Paediatrics (RCH) - Theses
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ItemRespiratory function tracking in survivors of prematurity and low birth weight( 2009)INTRODUCTION: To investigate longitudinal ‘tracking’ in lung growth, decline or stability of adult preterm/very low birth weight survivors over the study period. To investigate whether those who have clinically abnormal lung function fall further behind their contemporaries or demonstrate evidence of ‘catch-up’ growth. METHODS: 210 babies born ≤34 weeks’ gestation and with birth weights ≤ 1500g in 1977-1982 were followed up at 8, 11, 14, 18 and 25 years of age. Respiratory outcome was evaluated using Spirometry. Spirometry was performed at each of the follow-up periods. Mixed model regression was used to assess longitudinal lung function trajectories and the influence of Bronchopulmonary dysplasia, being small for gestational age and abnormal lung function. Restricted maximum likelihood modelling was used for longitudinal FEV1 z-score as it allows for analysis of data from different time points that are not necessarily evenly spaced, without being affected by missing data. RESULTS: 137 VLBW children completed lung function testing at 8 years of age. Twenty VLBW children (14.6%) had abnormal FEV1 z-scores and 26 (21.0%) [Defined as >2 standard deviation’s below the mean]. VLBW survivors showed minimal ‘catch-up’ in FEV1 z-score over the 13 years of the study; those without BPD (Bronchopulmonary dysplasia) FEV1 improved 0.034 (p=0.014) z-scores, those with BPD FEV1 improved 0.033 (p=0.039) z-scores. VLBW with BPD survivors did not return to within normal limits; those with abnormal FEF25-75 z-scores did not show significant ‘catch-up’ growth (p=0.41) and remained abnormal. CONCLUSIONS: Mixed models do not reveal any significant effects from being born with VLBW and its interaction with age; it does lead to a reduction in FEV1/FVC mean z-score. Although those VLBW individuals who were small for gestational age had significantly reduced FEV1, FVC and FEV1/FVC mean z-scores and these small for gestational age individuals show evidence of ‘catch-up’ growth in terms of lung function, with the exception of FEV1/FVC z-score which falls further from their contemporaries. This effect on FEV1 and FVC z-scores may suggest some protective element or compensatory mechanism of being born small for gestational age. Reassuringly, Bronchopulmonary dysplasia as a neonate did not significantly affect lung function variables as these individuals as they age. Those with clinically abnormal lung function show a progressive failure to achieve optimal lung function whether or not they had Bronchopulmonary dysplasia.
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ItemThe influence of BCG vaccine strain on the immune response and protection against tuberculosis( 2009)More than 100 million doses of Bacille-Calmette-Guérin (BCG) vaccine are given each year to protect infants against tuberculosis (TB). BCG is a live attenuated strain derived from Mycobacterium bovis. Subsequent to its development and first use in 1921, BCG was distributed to laboratories worldwide. Culture under dissimilar conditions led to the evolution of more than 20 BCG vaccine strains in different countries. Phenotypic differences between these BCG vaccine strains were first recognised in the 1920s and, more recently, molecular studies have defined their genomic differences. Although several animal and human studies suggest that the particular BCG vaccine strain used for immunisation influences the mycobacterial-specific immune response, there is currently insufficient data to favour or recommend one BCG vaccine strain. The principal aim of this thesis was to investigate the influence of BCG vaccine strain on the mycobacterial-specific cellular immune response in infants. Related to this, three additional studies addressed questions that provided critical information for the design and interpretation of the main study. These studies investigated: (i) the BCG vaccine strains used in each country worldwide, (ii) the susceptibility of different BCG vaccine strains to antimycobacterial drugs; and (iii) the difference in the immune response induced by BCG immunisation in children and adults. For the main study in this thesis, newborns were randomly allocated to be immunised soon after birth with one of the three BCG vaccine strains currently most commonly used worldwide (BCG-Denmark, BCG-Japan or BCG-Russia). Ten weeks after BCG immunisation, the mycobacterial-specific cellular immune response was investigated using a comprehensive panel of immunological assays. This comprised flow cytometric analysis of intracellular cytokines and cytotoxicity in T cells, as well as the measurement of cytokines and chemokines in supernatants, from in vitro whole blood stimulation assays. Data from 167 BCG-immunised infants was included in the final analysis. Infants immunised with BCG-Denmark or BCG-Japan had significantly higher proportions of multifunctional CD4 T cells than infants immunised with BCG-Russia. Similarly, infants immunised with BCG-Japan had significantly higher levels of Th1 cytokines in supernatants than infants immunised with BCG-Denmark or BCG-Russia. These findings are particularly important in the light of recent evidence from animal studies that the frequency of multifunctional CD4 T cells induced by immunisation correlates with protection against intracellular pathogens such as Mycobacterium tuberculosis. This suggests that immunisation with BCG-Denmark or BCG-Japan is associated with better protection against TB than immunisation with BCG-Russia. Until correlates of protection against TB are determined in humans, cautious interpretation of these findings is warranted. Nonetheless, the findings from this thesis have important implications. The use of a BCG vaccine strain with even a moderately higher protective efficacy would have a large effect on TB morbidity and mortality in infants on a global scale. This thesis may therefore inform future BCG immunisation policy worldwide.
