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

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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.