School of Mathematics and Statistics - Research Publications

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    Large-scale manipulation of promoter DNA methylation reveals context-specific transcriptional responses and stability
    de Mendoza, A ; Trung, VN ; Ford, E ; Poppe, D ; Buckberry, S ; Pflueger, J ; Grimmer, MR ; Stolzenburg, S ; Bogdanovic, O ; Oshlack, A ; Farnham, PJ ; Blancafort, P ; Lister, R (BMC, 2022-07-26)
    BACKGROUND: Cytosine DNA methylation is widely described as a transcriptional repressive mark with the capacity to silence promoters. Epigenome engineering techniques enable direct testing of the effect of induced DNA methylation on endogenous promoters; however, the downstream effects have not yet been comprehensively assessed. RESULTS: Here, we simultaneously induce methylation at thousands of promoters in human cells using an engineered zinc finger-DNMT3A fusion protein, enabling us to test the effect of forced DNA methylation upon transcription, chromatin accessibility, histone modifications, and DNA methylation persistence after the removal of the fusion protein. We find that transcriptional responses to DNA methylation are highly context-specific, including lack of repression, as well as cases of increased gene expression, which appears to be driven by the eviction of methyl-sensitive transcriptional repressors. Furthermore, we find that some regulatory networks can override DNA methylation and that promoter methylation can cause alternative promoter usage. DNA methylation deposited at promoter and distal regulatory regions is rapidly erased after removal of the zinc finger-DNMT3A fusion protein, in a process combining passive and TET-mediated demethylation. Finally, we demonstrate that induced DNA methylation can exist simultaneously on promoter nucleosomes that possess the active histone modification H3K4me3, or DNA bound by the initiated form of RNA polymerase II. CONCLUSIONS: These findings have important implications for epigenome engineering and demonstrate that the response of promoters to DNA methylation is more complex than previously appreciated.
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    A Bayesian method for comparing and combining binary classifiers in the absence of a gold standard.
    Keith, JM ; Davey, CM ; Boyd, SE (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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    Statistical challenges in longitudinal microbiome data analysis.
    Kodikara, S ; Ellul, S ; Lê Cao, K-A (Oxford University Press (OUP), 2022-07-18)
    The microbiome is a complex and dynamic community of microorganisms that co-exist interdependently within an ecosystem, and interact with its host or environment. Longitudinal studies can capture temporal variation within the microbiome to gain mechanistic insights into microbial systems; however, current statistical methods are limited due to the complex and inherent features of the data. We have identified three analytical objectives in longitudinal microbial studies: (1) differential abundance over time and between sample groups, demographic factors or clinical variables of interest; (2) clustering of microorganisms evolving concomitantly across time and (3) network modelling to identify temporal relationships between microorganisms. This review explores the strengths and limitations of current methods to fulfill these objectives, compares different methods in simulation and case studies for objectives (1) and (2), and highlights opportunities for further methodological developments. R tutorials are provided to reproduce the analyses conducted in this review.
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    Loss of TIP60 (KAT5) abolishes H2AZ lysine 7 acetylation and causes p53, INK4A, and ARF-independent cell cycle arrest
    Wichmann, J ; Pitt, C ; Eccles, S ; Garnham, AL ; Li-Wai-Suen, CSN ; May, R ; Allan, E ; Wilcox, S ; Herold, MJ ; Smyth, GK ; Monahan, BJ ; Thomas, T ; Voss, AK (SPRINGERNATURE, 2022-07-20)
    Histone acetylation is essential for initiating and maintaining a permissive chromatin conformation and gene transcription. Dysregulation of histone acetylation can contribute to tumorigenesis and metastasis. Using inducible cre-recombinase and CRISPR/Cas9-mediated deletion, we investigated the roles of the histone lysine acetyltransferase TIP60 (KAT5/HTATIP) in human cells, mouse cells, and mouse embryos. We found that loss of TIP60 caused complete cell growth arrest. In the absence of TIP60, chromosomes failed to align in a metaphase plate during mitosis. In some TIP60 deleted cells, endoreplication occurred instead. In contrast, cell survival was not affected. Remarkably, the cell growth arrest caused by loss of TIP60 was independent of the tumor suppressors p53, INK4A and ARF. TIP60 was found to be essential for the acetylation of H2AZ, specifically at lysine 7. The mRNA levels of 6236 human and 8238 mouse genes, including many metabolism genes, were dependent on TIP60. Among the top 50 differentially expressed genes, over 90% were downregulated in cells lacking TIP60, supporting a role for TIP60 as a key co-activator of transcription. We propose a primary role of TIP60 in H2AZ lysine 7 acetylation and transcriptional activation, and that this fundamental role is essential for cell proliferation. Growth arrest independent of major tumor suppressors suggests TIP60 as a potential anti-cancer drug target.
