An improved method for bivariate meta-analysis when within-study correlations are unknown

Res Synth Methods. 2018 Mar;9(1):73-88. doi: 10.1002/jrsm.1274. Epub 2017 Dec 7.


Multivariate meta-analysis, which jointly analyzes multiple and possibly correlated outcomes in a single analysis, is becoming increasingly popular in recent years. An attractive feature of the multivariate meta-analysis is its ability to account for the dependence between multiple estimates from the same study. However, standard inference procedures for multivariate meta-analysis require the knowledge of within-study correlations, which are usually unavailable. This limits standard inference approaches in practice. Riley et al proposed a working model and an overall synthesis correlation parameter to account for the marginal correlation between outcomes, where the only data needed are those required for a separate univariate random-effects meta-analysis. As within-study correlations are not required, the Riley method is applicable to a wide variety of evidence synthesis situations. However, the standard variance estimator of the Riley method is not entirely correct under many important settings. As a consequence, the coverage of a function of pooled estimates may not reach the nominal level even when the number of studies in the multivariate meta-analysis is large. In this paper, we improve the Riley method by proposing a robust variance estimator, which is asymptotically correct even when the model is misspecified (ie, when the likelihood function is incorrect). Simulation studies of a bivariate meta-analysis, in a variety of settings, show a function of pooled estimates has improved performance when using the proposed robust variance estimator. In terms of individual pooled estimates themselves, the standard variance estimator and robust variance estimator give similar results to the original method, with appropriate coverage. The proposed robust variance estimator performs well when the number of studies is relatively large. Therefore, we recommend the use of the robust method for meta-analyses with a relatively large number of studies (eg, m≥50). When the sample size is relatively small, we recommend the use of the robust method under the working independence assumption. We illustrate the proposed method through 2 meta-analyses.

Keywords: correlation; multivariate meta-analysis; random effects; robust variance estimator.

MeSH terms

  • Algorithms
  • Biomarkers, Tumor / metabolism
  • Computer Simulation
  • Data Collection
  • Data Interpretation, Statistical
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Likelihood Functions
  • Meta-Analysis as Topic*
  • Models, Statistical
  • Multivariate Analysis*
  • N-Myc Proto-Oncogene Protein / metabolism
  • Neuroblastoma / metabolism
  • Research Design
  • Sample Size
  • Statistics as Topic*
  • Stomach Neoplasms / surgery


  • Biomarkers, Tumor
  • MYCN protein, human
  • N-Myc Proto-Oncogene Protein