School of Mathematics and Statistics - Research Publications
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ItemNo Preview AvailableEvolving gene/transcript definitions significantly alter the interpretation of GeneChip data(OXFORD UNIV PRESS, 2005)Genome-wide expression profiling is a powerful tool for implicating novel gene ensembles in cellular mechanisms of health and disease. The most popular platform for genome-wide expression profiling is the Affymetrix GeneChip. However, its selection of probes relied on earlier genome and transcriptome annotation which is significantly different from current knowledge. The resultant informatics problems have a profound impact on analysis and interpretation the data. Here, we address these critical issues and offer a solution. We identified several classes of problems at the individual probe level in the existing annotation, under the assumption that current genome and transcriptome databases are more accurate than those used for GeneChip design. We then reorganized probes on more than a dozen popular GeneChips into gene-, transcript- and exon-specific probe sets in light of up-to-date genome, cDNA/EST clustering and single nucleotide polymorphism information. Comparing analysis results between the original and the redefined probe sets reveals approximately 30-50% discrepancy in the genes previously identified as differentially expressed, regardless of analysis method. Our results demonstrate that the original Affymetrix probe set definitions are inaccurate, and many conclusions derived from past GeneChip analyses may be significantly flawed. It will be beneficial to re-analyze existing GeneChip data with updated probe set definitions.
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ItemNo Preview AvailableThe impact of low-cost, genome-wide resequencing on association studies.(Springer Science and Business Media LLC, 2005-06)
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ItemNo Preview AvailableA chain multinomial model for estimating the real-time fatality rate of a disease, with an application to severe acute respiratory syndrome(OXFORD UNIV PRESS INC, 2005-04-01)It is well known that statistics using cumulative data are insensitive to changes. World Health Organization (WHO) estimates of fatality rates are of the above type, which may not be able to reflect the latest changes in fatality due to treatment or government policy in a timely fashion. Here, the authors propose an estimate of a real-time fatality rate based on a chain multinomial model with a kernel function. It is more accurate than the WHO estimate in describing fatality, especially earlier in the course of an epidemic. The estimator provides useful information for public health policy makers for understanding the severity of the disease or evaluating the effects of treatments or policies within a shorter time period, which is critical in disease control during an outbreak. Simulation results showed that the performance of the proposed estimator is superior to that of the WHO estimator in terms of its sensitivity to changes and its timeliness in reflecting the severity of the disease.
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ItemRethinking the "diseases of affluence" paradigm: Global patterns of nutritional risks in relation to economic development(PUBLIC LIBRARY SCIENCE, 2005-05)BACKGROUND: Cardiovascular diseases and their nutritional risk factors--including overweight and obesity, elevated blood pressure, and cholesterol--are among the leading causes of global mortality and morbidity, and have been predicted to rise with economic development. METHODS AND FINDINGS: We examined age-standardized mean population levels of body mass index (BMI), systolic blood pressure, and total cholesterol in relation to national income, food share of household expenditure, and urbanization in a cross-country analysis. Data were from a total of over 100 countries and were obtained from systematic reviews of published literature, and from national and international health agencies. BMI and cholesterol increased rapidly in relation to national income, then flattened, and eventually declined. BMI increased most rapidly until an income of about ID 5,000 (international dollars) and peaked at about ID 12,500 for females and ID 17,000 for males. Cholesterol's point of inflection and peak were at higher income levels than those of BMI (about ID 8,000 and ID 18,000, respectively). There was an inverse relationship between BMI/cholesterol and the food share of household expenditure, and a positive relationship with proportion of population in urban areas. Mean population blood pressure was not correlated or only weakly correlated with the economic factors considered, or with cholesterol and BMI. CONCLUSIONS: When considered together with evidence on shifts in income-risk relationships within developed countries, the results indicate that cardiovascular disease risks are expected to systematically shift to low-income and middle-income countries and, together with the persistent burden of infectious diseases, further increase global health inequalities. Preventing obesity should be a priority from early stages of economic development, accompanied by population-level and personal interventions for blood pressure and cholesterol.
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ItemRooting a phylogenetic tree with nonreversible substitution models(BMC, 2005-01-04)BACKGROUND: We compared two methods of rooting a phylogenetic tree: the stationary and the nonstationary substitution processes. These methods do not require an outgroup. METHODS: Given a multiple alignment and an unrooted tree, the maximum likelihood estimates of branch lengths and substitution parameters for each associated rooted tree are found; rooted trees are compared using their likelihood values. Site variation in substitution rates is handled by assigning sites into several classes before the analysis. RESULTS: In three test datasets where the trees are small and the roots are assumed known, the nonstationary process gets the correct estimate significantly more often, and fits data much better, than the stationary process. Both processes give biologically plausible root placements in a set of nine primate mitochondrial DNA sequences. CONCLUSIONS: The nonstationary process is simple to use and is much better than the stationary process at inferring the root. It could be useful for situations where an outgroup is unavailable.
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ItemEvolution of the relaxin-like peptide family(BMC, 2005-02-12)BACKGROUND: The relaxin-like peptide family belongs in the insulin superfamily and consists of 7 peptides of high structural but low sequence similarity; relaxin-1, 2 and 3, and the insulin-like (INSL) peptides, INSL3, INSL4, INSL5 and INSL6. The functions of relaxin-3, INSL4, INSL5, INSL6 remain uncharacterised. The evolution of this family has been contentious; high sequence variability is seen between closely related species, while distantly related species show high similarity; an invertebrate relaxin sequence has been reported, while a relaxin gene has not been found in the avian and ruminant lineages. RESULTS: Sequence similarity searches of genomic and EST data identified homologs of relaxin-like peptides in mammals, and non-mammalian vertebrates such as fish. Phylogenetic analysis was used to resolve the evolution of the family. Searches were unable to identify an invertebrate relaxin-like peptide. The published relaxin cDNA sequence in the tunicate, Ciona intestinalis was not present in the completed C. intestinalis genome. The newly discovered relaxin-3 is likely to be the ancestral relaxin. Multiple relaxin-3-like sequences are present in fugu fish (Takifugu rubripes) and zebrafish (Danio rerio), but these appear to be specific to the fish lineage. Possible relaxin-1 and INSL5 homologs were also identified in fish and frog species, placing their emergence prior to mammalia, earlier than previously believed. Furthermore, estimates of synonymous and nonsynonymous substitution rates (dN/dS) suggest that the emergence of relaxin-1, INSL4 and INSL6 during mammalia was driven by positive Darwinian selection, hence these peptides are likely to have novel and in the case of relaxin-1, which is still under positive selection in humans and the great apes, possibly still evolving functions. In contrast, relaxin-3 is constrained by strong purifying selection, demonstrating it must have a highly conserved function, supporting its hypothesized important neuropeptide role. CONCLUSIONS: We present a phylogeny describing the evolutionary history of the relaxin-like peptide family and show that positive selection has driven the evolution of the most recent members of the family.
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ItemNo Preview AvailableGeneralised permutation branes(SPRINGER, 2005-11)
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ItemTwo notes on financial mathematics(Centre for Actuarial Studies, The University of Melbourne, 2005)
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ItemAn analytic modelling approach for network routing algorithms that use "ant-like" mobile agents(ELSEVIER SCIENCE BV, 2005-10-05)