Orofacial clefts are a group of congenital craniofacial deformities characterized by structural defects within and around the oral cavity. While some orofacial clefts are associated with an identifiable genetic or teratogenic syndrome, most are isolated or nonsyndromic. It has been well-documented that children born with nonsyndromic cleft lip and/or palate (NCL/P) are at-risk for poorer academic outcomes, especially within reading. Research into the cognitive functioning of patients with NCL/P has demonstrated that auditory-verbal memory and rapid naming are significant neuropsychological predictors of their lower reading achievement. Despite a solid compendium of research into the reading outcomes of those affected by NCL/P, very little research into the mathematical skills of this population exists. The current study examined whether the arithmetical computation skills of children, adolescents, and young adults with NCL/P differ significantly from healthy control participants. Comparisons of potential neuropsychological predictors of arithmetical computation were also conducted to determine whether these variables differ significantly for participants with NCL/P. Given the influence of language on both reading and mathematics and clear evidence of language impairments in individuals with NCL/P, it was hypothesized that arithmetical computation would be significantly lower for the NCL/P group. It was also hypothesized that the neuropsychological variables associated with lowered reading in NCL/P would be the strongest predictors of arithmetical computation. Results confirmed that arithmetical computation was significantly lower for the NCL/P group. Sustained attention, visual-spatial organization, auditory-verbal memory and rapid naming were significant predictors for the NCL/P group; rapid naming was the lone variable that was significantly more predictive of arithmetical computation for the NCL/P group than for control participants. These results suggest that inefficient verbal label retrieval related to short-term memory deficits underlie the computational difficulties of individuals with NCL/P. These findings have implications for approaches to remediation, as well as future research.

Background: Cleft lip and/or palate (CL/P) is a complex, heterogeneous disorder which occurs due to the interplay between environmental and biological risk factors. Individuals in lower-middle-income countries (LMICs) are exposed to a multitude of risk factors resulting in a greater occurrence of CL/P. Research and knowledge of which risk factors are associated with CL/P in LMICs may aid health care professionals such as speech-language therapists in low-income countries in the early identification of at-risk infants. Objective: To identify and review published data on the risks associated with CL/P in LMICs. Design: A systematic review of literature was performed on electronic databases using the PRISMA-P. Literature on risks associated with CL/P in LMICs, from 2010 to 2020 was included. Results: Seventeen studies met the inclusion criteria. All studies adopted an observational study design. Biological and environmental risks were identified. Maternal and paternal age (n=7) and low socioeconomic status (n=5) were the most prominently associated environmental risk factors. Regarding biological risk factors, a strong association was identified between family history of cleft (n=7) and CL/P occurrence. Conclusion: Environmental risk factors are now being investigated more than biological risk factors in LMICs, hindering health care workers in the early identification (EI) of the possible cumulative effects of risks in CL/P. Contextually-relevant tools are recommended to promote the EI of at-risk infants. / Dissertation (MA (Speech-Language Pathology))--University of Pretoria, 2021. / Speech-Language Pathology and Audiology / MA (Speech-Language Pathology) / Unrestricted

Background: The management of cleft lip and/or palate (CL/P) includes multidisciplinary care beginning in infancy and continuing through to adulthood. Outcomes of cleft care have been difficult to measure because of the subjective nature of evaluating concepts such as appearance and speech. Including the patient perspective in outcome evaluation through the use of a patient-reported outcome (PRO) measure would provide a more accurate reflection of a patient’s status. The overall objective of this thesis is to show that through adherence to rigorous methods of development, a PRO measure can provide clinically meaningful outcome evaluation in cleft care. Methods: The first paper uses the qualitative method of interpretive description to define a conceptual framework to guide the development of a PRO