Confidence intervals for survival quantiles in the Cox regression model

Median survival times and their associated confidence intervals are often used to summarize the survival outcome of a group of patients in clinical trials with failure-time endpoints. Although there is an extensive literature on this topic for the case in which the patients come from a homogeneous population, few papers have dealt with the case in which covariates are present as in the proportional hazards model. In this paper we propose a new approach to this problem and demonstrate its advantages over existing methods, not only for the proportional hazards model but also for the widely studied cases where covariates are absent and where there is no censoring. As an illustration, we apply it to the Stanford Heart Transplant data. Asymptotic theory and simulation studies show that the proposed method indeed yields confidence intervals and bands with accurate coverage errors.     

Semiparametric regression analysis of two‐sample current status data,with applications to tumorigenicity experiments

Current status data frequently occur in failure time studies, particularly in demographical studies and tumorigenicity experiments. Although commonly used in this context, proportional hazards and odds models are inadequate when survival functions cross. The authors consider a class of two‐sample models which is suitable for this situation and encompasses the proportional hazards and odds models. The estimating equations they propose lead to consistent and asymptotically Gaussian estimates of regression parameters in the extended model. Their approach is assessed through simulations and illustrated using data from a tumorigenicity experiment.     

Jointly modeling longitudinal proportional data and survival times with an application to the quality of life data in a breast cancer trial

Motivated by the joint analysis of longitudinal quality of life data and recurrence free survival times from a cancer clinical trial, we present in this paper two approaches to jointly model the longitudinal proportional measurements, which are confined in a finite interval, and survival data. Both approaches assume a proportional hazards model for the survival times. For the longitudinal component, the first approach applies the classical linear mixed model to logit transformed responses, while the second approach directly models the responses using a simplex distribution. A semiparametric method based on a penalized joint likelihood generated by the Laplace approximation is derived to fit the joint model defined by the second approach. The proposed procedures are evaluated in a simulation study and applied to the analysis of breast cancer data motivated this research.     

Confidence bands for the difference of two survival functions under the additive risk model

In many clinical studies, a commonly encountered problem is to compare the survival probabilities of two treatments for a given patient with a certain set of covariates, and there is often a need to make adjustments for other covariates that may affect outcomes. One approach is to plot the difference between the two subject-specific predicted survival estimates with a simultaneous confidence band. Such a band will provide useful information about when these two treatments differ and which treatment has a better survival probability. In this paper, we show how to construct such a band based on the additive risk model and we use the martingale central limit theorem to derive its asymptotic distribution. The proposed method is evaluated from a simulation study and is illustrated with two real examples.     

The proportional hazards model with covariate measurement error

The proportional hazards regression model is commonly used to evaluate the relationship between survival and covariates. Covariates are frequently measured with error. Substituting mismeasured values for the true covariates leads to biased estimation. Hu et al. (Biometrics 88 (1998) 447) have proposed to base estimation in the proportional hazards model with covariate measurement error on a joint likelihood for survival and the covariate variable. Nonparametric maximum likelihood estimation (NPMLE) was used and simulations were conducted to assess the asymptotic validity of this approach. In this paper, we derive a rigorous proof of asymptotic normality of the NPML estimators.     

The glm log-rank test:general linear modeling of log-rank scores as a method of analysis for survival data

The use of general linear modeling (GLM) procedures based on log-rank scores is proposed for the analysis of survival data and compared to standard survival analysis procedures. For the comparison of two groups, this approach performed similarly to the traditional log-rank test. In the case of more complicated designs - without ties in the survival times - the approach was only marginally less powerful than tests from proportional hazards models, and clearly less powerful than a likelihood ratio test for a fully parametric model; however, with ties in the survival time, the approach proved more powerful than tests from Cox's semi-parametric proportional hazards procedure. The method appears to provide a reasonably powerful alternative for the analysis of survival data, is easily used in complicated study designs, avoids (semi-)parametric assumptions, and is quite computationally easy and inexpensive to employ.     

