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

> **NIH NIH R21** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2020 · $275,091

## Abstract

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.

## Key facts

- **NIH application ID:** 10046248
- **Project number:** 1R21HD103348-01
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Jeffrey L Neul
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $275,091
- **Award type:** 1
- **Project period:** 2020-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10046248

## Citation

> US National Institutes of Health, RePORTER application 10046248, Development of a reliable, valid, and sensitive outcome measure in Rett syndrome (1R21HD103348-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10046248. Licensed CC0.

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