measure for patients with CL/P, the CLEFT-Q. The second paper describes the protocol for the entire development of the CLEFT-Q. The third paper analyzes the results of the cross-sectional field-test of the CLEFT-Q scales to determine whether or not the CLEFT-Q is able to detect differences between specific cleft types. Results: The qualitative study included 138 patients with CL/P from six countries. The final conceptual framework contained thirteen concepts within the domains of appearance, facial function, and health-related quality of life. The second paper details the process of designing the CLEFT-Q scales. The field-test included 2,434 patients from thirty sites in twelve countries, and CLEFT-Q scores were found to vary with cleft type for all scales. Conclusions: PRO measures need to be rigorously designed in order to provide scientifically sound, clinically meaningful measurement. The CLEFT-Q is able to detect differences between patients with various cleft types, and will be a useful tool to provide the patient perspective in future outcome evaluation in cleft care. / Thesis / Doctor of Philosophy (PhD) / Measuring outcomes of treatment for cleft lip and/or palate (CL/P) should include the patient perspective. The objective of this thesis is to show that through rigorous methods of development, a patient-reported outcome (PRO) measure, the CLEFT-Q, can provide clinically meaningful evaluation of outcomes. First, 136 patients with CL/P from six countries were interviewed to learn what concepts related to having a cleft or its treatment are important to them. A conceptual framework was developed that informed the CLEFT-Q scales. Describing the methodology behind developing the CLEFT-Q then served to inform and engage members of the community. A field-test of the CLEFT-Q scales showed that in a sample of 2,434 patients with CL/P from twelve countries, CLEFT-Q outcomes varied in patients with different types of CL/P. The CLEFT-Q can be used to provide rigorous measurement of PROs in patients with CL/P in the future.

A saúde bucal é um fator indispensável no sucesso da reabilitação estética e funcional dos indivíduos portadores de fissuras labiopalatinas. O objetivo deste estudo foi verificar a prevalência de cárie dental em crianças com fissura de lábio e/ou palato na faixa etária entre 6 e 36 meses. A pesquisa foi desenvolvida na FOUSP, com crianças fissuradas registradas no ambulatório de Prótese Buco Maxilo Facial desde os primeiros meses de vida, apresentando pelo menos dois elementos dentais erupcionados e utilizando água de abastecimento público fluoretada. Selecionou-se 143 crianças, 73 meninos e 70 meninas, com distribuição homogênea em 5 faixas etárias: 6-12, 13-18, 19-24, 25-30, 31-36, sendo agrupadas segundo a classificação de Spina em 88 crianças com fissura transforame incisivo, 20 com fissura pré-forame incisivo e 35 com fissura pós-forame incisivo. Um único examinador efetuou o exame clínico após profilaxia dental, através de luz artificial, espelho clínico e sonda exploradora de ponta romba para diagnosticar a presença de cárie, a qual foi relacionada com tipo de fissura, gênero e idade. Paralelamente, foi aplicado um questionário em forma de diálogo para averiguar a experiência de cárie em relação aos fatores de risco: amamentação noturna, introdução de açúcar e ausência de higiene oral. Os dados foram tabelados e submetidos à análise estatística aplicando o teste de Qui-quadrado ajustado pela estatística de Fischer. As crianças acometidas por cárie corresponderam a 18,88% da amostra com distribuição similar entre os gêneros, e embora a prevalência de cárie tenha sido maior nas fissuras tranforame incisivo, essa relação não mostrou significância estatística. A medida que aumentou a idade, o número de crianças com experiência de cárie também aumentou (p<0,001). Quanto aos fatores de risco, o único a mostrar associação foi a introdução de açúcar (p=0,001). Um total de 1743 elementos dentais foi avaliado, dos quais 62 estavam cariados e 5 obturados, determinando um ceo-d médio de 0,46 e um ceo-s médio de 0,74, definindo uma severidade muito baixa. A cárie prevaleceu na arcada superior, sendo que os incisivos centrais foram os mais acometidos (p=0,044). Na arcada inferior, a cárie prevaleceu nos primeiros molares (p<0,001). Conclui-se que as crianças com fissuras de lábio e/ou palato, independente do gênero, não manifestam um alto índice de cárie e não há associação entre a presença de cárie e o tipo de fissura. A prevalência de cárie acresce com o aumento da idade e mostra relação com a introdução de açúcar na dieta, sendo que o incisivo central superior é o dente mais acometido. / The oral health is one of the important factors to