Fitting a Semi-Parametric Mixture Model for Competing Risks in Survival Data

A model for survival analysis is studied that is relevant for samples which are subject to multiple types of failure. In comparison with a more standard approach, through the appropriate use of hazard functions and transition probabilities, the model allows for a more accurate study of cause-specific failure with regard to both the timing and type of failure. A semiparametric specification of a mixture model is employed that is able to adjust for concomitant variables and allows for the assessment of their effects on the probabilities of eventual causes of failure through a generalized logistic model, and their effects on the corresponding conditional hazard functions by employing the Cox proportional hazards model. A carefully formulated estimation procedure is presented that uses an EM algorithm based on a profile likelihood construction. The methods discussed, which could also be used for reliability analysis, are applied to a prostate cancer data set.     

A nonparametric test to compare survival distributions with covariate adjustment

Summary.  The analysis of covariance is a technique that is used to improve the power of a k -sample test by adjusting for concomitant variables. If the end point is the time of survival, and some observations are right censored, the score statistic from the Cox proportional hazards model is the method that is most commonly used to test the equality of conditional hazard functions. In many situations, however, the proportional hazards model assumptions are not satisfied. Specifically, the relative risk function is not time invariant or represented as a log-linear function of the covariates. We propose an asymptotically valid k -sample test statistic to compare conditional hazard functions which does not require the assumption of proportional hazards, a parametric specification of the relative risk function or randomization of group assignment. Simulation results indicate that the performance of this statistic is satisfactory. The methodology is demonstrated on a data set in prostate cancer.     

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.     

Efficient estimation for the proportional hazards model with bivariate current status data

We consider efficient estimation of regression and association parameters jointly for bivariate current status data with the marginal proportional hazards model. Current status data occur in many fields including demographical studies and tumorigenicity experiments and several approaches have been proposed for regression analysis of univariate current status data. We discuss bivariate current status data and propose an efficient score estimation approach for the problem. In the approach, the copula model is used for joint survival function with the survival times assumed to follow the proportional hazards model marginally. Simulation studies are performed to evaluate the proposed estimates and suggest that the approach works well in practical situations. A real life data application is provided for illustration.     

Estimating Survival Curves Under Proportional Hazards Model with Covariate Measurement Errors

For the Cox proportional hazards model with additive covariate measurement errors, we propose a corrected cumulative baseline hazard estimator that reduces the bias of the na]ve Breslow estimator. We also derive corresponding modified estimators for the hazard functions and the survival functions of individuals with particular covariate values. Using a Monte Carlo technique developed by Lin et al . (1994), we construct confidence bands for such hazard and survival functions.     

Risk patterns in drug safety study using relative times by accelerated failure time models when proportional hazards assumption is questionable: an illustrative case study of cancer risk of patients on glucose‐lowering therapies

Observational drug safety studies may be susceptible to confounding or protopathic bias. This bias may cause a spurious relationship between drug exposure and adverse side effect when none exists and may lead to unwarranted safety alerts. The spurious relationship may manifest itself through substantially different risk levels between exposure groups at the start of follow‐up when exposure is deemed too short to have any plausible biological effect of the drug. The restrictive proportional hazards assumption with its arbitrary choice of baseline hazard function renders the commonly used Cox proportional hazards model of limited use for revealing such potential bias. We demonstrate a fully parametric approach using accelerated failure time models with an illustrative safety study of glucose‐lowering therapies and show that its results are comparable against other methods that allow time‐varying exposure effects. Our approach includes a wide variety of models that are based on the flexible generalized gamma distribution and allows direct comparisons of estimated hazard functions following different exposure‐specific distributions of survival times. This approach lends itself to two alternative metrics, namely relative times and difference in times to event, allowing physicians more ways to communicate patient's prognosis without invoking the concept of risks, which some may find hard to grasp. In our illustrative case study, substantial differences in cancer risks at drug initiation followed by a gradual reduction towards null were found. This evidence is compatible with the presence of protopathic bias, in which undiagnosed symptoms of cancer lead to switches in diabetes medication. Copyright © 2015 John Wiley & Sons, Ltd.     

