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

项目摘要/摘要 神经发育障碍(NDD)是一组广泛的疾病，在出生后表现出来， 与精神运动发育异常和其他临床特征有关，如癫痫、运动 畸形和智力残疾。最常见和最著名的NDD是自闭症，这是一种 由无数已知和未知的病因引起的一系列临床特征。Rett综合征(RTT， MIM312750)，是一种严重的NDD，几乎总是由甲基CpG-1功能缺失突变引起 结合蛋白2(MECP2)，被认为是典型的新城疫，因为它有许多临床特征 与其他新城疫。在有症状的小鼠中进行MECP2的遗传恢复可以逆转表型异常， 为RTT和其他NDD找到疾病修饰疗法带来了希望。成功且 临床试验的有效完成有赖于明确定义和有效的临床结果评估(COA)。 不幸的是，Rett综合征不存在完全心理测量学验证的COA。利用现有的纵向 来自罕见疾病临床研究网络Rett综合征自然史研究(NHS)的数据，我们有 产生了一个新的潜在临床医生报告的COA，修订的运动行为评估(R-MBA)，它已经 良好的内部一致性、条目响应、领域覆盖率和有效性的初步证据。为了 确定R-MBA是否将成为临床试验的可用COA，关键是充分建立 心理测量学特性包括评估信度、效度、敏感度和响应性。 此外，为了实现这种COA的多站点试用，需要一个培训和认证评分员的平台。 因此，本项目的总体目标是完成R-MBA的心理测评。这将是 实现了三个目标。目标1：使用视频建立评分员间、评分员内和重测的可靠性 由三个独立评分员评分的记录式结构化考试。录像将被用来开发一种 基于视频的评分员培训和评估平台。目标2：评估测验的收敛和发散效度 R-MBA通过与同时评估的有效措施进行比较。目标3：确定对年龄的敏感性- 利用现有的NHS纵向数据对R-MBA的相关变化进行分析，并表征对 在RTT已完成或正在进行的临床试验的背景下，通过评估R-MBA进行干预。成功 该项目的完成将扩大RTT的临床试验准备，建立可靠性、有效性、 临床医生报告的COA-R-MBA的敏感度和反应性。此外，开发一种 基于视频的评分员培训和可靠性评估平台将促进采用和使用 在RTT的多点临床试验中广泛测量。

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.