Medicine & Health

Publication Search Results

Now showing 1 - 10 of 68
  • (2023) Wu, Verena
    Thesis
    Background: Chinese-Australian immigrant patients with cancer report poorer psychosocial outcomes compared to Anglo-Australians. Additionally, Chinese immigrant caregivers experience burden and anxiety associated with caregiving. Presently, there are limited resources available that can support them in coping with these challenges. This thesis aims to address this gap by developing and evaluating the acceptability and feasibility of a culturally appropriate self-management (SM) resource, WeCope, for Chinese-Australian immigrant patients and caregivers affected by cancer. Methods: A systematic review was conducted to identify the unmet supportive care needs of Chinese patients and caregivers with cancer to identify areas of concern requiring support (Chapter 2). An overview of self-management interventions, including theoretical underpinnings and evidence for effectiveness on psychological outcomes and unmet needs was provided (Chapter 3). The cultural sensitivity framework and community participatory approach were explored to guide the methods for developing WeCope with content based on a previous dyadic resource, Coping-Together (Chapter 4). Acceptability among patients, caregivers and community members was explored in a qualitative study (Chapter 5), and feasibility of WeCope as an intervention and the study methods employed were assessed in a mixed methods study (Chapter 6). Results: The systematic review (Chapter 2) showed that health system and information needs was the predominant domain of unmet need frequently reported by Chinese patients and caregivers. The qualitative study (Chapter 4) indicated overall acceptability with suggestions for additional information which informed modifications to the WeCope booklets. The feasibility study (Chapter 5) indicated barriers to the feasibility of WeCope as an intervention across several aspects: demand, acceptability, practicality, and implementation. Preliminary efficacy of WeCope could not be assessed due to low recruitment and response rates, and the study methods were deemed unfeasible for a larger trial. Conclusion: This thesis reports the acceptability and preliminary feasibility of a SM intervention for Chinese-Australian immigrants affected by cancer. While WeCope demonstrated some degree of acceptability, feasibility of the intervention and study methods were limited. Considerable additional resources and refinement of the study methods are needed if a large-scale study is undertaken.

  • (2023) Mulligan, Christopher
    Thesis
    Background Powered off-road vehicles, such as quad-bikes and two-wheeled motorcycles, are popularly used recreationally by children, and are also used in a variety of farming and agricultural contexts. However, crashes can result in serious injuries and deaths, and as such are an important public health concern for Australian children. Compared to adults, children have different riding patterns, injury causes and risk factors relating to their level of development, as well as different patterns of injury outcomes and severity. Aims This work aims to investigate paediatric quad-bike and motorcycle riding patterns and behaviours, along with risk factors, injury severity, outcomes and potential avenues for injury prevention counter-measures. The work consists of five related studies. Methods and Results The first study was a survey of paediatric off-road vehicle riders, which was undertaken to characterise patterns of use, rider behaviours, experience and attitudes. Recreational motorcycle riding was most common, with children having high rates of previous riding experience and often participating in ‘structured’ riding within organised motorsports competitions and events. There was a small proportion of ‘unstructured’ riding in the context of agriculture or on private properties. Riders generally rode frequently and used helmets and other protective gear. The second study examined a group of children admitted to a paediatric hospital as a result of injury sustained from an off-road vehicle crash. In-depth crash investigation techniques examined injury mechanisms and related them to injury outcomes, along with rider, environmental and vehicular risk factors. A variety of recurring mechanisms emerged, particularly loss-of-control events leading to impacts with the ground or vehicle. A wide range of injuries were also observed, particularly to the extremities. A case-control component of the study identified a lower rider to vehicle weight ratio as a factor associated with higher crash risk. The third and fourth studies used large, linked population-level hospital admission and mortality datasets. The first of these examined injury epidemiology and outcomes for paediatric off-road vehicle crashes across New South Wales over a 17-year time period. The outcomes for different vehicle types were compared. The findings demonstrated the large burden of injury caused by ORV crashes in terms of hospital admissions and operative interventions. Furthermore, although on an individual level, quad-bike injuries were associated with higher injury severity, the far greater number of two-wheeled