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Heather A. Harrington

Publications and source records attributed to Heather A. Harrington.

At least 55 records · Page 3Linked to original sources

Topological Data Analysis of Task-Based fMRI Data from Experiments on Schizophrenia

We use methods from computational algebraic topology to study functional brain networks, in which nodes represent brain regions and weighted edges encode the similarity of fMRI time series from each region. With these tools, which allow one to characterize topological invariants such as loops in high-dimensional data, we are able to gain understanding into low-dimensional structures in networks in a way that complements traditional approaches that are based on pairwise interactions. In the present paper, we use persistent homology to analyze networks that we construct from task-based fMRI data from schizophrenia patients, healthy controls, and healthy siblings of schizophrenia patients. We thereby explore the persistence of topological structures such as loops at different scales in these networks. We use persistence landscapes and persistence images to create output summaries from our persistent-homology calculations, and we study the persistence landscapes and images using $k$-means clustering and community detection. Based on our analysis of persistence landscapes, we find that the members of the sibling cohort have topological features (specifically, their 1-dimensional loops) that are distinct from the other two cohorts. From the persistence images, we are able to distinguish all three subject groups and to determine the brain regions in the loops (with four or more edges) that allow us to make these distinctions.

q-bio.QM↗

Double branched covers of knotoids

By using double branched covers, we prove that there is a 1-1 correspondence between the set of knotoids in the 2-sphere, up to orientation reversion and rotation, and knots with a strong inversion, up to conjugacy. This correspondence allows us to study knotoids through tools and invariants coming from knot theory. In particular, concepts from geometrisation generalise to knotoids, allowing us to characterise invertibility and other properties in the hyperbolic case. Moreover, with our construction we are able to detect both the trivial knotoid in the 2-sphere and the trivial planar knotoid.

math.GT↗

Grid diagrams as tools to investigate knot spaces and topoisomerase-mediated simplification of DNA topology

Grid diagrams with their relatively simple mathematical formalism provide a convenient way to generate and model projections of various knots. It has been an open question whether these 2D diagrams can be used to model a complex 3D process such as the topoisomerase-mediated preferential unknotting of DNA molecules. We model here topoisomerase-mediated passages of double-stranded DNA segments through each other using the formalism of grid diagrams. We show that this grid diagram-based modelling approach captures the essence of the preferential unknotting mechanism, based on topoisomerase selectivity of hooked DNA juxtapositions as the sites of intersegmental passages. We show that grid diagram-based approach provide an important, new and computationally convenient framework for investigating entanglement in biopolymers.

q-bio.BM↗

Stratifying multiparameter persistent homology

A fundamental tool in topological data analysis is persistent homology, which allows extraction of information from complex datasets in a robust way. Persistent homology assigns a module over a principal ideal domain to a one-parameter family of spaces obtained from the data. In applications data often depend on several parameters, and in this case one is interested in studying the persistent homology of a multiparameter family of spaces associated to the data. While the theory of persistent homology for one-parameter families is well-understood, the situation for multiparameter families is more delicate. Following Carlsson and Zomorodian we recast the problem in the setting of multigraded algebra, and we propose multigraded Hilbert series, multigraded associated primes and local cohomology as invariants for studying multiparameter persistent homology. Multigraded associated primes provide a stratification of the region where a multigraded module does not vanish, while multigraded Hilbert series and local cohomology give a measure of the size of components of the module supported on different strata. These invariants generalize in a suitable sense the invariant for the one-parameter case.

math.AT↗

Linear compartmental models: input-output equations and operations that preserve identifiability

This work focuses on the question of how identifiability of a mathematical model, that is, whether parameters can be recovered from data, is related to identifiability of its submodels. We look specifically at linear compartmental models and investigate when identifiability is preserved after adding or removing model components. In particular, we examine whether identifiability is preserved when an input, output, edge, or leak is added or deleted. Our approach, via differential algebra, is to analyze specific input-output equations of a model and the Jacobian of the associated coefficient map. We clarify a prior determinantal formula for these equations, and then use it to prove that, under some hypotheses, a model's input-output equations can be understood in terms of certain submodels we call "output-reachable". Our proofs use algebraic and combinatorial techniques.

math.AG↗

Tensor clustering with algebraic constraints gives interpretable groups of crosstalk mechanisms in breast cancer

