Detecting multiple change points in piecewise constant hazard functions

The National Cancer Institute (NCI) suggests a sudden reduction in prostate cancer mortality rates, likely due to highly successful treatments and screening methods for early diagnosis. We are interested in understanding the impact of medical breakthroughs, treatments, or interventions, on the survival experience for a population. For this purpose, estimating the underlying hazard function, with possible time change points, would be of substantial interest, as it will provide a general picture of the survival trend and when this trend is disrupted. Increasing attention has been given to testing the assumption of a constant failure rate against a failure rate that changes at a single point in time. We expand the set of alternatives to allow for the consideration of multiple change-points, and propose a model selection algorithm using sequential testing for the piecewise constant hazard model. These methods are data driven and allow us to estimate not only the number of change points in the hazard function but where those changes occur. Such an analysis allows for better understanding of how changing medical practice affects the survival experience for a patient population. We test for change points in prostate cancer mortality rates using the NCI Surveillance, Epidemiology, and End Results dataset.     

Bayesian Semiparametric Cure Rate Model with an Unknown Threshold

Abstract.  We propose a Bayesian semiparametric model for survival data with a cure fraction. We explicitly consider a finite cure time in the model, which allows us to separate the cured and the uncured populations. We take a mixture prior of a Markov gamma process and a point mass at zero to model the baseline hazard rate function of the entire population. We focus on estimating the cure threshold after which subjects are considered cured. We can incorporate covariates through a structure similar to the proportional hazards model and allow the cure threshold also to depend on the covariates. For illustration, we undertake simulation studies and a full Bayesian analysis of a bone marrow transplant data set.     

Change point-cure models with application to estimating the change-point effect of age of diagnosis among prostate cancer patients

Previous research on prostate cancer survival trends in the United States National Cancer Institute's Surveillance Epidemiology and End Results database has indicated a potential change-point in the age of diagnosis of prostate cancer around age 50. Identifying a change-point value in prostate cancer survival and cure could have important policy and health care management implications. Statistical analysis of this data has to address two complicating features: (1) change-point models are not smooth functions and so present computational and theoretical difficulties; and (2) models for prostate cancer survival need to account for the fact that many men diagnosed with prostate cancer can be effectively cured of their disease with early treatment. We develop a cure survival model that allows for change-point effects in covariates to investigate a potential change-point in the age of diagnosis of prostate cancer. Our results do not indicate that age under 50 is associated with increased hazard of death from prostate cancer.     

Exploring Parameter Relations for Multi‐Stage Models in Stage‐Wise Constant and Time Dependent Hazard Rates

Single cohort stage‐frequency data are considered when assessing the stage reached by individuals through destructive sampling. For this type of data, when all hazard rates are assumed constant and equal, Laplace transform methods have been applied in the past to estimate the parameters in each stage‐duration distribution and the overall hazard rates. If hazard rates are not all equal, estimating stage‐duration parameters using Laplace transform methods becomes complex. In this paper, two new models are proposed to estimate stage‐dependent maturation parameters using Laplace transform methods where non‐trivial hazard rates apply. The first model encompasses hazard rates that are constant within each stage but vary between stages. The second model encompasses time‐dependent hazard rates within stages. Moreover, this paper introduces a method for estimating the hazard rate in each stage for the stage‐wise constant hazard rates model. This work presents methods that could be used in specific types of laboratory studies, but the main motivation is to explore the relationships between stage maturation parameters that, in future work, could be exploited in applying Bayesian approaches. The application of the methodology in each model is evaluated using simulated data in order to illustrate the structure of these models.     

The negative binomial–beta Weibull regression model to predict the cure of prostate cancer

In this article, for the first time, we propose the negative binomial–beta Weibull (BW) regression model for studying the recurrence of prostate cancer and to predict the cure fraction for patients with clinically localized prostate cancer treated by open radical prostatectomy. The cure model considers that a fraction of the survivors are cured of the disease. The survival function for the population of patients can be modeled by a cure parametric model using the BW distribution. We derive an explicit expansion for the moments of the recurrence time distribution for the uncured individuals. The proposed distribution can be used to model survival data when the hazard rate function is increasing, decreasing, unimodal and bathtub shaped. Another advantage is that the proposed model includes as special sub-models some of the well-known cure rate models discussed in the literature. We derive the appropriate matrices for assessing local influence on the parameter estimates under different perturbation schemes. We analyze a real data set for localized prostate cancer patients after open radical prostatectomy.     

Proportional hazards estimate of the conditional survival function

We introduce a new estimator of the conditional survival function given some subset of the covariate values under a proportional hazards regression. The new estimate does not require estimating the base-line cumulative hazard function. An estimate of the variance is given and is easy to compute, involving only those quantities that are routinely calculated in a Cox model analysis. The asymptotic normality of the new estimate is shown by using a central limit theorem for Kaplan–Meier integrals. We indicate the straightforward extension of the estimation procedure under models with multiplicative relative risks, including non-proportional hazards, and to stratified and frailty models. The estimator is applied to a gastric cancer study where it is of interest to predict patients' survival based only on measurements obtained before surgery, the time at which the most important prognostic variable, stage, becomes known.     