off-road motorcycle crash admissions suggest that motorcycles should be an injury prevention priority. The second linked data study examined the subset of children who have multiple hospital admissions following off-road vehicle crashes. Children who re-present to hospital repeatedly are a particularly vulnerable group, prone to more serious injury, and higher overall costs to the healthcare system. ‘Recidivist’ riders were compared to non-recidivists across various demographic, vehicle and injury outcome factors, highlighting the areas in which potential recidivists may be identified or targeted for injury prevention interventions. The fifth study was a systematic review of injury prevention countermeasures delivered through clinical environments such as hospitals and Emergency Departments, centred around the concept of the ‘Teachable Moment’: that children may be more receptive or amenable to behaviour change after sustaining an injury. The strengths and weaknesses of interventions that apply this model were identified, which may inform potential interventions pertaining to off-road crashes. The review found that multi-modal approaches combining face-to-face counselling or teaching, supplemented with other forms of written or visual communication, often paired with the provision of safety equipment and accurate monitoring as the most effective means of intervention. However, injury prevention programs are often limited by short-term and largely self-reported outcome measures, so research and programs applying these findings to off-road vehicle riders should be designed with robust design methods and appropriate measures of behaviour change, knowledge gain or injury reduction. Conclusion The results of the project overall demonstrate that off-road vehicle injuries are a large and important cause of injury, disability and death for Australian children. An overarching theme of this project is to demonstrate that children who participate in off-road riding are a unique and vulnerable population. Riding patterns are largely recreational, and the resultant injuries are common, spanning the spectrum of severity. Factors associated with worse injury outcomes and recidivism are explored, which, along with the review of injury prevention countermeasures delivered in clinical settings, may help re-prioritise and target injury prevention resources and research. Ultimately the goal of this project, as with any injury research, is to try to prevent or mitigate the severity off-road crashes. The studies investigate various aspects of paediatric off-road riding and provide important foundational knowledge for researchers and clinicians to work towards real-world applications and interventions.

  • (2023) Tonini, Emiliana
    Thesis
    Schizotypy is a unifying construct that draws a continuum between subclinical and clinical symptoms of psychotic disorders, reflected in commonly occurring cognitive, behavioural, and personality features. This thesis aims to carry out a holistic investigation of the genetic, neurocognitive, and environmental contributions to schizotypy in cohort of healthy individuals and those diagnosed with schizophrenia and bipolar disorder, to benefit from exploring the full range of schizotypal expressions. The main empirical chapters examine the impact of environmental factors and genetic vulnerability for schizophrenia on schizotypy and its component dimensions, with the final empirical chapter focused on the functional neural correlates of schizotypy during specific cognitive task. Participants for these studies were drawn from a cohort of 245 adults (mean age=38.58, sd=11.83, range=18.26 to 60.52), comprising 79 healthy controls, 86 individuals diagnosed with bipolar disorder, and 80 individuals diagnosed with schizophrenia. Study 1 reports positive associations between childhood trauma and schizotypy, while demonstrating the role of sociodemographic disadvantage as partial mediator of these associations. Study 2 reports that associations between childhood trauma and schizotypy are moderated by polygenic risk score for schizophrenia. Study 3 consisted of a systematic review of the available literature on structural and functional neural correlates of schizotypy. The high degree of methodological and conceptual heterogeneity across studies precluded the identification of a distinct pattern of schizotypy-associated brain alterations. Finally, Study 4 investigated the associations between schizotypy and brain activity during facial emotion processing using a data-driven approach. Overall, the findings from this thesis emphasised the relevance of investigating schizotypy in psychotic disorders, not restricted to schizophrenia, as well as the complex interaction between genetic and environmental risk factors in association with higher levels of schizotypy. Future research of schizotypy would be enhanced with utilization of longitudinal designs, with repeated measures of schizotypy over time, while incorporating data on exposure to childhood and adulthood environmental risk variables and genetic vulnerability. In addition, neuroimaging studies of schizotypy would benefit from multimodal, data-driven approaches, as well as being informed by environmental risk factors.