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ItemMeasurement of 'community readiness' for the prevention of adolescent substance abuse: a pilot study in four Australian regional communities( 2009)Health promotion and public health research increasingly recognise that a range of community organisation and attitudinal factors are important to a community’s level of readiness, or capacity, to undertake effective prevention activity required to reduce population rates of adolescent substance abuse. Although the importance of tailoring community capacity building to readiness levels is acknowledged, little research has been done to date, to develop a systematic framework for measuring readiness in Australia. Equally in Australia where national and state government drive public health drug policy and programme development, their interaction and support of community level interventions and efforts has not been widely examined. This methodological study of 100 telephone interviews with 60 community practitioners (15 in each community) was conducted to identify and assess the specific attitudinal, systemic and resource characteristics of four regional communities in order to extend their capacity or readiness to address adolescent substance abuse within their community. The study provided the opportunity to assess the feasibility, reliability and validity and utility of two North American questionnaires that had been developed to provide quantitative measurement of community readiness. Additional questions were included to try and gauge to what extent state government engaged with, and responded to, the four regional communities in the planning and initiation of prevention activity. Examination of this domain would also contribute to the understanding of state and community engagement with community empowerment. Each of the readiness questionnaires appeared comprehensible within the Australian context, requiring only minor modifications to wording and format to obtain reliable responses from community practitioners. Community readiness ratings for the four communities were consistent across the two instruments with each questionnaire assessing some overlapping and some distinct domains. The comparison of results from the two community readiness survey instruments suggested some advantages for the TECPR instrument in its slightly higher face validity to key informants and its ability to significantly discriminate the total readiness scores for the four communities. Analysis revealed some associations between the two readiness assessment methods; supporting the view that they were assessing some common underlying dimensions but also that they each provided some unique information. Analysis of the additional questions related to community empowerment suggested that the two assessment methods each contributed unique information in predicting local perceptions of community empowerment. It is concluded that each questionnaire has the potential to elicit detailed and reliable data concerning community-readiness, which can be quantitatively analysed; and is not unduly time-consuming or burdensome to the researcher or the respondents. One of the questionnaires holds particular merit for communities where research expertise in not available. Measurement of community readiness appears feasible in the Australian context opening opportunities for improved planning and evaluating of community development initiatives aimed at preventing adolescent substance abuse.
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ItemA profile of young adults aged 20-30 years with cerebral palsy in Victoria: health, function, pain, quality of life, social participation, and service utilisation( 2009)INTRODUCTION AND BACKGROUND: Cerebral palsy (CP) is the most common physical disability in childhood with a prevalence of approximately 2-2.5 per 100 live births. Improvements in paediatric care have increased the survival of individuals with CP. Overall 90% are expected to grow into adulthood yet little is known about the outcomes of young adults with this condition. In order to provide holistic services for this population, an understanding of various aspects of their lives is required. AIMS: To examine the outcome of young adults with CP from the perspective of perceived health status, functional ability, pain, quality of life (QOL), social participation, and healthcare service utilizations, compared with their able-bodied peers. To explore the determinants that contribute to the variation of these outcomes in the context of impairments, activity, participation, and personal and environmental factors. METHODS: This is a population based cross sectional study of young adults with CP based on the WHO International Classification of Functioning, Disability and Health (ICF) model. A cohort of 335 young adults with cerebral palsy born in Victoria, aged 20 to 30 years, was recruited from the Victorian Cerebral Palsy Register. Data of typically developed peers selected from the Household, Income and Labour Dynamics in Australia Survey 2004 were used for comparison for the outcomes of perceived health, pain, and social participation. Data from a population-based sample of 751 young adults in U.S. were used for comparative analyses of QOL. Participants were asked to complete a multidimensional questionnaire by self report, or proxy report by parents or carers for those with intellectual or severe physical impairments. The questionnaire was comprised of the Quality of Life Instrument for Young Adults, the Short Form-36 Health Survey Questionnaire version 2, the Gross Motor Function Classification System, the Barthel Index, and a demographic section. RESULTS: A total of 335 young adults with CP participated; 207 (62%) were able to self report and 128 (38%) were proxy reported. Compared with their able-bodied peers, self reported physical health in this population was lower but mental health was similar. Gross motor function, independence in self care, and limb distribution together explained 60% of the variance in the physical health data. They experienced more pain, impaired function, and reduced social participation, but despite this, their contact with medical and allied health professionals was low. Pain was linked with limb distribution and had a negative impact on functional ability, employment participation and QOL. Impaired functional ability, intellectual disability, and communication impairments had major effects in reducing social participation. Self reported QOL was similar to their peers in social relationship and environmental context domains, but was lower in the domains of physical health, psychological well-being, and role function. The impact of CP on the individuals’ QOL was on physical and functional aspects, and sometimes on social relationships, but not on psychological well-being. CONCLUSION: This study has demonstrated that greater efforts are needed to improve the health, function, QOL, and social participation in individuals with CP, accompanied by more research to monitor the effectiveness of interventions for them.
