Blood gene expression signatures predict exposure levels

Biostatistics Branch, Environmental Stress and Cancer Group, Environmental Toxicology Program, Microarray Group, **Cancer Biology Group, National Institute of Environmental Health Sciences, P.O. Box 12233, Research Triangle Park, NC 27709.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 12/2007; 104(46):18211-6. DOI: 10.1073/pnas.0706987104
Source: PubMed


To respond to potential adverse exposures properly, health care providers need accurate indicators of exposure levels. The indicators are particularly important in the case of acetaminophen (APAP) intoxication, the leading cause of liver failure in the U.S. We hypothesized that gene expression patterns derived from blood cells would provide useful indicators of acute exposure levels. To test this hypothesis, we used a blood gene expression data set from rats exposed to APAP to train classifiers in two prediction algorithms and to extract patterns for prediction using a profiling algorithm. Prediction accuracy was tested on a blinded, independent rat blood test data set and ranged from 88.9% to 95.8%. Genomic markers outperformed predictions based on traditional clinical parameters. The expression profiles of the predictor genes from the patterns extracted from the blood exhibited remarkable (97% accuracy) transtissue APAP exposure prediction when liver gene expression data were used as a test set. Analysis of human samples revealed separation of APAP-intoxicated patients from control individuals based on blood expression levels of human orthologs of the rat discriminatory genes. The major biological signal in the discriminating genes was activation of an inflammatory response after exposure to toxic doses of APAP. These results support the hypothesis that gene expression data from peripheral blood cells can provide valuable information about exposure levels, well before liver damage is detected by classical parameters. It also supports the potential use of genomic markers in the blood as surrogates for clinical markers of potential acute liver damage.

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    • "ALT elevation and histopathological changes showed only minor differences among the three toxic dose groups at 24 h, so all of these animals were combined as one group for further analysis. In this study, there was a good correlation between ALT elevation and histological evidence of liver injury (Bushel et al., 2007). "
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    • "Blood-based mRNA biomarkers have been investigated in almost all disease areas with promising results for detecting and monitoring disease and treatment outcomes (Chaussabel et al. 2010; Fang 2007; Han et al. 2008; Hanash et al. 2011; Julia et al. 2009; Marshall et al. 2010; Pankla et al. 2009; Pascual et al. 2010; Quartier et al. 2011; Tattermusch et al. 2012). Efforts were made even in areas not obviously or traditionally connected with blood, such as in neurological diseases (Kurian et al. 2011; Le-Niculescu et al. 2009; Runne et al. 2007; Scherzer et al. 2007) and drug toxicology (Bushel et al. 2007; Fannin et al. 2010; Huang et al. 2010; Lobenhofer et al. 2008). The biomarker discovery process is usually initiated with genome-wide expression profiling to identify significantly modulated gene sets, followed by employing more stringent criteria to down-select a small subset of genes for assay development (Barth and Hare 2006; van't Veer and Bernards 2008). "
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    • "To give an overview of the studies, these experiments are summarized and characterized as follows. Using a blood gene expression dataset in rat, Bushel et al. (2007) reported a gene signature that predicted an endpoint of APAP exposure and classified the endpoint by level (no dose/low dose vs. high dose). Here into called the Dose-Classification. "
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