Table 2.

Quality assessment in included studies.

1. Planning	Olbrecht, et al. [31]	Bonnert, et al. [32]	Lalouni, et al. [29]	Levy, et al. [28]	Kashikar-Zuck, et al. [33]	Wicksell, et al. [30]
1.1. Was the mediation analyses planned a priori in the trial protocol?	✘	✓	✓	✘	✘	✘
1.2.1. Was the choice of mediators based on clinical rationale underlying the mechanisms through which the treatment affects the outcome?	✓	✓	✓	✓	✓	✓
1.2.2. Was the choice of mediators based on independent data?	✘	✓	✓	✓	✓	✓
1.3.1. Was there a plan to collect pre- and post-randomization confounders of the exposure-mediator relationship?	✓	n/a	n/a	n/a	n/a	n/a
1.3.2. Was there a plan to collect pre- and post-randomization confounders of the mediator-mediator relationship?	n/a	✘	✘	✘	✘	✘
1.3.3. Was there a plan to collect pre- and post-randomization confounders of the mediator-outcome relationship?	✓	✘	✘	✘	✘	✘
1.4.1. Were the mediators measured prior to the outcome to assure the causal interpretation of the findings?	✓	✓	✓	✓	✓	✓
1.4.2. Was the mediator(s) measured repeatedly?	✘	✓	✓	✘	✘	✘
1.5. Was a causal diagram reported, underlying the causal relationship of the treatment, mediator(s) and outcome?	✓	✓	✓	✓	✘	✘
1.6. Was the sample size for the mediation analysis estimated?	✘	✘	✘	✘	✘	✘
1.7. Was the conduct of a mediation analysis dependent on whether a statistically significant intention-to-treat treatment effect was found?	?	?	?	?	?	?
‘Planning’ domain summary score	5/10	6/10	6/10	4/10	3/10	3/10
2. Conduct
2.1.1 Was multiple imputation (or other valid approaches) used to handle missing data?	✓	✓	✓	✓	n/a	✘
2.1.2 If a complete-case analysis was used, did they adjust for baseline covariates that were differentially distributed between responders and non-responders?	✓	n/a	n/a	n/a	n/a	?
2.1.3 Was a sensitivity analysis conducted to assess the impact of different approaches on the findings?	✘	✘	✘	✘	n/a	✘
2.2 Does the study report separate analyses for separate mediators?	n/a	✓	✓	✓	✓	✓
2.3 Does the study use an appropriate framework for analysis?	✓	✓	✓	✓	✓	✓
2.4.1 Does the study evaluate the goodness-of-fit of each model?	✘	✘	✘	✘	✘	✘
2.4.2 Does the study assess potential interaction(s) between treatment and confounding factors, treatment and mediator, mediator and mediator in the mediator and outcome models?	✘	✘	✘	✘	✘	✘
2.5.1a Does the study adjust for exposure-mediator and confounders?	✓	n/a	n/a	n/a	n/a	n/a
2.5.2 Does the study adjust for mediator-mediator confounders?	n/a	✘	✘	✘	✘	✘
2.5.3 Does the study adjust for mediator-outcome confounders?	✓	✓	✘	✓	✘	✘
2.6.1 Does the study perform sensitivity analysis to assess sensitivity of the results to the assumption of no measured mediator-mediator or mediator-outcome confounder?	✘	✘	✘	✘	✘	✘
2.6.2 Does the study perform sensitivity analysis to assess sensitivity of the results to potential measurement errors of the mediators?	✘	✘	✘	✘	✘	✘
2.7 Does the study use apt strategies when some of the mediator-mediator or mediator-outcome confounders are potentially affected by the treatment (e.g., by considering confounders as mediators themselves)?	✘	✘	✘	✘	✘	✘
‘Conduct’ domain summary score	5/11	4/11	3/11	4/11	2/9	2/12
3. Reporting
3.1.1. Does the study report the approaches used for mediation analysis?	✓	✓	✓	✓	✓	✓
3.1.2. Does the study provide a causal diagram that underlies the analysis?	✓	✓	✓	✓	✘	✘
3.2.1. Does the study report the sample size calculation?	✘	✘	✘	✘	✘	✘
3.2.2. Does the study report the actual sample size of the mediation analysis?	✓	✓	✓	✓	✓	✓
3.2.3. Does the study report how missing data is handled?	✓	✓	✓	✓	n/a	✘
3.3. Does the study report all confounders considered and adjusted for in the analysis?	✓	✘	✘	✓	✘	✘
3.4.1. Does the study report the model building procedure and the final form of all models used in the analysis?	✘	✘	✘	✘	✘	✘
3.4.2. Does the study report the goodness-of-fit of the models?	✘	✘	✘	✘	✘	✘
3.5. Does the study report the point estimates and the confidence intervals of the different direct, indirect and total treatment effects?	✘	✘	✘	✘	✘	✘
3.6. Does the study report the methods and results of all sensitivity and other additional analyses (in the main paper or appendices)?	n/a	✓	n/a	n/a	n/a	✓
3.7. Does the study discuss the validity of all causal assumptions underlying the analysis (in the main paper or appendices)?	✘	✘	✓	✘	✘	✘
‘Reporting’ domain summary score	5/10	5/11	5/10	5/10	2/9	3/11