GRADE Guidelines: 29. Rating the certainty in time-to-event outcomes-Study limitations due to censoring of participants with missing data in intervention studies

Marius Goldkuhle; Ralf Bender; Elie A Akl; Elvira C van Dalen; Sarah Nevitt; Reem A Mustafa; Gordon H Guyatt; Marialene Trivella; Benjamin Djulbegovic; Holger Schünemann; Michela Cinquini; Nina Kreuzberger; Nicole Skoetz; GRADE Working Group

doi:10.1016/j.jclinepi.2020.09.017

GRADE Guidelines: 29. Rating the certainty in time-to-event outcomes-Study limitations due to censoring of participants with missing data in intervention studies

J Clin Epidemiol. 2021 Jan:129:126-137. doi: 10.1016/j.jclinepi.2020.09.017. Epub 2020 Sep 30.

Authors

Affiliations

¹ Department of Internal Medicine, University of Cologne, Faculty of Medicine and University Hospital Cologne, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Kerpener Str. 62, 50937, Cologne, Germany. Electronic address: marius.goldkuhle@uk-koeln.de.
² Department of Medical Biometry, Institute for Quality and Efficiency in Health Care, Im Mediapark 8, D-50670 Cologne, Germany.
³ Department of Internal Medicine, American University of Beirut, P.O.Box 11-0236, Lebanon, Canada; Department of Health Research Methods, Evidence, and Impact, McMaster University, 1280 Main St. W., Hamilton, Ontario, L8S 4K1, Canada.
⁴ Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584CS, Utrecht, The Netherlands.
⁵ Department of Biostatistics, University of Liverpool, Block F, Waterhouse Building, 1-5 Brownlow Street, Liverpool, L69 3GL, UK.
⁶ Department of Health Research Methods, Evidence, and Impact, McMaster University, 1280 Main St. W., Hamilton, Ontario, L8S 4K1, Canada; Department of Medicine, University of Kansas Health System, 3901 Rainbow Blvd, MS3002, Kansas City, KS, 66160, USA.
⁷ Department of Health Research Methods, Evidence, and Impact, McMaster University, 1280 Main St. W., Hamilton, Ontario, L8S 4K1, Canada; Department of Medicine, McMaster University, 1280 Main St. W., Hamilton, Ontario, L8S 4K1, Canada; McMaster GRADE Centre & Michael G DeGroote Cochrane Canada Centre, McMaster University, Hamilton, Ontario, Canada.
⁸ Centre for Statistics in Medicine, University of Oxford, Botnar Research Centre, Windmill Rd, Oxford, OX3 7LD, UK.
⁹ City of Hope, 1500 Duarte Rd, Duarte, CA, 91010, USA.
¹⁰ Unit of Systematic Reviews and Guidelines Production, Mario Negri Institute for Pharmacological Research IRCCS, Via Giuseppe La Masa 19, 20156, Milan, Italy.
¹¹ Department of Internal Medicine, University of Cologne, Faculty of Medicine and University Hospital Cologne, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Kerpener Str. 62, 50937, Cologne, Germany.

PMID: 33007458
DOI: 10.1016/j.jclinepi.2020.09.017

Abstract

Objectives: To provide Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) guidance for the consideration of study limitations (risk of bias) due to missing participant outcome data for time-to-event outcomes in intervention studies.

Study design and setting: We developed this guidance through an iterative process that included membership consultation, feedback, presentation, and iterative discussion at meetings of the GRADE working group.

Results: The GRADE working group has published guidance on how to account for missing participant outcome data in binary and continuous outcomes. When analyzing time-to-event outcomes (e.g., overall survival and time-to-treatment failure) data of participants for whom the outcome of interest (e.g., death and relapse) has not been observed are dealt with through censoring. To do so, standard methods require that censored individuals are representative for those remaining in the study. Two types of censoring can be distinguished, end of study censoring and censoring because of missing data, commonly named loss to follow-up censoring. However, both types are not distinguishable with the usual information on censoring available to review authors. Dealing with individuals for whom data are missing during follow-up in the same way as individuals for whom full follow-up is available at the end of the study increases the risk of bias. Considerable differences in the treatment arms in the distribution of censoring over time (early versus late censoring), the overall degree of missing follow-up data, and the reasons why individuals were lost to follow-up may reduce the certainty in the study results. With often only very limited data available, review and guideline authors are required to make transparent and well-considered judgments when judging risk of bias of individual studies and then come to an overall grading decision for the entire body of evidence.

Conclusion: Concern for risk of bias resulting from censoring of participants for whom follow-up data are missing in the underlying studies of a body of evidence can be expressed in the study limitations (risk of bias) domain of the GRADE approach.

Keywords: Censoring missing data; Certainty of the evidence; GRADE; Loss to follow-up; Risk of bias; Survival analysis; Time-to-event outcomes.

MeSH terms

Bias
Clinical Studies as Topic* / methods
Clinical Studies as Topic* / standards
GRADE Approach*
Humans
Lost to Follow-Up
Outcome Assessment, Health Care / methods
Outcome Assessment, Health Care / organization & administration
Patient Dropouts
Research Design / standards
Risk Assessment