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A Guideline for Reporting Mediation Analyses of Randomized Trials and Observational StudiesThe AGReMA Statement

Educational Objective
To understand the elements of studies that use mediation analyses.
1 Credit CME
Key Points

Question  What information should be reported in studies that include mediation analyses of randomized trials and observational studies?

Findings  An international Delphi and consensus process (using the Enhancing Quality and Transparency of Health Research methodological framework) generated a 25-item reporting guideline for primary reports of mediation analyses and a 9-item short form for secondary reports of mediation analyses.

Meaning  Using the 25-item or 9-item reporting guideline may facilitate peer review and could help ensure that studies using mediation analyses are completely, accurately, and transparently reported.


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.

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Article Information

Accepted for Publication: August 4, 2021.

Corresponding Author: Hopin Lee, PhD, Botnar Research Centre, Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Sciences, University of Oxford, Windmill Road, Oxford OX3 7LD, England (hopin.lee@ndorms.ox.ac.uk).

The AGReMA group authors: A. Russell Localio, PhD; Ludo van Amelsvoort, PhD; Eliseo Guallar, PhD; Judith Rijnhart, PhD; Kimberley Goldsmith, PhD; Amanda J. Fairchild, PhD; Cara C. Lewis, PhD; Steven J. Kamper, PhD; Christopher M. Williams, PhD; Nicholas Henschke, PhD.

Affiliations of The AGReMA group authors: School of Medicine and Public Health, University of Newcastle, Callaghan, Australia (Williams); Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia (Localio); Associate Editor, Annals of Internal Medicine (Localio); Faculty of Health, Medicine, and Life Sciences, Maastricht University, Maastricht, the Netherlands (van Amelsvoort); Assoicate Editor, Journal of Clinical Epidemiology (van Amelsvoort); Welch Center for Prevention, Epidemiology, and Clinical Research, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland (Guallar); Deputy Editor, Annals of Internal Medicine (Guallar); Department of Epidemiology and Data Science, Amsterdam Public Health Research Institute, Amsterdam University Medical Center, Amsterdam, the Netherlands (Rijnhart); Institute of Psychiatry, Psychology, and Neuroscience, King’s College London, London, England (Goldsmith); Department of Psychology, University of South Carolina, Columbia (Fairchild); Kaiser Permanente Washington Health Research Institute, Seattle (Lewis); School of Health Sciences, University of Sydney, Sydney, Australia (Kamper); Nepean Blue Mountains Local Health District, Kingswood, Australia (Kamper); School of Public Health, University of Sydney, Sydney, Australia (Henschke).

Author Contributions: Drs Lee and Cashin had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Lee, Cashin, Lamb, Hopewell, VanderWeele, MacKinnon, Mansell, Golub, McAuley, Localio, van Amelsvoort, Guallar, Fairchild, Kamper, Williams, Henschke.

Acquisition, analysis, or interpretation of data: Lee, Cashin, Lamb, Hopewell, Vansteelandt, VanderWeele, MacKinnon, Collins, McAuley, Localio, van Amelsvoort, Rijnhart, Goldsmith, Lewis, Williams, Henschke.

Drafting of the manuscript: Lee, Cashin, Lamb, Hopewell, Mansell, Collins, Golub, McAuley.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Lee, MacKinnon, Collins, Localio.

Obtained funding: Lee, McAuley, Kamper, Henschke.

Administrative, technical, or material support: Lee, Cashin, VanderWeele, Fairchild, Henschke.

Supervision: Lee, Lamb, Vansteelandt, MacKinnon, McAuley, Kamper, Williams, Henschke.

Conflict of Interest Disclosures: Dr Lamb reported being a member of boards for the Health Technology Assessment (additional capacity funding board, end of life care and add-on studies board, prioritization group board, and trauma board). Dr VanderWeele reported receiving personal fees from Statistical Horizons. Dr Localio reported receiving grants from the Annals of Internal Medicine. Dr Guallar reported receiving personal fees from the American College of Physicians (Annals of Internal Medicine). Dr Kamper reported receiving grants from the National Health and Medical Research Council of Australia Fellowship. No other disclosures were reported.

Funding/Support: 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.

Role of the Funders/Sponsors: The funders/sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Disclaimer: Dr Golub is Deputy Editor of JAMA, but he was not involved in any of the decisions regarding review of the manuscript or its acceptance.

Additional Contributions: We thank Anika Jamieson, BBA (Neuroscience Research Australia), for administrative support and Rob Froud, PhD (director and shareholder of Clinvivo), and the wider Clinvivo team for their services in executing the Delphi study. Ms Jamieson and Dr Froud were not compensated for their roles. The Clinvivo team was compensated for their role in the study. We acknowledge the contributions made by the Delphi panelists, the AGReMA international consensus meeting participants, the AGReMA external review experts (eTable 1 in the Supplement), and the UK EQUATOR Centre for administrative support.

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