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ItemAttitudes towards newborn screening for Pompe disease among affected adults, family members and parents of ‘healthy’ children( 2009)Pompe disease is a rare autosomal recessive condition caused by a deficiency in lysosomal alpha glucosidase. It is a progressive and often fatal muscular disease with wide variation in clinical presentation. Two broad clinical categories of Pompe disease have been identified; infantile- and late- onset. In the past decade, enzyme replacement therapy has shown promising results in treating the underlying pathology, resulting in improved clinical outcome. Clinical trials indicating that initiation of treatment at an earlier disease stage leads to a higher chance of preventing permanent damage have led to the proposition of introducing newborn screening for Pompe disease. All forms of Pompe disease are caused by the same pathology, and thus newborn screening has the potential to identify those affected with the more severe infantile-onset form as well as those with late-onset disease who may not present with symptoms until late in life. The aim of this study was to investigate attitudes towards newborn screening for Pompe disease among affected adults, their family members and parents of ‘healthy’ children. Affected adults were recruited through support groups in Australia, the United Kingdom and United States; family members of affected adults were recruited from Australia; and parents of ‘healthy’ children were recruited through maternal child health clinics in Victoria, Australia. Participants completed questionnaires exploring their experiences of Pompe disease and/or newborn screening and their attitudes towards newborn screening for Pompe disease. Support for newborn screening for Pompe disease was high among adults with Pompe disease (85.4%), parents of ‘healthy’ children (93.9%) and all three family members of affected adults who participated in this study. However, when offered a theoretical screening test that would only identify infantile-onset Pompe disease, 42.1% of adults with Pompe disease and 53.1% of parents of ‘healthy’ children preferred this screen, indicating that these stakeholders have some concerns regarding detection of late-onset disease in infancy. Factors influencing attitudes were investigated and support for newborn screening in affected adults was highly correlated with age of onset of disease; a preference to have been diagnosed in infancy; a belief that an earlier diagnosis would have made symptoms easier to cope with; and a stronger confidence in the efficacy of enzyme replacement therapy. Potential benefits of diagnosis of late-onset disease in infancy were identified as being able to avoid the diagnosis odyssey, access enzyme replacement therapy at the optimal time, and allow individuals to make appropriate life choices. Participants identified increased anxiety in parents and the potential for over-protectiveness, in addition to possible discrimination, as harms of newborn screening for Pompe disease. Families in which an infant is identified with the potential for late-onset Pompe disease will need assistance to adapt to and manage this diagnosis, so that anxiety is minimised and unnecessary limitations are not placed on the child. Whilst potential medical and psychosocial benefits can result from newborn screening, it is important to carefully consider the potential for harm and the resources required to appropriately manage these so that ultimately benefit outweighs harm.
