Abstract
It has become increasingly evident that the descriptions of many complex diseases are only possible by taking into account multiple influences at different physiological scales. To do this with computational models often requires the integration of several models that have overlapping scales (genes to molecules, molecules to cells, cells to tissues). The Virtual Physiological Rat (VPR) Project, a National Institute of General Medical Sciences (NIGMS) funded National Center of Systems Biology, is tasked with mechanistically describing several complex diseases and is therefore identifying methods to facilitate the process of model integration across physiological scales. In addition, the VPR has a considerable experimental component and the resultant data must be integrated into these composite multiscale models and made available to the research community. A perspective of the current state of the art in model integration and sharing along with archiving of experimental data will be presented here in the context of multiscale physiological models. It was found that current ontological, model and data repository resources and integrative software tools are sufficient to create composite models from separate existing models and the example composite model developed here exhibits emergent behavior not predicted by the separate models.
Highlights
Rather than the result of a single mechanism operating at a single physiological scale, the phenotypes that define a complex disease and/or normal physiological function are often emergent properties of the interaction of a multitude of mechanisms acting across multiple scales
As systems-level modeling has increased in complexity over the years, researchers have recognized the need for representation standards that enable broad model sharing and reuse
Describing multiscale processes in mouse development mathematical models using a combination of Gene Ontology (GO) and Cell Type Ontology (CL) terms has been shown to be extremely effective to provide clear definitions of function and to allow comparison of function under different conditions
Summary
Rather than the result of a single mechanism operating at a single physiological scale, the phenotypes that define a complex disease and/or normal physiological function are often emergent properties of the interaction of a multitude of mechanisms acting (and interacting) across multiple scales. URL http://sbp.bhi.washington.edu/projects/semgen http://www.physiome.org/jsim/ www.virtualrat.org http://www.systemscenters.org/ http://www.ebi.ac.uk/biomodels-main/ http://www.cellml.org/ http://www.physiome.org/Models/ http://semanticsbml.org/ http://antimony.sourceforge.net/ http://sabio.villa-bosch.de/ http://sourceforge.net/apps/mediawiki/saint-annotate/ http://sedml.org/ http://www.comp-sys-bio.org/tiki-index.php?page=SBRML http://code.google.com/p/numl/ http://sig.biostr.washington.edu/projects/fm/ http://sbp.bhi.washington.edu/projects/the-ontology-of-physics-for-biology-opb http://www.ebi.ac.uk/ http://www.imagwiki.nibib.nih.gov/mediawiki/index.php?title=Data_Sharing_Working_Group http://www.physionet.org/ http://www.virtualrat.org/VPR1002/ http://www.cellml.org/tools/opencell. Such efforts are nontrivial because manual model integration is highly time-consuming, prone to errors in realizing and reproducing models, and requires physiological as well as computational domain expertise. JSim, a simulation and modeling analysis software suite developed as part of the Physiome Project at University of Washington and can be downloaded from their website (JSim, Table 1) This pilot study further reveals a number of gaps in the way existing tools operate and interact that represent major opportunities for current and future development
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