  • (2023) Beshara, Peter
    Thesis
    Rotator cuff tears are a common cause of shoulder pain in the general community. Approximately one-third of patients with rotator cuff tears proceed to surgery following the failure of conservative treatments such as physiotherapy, non-steroidal anti- inflammatory drugs, opioid analgesics, and cortisone injections. However, rotator cuff tears continue to develop over time, and the burden of illness for patients awaiting rotator cuff repair is substantial, resulting in loss of strength, functional status, and poor quality of life. This dissertation proposes a three-stage approach for the management of rotator tears in patients awaiting surgery, which includes an accurate and reliable evaluation of shoulder range of motion (ROM) and strength, a pre-operative intervention to improve function and quality of life, and an appraisal of potential prognostic factors that can lead to better future clinical outcomes. Therefore, the organisation of this thesis is divided into three sections covering shoulder assessment, intervention, and prognosis. Chapter 1 introduces the concept of prehabilitation, a rapid systematic review, evidence gaps in the literature, and the rationale for shoulder prehabilitation. Prehabilitation is defined as enhancing a patient's functional ability before surgery to improve clinical outcomes following surgery. The rapid systematic review included only high-quality studies based on the National Health and Medical Research Council (Australia) evidence guidelines and the Physiotherapy Evidence Database (PEDro) rating scale. Only pre-operative exercise intervention studies for surgical knee and hip populations were identified. To date, no studies have investigated the efficacy of prehabilitation for patients scheduled for shoulder surgery. This finding necessitated a review of the considerable body of research on rotator cuff tears. Chapter 2 provides a synthesis of the current literature regarding shoulder anatomy, biomechanics of the rotator cuff, epidemiology, aetiology and classification of rotator cuff tears, shoulder assessment methods, an overview of management options, evidence for post-operative rehabilitation, and prognostic factors and potential predictors of outcome associated with rotator cuff surgery. Chapter 3 presents a published study examining the intra- and inter-rater reliability of a variety of testing protocols to measure ROM and strength in healthy participants. The objective measurement of ROM and strength is an integral part of the physical examination of patients with rotator cuff tears and is vital in quantifying improvement after conservative or surgical intervention. Correctly evaluating and interpreting objective shoulder measurements informs the clinical reasoning underlying treatment. Since pre- operative ROM and strength are potentially modifiable predictors for rotator cuff repair success, a precise assessment using reliable instruments and testing methods is essential. The outcomes of this study supported the selection of assessment methods for a randomised controlled trial (Chapter 7) on shoulder prehabilitation. Chapter 4 presents a published systematic review and meta-analysis on the reliability of the Kinect and ambulatory motion-tracking devices to measure shoulder ROM. According to our reliability study findings in Chapter 3, existing methods for evaluating shoulder ROM are less reliable. Emerging inertial sensor technologies and optical markerless motion-tracking systems are valid alternatives to standard ROM assessment methods. However, reliability must also be established before this technology can be used routinely in clinical settings. Chapter 5 presents a published validity and reliability study on the HumanTrak system to measure shoulder ROM in healthy subjects. Based on our findings in Chapter 4, we evaluated the clinical potential of using a movement analysis system that combines inertial sensors with the Microsoft Kinect (HumanTrak) to measure shoulder ROM reliably and accurately. Chapter 6 is a systematic review and meta-analysis of prehabilitation for the management of orthopaedic surgery. The initial rapid systematic review in Chapter 1 only identified orthopaedic prehabilitation programmes for patients undergoing lower limb joint arthroplasty, anterior cruciate ligament reconstruction, and spinal surgery. Given the growing research and clinical adoption of prehabilitation over the past decade, we undertook an updated