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IntroductionElectrocardiographic (ECG) markers of ventricular depolarisation and repolarisation are associated with an increased risk of arrhythmia and sudden cardiac death. Our prior work indicated lower serum calcium concentrations are associated with longer QT and JT intervals in the general population. Here, we investigate whether serum calcium is a causal risk factor for changes in ECG measures using Mendelian Randomisation (MR).MethodsWe performed a new genome-wide association study (GWAS) for serum calcium in >300,000 European-ancestry participants from UK-Biobank. Independent lead variants were extracted to be used as instrumental variables (figure 1). Two-sample MR analyses were performed to approximate the causal effect of serum calcium on QT, JT and QRS intervals using an inverse-weighted method in 76,226 UK-Biobank participants with ECG data, not contributing to the serum calcium GWAS. A secondary analysis wase performed using lead variants from a calcium GWAS corrected for serum albumin. Sensitivity analyses were performed using contemporary methods to test for the presence of horizontal pleiotropy.Results205 independent lead calcium-associated variants were used as instrumental variables for Mendelian Randomisation. A decrease of 0.1 mmol/L genetically-determined serum calcium, was associated with longer QT (3.01ms (95% CI 2.03, 3.99)) and JT (2.89ms (1.91, 3.87)) intervals. A weak association was observed for QRS duration in secondary analyses only (0.39ms (0.08, 0.69)). Results were concordant in all sensitivity analyses.Abstract BS8 Figure 1ConclusionThese analyses support a causal effect of serum calcium levels on ventricular repolarisation, in a middle-aged population of European-ancestry where serum calcium concentrations are likely stable and chronic. Modulation of calcium concentration may therefore directly influence cardiovascular disease risk. Further research into the effects of serum calcium concentration on arrhythmogenesis is warranted and calcium variants could be considered for inclusion in genetic risk score models for predictive testing.Conflict of InterestNone

BackgroundExisting evidence concerning the relationship between daytime napping and type 2 diabetes (T2D) is inconsistent, and whether the effects of napping differ by body fat percentage (BFP) and C‐reactive protein (CRP) is unclear. We aimed to investigate the association between daytime napping frequency and T2D risk and whether such an association was modified by BFP and CRP.MethodsWe included 435 342 participants free of diabetes from the UK Biobank. Participants were categorized as nonnappers, occasional nappers, and frequent nappers based on napping frequency, and BFP/CRP was divided into quartiles. Cox proportional hazards models were used.ResultsDuring a median follow‐up of 9.2 years, 17 592 T2D cases occurred. Higher frequency of daytime napping was significantly associated with an increased risk of T2D. Compared with nonnappers, the adjusted hazard ratios (HRs) for occasional nappers and habitual nappers were 1.28 (95% confidence interval [CI]: 1.24–1.32) and 1.49 (95% CI: 1.41–1.57), respectively. There was a significant additive and multiplicative interaction (relative excess risk due to interaction [RERI] = 0.490, 95% CI 0.307–0.673; p for multiplicative interaction <.001) between napping and BFP, whereby a higher hazard of T2D associated with more frequent napping was greatest among participants in the highest BFP quartile (HR = 4.45, 95% CI: 3.92–5.06). The results for CRP were similar (RERI = 0.266, 95% CI: 0.094–0.439; p for multiplicative interaction <.001).ConclusionsHigher daytime napping frequency is associated with an increased T2D risk, and such relationships are modified by BFP and CRP. These findings underscore the importance of adiposity and inflammation control to mitigate diabetes risk.

