The metabolism of vitamin D commences with exposure of the skin to sunlight. The growing recognition of its role in insulin resistance, autoimmune disorders, infections, cancer, as well as the health of cells that influence physical and mental function have profound implications on how we define vitamin D requirements and why we should care whether they are met or not. Most of the actions of vitamin D are mediated by the vitamin D receptor (VDR), a protein whose gene sequence can vary, giving rise to polymorphic forms which are potent enough to affect the binding capacity of this protein to vitamin D. Some of these polymorphic forms of VDR gene may be associated with reduced effectiveness of vitamin D and hence predispose individuals to diseases such as type 2 diabetes and insulin resistance. An earlier study, the Surya Study, looked at the responsiveness of the South-Asian women living in Auckland to vitamin D. The research described here is an extension of this study and its focus was to identify the associations/linkages between certain polymorphic forms of the VDR gene and the disease conditions and intervention responsiveness in the same women. The first objective was to compare two well known techniques for genotyping single nucleotide polymorphisms (SNPs) of the VDR gene at the 3’ end, namely BsmI, ApaI and TaqI: the newer real-time polymerase chain reaction (qPCR) and the traditional restriction fragment length polymorphism polymerase chain reaction (RFLP-PCR) techniques. This comparison was performed to evaluate alternative methods for genotyping which consumed less time than RFLP-PCR. When the presence of each polymorphism by both the techniques was compared in this cohort of South-Asian women, it was found that RFLP-PCR proved to be a more reliable technique than qPCR for genotyping the VDR gene. Another objective of this project was to investigate the prevalence of the above three polymorphisms along with Cdx-2 and FokI SNPs which are present at the 5’ end of the VDR gene, in the population under study and their possible association with phenotypes such as vitamin D responsiveness and insulin resistance. These women were screened and biochemical data was collected during the earlier Surya Study. Of these, eighty-one women were then selected for intervention based on them having high insulin resistance (HOMA-IR>1.93) and serum 25(OH)D<50 nmol/L. Out of these eighty-one women, forty-two were given vitamin D supplement and thirty-nine were given a placebo for six months. Baseline and endpoint measurements included insulin resistance (HOMA-IR), insulin sensitivity (HOMA2%S) etc. How each individual responded to treatment in the intervention group was analysed in the context of the polymorphisms that they had. An association of insulin resistance with BsmI, ApaI and TaqI SNPs was observed in this cohort of 239 women. The response to insulin resistance in the vitamin D supplemented group significantly differed for FokI genotype compared to other genotypes. This explained why certain women responded to treatment better than the others. When the frequencies of the genotypes of these five SNPs of the VDR gene were compared to other studies of different ethnicities, the results of this study were consistent with few studies but contradictory to others. The possible reasons for these differences could be because of small sample size and different ethnicities under study due to which the frequency of alleles and hence the genotypes differed.

The metabolism of vitamin D commences with exposure of the skin to sunlight. The growing recognition of its role in insulin resistance, autoimmune disorders, infections, cancer, as well as the health of cells that influence physical and mental function have profound implications on how we define vitamin D requirements and why we should care whether they are met or not. Most of the actions of vitamin D are mediated by the vitamin D receptor (VDR), a protein whose gene sequence can vary, giving rise to polymorphic forms which are potent enough to affect the binding capacity of this protein to vitamin D. Some of these polymorphic forms of VDR gene may be associated with reduced effectiveness of vitamin D and hence predispose individuals to diseases such as type 2 diabetes and insulin resistance. An earlier study, the Surya Study, looked at the responsiveness of the South-Asian women living in Auckland to vitamin D. The research described here is an extension of this study and its focus was to identify the associations/linkages between certain polymorphic forms of the VDR gene and the disease conditions and intervention responsiveness in the same women. The first objective was to compare two well known techniques for genotyping single nucleotide polymorphisms (SNPs) of the VDR gene at the 3’ end, namely BsmI, ApaI and TaqI: the newer real-time polymerase chain reaction (qPCR) and the traditional restriction fragment length polymorphism polymerase chain reaction (RFLP-PCR) techniques. This comparison was performed to evaluate alternative methods for genotyping which consumed less time than RFLP-PCR. When the presence of each polymorphism by both the techniques was compared in this cohort of South-Asian women, it was found that RFLP-PCR proved to be a more reliable technique than qPCR for genotyping the VDR gene. Another objective of this project was to investigate the prevalence of the above three polymorphisms along with Cdx-2 and FokI SNPs which are present at the 5’ end of the VDR gene, in the population under study and their possible association with phenotypes such as vitamin D responsiveness and insulin resistance. These women were screened and biochemical data was collected during the earlier Surya Study. Of these, eighty-one women were then selected for intervention based on them having high insulin resistance (HOMA-IR>1.93) and serum 25(OH)D<50 nmol/L. Out of these eighty-one women, forty-two were given vitamin D supplement and thirty-nine were given a placebo for six months. Baseline and endpoint measurements included insulin resistance (HOMA-IR), insulin sensitivity (HOMA2%S) etc. How each individual responded to treatment in the intervention group was analysed in the context of the polymorphisms that they had. An association of insulin resistance with BsmI, ApaI and TaqI SNPs was observed in this cohort of 239 women. The response to insulin resistance in the vitamin D supplemented group significantly differed for FokI genotype compared to other genotypes. This explained why certain women responded to treatment better than the others. When the frequencies of the genotypes of these five SNPs of the VDR gene were compared to other studies of different ethnicities, the results of this study were consistent with few studies but contradictory to others. The possible reasons for these differences could be because of small sample size and different ethnicities under study due to which the frequency of alleles and hence the genotypes differed.