the success of an aesthetic and functional oral rehabilitation of the individuals carrying cleft lip and palate. The main objective of that study was to evaluate the dental caries prevalence in children carrying cleft lip and/or palate, aged 6 to 36 months. The research was developed in FOUSP, with children carrying cleft lip and/or palate enrolled by treatment in the ambulatory of Bucco-Maxillo-Facial Prostheses, since their first months of age. Those children used to have public fluoridate water supply and at least two erupted dental elements. Were selected 143 children, 73 from the male gender and 70 from the female, uniformly distributed into 5 age groups 6-12, 13-18, 19-24, 25-30, 31-36 months old. From the sample, 88 children had cleft lip and palate (CLP), 20 had cleft lip (CL) and 35 had cleft palate (CP). A single investigator carried out the clinic exam after the dental prophylaxis, using dental operating light, dental mirror and probe to diagnose the presence of caries and its relationship to the cleft type, gender and age of the individual. At the same time, a questionnaire in dialogue form was applied to check the caries experience related to the risk factors: nighttime bottle, introduction of sugar in dietary and lack of oral hygiene. The data were placed in a table and submitted to the statistical analysis using the Q-Square test adjusted by Fischer\'s statistic method. The children affected by caries had corresponded to 18.88% of the sample with a similar distribution among the gender and, despite the caries prevalence had been bigger in the CLP, that relation didn\'t show statistical significance. When increasing the age, the number of children with caries prevalence also increased (p<0,001). Considering the risk factors, the only one showed relationship was the introduction of sugar in dietary (p=0,001). A total of 1743 teeth were evaluated and 62 of them were decayed and 5 filled, determining an average dmf-t of 0.46 and an average dmf-s of 0.74, determining a very low severity. The caries prevailed at the upper maxillary, being the upper maxillary incisor teeth the most affected element (p=0,044). In the mandible the caries prevail in the first molar teeth (p<0,001). The findings of that research showed that the children with CLP, regardless of gender, didn\'t show a high index of caries and a statistical significant relationship between caries prevalence and CLP types. The caries prevalence increases when increasing the age showing a relationship with the sugar introduction in the dietary being the upper maxillary incisor tooth the most affected element.

Objetivo: Caracterizar e analisar os aspectos psicossociais e familiares de indivíduos com e sem distúrbios da comunicação decorrentes da fissura labiopalatina. Modelo: Estudo descritivo e comparativo de dois grupos: GI - com distúrbios da comunicação decorrentes da disfunção velofaríngea, alterações dento-oclusais e/ou atrasos no desenvolvimento da fala e GII - indivíduos sem distúrbios da comunicação. Local: Hospital de Reabilitação de Anomalias Craniofaciais - Universidade de São Paulo, Bauru. Participantes: 38 indivíduos distribuídos: GI - 20 e GII - 18; acima de 4 anos participantes do “Projeto Flórida", com fissura transforame unilateral, sem outras deficiências e/ou anomalias associadas. Intervenções: Análise documental e entrevista abordando questões sobre estratificação social, histórico e dinâmica familiar, relações sociais de indivíduos e família, tratamento reabilitador e recursos organizacionais e comunitários. Resultados/Conclusão: Não foram constatadas relações significativas entre os resultados pós tratamento no que se refere a fala e a condição socioeconômica dos pacientes. Não foram detectadas diferenças significativas entre os aspectos psicossociais e familiares entre os grupos com e sem distúrbios exceto no cotidiano escolar de uma minoria de pacientes (com distúrbios). Embora algumas categorias não apresentaram significância estatística, todas se configuraram como expressivas, e determinantes para o conhecimento qualitativo dos aspectos psicossociais e familiares e para a atuação da equipe de reabilitação que, com sua visão de totalidade, busca com os pais e a sociedade, a inclusão social do paciente. / Objetive: To characterize and analyze the psychosocial and familiar aspects of individuals with and without communication disorders related to cleft lip and palate. Design: Descriptive and comparative study of two groups: GI – group of individuals with communication disorders related to velopharyngeal dysfunction, dento-occlusal alterations and/or delays in speech development, and GII - group of individuals without communication disorders. Research Site: Hospital