Paediatrics (RCH) - Theses

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    Early lifecourse body composition and adolescent cardiovascular function and structure: A community-based longitudinal cohort study
    Gillespie, Alanna Nicole ( 2021)
    http://hdl.handle.net/11343/321883 Background: Understanding if the timing, duration and severity of childhood body composition, from lean to obese, is associated differentially with adolescent cardiovascular phenotype will enable a better understanding of the timing and nature of adiposity-associated cardiovascular risk. Aims: To examine how adolescent cardiovascular function and structure are associated with (1a) individual or (1b) combined measures of adolescent body composition; (2) body mass index (BMI) trajectories between birth and 14 years; and (3) BMI, fat mass index (FMI), lean mass index (LMI) and waist-to-height ratio (WHtR) trajectories between 4 and 14 years. Methods: Design: Participants from the PEAS Kids Growth Study, a longitudinal community-based cohort in Melbourne, Australia, were measured on 16 occasions from birth (n=493) to 14-17 years (n=196 with cardiovascular data). Measures: Body composition: BMI/waist z-score, WHtR, FMI, LMI. Cardiovascular phenotypes: Systolic/diastolic blood pressure (S/DBP), augmentation index (AIx), pulse wave velocity (PWV), retinal arteriole-to-venule ratio (AVR), carotid intima media thickness (cIMT). Analysis: Aim 1-3: Adjusted linear regression models assessed associations between adolescent body composition/childhood trajectory and cardiovascular phenotype. Aims 2-3: Latent class analysis identified participants with similar childhood body composition trajectories. Results: 196 PEAS adolescents (75% of invited, 46% male) completed a direct assessment of cardiovascular phenotype. Aim 1: Each SD increase in adolescent BMI z-score was associated with higher SBP (2.5mmHg, CI: 0.9 to 4.0) and AIx (2.9%, CI 1.2 to 4.6). Higher waist z-score, FMI and LMI were also associated with higher SBP and AIx; but not DBP, PWV, AVR, or cIMT. Moderate variance was explained by each adjusted model (highest for BMI z score with SBP, R2=0.24). Aim 2: Three BMI trajectories were identified: low normal, high normal, and consistently overweight between birth and 14 years. Consistently overweight children had higher AIx (7.8%, CI 2.6 to 13.0, R2=0.13) but no other differences in cardiovascular phenotype compared the reference group. Aim 3: Three trajectory groups of BMI, WHtR, FMI and LMI (low, medium, and high) were identified between 4-14 years. Children following the high FMI trajectory had higher SBP (5.6mmHg, CI 1.1 to 10.1, R2=0.22) and DBP (3.9mmHg, CI 0.7 to 7.2, R2=0.08), compared to the reference group. Those in high BMI and WHtR trajectories had higher AIx and SBP (WHtR trajectory only); but vascular structure was similar for all, regardless of body composition trajectory. In contrast, LMI trajectories were not associated with any measure of function or structure. Discussion: Associations were evident between adolescent and 10-year trajectories of BMI, FMI, and WHtR with cardiovascular function. Interestingly, associations between LMI and cardiovascular function were only evident cross-sectionally in adolescence. Nonetheless, despite high BMI, FMI and WHtR for over a decade, and poorer cardiovascular function, following a high trajectory during childhood was not associated with worse vascular structure in mid-adolescence in this cohort. This may be due to the small number of very obese adolescents in this sample. Future studies measuring body composition and cardiovascular phenotype throughout childhood and into adulthood are necessary to understand how to minimise adiposity-associated lifecourse cardiovascular risk.
