Quantitative Biomarkers for Monitoring Alcohol Abstinence

想象一下，在一个可以像我们这样评估和监控酒精中毒的世界里 糖化血红蛋白(HbA1c)诊断和监测糖尿病。在最近的一个第二阶段项目中(其 主题集合已关闭)，行为诊断学已经向更美好的世界迈出了第一步，通过开发 一种水滴数字聚合酶链式反应(DdPCR)面板，能够通过接收器识别重度酒精消费 -gt；0.98曲线下的操作员特征(ROC)面积(AUC)。这个面板使用了来自 只有一滴血，已经在最初的商业引进中。 为了履行我们在接受上述项目资助时所作的承诺，我们现在提议 目的：鉴定和开发一种灵敏、特异地评估戒酒行为的ddPCR标记板。 一旦完成，这个工具可能会对临床治疗产生重大影响。具体地说，就是 这些ddPCR标记可以用来精确监测门诊酒精治疗的患者 治疗依从性-有可能为这些患者腾出更密集的、通常是住院的治疗资源 门诊治疗失败的患者。 为了完成这项任务，我们建议延长我们之前2014年对禁欲诱导的甲基化的研究 70例重度饮酒受试者DNA全基因组甲基化检测的变化 他们从30天的住院治疗中进入(T1)和退出(T2)。我们将对这些数据进行荟萃分析，以确定 CpG基因座的甲基化改变与戒酒密切相关。到时候我们会的 构建这些基因座的子集的ddPCR甲基化检测，使用Illumina验证检测性能 阵列数据，然后在由40名受试者组成的独立测试集中使用T1和T2数据来测试它们的性能。 这个项目是高度可行的，因为所有的生物材料和数据都已经收集好了。这个团队是 做好充分的准备，并在这类方法方面有公开的记录。菲利伯特博士是 行为诊断学和表观遗传学和ddPCR方面的国际知名专家。他得到了 大数据分析专家Meesha Dogan博士，知名生物统计学家、生物伦理学家Jeff Long博士， 谢丽尔·欧文博士和著名成瘾专家约翰·门德尔森博士。它的创新性是因为这些 下一代方法尚未在临床上实施，但仍是迫切需要的。最后， 环境非常好。行为诊断公司是一家拥有保护性知识产权的公司。作为一种直接 结果，我们将开发一种检测其甲基化状态变化最能预测酒精的基因座 停止。在第二阶段，我们将进一步将其转化为指导临床治疗和 改进戒酒治疗。

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.