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    A Multiscale Mathematical Model of Plasmodium Vivax Transmission
    Anwar, MN ; Hickson, RI ; Mehra, S ; McCaw, JM ; Flegg, JA (SPRINGER, 2022-08-01)
    Malaria is caused by Plasmodium parasites which are transmitted to humans by the bite of an infected Anopheles mosquito. Plasmodium vivax is distinct from other malaria species in its ability to remain dormant in the liver (as hypnozoites) and activate later to cause further infections (referred to as relapses). Mathematical models to describe the transmission dynamics of P. vivax have been developed, but most of them fail to capture realistic dynamics of hypnozoites. Models that do capture the complexity tend to involve many governing equations, making them difficult to extend to incorporate other important factors for P. vivax, such as treatment status, age and pregnancy. In this paper, we have developed a multiscale model (a system of integro-differential equations) that involves a minimal set of equations at the population scale, with an embedded within-host model that can capture the dynamics of the hypnozoite reservoir. In this way, we can gain key insights into dynamics of P. vivax transmission with a minimum number of equations at the population scale, making this framework readily scalable to incorporate more complexity. We performed a sensitivity analysis of our multiscale model over key parameters and found that prevalence of P. vivax blood-stage infection increases with both bite rate and number of mosquitoes but decreases with hypnozoite death rate. Since our mathematical model captures the complex dynamics of P. vivax and the hypnozoite reservoir, it has the potential to become a key tool to inform elimination strategies for P. vivax.
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    A Model for Cell Proliferation in a Developing Organism
    Pollett, PK ; Tafakori, L ; Taylor, PG (SPRINGER HEIDELBERG, 2022-06-01)
    In mathematical biology, there is a great deal of interest in producing continuum models by scaling discrete agent-based models governed by local stochastic rules. We discuss a particular example of this approach: a model for the proliferation of neural crest cells that can help us understand the development of Hirschprung's disease, a potentially-fatal condition in which the enteric nervous system of a new-born child does not extend all the way through the intestine and colon. Our starting point is a discrete-state, continuous-time Markov chain model proposed by Hywood et al. (2013a) for the location of the neural crest cells that make up the enteric nervous system. Hywood et al. (2013a) scaled their model to derive an approximate second order partial differential equation describing how the limiting expected number of neural crest cells evolve in space and time. In contrast, we exploit the relationship between the above-mentioned Markov chain model and the well-known Yule-Furry process to derive the exact form of the scaled version of the process. Furthermore, we provide expressions for other features of the domain agent occupancy process, such as the variance of the marginal occupancy at a particular site, the distribution of the number of agents that are yet to reach a given site and a stochastic description of the process itself.
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    A semantics, energy-based approach to automate biomodel composition
    Shahidi, N ; Pan, M ; Tran, K ; Crampin, EJ ; Nickerson, DP ; Brusch, L (PUBLIC LIBRARY SCIENCE, 2022-01-01)
    Hierarchical modelling is essential to achieving complex, large-scale models. However, not all modelling schemes support hierarchical composition, and correctly mapping points of connection between models requires comprehensive knowledge of each model's components and assumptions. To address these challenges in integrating biosimulation models, we propose an approach to automatically and confidently compose biosimulation models. The approach uses bond graphs to combine aspects of physical and thermodynamics-based modelling with biological semantics. We improved on existing approaches by using semantic annotations to automate the recognition of common components. The approach is illustrated by coupling a model of the Ras-MAPK cascade to a model of the upstream activation of EGFR. Through this methodology, we aim to assist researchers and modellers in readily having access to more comprehensive biological systems models.
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    Are Experts Well-Calibrated? An Equivalence-Based Hypothesis Test.
