Orofacial clefts (OFCs) are among the most common structural birth defects and a public health problem. Several studies suggest that maternal obesity pre-existing diabetes mellitus (DM), and the underlying metabolic abnormalities, may be involved in the pathogenesis of cleft lip (CL) and cleft palate (CP) birth defects. Although hypertension and gestational diabetes mellitus (GDM) have been associated in a few studies with congenital birth defects, studies examining the risk associated with OFCs are limited. The overall objective of this dissertation was to examine the association between maternal obesity, DM, GDM, and hypertension and the risk of OFCs in case-control studies. Analyses of data from an international consortium revealed that maternal obesity (pre-pregnancy BMI >30), compared to normal weight (18.525), was associated with an increased risk of cleft palate with or without cleft lip (CP/L) (adjusted odds ratio (aOR) =1.13 [95% confidence intervals (CI) 1.01-1.25]). We also found a marginal association between maternal underweight and CP/L (1.0 [reference]; aOR=1.14 [0.97-1.34]. CL only was not associated with maternal bodyweight. Interestingly, among college-graduates, there was no increased risk of CP, but mothers with less than a completed college education had an increased risk of CP for underweight and obesity. Investigation of the Utah OFC data provided evidence that maternal GDM is significantly associated with isolated (aOR=2.63 [1.30-5.34]) and non-isolated clefts (aOR=2.66 [1.02-6.97]). Maternal hypertension is significantly associated with non-isolated clefts (aOR=6.56 [2.18-19.77]). We found a further elevated risk of OFCs among GDM mothers and those with hypertension who were also obese. The analyses of data from an international consortium revealed significant associations between maternal diabetes and the risk of OFCs. The estimated relative risk of DM for isolated OFCs was 1.33 [1.14-1.54] and was slightly higher for multiple OFCs (aOR=1.86 [1.44-2.40]). Diabetic mothers with abnormal body-mass-index had an increased risk for having inborn with OFCs. Throughout the dissertation, we demonstrated the extent in which maternal obesity, pre-existing DM, GDM, and maternal hypertension may increase the risk of OFC birth defects. The results highlight the need for pre-conceptional program planning for the prevention of OFCs with screening for abnormal glucose tolerance and hypertension.

Diabetic embryopathy is a major complication of pregnant women with type I diabetes. Immune defects in the pathogenesis of diabetic embryopathy have been suggested. We hypothesized that activated immune system can counteract diabetic effect and result in prevention of diabetic embryopathy. Diabetes was induced in pregnant ICR mice by streptozocin injection. Three different techniques of maternal immune stimulation, complete Freund's adjuvant (CFA), granulocyte-macrophage colony-stimulating factor (GM-CSF), or interferon-gamma (IFN-g), were used to stimulate the maternal immune system. Approximately 50% of fetuses from hyperglycemic (>27 mM/L) dams were malformed, with neural tube defects predominating. Maternal immune stimulation during the time of normoglycemia, i.e. prior to onset of hyperglycemia, was necessary for reducing teratogenic effects associated with hyperglycemia. The immune-stimulated diabetic mice then produced significantly lower numbers of malformed fetuses: CFA 20.9%, GM-CSF 23.3%, IFN-g 13.9%. A gene microarray was then used to examine a selected panel of placental and splenic genes. We hypothesized that a shared profile of placental or splenic gene expression changes may correlate to the reduced birth defect outcome induced by the different immune stimulation procedures. Diabetes did not cause significant changes in placenta or spleen gene expression profile. In placenta, CFA and GM-CSF changed placental gene expression relative to control or diabetes, but differentially affected such genes relative to each other; further, IFN-g did not affect gene expression relative to control or diabetes. Thus no common pattern of improved placental cytokine, cell-cycle, apoptotic, transcription factor, or other gene expression was identified in the immune-stimulated mice. In spleen, all 3 immune activators produced a common altered gene expression profile. The overall gene expression profile after all immune stimulation procedures suggested increased splenocyte activity and cytokine production. The cytokine GM-CSF, in particular, was up-regulated in splenic leukocytes. This cytokine has previously been associated with reduced cleft palate in urethane-exposed mice after immune stimulation, and with reduced limb malformations in cyclophosphamide-treated mice after intra-uterine administration. In contrast, the TGF-beta3 gene was down-regulated in immune-stimulated diabetic mice. This gene was up-regulated in urethane-exposed mice, an effect that may be associated with reduced cleft palate. Thus unlike urethane, TGF-beta3 gene expression did not show a relationship with reduced diabetes-induced birth defects. Taken together, these data prove our hypotheses and suggest that mechanistically diverse forms of immune activation result in protection against diabetes-related teratogenesis, but only if given prior to onset of hyperglycemia. Such immune stimulation in mice may act through systemic immune organs, i.e. spleen, over-riding adverse effects of diabetes on development. / Ph. D.

