. The exclusion criteria were as follows: Selection of Initiatives a) initiatives that only integrate population cohorts or clinical Initiatives that were obtained from the systematic searches and trials, without including patient cohorts; provided by the partners were evaluated against the inclusion b) initiatives published before the year 2000; and and exclusion criteria by two different investigators. In case of c) initiatives that did not provide information in English. a disagreement, a third reviewer was consulted. Database Searches Extraction of Information MEDLINE Search The following information was extracted from each initiative: The process started with searches restricted to papers published name of the initiative, principal investigator, partners, name of in English from 2000 to 2019 using the terms selected by the institution responsible for the initiative, funding resources, consensus among the SYNCHROS partners. Those terms which contact person, information source, whether the research obtained fewer than 500 hits were retained, and the abstracts team is currently active, main objectives, criteria for the of the hits were reviewed to find new terms that were used in cohorts to be included in the initiative, type of harmonization subsequent searches. In some cases, the term “cohort” was added (prospective/retrospective), number of cohorts included in the to these searches to limit the number of hits. initiative (the total number and the number of harmonized The final search strategy used is given as follows: cohorts), whether more cohorts are foreseen to be harmonized, (cohort OR “prospective study” OR “longitudinal study” OR number of participants (the total number and the number of “individual meta-analysis”[All Fields] OR “individual participant participants with harmonized data), age range of the sample, data meta-analysis”[All Fields] OR “individual patient data meta- threats to representativeness of the sample, maximum number analysis”[All Fields] OR “individual meta analysis”[All Fields] of variables that have been harmonized, including those where OR “individual participant data meta analysis”[All Fields] OR harmonization was not possible for all the cohorts, setting of “individual patient data meta analysis”[All Fields] OR “meta the harmonized cohorts (local-regional/national/international, analysis using individual”[All Fields] OR “meta-analysis using including country of origin of the cohorts), and a brief individual”[All Fields] OR “meta analysis of individual”[All description of the population considered by the initiative. Fields] OR “meta-analysis of individual”[All Fields] OR “mega- All this information was retrieved from the webpage and/or analysis”[All Fields] OR “mega analysis”[All Fields]) the scientific article that presented the initiative. Missing AND information was requested from the principal investigators of the (“harmonization study” OR “integration study” OR projects, who were contacted initially by email and, if there was “integration initiative” OR “integrated study” OR “merged no answer, by phone call or by post. cohort” OR “data pooling” OR “pooled sample” OR “combined data” OR “combining data” OR “harmonized ANALYSIS data” OR “harmonised data” OR “harmonizing data” OR “data harmonization” OR “data harmonisation” OR “data sharing” Results of the identification process of the initiatives are OR “common database” OR “multiple cohorts” OR “multiple presented in Figure 1. longitudinal studies” OR “international consortium” OR Partners of the SYNCHROS project provided 39 initiatives. “collaborative effort”). Of those, 28 were excluded, mainly because there was no data harmonization or because eligibility could not be ascertained 2 https://www.maelstrom-research.org/maelstrom-catalogue. due to unresponsiveness from the principal investigators. The Frontiers in Public Health | www.frontiersin.org 2 July 2021 | Volume 9 | Article 666844 Rodríguez-Laso et al. A Map of the Initiatives That Harmonize Patient Cohorts Across the World FIGURE 1 | Results of the search for harmonization initiatives of patient cohorts. remaining 11 initiatives were selected. The descendent search In the selected initiatives, the most represented group from these initiatives provided two additional ones. of diseases is cancer (10 initiatives), followed by infectious In the MEDLINE search, out of 843 hits obtained, 677 were diseases (8 initiatives, of which 5 focus on HIV) and excluded after reading their title and abstract. Of the remaining cardiovascular disease (4 initiatives). There are five initiatives