for Rehabilitation of Craniofacial Anomalies, University of São Paulo, Bauru, Brazil. Participants: 38 individuals distributed into two groups (GI: N=20 and GII: N=18); all participants were at least four years of age and were enrolled in the “Florida Project", presenting with unilateral transforame cleft not associated to other malformations or anomalies. Methods: Interview and data analysis focusing on socioeconomic status, family dynamics and history, individuals and family social relationship, care and management of anomaly and support community resources. Results/Conclusion: There were no significant differences in the socioeconomic status between children with and without communication disorders. There were no significant differences in the psychosocial and familiar aspects between children with and without communication disorders except regarding school routine which was distinct for a minority in the group with communication disorders. Even though some of the aspects studied did not show significant, the findings provided qualitative information regarding the psychosocial and familiar aspects supporting team management in a search for patient’s inclusion in a partnership with the parents and the community.

Orofacial clefts are among the most common congenital defects in the United States, affecting roughly 1 in 600 births annually. A majority of these cases are considered to be “isolated” clefts of the lip and/or palate (ICLP). However the term “isolated” is somewhat of a misnomer, as functional deficits frequently accompany ICLP. One of the most problematic yet understudied of these deficits involves the high prevalence of reading disabilities in this population. It has been estimated that as high as 46% of children with ICLP will be diagnosed with a reading disability, particularly dyslexia. Despite this high prevalence and the well-established neurological basis of dyslexia, relatively little attention has been paid to the role that brain development plays in the reading problems in ICLP. Previous studies from our lab have demonstrated significant changes in brain structure in children with ICLP (that have importantly correlated with functional measures). However we have yet to combine both a structural and functional neuroimaging study with an in-depth analysis of reading dysfunction in this population. The current study examined boys with ICLP, age 8-12 (boys have a higher prevalence of ICLP and show more significant reading problems that girls with ICLP) compared to healthy control boys. Measures of cognitive functioning were obtained with an emphasis on reading and language skills. In addition MRI scans were obtained which included volumetric measures, diffusion-weighted measures (DWI; white matter), and connectivity measures (resting-state fMRI). Even after controlling for the effect of socioeconomic status, boys with ICLP showed significant decreases in reading and language skills (particularly reading fluency). Boys with ICLP did not show significant differences on phonlogical measures (the primary cause of dyslexia). In addition, phonological measures were not predictive of reading fluency, while object naming tasks were predictive of reading fluency in boys with ICLP. For white matter integrity, measures of fractional anisotropy (FA) were found to be increased in the right occipital lobe for boys with ICLP indicating more organized white matter in this region. This increase in right occipital FA was also predictive of better reading outcomes, particularly reading fluency. For more specific white matter tracts, only the fornix and the tapetum (both associated with the temporal lobes) showed a significant difference with a decrease in FA for boys with ICLP. The decrease in FA in the tapetum was also predictive of better reading outcomes in ICLP. When looking at resting-state networks, boys with ICLP showed an increase in connectivity within posterior and subcortical regions when compared to healthy control boys, indicating stronger network connections within the posterior language regions of the brain. Taken together, these results point to differences in both structural and functional connectivity in the brains boys with ICLP. Furthermore, this pattern is different than that found in children with developmental dyslexia as there appears to be no disruption of the posterior reading systems. Cognitive measures also indicate normal phonological awareness in this group, further distinguishing them from dyslexic children. Boys with ICLP instead may be over-relying on these posterior, more visually oriented reading systems as a compensatory mechanism to overcome problems with the development of the typical “lexical route” of reading.

