Chaste: A test-driven approach to software development for biological modelling

Pitt-Francis, Joe; Pathmanathan, Pras; Bernabéu, Miguel O.; Bordas, Rafel; Cooper, Jonathan; Fletcher, Alexander G.; Mirams, Gary R.; Murray, Philip J.; Osborne, James M.; Walter, A.; Chapman, S. Jonathan; Garny, Alan; Leeuwen, Ingeborg M.M. van; Maini, Philip K.; Rodríguez, Blanca; Waters, Sarah L.; Whiteley, Jonathan; Byrne, Helen M.; Gavaghan, David

doi:10.1016/j.cpc.2009.07.019

Cited by 215 publications

(184 citation statements)

References 42 publications

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“…Simulations were carried out using CVODE, an adaptive time step ordinary differential equation (ODE) solver, implemented within CHASTE (26), an open source software framework for modeling in computational biology. Each model was initially left in quiescent state Fig.…”

Section: Methodsmentioning

confidence: 99%

Experimentally calibrated population of models predicts and explains intersubject variability in cardiac cellular electrophysiology

Britton

Bueno‐Orovio

Ammel

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

287

379

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Cellular and ionic causes of variability in the electrophysiological activity of hearts from individuals of the same species are unknown. However, improved understanding of this variability is key to enable prediction of the response of specific hearts to disease and therapies. Limitations of current mathematical modeling and experimental techniques hamper our ability to provide insight into variability. Here, we describe a methodology to unravel the ionic determinants of intersubject variability exhibited in experimental recordings, based on the construction and calibration of populations of models. We illustrate the methodology through its application to rabbit Purkinje preparations, because of their importance in arrhythmias and safety pharmacology assessment. We consider a set of equations describing the biophysical processes underlying rabbit Purkinje electrophysiology, and we construct a population of over 10,000 models by randomly assigning specific parameter values corresponding to ionic current conductances and kinetics. We calibrate the model population by closely comparing simulation output and experimental recordings at three pacing frequencies. We show that 213 of the 10,000 candidate models are fully consistent with the experimental dataset. Ionic properties in the 213 models cover a wide range of values, including differences up to ±100% in several conductances. Partial correlation analysis shows that particular combinations of ionic properties determine the precise shape, amplitude, and rate dependence of specific action potentials. Finally, we demonstrate that the population of models calibrated using data obtained under physiological conditions quantitatively predicts the action potential duration prolongation caused by exposure to four concentrations of the potassium channel blocker dofetilide.cardiac electrophysiology | computational biology | mathematical modeling | systems biology | drug B iological variability is exhibited at all levels in all organs of living organisms. It manifests itself as differences in physiological function between individuals of the same species and often more drastically by significant differences in the outcome of their exposure to pathological conditions. Thus, healthy cardiac cells of the same species and location exhibit a qualitatively similar response to a stimulus, i.e., the action potential (AP). However, significant quantitative intersubject differences exist in AP morphology and duration, which may explain the different individual response of each of the cells (and patients) to disease or drug action.The variability underlying the physiological and pathological responses of different individuals has often been ignored in experimental and theoretical research, ultimately hampering the extrapolation of results to a population level. Experimentalists often average the results obtained in different preparations to reduce experimental error, therefore also averaging out the effects of intersubject variation and resulting in an important loss of information. T...

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Section: Methodsmentioning

confidence: 99%

Experimentally calibrated population of models predicts and explains intersubject variability in cardiac cellular electrophysiology

Britton

Bueno‐Orovio

Ammel

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

287

379

View full text Add to dashboard Cite

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“…It is recognized from the outset that the models describing these processes represent considerable simplifications of complex biology and geometry [4], which may be better described by a more sophisticated computational framework [5]. However, we believe simpler mathematical models play an important role in developing more complex schemes by providing what might be described as 'semi-quantitative' understanding of the biological transport mechanisms, and offering a simple approach to assessing the relative merits of different protocols.…”

Section: Introductionmentioning

confidence: 99%

“…Three approaches to modelling the spatio-temporal evolution of drug concentrations in a tumour cord are compared, each of which is representative of a class of models: (i) a multi-dimensional cell-centre model that defines a network of nodes (each node corresponding to a computational cell which is identifiable with a biological cell), in which drug transport is defined locally between nodes and their nearest neighbours; (ii) a compartmental model, which makes use of the concentric-layer structure of tumour cords; and (iii) a continuum model that assumes Fickian diffusion in the cylindrical geometry of the cord. The first of these approaches is amenable to multi-scale modelling [5,15], because each node may be characterized by a bespoke microenvironment consisting of, for example, a cell cycle and molecular pathways. The remaining models are tailored to the tumour cord geometry, so are less flexible but much simpler (and faster) computationally.…”

