Showing papers by "Debbie A Lawlor published in 2016"

Commentary: Two-sample Mendelian randomization: opportunities and challenges.

Abstract: In this volume of the IJE , Gao and colleagues explore the causal effect of adiposity on several cancers using two-sample Mendelian randomization (MR), and find some evidence that greater adult body mass index (BMI) causally reduces the risk of breast cancer while increasing ovarian, lung and colorectal cancer. 1 The authors conclude that the study provides ‘…additional understanding of the complex relationship between adiposity and cancer risks’. Beyond the study findings themselves, this paper is interesting in its use of publicly available genome-wide association study (GWAS) summary data in a two-sample MR approach. Whereas MR has been increasingly used over the past decade since it was first proposed in the IJE , 2 two-sample MR is a relatively recent extension. 3 With the increasing availability of complete summary results from GWAS consortia that are easily accessible on the internet, the use of two-sample MR is likely to increase considerably over the next decade. 4 By complete summary data I mean results for all genetic loci with a trait or disease outcome, and not just those reaching a pre-specified P -value threshold as shown in journal publications. It is this extensive availability of results that allows Gao et al. to relate genetic variants used as instrumental variables for adiposity traits to the cancer outcomes that they are interested in; the published GWAS for the cancer outcomes would not have reported on the adiposity variants unless they reached a pre-specified GWAS significance value.

Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function

Abstract: Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways.

Genome-wide associations for birth weight and correlations with adult disease

Abstract: Birth weight (BW) has been shown to be influenced by both fetal and maternal factors and in observational studies is reproducibly associated with future risk of adult metabolic diseases including type 2 diabetes (T2D) and cardiovascular disease1. These life-course associations have often been attributed to the impact of an adverse early life environment. Here, we performed a multi-ancestry genome-wide association study (GWAS) meta-analysis of BW in 153,781 individuals, identifying 60 loci where fetal genotype was associated with BW (P < 5 × 10−8). Overall, approximately 15% of variance in BW was captured by assays of fetal genetic variation. Using genetic association alone, we found strong inverse genetic correlations between BW and systolic blood pressure (Rg = −0.22, P = 5.5 × 10−13), T2D (Rg = −0.27, P = 1.1 × 10−6) and coronary artery disease (Rg = −0.30, P = 6.5 × 10−9). In addition, using large -cohort datasets, we demonstrated that genetic factors were the major contributor to the negative covariance between BW and future cardiometabolic risk. Pathway analyses indicated that the protein products of genes within BW-associated regions were enriched for diverse processes including insulin signalling, glucose homeostasis, glycogen biosynthesis and chromatin remodelling. There was also enrichment of associations with BW in known imprinted regions (P = 1.9 × 10−4). We demonstrate that life-course associations between early growth phenotypes and adult cardiometabolic disease are in part the result of shared genetic effects and identify some of the pathways through which these causal genetic effects are mediated.

Genome-wide association analysis identifies novel loci for chronotype in 100,420 individuals from the UK Biobank

Abstract: Our sleep timing preference, or chronotype, is a manifestation of our internal biological clock. Variation in chronotype has been linked to sleep disorders, cognitive and physical performance, and chronic disease. Here we perform a genome-wide association study of self-reported chronotype within the UK Biobank cohort (n=100,420). We identify 12 new genetic loci that implicate known components of the circadian clock machinery and point to previously unstudied genetic variants and candidate genes that might modulate core circadian rhythms or light-sensing pathways. Pathway analyses highlight central nervous and ocular systems and fear-response-related processes. Genetic correlation analysis suggests chronotype shares underlying genetic pathways with schizophrenia, educational attainment and possibly BMI. Further, Mendelian randomization suggests that evening chronotype relates to higher educational attainment. These results not only expand our knowledge of the circadian system in humans but also expose the influence of circadian characteristics over human health and life-history variables such as educational attainment.

Hyperglycaemia and risk of adverse perinatal outcomes: systematic review and meta-analysis

