Publications by authors named "Ken K Ong"

268 Publications

Metabolomics in early life and the association with body composition at age 2 years.

Pediatr Obes 2021 Oct 13:e12859. Epub 2021 Oct 13.

Core Metabolomics and Lipidomics Laboratory, Metabolic Research Laboratories, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.

Background And Objectives: Early life is a critical window for adiposity programming. Metabolic-profile in early life may reflect this programming and correlate with later life adiposity. We investigated if metabolic-profile at 3 months of age is predictive for body composition at 2 years and if there are differences between boys and girls and between infant feeding types.

Methods: In 318 healthy term-born infants, we determined body composition with skinfold measurements and abdominal ultrasound at 3 months and 2 years of age. High-throughput-metabolic-profiling was performed on 3-month-blood-samples. Using random-forest-machine-learning-models, we studied if the metabolic-profile at 3 months can predict body composition outcomes at 2 years of age.

Results: Plasma metabolite-profile at 3 months was found to predict body composition at 2 years, based on truncal: peripheral-fat-skinfold-ratio (T:P-ratio), with a predictive value of 75.8%, sensitivity of 100% and specificity of 50%. Predictive value was higher in boys (Q  = 0.322) than girls (Q  = 0.117). Of the 15 metabolite variables most strongly associated with T:P-ratio, 11 were also associated with visceral fat at 2 years of age.

Conclusion: Several plasma metabolites (LysoPC(22:2), dimethylarginine and others) at 3 months associate with body composition outcome at 2 years. These results highlight the importance of the first months of life for adiposity programming.
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http://dx.doi.org/10.1111/ijpo.12859DOI Listing
October 2021

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

Nat Genet 2021 09 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

Extensive Study of Breast Milk and Infant Growth: Protocol of the Cambridge Baby Growth and Breastfeeding Study (CBGS-BF).

Nutrients 2021 Aug 21;13(8). Epub 2021 Aug 21.

Department of Paediatrics, University of Cambridge, Cambridge CB2 0QQ, UK.

Growth and nutrition during early life have been strongly linked to future health and metabolic risks. The Cambridge Baby Growth Study (CBGS), a longitudinal birth cohort of 2229 mother-infant pairs, was set up in 2001 to investigate early life determinant factors of infant growth and body composition in the UK setting. To carry out extensive profiling of breastmilk intakes and composition in relation to infancy growth, the Cambridge Baby Growth and Breastfeeding Study (CBGS-BF) was established upon the original CBGS. The strict inclusion criteria were applied, focusing on a normal birth weight vaginally delivered infant cohort born of healthy and non-obese mothers. Crucially, only infants who were exclusively breastfed for the first 6 weeks of life were retained in the analysed study sample. At each visit from birth, 2 weeks, 6 weeks, and then at 3, 6, 12, 24, and 36 months, longitudinal anthropometric measurements and blood spot collections were conducted. Infant body composition was assessed using air displacement plethysmography (ADP) at 6 weeks and 3 months of age. Breast milk was collected for macronutrients and human milk oligosaccharides (HMO) measurements. Breast milk intake volume was also estimated, as well as sterile breastmilk and infant stool collection for microbiome study.
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http://dx.doi.org/10.3390/nu13082879DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8400677PMC
August 2021

Associations between Maternal Iron Supplementation in Pregnancy and Changes in Offspring Size at Birth Reflect Those of Multiple Micronutrient Supplementation.

Nutrients 2021 Jul 20;13(7). Epub 2021 Jul 20.

Department of Paediatrics, University of Cambridge, Cambridge CB2 0QQ, UK.

It was previously observed that in a population of a high-income country, dietary multiple micronutrient supplementation in pregnancy was associated with an increased risk of gestational diabetes (GDM) and increased offspring size at birth. In this follow-up study, we investigated whether similar changes are observed with dietary iron supplementation. For this we used the prospective Cambridge Baby Growth Study with records of maternal GDM status, nutrient supplementation, and extensive offspring birth size measurements. Maternal iron supplementation in pregnancy was associated with GDM development (risk ratio 1.67 (1.01-2.77), = 0.048, = 677) as well as offspring size and adiposity ( = 844-868) at birth in terms of weight (β' = 0.078 (0.024-0.133); = 0.005), head circumference (β' = 0.060 (0.012-0.107); = 0.02), body mass index (β' = 0.067 (0.014-0.119); = 0.01), and various skinfold thicknesses (β' = 0.067-0.094; = 0.03-0.003). In a subset of participants for whom GDM statuses were available, all these associations were attenuated by adjusting for GDM. Iron supplementation also attenuated the associations between multiple micronutrient supplementation and these same measures. These results suggest that iron supplementation may mediate the effects associated with multiple micronutrient supplementation in pregnancy in a high-income country, possibly through the increased risk of developing GDM.
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http://dx.doi.org/10.3390/nu13072480DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8308651PMC
July 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
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611832PMC
August 2021

GIGYF1 loss of function is associated with clonal mosaicism and adverse metabolic health.

Nat Commun 2021 07 7;12(1):4178. Epub 2021 Jul 7.

MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.

