Page 33 - Demo

N-of-1 studies in rare genetic neurodevelopmental disorders312IntroductionMillions of people worldwide are affected by one of the nearly 8,000 rare disorders, defined as a condition affecting less than 1 in 2,000 individuals according to European definitions.1 Around 80% of these rare disorders are genetic and associated with neurodevelopmental disorders and/or inborn errors of metabolism (IEMs).2 Treatment targets are increasingly identified,3,4 although the lack of evidence now leads to patients missing out on possibly effective interventions. As parallel group randomized controlled trials (RCTs) are often not feasible in these small and heterogeneous populations, a new methodological framework needs to be developed.N-of-1 studies are randomized, controlled, multiple crossover trials in a single patient (Figure 1 and Table 1)5,6 and closely follow indications of causality between agent and effect.7,8 Where RCTs generally assess an average treatment effect, N-of-1 series identify individual particular characteristics that may modify response to the intervention, addressing the question of interindividual variability in treatment response.9 Aggregated data of an N-of-1 series can even produce treatment effect estimates at a population level, which may be as robust as traditional RCTs.10,11 Furthermore, the personalized approach has the potential of maximizing treatment adherence.5,12–14Now guidelines on the design and reporting of N-of-1 trials are available,6,8,15,16 and specific information is needed to improve N-of-1 studies in patients with rare neurodevelopmental disorders, as these patient populations are particularly complex, heterogeneous, vulnerable, and understudied. Our aim is to (1) provide a systematic review of the literature on N-of-1 trials in individuals with rare genetic neurodevelopmental disorders and (2) formulate recommendations to optimize future use and impact.Annelieke Muller sHL.indd 31 14-11-2023 09:07