Publications by authors named "Laura D Howe"

140 Publications

Long-term cost-effectiveness of interventions for obesity: A mendelian randomisation study.

PLoS Med 2021 Aug 27;18(8):e1003725. Epub 2021 Aug 27.

MRC Integrative Epidemiology Unit (IEU), Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom.

Background: The prevalence of obesity has increased in the United Kingdom, and reliably measuring the impact on quality of life and the total healthcare cost from obesity is key to informing the cost-effectiveness of interventions that target obesity, and determining healthcare funding. Current methods for estimating cost-effectiveness of interventions for obesity may be subject to confounding and reverse causation. The aim of this study is to apply a new approach using mendelian randomisation for estimating the cost-effectiveness of interventions that target body mass index (BMI), which may be less affected by confounding and reverse causation than previous approaches.

Methods And Findings: We estimated health-related quality-adjusted life years (QALYs) and both primary and secondary healthcare costs for 310,913 men and women of white British ancestry aged between 39 and 72 years in UK Biobank between recruitment (2006 to 2010) and 31 March 2017. We then estimated the causal effect of differences in BMI on QALYs and total healthcare costs using mendelian randomisation. For this, we used instrumental variable regression with a polygenic risk score (PRS) for BMI, derived using a genome-wide association study (GWAS) of BMI, with age, sex, recruitment centre, and 40 genetic principal components as covariables to estimate the effect of a unit increase in BMI on QALYs and total healthcare costs. Finally, we used simulations to estimate the likely effect on BMI of policy relevant interventions for BMI, then used the mendelian randomisation estimates to estimate the cost-effectiveness of these interventions. A unit increase in BMI decreased QALYs by 0.65% of a QALY (95% confidence interval [CI]: 0.49% to 0.81%) per year and increased annual total healthcare costs by £42.23 (95% CI: £32.95 to £51.51) per person. When considering only health conditions usually considered in previous cost-effectiveness modelling studies (cancer, cardiovascular disease, cerebrovascular disease, and type 2 diabetes), we estimated that a unit increase in BMI decreased QALYs by only 0.16% of a QALY (95% CI: 0.10% to 0.22%) per year. We estimated that both laparoscopic bariatric surgery among individuals with BMI greater than 35 kg/m2, and restricting volume promotions for high fat, salt, and sugar products, would increase QALYs and decrease total healthcare costs, with net monetary benefits (at £20,000 per QALY) of £13,936 (95% CI: £8,112 to £20,658) per person over 20 years, and £546 million (95% CI: £435 million to £671 million) in total per year, respectively. The main limitations of this approach are that mendelian randomisation relies on assumptions that cannot be proven, including the absence of directional pleiotropy, and that genotypes are independent of confounders.

Conclusions: Mendelian randomisation can be used to estimate the impact of interventions on quality of life and healthcare costs. We observed that the effect of increasing BMI on health-related quality of life is much larger when accounting for 240 chronic health conditions, compared with only a limited selection. This means that previous cost-effectiveness studies have likely underestimated the effect of BMI on quality of life and, therefore, the potential cost-effectiveness of interventions to reduce BMI.
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http://dx.doi.org/10.1371/journal.pmed.1003725DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8437285PMC
August 2021

Early adulthood socioeconomic trajectories contribute to inequalities in adult cardiovascular health, independently of childhood and adulthood socioeconomic position.

J Epidemiol Community Health 2021 Aug 6. Epub 2021 Aug 6.

MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.

Background: Cardiovascular health shows significant socioeconomic inequalities, however there is little understanding of the role of early adulthood in generation of these inequalities. We assessed the contribution of socioeconomic trajectories during early adulthood (16-24 years) to cardiovascular health in mid-adulthood (46 years).

Methods: Participants from the 1970 British Cohort Study with socioeconomic data available in early adulthood were included (n=12 423). Longitudinal latent class analysis identified socioeconomic trajectories, based on patterns of economic activity throughout early adulthood. Cardiometabolic risk factors (46 years) were regressed on socioeconomic trajectory class (16-24 years), testing mediation by adult socioeconomic position (46 years). Models were stratified by sex and adjusted for childhood socioeconomic position (SEP) and adolescent health.

Results: Six early adulthood socioeconomic trajectories were identified: (1) Continued Education (20.2%), (2) Managerial Employment (16.0%), (3) Skilled Non-manual Employment (20.9%), (4) Skilled Manual Employment (18.9%), (5) Partly Skilled Employment (15.8%) and (6) Economically Inactive (8.1%). The 'Continued Education' trajectory class showed the best cardiovascular health at age 46 years, with the lowest levels of cardiometabolic risk factors. For example, systolic blood pressure was 128.9 mm Hg (95% CI 127.8 to 130.0) among men in the 'Continued Education' class, compared with 131.3 mm Hg (95% CI 130.4 to 132.2) among men in the 'Skilled Manual' class. Patterns across classes 2-6 differed by risk factor and sex. The observed associations were largely not mediated by SEP at age 46 years.

Conclusion: Findings suggest an independent contribution of early adulthood socioeconomic trajectories to development of later life cardiovascular inequalities. Further work is needed to understand mediators of this relationship and potential for interventions to mitigate these pathways.
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http://dx.doi.org/10.1136/jech-2021-216611DOI Listing
August 2021

Testosterone and socioeconomic position: Mendelian randomization in 306,248 men and women in UK Biobank.

Sci Adv 2021 Jul 28;7(31). Epub 2021 Jul 28.

MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.

Men with more advantaged socioeconomic position (SEP) have been observed to have higher levels of testosterone. It is unclear whether these associations arise because testosterone has a causal impact on SEP. In 306,248 participants of UK Biobank, we performed sex-stratified genome-wide association analysis to identify genetic variants associated with testosterone. Using the identified variants, we performed Mendelian randomization analysis of the influence of testosterone on socioeconomic position, including income, employment status, neighborhood-level deprivation, and educational qualifications; on health, including self-rated health and body mass index; and on risk-taking behavior. We found little evidence that testosterone affected socioeconomic position, health, or risk-taking. Our results therefore suggest that it is unlikely that testosterone meaningfully affects these outcomes in men or women. Differences between Mendelian randomization and multivariable-adjusted estimates suggest that previously reported associations with socioeconomic position and health may be due to residual confounding or reverse causation.
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http://dx.doi.org/10.1126/sciadv.abf8257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8318368PMC
July 2021

Cross-sectional analysis of educational inequalities in primary prevention statin use in UK Biobank.

Heart 2021 Jul 27. Epub 2021 Jul 27.

Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, UK.

Objective: Identify whether participants with lower education are less likely to report taking statins for primary cardiovascular prevention than those with higher education, but an equivalent increase in underlying cardiovascular risk.