Mosaic loss of chromosome Y (LOY) in leukocytes is the most common form of clonal mosaicism, caused by dysregulation in cell-cycle and DNA damage response pathways. Previous genetic studies have focussed on identifying common variants associated with LOY, which we now extend to rarer, protein-coding variation using exome sequences from 82,277 male UK Biobank participants. We find that loss of function of two genes-CHEK2 and GIGYF1-reach exome-wide significance. Rare alleles in GIGYF1 have not previously been implicated in any complex trait, but here loss-of-function carriers exhibit six-fold higher susceptibility to LOY (OR = 5.99 [3.04-11.81], p = 1.3 × 10). These same alleles are also associated with adverse metabolic health, including higher susceptibility to Type 2 Diabetes (OR = 6.10 [3.51-10.61], p = 1.8 × 10), 4 kg higher fat mass (p = 1.3 × 10), 2.32 nmol/L lower serum IGF1 levels (p = 1.5 × 10) and 4.5 kg lower handgrip strength (p = 4.7 × 10) consistent with proposed GIGYF1 enhancement of insulin and IGF-1 receptor signalling. These associations are mirrored by a common variant nearby associated with the expression of GIGYF1. Our observations highlight a potential direct connection between clonal mosaicism and metabolic health.
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http://dx.doi.org/10.1038/s41467-021-24504-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8263756PMC
July 2021

Longitudinal associations between prepubertal childhood total energy and macronutrient intakes and subsequent puberty timing in UK boys and girls.

Eur J Nutr 2021 Jul 7. Epub 2021 Jul 7.

MRC Epidemiology Unit, Institute of Metabolic Science, School of Clinical Medicine, University of Cambridge, Cambridge Biomedical Campus Box 285, Cambridge, CB2 0QQ, UK.

Purpose: Early puberty is associated with adverse health outcomes. To identify potential modifiable factors for puberty timing, we examined the associations of prepubertal childhood macronutrient intakes with puberty timing in boys and girls.

Methods: In the Avon Longitudinal Study of Parents and Children, macronutrient intakes at age 6 years were predicted using random intercepts linear regression models of dietary data at 3, 4, 7 (assessed by food frequency questionnaires) and 7.5 years (by 3-day food diaries). Timings of puberty onset (Tanner stage 2 genital or breast (B2) development) and puberty completion (voice breaking (VB) or menarche) were calculated from annual parental and child reports at 8-17 years. Age at peak height velocity (PHV) was derived from repeated height measurements at 5-20 years. Linear regression models were fit to estimate the associations of total energy (TEI) and macronutrient intakes (carbohydrate, fat, protein) with puberty timing traits, adjusting for maternal and infant characteristics.

Results: Among 3811 boys, higher TEI, but no macronutrient, was associated with earlier VB. Among 3919 girls, higher TEI was associated with earlier ages at B2, PHV, and menarche. Higher protein intake but not carbohydrate or fat intake (in energy partition models) and substitution of dietary protein for carbohydrate (in nutrient density and residual models) was associated with earlier B2, PHV, and menarche in girls. Findings were not attenuated on additional adjustment for body fat percentage during adolescence.

Conclusions: These findings suggest habitual total energy intakes in children, and protein intakes in girls, as potential modifiable determinants of puberty timing.
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http://dx.doi.org/10.1007/s00394-021-02629-6DOI Listing
July 2021

Identification of 371 genetic variants for age at first sex and birth linked to externalising behaviour.

Nat Hum Behav 2021 Jul 1. Epub 2021 Jul 1.

MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom.

Age at first sexual intercourse and age at first birth have implications for health and evolutionary fitness. In this genome-wide association study (age at first sexual intercourse, N = 387,338; age at first birth, N = 542,901), we identify 371 single-nucleotide polymorphisms, 11 sex-specific, with a 5-6% polygenic score prediction. Heritability of age at first birth shifted from 9% [CI = 4-14%] for women born in 1940 to 22% [CI = 19-25%] for those born in 1965. Signals are driven by the genetics of reproductive biology and externalising behaviour, with key genes related to follicle stimulating hormone (FSHB), implantation (ESR1), infertility and spermatid differentiation. Our findings suggest that polycystic ovarian syndrome may lead to later age at first birth, linking with infertility. Late age at first birth is associated with parental longevity and reduced incidence of type 2 diabetes and cardiovascular disease. Higher childhood socioeconomic circumstances and those in the highest polygenic score decile (90%+) experience markedly later reproductive onset. Results are relevant for improving teenage and late-life health, understanding longevity and guiding experimentation into mechanisms of infertility.
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http://dx.doi.org/10.1038/s41562-021-01135-3DOI Listing
July 2021

The High-Risk Type 1 Diabetes HLA-DR and HLA-DQ Polymorphisms Are Differentially Associated With Growth and IGF-I Levels in Infancy: The Cambridge Baby Growth Study.

Diabetes Care 2021 08 25;44(8):1852-1859. Epub 2021 Jun 25.

Department of Paediatrics, University of Cambridge, Cambridge, U.K.

Objective: This study explored the link between HLA polymorphisms that predispose to type 1 diabetes and birth size, infancy growth, and/or circulating IGF-I in a general population-based birth cohort.

Research Design And Methods: The Cambridge Baby Growth Study is a prospective observational birth cohort study that recruited 2,229 newborns for follow-up in infancy. Of these, 612 children had DNA available for genotyping single nucleotide polymorphisms in the HLA region that capture the highest risk of type 1 diabetes: rs17426593 for , rs2187668 for , and rs7454108 for . Multivariate linear regression models at critical ages (cross-sectional) and mixed-effects models (longitudinal) were performed under additive genetic effects to test for associations between HLA polymorphisms and infancy weight, length, skinfold thickness (indicator of adiposity), and concentrations of IGF-I and IGF-binding protein-3 (IGFBP-3).

