Paediatrics (RCH) - Theses
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ItemThe epidemiology and risk factors of anaphylaxis and food-induced anaphylaxis worldwide( 2019)Anaphylaxis is a severe allergic reaction that is rapid in onset and may cause death. There are increasing reports from individual countries and regions on anaphylaxis prevalence or incidence; however, there has been no systematic summary of the worldwide evidence among the paediatric population. An increasing rate of hospital admissions for food-induced anaphylaxis was observed in Australia from 1993 to 2012, especially among young children. Although rising rates of anaphylaxis have also been reported in other western countries, little is known about the time trends in Asian regions. Time trends of adrenaline auto-injectors (AAI) prescription is a good supplement surrogate for the time trends of anaphylaxis risk in the community. Some studies reported time trends of AAI prescription internationally, such as USA, UK and Canada; however, there is little information on the time trends of AAI prescription or dispensing in Australia in recent years. Previous international studies have reported that ethnicity is associated with the risk of anaphylaxis. Food allergy was found to be more common in children born in Australia with Asian parents than children born in Australia with Caucasian parents. However, it is not known whether ethnicity is also a risk factor for the development of anaphylaxis and food-induced anaphylaxis in Australia. Food allergy is an important cause of anaphylaxis. People with food allergy have a high risk of anaphylaxis, but not all of them will have an anaphylactic reaction. It is hence crucial to know the risk factors of having anaphylactic reactions in the food allergic population. Few studies have examined risk factors for food-induced anaphylaxis in food-allergic children. The characteristics of children with food allergy who are more likely to experience anaphylaxis are unknown. Therefore, this thesis aims to describe the worldwide incidence and prevalence of anaphylaxis and identify risk factors for anaphylaxis and food-induced anaphylaxis in both the general population and the food-allergic population. Firstly, I conducted a systematic review to describe the incidence and prevalence of anaphylaxis in children worldwide. I found a high heterogeneity between studies which limited the interpretation of an overall combined incidence and prevalence. I found increasing time trends of all-cause anaphylaxis and food-induced anaphylaxis in children from included studies and studies in developing areas were underrepresented. By using hospital admission data for anaphylaxis from the Hospital Authority of Hong Kong, I reported increasing time trends of both all-cause anaphylaxis and food-induced anaphylaxis in the paediatric population in Hong Kong between 2001 and 2015. By analysing AAI dispensing data from the Australian Pharmaceutical Benefits Scheme (PBS) database, I found an increasing incidence rate of patients with AAI in Australia from 2005 to 2014. Different trends were reported by sex, age and state. I found a shift towards more AAI prescriptions being provided by general practitioners (GPs) rather than specialists in most regions in Australia. By using the data from the School Entrant Health Questionnaire in Victoria, Australia, I investigated the risk factors of anaphylaxis in the general population. I found an association between Asian ethnicity and anaphylaxis risk in children living in Australia and identified the high-risk group (Australian-born children with Asian-born mothers) for anaphylaxis. Lastly, I used data from the HealthNuts study to explore the frequency and risk factors of anaphylaxis in food allergic children from a community setting. I found a high frequency of experiencing anaphylactic reactions (11.5%) in the preceding 12 months in children with food allergy. In summary, the results presented in this thesis have provided further knowledge on the epidemiology of anaphylaxis and food-induced anaphylaxis in the general population and identified important predictors of anaphylaxis in the general population and the food allergic population. The identification of these essential predictors has important implications for the management of anaphylaxis and will improve our understanding of the development of anaphylaxis.
