Publications by authors named "Deborah A Lawlor"

117 Publications

Association of physical activity intensity and bout length with mortality: An observational study of 79,503 UK Biobank participants.

PLoS Med 2021 Sep 15;18(9):e1003757. Epub 2021 Sep 15.

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

Background: Spending more time active (and less sedentary) is associated with health benefits such as improved cardiovascular health and lower risk of all-cause mortality. It is unclear whether these associations differ depending on whether time spent sedentary or in moderate-vigorous physical activity (MVPA) is accumulated in long or short bouts. In this study, we used a novel method that accounts for substitution (i.e., more time in MVPA means less time sleeping, in light activity or sedentary) to examine whether length of sedentary and MVPA bouts associates with all-cause mortality.

Methods And Findings: We used data on 79,503 adult participants from the population-based UK Biobank cohort, which recruited participants between 2006 and 2010 (mean age at accelerometer wear 62.1 years [SD = 7.9], 54.5% women; mean length of follow-up 5.1 years [SD = 0.73]). We derived (1) the total time participants spent in activity categories-sleep, sedentary, light activity, and MVPA-on average per day; (2) time spent in sedentary bouts of short (1 to 15 minutes), medium (16 to 40 minutes), and long (41+ minutes) duration; and (3) MVPA bouts of very short (1 to 9 minutes), short (10 to 15 minutes), medium (16 to 40 minutes), and long (41+ minutes) duration. We used Cox proportion hazards regression to estimate the association of spending 10 minutes more average daily time in one activity or bout length category, coupled with 10 minutes less time in another, with all-cause mortality. Those spending more time in MVPA had lower mortality risk, irrespective of whether this replaced time spent sleeping, sedentary, or in light activity, and these associations were of similar magnitude (e.g., hazard ratio [HR] 0.96 [95% CI: 0.94, 0.97; P < 0.001] per 10 minutes more MVPA, coupled with 10 minutes less light activity per day). Those spending more time sedentary had higher mortality risk if this replaced light activity (HR 1.02 [95% CI: 1.01, 1.02; P < 0.001] per 10 minutes more sedentary time, with 10 minutes less light activity per day) and an even higher risk if this replaced MVPA (HR 1.06 [95% CI: 1.05, 1.08; P < 0.001] per 10 minutes more sedentary time, with 10 minutes less MVPA per day). We found little evidence that mortality risk differed depending on the length of sedentary or MVPA bouts. Key limitations of our study are potential residual confounding, the limited length of follow-up, and use of a select sample of the United Kingdom population.

Conclusions: We have shown that time spent in MVPA was associated with lower mortality, irrespective of whether it replaced time spent sleeping, sedentary, or in light activity. Time spent sedentary was associated with higher mortality risk, particularly if it replaced MVPA. This emphasises the specific importance of MVPA. Our findings suggest that the impact of MVPA does not differ depending on whether it is obtained from several short bouts or fewer longer bouts, supporting the recent removal of the requirement that MVPA should be accumulated in bouts of 10 minutes or more from the UK and the United States policy. Further studies are needed to investigate causality and explore health outcomes beyond mortality.
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http://dx.doi.org/10.1371/journal.pmed.1003757DOI Listing
September 2021

Genomic and phenotypic insights from an atlas of genetic effects on DNA methylation.

Nat Genet 2021 Sep 6;53(9):1311-1321. Epub 2021 Sep 6.

Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia.

Characterizing genetic influences on DNA methylation (DNAm) provides an opportunity to understand mechanisms underpinning gene regulation and disease. In the present study, we describe results of DNAm quantitative trait locus (mQTL) analyses on 32,851 participants, identifying genetic variants associated with DNAm at 420,509 DNAm sites in blood. We present a database of >270,000 independent mQTLs, of which 8.5% comprise long-range (trans) associations. Identified mQTL associations explain 15-17% of the additive genetic variance of DNAm. We show that the genetic architecture of DNAm levels is highly polygenic. Using shared genetic control between distal DNAm sites, we constructed networks, identifying 405 discrete genomic communities enriched for genomic annotations and complex traits. Shared genetic variants are associated with both DNAm levels and complex diseases, but only in a minority of cases do these associations reflect causal relationships from DNAm to trait or vice versa, indicating a more complex genotype-phenotype map than previously anticipated.
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http://dx.doi.org/10.1038/s41588-021-00923-xDOI Listing
September 2021

Do Mass Spectrometry-Derived Metabolomics Improve the Prediction of Pregnancy-Related Disorders? Findings from a UK Birth Cohort with Independent Validation.

Metabolites 2021 Aug 10;11(8). Epub 2021 Aug 10.

MRC Integrative Epidemiology Unit, University of Bristol, Bristol BS8 2BN, UK.

Many women who experience gestational diabetes (GDM), gestational hypertension (GHT), pre-eclampsia (PE), have a spontaneous preterm birth (sPTB) or have an offspring born small/large for gestational age (SGA/LGA) do not meet the criteria for high-risk pregnancies based upon certain maternal risk factors. Tools that better predict these outcomes are needed to tailor antenatal care to risk. Recent studies have suggested that metabolomics may improve the prediction of these pregnancy-related disorders. These have largely been based on targeted platforms or focused on a single pregnancy outcome. The aim of this study was to assess the predictive ability of an untargeted platform of over 700 metabolites to predict the above pregnancy-related disorders in two cohorts. We used data collected from women in the Born in Bradford study (BiB; two sub-samples, = 2000 and = 1000) and the Pregnancy Outcome Prediction study (POPs; = 827) to train, test and validate prediction models for GDM, PE, GHT, SGA, LGA and sPTB. We compared the predictive performance of three models: (1) risk factors (maternal age, pregnancy smoking, BMI, ethnicity and parity) (2) mass spectrometry (MS)-derived metabolites ( = 718 quantified metabolites, collected at 26-28 weeks' gestation) and (3) combined risk factors and metabolites. We used BiB for the training and testing of the models and POPs for independent validation. In both cohorts, discrimination for GDM, PE, LGA and SGA improved with the addition of metabolites to the risk factor model. The models' area under the curve (AUC) were similar for both cohorts, with good discrimination for GDM (AUC (95% CI) BiB 0.76 (0.71, 0.81) and POPs 0.76 (0.72, 0.81)) and LGA (BiB 0.86 (0.80, 0.91) and POPs 0.76 (0.60, 0.92)). Discrimination was improved for the combined models (compared to the risk factors models) for PE and SGA, with modest discrimination in both studies (PE-BiB 0.68 (0.58, 0.78) and POPs 0.66 (0.60, 0.71); SGA-BiB 0.68 (0.63, 0.74) and POPs 0.64 (0.59, 0.69)). Prediction for sPTB was poor in BiB and POPs for all models. In BiB, calibration for the combined models was good for GDM, LGA and SGA. Retained predictors include 4-hydroxyglutamate for GDM, LGA and PE and glycerol for GDM and PE. MS-derived metabolomics combined with maternal risk factors improves the prediction of GDM, PE, LGA and SGA, with good discrimination for GDM and LGA. Validation across two very different cohorts supports further investigation on whether the metabolites reflect novel causal paths to GDM and LGA.
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http://dx.doi.org/10.3390/metabo11080530DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8399752PMC
August 2021

Exploiting collider bias to apply two-sample summary data Mendelian randomization methods to one-sample individual level data.

