Clinical Profile and Predictors of Severe Illness in young South African Infants

Background. Most childhood deaths occur within the first 2 months of life. Simple symptoms and signs that reliably indicate the presence of severe illness that would warrant urgent hospital management are of major public health importance. Objectives. To describe the disease profile of sick young infants aged 0 - 59 days presenting at King Edward VIII Hospital, Durban, and to assess the association between clinical features assessed by primary health workers and the presence of severe illness. Methods. Specific clinical signs were evaluated in young infants by a health worker (nurse), using a standardised list. These signs were compared with an assessment by an experienced paediatrician for the need for urgent hospital- or clinic-based care. Results. Nine hundred and twenty-five young infants were enrolled; 61 wer

A comparison of strategies for selecting auxiliary variables for multiple imputation

Multiple imputation (MI) is a popular method for handling missing data. Auxiliary variables can be added to the imputation model(s) to improve MI estimates. However, the choice of which auxiliary variables to include is not always straightforward. Several data-driven auxiliary variable selection strategies have been proposed, but there has been limited evaluation of their performance. Using a simulation study we evaluated the performance of eight auxiliary variable selection strategies: (1, 2) two versions of selection based on correlations in the observed data; (3) selection using hypothesis tests of the “missing completely at random” assumption; (4) replacing auxiliary variables with their principal components; (5, 6) forward and forward stepwise selection; (7) forward selection based on the estimated fraction of missing information; and (8) selection via the least absolute shrinkage and selection operator (LASSO). A complete case analysis and an MI analysis using all auxiliary variables (the “full model”) were included for comparison. We also applied all strategies to a motivating case study. The full model outperformed all auxiliary variable selection strategies in the simulation study, with the LASSO strategy the best performing auxiliary variable selection strategy overall. All MI analysis strategies that we were able to apply to the case study led to similar estimates, although computational time was substantially reduced when variable selection was employed. This study provides further support for adopting an inclusive auxiliary variable strategy where possible. Auxiliary variable selection using the LASSO may be a promising alternative when the full model fails or is too burdensome

Analysis and Reporting of Randomized Trials in Cleft Palate Surgery: Learning from the Timing of Primary Surgery (TOPS) Trial

\ua9 2024, American Cleft Palate Craniofacial Association.The Timing of Primary Surgery (TOPS) trial was published August 2023 in the New England Journal of Medicine and is a milestone achievement for a study focused on cleft palate. Due to the complexity of outcome reporting in cleft and the rarity of such comparative trials, TOPS presents a useful opportunity to critically review the design, analysis and reporting strategies utilised. This perspective article focused on the inclusion of participants, the choice of the primary outcome measure and the analysis of ordinal data within the trial. Considerations for future comparative studies in cleft care are discussed

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)

The forgotten girls: the state of evidence for health interventions for pregnant adolescents and their newborns in low-income and middle-income countries

Every year, an estimated 21 million girls aged 15–19 years become pregnant in low-income and middle-income countries (LMICs). Policy responses have focused on reducing the adolescent birth rate whereas efforts to support pregnant adolescents have developed more slowly. We did a systematic review of interventions addressing any health-related outcome for pregnant adolescents and their newborn babies in LMICs and mapped its results to a framework describing high-quality health systems for pregnant adolescents. Although we identified some promising interventions, such as micronutrient supplementation, conditional cash transfers, and well facilitated group care, most studies were at high risk of bias and there were substantial gaps in evidence. These included major gaps in delivery, abortion, and postnatal care, and mental health, violence, and substance misuse-related outcomes. We recommend that the fields of adolescent, maternal, and sexual and reproductive health collaborate to develop more adolescent-inclusive maternal health care and research, and specific interventions for pregnant adolescents. We outline steps to develop high-quality, evidence-based care for the millions of pregnant adolescents and their newborns who currently do not receive this

Growth and adrenarche: findings from the CATS observational study

BACKGROUND: There is increasing evidence that patterns of pubertal maturation are associated with different patterns of health risk. This study aimed to explore the associations between anthropometric measures and salivary androgen concentrations in pre-adolescent children. METHODS: We analysed a stratified random sample (N=1151) of pupils aged 8-9 years old from 43 primary schools in Melbourne, Australia from the Childhood to Adolescence Transition Study. Saliva samples were assayed for dehydroepiandrosterone (DHEA), DHEA-sulfate and testosterone. Anthropometric measures included height, weight, body mass index (BMI) and waist circumference. Associations between (1) anthropometric measures and each androgen, and (2) hormone status with obesity and parental report of pubertal development were investigated using linear regression modelling with general estimating equations. RESULTS: Greater height, weight, BMI and waist circumference were positively associated with higher androgen concentrations, after adjusting for sex and socioeconomic status. Being overweight or obese was associated with higher testosterone and DHEA concentrations compared with the normal BMI category. Those who were obese were more likely (OR=2.7, 95% CI 1.61 to 4.43, p<0.001) to be in the top tertile of age-adjusted androgen status in both sexes. CONCLUSION: This study provides clear evidence for an association between obesity and higher androgen levels in mid-childhood. The adrenal transition may be a critical time period for weight management intervention strategies in order to manage the risk for metabolic problems in later life for high-risk individuals

