Search

Background: The Medical Certificate of Stillbirth (MCS) records data about a baby's death after 24 weeks of gestation but before birth. Major errors that could alter interpretation of the MCS were widespread in two UK-based regional studies., Methods: A multicentre evaluation was conducted, examining MCS issued 1 January 2018 to 31 December 2018 in 76 UK obstetric units. A systematic case-note review of stillbirths was conducted by Obstetric and Gynaecology trainees, generating individual 'ideal MCSs' and comparing these to the actual MCS issued. Anonymized central data analysis described rates and types of error, agreement and factors associated with major errors., Results: There were 1120 MCSs suitable for assessment, with 126 additional submitted data sets unsuitable for accuracy analysis (total 1246 cases). Gestational age demonstrated 'substantial' agreement [K = 0.73 (95% CI 0.70-0.76)]. Primary cause of death (COD) showed 'fair' agreement [K = 0.26 (95% CI 0.24-0.29)]. Major errors [696/1120; 62.1% (95% CI 59.3-64.9%)] included certificates issued for fetal demise at <24 weeks' gestation [23/696; 3.3% (95% CI 2.2-4.9%)] or neonatal death [2/696; 0.3% (95% CI 0.1-1.1%)] or incorrect primary COD [667/696; 95.8% (95% CI 94.1-97.1%)]. Of 540/1246 [43.3% (95% CI 40.6-46.1%)] 'unexplained' stillbirths, only 119/540 [22.0% (95% CI 18.8-25.7%)] remained unexplained; the majority were redesignated as either fetal growth restriction [FGR: 195/540; 36.1% (95% CI 32.2-40.3%)] or placental insufficiency [184/540; 34.1% (95% CI 30.2-38.2)]. Overall, FGR [306/1246; 24.6% (95% CI 22.3-27.0%)] was the leading primary COD after review, yet only 53/306 [17.3% (95% CI 13.5-22.1%)] FGR cases were originally attributed correctly., Conclusion: This study demonstrates widespread major errors in MCS completion across the UK. MCS should only be completed following structured case-note review, with particular attention on the fetal growth trajectory., (© The Author(s) 2022. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Good data curation is integral to cohort studies, but it is not always done to a level necessary to ensure the longevity of the data a study holds. In this opinion paper, we introduce the concept of data curation debt-the data curation equivalent to the software engineering principle of technical debt. Using the context of UK cohort studies, we define data curation debt-describing examples and their potential impact. We highlight that accruing this debt can make it more difficult to use the data in the future. Additionally, the long-running nature of cohort studies means that interest is accrued on this debt and compounded over time-increasing the impact a debt could have on a study and its stakeholders. Primary causes of data curation debt are discussed across three categories: longevity of hardware, software and data formats; funding; and skills shortages. Based on cross-domain best practice, strategies to reduce the debt and preventive measures are proposed-with importance given to the recognition and transparent reporting of data curation debt. Describing the debt in this way, we encapsulate a multi-faceted issue in simple terms understandable by all cohort study stakeholders. Data curation debt is not only confined to the UK, but is an issue the international community must be aware of and address. This paper aims to stimulate a discussion between cohort studies and their stakeholders on how to address the issue of data curation debt. If data curation debt is left unchecked it could become impossible to use highly valued cohort study data, and ultimately represents an existential risk to studies themselves. [ABSTRACT FROM AUTHOR]

Background: Coffee consumption has been associated with several adverse pregnancy outcomes, although data from randomized-controlled trials are lacking. We investigate whether there is a causal relationship between coffee consumption and miscarriage, stillbirth, birthweight, gestational age and pre-term birth using Mendelian randomization (MR).Methods: A two-sample MR study was performed using summary results data from a genome-wide association meta-analysis of coffee consumption (N = 91 462) from the Coffee and Caffeine Genetics Consortium. Outcomes included self-reported miscarriage (N = 49 996 cases and 174 109 controls from a large meta-analysis); the number of stillbirths [N = 60 453 from UK Biobank (UKBB)]; gestational age and pre-term birth (N = 43 568 from the 23andMe, Inc cohort) and birthweight (N = 297 356 reporting own birthweight and N = 210 248 reporting offspring's birthweight from UKBB and the Early Growth Genetics Consortium). Additionally, a one-sample genetic risk score (GRS) analysis of coffee consumption in UKBB women (N up to 194 196) and the Avon Longitudinal Study of Parents and Children (N up to 6845 mothers and 4510 children) and its relationship with offspring outcomes was performed.Results: Both the two-sample MR and one-sample GRS analyses showed no change in risk of sporadic miscarriages, stillbirths, pre-term birth or effect on gestational age connected to coffee consumption. Although both analyses showed an association between increased coffee consumption and higher birthweight, the magnitude of the effect was inconsistent.Conclusion: Our results suggest that coffee consumption during pregnancy might not itself contribute to adverse outcomes such as stillbirth, sporadic miscarriages and pre-term birth or lower gestational age or birthweight of the offspring. [ABSTRACT FROM AUTHOR]

Background Intake of macronutrients and its components are associated with mortality and morbidity. Isocaloric substitution analysis is a tool to examine how changing the source of energy intake (e.g. from saturated to monounsaturated fat) is associated with health. However, conventional methods assume linearity, which may be untrue in many cases. This paper presents a nonlinear alternative, using UK Biobank data as an example data set. Methods Nonlinear isocaloric substitution analysis was conducted using penalised cubic splines in Cox proportional hazard models. In the UK Biobank, 195,658 participants completed at least one dietary questionnaire and were included in the analyses. Diet was assessed using the Oxford WebQ, a web-based 24-hour recall questionnaire. Prospective all-cause mortality was derived from on linked death records. Results More than half of the associations between macronutrient intake and all-cause mortality were nonlinear. Nonlinear isocaloric substitution analysis provides effect sizes conditional on the current intake, while conventional analysis provides an average over the whole range of intake. For example, conventional isocaloric substitution estimated no effect of replacing sugar with starch. However, the nonlinear method revealed that replacing sugar with starch was associated with a higher risk when the current starch intake was greater than 30% of total energy, and with a lower risk when current intake was less than 25%. Conclusions Nonlinear isocaloric substitution provides an alternative to conventional isocaloric substitution analysis when the underlying association is nonlinear. Key messages Nonlinear associations are common in nutritional epidemiology. In such cases, nonlinear isocaloric substitution analyses should be used. [ABSTRACT FROM AUTHOR]

Background: There is evidence that mental health problems are increasing and substance use behaviours are decreasing. This paper aimed to investigate recent trends in mental ill health and health-related behaviours in two cohorts of UK adolescents in 2005 and 2015.Methods: Prevalences in mental health (depressive symptoms, self-harm, anti-social behaviours, parent-reported difficulties) and health-related behaviours (substance use, weight, weight perception, sleep, sexual intercourse) were examined at age 14 in two UK birth cohorts; Avon Longitudinal Study of Parents and Children (ALSPAC, N = 5627, born 1991-92) and Millennium Cohort Study (MCS, N = 11 318, born 2000-02). Prevalences and trend estimates are presented unadjusted and using propensity score matching and entropy balancing to account for differences between samples.Results: Depressive symptoms (9% to 14.8%) and self-harm (11.8% to 14.4%) were higher in 2015 compared with 2005. Parent-reported emotional difficulties, conduct problems, hyperactivity and peer problems were higher in 2015 compared with 2005 (5.7-8.9% to 9.7-17.7%). Conversely, substance use (tried smoking, 9.2% to 2.9%; tried alcohol, 52.1% to 43.5%, cannabis, 4.6% to 3.9%), sexual activity (2% to 0.9%) and anti-social behaviours (6.2-40.1% to 1.6-27.7%) were less common or no different. Adolescents in 2015 were spending less time sleeping (<8 h 5.7% to 11.5%), had higher body mass index (BMI) (obese, 3.8% to 7.3%) and a greater proportion perceived themselves as overweight (26.5% to 32.9%). The findings should be interpreted bearing in mind limitations in ability to adequately harmonize certain variables and account for differences in attrition rates and generalizability of the two cohorts.Conclusions: Given health-related behaviours are often cited as risk factors for poor mental health, our findings suggest relationships between these factors might be more complex and dynamic in nature than currently understood. Substantial increases in mental health difficulties, BMI and poor sleep-related behaviours highlight an increasing public health challenge. [ABSTRACT FROM AUTHOR]

