Paediatrics (RCH) - Theses
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ItemAssociations between executive function, adaptive behaviour, participation and self-reported quality of life in adolescents with autism spectrum disorder without intellectual disability( 2018)Background ASD is a neurodevelopmental condition that affects an individual’s ability to communicate and interact with others. There has been an increase in the prevalence of ASD diagnosis, with the most considerable increase in adolescents who are intellectually able. These adolescents have difficulties with adaptive behaviour and struggle to participate in society, even if their intelligence is in the average or superior range. A better understanding of the relationship between impairments associated with ASD such as social impairments, executive function, adaptive behaviour, and participation and quality of life (QoL) is needed in intellectually able adolescents with autism. Aims Using the International Classification of Functioning, Disability and Health (ICF), with subjective functioning added, as a framework, this thesis aimed to study the association between 1) executive function (EF) and adaptive behaviour, over and above the contribution to adaptive behaviour of social impairment and intelligence; 2) EF and participation and the mediating role of adaptive behaviour in their association; 3) participation and self-reported QoL, over and above the contribution to self-reported QoL of social impairment and symptoms of anxiety and depression, in adolescents with ASD and without ID. Methods To address these aims, a cross-sectional study of 39 adolescents with ASD, aged from 10 to 16 years and 11 months (M = 13 years 4 months; SD = 3 months) and with Full Scale Intelligence Quotient (FSIQ) ranging between 78 and 144 (M = 107.97; SD = 18.25) was conducted. Adolescents completed a battery of tests to assess the ICF domains of Health Condition (social impairment, anxiety and depressive symptoms), Body Functions/impairments (EF, such as cognitive flexibility, inhibition, generativity, planning), Activity (adaptive behaviour), Participation (participation in extra-curricular activities) as well as the domain of subjective functioning (self-reported QoL). The domains of Environmental Factors (family social advantage) and Personal Factors (sex, age and intelligence) were also considered for each participant. Measures were chosen based on their use in clinical practice and research with young people with ASD, with the exception of participation, as there was no clear understanding of how to measure this domain for young people with ASD. To identify how participation has been measured in young people with ASD a systematic review of the literature was performed, with consideration of the measurement properties of the tools identified. As published, nine studies out of the 2539 screened investigated the measurement properties of the tool to assess participation in young people with ASD. These nine studies included seven tests, namely Adolescent and Young Adult Activity Card Sort, the Children’s Assessment of Participation and Enjoyment/Preference for Activities of Children (CAPE/PAC); the Experience Sampling Method; the Pediatric Evaluation of Disability Inventory Computer Adaptive Test (PEDI-CAT) and the School Function Assessment. The tests’ measurement properties were investigated in studies with high risk of bias and therefore, the quality of the evidence for these tools is limited. The PEDI-CAT demonstrated adequate measurement properties but lacked the assessment of the subjective dimension of participation. For this reason, the CAPE was chosen in this study. Preliminary analysis of the data from the cross-sectional study comprised a description of the sample, univariate analysis of the association between independent and dependent variables by hypothesis, and explorative univariate analysis of the association between covariates and dependent variables. To address the three aims of this thesis, three hierarchical regressions were performed with covariates entered in the first steps, and the independent variables by hypothesis entered last. Results The descriptive statistics fit well with the conceptualisation of autism as a spectrum condition with scores on measures of the constructs mentioned earlier varying between participants. Hierarchical regression relative to aim 1 showed that inhibition was positively associated with adaptive behaviour, above and beyond social abilities (reversed social impairments) and intelligence. Inhibition and social abilities were positively associated with adaptive behaviour and explained 50% of its variance. There was no association between cognitive flexibility, generativity, planning and adaptive behaviour over and above the contribution of social abilities and intelligence. Hierarchical regression relative to aim 2 showed that there was no association between EF abilities and participation. Furthermore, there was no association between adaptive behaviour and participation and, as such, adaptive behaviour was not found to be a mediator in the association between EF and participation. Hierarchical regression relative to aim 3 showed that there was no association between participation and self-reported QoL, above and beyond reversed anxiety and depressive symptoms. Reversed depressive symptoms were positively associated with self-reported QoL and explained 49% of the variance in self-reported QoL. Discussion Assessment of EF abilities, together with the assessment of social abilities, should become routine in the care of adolescents with ASD who have difficulties with adaptive behaviour. However, there is a need to investigate other factors in addition to EF abilities and adaptive behaviour which may influence participation in extra-curricular activities as impairments in the former are not associated with those in participation. Treating comorbid mental health symptoms of young people with ASD, in particular depressive symptoms, may result in an improvement of these young people’s self-reported QoL.
