Immortal Time Bias in Epidemiology
Purpose of Review
Immortal time occurs when study subjects’ person-time is misclassified. For example, if exposure is assigned over time, but treated as a binary “ever-exposed” variable, subjects in the exposed group are “immortal” prior to their exposure. We describe immortal time and the context in which it introduces bias and describe several approaches to avoid immortal time bias via design or mitigate it through analysis.
Several authors have described examples of immortal time bias in clinical epidemiology, pharmacoepidemiology, and perinatal epidemiology. Solutions to immortal time bias include analyses that appropriately account for time-varying exposure, and design solutions that align exposure with the start of follow-up.
Immortal time bias is pervasive in epidemiology. It can cause substantial bias. It is, however, easily avoided and can be controlled using appropriate analytic and design strategies.
KeywordsImmortal time Time-varying exposure Target trial
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no conflict of interest.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Papers of particular interest, published recently, have been highlighted as: • Of importance
- 2.Farr W. Vital statistics. London: The Sanitary Institute; 1885.Google Scholar
- 6.Weberpals J, Jansen L, Herk-Sukel MPP, Kuiper JG, Aarts MJ, Vissers PAJ, et al. Immortal time bias in pharmacoepidemiological studies on cancer patient survival: empirical illustration for beta-blocker use in four cancers with different prognosis. Eur J Epidemiol. 2017;3(3):1–13.Google Scholar
- 9.Vazquez-Benitez G, Kharbanda EO, Naleway AL, Lipkind H, Sukumaran L, McCarthy NL, et al. Risk of preterm or small-for-gestational-age birth after influenza vaccination during pregnancy: caveats when conducting retrospective observational studies. Am J Epidemiol. 2016:kww043–11.Google Scholar
- 11.• Hutcheon JA, Kuret V, Joseph KS, Sabr Y, Lim K. Immortal time bias in the study of stillbirth risk factors. Epidemiology. 2013;24(6):787–90 This paper shows the occurrence of immortal time bias in pregnancy, and in other cases where occurrence of the outcome affects time at risk.CrossRefGoogle Scholar
- 14.Mi X, Hammill BG, Curtis LH, Lai EC-C, Setoguchi S. Use of the landmark method to address immortal person-time bias in comparative effectiveness research: a simulation study. Stat Med. 2016:1–13.Google Scholar
- 16.• Hernán MA, Sauer BC, Hernández-Diaz S, Platt RW, Shrier I. Specifying a target trial prevents immortal time bias and other self-inflicted injuries in observational analyses. J Clin Epidemiol. 2016;79(C):70–5 This paper describes how the use of a target randomized trial as a model for an observational design can help understand the causes of immortal time bias and prevent it.CrossRefGoogle Scholar
- 18.Brookhart MA. Counterpoint: the treatment decision design. Am J Epidemiol. 2015:kwv214–6.Google Scholar