Development of the Instrument to assess the Credibility of Effect Modification Analyses (ICEMAN) in randomized controlled trials and meta-analyses

Stefan Schandelmaier; Matthias Briel; Ravi Varadhan; Christopher H Schmid; Niveditha Devasenapathy; Rodney A Hayward; Joel Gagnier; Michael Borenstein; Geert J M G van der Heijden; Issa J Dahabreh; Xin Sun; Willi Sauerbrei; Michael Walsh; John P A Ioannidis; Lehana Thabane; Gordon H Guyatt

doi:10.1503/cmaj.200077

Development of the Instrument to assess the Credibility of Effect Modification Analyses (ICEMAN) in randomized controlled trials and meta-analyses

CMAJ. 2020 Aug 10;192(32):E901-E906. doi: 10.1503/cmaj.200077.

Authors

Stefan Schandelmaier¹, Matthias Briel², Ravi Varadhan², Christopher H Schmid², Niveditha Devasenapathy², Rodney A Hayward², Joel Gagnier², Michael Borenstein², Geert J M G van der Heijden², Issa J Dahabreh², Xin Sun², Willi Sauerbrei², Michael Walsh², John P A Ioannidis², Lehana Thabane², Gordon H Guyatt²

Affiliations

¹ Departments of Health Research Methods, Evidence, and Impact (Schandelmaier, Briel, Walsh, Thabane, Guyatt), Medicine (Walsh, Guyatt), Pediatrics (Thabane) and Anesthesia (Thabane), McMaster University, Hamilton, Ont.; Institute for Clinical Epidemiology and Biostatistics (Schandelmaier, Briel), Department of Clinical Research, Basel University, Basel, Switzerland; Division of Biostatistics and Bioinformatics (Varadhan), Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Md.; Department of Biostatistics (Schmid), Brown University School of Public Health, Brown University, Providence, RI; Indian institute of Public Health-Delhi (Devasenapathy), Public Health Foundation of India, New Delhi, India; VA Center for Clinical Management and Research (Hayward); Department of Internal Medicine (Hayward), University of Michigan School of Medicine; Department of Orthopaedic Surgery (Gagnier), University of Michigan; Department of Epidemiology (Gagnier), School of Public Health, University of Michigan, Ann Arbor, Mich.; Biostat (Borenstein), Englewood, NJ; Department of Social Dentistry (van der Heijden), Academic Center for Dentistry Amsterdam, University of Amsterdam and VU University Amsterdam, Amsterdam, Netherlands; Center for Evidence Synthesis in Health (Dahabreh) and Departments of Health Services, Policy, and Practice (Dahabreh) and Epidemiology (Dahabreh), School of Public Health, Brown University, Providence, RI; Chinese Evidence-Based Medicine Center (Sun), West China Hospital, Sichuan University, Chengdu, China; Institute of Medical Biometry and Statistics (Sauerbrei), Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany; Population Health Research Institute (Walsh), Hamilton Health Sciences/McMaster University, Hamilton, Ont.; Departments of Medicine (Ioannidis), Health Research and Policy (Ioannidis) and Biomedical Data Science (Ioannidis), and Statistics and Meta-Research Innovation Center at Stanford (METRICS) (Ioannidis), Stanford University, Stanford, Calif.; Biostatistics Unit (Thabane), St. Joseph's Healthcare, Hamilton, Ont. [email protected].
² Departments of Health Research Methods, Evidence, and Impact (Schandelmaier, Briel, Walsh, Thabane, Guyatt), Medicine (Walsh, Guyatt), Pediatrics (Thabane) and Anesthesia (Thabane), McMaster University, Hamilton, Ont.; Institute for Clinical Epidemiology and Biostatistics (Schandelmaier, Briel), Department of Clinical Research, Basel University, Basel, Switzerland; Division of Biostatistics and Bioinformatics (Varadhan), Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Md.; Department of Biostatistics (Schmid), Brown University School of Public Health, Brown University, Providence, RI; Indian institute of Public Health-Delhi (Devasenapathy), Public Health Foundation of India, New Delhi, India; VA Center for Clinical Management and Research (Hayward); Department of Internal Medicine (Hayward), University of Michigan School of Medicine; Department of Orthopaedic Surgery (Gagnier), University of Michigan; Department of Epidemiology (Gagnier), School of Public Health, University of Michigan, Ann Arbor, Mich.; Biostat (Borenstein), Englewood, NJ; Department of Social Dentistry (van der Heijden), Academic Center for Dentistry Amsterdam, University of Amsterdam and VU University Amsterdam, Amsterdam, Netherlands; Center for Evidence Synthesis in Health (Dahabreh) and Departments of Health Services, Policy, and Practice (Dahabreh) and Epidemiology (Dahabreh), School of Public Health, Brown University, Providence, RI; Chinese Evidence-Based Medicine Center (Sun), West China Hospital, Sichuan University, Chengdu, China; Institute of Medical Biometry and Statistics (Sauerbrei), Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany; Population Health Research Institute (Walsh), Hamilton Health Sciences/McMaster University, Hamilton, Ont.; Departments of Medicine (Ioannidis), Health Research and Policy (Ioannidis) and Biomedical Data Science (Ioannidis), and Statistics and Meta-Research Innovation Center at Stanford (METRICS) (Ioannidis), Stanford University, Stanford, Calif.; Biostatistics Unit (Thabane), St. Joseph's Healthcare, Hamilton, Ont.

Abstract

Background: Most randomized controlled trials (RCTs) and meta-analyses of RCTs examine effect modification (also called a subgroup effect or interaction), in which the effect of an intervention varies by another variable (e.g., age or disease severity). Assessing the credibility of an apparent effect modification presents challenges; therefore, we developed the Instrument for assessing the Credibility of Effect Modification Analyses (ICEMAN).

Methods: To develop ICEMAN, we established a detailed concept; identified candidate credibility considerations in a systematic survey of the literature; together with experts, performed a consensus study to identify key considerations and develop them into instrument items; and refined the instrument based on feedback from trial investigators, systematic review authors and journal editors, who applied drafts of ICEMAN to published claims of effect modification.

Results: The final instrument consists of a set of preliminary considerations, core questions (5 for RCTs, 8 for meta-analyses) with 4 response options, 1 optional item for additional considerations and a rating of credibility on a visual analogue scale ranging from very low to high. An accompanying manual provides rationales, detailed instructions and examples from the literature. Seventeen potential users tested ICEMAN; their suggestions improved the user-friendliness of the instrument.

Interpretation: The Instrument for assessing the Credibility of Effect Modification Analyses offers explicit guidance for investigators, systematic reviewers, journal editors and others considering making a claim of effect modification or interpreting a claim made by others.

MeSH terms

Consensus
Humans
Meta-Analysis as Topic*
Randomized Controlled Trials as Topic*
Research Design / standards*