Results: In longitudinal models, the minor allele of rs2187668 tagging was associated with faster linear growth ( = 0.007), which was more pronounced in boys ( = 3 × 10) than girls ( = 0.07), and was also associated with increasing IGF-I ( = 0.002) and IGFBP-3 ( = 0.003) concentrations in infancy. Cross-sectionally, the minor alleles of rs7454108 tagging and rs17426593 tagging were associated with lower IGF-I concentrations at age 12 months ( = 0.003) and greater skinfold thickness at age 24 months ( = 0.003), respectively.

Conclusions: The variable associations of , , and alleles with growth measures and IGF-I levels in infants from the general population could explain the heterogeneous growth trajectories observed in genetically at-risk cohorts. These findings could suggest distinct mechanisms involving endocrine pathways related to the HLA-conferred type 1 diabetes risk.
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http://dx.doi.org/10.2337/dc20-2820DOI Listing
August 2021

A one-year study of human milk oligosaccharide profiles in the milk of healthy UK mothers and their relationship to maternal FUT2 genotype.

Glycobiology 2021 Jun 15. Epub 2021 Jun 15.

Department of Food Science and Technology, University of California, Davis, USA.

Human milk oligosaccharides (HMOs) are indigestible carbohydrates with prebiotic, pathogen decoy, and immunomodulatory activities that are theorized to substantially impact infant health. The objective of this study was to monitor HMO concentrations over one year to develop a long-term longitudinal dataset. HMO concentrations in the breast milk of healthy lactating mothers of the Cambridge Baby Growth and Breastfeeding Study (CBGS-BF) were measured at birth, 2 weeks, 6 weeks, 3 months, 6 months and 12 months postpartum. HMO quantification was conducted by high-performance anion-exchange chromatography with pulsed amperometric detection using a newly validated "dilute-and-shoot" method. This technique minimizes sample losses and expedites throughput, making it particularly suitable for the analysis of large sample sets. Varying patterns of individual HMO concentrations were observed with changes in lactation timepoint and maternal secretor status, with the most prominent temporal changes occurring during the first 3 months. This data provides valuable information for the development of human milk banks in view of targeted distribution of donor milk based on infant age. Maternal FUT2 genotype was determined based on identification at single-nucleotide polymorphism rs516246 and compared with the genotype expected based on phenotypic markers in the HMO profile. Surprisingly, two mothers genotyped as secretors produced milk that displayed very low levels of 2'-fucosylated moieties. This unexpected discrepancy between genotype and phenotype suggests that differential enzyme expression may cause substantial variation in HMO profiles between genotypically similar mothers, and current genotypic methods of secretor status determination may require validation with HMO markers from milk analysis.
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http://dx.doi.org/10.1093/glycob/cwab057DOI Listing
June 2021

Anthropometry-based prediction of body composition in early infancy compared to air-displacement plethysmography.

Pediatr Obes 2021 Nov 10;16(11):e12818. Epub 2021 Jun 10.

MRC Epidemiology Unit, University of Cambridge, Cambridge, UK.

Background: Anthropometry-based equations are commonly used to estimate infant body composition. However, existing equations were designed for newborns or adolescents. We aimed to (a) derive new prediction equations in infancy against air-displacement plethysmography (ADP-PEA Pod) as the criterion, (b) validate the newly developed equations in an independent infant cohort and (c) compare them with published equations (Slaughter-1988, Aris-2013, Catalano-1995).

Methods: Cambridge Baby Growth Study (CBGS), UK, had anthropometry data at 6 weeks (N = 55) and 3 months (N = 64), including skinfold thicknesses (SFT) at four sites (triceps, subscapular, quadriceps and flank) and ADP-derived total body fat mass (FM) and fat-free mass (FFM). Prediction equations for FM and FFM were developed in CBGS using linear regression models and were validated in Sophia Pluto cohort, the Netherlands, (N = 571 and N = 447 aged 3 and 6 months, respectively) using Bland-Altman analyses to assess bias and 95% limits of agreement (LOA).

Results: CBGS equations consisted of sex, age, weight, length and SFT from three sites and explained 65% of the variance in FM and 79% in FFM. In Sophia Pluto, these equations showed smaller mean bias than the three published equations in estimating FM: mean bias (LOA) 0.008 (-0.489, 0.505) kg at 3 months and 0.084 (-0.545, 0.713) kg at 6 months. Mean bias in estimating FFM was 0.099 (-0.394, 0.592) kg at 3 months and -0.021 (-0.663, 0.621) kg at 6 months.

Conclusions: CBGS prediction equations for infant FM and FFM showed better validity in an independent cohort at ages 3 and 6 months than existing equations.
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http://dx.doi.org/10.1111/ijpo.12818DOI Listing
November 2021

Meta-analysis of epigenome-wide association studies of carotid intima-media thickness.

Eur J Epidemiol 2021 Jun 6. Epub 2021 Jun 6.

Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.