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ItemEnvironmental and genetic risk factors for food allergy in children with Asian ancestry( 2019)Epidemiological and genetic studies on food allergy to date have focused primarily on the Caucasian population. This is despite emerging evidence that food allergy appears to be rising in Asian countries, alongside the increasing Westernisation and urbanisation in these countries. Even less is known about Asian migrants living in Western countries. A population-based study on food allergy found the risk of food allergy to be three times higher in infants of East Asian ancestry than infants of Caucasian ancestry. It is thought that infants growing up in Australia are exposed to environmental agents that have a differential effect on the immune system depending on their genetic background. However, the influence of specific genetic and environmental risk factors is currently unknown. It is also unclear if the increased risk of food allergy translates to higher risk of other allergic diseases later in childhood. The main objective of this thesis is to identify specific environmental and genetic factors on the risk of food allergy in the Asian population living in Australia. This thesis aims to quantify the prevalence of, and identify risk factors for food allergy and allergic comorbidities in the Asian population. An additional aim is to identify genetic variants that increase the risk of food allergy in the East Asian population and compare this to the Caucasian population living in Australia. This thesis primarily used data and samples from the longitudinal HealthNuts study where 5,276 1-year-old infants attending council run vaccination sessions across Melbourne were recruited. Skin prick tests to a range of food were carried out on infants and those with a wheal size less than 1 mm underwent an oral food challenge. The 1-year-old infants were followed up again at age 6 years and data collected at this follow-up visit were also used for analyses in this thesis. Additionally, data collected from a Growing Up in Singapore Towards Healthy Outcomes (GUSTO) birth cohort was also used to compare the risk factors and prevalence of allergic diseases between East Asians living in Melbourne and East Asians living in Singapore. This thesis reports that Australian-born children with East Asian parents have a higher burden of allergic rhinitis, eczema and aeroallergen sensitisation but not asthma, in the first six years of life compared to children of Caucasian ancestry. Moreover, children with IgE-mediated food allergy and eczema in infancy were 3 times more likely to have asthma and 2 times more likely to have allergic rhinitis at age 6 years, irrespective of ancestry. Additionally, East Asian children living in Melbourne have a higher risk of food allergy compared to East Asian children living in Singapore. Despite delayed introduction of allergens into the diet compared to the Asian population in Melbourne, Asian children in Singapore had less food allergy. While eczema rates were lower in Singapore than in Melbourne, early onset eczema was associated with an increased risk of food allergy in both Singapore and Melbourne. In terms of genetic risk factors, a systematic review conducted as part of this thesis identified several genes of interest known to be involved in immune regulation, cell function and epidermal barrier function. However, studies were of varied quality and the reproducibility of findings for the same SNPs were minimal. Some of the highly re-producible genes identified from the literature include HLA, FLG and IL13. Additionally, there was also a paucity of studies carried out in the Asian population that were able to elucidate underlying mechanisms for the differential food allergy risks observed in the population. This highlighted the need for genetic studies focused in this population. This thesis found that HLA rs7192 minor allele was associated with increased risk of peanut allergy in the Caucasian population but not East Asian population. Among sensitised children with two East Asian born parents, those with the minor allele for rs231735, rs231804 or rs11571291 (all CTLA4) have a reduced risk of egg allergy. The findings of this thesis identify Asian children living in Australia as a high risk allergic group not just in infancy but throughout early childhood. As a multifactorial disease, both environmental and genetic factors are known to contribute to the pathogenesis of food allergy. Therefore, it may be that the increased risk of food allergy observed in genetically predisposed East Asian children living in Melbourne unmasked upon exposure to environmental risk factors.