and more comprehensive systematic review to identify and critically appraise the content and reporting of prehabilitation programmes for all orthopaedic surgeries. Exercise therapy is commonly first line treatment for older patients with non-traumatic rotator cuff tears. Despite growing evidence that exercise therapy and surgery can achieve comparable clinical outcomes, there is a paucity of high-quality studies on the impact of pre-operative exercise or education for patients awaiting rotator cuff surgery. Hence, the main aim of this thesis is to investigate the efficacy of a combined pre-operative exercise and education programme on function and quality of life before and after rotator cuff surgery. Chapter 7 is a randomised control trial (RCT) investigating whether the addition of a pre-operative exercise and education programme to usual care for patients awaiting rotator cuff surgery is more effective than usual care alone. Fifty patients with unilateral rotator cuff tears received either an 8-week shoulder exercise and education prehabilitation (SPrEE) programme or usual care (UC). The SPrEE programme compared to UC resulted in superior and statistically significant improvements in the primary outcomes of SPADI, WORC and SF-36 in the pre-operative phase. The SPrEE program was not more effective than UC alone in improving primary outcomes at 3-, 6- or 12 month follow-up timepoints. There were no statistically significant between-group differences in SPrEE and UC secondary outcomes for surgical or non-surgical patients. Chapter 8 investigated any correlations between pre-operative magnetic resonance imaging (MRI) characteristics and patient-reported outcome measures for patients who underwent rotator cuff repair or no surgery and received either prehabilitation or usual care in the RCT (Chapter 7). Prognosis-based prehabilitation can effectively identify patients who will derive the greatest benefit. Chapter 9 summarises thesis findings, strengths, and directions for future research to optimise function and quality of life prior to rotator cuff surgery.

  • (2023) Al Arkawi, Dunia
    Thesis
    Fractures, the main consequences of osteoporosis, are associated with subsequent fractures and mortality. However, limited evidence exists on the impact of non-hip non-vertebral (NHNV) fractures and subsequent fractures on mortality in ageing populations. Bisphosphonates (BPs), the most used osteoporosis treatment, have been associated with reduced mortality. Denosumab (Dmab), an increasingly prescribed osteoporosis treatment, is effective at reducing fractures, but unlike BPs, its effect on mortality has not been well-explored. Moreover, the safety of BPs is unclear in patients with moderate-severe chronic kidney disease (CKD) who have a high risk of fracture and are usually excluded from drug trials. Therefore, using data from Norway, UK, Spain and Australia, this thesis explores the impact of osteoporotic fracture types and subsequent fractures on mortality. It also examines the association between BPs and Dmab and mortality and investigates the effect of BPs on mortality in patients with moderate-severe (Grade 3B-5D) chronic kidney disease (CKD). Norway has one of the highest fracture rates in the world. Using data from the Tromsø Study, Norway, this research demonstrated two-fold increased mortality following hip fractures, and proximal NHNV fractures were associated with an increased mortality risk of 49% in women and 81% in men. A subsequent fracture following any initial fracture increased mortality risk by 89% in women and 77% in men. The Sax Institute’s 45 and Up Study, NSW, Australia, demonstrated that oBPs in both genders and Dmab in women were associated with 44% and 48% reduced mortality risk post-fracture, respectively. Furthermore, data from the UK and Spain demonstrated that oral BPs (oBPs) were not associated with increased mortality among patients with moderate-severe CKD. Instead, oBPs in the UK cohort were associated with a decreased risk of mortality by 8% in the whole cohort, 11% in women, 20% in those with prior history of fracture, and 30% in those with CKD Grade 4-5D. In summary, this thesis confirmed the high mortality risk associated with different osteoporotic fractures and subsequent fractures, highlighting the need for personalised risk assessment post-fracture. It demonstrated that antiresorptive treatment improves survival in the general population, and oBPs are generally safe in moderate-severe CKD.

