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首页> 外文期刊>Toxicology: An International Journal Concerned with the Effects of Chemicals on Living Systems >Gene set assembly for quantitative prediction of developmental toxicity in the embryonic stem cell test.
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Gene set assembly for quantitative prediction of developmental toxicity in the embryonic stem cell test.

机译：用于胚胎干细胞测试中发育毒性定量预测的基因集装配。

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摘要

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.
机译：胚胎干细胞测试（EST）是一种基于化合物诱导的胚胎干细胞（ESC）分化抑制作用来预测发育毒性的体外方法。先前，我们描述了如何通过我们的分化追踪算法，将EST中的基因表达分析用于描述正常的ESC分化以及鉴定化合物的发育毒性。在这项研究中，我们将来自先前三项研究的原始数据合并到一个新的综合分析中，以鉴定可改善预测的基因集。通过评估100,000个随机选择的基因集的预测，我们确定了哪些基因对预测的可靠性有重大贡献。通过额外的交叉验证，我们确定了52个基因的集合，这些基因可改善毒性预测。使用该基因集的预测值与EST终点的大小之间的相关性是0.85，该基因集预测发育毒性的准确度为83％（曲线下的面积为89％）。如果排除由于测试浓度太低或样品之间的差异太大而导致数据无效的化合物，则基于15种化合物甚至可以达到100％的准确度。这个新的基因集主要由参与干细胞分化或其他发育过程的基因组成。我们希望这套方法可以在未来的研究中使用，以改进用于风险评估的EST，从而朝着该方法的法规实施迈出下一步。

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