The purpose of this study was to develop and describe a model for the enhancement of self-concept of people with oculocutaneous albinism based on the experience of the participants. The need to conduct the study was triggered by the researcher’s long-term interaction with people with oculocutaneous albinism, and observation that they are still stigmatised and marginalised by the community. A purposive sample of fifteen participants, consisting of twelve females and three males with oculocutaneous albinism, aged between 18 and 48, participated in the study. The study was conducted in urban and semi-urban areas around the Gauteng Province in South Africa. The study had two theory generative objectives, namely to identify the main concepts of the model from the findings, and to describe the model structure and process. A theory generative, qualitative, explorative, descriptive and contextual research design was used to achieve these objectives. Chinn and Kramer’s (1995:92) four steps of theory-generation were used, namely concept analysis, construction of theoretical relationships, description of the model, and development of guidelines to operationalise the model.Concept analysis involved identification, definition and classification of the concepts to develop the model. In-depth, phenomenological interviews were conducted to explore the participants’ experience. Data analysis and interpretation revealed three main themes from the findings: the participants’ perception of the self; experience with the external environment, and expression of need for development and growth. The main concepts deducted from the findings were “self-concept” and “enhancement” hence “A model for enhancement of self-concept of people with albinism”. Construction of theoretical relationships entailed using deductive reasoning to describe the interaction between the concepts of the model. Description of the model entailed visually portraying and describing the structure and process of the model, as well as evaluating it. Developing guidelines to operationalise the model entailed describing practical strategies to assist health professionals to enhance the self-concept of people with oculocutaneous albinism. / Health Studies / D. Litt. et Phil. (Health Studies)

Introdução: O Sistema de Informação sobre Nascidos Vivos (SINASC) é um instrumento importante para o monitoramento de defeitos congênitos (DC) ao nascer, porém há falhas de preenchimento dessa informação e possivelmente são registrados nas Declarações de Nascido Vivo (DN) os DC mais aparentes, o que pode subestimar a prevalência dos mesmos. A linkage de bancos de dados do SINASC e do SIM (Sistema de Informação de Mortalidade) permite recuperar as informações sobre DC registrados no SIM complementando os dados e fornecendo uma estimativa mais real da prevalência dos DC. Objetivo: Estimar a prevalência de DC em uma coorte de nascidos vivos (NV) vinculando-se os bancos de dados do SIM e do SINASC. Método: Estudo descritivo para avaliar as DN como fonte de informação sobre DC. A população de estudo são os NV hospitalares do 1º semestre de 2006 de mães residentes e ocorridos no Município de São Paulo no período de 01/01/2006 a 30/06/2006 e óbitos neonatais provenientes da coorte. As diferenças entre portadores e não portadores de DC foram testadas através do risco relativo, valor de p e IC 95%. Resultados: Os defeitos congênitos mais prevalentes segundo o SINASC foram: malformações congênitas e