{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,6]],"date-time":"2026-03-06T11:46:48Z","timestamp":1772797608085,"version":"3.50.1"},"reference-count":51,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2023,4,17]],"date-time":"2023-04-17T00:00:00Z","timestamp":1681689600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Central Government Guided Local Science and Technology Development Fund Project","award":["226Z5601G"],"award-info":[{"award-number":["226Z5601G"]}]},{"name":"Central Government Guided Local Science and Technology Development Fund Project","award":["H2022206026"],"award-info":[{"award-number":["H2022206026"]}]},{"name":"Central Government Guided Local Science and Technology Development Fund Project","award":["2018YFC0807204"],"award-info":[{"award-number":["2018YFC0807204"]}]},{"name":"Natural Science Foundation for Outstanding Youth of Hebei Province","award":["226Z5601G"],"award-info":[{"award-number":["226Z5601G"]}]},{"name":"Natural Science Foundation for Outstanding Youth of Hebei Province","award":["H2022206026"],"award-info":[{"award-number":["H2022206026"]}]},{"name":"Natural Science Foundation for Outstanding Youth of Hebei Province","award":["2018YFC0807204"],"award-info":[{"award-number":["2018YFC0807204"]}]},{"name":"National 13th Five-Year Key R&amp;D Plan","award":["226Z5601G"],"award-info":[{"award-number":["226Z5601G"]}]},{"name":"National 13th Five-Year Key R&amp;D Plan","award":["H2022206026"],"award-info":[{"award-number":["H2022206026"]}]},{"name":"National 13th Five-Year Key R&amp;D Plan","award":["2018YFC0807204"],"award-info":[{"award-number":["2018YFC0807204"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Metabolites"],"abstract":"<jats:p>Fatal intoxication with sedative-hypnotic drugs is increasing yearly. However, the plasma drug concentration data for fatal intoxication involving these substances are not systematic and even overlap with the intoxication group. Therefore, developing a more precise and trustworthy approach to determining the cause of death is necessary. This study analyzed mice plasma and brainstem samples using the liquid chromatography-high resolution tandem mass spectrometry (LC-HR MS\/MS)-based metabolomics method to create discriminative classification models for estazolam fatal intoxication (EFI). The most perturbed metabolic pathway between the EFI and EIND (estazolam intoxication non-death) was examined, Both EIND and EFI groups were administered 500 mg of estazolam per 100 g of body weight. Mice that did not die beyond 8 hours were treated with cervical dislocation and were classified into the EIND groups; the lysine degradation pathway was verified by qPCR (Quantitative Polymerase Chain Reaction), metabolite quantitative and TEM (transmission electron microscopy) analysis. Non-targeted metabolomics analysis with EFI were the experimental group and four hypoxia-related non-drug-related deaths (NDRDs) were the control group. Mass spectrometry data were analyzed with Compound Discoverer (CD) 3.1 software and multivariate statistical analyses were performed using the online software MetaboAnalyst 5.0. After a series of analyses, the results showed the discriminative classification model in plasma was composed of three endogenous metabolites: phenylacetylglycine, creatine and indole-3-lactic acid, and in the brainstem was composed of palmitic acid, creatine, and indole-3-lactic acid. The specificity validation results showed that both classification models distinguished between the other four sedatives\u2013hypnotics, with an area under ROC curve (AUC) of 0.991, and the classification models had an extremely high specificity. When comparing different doses of estazolam, the AUC value of each group was larger than 0.80, and the sensitivity was also high. Moreover, the stability results showed that the AUC value was equal to or very close to 1 in plasma samples stored at 4 \u00b0C for 0, 1, 5, 10 and 15 days; the predictive power of the classification model was stable within 15 days. The results of lysine degradation pathway validation revealed that the EFI group had the highest lysine and saccharopine concentrations (mean (ng\/mg) = 1.089 and 1.2526, respectively) when compared to the EIND and control group, while the relative expression of SDH (saccharopine dehydrogenase) showed significantly lower in the EFI group (mean = 1.206). Both of these results were statistically significant. Furthermore, TEM analysis showed that the EFI group had the more severely damaged mitochondria. This work gives fresh insights into the toxicological processes of estazolam and a new method for identifying EFI-related causes of mortality.