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OBJECTIVE: Metabolic syndrome (MetS) has been linked to dementia. In this study, we examined the association of MetS with neuroimaging and cognition in dementia-free adults, offering insight into the impact of MetS on brain health prior to dementia onset. RESEARCH DESIGN AND METHODS: We included 37,395 dementia-free adults from the UK Biobank database. MetS was defined as having at least three of the following components: larger waist circumference; elevated levels of triglycerides, blood pressure, HbA1c; or reduced HDL cholesterol levels. Multivariable-adjusted linear regression was used to assess associations of MetS with structural neuroimaging and cognitive domains. RESULTS: MetS was associated with lower total brain (standardized β: −0.06; 95% CI −0.08, −0.04), gray matter (β: −0.10; 95% CI −0.12, −0.08) and hippocampal (for left side, β: −0.03, 95% CI −0.05, −0.01; for right side, β: −0.04, 95% CI −0.07, −0.02) volumes, and greater white matter hyperintensity (WMH) volume (β: 0.08; 95% CI 0.06, 0.11). Study participants with MetS performed poorer on cognitive tests of working memory (β: −0.10; 95% CI −0.13, −0.07), verbal declarative memory (β: −0.08; 95% CI −0.11, −0.05), processing speed (β: −0.06; 95% CI −0.09, −0.04), verbal and numerical reasoning (β: −0.07; 95% CI −0.09, −0.04), nonverbal reasoning (β: −0.03; 95% CI −0.05, −0.01), and on tests of executive function, where higher scores indicated poorer performance (β: 0.05; 95% CI 0.03, 0.08). More MetS components were also associated with less brain volume, greater WMH, and poorer cognition across all domains. CONCLUSIONS: MetS was associated poorer brain health in dementia-free adults, characterized by less brain volume, greater vascular pathology, and poorer cognition. Further research is necessary to understand whether reversal or improvement of MetS can improve brain health. [ABSTRACT FROM AUTHOR]

Cancer risk is associated with the widely debated measure body mass index (BMI). Fat mass and fat-free mass measurements from bioelectrical impedance may further clarify this association. The UK Biobank is a rare resource in which bioelectrical impedance and BMI data was collected on ~ 500,000 individuals. Using this dataset, a comprehensive analysis using regression, principal component and genome-wide genetic association, provided multiple levels of evidence that increasing whole body fat (WBFM) and fat-free mass (WBFFM) are both associated with increased post-menopausal breast cancer risk, and colorectal cancer risk in men. WBFM was inversely associated with prostate cancer. We also identified rs615029[T] and rs1485995[G] as associated in independent analyses with both PMBC (p = 1.56E–17 and 1.78E–11) and WBFFM (p = 2.88E–08 and 8.24E–12), highlighting splice variants of the intriguing long non-coding RNA CUPID1 (LINC01488) as a potential link between PMBC risk and fat-free mass. [ABSTRACT FROM AUTHOR]

Body mass index (BMI; weight (kg)/height (m)2) is commonly used to measure general adiposity. However, evidence of its appropriateness for males and females remains inconsistent. We aimed to identify the most appropriate sex-specific power value that height should be raised to in the formula and the value that would make it achieve height independency and body fatness dependency. We randomly assigned UK Biobank participants recruited in the United Kingdom between 2006 and 2010 (n  = 489,873; mean age = 56.5 years; 94.2% White) to training and testing sets (80%:20%). Using height raised to the power of −50.00 to 50.00, we identified the optimal power value that either minimized correlation with height or maximized correlation with body fat percentage, using age-adjusted correlations. The optimal power values for height were 1.77 for males and 1.39 for females. The new formulas resulted in 4.5% of females and 2.4% of males being reclassified into a different BMI category. The formulas did not show significant improvement (in terms of area under the receiver operating characteristic curve, sensitivity, and specificity) in identifying individuals with excessive body fat percentage or in predicting risk of all-cause mortality. Therefore, the conventional BMI formula is still valuable in research and disease screening for both sexes. [ABSTRACT FROM AUTHOR]

The UK Biobank has made general practitioner (GP) data (censoring date 2016–2017) available for approximately 45% of the cohort, whilst hospital inpatient and death registry (referred to as "HES/Death") data are available cohort-wide through 2018–2022 depending on whether the data comes from England, Wales or Scotland. We assessed the importance of case ascertainment via different data sources in UKB for three diseases that are usually first diagnosed in primary care: Parkinson's disease (PD), type 2 diabetes (T2D), and all-cause dementia. Including GP data at least doubled the number of incident cases in the subset of the cohort with primary care data (e.g. from 619 to 1390 for dementia). Among the 786 dementia cases that were only captured in the GP data before the GP censoring date, only 421 (54%) were subsequently recorded in HES. Therefore, estimates of the absolute incidence or risk-stratified incidence are misleadingly low when based only on the HES/Death data. For incident cases present in both HES/Death and GP data during the full follow-up period (i.e. until the HES censoring date), the median time difference between an incident diagnosis of dementia being recorded in GP and HES/Death was 2.25 years (i.e. recorded 2.25 years earlier in the GP records). Similar lag periods were also observed for PD (median 2.31 years earlier) and T2D (median 2.82 years earlier). For participants with an incident GP diagnosis, only 65.6% of dementia cases, 69.0% of PD cases, and 58.5% of T2D cases had their diagnosis recorded in HES/Death within 7 years since GP diagnosis. The effect estimates (hazard ratios, HR) of established risk factors for the three health outcomes mostly remain in the same direction and with a similar strength of association when cases are ascertained either using HES only or further adding GP data. The confidence intervals of the HR became narrower when adding GP data, due to the increased statistical power from the additional cases. In conclusion, it is desirable to extend both the coverage and follow-up period of GP data to allow researchers to maximise case ascertainment of chronic health conditions in the UK. [ABSTRACT FROM AUTHOR]

Population-based prospective studies, such as UK Biobank, are valuable for generating and testing hypotheses about the potential causes of human disease. We describe how UK Biobank's study design, data access policies, and approaches to statistical analysis can help to minimize error and improve the interpretability of research findings, with implications for other population-based prospective studies being established worldwide. [ABSTRACT FROM AUTHOR]

Recently, large scale genomic projects such as All of Us and the UK Biobank have introduced a new research paradigm where data are stored centrally in cloud-based Trusted Research Environments (TREs). To characterize the advantages and drawbacks of different TRE attributes in facilitating cross-cohort analysis, we conduct a Genome-Wide Association Study of standard lipid measures using two approaches: meta-analysis and pooled analysis. Comparison of full summary data from both approaches with an external study shows strong correlation of known loci with lipid levels (R2 ~ 83–97%). Importantly, 90 variants meet the significance threshold only in the meta-analysis and 64 variants are significant only in pooled analysis, with approximately 20% of variants in each of those groups being most prevalent in non-European, non-Asian ancestry individuals. These findings have important implications, as technical and policy choices lead to cross-cohort analyses generating similar, but not identical results, particularly for non-European ancestral populations. The emergence of large-scale genomics projects has led to genetic studies across cohorts. Here, the authors conduct genome-wide association studies meta-analyzing in trusted research environments or pooling together and find similar, but not identical results. [ABSTRACT FROM AUTHOR]

Background: Whilst multi-morbidity is known to be a concern in people with cancer, very little is known about the risk of cancer in multi-morbid patients. This study aims to investigate the risk of being diagnosed with lung, colorectal, breast and prostate cancer associated with multi-morbidity. Methods: We investigated the association between multi-morbidity and subsequent risk of cancer diagnosis in UK Biobank. Cox models were used to estimate the relative risks of each cancer of interest in multi-morbid participants, using the Cambridge Multimorbidity Score. The extent to which reverse causation, residual confounding and ascertainment bias may have impacted on the findings was robustly investigated. Results: Of the 436,990 participants included in the study who were cancer-free at baseline, 21.6% (99,965) were multi-morbid (≥ 2 diseases). Over a median follow-up time of 10.9 [IQR 10.0–11.7] years, 9,019 prostate, 7,994 breast, 5,241 colorectal, and 3,591 lung cancers were diagnosed. After exclusion of the first year of follow-up, there was no clear association between multi-morbidity and risk of colorectal, prostate or breast cancer diagnosis. Those with ≥ 4 diseases at recruitment had double the risk of a subsequent lung cancer diagnosis compared to those with no diseases (HR 2.00 [95% CI 1.70–2.35] p for trend < 0.001). These findings were robust to sensitivity analyses aimed at reducing the impact of reverse causation, residual confounding from known cancer risk factors and ascertainment bias. Conclusions: Individuals with multi-morbidity are at an increased risk of lung cancer diagnosis. While this association did not appear to be due to common sources of bias in observational studies, further research is needed to understand what underlies this association. [ABSTRACT FROM AUTHOR]

