Abstract：
The assessment of the sensitivity and specificity of any potential biomarker against the gold standard is an important step in the process of its qualification by regulatory authorities. Such qualification is an important step towards incorporating the biomarker into the panel of tools available for drug development. In the current study we analyzed the sensitivity and specificity of T2 MRI relaxometry to detect trimethyltin-induced neurotoxicity in rats. Seventy-five male Sprague-Dawley rats were injected with a single intraperitoneal dose of either TMT (8, 10, 11, or 12 mg/kg) or saline (2 ml/kg) and imaged with 7 T MRI before and 3, 7, 14, and 21 days after injection using a quantitative T2 mapping. Neurohistopathology (the gold standard in the case of neurotoxicity) was performed at the end of the observation and used as an outcome qualifier in receiver-operator characteristic (ROC) curve analysis of T2 changes as a predictor of neurotoxicity. TMT treatment led to a significant increase in T2 values in many brain areas. The biggest changes in T2 values were seen around the lateral ventricles, which was interpreted as ventricular dilation. The area under the ROC curve for the volume of the lateral ventricles was 0.878 with the optimal sensitivity/specificity of 0.805/0.933, respectively. T2 MRI is a promising method for generating a non-invasive biomarkers of neurotoxicity, which shows the dose-response behavior with substantial sensitivity and specificity. While its performance was strong in the TMT model, further characterization of the sensitivity and specificity of T2 MRI with other neurotoxicants is warranted.
摘要：
对任何潜在生物标志物相对于金标准的敏感性和特异性的评估是监管机构对其进行鉴定的过程中的重要步骤。这种鉴定是将生物标志物纳入可用于药物开发的工具组中的重要步骤。在当前的研究中，我们分析了T2MRI弛豫测定法检测三甲基锡诱导的大鼠神经毒性的敏感性和特异性。对75只雄性Sprague-Dawley大鼠注射单次腹膜内剂量的TMT（8、10、11或12mg/kg）或盐水（2ml/kg），并在注射前和注射后3、7、14和21天使用定量T2作图。在观察结束时进行神经组织病理学（神经毒性情况下的金标准），并将其用作T2变化的接受者-操作者特征（ROC）曲线分析中的结果限定符，以预测神经毒性。TMT治疗导致许多大脑区域的T2值显著增加。T2值的最大变化出现在侧脑室周围，这被解释为心室扩张。侧脑室容积的ROC曲线下面积为0.878，最佳敏感性/特异性分别为0.805/0.933。T2MRI是产生神经毒性的非侵入性生物标志物的一种有前途的方法，这表明剂量反应行为具有相当的敏感性和特异性。虽然其在TMT模式中表现强劲，需要进一步确定T2MRI与其他神经毒物的敏感性和特异性.
