Optimizing Use, Impact of N-of-1 Studies of Rare Neurodevelopmental Disorders

Doctor viewing a patients brain scans on a computer screen.
In a systematic review and analysis, researchers provided several recommendations for improving N-of-1 studies for rare genetic neurodevelopmental disorders.

In a systematic review on literature of N-of-1 studies – randomized, controlled, multiple crossover trials in 1 patient – study researchers formulated several recommendations to optimize their future use and impact.

They sought to improve N-of-1 studies, particularly of patients with rare neurodevelopmental disorders, as these patient populations are particularly complex, vulnerable and understudied. The methodologic framework was published in the PROSPERO International Prospective Register of Systematic Reviews.

The study researchers used 2 search engines to find peer-reviewed, single-case experimental design or “N-of-1” studies from 1947 to 2019 that employed at least 3 controlled episodes of treatment or comparator. They also separately searched through the past 10 years of studies for clinical trials of all rare genetic neurodevelopmental disorders and chromosome disorders and inborn errors of metabolism from the Genetic and Rare Diseases Information Center of the National Institutes of Health.

Of the 18,483 identified citations, only 12 studies met the fundamental N-of-1 criteria of being a controlled multiple crossover trial, which indicated limited use. Institutional ethics approval was explicitly mentioned in 8 studies.

Study researchers noted that the population component of studies would benefit from clarifying diagnostic and eligibility criteria, comorbid conditions, and concurrent conditions. They recommended thoroughly describing these components to optimize interpretation and generalizability to other patient populations.

They also urged specifying whether a trial will focus on syndrome-specific or common manifestations, in addition to distinguishing between disorder-specific and disease-modifying drug interventions to support generalizability. The generalizability of their intervention to other populations was also emphasized.

Regarding design, the study researchers noted a need for common terminology because only 2 studies’ authors explicitly identified that the study was an N-of-1 trial. The rationale for the design was generally not specified. There was also unclear justification of trial and intervention duration, lack of run-in periods, carry-over effects, randomization, and blinding.

Pharmacokinetics and dosage should be considered to substantiate the interventional period duration, and dosage should be based on factors including half-life time, age, weight, and daily timing. Study researchers encouraged adding a run-in and washout period to minimize both biological and psychological carry-over effects, noting that only 1 study included a run-in and 1 study included a washout period.

The study researchers praised the personalized care in the included studies, and they found that patient involvement on the intervention, design, and outcome measures appears to greatly contribute to the relevance and enthusiasm of the participant, although this mechanism may also strengthen potential placebo effects.

They noted that proxy-friendly assessment tools are required for trial compliance and that study authors can both minimize the burden on the raters and consider assessment by multiple raters.

Additionally, to improve reliability, more sensitive and disorder-specific evaluation strategies as well as parametric, nonparametric, and ancillary analyses are needed to measure effectiveness.

Limitations of this systematic review included the possibility that some studies may have been inappropriately excluded or that N-of-1 studies that were directed toward symptoms without mentioning underlying disorders may have been missed. Recommendations were based on investigators’ opinions, rather than systematically derived consensus.

The study researchers concluded that these recommendations may “enhance methodological and statistical quality as well as generalizability, feasibility and personalization. Future use of this N-of-1 framework will assist in realizing the sorely needed evidence-based interventions for these vulnerable patients.


Müller AR, Brands MM, van de Ven PM, et al. The power of 1: systematic review of N-of-1 studies in rare genetic neurodevelopmental disorders. Neurology. Published online January 27, 2021. doi:10.1212/WNL.0000000000011597