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ItemClowns in the midst: understanding clown doctors at The Royal Children's Hospital Melbourne( 2018)Clown doctors are a feature in paediatric hospitals, visiting children and families, providing a welcome escape from the reality of hospitalisation. Though the use of humour to improve health and wellbeing has been widely researched, limited exploration of the clown doctors has occurred. This study aims to elucidate the work of clown doctors within a major paediatric hospital. This was an ethnographic study. Ethnography is an innovative approach to paediatric research, giving an intricate view that is otherwise difficult to attain. Participants for this study included the clown doctors employed at The Royal Children’s Hospital, and every person they had a meaningful encounter with during the course of their work, including patients, families, clinical and non-clinical staff. Data was collected via participant observation, with approximately 1,500 hours of ‘clown ward rounds’ documented over one year. Furthermore, 25 hour-long semi-structured interviews were conducted with a range of key informants. A constructivist framework was used to analyse emergent concepts. Constructivism explores how relationships and interactions create the individual’s understanding of the world. Furthermore, how different understanding, or meaning, can be derived from interactions based on individual context, background, culture and personal history. When asking people about the clown doctors, most ascribed a function, such as: distraction, anxiety reduction and procedural assistance; entertainment and making people laugh; emotional support and providing comfort; and communication, including translating clinical information to families. These functional elements of the clown doctors are the result of a more complex, intimate human connection that develops due to the nature of clown doctors being low-status, open, vulnerable and, in particular, existing as outsiders to the medical establishment. Clown doctors use humour to break down the emotional barriers created by illness, which they achieve through being person-centric and offsetting medically driven interactions the hospital often demands. They empower patients, returning a sense of control that is generally absent for hospitalised children. While almost universally acknowledged as a positive addition to the hospital, most people who encounter the clown doctors have little conception about the scope of their work. Although clown doctors are often described in concrete clinical terms, their real power lies in their ability to connect with people, and the psychosocial advantages that connection provides. The results of this descriptive study deliver valuable insight and a comprehensive understanding of clown doctors and the complexity of human relationships within a major paediatric hospital. Through this research we can identify what the clown doctors bring to the hospital environment, how paediatric staff can employ their unique skills more effectively, and finally give long-overdue credence to the notion that laughter, mirth, creativity and child-like wonder has as much place in a hospital as medicine.
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ItemProximal femoral osteotomy in children and adolescents with cerebral palsy( 2018)Background Cerebral Palsy (CP) is the most common cause of physical disability affecting children in developed countries. Approximately one third of children with CP may develop hip displacement. Non-ambulant children at Gross Motor Function Classification System (GMFCS) levels IV and V are at highest risk. Without early detection through surveillance programs, hip displacement can progress to hip dislocation, which is frequently painful and negatively impacts health-related quality of life (HRQoL). Injections of Botulinum Neurotoxin A (BoNT-A) have no role, and soft tissue surgery has a limited role in preventing hip displacement in non-ambulant children with CP. Bony hip reconstruction surgery such as a proximal femoral osteotomy (PFO) is effective in stabilising the hip and HRQoL. PFOs include Femoral Derotation Osteotomies (FDO) which aim to improve the gait of an ambulant child (GMFCS I-III), and Varus Derotation Osteotomies (VDRO) which aim to contain the hips in non-ambulant children (GMFCS IV-V). However, PFOs can carry high risks, especially in children with medical co-morbidities such as respiratory disease, nutritional deficiencies, hypertonia and osteopenia. Aim This thesis involved a series of three studies, which aimed to expand our knowledge of the trainee learning curve, outcomes and adverse events relating to PFO in children and adolescents with CP. Method and Results A new implant combining locking and cannulated technology (Locking Cannulated Blade Plate, LCBP) was recently developed for use in PFO. A pilot study was performed on the first 25 patients who had surgery with the LCBP, at the Royal Children’s