Using cure models and multiple imputation to utilize recurrence as an auxiliary variable for overall survival

Anna S C Conlon, Jeremy M G Taylor, Daniel J. Sargent, Greg Yothers

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Background Intermediate outcome variables can often be used as auxiliary variables for the true outcome of interest in randomized clinical trials. For many cancers, time to recurrence is an informative marker in predicting a patient's overall survival outcome and could provide auxiliary information for the analysis of survival times.Purpose To investigate whether models linking recurrence and death combined with a multiple imputation procedure for censored observations can result in efficiency gains in the estimation of treatment effects and be used to shorten trial lengths.Methods Recurrence and death times are modeled using data from 12 trials in colorectal cancer. Multiple imputation is used as a strategy for handling missing values arising from censoring. The imputation procedure uses a cure model for time to recurrence and a time-dependent Weibull proportional hazards model for time to death. Recurrence times are imputed, and then death times are imputed conditionally on recurrence times. To illustrate these methods, trials are artificially censored 2 years after the last accrual, the imputation procedure implemented, and a log-rank test and Cox model used to analyze and compare these new data with the original data.Results The results show modest, but consistent gains in efficiency in the analysis using the auxiliary information in recurrence times. Comparison of analyses show the treatment effect estimates and log-rank test results from the 2-year censored imputed data to be in between the estimates from the original data and the artificially censored data, indicating that the procedure was able to recover some of the lost information due to censoring.Limitations The models used are all fully parametric, requiring distributional assumptions of the data.Conclusions The proposed models may be useful in improving the efficiency in estimation of treatment effects in cancer trials and shortening trial length.

Original languageEnglish (US)
Pages (from-to)581-590
Number of pages10
JournalClinical Trials
Volume8
Issue number5
DOIs
StatePublished - Oct 2011
Externally publishedYes

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Recurrence
Survival
Proportional Hazards Models
Survival Analysis
Colorectal Neoplasms
Neoplasms
Randomized Controlled Trials
Therapeutics

ASJC Scopus subject areas

  • Medicine(all)
  • Pharmacology

Cite this

Using cure models and multiple imputation to utilize recurrence as an auxiliary variable for overall survival. / Conlon, Anna S C; Taylor, Jeremy M G; Sargent, Daniel J.; Yothers, Greg.

In: Clinical Trials, Vol. 8, No. 5, 10.2011, p. 581-590.

Research output: Contribution to journalArticle

Conlon, Anna S C ; Taylor, Jeremy M G ; Sargent, Daniel J. ; Yothers, Greg. / Using cure models and multiple imputation to utilize recurrence as an auxiliary variable for overall survival. In: Clinical Trials. 2011 ; Vol. 8, No. 5. pp. 581-590.
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abstract = "Background Intermediate outcome variables can often be used as auxiliary variables for the true outcome of interest in randomized clinical trials. For many cancers, time to recurrence is an informative marker in predicting a patient's overall survival outcome and could provide auxiliary information for the analysis of survival times.Purpose To investigate whether models linking recurrence and death combined with a multiple imputation procedure for censored observations can result in efficiency gains in the estimation of treatment effects and be used to shorten trial lengths.Methods Recurrence and death times are modeled using data from 12 trials in colorectal cancer. Multiple imputation is used as a strategy for handling missing values arising from censoring. The imputation procedure uses a cure model for time to recurrence and a time-dependent Weibull proportional hazards model for time to death. Recurrence times are imputed, and then death times are imputed conditionally on recurrence times. To illustrate these methods, trials are artificially censored 2 years after the last accrual, the imputation procedure implemented, and a log-rank test and Cox model used to analyze and compare these new data with the original data.Results The results show modest, but consistent gains in efficiency in the analysis using the auxiliary information in recurrence times. Comparison of analyses show the treatment effect estimates and log-rank test results from the 2-year censored imputed data to be in between the estimates from the original data and the artificially censored data, indicating that the procedure was able to recover some of the lost information due to censoring.Limitations The models used are all fully parametric, requiring distributional assumptions of the data.Conclusions The proposed models may be useful in improving the efficiency in estimation of treatment effects in cancer trials and shortening trial length.",
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