Direct parametric inference for the cumulative incidence function

Summary.  In survival data that are collected from phase III clinical trials on breast cancer, a patient may experience more than one event, including recurrence of the original cancer, new primary cancer and death. Radiation oncologists are often interested in comparing patterns of local or regional recurrences alone as first events to identify a subgroup of patients who need to be treated by radiation therapy after surgery. The cumulative incidence function provides estimates of the cumulative probability of locoregional recurrences in the presence of other competing events. A simple version of the Gompertz distribution is proposed to parameterize the cumulative incidence function directly. The model interpretation for the cumulative incidence function is more natural than it is with the usual cause-specific hazard parameterization. Maximum likelihood analysis is used to estimate simultaneously parametric models for cumulative incidence functions of all causes. The parametric cumulative incidence approach is applied to a data set from the National Surgical Adjuvant Breast and Bowel Project and compared with analyses that are based on parametric cause-specific hazard models and nonparametric cumulative incidence estimation.     

A 3-parameter Gompertz distribution for survival data with competing risks,with an application to breast cancer data

The cumulative incidence function is of great importance in the analysis of survival data when competing risks are present. Parametric modeling of such functions, which are by nature improper, suggests the use of improper distributions. One frequently used improper distribution is that of Gompertz, which captures only monotone hazard shapes. In some applications, however, subdistribution hazard estimates have been observed with unimodal shapes. An extension to the Gompertz distribution is presented which can capture unimodal as well as monotone hazard shapes. Important properties of the proposed distribution are discussed, and the proposed distribution is used to analyze survival data from a breast cancer clinical trial.     

A Method for Analyzing Disease-Specific Mortality with Missing Cause of Death Information

In this paper, we examine a method for analyzing competing risks data where the failure type of interest is missing or incomplete, but where there is an intermediate event, and only patients who experience the intermediate event can die of the cause of interest. In some applications, a method called “log-rank subtraction” has been applied to these problems. There has been no systematic study of this methodology, though. We investigate the statistical properties of the method and further propose a modified method by including a weight function in the construction of the test statistic to correct for potential biases. A class of tests is then proposed for comparing the disease-specific mortality in the two groups. The tests are based on comparing the difference of weighted log-rank scores for the failure type of interest. We derive the asymptotic properties for the modified test procedure. Simulation studies indicate that the tests are unbiased and have reasonable power. The results are also illustrated with data from a breast cancer study.     

A Bayesian approach to Markov modelling in cost-effectiveness analyses: application to taxane use in advanced breast cancer

Summary. The paper demonstrates how cost-effectiveness decision analysis may be implemented from a Bayesian perspective, using Markov chain Monte Carlo simulation methods for both the synthesis of relevant evidence input into the model and the evaluation of the model itself. The desirable aspects of a Bayesian approach for this type of analysis include the incorporation of full parameter uncertainty, the ability to perform all the analysis, including each meta-analysis, in a single coherent model and the incorporation of expert opinion either directly or regarding the relative credibility of different data sources. The method is described, and its ease of implementation demonstrated, through a practical example to evaluate the cost-effectiveness of using taxanes for the second-line treatment of advanced breast cancer compared with conventional treatment. For completeness, the results from the Markov chain Monte Carlo simulation model are compared and contrasted with those from a classical Monte Carlo simulation model.     

A parametric dynamic survival model applied to breast cancer survival times

Summary. Much current analysis of cancer registry data uses the semiparametric proportional hazards Cox model. In this paper, the time-dependent effect of various prognostic indicators on breast cancer survival times from the West Midlands Cancer Intelligence Unit are investigated. Using Bayesian methodology and Markov chain Monte Carlo estimation methods, we develop a parametric dynamic survival model which avoids the proportional hazards assumption. The model has close links to that developed by both Gamerman and Sinha and co-workers: the log-base-line hazard and covariate effects are piecewise constant functions, related between intervals by a simple stochastic evolution process. Here this evolution is assigned a parametric distribution, with a variance that is further included as a hyperparameter. To avoid problems of convergence within the Gibbs sampler, we consider using a reparameterization. It is found that, for some of the prognostic indicators considered, the estimated effects change with increasing follow-up time. In general those prognostic indicators which are thought to be representative of the most hazardous groups (late-staged tumour and oldest age group) have a declining effect.     

Estimation of conditional cumulative incidence functions under generalized semiparametric regression models with missing covariates,with application to analysis of biomarker correlates in vaccine trials

This article presents generalized semiparametric regression models for conditional cumulative incidence functions with competing risks data when covariates are missing by sampling design or happenstance. A doubly robust augmented inverse probability weighted (AIPW) complete-case approach to estimation and inference is investigated. This approach modifies IPW complete-case estimating equations by exploiting the key features in the relationship between the missing covariates and the phase-one data to improve efficiency. An iterative numerical procedure is derived to solve the nonlinear estimating equations. The asymptotic properties of the proposed estimators are established. A simulation study examining the finite-sample performances of the proposed estimators shows that the AIPW estimators are more efficient than the IPW estimators. The developed method is applied to the RV144 HIV-1 vaccine efficacy trial to investigate vaccine-induced IgG binding antibodies to HIV-1 as correlates of acquisition of HIV-1 infection while taking account of whether the HIV-1 sequences are near or far from the HIV-1 sequences represented in the vaccine construct.     