deformidades do aparelho osteomuscular (44,7%), malformação congênita do sistema nervoso (10,0%) e anomalias cromossômicas não classificadas em outra parte (8,6%). Através da linkage, houve uma recuperação de 48 casos (80,0%) de DC do aparelho circulatório, 11 casos (73,3%) de DC do aparelho respiratório e 5 casos (62,5%) de outros DC do aparelho digestivo. O SINASC fez 55,2% das notificações de DC e o SIM notificou 44,8%, mostrando-se importante para a recuperação dos dados de DC presentes na Declaração de Óbito (DO). A taxa de prevalência para os DC da coorte segundo o SINASC foi de 75,4/10.000 NV; com os dados corrigidos pelo SIM, essa taxa passou para 86,2/10.000 NV. As variáveis idade da mãe, idade gestacional, tipo de parto, Apgar, sexo e peso ao nascer mostraram-se associadas à presença de DC (p<0,001). Não foi encontrada associação entre anos de estudo, estado marital, paridade, filhos mortos anteriores, pré-natal, tipo de gravidez, raça/cor e a presença de DC. Conclusão: A complementação dos dados pelo SIM fornece um perfil diferente da prevalência de DC do que aquele que seria registrado apenas pelo SINASC, mostrando a importância do uso conjunto das duas fontes de dados. / Introduction: Live Birth Information System (SINASC) is an important instrument to monitor birth defects (BD) at the birth, however it has fulfilling imperfections of this information and they are probably registered in the Birth Certificates (BC) the BD more apparent, what can under estimate the prevalence of the some ones. The linkage of the data of SINASC and of SIM (Mortality Information System) allows the recovery of information about BD registered in SIM complementing the data and supplying a more real estimate of the prevalence of BD. Objective: Come with the prevalence of BD in a cohort of live birth (LB) associating the data base of SIM and the SINASC. Methods: Descriptive study to evaluate BD as source of information about BD. The population of study is the LB hospital of 1° semester of 2006 of resident mothers and that had happened in São Paulo city in the period from 01/01/2006 to 06/30/2006 and neonatal deaths from the cohort. The differences of carriers and not carrying of BD had been tested through the relative risk, p value and CI 95%. Results: According to SINASC the most prevalent birth defects were: birth defects and osteomuscular system deformity (44,7%), birth defects of nervous system (10,0%) and cromossomics anomalies not classified in another part (8,6%). Through linkage, it had a recovery of 48 cases (80,0%) of BD of circulatory system, 11 cases (73,3%) of BD of respiratory system and 5 cases (62,5%) of other BD of digestive system. SINASC made 55,2% of the notifications of BD and SIM notified 44,8%, showing its importance to recovery data of BD presents in Death Certificate (DC). The tax of prevalence for the BD of cohort according to SINASC was 75,4/10.000 LB; with all the data corrected by SIM, this tax changed for 86,2/10.000 LB. The variable age of mother, pregnancy age, birth type, Apgar, sex and weight at birth are associated to the presence of BD (p<0,001). Association between the years of study, marital status, parity, previous dead children, prenatal, pregnancy type, race and the presence of BD were not found. Conclusion: Data complementing by SIM supplies a different profile of prevalence of BD from those ones that would be registered only by SINASC showing the importance of the usage of two data sources.

