Modelling timing and tempo of adrenarche in a prospective cohort study

To better understand how health risk processes are linked to adrenarche, measures of adrenarcheal timing and tempo are needed. Our objective was to describe and classify adrenal trajectories, in terms of timing and tempo, in a population of children transitioning to adolescence with repeated measurements of salivary dehydroepiandrosterone (DHEA), DHEAsulphate, and testosterone. We analysed data from the Childhood to Adolescence Transition Study (CATS), a longitudinal study of 1239 participants, recruited at 8-9 years old and followed up annually. Saliva samples were assayed for adrenal hormones. Linear mixedeffect models with subject-specific random intercepts and slopes were used to model longitudinal hormone trajectories by sex and derive measures of adrenarcheal timing and tempo. The median values for all hormones were higher at each consecutive study wave for both sexes, and higher for females than males. For all hormones, between-individual variation in hormone levels at age 9 (timing) was moderately large and similar for females and males. Between-individual variation in hormone progression over time (tempo) was of moderate magnitude compared with the population average age-slope, which itself was small compared with overall hormone level at each age. This suggests that between-individual variation in tempo was less important for modelling hormone trajectories. Between-individual variation in timing was more important for determining relative adrenal hormonal level in childhood than tempo. This finding suggests that adrenal hormonal levels at age 8-9 years can be used to predict relative levels in early adolescence (up to 13 years)

Learning outcomes in primary school children with emotional problems: a prospective cohort study

BACKGROUND: Academic difficulties are common in adolescents with mental health problems. Although earlier childhood emotional problems, characterised by heightened anxiety and depressive symptoms are common forerunners to adolescent mental health problems, the degree to which mental health problems in childhood may contribute independently to academic difficulties has been little explored. METHODS: Data were drawn from a prospective cohort study of students in Melbourne, Australia (N = 1239). Data were linked with a standardised national assessment of academic performance at baseline (9 years) and wave three (11 years). Depressive and anxiety symptoms were assessed at baseline and wave two (10 years). Regression analyses estimated the association between emotional problems (9 and/or 10 years) and academic performance at 11 years, adjusting for baseline academic performance, sex, age and socioeconomic status, and hyperactivity/inattention symptoms. RESULTS: Students with depressive symptoms at 9 years of age had lost nearly 4 months of numeracy learning two years later after controlling for baseline academic performance and confounders. Results were similar for anxiety symptoms. Regardless of when depressive symptoms occurred there were consistent associations with poorer numeracy performance at 11 years. The association of depressive symptoms with reading performance was weaker than for numeracy if they were present at wave two. Persistent anxiety symptoms across two waves led to nearly a 4 month loss of numeracy learning at 11 years, but the difference was not meaningful for reading. Findings were similar when including hyperactivity/inattention symptoms. CONCLUSIONS: Childhood anxiety and depression are not only forerunners of later mental health problems but predict academic achievement. Partnerships between education and health systems have the potential to not only improve childhood emotional problems but also improve learning

Self-harm in primary school-aged children: Prospective cohort study

Introduction No prospective studies have examined the prevalence, antecedents or concurrent characteristics associated with self-harm in non-treatment-seeking primary school-aged children. Methods In this cohort study from Melbourne, Australia we assessed 1239 children annually from age 8–9 years (wave 1) to 11–12 years (wave 4) on a range of health, social, educational and family measures. Past-year self-harm was assessed at wave 4. We estimated the prevalence of self-harm and used multivariable logistic regression to examine associations with concurrent and antecedent factors. Results 28 participants (3% of the 1059 with self-harm data; 18 girls [3%], 10 boys [2%]) reported self-harm at age 11–12 years. Antecedent (waves 1–3) predictors of self-harm were: persistent symptoms of depression (sex-age-socioeconomic status adjusted odds ratio [aOR]: 7.8; 95% confidence intervals [CI] 2.6 to 24) or anxiety (aOR: 5.1; 95%CI 2.1 to 12), frequent bullying victimisation (aOR: 24.6; 95%CI 3.8 to 158), and recent alcohol consumption (aOR: 2.9; 95%CI 1.2 to 7.1). Concurrent (wave 4) associations with self-harm were: having few friends (aOR: 8.7; 95%CI 3.2 to 24), poor emotional control (aOR: 4.2; 95%CI 1.9 to 9.6), antisocial behaviour (theft—aOR: 3.1; 95%CI 1.2 to 7.9; carrying a weapon—aOR: 6.9; 95%CI 3.1 to 15), and being in mid-puberty (aOR: 6.5; 95%CI 1.5 to 28) or late/post-puberty (aOR: 14.4; 95%CI 2.9 to 70)

