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The ToxCast Pipeline: Updates to Curve-fitting Approaches and Database Structure
Citation:
Feshuk, M., L. Kolaczkowski, K. Dunham, S. Davidson-Fritz, K. Carstens, J. Brown, R. Judson, AND K. Friedman. The ToxCast Pipeline: Updates to Curve-fitting Approaches and Database Structure. Frontiers in Toxicology. Frontiers, Lausanne, Switzerland, 5:1275980, (2023). https://doi.org/10.3389/ftox.2023.1275980
Impact/Purpose:
The purpose of this manuscript is to communicate extensive updates to the ToxCast Pipeline for our internal and external stakeholders. · The ToxCast program makes targeted in vitro screening assay data publicly available for prioritization and hazard characterization. · Data needs in next generation risk assessment necessitated software and database updates for consistent and reproducible curve-fitting and data management across screening efforts. · Updates include additional models, bidirectional curve-fitting, and continuous hit calling. · Annotation structure, fit categories, and cautionary flags on curve-fitting behavior were modified for future invitrodb release. · Curve-fitting updates resulted in small changes in activity hit calls and potency estimates but without a uniform trend.
Description:
Bioactivity data can be utilized in a tiered screening strategy for next generation risk assessment. The US Environmental Protection Agency Toxicity Forecaster (ToxCast) program makes in vitro medium- and high-throughput screening assay data publicly available for the prioritization and hazard characterization of thousands of chemicals of interest. The assays included employ a variety of technologies to evaluate the effects of chemical exposure on diverse biological targets from distinct proteins to more complex cellular processes like mitochondrial toxicity, nuclear receptor signaling, immune responses, and developmental toxicity. The ToxCast data pipeline (tcpl) is an open-source R package that stores, manages, curve-fits, and visualizes ToxCast data as well as populating the linked MySQL Database, InvitroDB. In the InvitroDB v3.5 release (Summer 2022), the number of publicly available data has increased with new endpoints related to steroidogenesis, cardiotoxicity, and acute and developmental neurotoxicity, with updates in assay annotations to enable better data aggregation. The InvitroDB v4.0 release will include the same data as v3.5, but reprocessed with tcpl v3.0 in an updated database schema to accommodate the addition of more curve-fitting models. Seven additional models (linear and quadratic polynomial, power, and four exponential variants) based on BMDExpress2 and encoded by the R package dependency, tcplFit2, have been added to the previous constant, Hill, and gain-loss models available in tcpl v2. Along with bidirectional curve-fitting, tcpl v3.0 will provide tcplFit2 model parameters, continuous hit call probabilities, and interactive, yet consistent visualization of concentration-response curves within a new utility called tcplPlot. Tcpl and InvitroDB provide a standard for consistent and reproducible data management and curve-fitting for diverse in vitro assay data with readily available documentation, thus enabling interoperability and use. These enhancements will support the continued utility of ToxCast in vitro screening results as a resource for bioactivity data in myriad toxicology applications.
URLs/Downloads:
DOI: The ToxCast Pipeline: Updates to Curve-fitting Approaches and Database Structure
https://pubmed.ncbi.nlm.nih.gov/37808181/