Kernel Estimation of Rate Function for Recurrent Event Data

Recurrent event data are largely characterized by the rate function but smoothing techniques for estimating the rate function have never been rigorously developed or studied in statistical literature. This paper considers the moment and least squares methods for estimating the rate function from recurrent event data. With an independent censoring assumption on the recurrent event process, we study statistical properties of the proposed estimators and propose bootstrap procedures for the bandwidth selection and for the approximation of confidence intervals in the estimation of the occurrence rate function. It is identified that the moment method without resmoothing via a smaller bandwidth will produce curve with nicks occurring at the censoring times, whereas there is no such problem with the least squares method. Furthermore, the asymptotic variance of the least squares estimator is shown to be smaller under regularity conditions. However, in the implementation of the bootstrap procedures, the moment method is computationally more efficient than the least squares method because the former approach uses condensed bootstrap data. The performance of the proposed procedures is studied through Monte Carlo simulations and an epidemiological example on intravenous drug users.

Survival Analysis with Large Dimensional Covariates: An Application in Microarray Studies

Use of microarray technology often leads to high-dimensional and low- sample size data settings. Over the past several years, a variety of novel approaches have been proposed for variable selection in this context. However, only a small number of these have been adapted for time-to-event data where censoring is present. Among standard variable selection methods shown both to have good predictive accuracy and to be computationally efficient is the elastic net penalization approach. In this paper, adaptation of the elastic net approach is presented for variable selection both under the Cox proportional hazards model and under an accelerated failure time (AFT) model. Assessment of the two methods is conducted through simulation studies and through analysis of microarray data obtained from a set of patients with diffuse large B-cell lymphoma where time to survival is of interest. The approaches are shown to match or exceed the predictive performance of a Cox-based and an AFT-based variable selection method. The methods are moreover shown to be much more computationally efficient than their respective Cox- and AFT- based counterparts.

Estimation with Interval Censored Data in Longitudinal Studies

In biostatistical applications interest often focuses on the estimation of the distribution of a time-until-event variable T. If one observes whether or not T exceeds an observed monitoring time at a random number of monitoring times, then the data structure is called interval censored data. We extend this data structure by allowing the presence of a possibly time-dependent covariate process that is observed until end of follow up. If one only assumes that the censoring mechanism satisfies coarsening at random, then, by the curve of dimensionality, typically no regular estimators will exist. To fight the curse of dimensionality we follow the approach of Robins and Rotnitzky (1992) by modeling parameters of the censoring mechanism. We model the right-censoring mechanism by modeling the hazard of the follow up time, conditional on T and the covariate process. For the monitoring mechanism we avoid modeling the joint distribution of the monitoring times by only modeling a univariate hazard of the pooled monitoring times, conditional on the follow up time, T, and the covariates process, which can be estimated by treating the pooled sample of monitoring times as i.i.d. In particular, it is assumed that the monitoring times and the right-censoring times only depend on T through the observed covariate process. We introduce inverse probability of censoring weighted (IPCW) estimator of the distribution of T and of smooth functionals thereof which are guaranteed to be consistent and asymptotically normal if we have available correctly specified semiparametric models for the two hazards of the censoring process. Furthermore, given such correctly specified models for these hazards of the censoring process, we propose a one-step estimator which will improve on the IPCW estimator if we correctly specify a lower-dimensional working model for the conditional distribution of T, given the covariate process, that remains consistent and asymptotically normal if this latter working model is misspecified. It is shown that the one-step estimator is efficient if each subject is at most monitored once and the working model contains the truth. In general, it is shown that the one-step estimator optimally uses the surrogate information if the working model contains the truth. It is not optimal in using the interval information provided by the current status indicators at the monitoring times, but simulations in Peterson, van der Laan (1997) show that the efficiency loss is small.