  • (2023) Tavella, Gabriela
    Thesis
    Burnout is hot topic in public discourse, with members of the general public quick to self-diagnose as suffering from the syndrome. However, there is a lack of consensus among scientists and practitioners as to how burnout should best be conceptualised and whether/how it should be diagnosed. This thesis reports five studies examining self-diagnosed burnout and how it should best be defined, measured and distinguished from clinical depression. The literature review presented in Part I critiques the currently promulgated three-factor conceptualisation of burnout and highlights the inconclusive research findings regarding burnout’s overlap with depression. Part II contains three studies designed to re-define the burnout syndrome. In Study 1, qualitative and quantitative analyses were used to identify key syndromal features of self-diagnosed burnout. In Study 2, a series of bifactor analyses was undertaken to derive a new definitional model and preliminary measure of the syndrome. In Study 3, mixture modelling was used to examine whether the new burnout definition was best modelled dimensionally or categorically. The results of Part II indicated that burnout as experienced by the general population is characterised by several symptoms beyond the traditional triadic symptom model, and that categorical differences in burnout may exist between those with and without a history of mental illness. Part III contains two studies undertaken to evaluate the degree of overlap between burnout and depression. Study 4 assessed for qualitative differences between burnout and depression experienced by participants who reported having experienced both states. Study 5 compared participants with self-diagnosed burnout to participants with clinically-diagnosed depression across several symptom and causal variables. The results of Part III indicated that the new definitional burnout model derived in Part II showed poor differentiation overall between burnout and depression, but that several other phenomenological, symptom and causal differences are likely to exist between the two states. The results of Study 5 also suggested that burnout overlaps more with non-melancholic than melancholic depression. When taken together, as discussed in Part IV, the studies in this thesis extend knowledge of how self-diagnosed burnout should be defined and illuminate how burnout both converges with and diverges from clinical depression.

  • (2023) Raichand, Smriti
    Thesis
    Background: Teratogenic medicines when used in pregnancy increase the risk of foetal defects. The doses above which these risks increase are published for some medicines including four antiepileptics. Among antiepileptics, valproate is associated with the highest risk of foetal harm. It is, therefore, important to understand the utilisation of teratogenic medicines among pregnant women and women of child-bearing age. Study 1 in this thesis measured the prevalence of teratogenic medicine utilisation before and during pregnancy. Study 2 estimated utilisation of teratogenic antiepileptics as average daily doses (ADDs) dispensed to women of child-bearing age. Study 3 examined valproate utilisation in pregnancy, factors associated with continuation in pregnancy, and recent trends in women of child-bearing age. Methods: In Study 1 and Study 3 we used linked administrative health records, which contained pregnancy-related details and mothers’ health service use, including dispensed prescription medicines. The cohorts comprised concessional beneficiaries who gave birth in New South Wales in 2004-2012. To examine medicine utilisation among women of child-bearing age (Study 2, Study 3) we used medicine dispensing records for 10% of the Australian population in 2012-2020. We presented prevalence as percentages and n per 1000 women, ADDs as mg/day, and associations as odds ratios (ORs). Results: The prevalence of teratogenic medicine utilisation at any time during pregnancy was 2.0%, steadily decreasing from first trimester through to birth. Teratogenic antiepileptics (carbamazepine, lamotrigine, and valproate) except phenobarbital, were dispensed at ADDs below the published high-risk dose thresholds, to women of child-bearing age. Prevalence of valproate utilisation was 5.2 in 1000 pregnant women, and approximately 24% continued use in pregnancy. Having a diagnosis of epilepsy (OR 10.2, 95% CI 5.7-18.4) was significantly associated with valproate continuation in pregnancy. Valproate utilisation among women of child-bearing age decreased from 5.8 to 3.5 per 1000 women in 2013-2020. Conclusions: Taken together, our findings on teratogenic medicine use among pregnant women, antiepileptic ADDs among women of child-bearing age and valproate exposure in these populations suggest that Australian prescribers and patients were aware of the potential harms posed by these medicines.