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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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ItemIntragenic DNA methylation and neurodevelopmental outcomes in children with fragile X-related disorders( 2019)The type and severity of clinical involvement in children with fragile X syndrome (FXS) and disorders related to premutations (PM) of the fragile X mental retardation 1 gene (FMR1), herein collectively denoted as fragile X-related disorders (FXDs), is highly variable. Multiple molecular factors contribute to the heterogeneity of neurodevelopmental outcomes. Increased intragenic DNA methylation (DNAm) in blood of the fragile X-related epigenetic element 2 (FREE2) region, located at the FMR1 exon 1/intron 1 boundary, was associated with lower intellectual functioning in a cohort of female children and adults with FXS and with neuro-cognitive and psychiatric phenotypes in women with PM. Nevertheless, FREE2 DNAm has not yet been investigated in exclusively paediatric male and female FXDs cohorts. The overarching aim of this thesis was to explore FREE2 DNAm and neurodevelopmental outcomes of Australian male and female children with FXDs. Matrix assisted laser desorption/ionization time-of-flight mass spectrometry and methylation specific-quantitative melt analysis were used to analyse FREE2 DNAm in venous blood, buccal epithelial cells (BEC) and retrieved newborn blood spots (NBS). In addition, FMR1 mRNA levels in blood were assessed using real-time polymerase chain reaction (PCR) relative standard curve method. The evaluation of the neurodevelopmental outcomes concentrated on direct clinical assessment of intellectual functioning and autism spectrum disorder (ASD) symptom severity. Intelligence Quotient (IQ) scores were corrected for floor effect using the Whitaker and Gordon (WG) extrapolation method. The findings highlighted the variability of the clinical presentation of children with PM. Results also showed that compared to sex-matched paediatric controls, children with FXS had significantly higher levels of FREE2 DNAm levels in blood and BEC and, within the FXS group, higher FREE2 DNAm levels in blood correlated with lower FMR1 mRNA levels. In children with FXS, the application of the WG method effectively addressed the floor effect inherent in standardised intelligence scales, unmasked inter-individual variability in IQ scores and uncovered significant associations between intragenic DNAm and neurodevelopmental outcomes. Strength and statistical significance of these epigenotype-phenotype relationships varied based on sex, position of the differentially methylated sites, tissue analysed, assay used and neurodevelopmental domain investigated. The most significant finding was in males with FXS, for whom higher levels of BEC FREE2 DNAm were associated with lower WG-corrected Full Scale IQ (cFSIQ) and Performance IQ (cPIQ) scores. Finally, findings showed that the best-performing FREE2 biomarker had sensitivity, specificity, negative and positive predictive values of 100% for detection of full mutation alleles in NBS of males and females with FXS. Additionally, this study revealed that for males with FXS, FREE2 DNAm in NBS was significantly associated with lower cFSIQ and cPIQ scores obtained in childhood and adolescence. This is the first study in any monogenic neurodevelopmental disorder associated with intellectual disability, showing that a perinatal epigenetic biomarker is significantly associated with paediatric neuropsychological outcomes. In conclusion, the results of this thesis contribute to the characterisation of the neurodevelopmental outcomes in children with FXDs, provide evidence that FREE2 DNAm is a sensitive epigenetic biomarker significantly associated with the variability of intellectual functioning in male children with FXS, and may have implications for the development of new methylation specific tests for earlier diagnosis with potential prognostic applications.
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ItemPrediction and prevention of central venous catheter complications in children with cancer( 2018)Although long-term central venous catheters (CVCs) are essential to paediatric cancer treatment, serious CVC-related complications are common. Around a quarter of children undergoing treatment for cancer experience at least one episode of central line-associated bloodstream infection (CLABSI), and up to a third experience CVC occlusion. CLABSI can cause sepsis or death, and CVC occlusion is associated with device fracture, venous thrombosis, CLABSI and mortality. Conservative treatment of CLABSI often fails, leading to persistent or recurrent infection or necessitating CVC removal. This thesis encompasses three clinical studies of approaches to reduce CVC-related complications in children with cancer. The first study (Chapter 2) was a prospective, double-blind, placebo-controlled trial of ethanol lock therapy (ELT) as adjunctive treatment and secondary prophylaxis in paediatric oncology patients with CLABSI. Ninety-four evaluable participants (48 ELT and 46 placebo) were enrolled. Treatment failure risk was almost identical with ELT and placebo (44% vs. 43%; P=0.98), but thrombolytic therapy for catheter occlusion was more common with ELT (58% vs. 33%; P=0.012). Although this study was not powered to prove equivalence (i.e. to exclude a clinically meaningful difference in outcomes between groups), it found that ELT was ineffective and can cause harm, suggesting that it should not be used in routine practice. The second study (Chapter 3) was a