ToxSci Advance Access originally published online on September 23, 2009
Toxicological Sciences 2009 112(2):311-321; doi:10.1093/toxsci/kfp233
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Use of Short-term Transcriptional Profiles to Assess the Long-term Cancer-Related Safety of Environmental and Industrial Chemicals
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* The Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina 27709
SAS Institute Inc., Cary, North Carolina 27513
Vavilov Institute of General Genetics, Moscow B333, 117809, Russia
GeneGo, Inc., St Joseph, Michigan 49085
1 To whom correspondence should be addressed. Fax: (919)-558-1300. E-mail: rthomas{at}thehamner.org.
Received July 13, 2009; accepted August 25, 2009
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Abstract |
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The process for evaluating chemical safety is inefficient, costly, and animal intensive. There is growing consensus that the current process of safety testing needs to be significantly altered to improve efficiency and reduce the number of untested chemicals. In this study, the use of short-term gene expression profiles was evaluated for predicting the increased incidence of mouse lung tumors. Animals were exposed to a total of 26 diverse chemicals with matched vehicle controls over a period of 3 years. Upon completion, significant batch-related effects were observed. Adjustment for batch effects significantly improved the ability to predict increased lung tumor incidence. For the best statistical model, the estimated predictive accuracy under honest fivefold cross-validation was 79.3% with a sensitivity and specificity of 71.4 and 86.3%, respectively. A learning curve analysis demonstrated that gains in model performance reached a plateau at 25 chemicals, indicating that the size of current data set was sufficient to provide a robust classifier. The classification results showed that a small subset of chemicals contributed disproportionately to the misclassification rate. For these chemicals, the misclassification was more closely associated with genotoxicity status than with efficacy in the original bioassay. Statistical models were also used to predict dose-response increases in tumor incidence for methylene chloride and naphthalene. The average posterior probabilities for the top models matched the results from the bioassay for methylene chloride. For naphthalene, the average posterior probabilities for the top models overpredicted the tumor response, but the variability in predictions was significantly higher. The study provides both a set of gene expression biomarkers for predicting chemically induced mouse lung tumors and a broad assessment of important experimental and analysis criteria for developing microarray-based predictors of safety-related end points.
Key Words: genomics; biomarkers; rodent cancer bioassays.