PLoS Genet 2021 Aug 9;17(8):e1009703. Epub 2021 Aug 9.

Exeter Diabetes Group (ExCEED), College of Medicine and Health, University of Exeter, Exeter, United Kingdom.

Over the last decade the availability of SNP-trait associations from genome-wide association studies has led to an array of methods for performing Mendelian randomization studies using only summary statistics. A common feature of these methods, besides their intuitive simplicity, is the ability to combine data from several sources, incorporate multiple variants and account for biases due to weak instruments and pleiotropy. With the advent of large and accessible fully-genotyped cohorts such as UK Biobank, there is now increasing interest in understanding how best to apply these well developed summary data methods to individual level data, and to explore the use of more sophisticated causal methods allowing for non-linearity and effect modification. In this paper we describe a general procedure for optimally applying any two sample summary data method using one sample data. Our procedure first performs a meta-analysis of summary data estimates that are intentionally contaminated by collider bias between the genetic instruments and unmeasured confounders, due to conditioning on the observed exposure. These estimates are then used to correct the standard observational association between an exposure and outcome. Simulations are conducted to demonstrate the method's performance against naive applications of two sample summary data MR. We apply the approach to the UK Biobank cohort to investigate the causal role of sleep disturbance on HbA1c levels, an important determinant of diabetes. Our approach can be viewed as a generalization of Dudbridge et al. (Nat. Comm. 10: 1561), who developed a technique to adjust for index event bias when uncovering genetic predictors of disease progression based on case-only data. Our work serves to clarify that in any one sample MR analysis, it can be advantageous to estimate causal relationships by artificially inducing and then correcting for collider bias.
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http://dx.doi.org/10.1371/journal.pgen.1009703DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8376220PMC
August 2021

Genetic insights into biological mechanisms governing human ovarian ageing.

Nature 2021 08 4;596(7872):393-397. Epub 2021 Aug 4.

Genome Integrity and Instability Group, Institut de Biotecnologia i Biomedicina, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Spain.

Reproductive longevity is essential for fertility and influences healthy ageing in women, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease.
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http://dx.doi.org/10.1038/s41586-021-03779-7DOI Listing
August 2021

Additional Counseling Support for Mothers With Gestational Hypertensive Disorders Regarding Neurodevelopmental Outcomes in Their Children-Reply.

JAMA Pediatr 2021 Jul 12. Epub 2021 Jul 12.

Clinical Epidemiology and Biostatistics, School of Medical Sciences, Örebro University, Örebro, Sweden.

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http://dx.doi.org/10.1001/jamapediatrics.2021.2071DOI Listing
July 2021

Combining Longitudinal Data From Different Cohorts to Examine the Life-Course Trajectory.

Am J Epidemiol 2021 Jul 2. Epub 2021 Jul 2.

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

Longitudinal data are necessary to reveal changes within the same individual as they age. However, rarely will a single cohort capture data throughout the lifespan. We describe in detail the steps needed to develop life-course trajectories from cohorts that cover different and overlapping periods of life. Such independent studies are likely from heterogenous populations which raises several challenges including: data harmonisation (deriving new harmonised variables from differently measured variables by identifying common elements across all studies); systematically missing data (variables not measured are missing for all participants of a cohort); and model selection with differing age ranges and measurement schedules. We illustrate how to overcome these challenges using an example which examines the effects of parental education, sex, and ethnicity on weight trajectories. Data were from five prospective cohorts (Belarus and four UK regions), spanning from birth to early adulthood during differing calendar periods (1936-1964, 1972-1979, 1990-2012, 1996-2016, and 2007-2015). Key strengths of our approach include modelling trajectories over wide age ranges, sharing of information across studies and direct comparison of the same parts of the life-course in different geographical regions and time periods. We also introduce a novel approach of imputing individual-level covariates of a multilevel model with a nonlinear growth trajectory and interactions.
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http://dx.doi.org/10.1093/aje/kwab190DOI Listing
July 2021

Genome-wide association studies identify 137 genetic loci for DNA methylation biomarkers of aging.

Genome Biol 2021 06 29;22(1):194. Epub 2021 Jun 29.

Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA.

Background: Biological aging estimators derived from DNA methylation data are heritable and correlate with morbidity and mortality. Consequently, identification of genetic and environmental contributors to the variation in these measures in populations has become a major goal in the field.

Results: Leveraging DNA methylation and SNP data from more than 40,000 individuals, we identify 137 genome-wide significant loci, of which 113 are novel, from genome-wide association study (GWAS) meta-analyses of four epigenetic clocks and epigenetic surrogate markers for granulocyte proportions and plasminogen activator inhibitor 1 levels, respectively. We find evidence for shared genetic loci associated with the Horvath clock and expression of transcripts encoding genes linked to lipid metabolism and immune function. Notably, these loci are independent of those reported to regulate DNA methylation levels at constituent clock CpGs. A polygenic score for GrimAge acceleration showed strong associations with adiposity-related traits, educational attainment, parental longevity, and C-reactive protein levels.

Conclusion: This study illuminates the genetic architecture underlying epigenetic aging and its shared genetic contributions with lifestyle factors and longevity.
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http://dx.doi.org/10.1186/s13059-021-02398-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8243879PMC
June 2021

Separating parental and treatment contributions to perinatal health after fresh and frozen embryo transfer in assisted reproduction: A cohort study with within-sibship analysis.

PLoS Med 2021 Jun 25;18(6):e1003683. Epub 2021 Jun 25.

Department of Public Health and Nursing, Norwegian University of Science and Technology, Trondheim, Norway.

Background: Compared to naturally conceived children, adverse perinatal outcomes are more common among children born after assisted reproductive technology with fresh embryo transfer (fresh-ET) or frozen embryo transfer (frozen-ET). However, most previous studies could not adequately control for family confounding factors such as subfertility. We compared birth size and duration of pregnancy among infants born after fresh-ET or frozen-ET versus natural conception, using a within-sibship design to account for confounding by maternal factors.

