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Workflow for Defining Reference Chemicals to Assess Performance of In Vitro Assays
Citation:
Simha, A., R. Judson, R. Thomas, N. Baker, X. Howey, C. Marable, N. Kleinstreuer, AND K. Houck. Workflow for Defining Reference Chemicals to Assess Performance of In Vitro Assays. Presented at Society of Toxicology Annual Meeting, Baltimore, MD, March 10 - 14, 2019. https://doi.org/10.23645/epacomptox.7874000
Impact/Purpose:
Reference chemicals are crucial for instilling confidence in new in vitro assays and for determining the assays' domain of applicability. Here we present a novel semi-automated workflow for quickly defining reference chemicals through existing literature.
Description:
Instilling confidence in use of in vitro assays for predictive toxicology requires evaluation of assay performance. Performance is typically assessed using reference chemicals--compounds with defined activity or inactivity against the test system target. However, developing reference chemical lists has historically been very resource-intensive. We have developed a semi-automated process for selecting and annotating reference chemicals across many targets in a standardized format and we demonstrate the workflow here. A series of required fields defines the potential reference chemical: the in vitro molecular target, pathway, or phenotype affected; and the chemical’s mode (e.g. agonist, antagonist, inhibitor). Activity information was extracted into a database, using automated scripts, from multiple public sources including non-curated scientific literature and curated chemical-biological databases, resulting in the identification of chemical activity in 2995 molecular targets. The sample data from literature sources covering 54 molecular targets ranging from data-poor to data-rich was manually checked for accuracy. Precision rates were 82.7% from curated data sources and 39.5% from the automated literature extraction. We applied the final reference chemical lists to evaluating performance of EPA’s ToxCast program in vitro bioassays. The level of support, i.e. the number of independent reports in the database linking a chemical to a target, was found to strongly correlate with likelihood of positive results in the ToxCast assays, although individual assay performance had considerable variation. This overall approach allows rapid development of candidate reference chemical lists for a wide variety of targets that can facilitate performance evaluation of in vitro assays as a critical step in imparting confidence in alternative approaches. The views expressed are those of the authors and do not necessarily represent the views or policies of the U.S. EPA.
URLs/Downloads:
DOI: Workflow for Defining Reference Chemicals to Assess Performance of In Vitro Assays
SIMHA_SOT_2019.PDF (PDF, NA pp, 441.029 KB, about PDF)