retrospective, matched cohort study of adjunctive antibiotic lock therapy (ALT) for treatment of CVC-related bloodstream infection in paediatric oncology patients. Thirty-eight ALT episodes were matched with 73 episodes treated with systemic therapy (ST) only. Treatment failure was similar between the ALT and ST groups (50% vs. 38%; P=0.24), but timing differed: immediate CVC removal was less common with ALT (0% vs. 12%; P=0.03) but delayed removal (4–13 days) or relapse was more common (50% vs. 25%; P=0.01). Although this study had some limitations, the results did not provide any evidence for efficacy of ALT. Further prospective studies are needed before this intervention can be recommended. The third study (Chapter 4) was a prospective trial of a novel method to predict CVC occlusion. The study evaluated feasibility, acceptability and accuracy of CVC resistance monitoring (CRM) in paediatric oncology patients. Ten patients were enrolled and attended 113 of 116 expected CRM visits. The intervention was highly acceptable, and resistance data were evaluable for all visits. Maximal resistance change was higher preceding clinical CVC occlusion (median 17.1% vs. 3.3%; P=0.01), and a resistance increase greater than 8.8% predicted subsequent CVC occlusion (sensitivity of 75%; specificity of 67%; P<0.01). A combined prediction model comprising this increase in resistance or a non-laminar flow result also predicted subsequent CVC occlusion (sensitivity 80% and specificity 63%; P=0.002). In this population, CRM is feasible, acceptable, and might predict imminent catheter occlusion. In summary, these studies found that two commonly used treatments for CLABSI were ineffective and possibly harmful, and showed the feasibility and promise of a novel method to predict catheter occlusion, one which might facilitate pre-emptive therapy. These results provide evidence to guide clinical care and a basis for further studies to protect patients from CVC-related complications.
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ItemAsymptomatic thrombosis following the use of central venous catheters in children( 2017)Central venous catheters (CVCs) are the major cause of thrombosis in acutely unwell neonates and children. This thesis reports the outcomes of a prospective study of 189 children in a paediatric intensive care unit (PICU) that aimed to determine the frequency of asymptomatic CVC-related thrombosis during hospital admission, and the incidence of residual CVC-related thrombosis and clinically significant post thrombotic syndrome (PTS) two years following CVC placement. The study also sought to identify risk factors predictive of CVC-related thrombosis and clinically significant PTS and determine the utility of ultrasound screening for asymptomatic CVC-related thrombosis in acutely unwell children. This study is distinct from previous work as children in this cohort identified to have asymptomatic CVC-related thrombosis were not treated and were followed for two years to determine the natural history of asymptomatic thrombosis. The incidence of asymptomatic CVC-related thrombus during hospital admission was 21.2% (n=31), despite over 80% of the cohort having received thromboprophylaxis. One child had a symptomatic CVC-related thrombosis. Sixteen children had new or residual thrombus identified on the follow-up ultrasound, performed a mean of 26 months post CVC placement. Of 126 PTS assessments completed at follow-up, 10.3% of children were diagnosed with mild PTS as classified by both the Manco-Johnson instrument and Modified Villalta scale. Only two children were identified to have clinically significant PTS (Manco-Johnson instrument only), one of whom had a symptomatic CVC-related thrombosis. Whilst over one fifth of the cohort had asymptomatic CVC-related thrombosis, only one of these children developed clinically significant PTS. There were no clinical embolic phenomenon or deaths attributable to CVC-related thrombosis. These findings suggest that ultrasound screening for asymptomatic CVC-related thrombosis is not indicated in children in PICU as, despite no treatment (in all but one child), the incidence of any thrombosis-associated morbidity was extremely low. In addition, the study’s findings support previous evidence that thromboprophylaxis provides no protection against CVC-related thrombosis in children. Neither D-dimer nor Factor VIII were predictive of CVC-related thrombosis. However, this study identified that children with femoral CVCs had a significantly higher incidence of residual thrombosis and thrombosis-associated morbidity. Children with femoral CVCs were also significantly more likely to have a higher PIM2 probability of death, cardiac arrest, hypotension, elevated D-dimer and Factor VIII compared to children with jugular CVCs. Whether the placement of the CVC in the femoral veins or the apparent higher acuity of this sub-group of patients is the mediator of increased risk (residual thrombosis and morbidity) compared to jugular CVC placement remains unclear. This study contributes novel insights into the natural history of asymptomatic CVC-related thrombosis, demonstrating a very low morbidity associated with jugular CVC placement. This study informs future clinical research targeting children most at risk of long-term CVC-related thrombosis associated morbidity. Specifically, further investigation of similar cohorts of children to those in whom femoral CVC placement occurred in this study is needed to elucidate risk factors for poor outcomes and the potential for a risk stratified approach to the treatment of asymptomatic CVC related thrombosis.