Methods And Findings: This registry-based cohort study with nationwide data from Denmark (1994-2014), Norway (1988-2015), and Sweden (1988-2015) consisted of 4,510,790 live-born singletons, 4,414,703 from natural conception, 78,095 from fresh-ET, and 17,990 from frozen-ET. We identified 33,056 offspring sibling groups with the same mother, conceived by at least 2 different conception methods. Outcomes were mean birthweight, small and large for gestational age, mean gestational age, preterm (<37 weeks, versus ≥37), and very preterm birth (<32 weeks, versus ≥32). Singletons born after fresh-ET had lower mean birthweight (-51 g, 95% CI -58 to -45, p < 0.001) and increased odds of small for gestational age (odds ratio [OR] 1.20, 95% CI 1.08 to 1.34, p < 0.001), while those born after frozen-ET had higher mean birthweight (82 g, 95% CI 70 to 94, p < 0.001) and increased odds of large for gestational age (OR 1.84, 95% CI 1.56 to 2.17, p < 0.001), compared to naturally conceived siblings. Conventional population analyses gave similar results. Compared to naturally conceived siblings, mean gestational age was lower after fresh-ET (-1.0 days, 95% CI -1.2 to -0.8, p < 0.001), but not after frozen-ET (0.3 days, 95% CI 0.0 to 0.6, p = 0.028). There were increased odds of preterm birth after fresh-ET (OR 1.27, 95% CI 1.17 to 1.37, p < 0.001), and in most models after frozen-ET, versus naturally conceived siblings, with somewhat stronger associations in population analyses. For very preterm birth, population analyses showed increased odds for both fresh-ET (OR 2.03, 95% CI 1.90 to 2.12, p < 0.001) and frozen-ET (OR 1.66, 95% CI 1.42 to 1.94, p < 0.001) compared with natural conception, but results were notably attenuated within siblings (OR 1.18, 95% CI 1.0 to 1.41, p = 0.059, and OR 0.92, 95% CI 0.67 to 1.27, p = 0.6, for fresh-ET and frozen-ET, respectively). Sensitivity analyses in full siblings, in siblings born within 3-year interval, by birth order, and restricting to single embryo transfers and blastocyst transfers were consistent with the main analyses. Main limitations were high proportions of missing data on maternal body mass index and smoking.

Conclusions: We found that infants conceived by fresh-ET had lower birthweight and increased odds of small for gestational age, and those conceived by frozen-ET had higher birthweight and increased odds of large for gestational age. Conception by either fresh-ET or frozen-ET was associated with increased odds of preterm birth. That these findings were observed within siblings, as well as in conventional multivariable population analyses, reduces the likelihood that they are explained by confounding or selection bias.

Trial Registration: ClinicalTrials.gov ISRCTN11780826.
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http://dx.doi.org/10.1371/journal.pmed.1003683DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8274923PMC
June 2021

Association of medically assisted reproduction with offspring cord blood DNA methylation across cohorts.

Hum Reprod 2021 07;36(8):2403-2413

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

Study Question: Is cord blood DNA methylation associated with having been conceived by medically assisted reproduction?

Summary Answer: This study does not provide strong evidence of an association of conception by medically assisted reproduction with variation in infant blood cell DNA methylation.

What Is Known Already: Medically assisted reproduction consists of procedures used to help infertile/subfertile couples conceive, including ART. Due to its importance in gene regulation during early development programming, DNA methylation and its perturbations associated with medically assisted reproduction could reveal new insights into the biological effects of assisted reproductive technologies and potential adverse offspring outcomes.

Study Design, Size, Duration: We investigated the association of DNA methylation and medically assisted reproduction using a case-control study design (N = 205 medically assisted reproduction cases and N = 2439 naturally conceived controls in discovery cohorts; N = 149 ART cases and N = 58 non-ART controls in replication cohort).

Participants/materials, Settings, Methods: We assessed the association between medically assisted reproduction and DNA methylation at birth in cord blood (205 medically assisted conceptions and 2439 naturally conceived controls) at >450 000 CpG sites across the genome in two sub-samples of the UK Avon Longitudinal Study of Parents and Children (ALSPAC) and two sub-samples of the Norwegian Mother, Father and Child Cohort Study (MoBa) by meta-analysis. We explored replication of findings in the Australian Clinical review of the Health of adults conceived following Assisted Reproductive Technologies (CHART) study (N = 149 ART conceptions and N = 58 controls).

Main Results And The Role Of Chance: The ALSPAC and MoBa meta-analysis revealed evidence of association between conception by medically assisted reproduction and DNA methylation (false-discovery-rate-corrected P-value < 0.05) at five CpG sites which are annotated to two genes (percentage difference in methylation per CpG, cg24051276: Beta = 0.23 (95% CI 0.15,0.31); cg00012522: Beta = 0.47 (95% CI 0.31, 0.63); cg17855264: Beta = 0.31 (95% CI 0.20, 0.43); cg17132421: Beta = 0.30 (95% CI 0.18, 0.42); cg18529845: Beta = 0.41 (95% CI 0.25, 0.57)). Methylation at three of these sites has been previously linked to cancer, aging, HIV infection and neurological diseases. None of these associations replicated in the CHART cohort. There was evidence of a functional role of medically assisted reproduction-induced hypermethylation at CpG sites located within regulatory regions as shown by putative transcription factor binding and chromatin remodelling.

Limitations, Reasons For Cautions: While insufficient power is likely, heterogeneity in types of medically assisted reproduction procedures and between populations may also contribute. Larger studies might identify replicable variation in DNA methylation at birth due to medically assisted reproduction.

Wider Implications Of The Findings: Newborns conceived with medically assisted procedures present with divergent DNA methylation in cord blood white cells. If these associations are true and causal, they might have long-term consequences for offspring health.

Study Funding/competing Interests(s): This study has been supported by the US National Institute of Health (R01 DK10324), the European Research Council under the European Union's Seventh Framework Programme (FP7/2007-2013)/ERC Grant agreement no. 669545, European Union's Horizon 2020 research and innovation programme under Grant agreement no. 733206 (LifeCycle) and the NIHR Biomedical Centre at the University Hospitals Bristol NHS Foundation Trust and the University of Bristol. The UK Medical Research Council and Wellcome (Grant ref: 102215/2/13/2) and the University of Bristol provide core support for ALSPAC. Methylation data in the ALSPAC cohort were generated as part of the UK BBSRC funded (BB/I025751/1 and BB/I025263/1) Accessible Resource for Integrated Epigenomic Studies (ARIES, http://www.ariesepigenomics.org.uk). D.C., J.J., C.L.R. D.A.L and H.R.E. work in a Unit that is supported by the University of Bristol and the UK Medical Research Council (Grant nos. MC_UU_00011/1, MC_UU_00011/5 and MC_UU_00011/6). B.N. is supported by an NHMRC (Australia) Investigator Grant (1173314). ALSPAC GWAS data were generated by Sample Logistics and Genotyping Facilities at Wellcome Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe. The Norwegian Mother, Father and Child Cohort Study is supported by the Norwegian Ministry of Health and Care Services and the Ministry of Education and Research, NIH/NIEHS (Contract no. N01-ES-75558), NIH/NINDS (Grant nos. (i) UO1 NS 047537-01 and (ii) UO1 NS 047537-06A1). For this work, MoBa 1 and 2 were supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01-ES-49019) and the Norwegian Research Council/BIOBANK (Grant no. 221097). This work was partly supported by the Research Council of Norway through its Centres of Excellence funding scheme, Project no. 262700.D.A.L. has received support from national and international government and charity funders, as well as from Roche Diagnostics and Medtronic for research unrelated to this study. The other authors declare no conflicts of interest.