Methods: Using data from a large prospective cohort study, UK Biobank, we calculated a QRISK3 cardiovascular risk score for 472 097 eligible participants with complete data on self-reported educational attainment and statin use (55% female participants; mean age 56 years). We used logistic regression to explore the association between (i) QRISK3 score and (ii) educational attainment on self-reported statin use. We then stratified the association between QRISK3 score and statin use, by educational attainment to test for interactions.

Results: There was evidence of an interaction between QRISK3 score and educational attainment. Per unit increase in QRISK3 score, more educated individuals were more likely to report taking statins. In women with ≤7 years of schooling, a one unit increase in QRISK3 score was associated with a 7% higher odds of statin use (OR 1.07, 95% CI 1.07 to 1.07). In women with ≥20 years of schooling, a one unit increase in QRISK3 score was associated with an 14% higher odds of statin use (OR 1.14, 95% CI 1.14 to 1.15). Comparable ORs in men were 1.04 (95% CI 1.04 to 1.05) for ≤7 years of schooling and 1.08 (95% CI 1.08, 1.08) for ≥20 years of schooling.

Conclusion: Per unit increase in QRISK3 score, individuals with lower educational attainment were less likely to report using statins, likely contributing to health inequalities.
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http://dx.doi.org/10.1136/heartjnl-2021-319238DOI Listing
July 2021

Interrogating structural inequalities in COVID-19 mortality in England and Wales.

J Epidemiol Community Health 2021 Jul 20. Epub 2021 Jul 20.

Department of Public Health and Policy, University of Liverpool, Liverpool, UK.

Background: Numerous observational studies have highlighted structural inequalities in COVID-19 mortality in the UK. Such studies often fail to consider the hierarchical, spatial nature of such inequalities in their analysis, leading to the potential for bias and an inability to reach conclusions about the most appropriate structural levels for policy intervention.

Methods: We use publicly available population data on COVID-19-related mortality and all-cause mortality between March and July 2020 in England and Wales to investigate the spatial scale of such inequalities. We propose a multiscale approach to simultaneously consider three spatial scales at which processes driving inequality may act and apportion inequality between these.

Results: Adjusting for population age structure and number of local care homes we find highest regional inequality in March and June/July. We find finer grained within region inequality increased steadily from March until July. The importance of spatial context increases over the study period. No analogous pattern is visible for non-COVID-19 mortality. Higher relative deprivation is associated with increased COVID-19 mortality at all stages of the pandemic but does not explain structural inequalities.

Conclusions: Results support initial stochastic viral introduction in the South, with initially high inequality decreasing before the establishment of regional trends by June and July, prior to reported regionality of the 'second-wave'. We outline how this framework can help identify structural factors driving such processes, and offer suggestions for a long-term, locally targeted model of pandemic relief in tandem with regional support to buffer the social context of the area.
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http://dx.doi.org/10.1136/jech-2021-216666DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8295019PMC
July 2021

Effects of increased body mass index on employment status: a Mendelian randomisation study.

Int J Obes (Lond) 2021 08 22;45(8):1790-1801. Epub 2021 Jun 22.

MRC/CSO Social & Public Health Sciences Unit, University of Glasgow, Glasgow, UK.

Background: The obesity epidemic may have substantial implications for the global workforce, including causal effects on employment, but clear evidence is lacking. Obesity may prevent people from being in paid work through poor health or through social discrimination. We studied genetic variants robustly associated with body mass index (BMI) to investigate its causal effects on employment.

Dataset/methods: White UK ethnicity participants of working age (men 40-64 years, women 40-59 years), with suitable genetic data were selected in the UK Biobank study (N = 230,791). Employment status was categorised in two ways: first, contrasting being in paid employment with any other status; and second, contrasting being in paid employment with sickness/disability, unemployment, early retirement and caring for home/family. Socioeconomic indicators also investigated were hours worked, household income, educational attainment and Townsend deprivation index (TDI). We conducted observational and two-sample Mendelian randomisation (MR) analyses to investigate the effect of increased BMI on employment-related outcomes.

Results: Regressions showed BMI associated with all the employment-related outcomes investigated. MR analyses provided evidence for higher BMI causing increased risk of sickness/disability (OR 1.08, 95% CI 1.04, 1.11, per 1 Kg/m BMI increase) and decreased caring for home/family (OR 0.96, 95% CI 0.93, 0.99), higher TDI (Beta 0.038, 95% CI 0.018, 0.059), and lower household income (OR 0.98, 95% CI 0.96, 0.99). In contrast, MR provided evidence for no causal effect of BMI on unemployment, early retirement, non-employment, hours worked or educational attainment. There was little evidence for causal effects differing by sex or age. Robustness tests yielded consistent results.

Discussion: BMI appears to exert a causal effect on employment status, largely by affecting an individual's health rather than through increased unemployment arising from social discrimination. The obesity epidemic may be contributing to increased worklessness and therefore could impose a substantial societal burden.
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http://dx.doi.org/10.1038/s41366-021-00846-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8310793PMC
August 2021

Blood pressure variability and night-time dipping assessed by 24-hour ambulatory monitoring: Cross-sectional association with cardiac structure in adolescents.

PLoS One 2021 16;16(6):e0253196. Epub 2021 Jun 16.

MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, United Kingdom.

Greater blood pressure (BP) is associated with greater left ventricular mass indexed to height2.7 (LVMi2.7) in adolescents. This study examined whether greater BP variability and reduced night-time dipping are associated with cardiac remodeling in a general population of adolescents. A cross-sectional analysis was undertaken in 587 UK adolescents (mean age 17.7 years; 43.1% male). BP was measured in a research clinic and using 24-hour ambulatory monitoring. We examined associations (for both systolic and diastolic BP) of: 1) clinic and 24-hour mean BP; 2) measures of 24-hour BP variability: standard deviation weighted for day/night (SDdn), variability independent of the mean (VIM) and average real variability (ARV); and 3) night-time dipping with cardiac structures. Cardiac structures were assessed by echocardiography: 1) LVMi2.7; 2) relative wall thickness (RWT); 3) left atrial diameter indexed to height (LADi) and 4) left ventricular internal diameter in diastole (LVIDD). Higher systolic BP was associated with greater LVMi2.7. Systolic and diastolic BP were associated with greater RWT. Associations were inconsistent for LADi and LVIDD. There was evidence for associations between both greater SDdn and ARV and higher RWT (per 1 SD higher diastolic ARV, mean difference in RWT was 0.13 SDs, 95% CI 0.045 to 0.21); these associations with RWT remained after adjustment for mean BP. There was no consistent evidence of associations between night-time dipping and cardiac structure. Measurement of BP variability, even in adolescents with blood pressure in the physiologic range, might benefit risk of cardiovascular remodeling assessment.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0253196PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8208567PMC
June 2021

Is genetic liability to ADHD and ASD causally linked to educational attainment?

