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Chapter 368between-subjects heterogeneity in treatment effect through inclusion of the random treatment effect. Small amounts of missing data will not pose problems for the mixed model analysis because of the many data points per period, assuming data is missing at random. If issues such as singularity arise due to complexity of the models, an analysis based on a summary measure will be performed. A similar method will be used for estimating treatment effects on secondary study parameters. A two-sided significance level of 5% will be used. Analyses will be performed in R, using the lmer package.DiscussionTo date, research on the efficacy of treatment strategies for behavioural aspects of SMS has been limited. In this N-of-1 series of randomized, placebo-controlled, double-blind multiple crossover trials in patients with SMS and ADHD, the effectiveness of MPH for ADHD symptoms will be examined, including personalized goals as additional outcomes.N-of-1 studies provide a powerful alternative to larger RCTs, but are still only sporadically reported in rare genetic neurodevelopmental disorders.45Debate is still ongoing to what extent an N-of-1 study represents medical research or is part of evidence-based clinical care.46,47,48 For instance, for some practitioners starting MPH treatment, blinded crossover periods, the use of placebo and filling out questionnaires is already part of standard care. To provide evidence-based treatment decisions and to prevent polypharmacy, N-of-1 studies might be considered as a much-needed part of clinical care especially in complex patient populations such as individuals with SMs.Combining personalized and relevant treatment targets while pursuing optimal generalizability is challenging in heterogeneous patient populations such as SMs. Because SMs is accompanied by various and often variable levels of ID and comorbidities, clear diagnostic and eligibility criteria are necessary and baseline characteristics, concurrent therapies, comorbid conditions and target symptoms will be clearly defined to optimize Annelieke Muller sHL.indd 68 14-11-2023 09:07