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Fusing and Composing Macromolecular Regulatory Network Models
Ranjit Randhawa*Clifford A. Shaffer*
John J. Tyson+
Departments of Computer Science* and Biology+
Virginia TechBlacksburg, VA 24061
Regulatory Network Modeling Wish to deduce physiological properties of a
cell from wiring diagrams of control systems
Frogegg Model
Budding Yeast Model
Wiring diagrams are converted to reactions for simulation
Example: Chen and Tyson’s budding yeast model contains over 30 ODEs, some nonlinear.
About 140 rate constant parameters Validate model by comparing simulation results
against morphological outcomes from over 100 mutants defective in the regulatory network.
Budding Yeast Wiring Diagram
Budding Yeast Model
Problem
These models are reaching the limits of human comprehension
Making the model suitable for stochastic simulation increases the number of reactions by a factor of 3-5.
Models of the Mammalian cell cycle will require 100-1000 (more for stochastic simulation).
Solution
Some mechanism must be found to describe models as collections of small building blocks that are combined to form the full model.
Systems Biology Markup Language
SBML is the current standard interchange language within the community of systems biology modelers.
We implement our proposals within the context of SBML language additions.
Sample Models
Fused and Composed Models
Fusion
Given two or more existing models, we wish to create a new model that combines the information.
Remains standard SBML We provide a tool to support users combining
models. Implemented in “wizard” style
Fusion: Matching Tables
Fusion is done primarily by defining matching of SBML components Compartments, reactions, species, etc.
A series of matching tables Order is important to deal with dependencies
mf m1 m2
1 A A A
2 B B
3 D D
mf m1 m2
1 A1 A
2 C B D
3 A2 A
Fusion Tool Setup Wizard
Species Mapping Table
Reaction Mapping Table
Composition
Connects submodels together to form a hierarchy of models
Submodels are each valid SBML models Add language features to SBML to support
composition Describe hierarchy Describe interactions, links, replacements
No information hiding within models
Composition and the Fusion Wizard There are significant similarities between fusion and
composition Fusion defines a series of steps taken to merge
models Series of steps captured by the fusion tool can be
viewed as an “audit trail” used in generating the mapping tables
Precisely this same information can be used to describe the set of instructions needed to connect/link the submodels for composition
Composition Hierarchy
<model id="Big"> <listOfCompartments> <compartment id="comp1" volume="1"/> </listOfCompartments> <listOfSubmodels> <model id="Little"> <listOfCompartments> <compartment id="comp2" volume="1"/> </listOfCompartments> </model> </listOfSubmodels></model>
Links
<link>
<from object="comp1"/>
<to object="Submodel_Little"
<subobject object="comp2"/>
</to>
</link>
Is Composition the Right Model?
Composition allows us to take existing models and use them as components to build larger models
No information hiding Submodels might fit together more or less well
Links let us replace things in one model with things in another
Good for legacy models(?) We might do better to build models from components
designed to work as components, with proper information hiding.
Aggregation
In aggregation, models are built up from components Each component could be, for example, a collection
of reactions This collection exposes certain variables for
input/output via “ports” Hopefully this is a natural concept for modelers Not intended as a solution for reusing legacy models.
Toggle Switch
Iconified Toggle Switch
Toggle Switch Component
Flattening
Flattening generates a standard SBML file from our modified file, for the purpose of running simulations, etc.
An automated form of fusion. The additional language features provide
what the user would provide during fusion, so automation is possible.
Summary
We recognize four distinct activities related to model decomposition [Status] Fusion: Take existing models and merge them
[Implemented] Composition: Build up from existing models, no
information hiding [Implemented] Aggregation: Build up from building blocks,
controlled interfaces [Designing stage] Flattening: Merge the building blocks back into a
“flat” (non-composed) model (for making simulation runs) [Implemented]
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