Trial Registration Number: N/A.
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http://dx.doi.org/10.1093/humrep/deab137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8289315PMC
July 2021

Childhood overeating is associated with adverse cardiometabolic and inflammatory profiles in adolescence.

Sci Rep 2021 Jun 14;11(1):12478. Epub 2021 Jun 14.

Department of Pediatrics Gynaecology and Obstetrics, Faculty of Medicine, University of Geneva, Geneva, Switzerland.

Childhood eating behaviour contributes to the rise of obesity and related noncommunicable disease worldwide. However, we lack a deep understanding of biochemical alterations that can arise from aberrant eating behaviour. In this study, we prospectively associate longitudinal trajectories of childhood overeating, undereating, and fussy eating with metabolic markers at age 16 years to explore adolescent metabolic alterations related to specific eating patterns in the first 10 years of life. Data are from the Avon Longitudinal Study of Parents and Children (n = 3104). We measure 158 metabolic markers with a high-throughput (H) NMR metabolomics platform. Increasing childhood overeating is prospectively associated with an adverse cardiometabolic profile (i.e., hyperlipidemia, hypercholesterolemia, hyperlipoproteinemia) in adolescence; whereas undereating and fussy eating are associated with lower concentrations of the amino acids glutamine and valine, suggesting a potential lack of micronutrients. Here, we show associations between early behavioural indicators of eating and metabolic markers.
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http://dx.doi.org/10.1038/s41598-021-90644-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8203659PMC
June 2021

The trans-ancestral genomic architecture of glycemic traits.

Nat Genet 2021 06 31;53(6):840-860. Epub 2021 May 31.

Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 × 10), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.
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http://dx.doi.org/10.1038/s41588-021-00852-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610958PMC
June 2021

Prenatal and postnatal exposure to acetaminophen in relation to autism spectrum and attention-deficit and hyperactivity symptoms in childhood: Meta-analysis in six European population-based cohorts.

Eur J Epidemiol 2021 May 28. Epub 2021 May 28.

ISGlobal, Barcelona Institute for Global Health, C. Doctor Aiguader 88, 08003, Barcelona, Spain.

The potential etiological role of early acetaminophen exposure on Autism Spectrum Conditions (ASC) and Attention-Deficit/Hyperactivity Disorder (ADHD) is inconclusive. We aimed to study this association in a collaborative study of six European population-based birth/child cohorts. A total of 73,881 mother-child pairs were included in the study. Prenatal and postnatal (up to 18 months) acetaminophen exposure was assessed through maternal questionnaires or interviews. ASC and ADHD symptoms were assessed at 4-12 years of age using validated instruments. Children were classified as having borderline/clinical symptoms using recommended cutoffs for each instrument. Hospital diagnoses were also available in one cohort. Analyses were adjusted for child and maternal characteristics along with indications for acetaminophen use. Adjusted cohort-specific effect estimates were combined using random-effects meta-analysis. The proportion of children having borderline/clinical symptoms ranged between 0.9 and 12.9% for ASC and between 1.2 and 12.2% for ADHD. Results indicated that children prenatally exposed to acetaminophen were 19% and 21% more likely to subsequently have borderline or clinical ASC (OR = 1.19, 95% CI 1.07-1.33) and ADHD symptoms (OR = 1.21, 95% CI 1.07-1.36) compared to non-exposed children. Boys and girls showed higher odds for ASC and ADHD symptoms after prenatal exposure, though these associations were slightly stronger among boys. Postnatal exposure to acetaminophen was not associated with ASC or ADHD symptoms. These results replicate previous work and support providing clear information to pregnant women and their partners about potential long-term risks of acetaminophen use.
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http://dx.doi.org/10.1007/s10654-021-00754-4DOI Listing
May 2021

Effect of Maternal Prepregnancy/Early-Pregnancy Body Mass Index and Pregnancy Smoking and Alcohol on Congenital Heart Diseases: A Parental Negative Control Study.

J Am Heart Assoc 2021 Jun 27;10(11):e020051. Epub 2021 May 27.

Population Health Science Bristol Medical School Bristol United Kingdom.

Background Congenital heart diseases (CHDs) are the most common congenital anomaly. The causes of CHDs are largely unknown. Higher prenatal body mass index (BMI), smoking, and alcohol consumption are associated with increased risk of CHDs. Whether these are causal is unclear. Methods and Results Seven European birth cohorts, including 232 390 offspring (2469 CHD cases [1.1%]), were included. We applied negative exposure paternal control analyses to explore the intrauterine effects of maternal BMI, smoking, and alcohol consumption during pregnancy, on offspring CHDs and CHD severity. We used logistic regression, adjusting for confounders and the other parent's exposure and combined estimates using a fixed-effects meta-analysis. In adjusted analyses, maternal overweight (odds ratio [OR], 1.15 [95% CI, 1.01-1.31]) and obesity (OR, 1.12 [95% CI, 0.93-1.36]), compared with normal weight, were associated with higher odds of CHD, but there was no clear evidence of a linear increase in odds across the whole BMI distribution. Associations of paternal overweight, obesity, and mean BMI were similar to the maternal associations. Maternal pregnancy smoking was associated with higher odds of CHD (OR, 1.11 [95% CI, 0.97-1.25]) but paternal smoking was not (OR, 0.96 [95% CI, 0.85-1.07]). The positive association with maternal smoking appeared to be driven by nonsevere CHD cases (OR, 1.22 [95% CI, 1.04-1.44]). Associations with maternal moderate/heavy pregnancy alcohol consumption were imprecisely estimated (OR, 1.16 [95% CI, 0.52-2.58]) and similar to those for paternal consumption. Conclusions We found evidence of an intrauterine effect for maternal smoking on offspring CHDs, but no evidence for higher maternal BMI or alcohol consumption. Our findings provide further support for the importance of smoking cessation during pregnancy.
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http://dx.doi.org/10.1161/JAHA.120.020051DOI Listing
June 2021

The Avon Longitudinal Study of Parents and Children - A resource for COVID-19 research: Generation 2 questionnaire data capture May-July 2020.

Wellcome Open Res 2020 14;5:278. Epub 2021 Apr 14.

ALSPAC, Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, BS8 2BN, UK.

