A critical review of methods for the assessment of patient-level interactions in individual participant data meta-analysis of randomized trials, and guidance for practitioners

Abstract Objective Treatments may be more effective in some patients than others, and individual participant data (IPD) meta-analysis of randomized trials provides perhaps the best method of investigating treatment-covariate interactions. Various methods are used; we provide a comprehensive critique and develop guidance on method selection. Study Design and Setting We searched MEDLINE to identify all frequentist methods and appraised them for simplicity, risk of bias, and power. IPD data sets were reanalyzed. Results Four methodological categories were identified: PWT: pooling of within-trial covariate interactions; OSM: “one-stage” model with a treatment-covariate interaction term; TDCS: testing for difference between covariate subgroups in their pooled treatment effects; and CWA: combining PWT with meta-regression. Distinguishing across- and within-trial information is important, as the former may be subject to ecological bias. A strategy is proposed for method selection in different circumstances; PWT or CWA are natural first steps. The OSM method allows for more complex analyses; TDCS should be avoided. Our reanalysis shows that different methods can lead to substantively different findings. Conclusion The choice of method for investigating interactions in IPD meta-analysis is driven mainly by whether across-trial information is considered for inclusion, a decision, which depends on balancing possible improvement in power with an increased risk of bias.