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    Inter-arm blood pressure differences at rest and exercise: significance in children and potential mechanisms
    Clarke, Melanie ( 2021)
    High blood pressure (BP) is one of the leading risk factors for cardiovascular disease and is a key contributor to arterial stiffening, end organ damage, and cognitive decline. Importantly, high BP often begins in childhood, and if left untreated may track into adulthood. However, if diagnosed and treated, reducing high BP lowers the risk of disease. Clinical guidelines for best practice with regards to BP measurement have been established for both adults and children. Although not routinely followed in many settings, a common recommendation for both adult and paediatric populations is to measure BP in both arms. The measurement of bilateral BP holds clinical importance as an inter-arm blood pressure difference (IAD) of greater than or equal to 10 mmHg (IAD+) is associated with cardiovascular disease and premature morbidity and mortality in adults. Additionally, both the magnitude and prevalence of IAD+ has been shown to increase with exercise. While IAD has been investigated in adults, no studies exist on IAD in children despite the recommendation to measure bilateral BP in clinical guidelines. Further, the mechanisms which cause this difference remain unknown. Therefore, the primary purpose of this thesis was to examine IAD in children and adolescents under resting conditions, exercise conditions, and explore a potential mechanism which may result in IAD. Four investigations were performed that 1) quantified the magnitude of IAD and the frequency of IAD+, as well as determined inter-arm BP classification differences, under resting conditions in children and adolescents; 2) generated normative data for exercise BP response in children and adolescents undergoing treadmill exercise stress tests to enable objective assessment of exercise BP classification; 3) quantified the magnitude of IAD and frequency of IAD+ and inter-arm classification differences under exercise conditions in children and adolescents; 4) used a one-dimensional computational model to investigate inter-arm difference in arterial stiffness as a potential mechanism underlying IAD. The frequency of IAD+ in children and adolescents was similar to that of adults under both resting an exercise conditions. The average magnitude of IAD was 5 mmHg under resting conditions and 7 mmHg under exercise conditions.The inter-arm classification difference was ~20% under resting conditions. Normative data generated from treadmill exercise tests was used to determine that ~10% of children and adolescents have an exercising inter-arm classification difference. Lastly, the modelling study supported the hypothesis that inter-arm differences in regional arterial stiffness may contribute to IAD. Data presented in this thesis supports the recommendation to measure BP in both arms and provides a strong rationale for conducting this measurement in apparently healthy children. Measuring BP in both arms under both resting and exercise conditions may be important for detecting high BP in children and adolescents. Lastly, it was shown that mechanistic investigations with regards to IAD can be performed using 1D models and may be useful where in-vivo studies are not physiologically possible.
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    Exome sequencing in infants with congenital deafness, a model for genomic newborn screening
    Downie, Lilian Claire ( 2021)
    Background Genomic technology is emerging as a powerful diagnostic tool to provide precision management and personalised care. It also has potential to be used at a population level to provide predictive and tailored health information, including as part of newborn screening (NBS). NBS traditionally detects serious and treatable childhood conditions, including congenital hearing impairment. As the majority of childhood hearing impairment has an underlying genetic cause, genomics is the ideal technology to investigate this condition. Aims and Methods The aims of this research were to: a) characterise the genetic causes of congenital hearing impairment in the population; b) understand the impact genomic testing has on the pathway of care following this diagnosis; and c) examine the factors that may influence the uptake and success of a genomic NBS tool. The methods used to investigate these aims were: 1. Offering diagnostic genomic testing to a cohort of infants with hearing impairment and observing the effect of this investigation on their healthcare journey; 2. Determining the cost-effectiveness of this genomic testing pathway when compared with the standard of care; 3. Offering parents additional analysis of non-deafness genes and investigating what factors influence their choices around seeking predictive health information for their infant; 4. Undertaking a systematic literature review to understand the current status of the field of genomics as a potential tool for NBS. Results Genomic sequencing was performed on 106 infants diagnosed with congenital deafness through newborn screening. Fifty-nine infants (56%) had a genetic cause for their hearing impairment. The majority (n=38, 36%) had a diagnosis that indicated their hearing impairment was isolated, such that they did not need to undertake surveillance for other health conditions. Those who received a syndrome diagnosis (n=21, 20%) were able to access accurate prognostic information, support and tailored healthcare. Streamlining the care of this cohort according to their underlying diagnosis was cost-effective when compared to standard of care, where most infants do not have a cause for their hearing impairment identified. Genomic testing also had non-health related benefits for families, i.e., personal utility. Parents made varying choices regarding receiving predictive information from the testing. Seventy-two parents (68%) accepted the offer of additional information. These findings are consistent with those identified in our systematic review of the literature – that “one size does not fit all”. Conclusion Offering genomic sequencing to a cohort of infants with congenital hearing impairment served as an ideal model to investigate genomic NBS. It re-enforced the diagnostic power of the test for congenital hearing impairment, translating into a cost-effectiveness analysis and an application for a Medicare item number. More broadly, this research identified the key elements required for genomic NBS to be acceptable and successful at a population level. Areas for future work are to refine the scope of testing with a strategy for gene list composition, and to identify the optimum timing and consent process. Getting these elements right will enhance newborn screening by increasing its scope and sensitivity, not just for congenital hearing impairment, but for improving the health of many children and their families.