Understanding the genetic and environmental risk factors for serious bacterial infections in ageing populations remains incomplete. Utilising the UK Biobank (UKB), a prospective cohort study of 500,000 adults aged 40–69 years at recruitment (2006–2010), can help address this. Partial implementation of such a system helped groups around the world make rapid progress understanding risk factors for SARS-CoV-2 infection and COVID-19, with insights appearing as early as May 2020. In principle, such approaches could also to be used for bacterial isolations. Here we report feasibility testing of linking an England-wide dataset of microbial reporting to UKB participants, to enable characterisation of microbial infections within the UKB Cohort. These records pertain mainly to bacterial isolations; SARS-CoV-2 isolations were not included. Microbiological infections occurring in patients in England, as recorded in the Public Health England second generation surveillance system (SGSS), were linked to UKB participants using pseudonymised identifiers. By January 2015, ascertainment of laboratory reports from UKB participants by SGSS was estimated at 98%. 4.5% of English UKB participants had a positive microbiological isolate in 2015. Half of UKB isolates came from 12 laboratories, and 70% from 21 laboratories. Incidence rate ratios for microbial isolation, which is indicative of serious infection, from the UKB cohort relative to the comparably aged general population ranged from 0.6 to 1, compatible with the previously described healthy participant bias in UKB. Data on microbial isolations can be linked to UKB participants from January 2015 onwards. This linked data would offer new opportunities for research into the role of bacterial agents on health and disease in middle to-old age. [ABSTRACT FROM AUTHOR]

UK Biobank is an intensively characterised prospective cohort of 500,000 adults aged 40-69 years when recruited between 2006 and 2010. The study was established to enable researchersworldwide to undertake health-related research in the public interest. The existence of such a large, detailed prospective cohort with a high degree of participant engagement enabled its rapid repurposing for coronavirus disease-2019 (COVID-19) research. In response to the pandemic, the frequency of updates on hospitalisations and deaths among participants was immediately increased, and new data linkages were established to national severe acute respiratory syndrome coronavirus 2 (SARSCoV-2) testing and primary care health records to facilitate research into the determinants of severe COVID-19. UK Biobank also instigated several sub-studies on COVID-19. In 2020, monthly blood samples were collected from approximately 20,000 individuals to investigate the distribution and determinants of SARS-CoV-2 infection, and to assess the persistence of antibodies following infection with another blood sample collected after 12 months. UK Biobank also performed repeat imaging of approximately 2,000 participants (half of whom had evidence of previous SARS-CoV-2 infection and half did not) to investigate the impact of the virus on changes in measures of internal organ structure and function. In addition, approximately 200,000 UK Biobank participants took part in a self-test SARS-CoV-2 antibody sub-study (between February and November 2021) to collect objective data on previous SARS-CoV-2 infection. These studies are enabling unique research into the genetic, lifestyle and environmental determinants of SARSCoV-2 infection and severe COVID-19, as well as their long-term health effects. UK Biobank's contribution to the national and international response to the pandemic represents a case study for its broader value, now and in the future, to precision medicine research. [ABSTRACT FROM AUTHOR]

Importance: A lack of internationally agreed standards for combining available data sources at scale risks inconsistent disease phenotyping limiting research reproducibility. Objective: To develop and then evaluate if a rules-based algorithm can identify coronary artery disease (CAD) sub-phenotypes using electronic health records (EHR) and questionnaire data from UK Biobank (UKB). Design: Case-control and cohort study. Setting: Prospective cohort study of 502K individuals aged 40–69 years recruited between 2006–2010 into the UK Biobank with linked hospitalization and mortality data and genotyping. Participants: We included all individuals for phenotyping into 6 predefined CAD phenotypes using hospital admission and procedure codes, mortality records and baseline survey data. Of these, 408,470 unrelated individuals of European descent had a polygenic risk score (PRS) for CAD estimated. Exposure: CAD Phenotypes. Main outcomes and measures: Association with baseline risk factors, mortality (n = 14,419 over 7.8 years median f/u), and a PRS for CAD. Results: The algorithm classified individuals with CAD into prevalent MI (n = 4,900); incident MI (n = 4,621), prevalent CAD without MI (n = 10,910), incident CAD without MI (n = 8,668), prevalent self-reported MI (n = 2,754); prevalent self-reported CAD without MI (n = 5,623), yielding 37,476 individuals with any type of CAD. Risk factors were similar across the six CAD phenotypes, except for fewer men in the self-reported CAD without MI group (46.7% v 70.1% for the overall group). In age- and sex- adjusted survival analyses, mortality was highest following incident MI (HR 6.66, 95% CI 6.07–7.31) and lowest for prevalent self-reported CAD without MI at baseline (HR 1.31, 95% CI 1.15–1.50) compared to disease-free controls. There were similar graded associations across the six phenotypes per SD increase in PRS, with the strongest association for prevalent MI (OR 1.50, 95% CI 1.46–1.55) and the weakest for prevalent self-reported CAD without MI (OR 1.08, 95% CI 1.05–1.12). The algorithm is available in the open phenotype HDR UK phenotype library (https://portal.caliberresearch.org/). Conclusions: An algorithmic, EHR-based approach distinguished six phenotypes of CAD with distinct survival and PRS associations, supporting adoption of open approaches to help standardize CAD phenotyping and its wider potential value for reproducible research in other conditions. [ABSTRACT FROM AUTHOR]

Certain infectious agents are recognised causes of cancer and other chronic diseases. To understand the pathological mechanisms underlying such relationships, here we design a Multiplex Serology platform to measure quantitative antibody responses against 45 antigens from 20 infectious agents including human herpes, hepatitis, polyoma, papilloma, and retroviruses, as well as Chlamydia trachomatis, Helicobacter pylori and Toxoplasma gondii, then assayed a random subset of 9695 UK Biobank participants. We find seroprevalence estimates consistent with those expected from prior literature and confirm multiple associations of antibody responses with sociodemographic characteristics (e.g., lifetime sexual partners with C. trachomatis), HLA genetic variants (rs6927022 with Epstein-Barr virus (EBV) EBNA1 antibodies) and disease outcomes (human papillomavirus-16 seropositivity with cervical intraepithelial neoplasia, and EBV responses with multiple sclerosis). Our accessible dataset is one of the largest incorporating diverse infectious agents in a prospective UK cohort offering opportunities to improve our understanding of host-pathogen-disease relationships with significant clinical and public health implications. Here, the authors design a multiplex serology platform to quantitatively measure antibodies against 20 infectious agents in UK Biobank participants and confirm associations of antibody responses with sociodemographic characteristics, HLA genetic variants, and disease outcomes. [ABSTRACT FROM AUTHOR]

While there is strong epidemiological evidence that circulating insulin-like growth factor-I (IGF-I) is associated with a higher risk of several cancers, little is known about its association with non-cancer outcomes. We investigated associations of circulating IGF-I with risk of 25 common conditions, other than cancer, in a large British cohort. Study participants were 318,749 middle-aged adults enrolled in the UK Biobank Study. Serum IGF-I concentration was measured in samples collected at baseline (2006–2010), and re-measured in 12,334 participants after an average of 4.3 years. We followed-up participants over an average of 11.5 years by linking to hospital admissions and mortality registries. Multivariable-adjusted Cox regressions estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between circulating IGF-I and 25 common conditions, using the repeated IGF-I measurements to correct for regression dilution bias. After correction for multiple testing (P < 0.002), IGF-I was positively associated with carpal tunnel syndrome (HR per 5 nmol/l higher concentration = 1.12, 95% CI 1.08–1.16), and inversely associated with varicose veins (0.90, 0.85–0.95), cataracts (0.97, 0.95–0.99), diabetes (0.92, 0.90–0.95), and iron deficiency anaemia (0.90, 0.86–0.93). The associations for cataracts and diabetes attenuated when restricted to cases diagnosed after five or more years of follow-up, suggesting that these associations were likely affected by reverse causality. Higher IGF-I concentration might be associated with the risk for several conditions, but genetic studies are needed to clarify which associations may be causal. [ABSTRACT FROM AUTHOR]