Int J Epidemiol 2021 Jun 7. Epub 2021 Jun 7.

Medical Research Council Integrative Epidemiology Unit, Bristol Medical School, University of Bristol, Bristol, UK.

Background: The association patterns of Attention Deficit Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD) with educational attainment (EA) are complex; children with ADHD and ASD are at risk of poor academic outcomes, and parental EA has been associated with risk of ADHD/ASD in the offspring. Little is known on the causal links between ADHD, ASD, EA and the potential contribution of cognitive ability.

Methods: Using the latest genome-wide association studies (GWAS) summary data on ADHD, ASD and EA, we applied two-sample Mendelian randomization (MR) to assess the effects of genetic liability to ADHD and ASD on EA. Reverse direction analyses were additionally performed. Multivariable MR was performed to estimate any effects independent of cognitive ability.

Results: Genetic liability to ADHD had a negative effect on EA, independently of cognitive ability (MVMRIVW: -1.7 months of education per doubling of genetic liability to ADHD; 95% CI: -2.8 to -0.7), whereas genetic liability to ASD a positive effect (MVMRIVW: 30 days per doubling of the genetic liability to ASD; 95% CI: 2 to 53). Reverse direction analyses suggested that genetic liability to higher EA had an effect on lower risk of ADHD, independently of cognitive ability (MVMRIVWOR: 0.33 per SD increase; 95% CI: 0.26 to 0.43) and increased risk of ASD (MRIVWOR: 1.51 per SD increase; 95% CI: 1.29 to 1.77), which was partly explained by cognitive ability (MVMRIVWOR per SD increase: 1.24; 95%CI: 0.96 to 1.60).

Conclusions: Genetic liability to ADHD and ASD is likely to affect educational attainment, independently of underlying cognitive ability.
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http://dx.doi.org/10.1093/ije/dyab107DOI Listing
June 2021

How does childhood maltreatment influence cardiovascular disease? A sequential causal mediation analysis.

Int J Epidemiol 2021 May 26. Epub 2021 May 26.

Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.

Background: Childhood maltreatment has been consistently associated with cardiovascular disease (CVD). However, the mechanisms of this relationship are not yet fully understood. We explored the relative contribution of anxiety/depression, smoking, body mass index (BMI) and inflammation (C-reactive protein, CRP) to the association between childhood maltreatment and CVD in men and women aged 40-69 years in the UK.

Methods: We used data from 40 596 men and 59 511 women from UK Biobank. To estimate the indirect effects of childhood maltreatment (physical, sexual and emotional abuse, and emotional and physical neglect) on incident CVD via each of the mediators, we applied a sequential mediation approach.

Results: All forms of maltreatment were associated with increased CVD risk [hazard ratios (HRs) ranging from 1.09 to 1.27]. Together, anxiety/depression, smoking, BMI and inflammation (indexed by CRP) mediated 26-90% of the association between childhood maltreatment and CVD, and the contribution of these mediators differed by type of maltreatment and sex. Anxiety/depression mediated the largest proportion of the association of sexual abuse, emotional abuse and emotional neglect with CVD (accounting for 16-43% of the total effect), especially in women. In men, BMI contributed the most to the indirect effect of associations of physical abuse and physical neglect with CVD; in women, anxiety/depression and BMI had similar contributions.

Conclusions: These findings add to the understanding of how childhood maltreatment affects CVD risk and identify modifiable mediating factors that could potentially reduce the burden of CVD in people exposed to maltreatment in early life.
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http://dx.doi.org/10.1093/ije/dyab085DOI Listing
May 2021

Mendelian randomisation for mediation analysis: current methods and challenges for implementation.

Eur J Epidemiol 2021 May 7;36(5):465-478. Epub 2021 May 7.

MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.

Mediation analysis seeks to explain the pathway(s) through which an exposure affects an outcome. Traditional, non-instrumental variable methods for mediation analysis experience a number of methodological difficulties, including bias due to confounding between an exposure, mediator and outcome and measurement error. Mendelian randomisation (MR) can be used to improve causal inference for mediation analysis. We describe two approaches that can be used for estimating mediation analysis with MR: multivariable MR (MVMR) and two-step MR. We outline the approaches and provide code to demonstrate how they can be used in mediation analysis. We review issues that can affect analyses, including confounding, measurement error, weak instrument bias, interactions between exposures and mediators and analysis of multiple mediators. Description of the methods is supplemented by simulated and real data examples. Although MR relies on large sample sizes and strong assumptions, such as having strong instruments and no horizontally pleiotropic pathways, our simulations demonstrate that these methods are unaffected by confounders of the exposure or mediator and the outcome and non-differential measurement error of the exposure or mediator. Both MVMR and two-step MR can be implemented in both individual-level MR and summary data MR. MR mediation methods require different assumptions to be made, compared with non-instrumental variable mediation methods. Where these assumptions are more plausible, MR can be used to improve causal inference in mediation analysis.
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http://dx.doi.org/10.1007/s10654-021-00757-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8159796PMC
May 2021

Early childhood weight gain: Latent patterns and body composition outcomes.

Paediatr Perinat Epidemiol 2021 Sep 7;35(5):557-568. Epub 2021 May 7.

School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, UK.

Background: Despite early childhood weight gain being a key indicator of obesity risk, we do not have a good understanding of the different patterns that exist.

Objectives: To identify and characterise distinct groups of children displaying similar early-life weight trajectories.

Methods: A growth mixture model captured heterogeneity in weight trajectories between 0 and 60 months in 1390 children in the Avon Longitudinal Study of Parents and Children. Differences between the classes in characteristics and body size/composition at 9 years were investigated.

Results: The best model had five classes. The "Normal" (45%) and "Normal after initial catch-down" (24%) classes were close to the 50th centile of a growth standard between 24 and 60 months. The "High-decreasing" (21%) and "Stable-high" (7%) classes peaked at the ~91st centile at 12-18 months, but while the former declined to the ~75th centile and comprised constitutionally big children, the latter did not. The "Rapidly increasing" (3%) class gained weight from below the 50th centile at 4 months to above the 91st centile at 60 months. By 9 years, their mean body mass index (BMI) placed them at the 98th centile. This class was characterised by the highest maternal BMI; highest parity; highest levels of gestational hypertension and diabetes; and the lowest socio-economic position. At 9 years, the "Rapidly increasing" class was estimated to have 68.2% (95% confidence interval [CI] 48.3, 88.1) more fat mass than the "Normal" class, but only 14.0% (95% CI 9.1, 18.9) more lean mass.

