Paediatrics (RCH) - Theses
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ItemPredictors of complications in anorexia nervosa and atypical anorexia nervosa in adolescents: degree of underweight or extent and recency of weight loss?( 2019)Anorexia Nervosa (AN) is the eating disorder characterised by emaciation and underweight, commonly precipitated by dietary restriction that progresses to increasing restriction and self-starvation. AN predominantly develops during adolescence. It is uncommon, with an estimated lifetime prevalence of 0.3% in the general adolescent population. Since the 1800s, the literature has extensively described the significant morbidity and mortality associated with the severity of underweight in people with AN. Over the last 15 years a new ED has increasingly been identified in adolescents who have lost significant amounts of weight, but notably are not underweight. Severe complications from weight loss have been observed in this group of higher weight adolescents despite the absence of underweight. The clinical significance of this ‘non-underweight’ ED has recently been acknowledged with the establishment of distinct diagnostic criteria for Atypical Anorexia Nervosa (AAN). Limited data are available about AAN, including in relation to the prevalence, clinical trajectory or optimal treatment. However, beyond these aspects, the absence of underweight in AAN poses questions about the relative contribution of weight loss compared to weight as predictors of the clinical complications in AN and AAN, that have long been thought to result from underweight. This thesis focusses on AAN to gain greater understanding and knowledge about the prevalence, clinical trajectory and outcomes of this recently described ED. The proportion of adolescents diagnosed with AAN and hospitalised at the Royal Children’s Hospital (RCH) over a nine year period is assessed. A case study describes an adolescent who, despite significant weight loss and physical complications associated with AN, was not initially considered for diagnosis of an ED as she was not underweight. A comparison between AN and AAN is undertaken to compare the characteristics of these two diagnoses. The result of this thesis questions the fundamental aspect of nutrition in restrictive AN that is, the validity of assessing malnutrition by the degree of underweight rather than weight loss. Over the nine year study period AAN emerged as a significant ED with a dramatic five-fold increase in hospital admissions to the RCH. Adolescents diagnosed with AAN were found to experience a similar profile of life-threatening complications as adolescents who had AN, including early refeeding syndrome. The only differences detected between the diagnostic groups were higher premorbid weight and weight at admission in AAN, and in AN a lower systolic blood pressure nadir during hospitalisation. Notably, the duration of weight loss and amount of weight loss were found to be similar in the two diagnostic groups. Finally, the very important question of the contribution of weight loss compared to underweight as predictors of clinical complications is addressed. The critical finding was that weight loss, not underweight, predicted the potentially life-threatening complications of sinus bradycardia and lower pulse rate nadir. Similarly, recent weight loss was associated with greater severity of ED cognitions, with no association between underweight and ED cognitions. Several complications were predicted by both lower weight and greater weight loss, but no outcome was independently associated with weight itself. For the first time weight loss, rather than weight itself was found to be a stronger predictor of some of the serious complications following self-starvation in adolescents diagnosed with AN and AAN. No complication was predicted by underweight itself, suggesting that underweight as a marker of starvation and malnutrition is now out of step with current trends towards patients having higher weight. It is hoped that the outcomes of this thesis will raise awareness of the prevalence and severity of complications in AAN, and also inform future research directions.
