Optimizing Usage, Impact of N-of-1 Studies on Rare Neurodevelopmental Disorders

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

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

The study researchers used 2 search engines to find peer-reviewed individual case studies or “N-of-1” studies from 1947 to 2019 in which at least 3 controlled treatment or comparison episodes were used. They also separately searched the last 10 years of studies for clinical trials of all rare genetic neurodevelopmental and chromosomal disorders, and congenital metabolic disorders, from the National Institutes of Health Information Center on Genetic and Rare Diseases.

Of the 18,483 citations identified, only 12 studies met the basic N-of-1 criteria of a controlled multiple crossover study that indicated limited use. The institutional ethics approval was explicitly mentioned in 8 studies.

The study’s researchers found that the population component of the trials would benefit from clarifying diagnostic and eligibility criteria, comorbid conditions, and concurrent conditions. They recommended describing these components thoroughly in order to optimize interpretation and generalizability for other patient groups.

They also urged to indicate whether a study will focus on syndrome-specific or common manifestations, in addition to distinguishing between disorder-specific and disease-modifying drug interventions to aid generalizability. The generalizability of their intervention to other population groups was also highlighted.

Regarding the design, the study researchers noted that a common terminology is needed as only two authors of the study specifically identified that the study was an N-of-1 study. The reasons for the design were generally not given. There was also an unclear justification for the duration of the trial and intervention, lack of run-in times, transference effects, randomization and blinding.

Pharmacokinetics and dosage should be considered to establish the length of the intervention period and dosage should be based on factors such as half-life, age, weight and time of day. The study’s researchers encouraged adding a break-in and wash-out period to minimize both biological and psychological carry-over effects, noting that only 1 study had a break-in and 1 study had a wash-out period.

The study researchers praised the personalized care in the included studies and noted that patient involvement in the intervention, design, and outcome measures appears to make a large contribution to the participant’s relevance and enthusiasm, although this mechanism can also amplify potential placebo effects.

They found that study compliance requires proxy-friendly assessment tools and that the study authors can both minimize the burden on assessors and consider multi-assessor assessment.

Also, to improve reliability, more sensitive and disorder specific assessment strategies, as well as parametric, nonparametric, and complementary analysis are required to measure effectiveness.

restrictions This systematic review included the possibility that some studies were inappropriately excluded or that N-of-1 studies targeting symptoms without mentioning the underlying disorders may have been overlooked. The recommendations were based more on the investigators’ opinions than on a systematically derived consensus.

The study’s researchers concluded that these recommendations “can improve methodological and statistical quality, as well as generalizability, feasibility, and personalization. The future use of this N-of-1 framework will help deliver the much-needed evidence-based interventions for these vulnerable patients.


Müller AR, Brands MM, PM van de Ven 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

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