03/16/2020 @ 10:45 AM – 12:30 PM | Exhibit Hall – Poster Board No. P468
Defining the Reproducibility and Applicability Domain of devTOX quickPredict, a Human Pluripotent Stem Cell-Based Developmental Toxicity Assay
J.A. Palmer1, E.L. Donley1, A.M. Smith1, M.R. Colwell1, and R.E. Burrier1
1 Stemina Biomarker Discovery, Inc., Madison, WI USA
The assay predicted the developmental toxicity potential across this diverse set of chemicals with 87% accuracy (88% sensitivity, 86% specificity). Within individual chemical classes (i.e., pharmaceuticals or pesticides), assay accuracy ranged from 81% to 94%, demonstrating the broad applicability of the assay.
The reproducibility of the predictive model was evaluated using independent replicates of three chemical treatments (carbamazepine, n=34; methotrexate, n=34; thalidomide, n=9) conducted by multiple technicians with multiple iPS cell lines, freeze lots and reagents over the course of 5 years. The interpolated developmental toxicity potential (dTP) values (determined using the devTOXqP predictive model) were within two standard deviations of the mean for each of the chemicals, demonstrating that the assay endpoints are reproducible over time.
To understand the applicability domain of the assay, the results were separated into different pharmacological categories and performance was assessed. The assay’s sensitivity in the different pharmacological categories ranged from 50% to 100% and provides insight into the assay’s biological applicability domain. For example, developmental toxicants classified as channel, kinase, and transcription modulators and DNA modifiers were predicted as developmentally toxic with 100% sensitivity. In contrast, receptor modulators were predicted with 50% sensitivity, and were highly dependent upon whether the iPS cells expressed the specific receptor being modulated. These data demonstrate the importance of understanding a NAM’s biological system, its strengths and its limitations.
Taken together, these data demonstrate the accuracy, reproducibility, and broad applicability domain of the devTOXqP assay and support its use as an alternative to animal models for developmental toxicity testing.