Penalized survival models for the analysis of alternating recurrent event data.
ABSTRACT: Recurrent event data are widely encountered in clinical and observational studies. Most methods for recurrent events treat the outcome as a point process and, as such, neglect any associated event duration. This generally leads to a less informative and potentially biased analysis. We propose a joint model for the recurrent event rate (of incidence) and duration. The two processes are linked through a bivariate normal frailty. For example, when the event is hospitalization, we can treat the time to admission and length-of-stay as two alternating recurrent events. In our method, the regression parameters are estimated through a penalized partial likelihood, and the variance-covariance matrix of the frailty is estimated through a recursive estimating formula. Moreover, we develop a likelihood ratio test to assess the dependence between the incidence and duration processes. Simulation results demonstrate that our method provides accurate parameter estimation, with a relatively fast computation time. We illustrate the methods through an analysis of hospitalizations among end-stage renal disease patients.
Project description:In clinical and observational studies, the event of interest can often recur on the same subject. In a more complicated situation, there exists a terminal event (e.g., death) which stops the recurrent event process. In many such instances, the terminal event is strongly correlated with the recurrent event process. We consider the recurrent/terminal event setting and model the dependence through a shared gamma frailty that is included in both the recurrent event rate and terminal event hazard functions. Conditional on the frailty, a model is specified only for the marginal recurrent event process, hence avoiding the strong Poisson-type assumptions traditionally used. Analysis is based on estimating functions that allow for estimation of covariate effects on the recurrent event rate and terminal event hazard. The method also permits estimation of the degree of association between the two processes. Closed-form asymptotic variance estimators are proposed. The proposed method is evaluated through simulations to assess the applicability of the asymptotic results in finite samples and the sensitivity of the method to its underlying assumptions. The methods can be extended in straightforward ways to accommodate multiple types of recurrent and terminal events. Finally, the methods are illustrated in an analysis of hospitalization data for patients in an international multi-center study of outcomes among dialysis patients.
Project description:Recurrent events could be stopped by a terminal event, which commonly occurs in biomedical and clinical studies. In this situation, dependent censoring is encountered because of potential dependence between these two event processes, leading to invalid inference if analyzing recurrent events alone. The joint frailty model is one of the widely used approaches to jointly model these two processes by sharing the same frailty term. One important assumption is that recurrent and terminal event processes are conditionally independent given the subject-level frailty; however, this could be violated when the dependency may also depend on time-varying covariates across recurrences. Furthermore, marginal correlation between two event processes based on traditional frailty modeling has no closed form solution for estimation with vague interpretation. In order to fill these gaps, we propose a novel joint frailty-copula approach to model recurrent events and a terminal event with relaxed assumptions. Metropolis-Hastings within the Gibbs Sampler algorithm is used for parameter estimation. Extensive simulation studies are conducted to evaluate the efficiency, robustness, and predictive performance of our proposal. The simulation results show that compared with the joint frailty model, the bias and mean squared error of the proposal is smaller when the conditional independence assumption is violated. Finally, we apply our method into a real example extracted from the MarketScan database to study the association between recurrent strokes and mortality.
Project description:The process by which patients experience a series of recurrent events, such as hospitalizations, may be subject to death. In cohort studies, one strategy for analyzing such data is to fit a joint frailty model for the intensities of the recurrent event and death, which estimates covariate effects on the two event types while accounting for their dependence. When certain covariates are difficult to obtain, however, researchers may only have the resources to subsample patients on whom to collect complete data: one way is using the nested case-control (NCC) design, in which risk set sampling is performed based on a single outcome. We develop a general framework for the design of NCC studies in the presence of recurrent and terminal events and propose estimation and inference for a joint frailty model for recurrence and death using data arising from such studies. We propose a maximum weighted penalized likelihood approach using flexible spline models for the baseline intensity functions. Two standard error estimators are proposed: a sandwich estimator and a perturbation resampling procedure. We investigate operating characteristics of our estimators as well as design considerations via a simulation study and illustrate our methods using two studies: one on recurrent cardiac hospitalizations in patients with heart failure and the other on local recurrence and metastasis in patients with breast cancer.
Project description:In the analysis of multivariate event times, frailty models assuming time-independent regression coefficients are often considered, mainly due to their mathematical convenience. In practice, regression coefficients are often time dependent and the temporal effects are of clinical interest. Motivated by a phase III clinical trial in multiple sclerosis, we develop a semiparametric frailty modelling approach to estimate time-varying effects for overdispersed recurrent events data with treatment switching. The proposed model incorporates the treatment switching time in the time-varying coefficients. Theoretical properties of the proposed model are established and an efficient expectation-maximization algorithm is derived to obtain the maximum likelihood estimates. Simulation studies evaluate the numerical performance of the proposed model under various temporal treatment effect curves. The ideas in this paper can also be used for time-varying coefficient frailty models without treatment switching as well as for alternative models when the proportional hazard assumption is violated. A multiple sclerosis dataset is analysed to illustrate our methodology.
