Sensitivity subgroup analysis based on single-center vs. multi-center trial status when interpreting meta-analyses pooled estimates: the logical way forward

J Clin Epidemiol. 2016 Jun;74:80-92. doi: 10.1016/j.jclinepi.2015.08.027. Epub 2015 Nov 17.


Objectives: Prior studies regarding whether single-center trial estimates are larger than multi-center are equivocal. We examined the extent to which single-center trials yield systematically larger effects than multi-center trials.

Study design and setting: We searched the 119 core clinical journals and the Cochrane Database of Systematic Reviews for meta-analyses (MAs) of randomized controlled trials (RCTs) published during 2012. In this meta-epidemiologic study, for binary variables, we computed the pooled ratio of ORs (RORs), and for continuous outcomes mean difference in standardized mean differences (SMDs), we conducted weighted random-effects meta-regression and random-effects MA modeling. Our primary analyses were restricted to MAs that included at least five RCTs and in which at least 25% of the studies used each of single trial center (SC) and more trial center (MC) designs.

Results: We identified 81 MAs for the odds ratio (OR) and 43 for the SMD outcome measures. Based on our analytic plan, our primary analysis (core) is based on 25 MAs/241 RCTs (binary outcome) and 18 MAs/173 RCTs (continuous outcome). Based on the core analysis, we found no difference in magnitude of effect between SC and MC for binary outcomes [RORs: 1.02; 95% confidence interval (CI): 0.83, 1.24; I(2) 20.2%]. Effect sizes were systematically larger for SC than MC for the continuous outcome measure (mean difference in SMDs: -0.13; 95% CI: -0.21, -0.05; I(2) 0%).

Conclusions: Our results do not support prior findings of larger effects in SC than MC trials addressing binary outcomes but show a very similar small increase in effect in SC than MC trials addressing continuous outcomes. Authors of systematic reviews would be wise to include all trials irrespective of SC vs. MC design and address SC vs. MC status as a possible explanation of heterogeneity (and consider sensitivity analyses).

Keywords: Heterogeneity; Mean difference in SMD; Meta-analyses; Metabias; Multi-center; Ratio of odds ratio; Single center.

Publication types

  • Multicenter Study
  • Review

MeSH terms

  • Epidemiologic Research Design*
  • Humans
  • Meta-Analysis as Topic*
  • Odds Ratio
  • Outcome Assessment, Health Care / methods*
  • Outcome Assessment, Health Care / statistics & numerical data*
  • Randomized Controlled Trials as Topic / methods*
  • Randomized Controlled Trials as Topic / statistics & numerical data*
  • Sensitivity and Specificity