Abstract: Objectives To assess the association between maternal glucose concentrations and adverse perinatal outcomes in women without gestational or existing diabetes and to determine whether clear thresholds for identifying women at risk of perinatal outcomes can be identified. Design Systematic review and meta-analysis of prospective cohort studies and control arms of randomised trials. Data sources Databases including Medline and Embase were searched up to October 2014 and combined with individual participant data from two additional birth cohorts. Eligibility criteria for selecting studies Studies including pregnant women with oral glucose tolerance (OGTT) or challenge (OGCT) test results, with data on at least one adverse perinatal outcome. Appraisal and data extraction Glucose test results were extracted for OGCT (50 g) and OGTT (75 g and 100 g) at fasting and one and two hour post-load timings. Data were extracted on induction of labour; caesarean and instrumental delivery; pregnancy induced hypertension; pre-eclampsia; macrosomia; large for gestational age; preterm birth; birth injury; and neonatal hypoglycaemia. Risk of bias was assessed with a modified version of the critical appraisal skills programme and quality in prognostic studies tools. Results 25 reports from 23 published studies and two individual participant data cohorts were included, with up to 207 172 women (numbers varied by the test and outcome analysed in the meta-analyses). Overall most studies were judged as having a low risk of bias. There were positive linear associations with caesarean section, induction of labour, large for gestational age, macrosomia, and shoulder dystocia for all glucose exposures across the distribution of glucose concentrations. There was no clear evidence of a threshold effect. In general, associations were stronger for fasting concentration than for post-load concentration. For example, the odds ratios for large for gestational age per 1 mmol/L increase of fasting and two hour post-load glucose concentrations (after a 75 g OGTT) were 2.15 (95% confidence interval 1.60 to 2.91) and 1.20 (1.13 to 1.28), respectively. Heterogeneity was low between studies in all analyses. Conclusions This review and meta-analysis identified a large number of studies in various countries. There was a graded linear association between fasting and post-load glucose concentration across the whole glucose distribution and most adverse perinatal outcomes in women without pre-existing or gestational diabetes. The lack of a clear threshold at which risk increases means that decisions regarding thresholds for diagnosing gestational diabetes are somewhat arbitrary. Research should now investigate the clinical and cost-effectiveness of applying different glucose thresholds for diagnosis of gestational diabetes on perinatal and longer term outcomes. Systematic review registration PROSPERO CRD42013004608

Genetic evidence for causal relationships between maternal obesity-related traits and birth weight

Abstract: Importance Neonates born to overweight or obese women are larger and at higher risk of birth complications. Many maternal obesity-related traits are observationally associated with birth weight, but the causal nature of these associations is uncertain. Objective To test for genetic evidence of causal associations of maternal body mass index (BMI) and related traits with birth weight. Design, Setting, and Participants Mendelian randomization to test whether maternal BMI and obesity-related traits are potentially causally related to offspring birth weight. Data from 30 487 women in 18 studies were analyzed. Participants were of European ancestry from population- or community-based studies in Europe, North America, or Australia and were part of the Early Growth Genetics Consortium. Live, term, singleton offspring born between 1929 and 2013 were included. Exposures Genetic scores for BMI, fasting glucose level, type 2 diabetes, systolic blood pressure (SBP), triglyceride level, high-density lipoprotein cholesterol (HDL-C) level, vitamin D status, and adiponectin level. Main Outcome and Measure Offspring birth weight from 18 studies. Results Among the 30 487 newborns the mean birth weight in the various cohorts ranged from 3325 g to 3679 g. The maternal genetic score for BMI was associated with a 2-g (95% CI, 0 to 3 g) higher offspring birth weight per maternal BMI-raising allele ( P = .008). The maternal genetic scores for fasting glucose and SBP were also associated with birth weight with effect sizes of 8 g (95% CI, 6 to 10 g) per glucose-raising allele ( P = 7 × 10 −14 ) and −4 g (95% CI, −6 to −2g) per SBP-raising allele ( P = 1×10 −5 ), respectively. A 1-SD ( ≈ 4 points) genetically higher maternal BMI was associated with a 55-g higher offspring birth weight (95% CI, 17 to 93 g). A 1-SD ( ≈ 7.2 mg/dL) genetically higher maternal fasting glucose concentration was associated with 114-g higher offspring birth weight (95% CI, 80 to 147 g). However, a 1-SD ( ≈ 10 mm Hg) genetically higher maternal SBP was associated with a 208-g lower offspring birth weight (95% CI, −394 to −21 g). For BMI and fasting glucose, genetic associations were consistent with the observational associations, but for systolic blood pressure, the genetic and observational associations were in opposite directions. Conclusions and Relevance In this mendelian randomization study, genetically elevated maternal BMI and blood glucose levels were potentially causally associated with higher offspring birth weight, whereas genetically elevated maternal SBP was potentially causally related to lower birth weight. If replicated, these findings may have implications for counseling and managing pregnancies to avoid adverse weight-related birth outcomes.

Linear spline multilevel models for summarising childhood growth trajectories: A guide to their application using examples from five birth cohorts

Abstract: Childhood growth is of interest in medical research concerned with determinants and consequences of variation from healthy growth and development. Linear spline multilevel modelling is a useful approach for deriving individual summary measures of growth, which overcomes several data issues (co-linearity of repeat measures, the requirement for all individuals to be measured at the same ages and bias due to missing data). Here, we outline the application of this methodology to model individual trajectories of length/height and weight, drawing on examples from five cohorts from different generations and different geographical regions with varying levels of economic development. We describe the unique features of the data within each cohort that have implications for the application of linear spline multilevel models, for example, differences in the density and inter-individual variation in measurement occasions, and multiple sources of measurement with varying measurement error. After providing example Stata syntax and a suggested workflow for the implementation of linear spline multilevel models, we conclude with a discussion of the advantages and disadvantages of the linear spline approach compared with other growth modelling methods such as fractional polynomials, more complex spline functions and other non-linear models.