Background: Physical inactivity is associated with an increased risk of major chronic diseases, although uncertainty exists about which chronic diseases, themselves, might contribute to physical inactivity. The objective of this study was to compare the physical activity of those with chronic diseases to healthy individuals using an objective measure of physical activity.Methods: We conducted a cross-sectional analysis of data from 96 706 participants aged 40 years or older from the UK Biobank prospective cohort study (2006-10). Diagnoses were identified through ICD 9 and 10 coding within hospital admission records and a cancer registry linked to UK Biobank participants. We extracted summary physical activity information from participants who wore a wrist-worn triaxial accelerometer for 7 days. Statistical analyses included computation of adjusted geometric means and means using general linear models.Results: Participants with chronic disease undertook 9% or 61 minutes (95% confidence interval: 57.8-64.8) less moderate activity and 11% or 3 minutes (95% confidence interval: 2.7-3.3) less vigorous activity per week than individuals without chronic disease. Participants in every chronic-disease subgroup undertook less physical activity than those without chronic disease. Sixty-seven diagnoses within these subgroups were associated with lower moderate activity.Conclusions: The cross-sectional association of physical activity with chronic disease is broad. Given the substantial health benefits of being physically active, clinicians and policymakers should be aware that their patients with any chronic disease are at greater health risk from other diseases than anticipated because of their physical inactivity. [ABSTRACT FROM AUTHOR]

Background Measurement error in exposures and confounders can bias exposure–outcome associations but is rarely considered. We aimed to assess random measurement error of all continuous variables in UK Biobank and explore approaches to mitigate its impact on exposure–outcome associations. Methods Random measurement error was assessed using intraclass correlation coefficients (ICCs) for all continuous variables with repeat measures. Regression calibration was used to correct for random error in exposures and confounders, using the associations of red blood cell distribution width (RDW), C-reactive protein (CRP) and 25-hydroxyvitamin D [25(OH)D] with mortality as illustrative examples. Results The 2858 continuous variables with repeat measures varied in sample size from 109 to 49 121. They fell into three groups: (i) baseline visit [529 variables; median (interquartile range) ICC = 0.64 (0.57, 0.83)]; (ii) online diet by 24-h recall [22 variables; 0.35 (0.30, 0.40)] and (iii) imaging measures [2307 variables; 0.85 (0.73, 0.94)]. Highest ICCs were for anthropometric and medical history measures, and lowest for dietary and heart magnetic resonance imaging. The ICCs (95% confidence interval) for RDW, CRP and 25(OH)D were 0.52 (0.51, 0.53), 0.29 (0.27, 0.30) and 0.55 (0.54, 0.56), respectively. Higher RDW and levels of CRP were associated with higher risk of all-cause mortality, and higher concentration of 25(OH)D with lower risk. After correction for random measurement error in the main exposure, the associations all strengthened. Confounder correction did not influence estimates. Conclusions Random measurement error varies widely and is often non-negligible. For UK Biobank we provide relevant statistics and adaptable code to help other researchers explore and correct for this. [ABSTRACT FROM AUTHOR]

Background Previous Mendelian randomization (MR) studies using population samples (population MR) have provided evidence for beneficial effects of educational attainment on health outcomes in adulthood. However, estimates from these studies may have been susceptible to bias from population stratification, assortative mating and indirect genetic effects due to unadjusted parental genotypes. MR using genetic association estimates derived from within-sibship models (within-sibship MR) can avoid these potential biases because genetic differences between siblings are due to random segregation at meiosis. Methods Applying both population and within-sibship MR, we estimated the effects of genetic liability to educational attainment on body mass index (BMI), cigarette smoking, systolic blood pressure (SBP) and all-cause mortality. MR analyses used individual-level data on 72 932 siblings from UK Biobank and the Norwegian HUNT study, and summary-level data from a within-sibship Genome-wide Association Study including >140 000 individuals. Results Both population and within-sibship MR estimates provided evidence that educational attainment decreased BMI, cigarette smoking and SBP. Genetic variant–outcome associations attenuated in the within-sibship model, but genetic variant–educational attainment associations also attenuated to a similar extent. Thus, within-sibship and population MR estimates were largely consistent. The within-sibship MR estimate of education on mortality was imprecise but consistent with a putative effect. Conclusions These results provide evidence of beneficial individual-level effects of education (or liability to education) on adulthood health, independently of potential demographic and family-level confounders. [ABSTRACT FROM AUTHOR]

Background Epidemiological studies demonstrated that adverse in utero environment was associated with increased risk of offspring high blood pressure, by using birthweight as the proxy of maternal intrauterine exposure; however, the nature of such association remains less understood. Methods With maternal/fetal-specific summary statistics of birthweight (n  =   297 356 for own birthweight and n  =   210 248 for offspring birthweight) and summary statistics of blood pressure [i.e. systolic blood pressure (SBP), diastolic blood pressure (DBP) and pulse pressure (PP)] (n  =   757 601), we evaluated the genetic correlation between fetal-specific birthweight and blood pressure using cross-trait linkage disequilibrium score regression, and next detected pleiotropic genes for them with a pleiotropy mapping method called mixture-adjusted intersect-union pleiotropy test. Furthermore, we conducted a genetic risk score (GRS)-based Mendelian randomization analysis in parent-offspring pairs (n  =   6031) of the UK Biobank cohort, to assess the causal relation between maternal-specific GRS and blood pressure conditioning on fetal genotypes. Results We found fetal-specific birthweight had a negative genetic correlation with DBP (⁠ ρ ^ g  = −0.174, P  =   1.68 × 10–10), SBP (⁠ ρ ^ g  = −0.198, P  =   8.09 × 10–12), and PP (⁠ ρ ^ g  = −0.152, P  =   6.04 × 10–8), and detected 143, 137 and 135 pleiotropic genes shared between fetal-specific birthweight and PP, SBP and DBP, respectively. These genes often exhibited opposite genetic effects, and were more likely to be differentially expressed in pancreas, liver, heart, brain, whole blood and muscle skeletal tissues. A causal negative association of maternal-specific birthweight was identified with SBP (P  =   2.20 × 10–2) and PP (P  =   7.67 × 10–3) but not DBP (P  =   0.396) in mother-offspring pairs, after accounting for the influence of fetal-specific GRS; and the two significant relations were robust against the horizontal pleiotropy of instruments and the confounding influence of gestational duration and preterm birth. However, these causal associations could not be detected in father-offspring pairs. Conclusions This study revealed common genetic components underlying birthweight and blood pressure, and provided important insight into aetiology and early prevention of high blood pressure. [ABSTRACT FROM AUTHOR]

Background To investigate prospective association of coffee and tea intake with incident irritable bowel syndrome (IBS) in a long-term cohort. Methods Participants free of IBS, coeliac disease, inflammatory bowel disease and any cancer at baseline from UK Biobank were included. Coffee and tea intake was measured separately via baseline touchscreen questionnaire, with four categories for each intake (0, 0.5–1, 2–3 and ≥4 cups/day). Primary outcome was incident IBS. Cox proportional hazard model was used to estimate associated risk. Results Among 425 387 participants, 83 955(19.7%) and 186 887(43.9%) consumed ≥4 cups/day of coffee and tea at baseline, respectively. During median 12.4-year follow-up, incident IBS was identified in 7736 participants. Compared with no coffee intake, consumption of 0.5–1, 2–3 and ≥4 cups/day was associated with lower IBS risk [hazard ratio (HR)=0.93, 95% CI: 0.87–0.99; 0.91, 0.85–0.97; 0.81, 0.76–0.88; P trend < 0.001]. Specifically, decreased risk was evident in individuals who consumed instant (HR = 0.83, 0.78–0.88) or ground coffee (HR = 0.82, 0.76–0.88) compared with no coffee drink. Regarding tea intake, protective association was only found in individuals who consumed 0.5–1 cup/day (HR = 0.87, 0.80–0.95), whereas no significant association was detected in those who consumed 2–3 (HR = 0.94, 0.88–1.01) or ≥4 cups/day (HR = 0.95, 0.89–1.02) compared with no-tea intake (P trend = 0.848). Conclusions Higher intake of coffee, particularly instant and ground coffee, is associated with lower risk of incident IBS, with significant dose–response relationship. Moderate-tea intake (0.5–1 cup/day) is associated with lower IBS risk. [ABSTRACT FROM AUTHOR]