The central goal of human genetics is to understand genetic differences both within and between populations and how these differences contribute to phenotypic variation. Recent advances in genotyping technologies and statistical methodology mean that we can now examine population differences at high genetic resolution, and attempt to find common variants that underlie variation in complex traits in the population. In this thesis, differences in maternal genetic ancestry in Australia were examined and a number of genetic association studies were undertaken in an attempt to map genetic variants that underlie complex traits. Abstract Before presenting the results from the five main genetic analyses, an overview is given of the history of gene-mapping in humans, the challenges this has presented, and the major discoveries from both empirical and theoretical studies that have advanced the field of human genetics to the point where hypothesis-free association testing of common variants with complex traits is now possible. The reasons why mitochondrial DNA has proved so useful in examining the history of populations, and the major findings from the field of mitochondrial population genetics are summarised. In addition, some of the major evidence of a role for mitochondrial variants in complex trait variation is presented. For the first main paper, data from 69 mitochondrial variants that tag the majority of common mitochondrial SNPs in European populations was used to test whether there is evidence for population stratification (i.e. the presence of more than one randomly mating population) in the maternal genetic line of modern Australians. By combining the genetic data with self-reported maternal ancestry data, it was shown that there are significant differences in the patterns of mitochondrial variation between groups of individuals whose maternal ancestors came from different areas of the world. Specifically, it was shown that there are significant differences between groups from different regions of Europe, with those from Eastern Europe showing large differences in SNP and haplogroup frequencies compared to the other groups. A test for assortative mating was performed by comparing whether mates in our sample shared more mitochondrial variants in common when compared to randomly drawn pairs from the population. No evidence of increased sharing was found. The second study involved testing whether common mitochondrial variants are associated with a number of physiological and biochemical traits, the majority of which are risk factors for the metabolic syndrome and type 2 diabetes. Phenotypic and genotypic data was available for just over 2,000 adolescent twins measured at three different timepoints. This is the first known mitochondrial association study to use family data, and a methodology based on a linear model was presented for performing such an association. In spite of having power to detect variants of modest effect, only viii one significant association was found between mt14365 and triacyglycerol levels in twins measured at age 12. This association was not replicated across the other age groups. The third study used the methodology developed for family-based mitochondrial association studies to test for association between mitochondrial variants and a battery of cognitive tests in twins aged 16. A previous study with a small sample size had shown an association between mitochondria and IQ, but this had never been replicated or followed-up. A total of 1,385 individuals from 665 families were included, but no statistically significant associations were found. The most strongly associated SNP was found in a gene in which variants have been shown to influence cognition in mice with a homogeneous nuclear genetic background. For the fourth study, a genome-wide association analysis was carried out of 6 self-reported traits related to the menstrual cycle. Sample sizes ranged from 468 for age at menopause to 5,743 for age at menarche. No SNPs were found to be associated at a genome-wide significant level, however, the results from previous association analyses of age at menarche and age at menopause were replicated. A number of regions for each trait that show modest evidence of association have been identified, and these should be targeted for replication in another sample. In addition, a number of genes that show strong evidence for association with each trait were identified and using a multivariate approach, a SNP in the RNA polymerase III subunit B gene was shown to potentially have a pleiotropic effect on age at menarche and duration of menses. In the final study, a genome-wide association study data for self-reported caffeine consumption and caffeine-related sleep disturbance was performed. A number of loci that potentially influence each trait were identified. The association data was combined with gene expression data from three cell types that had been treated with caffeine. A gene-based test was performed to test whether genes that were found to be consistently up- or down-regulated by caffeine treatment show increased evidence of association. There was no evidence of increased association signals in these genes. A number of the caffeine-regulated genes show strong evidence for overall association and represent good candidate genes for targeted replication in a larger sample. Finally, a synthesis of the main results of each study is presented including potential limitations of this research. This discussion includes a critical assessment of the current findings in both mitochondrial genetics and genome-wide association studies, and potential future directions in the field of gene-mapping in humans.