Metabolic profiling of pregnancy: cross-sectional and longitudinal evidence

Abstract: Pregnancy triggers well-known alterations in maternal glucose and lipid balance but its overall effects on systemic metabolism remain incompletely understood. Detailed molecular profiles (87 metabolic measures and 37 cytokines) were measured for up to 4260 women (24–49 years, 322 pregnant) from three population-based cohorts in Finland. Circulating molecular concentrations in pregnant women were compared to those in non-pregnant women. Metabolic profiles were also reassessed for 583 women 6 years later to uncover the longitudinal metabolic changes in response to change in the pregnancy status. Compared to non-pregnant women, all lipoprotein subclasses and lipids were markedly increased in pregnant women. The most pronounced differences were observed for the intermediate-density, low-density and high-density lipoprotein triglyceride concentrations. Large differences were also seen for many fatty acids and amino acids. Pregnant women also had higher concentrations of low-grade inflammatory marker glycoprotein acetyls, higher concentrations of interleukin-18 and lower concentrations of interleukin-12p70. The changes in metabolic concentrations for women who were not pregnant at baseline but pregnant 6 years later (or vice versa) matched (or were mirror-images of) the cross-sectional association pattern. Cross-sectional results were consistent across the three cohorts and similar longitudinal changes were seen for 653 women in 4-year and 497 women in 10-year follow-up. For multiple metabolic measures, the changes increased in magnitude across the three trimesters. Pregnancy initiates substantial metabolic and inflammatory changes in the mothers. Comprehensive characterisation of normal pregnancy is important for gaining understanding of the key nutrients for fetal growth and development. These findings also provide a valuable molecular reference in relation to studies of adverse pregnancy outcomes.

Adult height, coronary heart disease and stroke: a multi-locus Mendelian randomization meta-analysis

Abstract: Background: We investigated causal effect of completed growth, measured by adult height, on coronary heart disease (CHD), stroke and cardiovascular traits, using instrumental variable (IV) Mendelian randomization meta-analysis. Methods: We developed an allele score based on 69 single nucleotide polymorphisms (SNPs) associated with adult height, identified by the IBCCardioChip, and used it for IV analysis against cardiovascular risk factors and events in 21 studies and 60 028 participants. IV analysis on CHD was supplemented by summary data from 180 height-SNPs from the GIANT consortium and their corresponding CHD estimates derived from CARDIoGRAMplusC4D. Results: IV estimates from IBCCardioChip and GIANT-CARDIoGRAMplusC4D showed that a 6.5-cm increase in height reduced the odds of CHD by 10% [odds ratios 0.90; 95% confidence intervals (CIs): 0.78 to 1.03 and 0.85 to 0.95, respectively],which agrees with the estimate from the Emerging Risk Factors Collaboration (hazard ratio 0.93; 95% CI: 0.91 to 0.94). IV analysis revealed no association with stroke (odds ratio 0.97; 95% CI: 0.79 to 1.19). IV analysis showed that a 6.5-cm increase in height resulted in lower levels of body mass index (P < 0.001), triglycerides (P < 0.001), non high-density (non-HDL) cholesterol (P < 0.001), C-reactive protein (P = 0.042), and systolic blood pressure (P = 0.064) and higher levels of forced expiratory volume in 1 s and forced vital capacity (P < 0.001 for both). Conclusions: Taller individuals have a lower risk of CHD with potential explanations being that taller people have a better lung function and lower levels of body mass index, cholesterol and blood pressure.

Metabolomic Profiling of Statin Use and Genetic Inhibition of HMG-CoA Reductase

Abstract: Background Statins are first-line therapy for cardiovascular disease prevention, but their systemic effects across lipoprotein subclasses, fatty acids, and circulating metabolites remain incompletely characterized.

DNA Methylation and BMI: Investigating Identified Methylation Sites at HIF3A in a Causal Framework

Abstract: Multiple differentially methylated sites and regions associated with adiposity have now been identified in large-scale cross-sectional studies. We tested for replication of associations between previously identified CpG sites at HIF3A and adiposity in ∼1,000 mother-offspring pairs from the Avon Longitudinal Study of Parents and Children (ALSPAC). Availability of methylation and adiposity measures at multiple time points, as well as genetic data, allowed us to assess the temporal associations between adiposity and methylation and to make inferences regarding causality and directionality. Overall, our results were discordant with those expected if HIF3A methylation has a causal effect on BMI and provided more evidence for causality in the reverse direction (i.e., an effect of BMI on HIF3A methylation). These results are based on robust evidence from longitudinal analyses and were also partially supported by Mendelian randomization analysis, although this latter analysis was underpowered to detect a causal effect of BMI on HIF3A methylation. Our results also highlight an apparent long-lasting intergenerational influence of maternal BMI on offspring methylation at this locus, which may confound associations between own adiposity and HIF3A methylation. Further work is required to replicate and uncover the mechanisms underlying the direct and intergenerational effect of adiposity on DNA methylation.