Common carotid intima-media thickness (cIMT) is an index of subclinical atherosclerosis that is associated with ischemic stroke and coronary artery disease (CAD). We undertook a cross-sectional epigenome-wide association study (EWAS) of measures of cIMT in 6400 individuals. Mendelian randomization analysis was applied to investigate the potential causal role of DNA methylation in the link between atherosclerotic cardiovascular risk factors and cIMT or clinical cardiovascular disease. The CpG site cg05575921 was associated with cIMT (beta = -0.0264, p value = 3.5 × 10) in the discovery panel and was replicated in replication panel (beta = -0.07, p value = 0.005). This CpG is located at chr5:81649347 in the intron 3 of the aryl hydrocarbon receptor repressor gene (AHRR). Our results indicate that DNA methylation at cg05575921 might be in the pathway between smoking, cIMT and stroke. Moreover, in a region-based analysis, 34 differentially methylated regions (DMRs) were identified of which a DMR upstream of ALOX12 showed the strongest association with cIMT (p value = 1.4 × 10). In conclusion, our study suggests that DNA methylation may play a role in the link between cardiovascular risk factors, cIMT and clinical cardiovascular disease.
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http://dx.doi.org/10.1007/s10654-021-00759-zDOI Listing
June 2021

Prepubertal Dietary and Plasma Phospholipid Fatty Acids Related to Puberty Timing: Longitudinal Cohort and Mendelian Randomization Analyses.

Nutrients 2021 May 30;13(6). Epub 2021 May 30.

MRC Epidemiology Unit, Institute of Metabolic Science, Cambridge Biomedical Campus Box 285, University of Cambridge School of Clinical Medicine, Cambridge CB2 0QQ, UK.

Dietary intakes of polyunsaturated, monounsaturated and saturated fatty acids (FAs) have been inconsistently associated with puberty timing. We examined longitudinal associations of prepubertal dietary and plasma phospholipid FAs with several puberty timing traits in boys and girls. In the Avon Longitudinal Study of Parents and Children, prepubertal fat intakes at 3-7.5 years and plasma phospholipid FAs at 7.5 years were measured. Timings of Tanner stage 2 genital or breast development and voice breaking or menarche from repeated reports at 8-17 years, and age at peak height velocity (PHV) from repeated height measurements at 5-20 years were estimated. In linear regression models with adjustment for maternal and infant characteristics, dietary substitution of polyunsaturated FAs for saturated FAs, and higher concentrations of dihomo-γ-linolenic acid (20:3n6) and palmitoleic acid (16:1n7) were associated with earlier timing of puberty traits in girls ( = 3872) but not boys ( = 3654). In Mendelian Randomization models, higher genetically predicted circulating dihomo-γ-linolenic acid was associated with earlier menarche in girls. Based on repeated dietary intake data, objectively measured FAs and genetic causal inference, these findings suggest that dietary and endogenous metabolic pathways that increase plasma dihomo-γ-linolenic acid, an intermediate metabolite of n-6 polyunsaturated FAs, may promote earlier puberty timing in girls.
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http://dx.doi.org/10.3390/nu13061868DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8228200PMC
May 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

Association between perinatal factors, genetic susceptibility to obesity and age at adiposity rebound in children of the EDEN mother-child cohort.

Int J Obes (Lond) 2021 08 13;45(8):1802-1810. Epub 2021 May 13.

Université de Paris, CRESS, INSERM, INRAE, F-75004, Paris, France.

Background: Early adiposity rebound (AR) has been associated with increased risk of overweight or obesity in adulthood. However, little is known about early predictors of age at AR. We aimed to study the role of perinatal factors and genetic susceptibility to obesity in the kinetics of AR.

Methods: Body mass index (BMI) curves were modelled by using mixed-effects cubic models, and age at AR was estimated for 1415 children of the EDEN mother-child cohort study. A combined obesity risk-allele score was calculated from genotypes for 27 variants identified by genome-wide association studies of adult BMI. Perinatal factors of interest were maternal age at delivery, parental education, parental BMI, gestational weight gain, maternal smoking during pregnancy, and newborn characteristics (sex, prematurity, and birth weight). We used a hierarchical level approach with multivariable linear regression model to investigate the association between these factors, obesity risk-allele score, and age at AR.

Results: A higher genetic susceptibility to obesity score was associated with an earlier age at AR. At the most distal level of the hierarchical model, maternal and paternal educational levels were positively associated with age at AR. Children born to parents with higher BMI were more likely to exhibit earlier age at AR. In addition, higher gestational weight gain was related to earlier age at AR. For children born small for gestational age, the average age at AR was 88 [±39] days lower than for children born appropriate for gestational age and 91 [±56] days lower than for children born large for gestational age.

Conclusion: The timing of AR seems to be an early childhood manifestation of the genetic susceptibility to adult obesity. We further identified low birth weight and gestational weight gain as novel predictors of early AR, highlighting the role of the intrauterine environment in the kinetics of adiposity.
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http://dx.doi.org/10.1038/s41366-021-00847-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8310796PMC
August 2021

An investigation of the diet, exercise, sleep, BMI, and health outcomes of autistic adults.

Mol Autism 2021 05 8;12(1):31. Epub 2021 May 8.

Autism Research Centre, Department of Psychiatry, University of Cambridge, Douglas House, 18B Trumpington Road, Cambridge, England, CB2 8AH.

Background: Studies of autistic children suggest that restricted eating, reduced physical activity, and sleep disorders are common; however, no studies attempt to broadly describe the diet, exercise, and sleep patterns of autistic adults or consider relationships between lifestyle behaviors and the widely reported increased risks of obesity and chronic conditions. To address this, the authors developed the largest study of lifestyle patterns of autistic adults and assessed their relationships to body mass index, health outcomes, and family history.

