Impact/Purpose:

Enhancing Quantitative Risk Assessment - Development and Implementation of Advanced Biological Models and Systems Biology

Description:

The PBPK modeling community has had a long-standing problem with modeling software compatibility. The numerous software packages used for PBPK models are, at best, minimally compatible. This creates problems ranging from model obsolescence due to software support discontinuation to difficulty in linking models created in different packages.

The objective of this research effort is to create an XML extension to be used in conjunction with the systems biology markup language (SBML), an XML-based, machine-readable format for representing models of biochemical reaction networks, including metabolic networks, cell-signaling pathways, and regulatory networks. This extension will augment SBML to accommodate PBPK models with reasonable complexity, including full documentation, PBPK modeling vocabulary, and examples for instructional and demonstrational purposes. This extension will be constructed to permit seamless linking of PBPK models to the biological pathway models abundantly available in SBML format. A secondary goal is to develop a pseudo-generalized visualization program that is capable of translating an SBML file for a PBPK model into a visual schematic along with equations representing the schematic in differential equation form, accompanied by parameter values and references for the parameters.

End-users of a PBPK model, such as risk assessors, would benefit greatly from being able to use the software of their choice to run the model and to visualize the model itself and documentation for it, making incorporation of PBPK models in the risk assessment process easier and more efficient.

Record Details:

Record Type:PROJECT

Projected Completion Date:09/30/2008

OMB Category:Other

Record ID: 149183

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Project Information:

Progress :A team has been assembled to develop the schema as well as advise and manage the project. Some necessary features of the extension have been determined and we are currently coding a simple PBPK model in SBML as part of the process of determining all necessary attributes. The interest of the PBPK community has been assessed and a list of interested parties, some possibly for collaboration, has been created.

Approach :We will begin by coding simple to moderately complex PBPK models in SBML and testing the results. This initial step will map out the limitations and weaknesses of SBML for accommodating PBPK models and give insight into the magnitude of the work involved in creating an appropriate SBML extension. This initial step will be an iterative process with complexity of the models increasing until all major necessary attributes of the extension are uncovered. The next step will be to create an initial version of the schema and extensively test it. An NCCT-sponsored meeting will be held with all interested parties where the schema will be presented and a plan for moving forward will be presented and debated. This plan will include formal and informal collaborations and partnerships. Once a final version of the extension has been developed and fully tested, a formal SBML workgroup will be formed and a proposal will be written to the SBML Community at Large for incorporation of the extension into the current version of the base SBML schema. At this point, SBML would fully accommodate PBPK models. Simultaneously, we will be developing the visualization program with the objective of using it not only as an aid in the development and usage of PBPK models, but also as a powerful educational tool.

Relevance :The ability to create, transfer, use, augment, and review PBPK models without the limitation of software compatibility is a long-standing desire in the PBPK community. The ability to seamlessly link PBPK models to biological pathway models is of great interest, since this gives the modeler a fast and efficient means of extending the estimations of tissue dose from the PBPK model to cellular-level responses, thereby facilitating a quantitative investigation of dose-response relationships through mode/mechanism of action. By making the use of PBPK models faster, easier, and more reliable, this product will make the use of these models more common and widespread in risk assessment.

Project IDs:

ID Code :IIID-3

Project type :Partner Specific