Individual (N-of-1) trials can be combined to give population comparative treatment effect estimates: methodologic considerations.
OBJECTIVE
To compare different statistical models for combining N-of-1 trials to estimate a population treatment effect.


METHODS
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.


CONCLUSIONS
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.
Zucker
Deborah R
DR
Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, Tufts University, 800 Washington Street, Boston, MA 02111, USA. dzucker@post.harvard.edu
Ruthazer
Robin
R
Schmid
Christopher H
CH
D000639:Amitriptyline / Q000627:therapeutic use; D000928:Antidepressive Agents / Q000627:therapeutic use; D001499:Bayes Theorem; D002908:Chronic Disease; D002986:Clinical Trials as Topic / Q000592:standards*; D004359:Drug Therapy, Combination; D005473:Fluoxetine / Q000627:therapeutic use; D006801:Humans; D015201:Meta-Analysis as Topic; D015233:Models, Statistical; D017063:Outcome Assessment, Health Care / Q000592:standards*; D057285:Precision Medicine / Q000706:statistics & numerical data*; D012107:Research Design / Q000592:standards*
D000928:Antidepressive Agents; D005473:Fluoxetine; D000639:Amitriptyline