articles, 166 were read and, from those, 140 excluded. The that have harmonized data from more than one type of main reasons for exclusion were that initiatives dealt only with disease. Other diseases and conditions producing a high population cohorts, that they had already been submitted by burden in the high-income countries (6) are represented partners or already presented in another reference, or that the (dementia, osteoarthritis), but others included in this integration was only cross-sectional. In the end, 26 initiatives list (unipolar depressive disorders, alcohol use disorders, were selected. The reference list of these initiatives included five hearing loss, chronic obstructive pulmonary disease, diabetes additional ones. mellitus, road traffic accidents) or poor-defined conditions The search in the Maelstrom catalog only provided initiatives with a well-defined impact on life-expectancy and quality that harmonized population cohorts. of life (like back pain or functional deterioration) are Overall, 44 initiatives were retrieved. They are presented in missing. There is one initiative about a specific rare disease Table 1. (Sjögren syndrome). Table 1 shows a selection of the most relevant information There is a sizable number of initiatives that have harmonized obtained from each of the initiatives. Complete information can other types of cohorts in addition to patient cohorts. After Breast be found in the repository of the SYNCHROS project.3 They are Cancer Pooling Project, BIOMAP, CLL-IPI, HARMONY, and ordered by types of diseases covered (starting with those which the initiatives on obsessive-compulsive disorder and pulmonary consider several diseases) and by alphabetical order. Of the 44 embolism have harmonized at least one clinical trial cohort. initiatives found, no further information could be obtained from CINECA, ESCAPE-NET, Lifebrain, and the project “Seasonal principal investigators in almost half (20) of them. plasticity of cognition” have also harmonized population Eight initiatives (BIOMAP, CINECA, EHDEN, ESCAP- cohorts. BiomarCaRE and the National Cancer Institute Cohort NET, HarmonicSS, HARMONY, Lifebrain, and ReCoDID) have Consortium have harmonized the three types of cohorts: patient, recently started adding cohorts; 21 are led by active research population and clinical trials cohorts. teams; and 12 are adding, or considering adding, cohorts now. Most of them (33) have an international scope, compared Nevertheless, there is plenty of missing information on the to seven national initiatives and one regional/local initiative. activity status of the initiatives. Two initiatives report that they include cohorts from across the world and eight initiatives incorporate cohorts from high- and 3 https://www.synchros.es. low- and middle-income countries (LMIC); 30 (75%) initiatives Frontiers in Public Health | www.frontiersin.org 3 July 2021 | Volume 9 | Article 666844 Frontiers in Public Health | www.frontiersin.org Rodríguez-Laso et al. TABLE 1 | Initiatives that harmonize patient cohorts ordered by different categories of diseases (selected information). Initiative Types of cohorts Region, Country Main objective Number of More Number of Age range No. of Population were the cohorts cohorts with cohorts participants of the harmonized were collected harmonized data foreseen to with sample variables be harmonized (Maximum) harmonized? data CINECA: Disease cohorts. Africa, Canada To develop a federated cloud enabled In progress Possibly In progress Birth to old In progress The dataset provides a Common Population and Europe infrastructure to make population scale age diverse representation Infrastructure for cohorts genomic and biomolecular data of studies in rare National Cohorts accessible across international borders, disease, common in Europe, Canada to accelerate research, and improve the disease and national and Africa health of individuals across continents cohorts over time (longitudinal) CNODES: the Disease cohorts Canada, US and Use collaborative, population-based Depends on the No Depends on All ages Depends on Population of Canada, Canadian Network UK approaches to obtain rapid answers to research question the research the research UK and US which is for Observational questions about drug safety and question question prescribed or Drug Effect effectiveness dispensed drugs Studies EHDEN: European Disease cohorts All Horizon 2020 Harmonize in excess of 100 million In progress 18 Considerable European patients Health Data and member states anonymized health records to the aged 18+ Evidence