<\/jats:p>","DOI":"10.3390\/metabo13040567","type":"journal-article","created":{"date-parts":[[2023,4,17]],"date-time":"2023-04-17T04:45:32Z","timestamp":1681706732000},"page":"567","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["A Metabolomics-Based Study on the Discriminative Classification Models and Toxicological Mechanism of Estazolam Fatal Intoxication"],"prefix":"10.3390","volume":"13","author":[{"given":"Xiaohui","family":"Dai","sequence":"first","affiliation":[{"name":"Hebei Key Laboratory of Forensic Medicine, Collaborative Innovation Center of Forensic Medical Molecular Identification, College of Forensic Medicine, Hebei Medical University, Shijiazhuang 050017, China"},{"name":"Research Unit of Digestive Tract Microecosystem Pharmacology and Toxicology, Chinese Academy of Medical Sciences, Shijiazhuang 050017, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rui","family":"Bai","sequence":"additional","affiliation":[{"name":"Hebei Key Laboratory of Forensic Medicine, Collaborative Innovation Center of Forensic Medical Molecular Identification, College of Forensic Medicine, Hebei Medical University, Shijiazhuang 050017, China"},{"name":"Research Unit of Digestive Tract Microecosystem Pharmacology and Toxicology, Chinese Academy of Medical Sciences, Shijiazhuang 050017, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bing","family":"Xie","sequence":"additional","affiliation":[{"name":"Hebei Key Laboratory of Forensic Medicine, Collaborative Innovation Center of Forensic Medical Molecular Identification, College of Forensic Medicine, Hebei Medical University, Shijiazhuang 050017, China"},{"name":"Research Unit of Digestive Tract Microecosystem Pharmacology and Toxicology, Chinese Academy of Medical Sciences, Shijiazhuang 050017, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiahong","family":"Xiang","sequence":"additional","affiliation":[{"name":"Hebei Key Laboratory of Forensic Medicine, Collaborative Innovation Center of Forensic Medical Molecular Identification, College of Forensic Medicine, Hebei Medical University, Shijiazhuang 050017, China"},{"name":"Research Unit of Digestive Tract Microecosystem Pharmacology and Toxicology, Chinese Academy of Medical Sciences, Shijiazhuang 050017, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xingang","family":"Miao","sequence":"additional","affiliation":[{"name":"Hebei Key Laboratory of Forensic Medicine, Collaborative Innovation Center of Forensic Medical Molecular Identification, College of Forensic Medicine, Hebei Medical University, Shijiazhuang 050017, China"},{"name":"Research Unit of Digestive Tract Microecosystem Pharmacology and Toxicology, Chinese Academy of Medical Sciences, Shijiazhuang 050017, China"},{"name":"Forensic Science Centre of WATSON, Guangzhou 510440, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yan","family":"Shi","sequence":"additional","affiliation":[{"name":"Shanghai Key Laboratory Medicine, Department of Forensic Toxicology, Shanghai Forensic Service Platform, Academy of Forensic Science, Shanghai 200063, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Feng","family":"Yu","sequence":"additional","affiliation":[{"name":"Hebei Key Laboratory of Forensic Medicine, Collaborative Innovation Center of Forensic Medical Molecular Identification, College of Forensic Medicine, Hebei Medical University, Shijiazhuang 050017, China"},{"name":"Research Unit of Digestive Tract Microecosystem Pharmacology and Toxicology, Chinese Academy of Medical Sciences, Shijiazhuang 050017, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bin","family":"Cong","sequence":"additional","affiliation":[{"name":"Hebei Key Laboratory of Forensic Medicine, Collaborative Innovation Center of Forensic Medical Molecular Identification, College of Forensic Medicine, Hebei Medical University, Shijiazhuang 050017, China"},{"name":"Research Unit of Digestive Tract Microecosystem Pharmacology and Toxicology, Chinese Academy of Medical Sciences, Shijiazhuang 050017, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Di","family":"Wen","sequence":"additional","affiliation":[{"name":"Hebei Key Laboratory of Forensic Medicine, Collaborative Innovation Center of Forensic Medical Molecular Identification, College of Forensic Medicine, Hebei Medical University, Shijiazhuang 050017, China"},{"name":"Research Unit of Digestive Tract Microecosystem Pharmacology and Toxicology, Chinese Academy of Medical Sciences, Shijiazhuang 050017, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chunling","family":"Ma","sequence":"additional","affiliation":[{"name":"Hebei Key Laboratory of Forensic Medicine, Collaborative Innovation Center of Forensic Medical Molecular Identification, College of Forensic Medicine, Hebei Medical University, Shijiazhuang 050017, China"},{"name":"Research Unit of Digestive Tract Microecosystem Pharmacology and Toxicology, Chinese Academy of Medical Sciences, Shijiazhuang 050017, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,4,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1072","DOI":"10.1080\/15563650.2017.1388087","article-title":"2016 Annual Report of the American Association of Poison Control Centers\u2019 National Poison Data System (NPDS): 34th Annual Report","volume":"55","author":"Gummin","year":"2017","journal-title":"Clin. Toxicol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1213","DOI":"10.1080\/15563650.2018.1533727","article-title":"2017 Annual Report of the American Association of Poison Control Centers\u2019 National Poison Data System (NPDS): 35th Annual Report","volume":"56","author":"Gummin","year":"2018","journal-title":"Clin. Toxicol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1220","DOI":"10.1080\/15563650.2019.1677022","article-title":"2018 Annual Report of the American Association of Poison Control Centers\u2019 National Poison Data System (NPDS): 36th Annual Report","volume":"57","author":"Gummin","year":"2019","journal-title":"Clin. Toxicol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1360","DOI":"10.1080\/15563650.2020.1834219","article-title":"2019 Annual Report of the American Association of Poison Control Centers\u2019 National Poison Data System (NPDS): 37th Annual Report","volume":"58","author":"Gummin","year":"2020","journal-title":"Clin. Toxicol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1282","DOI":"10.1080\/15563650.2021.1989785","article-title":"2020 Annual Report of the American Association of Poison Control Centers\u2019 National Poison Data System (NPDS): 38th Annual Report","volume":"59","author":"Gummin","year":"2021","journal-title":"Clin. Toxicol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"i3","DOI":"10.1093\/alcalc\/agu052.5","article-title":"SY01-5 current conditions and treatment of prescription drug abuse in Japan","volume":"49","author":"Nakano","year":"2014","journal-title":"Alcohol. Alcohol."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"V\u00e4rnik, A., Sisask, M., V\u00e4rnik, P., Wu, J., K\u00f5lves, K., Arensman, E., Maxwell, M., Reisch, T., Gusm\u00e3o, R., and van Audenhove, C. (2011). Drug suicide: A sex-equal cause of death in 16 European countries. BMC Public. Health, 11.","DOI":"10.1186\/1471-2458-11-61"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1573","DOI":"10.1001\/jama.2021.18416","article-title":"Assessing a Veterinary Sedative\u2019s Role in Drug Overdose Deaths","volume":"326","author":"Kuehn","year":"2021","journal-title":"JAMA"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1093\/jat\/bkac049","article-title":"Xylazine: Pharmacology review and prevalence and drug combinations in forensic toxicology casework","volume":"46","author":"Kacinko","year":"2022","journal-title":"J. Anal. Toxicol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1097\/PAF.0000000000000465","article-title":"Correctly Identifying Deaths Due to Drug Toxicity without a Forensic Autopsy","volume":"40","author":"Dye","year":"2019","journal-title":"Am. J. Forensic Med. Pathol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/j.forsciint.2016.11.042","article-title":"Pentobarbital in the context of possible suicides: Analysis of a Case","volume":"274","author":"Melo","year":"2017","journal-title":"Forensic Sci. Int."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1326","DOI":"10.1002\/dta.2655","article-title":"Summary statistics for drug concentrations in post-mortem femoral blood representing all causes of death","volume":"11","author":"Ketola","year":"2019","journal-title":"Drug. Test. Anal."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1016\/j.forsciint.2014.01.005","article-title":"Sedative and hypnotic drugs--fatal and non-fatal reference blood concentrations","volume":"236","author":"Espnes","year":"2014","journal-title":"Forensic Sci. Int."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1093\/jat\/bkaa107","article-title":"Postmortem Drug Redistribution: A Compilation of Postmortem\/Antemortem Drug Concentration Ratios","volume":"45","author":"Mantinieks","year":"2021","journal-title":"J. Anal. Toxicol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Szeremeta, M., Pietrowska, K., Niemcunowicz-Janica, A., Kretowski, A., and Ciborowski, M. (2021). Applications of Metabolomics in Forensic Toxicology and Forensic Medicine. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22063010"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Dawidowska, J., Krzy\u017canowska, M., Markuszewski, M.J., and Kaliszan, M. (2021). The Application of Metabolomics in Forensic Science with Focus on Forensic Toxicology and Time-of-Death Estimation. Metabolites, 11.","DOI":"10.3390\/metabo11120801"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.legalmed.2014.01.002","article-title":"Forensic molecular pathology: Its impacts on routine work, education and training","volume":"16","author":"Maeda","year":"2014","journal-title":"Leg. