School of Mathematics and Statistics - Research Publications

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An intersection-theoretic proof of the Harer-Zagier formula

Giacchetto, A ; Lewanski, D ; Norbury, P (EUROPEAN MATHEMATICAL SOC-EMS, 2023-03)
WHAM-A Prospective Study of Weight and Body Composition After Risk-Reducing Bilateral Salpingo-oophorectomy

Price, SAL ; Finch, S ; Krejany, E ; Jiang, H ; Kale, A ; Domchek, S ; Wrede, D ; Wark, JD ; Hickey, M (ENDOCRINE SOC, 2023-07-06)

CONTEXT: Body weight and composition may change over the natural menopause transition. Whether surgical menopause has similar effects, and the impact of HRT, are unknown. Understanding the metabolic effects of surgical menopause will inform clinical care. OBJECTIVE: To prospectively measure weight and body composition over 24-months following surgical menopause compared to a similar comparison group who retained their ovaries. METHODS: Prospective observational study of weight change from baseline to 24-months in 95 premenopausal women at elevated risk of ovarian cancer planning risk-reducing oophorectomy (RRSO) and 99 comparators who retained their ovaries. Change in body composition from baseline to 24-months was also assessed by DXA in a subgroup of 54 women who underwent RRSO and 81 comparators who retained their ovaries. In the sub-group, weight, fat mass, lean mass, and abdominal fat measures were compared between groups. RESULTS: At 24-months both groups had gained weight (RRSO 2760 ± 4860 g vs Comparators 1620 ± 4540 g) with no difference between groups (mean difference 730 g; 95% CI 920 g, 2380 g; p = 0.383). In the body composition subgroup, there was no difference in weight between groups at 24-months (mean difference 944 g; 95%CI -1120 g, 2614 g; p = 0.431). RRSO women may have gained slightly more abdominal visceral adipose tissue (mean difference 99.0 g; 95% CI 8.8 g, 189.2 g, p = 0.032) but there were no other differences in body composition. There were also no differences in weight or body composition between HRT users and non-users at 24-months. CONCLUSION: 24-months after RRSO, there was no difference in body weight compared with women who retained their ovaries. RRSO women gained more abdominal visceral adipose tissue than comparators, but there were no other differences in body composition. Use of HRT following RRSO had no effect on these outcomes.
Toblerone: detecting exon deletion events in cancer using RNA-seq.

Lonsdale, A ; Halman, A ; Brown, L ; Kosasih, H ; Ekert, P ; Oshlack, A (F1000 Research Ltd, 2023)

Cancer is driven by mutations of the genome that can result in the activation of oncogenes or repression of tumour suppressor genes. In acute lymphoblastic leukemia (ALL) focal deletions in IKAROS family zinc finger 1 (IKZF1) result in the loss of zinc-finger DNA-binding domains and a dominant negative isoform that is associated with higher rates of relapse and poorer patient outcomes. Clinically, the presence of IKZF1 deletions informs prognosis and treatment options. In this work we developed a method for detecting exon deletions in genes using RNA-seq with application to IKZF1. We developed a pipeline that first uses a custom transcriptome reference consisting of transcripts with exon deletions. Next, RNA-seq reads are mapped using a pseudoalignment algorithm to identify reads that uniquely support deletions. These are then evaluated for evidence of the deletion with respect to gene expression and other samples. We applied the algorithm, named Toblerone, to a cohort of 99 B-ALL paediatric samples including validated IKZF1 deletions. Furthermore, we developed a graphical desktop app for non-bioinformatics users that can quickly and easily identify and report deletions in IKZF1 from RNA-seq data with informative graphical outputs.
Mathematical models of developmental vascular remodelling: A review.

Crawshaw, JR ; Flegg, JA ; Bernabeu, MO ; Osborne, JM ; Marsden, AL (Public Library of Science (PLoS), 2023-08)

Over the past 40 years, there has been a strong focus on the development of mathematical models of angiogenesis, while developmental remodelling has received little such attention from the mathematical community. Sprouting angiogenesis can be seen as a very crude way of laying out a primitive vessel network (the raw material), while remodelling (understood as pruning of redundant vessels, diameter control, and the establishment of vessel identity and hierarchy) is the key to turning that primitive network into a functional network. This multiscale problem is of prime importance in the development of a functional vasculature. In addition, defective remodelling (either during developmental remodelling or due to a reactivation of the remodelling programme caused by an injury) is associated with a significant number of diseases. In this review, we discuss existing mathematical models of developmental remodelling and explore the important contributions that these models have made to the field of vascular development. These mathematical models are effectively used to investigate and predict vascular development and are able to reproduce experimentally observable results. Moreover, these models provide a useful means of hypothesis generation and can explain the underlying mechanisms driving the observed structural and functional network development. However, developmental vascular remodelling is still a relatively new area in mathematical biology, and many biological questions remain unanswered. In this review, we present the existing modelling paradigms and define the key challenges for the field.
Nonsense-mediated decay machinery in Plasmodium falciparum is inefficient and non-essential

