title: A Systematic Strategy for Screening and Application of Specific Biomarkers in Hepatotoxicity Using Metabolomics Combined With ROC Curves and SVMs.
abstract: Current studies that evaluate toxicity based on metabolomics have primarily focused on the screening of biomarkers while largely neglecting further verification and biomarker applications. For this reason, we used drug-induced hepatotoxicity as an example to establish a systematic strategy for screening specific biomarkers and applied these biomarkers to evaluate whether the drugs have potential hepatotoxicity toxicity. Carbon tetrachloride (5 ml/kg), acetaminophen (1500 mg/kg), and atorvastatin (5 mg/kg) are established as rat hepatotoxicity models. Fifteen common biomarkers were screened by multivariate statistical analysis and integration analysis-based metabolomics data. The receiver operating characteristic curve was used to evaluate the sensitivity and specificity of the biomarkers. We obtained 10 specific biomarker candidates with an area under the curve greater than 0.7. Then, a support vector machine model was established by extracting specific biomarker candidate data from the hepatotoxic drugs and nonhepatotoxic drugs; the accuracy of the model was 94.90% (92.86% sensitivity and 92.59% specificity) and the results demonstrated that those ten biomarkers are specific. 6 drugs were used to predict the hepatotoxicity by the support vector machines model; the prediction results were consistent with the biochemical and histopathological results, demonstrating that the model was reliable. Thus, this support vector machine model can be applied to discriminate the between the hepatic or nonhepatic toxicity of drugs. This approach not only presents a new strategy for screening-specific biomarkers with greater diagnostic significance but also provides a new evaluation pattern for hepatotoxicity, and it will be a highly useful tool in toxicity estimation and disease diagnoses.
authors.affiliation: *Tianjin State Key Laboratory of Modern Chinese Medicine, School of Traditional Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China and.
authors.forename: Yubo
authors.initials: Y
authors.lastname: Li
authors.affiliation: *Tianjin State Key Laboratory of Modern Chinese Medicine, School of Traditional Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China and.
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.affiliation: *Tianjin State Key Laboratory of Modern Chinese Medicine, School of Traditional Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China and.
authors.forename: Liang
authors.initials: L
authors.lastname: Ju
authors.affiliation: *Tianjin State Key Laboratory of Modern Chinese Medicine, School of Traditional Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China and.
authors.forename: Haoyue
authors.initials: H
authors.lastname: Deng
authors.affiliation: *Tianjin State Key Laboratory of Modern Chinese Medicine, School of Traditional Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China and.
authors.forename: Zhenzhu
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: *Tianjin State Key Laboratory of Modern Chinese Medicine, School of Traditional Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China and.
authors.forename: Zhiguo
authors.initials: Z
authors.lastname: Hou
authors.affiliation: *Tianjin State Key Laboratory of Modern Chinese Medicine, School of Traditional Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China and.
authors.forename: Jiabin
authors.initials: J
authors.lastname: Xie
authors.affiliation: *Tianjin State Key Laboratory of Modern Chinese Medicine, School of Traditional Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China and.
authors.forename: Yuming
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China tianjin_tcm001@sina.com.
authors.forename: Yanjun
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000082:Acetaminophen / Q000633:toxicity; D000818:Animals; D000069059:Atorvastatin / Q000633:toxicity; D015415:Biomarkers / Q000097:blood*; D002251:Carbon Tetrachloride / Q000633:toxicity; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood* / Q000209:etiology; D002851:Chromatography, High Pressure Liquid; D008099:Liver / Q000187:drug effects*; D008297:Male; D055432:Metabolomics / Q000379:methods* / Q000706:statistics & numerical data; D012372:ROC Curve; D017208:Rats, Wistar; D012680:Sensitivity and Specificity; D060388:Support Vector Machine
chemical_list: D015415:Biomarkers; D000082:Acetaminophen; D000069059:Atorvastatin; D002251:Carbon Tetrachloride
keywords: ROC curves; hepatotoxicity; metabolomics; specific biomarkers; support vector machines