Quantitative Biomarkers for Monitoring Alcohol Abstinence

想象一下，在一个世界里，酒精中毒可以被评估和监测，就像我们 用血红蛋白A1 c（HbA 1c）诊断和监测糖尿病。在最近的第二阶段项目（其 主题收藏已关闭），行为诊断已经迈出了第一步，更美好的世界， 液滴数字PCR（ddPCR）面板，能够通过接收器识别重度饮酒 操作者特征（ROC）曲线下面积（AUC）>0.98。这个小组使用了 只有一滴血，已经初步商业化。 为履行我们在接受上述计划拨款时所作的承诺，我们现建议 鉴定和开发ddPCR标记物组，用于敏感和特异性地评估酒精戒断。 完成后，该工具可能对临床治疗产生重大影响。具体而言，指数 这些ddPCR标记物可用于精确监测接受门诊酒精治疗的患者， 治疗依从性-可能会为那些 门诊治疗失败的病人 为了完成这一任务，我们建议扩展我们之前2014年关于禁欲诱导甲基化的研究。 随着来自70名重度饮酒受试者的DNA的额外全基因组甲基化评估的变化， 他们进入（T1）和退出（T2）30天的住院治疗。我们将对这些数据进行荟萃分析， 甲基化改变与戒酒最密切相关的CpG位点。然后我们将 为这些基因座的子集构建ddPCR甲基化测定，使用Illumina 阵列数据，然后测试他们的表现在一个独立的测试集的40名受试者与T1和T2数据。 该项目是高度可行的，因为所有的生物材料和数据已经收集。该团队正在 准备充分，并有公开的跟踪记录与这种类型的方法。Philibert博士是 行为诊断和国际知名的表观遗传学和ddPCR专家。他得到了以下方面的协助： 博士Meesha Dogan，大数据分析专家，Jeff Long博士，著名的生物统计学家，生物伦理学家， 博士谢丽尔·欧文和约翰·门德尔松博士，一位著名的成瘾专家。这是一种创新，因为 NextGen方法尚未在临床上实施，但迫切需要。最后 环境很好。Behavioral Diagnostics是一家拥有保护性IP的公司。直接 因此，我们将开发一种检测基因座的甲基化状态的变化是最预测酒精 停止在第二阶段，我们将进一步将其转化为指导临床治疗的高灵敏度工具， 改善戒酒治疗。

Imagine a world where alcoholism can be assessed and monitored in the same way that we diagnose and monitor diabetes with a Hemoglobin A1c (HbA1c). In a recent Phase II project (whose subject collection has closed), Behavioral Diagnostics has taken the first step to that better world by developing a droplet digital PCR (ddPCR) panel that is capable of identifying heavy alcohol consumption with an Receiver Operator Characteristic (ROC) area under the curve (AUC) of >0.98. This panel, which uses the DNA from only one drop of blood, is already in initial commercial introduction. In completion to a pledge that we made when we accepted funding for the above project, we now propose to identify and develop a ddPCR marker panel for sensitively and specifically assessing alcohol abstinence. When completed, this tool could have substantial impact on clinical treatment. Specifically, an index of these ddPCR markers could be used to precisely monitor patients undergoing outpatient alcohol therapy for compliance with treatment-potentially freeing up more intensive, often inpatient treatment resources for those patients who are failing outpatient treatment. To accomplish this task, we propose to extend our prior 2014 studies of abstinence induced methylation changes with an additional genome wide methylation assessment of DNA from 70 heavily drinking subjects as they enter (T1) and exit (T2) from 30 day residential therapy. We will meta-analyze those data to identify the CpG loci whose change in methylation is most highly associated with alcohol abstinence. We will then construct ddPCR methylation assays for a subset of these loci, validate assay performance using the Illumina array data, and then test their performance in an independent test set of 40 subjects with both T1 and T2 data. This project is highly feasible because all of the biomaterial and data have been collected. The team is well prepared and has a published track record with this type of approach. Dr. Philibert is the CEO of Behavioral Diagnostics and an internationally known expert in both epigenetics and ddPCR. He is assisted by Dr. Meesha Dogan, an expert in big data analyses, Dr. Jeff Long, a well-known biostatistician, a bioethicist, Dr. Cheryl Erwin and Dr. John Mendelson, a well-known addiction specialist. It is innovative because these NextGen approaches have not yet been clinically implemented but yet are desperately needed. Finally, the environment is excellent. Behavioral Diagnostics is established company with protective IP. As a direct result, we will develop an assay for loci whose change in methylation status is most predictive of alcohol cessation. In Phase II, we will further translate this into a highly sensitive tool for guiding clinical treatment and improving treatment of alcohol cessation.