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American Journal of Epidemiology Advance Access originally published online on December 3, 2007
American Journal of Epidemiology 2008 167(4):492-499; doi:10.1093/aje/kwm324
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American Journal of Epidemiology © The Author 2007. Published by the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org.

PRACTICE OF EPIDEMIOLOGY

Immortal Time Bias in Pharmacoepidemiology

Samy Suissa

From the Department of Epidemiology and Biostatistics, and Department of Medicine, McGill University, Montreal, Canada

Correspondence to Dr. Samy Suissa, McGill Pharmacoepidemiology Research Unit, Royal Victoria Hospital, 687 Pine Avenue West, Ross 4.29, Montreal, Québec, Canada H3A 1A1 (e-mail: samy.suissa{at}clinepi.mcgill.ca).

Received for publication December 22, 2006. Accepted for publication October 3, 2007.

Immortal time is a span of cohort follow-up during which, because of exposure definition, the outcome under study could not occur. Bias from immortal time was first identified in the 1970s in epidemiology in the context of cohort studies of the survival benefit of heart transplantation. It recently resurfaced in pharmacoepidemiology, with several observational studies reporting that various medications can be extremely effective at reducing morbidity and mortality. These studies, while using different cohort designs, all involved some form of immortal time and the corresponding bias. In this paper, the author describes various cohort study designs leading to this bias, quantifies its magnitude under different survival distributions, and illustrates it by using data from a cohort of lung cancer patients. The author shows that for time-based, event-based, and exposure-based cohort definitions, the bias in the rate ratio resulting from misclassified or excluded immortal time increases proportionately to the duration of immortal time. The bias is more pronounced with a decreasing hazard function for the outcome event, as illustrated with the Weibull distribution compared with a constant hazard from the exponential distribution. In conclusion, observational studies of drug benefit in which computerized databases are used must be designed and analyzed properly to avoid immortal time bias.

bias (epidemiology); cohort studies; databases; epidemiologic methods; pharmaceutical preparations; relative biological effectiveness; statistics; treatment outcome

Abbreviations: CI, confidence interval; COPD, chronic obstructive pulmonary disease; HR, hazard ratio; RR, rate ratio


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