Use of short-term transcriptional profiles to assess the long-term cancer-related safety of environmental and industrial chemicals.
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.
The Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina 27709, USA. rthomas@thehamner.org
Russell S
RS
Thomas
Wenjun
W
Bao
Tzu-Ming
TM
Chu
Marina
M
Bessarabova
Tatiana
T
Nikolskaya
Yuri
Y
Nikolsky
Melvin E
ME
Andersen
Russell D
RD
Wolfinger
D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D004781:Environmental Exposure; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009374:Neoplasms, Experimental / Q000139:chemically induced*; D016273:Occupational Exposure; D020411:Oligonucleotide Array Sequence Analysis; D014158:Transcription, Genetic / Q000187:drug effects*
D002273:Carcinogens