Conclusions: Criteria used in growth monitoring practice are unlikely to consistently distinguish between the different patterns of weight gain reported here.
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http://dx.doi.org/10.1111/ppe.12754DOI Listing
September 2021

Cardiorespiratory fitness, fatness, and the acute blood pressure response to exercise in adolescence.

Scand J Med Sci Sports 2021 Aug 8;31(8):1693-1698. Epub 2021 May 8.

Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia.

Objective: Exaggerated exercise blood pressure (BP) is associated with cardiovascular risk factors in adolescence. Cardiorespiratory fitness and adiposity (fatness) are independent contributors to cardiovascular risk, but their interrelated associations with exercise BP are unknown. This study aimed to determine the relationships between fitness, fatness, and the acute BP response to exercise in a large birth cohort of adolescents.

Methods: 2292 adolescents from the Avon Longitudinal Study of Parents and Children (aged 17.8 ± 0.4 years, 38.5% male) completed a sub-maximal exercise step test that allowed fitness (VO ) to be determined from workload and heart rate using a validated equation. Exercise BP was measured immediately on test cessation and fatness calculated as the ratio of total fat mass to total body mass measured by DXA.

Results: Post-exercise systolic BP decreased stepwise with tertile of fitness (146 (18); 142 (17); 141 (16) mmHg) but increased with tertile of fatness (138 (15); 142 (16); 149 (18) mmHg). In separate models, fitness and fatness were associated with post-exercise systolic BP adjusted for sex, age, height, smoking, and socioeconomic status (standardized β: -1.80, 95%CI: -2.64, -0.95 mmHg/SD and 4.31, 95%CI: 3.49, 5.13 mmHg/SD). However, when fitness and fatness were included in the same model, only fatness remained associated with exercise BP (4.65, 95%CI: 3.69, 5.61 mmHg/SD).

Conclusion: Both fitness and fatness are associated with the acute BP response to exercise in adolescence. The fitness-exercise BP association was not independent of fatness, implying the cardiovascular protective effects of cardiorespiratory fitness may only be realized with more favorable body composition.
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http://dx.doi.org/10.1111/sms.13976DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611236PMC
August 2021

Puberty timing and markers of cardiovascular structure and function at 25 years: a prospective cohort study.

BMC Med 2021 03 25;19(1):78. Epub 2021 Mar 25.

School of Public Health, University College Cork, Cork, Ireland.

Background: Whether earlier onset of puberty is associated with higher cardiovascular risk in early adulthood is not well understood. Our objective was to examine the association between puberty timing and markers of cardiovascular structure and function at age 25 years.

Methods: We conducted a prospective birth cohort study using data from the Avon Longitudinal Study of Parents and Children (ALSPAC). Participants were born between April 1, 1991, and December 31, 1992. Exposure of interest was age at peak height velocity (aPHV), an objective and validated growth-based measure of puberty onset. Outcome measures included cardiovascular structure and function at age 25 years: carotid intima-media thickness (CIMT), left ventricular mass index (LVMI) and relative wall thickness (RWT), pulse wave velocity (PWV) and systolic blood pressure (SBP). Multiple imputation was used to impute missing data on covariates and outcomes. Linear regression was used to examine the association between aPHV and each measure of cardiac structure and function, adjusting for maternal age, gestational age, household social class, maternal education, mother's partner's education, breastfeeding, parity, birthweight, maternal body mass index, maternal marital status, maternal prenatal smoking status and height and fat mass at age 9. All analyses were stratified by sex.

Results: A total of 2752-4571 participants were included in the imputed analyses. A 1-year older aPHV was not strongly associated with markers of cardiac structure and function in males and females at 25 years and most results spanned the null value. In adjusted analyses, a 1-year older aPHV was associated with 0.003 mm (95% confidence interval (CI) 0.00001, 0.006) and 0.0008 mm (95% CI - 0.002, 0.003) higher CIMT; 0.02 m/s (95% CI - 0.05, 0.09) and 0.02 m/s (95% CI - 0.04, 0.09) higher PWV; and 0.003 mmHg (95% CI - 0.60, 0.60) and 0.13 mmHg (95% CI - 0.44, 0.70) higher SBP, among males and females, respectively. A 1-year older aPHV was associated with - 0.55 g/m (95% CI - 0.03, - 1.08) and - 0.89 g/m (95% CI - 0.45, - 1.34) lower LVMI and - 0.001 (95% CI - 0.006, 0.002) and - 0.002 (95% CI - 0.006, 0.002) lower RWT among males and females.

Conclusions: Earlier puberty is unlikely to have a major impact on pre-clinical cardiovascular risk in early adulthood.
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http://dx.doi.org/10.1186/s12916-021-01949-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7992788PMC
March 2021

Is being a 'left-behind' child associated with an increased risk of self-poisoning in adulthood? Findings from a case-control study in Sri Lanka.

BMJ Glob Health 2021 03;6(3)

South Asian Clinical Toxicology Research Collaboration, Faculty of Medicine, University of Peradeniya, Peradeniya, Sri Lanka.

Purpose: The long-term consequences of parental emigration on offspring self-harm risk is unknown.

Methods: We investigated the association between experiencing parental emigration in childhood with hospital presentations for self-poisoning in adulthood using a hospital case-control study. Cases were adult self-poisoning patients (≥18 year olds) admitted to the medical toxicology ward Teaching Hospital Peradeniya, Sri Lanka. Sex and age frequency matched controls were recruited from the outpatient department or nearby specialist clinics at the same hospital. Details of parental emigration were collected using a pre-piloted questionnaire. The relationship between parental emigration and self-poisoning in adulthood was estimated using logistic regression models.

Results: 298 cases, and 500 hospital controls were interviewed for the study. We estimate that one in five adults experienced parental emmigration as children (95% CI 17% to 24%). We find limited evidence that children from households with emigrating parents were more likely to experience adverse childhood experiences than those with non-emigrating parents. We found no statistical evidence of an increased risk of self-poisoning in adulthood in individuals who experienced parental emigration (maternal or paternal) during childhood. There was no statistical evidence that the impact differed by the sex of the participant.

Conclusion: Adults who experienced parental emigration as children were no more likely to self-poison than adults with non-emigrating parents. Further research using longitudinal data are needed to understand whether any adverse outcomes observed in 'left-behind' children are a consequence of parental emigration or due to factors associated but predate the emigration. Prospective data are also important to investigate whether there are any lasting effects on children who experience parental emigration.
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http://dx.doi.org/10.1136/bmjgh-2020-003734DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7925243PMC
March 2021

Sex differences in systemic metabolites at four life stages: cohort study with repeated metabolomics.

