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N-of-1 studies in rare genetic neurodevelopmental disorders332MethodsWe followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocol (Figure 2).17 The methodological framework was published in advance in the PROSPERO International Prospective Register of Systematic Reviews (CRD42020154720). Relevant definitions of terms that were used in this review are provided in the box.EligibilityPeer-reviewed studies that used at least 3 controlled episodes of treatment or comparator (placebo, treatment as usual, no intervention, an alternative intervention, or other doses of the same intervention) were included in the review. Genetic neurodevelopmental disorders were defined as disorders with a genetic etiology affecting the nervous system in early development. IEMs, constituting a subgroup of rare genetic disorders, were defined as monogenic conditions in which the impairment of a biochemical pathway is essential to the pathophysiology of the disorder, typically resulting in either accumulation of toxic metabolites or shortage of energy and building blocks for cells. Those presented with intellectual disability (ID) were considered neurodevelopmental.18,19 Exclusion criteria included idiopathic psychiatric disorders according to the DSM-5 criteria and genetic etiologies not confirmed with standard methods. Experts were consulted to determine whether the phenotypes of Rett syndrome (in the absence of molecular confirmation) and cerebellar hypoplasia tapetoretinal degeneration syndrome were consistent with the tight diagnosis.20,21Search Strategy, Study Selection, Risk of Bias, and Quality AssessmentTwo separate search strategies were conducted with assistance of a clinical research librarian (J.G.D.) in 2 search engines: MEDLINE (Ovid), 1946 to November 8, 2019, and EMBASE (Ovid), 1947 to November 8, 2019. First, the term N-of-1 and synonyms for all single-case experimental designs were searched. Second, because few studies explicitly used this N-of-1 terminology, all rare genetic neurodevelopmental disorders were separately searched in combination with terms for clinical trials. Specifically, a list containing all rare genetic and chromosome disorders and IEMs from the Genetic and Rare Diseases Information Center of the NIH was used. A Annelieke Muller sHL.indd 33 14-11-2023 09:07