Purpose: Physical activity may reduce the risk of some types of cancer in men. Biological mechanisms may involve changes in hormone concentrations; however, this relationship is not well established. Therefore, we aimed to investigate the associations of physical activity with circulating insulin-like growth factor-I (IGF-I), sex hormone-binding globulin (SHBG, which modifies sex hormone activity), and total and free testosterone concentrations, and the extent these associations might be mediated by body mass index (BMI). Methods: Circulating concentrations of these hormones and anthropometric measurements and self-reported physical activity data were available for 117,100 healthy male UK Biobank participants at recruitment. Objectively measured accelerometer physical activity levels were also collected on average 5.7 years after recruitment in 28,000 men. Geometric means of hormone concentrations were estimated using multivariable-adjusted analysis of variance, with and without adjustment for BMI. Results: The associations between physical activity and hormones were modest and similar for objectively measured (accelerometer) and self-reported physical activity. Compared to men with the lowest objectively measured physical activity, men with high physical activity levels had 14% and 8% higher concentrations of SHBG and total testosterone, respectively, and these differences were attenuated to 6% and 3% following adjustment for BMI. Conclusion: Our results suggest that the associations of physical activity with the hormones investigated are, at most, modest; and following adjustment for BMI, the small associations with SHBG and total testosterone were largely attenuated. Therefore, it is unlikely that changes in these circulating hormones explain the associations of physical activity with risk of cancer either independently or via BMI. [ABSTRACT FROM AUTHOR]

Background: Better phenotyping of routinely collected coded data would be useful for research and health improvement. For example, the precision of coded data for hemorrhagic stroke (intracerebral hemorrhage [ICH] and subarachnoid hemorrhage [SAH]) may be as poor as < 50%. This work aimed to investigate the feasibility and added value of automated methods applied to clinical radiology reports to improve stroke subtyping.Methods: From a sub-population of 17,249 Scottish UK Biobank participants, we ascertained those with an incident stroke code in hospital, death record or primary care administrative data by September 2015, and ≥ 1 clinical brain scan report. We used a combination of natural language processing and clinical knowledge inference on brain scan reports to assign a stroke subtype (ischemic vs ICH vs SAH) for each participant and assessed performance by precision and recall at entity and patient levels.Results: Of 225 participants with an incident stroke code, 207 had a relevant brain scan report and were included in this study. Entity level precision and recall ranged from 78 to 100%. Automated methods showed precision and recall at patient level that were very good for ICH (both 89%), good for SAH (both 82%), but, as expected, lower for ischemic stroke (73%, and 64%, respectively), suggesting coded data remains the preferred method for identifying the latter stroke subtype.Conclusions: Our automated method applied to radiology reports provides a feasible, scalable and accurate solution to improve disease subtyping when used in conjunction with administrative coded health data. Future research should validate these findings in a different population setting. [ABSTRACT FROM AUTHOR]

Insulin‐like growth factor‐I (IGF‐I) and testosterone have been implicated in prostate cancer aetiology. Using data from a large prospective full‐cohort with standardised assays and repeat blood measurements, and genetic data from an international consortium, we investigated the associations of circulating IGF‐I, sex hormone‐binding globulin (SHBG), and total and calculated free testosterone concentrations with prostate cancer incidence and mortality. For prospective analyses, risk was estimated using multivariable‐adjusted Cox regression in 199 698 male UK Biobank participants. Hazard ratios (HRs) were corrected for regression dilution bias using repeat hormone measurements from a subsample. Two‐sample Mendelian randomisation (MR) analysis of IGF‐I and risk used genetic instruments identified from UK Biobank men and genetic outcome data from the PRACTICAL consortium (79 148 cases and 61 106 controls). We used cis‐ and all (cis and trans) SNP MR approaches. A total of 5402 men were diagnosed with and 295 died from prostate cancer (mean follow‐up 6.9 years). Higher circulating IGF‐I was associated with elevated prostate cancer diagnosis (HR per 5 nmol/L increment = 1.09, 95% CI 1.05‐1.12) and mortality (HR per 5 nmol/L increment = 1.15, 1.02‐1.29). MR analyses also supported the role of IGF‐I in prostate cancer diagnosis (cis‐MR odds ratio per 5 nmol/L increment = 1.34, 1.07‐1.68). In observational analyses, higher free testosterone was associated with a higher risk of prostate cancer (HR per 50 pmol/L increment = 1.10, 1.05‐1.15). Higher SHBG was associated with a lower risk (HR per 10 nmol/L increment = 0.95, 0.94‐0.97), neither was associated with prostate cancer mortality. Total testosterone was not associated with prostate cancer. These findings implicate IGF‐I and free testosterone in prostate cancer development and/or progression. What's new? Testosterone, insulin‐like growth factor‐I (IGF‐I), and sex hormone‐binding globulin (SHBG) all have been associated with prostate‐cancer risk. In this large, prospective study, the authors analyzed how these circulating hormones might impact mortality as well as risk. They found that men with higher IGF‐I had a higher risk of both prostate‐cancer diagnosis and mortality. Men with higher free testosterone had an increased risk of prostate cancer, while men with higher SHBG had a decreased risk. These results support the roles of IGF‐I and testosterone in prostate cancer development. [ABSTRACT FROM AUTHOR]

Background The number of gluten-free diet followers without celiac disease (CD) is increasing. However, little is known about the characteristics of these individuals. Objectives We address this issue by investigating a wide range of genetic and phenotypic characteristics in association with following a gluten-free diet. Methods The cross-sectional association between lifestyle and health-related characteristics and following a gluten-free diet was investigated in 124,447 women and men aged 40–69 y from the population-based UK Biobank study. A genome-wide association study (GWAS) of following a gluten-free diet was performed. Results A total of 1776 (1.4%) participants reported following a gluten-free diet. Gluten-free diet followers were more likely to be women, nonwhite, highly educated, living in more socioeconomically deprived areas, former smokers, have lost weight in the past year, have poorer self-reported health, and have made dietary changes as a result of illness. Conversely, these individuals were less likely to consume alcohol daily, be overweight or obese, have hypertension, or use cholesterol-lowering medication. Participants with hospital inpatient diagnosed blood and immune mechanism disorders (OR: 1.62; 95% CI: 1.18, 2.21) and non-CD digestive system diseases (OR: 1.58; 95% CI: 1.42, 1.77) were more likely to follow a gluten-free diet. The GWAS demonstrated that no genetic variants were associated with being a gluten-free diet follower. Conclusions Gluten-free diet followers have a better cardiovascular risk profile than non-gluten-free diet followers but poorer self-reported health and a higher prevalence of blood and immune disorders and digestive conditions. Reasons for following a gluten-free diet warrant further investigation. [ABSTRACT FROM AUTHOR]