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ItemPrevalence, risk factors and outcomes of hearing loss in Australian children and adults: growing up in Australia’s child health CheckPoint study( 2019)Background Hearing loss of ageing is being reframed as a lifecourse problem with childhood origins. Supporting this theory, recent studies suggest a possible role of obesity, inflammation and telomere shortening in the pathogenesis of hearing loss in older adults. However, whether and when these associations emerge in populations is not known. Unlike clinical hearing loss requiring hearing aids and cochlear implantation, less is known about the outcomes of milder losses, which is a requisite for evidence-based hearing policy. Aims In 1485 child-parent dyads at child age 11-12 years, this thesis aimed to: 1) describe the current prevalence of hearing loss in Australian children and mid-life adults; 2) examine associations of obesity, inflammation and telomere length with hearing acuity in children and mid-life adults; 3) investigate child outcomes of slight-mild hearing loss. Methods Design & Participants: Children and parents in the national population-based cross-sectional Child Health CheckPoint sub-study nested within the Longitudinal Study of Australian Children (LSAC). LSAC recruited 5107 infants aged 3 to 19 months in 2004, following them across 8 biennial waves. Measures (all CheckPoint unless specified): Pure-tone audiometry; anthropometry (body mass index (BMI, kg/m2), fat/fat-free mass indices, waist-to-height ratio; LSAC waves 2-6 - BMI); plasma Glycoprotein A (GlycA, a biomarker of chronic inflammation); relative telomere length (T/S ratio); and child outcomes (health-related quality of life; academic and behavioural outcomes from LSAC wave 6). Analysis: We calculated prevalence of hearing loss with 95% Confidence Intervals (CIs). Linear/logistic regression quantified associations of body composition/trajectories (derived from latent class analysis), GlycA and telomere length with hearing threshold/loss. Linear regression quantified associations of hearing threshold/loss with outcomes. Results Aim 1: In children (n=1485, mean age 11.4 (standard deviation (SD) 0.5) years) and adults (n=1485, mean age 42.9 (SD 5.1) years), the prevalence of bilateral hearing loss >15 dB HL (slight or worse) was 9.3% and 27.3% respectively within speech frequencies. Prevalence in children rose substantively since 1990. Aim 2: Concurrent obesity, decade-long BMI trajectories and GlycA (but not telomere length) showed small associations with poorer hearing, particularly in lower frequencies. Associations evident by age 11-12 years were generally stronger in mid-life. Compared with those of normal weight, women with persistent severe obesity showed three times the odds of hearing loss. For every SD rise in GlycA, the odds of hearing loss rose by around 10% for children and 20% for adults. Aim 3: Scores of children with slight-mild bilateral hearing loss were 0.2-0.3 SD lower for sentence repetition, teacher-reported learning and physical PedsQL, but not other outcomes (e.g. receptive vocabulary, mathematical thinking, behaviour, psychosocial PedsQL). Conclusion Slight or worse hearing loss in childhood is prevalent and may be increasing. This may presage the profound later burden of age-related hearing loss. Like other age-related diseases, hearing loss may have adipose and inflammatory antecedents. Replication and mechanistic studies could inform causal inference and early prevention efforts. Slight-mild hearing loss showed small associations with some child outcomes; future research should investigate longitudinal and indirect effects, and the cost-benefit of identification and management strategies by age.
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ItemDeterminants and outcomes of dietary trajectories and obesity measures in children/adolescents and their parents: the longitudinal study of Australian children( 2018)Aims: The aims of this thesis were to investigate the (1) extent to which dietary scores and patterns remain stable from 2-3 to 10-11, and from 4-5 to 14-15, years of age; (2) determinants of this stability or change, including (a) early life socioeconomic factors and (b) parental health behaviours; and (3) associations (which may be bidirectional) between dietary patterns and scores, and measures of obesity (body mass index (BMI) and waist-to-height ratio (WHtR)). Methods: This PhD used data from waves two to six of the B Cohort and one to six of the K Cohort of the Longitudinal Study of Australian Children. Children or parents reported biennially on the child’s consumption of 12-16 individual or grouped food or drink items consumed during the previous 24 hours. At each wave, I derived guideline-based dietary scores, indicating a healthier or less healthy diet. I also derived dietary patterns at each wave, using exploratory factor analyses. Aim 1: I generated trajectories of dietary scores and patterns using group-based trajectory modelling, for 4504 B and 4640 K Cohort children. Aim 2: I examined associations of baseline socioeconomic factors (including parental education, socioeconomic position and neighbourhood disadvantage) and parental health behaviours (fruit/vegetable consumption, alcohol, smoking and physical activity) in both parents with children’s dietary trajectories, using multinomial logistic regression analyses. Aim 3: I investigated cross-lagged associations (n=1972 to 2882) between diet, and BMI z-score and WHtR, using structural-equation modelling. Results: Aim 1: There was moderate to high stability of dietary scores and patterns in both cohorts. In both cohorts, I obtained four trajectories of dietary scores and ‘healthy’ patterns: ‘never healthy’, ‘moderately healthy’, ‘becoming less healthy’ and ‘always healthy’, and four trajectories of ‘unhealthy’ patterns: ‘always unhealthy’, ‘moderately unhealthy’, ‘becoming unhealthy’ and ‘never unhealthy’. For unstable dietary trajectories, diet tended to worsen at around 7 years of age in both cohorts. Aim 2: Low parental education and low socioeconomic position were associated with children following the least healthy or unhealthiest dietary trajectories in both cohorts. Moreover, low fruit and vegetable consumption in the primary caregiver was strongly associated with children following the least healthy dietary trajectories. Smaller associations were found between secondary caregiver fruit and vegetable consumption, and children’s dietary trajectories. Aim 3: Children’s dietary patterns and scores were generally not associated with BMI z-score and WHtR in the next wave, and BMI z-score and WHtR were generally not associated with either dietary measure in the next wave. Conclusions: Diet was moderately to highly stable over childhood and early adolescence. I observed strong associations between socioeconomic status and parental health behaviours, and subsequent dietary trajectories in children. Future research should investigate underlying pathways relating to socioeconomic determinants of diet and prediction tools, based on parental diet. Children’s dietary patterns and scores were generally not associated with BMI z-score or WHtR in either direction. Therefore, better quantitative childhood dietary tools feasible for large-scale studies are needed to determine how energy intake, dietary patterns and anthropometry co-develop.