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ItemAnxiety and stuttering: closing the research gaps( 2017)Background: Adults who seek treatment for stuttering are significantly more likely to be diagnosed with social anxiety disorder than non-stuttering controls. However, it is unclear when the onset of anxiety in stuttering typically occurs, and whether there are differences between children who stutter in the general community and those who seek treatment. Aims: The aims of this thesis were to: 1. Review the research pertaining to anxiety and stuttering in children and adolescents, to identify trends and determine the timing of anxiety onset in stuttering; 2. Compare anxiety symptoms, emotional and behavioural functioning, and temperament traits in children from a community sample who (i) stutter, (ii) have recovered from stuttering, and (iii) have never stuttered; 3. Compare anxiety symptoms, and emotional and behavioural functioning, for children who stutter from: (i) a community cohort study (community stuttering cases) and; (ii) a clinical case-control study (clinical stuttering cases), and children who have never stuttered and; 4. Compare family and environmental characteristics, and social and emotional functioning, for control groups recruited to a community cohort study and clinical case-control study. Methods: For Aim 1, peer-reviewed publications investigating anxiety in preschoolers, children, and adolescents who stutter were identified using specific search terms in Medline, CINAHL and psycINFO databases. Known risk factors for anxiety in stuttering children and adolescents were identified, and the research evidence related to anxiety in this population was appraised. For Aim 2, measures of child anxiety, temperament, and emotional and behavioural functioning were completed by children and parents from a community cohort study, including (i) children who stuttered, (ii) children who had recovered from stuttering, and (iii) non-stuttering controls. Linear regression modelling compared outcomes between the three groups, controlling for a range of child, family and environmental variables. For Aims 3-4, outcomes were then compared to those from children who stutter and non-stuttering controls from a clinical case-control study. Results: Regarding Aim 1, based on a review of the literature, the age of anxiety onset in stuttering could not be reliably determined. Regarding Aims 2 - 4, all groups in the community cohort study had scores within the normal range on measures of anxiety, and emotional and behavioural functioning, with no significant differences between groups. Similarly, scores on all measures fell within the normal range for the children in the clinical case-control study. However, children who stutter from both the clinical and community studies reported higher social anxiety and internalizing symptoms compared with non-stuttering controls. As a group, the clinical stuttering cases reported higher generalised anxiety symptoms than the community stuttering cases. The controls participating in the case-control study came from a higher socioeconomic background than the other three groups. They also had lower anxiety scores than the community controls. Conclusion: While in the normal range, higher social anxiety symptoms among school-age children who stutter from clinical and community samples may mark the start of the development of social anxiety disorder in stuttering. Higher general anxiety symptoms among clinical stuttering cases compared with community stuttering cases may be a driver for seeking treatment for stuttering. Differences in socioeconomic status and anxiety among participants recruited to clinical and community stuttering studies highlights the need for understanding the nature of control groups when interpreting research findings. Further research with community samples of children who stutter is needed to further clarify risk factors for the development of social anxiety in stuttering.
