Developing Meaningful Score Differences for the Bayley-4 and Vineland-3 in Angelman Syndrome using a Delphi Panel

Area of Science:

• Neurodevelopmental disorders
• Clinical psychology
• Pediatric medicine

Background:

• Regulatory approval for drug development requires demonstrating both statistical significance and clinical meaningfulness of treatment effects.
• Clinical trials for Angelman syndrome (AS) are ongoing, but established within-person meaningful score difference (MSD) thresholds for key outcome measures like the Bayley Scales of Infant Development (Bayley-4) and Vineland Adaptive Behavior Scales (Vineland-3) are lacking.
• These established thresholds are essential for interpreting treatment efficacy in AS.

Purpose of the Study:

• To develop within-patient meaningful score differences (MSDs) for the Bayley Scales of Infant Development, Fourth Edition (Bayley-4) and the Vineland Adaptive Behavior Scales, Third Edition (Vineland-3) specifically for individuals with Angelman syndrome (AS).
• To incorporate the caregiver perspective in defining what constitutes a meaningful change in functioning for individuals with AS.

Main Methods:

• A Delphi method was employed, engaging a panel of 19 caregivers of individuals with AS.
• Caregivers rated vignettes describing varying baseline functioning levels to establish MSDs for Bayley-4 and Vineland-3 Growth Scale Values.
• An iterative process with three rating rounds and two discussion rounds was used to achieve consensus, with the median caregiver rating from round 3 being the final recommended MSD.

Main Results:

• High agreement rates (70% or higher) were achieved for the final MSD ratings across the five subscales of the Bayley-4 and 10 subscales of the Vineland-3.
• The study found that MSD thresholds are not fixed cut-offs but rather a range of values that depend on the individual's baseline level of functioning.
• Caregiver-defined MSDs varied based on the severity of the child's presentation.

Conclusions:

• The Delphi panel method successfully incorporated caregiver perspectives to generate preliminary, patient-informed MSD estimates for the Bayley-4 and Vineland-3 in individuals with AS.
• These findings provide crucial benchmarks for evaluating the clinical meaningfulness of treatment effects in AS research and drug development.
• The results highlight the importance of considering baseline severity when interpreting score changes in individuals with AS.