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ItemEarly-life predictors of vascular phenotypes : in the Child Health CheckPoint and Longitudinal Study of Australian Children( 2018)Background: Cardiovascular disease (CVD) is a leading cause of global mortality and morbidity in the 21st century. The main pathological mechanism in CVD, atherosclerosis, begins early in life. Effective CVD prevention strategies require better understanding of the early-life patterns of CVD risk. Aims: In a cohort of Australian 11- to 12-year-old children and their parents, I sought to describe, in the early-life period, patterns in CVD risk factors and vascular phenotypes indicative of atherosclerosis. Specifically, I sought: I. To investigate, through systematic review, whether early-life SEP influences adult inflammation II. To examine whether early-life SEP is associated with child vascular phenotypes III. To examine whether traditional risk factors (BP, body mass index (BMI), glucose, cholesterol, smoking, diet and physical exercise) in the Ideal Cardiovascular Health (ICVH) score, are associated with child vascular phenotypes IV. To determine whether inflammation, measured by glycoprotein acetyls (GlycA), is associated with child risk factors, and to what extent inflammation also predicts child vascular phenotypes Methods: To address the first aim, I conducted a systematic review and meta-analysis of cross-sectional and longitudinal studies examining child SEP and adult inflammation, in particular C-reactive protein (CRP). The next three aims utilised data from the Child Health CheckPoint (n=1874 child-parent dyads, 49% girls, 88% mothers), a biophysical markers cross-sectional study nested within the Longitudinal Study of Australian Children. It was conducted in 2015 sequentially across 15 cities and towns around Australia. Associations were evaluated with multivariable linear regression, supplemented with survey weights and methods and multiple imputation. Adult associations were examined in parallel when equivalent data were available. Results: In addressing the first aim, meta-analysis showed individuals with parents in the lowest SEP bracket had 25% higher CRP levels than those in the highest SEP bracket in age- and sex-adjusted analyses. The inclusion of adult BMI into models attenuated this association. In the following CheckPoint analyses, both family and neighbourhood socioeconomic disadvantage were associated with structural and functional vascular phenotypes at age 11-12 years, in age- and sex-adjusted linear regression analyses. Structural vascular phenotype associations were independent of traditional CVD risk factors, while functional vascular phenotype associations largely attenuated when adjusted for BMI. The absence of adequate grandparental SEP data precluded parallel adult analyses. Further, each additional CVD risk factor at age 11-12 years was cross-sectionally associated with adverse functional, but not structural, vascular phenotypes. Adult associations were larger in magnitude and associations existed for both structural and functional vascular phenotypes. Associations with BP and BMI were largest in magnitude and independent of other CVD risk factors. Finally, in addressing the last aim, I observed GlycA at age 11-12 years was associated with structural and functional vascular phenotypes in age- and sex-adjusted models. Associations attenuated with inclusion of traditional CVD risk factors, specifically BMI and BP. Adult associations were similar, however GlycA remained associated with PWV independent of CVD risk factors. Conclusion: Socioeconomic gradients in childhood were associated with vascular phenotypes and CVD risk factors. These risk factors were themselves associated with functional vascular phenotypes in children. In adults, CVD risk factors were associated with both vascular structure and function. These findings broadly support CVD prevention strategies starting earlier in life. Further investigation of socioeconomic influences on both novel and traditional CVD risk factors may afford opportunities to improve population cardiovascular health.
