Cohort Profile: The Danish Blood Donor Study.

The DBDS is a platform for studies carried out by the Danish blood centres and collaborators. The study is managed by a steering committee who respond to enquiries regarding collaboration. The blood donors participate in the DBDS to increase the scope of their donation, i.e. to help produce valuable research for the benefit of future patients. Additional information can be found at our home page [ http://www.dbds.dk ]. We invite researchers to collaborate by contacting the steering committee [ [email protected] ]. Data access requires that projects and applicants obtain permission from the Regional Committees on Health Research Ethics and the Danish Data Protection Agency [ http://www.datatilsynet.dk ].

Whenever a participant donates blood, the data from the donation becomes available for the study. The possibility for measuring biomarkers in consecutive samples from the same donor allows for detailed studies of biomarker dynamics. This is, to our knowledge, the most comprehensive platform for collecting sequential samples in any cohort study. By February 2022, a total of 2 293 916 unique plasma samples were available ( Table 2 ). After enrolment, the participants are followed at subsequent blood donations and through national health registers. The blood bank follow-up allows for additional data collection: the donor may be asked to fill out new questionnaires and biological sampling may take place. The participants are followed through the national registers also after ceasing their blood donor career. Outcomes, exposures and confounding factors can be assessed by register linkage via the unique personal identification number to a collection of nationwide registers regarding sociodemographics (education, employment, income, civil status, vital status, history of emigration) and health (filled prescriptions, general practitioner contacts, inpatient and outpatient hospital contacts, causes of death) as outlined elsewhere. 16 Loss to follow-up in the traditional sense does not occur.

The DBDS is an ongoing, national prospective cohort of blood donors. Before or during donation, blood donors aged 18 years or above who have previously donated blood at least once receive oral and written information about the study and are invited to join the cohort by signing a consent form. The participants can withdraw consent at any time; see Table 1 for characteristics of participants (at baseline) and non-participants in the study. In the current dataset (28 February 2022), 138 491 participants have completed a total of 371 589 questionnaires ( Table 2 ). To define the population of blood donors not included in DBDS, we identified all donations from non-participants (not yet invited blood donors) from 1 March 2010 to 28 February 2022 from SCANDAT. A single donation from each non-participating donor was sampled randomly as the index donation for that donor, and the age and measurements at that donation were used to characterize the donor. By this method, participants were slightly older, had more donations in the previous 5 years and had similar haemoglobin values compared with non-participants. The number of blood donors who have declined to participate upon invitation is 4.0%. Characterization of the cohort Results are reported as medians (interquartile ranges), numbers, or percentages. BMI, body mass index; Short form 12, The 12-Item Short Form Health Survey. Blood donors not participating are defined as donors who had not yet received invitation and participant information. The number of blood donors who have declined to participate upon invitation is 4.0%. Full blood donors/plasma donors are defined as donors with at least one full blood/plasma donation during the past year before inclusion (including the inclusion donation). Short form 12: higher scores reflect higher self-reported health-related quality of life. Samples and data collected Short form 12 self-reported health-related quality of life (HRQL) Vitamin and iron supplements, diet and alcohol consumption Smoking habits Mononucleosis Menopause status and use of contraceptives Exercise, height and weight Asthma and allergy ADHD Restless legs syndrome Hidradenitis suppurativa and acnes Depression Migraine Height and weight Smoking and alcohol habits Short form 12 HRQL Endometriosis Sleep pattern Stress Migraine Skin diseases (hidradenitis suppurativa, hyperhidrosis, xerosis, psoriasis, atopic dermatitis) General infections Pain Family disease history Height and weight Smoking and alcohol habits Short form 12 HRQL Sleep pattern Stress Pain Skin diseases (hidradenitis suppurativa, hyperhidrosis, xerosis, psoriasis, atopic dermatitis, superficial fungus infection) Gastrointestinal symptoms and defaecation pattern Dental status and history of caries Family disease history Height and weight Smoking habits Short form 12 HRQL Questionnaire data, samples and measurements collected during the years. EDTA, ethylenediamine tetraacetic acid; suPAR:,soluble urokinase-type plasminogen activator receptor; IgE, immunoglobulin E; ADHD, attention-deficit/hyperactivity disorder. e-Boks is a public digital mailbox, which all citizens aged 15 years or above use for communication with the Danish public authorities. Infinium Global Screening Array, Illumina. Specific IgE for the nine most common respiratory sensitizers, Phadiatop. To ensure a cost-effective design that allows donors to be enrolled even after their donation has begun, only routine blood samples are used in the study. In Denmark, archive samples (5 mL EDTA gel-separated tubes, various vendors) are routinely collected at every donation. For study participants, 1.2 mL of plasma from all archive samples are reserved for research purposes whether drawn at inclusion, at subsequent donations or from historical samples. Samples used for blood group typing or viral screening are recapped and whole blood is made available for DNA extraction.