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    Modelling development of the human adaptive immune system in vitro
    Sun, Shicheng ( 2021)
    The human adaptive immune system provides a specialized function in the defense of the body against invading pathogens. Abnormal development of the adaptive immune system is thought to cause autoimmune disorders. Its development requires spatiotemporal coordination of multiple embryonic activities, including hematopoiesis, development of lymphoid organs, and hematopoietic colonization. Here, we focus on T cell and thymus development and use pluripotent stem cells (PSCs) to create multiple cell types that are known to contribute to thymus ontogeny. We demonstrate new methods for generating human hematopoietic cells, endothelial cells and thymic epithelial cells from PSCs in vitro, supported by three results chapters. Chapter 3 describes the generation of macrophages from PSCs and comprises a submitted manuscript in the journal format. The manuscript describes a novel streamlined protocol that enables the differentiation of macrophages from different PSC lines and shows that these PSC-derived macrophages can be infected with Mycobacterium abscessus. This submitted manuscript also includes a proof-of-principle demonstrating that this platform can be used to assess antibiotic sensitivities. Chapter 4 describes the derivation and characterization of thymic epithelial cells from PSCs and primary human thymus. This work comprises a manuscript which has been peer-reviewd and published in the journal Frontiers in Immunology; the published version is included in Chapter 4. The manuscript shows the identification of a new CD90 (THY1) + thymic epithelial cell population expressing genes associated with both epithelial and mesenchymal cell profiles, highlighting the ambiguous cell identity of thymic epithelial cells. Chapter 5 describes the derivation of arterial-like endothelial cells expressing DLL4, a ligand that is important for inducing hematopoietic stem cells to commit to the T cell lineage. Additional experiments explored the effects of different concentrations of SCF and IL7 on the production of CD4+CD8+ T cell progenitors, assessed by expression of RAG1:GFP, CD7 and IL7R, and CD4 and CD8. These experiments suggest opposing functions of SCF and IL7 in lymphoid cell production. This chapter also describes a pilot coculture experiment aimed at assembling an artificial thymus using the above materials. This thesis examined multiple lineages that are known to be important during the ontogeny of the human adaptive immune system, with a particular emphasis on events related to thymus development. This work lays a foundation for future studies aimed at understanding and manipulating the generation of human immune cells. This thesis also includes three scientific blog articles in the Appendix, written and published for the International Society for Stem Cell Research for scientific communication and public engagement.
