Cohort Profile: Cooperative Health Research in the Region of Augsburg (KORA) 1984–2024

The KORA study (Cooperative Health Research in the Region of Augsburg) is a German population-based prospective cohort study investigating risk factors, early detection, and prevention of chronic diseases. KORA focuses on cardiovascular disease, diabetes, mental health, health in old age, lung health, and the role of social determinants and environmental exposures. The KORA study recruited 17 602 adult participants aged 25–74 years in four baseline surveys conducted between 1984 and 2001 in the Region of Augsburg, Germany. It includes up to 40 years of active follow-up for the initial participants and is ongoing to date. In 2021, of the initial 17 602 participants, 6493 participants were deceased and 2000 participants were lost to follow-up. Besides morbidity and mortality follow-ups, repeated follow-up examinations were conducted in subpopulations with questionnaire-based risk factor and socio-economic assessments. Genetic and molecular phenotyping contributed to identifying the underlying genomic, epigenomic, transcriptomic, proteomic, and metabolomic signatures of non-communicable diseases. Furthermore, the study is enriched by detailed environmental data at the place of residence and the establishment of a unique air-pollution measurement station. Data and biosamples can be requested for research projects via the KORA.PASST use and access hub (https://helmholtz-muenchen.managed-otrs.com/external). The KORA (Cooperative Health Research in the Region of Augsburg) study is a prospective population-based adult cohort study in Germany. It started in 1984 as the MONICA Augsburg study site in the international World Health Organization MONItoring of trends and determinants in CArdiovascular disease (WHO MONICA) project [1] and was renamed KORA in 1996 [2]. The KORA study is financed by the Helmholtz Zentrum München—German Research Center for Environmental Health and third-party funding. The KORA study now includes up to 40 years of active follow-up for the initial participants and is ongoing to date. The overarching aims are health research and its translation into healthcare, improvement in prevention, diagnostics, and therapy, as well as policy advice. The scientific scope built on the cardiovascular focus of the MONICA project and extended to other non-communicable diseases, in particular type 2 diabetes, lung diseases, and mental health, and included several assessments of healthy ageing. The KORA study has four independent cross-sectional baseline surveys, called S1 to S4. The study area covers the City of Augsburg and the two bordering districts of Augsburg and Aichach-Friedberg (Fig. 1). Participants were identified based on age- and sex-stratified samples randomly drawn from the resident registration offices within the study area [1]. Specifically, samples were drawn in a two-stage procedure: first, the City of Augsburg and 16 communities from the adjacent districts were selected by cluster sampling and, second, stratified random sampling was performed within each community. KORA study area in the Region of Augsburg. The number of KORA participants in 2021 is shown per postcode (positioned centrally). © GeoBasis-DE/BKG (2020) and © Deutsche Post Direkt GmbH. Inclusion criteria were being 25–74 years of age (25–64 years in S1), having the main place of residence in the study area, and being of German nationality [2]. Participants were excluded if they were lost to follow-up in the time interval between sampling and examination due to movement out of the study area, errors in the population register, death, or confinement in an institution. In total, 18 079 participants took part in the four baseline surveys (Table 1 and Fig. 2). The number of participants was as follows: N = 4022 (overall response: 79.3%) in S1, N = 4940 (76.9%) in S2, N = 4856 (74.9%) in S3, and N = 4261 (66.8%) in S4. The overall response is defined as the proportion of participants out of all eligible participants (i.e. sampled persons excluding sample losses). The response did not differ between men and women, but increased per 10-year age groups, except for the oldest group in all surveys. In S4, 49% of the final non-responders completed a short questionnaire. They reported worse subjective health and a higher prevalence of myocardial infarction (MI) and diabetes [3]. The follow-up studies showed that there was duplicate participation. In total, N = 17 602 unique individuals participated in the study excluding 477 duplicate participants. KORA study overview. The KORA study has four independent cross-sectional baseline surveys, called S1 to S4. The entire baseline surveys S3 and S4 were followed up in F3 and F4/FF4/FFF4, respectively. In addition, selected birth years from surveys S1–S4 were followed up with a specific scientific focus: AGE (participants born in or before 1943) on health in old age and FIT (participants born in 1945–1964) on fitness in older adults. The AGE study consisted of a telephone interview to all KORA participants born in or before 1943 and a medical examination of an age- and sex-stratified subsample. In the follow-up AGE3 in 2016, S1–S4 participants born in or before 1950 were added to the AGE cohort for comparison with the 2008/2009 sample. General health follow-up (GEFU) mailings on chronic disease status were conducted five times. Overview of all KORA baseline and follow-up studies with recruitment periods, ethics committee numbers, and information on participation. The