School of Mathematics and Statistics - Research Publications
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ItemNo Preview AvailableGata-3 Negatively Regulates the Tumor-Initiating Capacity of Mammary Luminal Progenitor Cells and Targets the Putative Tumor Suppressor Caspase-14(AMER SOC MICROBIOLOGY, 2011-11)The transcription factor Gata-3 is a definitive marker of luminal breast cancers and a key regulator of mammary morphogenesis. Here we have explored a role for Gata-3 in tumor initiation and the underlying cellular mechanisms using a mouse model of "luminal-like" cancer. Loss of a single Gata-3 allele markedly accelerated tumor progression in mice carrying the mouse mammary tumor virus promoter-driven polyomavirus middle T antigen (MMTV-PyMT mice), while overexpression of Gata-3 curtailed tumorigenesis. Through the identification of two distinct luminal progenitor cells in the mammary gland, we demonstrate that Gata-3 haplo-insufficiency increases the tumor-initiating capacity of these progenitors but not the stem cell-enriched population. Overexpression of a conditional Gata-3 transgene in the PyMT model promoted cellular differentiation and led to reduced tumor-initiating capacity as well as diminished angiogenesis. Transcript profiling studies identified caspase-14 as a novel downstream target of Gata-3, in keeping with its roles in differentiation and tumorigenesis. A strong association was evident between GATA-3 and caspase-14 expression in preinvasive ductal carcinoma in situ samples, where GATA-3 also displayed prognostic significance. Overall, these studies identify GATA-3 as an important regulator of tumor initiation through its ability to promote the differentiation of committed luminal progenitor cells.
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ItemNo Preview AvailableOn the Conjecture by Demyanov–Ryabova in Converting Finite Exhausters(Springer, 2017-09)The Demyanov–Ryabova conjecture is a geometric problem originating from duality relations between nonconvex objects. Given a finite collection of polytopes, one obtains its dual collection as convex hulls of the maximal facet of sets in the original collection, for each direction in the space (thus constructing upper convex representations of positively homogeneous functions from lower ones and, vice versa, via Minkowski duality). It is conjectured that an iterative application of this conversion procedure to finite families of polytopes results in a cycle of length at most two. We prove a special case of the conjecture assuming an affine independence condition on the vertices of polytopes in the collection. We also obtain a purely combinatorial reformulation of the conjecture.
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ItemPregnant women maintain body temperatures within safe limits during moderate-intensity aqua-aerobic classes conducted in pools heated up to 33 degrees Celsius: an observational study(AUSTRALIAN PHYSIOTHERAPY ASSOC, 2015-10)QUESTION: What is the body temperature response of healthy pregnant women exercising at moderate intensity in an aqua-aerobics class where the water temperature is in the range of 28 to 33 degrees Celsius, as typically found in community swimming pools? DESIGN: An observational study. PARTICIPANTS: One hundred and nine women in the second and third trimester of pregnancy who were enrolled in a standardised aqua-aerobics class. OUTCOME MEASURES: Tympanic temperature was measured at rest pre-immersion (T1), after 35minutes of moderate-intensity aqua-aerobic exercise (T2), after a further 10minutes of light exercise while still in the water (T3) and finally on departure from the facility (T4). The range of water temperatures in seven indoor community pools was 28.8 to 33.4 degrees Celsius. RESULTS: Body temperature increased by a mean of 0.16 degrees Celsius (SD 0.35, p<0.001) at T2, was maintained at this level at T3 and had returned to pre-immersion resting values at T4. Regression analysis demonstrated that the temperature response was not related to the water temperature (T2 r = -0.01, p = 0.9; T3 r = -0.02, p=0.9; T4 r=0.03, p=0.8). Analysis of variance demonstrated no difference in body temperature response between participants when grouped in the cooler, medium and warmer water temperatures (T2 F=0.94, p=0.40; T3 F=0.93, p=0.40; T4 F=0.70, p=0.50). CONCLUSIONS: Healthy pregnant women maintain body temperatures within safe limits during moderate-intensity aqua-aerobic exercise conducted in pools heated up to 33 degrees Celsius. The study provides evidence to inform guidelines for safe water temperatures for aqua-aerobic exercise during pregnancy.