The Avon Longitudinal Study of Parents and Children (ALSPAC) is a prospective population-based cohort study which recruited pregnant women in 1990-1992 from the Bristol area (UK). ALSPAC has followed these women, their partners (Generation 0; G0) and their offspring (Generation 1; G1) ever since. From 2012, ALSPAC has identified G1 participants who were pregnant (or their partner was) or had become parents, and enrolled them, their partners, and children in the ALSPAC-Generation 2 (ALSPAC-G2) study, providing a unique multi-generational cohort. At present, approximately 1,100 G2 children (excluding those ) from 810 G1 participants have been enrolled. In response to the COVID-19 pandemic, ALSPAC rapidly deployed two online questionnaires; one during the initial lockdown phase in 2020 (9 April-15 May), and another when national lockdown restrictions were eased (26 May-5 July). As part of this second questionnaire, G1 parents completed a questionnaire about each of their G2 children. This covered: parental reports of children's feelings and behaviour since lockdown, school attendance, contact patterns, and health. A total of 289 G1 participants completed this questionnaire on behalf of 411 G2 children. This COVID-19 G2 questionnaire data can be combined with pre-pandemic ALSPAC-G2 data, plus ALSPAC-G1 and -G0 data, to understand how children's health and behaviour has been affected by the pandemic and its management. Data from this questionnaire will be complemented with linkage to health records and results of biological testing as they become available. Prospective studies are necessary to understand the impact of this pandemic on children's health and development, yet few relevant studies exist; this resource will aid these efforts. Data has been released as: 1) a freely-available dataset containing participant responses with key sociodemographic variables; and 2) an ALSPAC-held dataset which can be combined with existing ALSPAC data, enabling bespoke research across all areas supported by the study.
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http://dx.doi.org/10.12688/wellcomeopenres.16414.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7968471.2PMC
April 2021

Ascertaining and classifying cases of congenital anomalies in the ALSPAC birth cohort.

Wellcome Open Res 2020 14;5:231. Epub 2021 Apr 14.

Department of Population Health Science, Bristol Medical School, University of Bristol, Bristol, BS8 2BN, UK.

Congenital anomalies (CAs) are structural or functional disorders that occur during intrauterine life. Longitudinal cohort studies provide unique opportunities to investigate potential causes and consequences of these disorders. In this data note, we describe how we identified cases of major CAs, with a specific focus on congenital heart diseases (CHDs), in the Avon Longitudinal Study of Parents and Children (ALSPAC). We demonstrate that combining multiple sources of data including data from antenatal, delivery, primary and secondary health records, and parent-reported information can improve case ascertainment. Our approach identified 590 participants with a CA according to the European Surveillance of Congenital Anomalies (EUROCAT) guidelines, 127 of whom had a CHD. We describe the methods that identified these cases and provide statistics on subtypes of anomalies. The data note contains details on the processes required for researchers to access these data.
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http://dx.doi.org/10.12688/wellcomeopenres.16339.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7871361.2PMC
April 2021

Locus of Control and Negative Cognitive Styles in Adolescence as Risk Factors for Depression Onset in Young Adulthood: Findings From a Prospective Birth Cohort Study.

Front Psychol 2021 25;12:599240. Epub 2021 Mar 25.

Centre for Academic Mental Health at the University of Bristol, Oakfield House, Bristol, United Kingdom.

Whilst previous observational studies have linked negative thought processes such as an external locus of control and holding negative cognitive styles with depression, the directionality of these associations and the potential role that these factors play in the transition to adulthood and parenthood has not yet been investigated. This study examined the association between locus of control and negative cognitive styles in adolescence and probable depression in young adulthood and whether parenthood moderated these associations. Using a UK prospective population-based birth cohort study: the Avon Longitudinal Study of Parents and Children (ALSPAC), we examined the association between external locus of control and negative cognitive styles in adolescence with odds of depression in 4,301 young adults using logistic regression models unadjusted and adjusted for potential confounding factors. Interaction terms were employed to examine whether parenthood (i.e., having become a parent or not) moderated these associations. Over 20% of young adults in our sample were at or above the clinical threshold indicating probable depression. For each standard deviation (SD) increase in external locus of control in adolescence, there was a 19% (95% CI: 8-32%) higher odds of having probable depression in young adulthood, after adjusting for various confounding factors including baseline mood and different demographic and life events variables. Similarly, for each SD increase in negative cognitive styles in adolescence, there was a 29% (95% CI: 16-44%) higher odds of having probable depression in the adjusted model. We found little evidence that parenthood status moderated the relationship between external locus of control or negative cognitive styles in adolescence and probable depression following adjustment for confounding factors. Effect estimates were comparable when performed in the complete case dataset. These findings suggest that having an external locus of control and holding negative cognitive styles in mid- to late adolescence is associated with an increased likelihood of probable depression in young adulthood.
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http://dx.doi.org/10.3389/fpsyg.2021.599240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8080877PMC
March 2021

2008 financial crisis versus 2020 economic fallout: how COVID-19 might influence fertility treatment and live births.

Reprod Biomed Online 2021 06 23;42(6):1087-1096. Epub 2021 Mar 23.

School of Medicine, University of Glasgow, UK; NIHR Bristol Biomedical Research Centre Bristol, UK; The Fertility Partnership, Oxford, UK. Electronic address:

Research Question: The economic and reproductive medicine response to the coronavirus disease 2019 (COVID-19) pandemic in the USA has reduced the affordability and accessibility of fertility care. What is the impact of the 2008 financial recession and the COVID-19 recession on fertility treatments and cumulative live births?

Design: The study examined annual US natality, Centers for Disease Control and Prevention IVF cycle activity and live birth data from 1999 to 2018 encompassing 3,286,349 treatment cycles, to estimate the age-stratified reduction in IVF cycles undertaken after the 2008 financial recession, with forward quantitative modelling of IVF cycle activity and cumulative live births for 2020 to 2023.

Results: The financial recession of 2008 caused a 4-year plateau in fertility treatments with a predicted 53,026 (95% confidence interval [CI] 49,581 to 56,471) fewer IVF cycles and 16,872 (95% CI 16,713 to 17,031) fewer live births. A similar scale of economic recession would cause 67,386 (95% CI 61,686 to 73,086) fewer IVF cycles between 2020 and 2023, with women younger than 35 years overall undertaking 22,504 (95% CI 14,320 to 30,690) fewer cycles, compared with 4445 (95% CI 3144 to 5749) fewer cycles in women over the age of 40 years. This equates to overall 25,143 (95% CI 22,408 to 27,877) fewer predicted live births from IVF, of which only 490 (95% CI 381 to 601) are anticipated to occur in women over the age of 40 years.

Conclusions: The COVID-19 recession could have a profound impact on US IVF live birth rates in young women, further aggravating pre-existing declines in total fertility rates.
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http://dx.doi.org/10.1016/j.rbmo.2021.03.017DOI Listing
June 2021

Neonatal and early childhood outcomes following maternal anesthesia for cesarean section: a population-based cohort study.

Reg Anesth Pain Med 2021 06 8;46(6):482-489. Epub 2021 Apr 8.

School of Medicine, University of Glasgow, Glasgow, UK.

Background: The fetus is vulnerable to maternal drug exposure. We determined associations of exposure to spinal, epidural, or general anesthesia on neonatal and childhood development outcomes during the first 1000 days of life.