The identification and treatment of women with hyperglycaemia in pregnancy: an analysis of individual participant data, systematic reviews, meta-analyses and an economic evaluation

Abstract: BACKGROUND: Gestational diabetes mellitus (GDM) is associated with a higher risk of important adverse outcomes. Practice varies and the best strategy for identifying and treating GDM is unclear. AIM: To estimate the clinical effectiveness and cost-effectiveness of strategies for identifying and treating women with GDM. METHODS: We analysed individual participant data (IPD) from birth cohorts and conducted systematic reviews to estimate the association of maternal glucose levels with adverse perinatal outcomes; GDM prevalence; maternal characteristics/risk factors for GDM; and the effectiveness and costs of treatments. The cost-effectiveness of various strategies was estimated using a decision tree model, along with a value of information analysis to assess where future research might be worthwhile. Detailed systematic searches of MEDLINE ® and MEDLINE In-Process & Other Non-Indexed Citations ®, EMBASE, Cumulative Index to Nursing and Allied Health Literature Plus, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, Health Technology Assessment database, NHS Economic Evaluation Database, Maternity and Infant Care database and the Cochrane Methodology Register were undertaken from inception up to October 2014. RESULTS: We identified 58 studies examining maternal glucose levels and outcome associations. Analyses using IPD alone and the systematic review demonstrated continuous linear associations of fasting and post-load glucose levels with adverse perinatal outcomes, with no clear threshold below which there is no increased risk. Using IPD, we estimated glucose thresholds to identify infants at high risk of being born large for gestational age or with high adiposity; for South Asian (SA) women these thresholds were fasting and post-load glucose levels of 5.2 mmol/l and 7.2 mmol/l, respectively and for white British (WB) women they were 5.4 and 7.5 mmol/l, respectively. Prevalence using IPD and published data varied from 1.2% to 24.2% (depending on criteria and population) and was consistently two to three times higher in SA women than in WB women. Lowering thresholds to identify GDM, particularly in women of SA origin, identifies more women at risk, but increases costs. Maternal characteristics did not accurately identify women with GDM; there was limited evidence that in some populations risk factors may be useful for identifying low-risk women. Dietary modification additional to routine care reduced the risk of most adverse perinatal outcomes. Metformin (Glucophage, ® Teva UK Ltd, Eastbourne, UK) and insulin were more effective than glibenclamide (Aurobindo Pharma - Milpharm Ltd, South Ruislip, Middlesex, UK). For all strategies to identify and treat GDM, the costs exceeded the health benefits. A policy of no screening/testing or treatment offered the maximum expected net monetary benefit (NMB) of £1184 at a cost-effectiveness threshold of £20,000 per quality-adjusted life-year (QALY). The NMB for the three best-performing strategies in each category (screen only, then treat; screen, test, then treat; and test all, then treat) ranged between -£1197 and -£1210. Further research to reduce uncertainty around potential longer-term benefits for the mothers and offspring, find ways of improving the accuracy of identifying women with GDM, and reduce costs of identification and treatment would be worthwhile. LIMITATIONS: We did not have access to IPD from populations in the UK outside of England. Few observational studies reported longer-term associations, and treatment trials have generally reported only perinatal outcomes. CONCLUSIONS: Using the national standard cost-effectiveness threshold of £20,000 per QALY it is not cost-effective to routinely identify pregnant women for treatment of hyperglycaemia. Further research to provide evidence on longer-term outcomes, and more cost-effective ways to detect and treat GDM, would be valuable. STUDY REGISTRATION: This study is registered as PROSPERO CRD42013004608. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Role of Adiponectin in Coronary Heart Disease Risk: A Mendelian Randomization Study.

Abstract: Rationale:Hypoadiponectinemia correlates with several coronary heart disease (CHD) risk factors. However, it is unknown whether adiponectin is causally implicated in CHD pathogenesis. Objective:We aimed to investigate the causal effect of adiponectin on CHD risk. Methods and Results:We undertook a Mendelian randomization study using data from genome-wide association studies consortia. We used the ADIPOGen consortium to identify genetic variants that could be used as instrumental variables for the effect of adiponectin. Data on the association of these genetic variants with CHD risk were obtained from CARDIoGRAM (22 233 CHD cases and 64 762 controls of European ancestry) and from CARDIoGRAMplusC4D Metabochip (63 746 cases and 130 681 controls; ≈ 91% of European ancestry) consortia. Data on the association of genetic variants with adiponectin levels and with CHD were combined to estimate the influence of blood adiponectin on CHD risk. In the conservative approach (restricted to using variants within the adi...

Causal inference—so much more than statistics

Abstract: Causal inference—so much more than statistics Neil Pearce* and Debbie A Lawlor Department of Medical Statistics and Centre for Global NCDs, London School of Hygiene and Tropical Medicine, London, UK, Centre for Public Health Research, Massey University, Wellington, New Zealand, MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK and School of Social and Community Medicine, University of Bristol, Bristol, UK

Hypertensive Disorders of Pregnancy and Offspring Cardiac Structure and Function in Adolescence

