MOTIVATION: Comparing mathematical models offers a means to evaluate competing scientific theories. However, exact methods of model calibration are not applicable to many probabilistic models which simulate high-dimensional spatio-temporal data. Approximate Bayesian Computation is a widely used method for parameter inference and model selection in such scenarios, and it may be combined with Topological Data Analysis to study models which simulate data with fine spatial structure. RESULTS: We develop a flexible pipeline for parameter inference and model selection in spatio-temporal models. Our pipeline identifies topological summary statistics which quantify spatio-temporal data and uses them to approximate parameter and model posterior distributions. We validate our pipeline on models of tumour-induced angiogenesis, inferring four parameters in three established models and identifying the correct model in synthetic test-cases. AVAILABILITY AND IMPLEMENTATION: Simulation code for all models, data analyses, parameter inference and model selection is available online at https://github.com/rmcdomaths/tms/ and archived at https://doi.org/10.5281/zenodo.17392787.

Classical unsupervised learning methods like clustering and linear dimensionality reduction parametrize large-scale geometry when it is discrete or linear, while more modern methods from manifold learning find low dimensional representation or infer local geometry by constructing a graph on the input data. More recently, topological data analysis popularized the use of simplicial complexes to represent data topology with two main methodologies: topological inference with geometric complexes and large-scale topology representation with Mapper graphs -- central to these is the nerve construction from topology, which builds a simplicial complex given any cover of a space by subsets. While successful, these have limitations: geometric complexes scale poorly with data size, and Mapper graphs can be hard to tune and only contain low dimensional information. In this paper, we propose to study the problem of learning covers in its own right, and from the perspective of optimization. We describe a method to learn topologically-faithful covers of geometric datasets, and show that the simplicial complexes thus obtained can outperform standard topological inference approaches in terms of size, and Mapper-type algorithms in terms of representation of large-scale topology.

Multiplexed imaging allows multiple cell types to be simultaneously visualised in a single tissue sample, generating unprecedented amounts of spatially-resolved, biological data. In topological data analysis, persistent homology provides multiscale descriptors of "shape" suitable for the analysis of such spatial data. Here we propose a novel visualisation of persistent homology (PH) and fine-tune vectorisations thereof (exploring the effect of different weightings for persistence images, a prominent vectorisation of PH). These approaches offer new biological interpretations and promising avenues for improving the analysis of complex spatial biological data especially in multiple cell type data. To illustrate our methods, we apply them to a lung data set from fatal cases of COVID-19 and a data set from lupus murine spleen.

MOTIVATION: Inferring the parameters of models describing biological systems is an important problem in the reverse engineering of the mechanisms underlying these systems. Much work has focused on parameter inference of stochastic and ordinary differential equation models using Approximate Bayesian Computation (ABC). While there is some recent work on inference in spatial models, this remains an open problem. Simultaneously, advances in topological data analysis (TDA), a field of computational mathematics, have enabled spatial patterns in data to be characterized. RESULTS: Here, we focus on recent work using TDA to study different regimes of parameter space for a well-studied model of angiogenesis. We propose a method for combining TDA with ABC to infer parameters in the Anderson-Chaplain model of angiogenesis. We demonstrate that this topological approach outperforms ABC approaches that use simpler statistics based on spatial features of the data. This is a first step toward a general framework of spatial parameter inference for biological systems, for which there may be a variety of filtrations, vectorizations and summary statistics to be considered. AVAILABILITY AND IMPLEMENTATION: All code used to produce our results is available as a Snakemake workflow from github.com/tt104/tabc_angio.