  • (2023) Mastrogiovanni, Chiara
    Thesis
    Introduction: The benefits of physical activity for reducing falls risk and improving mood and mental functioning have been well documented. However, programs targeting both falls risk and mental health are lacking. The COVID-19 pandemic also highlighted that older adults are at an increased risk of social isolation and physical inactivity. The aim of this trial was to investigate the effect of a Facebook-delivered, combined health promotion, balance training, exercise program, and support group (MovingTogether) on mental and physical health for community dwelling older adults. Methods: Adults aged 60+ years were recruited via social and print media to a randomised controlled trial with a waitlist control. Participants were required to have access to Facebook and a computer or tablet and be inactive as per WHO guidelines. The intervention group joined a private Facebook group where allied health facilitators provided targeted healthy lifestyle education throughout a 10-week program with weekly telehealth group calls. Intervention participants also had access to an evidence-based eHealth balance exercise program, StandingTall and tailored strength and aerobic exercise guidance. Outcomes included psychological distress (primary outcome), physical activity, social capital, concern about falling, loneliness, physical functioning, quality of life and physical activity enjoyment (secondary outcomes). These were assessed at baseline, post-program (week 10) and 1-month follow-up. Linear mixed models were applied for each outcome measure excluding physical activity evaluated by a generalised linear mixed model, as per an intention-to-treat approach to determine between group differences. Results: Participants (N = 80) were 89% female, with a mean age of 66.3 years (SD = 4.92). Participants were randomised to intervention (n = 37) and waitlist control (n = 43) groups. The intervention group had a program completion rate of 59% (22 out of 37) and 64% of all participants (51 out of 80) completed post-program questionnaires. At week 10, there was a significant difference between groups in psychological distress (P=0.04), but no significant difference in physical activity, social capital, concern about falling, loneliness, physical functioning, quality of life or physical activity enjoyment. No significant changes were found at the 1-month follow-up point. Discussion: A 10-week Facebook-delivered health promotion program significantly improved levels of psychological distress but did not change secondary outcomes in older adults. The high dropout rate (36%) is important to note. High Facebook engagement warrants further investigation of Facebook delivery. Future research should consider strategies to account for high dropout rates. Conclusion: MovingTogether significantly improved psychological distress in older adults, although results may have been affected by dropout rate. This trial has implications for the recruitment, engagement, and delivery of physical activity programs for older adults, and offers directions for future research in these areas.