Background Smoking prevalence is higher among individuals with schizophrenia or depression, and previous work has suggested this relationship is causal. However, this may be due to dynastic effects, for example reflecting maternal smoking during pregnancy rather than a direct effect of smoking. We used a proxy gene-by-environment Mendelian randomization approach to investigate whether there is a causal effect of maternal heaviness of smoking during pregnancy on offspring mental health. Methods Analyses were performed in the UK Biobank cohort. Individuals with data on smoking status, maternal smoking during pregnancy, a diagnosis of schizophrenia or depression, and genetic data were included. We used participants' genotype (rs16969968 in the CHRNA5 gene) as a proxy for their mothers' genotype. Analyses were stratified on participants' own smoking status in order to estimate the effect of maternal smoking heaviness during pregnancy independently of offspring smoking. Results The effect of maternal smoking on offspring schizophrenia was in opposing directions when stratifying on offspring smoking status. Among offspring of never smokers, each additional risk allele for maternal smoking heaviness appeared to have a protective effect [odds ratio (OR)   =   0.77, 95% confidence interval (CI) 0.62 to 0.95, P =  0.015], whereas among ever smokers the effect of maternal smoking was in the reverse direction (OR = 1.23, 95% CI 1.05 to 1.45, P =  0.011, P interaction   <0.001). There was no clear evidence of an association between maternal smoking heaviness and offspring depression. Conclusions These findings do not provide clear evidence of an effect of maternal smoking during pregnancy on offspring schizophrenia or depression, which implies that any causal effect of smoking on schizophrenia or depression is direct. [ABSTRACT FROM AUTHOR]

Background Physical activity (PA) has been associated with benefits for cognitive function (CF), but previous estimates of the strength of this relationship may have been biased due to limitations in statistical modelling practices that are common among observational studies. We aimed to address this by using a rigorously constructed conceptual causal model to guide an empirical analysis estimating the effect of PA on CF in the UK Biobank cohort of middle-aged and older adults. Methods This study analysed a subsample of 334 227 adults from the UK Biobank prospective cohort study. PA was measured subjectively by self-report and by device using accelerometry, and CF was measured using objective cognitive tests. Composite CF measures were derived to represent general and domain-specific performance. Effect coefficients were estimated using regression models, adjusting for a wide range of confounders specified by the assumed causal model, including genetic risk factors, and relevant health, sociodemographic and behavioural variables from across the lifespan. Results Results indicated very small effect sizes (standardized mean difference estimates all <0.01) of inconsistent direction, for both cross-sectional and longitudinal analyses. Conclusions The expected protective effect of PA on CF was not observed. This may reflect selection bias within UK Biobank, or the relatively young age of the sample at follow-up. [ABSTRACT FROM AUTHOR]

Introduction Genetic associations for variants identified through genome-wide association studies (GWASs) tend to be overestimated in the original discovery data set as, if the association was underestimated, the variant may not have been detected. This bias, known as winner's curse, can affect Mendelian randomization estimates, but its severity and potential impact are unclear. Methods We performed an empirical investigation to assess the potential bias from winner's curse in practice. We considered Mendelian randomization estimates for the effect of body mass index (BMI) on coronary artery disease risk. We randomly divided a UK Biobank data set 100 times into three equally sized subsets. The first subset was treated as the 'discovery GWAS'. We compared genetic associations estimated in the discovery GWAS to those estimated in the other subsets for each of the 100 iterations. Results For variants associated with BMI at P  <   5 × 10–8 in at least one iteration, genetic associations with BMI were up to 5-fold greater in iterations in which the variant was associated with BMI at P  <   5 × 10–8 compared with its mean association across all iterations. If the minimum P -value for association with BMI was P  =   10–13 or lower, then this inflation was <25%. Mendelian randomization estimates were affected by winner's curse bias. However, bias did not materially affect results; all analyses indicated a deleterious effect of BMI on coronary artery disease risk. Conclusions Winner's curse can bias Mendelian randomization estimates, although its practical impact may not be substantial. If avoiding sample overlap is infeasible, analysts should consider performing a sensitivity analysis based on variants strongly associated with the exposure. [ABSTRACT FROM AUTHOR]

Objectives Increased iron stores have been associated with elevated risks of different infectious diseases, suggesting that iron supplementation may increase the risk of infections. However, these associations may be biased by confounding or reverse causation. This is important, since up to 19% of the population takes iron supplementation. We used Mendelian randomization (MR) to bypass these biases and estimate the causal effect of iron on infections. Methods As instrumental variables, we used genetic variants associated with iron biomarkers in two genome-wide association studies (GWASs) of European ancestry participants. For outcomes, we used GWAS results from the UK Biobank, FinnGen, the COVID-19 Host Genetics Initiative or 23andMe, for seven infection phenotypes: 'any infections', combined, COVID-19 hospitalization, candidiasis, pneumonia, sepsis, skin and soft tissue infection (SSTI) and urinary tract infection (UTI). Results Most of our analyses showed increasing iron (measured by its biomarkers) was associated with only modest changes in the odds of infectious outcomes, with all 95% odds ratios confidence intervals within the 0.88 to 1.26 range. However, for the three predominantly bacterial infections (sepsis, SSTI, UTI), at least one analysis showed a nominally elevated risk with increased iron stores (P  <0.05). Conclusion Using MR, we did not observe an increase in risk of most infectious diseases with increases in iron stores. However for bacterial infections, higher iron stores may increase odds of infections. Hence, using genetic variation in iron pathways as a proxy for iron supplementation, iron supplements are likely safe on a population level, but we should continue the current practice of conservative iron supplementation during bacterial infections or in those at high risk of developing them. [ABSTRACT FROM AUTHOR]

Background: A later age at natural menopause (ANM) has been linked to several ageing-associated traits including an increased risk of breast and endometrial cancer and a decreased risk of lung cancer, osteoporosis and Alzheimer disease. However, ANM is also related to several proxies for overall health that may confound these associations.Methods: We investigated the causal association of ANM with these clinical outcomes using Mendelian randomization (MR). Participants and outcomes analysed were restricted to post-menopausal females. We conducted a one-sample MR analysis in both the Women's Health Initiative and UK Biobank. We further analysed and integrated several additional data sets of post-menopausal women using a two-sample MR design. We used ≤55 genetic variants previously discovered to be associated with ANM as our instrumental variable.Results: A 5-year increase in ANM was causally associated with a decreased risk of osteoporosis [odds ratio (OR) = 0.80, 95% CI (0.70-0.92)] and fractures (OR = 0.76, 95% CI, 0.62-0.94) as well as an increased risk of lung cancer (OR = 1.35, 95% CI, 1.06-1.71). Other associations including atherosclerosis-related outcomes were null.Conclusions: Our study confirms that the decline in bone density with menopause causally translates into fractures and osteoporosis. Additionally, this is the first causal epidemiological analysis to our knowledge to find an increased risk of lung cancer with increasing ANM. This finding is consistent with molecular and epidemiological studies suggesting oestrogen-dependent growth of lung tumours. [ABSTRACT FROM AUTHOR]

Background Genetic and lifestyle factors are associated with cancer risk. We investigated the benefits of adhering to lifestyle advice by the World Cancer Research Fund (WCRF) with the risk of 13 types of cancer and whether these associations differ according to genetic risk using data from the UK Biobank. Methods In 2006–2010, participants aged 37–73 years had their lifestyle assessed and were followed up for incident cancers until 2015–2019. Analyses were restricted to those of White European ancestry with no prior history of malignant cancer (n  = 195 822). Polygenic risk scores (PRSs) were computed for 13 cancer types and these cancers combined ('overall cancer'), and a lifestyle index was calculated from WCRF recommendations. Associations with cancer incidence were estimated using Cox regression, adjusting for relevant confounders. Additive and multiplicative interactions between lifestyle index and PRSs were assessed. Results There were 15 240 incident cancers during the 1 926 987 person-years of follow-up (median follow-up = 10.2 years). After adjusting for confounders, the lifestyle index was associated with a lower risk of overall cancer [hazard ratio per standard deviation increase (95% CI) = 0.89 (0.87, 0.90)] and of eight specific cancer types. There was no evidence of interactions on the multiplicative scale. There was evidence of additive interactions in risks for colorectal, breast, pancreatic, lung and bladder cancers, such that the recommended lifestyle was associated with greater change in absolute risk for persons at higher genetic risk (P  <   0.0003 for all). Conclusions The recommended lifestyle has beneficial associations with most cancers. In terms of absolute risk, the protective association is greater for higher genetic risk groups for some cancers. These findings have important implications for persons most genetically predisposed to those cancers and for targeted strategies for cancer prevention. [ABSTRACT FROM AUTHOR]

