Cross-platform toxicogenomics for the prediction of non-genotoxic hepatocarcinogenesis in rat

PLoS One. 2014 May 15;9(5):e97640. doi: 10.1371/journal.pone.0097640. eCollection 2014.

Abstract

In the area of omics profiling in toxicology, i.e. toxicogenomics, characteristic molecular profiles have previously been incorporated into prediction models for early assessment of a carcinogenic potential and mechanism-based classification of compounds. Traditionally, the biomarker signatures used for model construction were derived from individual high-throughput techniques, such as microarrays designed for monitoring global mRNA expression. In this study, we built predictive models by integrating omics data across complementary microarray platforms and introduced new concepts for modeling of pathway alterations and molecular interactions between multiple biological layers. We trained and evaluated diverse machine learning-based models, differing in the incorporated features and learning algorithms on a cross-omics dataset encompassing mRNA, miRNA, and protein expression profiles obtained from rat liver samples treated with a heterogeneous set of substances. Most of these compounds could be unambiguously classified as genotoxic carcinogens, non-genotoxic carcinogens, or non-hepatocarcinogens based on evidence from published studies. Since mixed characteristics were reported for the compounds Cyproterone acetate, Thioacetamide, and Wy-14643, we reclassified these compounds as either genotoxic or non-genotoxic carcinogens based on their molecular profiles. Evaluating our toxicogenomics models in a repeated external cross-validation procedure, we demonstrated that the prediction accuracy of our models could be increased by joining the biomarker signatures across multiple biological layers and by adding complex features derived from cross-platform integration of the omics data. Furthermore, we found that adding these features resulted in a better separation of the compound classes and a more confident reclassification of the three undefined compounds as non-genotoxic carcinogens.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Algorithms
  • Animals
  • Area Under Curve
  • Artificial Intelligence
  • Carcinogenicity Tests*
  • Carcinogens / chemistry*
  • Cluster Analysis
  • Computational Biology
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Liver Neoplasms, Experimental / chemically induced
  • Liver Neoplasms, Experimental / metabolism*
  • Male
  • Models, Statistical
  • Protein Array Analysis
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Wistar
  • Toxicogenetics / methods*

Substances

  • Carcinogens
  • RNA, Messenger

Grant support

The research leading to these results has received funding from the Innovative Medicine Initiative Joint Undertaking (IMI JU) under grant agreement nr. 115001 (MARCAR project). The authors acknowledge support by Deutsche Forschungsgemeinschaft and Open Access Publishing Fund of Tuebingen University. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.