    Dharmarathne, G ; Hanea, AM ; Robinson, A (MDPI AG, 2022-05-27)
    Estimates based on expert judgements of quantities of interest are commonly used to supplement or replace measurements when the latter are too expensive or impossible to obtain. Such estimates are commonly accompanied by information about the uncertainty of the estimate, such as a credible interval. To be considered well-calibrated, an expert's credible intervals should cover the true (but unknown) values a certain percentage of time, equal to the percentage specified by the expert. To assess expert calibration, so-called calibration questions may be asked in an expert elicitation exercise; these are questions with known answers used to assess and compare experts' performance. An approach that is commonly applied to assess experts' performance by using these questions is to directly compare the stated percentage cover with the actual coverage. We show that this approach has statistical drawbacks when considered in a rigorous hypothesis testing framework. We generalize the test to an equivalence testing framework and discuss the properties of this new proposal. We show that comparisons made on even a modest number of calibration questions have poor power, which suggests that the formal testing of the calibration of experts in an experimental setting may be prohibitively expensive. We contextualise the theoretical findings with a couple of applications and discuss the implications of our findings.
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    Simultaneous visualization of flow fields and oxygen concentrations to unravel transport and metabolic processes in biological systems.
    Ahmerkamp, S ; Jalaluddin, FM ; Cui, Y ; Brumley, DR ; Pacherres, CO ; Berg, JS ; Stocker, R ; Kuypers, MMM ; Koren, K ; Behrendt, L (Elsevier BV, 2022-05-23)
    From individual cells to whole organisms, O2 transport unfolds across micrometer- to millimeter-length scales and can change within milliseconds in response to fluid flows and organismal behavior. The spatiotemporal complexity of these processes makes the accurate assessment of O2 dynamics via currently available methods difficult or unreliable. Here, we present "sensPIV," a method to simultaneously measure O2 concentrations and flow fields. By tracking O2-sensitive microparticles in flow using imaging technologies that allow for instantaneous referencing, we measured O2 transport within (1) microfluidic devices, (2) sinking model aggregates, and (3) complex colony-forming corals. Through the use of sensPIV, we find that corals use ciliary movement to link zones of photosynthetic O2 production to zones of O2 consumption. SensPIV can potentially be extendable to study flow-organism interactions across many life-science and engineering applications.
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    Traffic Patterns of the Migrating Endothelium: How Force Transmission Regulates Vascular Malformation and Functional Shunting During Angiogenic Remodelling
    Edgar, LT ; Park, H ; Crawshaw, JR ; Osborne, JM ; Eichmann, A ; Bernabeu, MO (FRONTIERS MEDIA SA, 2022-05-19)
    Angiogenesis occurs in distinct phases: initial spouting is followed by remodelling in which endothelial cells (ECs) composing blood vessels rearrange by migrating against the direction of flow. Abnormal remodelling can result in vascular malformation. Such is the case in mutation of the Alk1 receptor within the mouse retina which disrupts flow-migration coupling, creating mixed populations of ECs polarised with/against flow which aggregate into arteriovenous malformations (AVMs). The lack of live imaging options in vivo means that the collective EC dynamics that drive AVM and the consequences of mixed populations of polarity remain a mystery. Therefore, our goal is to present a novel agent-based model to provide theoretical insight into EC force transmission and collective dynamics during angiogenic remodelling. Force transmission between neighbouring agents consists of extrusive forces which maintain spacing and cohesive forces which maintain the collective. We performed migration simulations within uniformly polarised populations (against flow) and mixed polarity (with/against flow). Within uniformly polarised populations, extrusive forces stabilised the plexus by facilitating EC intercalation which ensures that cells remained evenly distributed. Excess cohesion disrupts intercalation, resulting in aggregations of cells and functional shunting. Excess cohesion between ECs prevents them from resolving diameter balances within the plexus, leading to prolonged flow reversals which exert a critical behaviour change within the system as they switch the direction of cell migration and traffic patterns at bifurcations. Introducing mixtures of cell polarity dramatically changed the role of extrusive forces within the system. At low extrusion, opposing ECs were able to move past each other; however, at high extrusion the pushing between cells resulted in migration speeds close to zero, forming traffic jams and disrupting migration. In our study, we produced vascular malformations and functional shunting with either excess cohesion between ECs or mixtures of cell polarity. At the centre of both these mechanisms are cell-cell adherens junctions, which are involved in flow sensing/polarity and must remodelling dynamically to allow rearrangements of cells during vascular patterning. Thus, our findings implicate junctional dysfunction as a new target in the treatment and prevention of vascular disease and AVMs.