Knowledge Discovery in Databases (KDD), or Data Mining is used to discover interesting or useful patterns and relationships in data, with an emphasis on large volume of observational databases. Among many other types of information (knowledge) that can be discovered in data, patterns that are expressed in terms of features are popular because they can be understood and used directly by people. The recently proposed Emerging Pattern (EP) is one type of such knowledge patterns. Emerging Patterns are sets of items (conjunctions of attribute values) whose frequency change significantly from one dataset to another. They are useful as a means of discovering distinctions inherently present amongst a collection of datasets and have been shown to be a powerful method for constructing accurate classifiers. (For complete abstract open document)

Australia has the highest incidence of melanoma in the world. Melanocytic nevi and mutations in the CDKN2A gene are the main risk factors for the development of cutaneous melanocytic melanoma, and particularly in those of European descent. My study uses genetic epidemiological methods to investigate causes of variation in the number of melanocytic nevi and pigmentary traits such as freckles, eye colour, hair colour and skin colour collected on a sample of adolescent twins and siblings from the Brisbane Twin Nevus Study (1992-2006). Information was available for 2524 individuals from 973 families (from the first visit when the twins were aged 12 years), and from a repeat visit (two years later) for 1598 individuals from 791 families. Using the twin study design extended to siblings and parents, variance components analyses showed that the proportion of phenotypic variance explained by genetic factors ranged from 43 to 99 percent for the traits studied. The atypical nevus count and freckles showed sex differences in the magnitude of genetic and environmental effects. Genetic correlations among counts of three types of nevus (flat, raised and clinically atypical) ranged from 0.46 to 0.63. Nevus count was genetically correlated with skin colour (r=0.23). I analysed genome-wide linkage data using a total of 1190 microsatellite (STR) markers from three scans for 644 families with 1646 twins and siblings, plus genotypes for 1033 parents. These were combined with an additional 169 families with genome-wide association 100K SNP (single nucleotide polymorphism) data, where I selected a linkage analysis panel of 13,000 SNPs making a total of 3365 individuals from 811 families (each individual had more than 200 markers typed). Suggestive linkages for flat nevus count (FNC) were identified on chromosomes 2p25 and 9p21 with lod scores of 3.19 and 2.62 respectively. For raised nevus count (RNC), a suggestive QTL with a lod score of 2.20 was found on chromosome 2q37.2, and for atypical nevus count (ANC) a lod score of 2.71 was found on chromosome 7p14.1. There was suggestive evidence of linkage for freckling on chromosomes 2 and 9. Eye colour was strongly linked (lod=17.86) to chromosome 15, at the OCA2 locus. I have also carried out genetic association analyses using the 100K SNP data in 169 families, and additional fine mapping using SNPs (as well as STR markers) in the complete data set. A sample size of 169 families (461 twins) for genome-wide association data means that statistical power is low. From the 100K SNP data, the best association for total nevus count (TNC) was with SNP rs2420070, p=6.0×10-6 on chromosome 10, and included another two nearby SNPs; rs7086663, p=2.0×10-4 and rs7090904, p=1.5×10-4. These 3 SNPs also showed possible association with FNC; rs2420070, p=3.9×10-6, rs2420070, p=1.3×10-4 and rs2420070, p=8.9×10-5. For raised nevus count the top three associated SNPs were rs1885238, p=1.8×10-5 on chromosome 9; rs10503048, p=3.7×10-5 on chromosome 18 and rs4769189, p=4.0×10-5 on chromosome 13. SNP rs1412341 which is located near CDKN2A on chromosome 9, was also associated with p=2.8×10-4. There were a total 18 SNPs which showed evidence of association with atypical nevus count, the strongest signal being with rs951099 (p=3.7×10-5) on chromosome 9. In a fine-mapping dataset, I studied the association of CDKN2A SNP rs2218220 with TNC, FNC, RNC and ANC. The best SNP, rs2218220, gave p values of 2.8×10-10, 7.7×10-8, 2.7×10-12 and 9.1×10-8, respectively. A SNP, rs1800407 (R419Q) located in the OCA2 gene (chromosome 15q11.2-15q12) showed evidence of association with eye colour and particularly with blue and green eye colours, (p=1.7×10-12 and p=6.0×10-7). SNP rs12913832 from the Hect Domain and RCC1-like Domain 2 gene (HERC2) on chromosome 15q13.1, was also strongly associated with eye colour p=3.6×10-155. This SNP was associated with blue (p= 7.9×10-150) and brown (p=5.3×10-158), but not green eye colour. In addition I confirmed the association of the MC1R SNP rs1805007 and freckling (p=4.8×10-12). This SNP was also associated with FNC (p=3.5×10-8), a finding not previously described in the literature. I also carried out multi-allelic association analysis using STR markers with these traits and uncovered suggestive findings for several regions. Finally, I conducted a multivariate association analysis searching for SNPs with pleiotropic effects. The most interesting results for all types of nevi were with rs801840, p=3.5×10-5, and rs10487075, p=4.9×10-5, both on chromosome 7q21.13. Another four SNPs on chromosome 8p23.1 also showed associations, rs7009724, p=1.4×10-4, rs10503389, p=1.9×10-4, rs7832398, p=6.2×10-4 and rs7005133, p=6.9×10-4 (close to a candidate gene, MFHAS1, implicated in sarcoma risk). In conclusion I have characterised a number of definite and possible genetic factors influencing important risk factors for melanoma.

