Toxicogenomic analysis methods for predictive toxicology.

Abstract

Toxicogenomics, the application of genomic data to elucidate or predict an organism's response to a toxicant, can inform the drug development process in important ways. It is apparent that standardized approaches to many types of toxicogenomic questions are still being formulated. Specifically, a significant body of proof of principle studies has emerged that demonstrates a range of statistical methodologies applied to predictive toxicology. These studies rely on class prediction methods--mathematical models generated using the gene expression profiles of known toxins from representative toxicological classes--to predict the toxicological effect of a compound based on the similarities between its gene expression profile and the profiles of a given toxicological class. Class prediction methods hold promise for increasing the rate at which compounds can be evaluated for toxicity early in the drug discovery process, while at the same time reducing the length of toxicological studies and their associated costs. Class prediction methods are informed by class comparison and class discovery steps, which inform, respectively, the selection of genes whose response can be used to distinguish among the toxicological classes and the number of classes distinguishable using the response of these genes. Together these steps use a variety of complementary statistical techniques to achieve a successful class prediction model. This report attempts to review some of the themes that appear to be emerging in the application of these techniques to predictive toxicology methods over toxicogenomics' short history.