Hospital (RCH), Melbourne. This study established safety for use in children as young as three, with weights as low as eleven kilograms. A further prospective, parallel cohort study of 90 consecutive children with CP was conducted to compare the LCBP against with existing non-cannulated, non-locking implant (Angled Blade Plate, ABP). Technical and radiological outcomes of surgery were similar between implants. However, the surgical technique was reported by trainees to be easier when using the LCBP, with less technical errors. Approximately 60 percent of the children experienced minor adverse events including: constipation, inadequate pain control, and respiratory compromise. However, a CP specific tool was not available to classify the severity of events. Study three was performed to clarify the Modified Clavien-Dindo (MCD) system for lower limb surgery in children with CP and test its’ reliability for classifying adverse events. Very good reliability was demonstrated amongst members within a multidisciplinary team. Conclusion Novel findings from these studies may help improve the safety and efficacy of the management of hip displacement in children with CP. Further research should address the long-term outcomes of PFO in children with CP, evaluate the validity of the MCD for children in CP and determine if the MCD can be embedded in the electronic medical records (EMR) as a routine tool for audit and clinical research.
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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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ItemImproving oxygen therapy for children and newborns in Nigerian hospitals( 2018)Oxygen is a long-established medical therapy that can be life-saving for severely ill children admitted to hospital. Effective provision of oxygen to patients requires a multifaceted system that involves technical, clinical, supply chain, financing, and other managerial and policy elements. However, this system is currently difficult to achieve in many low-resource settings resulting in poor access to, and use of, oxygen and subsequent excess mortality. Previous work has shown that improved hospital oxygen systems can improve patient access to oxygen therapy and reduce inpatient case fatality rates from childhood pneumonia. However, studies have shown variable impact in different settings due to contextual factors that are not well understood. In addition, the burden of hypoxaemia and impact of oxygen on conditions other than pneumonia is unclear – particularly in the large neonatal population. This study aimed to understand how to improve oxygen systems in particular contexts, and generate evidence to support the scale-up of effective oxygen systems in Nigeria and globally. My realist review of past oxygen projects developed a theoretical framework describing how improved oxygen systems could improve clinical outcomes in particular contexts – highlighting the interaction between efforts to improve oxygen access and the clinical use of oxygen. My oxygen needs assessment in 12 secondary-level Nigerian hospitals provided detailed data on existing oxygen systems – highlighting the impact of poor power supplies, weak maintenance systems, and lack of pulse oximetry. My prospective cohort study provided new data on the epidemiology of hypoxaemia in the Nigerian context. This study showed high prevalence of hypoxaemia among admitted children and neonates with a range of conditions, highlighted the strong association between hypoxaemia and death, and demonstrated poor accuracy of clinical signs to predict hypoxaemia (particularly for children with non-respiratory conditions). My mixed-methods realist evaluation identified how pulse oximetry could be most effectively adopted into routine paediatric and neonatal care – highlighting the role of key influencers to model behaviour, practical training and ongoing encouragement, personal experience of benefit, and the reasons why nurses valued pulse oximetry. My stepped wedge trial evaluated the effect of our intervention (improved oxygen system) on clinical outcomes and care practices. This study demonstrated mortality benefit for children admitted with pneumonia, and suggested that the introduction of pulse oximetry generated most of this benefit by stimulating better use of existing oxygen supplies. We found no mortality benefit for children with other conditions or neonates, and detected an unexpected trend towards higher mortality in the “full oxygen system” period compared to the “pulse oximetry period” for neonates. Post-hoc analysis tested some potential explanatory theories for these findings – highlighting the effects of pre-existing oxygen access and external factors. In conclusion, improving oxygen systems is complex. The studies contained in this thesis have helped fill evidence gaps that are hindering oxygen policy and planning decision-making in Nigeria and globally. They have directly informed national and global policies and program planning.
