Nonparametric estimation from current status data with competing risks

This paper considers joint analysis of current status and marker data using a threshold model based on first hitting times. A failure time is defined as the time at which a subject's latent health status process first decreases to zero. We extend the bivariate Wiener process model in Whitmore et al. (1998) to the case when only current status data are available. We develop maximum likelihood estimation procedures and provide simulation studies. We apply our methods to a motivating example involving liver tumors in mice.

In studies involving subclinical events, times of events are often subject to interval censoring since their occurrence is only detected at inspection times. When individuals are event-free at an initial time and a single follow-up inspection is made, current status data are obtained. In many settings, however, the population comprised a susceptible and a nonsusceptible subpopulation, where only susceptible individuals will go on to experience the event. Then interest often lies primarily in identifying prognostic variables for susceptibility, and secondarily in the event time distribution among the susceptible individuals. We give a simple mixture model that facilitates estimation of the proportion of susceptible individuals, covariate effects on the odds of susceptibility, and the event time distribution under a current status observation scheme. Asymptotic relative efficiency of maximum likelihood estimators is considered based on the Fisher information for a variety of settings. EM algorithms are proposed for parametric, weakly parametric, and nonparametric estimation of the event time distribution. The methods are applied to motivating studies examining an immunological response to low molecular weight heparin in patients undergoing orthopedic surgery.

The authors propose a reduction technique and versions of the EM algorithm and the vertex exchange method to perform constrained nonparametric maximum likelihood estimation of the cumulative distribution function given interval censored data. The constrained vertex exchange method can be used in practice to produce likelihood intervals for the cumulative distribution function. In particular, the authors show how to produce a confidence interval with known asymptotic coverage for the survival function given current status data. Estimation sous contrainte et intervalles de vraisemblance pour données censurées: Les auteurs proposent une technique de réduction des données ainsi que deux algorithmes dérivés respectivement de l'algorithme EM et de la méthode d'échange des sommets (MES) conduisant à un estimateur du maximum de vraisemblance non paramétrique sous contrainte de la fonction de répartition avec données censurées par i ntervalle. La MES sous contrainte peut être utilisée en pratique pour produire des intervalles de vraisemblance pour la fonction de répartition. Plus particulièrement, les auteurs montremt comment produire un intervalle de confiance pour la fonction de survie de couverture asymptotique connue lorsque les données sont censurées à gauche ou à droite.

We develop the non-parametric maximum likelihood estimator (MLE) of the full Mbh capture-recapture model which utilizes both initial capture and recapture data and permits both heterogeneity (h) between animals and behavioural (b) response to capture. Our MLE procedure utilizes non-parametric maximum likelihood estimation of mixture distributions (Lindsay, 1983; Lindsay and Roeder, 1992) and the EM algorithm (Dempsteret al., 1977). Our MLE estimate provides the first non-parametric estimate of the bivariate capture-recapture distribution. Since non-parametric maximum likelihood estimation exists for submodels Mh (allowing heterogeneity only), Mb (allowing behavioural response only) and M0 (allowing no changes), we develop maximum likelihood-based model selection, specifically the Akaike information criterion (AIC) (Akaike, 1973). The AIC procedure does well in detecting behavioural response but has difficulty in detecting heterogeneity.

We consider a varying-coefficient partially linear proportional odds model with current status data. This model enables one to examine the extent to which some covariates interact nonlinearly with an exposure variable, while other covariates present linear effects. B-spline approach and sieve maximum likelihood estimation method are used to get an integrated estimate for the linear coefficients, the varying-coefficient functions and the baseline function. The proposed parameter estimators are proved to be semiparametrically efficient and asymptotically normal, and the estimators for the nonparametric functions achieve the optimal rate of convergence. Simulation studies and a real data analysis are used for assessment and illustration.

The nonparametric maximum likelihood estimation (NPMLE) of the distribution function from the interval censored (IC) data has been extensively studied in the extant literature. The NPMLE was also developed for the subdistribution functions in an IC competing risks model and in an illness-death model under various interval-censoring scenarios. But the important problem of estimation of the cumulative intensities (CIs) in the interval-censored models has not been considered previously. We develop the NPMLE of the CI in a simple alive/dead model and of the CIs in a competing risks model. Assuming that data are generated by a discrete and finite mixed case interval censoring mechanism we provide a discussion and the simulation study of the asymptotic properties of the NPMLEs of the CIs. In particular we show that they are asymptotically unbiased; in contrast the ad hoc estimators presented in extant literature are substantially biased. We illustrate our methods with the data from a prospective cohort study on the longevity of dental veneers.

We study efficient nonparametric estimation of distribution functions of several scientifically meaningful sub-populations from data consisting of mixed samples where the sub-population identifiers are missing. Only probabilities of each observation belonging to a sub-population are available. The problem arises from several biomedical studies such as quantitative trait locus (QTL) analysis and genetic studies with ungenotyped relatives where the scientific interest lies in estimating the cumulative distribution function of a trait given a specific genotype. However, in these studies subjects' genotypes may not be directly observed. The distribution of the trait outcome is therefore a mixture of several genotype-specific distributions. We characterize the complete class of consistent estimators which includes members such as one type of nonparametric maximum likelihood estimator (NPMLE) and least squares or weighted least squares estimators. We identify the efficient estimator in the class that reaches the semiparametric efficiency bound, and we implement it using a simple procedure that remains consistent even if several components of the estimator are mis-specified. In addition, our close inspections on two commonly used NPMLEs in these problems show the surprising results that the NPMLE in one form is highly inefficient, while in the other form is inconsistent. We provide simulation procedures to illustrate the theoretical results and demonstrate the proposed methods through two real data examples.

