title: Gene set assembly for quantitative prediction of developmental toxicity in the embryonic stem cell test.
abstract: The embryonic stem cell test (EST) is an in vitro method for predicting developmental toxicity based on compound-induced inhibition of embryonic stem cell (ESC) differentiation. We previously described how gene expression analysis in the EST can be used to describe normal ESC differentiation as well as identify compound developmental toxicity, by means of our differentiation track algorithm. In this study, we combined raw data from our three previous studies in a new integrated analysis, to identify a gene set that allows for improved prediction. By evaluating predictions of 100,000 randomly selected gene sets, we identified which genes contribute significantly to the prediction reliability. By additional cross-validation, we identified a set of 52 genes that allows for improved prediction of toxicity. The correlation between the predictions using this gene set and the magnitude of the EST endpoint was 0.85, and the gene set predicted developmental toxicity with 83% accuracy (area under the curve 89%). If compounds with ineffective data because of a too low tested concentration or too much variation between samples were excluded, even 100% accuracy could be reached based on 15 compounds. This novel gene set consists mainly of genes involved in the stem cell differentiation or other developmental processes. We expect that this set can be of use in future studies aimed at improving the EST for risk assessment, thus making a next step towards regulatory implementation of this method.
authors.affiliation: Laboratory for Health Protection Research, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands. Jeroen.Pennings@rivm.nl
authors.forename: Jeroen L A
authors.initials: JL
authors.lastname: Pennings
authors.forename: Dorien A M
authors.initials: DA
authors.lastname: van Dartel
authors.forename: Joshua F
authors.initials: JF
authors.lastname: Robinson
authors.forename: Tessa E
authors.initials: TE
authors.lastname: Pronk
authors.forename: Aldert H
authors.initials: AH
authors.lastname: Piersma
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D003603:Cytotoxins / Q000633:toxicity; D030541:Databases, Genetic; D053595:Embryonic Stem Cells / Q000187:drug effects* / Q000502:physiology; D005544:Forecasting; D020869:Gene Expression Profiling / Q000379:methods*; D053263:Gene Regulatory Networks / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D009152:Mutagenicity Tests / Q000379:methods
chemical_list: D003603:Cytotoxins