On heteroscedastic hazards regression models: theory and application

A class of non-proportional hazards regression models is considered to have hazard specifications consisting of a power form of cross-effects on the base-line hazard function. The primary goal of these models is to deal with settings in which heterogeneous distribution shapes of survival times may be present in populations characterized by some observable covariates. Although effects of such heterogeneity can be explicitly seen through crossing cumulative hazards phenomena in k -sample problems, they are barely visible in a one-sample regression setting. Hence, heterogeneity of this kind may not be noticed and, more importantly, may result in severely misleading inference. This is because the partial likelihood approach cannot eliminate the unknown cumulative base-line hazard functions in this setting. For coherent statistical inferences, a system of martingale processes is taken as a basis with which, together with the method of sieves, an overidentified estimating equation approach is proposed. A Pearson's χ² type of goodness-of-fit testing statistic is derived as a by-product. An example with data on gastric cancer patients' survival times is analysed.     

Influence diagnostics for the Weibull-Negative-Binomial regression model with cure rate under latent failure causes

In this paper, we propose a flexible cure rate survival model by assuming that the number of competing causes of the event of interest follows the Negative Binomial distribution and the time to event follows a Weibull distribution. Indeed, we introduce the Weibull-Negative-Binomial (WNB) distribution, which can be used in order to model survival data when the hazard rate function is increasing, decreasing and some non-monotonous shaped. Another advantage of the proposed model is that it has some distributions commonly used in lifetime analysis as particular cases. Moreover, the proposed model includes as special cases some of the well-know cure rate models discussed in the literature. We consider a frequentist analysis for parameter estimation of a WNB model with cure rate. Then, we derive the appropriate matrices for assessing local influence on the parameter estimates under different perturbation schemes and present some ways to perform global influence analysis. Finally, the methodology is illustrated on a medical data.     

Estimating the hazard functions of two alternating recurrent events in the presence of covariates

The motivation for this paper is a cystic fibrosis data which records a patient’s times to relapse and times to cure under several recurrences of the disease. The idea is to study the impact of covariates on the hazard rates of two alternately occurring events. The dependence between the times to the two events over the different cycles is modeled through an autoregressive-type setup. The partial likelihood function is then derived and the estimators obtained. The estimators are shown to be consistent and asymptotically normal. The technique is applied to study the motivating data. A simulation study is also conducted to corroborate the results.     

The Dynamic Model for Cancer Relapse Based on Two-Stage Model of Carcinogenesis

In this article, the time from the start of chemotherapy randomization until cancer relapse is of primary interest. Here, cancer relapse refers to the appearance of the first observable malignant clone after therapy. A dynamic model for cancer relapse after chemotherapy is developed. The model differs from the traditional cure rate models in that it takes into consideration the growth kinetics of malignant tumors using a two-stage carcinogenesis model. The survival and hazard functions for cancer relapse time are derived, and a simulation study is performed to validate the underlying model.     

Mark-specific additive hazards regression with continuous marks

For survival data, mark variables are only observed at uncensored failure times, and it is of interest to investigate whether there is any relationship between the failure time and the mark variable. The additive hazards model, focusing on hazard differences rather than hazard ratios, has been widely used in practice. In this article, we propose a mark-specific additive hazards model in which both the regression coefficient functions and the baseline hazard function depend nonparametrically on a continuous mark. An estimating equation approach is developed to estimate the regression functions, and the asymptotic properties of the resulting estimators are established. In addition, some formal hypothesis tests are constructed for various hypotheses concerning the mark-specific treatment effects. The finite sample behavior of the proposed estimators is evaluated through simulation studies, and an application to a data set from the first HIV vaccine efficacy trial is provided.     

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 generalization of the compound rayleigh distribution: using a bayesian method on cancer survival times

In this paper the generalized compound Rayleigh model, exhibiting flexible hazard rate, is high¬lighted. This makes it attractive for modelling survival times of patients showing characteristics of a random hazard rate. The Bayes estimators are derived for the parameters of this model and some survival time parameters from a right censored sample. This is done with respect to conjugate and discrete priors on the parameters of this model, under the squared error loss function, Varian's asymmetric linear-exponential (linex) loss function and a weighted linex loss function. The future survival time of a patient is estimated under these loss functions. A Monte Carlo simu¬lation procedure is used where closed form expressions of the estimators cannot be obtained. An example illustrates the proposed estimators for this model.     

