Household income and maternal education in early childhood and risk of overweight and obesity in late childhood: Findings from seven birth cohort studies in six high-income countries.

BACKGROUND/OBJECTIVES: This study analysed the relationship between early childhood socioeconomic status (SES) measured by maternal education and household income and the subsequent development of childhood overweight and obesity. SUBJECTS/METHODS: Data from seven population-representative prospective child cohorts in six high-income countries: United Kingdom, Australia, the Netherlands, Canada (one national cohort and one from the province of Quebec), USA, Sweden. Children were included at birth or within the first 2 years of life. Pooled estimates relate to a total of N = 26,565 included children. Overweight and obesity were defined using International Obesity Task Force (IOTF) cut-offs and measured in late childhood (8-11 years). Risk ratios (RRs) and pooled risk estimates were adjusted for potential confounders (maternal age, ethnicity, child sex). Slope Indexes of Inequality (SII) were estimated to quantify absolute inequality for maternal education and household income. RESULTS: Prevalence ranged from 15.0% overweight and 2.4% obese in the Swedish cohort to 37.6% overweight and 15.8% obese in the US cohort. Overall, across cohorts, social gradients were observed for risk of obesity for both low maternal education (pooled RR: 2.99, 95% CI: 2.07, 4.31) and low household income (pooled RR: 2.69, 95% CI: 1.68, 4.30); between-cohort heterogeneity ranged from negligible to moderate (p: 0.300 to < 0.001). The association between RRs of obesity by income was lowest in Sweden than in other cohorts. CONCLUSIONS: There was a social gradient by maternal education on the risk of childhood obesity in all included cohorts. The SES associations measured by income were more heterogeneous and differed between Sweden versus the other national cohorts; these findings may be attributable to policy differences, including preschool policies, maternity leave, a ban on advertising to children, and universal free school meals.

Can adult polygenic scores improve prediction of body mass index in childhood?

BACKGROUND/OBJECTIVES: Modelling genetic pre-disposition may identify children at risk of obesity. However, most polygenic scores (PGSs) have been derived in adults, and lack validation during childhood. This study compared the utility of existing large-scale adult-derived PGSs to predict common anthropometric traits (body mass index (BMI), waist circumference, and body fat) in children and adults, and examined whether childhood BMI prediction could be improved by combining PGSs and non-genetic factors (maternal and earlier child BMI). SUBJECTS/METHODS: Participants (n = 1365 children, and n = 2094 adults made up of their parents) were drawn from the Longitudinal Study of Australian Children. Children were weighed and measured every two years from 0-1 to 12-13 years, and adults were measured or self-reported measurements were obtained concurrently (average analysed). Participants were genotyped from blood or oral samples, and PGSs were derived based on published genome-wide association studies. We used linear regression to compare the relative utility of these PGSs to predict their respective traits at different ages. RESULTS: BMI PGSs explained up to 12% of child BMI z-score variance in 10-13 year olds, compared with up to 15% in adults. PGSs for waist circumference and body fat explained less variance (up to 8%). An interaction between BMI PGSs and puberty (p = 0.001-0.002) suggests the effect of some variants may differ across the life course. Individual BMI measures across childhood predicted 10-60% of the variance in BMI at 12-13 years, and maternal BMI and BMI PGS each added 1-9% above this. CONCLUSION: Adult-derived PGSs for BMI, particularly those derived by modelling between-variant interactions, may be useful for predicting BMI during adolescence with similar accuracy to that obtained in adulthood. The level of precision presented here to predict BMI during childhood may be relevant to public health, but is likely to be less useful for individual clinical purposes.

Social gradients in ADHD by household income and maternal education exposure during early childhood: Findings from birth cohort studies across six countries.

