Meta-analysis of absolute mean differences from randomised trials with treatment-related clustering associated with care providers

Nesting of patients within care providers in trials of physical and talking therapies creates an additional level within the design. The statistical implications of this are analogous to those of cluster randomised trials, except that the clustering effect may interact with treatment and can be restricted to one or more of the arms. The statistical model that is recommended at the trial level includes a random effect for the care provider but allows the provider and patient level variances to differ across arms. Evidence suggests that, while potentially important, such within-trial clustering effects have rarely been taken into account in trials and do not appear to have been considered in meta-analyses of these trials. This paper describes summary measures and individual-patient-data methods for meta-analysing absolute mean differences from randomised trials with two-level nested clustering effects, contrasting fixed and random effects meta-analysis models. It extends methods for incorporating trials with unequal variances and homogeneous clustering to allow for between-arm and between-trial heterogeneity in intra-class correlation coefficient estimates. The work is motivated by a meta-analysis of trials of counselling in primary care, where the control is no counselling and the outcome is the Beck Depression Inventory. Assuming equal counsellor intra-class correlation coefficients across trials, the recommended random-effects heteroscedastic model gave a pooled absolute mean difference of −2.53 (95% CI −5.33 to 0.27) using summary measures and −2.51 (95% CI −5.35 to 0.33) with the individual-patient-data. Pooled estimates were consistently below a minimally important clinical difference of four to five points on the Beck Depression Inventory.