Abstract: Background Fetal exposure to preeclampsia is associated with higher blood pressure and later risk of stroke. We aimed to investigate the associations of maternal preeclampsia, gestational hypertension, and maternal blood pressure change in pregnancy with offspring cardiac structure and function in adolescence. Methods and Results Using data from a prospective birth cohort study, we included offspring who underwent echocardiography (mean age, 17.7 years; SD, 0.3; N=1592). We examined whether hypertensive disorders of pregnancy were associated with offspring cardiac structure and systolic/diastolic function using linear regression. Using multilevel linear spline models (measurement occasions within women), we also investigated whether rate of maternal systolic/diastolic blood pressure change during pregnancy (weeks 8–18, 18–30, 30–36, and 36 or more) were associated with offspring outcomes. Main models were typically adjusted for maternal age, offspring age and sex, prepregnancy body mass index, parity, glycosuria/diabetes mellitus, education, and maternal smoking. Exposure to maternal preeclampsia (0.025; 95% CI, 0.008–0.043) and gestational hypertension (0.010; 0.002–0.017) were associated with greater relative wall thickness. Furthermore, preeclampsia was also associated with a smaller left ventricular end‐diastolic volume (−9.0 mL; −15 to −3.1). No associations were found between hypertensive disorders of pregnancy and offspring cardiac function. Positive rate of maternal systolic blood pressure change during weeks 8 to 18 was associated with greater offspring left ventricular end‐diastolic volume, left ventricular mass indexed to height2.7, and E/A. Conclusions Adolescent offspring exposed to maternal preeclampsia had greater relative wall thickness and reduced left ventricular end‐diastolic volume, which could be early signs of concentric remodeling and affect future cardiac function as well as risk of cardiovascular disease.

Born in Bradford’s Better Start: an experimental birth cohort study to evaluate the impact of early life interventions

Abstract: Early interventions are recognised as key to improving life chances for children and reducing inequalities in health and well-being, however there is a paucity of high quality research into the effectiveness of interventions to address childhood health and development outcomes. Planning and implementing standalone RCTs for multiple, individual interventions would be slow, cumbersome and expensive. This paper describes the protocol for an innovative experimental birth cohort: Born in Bradford’s Better Start (BiBBS) that will simultaneously evaluate the impact of multiple early life interventions using efficient study designs. Better Start Bradford (BSB) has been allocated £49 million from the Big Lottery Fund to implement 22 interventions to improve outcomes for children aged 0–3 in three key areas: social and emotional development; communication and language development; and nutrition and obesity. The interventions will be implemented in three deprived and ethnically diverse inner city areas of Bradford. The BiBBS study aims to recruit 5000 babies, their mothers and their mothers’ partners over 5 years from January 2016-December 2020. Demographic and socioeconomic information, physical and mental health, lifestyle factors and biological samples will be collected during pregnancy. Parents and children will be linked to their routine health and local authority (including education) data throughout the children’s lives. Their participation in BSB interventions will also be tracked. BiBBS will test interventions using the Trials within Cohorts (TwiCs) approach and other quasi-experimental designs where TwiCs are neither feasible nor ethical, to evaluate these early life interventions. The effects of single interventions, and the cumulative effects of stacked (multiple) interventions on health and social outcomes during the critical early years will be measured. The focus of the BiBBS cohort is on intervention impact rather than observation. As far as we are aware BiBBS is the world’s first such experimental birth cohort study. While some risk factors for adverse health and social outcomes are increasingly well described, the solutions to tackling them remain elusive. The novel design of BiBBS can contribute much needed evidence to inform policy makers and practitioners about effective approaches to improve health and well-being for future generations.

Early Antenatal Prediction of Gestational Diabetes in Obese Women: Development of Prediction Tools for Targeted Intervention.

Abstract: All obese women are categorised as being of equally high risk of gestational diabetes (GDM) whereas the majority do not develop the disorder. Lifestyle and pharmacological interventions in unselected obese pregnant women have been unsuccessful in preventing GDM. Our aim was to develop a prediction tool for early identification of obese women at high risk of GDM to facilitate targeted interventions in those most likely to benefit. Clinical and anthropometric data and non-fasting blood samples were obtained at 15+0-18+6 weeks' gestation in 1303 obese pregnant women from UPBEAT, a randomised controlled trial of a behavioural intervention. Twenty one candidate biomarkers associated with insulin resistance, and a targeted nuclear magnetic resonance (NMR) metabolome were measured. Prediction models were constructed using stepwise logistic regression. Twenty six percent of women (n = 337) developed GDM (International Association of Diabetes and Pregnancy Study Groups criteria). A model based on clinical and anthropometric variables (age, previous GDM, family history of type 2 diabetes, systolic blood pressure, sum of skinfold thicknesses, waist:height and neck:thigh ratios) provided an area under the curve of 0.71 (95%CI 0.68-0.74). This increased to 0.77 (95%CI 0.73-0.80) with addition of candidate biomarkers (random glucose, haemoglobin A1c (HbA1c), fructosamine, adiponectin, sex hormone binding globulin, triglycerides), but was not improved by addition of NMR metabolites (0.77; 95%CI 0.74-0.81). Clinically translatable models for GDM prediction including readily measurable variables e.g. mid-arm circumference, age, systolic blood pressure, HbA1c and adiponectin are described. Using a ≥35% risk threshold, all models identified a group of high risk obese women of whom approximately 50% (positive predictive value) later developed GDM, with a negative predictive value of 80%. Tools for early pregnancy identification of obese women at risk of GDM are described which could enable targeted interventions for GDM prevention in women who will benefit the most.