OBJECTIVE: This study aimed to examine social gradients in ADHD during late childhood (age 9-11 years) using absolute and relative relationships with socioeconomic status exposure (household income, maternal education) during early childhood (<5 years) in seven cohorts from six industrialised countries (UK, Australia, Canada, The Netherlands, USA, Sweden). METHODS: Secondary analyses were conducted for each birth cohort. Risk ratios, pooled risk estimates, and absolute inequality, measured by the Slope Index of Inequality (SII), were estimated to quantify social gradients in ADHD during late childhood by household income and maternal education measured during early childhood. Estimates were adjusted for child sex, mother age at birth, mother ethnicity, and multiple births. FINDINGS: All cohorts demonstrated social gradients by household income and maternal education in early childhood, except for maternal education in Quebec. Pooled risk estimates, relating to 44,925 children, yielded expected gradients (income: low 1.83(CI 1.38,2.41), middle 1.42(1.13,1.79), high (reference); maternal education: low 2.13(1.39,3.25), middle 1.42(1.13,1.79)). Estimates of absolute inequality using SII showed that the largest differences in ADHD prevalence between the highest and lowest levels of maternal education were observed in Australia (4% lower) and Sweden (3% lower); for household income, the largest differences were observed in Quebec (6% lower) and Canada (all provinces: 5% lower). CONCLUSION: Findings indicate that children in families with high household income or maternal education are less likely to have ADHD at age 9-11. Absolute inequality, in combination with relative inequality, provides a more complete account of the socioeconomic status and ADHD relationship in different high-income countries. While the study design precludes causal inference, the linear relation between early childhood social circumstances and later ADHD suggests a potential role for policies that promote high levels of education, especially among women, and adequate levels of household income over children's early years in reducing risk of later ADHD.

Synthesizing Core Outcome Sets for outcomes research in cohort studies: a systematic review.

BACKGROUND: Life course studies are designed to "collect once, use multiple times" for observational and, increasingly, interventional research. Core Outcome Sets (COS) are minimum sets developed for clinical trials by multi-stakeholder consensus methodologies. We aimed to synthesize published COS that might guide outcomes selection for early life cohorts with an interventional focus. METHODS: We searched PubMed, Medline, COMET, and CROWN for COS published before January 2021 relevant to four life stages (pregnancy, newborns, children <8 years, and parents (adults aged 18-50 years)). We synthesized core outcomes into overarching constructs. RESULTS: From 46 COS we synthesized 414 core outcomes into 118 constructs. "Quality of life", "adverse events", "medication use", "hospitalization", and "mortality" were consistent across all stages. For pregnancy, common constructs included "preterm birth", "delivery mode", "pre-eclampsia", "gestational weight gain", "gestational diabetes", and "hemorrhage"; for newborns, "birthweight", "small for gestational age", "neurological damage", and "morbidity" and "infection/sepsis"; for pediatrics, "pain", "gastrointestinal morbidity", "growth/weight", "breastfeeding", "feeding problems", "hearing", "neurodevelopmental morbidity", and "social development"; and for adults, "disease burden", "mental health", "neurological function/stroke", and "cardiovascular health/morbidity". CONCLUSION: This COS synthesis generated outcome constructs that are of high value to stakeholders (participants, health providers, services), relevant to life course research, and could position cohorts for trial capabilities. IMPACT: We synthesized existing Core Outcome Sets as a transparent methodology that could prioritize outcomes for lifecourse cohorts with an interventional focus. "Quality of life", "adverse events", "medication use", "hospitalization", and "mortality" are important outcomes across pregnancy, newborns, childhood, and early-to-mid-adulthood (the age range relevant to parents). Other common outcomes (such as "birthweight", "cognitive function/ability", "psychological health") are also highly relevant to lifecourse research. This synthesis could assist new early life cohorts to pre-select outcomes that are of high value to stakeholders (participants, health providers, services), are relevant to lifecourse research, and could position them for future trials and interventional capability.

Maximizing Participant Engagement, Participation, and Retention in Cohort Studies Using Digital Methods: Rapid Review to Inform the Next Generation of Very Large Birth Cohorts.

