Development of a reliable, valid, and sensitive outcome measure in Rett syndrome

开发可靠、有效且敏感的雷特综合征结果测量方法

• 批准号: 10249176
• 负责人: Jeffrey L Neul
• 金额: $ 21.95万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10249176
• 关键词: Adaptive Behaviors; Adoption; Affect; Behavior; Behavior assessment; Biological Markers; Birth; Caregivers; Clinical; Clinical Research; Clinical Trials; Clinical assessments; Data; Development; Discrimination; Disease; Dyskinetic syndrome; Etiology; Evaluation; Failure; Female; Funding; Future; Genetic; Goals; Growth; Growth Factor; Hand; Individual; Industry; Intellectual functioning disability; Intervention; Ketamine; Knowledge; Link; Measures; Methods; Methyl-CpG-Binding Protein 2; Movement Disorders; Multi-Institutional Clinical Trial; Mus; Natural History; Neurodevelopmental Disorder; Oral; Outcome Measure; Phenotype; Process; Property; Psychometrics; Quality of life; Questionnaires; Rare Diseases; Reporting; Rest; Rett Syndrome; Seizures; Severities; Structure; Testing; Therapeutic; Therapeutic Intervention; Training; United States National Institutes of Health; Video Recording; Walking; Work; age related; autism spectrum disorder; base; clinical examination; clinical outcome assessment; clinical trial implementation; clinical trial readiness; design; gene therapy; impression; loss of function mutation; motor behavior; mouse model; multi-site trial; postnatal; preclinical study; prospective; response; restoration; skills; sound; stereotypy; theories

Project Summary/Abstract Neurodevelopmental Disorders (NDD) are a broad group of disorders that manifest postnatally and are associated with abnormal psycho-motor development and other clinical features such as seizures, movement abnormalities, and intellectual disabilities. The most common and well-known NDD is Autism, which is a constellation of clinical features caused by a myriad of known and unknown etiologies. Rett syndrome (RTT, MIM312750), is a severe NDD that is nearly always caused by loss-of function mutations in Methyl-CpG- binding Protein 2 (MECP2) and is considered a “prototypical” NDD because it shares many clinical features with other NDD. Genetic restoration of MECP2 in symptomatic mice can reverse phenotypic abnormalities, providing hope that disease modifying therapies could be identified for RTT and other NDD. Successful and efficient completion of clinical trials rests well-defined and validated Clinical Outcome Assessments (COA). Unfortunately, no fully psychometrically validated COA exist in Rett syndrome. Using existing longitudinal data from the Rare Disease Clinical Research Network Rett Syndrome Natural History Study (NHS), we have generated a new potential clinician-reported COA, the Revised Motor Behavior Assessment (R-MBA) that has good internal consistency, item response, domain coverage, and preliminary evidence of validity. In order to determine whether the R-MBA will be a useable COA for clinical trials, it is critical to fully establish the psychometric properties including evaluating the reliability, validity, sensitivity, and responsivity. Furthermore, to enable multi-site trial utilization of this COA, a platform to train and certify raters is needed. Thus, the overall goal of this project is to complete the psychometric evaluation of the R-MBA. This will be achieved in three aims. Aim 1: Establish the inter-rater, intra-rater, and test-retest reliability using a video recorded structured exam rated by three independent raters. The video recording will be used to develop a video-based rater training and evaluation platform. Aim 2: Assess the convergent and divergent validity of the R-MBA by comparison to validated measures assess concurrently. Aim 3: Determine the sensitivity to age- related change of the R-MBA using existing longitudinal NHS data and characterize the responsiveness to intervention by evaluating R-MBA in the context of completed or ongoing clinical trials in RTT. Successful completion of this project will expand the clinical trial readiness in RTT by establishing the reliability, validity, sensitivity, and responsiveness of a clinician-reported COA, the R-MBA. Furthermore, the development of a video-based rater training and reliability-evaluating platform will facilitate adoption and utilization of this measure broadly in multi-site clinical trials in RTT.

项目概要/摘要 神经发育障碍 (NDD) 是一大类在出生后出现的疾病， 与精神运动发育异常和其他临床特征（如癫痫、运动）相关 最常见和众所周知的 NDD 是自闭症，这是一种 由无数已知和未知病因引起的一系列临床特征（RTT， MIM312750) 是一种严重的 NDD，几乎总是由甲基-CpG- 功能丧失突变引起 结合蛋白 2 (MECP2)，被认为是“原型”NDD，因为它具有许多共同的临床特征 与其他NDD一样，MECP2在有症状的小鼠中的基因恢复可以逆转表型异常， 为 RTT 和其他 NDD 成功确定疾病修饰疗法带来​​了希望。 临床试验的高效完成取决于明确定义和经过验证的临床结果评估 (COA)。 不幸的是，使用现有的纵向分析，不存在经过充分心理测量验证的 COA。 来自罕见疾病临床研究网络雷特综合征自然史研究 (NHS) 的数据，我们有 产生了一种新的潜在临床医生报告的 COA，即修订后的运动行为评估 (R-MBA)， 良好的内部一致性、项目响应、领域覆盖率和有效性的初步证据。 确定 R-MBA 是否成为临床试验可用的 COA，充分建立 R-MBA 至关重要 心理测量特性，包括评估可靠性、有效性、敏感性和响应性。 此外，为了实现该 COA 的多站点试用，需要一个培训和认证评估者的平台。 因此，该项目的总体目标是完成 R-MBA 的心理测量评估。 目标 1：使用视频建立评估者间、评估者内和重测可靠性。 由三名独立评分者评分的结构化考试将用于制定一份视频记录。 基于视频的评估者培训和评估平台。目标 2：评估收敛和发散的有效性。 R-MBA 通过与经过验证的措施进行比较来同时评估目标 3：确定对年龄的敏感性。 R-MBA 的相关变化使用现有的纵向 NHS 数据并表征对 通过在 RTT 成功完成或正在进行的临床试验中评估 R-MBA 进行干预。 该项目的完成将通过建立可靠性、有效性、 临床医生报告的 COA（R-MBA）的敏感性和反应性。 基于视频的评估员培训和可靠性评估平台将促进该技术的采用和利用 在 RTT 的多中心临床试验中进行广泛测量。