Background Mendelian randomization (MR) is a form of instrumental variable analysis used to investigate causality using observational data. Another important, although less frequently applied, use of this technique is to investigate confounding due to reverse causality. Methods We used a form of reverse MR and data from UK Biobank in a proof-of-principle study to investigate confounding due to reverse causation. Here we focus on the association between alcohol consumption (exposure) and outcomes including educational attainment, and physical and mental health. First, we examined the observational relationship between alcohol consumption and these outcomes. Allele scores were then derived for educational attainment, and physical and mental health, and the association with alcohol consumption (as the outcome) was explored. Sample sizes ranged from 114 941–336 473 in observational analyses and 142 093–336 818 in genetic analyses. Results Conventional observational analyses indicated associations between alcohol consumption and a number of outcomes (e.g. neuroticism, body mass index, educational attainment). Analyses using allele scores suggested evidence of reverse causation for several of these relationships (in particular physical health and educational attainment). Conclusion Allele scores allow us to investigate reverse causation in observational studies. Our findings suggest that observed associations implying beneficial effects of alcohol consumption may be due to confounding by reverse causation in many cases. [ABSTRACT FROM AUTHOR]

Background Non-random selection of analytic subsamples could introduce selection bias in observational studies. We explored the potential presence and impact of selection in studies of SARS-CoV-2 infection and COVID-19 prognosis. Methods We tested the association of a broad range of characteristics with selection into COVID-19 analytic subsamples in the Avon Longitudinal Study of Parents and Children (ALSPAC) and UK Biobank (UKB). We then conducted empirical analyses and simulations to explore the potential presence, direction and magnitude of bias due to this selection (relative to our defined UK-based adult target populations) when estimating the association of body mass index (BMI) with SARS-CoV-2 infection and death-with-COVID-19. Results In both cohorts, a broad range of characteristics was related to selection, sometimes in opposite directions (e.g. more-educated people were more likely to have data on SARS-CoV-2 infection in ALSPAC, but less likely in UKB). Higher BMI was associated with higher odds of SARS-CoV-2 infection and death-with-COVID-19. We found non-negligible bias in many simulated scenarios. Conclusions Analyses using COVID-19 self-reported or national registry data may be biased due to selection. The magnitude and direction of this bias depend on the outcome definition, the true effect of the risk factor and the assumed selection mechanism; these are likely to differ between studies with different target populations. Bias due to sample selection is a key concern in COVID-19 research based on national registry data, especially as countries end free mass testing. The framework we have used can be applied by other researchers assessing the extent to which their results may be biased for their research question of interest. [ABSTRACT FROM AUTHOR]

Background Higher urate levels are associated with higher systolic blood pressure (SBP) in adults, and in pregnancy with lower offspring birthweight. Mendelian randomization (MR) analyses suggest a causal effect of higher urate on higher SBP and of higher maternal SBP on lower offspring birthweight. If urate causally reduces birthweight, it might confound the effect of SBP on birthweight. We therefore tested for a causal effect of maternal urate on offspring birthweight. Methods We tested the association between maternal urate levels and offspring birthweight using multivariable linear regression in the Exeter Family Study of Childhood Health (EFSOCH; n  =   872) and UK Biobank (UKB; n  =   133 187). We conducted two-sample MR to test for a causal effect of maternal urate [114 single-nucleotide polymorphisms (SNPs); n  =   288 649 European ancestry] on offspring birthweight (n  =   406 063 European ancestry; maternal SNP effect estimates adjusted for fetal effects). We assessed a causal relationship between urate and SBP using one-sample MR in UKB women (n  =   199 768). Results Higher maternal urate was associated with lower offspring birthweight with similar confounder-adjusted magnitudes in EFSOCH [22 g lower birthweight per 1-SD higher urate (95% CI: –50, 6); P  =   0.13] and UKB [–28 g (95% CI: –31, –25); P  =   1.8  ×  10–75]. The MR causal effect estimate was directionally consistent, but smaller [–11 g (95% CI: –25, 3); P IVW   =   0.11]. In women, higher urate was causally associated with higher SBP [1.7 mmHg higher SBP per 1-SD higher urate (95% CI: 1.4, 2.1); P  =   7.8  ×  10–22], consistent with that previously published in women and men. Conclusion The marked attenuation of the MR result of maternal urate on offspring birthweight compared with the multivariable regression result suggests previous observational associations may be confounded. The 95% CIs of the MR result included the null but suggest a possible small effect on birthweight. Maternal urate levels are unlikely to be an important contributor to offspring birthweight. [ABSTRACT FROM AUTHOR]

Arthur Mitchell, sometime Commissioner in Lunacy for Scotland, outlined some of the principles of epidemiological studies in the 1860s. He was responsible for a system of care in the community for the insane that was, at the time, influential. In the course of his work he carried out studies that reflected concern with several of the methodological issues raised by contemporary epidemiological investigation. [ABSTRACT FROM AUTHOR]

Background: This study was to systematically test whether previously reported risk factors for chronic kidney disease (CKD) are causally related to CKD in European and East Asian ancestries using Mendelian randomization.Methods: A total of 45 risk factors with genetic data in European ancestry and 17 risk factors in East Asian participants were identified as exposures from PubMed. We defined the CKD by clinical diagnosis or by estimated glomerular filtration rate of <60 ml/min/1.73 m2. Ultimately, 51 672 CKD cases and 958 102 controls of European ancestry from CKDGen, UK Biobank and HUNT, and 13 093 CKD cases and 238 118 controls of East Asian ancestry from Biobank Japan, China Kadoorie Biobank and Japan-Kidney-Biobank/ToMMo were included.Results: Eight risk factors showed reliable evidence of causal effects on CKD in Europeans, including genetically predicted body mass index (BMI), hypertension, systolic blood pressure, high-density lipoprotein cholesterol, apolipoprotein A-I, lipoprotein(a), type 2 diabetes (T2D) and nephrolithiasis. In East Asians, BMI, T2D and nephrolithiasis showed evidence of causality on CKD. In two independent replication analyses, we observed that increased hypertension risk showed reliable evidence of a causal effect on increasing CKD risk in Europeans but in contrast showed a null effect in East Asians. Although liability to T2D showed consistent effects on CKD, the effects of glycaemic phenotypes on CKD were weak. Non-linear Mendelian randomization indicated a threshold relationship between genetically predicted BMI and CKD, with increased risk at BMI of >25 kg/m2.Conclusions: Eight cardiometabolic risk factors showed causal effects on CKD in Europeans and three of them showed causality in East Asians, providing insights into the design of future interventions to reduce the burden of CKD. [ABSTRACT FROM AUTHOR]

Background: With genome-wide association data for many exposures and outcomes now available from large biobanks, one-sample Mendelian randomization (MR) is increasingly used to investigate causal relationships. Many robust MR methods are available to address pleiotropy, but these assume independence between the gene-exposure and gene-outcome association estimates. Unlike in two-sample MR, in one-sample MR the two estimates are obtained from the same individuals, and the assumption of independence does not hold in the presence of confounding.Methods: With simulations mimicking a typical study in UK Biobank, we assessed the performance, in terms of bias and precision of the MR estimate, of the fixed-effect and (multiplicative) random-effects meta-analysis method, weighted median estimator, weighted mode estimator and MR-Egger regression, used in both one-sample and two-sample data. We considered scenarios differing by the: presence/absence of a true causal effect; amount of confounding; and presence and type of pleiotropy (none, balanced or directional).Results: Even in the presence of substantial correlation due to confounding, all two-sample methods used in one-sample MR performed similarly to when used in two-sample MR, except for MR-Egger which resulted in bias reflecting direction and magnitude of the confounding. Such bias was much reduced in the presence of very high variability in instrument strength across variants (IGX2 of 97%).Conclusions: Two-sample MR methods can be safely used for one-sample MR performed within large biobanks, expect for MR-Egger. MR-Egger is not recommended for one-sample MR unless the correlation between the gene-exposure and gene-outcome estimates due to confounding can be kept low, or the variability in instrument strength is very high. [ABSTRACT FROM AUTHOR]

Background: Two-sample Mendelian randomization (MR) allows the use of freely accessible summary association results from genome-wide association studies (GWAS) to estimate causal effects of modifiable exposures on outcomes. Some GWAS adjust for heritable covariables in an attempt to estimate direct effects of genetic variants on the trait of interest. One, both or neither of the exposure GWAS and outcome GWAS may have been adjusted for covariables.Methods: We performed a simulation study comprising different scenarios that could motivate covariable adjustment in a GWAS and analysed real data to assess the influence of using covariable-adjusted summary association results in two-sample MR.Results: In the absence of residual confounding between exposure and covariable, between exposure and outcome, and between covariable and outcome, using covariable-adjusted summary associations for two-sample MR eliminated bias due to horizontal pleiotropy. However, covariable adjustment led to bias in the presence of residual confounding (especially between the covariable and the outcome), even in the absence of horizontal pleiotropy (when the genetic variants would be valid instruments without covariable adjustment). In an analysis using real data from the Genetic Investigation of ANthropometric Traits (GIANT) consortium and UK Biobank, the causal effect estimate of waist circumference on blood pressure changed direction upon adjustment of waist circumference for body mass index.Conclusions: Our findings indicate that using covariable-adjusted summary associations in MR should generally be avoided. When that is not possible, careful consideration of the causal relationships underlying the data (including potentially unmeasured confounders) is required to direct sensitivity analyses and interpret results with appropriate caution. [ABSTRACT FROM AUTHOR]