We investigated the association between metabolic syndrome (MetS) and its components and risk of prostate cancer (PCa) in a cohort of men enrolled in the UK Biobank. Our study cohort included 220 622 PCa‐free men with baseline measurements of triglycerides (TGs), HDL‐cholesterol (HDL), glycated hemoglobin (HbA1c), blood pressure (BP), and waist circumference (WC). Multivariable Cox proportional hazards regression was used to analyze associations with PCa for: individual metabolic components (TG, HDL, HbA1c, BP, WC), combinations of two and three components, and MetS overall (three or more components). We conducted mediation analyses to examine potential hormonal and inflammatory pathways (total testosterone [TT], C‐reactive protein [CRP], insulin‐like growth factor 1 [IGF‐1]) through which MetS components may influence PCa risk. A total of 5409 men in the study developed PCa during a median follow‐up of 6.9 years. We found no significant association between MetS and PCa risk (hazard ratio [HR] = 0.99, 95% confidence interval [CI] = 0.92‐1.06). No associations were found with PCa risk and individual measurements of TG, HDL, BP, or WC. However, an inverse association was observed with elevated HbA1c (≥42 mmol/mol) (HR = 0.89, 95% CI = 0.79‐0.98). Consistent inverse associations were observed between HbA1c and risk of PCa. Mediation analysis revealed TT, CRP, and IGF‐1 as potential mediating factors for this association contributing 10.2%, 7.1%, and 7.9% to the total effect, respectively. Overall MetS had no association with PCa risk. However, a consistent inverse association with PCa risk was found for HbA1c. This association may be explained in part through hormonal and inflammatory pathways. What's new? Risk of prostate cancer is variously linked to obesity, type 2 diabetes mellitus, and other components of metabolic syndrome (MetS). Evidence for a clear association between prostate cancer and MetS and its components, however, remains elusive. In this large, prospective study, the authors found that MetS is not significantly associated with risk of prostate cancer. Glycated hemoglobin (HbA1c), however, was found to be inversely associated with risk. Analyses examining potential hormonal and inflammatory pathways identified total testosterone, C‐reactive protein, and insulin‐like growth factor 1 as potential mediating factors for the association between HbA1c and prostate cancer. [ABSTRACT FROM AUTHOR]

Previous studies on the association of adiposity with endometrial cancer risk have mostly used body mass index (BMI) as the main exposure of interest. Whether more precise measures of body fat, such as body fat percentage and fat mass estimated by bioimpedance analyses, are better indicators of risk than BMI is unknown. The role of central adiposity and fat‐free mass in endometrial cancer development remains unclear. We used Cox regression models to estimate hazard ratios (HR) and corresponding 95% confidence intervals (CI) for the associations of various measures of body size/composition with the risk of endometrial cancer among 135 110 postmenopausal women enrolled in UK Biobank. During a mean follow up of 6.8 years, 706 endometrial cancers were diagnosed, with a mean age at diagnosis of 65.5 years. The HRs (95% CIs) for endometrial cancer per 1 SD increase in BMI, body fat percentage and fat mass were broadly comparable, being 1.71 (1.61‐1.82), 1.92 (1.75‐2.11) and 1.73 (1.63‐1.85), respectively. There was an indication of positive association between central adiposity, as reflected by waist circumference (HRper 1‐SD increase = 1.08, 95% CI: 1.00‐1.17) and waist to hip ratio (HRper 1‐SD increase = 1.13, 95% CI: 1.01‐1.26), and endometrial cancer risk after accounting for BMI. Fat‐free mass was not an independent predictor of risk in this cohort. These findings suggest that body fat percentage and fat mass are not better indicators of endometrial cancer risk than BMI. Further studies are needed to establish whether central adiposity contributes to risk beyond overall adiposity. What's new? While body mass index (BMI) is linked to endometrial cancer risk, whether more precise measures of adiposity, namely body fat percentage and fat mass, are better risk indicators than BMI is unclear. Here, different measures of body size and composition were evaluated in relation to endometrial cancer risk among more than 135 000 postmenopausal women enrolled in the UK Biobank. Body fat percentage and fat mass, as reflected by bioimpedance analysis, were not found to be superior indicators of endometrial cancer risk compared to BMI. Further investigation is needed to establish the true contribution of central adiposity to endometrial cancer risk. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to quantify the associations of regional fat mass and fat-free mass with systolic blood pressure.Methods: This analysis combined individual participant data from two large-scale imaging studies: UK Biobank and Oxford BioBank. In both studies, participants were interviewed and measured, and they underwent dual-energy x-ray absorptiometry imaging. Linear regression was used to relate systolic blood pressure to anthropometric measures of adiposity (BMI, waist circumference, and waist to hip ratio) and dual-energy x-ray absorptiometry-derived measures of body composition (visceral android fat, subcutaneous android fat, subcutaneous gynoid fat, and fat-free mass).Results: Among 10,260 participants (mean age 49; 96% white), systolic blood pressure was positively associated with visceral android fat (3.2 mmHg/SD in men; 2.8 mmHg/SD in women) and fat-free mass (1.92 mmHg/SD in men; 1.64 mmHg/SD in women), but there was no evidence of an association with subcutaneous android or gynoid fat. Associations of systolic blood pressure with BMI were slightly steeper than those with waist circumference or waist to hip ratio; these associations remained unchanged following adjustment for fat-free mass, but adjustment for visceral android fat eliminated associations with waist circumference and waist to hip ratio and more than halved associations with BMI.Conclusions: This analysis indicates that visceral fat is the primary etiological component of excess adiposity underlying the development of adiposity-related hypertension. [ABSTRACT FROM AUTHOR]

Background: Feedback of potentially serious incidental findings (PSIFs) to imaging research participants generates clinical assessment in most cases. Understanding the factors associated with increased risks of PSIFs and of serious final diagnoses may influence individuals’ decisions to participate in imaging research and will inform the design of PSIFs protocols for future research studies. We aimed to determine whether, and to what extent, socio-demographic, lifestyle, other health-related factors and PSIFs protocol are associated with detection of both a PSIF and a final diagnosis of serious disease. Methods and findings: Our cohort consisted of all UK Biobank participants who underwent imaging up to December 2015 (n = 7334, median age 63, 51.9% women). Brain, cardiac and body magnetic resonance, and dual-energy x-ray absorptiometry images from the first 1000 participants were reviewed systematically by radiologists for PSIFs. Thereafter, radiographers flagged concerning images for radiologists’ review. We classified final diagnoses as serious or not using data from participant surveys and clinical correspondence from GPs up to six months following imaging (either participant or GP correspondence, or both, were available for 93% of participants with PSIFs). We used binomial logistic regression models to investigate associations between age, sex, ethnicity, socio-economic deprivation, private healthcare use, alcohol intake, diet, physical activity, smoking, body mass index and morbidity, with both PSIFs and serious final diagnoses. Systematic radiologist review generated 13 times more PSIFs than radiographer flagging (179/1000 [17.9%] versus 104/6334 [1.6%]; age- and sex-adjusted OR 13.3 [95% confidence interval (CI) 10.3–17.1] p<0.001) and proportionally fewer serious final diagnoses (21/179 [11.7%]; 33/104 [31.7%]). Risks of both PSIFs and of serious final diagnoses increased with age (sex-adjusted ORs [95% CI] for oldest [67–79 years] versus youngest [44–58 years] participants for PSIFs and serious final diagnoses respectively: 1.59 [1.07–2.38] and 2.79 [0.86 to 9.0] for systematic radiologist review; 1.88 [1.14–3.09] and 2.99 [1.09–8.19] for radiographer flagging). No other factor was significantly associated with either PSIFs or serious final diagnoses. Our study is the largest so far to investigate the factors associated with PSIFs and serious final diagnoses, but despite this, we still may have missed some associations due to sparsity of these outcomes within our cohort and small numbers within some exposure categories. Conclusion: Risks of PSIFs and serious final diagnosis are substantially influenced by PSIFs protocol and to a lesser extent by age. As only 1/5 PSIFs represent serious disease, evidence-based PSIFs protocols are paramount to minimise over-investigation of healthy research participants and diversion of limited health services away from patients in need. [ABSTRACT FROM AUTHOR]

Prospective, population-based studies that recruit participants in mid-life are valuable resources for dementia research. Follow-up in these studies is often through linkage to routinely-collected healthcare datasets. We investigated the accuracy of these datasets for dementia case ascertainment in a validation study using data from UK Biobank—an open access, population-based study of > 500,000 adults aged 40–69 years at recruitment in 2006–2010. From 17,198 UK Biobank participants recruited in Edinburgh, we identified those with ≥ 1 dementia code in their linked primary care, hospital admissions or mortality data and compared their coded diagnoses to clinical expert adjudication of their full-text medical record. We calculated the positive predictive value (PPV, the proportion of cases identified that were true positives) for all-cause dementia, Alzheimer's disease and vascular dementia for each dataset alone and in combination, and explored algorithmic code combinations to improve PPV. Among 120 participants, PPVs for all-cause dementia were 86.8%, 87.3% and 80.0% for primary care, hospital admissions and mortality data respectively and 82.5% across all datasets. We identified three algorithms that balanced a high PPV with reasonable case ascertainment. For Alzheimer's disease, PPVs were 74.1% for primary care, 68.2% for hospital admissions, 50.0% for mortality data and 71.4% in combination. PPV for vascular dementia was 43.8% across all sources. UK routinely-collected healthcare data can be used to identify all-cause dementia in prospective studies. PPVs for Alzheimer's disease and vascular dementia are lower. Further research is required to explore the geographic generalisability of these findings. [ABSTRACT FROM AUTHOR]