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    Early life oral exposures as risk factors for food allergy and the impact of infant feeding guidelines
    Soriano Harris, Victoria Ximena ( 2021)
    Food allergy is a severe immune reaction affecting around 10% of infants. The recent rise in food allergy is a growing public health concern. Susceptibility to food allergy is affected by environmental exposures that affect infant gut immunity, including oral food and microbial exposures. Changes in infant feeding guidelines recommending introduction of allergenic foods in the first year were the first public health measure introduced specifically to prevent food allergy. I aimed to evaluate their impact on timing of allergenic food introduction and prevalence of food allergy, as well as investigating oral microbial exposure as a potential food allergy risk factor. The effect of 2016 updates to infant feeding guidelines on food allergy was evaluated using two large population-based cross-sectional studies (n=5,300 and n=1,933) that recruited 12-month-old infants in Melbourne, Australia 10-years apart (2007-2011 and 2018-2019) to study allergenic food introduction and peanut allergy. Microbial exposure was investigated in relation to food allergy using data from a cohort study (n=1,072) based in south-east Australia which measured pacifier cleaning methods in the first year of life. Data were analyzed using multivariable logistic regression models and direct standardization. Regression models were adjusted for known food allergy risk factors, depending on the exposure. An overview of systematic reviews searched systematic reviews in four databases to examine age of complementary feeding in relation to other health outcomes. These studies are the first report that peanut introduction by 12 months of age (inclusive) in the population increased (88% in 2018-2019 vs 28% in 2007-2011) following the implementation of 2016 infant feeding guidelines. Despite this massive shift, peanut allergy prevalence did not decrease as much as expected (3.1% to 2.6%). However, the increase in peanut introduction seems to have halted the rise of peanut allergy in one-year-old infants. The systematic review found 27 reviews on age of complementary or allergenic food introduction on multiple outcomes. There was no evidence of a detrimental effect on other health outcomes of the recommended introduction of solids and allergenic foods starting around 6 months of age, though solids introduced earlier than 4 months could increase the risk of overweight. Furthermore, sanitization of infant pacifier with antiseptics at 6 months of age increased the risk of food allergy at age one, possibly an effect of the chemicals on oral or gut microbiome. An increase in early introduction following 2016 guideline changes has halted the overall rise in peanut allergy. Nevertheless, peanut allergy is still high in Melbourne, thus additional prevention strategies are required. Reassuringly, other health outcomes are not risked by the recommended age of allergenic food introduction. The findings on cleaning pacifiers with antiseptics suggests that suggests microbial exposure can protect against food allergy. This warrants further interventional studies to determine if microbial exposures could prevent food allergy. Moreover, early life risk factors, prior to food introduction, need to be explored further.
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    Effect of a high-level mobility skills training programme on sustained physical activity participation among ambulant children with cerebral palsy
    Kilgour, Gaela Marie ( 2021)
    Abstract: Objective: Sustained participation in physical activity is important for everyone. This thesis (i) systematically reviewed the evidence for the ability of physical activity interventions to enhance attendance and involvement in physical activity (study 1); (ii) assessed the effect of a community-based high-level mobility skills programme (HLMP) on participation in physical activity among ambulant children with cerebral palsy (study 2); and (iii) explored the children and their parents’ experiences of being active (study 3). Methods: Study 1 consisted of a systematic literature review. Seven databases were searched using PRISMA guidelines (2001-2020). Study 2 used a single-subject research design (SSRD) to evaluate quantitative outcomes after implementation of the HLMP. Ambulant children with cerebral palsy (aged 7–18 years) were invited to participate in a 12-week community-based HLMP that provided task-specific training of running skills. Each study participant set personal participation attendance, involvement, and physical competency goals and completed activity diaries for 56–58 weeks. Outcomes were collected during a baseline phase (4–6 weeks), an intervention phase (12 weeks), and during a nine-month follow-up phase that included a COVID lockdown. In study 3, semi-structured interviews were conducted at baseline, post-intervention, and at the end of follow-up with child-parent pairs. An interpretive description approach was used and guided coding and development of themes. Results: The systematic review included 11 randomised controlled trials and two cohort studies, all of which included only short-term follow-up. Two studies reported short-term gains in attendance in the 4–14 weeks following the physical activity intervention and one study reported an improvement in involvement during a follow-up period of one month. Eight ambulant children with cerebral palsy (aged 11–16 years, seven male) were recruited for study 2. Seven of the eight participants attended a median 23 of 24 HLMP sessions over 12 weeks, attained their involvement goal in at least two study phases and achieved at least one physical goal during the HLMP (11/15 goals), with continued attainment over the next 9 months (9/16 goals achieved). The frequency of attendance varied, with participant’s diaries indicating 0–17 sessions of being active per week during all study phases. Diversity of physical activities (variety and range of formal and informal physical activities) remained stable at 1–4 different activities per week (range 0–7). On testing, physical capacity increased post-intervention in the seven children who attended the HLMP and skill competency increased in six participants at the 6-month follow-up. Children and their parents valued being active now and into adulthood, reporting improved motivation, confidence, and physical well-being following the HLMP. Core themes were developed: ‘just doing it’, ‘getting the mix right’ (right people, right place, right time), ‘balancing the continua’ and ‘navigating the systems’. Co-designing, connecting and collaborating were seen as important to promote sustained participation for life. Conclusion: Children with cerebral palsy can achieve participation and physical goals, be highly involved in their chosen physical activities, and improve their physical competency. The community-based, task-specific goal-directed HLMP was able to keep some, but not all, children “on track” to achieve sustained participation in physical activity. Each child’s journey was complex and dynamic.
