Background NHS Blood and Transplant (NHSBT), the sole provider of blood to the National Health Service (NHS) in England, UK, must ensure a safe and sustainable supply of blood, whilst protecting donor health and wellbeing.

Objectives The primary objective of this thesis is to advance the evidence base for strategies aimed at optimising donor iron status and improving the efficiency and sustainability of the blood supply through reduced deferrals and improved return rates. To achieve this objective, this thesis provides a portfolio of complementary quantitative epidemiological studies, which aimed to: (i) assess temporal trends and contemporary patterns in blood collection and adverse events; (ii) identify individual and collection site characteristics associated with return behaviour; (iii) characterise in detail the cross-sectional associations of the three optimal indices for defining iron deficiency (i.e., haemoglobin, ferritin, and soluble transferrin receptor [sTfR]), particularly modifiable and genetic correlates; (iv) develop and validate risk prediction models for low haemoglobin deferral to determine the added value of different types of data. In addition, the extent to which participants from blood donor research studies are representative of the national donor population will be investigated. This thesis will leverage large-scale, detailed, and multi-purpose data sources to overcome some of the limitations of previous studies, reporting findings to a greater detail than has previously been possible, in order to inform future studies that will directly influence blood donation practice and policy.

Data sources Data extracts from the NHSBT national donor database (N=3,400,000) contained anonymised individual-level blood donation records from 2007-19 and were used to assess temporal trends and adverse events and to identify determinants of return behaviour, as well as to define comparator populations for the INTERVAL trial and COMPARE study for the purpose of assessing the representativeness of these cohorts. Data from the INTERVAL trial (2012-16; N=45,000), a large, parallel group, pragmatic, individually randomised trial, embedded in the routine blood service, evaluating the efficiency and safety of varying the frequency of whole blood donation over a 2-year period, was used to complement the analysis of return behaviour through study of adherence to assigned inter-donation intervals, in addition to contributing to the cross-sectional individual-participant data meta-analysis of correlates of iron levels and the development of risk prediction models for low haemoglobin deferral. Data from the COMPARE study (2016-17; N=30,000), a two-stage, systematic, within-person comparison diagnostic-accuracy study of different haemoglobin screening methods, contributed to the meta-analysis and was used to validate risk prediction models. The meta-analysis also included individual-participant data from the Cambridge BioResource (2007-9; N=7,500), Cambridge CardioResource (2010; N=2,500), and UK Blood Services Common Controls (2005; N=3,600). Study participants were well-characterised with extensive genetic, haematological, biochemical, lifestyle, health, and serially-assessed clinical information, in addition to routinely available demographic, donation history, and collection site characteristics, together with geographical and socioeconomic information through linkage to national datasets. Polygenic risk scores (PRSs) were derived for key iron measures using published variants.

Results In analyses of over 20 million donor attendances, overall blood collection declined by 24∙1% between 2009 and 2018, but collection trends differed at a blood group level with targeted increases in the proportion of donations comprising universal, rare, and minor blood groups. As a result, the donor population contracted, shifting toward an older and more ethnically diverse population, comprising fewer male donors. Deferral for low haemoglobin increased substantially following the introduction of revised screening procedures in 2017, whilst adverse events remained stable. INTERVAL trial and COMPARE study participants were broadly representative of the national donor population of England, with only minor differences in age, sex, and number of previous donations. In analyses of return behaviour, during a 2-year follow-up period, 67·0% of donors from the national donor comparator population and 93·3% of participants from the INTERVAL trial returned to donate, with male sex, older age, number of previous attendances, and number of opportunities to donate positively associated with return. By contrast, non-white ethnicity, distance to the donation venue, deferral and adverse events at the previous visit were negatively associated with return. Substantial deviations from model assumptions revealed time-dependent associations. To reliably quantify cross-sectional associations of iron measures, individual-participant data on 85,847 whole blood donors from five relevant independent UK studies was harmonised to establish a large national consortium, allowing concomitant assessment of haemoglobin, ferritin, and sTfR. The iron measures shared some important modifiable risk factors, but the overlap was imperfect. In aggregate, only around one sixth of the total variation in haemoglobin and sTfR levels was explained by all of the variables considered, whereas, for ferritin levels, this was approximately one third for men and one quarter for women, of which the majority was attributable to factors describing donation frequency. Modifiable lifestyle characteristics (such as smoking, alcohol consumption, physical activity) and dietary habits together explained only a few percent of the total variation in iron measures. Notably, for haemoglobin, the respective PRS accounted for the largest fraction of the total explained variation. The prevalence of all stages of iron deficiency increased with higher donation frequency and younger age in women. 2∙1% of men and 6∙0% of women were deferred for low haemoglobin at their first donation attempt during the INTERVAL trial. The cross-validated concordance (C)-index of a prediction model for low haemoglobin deferral including conventional risk factors alone was 0·937 (95% CI 0·927 to 0·947) for men and 0·859 (0·847 to 0·871) for women, which could largely be attributed to the previous haemoglobin level. The inclusion of additional data types did not significantly augment the predictive ability of the model.

Conclusions Differential trends by blood group highlight the increasing challenge for NHSBT of needing to reduce blood collection capacity to match declining overall demand and blood usage, whilst retaining donors of certain blood groups where demand is not falling. Perpetual large-scale population-based studies of temporal trends and contemporary patterns in blood collection and adverse events are needed to inform donor recruitment and retention strategies, and to prioritise research. Despite the INTERVAL trial and COMPARE study participants being broadly representative of the national donor population of England, the exact degree of generalisability remains somewhat uncertain. Key determinants of return behaviour were identified and point to possible opportunities for targeted retention strategies within the national donor population, as well as providing valuable information for the effective planning and delivery of short-term policies to allow more frequent donation. Evaluation of the correlates and possible determinants of iron measures has advanced understanding of the potential for prevention efforts to reduce the high prevalence of iron deficiency in whole blood donors to further safeguard donor health. Prediction models based on conventional risk factors alone provided accurate and reliable discrimination between those with low and acceptable haemoglobin levels at a subsequent donation attempt. Increased personalisation of blood donation, in the form of tailoring the inter-donation interval to the donor’s capacity to give blood safely, may reduce the number of deferrals for low haemoglobin, which in turn may yield improvements in operational efficiency and enhance donor health, satisfaction, and retention.