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ItemLanguage development in autism spectrum disorder: longitudinal comparison with a community cohort of children with language impairment and typical development( 2016)Background: Autism spectrum disorder (ASD) is a lifelong developmental disability that affects more than 1 in 50 children in Australia. Language difficulties are common in ASD with up to 30% of children unable to communicate using words. Despite a substantial number of studies examining language outcomes in individuals with ASD, it is difficult for families and clinicians to interpret study findings. This is because many studies use; selected clinical samples that may not generalise to the broader population, heterogeneous methodology, and the quality of studies varies. Rarely do studies use standardised language-specific tools. In addition, few studies have compared development in children with ASD to children without ASD, which means it is difficult to place differences in children with ASD within a developmental context. As a consequence, we do not yet fully understand how language develops in children with ASD and we are not able to accurately predict language outcomes. Parents and clinicians need evidence about language trajectories in ASD to inform decision-making and understand prognosis. Service providers and policy makers also require information for appropriate resource allocation for current and future needs. Aims: The overall aim of this thesis was to examine trajectories of language development in individuals diagnosed with ASD. To achieve this aim, three main studies were conducted. Study 1 systematically reviewed and synthesised the extant literature on language outcomes in individuals with ASD. Studies 2 and 3 examined individual and mean trajectories of language development in children with ASD from 1 to 2 years and 4 to 7 years, respectively, and compared these trajectories to large samples of children with language impairment (LI) and typical language development (TD). Study 3 described language trajectories for children with ASD and investigated predictors of language outcomes from 4 to 7 years in children with and without ASD. Method: Children in studies 2 and 3 were recruited from a prospective longitudinal community-based study of 1910 children in Victoria (the Early Language in Victoria Study; ELVS). Individual and mean trajectories were mapped from 1 to 2 years (ASD; n=41, LI: n=119, TD: n=861) and 4 to 7 years (ASD; n=27, LI n=110, TD: n=831). In Study 2, individual and mean communication trajectories were mapped using scores from two parent checklists, namely the Communication Symbolic Behaviour Scales Infant Toddler Checklist and the MacArthur Bates Communicative Development Inventories. We compared the proportion of children who lost specific communication skills between the three groups (ASD, LI, TD) and the spread of loss across different communication domains. In Study 3 we used the Clinical Evaluation of Language Fundamentals data collected in ELVS (preschool second edition and fourth edition) to map individual and mean language trajectories from 4 to 7 years. The proportion of children who had declined, remained stable or accelerated in language skills was compared across groups. Putative predictors of language outcomes were also investigated. Results: Language ability was heterogeneous, however, mean scores for children with ASD and LI were lower than scores for children with TD and reference norms, in all studies included in the systematic review and Studies 2 and 3 in the community sample. From 1 to 2 years, the gap between children with ASD and TD/LI grew larger in all communication domains except in the areas of speech and expressive vocabulary, which was similar for children with LI and ASD. From 4-7 years, despite having lower language ability on average compared with the typically developing group, most children with ASD were developing language at the same pace as the LI and TD children. A diagnosis of ASD did not predict a greater gap between receptive and expressive language ability. The child’s early language ability and IQ were most important in predicting language ability at a later age. Conclusion: Systematic review and synthesis of existing studies showed that children with ASD in all studies (with one exception) had lower scores at baseline when compared with reference norms but children tracked in parallel to reference norms. The limited amount of data available from studies investigating children over 9 years made it difficult to draw accurate conclusions on trajectories beyond this age, however the few studies that had presented data suggest rate of language progress may slow from around 10 years. In Studies 2 and 3 that utilised the ELVS, children with ASD demonstrated communication abilities that were not significantly different to other children at12 months of age in most areas. However, on average their language and social communication progressed at a slower rate than other children from around 12 months to 2 years in most areas of communication. Findings from children in the ELVS aged 4 to 7 years were consistent with the systematic review findings. In Study 3 children with ASD who were verbal and had IQ in the normal range demonstrated lower language scores at baseline and follow up on average, but tracked in parallel to reference norms over time. The knowledge gained from this thesis will help guide prognostic information to be provided to parents. It will also assist with planning for future support needs of individuals with ASD.