Methods: Population-based study of all singleton, cesarean livebirths of 24+0 to 43+6 weeks gestation between January 2007 and December 2016 in Scotland, stratified by urgency with follow-up to age 2 years. Models were adjusted for: maternal age, weight, ethnicity, socioeconomic status, smoking, drug-use, induction, parity, previous cesarean or abortion, pre-eclampsia, gestation, birth weight, and sex.

Results: 140 866 mothers underwent cesarean section (41.2% (57,971/140,866) elective, 58.8% (82,895/140,866) emergency) with general anesthesia used in 3.2% (1877/57,971) elective and 9.8% (8158/82,895) of emergency cases. In elective cases, general anesthesia versus spinal was associated with: neonatal resuscitation (crude event rate 16.2% vs 1.9% (adjusted RR 8.20, 95% CI 7.20 to 9.33), Apgar <7 at 5 min (4.6% vs 0.4% (adjRR 11.44, 95% CI 8.88 to 14.75)), and neonatal admission (8.6% vs 4.9% (adjRR 1.65, 95% CI 1.40 to 1.94)). Associations were similar in emergencies; resuscitation (32.2% vs 12.3% (adjRR 2.40, 95% CI 2.30 to 2.50)), Apgar <7 (12.6% vs 2.8% (adjRR 3.87, 95% CI 3.56 to 4.20), and admission (31.6% vs 19.9% (adjRR 1.20, 95% CI 1.15 to 1.25). There was a weak association between general anesthesia in emergency cases and having ≥1 concern noted in developmental assessment at 2 years (21.0% vs 16.5% (adjRR 1.08, 95% CI 1.01 to 1.16)).

Conclusions: General anesthesia for cesarean section, irrespective of urgency, is associated with neonatal resuscitation, low Apgar, and neonatal unit admission. Associations were strongest in non-urgent cases and at term. Further evaluation of long-term outcomes is warranted.
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http://dx.doi.org/10.1136/rapm-2020-102441DOI Listing
June 2021

Association Between Hypertensive Disorders of Pregnancy and Neurodevelopmental Outcomes Among Offspring.

JAMA Pediatr 2021 Jun;175(6):577-585

Clinical Epidemiology and Biostatistics, School of Medical Sciences, Örebro University, Örebro, Sweden.

Importance: Hypertensive disorders of pregnancy (HDP) have been associated with poorer neurodevelopmental outcomes in offspring, but the role of familial confounding in these associations is unclear.

Objective: To investigate associations of maternal HDP with risks in offspring of autism spectrum disorders (ASDs), attention-deficit/hyperactivity disorder (ADHD), and intellectual disability (ID), as well as variation in overall cognitive performance in offspring.

Design, Setting, And Participants: This Swedish register-based study used data from a birth cohort divided into 1 085 024 individuals born between 1987 and 1996 and followed up until December 31, 2014, and 285 901 men born between 1982 and 1992 who attended assessments for military conscription, including a cognitive function test. Statistical analysis was performed from April 1, 2019, to June 1, 2020.

Exposures: Diagnoses of HDP, which were provided by the Medical Birth Register.

Main Outcomes And Measures: Diagnoses of ASDs, ADHD, and ID were extracted from the National Patient Register. Cognitive function was assessed using written tests and summarized as a single 9-point score. Whole-cohort and within-sibship analyses were performed; the latter accounted for unmeasured familial confounding factors shared by siblings.

Results: The study included 1 085 024 individuals (556 912 male participants [51.3%]) born between 1987 and 1996 and 285 901 men born between 1982 and 1992 who attended assessments for military conscription. The prevalence of maternal HDP was 4.0% in the 1987-1996 birth cohort (n = 42 980) and 5.1% in the military conscription cohort (n = 14 515). A total of 15 858 participants received a diagnosis of ASD, 36 852 received a diagnosis of ADHD, and 8454 received a diagnosis of ID. The mean (SD) cognitive score among the men in the conscription cohort was 5.1 (1.9). In whole-cohort analyses with multivariable adjustment, HDP were associated with offspring ASDs (hazard ratio [HR], 1.22; 95% CI, 1.13-1.31), ADHD (HR, 1.10; 95% CI, 1.05-1.16), and ID (HR, 1.39; 95% CI, 1.27-1.53). Analyses comparing siblings discordant for HDP were less statistically powered but indicated estimates of similar magnitude for ASDs (HR, 1.19; 95% CI, 1.00-1.42) and possibly ADHD (HR, 1.09; 95% CI, 0.95-1.24), but not for ID (HR, 1.04; 95% CI, 0.83-1.29). Hypertensive disorders of pregnancy were associated with somewhat lower cognitive scores in whole-cohort analysis (mean difference comparing offspring exposed with those unexposed, -0.10; 95% CI, -0.13 to -0.07), but in within-sibship analysis, the association was null (mean difference, 0.00; 95% CI, -0.09 to 0.08).

Conclusions And Relevance: The study results suggest that HDP are associated with small increased risks of ASDs and possibly ADHD in offspring, whereas associations with ID and cognitive performance are likely confounded by shared familial (environmental or genetic) factors.
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http://dx.doi.org/10.1001/jamapediatrics.2020.6856DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7985818PMC
June 2021

Investigating the relationships between unfavourable habitual sleep and metabolomic traits: evidence from multi-cohort multivariable regression and Mendelian randomization analyses.

BMC Med 2021 Mar 18;19(1):69. Epub 2021 Mar 18.

Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.

Background: Sleep traits are associated with cardiometabolic disease risk, with evidence from Mendelian randomization (MR) suggesting that insomnia symptoms and shorter sleep duration increase coronary artery disease risk. We combined adjusted multivariable regression (AMV) and MR analyses of phenotypes of unfavourable sleep on 113 metabolomic traits to investigate possible biochemical mechanisms linking sleep to cardiovascular disease.

Methods: We used AMV (N = 17,368) combined with two-sample MR (N = 38,618) to examine effects of self-reported insomnia symptoms, total habitual sleep duration, and chronotype on 113 metabolomic traits. The AMV analyses were conducted on data from 10 cohorts of mostly Europeans, adjusted for age, sex, and body mass index. For the MR analyses, we used summary results from published European-ancestry genome-wide association studies of self-reported sleep traits and of nuclear magnetic resonance (NMR) serum metabolites. We used the inverse-variance weighted (IVW) method and complemented this with sensitivity analyses to assess MR assumptions.