Network and associated OMOP common data model, supported countries by an ecosystem of certified SMEs, and technical architecture for a federated network 4 MIRACUM: Disease cohorts Seven states of The spotlight is here on the data 11 No information No information 0 to the No Patients attended in Medical Germany integration centers that will be obtained obtained highest age information hospitals of seven Informatics in embedded in the hospital of patients obtained German states A Map of the Initiatives That Harmonize Patient Cohorts Across the World Research and IT-infrastructure and will facilitate the Care in University collection and exchange of data within Medicine the consortia university hospitals. Furthermore, we will elaborate a programme for strengthening medical informatics by extending the academic offer, including new professorships in the field of medical informatics, a novel, innovative master programme and personnel training. The MIRACUM partners have agreed to share data, based on interoperable data integration centers, develop common and July 2021 | Volume 9 | Article 666844 interoperable tools and services, realize the power of such data and tools in innovative IT solutions, which shall enhance patient-centered collaborative research as well as clinical care processes, and finally to strengthen biomedical informatics in research, teaching and continued education (Continued) Frontiers in Public Health | www.frontiersin.org Rodríguez-Laso et al. TABLE 1 | Continued Initiative Types of cohorts Region, Country Main objective Number of More Number of Age range No. of Population were the cohorts cohorts with cohorts participants of the harmonized were collected harmonized data foreseen to with sample variables be harmonized (Maximum) harmonized? data Sentinel initiative Disease cohorts US Serve as a system to analyze and 17 No information 310 million All ages No Population of US which assess safety risks in FDA-approved obtained information is prescribed or drugs and medical products using obtained dispensed drugs electronic health data BiomarCaRE: Disease cohorts. Australia, Europe, Assess the value of established and 4 No information 8.746 No No Patients with coronary Biomarker for Population Israel, Latin emerging biomarkers for cardiovascular obtained information information heart disease or at risk Cardiovascular cohorts. Clinical America, New risk prediction obtained obtained of developing it Risk Assessment trials Zealand, South across Europe Africa, United States CADISP: Cervical Disease cohorts Western Europe International Consortium performing No information No information No information No No Cervical artery Artery Dissection and Turkey research on ischemic stroke in young obtained obtained obtained information information dissection and and Ischemic and middle-aged adults and in particular obtained obtained ischemic stroke Patients on cervical artery dissection patients from some Western European 5 countries and Turkey Development and Disease cohorts US The objective of this study was the 2 No information 200 No 38 Individuals undergoing validation of the development of AMPREDICT-Mobility, a obtained information their first major lower AMPREDICT tool to predict the probability of obtained extremity amputation A Map of the Initiatives That Harmonize Patient Cohorts Across the World model independence in either basic or because of advanced mobility 1 year after complications of dysvascular major lower extremity peripheral artery amputation disease or diabetes ESCAPE-NET: Disease cohorts. Czech Republic, Aims to study: (1) risk factors and No information Yes No information No No Patients with sudden European Sudden Population Denmark, France, mechanisms for the occurrence of obtained obtained information information cardiac arrest Cardiac Arrest cohorts Italy, Sweden, The sudden cardiac arrest (SCA) in the obtained obtained network: toward Netherlands population, and (2) risk factors and Prevention, treatment strategies for survival after Education and SCA on a European scale NEw Treatment After Breast Disease cohorts China (Shanghai), Examine the role of physical activity, 4 Yes 18.314 20–83 No Breast cancer survivors July 2021 | Volume 9 | Article 666844 Cancer Pooling (one is based on US adiposity, dietary factors, supplement information (women). Cancers were Project the follow-up of a use, and quality of life in breast cancer obtained diagnosed between randomized prognosis 1976 and 2006 clinical controlled trial) (Continued) Frontiers in Public Health | www.frontiersin.org Rodríguez-Laso et