BMC Med 2021 02 24;19(1):58. Epub 2021 Feb 24.

MRC Integrative Epidemiology Unit at the University of Bristol, Oakfield House, Bristol, BS8 2BN, UK.

Background: Males experience higher rates of coronary heart disease (CHD) than females, but the circulating traits underpinning this difference are poorly understood. We examined sex differences in systemic metabolites measured at four life stages, spanning childhood to middle adulthood.

Methods: Data were from the Avon Longitudinal Study of Parents and Children (7727 offspring, 49% male; and 6500 parents, 29% male). Proton nuclear magnetic resonance (H-NMR) spectroscopy from a targeted metabolomics platform was performed on EDTA-plasma or serum samples to quantify 229 systemic metabolites (including lipoprotein-subclass-specific lipids, pre-glycaemic factors, and inflammatory glycoprotein acetyls). Metabolites were measured in the same offspring once in childhood (mean age 8 years), twice in adolescence (16 years and 18 years) and once in early adulthood (25 years), and in their parents once in middle adulthood (50 years). Linear regression models estimated differences in metabolites for males versus females on each occasion (serial cross-sectional associations).

Results: At 8 years, total lipids in very-low-density lipoproteins (VLDL) were lower in males; levels were higher in males at 16 years and higher still by 18 years and 50 years (among parents) for medium-or-larger subclasses. Larger sex differences at older ages were most pronounced for VLDL triglycerides-males had 0.19 standard deviations (SD) (95% CI = 0.12, 0.26) higher at 18 years, 0.50 SD (95% CI = 0.42, 0.57) higher at 25 years, and 0.62 SD (95% CI = 0.55, 0.68) higher at 50 years. Low-density lipoprotein (LDL) cholesterol, apolipoprotein-B, and glycoprotein acetyls were generally lower in males across ages. The direction and magnitude of effects were largely unchanged when adjusting for body mass index measured at the time of metabolite assessment on each occasion.

Conclusions: Our results suggest that males begin to have higher VLDL triglyceride levels in adolescence, with larger sex differences at older ages. Sex differences in other CHD-relevant metabolites, including LDL cholesterol, show the opposite pattern with age, with higher levels among females. Such life course trends may inform causal analyses with clinical endpoints in specifying traits which underpin higher age-adjusted CHD rates commonly seen among males.
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http://dx.doi.org/10.1186/s12916-021-01929-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903597PMC
February 2021

Risk factors for intimate partner violence and abuse among adolescents and young adults: findings from a UK population-based cohort.

Wellcome Open Res 2020 21;5:176. Epub 2021 Jan 21.

Department of Population Health Sciences, University of Bristol, Bristol, UK.

Approximately one-third of young people in the UK have suffered intimate partner violence and abuse (IPVA) on reaching adulthood. We need interventions to prevent IPVA in this population, but there is a lack of evidence on who is at greatest risk. We analysed questionnaire data from 3,279 participants of the Avon Longitudinal Study of Parents and Children population-based birth cohort. We estimated the prevalence of IPVA victimisation and perpetration by age 21, by sex, demographic, parenting, mental health, externalising behaviour (e.g. smoking), educational, employment, and adverse childhood factors. Overall, 29% of males and 41% of females reported IPVA victimisation, with 20% and 25% reporting perpetration, respectively (16% and 22% both). The most common type of IPVA was emotional, followed by physical, then sexual. History of anxiety, self-harm, anti-social behaviour, cannabis or illicit (non-cannabis) drug use, or risky sexual behaviour among males and females were associated with a 50% increase in likelihood of IPVA (victimisation or perpetration). Males reporting depression, sexual abuse (not by an intimate partner), witnessing domestic violence, or parental separation were also more likely to experience IPVA. Extreme parental monitoring, high academic achievement during adolescence, and NEET (not being in education, employment, or training) status in young adulthood were associated with reduced risks of IPVA. A range of demographic, mental health, and behavioural factors were associated with increased prevalence of IPVA victimisation or perpetration. Further study of likely complex pathways from these factors to IPVA, to inform primary prevention, is needed.
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http://dx.doi.org/10.12688/wellcomeopenres.16106.3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7848855PMC
January 2021

Exposure to multiple childhood social risk factors and adult body mass index trajectories from ages 20 to 64 years.

Eur J Public Health 2021 04;31(2):385-390

MRC Unit for Lifelong Health and Ageing at UCL, London, UK.

Background: While childhood social risk factors appear to be associated with adult obesity, it is unclear whether exposure to multiple childhood social risk factors is associated with accelerated weight gain during adulthood.

Methods: We used the Medical Research Council National Survey of Health and Development, a British population-based birth cohort study of participants born in 1946, height and weight were measured by nurses at ages 36, 43, 53 and 60-64 and self-reported at 20 and 26 years. The 9 childhood socioeconomic risk factors and 8 binary childhood psychosocial risk factors were measured, with 13 prospectively measured at age 4 years (or at 7 or 11 years if missing) and 3 were recalled when participants were age 43. Multilevel modelling was used to examine the association between the number of childhood social risk factors and changes in body mass index (BMI) with age.

Results: Increasing exposure to a higher number of childhood socioeconomic risk factors was associated with higher mean BMI across adulthood for both sexes and with a faster increase in BMI from 20 to 64 years, among women but not men. Associations remained after adjustment for adult social class. There was no evidence of an association between exposure to childhood psychosocial risk factors and mean BMI in either sex at any age.

Conclusions: Strategies for the prevention and management of weight gain across adulthood may need to tailor interventions in consideration of past exposure to multiple socioeconomic disadvantages experienced during childhood.
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http://dx.doi.org/10.1093/eurpub/ckaa237DOI Listing
April 2021

Common health conditions in childhood and adolescence, school absence, and educational attainment: Mendelian randomization study.

NPJ Sci Learn 2021 Jan 4;6(1). Epub 2021 Jan 4.

Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, BS8 2BN, UK.