The Danish Blood Donor Study (DBDS) was established as a platform for the study of health effects of blood donation and as a public health study. Previous results from the Scandinavian Donations and Transfusions Database (SCANDAT, a database including all electronically recorded Danish and Swedish blood donations since the 1980s and 1970s, respectively), 1 linked to the national health registers, demonstrated a lower mortality among blood donors when compared with the background population. 2 In addition, blood donors donating frequently had a lower mortality than infrequent donors. 3 The original research question was thus: is blood donation per se beneficial to the health of the blood donors, or are active blood donors healthier than the rest of the population because of donor selection bias? As a group, blood donors are healthier than the general population. This phenomenon is known as the Healthy Donor Effect (HDE) and results from a selection bias similar to the Healthy Worker Effect. 4 , 5 Just as the Healthy Worker Effect can mask possible occupational hazards, the HDE may mask deleterious effects of blood donation, inasmuch as only healthy individuals may donate. As blood banks, we are obligated to ensure that donors are in good health both before and after donating blood. We therefore need studies that reveal possible detrimental effects of blood donation, and to further elucidate the HDE. The cohort was also established to assess general health-related research questions. Despite the HDE, some blood donors ultimately fall ill, and with increasing ‘time since last donation’, the mortality among lapsed or deferred donors approaches the mortality of the background population. 2 , 3 Several features add value to the study of blood donors: blood donors typically return to donate blood several times over the span of years. A cohort of blood donors therefore provides a unique opportunity to track changes in health, lifestyle, disease emergence and other exposures/parameters between donations. Hence, large blood donor studies and biobanks with consecutive samples are useful to investigate plasma biomarkers predicting disease. Candidate biomarkers can be measured over time in the same donor and changes recorded. The DBDS has already proved to be a useful platform for the study of general health-related research questions. 6–15 Large-scale blood donor studies can thus be leveraged for public health research within biological, psychological and social aspects of general health, as long as the HDE is taken into account. Given our cohort infrastructure, we are also able to conduct recall by genotype or phenotype studies. The statistical noise from pre-existing disease on dynamic biomarkers is minimized by the fact that blood donors are only allowed to donate if they consider themselves to be in good health and are free of overt disease. For that reason, the cohort is also suitable for the identification of healthy controls for other studies. Furthermore, the high number of blood donations continuously taking place in all parts of the country, even during a pandemic, renders real-time surveillance studies of infectious diseases possible. The DBDS was initiated in the Capital and Central Denmark Regions in March 2010. From January 2012, the study was expanded to include the Zealand and North Denmark Regions. The Region of Southern Denmark joined the study in June 2015, at which point the cohort became nationwide.

The basic infrastructure needed for establishing this large public health study was readily available in the Danish blood services. Generally, blood banks routinely recruit new donors, handle contact information and obtain informed consent. Donors are accustomed to questionnaires at every donation, blood is already drawn from the donors, systems are in place for the unique labelling of samples and procedures for the correct handling storage, and analysis of samples are well established. Further, donors visit the blood banks as unpaid volunteers to give blood, whereas in other studies, participants must typically be invited, staff must be present solely for the inclusion of participants and a substantial infrastructure must be established for collection and handling of samples and data. In our experience, blood donors are generally willing to participate in research projects, which is reflected in a very high participation rate. Taken together, the DBDS is highly cost-effective compared with other large population studies. Because of the existing infrastructure, we are also able to include samples taken during prior visits to the blood bank, before the donor joined the study. Data and blood samples from these visits are thus available to research at little to no extra cost. A population study of this magnitude that includes consecutive plasma samples with such short sampling time intervals is unique to the DBDS. This design enables us to study disease pathology and biomarkers that change over time before disease becomes apparent andhence the study portrays a prospective cohort. For example, consider the validation of a new screening candidate for a specific disease. Participants with the disease can be identified in the National Patient Register. The biomarker can be measured in several samples before and as close to the date of the diagnosis as possible. Should the biomarker be positive/observed, earlier samples can be picked and the dynamics of the biomarker over time can be assessed ( Figure 2 ). 31 In contrast to blood donor and population studies in other parts of the world, the DBDS benefits from the unique Danish national registers. The registers offer a wide range of opportunities, including the study of generic health questions. The overall infrastructure in the Danish Blood Donor Study. Participants are included at an arbitrary donation and may donate several times over the range of years. At each visit a plasma sample is stored. Some participants may develop a disease, which is registered in the National Patient Register. All samples are available for measurements if a biomarker is to be assessed Some compromises have been made to increase the participation rate. The questionnaire is not as comprehensive as in many other studies. This is a deliberate choice to minimize the risk of causing delays in the waiting rooms, which would likely reduce the participation rate and increase the level of missing answers. Only 1.5 mL plasma is collected during each visit. This relatively small sample volume is necessary to facilitate the inclusion of donors already being bled and to reduce costs, since no extra blood samples need be drawn. Blood donors are healthier than the general population because they are selected and because donors are screened by questionnaires for risk factors associated with transfusion-transmissible infections. Therefore, a blood donor population cannot be used directly to assess the prevalence of health and disease in the general population. Similarly in the study of biomarkers, findings must be verified in other populations. However, the HDE may also be an advantage: in the study of biomarkers and other risk factors for disease, we can assume that the donor was asymptomatic when included. Consequently, it can generally be assumed that if a biomarker is present, it was there before symptoms/the clinical phenotype arose.

The DBDS was approved by the Central Denmark (1–10-72–95-13) and Zealand (SJ-740) Regional Committees on Health Research Ethics and the Data Protection Agency (P-2019–99). The DBDS GWA study was approved by the Danish National Committee on Health Research Ethics (1700407). SCANDAT was approved by the Data Protection Agency (2008–54-0472). The DBDS was conducted in accordance with the ethical principles outlined in the Declaration of Helsinki.