al. TABLE 1 | Continued Initiative Types of cohorts Region, Country Main objective Number of More Number of Age range No. of Population were the cohorts cohorts with cohorts participants of the harmonized were collected harmonized data foreseen to with sample variables be harmonized (Maximum) harmonized? data B-CAST: Breast Disease cohorts No information In B-CAST tools will be developed to No information No information No information No No Patients with breast CAncer obtained allow precise identification of the obtained obtained obtained information information cancer STratification individual risk of breast cancer, the obtained obtained subtype of cancer that is most likely to develop and the prognosis of that particular subtype Collaborative Disease cohorts Worldwide Study risk factors of oavarian cancer 58 No information 31,000 No No Women with ovarian Group on obtained information information cancer Epidemiological obtained obtained Studies of Ovarian Cancer GENIE: Genomics Disease cohorts Canada, France, It is a multi-phase, multi-year, 19 Yes 70,000 All ages No Cancer patients treated Evidence Netherlands, international data-sharing project that information at multiple international Neoplasia Spain, UK, USA aims to catalyze precision cancer obtained institutions Information medicine Exchange HARMONY: Disease cohorts. All Europe The HARMONY Alliance uses big data Acute Myeloid In progress 11,664 (aims All ages are It depends on Patients with blood European Clinical trials technologies to improve the treatment of Leukemia: 5 patient to harmonize considered the specific malignancies Public-Private seven hematologic malignancies cohorts. Multiple between research 6 Partnership for Big myeloma: 15 75,000 and question Data in patient cohorts 100,000 Hematology anonymized hematologic A Map of the Initiatives That Harmonize Patient Cohorts Across the World patients by the end of the funding period) International Disease cohorts Costa Rica, Study the effects of hormonal 9 No information 2,109 No No Women with cervical Collaboration of Denmark, Norway, contraceptive use and other factors on obtained information information cancer Epidemiological Sweden, UK, US the risk of cervical cancer obtained obtained Studies of Cervical Cancer MaGIC: Malignant Disease cohorts No information Developing more effective treatments for No information No information No information No No GCT patients all over Germ Cell obtained germ cell tumors (GCT) through obtained obtained obtained information information the world International scientific inquiry obtained obtained July 2021 | Volume 9 | Article 666844 Consortium NCI: National Disease cohorts. Australia, Canada, Foster communication among No information Yes No information 18+ No Breast and colon family Cancer Institute Population New Zealand, investigators leading cohort studies of obtained obtained information cancer patients and Cohort cohorts. Clinical USA cancer, promote collaborative research obtained their families Consortium trials projects for topics not easily addressed in a single study and identify common challenges in cohort research and search for solutions (Continued) Frontiers in Public Health | www.frontiersin.org Rodríguez-Laso et al. TABLE 1 | Continued Initiative Types of cohorts Region, Country Main objective Number of More Number of Age range No. of Population were the cohorts cohorts with cohorts participants of the harmonized were collected harmonized data foreseen to with sample variables be harmonized (Maximum) harmonized? data Second primary Disease cohorts France, Italy, Evaluate the risk of second cancer and 3 No 6,841 7–80 (at time Around 10 Patients with papillary malignancies in Sweden leukemia in patients with papillary or of diagnosis or follicular thyroid thyroid cancer follicular thyroid cancer treated with of thyroid cancer patients radioiodine or external beam radiation cancer) therapy The International Disease cohorts. France, Germany, We established an international 2 1,254 No 18 Chronic lymphocytic CLL-IPI working Clinical trials Poland, UK, US consortium with the aim to create an information leukemia patients group international prognostic index for chronic obtained lymphocytic leukemia (CLL-IPI) that integrates the major prognostic parameters COASt: Clinical Disease cohorts Europe Describe whether body mass index is a 4 No information 4,413 No 24 Patients receiving Outcomes in clinically meaningful predictor of patient obtained information primary THR for Arthroplasty Study reported outcomes following primary obtained osteoarthritis total hip