Effects of hormonal contraception on systemic metabolism: cross-sectional and longitudinal evidence

Abstract: BACKGROUND: Hormonal contraception is commonly used worldwide but its systemic effects across lipoprotein subclasses fatty acids circulating metabolites and cytokines remain poorly understood. METHODS: A comprehensive molecular profile (75 metabolic measures and 37 cytokines) was measured for up to 5841 women (age range 24-49 years) from three population-based cohorts. Women using combined oral contraceptive pills (COCPs) or progestin-only contraceptives (POCs) were compared with those who did not use hormonal contraception. Metabolomics profiles were reassessed for 869 women after 6 years to uncover the metabolic effects of starting stopping and persistently using hormonal contraception. RESULTS: The comprehensive molecular profiling allowed multiple new findings on the metabolic associations with the use of COCPs. They were positively associated with lipoprotein subclasses including all high-density lipoprotein (HDL) subclasses. The associations with fatty acids and amino acids were strong and variable in direction. COCP use was negatively associated with albumin and positively associated with creatinine and inflammatory markers including glycoprotein acetyls and several growth factors and interleukins. Our findings also confirmed previous results e.g. for increased circulating triglycerides and HDL cholesterol. Starting COCPs caused similar metabolic changes to those observed cross-sectionally: the changes were maintained in consistent users and normalized in those who stopped using. In contrast POCs were only weakly associated with metabolic and inflammatory markers. Results were consistent across all cohorts and for different COCP preparations and different types of POC delivery. CONCLUSIONS: Use of COCPs causes widespread metabolic and inflammatory effects. However persistent use does not appear to accumulate the effects over time and the metabolic perturbations are reversed upon discontinuation. POCs have little effect on systemic metabolism and inflammation. (c) The Author 2016. Published by Oxford University Press on behalf of the International Epidemiological Association.

Genetic Evidence for Causal Relationships Between Maternal Obesity-Related Traits and Birth Weight

Abstract: Importance Neonates born to overweight or obese women are larger and at higher risk of birth complications. Many maternal obesity-related traits are observationally associated with birth weight, but the causal nature of these associations is uncertain. Objective To test for genetic evidence of causal associations of maternal body mass index (BMI) and related traits with birth weight. Design, Setting, and Participants Mendelian randomization to test whether maternal BMI and obesity-related traits are potentially causally related to offspring birth weight. Data from 30 487 women in 18 studies were analyzed. Participants were of European ancestry from population- or community-based studies in Europe, North America, or Australia and were part of the Early Growth Genetics Consortium. Live, term, singleton offspring born between 1929 and 2013 were included. Exposures Genetic scores for BMI, fasting glucose level, type 2 diabetes, systolic blood pressure (SBP), triglyceride level, high-density lipoprotein cholesterol (HDL-C) level, vitamin D status, and adiponectin level. Main Outcome and Measure Offspring birth weight from 18 studies. Results Among the 30 487 newborns the mean birth weight in the various cohorts ranged from 3325 g to 3679 g. The maternal genetic score for BMI was associated with a 2-g (95% CI, 0 to 3 g) higher offspring birth weight per maternal BMI-raising allele ( P = .008). The maternal genetic scores for fasting glucose and SBP were also associated with birth weight with effect sizes of 8 g (95% CI, 6 to 10 g) per glucose-raising allele ( P = 7 × 10 −14 ) and −4 g (95% CI, −6 to −2g) per SBP-raising allele ( P = 1×10 −5 ), respectively. A 1-SD ( ≈ 4 points) genetically higher maternal BMI was associated with a 55-g higher offspring birth weight (95% CI, 17 to 93 g). A 1-SD ( ≈ 7.2 mg/dL) genetically higher maternal fasting glucose concentration was associated with 114-g higher offspring birth weight (95% CI, 80 to 147 g). However, a 1-SD ( ≈ 10 mm Hg) genetically higher maternal SBP was associated with a 208-g lower offspring birth weight (95% CI, −394 to −21 g). For BMI and fasting glucose, genetic associations were consistent with the observational associations, but for systolic blood pressure, the genetic and observational associations were in opposite directions. Conclusions and Relevance In this mendelian randomization study, genetically elevated maternal BMI and blood glucose levels were potentially causally associated with higher offspring birth weight, whereas genetically elevated maternal SBP was potentially causally related to lower birth weight. If replicated, these findings may have implications for counseling and managing pregnancies to avoid adverse weight-related birth outcomes.

Programming of Adiposity in Childhood and Adolescence: Associations With Birth Weight and Cord Blood Adipokines.