Canonical Causal Diagrams to Guide the Treatment of Missing Data in Epidemiological Studies

With incomplete data, the missing at random (MAR) assumption is widely understood to enable unbiased estimation with appropriate methods. The need to assess the plausibility of MAR and to perform sensitivity analyses considering missing not at random (MNAR) scenarios have been emphasized, but the practical difficulty of these tasks is rarely acknowledged. What MAR means with multivariable missingness is difficult to grasp, while in many MNAR scenarios unbiased estimation is possible using methods commonly associated with MAR. Directed acyclic graphs (DAGs) have been proposed as an alternative framework for specifying practically accessible assumptions beyond the MAR-MNAR dichotomy. However, there is currently no general algorithm for deciding how to handle the missing data given a specific DAG. We construct "canonical" DAGs capturing typical missingness mechanisms in epidemiological studies with incomplete exposure, outcome and confounders. For each DAG, we determine whether common target parameters are "recoverable", meaning that they can be expressed as functions of the observed data distribution and thus estimated consistently, or if sensitivity analyses are necessary. We investigate the performance of available case and multiple imputation procedures. Using the Longitudinal Study of Australian Children, we illustrate how our findings can guide the treatment of missing data in point-exposure studies

Characterization of Puberty in an Australian Population-Based Cohort Study

Purpose: Current knowledge of the characteristics of puberty beyond age at menarche and thelarche is limited, particularly within population-based cohorts. Secular trends and concerns of the health effects of early puberty reinforce the value of contemporary studies characterizing the timing, tempo, duration, and synchronicity of puberty. // Methods: The Childhood to Adolescence Transition Study is a unique Australian cohort of individuals followed annually from late childhood to late adolescence, with up to eight assessments of pubertal stage from 9 to 19 years of age (N = 1,183; 636 females). At each assessment, females reported their Tanner Stage of breast and pubic hair development, while males reported on genital/pubic hair development. Nonlinear mixed-effects models characterized pubertal trajectories and were used to derive each individual’s estimates of timing, tempo, and synchronicity. Parametric survival models were used to estimate the overall duration of puberty. // Results: Timing of mid-puberty (Tanner Stage 3) ranged from 12.5 to 13.5 years, with females developing approximately 6 months before males. Pubertal tempo (at mid-puberty) was similar across sex (between half and one Tanner Stage per year), but the overall duration of puberty was slightly shorter in males. Most females exhibited asynchronous changes of breast and pubic hair development. // Discussion: Estimates of pubertal timing and tempo are consistent with reports of cohorts from two or more decades ago, suggesting stabilization of certain pubertal characteristics in predominantly White populations. However, our understanding of the duration of puberty and individual differences in pubertal characteristics (e.g., synchronicity of physical changes) remains limited

Pre-conception self-harm, maternal mental health and mother-infant bonding problems:a 20-year prospective cohort study

Background: Self-harm in young people is associated with later problems in social and emotional development. However, it is unknown whether self-harm in young women continues to be a marker of vulnerability on becoming a parent. This study prospectively describes the associations between pre-conception self-harm, maternal depressive symptoms and mother&ndash;infant bonding problems.MethodsThe Victorian Intergenerational Health Cohort Study (VIHCS) is a follow-up to the Victorian Adolescent Health Cohort Study (VAHCS) in Australia. Socio-demographic and health variables were assessed at 10 time-points (waves) from ages 14 to 35, including self-reported self-harm at waves 3&ndash;9. VIHCS enrolment began in 2006 (when participants were aged 28&ndash;29 years), by contacting VAHCS women every 6 months to identify pregnancies over a 7-year period. Perinatal depressive symptoms were assessed with the Edinburgh Postnatal Depression Scale during the third trimester, and 2 and 12 months postpartum. Mother&ndash;infant bonding problems were assessed with the Postpartum Bonding Questionnaire at 2 and 12 months postpartum.ResultsFive hundred sixty-four pregnancies from 384 women were included. One in 10 women (9.7%) reported pre-conception self-harm. Women who reported self-harming in young adulthood (ages 20&ndash;29) reported higher levels of perinatal depressive symptoms and mother&ndash;infant bonding problems at all perinatal time points [perinatal depressive symptoms adjusted &beta; = 5.40, 95% confidence interval (CI) 3.42&ndash;7.39; mother&ndash;infant bonding problems adjusted &beta; = 7.51, 95% CI 3.09&ndash;11.92]. There was no evidence that self-harm in adolescence (ages 15&ndash;17) was associated with either perinatal outcome.ConclusionsSelf-harm during young adulthood may be an indicator of future vulnerability to perinatal mental health and mother&ndash;infant bonding problems.</jats:sec