Project description:Panel count data arise when the number of recurrent events experienced by each subject is observed intermittently at discrete examination times. The examination time process can be informative about the underlying recurrent event process even after conditioning on covariates. We consider a semiparametric accelerated mean model for the recurrent event process and allow the two processes to be correlated through a shared frailty. The regression parameters have a simple marginal interpretation of modifying the time scale of the cumulative mean function of the event process. A novel estimation procedure for the regression parameters and the baseline rate function is proposed based on a conditioning technique. In contrast to existing methods, the proposed method is robust in the sense that it requires neither the strong Poisson-type assumption for the underlying recurrent event process nor a parametric assumption on the distribution of the unobserved frailty. Moreover, the distribution of the examination time process is left unspecified, allowing for arbitrary dependence between the two processes. Asymptotic consistency of the estimator is established, and the variance of the estimator is estimated by a model-based smoothed bootstrap procedure. Numerical studies demonstrated that the proposed point estimator and variance estimator perform well with practical sample sizes. The methods are applied to data from a skin cancer chemoprevention trial.
Project description:BACKGROUND: Sickness absence (SA) is an important social, economic and public health issue. Identifying and understanding the determinants, whether biological, regulatory or, health services-related, of variability in SA duration is essential for better management of SA. The conditional frailty model (CFM) is useful when repeated SA events occur within the same individual, as it allows simultaneous analysis of event dependence and heterogeneity due to unknown, unmeasured, or unmeasurable factors. However, its use may encounter computational limitations when applied to very large data sets, as may frequently occur in the analysis of SA duration. METHODS: To overcome the computational issue, we propose a Poisson-based conditional frailty model (CFPM) for repeated SA events that accounts for both event dependence and heterogeneity. To demonstrate the usefulness of the model proposed in the SA duration context, we used data from all non-work-related SA episodes that occurred in Catalonia (Spain) in 2007, initiated by either a diagnosis of neoplasm or mental and behavioral disorders. RESULTS: As expected, the CFPM results were very similar to those of the CFM for both diagnosis groups. The CPU time for the CFPM was substantially shorter than the CFM. CONCLUSIONS: The CFPM is an suitable alternative to the CFM in survival analysis with recurrent events, especially with large databases.
Project description:We consider a random effects model for longitudinal data with the occurrence of an informative terminal event that is subject to right censoring. Existing methods for analyzing such data include the joint modeling approach using latent frailty and the marginal estimating equation approach using inverse probability weighting; in both cases the effect of the terminal event on the response variable is not explicit and thus not easily interpreted. In contrast, we treat the terminal event time as a covariate in a conditional model for the longitudinal data, which provides a straight-forward interpretation while keeping the usual relationship of interest between the longitudinally measured response variable and covariates for times that are far from the terminal event. A two-stage semiparametric likelihood-based approach is proposed for estimating the regression parameters; first, the conditional distribution of the right-censored terminal event time given other covariates is estimated and then the likelihood function for the longitudinal event given the terminal event and other regression parameters is maximized. The method is illustrated by numerical simulations and by analyzing medical cost data for patients with end-stage renal disease. Desirable asymptotic properties are provided.
Project description:Recurrent event data arise frequently in various fields such as biomedical sciences, public health, engineering, and social sciences. In many instances, the observation of the recurrent event process can be stopped by the occurrence of a correlated failure event, such as treatment failure and death. In this article, we propose a joint scale-change model for the recurrent event process and the failure time, where a shared frailty variable is used to model the association between the two types of outcomes. In contrast to the popular Cox-type joint modeling approaches, the regression parameters in the proposed joint scale-change model have marginal interpretations. The proposed approach is robust in the sense that no parametric assumption is imposed on the distribution of the unobserved frailty and that we do not need the strong Poisson-type assumption for the recurrent event process. We establish consistency and asymptotic normality of the proposed semiparametric estimators under suitable regularity conditions. To estimate the corresponding variances of the estimators, we develop a computationally efficient resampling-based procedure. Simulation studies and an analysis of hospitalization data from the Danish Psychiatric Central Register illustrate the performance of the proposed method.
Project description:It is often of interest to compare centers or healthcare providers on quality of care delivered. We consider the setting where evaluation of center performance on multiple competing events is of interest. We propose estimating center effects through cause-specific proportional hazards frailty models that allow correlation among a center's cause-specific effects. Estimation of our model proceeds via penalized partial likelihood and is implemented in R. To evaluate center performance, we also propose a directly standardized excess cumulative incidence (ECI) measure. Therefore, based on our proposed methods, practitioners can evaluate centers either through the cause-specific hazards or the cumulative incidence functions. We demonstrate, through simulations, the advantages of the proposed methods to detect outlying centers, by comparing the proposed methods and existing methods which assume uncorrelated random center effects. In addition, we develop a Correlation Score Test to test the null hypothesis that the competing event processes within a center are correlated. Using data from the Scientific Registry of Transplant Recipients, we apply our method to evaluate the performance of Organ Procurement Organizations on two competing risks: (i) receipt of a kidney transplant and (ii) death on the wait-list.
Project description:We propose a Bayesian semiparametric joint regression model for a recurrent event process and survival time. Assuming independent latent subject frailties, we define marginal models for the recurrent event process intensity and survival distribution as functions of the subject's frailty and baseline covariates. A robust Bayesian model, called Joint-DP, is obtained by assuming a Dirichlet process for the frailty distribution. We present a simulation study that compares posterior estimates under the Joint-DP model to a Bayesian joint model with lognormal frailties, a frequentist joint model, and marginal models for either the recurrent event process or survival time. The simulations show that the Joint-DP model does a good job of correcting for treatment assignment bias, and has favorable estimation reliability and accuracy compared with the alternative models. The Joint-DP model is applied to analyze an observational dataset from esophageal cancer patients treated with chemo-radiation, including the times of recurrent effusions of fluid to the heart or lungs, survival time, prognostic covariates, and radiation therapy modality.