Unraveling the mechanisms underlying drug-induced cholestatic liver injury: identifying key genes using machine learning techniques on human in vitro data sets

Jian Jiang*, Jonas van Ertvelde, Gökhan Ertaylan, Ralf Peeters, Danyel Jennen, Theo M de Kok, Mathieu Vinken*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Drug-induced intrahepatic cholestasis (DIC) is a main type of hepatic toxicity that is challenging to predict in early drug development stages. Preclinical animal studies often fail to detect DIC in humans. In vitro toxicogenomics assays using human liver cells have become a practical approach to predict human-relevant DIC. The present study was set up to identify transcriptomic signatures of DIC by applying machine learning algorithms to the Open TG-GATEs database. A total of nine DIC compounds and nine non-DIC compounds were selected, and supervised classification algorithms were applied to develop prediction models using differentially expressed features. Feature selection techniques identified 13 genes that achieved optimal prediction performance using logistic regression combined with a sequential backward selection method. The internal validation of the best-performing model showed accuracy of 0.958, sensitivity of 0.941, specificity of 0.978, and F1-score of 0.956. Applying the model to an external validation set resulted in an average prediction accuracy of 0.71. The identified genes were mechanistically linked to the adverse outcome pathway network of DIC, providing insights into cellular and molecular processes during response to chemical toxicity. Our findings provide valuable insights into toxicological responses and enhance the predictive accuracy of DIC prediction, thereby advancing the application of transcriptome profiling in designing new approach methodologies for hazard identification.
Original languageEnglish
Pages (from-to)2969-2981
Number of pages13
JournalArchives of Toxicology
Volume97
Issue number11
DOIs
Publication statusPublished - Nov 2023

Keywords

  • Drug-induced cholestasis
  • Feature selection
  • Machine learning
  • Supervised classification
  • Wrapper feature selection

Cite this