McHugh, E ; Bulloch, MS ; Batinovic, S ; Patrick, CJ ; Sarna, DK ; Ralph, SA ; Blader, IJ (AMER SOC MICROBIOLOGY, 2023-08-24)

Nonsense-mediated decay (NMD) is a conserved mRNA quality control process that eliminates transcripts bearing a premature termination codon. In addition to its role in removing erroneous transcripts, NMD is involved in post-transcriptional regulation of gene expression via programmed intron retention in metazoans. The apicomplexan parasite Plasmodium falciparum shows relatively high levels of intron retention, but it is unclear whether these variant transcripts are functional targets of NMD. In this study, we use CRISPR-Cas9 to disrupt and epitope-tag the P. falciparum orthologs of two core NMD components: PfUPF1 (PF3D7_1005500) and PfUPF2 (PF3D7_0925800). We localize both PfUPF1 and PfUPF2 to puncta within the parasite cytoplasm and show that these proteins interact with each other and other mRNA-binding proteins. Using RNA-seq, we find that although these core NMD orthologs are expressed and interact in P. falciparum, they are not required for degradation of nonsense transcripts. Furthermore, our work suggests that the majority of intron retention in P. falciparum has no functional role and that NMD is not required for parasite growth ex vivo. IMPORTANCE In many organisms, the process of destroying nonsense transcripts is dependent on a small set of highly conserved proteins. We show that in the malaria parasite, these proteins do not impact the abundance of nonsense transcripts. Furthermore, we demonstrate efficient CRISPR-Cas9 editing of the malaria parasite using commercial Cas9 nuclease and synthetic guide RNA, streamlining genomic modifications in this genetically intractable organism.
Bayesian modelling of effects of prenatal alcohol exposure on child cognition based on data from multiple cohorts

Dang, K-D ; Ryan, LM ; Hocagil, TA ; Cook, RJ ; Richardson, GA ; Day, NL ; Coles, CD ; Olson, HC ; Jacobson, SW ; Jacobson, JL (WILEY, 2023-09)

Summary High levels of prenatal alcohol exposure (PAE) result in significant cognitive deficits in children, but the exact nature of the dose‐response relationship is less well understood. To investigate this relationship, data were assembled from six longitudinal birth cohort studies examining the effects of PAE on cognitive outcomes from early school age through adolescence. Structural equation models (SEMs) are a natural approach to consider, because of the way they conceptualise multiple observed outcomes as relating to an underlying latent variable of interest, which can then be modelled as a function of exposure and other predictors of interest. However, conventional SEMs could not be fitted in this context because slightly different outcome measures were used in the six studies. In this paper we propose a multi‐group Bayesian SEM that maps the unobserved cognition variable to a broad range of observed outcomes. The relation between these variables and PAE is then examined while controlling for potential confounders via propensity score adjustment. By examining different possible dose‐response functions, the proposed framework is used to investigate whether there is a threshold PAE level that results in minimal cognitive deficit.
Instance Space Analysis of Search-Based Software Testing

Neelofar, N ; Smith-Miles, K ; Munoz, MA ; Aleti, A (IEEE COMPUTER SOC, 2023-04-01)
Knowledge Distillation for Feature Extraction in Underwater VSLAM

Yang, J ; Gong, M ; Nair, G ; Lee, JH ; Monty, J ; Pu, Y (IEEE, 2023-01-01)
Unpaired Image-to-Image Translation with Shortest Path Regularization

Xie, S ; Xu, Y ; Gong, M ; Zhang, K (IEEE, 2023-06)
Benchmarking single-cell hashtag oligo demultiplexing methods

Howitt, G ; Feng, Y ; Tobar, L ; Vassiliadis, D ; Hickey, P ; Dawson, MA ; Ranganathan, S ; Shanthikumar, S ; Neeland, M ; Maksimovic, J ; Oshlack, A (OXFORD UNIV PRESS, 2023-10-11)

Sample multiplexing is often used to reduce cost and limit batch effects in single-cell RNA sequencing (scRNA-seq) experiments. A commonly used multiplexing technique involves tagging cells prior to pooling with a hashtag oligo (HTO) that can be sequenced along with the cells' RNA to determine their sample of origin. Several tools have been developed to demultiplex HTO sequencing data and assign cells to samples. In this study, we critically assess the performance of seven HTO demultiplexing tools: hashedDrops, HTODemux, GMM-Demux, demuxmix, deMULTIplex, BFF (bimodal flexible fitting) and HashSolo. The comparison uses data sets where each sample has also been demultiplexed using genetic variants from the RNA, enabling comparison of HTO demultiplexing techniques against complementary data from the genetic 'ground truth'. We find that all methods perform similarly where HTO labelling is of high quality, but methods that assume a bimodal count distribution perform poorly on lower quality data. We also suggest heuristic approaches for assessing the quality of HTO counts in an scRNA-seq experiment.

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