Introduction Shift work may disrupt sleep and circadian rhythms, leading to adverse health outcomes. The objective of this study is to examine whether performing shift work is associated with frailty in middle- to older-aged adults. Methods We examined current shift work exposure and frailty risk in 242,126 UK Biobank participants (38-71 years old; 128,595 females). Using the baseline self-reported employment information, participants were categorized as shift workers (with ‘work schedule that falls outside of the normal daytime working hours of 9am-5pm’) or day workers if no shift work schedule. Based on a previously validated approach, frailty phenotype was identified when three or more of the following five criteria were fulfilled: self-reported weight loss, exhaustion, low physical activity, slow walking pace, and measured low grip strength. Multivariate logistic regression models were used to assess the association between shift work and frailty. Results Among 242,126 participants, 201,489 (83.2%) were day workers and 40,637 (16.8%) shift workers. Frailty was identified in 4,308 participants (1.8%), including 3,312 day workers (1.6%) and 996 shift workers (2.5%). Compared with day workers, shift workers were at higher risk for frailty after adjusting age, sex, and ethnicity, i.e., odds ratio (OR) =1.58 [95% CI, 1.47-1.70] (p < 0.0001). The effect of shift work appeared to be more pronounced in 5,659 permanent night shift workers (OR = 1.98 [95% CI, 1.68-2.32], p < 0.0001). The differences between day workers and shift workers persisted even after further adjusting for social economic status, sleep duration, and chronotype (OR = 1.38 [95% CI, 1.28-1.48] for all shift workers; OR = 1.53 [95% CI, 1.30-1.80] for permanent night shift workers, both p values < 0.0001). Conclusion Middle- to older-aged adults who were currently performing shift work, especially those permanent night shift workers, were more likely to be frail. Longitudinal and interventional studies are warranted to elucidate the causal relationship between shift work and the risk of frailty. Support (if any) BrightFocus Foundation (A2020886S), NIH (RF1AG059867, RF1AG064312)

PurposeThe Liverpool Research Eye Biobank (LREB) collects tissue for researchers who wish to study a wide range of ophthalmic conditions and develop new and more effective treatments. Historically the LREB has collected whole globes and conjunctiva from cadaveric donors but in 2021 we expanded to start collecting tissues from living donors who were undergoing ophthalmic surgery in the St Paul’s Eye Unit in Liverpool. The aim was to provide tissue and fluid samples from patients with specific eye disease to research projects and create a bank of ophthalmic samples that can be provided to future research projects. Here we reflect on our experience after a year of collections.MethodsThe clinical team discuss donation with patients during the pre-op appointment. Consent is taken on the day of surgery using an electronic consent form available on PENS. Samples are taken according to the patient’s consent preference and then stored appropriately within a fridge/freezer close to theatre. Samples are then transferred for processing to the University of Liverpool (UoL). Fluids such as aqueous and vitreous are preserved at -80°C. The majority of ocular tissue collected is preserved by fixing in 10% neutral buffered formalin then transferred to 70% ethanol for long term storage. On request samples have been preserved using alternative methods such as snap freezing in liquid nitrogen. All samples are logged using a laboratory information management system.ResultsCollections depend on the cooperation of the clinical teams and we have had very good engagement from them. The UoL works closely with St Pauls Eye Unit and the physical proximity between the two has been helpful. The location of the storage fridges close to theatre is important to limit extra effort for busy clinical teams. Regular training of consenters was key to ensure compliance with SOPs. In 11 months, we consented 419 donors and collected 673 samples including corneal tissue, iris, sclera, lens/capsule, retinal membranes, tenons, muscle, aqueous, vitreous, blood.ConclusionAfter the success of collections from one site we plan to expand to collect from multiple sites including Aintree and Alder Hey Children’s Hospital.

BackgroundRisk factors for heart failure (HF) are more prevalent among South Asians (SA). It is unclear whether this translates to a higher risk of HF. Some evidence suggests that there are baseline cardiovascular differences between SA and White Europeans (WE), however this has been previously based on echocardiography imaging which is less accurate compared to cardiac magnetic resonance (CMR).AimsTo investigate the differences in left ventricular (LV) volumes, cardiac output, CO, (both determined by CMR), incidence of HF and risk of HF between SA and WE, in a cohort without cardiovascular disease (CVD).MethodsThe core cohort (502,655) was derived from the UK Biobank prospective study. Data from the CMR sub-study (39,703) were used which utilised a 1.5 Tesla scanner and an automated scan analyser. Participants with a history of CVD and loop diuretic use were excluded. Baseline characteristics, including demographics, comorbidities, and biomarkers, were compared. LV volumes and CO were compared, and linearly regressed for an association with SA ethnicity. HF incidence rates were calculated from new HF hospitalisations (ICD10 codes: I50.0, I50.1, I50.9, I11.0, I13.0 and I13.2). Cox-proportional hazards analysis determined comparative risk of developing HF.ResultsNinety-four (1.3%) of SA had HF and 4,218 (1.0%) of WE had HF. Higher proportions of WE with HF had elevated levels of cholesterol and smoking history (e.g.: 41.2% vs. 11.7% of SA with HF, p<0.0001). Higher proportions of SA with HF had hypertension and type 2 diabetes (33.0% vs. 9.0%, p<0.0001) and duration of diabetes (13 years vs. 7 years, p=0.0018). All indexed LV parameters were smaller after adjustment for prevalent risk factors (e.g.: LV end diastolic volume reduced by 20.7 ml, p<0.0001). A trend for a higher risk of HF was present in SA, which was attenuated by cholesterol (HR: 1.25, p=0.072 and HR: 1.11, p=0.450).ConclusionA trend for a higher risk of HF is present in SA, potentially due to cholesterol and smaller cardiac structures promoting myocardial strain in maintaining ejection fraction. Future research should determine causes of new HF events and confirm subtypes.