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ItemA Bayesian method for comparing and combining binary classifiers in the absence of a gold standard.(Springer Science and Business Media LLC, 2012-07-27)BACKGROUND: Many problems in bioinformatics involve classification based on features such as sequence, structure or morphology. Given multiple classifiers, two crucial questions arise: how does their performance compare, and how can they best be combined to produce a better classifier? A classifier can be evaluated in terms of sensitivity and specificity using benchmark, or gold standard, data, that is, data for which the true classification is known. However, a gold standard is not always available. Here we demonstrate that a Bayesian model for comparing medical diagnostics without a gold standard can be successfully applied in the bioinformatics domain, to genomic scale data sets. We present a new implementation, which unlike previous implementations is applicable to any number of classifiers. We apply this model, for the first time, to the problem of finding the globally optimal logical combination of classifiers. RESULTS: We compared three classifiers of protein subcellular localisation, and evaluated our estimates of sensitivity and specificity against estimates obtained using a gold standard. The method overestimated sensitivity and specificity with only a small discrepancy, and correctly ranked the classifiers. Diagnostic tests for swine flu were then compared on a small data set. Lastly, classifiers for a genome-wide association study of macular degeneration with 541094 SNPs were analysed. In all cases, run times were feasible, and results precise. The optimal logical combination of classifiers was also determined for all three data sets. Code and data are available from http://bioinformatics.monash.edu.au/downloads/. CONCLUSIONS: The examples demonstrate the methods are suitable for both small and large data sets, applicable to the wide range of bioinformatics classification problems, and robust to dependence between classifiers. In all three test cases, the globally optimal logical combination of the classifiers was found to be their union, according to three out of four ranking criteria. We propose as a general rule of thumb that the union of classifiers will be close to optimal.
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ItemPsychosocial Well-Being and Functional Outcomes in Youth With Type 1 Diabetes 12 years After Disease Onset(AMER DIABETES ASSOC, 2010-07)OBJECTIVE: Type 1 diabetes in youth and community controls were compared on functional outcomes. Relationships were examined between psychosocial variables at diagnosis and functional outcome 12 years later. RESEARCH DESIGN AND METHODS: Participants were subjects with type 1 diabetes (n = 110, mean age 20.7 years, SD 4.3) and control subjects (n = 76, mean age 20.8 years, SD 4.0). The measures used included the Youth Self-Report and Young Adult Self-Report and a semi-structured interview of functional outcomes. Type 1 diabetes participants also provided information about current diabetes care and metabolic control from diagnosis. RESULTS: Type 1 diabetes participants and control subjects reported similar levels of current well-being but for the youth with type 1 diabetes, the mental health referral rates over the previous 12 years were higher by 19% and school completion rates were lower by 17%. Over one-third of clinical participants were not currently receiving specialist care and this group had higher mental health service usage in the past (61 vs. 33%) and lower current psychosocial well- being. Within the type 1 diabetes group, behavior problems, high activity, and low family cohesion at diagnosis predicted lower current well-being, but were not associated with metabolic control history. Poorer metabolic control was associated with higher mental health service usage. CONCLUSIONS: Type 1 diabetes participants report similar levels of current psychosocial well-being compared with control subjects, but higher levels of psychiatric morbidity since diagnosis and lower school completion rates. Psychiatric morbidity was associated with poor metabolic control and failure to transition to tertiary adult diabetes care.
