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General introduction 151 controlled, multiple crossover trials in a single patient and can provide rigorous evidence of treatment effects for individuals (Figure 3).44,45 They address the question of inter-individual variability in treatment response, and the lack of knowledge about effects in affected individuals who are typically excluded in RCTs. Where RCTs generally assess effectiveness of treatments using the average treatment effect, N-of-1 studies can identify individual particular characteristics that may modify response to the intervention.46 N-of-1 studies provide an ideal tool for perceiving little but significant changes and patterns over time. When the same N-of-1 design is used for several individuals, aggregated data can produce treatment effect estimates at population level which may be as robust as traditional RCTs.47 Furthermore, the personalized approach has the potential of maximizing treatment adherence that is both patient-centered and evidence-based.44,48–50 However, N-of-1 trials have been criticized because of challenged generalizability due to methodological and statistical bottlenecks with limited acceptance by investigators, medical ethical committees, health care institutes, and health insurance organizations.42,51–54 Given the potential, N-of-1 studies appear to be underused, despite the urgent call for personalized medicine and the challenge the field of RGNDs are facing with regard to evidence-based medicine.A B B A CRun-in WashoutPeriod PeriodPair / block BlockCycle CycleA: Active interventionB: PlaceboC: Alternate interventionN-of-1 designBaseline Follow-upFollow-up measurementFigure 3. Schematic representation of the N-of-1 design. Outcomes: how to measure what matters?Due to the complexity and variety of manifestations, various outcomes have been measured using several outcome measurement instruments to assess disease severity and functioning in interventional studies. Deciding upon the right outcome measure has far-reaching implications. Sample size calculations are often based on the primary outcome measure. Trials Annelieke Muller sHL.indd 15 14-11-2023 09:07