Proof of Principle for a Diagnostic Blood Test of Recurrent Seizures

复发性癫痫发作诊断性血液检测的原理证明

• 批准号: 8610363
• 负责人: Peter B Crino
• 金额: $ 34.04万
• 依托单位: COGNIZANCE BIOMARKERS, LLC
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-01 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8610363
• 关键词: Affect; Age; Anti-Inflammatory Agents; Anti-inflammatory; Area Under Curve; Biological Assay; Blood Tests; Blood specimen; CCL17 gene; CNS processing; Centers for Disease Control and Prevention (U.S.); Clinical; Collection; Communities; Data; Diagnosis; Diagnostic; Diagnostic Procedure; Diagnostic tests; Disease; Electroencephalogram; Encephalitis; Epilepsy; Etiology; Event; Functional disorder; Gold; Inpatients; Lead; Legal patent; Lymphocyte; Magnetic Resonance Imaging; Marketing; Measures; Medical; Monitor; Neurologic; Neurology; Notification; Patients; Pennsylvania; Phase; Physicians; Plasma; Population; Price; Process; Productivity; Proteins; Publications; ROC Curve; Recurrence; Research; Sampling; Seizures; Sensitivity and Specificity; Specificity; Syncope; Test Result; Testing; Universities; age group; base; clinical care; cohort; cost; cost effective; experience; impression; inflammatory marker; novel; phase 1 study; public health relevance; tool

DESCRIPTION (provided by applicant): Epilepsy is a serious and costly neurologic condition that affects approximately 3% of the US population, and is often both costly and difficult to diagnose. Presently, a physician's diagnosis is based on a combination of the physician's clinical impression, electroencephalogram (EEG), magnetic resonance imaging (MRI) and, where available, a multiday inpatient test combining closed circuit TV and EEG monitoring. Recent data have established brain inflammation as a critical factor in the pathophysiology of recurrent seizures, and we have built on this research to develop a patent-pending diagnostic blood test for recurrent seizures: CNS-specific Assay for Recurrent Paroxysmal Events (CARPE). CARPE is unique, as it measures plasma levels of sICAM5, an anti-inflammatory CNS origin protein, and TARC, a lymphocyte chemoattractor that we have found in consistently high concentrations in epilepsy patients. In pioneer data collected at the University of Pennsylvania, the CARPE blood test precisely separated patients with recurrent seizures from normal controls. [Here we will collect samples for CARPE testing from a cohort of 240 new patients at the Penn Epilepsy Center who will undergo a diagnostic workup, including an EEG. After six months of clinical care, an independent board of three epileptologists will determine each patient's diagnosis. To determine accuracy, we will construct ROC curves for CARPE's sensitivity and specificity by varying the threshold value for classifying epilepsy patients. Patients for whom the gold standard panel is unable to reach a conclusive diagnosis will be excluded from this analysis, and the area under the curve must significantly exceed 0.7. To determine the threshold values to be used in a subsequent pivotal study, we will analyze the entire group, using the gold standard panel's best estimate for patients with an unclear diagnosis. We aim to choose the threshold value of CARPE for identifying epilepsy patients with specificity of at least 0.8 and sensitivity of at least 0.8. At the conclusion of the study, we expct to demonstrate the accuracy of the CARPE test in diagnosing epilepsy and establish the diagnostic threshold values. Ultimately, we expect that patients whose CARPE test results indicate epilepsy will be able to forgo additional epilepsy diagnostic procedures.] In Phase II we will propose to validate the test in a multi-center pivotal study involving larger numbers of patients of all age groups. We expect this to lead to a successful de novo 510(k) Premarket Notification and marketing of the CARPE blood test as a rapid, widely accessible, and cost-effective diagnostic test for recurrent seizures. If successful, the CARPE diagnostic blood test will provide immediate and substantial benefits to patients and the medical community by offering a rapid, accessible, and cost-effective means of diagnosing epilepsy.

描述（由申请人提供）：癫痫是一种严重且昂贵的神经系统疾病，影响约3%的美国人口，并且通常既昂贵又难以诊断。目前，医生的诊断是基于医生的临床印象、脑电图（EEG）、磁共振成像（MRI）以及（在可用的情况下）结合闭路电视和EEG监测的多日住院测试的组合。最近的数据已经确定脑炎症是复发性癫痫发作的病理生理学中的一个关键因素，我们在这项研究的基础上开发了一种正在申请专利的复发性癫痫发作诊断血液检测：复发性阵发性事件的CNS特异性检测（CARPE）。CARPE是独一无二的，因为它测量sICAM 5（一种抗炎CNS来源蛋白）和TARC（一种淋巴细胞化学吸引物）的血浆水平，我们在癫痫患者中发现了持续高浓度的TARC。在宾夕法尼亚大学收集的先驱数据中，CARPE血液测试精确地将复发性癫痫患者与正常对照区分开来。[Here我们将从宾夕法尼亚癫痫中心的240名新患者中收集样本进行CARPE测试，这些患者将接受诊断检查，包括EEG。经过六个月的临床护理，一个由三名癫痫病学家组成的独立委员会将确定每位患者的诊断。为了确定准确性，我们将通过改变癫痫患者分类的阈值来构建CARPE敏感性和特异性的ROC曲线。金标准组无法得出结论性诊断的患者将从该分析中排除，曲线下面积必须显著超过0.7。为了确定在随后的关键性研究中使用的阈值，我们将使用金标准组对诊断不明确的患者的最佳估计来分析整个组。我们的目标是选择阈值的CARPE识别癫痫患者的特异性至少为0.8，灵敏度至少为0.8。在研究的最后，我们期望证明CARPE测试在诊断癫痫中的准确性，并建立诊断阈值。最终，我们预计CARPE测试结果表明癫痫的患者将能够放弃额外的癫痫诊断程序。在II期研究中，我们将提议在一项涉及所有年龄组大量患者的多中心关键性研究中验证该试验。我们预计这将导致CARPE血液检测作为复发性癫痫发作的快速、可广泛获得且具有成本效益的诊断检测成功获得重新分类510（k）上市前通知和上市。如果成功，CARPE诊断血液测试将通过提供快速，可访问和具有成本效益的癫痫诊断方法，为患者和医学界提供直接和实质性的好处。