Joe Pitt-Francis

Chaste: An Open Source C++ Library for Computational Physiology and Biology

Chaste — Cancer, Heart And Soft Tissue Environment — is an open source C++ library for the computational simulation of mathematical models developed for physiology and biology. Code development has been driven by two initial applications: cardiac electrophysiology and cancer development. A large number of cardiac electrophysiology studies have been enabled and performed, including high-performance computational investigations of defibrillation on realistic human cardiac geometries. New models for the initiation and growth of tumours have been developed. In particular, cell-based simulations have provided novel insight into the role of stem cells in the colorectal crypt. Chaste is constantly evolving and is now being applied to a far wider range of problems. The code provides modules for handling common scientific computing components, such as meshes and solvers for ordinary and partial differential equations (ODEs/PDEs). Re-use of these components avoids the need for researchers to ‘re-invent the wheel’ with each new project, accelerating the rate of progress in new applications. Chaste is developed using industrially-derived techniques, in particular test-driven development, to ensure code quality, re-use and reliability. In this article we provide examples that illustrate the types of problems Chaste can be used to solve, which can be run on a desktop computer. We highlight some scientific studies that have used or are using Chaste, and the insights they have provided. The source code, both for specific releases and the development version, is available to download under an open source Berkeley Software Distribution (BSD) licence at http://www.cs.ox.ac.uk/chaste, together with details of a mailing list and links to documentation and tutorials.

Multi-scale computational modelling in biology and physiology

Abstract Recent advances in biotechnology and the availability of ever more powerful computers have led to the formulation of increasingly complex models at all levels of biology. One of the main aims of systems biology is to couple these together to produce integrated models across multiple spatial scales and physical processes. In this review, we formulate a definition of multi-scale in terms of levels of biological organisation and describe the types of model that are found at each level. Key issues that arise in trying to formulate and solve multi-scale and multi-physics models are considered and examples of how these issues have been addressed are given for two of the more mature fields in computational biology: the molecular dynamics of ion channels and cardiac modelling. As even more complex models are developed over the coming few years, it will be necessary to develop new methods to model them (in particular in coupling across the interface between stochastic and deterministic processes) and new techniques will be required to compute their solutions efficiently on massively parallel computers. We outline how we envisage these developments occurring.

An integrative computational model for intestinal tissue renewal.

Objectives:  The luminal surface of the gut is lined with a monolayer of epithelial cells that acts as a nutrient absorptive engine and protective barrier. To maintain its integrity and functionality, the epithelium is renewed every few days. Theoretical models are powerful tools that can be used to test hypotheses concerning the regulation of this renewal process, to investigate how its dysfunction can lead to loss of homeostasis and neoplasia, and to identify potential therapeutic interventions. Here we propose a new multiscale model for crypt dynamics that links phenomena occurring at the subcellular, cellular and tissue levels of organisation.

Chaste: using agile programming techniques to develop computational biology software

Cardiac modelling is the area of physiome modelling where the available simulation software is perhaps most mature, and it therefore provides an excellent starting point for considering the software requirements for the wider physiome community. In this paper, we will begin by introducing some of the most advanced existing software packages for simulating cardiac electrical activity. We consider the software development methods used in producing codes of this type, and discuss their use of numerical algorithms, relative computational efficiency, usability, robustness and extensibility. We then go on to describe a class of software development methodologies known as test-driven agile methods and argue that such methods are more suitable for scientific software development than the traditional academic approaches. A case study is a project of our own, Cancer, Heart and Soft Tissue Environment, which is a library of computational biology software that began as an experiment in the use of agile programming methods. We present our experiences with a review of our progress thus far, focusing on the advantages and disadvantages of this new approach compared with the development methods used in some existing packages. We conclude by considering whether the likely wider needs of the cardiac modelling community are currently being met and suggest that, in order to respond effectively to changing requirements, it is essential that these codes should be more malleable. Such codes will allow for reliable extensions to include both detailed mathematical models—of the heart and other organs—and more efficient numerical techniques that are currently being developed by many research groups worldwide.

Computational assessment of drug-induced effects on the electrocardiogram: from ion channel to body surface potentials

Understanding drug effects on the heart is key to safety pharmacology assessment and anti‐arrhythmic therapy development. Here our goal is to demonstrate the ability of computational models to simulate the effect of drug action on the electrical activity of the heart, at the level of the ion‐channel, cell, heart and ECG body surface potential.

Development of a functional magnetic resonance imaging simulator for modeling realistic rigid-body motion artifacts.