Background: It is commonly assumed that high oestradiol levels in women are cardioprotective. We assessed the association between oestradiol and the risk of incident myocardial infarction (MI) in women.Methods: We used data from 263 295 female UK Biobank participants [mean age 56.2; standard deviation (SD) 8.0 years] without previous cardiovascular disease (CVD). Associations of oestradiol with age and other cardiovascular risk factors were assessed. Cox proportional hazards models estimated crude, ag- and multiple-adjusted hazard ratios (HR) for MI associated with oestradiol levels.Results: After a mean follow-up of 9 years, 2206 incident cases of MI had been recorded, including 230 events among the 57 204 women (mean age 48) with detectable oestradiol levels. In the unadjusted analyses, a unit higher in log-transformed oestradiol was associated with an HR [95% confidence interval (CI) for MI of 0.73 (0.58; 0.92)]. After adjusting for age, this HR became 0.94 (0.75; 1.17), and after further adjusting for classical CVD risk factors, it was 1.05 (0.83; 1.31. Results were similar in subgroup analyses defined by age, menopausal status, socioeconomic status, contraceptive pill use and the use of hormone replacement therapy. The multivariable-adjusted HR for the 171 431 women (mean age 59) with undetectable levels of oestradiol, compared with those with detectable levels, was 0.97 (0.92; 1.02).Conclusions: Higher levels of oestradiol were not associated with a decreased risk of MI. The presumed cardioprotective effects of oestradiol seem to be largely confounded by age and further confounded by other cardiovascular risk factors. [ABSTRACT FROM AUTHOR]

Background: Previous studies have often evaluated methods for Mendelian randomization (MR) analysis based on simulations that do not adequately reflect the data-generating mechanisms in genome-wide association studies (GWAS) and there are often discrepancies in the performance of MR methods in simulations and real data sets.Methods: We use a simulation framework that generates data on full GWAS for two traits under a realistic model for effect-size distribution coherent with the heritability, co-heritability and polygenicity typically observed for complex traits. We further use recent data generated from GWAS of 38 biomarkers in the UK Biobank and performed down sampling to investigate trends in estimates of causal effects of these biomarkers on the risk of type 2 diabetes (T2D).Results: Simulation studies show that weighted mode and MRMix are the only two methods that maintain the correct type I error rate in a diverse set of scenarios. Between the two methods, MRMix tends to be more powerful for larger GWAS whereas the opposite is true for smaller sample sizes. Among the other methods, random-effect IVW (inverse-variance weighted method), MR-Robust and MR-RAPS (robust adjust profile score) tend to perform best in maintaining a low mean-squared error when the InSIDE assumption is satisfied, but can produce large bias when InSIDE is violated. In real-data analysis, some biomarkers showed major heterogeneity in estimates of their causal effects on the risk of T2D across the different methods and estimates from many methods trended in one direction with increasing sample size with patterns similar to those observed in simulation studies.Conclusion: The relative performance of different MR methods depends heavily on the sample sizes of the underlying GWAS, the proportion of valid instruments and the validity of the InSIDE assumption. Down-sampling analysis can be used in large GWAS for the possible detection of bias in the MR methods. [ABSTRACT FROM AUTHOR]

Background: Low socio-economic position (SEP) is a risk factor for multiple health outcomes, but its molecular imprints in the body remain unclear.Methods: We examined SEP as a determinant of serum nuclear magnetic resonance metabolic profiles in ∼30 000 adults and 4000 children across 10 UK and Finnish cohort studies.Results: In risk-factor-adjusted analysis of 233 metabolic measures, low educational attainment was associated with 37 measures including higher levels of triglycerides in small high-density lipoproteins (HDL) and lower levels of docosahexaenoic acid (DHA), omega-3 fatty acids, apolipoprotein A1, large and very large HDL particles (including levels of their respective lipid constituents) and cholesterol measures across different density lipoproteins. Among adults whose father worked in manual occupations, associations with apolipoprotein A1, large and very large HDL particles and HDL-2 cholesterol remained after adjustment for SEP in later life. Among manual workers, levels of glutamine were higher compared with non-manual workers. All three indicators of low SEP were associated with lower DHA, omega-3 fatty acids and HDL diameter. At all ages, children of manual workers had lower levels of DHA as a proportion of total fatty acids.Conclusions: Our work indicates that social and economic factors have a measurable impact on human physiology. Lower SEP was independently associated with a generally unfavourable metabolic profile, consistent across ages and cohorts. The metabolites we found to be associated with SEP, including DHA, are known to predict cardiovascular disease and cognitive decline in later life and may contribute to health inequalities. [ABSTRACT FROM AUTHOR]

Objective: We assess the existence of unfair inequalities in health and death using the normative framework of inequality of opportunities, from birth to middle age in Great Britain.Methods: We use data from the 1958 National Child Development Study, which provides a unique opportunity to observe individual health from birth to the age of 54, including the occurrence of mortality. We measure health status combining self-assessed health and mortality. We compare and statistically test the differences between the cumulative distribution functions of health status at each age according to one childhood circumstance beyond people's control: the father's occupation.Results: At all ages, individuals born to a 'professional', 'senior manager or technician' father report a better health status and have a lower mortality rate than individuals born to 'skilled', 'partly skilled' or 'unskilled' manual workers and individuals without a father at birth. The gap in the probability to report good health between individuals born into high social backgrounds compared with low, increases from 12 percentage points at age 23 to 26 at age 54. Health gaps are even more marked in health states at the bottom of the health distribution when mortality is combined with self-assessed health.Conclusions: There is increasing inequality of opportunities in health over the lifespan in Great Britain. The tag of social background intensifies as individuals get older. Finally, there is added analytical value to combining mortality with self-assessed health when measuring health inequalities. [ABSTRACT FROM AUTHOR]

Background: We aimed to estimate the causal effect of health conditions and risk factors on social and socioeconomic outcomes in UK Biobank. Evidence on socioeconomic impacts is important to understand because it can help governments, policy makers and decision makers allocate resources efficiently and effectively.Methods: We used Mendelian randomization to estimate the causal effects of eight health conditions (asthma, breast cancer, coronary heart disease, depression, eczema, migraine, osteoarthritis, type 2 diabetes) and five health risk factors [alcohol intake, body mass index (BMI), cholesterol, systolic blood pressure, smoking] on 19 social and socioeconomic outcomes in 336 997 men and women of White British ancestry in UK Biobank, aged between 39 and 72 years. Outcomes included annual household income, employment, deprivation [measured by the Townsend deprivation index (TDI)], degree-level education, happiness, loneliness and 13 other social and socioeconomic outcomes.Results: Results suggested that BMI, smoking and alcohol intake affect many socioeconomic outcomes. For example, smoking was estimated to reduce household income [mean difference = -£22 838, 95% confidence interval (CI): -£31 354 to -£14 321] and the chance of owning accommodation [absolute percentage change (APC) = -20.8%, 95% CI: -28.2% to -13.4%], of being satisfied with health (APC = -35.4%, 95% CI: -51.2% to -19.5%) and of obtaining a university degree (APC = -65.9%, 95% CI: -81.4% to -50.4%), while also increasing deprivation (mean difference in TDI = 1.73, 95% CI: 1.02 to 2.44, approximately 216% of a decile of TDI). There was evidence that asthma decreased household income, the chance of obtaining a university degree and the chance of cohabiting, and migraine reduced the chance of having a weekly leisure or social activity, especially in men. For other associations, estimates were null.Conclusions: Higher BMI, alcohol intake and smoking were all estimated to adversely affect multiple social and socioeconomic outcomes. Effects were not detected between health conditions and socioeconomic outcomes using Mendelian randomization, with the exceptions of depression, asthma and migraines. This may reflect true null associations, selection bias given the relative health and age of participants in UK Biobank, and/or lack of power to detect effects. [ABSTRACT FROM AUTHOR]