Results: We found consistent evidence from AMV and MR analyses for associations of usual vs. sometimes/rare/never insomnia symptoms with lower citrate (- 0.08 standard deviation (SD)[95% confidence interval (CI) - 0.12, - 0.03] in AMV and - 0.03SD [- 0.07, - 0.003] in MR), higher glycoprotein acetyls (0.08SD [95% CI 0.03, 0.12] in AMV and 0.06SD [0.03, 0.10) in MR]), lower total very large HDL particles (- 0.04SD [- 0.08, 0.00] in AMV and - 0.05SD [- 0.09, - 0.02] in MR), and lower phospholipids in very large HDL particles (- 0.04SD [- 0.08, 0.002] in AMV and - 0.05SD [- 0.08, - 0.02] in MR). Longer total sleep duration associated with higher creatinine concentrations using both methods (0.02SD per 1 h [0.01, 0.03] in AMV and 0.15SD [0.02, 0.29] in MR) and with isoleucine in MR analyses (0.22SD [0.08, 0.35]). No consistent evidence was observed for effects of chronotype on metabolomic measures.

Conclusions: Whilst our results suggested that unfavourable sleep traits may not cause widespread metabolic disruption, some notable effects were observed. The evidence for possible effects of insomnia symptoms on glycoprotein acetyls and citrate and longer total sleep duration on creatinine and isoleucine might explain some of the effects, found in MR analyses of these sleep traits on coronary heart disease, which warrant further investigation.
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http://dx.doi.org/10.1186/s12916-021-01939-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7971964PMC
March 2021

Experiences of lockdown during the Covid-19 pandemic: descriptive findings from a survey of families in the Born in Bradford study.

Wellcome Open Res 2020 26;5:228. Epub 2021 Feb 26.

Department of Health Sciences, University of York, Seebohm Rowntree Building, Heslington, York, YO10 5DD, UK.

: Lockdown measures implemented to contain the Covid-19 virus have increased health inequalities, with families from deprived and ethnically diverse backgrounds most likely to be adversely affected. This paper describes the experiences of families living in the multi-ethnic and deprived city of Bradford, England. : A wave of survey data collection using a combination of email, text and phone with postal follow-up during the first Covid-19 UK lockdown (10th April to 30 June 2020) with parents participating in two longitudinal studies. Cross tabulations explored variation by ethnicity and financial insecurity. Text from open questions was analysed using thematic analysis. : Of 7,652 families invited, 2,144 (28%) participated. The results presented are based on the 2,043 (95%) mothers' responses: 957 (47%) of whom were of Pakistani heritage, 715 (35%) White British and 356 (18%) other ethnicity 971 (46%) lived in the most deprived decile of material deprivation in England. and 738 (37%) were financially insecure. Many families lived in poor quality (N=574, 28%), overcrowded (N=364, 19%) housing. Food (N=396, 20%), employment (N=728, 37%) and housing (N=204, 10%) insecurities were common, particularly in those who were furloughed, self-employed not working or unemployed. Clinically important depression and anxiety were reported by 372 (19%) and 318 (16%) mothers. Ethnic minority and financially insecure families had a worse experience during the lockdown across all domains, with the exception of mental health which appeared worse in White British mothers.  Open text responses corroborated these findings and highlighted high levels of anxiety and fear about Covid-19. : There is a need for policy makers and commissioners to better support vulnerable families during and after the pandemic. Future work will use longitudinal data from before the pandemic, and from future surveys during the pandemic, to describe trajectories and the long-term consequences of the pandemic on vulnerable populations.
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http://dx.doi.org/10.12688/wellcomeopenres.16317.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7927208.2PMC
February 2021

Using electronic patient records to assess the effect of a complex antenatal intervention in a cluster randomised controlled trial-data management experience from the DESiGN Trial team.

Trials 2021 Mar 8;22(1):195. Epub 2021 Mar 8.

Department of Women and Children's Health, School of Life Course Sciences, Faculty of Life Sciences and Medicine, King's College London, 10th Floor North Wing, St. Thomas' Hospital, Westminster Bridge Road, London, SE1 7EH, UK.

Background: The use of electronic patient records for assessing outcomes in clinical trials is a methodological strategy intended to drive faster and more cost-efficient acquisition of results. The aim of this manuscript was to outline the data collection and management considerations of a maternity and perinatal clinical trial using data from electronic patient records, exemplifying the DESiGN Trial as a case study.

Methods: The DESiGN Trial is a cluster randomised control trial assessing the effect of a complex intervention versus standard care for identifying small for gestational age foetuses. Data on maternal/perinatal characteristics and outcomes including infants admitted to neonatal care, parameters from foetal ultrasound and details of hospital activity for health-economic evaluation were collected at two time points from four types of electronic patient records held in 22 different electronic record systems at the 13 research clusters. Data were pseudonymised on site using a bespoke Microsoft Excel macro and securely transferred to the central data store. Data quality checks were undertaken. Rules for data harmonisation of the raw data were developed and a data dictionary produced, along with rules and assumptions for data linkage of the datasets. The dictionary included descriptions of the rationale and assumptions for data harmonisation and quality checks.

Results: Data were collected on 182,052 babies from 178,350 pregnancies in 165,397 unique women. Data availability and completeness varied across research sites; each of eight variables which were key to calculation of the primary outcome were completely missing in median 3 (range 1-4) clusters at the time of the first data download. This improved by the second data download following clarification of instructions to the research sites (each of the eight key variables were completely missing in median 1 (range 0-1) cluster at the second time point). Common data management challenges were harmonising a single variable from multiple sources and categorising free-text data, solutions were developed for this trial.

Conclusions: Conduct of clinical trials which use electronic patient records for the assessment of outcomes can be time and cost-effective but still requires appropriate time and resources to maximise data quality. A difficulty for pregnancy and perinatal research in the UK is the wide variety of different systems used to collect patient data across maternity units. In this manuscript, we describe how we managed this and provide a detailed data dictionary covering the harmonisation of variable names and values that will be helpful for other researchers working with these data.

Trial Registration: Primary registry and trial identifying number: ISRCTN 67698474 . Registered on 02/11/16.
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http://dx.doi.org/10.1186/s13063-021-05141-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7941939PMC
March 2021

Cardiometabolic health during early adulthood and risk of miscarriage: a prospective study.

Wellcome Open Res 2020 12;5:205. Epub 2021 Feb 12.

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

Several studies have found that women who are overweight or obese have an increased risk of miscarriage. There is also some evidence of associations of other aspects of cardiometabolic health, including blood pressure and lipids, with miscarriage risk, although these have not been examined to the same extent as body-mass index (BMI). Our objective was to investigate the risk of miscarriage according to pre-pregnancy cardiometabolic health. We examined pre-pregnancy levels of BMI, blood pressure, fasting insulin and metabolites profile at age 18 and risk of miscarriage by age 24. The study included adult female offspring in the Avon Longitudinal Study of Parents and Children with a pregnancy between 18 and 24 years of age (n=434 for BMI and blood pressure; n=265 for metabolites). We used log-binomial regression to calculate adjusted associations between cardiometabolic health measures and miscarriage. The overall risk of miscarriage was 22%.  The adjusted relative risks for miscarriage were 0.96 (95% CI: 0.92-1.00) for BMI (per unit increase), 0.98 (0.96-1.00) for systolic blood pressure, and 1.00 (0.97-1.04) for diastolic blood pressure (per 1 mmHg increase).  Total cholesterol, total lipids and phospholipids in HDL-cholesterol were associated with increased likelihood of miscarriage, but none of the p-values for the metabolites were below the corrected threshold for multiple testing (p-value ≤0.003). Our findings indicate no strong evidence to support a relationship between pre-pregnancy cardiometabolic health and risk of miscarriage in young, healthy women who became pregnant before age 24. Future studies are necessary that are able to evaluate this question in samples with a wider age range.
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http://dx.doi.org/10.12688/wellcomeopenres.16245.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7888356PMC
February 2021

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

BMC Med 2021 Feb 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

Bias in two-sample Mendelian randomization when using heritable covariable-adjusted summary associations.

