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General discussion2839Therefore, we investigated the effectiveness of methylphenidate in children and adults with Smith-Magenis syndrome (SMS), well-established as firstline pharmacological treatment for ADHD (Chapter 3).Choosing the right trial designAlthough new treatment targets are currently identified, lack of evidence may lead to affected individuals missing out on possibly effective interventions. Heterogeneity and small patient populations pose a great challenge to evidence-based medicine.14 Trial methodology is therefore paramount to generate evidence for RGNDs.Choice of a single-case experimental designsSingle-case experimental designs (SCEDs), including the N-of-1 design (Figure 1), provide a powerful alternative to the conventional parallelgroup randomized controlled trials (RCTs). These RCTs generally assess the average treatment effect, often exclude affected individuals due to strict eligibility criteria such as comorbidities, and cause difficulties with recruitment due to small sample sizes.1,15–17 SCEDs, however, examine the effect of an intervention for an individual who acts as their own control. Series can be conducted to pool data to draw conclusions about effectiveness for a larger group of individuals. They take into account heterogeneity both within and between participants and may be as robust as large parallel-group RCTs,18,19 provided that they are properly executed. Under certain conditions, SCEDs can reliably inform personalized evidencebased clinical treatment decisions. These designs are especially suitable for small populations who may also show great inter- and intra-individual variability of the disorder over time, preventing them from missing out on important therapies. Of the SCEDs, the N-of-1 design is preferred when possible, and might be considered the new ‘gold standard’ for demonstrating treatment efficacy in affected individuals in clinical practice. They incorporate much of the rigor of large parallel-group RCTs, but are designed for individuals, and a powerful alternative to the group clinical trials by aggregating results from an N-of-1 series.20 The N-of-1 design has even been elevated to the highest level of evidence for treatment efficacy of an individual with increased Annelieke Muller sHL.indd 283 14-11-2023 09:08