replacement (THR) surgery MARC-35: 35th Disease cohorts US Examine the association between the 17 No 920 0–1 Thousands Children age < 1 year Multicenter Airway infectious etiology of a child’s severe hospitalized with severe Research bronchiolitis and the level of serum bronchiolitis 7 Collaboration 25-hydroxyvitamin D (25[OH]D) during severe bronchiolitis, with the severity of this illness, and the subsequent development of recurrent wheezing by A Map of the Initiatives That Harmonize Patient Cohorts Across the World age 3 years and combine these clinical and laboratory data to derive the wheezing index that will identify children at higher risk of developing recurrent wheezing by age 3 years COSMIC: Cohort Disease cohorts The world Harmonizing shared, non-identifiable Data are Yes Data are 40–105 Harmonization 60+ years old Studies of Memory data from cohort studies that harmonized on a harmonized is done on a individuals from 29 in an International longitudinally examine change in project-by-project on a project- project-by- countries all over the Consortium cognitive function and the development basis, and only by-project project basis world of dementia in older individuals (60+ subgroups of the basis, and and the years). member studies only number of contribute to subgroups of studies per July 2021 | Volume 9 | Article 666844 particular projects the member project studies varies. For contribute to the largest particular project with projects 20 studies there are 16 harmonized variables (Continued) Frontiers in Public Health | www.frontiersin.org Rodríguez-Laso et al. TABLE 1 | Continued Initiative Types of cohorts Region, Country Main objective Number of More Number of Age range No. of Population were the cohorts cohorts with cohorts participants of the harmonized were collected harmonized data foreseen to with sample variables be harmonized (Maximum) harmonized? data Lifebrain: Healthy Disease cohorts. Western Europe Maximize the exploitation of brain 1 of anxiety and No information 2,981 No No Patients with anxiety or minds 0–100 Population imaging cohorts by bringing together depression patients obtained information information depression years: Optimizing cohorts studies on how differences and changes obtained obtained the use of in brain age relate to cognitive function European brain and mental health imaging cohorts Seasonal plasticity Disease cohorts. Canada, France, Test the hypotheses that season has a 2 No information 592 No No Alzheimer disease of cognition Population US significant association with cognition, obtained information information patients or patients cohorts the odds of being diagnosed with mild obtained obtained with cognitive disorders cognitive impairment or dementia, visited in tertiary care cerebrospinal fluid Alzheimer disease clinics biomarkers, and the expression of cognition-associated modules of coexpressed genes in the human brain HarmonicSS: Disease cohorts. Europe, US To bring together the largest No information No information No information No No Cohorts and clinical HARMONIzation Clinical trials well-characterized regional, national and obtained obtained obtained information information trials of patients with and integrative international longitudinal cohorts of obtained obtained Primary Sjögren’s analysis of patients with Primary Sjögren’s Syndrome 8 regional, national Syndrome (pSS) including those and international participating in clinical trials, and by Cohorts on taking into consideration the ethical, primary Sjögren’s legal, privacy and intelectual propiety A Map of the Initiatives That Harmonize Patient Cohorts Across the World Syndrome (pSS) rights issues for sharing data from toward improved different countries, to semantically stratification, interlink and harmonize them into an treatment and integrative pSS cohort structure on the health policy cloud making disease SABER: SAfety Disease cohorts US Understanding the absolute and 4 No information 239,806 All ages No Patients with Assessment of comparative risks of adverse events of obtained information autoimmune diseases Biologic ThERapy biologic treatments for patients with obtained who had at least one autoimmune diseases dispensing of a biologic agent or comparison non-biologic regimen July 2021 | Volume 9 | Article 666844 relevant to their autoimmune disease Thousand Faces Disease cohorts Canada Evaluate factors affecting therapeutic 10 No information 1,497 No No Patients who meet of Lupus approaches used in clinical practice for obtained information information American College of the management of systemic