Good health is positively related to children's educational outcomes, but relationships may not be causal. Demonstrating a causal influence would strongly support childhood and adolescent health as important for education policy. We applied genetic causal inference methods to assess the causal relationship of common health conditions at age 10 (primary/elementary school) and 13 (mid-secondary/mid-high school) with educational attainment at 16 and school absence at 14-16. Participants were 6113 children from the Avon Longitudinal Study of Parents and Children (ALSPAC). Exposures were symptoms of attention-deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), depression, asthma, migraines and BMI. Genetic liability for these conditions and BMI was indexed by polygenic scores. In non-genetic, multivariate-adjusted models, all health conditions except asthma and migraines were associated with poorer attainment and greater school absence. School absence substantially mediated effects of BMI (39.9% for BMI at 13) and migraines (72.0% at 10), on attainment with more modest mediation for emotional and neurodevelopmental conditions. In genetic models, a unit increase in standardized BMI at 10 predicted a 0.19 S.D. decrease (95% CI: 0.11, 0.28) in attainment at 16, equivalent to around a 1/3 grade lower in all subjects, and 8.7% more school absence (95% CI:1.8%,16.1%). Associations were similar at 13. Genetic liability for ADHD predicted lower attainment but not more absence. Triangulation across multiple approaches supports a causal, negative influence on educational outcomes of BMI and ADHD, but not of ASD, depression, asthma or migraine. Higher BMI in childhood and adolescence may causally impair educational outcomes.
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http://dx.doi.org/10.1038/s41539-020-00080-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7782810PMC
January 2021

Puberty timing and adiposity change across childhood and adolescence: disentangling cause and consequence.

Hum Reprod 2020 12;35(12):2784-2792

School of Public Health, University College Cork, Cork, Ireland.

Study Question: Is earlier puberty more likely a result of adiposity gain in childhood than a cause of adiposity gain in adulthood?

Summary Answer: Pre-pubertal fat mass is associated with earlier puberty timing but puberty timing is not associated with post-pubertal fat mass change.

What Is Known Already: Age at puberty onset has decreased substantially in the last several decades. Whether reducing childhood adiposity prevents earlier puberty and if early puberty prevention itself also has additional independent benefits for prevention of adult adiposity is not well understood.

Study Design, Size, Duration: Prospective birth cohort study of 4176 participants born in 1991/1992 with 18 232 repeated measures of fat mass from age 9 to 18 years.

Participants/materials, Setting, Methods: We used repeated measures of height from 5 to 20 years to identify puberty timing (age at peak height velocity, aPHV) and repeated measures of directly measured fat mass from age 9 to 18 years, from a contemporary UK birth cohort study to model fat mass trajectories by chronological age and by time before and after puberty onset. We then examined associations of these trajectories with puberty timing separately in females and males.

Main Results And The Role Of Chance: In models by chronological age, a 1-year later aPHV was associated with 20.5% (95% confidence interval (CI): 18.6-22.4%) and 23.4% (95% (CI): 21.3-25.5%) lower fat mass in females and males, respectively, at 9 years. These differences were smaller at age 18 years: 7.8% (95% (CI): 5.9-9.6%) and 12.4% (95% (CI): 9.6-15.2%) lower fat mass in females and males per year later aPHV. Trajectories of fat mass by time before and after puberty provided strong evidence for an association of pre-pubertal fat mass with puberty timing, and little evidence of an association of puberty timing with post-pubertal fat mass change. The role of chance is likely to be small in this study given the large sample sizes available.

Limitations, Reasons For Caution: Participants included in our analyses were more socially advantaged than those excluded. The findings of this work may not apply to non-White populations and further work examining associations of puberty timing and fat mass in other ethnicities is required.

Wider Implications Of The Findings: Previous research has relied on self-reported measures of puberty timing such as age of voice breaking in males, has lacked data on pre-and post-pubertal adiposity together and relied predominantly on indirect measures of adiposity such as BMI. This has led to conflicting results on the nature and direction of the association between puberty timing and adiposity in females and males. Our work provides important clarity on this, suggesting that prevention of adiposity in childhood is key for prevention of early puberty, adult adiposity and associated cardiovascular risk. In contrast, our findings suggest that prevention of early puberty without prevention of childhood adiposity would have little impact on prevention of adult adiposity.

Study Funding/competing Interest(s): The UK Medical Research Council and Wellcome (Grant ref: 102215/2/13/2) and the University of Bristol provide core support for Avon Longitudinal Study of Parents and Children (ALSPAC). L.M.O.K. is supported by a UK Medical Research Council Population Health Scientist fellowship (MR/M014509/1) and a Health Research Board (HRB) of Ireland Emerging Investigator Award (EIA-FA-2019-007 SCaRLeT). J.A.B. is supported by the Elizabeth Blackwell Institute for Health Research, University of Bristol and the Wellcome Trust Institutional Strategic Support Fund (204813/Z/16/Z). L.D.H. and A.F. are supported by Career Development Awards from the UK Medical Research Council (grants MR/M020894/1 and MR/M009351/1, respectively). All authors work in a unit that receives funds from the UK Medical Research Council (grant MC_UU_00011/3, MC_UU_00011/6). No competing interests to declare.

Trial Registration Number: N/A.
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http://dx.doi.org/10.1093/humrep/deaa213DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7744159PMC
December 2020

Metabolic profiles of socio-economic position: a multi-cohort analysis.

Int J Epidemiol 2021 07;50(3):768-782

Department of Epidemiology and Biostatistics, MRC Centre for Environment and Health, School of Public Health, Imperial College London, London, UK.

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.
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http://dx.doi.org/10.1093/ije/dyaa188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8271201PMC
July 2021

Is disrupted sleep a risk factor for Alzheimer's disease? Evidence from a two-sample Mendelian randomization analysis.

Int J Epidemiol 2021 07;50(3):817-828

MRC Integrative Epidemiology Unit, at the University of Bristol, Bristol, UK.

Background: It is established that Alzheimer's disease (AD) patients experience sleep disruption. However, it remains unknown whether disruption in the quantity, quality or timing of sleep is a risk factor for the onset of AD.

Methods: We used the largest published genome-wide association studies of self-reported and accelerometer-measured sleep traits (chronotype, duration, fragmentation, insomnia, daytime napping and daytime sleepiness), and AD. Mendelian randomization (MR) was used to estimate the causal effect of self-reported and accelerometer-measured sleep parameters on AD risk.

Results: Overall, there was little evidence to support a causal effect of sleep traits on AD risk. There was some suggestive evidence that self-reported daytime napping was associated with lower AD risk [odds ratio (OR): 0.70, 95% confidence interval (CI): 0.50-0.99). Some other sleep traits (accelerometer-measured 'eveningness' and sleep duration, and self-reported daytime sleepiness) had ORs of a similar magnitude to daytime napping, but were less precisely estimated.

Conclusions: Overall, we found very limited evidence to support a causal effect of sleep traits on AD risk. Our findings provide tentative evidence that daytime napping may reduce AD risk. Given that this is the first MR study of multiple self-report and objective sleep traits on AD risk, findings should be replicated using independent samples when such data become available.
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http://dx.doi.org/10.1093/ije/dyaa183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8271193PMC
July 2021

Adverse childhood experiences and early life inflammation in the Avon longitudinal study of parents and children.