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"122638","DOI":"10.1016\/j.jchromb.2021.122638","article-title":"Exploring metabolic alterations associated with death from asphyxia and the differentiation of asphyxia from sudden cardiac death by GC-HRMS-based untargeted metabolomics","volume":"1171","author":"Zhang","year":"2021","journal-title":"J. Chromatogr. B"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2100","DOI":"10.1021\/acsomega.0c05178","article-title":"The Use of Gas Chromatography Coupled with High-Resolution Mass Spectrometry-Based Untargeted Metabolomics to Discover Metabolic Changes and Help in the Determination of Complex Causes of Death: A Preliminary Study","volume":"6","author":"Zhang","year":"2021","journal-title":"ACS Omega"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Bai, R., Dai, X.H., Miao, X.G., Xie, B., Yu, F., Cong, B., Wen, D., and Ma, C.L. (2022). Dynamic Changes in Plasma Metabolic Profiles Reveal a Potential Metabolite Panel for Interpretation of Fatal Intoxication by Chlorpromazine or Olanzapine in Mice. Metabolites, 12.","DOI":"10.3390\/metabo12121184"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1016\/j.psychres.2018.08.118","article-title":"The anxiolytic-like effects of estazolam on a PTSD animal model","volume":"269","author":"Xu","year":"2018","journal-title":"Psychiatry Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"915823","DOI":"10.3389\/fpsyt.2022.915823","article-title":"Trends in Prescriptions for Insomnia in a Province in China Between 2015 and 2019","volume":"13","author":"Lou","year":"2022","journal-title":"Front. Psychiatry"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1093\/jat\/10.2.65","article-title":"A new method for the determination in blood and urine of a novel triazolobenzodiazepine (estazolam) by HPLC","volume":"10","author":"Ricci","year":"1986","journal-title":"J. Anal. Toxicol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/j.forsciint.2015.06.011","article-title":"Forensic application of microRNA-706 as a biomarker for drowning pattern identification","volume":"255","author":"Yu","year":"2015","journal-title":"Forensic Sci. Int."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"74526","DOI":"10.18632\/oncotarget.12931","article-title":"G6PC3, ALDOA and CS induction accompanies mir-122 down-regulation in the mechanical asphyxia and can serve as hypoxia biomarkers","volume":"7","author":"Zeng","year":"2016","journal-title":"Oncotarget"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1007\/s13577-019-00248-2","article-title":"Pathophysiological significance of clock genes BMAL1 and PER2 as erythropoietin-controlling factors in acute blood hemorrhage","volume":"32","author":"Tani","year":"2019","journal-title":"Hum. Cell."},{"key":"ref_27","first-page":"5","article-title":"A primary study on the influence of ethanol on the median lethal dose and metabolism in early stages of diazepam","volume":"30","author":"Wang","year":"2015","journal-title":"Chin. J. Forens. Med."},{"key":"ref_28","unstructured":"Drugfuture (2023, April 15). Chemical Identification: 2H-1,4-Benzodiazepin-2-one, 1,3-dihydro-7-nitro-5-phenyl-. Available online: https:\/\/www.drugfuture.com\/toxic\/q24-q496.html."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1097\/00000542-195105000-00010","article-title":"The LD50 of pentobarbital sodium for both nursed and unnursed newborn rats","volume":"12","author":"Carmichael","year":"1951","journal-title":"Anesthesiology"},{"key":"ref_30","unstructured":"Wang, L. (2020). Study on the Forensic Toxicokinetics of Diazepam Poisoning Biomarkers. [Ph.D. Thesis, Shanxi Medical University]."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1007\/s10545-017-0130-7","article-title":"Promises and pitfalls of untargeted metabolomics","volume":"41","author":"Gertsman","year":"2018","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1038\/s41586-019-1437-3","article-title":"Dietary methionine influences therapy in mouse cancer models and alters human metabolism","volume":"572","author":"Gao","year":"2019","journal-title":"Nature"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/j.cca.2019.08.017","article-title":"Plasma metabolites Xanthine, 4-Pyridoxate, and d-glutamic acid as novel potential biomarkers for pulmonary tuberculosis","volume":"498","author":"Huang","year":"2019","journal-title":"Clin. Chim. Acta"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Hemmer, S., Manier, S.K., Fischmann, S., Westphal, F., Wagmann, L., and Meyer, M.R. (2020). Comparison of Three Untargeted Data Processing Workflows for Evaluating LC-HRMS Metabolomics Data. Metabolites, 10.","DOI":"10.3390\/metabo10090378"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"e86","DOI":"10.1002\/cpbi.86","article-title":"Using MetaboAnalyst 4.0 for Comprehensive and Integrative Metabolomics Data Analysis","volume":"68","author":"Chong","year":"2019","journal-title":"Curr. Protoc. Bioinform."