Generalizing Randomized Clinical Trial Results: Implementation and Challenges Related to Missing Data in the Target Population

Am J Epidemiol. 2018 Apr 1;187(4):817-827. doi: 10.1093/aje/kwx287.


Statins are indicated in patients with elevated levels of high-sensitivity C-reactive protein and normal low-density lipoprotein cholesterol based on results of the multicountry trial, Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) (2003-2008), but the benefit in real-world populations remains unknown. We sought to generalize JUPITER results to trial-eligible population using data from the UK Clinical Practice Research Datalink (CPRD), 2001-2014. We multiply imputed missing baseline characteristics for the CPRD population and selected the trial-eligible participants as the target population based on observed and imputed values. Trial participants were weighted to be representative of the CPRD population (n = 383,418) based on individual predicted probability of selection into the trial. Trial participants were also standardized to the CPRD population without missing values (n = 2,677). In JUPITER, rosuvastatin reduced cardiovascular risk with a 3-year risk difference of -2.0% (95% confidence interval (CI): -2.9, -1.1). The rosuvastatin effect was muted in the first 2 years but remained strong at 3 years after standardizing to the imputed CPRD population (3-year risk difference = -2.7%; 95% CI: -5.8, 0.4) and the CPRD population without missing data (3-year risk difference = -1.7%; 95% CI: -3.5, 0.1). The study serves as an illustration of possible approaches to understanding generalizability of trials using real-world databases given limitations due to missing data on inclusion/exclusion criteria.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • C-Reactive Protein / analysis
  • Cardiovascular Diseases / prevention & control*
  • Cholesterol, LDL / blood
  • Data Interpretation, Statistical*
  • Epidemiologic Research Design*
  • Female
  • Humans
  • Male
  • Middle Aged
  • Risk Factors
  • Rosuvastatin Calcium / administration & dosage*
  • United Kingdom / epidemiology


  • Cholesterol, LDL
  • Rosuvastatin Calcium
  • C-Reactive Protein