Peter Donnelly’s research while affiliated with WWF United Kingdom and other places

We assess the UK Biobank (UKB) Polygenic Risk Score (PRS) Release, a set of PRSs for 28 diseases and 25 quantitative traits that has been made available on the individuals in UKB, using a unified pipeline for PRS evaluation. We also release a benchmarking software tool to enable like-for-like performance evaluation for different PRSs for the same disease or trait. Extensive benchmarking shows the PRSs in the UKB Release to outperform a broad set of 76 published PRSs. For many of the diseases and traits we also validate the PRS algorithms in a separate cohort (100,000 Genomes Project). The availability of PRSs for 53 traits on the same set of individuals also allows a systematic assessment of their properties, and the increased power of these PRSs increases the evidence for their potential clinical benefit.

Background and Aims A cardiovascular disease polygenic risk score (CVD-PRS) can stratify individuals into different categories of cardiovascular risk, but whether the addition of a CVD-PRS to clinical risk scores improves the identification of individuals at increased risk in a real-world clinical setting is unknown. Methods The Genetics and the Vascular Health Check Study (GENVASC) was embedded within the UK National Health Service Health Check (NHSHC) programme which invites individuals between 40–74 years of age without known CVD to attend an assessment in a UK general practice where CVD risk factors are measured and a CVD risk score (QRISK2) is calculated. Between 2012–2020, 44,141 individuals (55.7% females, 15.8% non-white) who attended an NHSHC in 147 participating practices across two counties in England were recruited and followed. When 195 individuals (cases) had suffered a major CVD event (CVD death, myocardial infarction or acute coronary syndrome, coronary revascularisation, stroke), 396 propensity-matched controls with a similar risk profile were identified, and a nested case-control genetic study undertaken to see if the addition of a CVD-PRS to QRISK2 in the form of an integrated risk tool (IRT) combined with QRISK2 would have identified more individuals at the time of their NHSHC as at high risk (QRISK2 10-year CVD risk of ≥10%), compared with QRISK2 alone. Results The distribution of the standardised CVD-PRS was significantly different in cases compared with controls (cases mean score .32; controls, −.18, P = 8.28×10−9). QRISK2 identified 61.5% (95% confidence interval [CI]: 54.3%–68.4%) of individuals who subsequently developed a major CVD event as being at high risk at their NHSHC, while the combination of QRISK2 and IRT identified 68.7% (95% CI: 61.7%–75.2%), a relative increase of 11.7% (P = 1×10−4). The odds ratio (OR) of being up-classified was 2.41 (95% CI: 1.03–5.64, P = .031) for cases compared with controls. In individuals aged 40–54 years, QRISK2 identified 26.0% (95% CI: 16.5%–37.6%) of those who developed a major CVD event, while the combination of QRISK2 and IRT identified 38.4% (95% CI: 27.2%–50.5%), indicating a stronger relative increase of 47.7% in the younger age group (P = .001). The combination of QRISK2 and IRT increased the proportion of additional cases identified similarly in women as in men, and in non-white ethnicities compared with white ethnicity. The findings were similar when the CVD-PRS was added to the atherosclerotic cardiovascular disease pooled cohort equations (ASCVD-PCE) or SCORE2 clinical scores. Conclusions In a clinical setting, the addition of genetic information to clinical risk assessment significantly improved the identification of individuals who went on to have a major CVD event as being at high risk, especially among younger individuals. The findings provide important real-world evidence of the potential value of implementing a CVD-PRS into health systems.

