A Guideline for Reporting Mediation Analyses of Randomized Trials and Observational Studies: The AGReMA Statement

Hopin Lee, Aidan G. Cashin, Sarah E. Lamb, Sally Hopewell, Stijn Vansteelandt, Tyler J. VanderWeele, David P. MacKinnon, Gemma Mansell, Gary S. Collins, Robert M. Golub, James H. McAuley, A. Russell Localio, Ludo van Amelsvoort, Eliseo Guallar, Judith Rijnhart, Kimberley Goldsmith, Amanda J. Fairchild, Cara C. Lewis, Steven J. Kamper, Christopher M. WilliamsNicholas Henschke

Research output: Contribution to journalArticlepeer-review


IMPORTANCE Mediation analyses of randomized trials and observational studies can generate
evidence about the mechanisms by which interventions and exposures may influence health
outcomes. Publications of mediation analyses are increasing, but the quality of their reporting
is suboptimal.
OBJECTIVE To develop international, consensus-based guidance for the reporting of
mediation analyses of randomized trials and observational studies (A Guideline for Reporting
Mediation Analyses; AGReMA).
DESIGN, SETTING, AND PARTICIPANTS The AGReMA statement was developed using the
Enhancing Quality and Transparency of Health Research (EQUATOR) methodological
framework for developing reporting guidelines. The guideline development process included
(1) an overview of systematic reviews to assess the need for a reporting guideline; (2) review
of systematic reviews of relevant evidence on reporting mediation analyses; (3) conducting
a Delphi survey with panel members that included methodologists, statisticians, clinical
trialists, epidemiologists, psychologists, applied clinical researchers, clinicians,
implementation scientists, evidence synthesis experts, representatives from the EQUATOR
Network, and journal editors (n = 19; June-November 2019); (4) having a consensus meeting
(n = 15; April 28-29, 2020); and (5) conducting a 4-week external review and pilot test that
included methodologists and potential users of AGReMA (n = 21; November 2020).
RESULTS A previously reported overview of 54 systematic reviews of mediation studies
demonstrated the need for a reporting guideline. Thirty-three potential reporting items were
identified from 3 systematic reviews of mediation studies. Over 3 rounds, the Delphi panelists
ranked the importance of these items, provided 60 qualitative comments for item
refinement and prioritization, and suggested new items for consideration. All items were
reviewed during a 2-day consensus meeting and participants agreed on a 25-item AGReMA
statement for studies in which mediation analyses are the primary focus and a 9-item
short-form AGReMA statement for studies in which mediation analyses are a secondary
focus. These checklists were externally reviewed and pilot tested by 21 expert
methodologists and potential users, which led to minor adjustments and consolidation
of the checklists.
CONCLUSIONS AND RELEVANCE The AGReMA statement provides recommendations for
reporting primary and secondary mediation analyses of randomized trials and observational
studies. Improved reporting of studies that use mediation analyses could facilitate
peer review and help produce publications that are complete, accurate, transparent,
and reproducible.
Original languageEnglish
Pages (from-to)1045-1056
Number of pages12
JournalJAMA: Journal of the American Medical Association
Issue number11
Publication statusPublished - 21 Sept 2021

Bibliographical note

Funding: This work was supported by project funding from the University of California, Berkeley, Initiative for Transparency in the Social Sciences, a program of the Center for Effective Global Action, with support from the Laura and John Arnold Foundation. Dr Lee was supported by the Neil Hamilton Fairley Early Career Fellowship award APP1126767 from the National Health and Medical Research Council. Dr VanderWeele reported receiving grant R01CA222147 from the National Cancer Institute. Dr MacKinnon was supported by grant R37DA09757 from the National Institute on Drug Abuse. Dr Collins was supported by the NIHR Oxford Biomedical Research Centre and programme grant C49297/A27294 from Cancer Research UK.


  • General Medicine


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