Methods: We administered an anonymized, online survey to n = 2386 adults (n = 1183 autistic) aged 16-90 years of age. We employed Fisher's exact tests and binomial logistic regression to describe diet, exercise, and sleep patterns; mediation of seizure disorders on sleep; body mass index (BMI); relationships of lifestyle factors to BMI, cardiovascular conditions, and diabetic conditions; and sex differences among autistic adults.

Results: Autistic adults, and particularly autistic females, exhibit unhealthy diet, exercise, and sleep patterns; they are also more likely to be underweight or obese. Limited sleep duration and high rates of sleep disturbances cannot be accounted for by epilepsy or seizure disorders. Lifestyle factors are positively related to higher risk of cardiovascular conditions among autistic males, even more than family history.

Limitations: Our sample may not be representative of all autistic and non-autistic people, as it primarily comprised individuals who are white, female, have a high school education or higher, and reside in the UK. Our sampling methods may also exclude some individuals on the autism spectrum, and particularly those with moderate to severe intellectual disability. This is a cross-sectional sample that can test for relationships between factors (e.g., lifestyle factors and health outcomes) but cannot assess the direction of these relationships.

Conclusions: Autistic adults are less likely to meet minimal health recommendations for diet, exercise, and sleep-and these unhealthy behaviors may relate to excess risk of cardiovascular conditions. Although the present study can only provide preliminary, correlational evidence, our findings suggest that diet, exercise, and sleep should be considered and further investigated as key targets for reducing the now widely reported and dramatically increased risks of health comorbidity and premature death among autistic individuals compared to others. Physicians should work cooperatively with patients to provide health education and develop individualized strategies for how to better manage challenges with diet, exercise, and sleep.
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http://dx.doi.org/10.1186/s13229-021-00441-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8106173PMC
May 2021

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

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

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

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

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

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

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

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

Folic acid supplementation during pregnancy and associations with offspring size at birth and adiposity: a cohort study.

BMC Res Notes 2021 Apr 30;14(1):160. Epub 2021 Apr 30.

Department of Paediatrics, University of Cambridge, Cambridge Biomedical Campus, Hills Road, Cambridge, CB2 0QQ, UK.

Objective: Previously we observed that maternal multiple micronutrient supplementation in pregnancy was associated with increased offspring size at birth and adiposity, as well as with maternal gestational diabetes risk, in the Cambridge Baby Growth Study. In this study we therefore investigated whether folic acid supplementation specifically is associated with similar changes, to test the hypothesis that folic acid supplementation mediates such changes.

Results: The majority of mothers who reported supplementing with folic acid in pregnancy (n = 776 in total, 526 of which took multiple micronutrient preparations) did so either from pre- (n = 139) or post-conception (n = 637) largely for all or just the first half of pregnancy. A minority of mothers (n = 198) reported not supplementing with folic acid. Folic acid supplementation in pregnancy was not associated with birth weight [β' = - 0.003, p = 0.9], height [β' = - 0.013, p = 0.6], head circumference [β' = 0.003, p = 0.09] or adiposity (ponderal index [β' = 0.020, p = 0.5], skinfolds thicknesses [β' = - 0.029 to + 0.008, p = 0.4-0.9]). Neither was it associated with the development of maternal gestational diabetes (risk ratio 1.2 [0.6‒2.2], p = 0.6). These results suggest that folic acid supplementation in pregnancy did not mediate the previously observed increases in offspring size at birth and adiposity, or the raised gestational diabetes risk, in response to supplementation with multiple micronutrients.
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http://dx.doi.org/10.1186/s13104-021-05575-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8086326PMC
April 2021

Associations between Children's Genetic Susceptibility to Obesity, Infant's Appetite and Parental Feeding Practices in Toddlerhood.

Nutrients 2021 Apr 26;13(5). Epub 2021 Apr 26.

Université de Paris, CRESS, INSERM, INRAE, F-75004 Paris, France.

Previous findings suggest that parental feeding practices may adapt to children's eating behavior and sex, but few studies assessed these associations in toddlerhood. We aimed to study the associations between infant's appetite or children's genetic susceptibility to obesity and parental feeding practices. We assessed infant's appetite (three-category indicator: low, normal or high appetite, labelled 4-to-24-month appetite) and calculated a combined obesity risk-allele score (genetic risk score of body mass index (BMI-GRS)) in a longitudinal study of respectively 1358 and 932 children from the EDEN cohort. Parental feeding practices were assessed at 2-year-follow-up by the CFPQ. Three of the five tested scores were used as continuous variables; others were considered as binary variables, according to the median. Associations between infant's appetite or child's BMI-GRS and parental feeding practices were assessed by linear and logistic regression models, stratified on child's sex if interactions were significant. 4-to-24-month appetite was positively associated with restrictive feeding practices among boys and girls. Among boys, high compared to normal 4-to-24-month appetite was associated with higher use of food to regulate child's emotions (OR [95% CI] = 2.24 [1.36; 3.68]). Child's BMI-GRS was not related to parental feeding practices. Parental feeding practices may adapt to parental perception of infant's appetite and child's sex.
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http://dx.doi.org/10.3390/nu13051468DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8146167PMC
April 2021

Genetic analyses identify widespread sex-differential participation bias.

Nat Genet 2021 05 22;53(5):663-671. Epub 2021 Apr 22.

Faculty of Behavioural and Movement Sciences, Biological Psychology, Vrije Universiteit, Amsterdam, the Netherlands.