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ItemExploring the experiences of people who have consented to tumour testing for a hereditary disposition to cancer( 2009)Due to the costly and technically challenging nature of genetic testing, methods have been developed to target more specifically those who are at increased risk of carrying the Hereditary Non-Polyposis Colorectal Cancer (HNPCC) mutation. HNPCC is an inherited colorectal cancer syndrome. Testing of tumour material (which has previously been removed during surgery) for features of HNPCC has been found to be an effective and economic method of identifying those at higher risk of having a mutation. Only those at higher risk of having a mutation will undergo genetic testing. This practice of “tumour testing” has become widespread. There is currently no clarity about requirements for consent prior to testing of stored tumour tissue. The person giving consent to tumour testing does not always have an appointment with a genetics service prior to giving consent. This can be contrasted to genetic testing on blood samples where laws and guidelines state that informed consent is required prior to genetic testing and that comprehensive genetic counselling and support should be provided as part of this process. Protocols for genetic testing have been developed as a result of extensive research around the impact and implications of genetic testing. Consumer opinion and participation through research is an important aspect of health policy and guideline development. Accordingly the purpose of this study was to contribute to such development by gaining insight into the experiences, understandings, decision making processes and opinions of those who had given consent to have their own or their relatives tumour tested. Seventeen people who had given consent for tumour testing either for themselves, or on behalf of a deceased relative were recruited through a Familial Cancer Centre and in-depth interviews conducted. The interviews were transcribed and analysed using thematic analysis. Some participants had no memory of consenting to tumour testing. Others remembered basic concepts. Negative implications of testing were unknown or viewed as unimportant. Participants did not understand the difference between tumour testing and germline testing. Despite lack of memory or understanding participants did not want additional or more detailed pre-test information although they did want more follow-up and support after receipt of results. The decision to consent to testing was made as soon as participants were informed of the availability of tumour testing - the major reason being to provide information for the family that would aid in cancer prevention. Participants were more concerned with accessibility to testing than pre test information and counselling. Findings in this study indicated participants made decisions heuristically rather than systematically and this as well as participants’ opinions and other decision-making research has implications for the traditional view of informed consent around genetic related decisions. This in turn has implications for policy and guidelines in the area. Implications for current practise as a result of findings from this study include ensuring participants understand negative implications of testing and follow up and support of those with negative as well as positive results to tumour testing.
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ItemThe role of the Parkin Co-Regulated Gene (PACRG) in male infertility( 2009)A leading cause of male infertility is genetic variation in genes required for sperm formation and/or function. There is evidence to suggest PACRG is involved in mammalian spermatogenesis. Specifically, the loss of Pacrg function causes a spermatogenic defect and male infertility in mice. To investigate if PACRG plays a similar role in human spermatogenesis, the localisation of PACRG was determined in human testis. Using an immunohistochemical approach, this study demonstrated that PACRG is localised to the human sperm flagella. To investigate a potential role for PACRG in human male infertility, sequence analysis and an association study were performed. Sequence analysis did not identify any pathological alterations. However, 1 of 3 variants identified (rs9347683) was shown to be significantly associated with male infertility by association analysis (p=0.009, Odds Ratio=1.6, n=766). A high degree of structural and functional conservation exists between different types of motile cilia/flagella. Evidence from studies in C.reinhardtii and T.brucei indicate Pacrg is necessary for axoneme formation and microtubule stability. To test the role of the mammalian homologue, this study characterised the Pacrg knockout mouse, quakingviable (qkv) and generated Pacrg transgenic qkv mice (qkv-Tg). Using immunohistochemistry and immunoelectron microscopy this study demonstrated that Pacrg was localised to the axonemal microtubule doublets of sperm and ependymal cilia. The absence of Pacrg was associated with compromised sperm flagella formation and male infertility. In addition, histological and MRI analysis of qkv mutant mice revealed hydrocephalus. Specifically, qkv mutant mice showed a ~2.5 fold expansion of the lateral ventricle area compared to wildtype mice. The hydrocephalus phenotype was associated with a reduction in ependymal cilial beat frequency (CBF). Transgenic expression of Pacrg was sufficient to rescue the hydrocephalus and infertility phenotypes. In conclusion, this study has demonstrated that Pacrg is a novel axonemal protein in a subset of motile cilia and loss of Pacrg function results in spermiogenic defects and hydrocephalus in mice. Further, this study has shown that variations in the human PACRG promoter are a risk factor in human male infertility. Collectively these data provide evidence for a conserved role of PACRG in the cilial axoneme. This suggests the protein may be a candidate for a variety of human diseases characterised by cilial dysfunction.
