How should meta-regression analyses be undertaken and interpreted?

Appropriate methods for meta-regression applied to a set of clinical trials, and the limitations and pitfalls in interpretation, are insufficiently recognized. Here we summarize recent research focusing on these issues, and consider three published examples of meta-regression in the light of this work. One principal methodological issue is that meta-regression should be weighted to take account of both within-trial variances of treatment effects and the residual between-trial heterogeneity (that is, heterogeneity not explained by the covariates in the regression). This corresponds to random effects meta-regression. The associations derived from meta-regressions are observational, and have a weaker interpretation than the causal relationships derived from randomized comparisons. This applies particularly when averages of patient characteristics in each trial are used as covariates in the regression. Data dredging is the main pitfall in reaching reliable conclusions from meta-regression. It can only be avoided by prespecification of covariates that will be investigated as potential sources of heterogeneity. However, in practice this is not always easy to achieve. The examples considered in this paper show the tension between the scientific rationale for using meta-regression and the difficult interpretative problems to which such analyses are prone.