BACKGROUND: Many current research needs can only be addressed using very large cohorts. In such studies, traditional one-on-one phone, face-to-face, or paper-based engagement may not be feasible. The only realistic mechanism for maintaining engagement and participation at this scale is via digital methods. Given the substantial investment being made into very large birth cohort studies, evidence for optimal methods of participant engagement, participation, and retention over sustained periods without in-person contact from researchers is paramount. OBJECTIVE: This study aims to provide an overview of systematic reviews and meta-analyses evaluating alternative strategies for maximizing participant engagement and retention rates in large-scale studies using digital methods. METHODS: We used a rapid review method by searching PubMed and Ovid MEDLINE databases from January 2012 to December 2019. Studies evaluating at least 1 e-engagement, participation, or retention strategy were eligible. Articles were screened for relevance based on preset inclusion and exclusion criteria. The methodological quality of the included reviews was assessed using the AMSTAR-2 (Assessing the Methodological Quality of Systematic Reviews 2) measurement tool, and a narrative synthesis of the data was conducted. RESULTS: The literature search yielded 19 eligible reviews. Overall, 63% (n=12) of these reviews reported on the effectiveness of e-engagement or participation promotion strategies. These evaluations were generally not conducted within very large observational digital cohorts. Most of the contributing reviews included multipurpose cohort studies (with both observational and interventional elements) conducted in clinical and research settings. Email or SMS text message reminders, SMS text messages or voice notifications, and incentives were the most commonly used design features to engage and retain participants. For parental outcomes, engagement-facilitation interventions influenced uptake and behavior change, including video feedback, goal setting, and intensive human facilitation and support. Participant-stated preferences for content included new knowledge, reminders, solutions, and suggestions about health issues presented in a clear, short, and personalized way. Perinatal and postpartum women valued self-monitoring and personalized feedback. Digital reminders and multiple SMS text messages were specific strategies that were found to increase adherence to medication and clinic attendance, respectively. CONCLUSIONS: This review adds to the growing literature evaluating methods to optimize engagement and participation that may apply to large-scale studies using digital methods; it is promising that most e-engagement and participation promotion strategies appear to be effective. However, these reviews canvassed relatively few strategies, suggesting that few alternative strategies have been experimentally evaluated. The reviews also revealed a dearth of experimental evidence generated within very large observational digital cohort studies, which may reflect the small number of such studies worldwide. Thus, very large studies may need to proactively build in experimental opportunities to test engagement and retention approaches to enhance the success of their own and other large digital contact studies.

Diet quality trajectories and cardiovascular phenotypes/metabolic syndrome risk by 11-12 years.

OBJECTIVE: To investigate associations between early-life diet trajectories and preclinical cardiovascular phenotypes and metabolic risk by age 12 years. METHODS: Participants were 1861 children (51% male) from the Longitudinal Study of Australian Children. At five biennial waves from 2-3 to 10-11 years: Every 2 years from 2006 to 2014, diet quality scores were collected from brief 24-h parent/self-reported dietary recalls and then classified using group-based trajectory modeling as 'never healthy' (7%), 'becoming less healthy' (17%), 'moderately healthy' (21%), and 'always healthy' (56%). At 11-12 years: During children's physical health Child Health CheckPoint (2015-2016), we measured cardiovascular functional (resting heart rate, blood pressure, pulse wave velocity, carotid elasticity/distensibility) and structural (carotid intima-media thickness, retinal microvasculature) phenotypes, and metabolic risk score (composite of body mass index z-score, systolic blood pressure, high-density lipoproteins cholesterol, triglycerides, and glucose). Associations were estimated using linear regression models (n = 1100-1800) adjusted for age, sex, and socioeconomic position. RESULTS: Compared to 'always healthy', the 'never healthy' trajectory had higher resting heart rate (2.6 bpm, 95% CI 0.4, 4.7) and metabolic risk score (0.23, 95% CI 0.01, 0.45), and lower arterial elasticity (-0.3% per 10 mmHg, 95% CI -0.6, -0.1) and distensibility (-1.2%, 95% CI -1.9, -0.5) (all effect sizes 0.3-0.4). Heart rate, distensibility, and diastolic blood pressure were progressively poorer for less healthy diet trajectories (linear trends p ≤ 0.02). Effects for systolic blood pressure, pulse wave velocity, and structural phenotypes were less evident. CONCLUSIONS: Children following the least healthy diet trajectory had poorer functional cardiovascular phenotypes and metabolic syndrome risk, including higher resting heart rate, one of the strongest precursors of all-cause mortality. Structural phenotypes were not associated with diet trajectories, suggesting the window to prevent permanent changes remains open to at least late childhood.

