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Identifying Functionally Linked Gene Modules Within Biological Pathways Assessed by ToxCast In Vitro Assays
Citation:
MORTENSEN, H. M., D. REIF, D. J. DIX, T. B. KNUDSEN, K. A. HOUCK, R. J. KAVLOCK, AND R. JUDSON. Identifying Functionally Linked Gene Modules Within Biological Pathways Assessed by ToxCast In Vitro Assays. Presented at Society of Toxicology Annual Meeting, Salt Lake City, UT, March 07 - 11, 2010.
Impact/Purpose:
ToxCast project
Description:
The US EPA ToxCast program is using in vitro high-throughput screening assays to profile the bioactivity of environmental chemicals, with the ultimate goal of predicting in vivo toxicity. We hypothesize that in modeling toxicity it will be more constructive to understand the perturbation of pathways (i.e. “toxicity pathways”) as opposed to individual genes or assays. Success in this pathway based approach requires good assay coverage of key gene modules, which we define as sets of functionally linked genes common to multiple pathways. A key challenge in delineating gene modules is to understand the nature of their biological cohesiveness and interactions. Here we focus on a set of 18,187 human genes represented in the GO, KEGG, and Ingenuity pathway databases. We compare cluster analysis and validation methods for the identification of candidate pathway modules. Preliminary hierarchical and partition clustering results for Ingenuity pathways (110 pathways, 3300 genes) indicate both distinct modules from a single pathway, and complex ckusters of genes from many canonical pathways. Further subdivision of complex clusters into distinct, coherent modules requires a secondary step using information on disease-gene and other associations. We have mapped assay targets from Phase I of ToxCast to the putative gene modules, and identified targets in modules not currently assessed that would be good candidates for new assays in later Phases of the project.
URLs/Downloads:
Identifying Functionally Linked Gene Modules Within Biological Pathways Assessed by ToxCast In Vitro Assays (poster) (PDF, NA pp, 206 KB, about PDF)Identifying Functionally Linked Gene Modules Within Biological Pathways Assessed by ToxCast In Vitro Assays (abs) (PDF, NA pp, 10 KB, about PDF)