Multivariate meta-analysis: a robust approach based on the theory of U-statistic.

Meta-analysis is the methodology for combining findings from similar research studies asking the same question. When the question of interest involves multiple outcomes, multivariate meta-analysis is used to synthesize the outcomes simultaneously taking into account the correlation between the outcomes. Likelihood-based approaches, in particular restricted maximum likelihood (REML) method, are commonly utilized in this context. REML assumes a multivariate normal distribution for the random-effects model. This assumption is difficult to verify, especially for meta-analysis with small number of component studies. The use of REML also requires iterative estimation between parameters, needing moderately high computation time, especially when the dimension of outcomes is large. A multivariate method of moments (MMM) is available and is shown to perform equally well to REML. However, there is a lack of information on the performance of these two methods when the true data distribution is far from normality. In this paper, we propose a new nonparametric and non-iterative method for multivariate meta-analysis on the basis of the theory of U-statistic and compare the properties of these three procedures under both normal and skewed data through simulation studies. It is shown that the effect on estimates from REML because of non-normal data distribution is marginal and that the estimates from MMM and U-statistic-based approaches are very similar. Therefore, we conclude that for performing multivariate meta-analysis, the U-statistic estimation procedure is a viable alternative to REML and MMM. Easy implementation of all three methods are illustrated by their application to data from two published meta-analysis from the fields of hip fracture and periodontal disease. We discuss ideas for future research based on U-statistic for testing significance of between-study heterogeneity and for extending the work to meta-regression setting.