Stepwise-Hierarchical Pooled Analysis for Synergistic Interpretation of Meta-analyses Involving Randomized and Observational Studies: Methodology Development.

Background: The necessity of including observational studies in meta-analyses has been discussed in the literature, but a synergistic analysis method for combining randomized and observational studies has not been reported. Observational studies differ in validity depending on the degree of the confounders' influence. Combining interpretations may be challenging, especially if the statistical directions are similar but the magnitude of the pooled results are different between randomized and observational studies (the "gray zone").

Objective: To overcome these hindrances, in this study, we aim to introduce a logical method for clinical interpretation of randomized and observational studies.

Methods: We designed a stepwise-hierarchical pooled analysis method to analyze both distribution trends and individual pooled results by dividing the included studies into at least three stages (eg, all studies, balanced studies, and randomized studies).

Results: According to the model, the validity of a hypothesis is mostly based on the pooled results of randomized studies (the highest stage). Ascending patterns in which effect size and statistical significance increase gradually with stage strengthen the validity of the hypothesis; in this case, the effect size of the observational studies is lower than that of the true effect (eg, because of the uncontrolled effect of negative confounders). Descending patterns in which decreasing effect size and statistical significance gradually weaken the validity of the hypothesis suggest that the effect size and statistical significance of the observational studies is larger than the true effect (eg, because of researchers' bias).

Conclusions: We recommend using the stepwise-hierarchical pooled analysis approach for meta-analyses involving randomized and observational studies.