KORA study consists of four independent cross-sectional baseline surveys, called S1 to S4, with medical examinations (E) and self-completion questionnaires (S). The surveys S3 and S4 were followed up in F3 and F4/FF4/FFF4, respectively, with medical examinations (E) and self-completion questionnaires (S). Selected birth years from surveys S1–S4 were followed up with a specific scientific focus: AGE (participants born in or before 1943) on health in old age and FIT (participants born in 1945–1964) on fitness in older adults. The AGE study consisted of a telephone interview (T) with all KORA participants born in or before 1943 and a medical examination (E) and self-completion questionnaires (S) in an age- and sex-stratified subsample. In AGE3 in 2016, S1–S4 participants born in or before 1950 were added to the telephone interview (T) group for comparison with the 2008/2009 sample. General health follow-up self-completion questionnaires (S) on chronic disease status were conducted five times (GEFU1 to GEFU5). In GEFU3 and GEFU4, the self-completion questionnaires (S) were combined with the telephone interviews (T) in AGE1 and AGE3. Alt Text: Overview of all KORA studies with recruitment period, ethics committee number, and information on participation. GEFU, general health follow-up.Dashes indicate that for these age groups no data is available. Overview of all KORA baseline and follow-up studies with recruitment periods, ethics committee numbers, and information on participation. The KORA study consists of four independent cross-sectional baseline surveys, called S1 to S4, with medical examinations (E) and self-completion questionnaires (S). The surveys S3 and S4 were followed up in F3 and F4/FF4/FFF4, respectively, with medical examinations (E) and self-completion questionnaires (S). Selected birth years from surveys S1–S4 were followed up with a specific scientific focus: AGE (participants born in or before 1943) on health in old age and FIT (participants born in 1945–1964) on fitness in older adults. The AGE study consisted of a telephone interview (T) with all KORA participants born in or before 1943 and a medical examination (E) and self-completion questionnaires (S) in an age- and sex-stratified subsample. In AGE3 in 2016, S1–S4 participants born in or before 1950 were added to the telephone interview (T) group for comparison with the 2008/2009 sample. General health follow-up self-completion questionnaires (S) on chronic disease status were conducted five times (GEFU1 to GEFU5). In GEFU3 and GEFU4, the self-completion questionnaires (S) were combined with the telephone interviews (T) in AGE1 and AGE3. Alt Text: Overview of all KORA studies with recruitment period, ethics committee number, and information on participation. GEFU, general health follow-up.Dashes indicate that for these age groups no data is available. The participants were followed up by using a combination of repeated examinations, postal and telephone questionnaires, and mortality follow-ups, building upon the MONICA approach. Figure 2 provides an overview of the major data-collection efforts within the cohort. Follow-up examinations of entire baseline surveys (F3 and F4/FF4/FFF4) as well as cohorts defined by selected birth years were conducted (AGE, FIT) with a specific scientific focus. Some of these projects, such as the AGE or the Magnetic Resonance Imaging (MRI) study, are described in detail elsewhere [4, 5]. Vital status is checked at regular intervals through the population registries inside and outside the study area and, in recent years, by requests from the civil register ‘Anstalt für Kommunale Datenverarbeitung in Bayern’ (https://www.zemaonline.de). Morbidity and mortality were followed up by mailing general health follow-up (GEFU) questionnaires to all participants. There were five waves of GEFU questionnaire mailings, collecting disease incidence and mortality information until 2021. Of the initial 17 602 unique participants, at the time of the GEFU5 follow-up in 2021, 6493 participants were deceased and 2000 participants were lost to follow-up (Fig. 3). The lost-to-follow-up group included participants who had moved out of the study region or out of Germany, or who had withdrawn consent to be re-contacted or to be part of the study. Table 1 shows the sex and age distributions at the baseline surveys and the follow-ups. Supplementary Table S1 illustrates the differences between those who died or were lost to follow-up and those who remained in the cohort until 2021. Over the 40-year period, willingness to participate in examinations remained high, but decreased from 79.6% to 53.8% for the examinations and from 82.3% to 66.6% for the questionnaire-based follow-ups (Table 1). KORA study attrition from the four cross-sectional baseline surveys S1–S4 to the general health follow-up mailings (GEFU) in 2009, 2016, and 2021. Due to duplicate participation, the numbers of participants differ between Table 1 and Fig. 3. A comprehensive list of the study methods of all major KORA studies are listed in the Supplementary Tables S2 and S3. Briefly, data collection in the baseline examinations S1–S3 followed the core MONICA protocols and included anthropometric measures of waist and hip circumference, blood pressure, resting electrocardiogram, and medication use in the past 7 days, and a face-to-face interview on socio-demographic and -economic status; alcohol-consumption recall; cigarette smoking; leisure-time physical activity; sleep quality and duration; food-frequency