Individual (N-of-1) trials can be combined to give population comparative treatment effect estimates: methodologic considerations

J Clin Epidemiol. 2010 Dec;63(12):1312-23. doi: 10.1016/j.jclinepi.2010.04.020. Epub 2010 Sep 22.


Objective: To compare different statistical models for combining N-of-1 trials to estimate a population treatment effect.

Study design and setting: Data from a published series of N-of-1 trials comparing amitriptyline (AMT) therapy and combination treatment (AMT+fluoxetine [FL]) were analyzed to compare summary and individual participant data meta-analysis; repeated-measure models; Bayesian hierarchical models; and single-period, single-pair, and averaged outcome crossover models.

Results: The best-fitting model included a random intercept (response on AMT) and fixed treatment effect (added FL). Results supported a common, uncorrelated within-patient covariance structure that is equal between treatments and across patients. Assuming unequal within-patient variances, a random-effect model was favored. Bayesian hierarchical models improved precision and were highly sensitive to within-patient variance priors.

Conclusion: Optimal models for combining N-of-1 trials need to consider goals, data sources, and relative within- and between-patient variances. Without sufficient patients, between-patient variation will be hard to explain with covariates. N-of-1 data with few observations per patients may not support models with heterogeneous within-patient variation. With common variances, models appear robust. Bayesian models may improve parameter estimation but are sensitive to prior assumptions about variance components. With limited resources, improving within-patient precision must be balanced by increased participants to explain population variation.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Amitriptyline / therapeutic use
  • Antidepressive Agents / therapeutic use
  • Bayes Theorem
  • Chronic Disease
  • Clinical Trials as Topic / standards*
  • Drug Therapy, Combination
  • Fluoxetine / therapeutic use
  • Humans
  • Meta-Analysis as Topic
  • Models, Statistical*
  • Outcome Assessment, Health Care / standards*
  • Precision Medicine / statistics & numerical data*
  • Research Design / standards*


  • Antidepressive Agents
  • Fluoxetine
  • Amitriptyline