Int J Epidemiol 2021 Feb 23. Epub 2021 Feb 23.

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

Background: Two-sample Mendelian randomization (MR) allows the use of freely accessible summary association results from genome-wide association studies (GWAS) to estimate causal effects of modifiable exposures on outcomes. Some GWAS adjust for heritable covariables in an attempt to estimate direct effects of genetic variants on the trait of interest. One, both or neither of the exposure GWAS and outcome GWAS may have been adjusted for covariables.

Methods: We performed a simulation study comprising different scenarios that could motivate covariable adjustment in a GWAS and analysed real data to assess the influence of using covariable-adjusted summary association results in two-sample MR.

Results: In the absence of residual confounding between exposure and covariable, between exposure and outcome, and between covariable and outcome, using covariable-adjusted summary associations for two-sample MR eliminated bias due to horizontal pleiotropy. However, covariable adjustment led to bias in the presence of residual confounding (especially between the covariable and the outcome), even in the absence of horizontal pleiotropy (when the genetic variants would be valid instruments without covariable adjustment). In an analysis using real data from the Genetic Investigation of ANthropometric Traits (GIANT) consortium and UK Biobank, the causal effect estimate of waist circumference on blood pressure changed direction upon adjustment of waist circumference for body mass index.

Conclusions: Our findings indicate that using covariable-adjusted summary associations in MR should generally be avoided. When that is not possible, careful consideration of the causal relationships underlying the data (including potentially unmeasured confounders) is required to direct sensitivity analyses and interpret results with appropriate caution.
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http://dx.doi.org/10.1093/ije/dyaa266DOI Listing
February 2021

Genome-wide association study of circulating interleukin 6 levels identifies novel loci.

Hum Mol Genet 2021 04;30(5):393-409

Institute of Cardiovascular Science, University College London, London WC1E 6BT, UK.

Interleukin 6 (IL-6) is a multifunctional cytokine with both pro- and anti-inflammatory properties with a heritability estimate of up to 61%. The circulating levels of IL-6 in blood have been associated with an increased risk of complex disease pathogenesis. We conducted a two-staged, discovery and replication meta genome-wide association study (GWAS) of circulating serum IL-6 levels comprising up to 67 428 (ndiscovery = 52 654 and nreplication = 14 774) individuals of European ancestry. The inverse variance fixed effects based discovery meta-analysis, followed by replication led to the identification of two independent loci, IL1F10/IL1RN rs6734238 on chromosome (Chr) 2q14, (Pcombined = 1.8 × 10-11), HLA-DRB1/DRB5 rs660895 on Chr6p21 (Pcombined = 1.5 × 10-10) in the combined meta-analyses of all samples. We also replicated the IL6R rs4537545 locus on Chr1q21 (Pcombined = 1.2 × 10-122). Our study identifies novel loci for circulating IL-6 levels uncovering new immunological and inflammatory pathways that may influence IL-6 pathobiology.
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http://dx.doi.org/10.1093/hmg/ddab023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8098112PMC
April 2021

Time-to-pregnancy and risk of cardiovascular disease among men and women.

Eur J Epidemiol 2021 Apr 25;36(4):383-391. Epub 2021 Jan 25.

Centre for Fertility and Health, Norwegian Institute of Public Health, P.O. Box 222, 0213, Skøyen, Oslo, Norway.

A few studies indicate that women with prolonged time-to-pregnancy (TTP) have an increased risk of cardiovascular disease (CVD). This has not been studied in men. We evaluated CVD risk by self-reported TTP among parous women (n = 64,064) and men (n = 50,533) participating in the Norwegian Mother, Father and Child Cohort Study. TTP was categorized as 0-3 (reference), 4-12 and > 12 months. CVD diagnosed between 2008 and 2017 were available from the national patient and general practitioner databases. Risk of CVD by TTP was estimated using Cox regression adjusting for baseline age, education, BMI, smoking, diabetes, and number of offspring in both sexes, and history of endometriosis, ovarian cysts, preterm birth and pre-eclampsia for women. Mean age was 33 for women and 35 for men at baseline (years). The rate of any CVD was 24 per 1000 person years among women and 22 per 1000 person years among men. Longer TTP was associated with increased rate of CVD among women, with adjusted hazard ratios (HRs) of 1.07 (95% CI: 1.03, 1.09) for TTP 4-12 months and 1.14 (1.08, 1.20) for TTP > 12 months. Among men, respective HRs for CVD were 1.06 (1.00, 1.10) for TTP 4-12 months and 1.07 (1.01, 1.14) for TTP > 12 months. We observed sex-differences in the relationship with CVD subtypes but none were statistically significant. In conclusion, both men and women with a prolonged TTP had a small increased risk of CVD, clinical significance of which is unclear. Further studies are necessary to investigate in detail what underlying causes of prolonged TTP might be reflected in the increased risk of CVD. Longer follow-up is required to confirm these preliminary findings.
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http://dx.doi.org/10.1007/s10654-021-00718-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8076115PMC
April 2021

Does death from Covid-19 arise from a multi-step process?

Eur J Epidemiol 2021 Jan 18;36(1):1-9. Epub 2021 Jan 18.

National Heart and Lung Institute, Imperial College London, London, UK.

The Covid-19 death rate increases exponentially with age, and the main risk factors are having underlying conditions such as hypertension, diabetes, cardiovascular disease, severe chronic respiratory disease and cancer. These characteristics are consistent with the multi-step model of disease. We applied this model to Covid-19 case fatality rates (CFRs) from China, South Korea, Italy, Spain and Japan. In all countries we found that a plot of log(CFR) against log(age) was approximately linear with a slope of about 5. We also conducted similar analyses for selected other respiratory diseases. SARS showed a similar log-log age-pattern to that of Covid-19, albeit with a lower slope, whereas seasonal and pandemic influenza showed quite different age-patterns. Thus, death from Covid-19 and SARS appears to follow a distinct age-pattern, consistent with a multi-step model of disease that in the case of Covid-19 is probably defined by comorbidities and age producing immune-related susceptibility.
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http://dx.doi.org/10.1007/s10654-020-00711-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812338PMC
January 2021
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