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ItemGenetic and early-life environmental influences on dental health in childhood: a study of twins( 2018)Through toothache, infection and tooth loss, dental diseases have a major impact on the health and well-being of children. Dental caries and hypomineralised second primary molars (HSPM) are two common diseases of childhood. Both are complex conditions, which are likely to be influenced by genetic and environmental factors. Although the cause of dental caries is generally well understood, persistently high rates in childhood suggests that more effective preventive strategies are needed. Targeting upstream factors, from early in life, before clinical signs occur and before caries risk is programmed may provide a novel target for caries prevention. In contrast, HSPM is a relatively poorly understood condition of unknown aetiology that is thought to be triggered during tooth formation, in the prenatal and early life period. Understanding prenatal and early life influences on dental health is hampered by a lack of prospective longitudinal studies. The aim of this project was to use a prospective longitudinal study of twin children to (1) investigate the contribution of genetics, shared and non-shared environment to the variation in risk of dental caries and HSPM; (2) to identify specific shared and non-shared factors from the pre- and perinatal period that are likely to be associated with disease; and (3) apply twin statistical methods to explore a potentially causal relationship between body mass index (BMI) and dental caries. Data collected from questionnaires, medical records, biosamples and dental examinations through the course of the study were used in this thesis. In order to evaluate the relative contribution of genetic and environmental factors to the variation in risk of the binary outcomes, dental caries and HSPM, case-wise concordances were derived and compared in monozygotic (MZ) and dizygotic (DZ) twins. Various general and twin specific regression based statistical methods (including within/between analyses) were applied to evaluate the association between the outcomes and a range of exposures. Finally, within/between pair analysis was applied to determine the strength and direction of a potential causal relationship between dental caries and BMI. As detailed in Chapter Four of this thesis, HSPM was found to be common, affecting 19.8% of the children in study, and the variation in risk was predominantly due to environmental factors. Dizygosity, infantile eczema, vitamin D levels at birth, in vitro fertilization, maternal smoking beyond the first trimester of pregnancy and higher socioeconomic status were risk factors for HSPM. As detailed in Chapter Five, dental caries affected 32.2% of children, with 24.1% of children showing signs of advanced dental caries. Environmental factors predominated over genetics in determining variation in dental caries risk. Water fluoridation, maternal obesity and HSPM were important risk factors for dental caries. Analysis of BMI and dental caries at six years of age revealed that although the relationship is heavily influenced by confounders, an inverse causal relationship is likely. However, due to the cross-sectional nature of the study, it was not possible to determine which is the determinant and which is the outcome. The findings of this thesis suggest that dental caries and HSPM risk are heavily influenced by environmental factors, some of which are modifiable and arise as early as the prenatal period. With replication in other longitudinal cohorts, these findings may provide novel targets for population-based preventive strategies to improve the oral health of children.
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ItemDevelopment and validation of the short language measure (SLaM): a brief measure of general language ability for children in their first year at school( 2018)The identification of children with language difficulties relies on the referral of children to speech-language services. Yet, the referrers of young school-aged children cannot always accurately discriminate those with and without language difficulties. Consequently, a high proportion of children with language difficulties are never referred for services and many children referred for suspected language difficulties have age-appropriate communication skills. The administration of a short language measure by speech-language therapists or paraprofessionals to identify children who require further language evaluation could improve the accuracy of language service referrals. However, existing short language measures for young school-aged children lack sufficient discrimination capacity. This may be due to the inadequate development of available measures, which have omitted crucial test development steps. The aim of this project was to create a sufficiently accurate, valid and reliable short language measure for children in their first year at school by applying stringent test development procedures.
