School of Mathematics and Statistics - Research Publications

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    SAfE transport: wearing face masks significantly reduces the spread of COVID-19 on trains
    Grzybowska, H ; Hickson, R ; Bhandari, B ; Cai, C ; Towke, M ; Itzstein, B ; Jurdak, R ; Liebig, J ; Najeebullah, K ; Plani, A ; El Shoghri, A ; Paini, D (BMC, 2022-08-17)
    COVID-19 has had a substantial impact globally. It spreads readily, particularly in enclosed and crowded spaces, such as public transport carriages, yet there are limited studies on how this risk can be reduced. We developed a tool for exploring the potential impacts of mitigation strategies on public transport networks, called the Systems Analytics for Epidemiology in Transport (SAfE Transport). SAfE Transport combines an agent-based transit assignment model, a community-wide transmission model, and a transit disease spread model to support strategic and operational decision-making. For this simulated COVID-19 case study, the transit disease spread model incorporates both direct (person-to-person) and fomite (person-to-surface-to-person) transmission modes. We determine the probable impact of wearing face masks on trains over a seven day simulation horizon, showing substantial and statistically significant reductions in new cases when passenger mask wearing proportions are greater than 80%. The higher the level of mask coverage, the greater the reduction in the number of new infections. Also, the higher levels of mask coverage result in an earlier reduction in disease spread risk. These results can be used by decision makers to guide policy on face mask use for public transport networks.
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    Prehabilitation in high-risk patients scheduled for major abdominal cancer surgery: a feasibility study
    Waterland, JL ; Ismail, H ; Granger, CL ; Patrick, C ; Denehy, L ; Riedel, B (BMC, 2022-08-23)
    BACKGROUND: Patients presenting for major surgery with low cardiorespiratory fitness (deconditioning) and other modifiable risk factors are at increased risk of postoperative complications. This study investigated the feasibility of delivering prehabilitation in high-risk patients scheduled for major abdominal cancer surgery. METHODS: Eligible patients in this single-center cohort study included patients with poor fitness (objectively assessed by cardiopulmonary exercise testing, CPET) scheduled for elective major abdominal cancer surgery. Patients were recruited to participate in a prehabilitation program that spanned up to 6 weeks pre-operatively and comprised aerobic and resistance exercise training, breathing exercise, and nutritional support. The primary outcome assessed pre-specified feasibility targets: recruitment >70%, retention >85%, and intervention adherence >70%. Secondary outcomes were assessed for improved pre-operative functional status and health-related quality of life and for postoperative complications. RESULTS: Eighty-two (34%) out of 238 patients screened between April 2018 and December 2019 were eligible for recruitment. Fifty (61%) patients (52% males) with a median age of 71 (IQR, 63-77) years participated in the study. Baseline oxygen consumption the at anaerobic threshold and at peak exercise (mean±SD: 9.8±1.8 and 14.0±2.9 mL/kg/min, respectively) confirmed the deconditioned state of the study cohort. The retention rate within the prehabilitation program was 84%, with 42 participants returning for repeat CPET testing. While >60% of participants preferred to do home-based prehabilitation, adherence to the intervention was low-with only 12 (28%) and 15 (35%) of patients having self-reported compliance >70% with their exercise prescriptions. CONCLUSION: Our prehabilitation program in high-risk cancer surgery patients did not achieve pre-specified targets for recruitment, retention, and self-reported program adherence. These findings underpin the importance of implementation research and strategies for the prehabilitation programs in major surgery. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ( ACTRN12620000073909 ) retrospectively registered.
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    Faecal microbiota transplant ameliorates gut dysbiosis and cognitive deficits in Huntington's disease mice.
    Gubert, C ; Choo, JM ; Love, CJ ; Kodikara, S ; Masson, BA ; Liew, JJM ; Wang, Y ; Kong, G ; Narayana, VK ; Renoir, T ; Lê Cao, KA ; Rogers, GB ; Hannan, AJ (Oxford University Press (OUP), 2022)
    Huntington's disease is a neurodegenerative disorder involving psychiatric, cognitive and motor symptoms. Huntington's disease is caused by a tandem-repeat expansion in the huntingtin gene, which is widely expressed throughout the brain and body, including the gastrointestinal system. There are currently no effective disease-modifying treatments available for this fatal disorder. Despite recent evidence of gut microbiome disruption in preclinical and clinical Huntington's disease, its potential as a target for therapeutic interventions has not been explored. The microbiota-gut-brain axis provides a potential pathway through which changes in the gut could modulate brain function, including cognition. We now show that faecal microbiota transplant (FMT) from wild-type into Huntington's disease mice positively modulates cognitive outcomes, particularly in females. In Huntington's disease male mice, we revealed an inefficiency of FMT engraftment, which is potentially due to the more pronounced changes in the structure, composition and instability of the gut microbial community, and the imbalance in acetate and gut immune profiles found in these mice. This study demonstrates a role for gut microbiome modulation in ameliorating cognitive deficits modelling dementia in Huntington's disease. Our findings pave the way for the development of future therapeutic approaches, including FMT and other forms of gut microbiome modulation, as potential clinical interventions for Huntington's disease.