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    Atrioventricular valve function during single ventricle palliation
    King, Gregory ( 2021)
    Single ventricle anomalies encompass a spectrum of the most severe congenital heart disease. Staged surgical palliation culminates in the Fontan circulation, wherein the functional single ventricle pumps blood to the systemic circulation and returning blood flows passively through the pulmonary circulation, without the support of a subpulmonic ventricle. Surgical modifications and advancements in non-operative management have led to a significant decline in early mortality following the Fontan operation. As such, the population of patients living with a Fontan circulation is expected to double over the next 20 years, including a growing proportion of patients surviving well into adulthood. Due to inherent anatomical and physiological limitations, the Fontan circulation is characterised by elevated systemic venous pressure and reduced cardiac output. Atrioventricular valve (AVV) regurgitation impairs pulmonary venous return leading to increased post-capillary venous pressures and further increasing systemic venous pressure. Furthermore, AVV regurgitation increases the volume load on the single ventricle which can lead to ventricular dilatation and impaired function. Studies have demonstrated that AVV regurgitation and AVV surgery are associated with worse clinical outcomes during the initial stages of single ventricle palliation, but little is known about the cumulative impact of AVV regurgitation and AVV surgery over the lifetime of patients undergoing single ventricle palliation. The aim of this thesis was to (i) determine the cumulative incidence of, and risk factors for, moderate or greater AVV regurgitation during the lifetime of patients undergoing Fontan palliation, (ii) determine the impact of moderate or greater AVV regurgitation on clinical outcomes in patients with a Fontan circulation, and (iii) determine the impact of AVV surgery on long-term AVV competency and clinical outcomes in patients undergoing single ventricle palliation. The studies contained within this thesis were conducted with data primarily from the Australia and New Zealand Fontan Registry, which is the largest database of Fontan survivors in the world. In this thesis I have demonstrated that: (i) there is a high rate of moderate or greater AVV regurgitation during the lifetime of patients with a Fontan circulation, (ii) risk factors for moderate or greater AVV regurgitation and AVV surgery include right ventricular (RV) dominance, atrioventricular septal defect (AVSD), mitral atresia, right atrial isomerism, aortic atresia, and prior AVV repair, (iii) moderate or greater AVV regurgitation in patients with a Fontan circulation is associated with an over two-fold increased risk of death or transplantation, but only in patients with RV dominance, (iv) in patients with AVSD and a Fontan circulation, the high rate of moderate or greater AVV regurgitation is primarily due to the anatomy of the common AVV, and is not impacted by ventricular dominance, (v) AVV surgery itself is not a risk factor for death or transplantation in patients with a Fontan circulation, but rather it is the patient’s characteristics necessitating AVV surgery that are associated with an increased risk of death or transplantation, (vi) patients with tricuspid valve repair failure are at high risk of death or transplantation, but successful tricuspid valve repair improves transplantation-free survival rates in patients with moderate or greater AVV regurgitation, (vii) patients with functional AVV regurgitation and impaired ventricular systolic function are at increased risk of death or transplantation after AVV repair, (viii) AVV closure is a safe and effective surgical technique for management of AVV regurgitation in patients with a Fontan circulation and two AVVs, where the diminutive valve is regurgitant. This thesis has revealed the enormous burden of AVV regurgitation and AVV surgery in patients with a Fontan circulation. In doing so, it has drawn attention to AVV regurgitation as one of the most important issues in the management of patients undergoing single ventricle palliation. Ultimately, by improving our understanding of the incidence and natural history of AVV regurgitation, this thesis will improve the long-term outcomes of many patients living with a single ventricle circulation.