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ItemEnvironment versus genetics in the development of health-related problems in childhood obesity( 2017)Introduction: Childhood obesity is a major health concern affecting a quarter of all Australian youth. Obese youth are at risk of multi-systemic obesity-related comorbidities (ORC), such as Prediabetes and Type 2 Diabetes Mellitus (T2DM), Hypertension, Hyperlipidaemia, Non-alcoholic fatty liver disease (NAFLD), Polycystic ovarian syndrome (PCOS), Obstructive sleep apnoea (OSA), mental health and orthopaedic issues. However, within the obese population, the severity of obesity is a poor predictor of these comorbidities. As such, current guidelines advise screening obese youth for all comorbidities, which is both time consuming and costly. ORC, as with obesity itself, are complex polygenic disorders involving interaction between genetic and environmental risk factors. Furthermore, many of these interactions are likely mediated by epigenetic variation, linking environmental exposures with genetic predisposition. Therefore, clarification of the role of environmental exposures, genetic risk factors and epigenetic profile in obese youth may provide valuable insight into determining which obese youth are at risk of developing ORC. The aim of this study was to characterise and investigate the associations between environmental, genetic and epigenetic factors with obesity-related comorbidities in obese youth. This information obtained will allow clinicians to better predict and profile the comorbidity burden in obese youth for targeting interventions to those most likely to benefit. Materials and Methods: The Childhood Overweight BioRepository of Australia collected comprehensive clinical and anthropometric data, as well as blood samples for genetic, metabolic and hormonal profile testing from patients (age 1 to 18 years) attending the Weight Management Clinic at the Royal Children’s Hospital, Melbourne. Anthropometric measures included standard measurements of weight, height and waist circumference (converted into BMI z-score (BMI-Z) and waist-height ratio for analyses) as well as total percentage body fat (%FM) and percentage truncal body fat (%truncal) using bioimpedance. Dietary intake was assessed using the Australian Child and Adolescent Eating Survey and physical activity was measured objectively using accelerometry. Genetic typing and epigenetic profiling of single nucleotide polymorphisms (SNP) and measures of DNA methylation were performed using the SEQUENOM MassARRAY platform. Results: 349 participants were included in the study. Both metabolic and non-metabolic ORC are common in obese youth. The most commonly used measure of adiposity, BMI-Z, was the anthropometric marker least associated with ORC, while important ORCs such as T2DM and hyperlipidaemia were not significantly associated with any of the anthropometric measures. The presence of two or more significantly elevated anthropometric markers was associated with the presence of a higher number of ORCs. Almost all obese youth reported poor vegetable intake and high sedentary behaviour (TV-watching and total media) time. Although initial analyses observed associations between sedentary behaviour (TV-watching and total media use time) with prediabetes and hyperlipidaemia, unhealthy food options with mental health issues, and high fruit intake with NAFLD, these associations lost significance after correction for multiple testing by false discovery procedure (FDR). However, low vitamin D levels were significantly associated with hypertension, independent of adiposity and season. The Fat Mass and Obesity (FTO) gene has the largest influence on adiposity amongst obesity-risk genes to date and has been associated with ORCs. In our cohort, the FTO risk allele was associated with poorer longitudinal weight outcomes in pre-pubertal children, but not pubertal adolescents. The FTO SNP however was not associated with any ORCs. We also examined the association between the top 22 T2DM risk SNPs identified from previous studies and Prediabetes or T2DM status. The SLC30A8 rs13266634 SNP appeared to be protective of prediabetes/T2DM status in unadjusted analysis but lost significant on FDR testing. The addition of T2DM SNPs profile to TV-watching time improved the predictive model for Prediabetes/T2DM status. We were not able to replicate the previously reported association of FTO CpG hypomethylation with prediabetes/T2DM in obese children and adolescents. However FTO hypomethylation was seen in obese youth with NAFLD, independent of age, sex and total body adiposity. FTO methylation was independent of FTO expression, which was not associated with any ORC. Conclusion: Anthropometry is not associated with comorbidities in childhood obesity. Environmental factors do not appear to be associated with comorbidities. Low vitamin D level is associated with hypertension. Genetic factors impact on weight gain but not comorbidities, and epigenetic factors may contribute to NAFLD. Combining these environmental and genetic elements with established clinical risk factors in the assessment of each individual ORC may assist in enhancing current clinical models of care for obese children and adolescents.