Introdução: O Sistema de Informação sobre Nascidos Vivos (SINASC) é um instrumento importante para o monitoramento de defeitos congênitos (DC) ao nascer, porém há falhas de preenchimento dessa informação e possivelmente são registrados nas Declarações de Nascido Vivo (DN) os DC mais aparentes, o que pode subestimar a prevalência dos mesmos. A linkage de bancos de dados do SINASC e do SIM (Sistema de Informação de Mortalidade) permite recuperar as informações sobre DC registrados no SIM complementando os dados e fornecendo uma estimativa mais real da prevalência dos DC. Objetivo: Estimar a prevalência de DC em uma coorte de nascidos vivos (NV) vinculando-se os bancos de dados do SIM e do SINASC. Método: Estudo descritivo para avaliar as DN como fonte de informação sobre DC. A população de estudo são os NV hospitalares do 1º semestre de 2006 de mães residentes e ocorridos no Município de São Paulo no período de 01/01/2006 a 30/06/2006 e óbitos neonatais provenientes da coorte. As diferenças entre portadores e não portadores de DC foram testadas através do risco relativo, valor de p e IC 95%. Resultados: Os defeitos congênitos mais prevalentes segundo o SINASC foram: malformações congênitas e deformidades do aparelho osteomuscular (44,7%), malformação congênita do sistema nervoso (10,0%) e anomalias cromossômicas não classificadas em outra parte (8,6%). Através da linkage, houve uma recuperação de 48 casos (80,0%) de DC do aparelho circulatório, 11 casos (73,3%) de DC do aparelho respiratório e 5 casos (62,5%) de outros DC do aparelho digestivo. O SINASC fez 55,2% das notificações de DC e o SIM notificou 44,8%, mostrando-se importante para a recuperação dos dados de DC presentes na Declaração de Óbito (DO). A taxa de prevalência para os DC da coorte segundo o SINASC foi de 75,4/10.000 NV; com os dados corrigidos pelo SIM, essa taxa passou para 86,2/10.000 NV. As variáveis idade da mãe, idade gestacional, tipo de parto, Apgar, sexo e peso ao nascer mostraram-se associadas à presença de DC (p<0,001). Não foi encontrada associação entre anos de estudo, estado marital, paridade, filhos mortos anteriores, pré-natal, tipo de gravidez, raça/cor e a presença de DC. Conclusão: A complementação dos dados pelo SIM fornece um perfil diferente da prevalência de DC do que aquele que seria registrado apenas pelo SINASC, mostrando a importância do uso conjunto das duas fontes de dados. / Introduction: Live Birth Information System (SINASC) is an important instrument to monitor birth defects (BD) at the birth, however it has fulfilling imperfections of this information and they are probably registered in the Birth Certificates (BC) the BD more apparent, what can under estimate the prevalence of the some ones. The linkage of the data of SINASC and of SIM (Mortality Information System) allows the recovery of information about BD registered in SIM complementing the data and supplying a more real estimate of the prevalence of BD. Objective: Come with the prevalence of BD in a cohort of live birth (LB) associating the data base of SIM and the SINASC. Methods: Descriptive study to evaluate BD as source of information about BD. The population of study is the LB hospital of 1° semester of 2006 of resident mothers and that had happened in São Paulo city in the period from 01/01/2006 to 06/30/2006 and neonatal deaths from the cohort. The differences of carriers and not carrying of BD had been tested through the relative risk, p value and CI 95%. Results: According to SINASC the most prevalent birth defects were: birth defects and osteomuscular system deformity (44,7%), birth defects of nervous system (10,0%) and cromossomics anomalies not classified in another part (8,6%). Through linkage, it had a recovery of 48 cases (80,0%) of BD of circulatory system, 11 cases (73,3%) of BD of respiratory system and 5 cases (62,5%) of other BD of digestive system. SINASC made 55,2% of the notifications of BD and SIM notified 44,8%, showing its importance to recovery data of BD presents in Death Certificate (DC). The tax of prevalence for the BD of cohort according to SINASC was 75,4/10.000 LB; with all the data corrected by SIM, this tax changed for 86,2/10.000 LB. The variable age of mother, pregnancy age, birth type, Apgar, sex and weight at birth are associated to the presence of BD (p<0,001). Association between the years of study, marital status, parity, previous dead children, prenatal, pregnancy type, race and the presence of BD were not found. Conclusion: Data complementing by SIM supplies a different profile of prevalence of BD from those ones that would be registered only by SINASC showing the importance of the usage of two data sources.