Population epidemiology and concordance for plasma amino acids and precursors in 11-12-year-old children and their parents.

Amino acid (AA) concentrations are influenced by both exogenous (e.g. diet, lifestyle) and endogenous factors (e.g. genetic, transcriptomic, epigenetic, and metabolomic). Fasting plasma AA profiles in adulthood are predictive of diabetes risk over periods of up to 12 years. Data on AA profiles in cross-generational cohorts, including individuals from shared gene-environment settings are scarce, but would allow the identification of the contribution of heritable and environmental factors characterising the levels of circulating AAs. This study aimed to investigate parent-child (familial dyad) concordance, absolute differences between generations- (children versus adults), age- (in adults: 28-71 years), and sex-dependent differences in plasma AA concentrations. Plasma AA concentrations were measured by UHPLC/MS-MS in 1166 children [mean (SD) age 11 (0.5) years, 51% female] and 1324 of their parents [44 (5.1) years, 87% female]. AA concentrations were variably concordant between parents and their children (5-41% of variability explained). Most AA concentrations were higher in adults than children, except for the non-essential AAs arginine, aspartic acid, glutamine, hydroxy-proline, proline, and serine. Male adults and children typically had higher AA concentrations than females. The exceptions were alanine, glutamine, glycine, hydroxy-proline, serine, and threonine in girls; and glycine and serine in women. Age, sex, and shared familial factors are important determinants of plasma AA concentrations.

Trimethylamine N-oxide (TMAO) Is not Associated with Cardiometabolic Phenotypes and Inflammatory Markers in Children and Adults.

BACKGROUND: Trimethylamine N-oxide (TMAO) is a diet- and microbiome-derived metabolite and a proposed biomarker of adverse cardiometabolic outcomes. TMAO studies have mainly been conducted in individuals with cardiometabolic disease, and studies in population-derived samples are limited. OBJECTIVE: We aimed to investigate the associations between plasma TMAO concentrations and its precursors [carnitine, choline, betaine, and dimethylglycine (DMG)] with metabolic syndrome (MetS) scores, preclinical cardiovascular phenotypes, and inflammatory biomarkers (i.e. high-sensitivity C-reactive protein and serum glycoprotein acetyls) in a population-derived cohort of children and their parents. METHODS: The concentrations of TMAO and its precursors were quantified using UHPLC coupled with tandem MS (UHPLC/MS-MS) in 1166 children (mean age 11 y ± 0.5 y, 51% female) and 1324 adults (44 y ± 5.1 y, 87% female) participating in The Growing Up in Australia's Child Health CheckPoint Study. We developed multivariable fractional polynomial models to analyze associations between TMAO, its precursors, MetS (adjusted for sex and age), and cardiovascular phenotypes (adjusted for sex, age, BMI, household income, and the urinary albumin to creatinine ratio). Pearson's correlations were computed to identify associations between TMAO, its precursors, and inflammatory biomarkers. RESULTS: The concentrations of TMAO precursors, but not TMAO itself, were associated with MetS, cardiovascular phenotypes, and inflammatory biomarkers in children and adults. CONCLUSIONS: TMAO precursors, but not TMAO itself, were associated with adverse cardiometabolic and inflammatory phenotypes in children and adults. TMAO precursor concentrations may better reflect cardiovascular health and inflammatory status within the wider population. Replication in other population settings and mechanistic studies are warranted.

