Composition%20and%20Aggregation%20in%20Modeling%20Regulatory%20Networks

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Composition and Aggregation in Modeling
Regulatory Networks

• Clifford A. Shaffer
• Ranjit Randhawa
• John J. Tyson
• Departments of Computer Science and Biology
• Virginia Tech
• Blacksburg, VA 24061

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Regulatory Network Modeling

• Wish to deduce physiological properties of a cell
  from wiring diagrams of control systems

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Frogegg Model
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Budding Yeast Model

• Wiring diagrams are converted to reactions for
  simulation
• Example Chen and Tysons 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.

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Budding Yeast Model
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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).

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Solution

• Some mechanism must be found to describe models
  as collections of small building blocks that are
  combined to form the full model.

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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.

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Prior Efforts

• Others (Finney Ginkel SchroderWeimar Webb)
  have made proposals for model decomposition
  within SBML.
• These various proposals for have never been
  implemented.
• A major problem appears to be that they view
  model decomposition as one monolithic problem to
  solve.
• There are actually various distinct mechanisms
  involved.

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Our Approach

• We recognize four distinct activities related to
  model decomposition
• Fusion Take existing models and merge them
• Composition Build up from existing models, no
  information hiding
• Aggregation Build up from building blocks,
  controlled interfaces
• Flattening Merge the building blocks back into a
  flat (non-composed) model (for making
  simulation runs)

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Relationships
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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
• Status Prototype

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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
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Fusion Tool Setup Wizard
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Species Mapping Table
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Reaction Mapping Table
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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
• Relationship to fusion the mappings are the glue.

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Composition Hierarchy

• ltmodel id"Big"gt
• ltlistOfCompartmentsgt
• ltcompartment id"comp1" volume"1"/gt
• lt/listOfCompartmentsgt
• ltlistOfSubmodelsgt
• ltmodel id"Little"gt
• ltlistOfCompartmentsgt
• ltcompartment id"comp2"
• volume"1"/gt
• lt/listOfCompartmentsgt
• lt/modelgt
• lt/listOfSubmodelsgt
• lt/modelgt

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Links

• ltlinkgt
• ltfrom object"comp1"/gt
• ltto object"Submodel_Little"
• ltsubobject object"comp2"/gt
• lt/togt
• lt/linkgt
• Issue Merge or replace attribute information?

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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.

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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.

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Toggle Switch
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Iconified Toggle Switch
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Toggle Switch Component
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Flattening

• Flattening generates a standard SBML file from
  our modified file, for the purpose of running
  simulations, etc.
• An automated form of fusion.
• The composition/aggregation language features
  provide what the user would provide during
  fusion, so automation is possible.