In many epidemiologic studies of human immunodeficiency virus (HIV) disease, interest focuses on the distribution of the length of the interval of time between two events. In many such cases, statistical estimation of properties of this distribution is complicated by the fact that observation of the times of both events is subject to intervalcensoring so that the length of time between the events is never observed exactly. Following DeGruttola and Lagakos, we call such data doubly-censored. Jewell, Malani and Vittinghoff showed that, with certain assumptions and for a particular doubly-censored data structure, non-parametric maximum likelihood estimation of the interval length distribution is equivalent to non-parametric estimation of a mixing distribution. Here, we extend these ideas to various other kinds of doubly-censored data. We consider application of the methods to various studies generated by investigations into the natural history of HIV disease with particular attention given to estimation of the distribution of time between infection of an individual (an index case) and transmission of HIV to their sexual partner.

We show that under reasonable conditions the nonparametric maximum likelihood estimate (NPMLE) of the distribution function from left-truncated and case 1 interval-censored data is inconsistent, in contrast to the consistency properties of the NPMLE from only left-truncated data or only interval-censored data. However, the conditional NPMLE is shown to be consistent. Numerical examples are provided to illustrate their finite sample properties.

We recently proposed a representation of the bivariate survivor function as a mapping of the hazard function for truncated failure time variates. The representation led to a class of estimators that includes van der Laan's repaired nonparametric maximum likelihood estimator (NPMLE) as an important special case. We proposed a Greenwood-like variance estimator for the repaired NPMLE but found somewhat poor agreement between the empirical variance estimates and these analytic estimates for the sample sizes and bandwidths considered in our simulation study. The simulation results also confirmed those of others in showing slightly inferior performance for the repaired NPMLE compared to other competing estimators as well as a sensitivity to bandwidth choice in moderate sized samples. Despite its attractive asymptotic properties, the repaired NPMLE has drawbacks that hinder its practical application. This paper presents a modification of the repaired NPMLE that improves its performance in moderate sized samples and renders it less sensitive to the choice of bandwidth. Along with this modified estimator, more extensive simulation studies of the repaired NPMLE and Greenwood-like variance estimates are presented. The methods are then applied to a real data example.

ABSTRACTIn this paper, we introduce a partially linear single-index additive hazards model with current status data. Both the unknown link function of the single-index term and the cumulative baseline hazard function are approximated by B-splines under a monotonicity constraint on the latter. The sieve method is applied to estimate the nonparametric and parametric components simultaneously. We show that, when the nonparametric link function is an exact B-spline, the resultant estimator of regression parameter vector is asymptotically normal and achieves the semiparametric information bound and the rate of convergence of the estimator for the cumulative baseline hazard function is optimal. Simulation studies are presented to examine the finite sample performance of the proposed estimation method. For illustration, we apply the method to a clinical dataset with current status outcome.

We investigate empirical likelihood for the additive hazards model with current status data. An empirical log-likelihood ratio for a vector or subvector of regression parameters is defined and its limiting distribution is shown to be a standard chi-squared distribution. The proposed inference procedure enables us to make empirical likelihood-based inference for the regression parameters. Finite sample performance of the proposed method is assessed in simulation studies to compare with that of a normal approximation method, it shows that the empirical likelihood method provides more accurate inference than the normal approximation method. A real data example is used for illustration.

In survival analysis, estimating the failure time distribution is an important and difficult task, since usually the data is subject to censoring. Specifically, in this paper we consider current status data, a type of data where the failure time cannot be directly observed. The format of the data is such that the failure time is restricted to knowledge of whether or not the failure time exceeds a random monitoring time. We propose a flexible kernel machine approach for estimation of the failure time expectation as a function of the covariates, with current status data. In order to obtain the kernel machine decision function, we minimize a regularized version of the empirical risk with respect to a new loss function. Using finite sample bounds and novel oracle inequalities, we prove that the obtained estimator converges to the true conditional expectation for a large family of probability measures. Finally, we present a simulation study and an analysis of real-world data that compares the performance of the proposed approach to existing methods. We show empirically that our approach is comparable to current state of the art, and in some cases is even better.

The cumulative incidence is the probability of failure from the cause of interest over a certain time period in the presence of other risks. A semiparametric regression model proposed by Fine and Gray (1999) has become the method of choice for formulating the effects of covariates on the cumulative incidence. Its estimation, however, requires modeling of the censoring distribution and is not statistically efficient. In this paper, we present a broad class of semiparametric transformation models which extends the Fine and Gray model, and we allow for unknown causes of failure. We derive the nonparametric maximum likelihood estimators (NPMLEs) and develop simple and fast numerical algorithms using the profile likelihood. We establish the consistency, asymptotic normality, and semiparametric efficiency of the NPMLEs. In addition, we construct graphical and numerical procedures to evaluate and select models. Finally, we demonstrate the advantages of the proposed methods over the existing ones through extensive simulation studies and an application to a major study on bone marrow transplantation.

The current status and panel count data frequently arise from cancer and tumorigenicity studies when events currently occur. A common and widely used class of two sample tests, for current status and panel count data, is the permutation class. We manipulate the double saddlepoint method to calculate the exact mid-p-values of the underlying permutation distributions of this class of tests. Permutation simulations are replaced by analytical saddlepoint computations which provide extremely accurate mid-p-values that are exact for most practical purposes and almost always more accurate than normal approximations. The method is illustrated using two real tumorigenicity panel count data. To compare the saddlepoint approximation with the normal asymptotic approximation, a simulation study is conducted. The speed and accuracy of the saddlepoint method facilitate the calculation of the confidence interval for the treatment effect. The inversion of the mid-p-values to calculate the confidence interval for the mean rate of development of the recurrent event is discussed.