Oral clefts are the most common form of birth defects in the United States (US) and the State of Utah has among the highest prevalence of oral clefts in the nation. The overall objective of this dissertation was to examine the spatial distribution of oral clefts and their linkage with a broad range of demographic, behavioral, social, economic, and environmental risk factors through the application of Geographic Information Systems (GIS) and spatial statistics. Using innovative linked micromaps plots, we investigated the geographic patterns of oral clefts occurrence from 1998 to 2002 and their relationships with maternal smoking rates and proportion of American Indians and Alaskan Natives (AIAN) at large scales across the US. The findings indicated higher oral clefts occurrence in the southwest and the midwest and lower occurrence in the east. Furthermore, these spatial patterns were significantly related to the smoking rates and AIAN. Then at the small area level, hierarchical Bayesian models were built to examine the spatial variation in oral clefts risk in the State of Utah from 1995 to 2004 and to assess association with mothers using tobacco, mothers consuming alcohol during pregnancy, and the proportion of mothers with no high school diploma. Next, multi-scalar spatial clustering and cluster techniques were used to test the hypothesis whether there was spatial clustering of oral clefts anywhere in the State of Utah and whether there were statistically significant local clusters with elevated oral cleft cases. Results generally revealed modest spatial variation in oral clefts risk in the State of Utah, with no pronounced spatial clustering, indicating environmental exposures are unlikely plausible cause of oral clefts. However, a few notable areas within Tri-County Local Health District, Provo/Brigham Young University, and North Orem had a tendency toward elevated oral clefts cases. Investigation of the maternal characteristics of these potential clusters supports the hypotheses that maternal smoking, lower education level, and family history are possible causes of oral clefts. Throughout this dissertation, we demonstrated how birth defects data collected by state and local surveillance systems coupled with GIS and spatial statistics methods can be useful in exploratory etiologic research of birth defects.

The purpose of this study was to develop and describe a model for the enhancement of self-concept of people with oculocutaneous albinism based on the experience of the participants. The need to conduct the study was triggered by the researcher’s long-term interaction with people with oculocutaneous albinism, and observation that they are still stigmatised and marginalised by the community. A purposive sample of fifteen participants, consisting of twelve females and three males with oculocutaneous albinism, aged between 18 and 48, participated in the study. The study was conducted in urban and semi-urban areas around the Gauteng Province in South Africa. The study had two theory generative objectives, namely to identify the main concepts of the model from the findings, and to describe the model structure and process. A theory generative, qualitative, explorative, descriptive and contextual research design was used to achieve these objectives. Chinn and Kramer’s (1995:92) four steps of theory-generation were used, namely concept analysis, construction of theoretical relationships, description of the model, and development of guidelines to operationalise the model.Concept analysis involved identification, definition and classification of the concepts to develop the model. In-depth, phenomenological interviews were conducted to explore the participants’ experience. Data analysis and interpretation revealed three main themes from the findings: the participants’ perception of the self; experience with the external environment, and expression of need for development and growth. The main concepts deducted from the findings were “self-concept” and “enhancement” hence “A model for enhancement of self-concept of people with albinism”. Construction of theoretical relationships entailed using deductive reasoning to describe the interaction between the concepts of the model. Description of the model entailed visually portraying and describing the structure and process of the model, as well as evaluating it. Developing guidelines to operationalise the model entailed describing practical strategies to assist health professionals to enhance the self-concept of people with oculocutaneous albinism. / Health Studies / D. Litt. et Phil. (Health Studies)

One of the first embryonic structures generated during early human development is the neural tube. The embryonic process of neurulation, including neural tube closure, is necessary for proper brain and spinal cord development, whereas improper closure leads to neural tube defects including anencephaly, spina bifida, and craniorachischisis. The mechanism by which these defects occur is unknown, but some evidence suggest that redox disruption may play a role. Cellular redox state is important in regulating key processes during neural tube closure, including differentiation, proliferation, gene expression, and apoptosis. This study aims to determine whether redox potential shifts and these key processes are affected similarly or differentially after treatment with three neural tube defect-inducing developmental toxicants: ceramide (C2), valproic acid (VPA), and fumonisin (FB1). Using the P19 cell model of neurogenesis, in both undifferentiated and terminally differentiated cells, we analyzed glutathione (GSH) redox (Eh) potential to evaluate the effect of each toxicant over time. We show that in C2 and VPA treated cultures an oxidizing shift occurs, but interestingly, FB1 treatment results in a reducing shift in embryonic GSH Eh as compared to untreated cultures. Using the chick embryo model, comparable redox shifts were observed as were seen in P19 cells, supporting similarity between the models. To better understand how differential shifts in the redox state can result in similar defects, we then examined potential variances in neuronal differentiation and cellular proliferation, survival, metabolism, adhesion, and gene expression under each treatment. We report changes to cellular and embryonic endpoints that support dysmorphogenesis, likely the result of oxidizing or reducing stress that altered redox state. These results support the need for broad comparative analyses such as this to determine whether toxicants that cause the same types of defects, whether NTDs or others, act through similar or different mechanisms. This can better inform preventative measures used to reduce the risk and occurrence of birth defects.

