A diagnostic plasma protein panel for alcohol abuse

酒精滥用诊断血浆蛋白组

• 批准号: 8867957
• 负责人: KENT E VRANA
• 金额: $ 33.39万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-15 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8867957
• 关键词: Abstinence; Address; Admission activity; Alcohol abuse; Alcohol consumption; Alcoholism; Alcohols; Biochemical; Biological Markers; Chronic; Classification; Clinical; Clinical Markers; Clinical Research; Clinical assessments; Collaborations; Data Analyses; Development; Diagnosis; Diagnostic; Diagnostic tests; FDA approved; Finland; General Population; Goals; Health; Heavy Drinking; Human; Immunoassay; Institutes; Kinetics; Laboratories; Legal patent; Machine Learning; Measurement; Measures; Medical; Medical center; Modeling; Monitor; Patient Self-Report; Patients; Performance; Phase; Phenotype; Physiology; Pilot Projects; Plasma; Plasma Proteins; Population; Populations at Risk; Predictive Value; Proteins; Proteome; Proteomics; Psychosocial Assessment and Care; Publishing; Questionnaires; Recording of previous events; Recovery; Reporting; Research; Research Project Grants; Sampling; Sensitivity and Specificity; Series; Site; Social Welfare; Solutions; Technology; Testing; Translating; Typology; United States Department of Veterans Affairs; United States National Institutes of Health; Universities; Veterans; Vulnerable Populations; Withdrawal; Work; alcohol research; clinical research site; cohort; comparative; design; drinking; drinking behavior; forest; hazardous drinking; innovation; medical schools; named group; nonhuman primate; novel; problem drinker; programs; research study; screening; success; tool

DESCRIPTION (provided by applicant): Alcohol abuse and alcoholism remain significant societal problems. Unfortunately, treatment for and monitoring of harmful alcohol consumption is hampered by the lack of a highly accurate diagnostic test of alcohol drinking behavior. Our long-term goal for this research project is to develop biomarkers of alcohol abuse for use in at- risk populations. In particular, we have identified highly sensitive and specific plasma protein biomarkers using a well-controlled nonhuman primate model of alcohol abuse. We propose, in this application to translate these findings from the nonhuman primate into potential diagnostic tools for monitoring alcohol abuse in humans. This will be undertaken in collaboration with three clinical sites around the world. Specifically, we will obtain de- identified clinical samples from he Coatesville Veterans Affairs Medical Center, the Yale University School of Medicine, and the Institute for Health and Welfare of Finland (Helsinki, Finland). Studies associated with this research program will be divided into two specific aims. Specific aim 1 will validate a novel plasma biomarker panel in recovering alcoholics. In this aim, our clinical collaborators (from Yale and the Coatesville VAMC) will provide anonymous, within-subject longitudinal samples from subjects undergoing withdrawal and early abstinence (21 to 28 days) from abusive drinking as well as from the general population. These well-annotated samples will be used to refine the list of 27 biomarkers to identify the set that is most diagnostic of the human drinking phenotype and withdrawal/ abstinence. These experiments will employ a multiplex quantitative solution-phase immunoassay designed for human analytes (Myriad RBM DiscoveryMAP v1.0). As with all biomarker discovery projects, our primary emphasis will be on identifying a plasma protein analyte panel with high sensitivity and specificity. Specific aim 2 will then refine the plasma biomarker panel to permit diagnosis of hazardous drinking in a cross-sectional population from multiple sites. Within- subject assessment of drinking behavior (Aim #1) is much easier because the test does not compare differing baseline physiologies. Requirements for general population screening are much more stringent and will be assessed in samples from three independent sites (Yale University, Coatesville PA Veterans Administration Medical Center and the Finland National Institute for Health and Welfare). These sites provide a rich number of samples and drinking behaviors from which to draw experimental cohorts. In summary, we believe this work is innovative in that it capitalizes on new concepts in biomarker development through the identification of novel targets. The specific aims will build on preceding successes in the nonhuman primate model by characterization of human samples. All of the proposed studies will involve correlation with normal clinical and psychosocial assessments of alcohol consumption (AUDIT self-reports; percentCDT, AST/ALT, GGT, etc.). In addition, because we are not using unitary biomarker measures, we will apply sophisticated biostatistical approaches (random forest, support vector machine, principle component analysis) to the data analysis.

描述（由申请人提供）：酗酒和酒精中毒仍然是重大的社会问题。不幸的是，缺乏对酒精饮酒行为的高度准确诊断测试，阻碍了对有害饮酒的治疗。我们对该研究项目的长期目标是开发滥用酗酒的生物标志物，以用于风险人群。特别是，我们使用良好的酗酒非人类灵长类动物模型确定了高度敏感和特定的等离子体蛋白生物标志物。我们建议在此应用中将这些发现从非人类灵长类动物转化为监测人类酗酒的潜在诊断工具。这将与世界各地的三个临床站点合作进行。具体来说，我们将从HE Coatesville退伍军人事务医学中心，耶鲁大学医学院以及芬兰卫生与福利研究所（芬兰赫尔辛基）那里获得已确定的临床样本。与该研究计划相关的研究将分为两个具体目标。特定的目标1将在恢复酗酒者时验证一个新型的血浆生物标志物面板。在此目标中，我们的临床合作者（来自耶鲁大学和科茨维尔VAMC）将提供匿名的，受试者的纵向样本，这些样本来自接受滥用和滥用早期（21至28天）的受试者，以及滥用虐待饮酒以及一般人群的戒酒（21至28天）。这些井井有条的样品将用于完善27个生物标志物的列表，以确定最诊断的人类饮酒表型和戒断/禁欲的套装。这些实验将采用专为人类分析物设计的多重定量溶液相免疫测定（MYRIAD RBM DiscoveryMAP V1.0）。与所有生物标志物发现项目一样，我们的主要重点将是识别具有高灵敏度和特异性的血浆蛋白分析物面板。然后，特定的目标2将完善血浆生物标志物面板，以允许诊断来自多个地点的横断面人群中的危险饮酒。饮酒行为的主题评估（AIM＃1）要容易得多，因为该测试不能比较不同的基线生理。对普通人群筛查的要求更加严格，将在三个独立地点的样品中进行评估（耶鲁大学，科茨维尔PA退伍军人管理局医疗中心和芬兰国家卫生与福利研究所）。这些地点提供了大量的样本和饮酒行为，从中可以从中绘制实验人群。总而言之，我们认为这项工作具有创新性，因为它通过识别新目标来利用生物标志物发展的新概念。具体的目标将以人类样本的表征在非人类灵长类动物模型中取得成功。所有提出的研究将涉及与饮酒的正常临床和社会心理评估（审计自我报告； PercentCDT，AST/ALT，GGT等）的相关性。此外，由于我们不使用统一的生物标志物措施，因此我们将应用复杂的生物统计学方法（随机森林，支持向量机，原理成分分析）。