Genetic association results are often interpreted with the assumption that study participation does not affect downstream analyses. Understanding the genetic basis of participation bias is challenging since it requires the genotypes of unseen individuals. Here we demonstrate that it is possible to estimate comparative biases by performing a genome-wide association study contrasting one subgroup versus another. For example, we showed that sex exhibits artifactual autosomal heritability in the presence of sex-differential participation bias. By performing a genome-wide association study of sex in approximately 3.3 million males and females, we identified over 158 autosomal loci spuriously associated with sex and highlighted complex traits underpinning differences in study participation between the sexes. For example, the body mass index-increasing allele at FTO was observed at higher frequency in males compared to females (odds ratio = 1.02, P = 4.4 × 10). Finally, we demonstrated how these biases can potentially lead to incorrect inferences in downstream analyses and propose a conceptual framework for addressing such biases. Our findings highlight a new challenge that genetic studies may face as sample sizes continue to grow.
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http://dx.doi.org/10.1038/s41588-021-00846-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611642PMC
May 2021

Identification of methylation changes associated with positive and negative growth deviance in Gambian infants using a targeted methyl sequencing approach of genomic DNA.

FASEB Bioadv 2021 Apr 5;3(4):205-230. Epub 2021 Feb 5.

Department of Pathology University of Cambridge Cambridge UK.

Low birthweight and reduced height gain during infancy (stunting) may arise at least in part from adverse early life environments that trigger epigenetic reprogramming that may favor survival. We examined differential DNA methylation patterns using targeted methyl sequencing of regions regulating gene activity in groups of rural Gambian infants: (a) low and high birthweight (DNA from cord blood ( = 16 and  = 20, respectively), from placental trophoblast tissue ( = 21 and  = 20, respectively), and DNA from peripheral blood collected from infants at 12 months of age ( = 23 and  = 17, respectively)), and, (b) the top 10% showing rapid postnatal length gain (high,  = 20) and the bottom 10% showing slow postnatal length gain (low,  = 20) based on z score change between birth and 12 months of age (LAZ) (DNA from peripheral blood collected from infants at 12 months of age). Using BiSeq analysis to identify significant methylation marks, for birthweight, four differentially methylated regions (DMRs) were identified in trophoblast DNA, compared to 68 DMRs in cord blood DNA, and 54 DMRs in 12-month peripheral blood DNA. Twenty-five DMRs were observed to be associated with high and low length for age (LAZ) at 12 months. With the exception of five loci (associated with two different genes), there was no overlap between these groups of methylation marks. Of the 194 CpG methylation marks contained within DMRs, 106 were located to defined gene regulatory elements (promoters, CTCF-binding sites, transcription factor-binding sites, and enhancers), 58 to gene bodies (introns or exons), and 30 to intergenic DNA. Distinct methylation patterns associated with birthweight between comparison groups were observed in DNA collected at birth (at the end of intrauterine growth window) compared to those established by 12 months (near the infancy/childhood growth transition). The longitudinal differences in methylation patterns may arise from methylation adjustments, changes in cellular composition of blood or both that continue during the critical postnatal growth period, and in response to early nutritional and infectious environmental exposures with impacts on growth and longer-term health outcomes.
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http://dx.doi.org/10.1096/fba.2020-00101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8019263PMC
April 2021

Antenatal Determinants of Childhood Obesity in High-Risk Offspring: Protocol for the DiGest Follow-Up Study.

Nutrients 2021 Mar 31;13(4). Epub 2021 Mar 31.

Institute of Metabolic Science, University of Cambridge, Cambridge CB2 0QQ, UK.

Childhood obesity is an area of intense concern internationally and is influenced by events during antenatal and postnatal life. Although pregnancy complications, such as gestational diabetes and large-for-gestational-age birthweight have been associated with increased obesity risk in offspring, very few successful interventions in pregnancy have been identified. We describe a study protocol to identify if a reduced calorie diet in pregnancy can reduce adiposity in children to 3 years of age. The dietary intervention in gestational diabetes (DiGest) study is a randomised, controlled trial of a reduced calorie diet provided by a whole-diet replacement in pregnant women with gestational diabetes. Women receive a weekly dietbox intervention from enrolment until delivery and are blinded to calorie allocation. This follow-up study will assess associations between a reduced calorie diet in pregnancy with offspring adiposity and maternal weight and glycaemia. Anthropometry will be performed in infants and mothers at 3 months, 1, 2 and 3 years post-birth. Glycaemia will be assessed using bloodspot C-peptide in infants and continuous glucose monitoring with HbA1c in mothers. Data regarding maternal glycaemia in pregnancy, maternal nutrition, infant birthweight, offspring feeding behaviour and milk composition will also be collected. The DiGest follow-up study is expected to take 5 years, with recruitment finishing in 2026.
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http://dx.doi.org/10.3390/nu13041156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8067255PMC
March 2021

A Polygenic Risk Score to Predict Future Adult Short Stature Among Children.

J Clin Endocrinol Metab 2021 06;106(7):1918-1928

Lady Davis Institute for Medical Research, Jewish General Hospital, Montréal, Canada.

Context: Adult height is highly heritable, yet no genetic predictor has demonstrated clinical utility compared to mid-parental height.

Objective: To develop a polygenic risk score for adult height and evaluate its clinical utility.

Design: A polygenic risk score was constructed based on meta-analysis of genomewide association studies and evaluated on the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort.

