Inferring Genes and Biological Functions That Are Sensitive to the Severity of Toxicity Symptoms

The effective development of new drugs relies on the identification of genes that are related to the symptoms of toxicity. Although many researchers have inferred toxicity markers, most have focused on discovering toxicity occurrence markers rather than toxicity severity markers. In this study, we aimed to identify gene markers that are relevant to both the occurrence and severity of toxicity symptoms. To identify gene markers for each of four targeted liver toxicity symptoms, we used microarray expression profiles and pathology data from 14,143 in vivo rat samples. The gene markers were found using sparse linear discriminant analysis (sLDA) in which symptom severity is used as a class label. To evaluate the inferred gene markers, we constructed regression models that predicted the severity of toxicity symptoms from gene expression profiles. Our cross-validated results revealed that our approach was more successful at finding gene markers sensitive to the aggravation of toxicity symptoms than conventional methods. Moreover, these markers were closely involved in some of the biological functions significantly related to toxicity severity in the four targeted symptoms.