The UK Biobank cohort is a population-based cohort of 500,000 participants recruited in the United Kingdom (UK) between 2006 and 2010. Approximately 9.2 million individuals aged 40-69 years who lived within 25 miles (40 km) of one of 22 assessment centers in England, Wales, and Scotland were invited to enter the cohort, and 5.5% participated in the baseline assessment. The representativeness of the UK Biobank cohort was investigated by comparing demographic characteristics between nonresponders and responders. Sociodemographic, physical, lifestyle, and health-related characteristics of the cohort were compared with nationally representative data sources. UK Biobank participants were more likely to be older, to be female, and to live in less socioeconomically deprived areas than nonparticipants. Compared with the general population, participants were less likely to be obese, to smoke, and to drink alcohol on a daily basis and had fewer self-reported health conditions. At age 70-74 years, rates of all-cause mortality and total cancer incidence were 46.2% and 11.8% lower, respectively, in men and 55.5% and 18.1% lower, respectively, in women than in the general population of the same age. UK Biobank is not representative of the sampling population; there is evidence of a "healthy volunteer" selection bias. Nonetheless, valid assessment of exposure-disease relationships may be widely generalizable and does not require participants to be representative of the population at large. [ABSTRACT FROM AUTHOR]

OBJECTIVE Meta-analyses of epidemiologic studies have suggested that metformin may reduce cancer incidence, but randomized controlled trials did not support this hypothesis. RESEARCH DESIGN AND METHODS A retrospective cohort study, Clinical Practice Research Datalink, was designed to investigate the association between use of metformin compared with other antidiabetes medications and cancer risk by emulating an intention-to-treat analysis as in a trial. A total of 95,820 participants with type 2 diabetes who started taking metformin and other oral antidiabetes medications within 12 months of their diagnosis (initiators) were followed up for first incident cancer diagnosis without regard to any subsequent changes in pharmacotherapy. Cox proportional hazards models were used to estimate multivariable-adjusted hazard ratios (HR) and 95% CI. RESULTS A total of 51,484 individuals (54%) were metformin initiators and 18,264 (19%) were sulfonylurea initiators, and 3,805 first incident cancers were diagnosed during a median follow-up time of 5.1 years. Compared with initiators of sulfonylurea, initiators of metformin had a similar incidence of total cancer (HR 0.96; 95% CI 0.89-1.04) and colorectal (HR 0.92; 95% CI 0.76-1.13), prostate (HR 1.02; 95% CI 0.83-1.25), lung (HR 0.85; 95% CI 0.68-1.07), or postmenopausal breast (HR 1.03; 95% CI 0.82-1.31) cancer or any other cancer. CONCLUSIONS In this large study, individuals with diabetes who used metformin had a similar risk of developing cancer compared with those who used sulfonylureas. [ABSTRACT FROM AUTHOR]

Abstract: UK Biobank is a very large prospective study which aims to provide a resource for the investigation of the genetic, environmental and lifestyle determinants of a wide range of diseases of middle age and later life. Between 2006 and 2010, over 500,000 men and women aged 40 to 69 years were recruited and extensive data on participants'' lifestyles, environment, medical history and physical measures, along with biological samples, were collected. The health of the participants is now being followed long-term, principally through linkage to a wide range of health-related records, with validation and characterisation of health-related outcomes. Further enhancements are also underway to improve phenotype characterisation, including internet-based dietary assessment, biomarker measurements on the baseline blood samples and, in sub-samples of the cohort, physical activity monitoring and proposals for extensive brain and body imaging. UK Biobank is now available for use by all researchers, without exclusive or preferential access, for any health-related research that is in the public interest. The open-access nature of the resource will allow researchers from around the world to conduct research that leads to better strategies for the prevention, diagnosis and treatment of a wide range of life-threatening and disabling conditions. [Copyright &y& Elsevier]

Background With the exception of breast cancer, little is known about the effect of moderate intakes of alcohol, or of particular types of alcohol, on cancer risk in women. Methods A total of 1280296 middle-aged women in the United Kingdom enrolled in the Million Women Study were routinely followed for incident cancer. Cox regression models were used to calculate adjusted relative risks and 95% confidence intervals (CIs) for 21 site-specific cancers according to amount and type of alcoholic beverage consumed. All statistical tests were two-sided. Results A quarter of the cohort reported drinking no alcohol; 98% of drinkers consumed fewer than 21 drinks per week, with drinkers consuming an average of 10 g alcohol (1 drink) per day. During an average 7.2 years of follow-up per woman 68775 invasive cancers occurred. Increasing alcohol consumption was associated with increased risks of cancers of the oral cavity and pharynx (increase per 10 g/d = 29%, 95% Cl = 14% to 45%, Ptrend <.001), esophagus (22%, 95% CI = 8% to 38%, Ptrend, = .002), larynx (44%, 95% Cl = 10% to 88%, Ptrend = .008), rectum (10%, 95% CI = 2% to 18%, Ptrend = .02), liver (24%, 95% Cl = 2% to 51%, Ptrend = .03), breast (12%, 95% Cl = 9% to 14%, Ptrend <.001), and total cancer (6%, 95% Cl = 4% to 7%, Ptrend < .001). The trends were similar in women who drank wine exclusively and other consumers of alcohol. For cancers of the upper aerodigestive tract, the alcohol-associated risk was confined to current smokers, with little or no effect of alcohol among never and past smokers (Pheterogeneity < .001). Increasing levels of alcohol consumption were associated with a decreased risk of thyroid cancer (Ptrend =.005), non-Hodgkin lymphoma (Ptrend =.001), and renal cell carcinoma (Ptrend=.03) Conclusions Low to moderate alcohol consumption in women increases the risk of certain cancers. For every additional drink regularly consumed per day, the increase in incidence up to age 75 years per 1000 for women in developed countries is estimated to be about 11 for breast cancer, 1 for cancers of the oral cavity and pharynx, 1 for cancer of the rectum, and 0.7 each for cancers of the esophagus, larynx and liver, giving a total excess of about 15 cancers per 1000 women up to age 75. [ABSTRACT FROM AUTHOR]

An increasing number of people are now living with cardiovascular disease (CVD), with concomitant CVD-related hospitalizations, operations, and prescriptions. To ultimately deliver optimal cardiovascular care, access to population-based biobanks with data on multiomics, phenotypes, and lifestyle risk factors are crucial. UK Biobank is a cohort study that incorporated data between 2006 and 2010 from over half a million individuals (40 to 69 years of age) at recruitment from across the United Kingdom. As one of the most accessible, largest, and in-depth cohort studies in the world, UK Biobank continues to enhance the resource with the addition of data from various omics platforms (eg, genomics, metabolomics, proteomics), multimodal imaging, self-reported risk factors and health outcomes, and linkage to electronic health records. The vision of UK Biobank is to allow as many researchers as possible to apply their expertise and imagination to undertake research to prevent, diagnose, and treat a wide range of chronic conditions, including CVD. [ABSTRACT FROM AUTHOR]