Subjects: Participants included 442 599 genotyped White British individuals in the UK Biobank and 941 genotyped child-parent trios of European ancestry in the ALSPAC cohort.

Interventions: None.

Main Outcome Measures: Standing height was measured using stadiometer; Standing height 2 SDs below the sex-specific population average was considered as short stature.

Results: Combined with sex, a polygenic risk score captured 71.1% of the total variance in adult height in the UK Biobank. In the ALSPAC cohort, the polygenic risk score was able to identify children who developed adulthood short stature with an area under the receiver operating characteristic curve (AUROC) of 0.84, which is close to that of mid-parental height. Combining this polygenic risk score with mid-parental height or only one of the child's parent's height could improve the AUROC to at most 0.90. The polygenic risk score could also substitute mid-parental height in age-specific Khamis-Roche height predictors and achieve an equally strong discriminative power in identifying children with a short stature in adulthood.

Conclusions: A polygenic risk score could be considered as an alternative or adjunct to mid-parental height to improve screening for children at risk of developing short stature in adulthood in European ancestry populations.
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http://dx.doi.org/10.1210/clinem/dgab215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8266463PMC
June 2021

Identification of nutritionally modifiable hormonal and epigenetic drivers of positive and negative growth deviance in rural African fetuses and infants: Project protocol and cohort description.

Gates Open Res 2020 24;4:25. Epub 2020 Feb 24.

Department of Anthropology, University of Colorado, Boulder, CO, 80309, USA.

Growth retardation (stunting, wasting and poor organ development) among children in low-income countries has major short and long-term health consequences yet very little is known about the nutritional and environmental influences on the key hormonal axes regulating child growth in these settings, nor the tempo and timing of faltering episodes. Here we describe the study protocol and provide a cohort description of the Hormonal and Epigenetic Regulators of Growth (HERO-G) study. This prospective cohort study from rural Gambia, West Africa, followed mothers and children longitudinally from pre-conception, through pregnancy, delivery, and to two years of child age A total of 251 eligible mother-infant pairs were recruited into the HERO-G study, with 206 (82%) followed up until two years of age. Women were seen at scheduled antenatal appointments at 20, 28 and 36 weeks of gestation, and at delivery, where possible. Between one week and 12 months of age, infants were visited every second day for collection of detailed anthropometry and morbidity data. Infants identified as about to enter a growth faltering episode at these visits entered a more detailed 20-day protocol, with the collection of dried blood spots, anthropometry and body composition. All infants were seen for scheduled clinic visits at 3, 6, 9, 12, 18 and 24 months of age for clinical examination and venous blood draw. Data from the HERO-G study is being used to explore three major mechanistic pathways influencing growth: 1) genome-wide investigations for signatures of epigenetic effects on any loci that might affect growth; 2) frequent anthropometric measurement coupled with non-invasive monitoring for rapid identification and interrogation of real-time faltering patterns and aetiology; 3) focused measurement of hormones and cytokines that act together in an integrated manner, both and after birth, to coordinate patterns of growth with immune activation, inflammation, and nutritional status.
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http://dx.doi.org/10.12688/gatesopenres.13101.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7921526PMC
February 2020

Pregnancy Serum DLK1 Concentrations Are Associated With Indices of Insulin Resistance and Secretion.

J Clin Endocrinol Metab 2021 05;106(6):e2413-e2422

Department of Paediatrics, Cambridge Biomedical Campus, Cambridge, UK.

Context: Delta like noncanonical notch ligand 1 (DLK1) is a paternally expressed imprinted gene that encodes an epidermal growth factor repeat-containing transmembrane protein. A bioactive, truncated DLK1 protein is present in the circulation and has roles in development and metabolism.

Objective: We sought to investigate links between maternal pregnancy circulating DLK1 concentrations and: (1) maternal and fetal DLK1 genotypes, (2) maternal insulin resistance and secretion, and (3) offspring size at birth.

Patients, Design, And Setting: We measured third-trimester maternal serum DLK1 concentrations and examined their associations with parentally transmitted fetal and maternal DLK1 genotypes, indices of maternal insulin resistance and secretion derived from 75-g oral glucose tolerance tests performed around week 28 of pregnancy, and offspring size at birth in 613 pregnancies from the Cambridge Baby Growth Study.

Results: Maternal DLK1 concentrations were associated with the paternally transmitted fetal DLK1 rs12147008 allele (P = 7.8 × 10-3) but not with maternal rs12147008 genotype (P = 0.4). Maternal DLK1 concentrations were positively associated with maternal prepregnancy body mass index (P = 3.5 × 10-6), and (after adjustment for maternal body mass index) with both maternal fasting insulin resistance (Homeostatic Model Assessment of Insulin Resistance: P = 0.01) and measures of maternal insulin secretion in response to oral glucose (insulinogenic index: P = 1.2 × 10-3; insulin disposition index: P = 0.049). Further positive associations were found with offspring weight (P = 0.02) and head circumference at birth (P = 0.04).

Conclusion: These results are consistent with a partial paternal or placental origin for the maternal circulating DLK1 which may lead to increased maternal circulating DLK1 concentrations, stimulation of maternal insulin resistance and compensatory hyperinsulinemia during pregnancy, and the promotion of fetal growth.
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http://dx.doi.org/10.1210/clinem/dgab123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8424055PMC
May 2021

Positive maternal attitudes to following healthy infant feeding guidelines attenuate the associations between infant appetitive traits and both infant milk intake and weight.