Psychoneuroendocrinology 2020 12 13;122:104914. Epub 2020 Oct 13.

Medical Research Council Integrative Epidemiology Unit at the University of Bristol, Population Health Sciences, Bristol Medical School, University of Bristol, United Kingdom. Electronic address:

Background: Adverse childhood experiences (ACEs) have been associated with poorer health across the life course. Previous studies have used cumulative risk scores (ACE scores) or individual ACEs but these two approaches have important shortcomings. ACE scores assume that each adversity is equally important for the outcome of interest and the single adversity approach assumes that ACEs do not co-occur. Latent class analysis (LCA) is an alternative approach to operationalising ACEs data, identifying groups of people co-reporting similar ACEs. Here we apply these three approaches for ACEs operationalisation with inflammation in childhood with the aim of identifying particular ACEs or ACE combinations that are particularly associated with higher inflammation in early life.

Methods: Using data from the Avon Longitudinal Study of Parents and Children (ALSPAC) we compare ACE scores, single adversities and LCA-derived ACE clusters in their relationships with Interleukin-6 at age 9 (n = 4935) and C-Reactive Protein (CRP) at age 9 (n = 4887). ACEs included were parental separation/divorce, parental alcohol problems, parental mental health problems, parental offending, inter-parental violence, parental drug misuse, and physical, emotional and sexual abuse.

Results: Two thirds of the sample reported at least one ACE. Mother's mental health problems was the most frequently reported ACE (32.3 %). LCA identified four ACE classes - 'Low ACEs' (81.1 %), 'Maternal mental health problems' (10.3 %), 'Maternal mental health problems and physical abuse' (6.3 %) and 'Parental conflict, mental health problems and emotional abuse' (2.4 %). Parental separation/divorce was associated with higher IL-6. Parental alcohol problems, paternal mental health problems, parental convictions and emotional abuse were associated with lower levels of IL-6. Associations for paternal mental health problems and emotional abuse were only observed for boys. ACE score and LCA-derived ACE classes were not associated with differences in IL-6. Girls in the 'Maternal mental health problems' cluster had lower CRP levels.

Conclusions: Specific adversities and adversity combinations are important for differences in childhood inflammation. Some associations were only observed for girls or boys.
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http://dx.doi.org/10.1016/j.psyneuen.2020.104914DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8188296PMC
December 2020

Joint Modeling of Individual Trajectories, Within-Individual Variability, and a Later Outcome: Systolic Blood Pressure Through Childhood and Left Ventricular Mass in Early Adulthood.

Am J Epidemiol 2021 04;190(4):652-662

Within-individual variability of repeatedly measured exposures might predict later outcomes (e.g., blood pressure (BP) variability (BPV) is an independent cardiovascular risk factor above and beyond mean BP). Because 2-stage methods, known to introduce bias, are typically used to investigate such associations, we introduce a joint modeling approach, examining associations of mean BP and BPV across childhood with left ventricular mass (indexed to height; LVMI) in early adulthood with data (collected 1990-2011) from the UK Avon Longitudinal Study of Parents and Children cohort. Using multilevel models, we allowed BPV to vary between individuals (a "random effect") as well as to depend on covariates (allowing for heteroskedasticity). We further distinguished within-clinic variability ("measurement error") from visit-to-visit BPV. BPV was predicted to be greater at older ages, at higher body weights, and in female participants and was positively correlated with mean BP. BPV had a weak positive association with LVMI (10% increase in within-individual BP variance was predicted to increase LVMI by 0.21%, 95% credible interval: -0.23, 0.69), but this association became negative (-0.78%, 95% credible interval: -2.54, 0.22) once the effect of mean BP on LVMI was adjusted for. This joint modeling approach offers a flexible method of relating repeatedly measured exposures to later outcomes.
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http://dx.doi.org/10.1093/aje/kwaa224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8024053PMC
April 2021

Role of the Metabolic Profile in Mediating the Relationship Between Body Mass Index and Left Ventricular Mass in Adolescents: Analysis of a Prospective Cohort Study.

J Am Heart Assoc 2020 10 8;9(20):e016564. Epub 2020 Oct 8.

MRC Integrative Epidemiology Unit Population Health Sciences University of Bristol United Kingdom.

Background We aimed to quantify the role of the plasma metabolic profile in explaining the effect of adiposity on cardiac structure. Methods and Results Body mass index (BMI) was measured at age 11 in the Avon Longitudinal Study of Parents and Children. Left ventricular mass indexed to height (LVMI) was assessed by echocardiography at age 17. The metabolic profile was quantified via H-nuclear magnetic resonance spectroscopy at age 15. Multivariable confounder (maternal age, parity, highest qualification, maternal smoking, prepregnancy BMI, prepregnancy height, household social class, adolescent birthweight, adolescent smoking, fruit and vegetable consumption, and physical activity)-adjusted linear regression estimated the association of BMI with LVMI and mediation by metabolic traits. We considered 156 metabolomic traits individually and jointly as principal components explaining 95% of the variance in the nuclear magnetic resonance platform and assessed whether the principal components for the metabolic traits added to the proportion of the association explained by putative cardiovascular risk factors (systolic and diastolic blood pressures, insulin, triglycerides, low-density lipoprotein cholesterol, and glucose). A 1 kg/m higher BMI was associated with a 0.70 g/m (95% CI, 0.53-0.88 g/m) and 0.66 g/m (95% CI, 0.53-0.79 g/m) higher LVMI in males (n=437) and females (n=536), respectively. Putative risk factors explained 3% (95% CI, 2%-5%) of this association in males, increasing to 10% (95% CI, 8%-13%) when including metabolic principal components. In females, the standard risk factors explained 3% (95% CI, 2%-5%) of the association and did not increase when including the metabolic principal components. Conclusions The addition of the nuclear magnetic resonance-measured metabolic traits appears to mediate more of the association of BMI on LVMI than the putative risk factors alone in adolescent males, but not females.
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http://dx.doi.org/10.1161/JAHA.120.016564DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7763376PMC
October 2020

The causal effects of health conditions and risk factors on social and socioeconomic outcomes: Mendelian randomization in UK Biobank.

Int J Epidemiol 2020 10;49(5):1661-1681

MRC Integrative Epidemiology Unit (IEU), Bristol Medical School, University of Bristol, Bristol, UK.

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.
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http://dx.doi.org/10.1093/ije/dyaa114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7746412PMC
October 2020

Avoiding dynastic, assortative mating, and population stratification biases in Mendelian randomization through within-family analyses.

Nat Commun 2020 07 14;11(1):3519. Epub 2020 Jul 14.

Medical Research Council Integrative Epidemiology Unit, University of Bristol, BS8 2BN, Bristol, UK.

