The Sbml Level 3 Flux Balance Constraints Package: A Community Driven Standard for the Encoding of Genome-Scale, Constraint-Based Models

Introduction

Constraint-based modeling is a widely used methodology, however, faced with a significant growth in the number and diversity of such models a critical need has arisen for an open, standard model encoding format. We present the Flux Balance Constraints (FBC) Package that extends SBML Level 3 Core enabling the tool-neutral encoding of constraint-based models.

Methods

In 2010 we realised the need for a standard format to encode constraint-based models and developed a prototype SBML Level 2 annotation. With the release of SBML Level 3 this proposal was reformulated, in line with the SBML Level 3 specification process [1,2] and an open, community development forum, the FBC Package Working Group (PWG) was formed [3].

A revised proposal [4] was accepted by the PWG and SBML community and subsequently reformulated as the FBC Package Version 1 specification [5]. The SBML development process requires software support for all packages during development and all FBC versions have been developed and implemented in the SBW FBA tool and CBMPy [6,7].

Following the version 1 release there is currently a growing and active participation in the development of the latest FBC version 2 specification. As FBC development is a community driven process, the yearly HARMONY and COMBINE meetings are utilised to meet and work on improving the standard and ensuring compatibility between tools.

Results

Annotation.
Each FBC component gains the benefit of the SBML annotation mechanism allowing the addition of MIRIAM compliant annotations.

Objective functions.
The FBC specification allows the definition of multiple, linear objective functions in a single model with one designated as active.

Extended SBML Species and Reactions.
The FBC package re-introduces the Species “charge” attribute and adds another for storing a chemical formula. The Reaction construct gets new “flux bound” attributes that refer to SBML Parameters.

Gene-protein-reaction associations.
The FBC package introduces a mechanism for the XML encoding of boolean expressions replacing the existing arbitrarily formatted annotations.

Programming libraries.
LibSBML is a popular library that enables applications to read / write SBML documents, with a unified interface providing support for C++, C#, Java, Python, Ruby, R, Javascript, PhP, Matlab and Octave [8]. We have extended libSBML to support FBC models in all supported languages and provide converters between existing formats and FBC. The SBML Toolbox has also been enhanced to support the FBC package while model validation is available via the SBML Online Validator [9].

Community tools.
In order to make it easy for implementors of the FBC package to ensure compliance with all mandatory features, we added a number of test cases to the SBML Test suite [10,11].

Discussion

Through a community development process, the SBML Level 3 FBC package has been developed to provide an unambiguous format to encode constraint-based models. This includes the re-encoding of legacy models, currently encoded in a variety of formats, as well as providing a platform for the encoding of next-generation models.

Acknowledgements

We would like to thank the members of the FBC Package Working Group for their active involvement as well as Michael Hucka, Ursula Kummer, Herbert Sauro and Bas Teusink for material support.

References