Aims The aim of the study was to assess the real-world feasibility, acceptability, and impact of an integrated risk tool for cardiovascular disease (CVD IRT, combining the standard QRISK®2 risk algorithm with a polygenic risk score), implemented within routine primary practice in the UK National Health Service. Methods and results The Healthcare Evaluation of Absolute Risk Testing Study (NCT05294419) evaluated participants undergoing primary care health checks. Both QRISK2 and CVD IRT scores were returned to the healthcare providers (HCPs), who then communicated the results to participants. The primary outcome of the study was feasibility of CVD IRT implementation. Secondary outcomes included changes in CVD risk (QRISK2 vs. CVD IRT) and impact of the CVD IRT on clinical decision-making. A total of 832 eligible participants (median age 55 years, 62% females, 97.5% White ethnicity) were enrolled across 12 UK primary care practices. Cardiovascular disease IRT scores were obtained on 100% of the blood samples. Healthcare providers stated that the CVD IRT could be incorporated into routine primary care in a straightforward manner in 90.7% of reports. Participants stated they were ‘likely’ or ‘very likely’ to recommend the use of this test to their family or friends in 86.9% of reports. Participants stated that the test was personally useful (98.8%) and that the results were easy to understand (94.6%). When CVD IRT exceeded QRISK2, HCPs planned changes in management for 108/388 (27.8%) of participants and 47% (62/132) of participants with absolute risk score changes of >2%. Conclusion Amongst HCPs and participants who agreed to the trial of genetic data for refinement of clinical risk prediction in primary care, we observed that CVD IRT implementation was feasible and well accepted. The CVD IRT results were associated with planned changes in prevention strategies.

Meiotic recombination commences with hundreds of programmed DNA breaks; however, the degree to which they are accurately repaired remains poorly understood. We report that meiotic break repair is eightfold more mutagenic for single-base substitutions than was previously understood, leading to de novo mutation in one in four sperm and one in 12 eggs. Its impact on indels and structural variants is even higher, with 100- to 1300-fold increases in rates per break. We uncovered new mutational signatures and footprints relative to break sites, which implicate unexpected biochemical processes and error-prone DNA repair mechanisms, including translesion synthesis and end joining in meiotic break repair. We provide evidence that these mechanisms drive mutagenesis in human germ lines and lead to disruption of hundreds of genes genome wide.

Mammalian meiotic recombination proceeds via repair of hundreds of programmed DNA double-strand breaks, which requires choreographed binding of RPA, DMC1, and RAD51 to single-stranded DNA substrates. High-resolution in vivo binding maps of these proteins provide insights into the underlying molecular mechanisms. When assayed in F 1 -hybrid mice, these maps can distinguish the broken chromosome from the chromosome used as template for repair, revealing more mechanistic detail and enabling the structure of the recombination intermediates to be inferred. By applying CRISPR-Cas9 mutagenesis directly on F 1 -hybrid embryos, we have extended this approach to explore the molecular detail of recombination when a key component is knocked out. As a proof of concept, we have generated hybrid biallelic knockouts of Dmc1 and built maps of meiotic binding of RAD51 and RPA in them. DMC1 is essential for meiotic recombination, and comparison of these maps with those from wild-type mice is informative about the structure and timing of critical recombination intermediates. We observe redistribution of RAD51 binding and complete abrogation of D-loop recombination intermediates at a molecular level in Dmc1 mutants. These data provide insight on the configuration of RPA in D-loop intermediates and suggest that stable strand exchange proceeds via multiple rounds of strand invasion with template switching in mouse. Our methodology provides a high-throughput approach for characterization of gene function in meiotic recombination at low animal cost.

Introduction: We have previously shown that combining a polygenic risk score (PRS) for cardiovascular disease (CVD), with standard clinical risk calculators such as QRISK®2, results in improved CVD risk prediction via an integrated risk tool (CVD-IRT). Research Question: The objective of this study was to explore the implementation of CVD-IRT within routine practice in the UK National Health Service (NHS), through participant and healthcare provider (HCP) surveys and interviews. Methods: The Healthcare Evaluation of Absolute Risk Testing Study (HEART) (NCT05294419), a prospective, single-arm pragmatic trial, enrolled 836 participants undergoing health checks across 12 NHS general practices. QRISK2 and CVD-IRT scores were returned to participants via HCPs. The primary outcome of the study was feasibility of CVD-IRT implementation. This was assessed by a mixed methods approach (quantitative and qualitative methods). Results: After the results were reported and discussed, 520 surveys were completed by participants and 824 surveys were completed by HCPs. Subsequently, 21 participants were interviewed and 13 HCPs attended focus groups or interviews to explore their experiences. 23 HCPs completed a final questionnaire (34.8% physician, 21.7% research nurse, 43.5% other). For 90.7% of reports, HCPs indicated that the CVD-IRT could be incorporated into routine primary care in a straightforward manner. 80% of HCPs agreed that having these tests could lead to better health outcomes for patients, and 68.4% believed that the CVD-IRT could help them manage their patients through a shared decision making process covering lifestyle and treatment options. Participants found the report personally useful (98.5%) and easy to understand (94.3%); agreed that genetic measures are important to identify the risks of developing CVD (85.2%); thought that the test should be widely made available (interview summaries); and would recommend to friends and family (86.8%). Conclusion: The implementation of the CVD-IRT into routine health-checks was recommendable, feasible and well received by both HCPs and participants, who felt that the information was useful, could support clinical decisions, and easy to understand.

