Hamburg is the second largest city in Germany with 1,830,584 million inhabitants (31.12.2017 [5] from all social classes living in 7 districts and 104 urban quarters. The city is mostly urban, but has also some rural areas and a large harbor contributing to the environmental exposures of the population. 839,389 persons are older than 45 years and in 2017 approximately 90,000 persons moved away. On an annual basis a sample census is carried out mapping social conditions of the German population including a random sample of 1% of the whole population. As shown in Box 2 the Hamburg population in comparison to the German population is characterized by 4% more other nationalities, people are 7% more often single, 14% have a higher education and a higher income.
Box 2 Selected characteristics of the target population: Results from the sample census (microcensus), Hamburg* A total of 45,000 inhabitants, aged 45–74 years are to be included, identified by a random sample from the official inhabitant data file divided into six age and gender strata. The HCHS is a joint interdisciplinary endeavor of physicians and scientists from the University Medical Center Hamburg-Eppendorf. Over 30 departments and institutes from the University Medical Center Hamburg-Eppendorf work together in a unique cooperation at a single study center.
Pilot study, timeline and examinations
From May 08, 2015 until January, 31 2016 1800 volunteers in the age group 18–85 were recruited by a commercial campaign in the leading newspaper from Hamburg and took part to validate the invitation process and train the study nurses in the examination procedures. Moreover, the manageability of the questionnaires was tested. This pilot study led to minor changes in these aspects. The first participant was enrolled on February 08, 2016 in the main study and the last participant is expected to be enrolled on November 30, 2022. The end of the first personal Follow-Up is planned 6 years later in 2028.
The participants are contacted by a letter to their home address containing the invitation and an information leaflet providing basic study information. Participants organize their own appointment at the epidemiological study center at the University Medical Center Hamburg-Eppendorf. The appointment is initiated by a study nurse explaining the study rationale and participants are asked to sign informed consent including study participation, an extraction of a skin punch to create induced pluripotent stem cells and either none, one or all of the following options: external, virtual or internal autopsy in the event of death. In the end, participants also sign a consent accepting that both double de-identified and pseudo-anonymized data may be transferred to cooperation partners. Participants are also asked for consent to match their health insurance and pension insurance data with the HCHS dataset. During a 7-h examination participants undergo validated examinations of different organ systems such as anthropometric measures, resting blood pressure measurements, ECG tracings as well as validated physical examinations. Novel parts include detailed cardiovascular, cognitive and oral health phenotyping, skin screening, pulmonary function test, muscle tests and optical coherence tomography (see Box 3 for an overview of all examinations). At the end of the visit, a letter is handed out containing results of all examinations and standardized recommendations to be followed by the participants. Following the discussion with the local ethical committee only clinically relevant results are provided to the participants. Before, during and after the baseline visit validated self-report questionnaires asking for life style and environmental conditions, dietary habits, quality of life, physical and sexual dysfunction, professional life, psychosocial context and burden, digital media use, medical and family history, occupational history as well as health care utilization are filled out (see Box 4 for an overview of all questionnaires).
Box 3 Overview of all components of the baseline examination high lightening novel and established clinical practice: the Hamburg City Health Study Box 4 Overview of all components of the self-reported questionnaires: the Hamburg City Health Study Validated risk scores are used to identify individuals at risk for coronary artery disease, atrial fibrillation, heart failure, stroke and dementia. After the baseline investigation, these score-positive participants are invited to the imaging examination including an MRI—examination of the heart and the thoracic aorta and/or brain depending on the target disease [6]. In order to establish a general control group, 1500 random participants are invited to an MRI as well. Participants at risk for osteoporosis or suspected bicuspid aortic valve disease, prostate cancer, HPV-infection or dementia are recommended a further medical clarification.