The purpose of this quantitative study was to examine data describing nitrate concentration and cases of congenital cardiac defects. Residents with private wells and other stakeholders need data to make informed environmental decisions about the adverse health implications of nitrate contamination of private well water. Researchers have examined the exposure of nitrate in contaminated groundwater, but they have not examined nitrate levels in unregulated water systems. This gap in the literature highlighted the need to provide nitrate data for future research and private well users. Guided by the social ecological model, a quantitative, cross-sectional, nonexperimental design was used to survey 231 adult participants about community perceptions of stakeholders' collaboration about groundwater and the sustainability of private water wells. Multiple linear regression was used to test the hypotheses. Survey results showed that gender, age group, and distance from animal waste sites or farmland were associated with barriers to community collaboration to achieve groundwater sustainability. Use of private wells for irrigation and distance from animal waste sites or farmland were associated with community members' perceptions of community collaboration to achieve groundwater sustainability. Community perceptions and barriers to stakeholders' collaboration were not affected by any demographic factors. The data will facilitate the design and implementation of effective public health outreach services for private well users. The implications for positive social change include increased understanding of stakeholders' perceptions of private well nitrate contamination and reduction of the risk factors for birth defects.

A compound-heterozygous variant occurs when a child inherits a variant from each parent, with these variants occurring at a different position within the same gene and on opposite homologous chromosomes. These inherited variants may result in two nonfunctional versions of the same gene. Compound-heterozygous variants cannot be identified unless a patients' DNA sequence data is phased. Phasing is a computationally demanding process that requires the use of multiple software tools in order to determine which nucleotide was inherited from which parent. First, in Chapter 1, we review the literature to better understand what research has been conducted on the role of compound-heterozygous variants in pediatric cancers and what methods are being used to identify them. In Chapter 2, we develop a pipeline to make it easier for us and other researchers to phase and identify compound-heterozygous variants using VCF files from trios or individuals. We then use this pipeline in Chapter 3 to survey the prevalence of compound-heterozygous variants across 7 pediatric disease types. We show the importance of identifying compound heterozygous and what information would be missed if this variant type was not included in study design. In Chapter 4, we develop a software tool to phase trio data using a combination of Mendelian inheritance logic and an existing phasing software program. We show that our software tool increases the total number of variants that can be phased. Finally, in Chapter 5, we use phased data of three nuclear families, each family having one child with pediatric cancer, to evaluate the potential to use inherited genomic variants to inform diagnostic decisions. The work contained within this dissertation shows the importance of not overlooking compound-heterozygous variants when trying to identify potentially causal genes in pediatric disease. In addition, this work provides software tools that are openly available for other researchers to use; these tools make it easier to phase patient DNA sequence data and to identify compound-heterozygous variants.