Section: Introductionmentioning

confidence: 99%

Mathematical and computational models of drug transport in tumours

Groh

Hubbard

Jones

et al. 2014

J. R. Soc. Interface.

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The ability to predict how far a drug will penetrate into the tumour microenvironment within its pharmacokinetic (PK) lifespan would provide valuable information about therapeutic response. As the PK profile is directly related to the route and schedule of drug administration, an in silico tool that can predict the drug administration schedule that results in optimal drug delivery to tumours would streamline clinical trial design. This paper investigates the application of mathematical and computational modelling techniques to help improve our understanding of the fundamental mechanisms underlying drug delivery, and compares the performance of a simple model with more complex approaches. Three models of drug transport are developed, all based on the same drug binding model and parametrized by bespoke in vitro experiments. Their predictions, compared for a 'tumour cord' geometry, are qualitatively and quantitatively similar. We assess the effect of varying the PK profile of the supplied drug, and the binding affinity of the drug to tumour cells, on the concentration of drug reaching cells and the accumulated exposure of cells to drug at arbitrary distances from a supplying blood vessel. This is a contribution towards developing a useful drug transport modelling tool for informing strategies for the treatment of tumour cells which are 'pharmacokinetically resistant' to chemotherapeutic strategies.

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“…Tissue simulations using the bidomain equations were performed in 1D fibres (2 cm length; spatial discretisation 0.4 mm; ODE and PDE time steps of 0.025 and 0.05 ms, respectively), ensuring numerical convergence of our solver [12]. Tissue conductivities were selected as described in [13] for human transmural propagation.…”

Section: Human Tissue Electrophysiology Modelmentioning

confidence: 99%

The Role of the Ina-Ik1 Complex on Human Ventricular Conduction Velocity

Marinov

Bueno‐Orovio

Rodríguez

2017

Computing in Cardiology Conference (CinC)

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Conduction velocity (CV) IntroductionSeveral cardiac diseases exhibit dispersion of electrical conduction velocity (CV), including atrial fibrillation [1], Brugada Syndrome [2], hypertrophic cardiomyopathy [3] and arrhythmogenic right ventricular cardiomyopathy (ARVC) [4]. Slow and heterogeneous CV, in combination with appropriate anatomical substrates, translates into an increased risk of re-entry. Even in the absence of structural heart changes, such as in early-stage ARVC patients with ion channel remodelling but otherwise healthy hearts [4], CV abnormalities have been shown to cause sudden cardiac death in young individuals [5].Cardiac voltage-gated sodium channels (INa) are transmembrane proteins responsible for regulating the flow of sodium ions. Loss-of-function mutations in INa channels have been implicated in lethal arrhythmias [6]. The inward rectifier current (IK1) stabilises the resting membrane potential of the human action potential (AP). IK1 downregulation has been also experimentally linked to the creation of regional differences in cardiac excitability [7].Emerging experimental evidence suggests that ionic channels are not regulated independently and are organised in macromolecular complexes. The INa-IK1 ion channels form one such complex, recently shown to control cardiac excitability and arrhythmia by Milstein et al. [8]. Their inter-species study concluded that an increase in functional expression of one channel reciprocally modulates the expression of the other to maximise cardiac excitability.The This study extends to human electrophysiology the in silico study by Varghese [10], where CV modulation by the INa-IK1 complex was investigated using a mammalian model. Importantly, we focus on INa-IK1 downregulation rather than its overexpression, given the reported role of reduced function of these channels in arrhythmogenesis. We further investigate rate-dependence interactions of the INa-IK1 complex on human ventricular CV, as well as its modulation by [K + ]o plasma levels. Methods Human tissue electrophysiology modelAt the cellular level, this study was conducted using the O'Hara-Rudy (ORd) model, as state-of-the-art and most extensively validated human cardiac electrophysiology model [11], which incorporates all main ionic channels and subcellular processes involved in the human AP.

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Chaste: A test-driven approach to software development for biological modelling

Cited by 215 publications

References 42 publications

Experimentally calibrated population of models predicts and explains intersubject variability in cardiac cellular electrophysiology

Experimentally calibrated population of models predicts and explains intersubject variability in cardiac cellular electrophysiology

Mathematical and computational models of drug transport in tumours

The Role of the Ina-Ik1 Complex on Human Ventricular Conduction Velocity

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