Background Factorial Mendelian randomization is the use of genetic variants to answer questions about interactions. Although the approach has been used in applied investigations, little methodological advice is available on how to design or perform a factorial Mendelian randomization analysis. Previous analyses have employed a 2 × 2 approach, using dichotomized genetic scores to divide the population into four subgroups as in a factorial randomized trial. Methods We describe two distinct contexts for factorial Mendelian randomization: investigating interactions between risk factors, and investigating interactions between pharmacological interventions on risk factors. We propose two-stage least squares methods using all available genetic variants and their interactions as instrumental variables, and using continuous genetic scores as instrumental variables rather than dichotomized scores. We illustrate our methods using data from UK Biobank to investigate the interaction between body mass index and alcohol consumption on systolic blood pressure. Results Simulated and real data show that efficiency is maximized using the full set of interactions between genetic variants as instruments. In the applied example, between 4- and 10-fold improvement in efficiency is demonstrated over the 2 × 2 approach. Analyses using continuous genetic scores are more efficient than those using dichotomized scores. Efficiency is improved by finding genetic variants that divide the population at a natural break in the distribution of the risk factor, or else divide the population into more equal-sized groups. Conclusions Previous factorial Mendelian randomization analyses may have been underpowered. Efficiency can be improved by using all genetic variants and their interactions as instrumental variables, rather than the 2 × 2 approach. [ABSTRACT FROM AUTHOR]

Background: Little is known about population levels of energy expenditure, as national surveillance systems typically employ only crude measures. The National Diet and Nutrition Survey (NDNS) in the UK measured energy expenditure in a 10% subsample by gold-standard doubly labelled water (DLW).Methods: DLW-subsample participants from the NDNS (383 males, 387 females) aged 4-91 years were recruited between 2008 and 2015 (rolling programme). Height and weight were measured and body-fat percentage estimated by deuterium dilution.Results: Absolute total energy expenditure (TEE) increased steadily throughout childhood, ranging from 6.2 and 7.2 MJ/day in 4- to 7-year-olds to 9.7 and 11.7 MJ/day for 14- to 16-year-old girls and boys, respectively. TEE peaked in 17- to 27-year-old women (10.7 MJ/day) and 28- to 43-year-old men (14.4 MJ/day), before decreasing gradually in old age. Physical-activity energy expenditure (PAEE) declined steadily with age from childhood (87 kJ/day/kg in 4- to 7-year-olds) through to old age (38 kJ/day/kg in 71- to 91-year-olds). No differences were observed by time, region and macronutrient composition. Body-fat percentage was strongly inversely associated with PAEE throughout life, irrespective of expressing PAEE relative to body mass or fat-free mass. Compared with females with <30% body fat, females with >40% recorded 29 kJ/day/kg body mass and 18 kJ/day/kg fat-free mass less PAEE in analyses adjusted for age, geographical region and time of assessment. Similarly, compared with males with <25% body fat, males with >35% recorded 26 kJ/day/kg body mass and 10 kJ/day/kg fat-free mass less PAEE.Conclusions: This first nationally representative study reports levels of human-energy expenditure as measured by gold-standard methodology; values may serve as a reference for other population studies. Age, sex and body composition are the main determinants of energy expenditure. Key Messages This is the first nationally representative study of human energy expenditure, covering the UK in the period 2008-2015. Total energy expenditure (MJ/day) increases steadily with age throughout childhood and adolescence, peaks in the 3rd decade of life in women and 4th decade of life in men, before decreasing gradually in old age. Physical activity energy expenditure (kJ/day/kg or kJ/day/kg fat-free mass) declines steadily with age from childhood to old age, more steeply so in males. Body-fat percentage is strongly inversely associated with physical activity energy expenditure. We found little evidence that energy expenditure varied by geographical region, over time, or by dietary macronutrient composition. [ABSTRACT FROM AUTHOR]

Background: Most of the previous studies on diet and colorectal cancer were based on diets consumed during the 1990s.Methods: We used Cox-regression models to estimate adjusted hazard ratios for colorectal cancer by dietary factors in the UK Biobank study. Men and women aged 40-69 years at recruitment (2006-10) reported their diet on a short food-frequency questionnaire (n = 475 581). Dietary intakes were re-measured in a large sub-sample (n = 175 402) who completed an online 24-hour dietary assessment during follow-up. Trends in risk across the baseline categories were calculated by assigning re-measured intakes to allow for measurement error and changes in intake over time.Results: During an average of 5.7 years of follow-up, 2609 cases of colorectal cancer occurred. Participants who reported consuming an average of 76 g/day of red and processed meat compared with 21 g/day had a 20% [95% confidence interval (CI): 4-37] higher risk of colorectal cancer. Participants in the highest fifth of intake of fibre from bread and breakfast cereals had a 14% (95% CI: 2-24) lower risk of colorectal cancer. Alcohol was associated with an 8% (95% CI: 4-12) higher risk per 10 g/day higher intake. Fish, poultry, cheese, fruit, vegetables, tea and coffee were not associated with colorectal-cancer risk.Conclusions: Consumption of red and processed meat at an average level of 76 g/d that meets the current UK government recommendation (≤90 g/day) was associated with an increased risk of colorectal cancer. Alcohol was also associated with an increased risk of colorectal cancer, whereas fibre from bread and breakfast cereals was associated with a reduced risk. [ABSTRACT FROM AUTHOR]

Background: The intrauterine environment is critical for fetal growth and development. However, observational associations between maternal gestational lipid concentrations and offspring birth weight (BW) have been inconsistent and ascertaining causality is challenging.Methods: We used a novel two-sample Mendelian randomization (MR) approach to estimate the causal effect of maternal gestational high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and triglyceride concentrations on offspring BW. Single nucleotide polymorphisms (SNPs) associated with serum HDL-C, LDL-C and triglyceride concentrations identified in the Global Lipids Genetics Consortium genome-wide association study meta-analysis (n = 188 577 European-ancestry individuals; sample 1) were selected as instrumental variables. The effects of these SNPs on offspring BW were estimated using a structural equation model in the UK Biobank and Early Growth Genetics consortium (n = 230 069 European-ancestry individuals; sample 2) that enabled partitioning of the genetic associations into maternal- (intrauterine) and fetal-specific effects.Results: We found no evidence for a causal effect of maternal gestational HDL-C, LDL-C or triglyceride concentrations on offspring BW [standard deviation change in BW per standard deviation higher in HDL-C = -0.005 (95% confidence interval: -0.039, 0.029), LDL-C = 0.014 (-0.017, 0.045), and triglycerides = 0.014 (-0.025, 0.052)].Conclusions: Our findings suggest that maternal gestational HDL-C, LDL-C and triglyceride concentrations play a limited role in determining offspring BW. However, we cannot comment on the impact of these and other lipid fractions on fetal development more generally. Our study illustrates the power and flexibility of two-sample MR in assessing the causal effect of maternal environmental exposures on offspring outcomes. [ABSTRACT FROM AUTHOR]

Background: Short and long sleep duration have been linked with poorer cognitive outcomes, but it remains unclear whether these associations are causal.Methods: We conducted the first Mendelian randomization (MR) study with 77 single-nucleotide polymorphisms (SNPs) for sleep duration using individual-participant data from the UK Biobank cohort (N = 395 803) and summary statistics from the International Genomics of Alzheimer's Project (N cases/controls = 17 008/37 154) to investigate the potential impact of sleep duration on cognitive outcomes.Results: Linear MR suggested that each additional hour/day of sleep was associated with 1% [95% confidence interval (CI) = 0-2%; P = 0.008] slower reaction time and 3% more errors in visual-memory test (95% CI = 0-6%; P = 0.05). There was little evidence to support associations of increased sleep duration with decline in visual memory [odds ratio (OR) per additional hour/day of sleep = 1.10 (95% CI = 0.76-1.57); P = 0.62], decline in reaction time [OR = 1.28 (95% CI = 0.49-3.35); P = 0.61], all-cause dementia [OR = 1.19 (95% CI = 0.65-2.19); P = 0.57] or Alzheimer's disease risk [OR = 0.89 (95% CI = 0.67-1.18); P = 0.41]. Non-linear MR suggested that both short and long sleep duration were associated with poorer visual memory (P for non-linearity = 3.44e-9) and reaction time (P for non-linearity = 6.66e-16).Conclusions: Linear increase in sleep duration has a small negative effect on reaction time and visual memory, but the true association might be non-linear, with evidence of associations for both short and long sleep duration. These findings suggest that sleep duration may represent a potential causal pathway for cognition. [ABSTRACT FROM AUTHOR]

Background: Mendelian randomization (MR) is a powerful tool in epidemiology that can be used to estimate the causal effect of an exposure on an outcome in the presence of unobserved confounding, by utilizing genetic variants that are instrumental variables (IVs) for the exposure. This has been extended to multivariable MR (MVMR) to estimate the effect of two or more exposures on an outcome.Methods and Results: We use simulations and theory to clarify the interpretation of estimated effects in a MVMR analysis under a range of underlying scenarios, where a secondary exposure acts variously as a confounder, a mediator, a pleiotropic pathway and a collider. We then describe how instrument strength and validity can be assessed for an MVMR analysis in the single-sample setting, and develop tests to assess these assumptions in the popular two-sample summary data setting. We illustrate our methods using data from UK Biobank to estimate the effect of education and cognitive ability on body mass index.Conclusion: MVMR analysis consistently estimates the direct causal effect of an exposure, or exposures, of interest and provides a powerful tool for determining causal effects in a wide range of scenarios with either individual- or summary-level data. [ABSTRACT FROM AUTHOR]