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    Autism spectrum disorder in children with neurofibromatosis type 1: A cross-sectional study of the autistic phenotype and sex- and age-differences in autistic symptoms
    Chisholm, Anita Katherine ( 2021)
    Background: Neurofibromatosis type 1 (NF1) is a monogenic syndrome associated with complex and impairing clinical and neurodevelopmental sequelae. Social difficulties are commonly reported and there is accumulating evidence for an elevated prevalence of autism spectrum disorder (ASD) in children with NF1. While the genetic specificity of NF1 offers a promising model for clarifying the causal pathways to ASD, the autistic symptom profile in children with NF1 remains poorly understood. Aims: This thesis aimed to critically evaluate ASD phenomenology in NF1, and to elucidate the autistic phenotype and the factors that might influence the expression of core autistic symptoms in children with NF1. Methods: We conducted a systematic review and meta-analysis to examine the existing evidence for social dysfunction and ASD in NF1. A cohort of children with NF1 that scored within the clinical range on the Social Responsiveness Scale, Second Edition (SRS-2) was assessed with the Autism Diagnostic Interview - Revised (ADI-R) and the Autism Diagnostic Observation Schedule, Second Edition (ADOS-2). Participants also underwent evaluation of their intellectual function and data pertaining to emotional and behavioural functioning were gathered via parent rating scales. Results: Meta-analytic data indicated a significantly increased incidence of social dysfunction (g = 0.79) and autistic symptomatology (g = 0.91) in NF1. In the NF1 cohort (N = 68; 3-16 years), a substantial proportion of children met algorithmic cut-offs on the ADI-R (63%) and ADOS-2 (34%). Social communication deficits were analogous to those observed in idiopathic ASD, but we detected a distinct profile of restricted and repetitive behaviours (RRBs) characterised by ‘insistence on sameness’ behaviours such as circumscribed interests and difficulties with minor changes. Males displayed greater social communication deficits relative to females, and age-related gains in social communication skills were evident in males but not females. Generally weak associations were found between autistic symptoms and child characteristics not specific to ASD (e.g., language delay, anxiety). However, sex differences in early language development and verbal intellect contributed to the observed sex disparities in social communication skills. Conclusions: Our novel findings identify a unique autistic phenotype in children with NF1 and establish the relative independence of autistic symptoms from common NF1-related neurodevelopmental comorbidities. This work also provides new insights into the modulating effects of sex and age on the severity of autistic symptoms and underscores the importance of taking non-specific child characteristics into account when interpreting scores from autism measures in this population. Current findings may be used to facilitate earlier and more accurate recognition of ASD in children with NF1 and represent a significant step towards the identification of precise genotype-phenotype relationships in NF1.
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    Sleep, telomere length and cardiorespiratory phenotypes in a population-based cohort of children and mid-life adults
    Nguyen, John Ace ( 2021)
    Background: Telomeres are biomarkers for health and aging. In older adults, short telomeres are associated with poorer cardiovascular and respiratory (cardiorespiratory) health, but little corresponding data is available at earlier ages. This is important given that the pathogenesis of such diseases begins in childhood. Cumulative modifiable exposures, such as sleep, also influence telomere length; however, there is a lack of studies in adults, and even fewer in childhood. This is critical, given that life-long health patterns are formed in childhood, making it an important period for intervention. Shortened telomeres may, therefore, partly mediate the relationship between sleep and cardiorespiratory phenotypes. Aims: In a national population-based cohort of children and their parents, my thesis aimed to (I) describe the epidemiology of telomere length and parent-child telomere length concordance; examine associations of (II) telomere length with cardiovascular phenotypes, (III) telomere length with respiratory phenotypes and (IV) sleep with telomere length; and (V) examine whether telomere length mediates the relationship between sleep and cardiorespiratory health. Methodology: Design and participants–Children aged 11–12 years and their parents in the Child Health CheckPoint study, a physical health assessment in 2015 nested in the Longitudinal Study of Australian Children. Measures–Sleep characteristics (sleep duration, timing, variability, efficiency), cardiovascular phenotypes (carotid intima-media thickness [carotid IMT], carotid elasticity, carotid-femoral pulse wave velocity [carotid-femoral PWV]), respiratory phenotypes (forced expired volume in 1 second [FEV1], forced vital capacity [FVC], FEV1/FVC ratio and maximum mid-expiratory flow [MMEF25-75]), relative telomere length (T/S ratio). Analysis–Distributions using means and standard deviations (SD) and density plots. Parent-child concordance using the Pearson correlations. Multivariable linear/logistic regression quantified associations of telomere length with