Partial Partial Likelihood

The maximum likelihood and maximum partial likelihood approaches to the proportional hazards model are unified. The purpose is to give a general approach to the analysis of the proportional hazards model, whether the baseline distribution is absolutely continuous, discrete, or a mixture. The advantage is that heavily tied data will be analyzed with a discrete time model, while data with no ties is analyzed with ordinary Cox regression. Data sets in between are treated by a compromise between the discrete time model and Efron's approach to tied data in survival analysis, and the transitions between modes are automatic. A simulation study is conducted comparing the proposed approach to standard methods of handling ties. A recent suggestion, that revives Breslow's approach to tied data, is finally discussed.     

Modelling Converging Hazards in Survival Analysis

The Cox proportional hazards model has become the standard model for survival analysis. It is often seen as the null model in that "... explicit excuses are now needed to use different models" (Keiding, Proceedings of the XIXth International Biometric Conference, Cape Town, 1998). However, converging hazards also occur frequently in survival analysis. The Burr model, which may be derived as the marginal from a gamma frailty model, is one commonly used tool to model converging hazards. We outline this approach and introduce a mixed model which extends the Burr model and allows for both proportional and converging hazards. Although a semi-parametric model in its own right, we demonstrate how the mixed model can be derived via a gamma frailty interpretation, suggesting an E-M fitting procedure. We illustrate the modelling techniques using data on survival of hospice patients.     

Partitioned log-rank tests for the overall homogeneity of hazard rate functions

In survival analysis, it is routine to test equality of two survival curves, which is often conducted by using the log-rank test. Although it is optimal under the proportional hazards assumption, the log-rank test is known to have little power when the survival or hazard functions cross. To test the overall homogeneity of hazard rate functions, we propose a group of partitioned log-rank tests. By partitioning the time axis and taking the supremum of the sum of two partitioned log-rank statistics over different partitioning points, the proposed test gains enormous power for cases with crossing hazards. On the other hand, when the hazards are indeed proportional, our test still maintains high power close to that of the optimal log-rank test. Extensive simulation studies are conducted to compare the proposed test with existing methods, and three real data examples are used to illustrate the commonality of crossing hazards and the advantages of the partitioned log-rank tests.     

Extension of the log-rank test

For the comparison of two groups of survival times subject to censoring the log-rank test is widely used. The log-rank test is known to be asymptotically fully efficient for the proportional hazards alternatives. But if the ratio of the hazards changes, the log-rank test may not detect the difference between the two groups. In this article a new test procedure is proposed. Simulation results show that the proposed test procedure provides good power against alternatives, where the hazard ratio between the two groups changes across 1.     

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.     

Adaptive-Cox model averaging for right-censored data

In medical studies, Cox proportional hazards model is a commonly used method to deal with the right-censored survival data accompanied by many explanatory covariates. In practice, the Akaike's information criterion (AIC) or the Bayesian information criterion (BIC) is usually used to select an appropriate subset of covariates. It is well known that neither the AIC criterion nor the BIC criterion dominates for all situations. In this paper, we propose an adaptive-Cox model averaging procedure to get a more robust hazard estimator. First, by applying AIC and BIC criteria to perturbed datasets, we obtain two model averaging (MA) estimated survival curves, called AIC-MA and BIC-MA. Then, based on Kullback–Leibler loss, a better estimate of survival curve between AIC-MA and BIC-MA is chosen, which results in an adaptive-Cox estimate of survival curve. Simulation results show the superiority of our approach and an application of the proposed method is also presented by analyzing the German Breast Cancer Study dataset.     

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.     

Proportionality of hazards in competing risk analysis

The proportional cause-specific hazards (CSHs) model and the proportional subdistribution (cumulative incidence function (CIF)) hazards model are widely used in competing risk analysis. In this paper, we prove that these two kinds of proportionalities cannot hold simultaneously for all CSH functions and all CIFs.