Introduction: We have previously shown that combining a polygenic risk score (PRS) for cardiovascular disease (CVD), a numerical summary of an individual’s genetic predisposition to CVD, with standard clinical risk calculators such as ASCVD-PCE and QRISK results in improved estimates of CVD risk. Implementation of such a cardiovascular integrated risk tool (CVD IRT) into real world clinical practice is a key focus for further study. Hypothesis: We assessed the hypothesis that a CVD IRT can be incorporated into routine primary care. Methods: The Healthcare Evaluation of Absolute Risk Testing Study (NCT05294419) is a prospective trial recruiting up to 1,000 healthy participants undergoing health checks across 12 UK NHS general practices. Both QRISK2 and CVD IRT scores were generated and returned to clinicians, who then communicated the results to participants. The primary outcome of this study is operational success as well as feedback from health care providers (HCPs) and participants. The study also measures the impact of the CVD IRT on clinical decision making. Results: These are interim analyses. As of April 2022, 624 eligible participants (62% female, mean age 55) have been recruited. A total of 371 CVD IRT reports have been generated, with 100% of blood samples generating scores that were all returned within the designated time frame. Among the primary care HCPs, 89% (8/9) agreed that the incorporation of CVD IRT into routine care could be done in a straightforward manner. Among the participants who have completed a survey to date, 93% (125/135) would likely or very likely recommend the CVD IRT to friends and family. Average QRISK2 (6.3%) and CVD IRT (6.6%) risk scores did not differ significantly, but there were broad changes in risk among individual patients, with 5% (19/371) of patients crossing above the risk threshold to treat according to NICE guidelines (10-year risk ≥ 10%) as well as 3% (11/371) of patients reclassified as very high risk (10-year risk ≥ 20%). Conclusions: The rollout of an integrated risk tool combining polygenic risk into a standardized CVD risk calculator within primary care is feasible and well accepted by clinicians and participants. The CVD IRT results suggest clinically actionable changes in a substantial proportion of this population.

We present and assess the UK Biobank (UKB) Polygenic Risk Score (PRS) Release, a set of PRSs for 28 diseases and 25 quantitative traits being made available on the individuals in UKB. We also release a benchmarking software tool to enable like-for-like performance evaluation for different PRSs for the same disease or trait. Extensive benchmarking shows the PRSs in the UKB Release to outperform a broad set of 81 published PRSs. For many of the diseases and traits we also validate the PRS algorithms in other cohorts. The availability of PRSs for 53 traits on the same set of individuals also allows a systematic assessment of their properties, and the increased power of these PRSs increases the evidence for their potential clinical benefit.

Mycobacterial infections, both tuberculosis and nontuberculous, are more common in patients with haematological malignancies and haematopoietic stem cell transplant recipients than in the general population—although these infections remain rare. Mycobacterial infections pose both diagnostic and therapeutic challenges. The management of mycobacterial infections is particularly complicated for patients in haematology because of the many drug–drug interactions between antimycobacterial drugs and haematological and immunosuppressive treatments. The management of mycobacterial infections must also consider the effect of delaying haematological management. We surveyed the management practices for latent tuberculosis infection (LTBI) in haematology centres in Europe. We then conducted a meticulous review of the literature on the epidemiology, diagnosis, and management of LTBI, tuberculosis, and nontuberculous mycobacterial infections among patients in haematology, and we formulated clinical guidelines according to standardised European Conference on Infections in Leukaemia (ECIL) methods. In this Review, we summarise the available literature and the recommendations of ECIL 8 for managing mycobacterial infections in patients with haematological malignancies.