lupus obtained obtained Rheumatology (ACR) erythematosus (SLE), in a multicenter criteria for Systemic cohort Lupus Erythematosus (Continued) Frontiers in Public Health | www.frontiersin.org Rodríguez-Laso et al. TABLE 1 | Continued Initiative Types of cohorts Region, Country Main objective Number of More Number of Age range No. of Population were the cohorts cohorts with cohorts participants of the harmonized were collected harmonized data foreseen to with sample variables be harmonized (Maximum) harmonized? data Tumor Necrosis Disease cohorts Canada and US Estimate the association between 3 No information 8,458 65+ No Rheumathoid arthritis Factor alpha treatment with biologic obtained information patients who had been antagonist use disease-modifying antirheumatic drugs obtained prescribed DMARDs or and cancer in (DMARDs) and development of cancer methotrexate patients with in patients with rheumatoid arthritis rheumatoid arthritis GEMRIC: Global Disease cohorts Japan, Western Creating a large database of multi-site 15 Yes 345 19–86 More than a Patients receiving ECT-MRI Europe and US. imaging data and thousand electroconvulsive Research Currently clinical/behavioral/physiological and because the therapy Collaboration approaching metadata for analysis of the neural initiative China mechanisms and predictors of includes electroconvulsive therapy-related clinical diagnostic response imaging variables 9 Predictors and Disease cohorts. Australia, Canada, Identify potential factors that affect the 8 No 359 18+ (very few Around 20 Patients with moderators of Clinical trials Europe, and US outcome of cognitive and behavioral over 65) obsessive-compulsive cognitive and treatments of obsessive-compulsive disorders behavioral therapy disorders A Map of the Initiatives That Harmonize Patient Cohorts Across the World outcomes for obsessive- compulsive dissorder Antibiotic Disease cohorts The Netherlands Assess the effects of different antibiotic 2 No 1,221 70+ Around 40 Elderly nursing home treatment and and US treatment strategies on survival of elderly residents with lower survival of nursing nursing home residents with lower respiratory tract home patients respiratory tract infections in the infections with lower United States and the Netherlands, respiratory tract where treatment approaches are quite infection different ART-CC: Disease cohorts Western Europe Estimate prognosis of HIV-1 positive, No information No information No information No No HIV-1 positive, July 2021 | Volume 9 | Article 666844 Antiretroviral and North America treatment naïve patients initiating highly obtained obtained obtained information information treatment naïve Therapy Cohort active antiretroviral therapy (ART) obtained obtained patients cohorts from Collaboration Europe and North America (Continued) Frontiers in Public Health | www.frontiersin.org Rodríguez-Laso et al. TABLE 1 | Continued Initiative Types of cohorts Region, Country Main objective Number of More Number of Age range No. of Population were the cohorts cohorts with cohorts participants of the harmonized were collected harmonized data foreseen to with sample variables be harmonized (Maximum) harmonized? data COHERE: Disease cohorts Western Europe Pool and harmonize existing longitudinal No information No information No information No Not reported HIV-infected people Collaboration of and North America data on HIV-positive persons collected obtained obtained obtained information residing in Europe Observational HIV across Europe to answer key research obtained Epidemiological questions that, in the era of potent Research Europe combination antiretroviral therapy (cART), could not be addressed adequately by individual cohorts Early Antibiotic Disease cohorts US Determine, in a well-characterized 2 No 802 2–72 months No Children aged 2–72 Treatment for sample of children with febrile urinary information months with a urinary Pediatric Febrile track infections, whether delay in the obtained tract infection Urinary Tract initiation of antimicrobial therapy was producing fever Infection and associated with the occurrence and Renal Scarring severity of renal scarring and to determine whether these associations persisted after adjusting for potential confounding factors HAART and early Disease cohorts Brazil and US Compare the early mortality pattern and 2 No information 1,774 No 10 HIV-infected patients mortality the causes of death among patients obtained information 10 starting HAART in Brazil and the obtained United States IeDEA: Disease cohorts Africa, Asia-Pacific Collect and define key