cardiorespiratory phenotypes, and sleep characteristics with telomere length. Results: Aim I–Children had longer telomeres than adults (n=1206, T/S ratio 1.09 vs. n=1343, 0.81 units), but also showed a wider spread to higher values, and did not differ by sex at either age. Parent-child telomere length concordance was greater in father-child than mother-child pairs, which was stronger in younger parents. Aim II–In adults, longer telomeres were associated with greater carotid elasticity, but not for carotid IMT or carotid-femoral PWV, or any measure in children. Aim III–In adults, longer telomeres were associated with higher FEV1/FVC and MMEF25-75 z-scores, but not for FEV1 or FVC, or any measure in children. Aim IV–Little evidence of association between sleep characteristics and telomere length at either age. Conclusion: At 11–12 years, both parents contribute to child telomere length and concordance may be stronger when the parent-child age gap is smaller. Associations between worse vascular function (e.g. lower carotid elasticity) and airflow limitation (lower FEV1/FVC and MMEF25-75) with shortened telomeres emerged by mid-life adulthood, and thus might imply that cardiorespiratory risk trajectories are at least partially established after 11–12 years. Regarding Aim V, telomere length appears to have a limited role in mediating the known link between sleep and cardiorespiratory health. The strength of the association could also be due to chance and hence requires replication, and ideally utilising longitudinal investigations with repeated sampling.
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    Understanding and supporting children and families on the pathway to autism assessment
    Bernie, Charmaine ( 2021)
    Delays accessing assessments for concerns relating to autism, a neurodevelopmental disorder affecting between one and four out of every 100 children, have been identified globally as an issue of concern. Even in developed countries where access to healthcare may be of a comparatively high standard and individuals with neurodevelopmental disorders have received care for decades, the time between initial identification of concerns and autism diagnosis can be in excess of two years. Assessment delays can have a negative impact on child, parent, and family outcomes, including long-term health and well-being. This is particularly the case when delays to diagnosis and targeted interventions occur during periods of optimal neuroplasticity. Despite efforts to reduce wait time across healthcare systems worldwide, waiting lists continue to cause delays for those seeking diagnostic classification and access to needed services. This experience is a common issue for parents of young children with autism-related concerns. In Australia, wait times for assessment for children with autism-related concerns are highly variable, depending on a service’s geographical location, service funding, models of service delivery, and a family’s own resources. These factors can affect a family’s pursuit of either public or private health care, which in turn can influence pathway length and associated experiences. While both pathways for assessment are available in Australia, accessing a private evaluation is not an option for many families due to financial constraints. In this scenario, children can wait between three months and two years for a publicly-funded autism assessment despite recently published national guidelines recommending that assessment commence within three months of referral. In the context of ongoing extensive waits for autism assessment, work is needed to understand how individuals and families can be supported during their waiting periods. For parents of children awaiting an autism assessment, as well as delaying needed care, the waiting time is a source of stress and uncertainty. Stress can be exacerbated when there is a large amount of conflicting information. Varying healthcare provider responses about a child’s presenting concerns, optimal services available, unproven interventions and the need for early life interventions that are difficult to access are also factors contributing to the family’s stress. Prospective research on the issues relating to the pre-diagnostic phase, particularly following identification and referral, has been limited to date. So too have investigations regarding best support for children and their families waiting for autism assessment. This thesis has aimed to address this research gap, by drawing on theory, data, and original research, in the context of the author’s clinical experience, to further understand the issues and support required for young children and their families waiting for an autism assessment. This work considers the appropriateness and feasibility of a brief function-focused intervention while waiting, as one solution worthy of further exploration. The motivation of this thesis emerged from clinical experience as an autism service coordinator and occupational therapist; supporting families as they attempt to manage the challenging, often lengthy period between referral and assessment. The current thesis is comprised of three original studies. Underpinned by well-established models and theories in clinical research, in addition to child and family health, well-being, function and participation, these investigations were embedded in a family-centred practice framework. The influence of family on child health and well-being has been at the forefront of each of the studies undertaken