Integrated multiple mediation analysis: A robustness–specificity trade-off in causal structure

Recent methodological developments in causal mediation analysis have addressed several issues regarding multiple mediators. However, these developed methods differ in their definitions of causal parameters, assumptions for identification, and interpretations of causal effects, making it unclear which method ought to be selected when investigating a given causal effect. Thus, in this study, we construct an integrated framework, which unifies all existing methodologies, as a standard for mediation analysis with multiple mediators. To clarify the relationship between existing methods, we propose four strategies for effect decomposition: two-way, partially forward, partially backward, and complete decompositions. This study reveals how the direct and indirect effects of each strategy are explicitly and correctly interpreted as path-specific effects under different causal mediation structures. In the integrated framework, we further verify the utility of the interventional analogues of direct and indirect effects, especially when natural direct and indirect effects cannot be identified or when cross-world exchangeability is invalid. Consequently, this study yields a robustness–specificity trade-off in the choice of strategies. Inverse probability weighting is considered for estimation. The four strategies are further applied to a simulation study for performance evaluation and for analyzing the Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer data set from Taiwan to investigate the causal effect of hepatitis C virus infection on mortality

The potential of intervening on childhood adversity to reduce socioeconomic inequities in body mass index and inflammation among Australian and UK children: A causal mediation analysis.

BACKGROUND: Lower maternal education is associated with higher body mass index (BMI) and higher chronic inflammation in offspring. Childhood adversity potentially mediates these associations. We examined the extent to which addressing childhood adversity could reduce socioeconomic inequities in these outcomes. METHODS: We analysed data from two early-life longitudinal cohorts: the Longitudinal Study of Australian Children (LSAC; n=1873) and the UK Avon Longitudinal Study of Parents and Children (ALSPAC; n=7085). EXPOSURE: low/medium (below university degree) versus high maternal education, as a key indicator of family socioeconomic position (0-1 year). OUTCOMES: BMI and log-transformed glycoprotein acetyls (GlycA) (LSAC: 11-12 years; ALSPAC: 15.5 years). Mediator: multiple adversities (≥2/<2) indicated by family violence, mental illness, substance abuse and harsh parenting (LSAC: 2-11 years; ALSPAC: 1-12 years). A causal mediation analysis was conducted. RESULTS: Low/medium maternal education was associated with up to 1.03 kg/m2 higher BMI (95% CI: 0.95 to 1.10) and up to 1.69% higher GlycA (95% CI: 1.68 to 1.71) compared with high maternal education, adjusting for confounders. Causal mediation analysis estimated that decreasing the levels of multiple adversities in children with low/medium maternal education to be like their high maternal education peers could reduce BMI inequalities by up to 1.8% and up to 3.3% in GlycA. CONCLUSIONS: Our findings in both cohorts suggest that slight reductions in socioeconomic inequities in children's BMI and inflammation could be achieved by addressing childhood adversities. Public health and social policy efforts should help those affected by childhood adversity, but also consider underlying socioeconomic conditions that drive health inequities

Development of the TrAnsparent ReportinG of observational studies Emulating a Target trial (TARGET) guideline [protocol].

BACKGROUND Observational studies are increasingly used to inform health decision-making when randomised trials are not feasible, ethical or timely. The target trial approach provides a framework to help minimise common biases in observational studies that aim to estimate the causal effect of interventions. Incomplete reporting of studies using the target trial framework limits the ability for clinicians, researchers, patients and other decision-makers to appraise, synthesise and interpret findings to inform clinical and public health practice and policy. This paper describes the methods that we will use to develop the TrAnsparent ReportinG of observational studies Emulating a Target trial (TARGET) reporting guideline. METHODS/DESIGN The TARGET reporting guideline will be developed in five stages following recommended guidance. The first stage will identify target trial reporting practices by systematically reviewing published studies that explicitly emulated a target trial. The second stage will identify and refine items to be considered for inclusion in the TARGET guideline by consulting content experts using sequential online surveys. The third stage will prioritise and consolidate key items to be included in the TARGET guideline at an in-person consensus meeting of TARGET investigators. The fourth stage will produce and pilot-test both the TARGET guideline and explanation and elaboration document with relevant stakeholders. The fifth stage will disseminate the TARGET guideline and resources via journals, conferences and courses. ETHICS AND DISSEMINATION Ethical approval for the survey has been attained (HC220536). The TARGET guideline will be disseminated widely in partnership with stakeholders to maximise adoption and improve reporting of these studies