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ItemAccurate RNA Sequencing From Formalin-Fixed Cancer Tissue to Represent High-Quality Transcriptome From Frozen Tissue(AMER SOC CLINICAL ONCOLOGY, 2018-01-26)PURPOSE: Accurate transcriptional sequencing (RNA-seq) from formalin-fixation and paraffin-embedding (FFPE) tumor samples presents an important challenge for translational research and diagnostic development. In addition, there are now several different protocols to prepare a sequencing library from total RNA. We evaluated the accuracy of RNA-seq data generated from FFPE samples in terms of expression profiling. METHODS: We designed a biospecimen study to directly compare gene expression results from different protocols to prepare libraries for RNA-seq from human breast cancer tissues, with randomization to fresh-frozen (FF) or FFPE conditions. The protocols were compared using multiple computational methods to assess alignment of reads to reference genome, and the uniformity and continuity of coverage; as well as the variance and correlation, of overall gene expression and patterns of measuring coding sequence, phenotypic patterns of gene expression, and measurements from representative multigene signatures. RESULTS: The principal determinant of variance in gene expression was use of exon capture probes, followed by the conditions of preservation (FF versus FFPE), and phenotypic differences between breast cancers. One protocol, with RNase H-based rRNA depletion, exhibited least variability of gene expression measurements, strongest correlation between FF and FFPE samples, and was generally representative of the transcriptome from standard FF RNA-seq protocols. CONCLUSION: Method of RNA-seq library preparation from FFPE samples had marked effect on the accuracy of gene expression measurement compared to matched FF samples. Nevertheless, some protocols produced highly concordant expression data from FFPE RNA-seq data, compared to RNA-seq results from matched frozen samples.
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ItemSemiglobal Practical Stability of a Class of Parameterized Networked Control Systems(IEEE, 2012-01-01)This paper studies a class of parameterized networked control systems that are designed via an emulation procedure. In the first step, a controller is designed ignoring network so that semiglobal practical stability is achieved for the closed-loop. In the second step, it is shown that if the same controller is emulated and implemented over a large class of networks, then the networked control system is also semiglobally practically asymptotically stable; in this case, the controller parameter needs to be sufficiently small and communication bandwidth sufficiently high.
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ItemCharge Has a Marked Influence on Hyperbranched Polymer Nanoparticle Association in Whole Human Blood(AMER CHEMICAL SOC, 2017-06)In this study, we synthesize charge-varied hyperbranched polymers (HBPs) and demonstrate surface charge as a key parameter directing their association with specific human blood cell types. Using fresh human blood, we investigate the association of 5 nm HBPs with six white blood cell populations in their natural milieu by flow cytometry. While most cell types associate with cationic HBPs at 4 °C, at 37 °C phagocytic cells display similar (monocyte, dendritic cell) or greater (granulocyte) association with anionic HBPs compared to cationic HBPs. Neutral HBPs display remarkable stealth properties. Notably, these charge-association patterns are not solely defined by the plasma protein corona and are material and/or size dependent. As HBPs progress toward clinical use as imaging and drug delivery agents, the ability to engineer HBPs with defined biological properties is increasingly important. This knowledge can be used in the rational design of HBPs for more effective delivery to desired cell targets.
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ItemErratum: Sequence data and association statistics from 12,940 type 2 diabetes cases and controls.(NATURE PUBLISHING GROUP, 2018-01-23)This corrects the article DOI: 10.1038/sdata.2017.179.
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ItemAn exponential filter model predicts lightness illusions(FRONTIERS MEDIA SA, 2015-06-24)Lightness, or perceived reflectance of a surface, is influenced by surrounding context. This is demonstrated by the Simultaneous Contrast Illusion (SCI), where a gray patch is perceived lighter against a black background and vice versa. Conversely, assimilation is where the lightness of the target patch moves toward that of the bounding areas and can be demonstrated in White's effect. Blakeslee and McCourt (1999) introduced an oriented difference-of-Gaussian (ODOG) model that is able to account for both contrast and assimilation in a number of lightness illusions and that has been subsequently improved using localized normalization techniques. We introduce a model inspired by image statistics that is based on a family of exponential filters, with kernels spanning across multiple sizes and shapes. We include an optional second stage of normalization based on contrast gain control. Our model was tested on a well-known set of lightness illusions that have previously been used to evaluate ODOG and its variants, and model lightness values were compared with typical human data. We investigate whether predictive success depends on filters of a particular size or shape and whether pooling information across filters can improve performance. The best single filter correctly predicted the direction of lightness effects for 21 out of 27 illusions. Combining two filters together increased the best performance to 23, with asymptotic performance at 24 for an arbitrarily large combination of filter outputs. While normalization improved prediction magnitudes, it only slightly improved overall scores in direction predictions. The prediction performance of 24 out of 27 illusions equals that of the best performing ODOG variant, with greater parsimony. Our model shows that V1-style orientation-selectivity is not necessary to account for lightness illusions and that a low-level model based on image statistics is able to account for a wide range of both contrast and assimilation effects.