We introduce a tensor-based clustering method to extract sparse, low-dimensional structure from high-dimensional, multi-indexed datasets. This framework is designed to enable detection of clusters of data in the presence of structural requirements which we encode as algebraic constraints in a linear program. Our clustering method is general and can be tailored to a variety of applications in science and industry. We illustrate our method on a collection of experiments measuring the response of genetically diverse breast cancer cell lines to an array of ligands. Each experiment consists of a cell line-ligand combination, and contains time-course measurements of the early-signalling kinases MAPK and AKT at two different ligand dose levels. By imposing appropriate structural constraints and respecting the multi-indexed structure of the data, the analysis of clusters can be optimized for biological interpretation and therapeutic understanding. We then perform a systematic, large-scale exploration of mechanistic models of MAPK-AKT crosstalk for each cluster. This analysis allows us to quantify the heterogeneity of breast cancer cell subtypes, and leads to hypotheses about the signalling mechanisms that mediate the response of the cell lines to ligands.

q-bio.QM↗

Sampling real algebraic varieties for topological data analysis

Topological data analysis (TDA) provides a growing body of tools for computing geometric and topological information about spaces from a finite sample of points. We present a new adaptive algorithm for finding provably dense samples of points on real algebraic varieties given a set of defining polynomials. The algorithm utilizes methods from numerical algebraic geometry to give formal guarantees about the density of the sampling and it 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 also demonstrate the implementation with several examples.

math.AT↗

Topological data analysis of continuum percolation with disks

We study continuum percolation with disks, a variant of continuum percolation in two-dimensional Euclidean space, by applying tools from topological data analysis. We interpret each realization of continuum percolation with disks as a topological subspace of $[0,1]^2$ and investigate its topological features across many realizations. We apply persistent homology to investigate topological changes as we vary the number and radius of disks. We observe evidence that the longest persisting invariant is born at or near the percolation transition.

cond-mat.stat-mech↗

The geometry of sloppiness

The use of mathematical models in the sciences often involves the estimation of unknown parameter values from data. Sloppiness provides information about the uncertainty of this task. In this paper, we develop a precise mathematical foundation for sloppiness and define rigorously its key concepts, such as `model manifold', in relation to concepts of structural identifiability. We redefine sloppiness conceptually as a comparison between the premetric on parameter space induced by measurement noise and a reference metric. This opens up the possibility of alternative quantification of sloppiness, beyond the standard use of the Fisher Information Matrix, which assumes that parameter space is equipped with the usual Euclidean metric and the measurement error is infinitesimal. Applications include parametric statistical models, explicit time dependent models, and ordinary differential equation models.

math.MG↗

A roadmap for the computation of persistent homology

Persistent homology (PH) is a method used in topological data analysis (TDA) to study qualitative features of data that persist across multiple scales. It is robust to perturbations of input data, independent of dimensions and coordinates, and provides a compact representation of the qualitative features of the input. The computation of PH is an open area with numerous important and fascinating challenges. The field of PH computation is evolving rapidly, and new algorithms and software implementations are being updated and released at a rapid pace. The purposes of our article are to (1) introduce theory and computational methods for PH to a broad range of computational scientists and (2) provide benchmarks of state-of-the-art implementations for the computation of PH. We give a friendly introduction to PH, navigate the pipeline for the computation of PH with an eye towards applications, and use a range of synthetic and real-world data sets to evaluate currently available open-source implementations for the computation of PH. Based on our benchmarking, we indicate which algorithms and implementations are best suited to different types of data sets. In an accompanying tutorial, we provide guidelines for the computation of PH. We make publicly available all scripts that we wrote for the tutorial, and we make available the processed version of the data sets used in the benchmarking.

math.AT↗

Persistent homology of time-dependent functional networks constructed from coupled time series

We use topological data analysis to study "functional networks" that we construct from time-series data from both experimental and synthetic sources. We use persistent homology with a weight rank clique filtration to gain insights into these functional networks, and we use persistence landscapes to interpret our results. Our first example uses time-series output from networks of coupled Kuramoto oscillators. Our second example consists of biological data in the form of functional magnetic resonance imaging (fMRI) data that was acquired from human subjects during a simple motor-learning task in which subjects were monitored on three days in a five-day period. With these examples, we demonstrate that (1) using persistent homology to study functional networks provides fascinating insights into their properties and (2) the position of the features in a filtration can sometimes play a more vital role than persistence in the interpretation of topological features, even though conventionally the latter is used to distinguish between signal and noise. We find that persistent homology can detect differences in synchronization patterns in our data sets over time, giving insight both on changes in community structure in the networks and on increased synchronization between brain regions that form loops in a functional network during motor learning. For the motor-learning data, persistence landscapes also reveal that on average the majority of changes in the network loops take place on the second of the three days of the learning process.