Background: Nonsyndromic cleft lip and palate (NSCL/P) is a complex trait caused by genetic and environmental factors that interact producing a wide spectrum of orofacial malformations, including dental anomalies. The underlying genetic etiology that accounts for phenotypic variation in affected families is poorly understood. Purpose: The purpose of this study is to utilize shape and microesthetic analysis to characterize the maxillary anterior dentition in unaffected parents of children with NSCL/P (cases) compared to control adults with no CL/P history to identify dental morphology features that are part of the NSCL/P phenotypic spectrum and can therefore be used in refining NSCL/P phenotypes and identifying genetic risk factors. Methods: Individuals were recruited from 5 sites including Iowa, Texas, Hungary, the Philippines, and Pittsburg, PA. From a total of 3202 individuals, 420 quailified after strict selective criteria. Digital photographs from 198 cases and 222 controls were analyzed using linear metrics and 2D-coordinate landmark-based geometric morphometrics (GM) to compare dental esthetics and deviations from golden proportions." Differences in central incisor and connector height proportions were evaluated using paired T-tests. Anterior tooth shapes were examined using GM techniques. Results: Three shape differences were found to be possible predictors of genetic risk. These included shorter maxillary anterior teeth overall, square shaped lateral incisors on the left side, as well as lateral incisors and canines with long axes angled inward toward the midline on the left side. Both the case and control groups were found to be significantly different than the proposed ideal values of tooth proportions. Conclusions: Significant differences in anterior dental morphology were found between cases and controls, with controls displaying a more ideal dental morphology than cases for most evaluated measures. The identification of these distinct dental features in carriers of NSCL/P genetic risk factors further characterizes the phenotypic spectrum of NSCL/P which can enhance the power of genetic studies.

Orofacial clefts are a heterogeneous group of craniofacial malformations that affect the lip and/or palate and represent the most common craniofacial birth defect in humans. In 30% of patients the cleft is accompanied by additional physical or cognitive abnormalities. Hundreds of these clefting syndromes have been described, many of which have Mendelian inheritance patterns. The most common of these is Van der Woude syndrome (VWS), caused by mutations in the transcription factor IRF6 (Kondo et al. 2002). The other 70% of patients lack additional features and are considered nonsyndromic. The etiology of nonsyndromic clefts is complex and involves the combined action of multiple genetic variants interacting with environmental factors. A common approach for identifying genetic risk factor for complex disorders such as nonsyndromic cleft lip with or without cleft palate (NSCL/P) is the genome wide association study (GWAS). We pursued a locus on 1p22 shown to be associated with NSCL/P by Beaty et al. (2010). Through a combination of expression studies in a mouse model and mutation screening in NSCL/P patients, we identified ARHGAP29 as a novel gene for NSCL/P and the likely etiologic gene at this locus. We identified eight rare variants in NSCL/P patients absent in controls including a nonsense and a frameshift mutation. These rare variants are reminiscent of previous resequencing studies that reported rare coding mutations in 20 different candidate genes for NSCL/P. We reviewed these variants and compared them with variants found in over 7000 exomes from the 1000 Genomes Project (1kGP) and NHLBI Exome Sequencing Project (ESP) to identify the variants and genes most likely to contain etiologic rare variants. We found good support for a role for rare variants in NSCL/P, particularly for MSX1 and genes of the FGF signaling pathway. We next performed several studies to understand the genetic architecture of syndromic forms of clefting, focusing on VWS and popliteal pterygium syndrome (PPS), which is allelic to VWS. We compiled all of the nearly 300 published IRF6 mutations and compared the distribution of these mutations with IRF6 variants obtained from the 1kGP and ESP exomes. We found that mutations causing VWS were significantly over-represented in the DNA-binding domain and for the most part were absent from control exomes, indicating that they are likely to be truly causative for VWS or PPS. These mutations in VWS and PPS only account for 70% of VWS and 97% of PPS. We next hypothesized that mutations in RIPK4, which causes an autosomal recessive pterygia syndrome, could underlie the remaining VWS and/or PPS cases. We found novel homozygous mutations in RIPK4 in two PPS patients. This result has significant clinical ramifications, as counseling of recurrence risk is very different for PPS patients whose disease is caused by dominant IRF6 mutations compared to recessive RIPK4 mutations. Finally, to understand the variable expressivity of VWS and PPS we performed an association study to identify genetic modifiers. We also looked for genotype-phenotype correlations between the type and location of IRF6 mutations. Although we did not find strong evidence that the candidate genes we selected from GWAS of NSCL/P or other clefting syndromes are modifiers of the VWS or PPS phenotypes, several marginal associations suggest that members of the IRF6 gene regulatory network could act as modifiers. Finally, we found evidence of a larger genotype-phenotype correlation by demonstrating that mutation-negative VWS families have a deficiency of cleft lip phenotypes. Together this work has advanced our understanding of the genetic basis of this diverse set of cleft lip and palate disorders, informing both the biology of craniofacial development and the clinical care of patients affected by these disorders.