Locally Efficient Estimation with Current Status Data and High Dimensional Covariates

In biostatistical applications, interest often focuses on the estimation of the distribution of time T between two consecutive events. If the initial event time is observed and the subsequent event time is only known to be larger or smaller than an observed monitoring time, then the data is described by the well known singly-censored current status model, also known as interval censored data, case I. We extend this current status model by allowing the presence of a time-dependent process, which is partly observed and allowing C to depend on T through the observed part of this time-dependent process. Because of the high dimension of the covariate process, no globally efficient estimators exist with a good practical performance at moderate sample sizes. We follow the approach of Robins and Rotnitzky (1992) by modeling the censoring variable, given the time-variable and the covariate-process, i.e., the missingness process, under the restriction that it satisfied coarsening at random. We propose a generalization of the simple current status estimator of the distribution of T and of smooth functionals of the distribution of T, which is based on an estimate of the missingness. In this estimator the covariates enter only through the estimate of the missingness process. Due to the coarsening at random assumption, the estimator has the interesting property that if we estimate the missingness process more nonparametrically, then we improve its efficiency. We show that by local estimation of an optimal model or optimal function of the covariates for the missingness process, the generalized current status estimator for smooth functionals become locally efficient; meaning it is efficient if the right model or covariate is consistently estimated and it is consistent and asymptotically normal in general. Estimation of the optimal model requires estimation of the conditional distribution of T, given the covariates. Any (prior) knowledge of this conditional distribution can be used at this stage without any risk of losing root-n consistency. We also propose locally efficient one step estimators. Finally, we show some simulation results.

Analyzing Panel Count Data with Informative Observation Times

In this paper, we study panel count data with informative observation times. We assume nonparametric and semiparametric proportional rate models for the underlying recurrent event process, where the form of the baseline rate function is left unspecified and a subject-specific frailty variable inflates or deflates the rate function multiplicatively. The proposed models allow the recurrent event processes and observation times to be correlated through their connections with the unobserved frailty; moreover, the distributions of both the frailty variable and observation times are considered as nuisance parameters. The baseline rate function and the regression parameters are estimated by maximizing a conditional likelihood function of observed event counts and solving estimation equations. Large sample properties of the proposed estimators are studied. Numerical studies demonstrate that the proposed estimation procedures perform well for moderate sample sizes. An application to a bladder tumor study is presented to illustrate the use of the proposed methods.

Modeling multilevel sleep transitional data via Poisson log-linear multilevel models

This paper proposes Poisson log-linear multilevel models to investigate population variability in sleep state transition rates. We specifically propose a Bayesian Poisson regression model that is more flexible, scalable to larger studies, and easily fit than other attempts in the literature. We further use hierarchical random effects to account for pairings of individuals and repeated measures within those individuals, as comparing diseased to non-diseased subjects while minimizing bias is of epidemiologic importance. We estimate essentially non-parametric piecewise constant hazards and smooth them, and allow for time varying covariates and segment of the night comparisons. The Bayesian Poisson regression is justified through a re-derivation of a classical algebraic likelihood equivalence of Poisson regression with a log(time) offset and survival regression assuming piecewise constant hazards. This relationship allows us to synthesize two methods currently used to analyze sleep transition phenomena: stratified multi-state proportional hazards models and log-linear models with GEE for transition counts. An example data set from the Sleep Heart Health Study is analyzed.

Analyzing Bivariate Survival Data with Interval Sampling and Application to Cancer Epidemiology

In medical follow-up studies, ordered bivariate survival data are frequently encountered when bivariate failure events are used as the outcomes to identify the progression of a disease. In cancer studies interest could be focused on bivariate failure times, for example, time from birth to cancer onset and time from cancer onset to death. This paper considers a sampling scheme where the first failure event (cancer onset) is identified within a calendar time interval, the time of the initiating event (birth) can be retrospectively confirmed, and the occurrence of the second event (death) is observed sub ject to right censoring. To analyze this type of bivariate failure time data, it is important to recognize the presence of bias arising due to interval sampling. In this paper, nonparametric and semiparametric methods are developed to analyze the bivariate survival data with interval sampling under stationary and semi-stationary conditions. Numerical studies demonstrate the proposed estimating approaches perform well with practical sample sizes in different simulated models. We apply the proposed methods to SEER ovarian cancer registry data for illustration of the methods and theory.