A disease concept model for STXBP1-related disorders

Abstract

ObjectiveSTXBP1-related disorders are common genetic epilepsies and neurodevelopmental disorders, but the impact of symptoms across clinical domains is poorly understood. Disease concept models are formal frameworks to assess the lived experience of individuals and their families and provide a basis for generating outcome measures. MethodsWe conducted semi-structured, qualitative interviews with 19 caregivers of 16 individuals with STXBP1-related disorders and 7 healthcare professionals. We systematically coded themes using NVivo software and grouped concepts into the domains of symptoms, symptom impact and caregiver impact. We quantified the frequency of concepts throughout the life span and across clinical subgroups stratified by seizure history and developmental trajectories. ResultsOver 25 hours of interviews, we coded a total of 3626 references to 38 distinct concepts. In addition to well recognized clinical features such as developmental delay (n=240 references), behavior (n=201), and seizures (n=147), we identified previously underrepresented symptoms including gastrointestinal (n=68) and respiratory symptoms (n=24) and pain (n=30). The most frequently referenced symptom impacts were autonomy (n=96), socialization (n=64), and schooling (n=61). Emotional impact (n=354), support (n=200), and daily life & activities (n=108) were highly cited caregiver impacts. We found that seizures (OR=8.84, 95% CI 5.97-13.1) were more commonly referenced in infancy than in other age groups, while behavior (OR=2.15, 95% CI 1.56-2.95), and socialization (OR=2.26, 95% CI 1.28-3.96) were more likely to be referred in childhood. We found that caregivers of individuals with ongoing seizures were less likely to reference developmental delay (OR=0.59, 95% CI 0.42-0.82), possibly due to the relatively high impact of seizures (OR=8.84, 95% CI 5.97-13.1). SignificanceSTXBP1-related disorders are complex conditions affecting a wide range of clinical and social domains. We comprehensively mapped symptoms and their impact on families to generate a comprehensive disease model as a foundation for clinical endpoints in future trials. Key points- Disease concept models (DCMs) are formal frameworks that capture the relationship between symptoms, concerns, and impact on daily life based on qualitative interviews - Endpoints for future clinic studies involving STXBP1-related disorder need to be relevant to patients and families - Interviewing a diverse cohort of caregivers and healthcare professionals allows DCMs to be generalizable and reveals high priority & novel disease concepts for treatment - Disease concepts can vary depending on an affected individuals age, necessitating longitudinal record of concepts - Disease concepts can differ across clinical subgroups stratified by epilepsy and developmental histories making inclusion of variable disorder presentations important