questionnaire; self-rated health; self-reported chronic diseases such as MI, stroke, and diabetes mellitus and their family history; pregnancy and menopause; somatic complaints; type A personality; social support; and healthcare utilization. In S4, an oral glucose tolerance test for those aged 55–74 years was added. In addition, accelerometry, Ankle–Brachial Index, allergies, bioimpedance, 5-min 12-lead resting and 24-h Holter electrocardiogram, lung function, myopia, neuropathy, skin examinations, thyroid measurements, and many more were added in the follow-ups. Validation of the survival status of non-responders was completed by contacting the municipal resident registration offices. Non-fatal and fatal clinical outcomes—especially diabetes mellitus, MI, and stroke—were validated by contacting physicians and/or reviewing hospital medical records and death certificates [6]. Death certificates were obtained from the district health departments in Bavaria and coded for the underlying causes of death according to the International Classification of Diseases (ICD-9 and, from 2000 onwards, additionally in ICD-10). Cardiovascular-related mortality consists of diseases of the circulatory system (ICD-9 codes 390–459, ICD-10 codes I00–I99) and sudden death with unknown cause (ICD-9 code 798, ICD-10 code R96). Cancer-related mortality consists of neoplasms (ICD-9 codes 140–208, ICD-10 codes C00–C97). Other disease-related mortality consists of the remaining causes of death, e.g. pneumonia (ICD-9 code 486, ICD-10 code J18), chronic bronchitis (ICD-9 code 491, ICD-10 codes J41, J42, J44), dementias (ICD-9 code 290, ICD-10 codes F03.90, F05, F01.50, F01.51), and deaths from suicide (ICD-9 E950–E959, ICD-10 X60–X84). Non-fatal and fatal MI events or coronary deaths were coded based on the myocardial infarction registry in Augsburg for events that occurred in the study area in the age range of 25–84 years (25–74 years until 2009) [7]. MI was initially defined according to the WHO MONICA protocol [1] and, since 2001, according to the European Society of Cardiology and American College of Cardiology criteria [8]. The linkage with the registry ceased in 2019 for technical and organizational reasons when it became part of the University Hospital Augsburg. For events that were not recorded in the registry and since 2020 exclusively, the diagnostic classification was performed by using death certificates, clinical diagnoses from the general practitioner’s notes, or hospital discharge letters. Non-fatal stroke and diabetes morbidity was validated by physicians who examined the clinical diagnoses from general practitioners’ notes or hospital discharge letters. Routine monitoring data of daily air-pollution concentrations and weather parameters are available through the services of the Bavarian Environment Agency or the German Weather Service. Since 2004, an aerosol measurement station has continuously monitored particulate matter including ultrafine particles and particle-size distributions [9]. In recent years, modelling of the spatial distribution of environmental factors has included air pollution, air temperature, relative humidity, noise, green space, as well as socio-economic neighbourhood data. Geocoded residential addresses of the study participants are linked with the environmental factors and assigned to each participant. Standardized biosamples such as blood, serum, plasma, and urine were collected in almost all of the KORA studies (Supplementary Table S4). All samples were processed and aliquoted according to Standard Operating Procedures (SOPs) and stored at –80°C before being transported to the Biobank at Helmholtz Munich (https://www.bbmri.de/ueber-gbn/german-biobank-alliance/muenchen-hmgu). The biobank is certified according to DIN EN ISO 9001:2015. Depending on the study designs and research questions, participants were either non-fasting (S1–S3, S4 for the 25- to 54-year-olds, F3, AGE) or fasting (all other examinations) (Supplementary Table S4). Serum chemistry and blood counts were determined on the day of the examination at a hospital laboratory and additional parameters were measured from frozen material later for specific scientific questions. Omics measurements such as genomic, epigenomic, transcriptomic, proteomic, and metabolomic profiling and other molecular phenotyping as well as microbiome analyses from multiple sampling sites including stool, saliva, skin, and others have been performed (Supplementary Table S5). Quality assurance and data management were implemented as part of the MONICA project and continuously adapted to the needs of the study. A pilot study was conducted before each examination to test novel procedures and timing. All project staff were trained to adhere to SOPs and quality-assurance measures were implemented. External audits at the KORA study centre were conducted for all examinations except FFF4. Data from the KORA study have been used in >2200 publications (https://www.helmholtz-munich.de/en/epi/publications/kora). These have been published by KORA scientists and contributed to national and international consortia such as BiomarCARe, CARDIoGRAMplusC4D, CHARGE, DeTecT2D, DIAB-CORE, DIAGRAM, DIAMANTE, DigiMed Bayern, DIRECT, ENGAGE, ELAPSE, ESCAPE, EXPANSE, EXHAUSTION, GCVRC, GESA, GIANT, GLGC, HaemGen, IDP-Work, MAGIC, METASTROKE, MONICA, MolPAGE, MORGAM, NCDRisk, NGFN, SpiroMeta, STAGE, and SUMMIT. Some results are highlighted in Fig. 4 and Supplementary Table S6. Selected KORA highlight publications. CHD, coronary heart disease; DNA, deoxyribonucleic