Advancing observer-reported outcome measurement: development of the MOOD-AS for observing distress in Angelman syndrome

Individuals with Angelman syndrome (AS) often experience profound communication impairment and intellectual disability, and as a result, are often unable to self-report on their experiences of emotional distress, including experiences of anxiety. However, existing measures of anxiety primarily depend on verbal descriptions of internal states, making them unsuitable tools for assessing the nature and severity of distress through observer-report for this population. To address this gap, we developed the Measure of Observable Outcomes of Distress in Angelman Syndrome (MOOD-AS), a novel observer-reported outcome (ObsRO) instrument built through a rigorous, caregiver-centered qualitative process focused on observable expressions of distress. Following FDA and ISPOR guidance for clinical outcome assessment development, we conducted concept elicitation interviews with caregivers in the United States and the Netherlands, drafted an initial item pool, mapped items against existing anxiety measures, and performed cognitive interviews to refine the instrument. Concept elicitation interviews were analyzed using content analysis, with saturation of concept assessed quantitatively. Cognitive interviews focused on evaluating item clarity, relevance, and usability. Caregivers identified 120 and 119 unique observable behaviors and situations in the U.S. (n = 17) and Netherlands (n = 8) sample. Saturation of concept was achieved. Mapping to nine existing anxiety measures revealed substantial gaps in coverage of caregiver-observable behaviors. Cognitive interviews (N = 9) confirmed strong item clarity and relevance, resulting in minor refinements to instructions, severity ratings, and caregiver impact response options. The final MOOD-AS consists of 71 caregiver-centered items assessing observable distress and anxiety-related behaviors. Psychometric properties will be assessed in the next phase of data collection. The MOOD-AS provides a rigorously developed ObsRO item set with strong qualitative evidence for content validity. Further psychometric evaluation will establish its measurement properties. Its development highlights the importance of systematically integrating caregiver observations when self-report is not feasible and offers a model for future outcome measure development in rare and nonverbal populations.