Background: Depression is more common in obese than non-obese individuals, especially in women, but the causal relationship between obesity and depression is complex and uncertain. Previous studies have used genetic variants associated with BMI to provide evidence that higher body mass index (BMI) causes depression, but have not tested whether this relationship is driven by the metabolic consequences of BMI nor for differences between men and women.Methods: We performed a Mendelian randomization study using 48 791 individuals with depression and 291 995 controls in the UK Biobank, to test for causal effects of higher BMI on depression (defined using self-report and Hospital Episode data). We used two genetic instruments, both representing higher BMI, but one with and one without its adverse metabolic consequences, in an attempt to 'uncouple' the psychological component of obesity from the metabolic consequences. We further tested causal relationships in men and women separately, and using subsets of BMI variants from known physiological pathways.Results: Higher BMI was strongly associated with higher odds of depression, especially in women. Mendelian randomization provided evidence that higher BMI partly causes depression. Using a 73-variant BMI genetic risk score, a genetically determined one standard deviation (1 SD) higher BMI (4.9 kg/m2) was associated with higher odds of depression in all individuals [odds ratio (OR): 1.18, 95% confidence interval (CI): 1.09, 1.28, P = 0.00007) and women only (OR: 1.24, 95% CI: 1.11, 1.39, P = 0.0001). Meta-analysis with 45 591 depression cases and 97 647 controls from the Psychiatric Genomics Consortium (PGC) strengthened the statistical confidence of the findings in all individuals. Similar effect size estimates were obtained using different Mendelian randomization methods, although not all reached P < 0.05. Using a metabolically favourable adiposity genetic risk score, and meta-analysing data from the UK biobank and PGC, a genetically determined 1 SD higher BMI (4.9 kg/m2) was associated with higher odds of depression in all individuals (OR: 1.26, 95% CI: 1.06, 1.50], P = 0.010), but with weaker statistical confidence.Conclusions: Higher BMI, with and without its adverse metabolic consequences, is likely to have a causal role in determining the likelihood of an individual developing depression. [ABSTRACT FROM AUTHOR]

Background: Mendelian randomization (MR) has developed into an established method for strengthening causal inference and estimating causal effects, largely due to the proliferation of genome-wide association studies. However, genetic instruments remain controversial, as horizontal pleiotropic effects can introduce bias into causal estimates. Recent work has highlighted the potential of gene-environment interactions in detecting and correcting for pleiotropic bias in MR analyses.Methods: We introduce MR using Gene-by-Environment interactions (MRGxE) as a framework capable of identifying and correcting for pleiotropic bias. If an instrument-covariate interaction induces variation in the association between a genetic instrument and exposure, it is possible to identify and correct for pleiotropic effects. The interpretation of MRGxE is similar to conventional summary MR approaches, with a particular advantage of MRGxE being the ability to assess the validity of an individual instrument.Results: We investigate the effect of adiposity, measured using body mass index (BMI), upon systolic blood pressure (SBP) using data from the UK Biobank and a single weighted allelic score informed by data from the GIANT consortium. We find MRGxE produces findings in agreement with two-sample summary MR approaches. Further, we perform simulations highlighting the utility of the approach even when the MRGxE assumptions are violated.Conclusions: By utilizing instrument-covariate interactions in MR analyses implemented within a linear-regression framework, it is possible to identify and correct for horizontal pleiotropic bias, provided the average magnitude of pleiotropy is constant across interaction-covariate subgroups. [ABSTRACT FROM AUTHOR]

We describe our experience in several settings, following a suggestion in 1983 to add questions on the smoking status of the deceased on the UK death certificate as an effective way to monitor the evolution of the smoking epidemic. In South Africa in 1997 and in Tianjin Municipality, China, in 2010, questions about the smoking habits of the deceased were inserted on the official death certificates. In both places a system now exists to routinely collect information on smoking status in relation to causes of death. Results from two million South African and 300 000 Chinese deceased individuals have been reported, and the sample size in both places continues to grow. An unsuccessful attempt was made in 2008 to insert smoking questions on the Australian death notification forms but comments and concerns from the registrars of births, marriages and deaths have international applicability. In both China and South Africa, inserting questions on smoking on the death notification forms was not a trivial task-in each it required, as a minimum, significant commitment from several government agencies. Benefits, however, include a better local understanding of the smoking epidemic and allowing for planning and monitoring of tobacco control programmes. Documenting the varied experiences of collecting information on smoking on death notification forms is useful to those wishing to introduce such questions in their own settings. This is pertinent especially at a time when vital registration systems are being improved, with an aim to monitoring sustainable development goals. [ABSTRACT FROM AUTHOR]

Background: There is little evidence on whether becoming re-employed in poor quality work is better for health and well-being than remaining unemployed. We examined associations of job transition with health and chronic stress-related biomarkers among a population-representative cohort of unemployed British adults.Methods: A prospective cohort of 1116 eligible participants aged 35 to 75 years, who were unemployed at wave 1 (2009/10) of the UK Household Longitudinal Study, were followed up at waves 2 (2010/11) and 3 (2011/12) for allostatic load biomarkers and self-reported health. Negative binomial and multiple regression models estimated the association between job adversity and these outcomes.Results: Compared with adults who remained unemployed, formerly unemployed adults who transitioned into poor quality jobs had higher levels of overall allostatic load (0.51, 0.32-0.71), log HbA1c (0.06, <0.001-0.12), log triglycerides (0.39, 0.22-0.56), log C-reactive protein (0.45, 0.16-0.75), log fibrinogen (0.09, 0.01-0.17) and total cholesterol to high-density lipoprotein (HDL) ratio (1.38, 0.88-1.88). Moreover, physically healthier respondents at wave 1 were more likely to transition into good quality and poor quality jobs after 1 year than those who remained unemployed.Conclusions: Formerly unemployed adults who transitioned into poor quality work had greater adverse levels of biomarkers compared with their peers who remained unemployed. The selection of healthier unemployed adults into these poor quality or stressful jobs was unlikely to explain their elevated levels of chronic stress-related biomarkers. Job quality cannot be disregarded from the employment success of the unemployed, and may have important implications for their health and well-being. [ABSTRACT FROM AUTHOR]

Background: There are currently no large general population epidemiological studies of Mycoplasma genitalium (MG), which include prevalence, risk factors, symptoms and co-infection in men and women across a broad age range.Methods: In 2010-–12, we conducted the third National Survey of Sexual Attitudes and Lifestyles (Natsal-3), a probability sample survey in Britain. Urine from 4507 sexually-experienced participants, aged 16–44 years, was tested for MG.Results: MG prevalence was 1.2% [95% confidence interval (CI): 0.7–1.8%] in men and 1.3% (0.9–1.9%) in women. There were no positive MG tests in men aged 16–19, and prevalence peaked at 2.1% (1.2–3.7%) in men aged 25–34 years. In women, prevalence was highest in 16–19 year olds, at 2.4% (1.2–4.8%), and decreased with age. Men of Black ethnicity were more likely to test positive for MG [adjusted odds ratio (AOR) 12.1; 95% CI: 3.7–39.4). For both men and women, MG was strongly associated with reporting sexual risk behaviours (increasing number of total and new partners, and unsafe sex, in the past year). Women with MG were more likely to report post-coital bleeding (AOR 5.8; 95%CI 1.4–23.3). However, the majority of men (94.4%), and over half of women (56.2%) with MG did not report any sexually transmitted infection (STI) symptoms. Men with MG were more likely to report previously diagnosed gonorrhoea, syphilis or non-specific urethritis, and women previous trichomoniasis.Conclusions: This study strengthens evidence that MG is an STI. MG was identified in over 1% of the population, including in men with high-risk behaviours in older age groups that are often not included in STI prevention measures. [ABSTRACT FROM AUTHOR]