This thesis provides a set of tools for analysing random images with a specific focus on applications in functional Magnetic Resonance Imaging (fMRI). To do so we employ Random Field Theory (RFT), a set of theoretical parametric results that can be used to analyse multidimensional random processes (known as random fields), and resampling methods, which draw samples from the data (with or without replacement). We extend the voxelwise inference framework of Worsley et al so that it provides accurate control of the familywise error rate in neuroimaging. We drop the standard RFT assumptions of high smoothness and stationarity and develop a quick parametric framework that provides powerful and valid inference even when the underlying data is non-Gaussian. We validate this using a massive resting state analysis, involving brain imaging data from 7000 subjects from the UK Biobank. We further use RFT techniques to derive an asymptotic distribution for the extent of a cluster above a threshold u in a non-stationary Gaussian random field as u → ∞. To do so we define the notion of horizontal-window (HW) conditioning and take advantage of recent advances (Cheng and Schwartzman (2015a)) on the HW-distribution of the height of a peak in a non-stationary Gaussian random field. Our results extend those of Nosko (1969) in which the asymptotic cluster size distribution is derived under the assumption of stationarity. In order to infer upon random fields whose mean is non-zero we derive asymptotic confidence regions for the location of a peak of the true signal given multiple realizations of random fields. These results are valid under non-stationarity and are derived using the theory of extremum estimators. Under the assumption of stationarity we improve upon these asymptotic results using a Monte Carlo approach that provides confidence regions for peaks of the mean which have better coverage in the finite sample. A second quantity of interest when considering fields whose mean is non-zero is the height of the true signal at the location of a peak in the observed random field. These peaks are typically subject to the winner's curse, which causes inflated effect sizes at peak locations (Vul et al., 2009). We develop a resampling based procedure that obtains low bias estimates of the true signal at the location of the peak. We validate this using task data from over 8000 subjects from the UK Biobank, setting aside 4000 subjects to compute a ground truth, and dividing the remaining subjects into small samples on which to test the results.

Introduction It is well known that the prevalence of clinical and subclinical sleep issues is quite high, with a great economic and social burden on the society. As it is expected that the numbers of people suffering from clinical and subclinical sleep problems will increase in the coming years, new primary and/or complementary methods to improve and prevent poor sleep health across the population are urgently needed. In the current study, we aimed to conduct the largest investigation of diet and sleep health to date, through systematically examining the UK Biobank (UKB) data to find out whether diet quality and food groups play a role on sleep health. Methods This cross-sectional population-based study involved 502,494 participants. UKB food frequency and sleep questionnaires at baseline were used. Also, healthy diet, healthy sleep, and partial fibre intake scores were created. ANCOVA and regression models were used to examine the associations of healthy diet and dietary fibre intake scores with sleep health. Adjusted models included age, sex, BMI, and mental health symptomatology. Results We showed that both healthy diet and high partial fibre intake scores were associated with increased healthy sleep scores. Also, higher intakes of vegetables, fruits, fish, and unprocessed red meat were found to be associated with increased healthy sleep scores. On the other hand, processed meat intake was inversely associated with sleep health. Conclusion A healthy dietary pattern, and food groups (vegetables, fruits, fish, water) and nutrients (fibre) that are consumed as a part of a healthy dietary pattern were associated with better sleep health. Further work is needed to identify underlying mechanisms behind the impact of diet on sleep health. Support (if any) Acknowledgements: This research has been conducted using the UK Biobank Resource under Application Number ‘61818’. Funding: Funds received from Unilever UK Central Resources Limited to cover application fees.

