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Improved precision in the analysis of randomized trials with survival outcomes, without assuming proportional hazards

Author

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  • Iván Díaz

    (Weill Cornell Medicine)

  • Elizabeth Colantuoni

    (Johns Hopkins Bloomberg School of Public Health)

  • Daniel F. Hanley

    (Johns Hopkins Medical Institutions)

  • Michael Rosenblum

    (Johns Hopkins Bloomberg School of Public Health)

Abstract

We present a new estimator of the restricted mean survival time in randomized trials where there is right censoring that may depend on treatment and baseline variables. The proposed estimator leverages prognostic baseline variables to obtain equal or better asymptotic precision compared to traditional estimators. Under regularity conditions and random censoring within strata of treatment and baseline variables, the proposed estimator has the following features: (i) it is interpretable under violations of the proportional hazards assumption; (ii) it is consistent and at least as precise as the Kaplan–Meier and inverse probability weighted estimators, under identifiability conditions; (iii) it remains consistent under violations of independent censoring (unlike the Kaplan–Meier estimator) when either the censoring or survival distributions, conditional on covariates, are estimated consistently; and (iv) it achieves the nonparametric efficiency bound when both of these distributions are consistently estimated. We illustrate the performance of our method using simulations based on resampling data from a completed, phase 3 randomized clinical trial of a new surgical treatment for stroke; the proposed estimator achieves a 12% gain in relative efficiency compared to the Kaplan–Meier estimator. The proposed estimator has potential advantages over existing approaches for randomized trials with time-to-event outcomes, since existing methods either rely on model assumptions that are untenable in many applications, or lack some of the efficiency and consistency properties (i)–(iv). We focus on estimation of the restricted mean survival time, but our methods may be adapted to estimate any treatment effect measure defined as a smooth contrast between the survival curves for each study arm. We provide R code to implement the estimator.

Suggested Citation

  • Iván Díaz & Elizabeth Colantuoni & Daniel F. Hanley & Michael Rosenblum, 2019. "Improved precision in the analysis of randomized trials with survival outcomes, without assuming proportional hazards," Lifetime Data Analysis: An International Journal Devoted to Statistical Methods and Applications for Time-to-Event Data, Springer, vol. 25(3), pages 439-468, July.
    • Handle: RePEc:spr:lifeda:v:25:y:2019:i:3:d:10.1007_s10985-018-9428-5
    DOI: 10.1007/s10985-018-9428-5
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    References listed on IDEAS

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    Cited by:

    1. David Benkeser & Iván Díaz & Alex Luedtke & Jodi Segal & Daniel Scharfstein & Michael Rosenblum, 2021. "Rejoinder: Improving precision and power in randomized trials for COVID‐19 treatments using covariate adjustment, for binary, ordinal, and time‐to‐event outcomes," Biometrics, The International Biometric Society, vol. 77(4), pages 1492-1494, December.
    2. David Benkeser & Iván Díaz & Alex Luedtke & Jodi Segal & Daniel Scharfstein & Michael Rosenblum, 2021. "Improving precision and power in randomized trials for COVID‐19 treatments using covariate adjustment, for binary, ordinal, and time‐to‐event outcomes," Biometrics, The International Biometric Society, vol. 77(4), pages 1467-1481, December.
    3. Nicholas Williams & Michael Rosenblum & Iván Díaz, 2022. "Optimising precision and power by machine learning in randomised trials with ordinal and time‐to‐event outcomes with an application to COVID‐19," Journal of the Royal Statistical Society Series A, Royal Statistical Society, vol. 185(4), pages 2156-2178, October.

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