  • (2023) Alajlouni, Dima
    Thesis
    Osteoporotic fractures represent a major public health problem worldwide. They are associated with financial costs, disability, subsequent fracture, and premature mortality. Therefore, it is necessary to identify those at higher risk of fracture. Fracture risk assessment tools such as Garvan FRC and FRAX, which estimate absolute fracture risk by incorporating clinical risk factors other than BMD, have shown improved predictive power over BMD alone. However, fracture prediction using these tools remains suboptimal. Sarcopenia components of muscle mass, muscle strength, and physical performance are fall risk factors but their association with fracture risk is controversial. The present thesis reports a series of studies aimed at: determining the contribution of muscle mass, muscle strength, and physical performance and their rate of decline to the risk of fracture; assessing whether the addition of muscle strength and performance improves the predictive accuracy of the existing fracture assessment tools Garvan and FRAX; and examining the contribution of muscle strength and physical performance to the risk of subsequent fracture and mortality in men who already sustained a fracture. Utilising data for 811 community-dwelling women and 440 men aged 60 years and over enrolled in the Dubbo Osteoporosis Epidemiology study and 5665 community-dwelling men aged 65 years and over enrolled in the prospective Osteoporotic Fractures in Men (MrOS) Study, with baseline and serial measurements of BMD and muscle strength and performance, the first study shows that poor quadriceps strength, get up go, and sit to stand test measurements, defined as worst quartiles, but not muscle mass, were associated with a 2-3-fold increase in fracture risk in men independent of bone mineral density (BMD), prior fractures, and falls, while greater rates of deterioration in these measurements were associated with a similar magnitude of fracture risk in both genders. The second study shows that incorporating grip strength and chair stand to Garvan or FRAX significantly improved the prediction of any fracture (net reclassification improvement [NRI] = 3.9% for grip strength and 3.2% for chair stand). The prediction of major osteoporotic fractures has also been improved (NRI = 5.2% for grip strength and 6.1% for chair stands). Gait speed improved the prediction of any hip (7.0%) and initial hip (5.7%) fracture. Combining grip strength and the relevant performance test further improved the models (NRI ranged from 5.7% to 9.4%). The improvement was predominantly driven by the upward reclassification of men with fractures. The third study showed that in 830 men with low-trauma index fracture, muscle strength and performance measured prior to fracture time were not significantly associated with subsequent fracture risk but were significantly associated with mortality. Moreover, the rates of decline in muscle strength and performance were associated with post-fracture mortality, independent of the index values and other confounders. The thesis contributes to clinical practice. Muscle strength and performance tests are simple to perform in GP clinic and have the potential to improve the identification of those at high risk of fracture in order to intervene with the appropriate measures. Our findings stress the importance of physical activity and rehabilitation (physical therapy and occupational therapy) to minimise the risk of fracture and premature death associated with declining muscle strength and physical performance following fracture.

  • (2023) SHAH, Anushi
    Thesis
    De novo mutations (DNMs) are novel mutations which occur for the first time in an offspring and are not inherited from the parents. High-Throughput Sequencing (HTS) technologies such as whole genome sequencing (WGS) and whole exome sequencing (WES) of trios have allowed the investigation of DNMs and their role in diseases. Increased contribution of DNMs in both rare monogenic and common complex disorders is now known. Identification of DNMs from WGS is challenging since the error rates in the HTS data are much higher than the expected DNM rate. To facilitate the evaluation of existing DNM callers and development of new callers, I developed TrioSim, the first automated tool to generate simulated WGS datasets for trios with a feature to spike-in DNMs in the offspring WGS data. Several computational methods have been developed to call DNMs from HTS data. I performed the first systematic evaluation of current DNM callers for WGS trio data using real dataset and simulated trio datasets and found that DNM callers have high sensitivity and can detect the majority of true DNMs. However, they suffer from very low specificity with thousands of false positive calls made by each caller. To address this, I developed MetaDeNovo, a consensus-based ensemble computational method to call DNMs using cloud-based technologies. MetaDeNovo is a fully automated methodology that utilises existing DNM callers and integrates their results. It demonstrates much higher specificity than all other callers while maintaining high sensitivity. Congenital Heart Disease (CHD) is the most common birth disorder worldwide. DNMs have been found to contribute to CHD causation. Most CHD cases are sporadic, suggesting role of DNMs in large proportion of them. I applied MetaDeNovo to detect DNMs in a WGS dataset of CHD trios to aid with genetic variant prioritisation. MetaDeNovo can dramatically reduce the number of false positive DNMs as compared to individual DNM callers. This has improved the current practices of identifying the genetic causes of disease in such cohorts. MetaDeNovo is applicable to other trio WGS datasets of other genetic diseases. This thesis has contributed new knowledge by in depth exploration of existing DNM callers, development of a novel tool (TrioSim) to simulate trio WGS data and an ensemble improved automated tool (MetaDeNovo) to identify DNMs with high specificity. MetaDeNovo demonstrates its use to identify disease-causing mutations in a trio analysis using WGS.