Sleep problems, internalizing and externalizing symptoms, and domains of health-related quality of life: bidirectional associations from early childhood to early adolescence.

STUDY OBJECTIVES: To examine longitudinal, bidirectional associations among behavioral sleep problems, internalizing and externalizing symptoms, and domains of health-related quality of life (HRQoL) from early childhood to adolescence in a population sample of Australian children. METHOD: Data were drawn from the Longitudinal Study of Australian Children, a national prospective cohort study with 4983 children participating in the Kindergarten cohort. Data were collected when children were aged 4-5, 6-7, 8-9, 10-11, and 12-13 years. At each study wave, the primary parent (97% mothers) reported on behavioral child sleep problems, internalizing and externalizing symptoms, and HRQoL domains (psychosocial and physical). Cross-lagged structural equation models were used to evaluate bidirectional associations. RESULTS: At nearly every age, behavioral sleep problems were associated with worse subsequent psychosocial and physical HRQoL. Despite bidirectional associations between mental health and HRQoL at many waves, HRQoL domains more strongly predicted later internalizing symptoms, while externalizing symptoms more strongly predicted later HRQoL. Many of the bidirectional associations among sleep, mental health, and HRQoL were found earlier in childhood. CONCLUSIONS: Behavioral sleep problems may forecast later HRQoL psychosocial and physical impairments. Attending to both sleep problems and HRQoL could prevent the progression of internalizing conditions, while a focus on externalizing concerns could prevent the worsening of these symptoms, sleep problems, and HRQoL, particularly during the transition to school.

Plasma Trimethylamine N-Oxide and Its Precursors: Population Epidemiology, Parent-Child Concordance, and Associations with Reported Dietary Intake in 11- to 12-Year-Old Children and Their Parents.

BACKGROUND: Trimethylamine N-oxide (TMAO) is a microbiome- and diet-derived metabolite implicated in adverse cardiovascular outcomes. To date, studies of plasma TMAO concentrations have largely focused on individuals with metabolic disease. As such, data on TMAO concentrations in population settings and parent-child dyads are lacking. OBJECTIVES: This study aimed to investigate parent-child concordance, age, and sex effects on plasma concentrations of TMAO and its precursors [l-carnitine, choline, betaine, and dimethylglycine (DMG)]. Associations between concentrations of TMAO and its precursors and self-reported dietary intakes of animal protein (i.e., red meat, meat products, chicken, fish, milk products, and cheese) and fast-food meals were also investigated. METHODS: A total of 1166 children (mean ± SD age: 11 ± 0.5 y, 51% female) and 1324 parents (mean ± SD age: 44 ± 5.1 y, 87% female) had a biomedical assessment as part of Growing Up in Australia's Child Health Checkpoint. Plasma TMAO and precursor concentrations were quantified using ultra-high-pressure LC coupled with tandem MS. RESULTS: Familial dyads significantly contributed to plasma TMAO and precursor concentrations (P < 0.0001), explaining 37% of variance for TMAO concentrations. Least-square mean ± SE plasma TMAO was lower in children (0.79 ± 0.02 µM on the log-scale) than in adults (1.22 ± 0.02 µM). By contrast, children's betaine (40.30 ± 0.34 µM) and DMG concentrations (1.02 ± 0.01 µM on the log-scale) were higher than adults' betaine (37.50 ± 0.32 µM) and DMG concentrations (0.80 ± 0.01 µM) (P < 0.0001). Mean values of all metabolites, except adult TMAO, were higher in males than in females (P < 0.001). Greater reported intake of red meat and fish was associated with higher TMAO concentrations in both children [estimates (95% CIs) for red meat: 0.06 (0.01, 0.10); fish: 0.11 (0.06, 0.17)] and adults [red meat: 0.13 (0.08, 0.17); meat products: 0.07 (0.03, 0.12); and fish: 0.09 (0.04, 0.14)]. CONCLUSIONS: Age, sex, and shared family factors, including diet, contribute to variation in plasma concentrations of TMAO and its precursors.