acid; EWAS, Epigenome-Wide Association Study; hsCRP, high sensitive C-reactive protein; T2D, type 2 diabetes; WHO MONICA Project, World Health Organization MONItoring of trends and determinants in CArdiovascular disease Project. For more details, see also Supplementary Table S6. The KORA study contributed significantly to the identification of novel biomarkers that improved risk prediction for cardiovascular events. Early work on high sensitive C-reactive protein (hsCRP) highlighted the strong positive association between increased levels of hsCRP and the risk of coronary heart disease [10]. More recently, it contributed to the development of the SCORE2 (Systematic Coronary Risk Evaluation 2) algorithm for the current risk prediction of cardiovascular disease in Europe [11] and the European Society of Cardiology guidelines on cardiovascular disease prevention in clinical practice [12]. The S4 study was the first population-based study in Germany to include an oral glucose tolerance test, revealing that ∼40% of the study population aged 55–74 years had impaired glucose metabolism or diabetes, with half of the cases undiagnosed [13]. KORA contributed to the establishment of subclinical inflammation as a risk marker for type 2 diabetes [14] and identified novel predictors of type 2 diabetes using plasma proteomics [15]. A very fruitful clinical project was the study on the subclinical disease of type 2 diabetes with publications to Data from an air-pollution in the KORA study area in the first of a response to air in the general population comprehensive molecular phenotyping in KORA the of air on to be In the research on the health of and the for was added KORA the of on the incidence of and other chronic diseases, on underlying For it was that the combined of hsCRP and was a more of cardiovascular disease in initially healthy men hsCRP work showed that due to was with inflammation and cardiovascular risk Since the determinants and of and in older have been in the AGE study to the reasons for in the general population and or quality of and mortality were health and were in and used to up to age for and and for the and of and disease, in age, were their for clinical practice The was to research in and multiple levels of data with repeated measurements are available It to the first association study of and is of the cohorts to signatures were to be with and diseases and the of was data were for improved diabetes and MI risk prediction The role of socio-economic differences in the of the of health such as German and the of for chronic diseases such as diabetes are of KORA has contributed to health it has contributed to the on to the role of such as a KORA population-based research can be if and in its and The main were as as well as underlying were by the from cardiovascular to and lung diseases, mental health, and with clinical the of the and with clinical and and international consortia novel into the determinants of non-communicable diseases. These research were into work on and the focus on environmental determinants of disease to work on the role of air and to with a focus on the and the role of repeated examinations the of early of non-communicable diseases. it is to highlight that cohorts in are for international and national and the for and assessments to the health of current and the KORA study is now a cohort study and is not of the general population in Germany. recruitment efforts at a high response and were the follow-up studies from participation, the healthy participants other cohort to are cohort management and the use of data via data linkage such as mortality follow-ups with Data and biosamples can be requested for research projects via the KORA.PASST use and access hub (https://helmholtz-muenchen.managed-otrs.com/external). the data as well as the KORA General and are The KORA is for and of the The of study participants, to and the of the KORA study the The European General Data to all The KORA study was performed in with the of the of consent was obtained from all participants at baseline as well as at each data-collection methods have been by the of the Bavarian of for each study since to all studies were by the and conducted in with the at the The ethics committee numbers of all major studies are listed in Table all participants for their to the KORA study, the staff for data collection and research data the of the KORA who are for the and of the study, and all the at Helmholtz Munich in the and in the for their and for with the KORA also to highlight that the KORA study its to with many at the German Center University of Augsburg, University of University of University of University of University of and of all and all All have and to the published of the Supplementary data is available at The KORA study was and financed by Zentrum München—German Research Center for Environmental is by the German of and Research and by the of Data collection in the KORA study is performed in with the University Hospital of Augsburg. Furthermore, KORA research was within Center of Health as part of The project to was financed by the German of and Research and as part of the in old 2019 to the KORA study was by the Bavarian of and through the research project DigiMed KORA are part of the German Center for Research Munich the German Center for Research the German Center for Research and the German Center for Health site and they to In addition, many projects and have contributed to the and research data the past 40 of the were used in except to the and