A multilevel analysis of longitudinal ordinal data: evaluation of the level of physical performance of women receiving adjuvant therapy for breast cancer

Longitudinal health-related quality-of-life (QOL) data are often collected as part of clinical studies. Here two analyses of QOL data from a prospective study of breast cancer patients evaluate how physical performance is related to factors such as age, menopausal status and type of adjuvant treatment. The first analysis uses summary statistic methods. The same questions are then addressed using a multilevel model. Because of the structure of the physical performance response, regression models for the analysis of ordinal data are used. The analyses of base-line and follow-up QOL data at four time points over two years from 257 women show that reported base-line physical performance was consistently associated with later performance and that women who had received chemotherapy in the month before the QOL assessment had a greater physical performance burden. There is a slight power gain of the multilevel model over the summary statistic analysis. The multilevel model also allows relationships with time-dependent covariates to be included, highlighting treatment-related factors affecting physical performance that could not be considered within the summary statistic analysis. Checking of the multilevel model assumptions is exemplified.     

Assessing the prediction accuracy of cure in the Cox proportional hazards cure model: an application to breast cancer data

A cure rate model is a survival model incorporating the cure rate with the assumption that the population contains both uncured and cured individuals. It is a powerful statistical tool for prognostic studies, especially in cancer. The cure rate is important for making treatment decisions in clinical practice. The proportional hazards (PH) cure model can predict the cure rate for each patient. This contains a logistic regression component for the cure rate and a Cox regression component to estimate the hazard for uncured patients. A measure for quantifying the predictive accuracy of the cure rate estimated by the Cox PH cure model is required, as there has been a lack of previous research in this area. We used the Cox PH cure model for the breast cancer data; however, the area under the receiver operating characteristic curve (AUC) could not be estimated because many patients were censored. In this study, we used imputation‐based AUCs to assess the predictive accuracy of the cure rate from the PH cure model. We examined the precision of these AUCs using simulation studies. The results demonstrated that the imputation‐based AUCs were estimable and their biases were negligibly small in many cases, although ordinary AUC could not be estimated. Additionally, we introduced the bias‐correction method of imputation‐based AUCs and found that the bias‐corrected estimate successfully compensated the overestimation in the simulation studies. We also illustrated the estimation of the imputation‐based AUCs using breast cancer data. Copyright © 2014 John Wiley & Sons, Ltd.     

An index of local sensitivity to non-ignorability for parametric survival models with potential non-random missing covariate: an application to the SEER cancer registry data

Several survival regression models have been developed to assess the effects of covariates on failure times. In various settings, including surveys, clinical trials and epidemiological studies, missing data may often occur due to incomplete covariate data. Most existing methods for lifetime data are based on the assumption of missing at random (MAR) covariates. However, in many substantive applications, it is important to assess the sensitivity of key model inferences to the MAR assumption. The index of sensitivity to non-ignorability (ISNI) is a local sensitivity tool to measure the potential sensitivity of key model parameters to small departures from the ignorability assumption, needless of estimating a complicated non-ignorable model. We extend this sensitivity index to evaluate the impact of a covariate that is potentially missing, not at random in survival analysis, using parametric survival models. The approach will be applied to investigate the impact of missing tumor grade on post-surgical mortality outcomes in individuals with pancreas-head cancer in the Surveillance, Epidemiology, and End Results data set. For patients suffering from cancer, tumor grade is an important risk factor. Many individuals in these data with pancreas-head cancer have missing tumor grade information. Our ISNI analysis shows that the magnitude of effect for most covariates (with significant effect on the survival time distribution), specifically surgery and tumor grade as some important risk factors in cancer studies, highly depends on the missing mechanism assumption of the tumor grade. Also a simulation study is conducted to evaluate the performance of the proposed index in detecting sensitivity of key model parameters.     

Bayesian inference: Weibull Poisson model for censored data using the expectation–maximization algorithm and its application to bladder cancer data

This article focuses on the parameter estimation of experimental items/units from Weibull Poisson Model under progressive type-II censoring with binomial removals (PT-II CBRs). The expectation–maximization algorithm has been used for maximum likelihood estimators (MLEs). The MLEs and Bayes estimators have been obtained under symmetric and asymmetric loss functions. Performance of competitive estimators have been studied through their simulated risks. One sample Bayes prediction and expected experiment time have also been studied. Furthermore, through real bladder cancer data set, suitability of considered model and proposed methodology have been illustrated.