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
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
PRACTICE OF EPIDEMIOLOGY |
Immortal Time Bias in Pharmacoepidemiology
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
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  F. D. Wolinsky, S. E. Bentler, L. Liu, J. F. Geweke, E. A. Cook, M. Obrizan, E. A. Chrischilles, K. B. Wright, M. P. Jones, G. E. Rosenthal, et al. Continuity of Care with a Primary Care Physician and Mortality in Older Adults J Gerontol A Biol Sci Med Sci, December 8, 2009; (2009) glp188v1. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. A. Rassen, N. K. Choudhry, J. Avorn, and S. Schneeweiss Cardiovascular Outcomes and Mortality in Patients Using Clopidogrel With Proton Pump Inhibitors After Percutaneous Coronary Intervention or Acute Coronary Syndrome Circulation, December 8, 2009; 120(23): 2322 - 2329. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. L Hui, W. Lide, J. Chan, J. Schottinger, M. Yoshinaga, and M. Millares Association Between Exposure to Topical Tacrolimus or Pimecrolimus and Cancers Ann. Pharmacother., December 1, 2009; 43(12): 1956 - 1963. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Ferrer, A. Artigas, D. Suarez, E. Palencia, M. M. Levy, A. Arenzana, X. L. Perez, J.-M. Sirvent, and for the Edusepsis Study Group Effectiveness of Treatments for Severe Sepsis: A Prospective, Multicenter, Observational Study Am. J. Respir. Crit. Care Med., November 1, 2009; 180(9): 861 - 866. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Suissa THE AUTHOR REPLIES Am. J. Epidemiol., September 1, 2009; 170(5): 668 - 669. [Full Text] [PDF]
|
|
|
|
|
|
V. A. Kiri and G. MacKenzie RE: "IMMORTAL TIME BIAS IN PHARMACOEPIDEMIOLOGY" Am. J. Epidemiol., September 1, 2009; 170(5): 667 - 668. [Full Text] [PDF]
|
|
|
|
 |
|
 T. L. Lash and S. R. Cole Immortal Person-Time in Studies of Cancer Outcomes J. Clin. Oncol., August 10, 2009; 27(23): e55 - e56. [Full Text] [PDF]
|
|
|
|
 |
|
 T. A. Lee, C. Wilke, M. Joo, K. T. Stroupe, J. A. Krishnan, G. T. Schumock, and A. S. Pickard Outcomes Associated With Tiotropium Use in Patients With Chronic Obstructive Pulmonary Disease Arch Intern Med, August 10, 2009; 169(15): 1403 - 1410. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Gardarsdottir, T. C. Egberts, J. J. Stolker, and E. R. Heerdink Duration of Antidepressant Drug Treatment and Its Influence on Risk of Relapse/Recurrence: Immortal and Neglected Time Bias Am. J. Epidemiol., August 1, 2009; 170(3): 280 - 285. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Suissa and P. J. Barnes Inhaled corticosteroids in COPD: the case against Eur. Respir. J., July 1, 2009; 34(1): 13 - 16. [Full Text] [PDF]
|
|
|
|
 |
|
 P. M. Ho, J. S. Rumsfeld, and L. Wang Adverse Outcomes Associated With Use of Proton Pump Inhibitors and Clopidogrel--Reply JAMA, July 1, 2009; 302(1): 31 - 31. [Full Text] [PDF]
|
|
|
|
|
|
V. Schneider-Lindner, K. B. Filion, and J. M. Brophy Adverse Outcomes Associated With Use of Proton Pump Inhibitors and Clopidogrel JAMA, July 1, 2009; 302(1): 29 - 30. [Full Text] [PDF]
|
|
|
|
 |
|
 M. M. Kitahata, S. J. Gange, A. G. Abraham, B. Merriman, M. S. Saag, A. C. Justice, R. S. Hogg, S. G. Deeks, J. J. Eron, J. T. Brooks, et al. Effect of Early versus Deferred Antiretroviral Therapy for HIV on Survival N. Engl. J. Med., April 30, 2009; 360(18): 1815 - 1826. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Suissa Statistical methods in pharmacoepidemiology: advances and challenges Statistical Methods in Medical Research, February 1, 2009; 18(1): 3 - 6. [PDF]
|
|
|
|
|
|
C. P. Kovesdy, J. E. Anderson, and K. Kalantar-Zadeh Vitamin D Use and Mortality in Chronic Kidney Disease: Immortal Time Bias--Reply Arch Intern Med, November 24, 2008; 168(21): 2385 - 2386. [Full Text] [PDF]
|
|
|
|
 |
|
 S Suissa and P Ernst Biases in the observational study of {beta} blockers in COPD Thorax, November 1, 2008; 63(11): 1026 - 1027. [Full Text] [PDF]
|
|
|
|
 |
|
 S. S. Daskalopoulou, J. A.C. Delaney, K. B. Filion, J. M. Brophy, N. E. Mayo, and S. Suissa Discontinuation of statin therapy following an acute myocardial infarction: a population-based study Eur. Heart J., September 1, 2008; 29(17): 2083 - 2091. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. A. McAlister, D. T. Eurich, S. R. Majumdar, and J. A. Johnson The risk of heart failure in patients with type 2 diabetes treated with oral agent monotherapy Eur J Heart Fail, July 1, 2008; 10(7): 703 - 708. [Abstract] [Full Text] [PDF]
|
|