Laboratory parameters and biobanking
A panel of basic laboratory analyses are performed on the day of the visit in the study center. The assessed markers include: sodium, potassium, HbA1c, prostate specific antigen (PSA), creatinine, high sensitivity measured CRP, glucose, thyroid stimulating hormone (TSH), triglycerides, total cholesterol, HDL-cholesterol, LDL/HDL ratio, and N-terminal pro B-type natriuretic peptide (NTproBNP). Furthermore, a complete blood count is performed. Biomaterials used for biobanking include serum, plasma (EDTA, citrate), genomic deoxyribonucleic acid (DNA), ribonucleic acid (RNA) from whole blood and peripheral blood mononuclear cells (PBMCs), blood cells (erythrocytes, PBMCs), urine, saliva as well as tooth fluid and tonsils swabs. Additionally, from a random subset of study participants, skin stanza are collected of which fibroblasts are separated. These fibroblasts will be used for the generation of human induced pluripotent stem cells (hiPSCs) (for an overview of all biomaterials collected and planned measurements see Box 5). Subsequently, the biomaterial will be examined by state-of-the-art and innovative, high throughput approaches including analyses on the different OMICS levels such as genomics, transcriptomics, proteomics and lipidomics profiling. One part of the biobank is used for research projects within the first 6 years, the second part is stored for projects performed during the studies follow up and in the future.
Box 5 Overview of all collected biospecimen and purposes: the Hamburg City Health Study Follow-up
Following the date of baseline examination, all participants will be contacted by mail containing a questionnaire which specifically ask participants to report any major medical event, medication, nutrition and lifestyle changes, physical and mental health, sexual dysfunction and overall quality of life as well as health care use. Participants are also asked to provide discharge letters or any kind of further information on their health such as diagnostic findings or images. This contact takes place on an annual basis for 5 years. An endpoint-committee will review all collected information for special endpoints. After 6 years all participants are invited to undergo the same examination and procedures as in the baseline visit. On a continuous basis the study center is in contact with public authorities and the cancer register about vital status, cause of death and cancer incidence and in contact with involved health and pension insurances to match with related individual routine data.
Statistical analysis plan
The integrity of the collected data in the databases are controlled by detailed, predefined quality control algorithms according to standardized operation procedures (SOP) concerning detection of outliers, logically implausibility, or detect mistaken identity. Only quality controlled data will be used for statistical analyses.
In the analyses of baseline data methods for cross-sectional analyses will be applied. Univariate statistics for categorical variables will be presented as counts and proportions, and numeric variables will be presented as means, percentiles and standard deviations. Associations between baseline characteristics will be estimated by means generalized linear regression models.
For the full cohort as well as for sub-cohorts, time-to-event methods constitute the major approach for identifying and assessing risk factors for mortality and incidence or progression of diseases. Thus, when studying rates of a single event type, e.g., overall mortality, regression models for censored data will be used to simultaneously investigate the effects of risk factors of interest while adjusting for potential confounders.
In all analyses, effect estimates will be presented both, in relative terms as prevalence or risk ratios, and in absolute terms as means, rates or risks, the latter to assess public health implications. All effect estimates and statistical summaries will be presented with 95% confidence intervals, and, when appropriate, adjusted for multiple testing. For disease-specific mortality or endpoints other than death, competing risks will be accounted for. For repeated measurements in the second examination, regression models for longitudinal data will be employed. In all analyses observations may be correlated either in time (repeated measures) or between subjects (e.g. relatives). Appropriate statistical methods will be used to account for correlated observations, e.g. by means of mixed effect models, or in marginal models by means of generalized estimating equations (GEE). Special attention will be paid to potentially informative drop-out or failure to obtain further measurements due to the occurrence of a specific event. These issues will be addressed by joint models for longitudinal and time-to-event data. In cases of a substantial amount of missingness in dependent or independent variables, multiple imputation will be incorporated in the analysis, as a supplement to the complete case analysis. To ensure transparency and reproducibility of results, all statistical methods and codes will be described and stored centrally as a supplement to study protocols. This material will be available to other researchers upon request.