Nonsyndromic cleft lip and/or palate (NS CL/P) is a common birth defect with estimated birth prevalence of 1/1000 worldwide. NS CL/P etiology may be explained by the action of as few as two or as many as 14 different genes (Schliekelman et al. 2002) as well as several environmental factors (e.g. smoking and folic acid) (Shi et al. 2008; Wehby et al. 2010). Convincing genetic and/or biologic evidence exists for the contribution of many genes: IRF6, 8q24, FGFR2, FOXE1, BMP4, TGFβ3, MSX1, MAFB , PAX7, ABCA4, and VAX1, to NS CL/P (Dixon et al. 2011). Clefts place substantial burdens on families and society with the estimated costs of cleft care and surgical repair around $100,000 in the United States (Jugessur et al. 2009). The health burden of NS CL/P does not end after the last surgery - impaired social development, surgical morbidity, and cancer are all reported in older children and adults with NS CL/P. Genes involved in clefting during development may be involved in other processes throughout life. We hypothesize that non-coding variation of the FGFR2 gene is associated with NS CL/P and these variants correlate with levels of gene expression. We investigate links between clefting, wound healing, and genes implicated in cancer in NS CL/P families. Analysis of family genotype data with the Transmission Disequilibrium Test (TDT), demonstrated suggestive association for two non-coding SNPs, rs2912770 with CL/P (p = 0.002 -USA) and rs2114684 with cleft palate (p = 0.002 - USA and all populations) but not for SNPs located within intron 2 - where genome wide association (GWA) signals overlap in both NS CL/P and breast cancer studies. Studies of foreskin tissue supported correlation of rs2912770 genotype with level of FGFR2 expression, though the magnitude of the effect was modest and did not remain significant after correction for multiple comparisons. Transcriptome array analysis suggested novel regions of regulated transcription, but their function as novel exons was not validated by real-time PCR (RT-PCR). As we expanded our focus from FGFR2, we examined association of cleft candidate genes with wound healing complications (WHC) with case-control and TDT analysis. Allelic and genotypic case-control analysis suggests association of rs2981582 with WHCs (p < 0.08). TDT analysis revealed WHC potential association with rs6478437 located upstream of the ( FOXE1) gene (p = 0.04). This study has medical implications, as the identification of children at high-risk for WHCs prior to surgical treatment and interventions may prevent post-surgical wound healing complications. We finally examined NS CL/P association with genes that had prior evidence for a role in clefting and cancer. In this analysis, we observed TDT association of rs4746409, located in intron 4 of the zinc finger 365 ( ZNF365) gene (p = 0.0003). Interestingly, this gene and SNP were tested due to suggestive association with breast cancer (Turnbull et al. 2010) and NS CL/P from GWA analyses (Beaty et al. 2010), which strengthens the connection between NSCL/P and breast cancer risk. Identification of NS CL/P patients at increased cancer risk could save lives and extend healthy life for current cleft patients as the field continues to seek ways to intervene and prevent cleft lip and palate from occurring.

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.