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    Spatiotemporal spread of Plasmodium falciparum mutations for resistance to sulfadoxine-pyrimethamine across Africa, 1990-2020.
    Flegg, JA ; Humphreys, GS ; Montanez, B ; Strickland, T ; Jacome-Meza, ZJ ; Barnes, KI ; Raman, J ; Guerin, PJ ; Hopkins Sibley, C ; Dahlström Otienoburu, S ; Perkins, A (Public Library of Science (PLoS), 2022-08)
    BACKGROUND: Sulfadoxine-pyrimethamine (SP) is recommended in Africa in several antimalarial preventive regimens including Intermittent Preventive Treatment in pregnant women (IPTp), Intermittent Preventive Treatment in infants (IPTi) and Seasonal Malaria Chemoprevention (SMC). The effectiveness of SP-based preventive treatments are threatened in areas where Plasmodium falciparum resistance to SP is high. The prevalence of mutations in the dihydropteroate synthase gene (pfdhps) can be used to monitor SP effectiveness. IPTi-SP is recommended only in areas where the prevalence of the pfdhps540E mutation is below 50%. It has also been suggested that IPTp-SP does not have a protective effect in areas where the pfdhps581G mutation, exceeds 10%. However, pfdhps mutation prevalence data in Africa are extremely heterogenous and scattered, with data completely missing from many areas. METHODS AND FINDINGS: The WWARN SP Molecular Surveyor database was designed to summarize dihydrofolate reductase (pfdhfr) and pfdhps gene mutation prevalence data. In this paper, pfdhps mutation prevalence data was used to generate continuous spatiotemporal surface maps of the estimated prevalence of the SP resistance markers pfdhps437G, pfdhps540E, and pfdhps581G in Africa from 1990 to 2020 using a geostatistical model, with a Bayesian inference framework to estimate uncertainty. The maps of estimated prevalence show an expansion of the pfdhps437G mutations across the entire continent over the last three decades. The pfdhps540E mutation emerged from limited foci in East Africa to currently exceeding 50% estimated prevalence in most of East and South East Africa. pfdhps540E distribution is expanding at low or moderate prevalence in central Africa and a predicted focus in West Africa. Although the pfdhps581G mutation spread from one focus in East Africa in 2000, to exceeding 10% estimated prevalence in several foci in 2010, the predicted distribution of the marker did not expand in 2020, however our analysis indicated high uncertainty in areas where pfdhps581G is present. Uncertainty was higher in spatial regions where the prevalence of a marker is intermediate or where prevalence is changing over time. CONCLUSIONS: The WWARN SP Molecular Surveyor database and a set of continuous spatiotemporal surface maps were built to provide users with standardized, current information on resistance marker distribution and prevalence estimates. According to the maps, the high prevalence of pfdhps540E mutation was to date restricted to East and South East Africa, which is reassuring for continued use of IPTi and SMC in West Africa, but continuous monitoring is needed as the pfdhps540E distribution is expanding. Several foci where pfdhps581G prevalence exceeded 10% were identified. More data on the pfdhps581G distribution in these areas needs to be collected to guide IPTp-SP recommendations. Prevalence and uncertainty maps can be utilized together to strategically identify sites where increased surveillance can be most informative. This study combines a molecular marker database and predictive modelling to highlight areas of concern, which can be used to support decisions in public health, highlight knowledge gaps in certain regions, and guide future research.
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    COVID-19 morbidity in Afghanistan: a nationwide, population-based seroepidemiological study.
