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N-of-1 studies in rare genetic neurodevelopmental disorders492patients, a hierarchical Bayesian model or linear mixed model with random treatment-by-patient interaction is required.Reporting an N-of-1 trial should satisfy particular N-of-1 items according to CENT 2015 and RoBiNT (Figure 4).15,23 Because of the differences in N-of-1 terminology that still exist, studies should identify the trial as an N-of-1 in both the title and the abstract. In addition to the items discussed above and in Figure 4, a rationale for using the N-of-1 design should be provided because N-of-1 trials may serve a number of different purposes53 and several singlecase experimental designs could be considered.32 More specifically, we especially recommend an N-of-1 study in rare genetic disorders when the intervention has a predictable duration of effect for which a valid off-period is possible and low recruitment rates are expected. Finally, trial registration and an accessible full trial protocol including specific methodological choices might be of pivotal importance for future N-of-1 studies. In line with recent guidelines for N-of-1 trial protocols and reporting,6,8 we recommend facilitation of entry of N-of-1 studies into primary registries within the World Health Organization’s International Trials Registry Network and clinicaltrials.gov.A strength of this study is the comprehensive search strategy necessitated by the historical lack of uniformity in N-of-1 terminology. The large amount of records identified through this search inadvertently may have resulted in inappropriate exclusions. N-of-1 studies that were directed toward symptoms solely without mentioning underlying disorders might also have been missed as our search was developed with a gene first approach. Of note, the recommendations reflect the authors’ opinions rather than a systematically derived consensus.ConclusionN-of-1 studies have great potential to provide evidence of effectiveness for individuals as well as groups of patients. The findings of this review show only limited use of N-of-1 studies in rare genetic neurodevelopmental disorders and that improvement of methodology is essential to provide a Annelieke Muller sHL.indd 49 14-11-2023 09:07