q-bio.QM↗

The Topological "Shape" of Brexit

Persistent homology is a method from computational algebraic topology that can be used to study the "shape" of data. We illustrate two filtrations --- the weight rank clique filtration and the Vietoris--Rips (VR) filtration --- that are commonly used in persistent homology, and we apply these filtrations to a pair of data sets that are both related to the 2016 European Union "Brexit" referendum in the United Kingdom. These examples consider a topical situation and give useful illustrations of the strengths and weaknesses of these methods.

cs.CG↗

The Role of the Hes1 Crosstalk Hub in Notch-Wnt Interactions of the Intestinal Crypt

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 beta-catenin in stabilising the Notch pathway and damping oscillations, demonstrating that Wnt-mediated actions on the Hes1 promoter can induce dynamical 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 beta-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.

q-bio.SC↗

Geometric combinatorics and computational molecular biology: branching polytopes for RNA sequences

Questions in computational molecular biology generate various discrete optimization problems, such as DNA sequence alignment and RNA secondary structure prediction. However, the optimal solutions are fundamentally dependent on the parameters used in the objective functions. The goal of a parametric analysis is to elucidate such dependencies, especially as they pertain to the accuracy and robustness of the optimal solutions. Techniques from geometric combinatorics, including polytopes and their normal fans, have been used previously to give parametric analyses of simple models for DNA sequence alignment and RNA branching configurations. Here, we present a new computational framework, and proof-of-principle results, which give the first complete parametric analysis of the branching portion of the nearest neighbor thermodynamic model for secondary structure prediction for real RNA sequences.

q-bio.BM↗

Decomposing the parameter space of biological networks via a numerical discriminant approach

Many systems in biology, physics and engineering can be described by systems of ordinary differential equation containing many parameters. When studying the dynamic behavior of these large, nonlinear systems, it is useful to identify and characterize the steady-state solutions as the model parameters vary, a technically challenging problem in a high-dimensional parameter landscape. Rather than simply determining the number and stability of steady-states at distinct points in parameter space, we decompose the parameter space into finitely many regions, the steady-state solutions being consistent within each distinct region. From a computational algebraic viewpoint, the boundary of these regions is contained in the discriminant locus. We develop global and local numerical algorithms for constructing the discriminant locus and classifying the parameter landscape. We showcase our numerical approaches by applying them to molecular and cell-network models.

q-bio.MN↗

Numerical algebraic geometry for model selection and its application to the life sciences

Researchers working with mathematical models are often confronted by the related problems of parameter estimation, model validation, and model selection. These are all optimization problems, well-known to be challenging due to non-linearity, non-convexity and multiple local optima. Furthermore, the challenges are compounded when only partial data is available. Here, we consider polynomial models (e.g., mass-action chemical reaction networks at steady state) and describe a framework for their analysis based on optimization using numerical algebraic geometry. Specifically, we use probability-one polynomial homotopy continuation methods to compute all critical points of the objective function, then filter to recover the global optima. Our approach exploits the geometric structures relating models and data, and we demonstrate its utility on examples from cell signaling, synthetic biology, and epidemiology.

q-bio.QM↗

Differential Algebra for Model Comparison

We present a method for rejecting competing models from noisy time-course data that does not rely on parameter inference. First we characterize ordinary differential equation models in only measurable variables using differential algebra elimination. Next we extract additional information from the given data using Gaussian Process Regression (GPR) and then transform the differential invariants. We develop a test using linear algebra and statistics to reject transformed models with the given data in a parameter-free manner. This algorithm exploits the information about transients that is encoded in the model's structure. We demonstrate the power of this approach by discriminating between different models from mathematical biology.

math.DS↗

Reduction of dimension for nonlinear dynamical systems

We consider reduction of dimension for nonlinear dynamical systems. We demonstrate that in some cases, one can reduce a nonlinear system of equations into a single equation for one of the state variables, and this can be useful for computing the solution when using a variety of analytical approaches. In the case where this reduction is possible, we employ differential elimination to obtain the reduced system. While analytical, the approach is algorithmic, and is implemented in symbolic software such as {\sc MAPLE} or {\sc SageMath}. In other cases, the reduction cannot be performed strictly in terms of differential operators, and one obtains integro-differential operators, which may still be useful. In either case, one can use the reduced equation to both approximate solutions for the state variables and perform chaos diagnostics more efficiently than could be done for the original higher-dimensional system, as well as to construct Lyapunov functions which help in the large-time study of the state variables. A number of chaotic and hyperchaotic dynamical systems are used as examples in order to motivate the approach.

nlin.CD↗