Functional magnetic resonance imaging (FMRI) is a noninvasive method of imaging brain function in vivo. However, images produced in FMRI experiments are imperfect and contain several artifacts that contaminate the data. These artifacts include rigid‐body motion effects, B0‐field inhomogeneities, chemical shift, and eddy currents. To investigate these artifacts, with the eventual aim of minimizing or removing them completely, a computational model of the FMR image acquisition process was built that can simulate all of the above‐mentioned artifacts. This paper gives an overview of the development of the FMRI simulator. The simulator uses the Bloch equations together with a geometric definition of the object (brain) and a varying T  2* model for the BOLD activations. Furthermore, it simulates rigid‐body motion of the object by solving Bloch equations for given motion parameters that are defined for an object moving continuously in time, including during the read‐out period, which is a novel approach in the area of MRI computer simulations. With this approach it is possible, in a controlled and precise way, to simulate the full effects of various rigid‐body motion artifacts in FMRI data (e.g. spin‐history effects, B0‐motion interaction, and within‐scan motion blurring) and therefore formulate and test algorithms for their reduction. Magn Reson Med, 2006.

Computational assessment of drug-induced effects on the electrocardiogram

Understanding drug effects on the heart is key to safety pharmacology assessment and anti‐arrhythmic therapy development. Here our goal is to demonstrate the ability of computational models to simulate the effect of drug action on the electrical activity of the heart, at the level of the ion‐channel, cell, heart and ECG body surface potential.

A numerical guide to the solution of the bidomain equations of cardiac electrophysiology

Simulation of cardiac electrical activity using the bi-domain equations can be a massively computationally demanding problem. This study provides a comprehensive guide to numerical bi-domain modelling. Each component of bi-domain simulations--discretization, ODE-solution, linear system solution, and parallelization--is discussed, and previously-used methods are reviewed, new methods are proposed, and issues which cause particular difficulty are highlighted. Particular attention is paid to the choice of stimulus currents, compatibility conditions for the equations, the solution of singular linear systems, and convergence of the numerical scheme.

Simulation of cardiac electrophysiology on next-generation high-performance computers

Models of cardiac electrophysiology consist of a system of partial differential equations (PDEs) coupled with a system of ordinary differential equations representing cell membrane dynamics. Current software to solve such models does not provide the required computational speed for practical applications. One reason for this is that little use is made of recent developments in adaptive numerical algorithms for solving systems of PDEs. Studies have suggested that a speedup of up to two orders of magnitude is possible by using adaptive methods. The challenge lies in the efficient implementation of adaptive algorithms on massively parallel computers. The finite-element (FE) method is often used in heart simulators as it can encapsulate the complex geometry and small-scale details of the human heart. An alternative is the spectral element (SE) method, a high-order technique that provides the flexibility and accuracy of FE, but with a reduced number of degrees of freedom. The feasibility of implementing a parallel SE algorithm based on fully unstructured all-hexahedra meshes is discussed. A major computational task is solution of the large algebraic system resulting from FE or SE discretization. Choice of linear solver and preconditioner has a substantial effect on efficiency. A fully parallel implementation based on dynamic partitioning that accounts for load balance, communication and data movement costs is required. Each of these methods must be implemented on next-generation supercomputers in order to realize the necessary speedup. The problems that this may cause, and some of the techniques that are beginning to be developed to overcome these issues, are described.

CHASTE: incorporating a novel multi-scale spatial and temporal algorithm into a large-scale open source library

Recent work has described the software engineering and computational infrastructure that has been set up as part of the Cancer, Heart and Soft Tissue Environment (Chaste) project. Chaste is an open source software package that currently has heart and cancer modelling functionality. This software has been written using a programming paradigm imported from the commercial sector and has resulted in a code that has been subject to a far more rigorous testing procedure than that is usual in this field. In this paper, we explain how new functionality may be incorporated into Chaste. Whiteley has developed a numerical algorithm for solving the bidomain equations that uses the multi-scale (MS) nature of the physiology modelled to enhance computational efficiency. Using a simple geometry in two dimensions and a purpose-built code, this algorithm was reported to give an increase in computational efficiency of more than two orders of magnitude. In this paper, we begin by reviewing numerical methods currently in use for solving the bidomain equations, explaining how these methods may be developed to use the MS algorithm discussed above. We then demonstrate the use of this algorithm within the Chaste framework for solving the monodomain and bidomain equations in a three-dimensional realistic heart geometry. Finally, we discuss how Chaste may be developed to include new physiological functionality—such as modelling a beating heart and fluid flow in the heart—and how new algorithms aimed at increasing the efficiency of the code may be incorporated.