Cross-sectional and longitudinal observational studies have shown that higher levels of testosterone are associated with better lung function in men and a small attenuation of lung function decline in women. We used multivariable Mendelian randomization (MVMR), which is not affected by classical confounding, to assess the independent causal effect of total testosterone (TT) and sex hormone-binding globulin (SHBG) on lung function (FVC and FEV1/FVC) in men and women.To select SNPs associated with TT and SHBG for MR, we performed genome-wide association studies and replicated results in independent UK Biobank samples (N=323,144/161,572). SNPs were considered replicated with same direction of effect and p-value < Bonferroni corrected p-value. For each replicated SNP, we estimated the effect on pre-bronchodilator lung function in UK Biobank (N=341,826) separately by sex adjusting for age, age2, height, genotyping batch, and centre and accounting for population stratification/relatedness (BOLT-LMM). We used several MVMR methods to investigate and adjust for pleiotropy. We performed subgroup analyses by level of moderate physical activity and by menopausal status in women. To assess a possible source of pleiotropy, we removed 25 SNPs associated with weight/obesity related outcomes.For TT, we replicated 63 SNP in females and 92 SNPs in males, and 308 SNPs were associated with SHBG in both sexes. In women, the MVMR analyses suggest that a natural log increase in TT is associated with a 33.9 mL increase in FVC independently of SHBG (figure 1A). Stratified analyses showed a beneficial effect of SHBG on FVC in physically active and post-menopausal women. In males, the MVMR analyses suggest that a log increase in SHBG is associated with 0.62% lower FEV1/FVC and 54.6 mL higher FVC independently of TT (figure 1A/B). However, no associations were found with TT in males in the main analysis nor subgroup analyses. For all analyses there was an indication of high heterogeneity (Q statistic p-value <0.0001), however results remained similar after removing SNPs associated with weight/obesity.Our MR analyses show that higher hormone levels are associated with better lung function, with higher TT levels being beneficial for FVC in women and higher SHBG levels being beneficial for FVC in males.Abstract T2 Figure 1The association of total testosterone (TT) and sex hormone-binding (SHBG) with FVC (A) and FEV:/FVC (B) in MVMR analyses separately per sex. Effect estimates show the difference in lung function (mL or%) per log increase in hormone level for 4 MR methods: Two-Stage Least Squares regression (2SLS), fixed-effect (F-IVW) and random-effect (R-IVW) inverse variance-weighted (IVW) meta-analysis; and MR-Egger.

Introduction and ObjectivesEosinophilic inflammation is recognised to play an important role in asthma. This is reflected in the recent British Thoracic Society (BTS) guidelines which focus on assessing fortype 2 inflammation, particularly elevated eosinophil count,when making a diagnosis of asthma. We investigated the pattern of eosinophilic inflammation in patients with asthma and chronic obstructive pulmonary disease (COPD) in the UK biobank.MethodsUK Biobank participants were screened for a coded diagnosis of asthma, COPD or asthma/COPD overlap at baseline or in linked clinical records. We recorded the highest ever eosinophil count taken since the year preceding diagnosis. Participants were separated into three groups: highest recorded eosinophil count ≥ 0.3 x 109/L, >0.15 and <0.3 x 109/L, and ≤0.15 x 109/L. This was compared to control data from participants without diagnosed asthma/COPD. Demographics and summary results are described in table 1.ResultsIn total there were 33191 patients with asthma, 8130 patients with COPD, and 6915 with both diagnoses. When taking the highest recorded value, 9761 (29.4%) patients with asthma, 2620 (32.2%) patients with COPD, and 2404 (34.8%) patients with both diagnoses had an eosinophil count ≥ 0.3 x 109/L. This was compared to 411382 controls, of whom 93781 (22.8%) had an eosinophil count ≥ 0.3 x 109/L.Abstract P301 Table 1Demographics and highest recorded eosinophil count of study participantsConclusionsRates of eosinophilic inflammation were similar in patients with asthma, COPD and asthma plus COPD. This suggests that there may be shared treatable traits across disease boundaries. The high rate of eosinophilic inflammation in COPD is particularly relevant given recent interest in monoclonal antibody therapy for COPD patients and suggests that a significant proportion of patients may be eligible for such treatment.It is evident from this data that elevated eosinophil count is a poor discriminator between asthma and COPD. Clinicians should be mindful of this, especially in the context of recent BTS asthma guidelines which may prompt a diagnosis of asthma in the setting of elevated eosinophil count. 70.6% of asthma patients have never had high eosinophils, emphasising the role of eosinophil count as a rule-in rather than rule-out test for asthma, with a low diagnostic sensitivity.