1932

Abstract

This article surveys results concerning the interpretation of the Cox hazard ratio in connection to causality in a randomized study with a time-to-event response. The Cox model is assumed to be correctly specified, and we investigate whether the typical end product of such an analysis, the estimated hazard ratio, has a causal interpretation as a hazard ratio. It has been pointed out that this is not possible due to selection. We provide more insight into the interpretation of hazard ratios and differences, investigating what can be learned about a treatment effect from the hazard ratio approaching unity after a certain period of time. The conclusion is that the Cox hazard ratio is not causally interpretable as a hazard ratio unless there is no treatment effect or an untestable and unrealistic assumption holds. We give a hazard ratio that has a causal interpretation and study its relationship to the Cox hazard ratio.

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2022-03-07
2024-05-03
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Literature Cited

  1. Aalen OO. 1989. A linear regression model for the analysis of life times. Stat. Med. 8:907–25
    [Google Scholar]
  2. Aalen OO, Cook RJ, Røysland K. 2015. Does Cox analysis of a randomized survival study yield a causal treatment effect?. Lifetime Data Anal. 21:4579–93
    [Google Scholar]
  3. Andersen PK, Borgan Ø, Gill RD, Keiding N. 1993. Statistical Models Based on Counting Processes New York: Springer
  4. Andersen PK, Perme MP, van Houwelingen HC, Cook RJ, Joly P et al. 2021. Analysis of time-to-event for observational studies: guidance to the use of intensity models. Stat. Med. 40:1185–211
    [Google Scholar]
  5. Bartlett JW, Morris TP, Stensrud MJ, Daniel RM, Vansteelandt SK, Burman CF. 2020. The hazards of period specific and weighted hazard ratios. Stat. Biopharm. Res. 12:4518–19
    [Google Scholar]
  6. Benkeser D, Carone M, Laan MJVD, Gilbert PB. 2017. Doubly robust nonparametric inference on the average treatment effect. Biometrika 104:4863–80
    [Google Scholar]
  7. Cox DR. 1972. Regression models and life-tables (with discussion). J. R. Stat. Soc. B 34:406–24
    [Google Scholar]
  8. Daniel R, Zhang J, Farewell D. 2021. Making apples from oranges: comparing noncollapsible effect estimators and their standard errors after adjustment for different covariate sets. Biom. J. 63:3528–57
    [Google Scholar]
  9. De Neve J, Gerds TA. 2020. On the interpretation of the hazard ratio in Cox regression. Biom. J. 62:3742–50
    [Google Scholar]
  10. Daz I, Colantuoni E, Hanley DF, Rosenblum M. 2019. Improved precision in the analysis of randomized trials with survival outcomes, without assuming proportional hazards. Lifetime Data Anal. 25:3439–68
    [Google Scholar]
  11. Hernán MA. 2004. A definition of causal effect for epidemiological research. J. Epidemiol. Community Health 58:4265–71
    [Google Scholar]
  12. Hernán MA. 2010. The hazards of hazard ratios. Epidemiology 21:113–15
    [Google Scholar]
  13. Hernán MA, Robins JM. 2020. Causal Inference Boca Raton, FL: Chapman & Hall/CRC
  14. Hernán MA, Taubman SL. 2008. Does obesity shorten life? The importance of well-defined interventions to answer causal questions. Int. J. Obes. 32:Suppl. 3S814
    [Google Scholar]
  15. Keiding N. 1998. Selection effects and nonproportional hazards in survival models and models for repeated events Rep., Dep. Biostat., Univ. Copenhagen Copenhagen, Den:.
  16. Lederle FA, Kyriakides TC, Stroupe KT, Freischlag JA, Padberg FT et al. 2019. Open versus endovascular repair of abdominal aortic aneurysm. N. Engl. J. Med. 380:222126–35
    [Google Scholar]
  17. Lin RS, Lin J, Roychoudhury S, Anderson KM, Hu T et al. 2020a. Alternative analysis methods for time to event endpoints under nonproportional hazards: a comparative analysis. Stat. Biopharm. Res. 12:2187–98
    [Google Scholar]
  18. Lin RS, Lin J, Roychoudhury S, Anderson KM, Hu T et al. 2020b. Rejoinder to letter to the editor ``The hazards of period specific and weighted hazard ratios. .'' Stat. Biopharm. Res. 12:4520–21
    [Google Scholar]
  19. Lu X, Tsiatis AA 2008. Improving the efficiency of the log-rank test using auxiliary covariates. Biometrika 95:3679–94
    [Google Scholar]
  20. Martinussen T, Scheike TH. 2006. Dynamic Regression Models for Survival Data New York: Springer
  21. Martinussen T, Vansteelandt S. 2013. On collapsibility and confounding bias in Cox and Aalen regression models. Lifetime Data Anal. 19:3279–96
    [Google Scholar]
  22. Martinussen T, Vansteelandt S, Andersen PK. 2020. Subtleties in the interpretation of hazard contrasts. Lifetime Data Anal. 26:4833–55
    [Google Scholar]
  23. Nelsen RB. 2006. An Introduction to Copulas New York: Springer
  24. Oakes D. 1989. Bivariate survival models induced by frailties. J. Am. Stat. Assoc. 84:406487–93
    [Google Scholar]
  25. Ozenne BMH, Scheike TH, Staerk L, Gerds TA. 2020. On the estimation of average treatment effects with right-censored time to event outcome and competing risks. Biom. J. 62:3751–63
    [Google Scholar]
  26. Primrose JN, Fox RP, Palmer DH, Malik HZ, Prasad R et al. 2019. Capecitabine compared with observation in resected biliary tract cancer (BILCAP): a randomised, controlled, multicentre, phase 3 study. Lancet Oncol. 20:5663–73
    [Google Scholar]
  27. Sjölander A, Dahlqwist E, Zetterqvist J 2016. A note on the noncollapsibility of rate differences and rate ratios. Epidemiology 27:3356–9
    [Google Scholar]
  28. Stensrud MJ, Aalen JM, Aalen OO, Valberg M. 2019. Limitations of hazard ratios in clinical trials. Eur. Heart J. 40:171378–83
    [Google Scholar]
  29. van der Laan MJ, Rose S. 2011. Targeted Learning New York: Springer
  30. van der Laan MJ, Rubin D. 2006. Targeted maximum likelihood learning. Int. J. Biostat. 2:111
    [Google Scholar]
  31. van der Vaart AW. 1998. Asymptotic Statistics Cambridge, UK: Cambridge Univ. Press
  32. Vansteelandt S, Martinussen T, Tchetgen Tchetgen EJ. 2014. On adjustment for auxiliary covariates in additive hazard models for the analysis of randomized experiments. Biometrika 101:1237–44
    [Google Scholar]
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