Reproducibility of aortic intima-media thickness in infants using edge-detection software and manual caliper measurements

Background: Aortic intima-media thickness measured by transabdominal ultrasound (aIMT) is an intermediate phenotype of cardiovascular risk. We aimed to (1) investigate the reproducibility of aIMT in a population-derived cohort of infants; (2) establish the distribution of aIMT in early infancy; (3) compare measurement by edge-detection software to that by manual sonographic calipers; and (4) assess the effect of individual and environmental variables on image quality. Methods. Participants were term infants recruited to a population-derived birth cohort study. Transabdominal ultrasound was performed at six weeks of age by one of two trained operators. Thirty participants had ultrasounds performed by both operators on the same day. Data were collected on environmental (infant sleeping, presence of a sibling, use of sucrose, timing during study visit) and individual (post-conception age, weight, gender) variables. Two readers assessed image quality and measured aIMT by edge-detection software and a subset by manual sonographic calipers. Measurements were repeated by the same reader and between readers to obtain intra-observer and inter-observer reliability. Results: Aortic IMT was measured successfully using edge-detection in 814 infants, and 290 of these infants also had aIMT measured using manual sonographic calipers. The intra-reader intra-class correlation (ICC) (n = 20) was 0.90 (95% CI 0.76, 0.96), mean difference 1.5 &mu;m (95% LOA -39, 59). The between reader ICC using edge-detection (n = 20) was 0.92 (95% CI 0.82, 0.97) mean difference 2 &mu;m (95% LOA -45.0, 49.0) and with manual caliper measurement (n = 290) the ICC was 0.84 (95% CI 0.80, 0.87) mean difference 5 &mu;m (95% LOA -51.8, 61.8). Edge-detection measurements were greater than those from manual sonographic calipers (mean aIMT 618 &mu;m (50) versus mean aIMT 563 &mu;m (49) respectively; p &lt; 0.001, mean difference 44 &mu;m, 95% LOA -54, 142). With the exception of infant crying (p = 0.001), no associations were observed between individual and environmental variables and image quality. Conclusion: In a population-derived cohort of term infants, aIMT measurement has a high level of intra and inter-reader reproducibility. Measurement of aIMT using edge-detection software gives higher inter-reader ICC than manual sonographic calipers. Image quality is not substantially affected by individual and environmental factors. &copy; 2014 McCloskey et al.; licensee BioMed Central Ltd

Allowing for missing outcome data and incomplete uptake of randomised interventions, with application to an Internet-based alcohol trial

Missing outcome data and incomplete uptake of randomised interventions are common problems, which complicate the analysis and interpretation of randomised controlled trials, and are rarely addressed well in practice. To promote the implementation of recent methodological developments, we describe sequences of randomisation-based analyses that can be used to explore both issues. We illustrate these in an Internet-based trial evaluating the use of a new interactive website for those seeking help to reduce their alcohol consumption, in which the primary outcome was available for less than half of the participants and uptake of the intervention was limited

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

A Cross-Cohort Study Examining the Associations of Metabolomic Profile and Subclinical Atherosclerosis in Children and Their Parents: The Child Health CheckPoint Study and Avon Longitudinal Study of Parents and Children

Background-High-throughput nuclear magnetic resonance profiling of circulating metabolites is suggested as an adjunct for cardiovascular risk evaluation. The relationship between metabolites and subclinical atherosclerosis remains unclear, particularly among children. Therefore, we examined the associations of metabolites with carotid intima-media thickness (cIMT) and arterial pulse wave velocity (PWV).Methods and Results-Data from two independent population-based studies was examined; (1) cross-sectional associations with cIMT and PWV in 1178 children (age 11-12 years, 51% female) and 1316 parents (mean age 45 years, 87% female) from the CheckPoint study (Australia); and (2) longitudinal associations in 4249 children (metabolites at 7-8 years, PWV at 10-11 years, 52% female), and cross-sectional associations in 4171 of their mothers (mean age 48 years, cIMT data) from ALSPAC (The Avon Longitudinal Study of Parents and Children; UK). Metabolites were measured by the same nuclear magnetic resonance platform in both studies, comprising of 69 biomarkers. Biophysical assessments included body mass index, blood pressure, cIMT and PWV. In linear regression analyses adjusted for age, sex, body mass index, and blood pressure, there was no evidence of metabolite associations in either children or adults for cIMT at a 10% false discovery threshold. In CheckPoint adults, glucose was positively, and some high-density lipoprotein-cholesterol derived measures and amino acids (glutamine, histidine, tyrosine) inversely associated with PWV.Conclusions-These data suggest that in children circulating metabolites have no consistent association with cIMT and PWV once adjusted for body mass index and blood pressure. In their middle-aged parents, some evidence of metabolite associations with PWV were identified that warrant further investigation