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ItemUnfractionated heparin therapy in paediatrics( 2009)Unfractionated heparin (UFH) therapy is frequently used in tertiary paediatric healthcare facilities despite a lack of paediatric-specific research informing the optimal therapeutic intensity, monitoring recommendations or side-effect-profile in infants and children. As a result, the majority of clinical recommendations regarding UFH management in children have been extrapolated from adult evidence. The process of developmental haemostasis, in association with the variable pathogenesis of thromboembolic disease (TED) in children compared to adults, suggests that extrapolation of adult guidelines for UFH management to children is not ideal. This study hypothesised that the process of developmental haemostasis would influence both the action and effect of UFH in children of different ages. This hypothesis was tested by addressing the following aims: 1. To determine the pharmacokinetics (PK) of UFH in children of different ages; 2. To compare the different methods of monitoring UFH in children of different ages; 3. To identify the impact of competitive plasma binding of UFH in children of different ages; 4. To determine the impact of UFH upon tissue factor pathway inhibitor (TFPI) release in children. A prospective cohort study of children receiving a single bolus dose of UFH for primary thromboprophylaxis in the setting of cardiac angiography was conducted. Venous blood samples were collected prior to the UFH, then at 15, 30, 45 and 120 minutes post-UFH bolus. Laboratory assays performed included activated partial thromboplastin time (APTT), anti-Xa assay, anti-IIa assay, thrombin clotting time (TCT), protamine titration and TFPI. Levels of two plasma proteins known to competitively bind UFH (vitronectin and platelet factor 4) were determined and the impact of competitive plasma binding upon UFH activity, as measured by the anti-Xa assay, was quantified. A population approach to pharmacokinetic analysis, based on protamine titration results, was performed using WinNonMix™ Professional 2.0.1 (®1998-2000 Pharsight Corporation, Mountain View, CA, USA). Results were analysed according to the following age-groups: less than one year; one to five years; six to ten years; 11-16 years. Sixty-four children were recruited, ranging in age from six months to fifteen-and-ahalf years. The mean dose/Kg of UFH across the entire cohort was 90.9± 15.5 IU/Kg. Pharmacokinetic model specifications were systematically assessed, investigating the impact of parameter covariates and different error models upon objective function value and/or curve fitting. A first-order kinetic model best fitted the data. This model used weight 0.75 as the covariate of clearance and total weight as the covariate for volume of distribution. Parameter estimates for clearance and volume of distribution both demonstrated variance from adult and small neonatal PK studies of UFH, however methodological differences in PK analysis techniques limited comparisons. The half-life of UFH reported in this study was consistently and significantly shorter than that previously reported for adults, but longer than that reported for neonates. All measures of UFH-effect demonstrated a significant and prolonged increase post- UFH bolus. The mean APTT was 261 seconds 102 ± 25 minutes post-UFH, representing a seven-fold increase from the mean baseline APTT (38 seconds). Anti- Xa assay levels were within the therapeutic range for TED management (0.35 to 0.7 IU/mL), or greater, at every post-UFH bolus timepoint. This prolonged UFH-effect was evident to nearly two hours post-UFH bolus, without concurrent UFH infusion. Age-related differences in UFH-response were evident for anti-Xa, anti-IIa and protamine titration results. Furthermore, during periods of high UFH concentration, the ratio of anti-Xa to anti-IIa activity in children less than one year of age significantly favoured UFH-mediated anti-Xa effect over anti-IIa effect (1.9), compared to teenagers (1.3). This study demonstrated poor correlation between protamine titration and both the anti-Xa assay (r2 = 0.47) and APTT (r2 = 0.56). Use of the anti-Xa assay (0.35 to 0.7 IU/mL) or protamine titration assay (0.2 to 0.4 IU/mL) to establish APTT-based reference ranges for therapeutic management of TED resulted in APTT ranges with upper limits greater than 250 seconds. No age-related quantitative differences in plasma levels of vitronectin or platelet factor 4 were identified across the childhood years. The addition of dextran sulphate (DS) to ex vivo study samples demonstrated no change in anti-Xa activity in samples collected within 20 minutes of UFH bolus, however a significant increase in anti-Xa activity following the addition of DS was evident at all later timepoints post-UFH bolus. The measurement of TFPI before and after a single bolus dose of UFH demonstrated children have a similar immediate increase in TFPI activity following intravenous UFH compared to adults. However, the children in this series demonstrated a significantly prolonged level of increased TFPI activity, out to 102 ± 25 minutes post-UFH, compared to that reported in adult patients. This study has developed the first paediatric-specific PK profile of UFH and has elucidated a number of age-dependent UFH-mechanisms of action that contribute to the previously reported age-dependent response to UFH in children. The results of this study support the hypothesis that developmental haemostasis influences both the action and effect of UFH in children of different ages.
