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Meta-analysis of time-to-event outcomes from randomized trials using restricted mean survival time: application to individual participant data.

ABSTRACT: Meta-analysis of time-to-event outcomes using the hazard ratio as a treatment effect measure has an underlying assumption that hazards are proportional. The between-arm difference in the restricted mean survival time is a measure that avoids this assumption and allows the treatment effect to vary with time. We describe and evaluate meta-analysis based on the restricted mean survival time for dealing with non-proportional hazards and present a diagnostic method for the overall proportional hazards assumption. The methods are illustrated with the application to two individual participant meta-analyses in cancer. The examples were chosen because they differ in disease severity and the patterns of follow-up, in order to understand the potential impacts on the hazards and the overall effect estimates. We further investigate the estimation methods for restricted mean survival time by a simulation study.

SUBMITTER: Wei Y

PROVIDER: S-EPMC5695659 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Meta-analysis of time-to-event outcomes from randomized trials using restricted mean survival time: application to individual participant data.

Wei Yinghui Y Royston Patrick P Tierney Jayne F JF Parmar Mahesh K B MK

Statistics in medicine 20150623 21

Meta-analysis of time-to-event outcomes using the hazard ratio as a treatment effect measure has an underlying assumption that hazards are proportional. The between-arm difference in the restricted mean survival time is a measure that avoids this assumption and allows the treatment effect to vary with time. We describe and evaluate meta-analysis based on the restricted mean survival time for dealing with non-proportional hazards and present a diagnostic method for the overall proportional hazard ...[more]

PMID: 26099573

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Project description:BackgroundRestricted mean survival time is a measure of average survival time up to a specified time point. There has been an increased interest in using restricted mean survival time to compare treatment arms in randomized clinical trials because such comparisons do not rely on proportional hazards or other assumptions about the nature of the relationship between survival curves.MethodsThis article addresses the question of whether covariate adjustment in randomized clinical trials that compare restricted mean survival times improves precision of the estimated treatment effect (difference in restricted mean survival times between treatment arms). Although precision generally increases in linear models when prognostic covariates are added, this is not necessarily the case in non-linear models. For example, in logistic and Cox regression, the standard error of the estimated treatment effect does not decrease when prognostic covariates are added, although the situation is complicated in those settings because the estimand changes as well. Because estimation of restricted mean survival time in the manner described in this article is also based on a model that is non-linear in the covariates, we investigate whether the comparison of restricted mean survival times with adjustment for covariates leads to a reduction in the standard error of the estimated treatment effect relative to the unadjusted estimator or whether covariate adjustment provides no improvement in precision. Chen and Tsiatis suggest that precision will increase if covariates are chosen judiciously. We present results of simulation studies that compare unadjusted versus adjusted comparisons of restricted mean survival time between treatment arms in randomized clinical trials.ResultsWe find that for comparison of restricted means in a randomized clinical trial, adjusting for covariates that are associated with survival increases precision and therefore statistical power, relative to the unadjusted estimator. Omitting important covariates results in less precision but estimates remain unbiased.ConclusionWhen comparing restricted means in a randomized clinical trial, adjusting for prognostic covariates can improve precision and increase power.

Project description:ObjectiveTo compare restricted mean survival time- (RMST-) based methods with traditional survival methods when multiple covariates are of interest.Methods4405 osteosarcomas were captured from Surveillance, Epidemiology, and End Results Program Database. RMST-based methods included group comparison using Kaplan-Meier (KM) method, pseudovalue (PV) regression, and inverse probability of censoring probability (IPCW) regressions with group-specific and individual weights. Log-rank test, Wilcoxon test, Cox regression, and its extension with time-dependent variables were selected as traditional methods. Proportional hazard (PH) assumption and homogeneity of censoring mechanism assumption were assessed. We estimated hazard ratio (HR) and difference in RMST and explored their relationships.ResultsWhen covariate violated PH assumption, time-varying HR was inconvenient to report as a single value but PH assumption-free RMST allowed to report a single value of difference in RMST. In univariable analyses, using the difference in RMST calculated by KM method as reference, PV regressions (slope = 1.02 and R 2 = 0.98) and IPCW regressions with group-specific weights (slope = 0.98 and R 2 = 0.99) gave more consistent estimation than IPCW with individual weights (slope = 0.31 and R 2 = 0.06), moreover, PV regressions presented more robust statistical power than IPCW regressions with group-specific weights. In multivariable analyses, IPCW regression with group-specific weights was limited when multiple covariates violated homogeneity of censoring mechanism assumption. For covariates met PH assumption, well-fitted logarithmic relationships between HR and difference in RMST estimated by PV regression were observed in both univariable and multivariable analyses (R 2 = 0.97 and R 2 = 0.94, respectively), which supported the robustness of PV regression and possible conversion between the two effect measures.ConclusionsDifference in RMST is more interpretable than time-varying HR. The performance supports KM method and PV regression to be the preferred ones in RMST-based methods. IPCW regression can be an alternative sensitivity analysis. We encourage adoption of both traditional methods and RMST-based methods to present effects of covariates comprehensively.

Dataset Information

Meta-analysis of time-to-event outcomes from randomized trials using restricted mean survival time: application to individual participant data.

Publications

Meta-analysis of time-to-event outcomes from randomized trials using restricted mean survival time: application to individual participant data.

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