Abstract: Context:Exposure to maternal adiposity during pregnancy is associated with higher offspring birthweight and greater adiposity through childhood and adult life. As birthweight reflects the summation of lean and fat mass, the extent to which fat mass at birth tracks into later life is unknown.Objective:Determine whether fat mass at birth is associated with child and adolescent adiposity.Design, Setting and Participants:UK birth cohort with markers of neonatal fat mass; cord blood leptin, adiponectin, and birthweight and adiposity outcomes at age 9 (N=2775) and 17years (N=2138).Main Outcomes:Offspring BMI, waist circumference, DXA-determined fat mass and obesity at age 9 and 17years.Results:Higher cord blood leptin was associated with higher z-scores of fat mass (difference in mean per 10pg/ml: 0.03SD,95%CI 0.00-0.06), waist circumference (0.04SD,95%CI 0.00-0.07), and BMI (0.04SD,95%CI 0.00-0.08), at age 9. However, by age 17 the adjusted results were attenuated to the null. Cord blood adiponectin was not as...

Metabolic signatures of birthweight in 18 288 adolescents and adults.

Abstract: Funding This study was supported by the Strategic Research Funding from the University of Oulu, Finland, the Sigrid Juselius Foundation, the Novo Nordisk Foundation, the Yrjo¨ Jahnsson Foundation, the Finnish Diabetes Research Foundation, the Finnish Medical Foundation, the Paulo Foundation, Biocenter Oulu, Finland, and the UK Medical Research Council via the University of Bristol Integrative Epidemiology Unit (IEU; MC_UU_12013/1 and MC_UU_12013/5). The Cardiovascular Risk in Young Finns Study is supported by the Academy of Finland (grants 286284, 134309, 126925, 121584, 124282, 129378, 117787 and 41071), Finnish Foundation for Cardiovascular Research, Oulu, Helsinki, Kuopio, Tampere, and Turku University Central Hospital Medical Funds, the Paavo Nurmi Foundation, the Juho Vainio Foundation, the Finnish Cultural Foundation and the Finnish Funding Agency for Technology and Innovation. The Northern Finland Birth Cohorts of 1966 and 1986 have received financial support from Academy of Finland, University Hospital Oulu, Biocenter Oulu, University of Oulu, the European Commission (EURO-BLCS, Framework 5 Award QLG1-CT-2000-01643, ENGAGE project and grant agree-ment HEALTH-F4-2007-201413, EurHEALTHAgeing (277849), European Regional Developmental Fund), EU H2020-PHC-2014 (grant no. 633595), DynaHEALTH, NHLBI grant 5R01HL087679-02 through the STAMPEED programme (1RL1MH083268-01), NIH/NIMH (5R01MH63706:02), Stanley Foundation, the UK Medical Research Council and Wellcome Trust. The UK Medical Research Council and Wellcome Trust (grant: 102215/2/13/2) and the University of Bristol provide core support for ALSPAC. The con-tribution of D.A.L to this study is supported by grants from the US National Institute of Health (R01 DK10324), European Research Council (ObesityDevelop: grant no. 669545) and UK National Institute for Health Research (NF-SI-0166-10196). F.D., D.A.L., G.D.S. and M.A.K. work in a Unit that is supported by the University of Bristol and UK Medical Research Council (MC_UU_12013/1 and MC_UU_12013/5). The FinnTwin-12 and FinnTwin-16 studies have received support from the National Institute on Alcohol Abuse and Alcoholism (R37-AA12502, R01-AA09203 and K05-AA00145). The views expressed in this paper are those of the authors and not necessarily any funding body. Conflict of interest: P.W., A.J.K., P.S. and M.A.K. are shareholders of Brainshake Ltd, a company offering NMR-based metabolic profiling (www.brainshake.fi). P.W., T.T., M.T., P.S. and A.J.K. re-port employment relation with Brainshake Ltd. D.A.L. has received funding for biomarker research, unrelated to this paper, from Roche Diagnostics and Ferring Pharmaceuticals. K.A. is currently em-ployed by GSK. No other authors reported disclosures.

International Genome-Wide Association Study Consortium Identifies Novel Loci Associated With Blood Pressure in Children and Adolescents

Abstract: Background— Our aim was to identify genetic variants associated with blood pressure (BP) in childhood and adolescence. Methods and Results— Genome-wide association study data from participating European ancestry cohorts of the Early Genetics and Lifecourse Epidemiology (EAGLE) Consortium was meta-analyzed across 3 epochs; prepuberty (4–7 years), puberty (8–12 years), and postpuberty (13–20 years). Two novel loci were identified as having genome-wide associations with systolic BP across specific age epochs: rs1563894 ( ITGA11 , located in active H3K27Ac mark and transcription factor chromatin immunoprecipitation and 5′-C-phosphate-G-3′ methylation site) during prepuberty ( P =2.86×10–8) and rs872256 during puberty ( P =8.67×10–9). Several single-nucleotide polymorphism clusters were also associated with childhood BP at P <5×10–3. Using a P value threshold of <5×10–3, we found some overlap in variants across the different age epochs within our study and between several single-nucleotide polymorphisms in any of the 3 epochs and adult BP-related single-nucleotide polymorphisms. Conclusions— Our results suggest that genetic determinants of BP act from childhood, develop over the lifecourse, and show some evidence of age-specific effects.