that contribute to this body of work. The studies were supported by the understanding that for young children in particular, the family context is a key consideration in overall health and well-being outcomes. Other social and environmental influences have also been considered throughout this thesis. This body of work acknowledges health service environments and their impact on service access, which can in turn affect the health and well-being of children and families. The influence of service structures on early access pathways have been subsequently considered throughout this thesis. The first of three original studies involved an analysis of existing clinical data, to explore local pathways to autism assessment for families of young children referred in Victoria. The second study explored existing interventions that have supported families in the pre-diagnostic stage, via a systematic review and meta-analysis. Finally, a pilot and feasibility study were undertaken, exploring “Coaching While Waiting” for families of children recently referred for autism assessment. Study results provide a basis upon which to conduct a future randomised control trial exploring the efficacy of the approach for children and families waiting for autism assessment. Following an in-depth literature review on the pathway to autism assessment, presented in Chapter 2, existing local data about referral and autism assessment was sourced. The aims of the study were threefold. First, to explore demographic and assessment pathway characteristics for children referred to a tertiary hospital in Melbourne for an autism assessment. Second, to understand differences in characteristics between those who proceed to receiving an autism diagnosis as opposed to those that do not. Finally, to assess which demographic and modifiable service-related factors on the pathway to assessment - inclusive of screening questionnaire results - may be predictive of an autism diagnosis. Observational pathway data was examined using bivariate and regression analyses. The findings identified lengthy waiting lists for multidisciplinary team diagnosis and discovered that a substantial minority (36%) of children referred with a query of autism do not go on to receive the diagnosis. Moreover, screening tools administered at triage were found not to be helpful in predicting service needs and diagnosis. The study added value by increasing an understanding of referral and diagnostic pathways in Victoria. It was concluded that alternative approaches were needed to help direct families to appropriate services at the point of triage. A systematic review was completed to investigate applied interventions for families while waiting for their child’s diagnostic assessment. The aims of this study were to explore the nature of interventions implemented and to evaluate the efficacy of parent-directed interventions compared with controls, with regard to improving child, family and service access outcomes whilst a child waits for diagnostic assessment as part of paediatric healthcare. Four controlled studies met the inclusion criteria, and moderate to high risk of bias was found across those included. To the authors’ knowledge, this was the first systematic review to explore parent-directed interventions whilst children wait for diagnostic assessments. Interventions, though variable, may have a positive effect on child, family and service-related outcomes, though more controlled studies with low risk of bias are needed before further efficacy conclusions can be drawn. Further studies should continue to focus on the three outcome areas explored; child, family, and service-related outcomes, in relation to the best intervention methods to support families in this interim period. With long wait times and lack of clarity around the best interventions for children and families whilst waiting, a pilot and feasibility study was undertaken. The study aimed to investigate whether a function-focused approach, inclusive of service navigation support and Occupational Performance Coaching, was acceptable and practical for families in this period. Additionally, the study established preliminary findings to support further efficacy testing in an appropriately-powered randomised control trial. Sixteen participants were recruited in three study arms: usual care, videoconference and face-to-face coaching. The design was feasible with completion rates reaching pre-set targets. Participants in the intervention group demonstrated clinically significant improvement across functional goals set, and improved service access at follow-up. The intervention holds promise as an appropriate approach for families waiting for their child’s autism assessment. Support for children and families while waiting for diagnostic evaluations is a research area requiring further attention. The approach adopted in the Coaching While Waiting trial has the potential to address key issues that are likely to benefit children with emerging support needs and their families, beyond those waiting for autism assessment. A trial exploring intervention effectiveness is planned, with key outcomes linked to whether children and families have timely and improved access to needed services, as well as achieving function-focused goals prior to diagnostic assessment. Such endeavours are critical if improvements in the early care pathway for children with autism and developmental concerns are to be realised, for the short and long-term benefit of children, families and services.