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ItemThe molecular pathology of a collagen II helix missense mutation( 2018)Collagen II (COL2A1) is a major structural component of the extracellular matrix in cartilaginous tissues, and mutations that affect the expression or structure of collagen II result in a range of chondrodysplasias. Many of the known COL2A1 mutations are glycine missense mutations that interfere with the folding and assembly of the critical triple helix structure of the collagen II protein trimer. Recent studies suggests that mutations in the C-terminal trimerisation domain can lead to dysfunctional collagen trimerisation that causes endoplasmic reticulum (ER) stress, which could in turn play a major role in chondrodysplasias. However, the cellular consequences of mutations in the triple helix are currently poorly understood. This study uses a mouse model with a Col2a1 mutation, which causes an arginine to cysteine (Arg1147Cys) substitution in the region that encodes for the triple helix. It presents with a chondrodyplasia that is phenotypically similar to human Spondyloepiphyseal dysplasia congenital (sedc) patients. Characterisation of this mouse model revealed numerous indicators of cellular stress, including distended ER, disorganisation in the extracellular matrix, numerous vacuoles within chondrocytes, and increased cell death compared to wild-type littermates. These attributes suggests that the unfolded protein response (UPR) pathway might be associated with the Col2a1 mutation. However, microarray analysis revealed that the canonical unfolded protein response (UPR) pathway was not activated in this mouse model. However, labelling experiments to investigate the procollagen biosynthesis in chondrocytes revealed that both lysosomal and ERAD-proteasomal pathways are involved in the clearing of aggregated/accumulated mutant type II procollagen in the chondrocytes. Also, the Col2a1 mutation affect molecular transport, cell death and survival, cellular assembly and organisation, cellular development, post-translational modifications, and DNA repair. However, these pathways and mechanisms do not appear to be definitive in causing the pathological changes in the cartilage. Proteomic analysis on cartilage suggests that the Col2a1 mutation causes vast changes to the cartilage protein composition, and revealed that cell death, cellular assembly and organisation, and protein synthesis were all affected by the type II collagen mutation. While no definitive mechanism for the pathology seen in this mouse model was unearthed in this study, it did identify additional extracellular matrix proteins and signalling pathways that could have novel roles in chondrocyte dysfunction. These studies have provided new information about the cellular and extracellular consequences of type II collagen mutation. While the exact molecular mechanism underlying the pathology of this mutation was not identified, the investigations have highlighted the complexity of these types of mutations and provided some potential candidate proteins and pathways that could be investigated further.
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ItemPhysiologic changes following fluid resuscitation for suspected paediatric sepsis: a point-of-care ultrasound study( 2018)Fluid bolus therapy is one of the most commonly administered forms of acute circulatory support in hospitalised children and adults. Early and aggressive fluid bolus therapy has been used as a cornerstone of the treatment for sepsis for over two decades, based on low-level observational evidence, and included in all current international treatment guidelines. More recent evidence from large, well conducted, randomised trials has called into question the safety of this approach. This represents a significant and serious evidence and translational gap, and may result in ongoing iatrogenic morbidity and mortality from continued reliance on aggressive fluid bolus therapy as a form of initial circulatory support in children with sepsis. Bedside clinicians are in a difficult position, making treatment decisions in the patients best interests without a clear ability to assess the potential benefits and risks of fluid bolus therapy for the individual patient. Bedside ultrasound may be a tool that helps clinicians balance the potential benefits and risks of fluid bolus therapy to individual patients and tailor treatment appropriately. The overall aim of this thesis was to use ultrasound to assess the physiological changes that occur in the first hour following fluid bolus therapy in children with sepsis. The primary outcome was the effect of fluid bolus therapy on cardiac index, and secondary aims were i) the ability of inferior vena cava collapsibility to predict the effect of fluid bolus therapy on cardiac index (fluid responsiveness), ii) the effect of fluid bolus therapy on extra-vascular lung water, and iii) the effect of fluid bolus therapy on vital signs. To achieve this aim, 50 children with sepsis were identified in the Emergency Department of The Royal Children’s Hospital, Melbourne, and trans-thoracic echocardiogram, inferior vena cava ultrasound, and lung ultrasound were performed, vital signs recorded (heart rate, respiratory rate, mean blood