Association of maternal diabetes/glycosuria and pre-pregnancy body mass index with offspring indicators of non-alcoholic fatty liver disease

Abstract: Little is known about early life determinants of non-alcoholic fatty liver disease (NAFLD). We examined associations of maternal pregnancy diabetes/glycosuria and pre-pregnancy body mass index (BMI) with offspring markers of NAFLD and liver pathology and examined mediation by birthweight and concurrent offspring adiposity. We used data from a UK prospective pregnancy cohort. Offspring underwent abdominal ultrasonography (USS) at mean age 17.8 years. Outcomes included USS-assessed fatty liver, estimated liver volume and shear velocity, a variant of elastography (a marker of liver fibrosis) (N = 1 215) and blood-based markers of liver pathology [alanine amino transferase, aspartate amino transferase, gamma- glutamyltransferase and haptoglobin] (N = 2 359). 2.1 % (N = 25) of participants had USS-assessed fatty liver [maternal diabetes/glycosuria (N = 7) and no diabetes/glycosuria (N = 18)]. Maternal diabetes/glycosuria was associated with greater odds of offspring USS fatty liver in confounder adjusted models [adjusted odds ratio (aOR) 6.74 (95 % confidence interval (CI) 2.47, 18.40)] and higher shear velocity [adjusted ratio of geometric mean (aRGM):1.10 (95 % CI 1.05, 1.15)]. These associations were not mediated by offspring birthweight or concurrent adiposity. Maternal diabetes/glycosuria was not associated with liver volume or blood-based outcomes. Greater maternal pre-pregnancy BMI was associated with greater odds of offspring USS fatty liver [aOR 2.72 (95 % CI: 1.20, 6.15)], higher liver volume [aRGM 1.03 (95 % CI 1.00, 1.07)] and shear velocity [aRGM1.03 (95 % CI: 1.01, 1.06)] in confounder adjusted models. These associations were largely mediated by offspring adiposity. Maternal pre-pregnancy BMI was not consistently associated with blood-based outcomes. Results suggest that maternal pregnancy diabetes/glycosuria is associated with offspring NAFLD through mechanisms other than offspring’s own adiposity.

A structured approach to hypotheses involving continuous exposures over the life course.

Abstract: BACKGROUND: Epidemiologists are often interested in examining different hypotheses for how exposures measured repeatedly over the life course relate to later-life outcomes. A structured approach for selecting the hypotheses most supported by theory and observed data has been developed for binary exposures. The aim of this paper is to extend this to include continuous exposures and allow for confounding and missing data. METHODS: We studied two examples, the association between: (i) maternal weight during pregnancy and birthweight; and (ii) stressful family events throughout childhood and depression in adolescence. In each example we considered several plausible hypotheses including accumulation, critical periods, sensitive periods, change and effect modification. We used least angle regression to select the hypothesis that explained the most variation in the outcome, demonstrating appropriate methods for adjusting for confounders and dealing with missing data. RESULTS: The structured approach identified a combination of sensitive periods: pre-pregnancy weight, and gestational weight gain 0-20 weeks and 20-40 weeks, as the best explanation for variation in birthweight after adjusting for maternal height. A sensitive period hypothesis best explained variation in adolescent depression, with the association strengthening with the proximity of stressful family events. For each example, these models have theoretical support at least as strong as any competing hypothesis. CONCLUSIONS: We have extended the structured approach to incorporate continuous exposures, confounding and missing data. This approach can be used in either an exploratory or a confirmatory setting. The interpretation, plausibility and consistency with causal assumptions should all be considered when proposing and choosing life course hypotheses.

Hypertensive disorders of pregnancy, respiratory outcomes and atopy in childhood.

Abstract: Few epidemiological studies have investigated the role of hypertensive disorders of pregnancy in the aetiology of childhood respiratory and atopic outcomes. In the Avon Longitudinal Study of Parents and Children we examined associations of maternal gestational hypertension, hypertension before pregnancy and pre-eclampsia with wheezing at 18 months, wheezing and asthma at 7 years and lung function at 8–9 years, after controlling for potential confounders (n=5322–8734, depending on outcome). Gestational hypertension was not associated with any of the outcomes. There was weak evidence for a positive association between pre-eclampsia and early wheezing (adjusted OR 1.31, 95% CI 0.94–1.82, compared to normotensive pregnancies) and for negative associations between pre-eclampsia and forced expiratory volume in 1 s (adjusted mean difference in sd score −0.14, 95% CI −0.33–0.06) and maximal mid-expiratory flow (−0.15, 95% CI −0.34–0.04). Hypertension before pregnancy was positively associated with wheezing (OR 1.63, 95% CI 1.16–2.31) and asthma (OR 1.34, 95% CI 1.00–1.79). Gestational hypertension is unlikely to be a risk factor for childhood respiratory disorders; hypertension before pregnancy may be a risk factor for childhood wheezing and asthma, but this finding needs replication. Larger studies are needed to confirm whether pre-eclampsia is associated with impaired childhood lung function.