Background: The independent effect of waist-to-height ratio (WHtR) and body fat percentage (BF%) on ischemic cardiovascular disease (CVD) remains uncertain., Objectives: This study aimed to investigate the independent associations of WHtR and BF% with ischemic CVD., Methods: This prospective cohort study used data from the UK Biobank. BF% was calculated as fat mass divided by body weight, measured by bioimpedance. Cox models estimated hazard ratios (HRs) with 95% confidence intervals (CIs) for overall and sex-specific associations of BF% and WHtR with risks of ischemic CVD and its main subtypes [myocardial infarction (MI) and ischemic stroke (IS)], adjusted for a range of potential confounders, including mutual adjustment for BF% and WHtR., Results: In total, 468,333 participants without existing CVD were included in the analysis. During 12 y of follow-up, 20,151 ischemic CVD events, 13,604 MIs, and 6681 ISs were recorded. WHtR was linearly associated with ischemic CVD, MI, and IS, with an HR per 5% increase of 1.23 (95% CI: 1.20, 1.25), 1.24 (95% CI: 1.21, 1.27), and 1.22 (95% CI: 1.18, 1.26), respectively, independent of BF%. A stronger association between WHtR and MI was seen in females than in males. The association of BF% with these outcomes was substantially attenuated in both sexes after adjustment for WHtR. For example, in females, the HR (highest compared with lowest fifth) was reduced from 1.94 (95% CI: 1.76, 2.15) to 1.04 (95% CI: 0.90, 1.01) for ischemic CVD, from 2.04 (95% CI: 1.79, 2.32) to 0.97 (95% CI: 0.81, 1.16) for MI, and from 1.81 (95% CI: 1.54, 2.13) to 1.07 (95% CI: 0.85, 1.33) for IS., Conclusions: WHtR, when used as a proxy measure for central obesity, is linearly associated with ischemic CVD in both sexes, which is independent of BF%. In contrast, the relationship of BF% with these health outcomes is predominantly driven by its correlation with WHtR., Competing Interests: Conflict of interest MW does consultancy for Amgen and Freeline outside the submitted work; no support from any organization for the submitted work; no other relationships or activities that could appear to have influenced the submitted work. All other authors report no conflicts of interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: The retina provides biomarkers of neuronal and vascular health that offer promising insights into cognitive ageing, mild cognitive impairment and dementia. This article described the rationale and methodology of eye and vision assessments with the aim of supporting the study of dementia in the UK Biobank Repeat Imaging study., Participants: UK Biobank is a large-scale, multicentre, prospective cohort containing in-depth genetic, lifestyle, environmental and health information from half a million participants aged 40-69 enrolled in 2006-2010 across the UK. A subset (up to 60 000 participants) of the cohort will be invited to the UK Biobank Repeat Imaging Study to collect repeated brain, cardiac and abdominal MRI scans, whole-body dual-energy X-ray absorptiometry, carotid ultrasound, as well as retinal optical coherence tomography (OCT) and colour fundus photographs., Findings to Date: UK Biobank has helped make significant advances in understanding risk factors for many common diseases, including for dementia and cognitive decline. Ophthalmic genetic and epidemiology studies have also benefited from the unparalleled combination of very large numbers of participants, deep phenotyping and longitudinal follow-up of the cohort, with comprehensive health data linkage to disease outcomes. In addition, we have used UK Biobank data to describe the relationship between retinal structures, cognitive function and brain MRI-derived phenotypes., Future Plans: The collection of eye-related data (eg, OCT), as part of the UK Biobank Repeat Imaging study, will take place in 2022-2028. The depth and breadth and longitudinal nature of this dataset, coupled with its open-access policy, will create a major new resource for dementia diagnostic discovery and to better understand its association with comorbid diseases. In addition, the broad and diverse data available in this study will support research into ophthalmic diseases and various other health outcomes beyond dementia., Competing Interests: Competing interests: PJF reports personal fees from Allergan, Carl Zeiss, Google/DeepMind and Santen, a grant from Alcon, outside the submitted work. PJP reports grants from Topcon Inc, outside the scope of the current report. AK reports personal fees from Abbvie, Aerie, Google Health, Novartis, Reichert, Santen and Thea, outside the submitted work. AP reports grant support for remyelination trials in multiple sclerosis to the Amsterdam University Medicam Centre, Department of Neurology, MS Centre (RESTORE trial) and UCL, London RECOVER trial; Fight for Sight (nimodipine in optic neuritis trial); royalties or licenses from Up-to-Date (Wolters Kluver) on a book chapter; speaker fees for the Heidelberg Academy; participation on Advisory Board SC Zeiss OCTA Angi-Network, SC Novartis OCTiMS study; equipment: OCTA from Zeiss (Plex Elite)., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

UK Biobank is a large-scale prospective study with deep phenotyping and genomic data. Its open-access policy allows researchers worldwide, from academia or industry, to perform health research in the public interest. Between 2006 and 2010, the study recruited 502,000 adults aged 40-69 years from the general population of the United Kingdom. At enrolment, participants provided information on a wide range of factors, physical measurements were taken, and biological samples (blood, urine and saliva) were collected for long-term storage. Participants have now been followed up for over a decade with more than 52,000 incident cancer cases recorded. The study continues to be enhanced with repeat assessments, web-based questionnaires, multi-modal imaging, and conversion of the stored biological samples to genomic and other '-omic' data. The study has already demonstrated its value in enabling research into the determinants of cancer, and future planned enhancements will make the resource even more valuable to cancer researchers. Over 26,000 researchers worldwide are currently using the data, performing a wide range of cancer research. UK Biobank is uniquely placed to transform our understanding of the causes of cancer development and progression, and drive improvements in cancer treatment and prevention over the coming decades., (© 2022. The Author(s).)

UK Biobank is an intensively characterized prospective study of 500 000 men and women, aged 40 to 69 years when recruited, between 2006 and 2010, from the general population of the United Kingdom. Established as an open-access resource for researchers worldwide to perform health research that is in the public interest, UK Biobank has collected (and continues to collect) a vast amount of data on genetic, physiological, lifestyle, and environmental factors, with prolonged follow-up of heath conditions through linkage to administrative electronic health records. The study has already demonstrated its unique value in enabling research into the determinants of common endocrine and metabolic diseases. The importance of UK Biobank, heralded as a flagship project for UK health research, will only increase over time as the number of incident disease events accrue, and the study is enhanced with additional data from blood assays (such as whole-genome sequencing, metabolomics, and proteomics), wearable technologies (including physical activity and cardiac monitors), and body imaging (magnetic resonance imaging and dual-energy X-ray absorptiometry). This unique research resource is likely to transform our understanding of the causes, diagnosis, and treatment of many endocrine and metabolic disorders., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.)

There is strong evidence of brain-related abnormalities in COVID-19 1-13 . However, it remains unknown whether the impact of SARS-CoV-2 infection can be detected in milder cases, and whether this can reveal possible mechanisms contributing to brain pathology. Here we investigated brain changes in 785 participants of UK Biobank (aged 51-81 years) who were imaged twice using magnetic resonance imaging, including 401 cases who tested positive for infection with SARS-CoV-2 between their two scans-with 141 days on average separating their diagnosis and the second scan-as well as 384 controls. The availability of pre-infection imaging data reduces the likelihood of pre-existing risk factors being misinterpreted as disease effects. We identified significant longitudinal effects when comparing the two groups, including (1) a greater reduction in grey matter thickness and tissue contrast in the orbitofrontal cortex and parahippocampal gyrus; (2) greater changes in markers of tissue damage in regions that are functionally connected to the primary olfactory cortex; and (3) a greater reduction in global brain size in the SARS-CoV-2 cases. The participants who were infected with SARS-CoV-2 also showed on average a greater cognitive decline between the two time points. Importantly, these imaging and cognitive longitudinal effects were still observed after excluding the 15 patients who had been hospitalised. These mainly limbic brain imaging results may be the in vivo hallmarks of a degenerative spread of the disease through olfactory pathways, of neuroinflammatory events, or of the loss of sensory input due to anosmia. Whether this deleterious effect can be partially reversed, or whether these effects will persist in the long term, remains to be investigated with additional follow-up., (© 2022. The Author(s).)

