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Series GSE183534 Query DataSets for GSE183534
Status Public on May 03, 2022
Title Optimization of the TeraTox assay for preclinical teratogenicity assessment
Organism Homo sapiens
Experiment type Expression profiling by high throughput sequencing
Summary Stem-cell-based in vitro systems are promising tools to predict human teratogenicity. However, current in vitro assays are limited because they either capture effects on a certain germ layer or focus on a subset of predictive markers. Here we report the characterization and critical assessment of TeraTox, a newly developed multi-lineage differentiation assay using 3D human induced pluripotent stem cells. TeraTox probes stem-cell-derived embryoid bodies with two endpoints, one quantifying cytotoxicity and the other inferring the teratogenicity potential with gene expression as a molecular phenotypic readout. To derive teratogenicity potential from gene expression profiles, we applied both unsupervised machine-learning tools including factor analysis, and supervised tools including classification and regression. To identify the best predictive model for the teratogenicity potential that is explainable, we systematically tested 64 machine-learning model architectures and identified the optimal model, which uses the expression of 77 representative germ-layer genes, summarized by 10 latent germ-layer factors, as input for random-forest regression. We combined measured cytotoxicity and inferred teratogenicity potential to predict concentration-dependent teratogenicity profiles of 33 approved pharmaceuticals and 12 proprietary drug candidates with known in vivo data. Compared with the mouse embryonic stem cell test, which has been in routine use for more than a decade, the TeraTox assay shows higher sensitivity, particularly towards teratogens impairing ectodermal development or stem-cell renewal, and a more balanced prediction performance. We envision that further refinement and development of TeraTox has the potential to reduce and replace animal research in drug discovery and to improve preclinical assessment of teratogenicity.
 
Overall design Commercial and proprietary compounds are tested in two batches (Run1 and Run2, respectively). Each compound is tested in dose-response (six or twelve points each), and each concentration is tested in two independent biological replicates. Samples are treated in 96-well plates, each containing DMSO controls (up to twelve replicates) and samples treated with one or more compounds.
Web link https://academic.oup.com/toxsci/advance-article/doi/10.1093/toxsci/kfac046/6575922
 
Contributor(s) Jaklin M, Schäfer N, Küng E, Zhang JD
Citation(s) 35485993
Submission date Sep 06, 2021
Last update date May 05, 2022
Contact name Jitao David Zhang
E-mail(s) jitao_david.zhang@roche.com
Phone +41616886251
Organization name F. Hoffmann-La Roche
Department Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel
Lab Pharmaceutical Sciences
Street address Grenzacherstrasse 124
City Basel
ZIP/Postal code 4070
Country Switzerland
 
Platforms (1)
GPL24676 Illumina NovaSeq 6000 (Homo sapiens)
Samples (1055)
GSM5558976 M1_1_DMSO_ctrl
GSM5558977 M1_2_DMSO_ctrl
GSM5558978 M1_3_DMSO_ctrl
Relations
BioProject PRJNA761146
SRA SRP335900

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE183534_FactorAnalysis-DGEList.gct.gz 2.7 Mb (ftp)(http) GCT
GSE183534_RAW.tar 8.3 Mb (http)(custom) TAR (of TSV)
SRA Run SelectorHelp
Raw data are available in SRA
Processed data provided as supplementary file

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