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Estimating the effect of immortal-time bias in urological research: a case example of testosterone-replacement therapy

Christopher J.D. Wallis, Refik Saskin, Steven A. Narod, Calvin Law, Girish S. Kulkarni, Arun Seth, Robert K. Nam

  • First published: 
  • DOI: 10.1111/bju.13918


To quantify the effect of immortal-time bias in an observational study examining the effect of cumulative testosterone exposure on mortality.

Patients and Methods

We used a population-based matched cohort study of men aged ≥66 years, newly treated with testosterone-replacement therapy (TRT), and matched-controls from 2007 to 2012 in Ontario, Canada to quantify the effects of immortal-time bias. We used generalised estimating equations to determine the association between cumulative TRT exposure and mortality. Results produced by models using time-fixed and time-varying exposures were compared. Further, we undertook a systematic review of PubMed to identify studies addressing immortal-time bias or time-varying exposures in the urological literature and qualitatively summated these.


Among 10 311 TRT-exposed men and 28 029 controls, the use of a time-varying exposure resulted in the attenuation of treatment effects compared with an analysis that did not account for immortal-time bias. While both analyses showed a decreased risk of death for patients in the highest tertile of TRT exposure, the effect was overestimated when using a time-fixed analysis (adjusted hazard ratio [aHR] 0.56, 95% confidence interval [CI]: 0.52–0.61) when compared to a time-varying analysis (aHR 0.67, 95% CI: 0.62–0.73). Of the 1 241 studies employing survival analysis identified in the literature, nine manuscripts met criteria for inclusion. Of these, five used a time-varying analytical method. Each of these was a large, population-based retrospective cohort study assessing potential harms of pharmacological agents.


Where exposures vary over time, a time-varying exposure is necessary to draw meaningful conclusions. Failure to use a time-varying analysis will result in overestimation of a beneficial effect. However, time-varying exposures are uncommonly utilised among manuscripts published in prominent urological journals.

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