Typescript (photocopy) / x, 342 leaves ; 30 cm / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.)--Dept. of History, University of Adelaide

This thesis examines the formation, development, role and behaviour of the Singapore National Employers' Federation (SNEF). Its focus is primarily the field of labour management. It addresses key issues in the role of the SNEF from its formation in 1980 to 2004, in the institutional context of Singapore's politics, economic development and industrial relations. This longitudinal study makes a substantial original contribution to understanding Singapore's leading national employers' association, and is a pioneering study of a national employers' association in East Asia. The thesis is a qualitative case-study, using fieldwork interviews, primary documents and the secondary literature as data sources. Through the critical event method, the work focuses analysis on key junctures for the SNEF's development and change during the period examined. In addition, the author employs the Sheldon and Thornthwaite (1999) model of employers' association strategy in framing the analysis of the thesis' central questions, and in examining SNEF's strategic decisions in response to changes in its external environment. By analysing how the SNEF's external roles and internal relations changed during each period, the research draws attention to the dynamic nature of this employers' association in the rapidly changing conditions marking Singapore's development. Given the central role of the People's Action Party (PAP) in Singaporean society, a central theme of this thesis is how the SNEF balances political pressures from Singapore's government-dominated corporatist system, with the needs of its diversified membership. The narrative core of the thesis identifies five distinct periods of Singaporean industrial relations - through the lens of the SNEF - reflecting larger economic developments through which the government guided the economy and society. The thesis finds that, while the SNEF is an independent and apolitical organisation, it is nevertheless deeply embedded in the Singaporean variant of corporatism. Accordingly, the SNEF's role and behaviour are inherently guided by the PAP's ideology of pragmatism and, in Singapore, sectoral interests deferred to and institutionally served national interests.

This thesis presents an in depth study of the expansion of settlement in Christchurch between 1850-62, the pre-Municipal Council years. It is confined spatially to the 'central city' area within the four Avenues. Four research problems are studied: (1) The laying out of Christchurch by the New Zealand Company surveyors for the Canterbury Association, in particular, the reasons for the use of a grid street pattern. It was found that many factors were involved in its use. These included the personal preferences of the surveyors and the Association committee members, the topographic nature of the site chosen and contemporary planning convention. (2) The initial selection of town sections by the colonists and the reasons behind their choices. The 'orders of choice' of the sections have been tabulated and mapped to show section preference and how the settlers perceived the economic value of particular areas of the town grid for their commercial prospects. Town section auctions, leases, sales and subdivisions as well as church land are investigated. (3) The sale of the Town Reserves surrounding the town section area is also studied; the reason for their early sale, the nature and characteristics of the sales including prices and purchasers and their occupations. It was found that the prices paid were significantly related to the spatial positions of the lots within the Reserve blocks and to the time of their sale, in response to contemporary land values. There was no significant relationship between prices and the occupations of the buyers. (4) Public works undertaken by the Association and the Provincial Government are studied and their relationship with immigration and population figures. The scale of public works carried out at particular times was found to relate both to available finance and to immigration, the source of labour. Various aspects of public works, for example, street and footpath formation and bridging and drainage work were found to be indicative of differential growth between periods of depression and prosperity.

Thesis (M.F.A.)--Rochester Institute of Technology, 1989. / Includes bibliographical references.

Thesis (Ed. D.)--Eastern Michigan University, 2006 / Includes bibliographical references (leaves 200-213). Also available online (PDF file) by a subscription to the set or by purchasing the individual file.