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ItemNasality in the Malay language: development of an assessment protocol for Malay speaking children with cleft lip and/or palate( 2009)The need for a standard approach for the diagnosis of speech disorders, in particular resonance disorders associated with cleft lip and/or palate, has been recognised. A reliable and valid measure of nasality is important, because it not only affects clinical decision making but is also essential for the evaluation of treatment outcomes. In order to allow cross-linguistic comparisons of the assessment of resonance, language specific stimuli developed according to a common set of guidelines have been recommended. The aim of this thesis was to contribute to the development of an assessment protocol for use in Malay speaking individuals with clefts of the lip and/or palate, specifically focusing on the detection of nasality. A series of four studies were completed which systematically developed and then validated a set of stimuli in the Malay language using both perceptual and instrumental measures. In the first study, three stimuli were developed for the assessment of nasality based on both the proportion of nasal phonemes in typical conversation samples in Malay and guidelines from the current international literature. The phonetic content of the stimuli were comparable to similar passages used in English and comprised of an Oral Passage, a Nasal Passage and a Set of Sentences. In the second study, the stimuli constructed were tested in a large number of typically developing (non-cleft) Malay speaking children using both instrumental and perceptual methods of assessment. The results of this study provide the first set of normative data of nasalance scores for the three newly developed stimuli. The mean nasalance score for the Oral Passage was 13.86% (SD = 5.11, 95% CI = 13.04–14.68), 60.28% (SD = 6.99, 95% CI = 59.15–61.41) for the Nasal Passage, and 27.72% (SD = 4.74, 95% CI = 26.96–28.49) for the Set of Sentences. These scores were significantly different from each other suggesting that they can be used to detect the different types of resonance disorder in speech (e.g. hypernasality and/or hyponasality). In the third study, the stimuli were validated in a sample of Malay speaking children with cleft of the lip and/or palate and compared with a control population. Nasality was measured using perceptual evaluation and nasometry. The results suggested that the Oral Passage and Set of Sentences developed in Malay were valid measures for detecting hypernasality for both perceptual evaluation of nasality, and for nasometry. Due to the small number of participants that were hyponasal, the validity of the Nasal Passage could not be determined. For nasometry to be clinically relevant threshold values that indicate abnormal nasality are required. The threshold values for each of the stimuli were first ascertained after obtaining typical nasality levels from a group of healthy Malay speaking children and then tested in a sample of cleft and non-cleft Malay speaking children. In contrast to the nasalance cutoffs obtained from typical Malay speaking children, the cutoffs obtained from the cleft children yielded better outcomes for detecting resonance disorders. The cutoffs were: ≥ 22% for the Oral Passage (sensitivity = 0.91, specificity = 0.93, overall efficiency = 0.92), ≥ 30% for the Set of Sentences (sensitivity = 0.96, specificity = 0.85, overall efficiency = 0.88) and ≤ 39 on the Nasal Passage (sensitivity = 1.00, specificity = 0.99, overall efficiency = 0.99). Finally, the fourth study explored the application of recently developed techniques for assessing nasality using spectral voice analysis and compared these results with nasometry using a sub-sample of Malay speaking children from the third study. The participants were children with cleft lip and/or palate with perceived hypernasality and a group of healthy controls perceived to have normal resonance. The potential of assessing nasality using vowels, which ideally can be an easier option to administer clinically and have minimal impact on language and literacy skills, were investigated. The findings showed that only the one-third-octave analysis method could be successfully used to detect hypernasality in the cleft population compared to the VLHR method. Using the one-third-octave analysis, the spectral characteristics of nasalised vowel /i/ taken from /pit/ and /tip/ showed an increase in amplitude in F1, between F1 and F2 regions. The amplitude of the formants at F3 region was lower in the cleft group but did not differ from the control group as reported in previous studies. Although, the one-third-octave analysis has some potential in detecting hypernasality, the accuracy of the analysis compared to perceptual ratings of nasality was only moderate. Compared to nasometry, the diagnostic value of the one-third-octave analysis in detecting hypernasality was lower. The overall findings suggest that, except for the Nasal Passage, the Oral Passage and the Set of Sentences developed in Malay using this systematic approach were culturally appropriate and valid for the assessment of nasality. Furthermore, by comparing two instrumental methods (nasometry and spectral analysis) with perceptual evaluation in a large number of cleft and typically developing children, the present thesis was able to demonstrate the clinical benefits of two recently proposed methods of spectral voice analyses and compare them to existing methods. Compared to spectral analysis, nasometry remains a superior method for assessing nasality. Threshold values that indicate abnormal nasality levels for the newly developed stimuli in Malay have been recommended.