variables, No information No information No information No No HIV/AIDS patients from International region, the harmonize data, and implement obtained obtained obtained information information Africa, the Asia-Pacific A Map of the Initiatives That Harmonize Patient Cohorts Across the World epidemiology Central/South methodology to effectively pool data as obtained obtained region, the Databases to America/Caribbean a cost-effective means of generating Central/South Evaluate AIDS region, and North large data sets to address the high America/Caribbean America priority research questions and region, and North streamline HIV/AIDS research America ReCoDID: Disease cohorts No information Develop an equitable, accessible, and No information In progress No information No No Patients with infectious Reconciliation of obtained sustainable model for the storage, obtained obtained information information diseases Cohort data in curation, and analyses of obtained obtained Infectious clinical-epidemiological and Diseases high-dimensional sample data collected by infectious disease cohorts in low-and-midle-income countries July 2021 | Volume 9 | Article 666844 RESPOND: Disease cohorts Australia, Georgia Build an innovative, flexible and dynamic No information No information No information No No People 18+ at high risk International and Western cohort consortium for the study of obtained obtained obtained information information of acquiring HIV and Cohort Europe infectious diseases, including HIV and obtained obtained people living with HIV Consortium of people at risk for HIV, as a generic and/or with other Infectious Disease structure for facilitating multi stakeholder infectious diseases or involvement across Europe, South America and Australia (Continued) Frontiers in Public Health | www.frontiersin.org Rodríguez-Laso et al. TABLE 1 | Continued Initiative Types of cohorts Region, Country Main objective Number of More Number of Age range No. of Population were the cohorts cohorts with cohorts participants of the harmonized were collected harmonized data foreseen to with sample variables be harmonized (Maximum) harmonized? data Adults Born Disease cohorts Australia, Canada, Our main aim was to identify factors that 9 No information 1,571 patients No No Very low birth weight Preterm Finland, either increase or decrease risk of high obtained and 777 information information and very preterm International Netherlands, blood pressure among adults born with controls obtained obtained babies who reach Collaboration Northern Ireland, very low birth weight adulthood Norway, US Necrotizing Disease cohorts Austria and The The first aim of the study was to 2 No information 57 24–40 weeks 13 Patients with enterocolitis (NEC) Netherlands correlate the occurrence of a blood obtained necrotizing enterocolitis study stream infection (BSI) during the early phase of necrotizing enterocolitis (NEC) with intestinal fatty acid-binding protein (I-FABP) levels, as a marker for loss of gut wall integrity owing to mucosal damage, and Interleukin (IL)-8 levels, as a biomarker for the pro-inflammatory cascade in NEC. The second aim of the 11 study was to investigate the relation between the occurrence of a BSI and disease outcome Recurrent leg Disease cohorts Eastern Australia Identify risk and protective factors for 3 Yes 250 26–96 24 Patients with a healed A Map of the Initiatives That Harmonize Patient Cohorts Across the World venous ulcers recurrence of venous leg ulcers leg ulcer of primarily study venous etiology MARS: Multicenter Disease cohorts Scotland and US Identify risk factors for intracranial 4 Yes 2,525 No 13 Patients with AVM Research hemorrhage in the natural history course information arteriovenous Study of brain arteriovenous malformations obtained malformations Pulmonary Disease cohorts Belgium, France Compare clinical characteristics 3 No 3,414 18–98 Around 30 Patients with a clinical embolism (one clinical trial) and Switzerland between women and men with suspicion of pulmonary presentation suspected and confirmed pulmonary embolism embolism (PE) and their impact on clinical probability prediction scores and on diagnostic work-up of PE, and to assess whether differences at July 2021 | Volume 9 | Article 666844 presentation could account for the increased recurrence rate in men BIOMAP: Disease cohorts. No information Examine the causes and mechanisms of No information In progress No information No No Patients with atopic Biomarkers in Clinical trials obtained atopic dermatitis and psoriasis to enable obtained obtained information