Angiogenesis is the process by which blood vessels form from pre-existing vessels. It plays a key role in many biological processes, including embryonic development and wound healing, and contributes to many diseases including cancer and rheumatoid arthritis. The structure of the resulting vessel networks determines their ability to deliver nutrients and remove waste products from biological tissues. Here we simulate the Anderson-Chaplain model of angiogenesis at different parameter values and quantify the vessel architectures of the resulting synthetic data. Specifically, we propose a topological data analysis (TDA) pipeline for systematic analysis of the model. TDA is a vibrant and relatively new field of computational mathematics for studying the shape of data. We compute topological and standard descriptors of model simulations generated by different parameter values. We show that TDA of model simulation data stratifies parameter space into regions with similar vessel morphology. The methodologies proposed here are widely applicable to other synthetic and experimental data including wound healing, development, and plant biology.

Topological data analysis (TDA) provides tools for computing geometric and topological information about spaces from a finite sample of points. We present an adaptive algorithm for finding provably dense samples of points on real algebraic varieties given a set of defining polynomials for use as input to TDA. The algorithm utilizes methods from numerical algebraic geometry to give formal guarantees about the density of the sampling, and also employs geometric heuristics to reduce the size of the sample. As TDA methods consume significant computational resources that scale poorly in the number of sample points, our sampling minimization makes applying TDA methods more feasible. We provide a software package that implements the algorithm, and showcase it through several examples.

The Notch pathway plays a vital role in determining whether cells in the intestinal epithelium adopt a secretory or an absorptive phenotype. Cell fate specification is coordinated via Notch's interaction with the canonical Wnt pathway. Here, we propose a new mathematical model of the Notch and Wnt pathways, in which the Hes1 promoter acts as a hub for pathway crosstalk. Computational simulations of the model can assist in understanding how healthy intestinal tissue is maintained, and predict the likely consequences of biochemical knockouts upon cell fate selection processes. Chemical reaction network theory (CRNT) is a powerful, generalised framework which assesses the capacity of our model for monostability or multistability, by analysing properties of the underlying network structure without recourse to specific parameter values or functional forms for reaction rates. CRNT highlights the role of β-catenin in stabilising the Notch pathway and damping oscillations, demonstrating that Wnt-mediated actions on the Hes1 promoter can induce dynamic transitions in the Notch system, from multistability to monostability. Time-dependent model simulations of cell pairs reveal the stabilising influence of Wnt upon the Notch pathway, in which β-catenin- and Dsh-mediated action on the Hes1 promoter are key in shaping the subcellular dynamics. Where Notch-mediated transcription of Hes1 dominates, there is Notch oscillation and maintenance of fate flexibility; Wnt-mediated transcription of Hes1 favours bistability akin to cell fate selection. Cells could therefore regulate the proportion of Wnt- and Notch-mediated control of the Hes1 promoter to coordinate the timing of cell fate selection as they migrate through the intestinal epithelium and are subject to reduced Wnt stimuli. Furthermore, mutant cells characterised by hyperstimulation of the Wnt pathway may, through coupling with Notch, invert cell fate in neighbouring healthy cells, enabling an aberrant cell to maintain its neighbours in mitotically active states.

Apoptosis is a highly regulated cell death mechanism involved in many physiological processes. A key component of extrinsically activated apoptosis is the death receptor Fas which, on binding to its cognate ligand FasL, oligomerize to form the death-inducing signaling complex. Motivated by recent experimental data, we propose a mathematical model of death ligand-receptor dynamics where FasL acts as a clustering agent for Fas, which form locally stable signaling platforms through proximity-induced receptor interactions. Significantly, the model exhibits hysteresis, providing an upstream mechanism for bistability and robustness. At low receptor concentrations, the bistability is contingent on the trimerism of FasL. Moreover, irreversible bistability, representing a committed cell death decision, emerges at high concentrations which may be achieved through receptor pre-association or localization onto membrane lipid rafts. Thus, our model provides a novel theory for these observed biological phenomena within the unified context of bistability. Importantly, as Fas interactions initiate the extrinsic apoptotic pathway, our model also suggests a mechanism by which cells may function as bistable life/death switches independently of any such dynamics in their downstream components. Our results highlight the role of death receptors in deciding cell fate and add to the signal processing capabilities attributed to receptor clustering.