Background: The Seven Countries Study in the 1960s showed very low mortality from coronary heart disease (CHD) in Japan, which was attributed to very low levels of total cholesterol. Studies of migrant Japanese to the USA in the 1970s documented increase in CHD rates, thus CHD mortality in Japan was expected to increase as their lifestyle became Westernized, yet CHD mortality has continued to decline since 1970. This study describes trends in CHD mortality and its risk factors since 1980 in Japan, contrasting those in other selected developed countries.Methods: We selected Australia, Canada, France, Japan, Spain, Sweden, the UK and the USA. CHD mortality between 1980 and 2007 was obtained from WHO Statistical Information System. National data on traditional risk factors during the same period were obtained from literature and national surveys.Results: Age-adjusted CHD mortality continuously declined between 1980 and 2007 in all these countries. The decline was accompanied by a constant fall in total cholesterol except Japan where total cholesterol continuously rose. In the birth cohort of individuals currently aged 50-69 years, levels of total cholesterol have been higher in Japan than in the USA, yet CHD mortality in Japan remained the lowest: >67% lower in men and > 75% lower in women compared with the USA. The direction and magnitude of changes in other risk factors were generally similar between Japan and the other countries.Conclusions: Decline in CHD mortality despite a continuous rise in total cholesterol is unique. The observation may suggest some protective factors unique to Japanese. [ABSTRACT FROM AUTHOR]

Background: Evidence suggests that in utero exposure to undernutrition and overnutrition might affect adiposity in later life. Epigenetic modification is suggested as a plausible mediating mechanism.Methods: We used multivariable linear regression and a negative control design to examine offspring epigenome-wide DNA methylation in relation to maternal and offspring adiposity in 1018 participants.Results: Compared with neonatal offspring of normal weight mothers, 28 and 1621 CpG sites were differentially methylated in offspring of obese and underweight mothers, respectively [false discovert rate (FDR)-corrected P-value < 0.05), with no overlap in the sites that maternal obesity and underweight relate to. A positive association, where higher methylation is associated with a body mass index (BMI) outside the normal range, was seen at 78.6% of the sites associated with obesity and 87.9% of the sites associated with underweight. Associations of maternal obesity with offspring methylation were stronger than associations of paternal obesity, supporting an intrauterine mechanism. There were no consistent associations of gestational weight gain with offspring DNA methylation. In general, sites that were hypermethylated in association with maternal obesity or hypomethylated in association with maternal underweight tended to be positively associated with offspring adiposity, and sites hypomethylated in association with maternal obesity or hypermethylated in association with maternal underweight tended to be inversely associated with offspring adiposity.Conclusions: Our data suggest that both maternal obesity and, to a larger degree, underweight affect the neonatal epigenome via an intrauterine mechanism, but weight gain during pregnancy has little effect. We found some evidence that associations of maternal underweight with lower offspring adiposity and maternal obesity with greater offspring adiposity may be mediated via increased DNA methylation. [ABSTRACT FROM AUTHOR]

The UK Millennium Cohort Study (MCS) is an observational, multidisciplinary cohort study that was set up to follow the lives of children born at the turn of the new century. The MCS is nationally representative and 18 552 families (18 827 children) were recruited to the cohort in the first sweep. There have currently been five main sweeps of data collection, at ages 9 months and 3, 5, 7 and 11 years. A further sweep of data collection is planned for age 14 years. A range of health-related data have been collected as well as measures concerning child development, cognitive ability and educational attainment. The data also include a wealth of information describing the social, economic and demographic characteristics of the cohort members and their families. In addition, the MCS data have been linked to administrative data resources including health records. The MCS provides a unique and valuable resource for the analysis of health outcomes and health inequalities. The MCS data are freely available to bona fide researchers under standard access conditions via the UK Data Service (http://ukdataservice.ac.uk) and the MCS website provides detailed information on the study (http://www.cls.ioe.ac.uk/mcs). [ABSTRACT FROM AUTHOR]

Background The UK Biobank study provides a unique opportunity to study the causes and consequences of disease. We aimed to use the UK Biobank data to study the well-established, but poorly understood, association between low birthweight and type 2 diabetes.Methods We used logistic regression to calculate the odds ratio for participants’ risk of type 2 diabetes given a one standard deviation increase in birthweight. To test for an association between parental diabetes and birthweight, we performed linear regression of self-reported parental diabetes status against birthweight. We performed path and mediation analyses to test the hypothesis that birthweight partly mediates the association between parental diabetes and participant type 2 diabetes status.Results Of the UK Biobank participants, 277 261 reported their birthweight. Of 257 715 individuals of White ethnicity and singleton pregnancies, 6576 had type 2 diabetes, 19 478 reported maternal diabetes (but not paternal), 20 057 reported paternal diabetes (but not maternal) and 2754 participants reported both parents as having diabetes. Lower birthweight was associated with type 2 diabetes in the UK Biobank participants. A one kilogram increase in birthweight was associated with a lower risk of type 2 diabetes (odds ratio: 0.74; 95% CI: 0.71, 0.76; P = 2 × 10−57). Paternal diabetes was associated with lower birthweight (45 g lower; 95% CI: 36, 54; P = 2 × 10−23) relative to individuals with no parental diabetes. Maternal diabetes was associated with higher birthweight (59 g increase; 95% CI: 50, 68; P = 3 × 10−37). Participants’ lower birthweight was a mediator of the association between reported paternal diabetes and participants’ type 2 diabetes status, explaining 1.1% of the association, and participants’ higher birthweight was a mediator of the association between reported maternal diabetes and participants’ type 2 diabetes status, explaining 1.2% of the association.Conclusions Data from the UK Biobank provides the strongest evidence by far that paternal diabetes is associated with lower birthweight, whereas maternal diabetes is associated with increased birthweight. Our findings with paternal diabetes are consistent with a role for the same genetic factors influencing foetal growth and type 2 diabetes. [ABSTRACT FROM PUBLISHER]

The UK's largest registry of adult twins, or TwinsUK Registry, started in 1992 and encompasses about 12 000 volunteer twins from all over the United Kingdom. More than 70% of the registered twins have filled at least one detailed health questionnaire and about half of them undergone a baseline comprehensive assessment and two follow-up clinical evaluations. The most recent follow-up visit, known as Healthy Ageing Twin Study (HATS), involved 3125 female twins aged >40 years with at least one previous clinical assessment to enable inspection of longitudinal changes in ageing traits and their genetic and environmental components. The study benefits from several state-of-the-art OMICs studies including genome-wide association, next-generation genome and transcriptome sequencing, and epigenetic and metabolomic profiles. This makes our cohort as one of the most deeply phenotyped and genotyped in the world. Several collaborative projects in the field of epidemiology of complex disorders are ongoing in our cohort and interested researchers are encouraged to get in contact for future collaborations. [ABSTRACT FROM PUBLISHER]

Sir James Mackenzie is generally accepted as the founder of research by general practitioners in Great Britain, studying their own patients where and how they actually live. His pioneering work on arrhythmias was a foundation for modern cardiology, consolidated by his pupil Thomas Lewis, Britain’s first full-time clinical researcher for the Medical Research Council. Mackenzie became a dominant figure in public imagination, more widely celebrated than any later generalist. At the clinical research institute he founded at St Andrews in 1919, he hoped to set in train a permanent and growing body of longitudinal clinical research outside hospitals, by community generalists studying their own patients. This article tries to explain the failure of this project: how it influenced later research by general practitioners and others in primary care after creation of the National Health Service (NHS) in 1948 and its relevance today to primary care research policy. Such research is now becoming an urgent necessity, for the British National Health Service to survive as a public service and as a foundation for democratic development of biosciences. [ABSTRACT FROM PUBLISHER]

Background Educational attainment is highly correlated with social inequalities in adult cognitive health; however, the nature of this correlation is in dispute. Recently, researchers have argued that educational inequalities are an artefact of selection by individual differences in prior cognitive ability, which both drives educational attainment and tracks across the rest of the life course. Although few would deny that educational attainment is at least partly determined by prior cognitive ability, a complementary, yet controversial, view is that education has a direct causal and lasting benefit on cognitive development.Methods We use observational data from three birth cohorts, with cognition measured in adolescence and adulthood. Ordinary least squares regression was used to model the relationship between adolescent cognition and adult fluid cognition and to test the sensitivity of our analyses to sample selection, projection and backdoor biases using propensity score matching.Results We find that having a university education is correlated with higher fluid cognition in adulthood, after adjustment for adolescent cognition. We do not find that adolescent cognition, gender or parental social class consistently modify this effect; however, women benefited more in the 1946 sample from Great Britain.Conclusions In all three birth cohorts, substantial educational benefit remained after adjustment for adolescent cognition and parental social class, offsetting an effect equivalent of 0.5 to 1.5 standard deviations lower adolescent cognition. We also find that the likelihood of earning a university degree depends in part on adolescent cognition, gender and parental social class. We conclude that inequalities in adult cognition derive in part from educational experiences after adolescence. [ABSTRACT FROM PUBLISHER]