Appetite 2021 06 19;161:105124. Epub 2021 Jan 19.

MRC Epidemiology Unit, Institute of Metabolic Science, School of Clinical Medicine, University of Cambridge, Cambridge, UK. Electronic address:

Appetitive traits influence food intake and weight gain throughout the life-course. Here, we investigated whether maternal attitudes to following healthy infant feeding guidelines could modify this association. Baseline data from 544 mother-infant formula-feeding dyads recruited to the Baby Milk Trial were included in this observational, cross-sectional analysis. Infant appetitive traits (food responsiveness and satiety responsiveness), maternal attitudes to following healthy infant feeding guidelines (self-efficacy, outcome-expectancy, intentions) and infant milk intakes were reported by mothers through questionnaires. Infant weight was measured using standard procedures. Associations between the maternal attitudes score or infant appetitive traits with infant milk intake and infant weight were evaluated in linear regression models adjusted for infant sex and age. To identify effect modification, the interaction term between the maternal attitudes score and infant appetitive trait was added to the model. Infants' mean age and weight were 2.3 months (SD = 0.9) and 5.5 kg (SD = 0.9), respectively. The mean daily infant milk intake reported by mothers was 895 ml/day (SD = 215). Higher maternal attitudes score was associated with lower infant milk intake (Beta = -68.4 ml/day/unit (95% CI: 96.6, -40.2)) and infant weight (Beta = -0.13 SD/unit (-0.25, -0.02)). The maternal attitudes score showed interactions with infant food responsiveness on infant milk intake (p = 0.049), and with infant satiety responsiveness on infant weight (p = 0.01). In both cases, a higher maternal attitudes score attenuated the associations between infant appetitive traits and those outcomes. This analysis provides evidence that positive maternal attitudes to following healthy infant feeding guidelines attenuate the effects of infant appetitive traits on infant milk intake and body weight.
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http://dx.doi.org/10.1016/j.appet.2021.105124DOI Listing
June 2021

A Novel method for the identification and quantification of weight faltering.

Am J Phys Anthropol 2021 05 1;175(1):282-291. Epub 2021 Jan 1.

Growth and Development Lab, Department of Anthropology, University of Colorado Boulder, Boulder, Colorado, USA.

Objective: We describe a new method for identifying and quantifying the magnitude and rate of short-term weight faltering episodes, and assess how (a) these episodes relate to broader growth outcomes, and (b) different data collection intervals influence the quantification of weight faltering.

Materials And Methods: We apply this method to longitudinal growth data collected every other day across the first year of life in Gambian infants (n = 124, males = 65, females = 59). Weight faltering episodes are identified from velocity peaks and troughs. Rate of weight loss and regain, maximum weight loss, and duration of each episode were calculated. We systematically reduced our dataset to mimic various potential measurement intervals, to assess how these intervals affect the ability to derive information about short-term weight faltering episodes. We fit linear models to test whether metrics associated with growth faltering were associated with growth outcomes at 1 year, and generalized additive mixed models to determine whether different collection intervals influence episode identification and metrics.

Results: Three hundred weight faltering episodes from 119 individuals were identified. The number and magnitude of episodes negatively impacted growth outcomes at 1 year. As data collection interval increases, weight faltering episodes are missed and the duration of episodes is overestimated, resulting in the rate of weight loss and regain being underestimated.

Conclusions: This method identifies and quantifies short-term weight faltering episodes, that are in turn negatively associated with growth outcomes. This approach offers a tool for investigators interested in understanding how short-term weight faltering relates to longer-term outcomes.
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http://dx.doi.org/10.1002/ajpa.24217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8247282PMC
May 2021

GLP-1 agonists for obesity and type 2 diabetes in children: Systematic review and meta-analysis.

Obes Rev 2021 06 22;22(6):e13177. Epub 2020 Dec 22.

Department of Paediatrics, University of Cambridge, Cambridge, UK.

Pharmacological options for management of obesity and type 2 diabetes mellitus (T2DM) in children are limited. We aimed to synthesize published randomized controlled trial (RCT) evidence on the efficacy of glucagon-like peptide-1 (GLP-1) agonists in T2DM, pre-diabetes, and obesity in children aged <18 years. Inclusion criteria were RCTs of any GLP-1 agonist, solely or in conjunction with other drugs, for the treatment of obesity, pre-diabetes, and/or T2DM in children aged <18 years old. Nine studies met the inclusion criteria (two for T2DM, one for pre-diabetes, and six for obesity without diabetes). In total, 286 children were allocated to GLP-1 agonist therapy. Compared with controls, GLP-1 agonist therapy reduced HbA1c by -0.30% (95% confidence interval [CI] -0.57, -0.04) with a larger effect in children with (pre-)diabetes (-0.72%; 95% CI -1.17, -0.28; three studies) than in children with obesity (-0.08%; 95% CI -0.13, -0.02; four studies). Conversely, GLP-1 agonist therapy reduced body weight more in children with obesity (-2.74 kg; 95% CI -3.77, -1.70; six studies) than in children with T2DM (-0.97 kg; 95% CI -2.01, 0.08; two studies). Adverse effects included gastrointestinal symptoms and minor hypoglycemic episodes, but not severe hypoglycemia. GLP-1 agonists are efficacious in treating children with obesity and/or T2DM. Effect sizes are comparable with those reported in adults.
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http://dx.doi.org/10.1111/obr.13177DOI Listing
June 2021
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