ToxSci Advance Access published online on February 14, 2008
Toxicological Sciences, doi:10.1093/toxsci/kfn022
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Inter-laboratory Evaluation of Genomic Signatures for Predicting Carcinogenicity in the Rat
1 Roche Palo Alto, Palo Alto, CA, USA 2 Johnson & Johnson Pharmaceutical Research & Development, Raritan, NJ 3 GlaxoSmithKline, Research Triangle Park, NC, USA 4 Abbott Laboratories, Abbott Park, IL, USA 5 Amgen, Thousand Oaks, CA, USA 6 AstraZeneca, Boston, MA, USA 7 AstraZeneca, Södertälje, Sweden 8 Boehringer-Ingelheim, Ridgefield, CT, USA 9 Bristol-Myers Squibb, Princeton, NJ and Wallingford, CT, USA 10 Critical Path Institute, Tucson, AZ, USA 11 Federal Institute for Drugs and Medical Devices, Bonn, Germany 12 Food and Drug Administration, Washington, DC, USA 13 Iconix Biosciences, Mountain View, CA, USA 14 Lilly Research Laboratories, Eli Lilly and Company, Greenfield, IN, USA 15 Merck Research Laboratories, West Point, PA, USA 16 Novartis Pharma AG, Basel, Switzerland 17 Pfizer, Groton, CT, USA 18 Sanofi-Aventis, Porcheville, France 19 Schering-Plough Research Institute, Summit, NJ, USA 20 Wyeth Research, Chazy, NY, USA
* Corresponding author: Mark R. Fielden, PhD, DABT, Roche Palo Alto LLC, 3431 Hillview Avenue, Palo Alto, CA, 94304, Tel: 650-855-5136, Fax: 650-855-558, Email: mark.fielden{at}roche.com
Received November 20, 2007; revision received January 29, 2008; accepted January 30, 2008
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Abstract |
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The Critical Path Institute recently established the Predictive Safety Testing Consortium, a collaboration between several companies and the FDA, aimed at evaluating and qualifying biomarkers for a variety of toxicological endpoints. The Carcinogenicity Working Group of the PSTC has concentrated on sharing data to test the predictivity of two published hepatic gene expression signatures, including the signature by Fielden et al. (Toxicol. Sci. 2007. 99:90-100) for predicting non-genotoxic hepatocarcinogens, and the signature by Nie et al. (Mol. Carcinog. 2006. 45:914–933) for predicting non-genotoxic carcinogens. While not a rigorous prospective validation exercise, the consortium approach created an opportunity to perform a meta-analysis to evaluate microarray data from short-term rat studies on over 150 compounds. Despite significant differences in study designs and microarray platforms between laboratories, the signatures proved to be relatively robust and more accurate than expected by chance. The accuracy of the Fielden et al. signature was between 63 and 69%, while the accuracy of the Nie et al. signature was between 55 and 64%. As expected, the predictivity was reduced relative to internal validation estimates reported under identical test conditions. While the signatures were not deemed suitable for use in regulatory decision making, they were deemed worthwhile in the early assessment of drugs to aid decision making in drug development. These results have prompted additional efforts to re-derive and evaluate a QPCR-based signature using these samples. When combined with a standardized test procedure and prospective inter-laboratory validation, the accuracy and potential utility in preclinical applications can be ascertained.