Prediction of PPARα activation using the Running Fisher’s algorithm.

<p>A. Heat map showing the expression of genes in the PPARα signature across 332 biosets. Biosets were ordered based on their similarity to the PPARα signature using the p-value from the Running Fisher’s algorithm. Biosets with positive correlation are on the left and biosets with negative correlation are on the right. The red vertical lines denote the position of biosets with a p-value = 10^-4. B. (Left) Correlation of the PPARα signature to contrasts from the three chemicals used to derive the signature in wild-type but not PPARα-null mice. All p-values were converted to –log10 values. Those comparisons which exhibited negative correlation to the signature were converted to a negative value. (Right) Correlation of the PPARα signature to chemical and synthetic triglyceride activators of PPARα from wild-type but not PPARα-null mice. The compounds were WY-14,643 (WY) (GSE8396), PFOA at 3 mg/kg/day (PFOA-3) (GSE9786), PFOS at 3 or 10 mg/kg/day (PFOS-3, -10) (GSE22871) or synthetic triglycerides composed of the indicated fatty acids (GSE8396). C. The PPARα signature correctly identifies PFNA and PFHxS as PPARα activators in wild-type but not PPARα-null mice. Exposure to the indicated chemicals is described in Study 1 (Methods). D. The PPARα signature correctly identifies the two known PPARα activators (WY and ciprofibrate) in male and female mice exposed to 12 diverse treatments. See Study 3 in Methods for details of exposure conditions. E. The signature genes separate known positives and negatives for PPARα activation using principal components analysis. The first three principal components are shown, derived from the unfiltered expression changes of the signature genes. Red and green, the three chemical treatments in wild-type or PPARα-null mice used to derive the signature, respectively. Blue and black, chemicals or synthetic triglycerides in wild-type or PPARα-null mice, respectively. F. Summary of the sensitivity and specificity of the test for PPARα activation. The signature was compared to chemicals in wild-type or PPARα-null mice that were known positives or negatives for PPARα activation.