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.

项目总结/摘要 神经发育障碍（NDD）是一组广泛的疾病，表现在出生后， 与异常的心理运动发育和其他临床特征相关，如癫痫发作、运动 异常和智力残疾。最常见和最知名的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。Rett综合征（RTT， MIM 312750），是一种严重的NDD，几乎总是由甲基-CpG-3基因的功能缺失突变引起的。 结合蛋白2（MECP 2），被认为是一个“原型”的NDD，因为它有许多共同的临床特征 其他NDD在有症状的小鼠中MECP 2的遗传恢复可以逆转表型异常， 这为RTT和其他NDD的疾病改善疗法提供了希望。成功和 临床试验的有效完成依赖于明确定义和有效的临床结局评估（COA）。 不幸的是，没有充分的心理测量学验证COA存在于Rett综合征。利用现有的纵向 根据罕见疾病临床研究网络Rett综合征自然史研究（NHS）的数据， 产生了一个新的潜在的临床医生报告的COA，修订的运动行为评估（R-MBA）， 良好的内部一致性，项目反应，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，关键是要充分建立 心理测量学特性，包括评估信度、效度、敏感度和反应度。 此外，为了使该COA能够在多个地点试用，需要一个平台来培训和认证评级员。 因此，本项目的总体目标是完成R-MBA的心理测量学评价。这将是 实现了三个目标。目的1：使用视频建立评分员间、评分员内和重测信度 由三位独立评分员进行评分的结构化考试。录像将用于开发一个 基于视频的评分员培训和评估平台。目标2：评估 R-MBA通过与经验证的措施进行比较，同时进行评估。目标3：确定对年龄的敏感性- 使用现有的纵向NHS数据，研究R-MBA的相关变化，并描述对 通过在已完成或正在进行的RTT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，发展一个 基于视频的评分员培训和可靠性评估平台将有助于采用和利用这一工具， 在RTT的多中心临床试验中广泛测量。