pressure), and a patient video recording taken immediately prior to fluid bolus therapy. At 5 and 60 minutes after fluid bolus therapy, trans-thoracic echocardiography and lung ultrasound were performed, vital signs were recorded, and a patient video recording taken. Trans-thoracic echocardiogram recordings were interpreted for cardiac index by a Paediatric Cardiologist blinded to the participant identity and status pre / post fluid bolus therapy. Inferior vena cava and lung ultrasound recordings were interpreted by a Paediatric Emergency Physician with a Diploma in Diagnostic Ultrasound blinded to the participant identity and status pre / post fliud bolus therapy. Video recordings were interpreted for capillary refill time and Glasgow Coma Scale score by a Paediatric Emergency Physician blinded to participant status pre / post fluid bolus therapy. The primary outcome, median cardiac index, increased over the first 5 minutes following fluid bolus therapy, and then fell back to baseline over the subsequent 60 minutes. Inferior vena cava collapsibility had poor ability to predict fluid responsiveness. Extravascular lung water as measured using lung ultrasound increased over the study period. Mean arterial blood pressure initially decreased following fluid bolus therapy, and increased back towards baseline over the subsequent 60 minutes. No change in capillary refill time or Glasgow Coma Scale score was observed over the study period. In conclusion, this study challenges some of the physiological assumptions that underpin fluid bolus therapy as a form of acute circulatory support in children with sepsis. The potential benefits of this therapy in this patient population seem to be limited, and the potential adverse effects on lung water highlighted. In addition, the effect of fluid bolus therapy on vital signs in this patient population raise questions about their utility as therapeutic targets. This study helps clarify the physiological changes in children with sepsis following fluid bolus therapy, and will help inform the design and conduct of future trials in this arena.
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ItemNon-invasive arterial wave analysis in congenital heart disease( 2018)Elevated large arterial stiffness is an independent risk factor for adult cardiovascular and cerebrovascular disease. Arterial dysfunction may already be evident in childhood, and children born preterm, or with a history of congenital cardiac surgery, particularly coarctation of the aorta, have a high burden of adult cardiovascular disease and hypertension. Novel arterial wave analyses such as Wave Intensity (WI) and Wave Power (WP) assess the interaction between the heart and great vessels, providing insights into mechanisms of hypertension. Non-invasive WI/WP analyses rely on accurate acquisition of velocity (U), and diameter (D) with ultrasound. Although ultrasound methods are well suited to measuring peak U, WI/WP rely on mean U, which is difficult to obtain routinely. Local pulse-wave speed (c), a measure of arterial stiffness, can also be determined by constructing PU or ln(D)U loops, which also rely on mean U. Errors in c with PU and ln(D)U loop methods due to inaccurate U were determined using MRI-based verification and simulated virtual cohort. A novel method for acquiring local c, which accounts for errors in U and those related to proximal wave reflections, was developed. This technique allowed for scaling factors to be derived to convert peak U into mean U, enabling WI/WP analysis using widely available clinical equipment. In an animal model, invasive and non-invasive WI/WP analyses were compared. The correlations for WI and WP indices were good, but agreement was poor- with a majority of the bias accounted for by either inaccurate invasive U or non-invasive flow estimation, and to non-invasive underestimation of peak P rates of change. Agreement and correlation for wave-related pressure changes were acceptable, and non-invasive WI analysis detected similar relative changes in wave indices during haemodynamic perturbations. Ex-preterm adolescents born at <28 weeks gestation and largely at appropriate weight for gestational age were found to have elevated systolic blood pressure, with no difference in conventional vascular indices. They had a smaller ascending aorta and greater wave reflection on non-invasive WI assessed in the aorta, which was associated with systolic blood pressure on multivariable analysis. Non-invasive WI/WP was also applied in a study of young adults after coarctation repair. They had higher aortic stiffness, but despite higher carotid IMT, there was no increased carotid stiffness. They had higher aortic WI indices, but not WP. In contrast, in the carotid artery both WI and WP indices were greater. Aortic stiffness was related to forward carotid WP in the coarctation group, but not controls. These findings demonstrate that greater stiffness of the aorta leads to increased transmission of wave energy towards the brain. Non-invasive WI/WP analyses have the potential to be more widely deployed using the methods developed in this thesis, and may yield novel insights into the circulatory phenomena that are encountered in children and young people with congenital cardiac and vascular disease.