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

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 畸形和智力障碍。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。雷特综合征（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。有症状小鼠中 MECP2 的基因恢复可以逆转表型异常， 为 RTT 和其他 NDD 的疾病修饰疗法找到希望。成功并 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，雷特综合征中不存在完全经过心理测量验证的 COA。利用现有的纵向 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。为了 确定 R-MBA 是否可用于临床试验的 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，本项目的总体目标是完成R-MBA的心理测量评估。这将是 实现了三个目标。目标 1：使用视频建立评估者间、评估者内和重测可靠性 由三位独立评分者评分的记录结构化考试。视频录制将用于开发 基于视频的评分员培训和评估平台。目标 2：评估收敛有效性和发散有效性 R-MBA 通过与经过验证的措施进行比较来同时进行评估。目标 3：确定对年龄的敏感性 使用现有纵向 NHS 数据进行 R-MBA 的相关变化，并表征对 通过在 RTT 中已完成或正在进行的临床试验中评估 R-MBA 进行干预。成功 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。此外，开发了一个 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。

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.