Background: Previous studies have yielded conflicting results on the association between human cytomegalovirus (HCMV) and cardiovascular disease (CVD). This study examined associations between HCMV and incident CVD, ischaemic heart disease (IHD) and stroke., Methods: This study included 8531 women and men of predominantly white ethnic background, aged 40-69 without prevalent CVD from the population-based UK Biobank study, recruited between 2006-2010 with HCMV antibody levels measured. CVD was ascertained via linkage to health administrative records collected until 2020. Multivariate Cox proportional-hazards models were used to determine associations between HCMV seropositivity and incident CVD, IHD and stroke. HCMV seropositive antibody levels in tertiles were used to assess dose-response associations., Results: Over a mean follow-up period of 10.2 years, HCMV seropositivity was not significantly associated with CVD (Cases = 626, Hazard Ratio [HR] =1.01, 95% confidence interval [CI], .86-1.20), IHD (Cases = 539, HR=1.03, 95% CI, .87-1.24) or stroke (Cases = 144, HR = 0.96, 95% CI, .68-1.36). There was no evidence of dose-response associations with any outcome., Conclusions: We found no significant association between HCMV seropositivity and risk of CVD, IHD or stroke. Further research within understudied populations, such as those of non-white ethnicity, and CVD subtypes is warranted., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: Dysregulation of endocrine pathways related to steroid and growth hormones may modify endometrial cancer risk; however, prospective data on testosterone, sex hormone-binding globulin (SHBG) and insulin-like growth factor (IGF)-1 are limited. To elucidate the role of these hormones in endometrial cancer risk we conducted complementary observational and Mendelian randomization (MR) analyses., Methods: The observational analyses included 159,702 women (80% postmenopausal) enrolled in the UK Biobank. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models. For MR analyses, genetic variants associated with hormone levels were identified and their association with endometrial cancer (12,906 cases/108,979 controls) was examined using two-sample MR., Results: In the observational analysis, higher circulating concentrations of total (HR per unit inverse normal scale = 1.38, 95% CI = 1.22-1.57) and free testosterone (HR per unit log scale = 2.07, 95% CI = 1.66-2.58) were associated with higher endometrial cancer risk. An inverse association was found for SHBG (HR per unit inverse normal scale = 0.76, 95% CI = 0.67-0.86). Results for testosterone and SHBG were supported by the MR analyses. No association was found between genetically predicted IGF-1 concentration and endometrial cancer risk., Conclusions: Our results support probable causal associations between circulating concentrations of testosterone and SHBG with endometrial cancer risk., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Antibodies against the HPV16 oncoprotein E6 are promising biomarkers for HPV16-driven oropharyngeal cancer (HPV16-OPC) due to their high sensitivity and specificity, and prospective manifestation. In previous studies, 0•7% of controls without HPV-associated malignancies were HPV16 E6 seropositive of which only a minority is expected to develop HPV16-driven cancer. We aimed to characterise HPV16 E6 antibodies in individuals without HPV-associated malignancies., Methods: We analysed serum antibodies against HPV16 E6, E7, L1 and HPV18 L1 in a random sample (n = 9,695) of the prospective UK Biobank cohort (UKB). Excluding individuals with potentially HPV-associated malignancies (n = 192), we assessed risk factors for seropositivity by logistic regression., Findings: In individuals without potentially HPV-associated malignancies (n = 9,503), the HPV16 E6 seroprevalence was 0•8%. Seropositivity against HPV16 E6 and all other HPV antigens was strongly associated with sexual behaviour. The seroprevalence of HPV16 E6, L1 and HPV18 L1 increased with the number of lifetime sex partners (p trend <0•005), and all HPV antibodies were associated with same-sex intercourse (OR E6 3•1, 95%CI 1•4-6•9; reference category: no same-sex intercourse). HPV16 E6 and L1 seropositivity were associated with young age (≤17 years) at sexual debut (OR E6 2•0, 95%CI 1•1-3•7) compared with individuals reporting sexual debut at age ≥20 years., Interpretation: This is the first study characterising HPV16 E6 antibodies in the general UK population. Their strong association with sexual behaviour, and overlapping risk factor profiles with other HPV antibodies support their relevance for HPV16-OPC disease prediction. However, additional risk stratification will be required to identify individuals at highest risk to develop HPV16-OPC., Competing Interests: Declaration of Competing Interest Dr. Brenner, Dr. Mentzer, Dr. Hill, Dr. Almond, Dr. Allen and Dr. Pawlita have nothing to disclose. Dr. Waterboer reports personal fees from MSD (Merck) Sharp & Dohme, outside the submitted work., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Although prostate cancer is a leading cause of cancer death, its aetiology is not well understood. We aimed to identify novel biochemical factors for prostate cancer incidence and mortality in UK Biobank., Methods: A range of cardiovascular, bone, joint, diabetes, renal and liver-related biomarkers were measured in baseline blood samples collected from up to 211,754 men at recruitment and in a subsample 5 years later. Participants were followed-up via linkage to health administrative datasets to identify prostate cancer cases. Hazard ratios (HRs) and 95% confidence intervals were calculated using multivariable-adjusted Cox regression corrected for regression dilution bias. Multiple testing was accounted for by using a false discovery rate controlling procedure., Results: After an average follow-up of 6.9 years, 5763 prostate cancer cases and 331 prostate cancer deaths were ascertained. Prostate cancer incidence was positively associated with circulating vitamin D, urea and phosphate concentrations and inversely associated with glucose, total protein and aspartate aminotransferase. Phosphate and cystatin-C were the only biomarkers positively and inversely, respectively, associated with risk in analyses excluding the first 4 years of follow-up. There was little evidence of associations with prostate cancer death., Conclusion: We found novel associations of several biomarkers with prostate cancer incidence. Future research will examine associations by tumour characteristics.

Objective: In UK Biobank (UKB), a large population-based prospective study, cases of many diseases are ascertained through linkage to routinely collected, coded national health datasets. We assessed the accuracy of these for identifying incident strokes., Methods: In a regional UKB subpopulation (n = 17,249), we identified all participants with ≥1 code signifying a first stroke after recruitment (incident stroke-coded cases) in linked hospital admission, primary care, or death record data. Stroke physicians reviewed their full electronic patient records (EPRs) and generated reference standard diagnoses. We evaluated the number and proportion of cases that were true-positives (i.e., positive predictive value [PPV]) for all codes combined and by code source and type., Results: Of 232 incident stroke-coded cases, 97% had EPR information available. Data sources were 30% hospital admission only, 39% primary care only, 28% hospital and primary care, and 3% death records only. While 42% of cases were coded as unspecified stroke type, review of EPRs enabled a pathologic type to be assigned in >99%. PPVs (95% confidence intervals) were 79% (73%-84%) for any stroke (89% for hospital admission codes, 80% for primary care codes) and 83% (74%-90%) for ischemic stroke. PPVs for small numbers of death record and hemorrhagic stroke codes were low but imprecise., Conclusions: Stroke and ischemic stroke cases in UKB can be ascertained through linked health datasets with sufficient accuracy for many research studies. Further work is needed to understand the accuracy of death record and hemorrhagic stroke codes and to develop scalable approaches for better identifying stroke types., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: Fluid intake and diet are thought to influence kidney stone risk. However, prospective studies have been limited to small samples sizes and/or restricted measures., Objective: To investigate whether fluid intake and dietary factors are associated with the risk of developing a first kidney stone., Design, Setting, and Participants: Participants were selected from UK Biobank, a population-based prospective cohort study., Outcome Measurements and Statistical Analysis: Cox proportional hazards models were used to investigate the association between fluid intake and dietary factors and the risk of a first incident kidney stone, ascertained from hospital inpatient records., Results and Limitations: After exclusion, 439 072 participants were available for the analysis, of whom 2057 had hospital admission with an incident kidney stone over a mean of 6.1 yr of follow-up. For every additional drink (200 ml) consumed per day of total fluid, the risk of kidney stones declined by 13% (hazard ratio [HR] = 0.87, 95% confidence interval [CI] 0.85-0.89). Similar patterns of associations were observed for tea, coffee, and alcohol, although no association was observed for water intake. Fruit and fibre intake was also associated with a lower risk (HR per 100 g increase of fruits per day = 0.88, 95% CI 0.83-0.93, and HR per 10 g fibre per day = 0.82, 95% CI 0.77-0.87), whereas meat and salt intake was associated with a higher risk (HR per 50 g increase in meat per week = 1.17, 95% CI 1.05-1.29, and HR for always vs never/rarely added salt to food = 1.33, 95% CI 1.12-1.58). Vegetable, fish, and cheese intake was not associated with kidney stone risk., Conclusions: The finding that high intake of total fluid, fruit, and fibre was associated with a lower risk of hospitalisation for a first kidney stone suggests that modifiable dietary factors could be targeted to prevent kidney stone development., Patient Summary: We found that higher intake of total fluid, specifically tea, coffee, and alcohol (but not water), and consumption of fruit and foods high in fibre are linked with a reduced likelihood of developing kidney stones., (Copyright © 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

