GRADE guidance 38: updated guidance for rating up certainty of evidence due to a dose-response gradient

Introduction: This updated guidance from the Grading of Recommendations Assessment, Development, and Evaluation addresses rating up certainty of evidence due to a dose-response gradient (DRG) observed in synthesis of intervention and exposure studies. Study design and setting: This guidance was developed using iterative discussions and consensus in multiple meetings and was presented to attendees of the Grading of Recommendations Assessment, Development, and Evaluation Working Group meeting for feedback in November 2022 and for final approval in May 2023. Results: The guidance consists of two steps. The first is to determine whether the DRG is credible. We describe five items for assessing credibility: a) is DRG identified using a proper analytical approach; b) is confounding the cause of the DRG; c) is there serious concern about ecological bias; d) is the DRG consistent across studies; and e) is there indirect evidence supporting the DRG. The first two of these items are the most critical. If the DRG was judged to be credible, then the second step is to apply the DRG domain and consider rating up, but only by one level due to the concern about residual confounding. Conclusion: Systematic review authors should only rate up certainty in evidence when a DRG is deemed credible.