The power of 1 Interventions and outcome measures for rare genetic neurodevelopmental disorders

The aim of this thesis is to enable evidence-based and personalized medicine for individuals with rare genetic neurodevelopmental disorders (RGNDs) and intellectual disability (ID). Treatment targets are increasingly identified. However, evidence for efficacy remains limited due to methodological challenges in these populations, such as rarity and heterogeneity, resulting in affected individuals missing out on possibly effective interventions.
This thesis comprises a number of studies aiming to improve interventional research for RGNDs and ID. The thesis discusses the use of the N-of-1 design, a powerful alternative to conventional randomized controlled trials as these are often not feasible in small and heterogeneous populations. It enables investigation of treatment effectiveness at both an individual and group level, and addresses inter-individual variability in treatment response. A methodological framework and recommendations for conducting N-of-1 trials are provided, along with protocols exemplifying their application. As it is of great importance to measure what really matters in clinical trials, the use of outcome measures for RGNDs and ID is explored, recommendations are provided, and a disorder-specific outcome measure has been developed and validated. Considering that a genetic diagnosis provides opportunities for disorder-specific care, reporting of genetic diagnoses in multidisciplinary ID care is explored. To provide evidence-based treatment decisions and to prevent polypharmacy, this thesis emphasizes the significance of reporting genetic diagnosis in individuals with ID, personalized treatment approaches, use of the N-of-1 design, and the thorough selection of appropriate and relevant outcome measures, providing a much-needed bridge between practice and science.