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ItemAppearance-altering facial surgery on children: An empirically informed ethical analysis( 2015)Using empirically informed ethical analysis, this thesis investigates the ethics of appearance-altering facial surgeries performed on children. These surgeries have attracted controversy in the media and ethics literature and are the subject of legislation and professional guidelines, which leave much to individual practitioners’ discretion. Despite their contentious nature, very little is known about surgeons’ practices and decision-making processes regarding these surgeries. This thesis is ‘empirically informed’ in two different ways: (1) by existing empirical data on psychosocial outcomes of children with facial differences and children who have undergone appearance-altering facial surgeries and (2) by new interview data from 22 surgeons who encounter requests for these surgeries. Using reflective equilibrium as my method of ethical analysis, these two kinds of empirical data are combined with established paediatric bioethical principles and concepts, including the zone of parental discretion and children’s assent and dissent, to arrive at a comprehensive position on the ethics of performing these surgeries. Using reflective equilibrium, I found some aspects of surgeons’ decision-making processes and practices diverged from existing ethical understandings about the relative roles of children and parents in medical decisions. One such area related to the ethical weight surgeons attach to children’s refusals. While most ethicists in the literature advocate including children in decisions, they do not necessarily recommend giving them decision-making authority. In contrast, most surgeons tended to give children a larger role in decisions about appearance-altering facial surgeries, viewing them as ultimate decision makers. In this thesis, I make normative claims about the relative levels of ethical weight surgeons should place on children’s and parents’ wishes when making decisions about these surgeries. Using the established ethical framework of the zone of parental discretion and related ethical concepts of harm and benefit, I claim that several morally relevant differences exist between these surgeries and other medical procedures requested for children. These include their uncertain risk-benefit ratio, their elective nature, uncertainty as to how the child will later perceive their facial difference and the acceptability of surgery, and the existence of alternative, less risky and invasive psychosocial interventions for alleviating appearance-related psychosocial harm. I argue these differences warrant placing greater (even absolute) ethical weight on children’s wishes, especially when children refuse these surgeries, and comparably less ethical weight on parents’ wishes, when making these decisions. Although my ethical position is similar to most of the surgeons’ judgments, I argue it would be worthwhile for surgeons to know about and use ethical principles and concepts more explicitly when making decisions and communicating with children and/or their parents. I also claim that surgeons ought to make more of a considered effort to ascertain children’s actual wishes and inform parents and/or children about non-surgical options for alleviating appearance-related psychosocial distress, and be taught strategies for saying no and how to articulate their ethical reasoning. These findings have significant implications for clinical practice, raise questions for further ethical analysis and contribute to refinement of existing understandings of children’s assent and dissent and parents’ role as proxy decision makers for their children.
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ItemCardiovascular associations of HIV infection in children( 2015)Vertically-acquired HIV infection is a devastating disease in childhood that may affect any organ, including the cardiovascular system. With increased survival of HIV infected children due to antiretroviral (ART) treatment availability, chronic cardiovascular problems become a confronting challenge, not only because HIV infection may cause cardiac problems readily manifesting in childhood but also because it potentially increases future cardiovascular disease risk in adulthood. This thesis explores various possible cardiovascular effects of HIV infection in children, particularly the differential effects of ART-naïve compared to ART-exposed HIV infection on left ventricular (LV) remodelling, pulmonary hypertension, and arterial elasticity. We conducted a cross-sectional study enrolling 56 ART-naïve, 59 ART-exposed HIV infected, and 51 healthy children in Jakarta, Indonesia and performed cardiac/vascular ultrasound, and blood tests for biomarkers. There were marked differences in the cardiovascular parameters between the two groups. We found that ART-naïve HIV infection was associated with LV dilation while the ART-exposed seemed to cause concentric hypertrophic remodelling. ART-exposed HIV infected children who showed evidence of higher pulmonary artery pressure than healthy children, whereas the ART-naïve children had reduced right ventricular function. For arterial elasticity, the ART-naïve had higher strain and lower elastic modulus, but thicker intima-media thickness, whereas the ART-exposed had similar vascular properties as healthy children. In conclusion, HIV infection in children have significant impacts on childhood cardiovascular system with particular differential effects between ART-naïve and ART exposed HIV infection. Routine cardiovascular surveillance is needed for children with HIV infection.