UK Biobank (UKB) is an international health resource enabling research into the genetic and lifestyle determinants of common diseases of middle and older age. It comprises 500 000 participants. Public Health England's Second Generation Surveillance System is a centralized microbiology database covering English clinical diagnostics laboratories that provides national surveillance of legally notifiable infections, bacterial isolations and antimicrobial resistance. We previously developed secure, pseudonymized, individual-level linkage of these systems. In this study, we implemented rapid dynamic linkage, which allows us to provide a regular feed of new COVID-19 (SARS-CoV-2) test results to UKB to facilitate rapid and urgent research into the epidemiological and human genetic risk factors for severe infection in the cohort. Here, we have characterized the first 1352 cases of COVID-19 in UKB participants, of whom 895 met our working definition of severe COVID-19 as inpatients hospitalized on or after 16 March 2020. We found that the incidence of severe COVID-19 among UKB cases was 27.4 % lower than the general population in England, although this difference varied significantly by age and sex. The total number of UKB cases could be estimated as 0.6 % of the publicly announced number of cases in England. We considered how increasing case numbers will affect the power of genome-wide association studies. This new dynamic linkage system has further potential to facilitate the investigation of other infections and the prospective collection of microbiological cultures to create a microbiological biobank (bugbank) for studying the interaction of environment, human and microbial genetics on infection in the UKB cohort.

UK Biobank is a population-based cohort of half a million participants aged 40-69 years recruited between 2006 and 2010. In 2014, UK Biobank started the world's largest multi-modal imaging study, with the aim of re-inviting 100,000 participants to undergo brain, cardiac and abdominal magnetic resonance imaging, dual-energy X-ray absorptiometry and carotid ultrasound. The combination of large-scale multi-modal imaging with extensive phenotypic and genetic data offers an unprecedented resource for scientists to conduct health-related research. This article provides an in-depth overview of the imaging enhancement, including the data collected, how it is managed and processed, and future directions.

Purpose: To describe the rationale, methods and research potential of eye and vision measures available in UK Biobank., Participants: UK Biobank is a large, multisite, prospective cohort study. Extensive lifestyle and health questionnaires, a range of physical measures and collection of biological specimens are collected. The scope of UK Biobank was extended midway through data collection to include assessments of other measures of health, including eyes and vision. The eye assessment at baseline included questionnaires detailing past ophthalmic and family history, measurement of visual acuity, refractive error and keratometry, intraocular pressure (IOP), corneal biomechanics, spectral domain optical coherence tomography (OCT) of the macula and a disc-macula fundus photograph. Since recruitment, UK Biobank has collected accelerometer data and begun multimodal imaging data (including brain, heart and abdominal MRI) in 100 000 participants. Dense genotypic data and a panel of 20 biochemistry measures are available, and linkage to medical health records for the full cohort has begun., Findings to Date: A total of 502 665 people aged between 40 and 69 were recruited to participate in UK Biobank. Of these, 117 175 took part in baseline assessment of vision, IOP, refraction and keratometry. A subgroup of 67 321 underwent OCT and retinal photography. The introduction of eye and vision measures in UK Biobank was accompanied by intensive training, support and a data monitoring quality control process., Future Plans: UK Biobank is one of the largest prospective cohorts worldwide with extensive data on ophthalmic diseases and conditions. Data collection is an ongoing process and a repeat of the baseline assessment including the questionnaires, measurements and sample collection will be performed in subsets of 25 000 participants every 2-3 years. The depth and breadth of this dataset, coupled with its open-access policy, will create a powerful resource for all researchers to investigate the eye diseases in later life., Competing Interests: Competing interests: This analysis was supported by the Eranda Foundation via the International Glaucoma Association in the design and conduct of the study. The UCL ORS and GRS programmes provided scholarship support for ZM, PTK, PJF, and PP and SYLC received salary support from the NIHR BRC at Moorfields Eye Hospital. PJF received support from the Richard Desmond Charitable Trust, via Fight for Sight, London. PJF reports personal fees from Allergan, Carl Zeiss, Google/DeepMind and Santen, a grant from Alcon, outside the submitted work., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: To estimate the number of new cases of age-related macular degeneration, cataract and glaucoma accruing in the UK Biobank cohort, over a period of 25 years from time of recruitment. Our secondary objective was to assess the statistical power of nested case-control studies of these eye diseases. We aimed to provide quantitative information relevant to UK Biobank's eye disease case ascertainment efforts and to the potential for UK Biobank-based research into the causes of eye disease., Methods: We constructed a Markov discrete-time state transition model to simulate the population dynamics of the eye disorders within the UK Biobank cohort, using prevalence data from population-based epidemiological studies to derive incidence, and Office for National Statistics data on mortality and migration overseas., Results: By 2023, >900 new cases of each of 'wet' (neovascular) and 'dry' age-related macular degeneration, >1200 cases of primary open angle glaucoma and almost 15 000 cases of cataracts are expected to have accrued in the subcohort of 68 500 participants who had ocular assessment at baseline, with around seven times as many cases of each disease in the whole cohort of 500 000 participants. These predicted incident case numbers generate good or substantial statistical power for a range of nested case-control studies of potential genetic, lifestyle and environmental determinants of disease., Conclusions: Over the next few years, UK Biobank is expected to generate sufficient numbers of new cases for statistically well-powered studies of the determinants of the major causes of sight loss: age-related macular degeneration, vision-impairing cataract and glaucoma., Competing Interests: Competing interests: DCM and AR received grant funding from UK Biobank for this work. NA is Senior Epidemiologist for UK Biobank and receives support from UKB for some of her academic time. CS is UK Biobank’s Chief Scientist and receives support from UKB for some of her academic time. She is a member of the Steering Group for the Dementias Platform UK and leads on its outcomes adjudication. She also receives some funding from the Scottish Funding Council., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

The UK Biobank project is a prospective cohort study with deep genetic and phenotypic data collected on approximately 500,000 individuals from across the United Kingdom, aged between 40 and 69 at recruitment. The open resource is unique in its size and scope. A rich variety of phenotypic and health-related information is available on each participant, including biological measurements, lifestyle indicators, biomarkers in blood and urine, and imaging of the body and brain. Follow-up information is provided by linking health and medical records. Genome-wide genotype data have been collected on all participants, providing many opportunities for the discovery of new genetic associations and the genetic bases of complex traits. Here we describe the centralized analysis of the genetic data, including genotype quality, properties of population structure and relatedness of the genetic data, and efficient phasing and genotype imputation that increases the number of testable variants to around 96 million. Classical allelic variation at 11 human leukocyte antigen genes was imputed, resulting in the recovery of signals with known associations between human leukocyte antigen alleles and many diseases.

Regular physical activity is believed to have a beneficial effect on bone health but may also increase the risk of fractures by increasing the incidence of injury. We examined the association between physical activity and fracture risk in a prospective study of self-reported incident fractures among 34 696 men and women aged 20 to 89 years in the United Kingdom. Over an average of 5.2 years of follow-up, 343 men and 1555 women reported one or more fractures. For the 72% of fractures caused by a fall, the only significant association with physical activity was the lower fracture rate among women with a standing occupation compared with women in sedentary or no employment [incidence rate ratio, 0.81 (95% CI, 0.69-0.95)]. There was a strong positive association between bicycling and fracture risk: P < 0.001 for trend for both sexes. Regular participation in exercise and sports other than walking and bicycling was also associated with an increased fracture risk, and fracture rates were significantly higher for male manual workers compared with men in sedentary or no employment. These positive associations of physical activity with fracture risk applied primarily to fractures not caused by a fall. The relatively low fracture risk among women with a standing occupation might be the result of a beneficial effect of weight-bearing exercise. The markedly increased risk of fractures associated with bicycling, and the moderately increased risk associated with other exercise and sports, are probably the result of an increased incidence of injury.