information dermatitis and psoriasis Atopic Dermatitis optimal treatments and an individualized obtained obtained and Psoriasis therapy scheme for each patient Rodríguez-Laso et al. A Map of the Initiatives That Harmonize Patient Cohorts Across the World only include cohorts from high-income countries, and none Of those which have declared the number of variables in their harmonize data from LMIC countries alone. harmonized database, there are between 10 and more than 1,000 Most initiatives are partnered with universities, hospitals, (median 24), with two out of 15 (13.3%) including more than and research institutes. Governmental institutions take part in 1,000 variables. a few of them (9). The presence of patient associations and Four initiatives harmonized administrative databases. Thirty- pharmaceutical companies as partners is anecdotal. The number three were retrospective vs. four prospective. The great of partners ranges between 2 and more than 100, with a median majority do not report major threats to the representativity of of 12. Three quarters comprise 20 partners or fewer. their samples. Most initiatives have been or are funded by American (12) or European (10) institutions. Canadian funding comes third (4). The vast majority have received public funding alone (22). DATA AVAILABILITY STATEMENT Five have received combined funding from public institutions and non-profit organizations. Private funding was provided in The dataset generated by this study can be found in the webpage isolation to one initiative (RESPOND), combined with public of the SYNCHROS project https://www.synchros.es. funding to another one (EHDEN), and combined with non-profit funding to a third one (Tumor necrosis factor α antagonist use). Their objectives may be classified into four general categories AUTHOR CONTRIBUTIONS (some initiatives share more than one): determining the ÁR-L performed the database searches, extracted the information prognosis of subgroups of patients (14), providing a repository from the initiatives, and drafted the article. ÁR-L, LR-U, and of patients (11), establishing the efficacy (6) or safety (4) CK evaluated the initiatives against inclusion and exclusion of treatments, and exploring risk factors and biomarkers of criteria. All authors made substantial contributions to the diseases (10). conception and design of the paper, analysis and interpretation The median number of cohorts included in each initiative is of data, reviewed the manuscript, and read and approved its 5, ranging from 1 (which also harmonizes population cohorts) final version. to 58; three quarters include 17 cohorts or fewer. The number of individuals included varies wildly, from 57 to 310 million (Sentinel initiative). The median is 6,841. Eight out of 37 FUNDING (21.6%) initiatives have harmonized fewer than 1,000 patients and the same proportion have harmonized 100,000 patients or This work was supported by the European Union’s H2020 more. Twenty-six have harmonized all or almost all the cohorts Programme under grant agreement number 825884. incorporated to the initiative, two (EHDEN and CINECA) are still in the process of harmonizing their cohorts and another two (CNODES and COSMIC) harmonize data on a project-by- ACKNOWLEDGMENTS project basis. Eight initiatives included patients from all ages, eight included The authors want to express their gratitude to all principal only adult patients, three included only children, and two investigators and project managers who answered our request for included exclusively older people. further information on their harmonization initiatives. REFERENCES 5. Thompson A. Thinking big: large-scale collaborative research in observational epidemiology. Eur J Epidemiol. (2009) 24:727– 1. Blettner M, Sauerbrei W, Schlehofer B, Scheuchenpflug T, Friedenreich 31. doi: 10.1007/s10654-009-9412-1 C. Traditional reviews, meta-analyses and pooled analyses in 6. World Health Organization. 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The use, distribution or reproduction in wf031 other forums is permitted, provided the original author(s) and the copyright owner(s) 4. Lyman GH, Kuderer NM. The strengths and limitations of meta- are credited and that the original publication in this journal is cited, in accordance analyses based on aggregate data. BMC Med Res Methodol. (2005) with accepted academic practice. No use, distribution or reproduction is permitted 5:14. doi: 10.1186/1471-2288-5-14 which does not comply with these terms. Frontiers in Public Health | www.frontiersin.org 12 July 2021 | Volume 9 | Article 666844