Partial logistic relevance vector machines in survival analysis

The use of relevance vector machines to flexibly model hazard rate functions is explored. This technique is adapted to survival analysis problems through the partial logistic approach. The method exploits the Bayesian automatic relevance determination procedure to obtain sparse solutions and it incorporates the flexibility of kernel-based models. Example results are presented on literature data from a head-and-neck cancer survival study using Gaussian and spline kernels. Sensitivity analysis is conducted to assess the influence of hyperprior distribution parameters. The proposed method is then contrasted with other flexible hazard regression methods, in particular the HARE model proposed by Kooperberg et al. [16]. A simulation study is conducted to carry out the comparison. The model developed in this paper exhibited good performance in the prediction of hazard rate. The application of this sparse Bayesian technique to a real cancer data set demonstrated that the proposed method can potentially reveal characteristics of the hazards, associated with the dynamics of the studied diseases, which may be missed by existing modeling approaches based on different perspectives on the bias vs. variance balance.     

Joint Modeling of Survival and Longitudinal Ordered Data Using a Semiparametric Approach

Medical research frequently focuses on the relationship between quality of life (QoL) and survival time of subjects. QoL may be one of the most important factors that could be used to predict survival, making it worth identifying factors that jointly affect survival and QoL. We propose a semiparametric joint model that consists of item response and survival components, where these two components are linked through latent variables. Several popular ordinal models are considered and compared in the item response component, while the Cox proportional hazards model is used in the survival component. We estimate the baseline hazard function and model parameters simultaneously, through a profile likelihood approach. We illustrate the method using an example from a clinical study.     

Maximum Likelihood Estimations and EM Algorithms with Length-biased Data

Length-biased sampling has been well recognized in economics, industrial reliability, etiology applications, epidemiological, genetic and cancer screening studies. Length-biased right-censored data have a unique data structure different from traditional survival data. The nonparametric and semiparametric estimations and inference methods for traditional survival data are not directly applicable for length-biased right-censored data. We propose new expectation-maximization algorithms for estimations based on full likelihoods involving infinite dimensional parameters under three settings for length-biased data: estimating nonparametric distribution function, estimating nonparametric hazard function under an increasing failure rate constraint, and jointly estimating baseline hazards function and the covariate coefficients under the Cox proportional hazards model. Extensive empirical simulation studies show that the maximum likelihood estimators perform well with moderate sample sizes and lead to more efficient estimators compared to the estimating equation approaches. The proposed estimates are also more robust to various right-censoring mechanisms. We prove the strong consistency properties of the estimators, and establish the asymptotic normality of the semi-parametric maximum likelihood estimators under the Cox model using modern empirical processes theory. We apply the proposed methods to a prevalent cohort medical study. Supplemental materials are available online.     

Cancer immunotherapy trial design with long-term survivors

Cancer immunotherapy often reflects the improvement in both short-term risk reduction and long-term survival. In this scenario, a mixture cure model can be used for the trial design. However, the hazard functions based on the mixture cure model between two groups will ultimately crossover. Thus, the conventional assumption of proportional hazards may be violated and study design using standard log-rank test (LRT) could lose power if the main interest is to detect the improvement of long-term survival. In this paper, we propose a change sign weighted LRT for the trial design. We derived a sample size formula for the weighted LRT, which can be used for designing cancer immunotherapy trials to detect both short-term risk reduction and long-term survival. Simulation studies are conducted to compare the efficiency between the standard LRT and the change sign weighted LRT.     

Mixed Discrete and Continuous Cox Regression Model

The Cox (1972) regression model is extended to include discrete and mixed continuous/discrete failure time data by retaining the multiplicative hazard rate form of the absolutely continuous model. Application of martingale arguments to the regression parameter estimating function show the Breslow (1974) estimator to be consistent and asymptotically Gaussian under this model. A computationally convenient estimator of the variance of the score function can be developed, again using martingale arguments. This estimator reduces to the usual hypergeometric form in the special case of testing equality of several survival curves, and it leads more generally to a convenient consistent variance estimator for the regression parameter. A small simulation study is carried out to study the regression parameter estimator and its variance estimator under the discrete Cox model special case and an application to a bladder cancer recurrence dataset is provided.     

Nonparametric modeling of the gap time in recurrent event data

Recurrent event data arise in many biomedical and engineering studies when failure events can occur repeatedly over time for each study subject. In this article, we are interested in nonparametric estimation of the hazard function for gap time. A penalized likelihood model is proposed to estimate the hazard as a function of both gap time and covariate. Method for smoothing parameter selection is developed from subject-wise cross-validation. Confidence intervals for the hazard function are derived using the Bayes model of the penalized likelihood. An eigenvalue analysis establishes the asymptotic convergence rates of the relevant estimates. Empirical studies are performed to evaluate various aspects of the method. The proposed technique is demonstrated through an application to the well-known bladder tumor cancer data.     

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.