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1016\/j.scijus.2021.04.002","article-title":"The distinction between discriminability and reliability in forensic science","volume":"61","author":"Smith","year":"2021","journal-title":"Sci. Justice"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"6093613","DOI":"10.1155\/2022\/6093613","article-title":"Speech as a Biomarker for COVID-19 Detection Using Machine Learning","volume":"2022","author":"Usman","year":"2022","journal-title":"Comput. Intell. Neurosci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"65","DOI":"10.3389\/fphys.2020.00065","article-title":"Identification of Serum-Based Metabolic Feature and Characteristic Metabolites in Paraquat Intoxicated Mouse Models","volume":"11","author":"Yu","year":"2020","journal-title":"Front. Physiol."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Salman Khan, M., Ullah, A., Khan, K.N., Riaz, H., Yousafzai, Y.M., Rahman, T., Chowdhury, M.E.H., and Abul Kashem, S.B. (2022). Deep Learning Assisted Automated Assessment of Thalassaemia from Haemoglobin Electrophoresis Images. Diagnostics, 12.","DOI":"10.3390\/diagnostics12102405"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Khan, A., and Mathelier, A. (2017). Intervene: A tool for intersection and visualization of multiple gene or genomic region sets. BMC Bioinform., 18.","DOI":"10.1186\/s12859-017-1708-7"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1016\/j.aca.2008.11.058","article-title":"Comprehensive two-dimensional gas chromatography\/time-of-flight mass spectrometry for metabonomics: Biomarker discovery for diabetes mellitus","volume":"633","author":"Li","year":"2009","journal-title":"Anal. Chim. Acta"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"4176","DOI":"10.1021\/pr100452b","article-title":"Identification of noninvasive biomarkers for alcohol-induced liver disease using urinary metabolomics and the Ppara-null mouse","volume":"9","author":"Manna","year":"2010","journal-title":"J. Proteome Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"3551","DOI":"10.1021\/ac0518351","article-title":"Metabolite projection analysis for fast identification of metabolites in metabonomics. Application in an amiodarone study","volume":"78","author":"Dieterle","year":"2006","journal-title":"Anal. Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"5765","DOI":"10.1007\/s00216-019-01956-2","article-title":"Quantitative monitoring of a panel of stress-induced biomarkers in human plasma by liquid chromatography-tandem mass spectrometry: An application in a comparative study between depressive patients and healthy subjects","volume":"411","author":"Cai","year":"2019","journal-title":"Anal. Bioanal. Chem."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1016\/j.patrec.2005.10.010","article-title":"An introduction to ROC analysis","volume":"27","author":"Fawcett","year":"2006","journal-title":"Pattern Recogn. Lett."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1016\/j.ins.2016.01.033","article-title":"An improved method to construct basic probability assignment based on the confusion matrix for classification problem","volume":"340","author":"Deng","year":"2016","journal-title":"Inform. Sci."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"7199290","DOI":"10.1155\/2022\/7199290","article-title":"Comparative Analysis of Machine Learning Methods for Breast Cancer Classification in Genetic Sequences","volume":"2022","author":"Kurian","year":"2022","journal-title":"J. Environ. Public. Health"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1176\/appi.ajp.2016.16030336","article-title":"Hypnotic medications and suicide: Risk, mechanisms, mitigation, and the FDA","volume":"174","author":"McCall","year":"2017","journal-title":"Am. J. Psychiatry"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1097\/SLA.0b013e318204a892","article-title":"Diagnostic accuracy and receiver-operating characteristics curve analysis in surgical research and decision making","volume":"253","year":"2011","journal-title":"Ann. Surg."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1083\/jcb.201901033","article-title":"Saccharopine, a lysine degradation intermediate, is a mitochondrial toxin","volume":"218","author":"Leandro","year":"2019","journal-title":"J. Cell. Biol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1083\/jcb.201807204","article-title":"The lysine catabolite saccharopine impairs development by disrupting mitochondrial homeostasis","volume":"218","author":"Zhou","year":"2019","journal-title":"J. Cell. Biol."}],"container-title":["Metabolites"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-1989\/13\/4\/567\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:17:12Z","timestamp":1760123832000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-1989\/13\/4\/567"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,4,17]]},"references-count":51,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2023,4]]}},"alternative-id":["metabo13040567"],"URL":"https:\/\/doi.org\/10.3390\/metabo13040567","relation":{},"ISSN":["2218-1989"],"issn-type":[{"value":"2218-1989","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,4,17]]}}}