CellML metadata standards, associated tools and repositories

Daniel A. Beard Randall Britten Mike T. Cooling Alan Garny Matt D.B. Halstead Peter J. Hunter James Lawson Catherine M. Lloyd Justin Marsh Andrew Miller David P. Nickerson Poul M.F. Nielsen () Taishin Nomura Shankar Subramanium Sarala M. Wimalaratne Tommy Yu 0 Department of Physiology, Medical College of Wisconsin , Milwaukee, WI 53226 , USA 1 Department of Physiology , Anatomy and Genetics , University of Oxford , Oxford OX1 2JD , UK 2 Auckland Bioengineering Institute, University of Auckland , Auckland 1142 , New Zealand 3 Department of Mechanical Science and Bioengineering, Osaka University , Suita, Osaka 565-0871 , Japan 4 Department of Bioengineering, University of California , San Diego, La Jolla, CA 92093 , USA 5 Division of Bioengineering, National University of Singapore , Singapore 117574 , Republic of Singapore Articles on similar topics can be found in the following collections computational biology (52 articles) computer modelling and simulation (82 articles) Receive free email alerts when new articles cite this article - sign up in the box at the top right-hand corner of the article or click here - Email alerting service CellML metadata standards, associated tools and repositories The development of standards for encoding mathematical models is an important component of model building and model sharing among scientists interested in understanding multi-scale physiological processes. CellML provides such a standard, particularly for models based on biophysical mechanisms, and a substantial number of models are now available in the CellML Model Repository. However, there is an urgent need to extend the current CellML metadata standard to provide biological and biophysical annotation of the models in order to facilitate model sharing, automated model reduction and connection to biological databases. This paper gives a broad overview of a number of new developments on CellML metadata and provides links to further methodological details available from the CellML website. 1. Introduction CellML (www.cellml.org; Lloyd et al. 2004) is an extensible markup language (XML, www.w3.org/XML) being developed by the International Union of Physiological Sciences (IUPS, www.iups.org) Physiome and European Virtual One contribution of 15 to a Theme Issue The virtual physiological human: tools and applications I. D. A. Beard et al. annotated against biophysical and biological processes annotated against biophysical and biological entities Physiological Human (VPH) projects to encode mathematical models of biological processes that are based on systems of ordinary differential equations (ODEs) and algebraic equationsso-called differential algebraic equations (DAEs). This has applications to all models of cellular processes where spatial gradients are ignored (spatial information is handled by a complementary standard called field modelling language (FieldML, www.fieldml.org), which is discussed by Christie et al. (2009)) and also to systems physiology models where a lumped parameter representation is used. The language is designed to support the definition and sharing of models of biological processes by including information about: model structure (how the parts of a model are organizationally related to one another); mathematics (equations describing the underlying biological processes); and metadata (additional information about the model; see 2 below). CellML is built on existing standards such as content Mathematical Markup Language (MathML) for encoding the mathematics (www.w3c.org/Math) and the Dublin Core for bibliographic information (www.dublincore.org). The current release of the CellML standard is available at www.cellml.org/specifications. Note that CellML, with its focus on biophysical processes, is complementary to another XML language called Systems Biology Markup Language (SBML, www.sbml.org), which principally represents biochemical reaction networks and is widely used in the systems biology community. CellML has a simple structure (figure 1) based on connected components. These components are abstract concepts providing well-defined interfaces to other components, and encapsulate concepts by hiding details from other components. Connections provide the means for sharing information by associating variables visible in the interface of one component with those in Developments in CellML metadata the interface of another component. Consistency is enforced by requiring that all variables be assigned appropriate physical units, the dimensions of which must match when variables are connected. Public and private interfaces enable encapsulation hierarchies, providing further mechanisms for information hiding and abstraction. Model reuse is facilitated by the import element, enabling new models to be constructed by combining existing models into model hierarchies. The CellML 1.1 standard is available at www.cellml.org/specifications/cellml_1.1. The CellML Model Repository currently contains over 370 models from peerreviewed publications of biological processes ranging from gene regulation, ion channel electrophysiology, signal transduction and metabolic pathways to bioengineering constitutive laws and larger scale systems physiology processes (www.cellml.org/models). Approximately half of these models have been curated to a level where they are internally consistent in their units and have all the necessary parameter values and initial conditions to numerically integrate successfully and give outputs that match those in the source publication (Lloyd et al. 2008). Freely available open-source CellML authoring and simulation software can be obtained from www.cellml.org/tools. The CellML project is an international open-source effort involving input from many people. Every attempt is made to be as open and inclusive as possible in the decision-making processes. Most of the current project activities are described as items in the Physiome Tracker (https://tracker.physiomeproject.org). Within the CellML project category, the tracker is organized according to subject area (i.e. the CellML specifications, CellML Model Repository, model repository software, etc.), and issues are able to be searched, sorted and organized according to attributes and keywords. Tracker items are usually open for feedback for a limited period of time. After the closing date, a panel of CellML members considers the tracker contributions and attempts to reach a consensus. If consensus is reached, one of the panel members will add a comment to the tracker item, describing the consensus and marking it as resolved. If the panel cannot reach consensus, the CellML project leader will either cast a deciding vote, or reframe and reopen the issue as she/he sees fit. The CellML group at the Auckland Bioengineering Institute meets regularly (typically weekly). Although this group represents only a portion of the CellML community, it is engaged in most of the core projects, such as the devel (...truncated)