Estimates from Mendelian randomization studies of unrelated individuals can be biased due to uncontrolled confounding from familial effects. Here we describe methods for within-family Mendelian randomization analyses and use simulation studies to show that family-based analyses can reduce such biases. We illustrate empirically how familial effects can affect estimates using data from 61,008 siblings from the Nord-Trøndelag Health Study and UK Biobank and replicated our findings using 222,368 siblings from 23andMe. Both Mendelian randomization estimates using unrelated individuals and within family methods reproduced established effects of lower BMI reducing risk of diabetes and high blood pressure. However, while Mendelian randomization estimates from samples of unrelated individuals suggested that taller height and lower BMI increase educational attainment, these effects were strongly attenuated in within-family Mendelian randomization analyses. Our findings indicate the necessity of controlling for population structure and familial effects in Mendelian randomization studies.
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http://dx.doi.org/10.1038/s41467-020-17117-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7360778PMC
July 2020

Sex differences in the association between childhood maltreatment and cardiovascular disease in the UK Biobank.

Heart 2020 09 14;106(17):1310-1316. Epub 2020 Jul 14.

Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.

Objectives: To assess and compare associations between childhood maltreatment and cardiovascular disease (CVD) in men and women in the UK. In secondary analyses, we also explored possible age differences and associations with early onset CVD (<50 years).

Methods: We included 157 311 participants from the UK Biobank who had information on physical, sexual or emotional abuse, emotional or physical neglect. CVD outcomes were defined as any CVD, hypertensive disease, ischaemic heart disease (IHD) and cerebrovascular disease. These were extracted from self-report, blood pressure measurements, hospital register and death register. The associations between maltreatment and CVD were assessed using Poisson regression with robust variance to estimate risk ratios, stratified by sex and adjusted for socioeconomic and demographic factors.

Results: All types of maltreatment were associated with increased risk of CVD and IHD in both sexes. Additionally, in women all types of maltreatment were associated with higher risk of hypertensive disease, and all, except emotional neglect, were associated with cerebrovascular disease. In men, all but sexual abuse, were associated with higher risk of hypertensive disease, and all, except physical and sexual abuse, were associated with cerebrovascular disease. Associations were generally stronger in women, and individuals who were younger at baseline had stronger associations of childhood maltreatment with any CVD and IHD, but age differences were less evident when only early onset CVD was considered.

Conclusions: Childhood maltreatment was consistently associated with CVD and stronger associations were generally observed in women and seemed to be stronger for early onset CVD.
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http://dx.doi.org/10.1136/heartjnl-2019-316320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7476280PMC
September 2020

The Clustering of Adverse Childhood Experiences in the Avon Longitudinal Study of Parents and Children: Are Gender and Poverty Important?

J Interpers Violence 2020 Jul 8:886260520935096. Epub 2020 Jul 8.

University College London, UK.

Previous research has demonstrated a graded relationship between the number of Adverse Childhood Experiences reported (an ACE score) and child outcomes. However, ACE scores lack specificity and ignore the patterning of adversities, which are informative for interventions. The aim of the present study was to explore the clustering of ACEs and whether this clustering differs by gender or is predicted by poverty. Data on 8,572 participants of the Avon Longitudinal Study of Parents and Children (ALSPAC) were used. ALSPAC is a regionally representative prenatal cohort of children born between 1991 and 1992 in the Avon region of South-West England. ACEs included parental divorce, death of a close family member, interparental violence, parental mental health problems, parental alcohol misuse, parental drug use, parental convictions, and sexual, emotional, and physical abuse, between birth and 19 years. Latent class analysis was used to derive ACE clusters and associations between poverty, gender, and the derived classes tested using multinomial logistic regression. Five latent classes were identified: "Low ACEs" (55%), "Parental separation and mother's mental health problems" (18%), "Parental mental health problems, convictions and separation" (15%), "Abuse and mental health problems" (6%), and "Poly adversity" (6%). Death of a close family member and sexual abuse did not cluster with other adversities. The clustering did not differ by gender. Poverty was strongly related to both individual ACEs and clusters. These findings demonstrate that ACEs cluster in specific patterns and that poverty is strongly related to this. Therefore, reducing child poverty might be one strategy for reducing ACEs.
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http://dx.doi.org/10.1177/0886260520935096DOI Listing
July 2020

Adverse childhood experiences, DNA methylation age acceleration, and cortisol in UK children: a prospective population-based cohort study.

Clin Epigenetics 2020 04 7;12(1):55. Epub 2020 Apr 7.

MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.

Background: Epigenetic mechanisms may partly explain the persistent effects of adverse childhood experiences (ACEs) on health outcomes in later life. DNA methylation can predict chronological age, and advanced methylation-predicted age beyond chronological age (DNA methylation age acceleration) is associated with ACEs, adverse mental and physical health, and elevated diurnal and baseline salivary cortisol. Childhood adversity is also associated with dysregulation of the hypothalamic-pituitary-adrenal axis, which produces the neuroendocrine hormone cortisol. It remains unknown whether these associations are specific to certain types of adversity. Herein, we investigate the associations of ACEs with DNA methylation age acceleration and plasma cortisol in the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort.

Methods: In this study of the children in ALSPAC, we used multiple linear regression to examine associations of cumulative exposure to ACE, as well as exposure to ten individual types of ACEs, with Horvath-estimated DNA methylation age acceleration and with baseline plasma cortisol. The ten ACEs were those included in the World Health Organization's ACE International Questionnaire. Data on ACEs were prospectively collected from age 0-14 years. DNA methylation age acceleration and plasma cortisol were measured at mean 17.1 years and 15.5 years, respectively.

Results: We included 974 UK children in the present study. Exposure to four or more ACEs compared to zero was associated with DNA methylation age acceleration in girls (β, 95% CI = 1.65, 0.25 to 3.04 years) but not in boys (β, 95% CI = - 0.11, - 1.48 to 1.26 years). Also, in girls, emotional abuse and physical abuse were each associated with DNA methylation age acceleration (β, 95% CI = 1.20, 0.15 to 2.26 years and β, 95% CI = 1.22, 0.06 to 2.38 years, respectively). No other ACEs were associated with accelerated DNA methylation age in either sex. Associations were also null between ACE and cortisol, and cortisol and DNA methylation age acceleration.

Conclusions: In this prospective population-based study of UK children, cumulative ACE exposure, emotional abuse, and physical abuse between age 0 and 14 years were each associated with Horvath-estimated DNA methylation age acceleration at age 17 years in girls but not in boys.
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http://dx.doi.org/10.1186/s13148-020-00844-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7137290PMC
April 2020
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