    Saeedzai, SA ; Sahak, MN ; Arifi, F ; Abdelkreem Aly, E ; Gurp, MV ; White, LJ ; Chen, S ; Barakat, A ; Azim, G ; Rasoly, B ; Safi, S ; Flegg, JA ; Ahmed, N ; Ahadi, MJ ; Achakzai, NM ; AbouZeid, A (BMJ, 2022-07-27)
    OBJECTIVE: The primary objectives were to determine the magnitude of COVID-19 infections in the general population and age-specific cumulative incidence, as determined by seropositivity and clinical symptoms of COVID-19, and to determine the magnitude of asymptomatic or subclinical infections. DESIGN, SETTING AND PARTICIPANTS: We describe a population-based, cross-sectional, age-stratified seroepidemiological study conducted throughout Afghanistan during June/July 2020. Participants were interviewed to complete a questionnaire, and rapid diagnostic tests were used to test for SARS-CoV-2 antibodies. This national study was conducted in eight regions of Afghanistan plus Kabul province, considered a separate region. The total sample size was 9514, and the number of participants required in each region was estimated proportionally to the population size of each region. For each region, 31-44 enumeration areas (EAs) were randomly selected, and a total of 360 clusters and 16 households per EA were selected using random sampling. To adjust the seroprevalence for test sensitivity and specificity, and seroreversion, Bernoulli's model methodology was used to infer the population exposure in Afghanistan. OUTCOME MEASURES: The main outcome was to determine the prevalence of current or past COVID-19 infection. RESULTS: The survey revealed that, to July 2020, around 10 million people in Afghanistan (31.5% of the population) had either current or previous COVID-19 infection. By age group, COVID-19 seroprevalence was reported to be 35.1% and 25.3% among participants aged ≥18 and 5-17 years, respectively. This implies that most of the population remained at risk of infection. However, a large proportion of the population had been infected in some localities, for example, Kabul province, where more than half of the population had been infected with COVID-19. CONCLUSION: As most of the population remained at risk of infection at the time of the study, any lifting of public health and social measures needed to be considered gradually.
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    The large-sample asymptotic behaviour of quartet-based summary methods for species tree inference.
    Chan, Y-B ; Li, Q ; Scornavacca, C (Springer Science and Business Media LLC, 2022-08-17)
    methods seek to infer a species tree from a set of gene trees. A desirable property of such methods is that of statistical consistency; that is, the probability of inferring the wrong species tree (the error probability) tends to 0 as the number of input gene trees becomes large. A popular paradigm is to infer a species tree that agrees with the maximum number of quartets from the input set of gene trees; this has been proved to be statistically consistent under several models of gene evolution. In this paper, we study the asymptotic behaviour of the error probability of such methods in this limit, and show that it decays exponentially. For a 4-taxon species tree, we derive a closed form for the asymptotic behaviour in terms of the probability that the gene evolution process produces the correct topology. We also derive bounds for the sample complexity (the number of gene trees required to infer the true species tree with a given probability), which outperform existing bounds. We then extend our results to bounds for the asymptotic behaviour of the error probability for any species tree, and compare these to the true error probability for some model species trees using simulations.
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    The impact of inter-observer variation in delineation on robustness of radiomics features in non-small cell lung cancer
    Kothari, G ; Woon, B ; Patrick, CJ ; Korte, J ; Wee, L ; Hanna, GG ; Kron, T ; Hardcastle, N ; Siva, S (NATURE PORTFOLIO, 2022-07-27)
    Artificial intelligence and radiomics have the potential to revolutionise cancer prognostication and personalised treatment. Manual outlining of the tumour volume for extraction of radiomics features (RF) is a subjective process. This study investigates robustness of RF to inter-observer variation (IOV) in contouring in lung cancer. We utilised two public imaging datasets: 'NSCLC-Radiomics' and 'NSCLC-Radiomics-Interobserver1' ('Interobserver'). For 'NSCLC-Radiomics', we created an additional set of manual contours for 92 patients, and for 'Interobserver', there were five manual and five semi-automated contours available for 20 patients. Dice coefficients (DC) were calculated for contours. 1113 RF were extracted including shape, first order and texture features. Intraclass correlation coefficient (ICC) was computed to assess robustness of RF to IOV. Cox regression analysis for overall survival (OS) was performed with a previously published radiomics signature. The median DC ranged from 0.81 ('NSCLC-Radiomics') to 0.85 ('Interobserver'-semi-automated). The median ICC for the 'NSCLC-Radiomics', 'Interobserver' (manual) and 'Interobserver' (semi-automated) were 0.90, 0.88 and 0.93 respectively. The ICC varied by feature type and was lower for first order and gray level co-occurrence matrix (GLCM) features. Shape features had a lower median ICC in the 'NSCLC-Radiomics' dataset compared to the 'Interobserver' dataset. Survival analysis showed similar separation of curves for three of four RF apart from 'original_shape_Compactness2', a feature with low ICC (0.61). The majority of RF are robust to IOV, with first order, GLCM and shape features being the least robust. Semi-automated contouring improves feature stability. Decreased robustness of a feature is significant as it may impact upon the features' prognostic capability.
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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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    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.