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Chapter 10306conducting a trial within rare and heterogeneous populations. As it is of great importance to measure what really matters in clinical trials, the use of outcome measures for RGNDs and ID is described in Part II. Considering that a genetic diagnosis provides opportunities for disorder-specific care, Part III explores reporting of genetic diagnoses in multidisciplinary ID care.Part I: N-of-1 studiesTo generate evidence for interventions for RGNDs, this thesis advocates for the use of N-of-1 design. This design is particularly suitable for small patient populations with high variability within and between disorders. It is considered a powerful approach for demonstrating treatment efficacy and can be used to inform personalized clinical treatment decisions. Remarkably, N-of-1 studies have been sporadically reported in RGNDs, as described in Chapter 2. To enhance methodological quality, feasibility, personalization and generalizability of N-of-1 studies, recommendations are provided to guide clinicians in realizing evidence-based interventions. For example, we recommend thorough description of baseline characteristics, target symptoms and outcomes, performing a power analysis, consideration of adding a baseline period, dose titration phase, run-in period, washout periods and follow-up measurement. Burden can be minimized by interim analyses and the choice of outcome measures. As an example of using the N-of-1 design, we started a series of N-of-1 trials with methylphenidate for attention-deficit/hyperactivity disorders (ADHD) in children and adults with Smith-Magenis syndrome (Chapter 3). In Chapter 4, we provide a protocol for the N-of-1 study with cannabidiol (CBD) for severe behavioral manifestations in children and adults with Tuberous Sclerosis Complex (TSC), mucopolysaccharidosis type III (MPS III), and Fragile X syndrome (FXS). In both double-blind, randomized and placebo-controlled clinical trials, we involved patient (representatives) in trial design and outcome measures. Although indications and accessibility of the medication differ, both studies aim to provide information on the effectiveness and adverse effects of the intervention. Methylphenidate is first-line pharmacological treatment for idiopathic ADHD. However, efficacy in RGNDs is unclear and there is Annelieke Muller sHL.indd 306 16-11-2023 09:26