Constrained estimation and likelihood intervals for censored data

SUMMARY A great deal of recent attention has focused on the estimation of survival distributions based on current status data, an extreme form of interval censored data. This particular data structure arises in a wide variety of applications where cross-sectional observation either naturally occurs or is preferred to more traditional forms of follow-up. Here we consider current status data in the context of competing risks. We briefly consider simple parametric models as a backdrop to nonparametric procedures. We make some brief comparisons and remarks regarding the nonparametric maximum likelihood estimator. The ideas are illustrated on the data of Krailo & Pike (1983) which considers estimation of the age distribution at both natural and operative menopause. We also consider the case where there is exact observation of failure times due to one of the competing risks when failure occurs prior to the monitoring time. Basic techniques of survival analysis focus on estimation of the survival distribution based on various forms of censored data. An extreme form of censoring arises where the only information on studied individuals is their survival status at a single monitoring time. This particular data structure is known as current status data. Nonparametric estimation of the survival function and semiparametric techniques for related regression models, based on current status data, have been much studied of late. Here, we consider estimation of sub-survival functions based on current status observations in the presence of competing risks. For simplicity, we describe only two competing risks, but the ideas are easily extended when there are more than two possible causes of failure. Let )j denote the cause-specific hazard function for cause j = 1, 2 (Kalbfleisch & Prentice, 2002, p. 252). If T and J are the random variables that measure time to failure and cause of failure, respectively, the two sub-distribution functions of interest are

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.

Monotone function, such as growth function and cumulative distribution function, is often a study of interest in statistical literature. In this dissertation, we propose a nonparametric least-squares method for estimating monotone functions induced from stochastic processes in which the starting time of the process is subject to interval censoring. We apply this method to estimate the mean function of tumor growth with the data from either animal experiments or tumor screening programs to investigate tumor progression. In this type of application, the tumor onset time is observed within an interval. The proposed method can also be used to estimate the cumulative distribution function of the elapsed time between two related events in human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) studies, such as HIV transmission time between two partners and AIDS incubation time from HIV infection to AIDS onset. In these applications, both the initial event and the subsequent event are only known to occur within some intervals. Such data are called doubly interval-censored data. The common property of these stochastic processes is that the starting time of the process is subject to interval censoring. A unified two-step nonparametric estimation procedure is proposed for these problems. In the first step of this method, the nonparametric maximum likelihood estimate (NPMLE) of the cumulative distribution function for the starting time of the stochastic process is estimated with the framework of interval-censored data. In the second step, a specially designed least-squares objective function is constructed with the above NPMLE plugged in and the nonparametric least-squares estimate (NPLSE) of the mean function of tumor growth or the cumulative distribution function of the elapsed time is obtained by minimizing the aforementioned objective function. The theory of modern empirical process is applied to prove the consistency

This paper proposes a data-driven approximation of the Cumulative Distribution Function using the Finite Mixtures of the Cumulative Distribution Function of Logistic distribution. Since it is not possible to solve the logistic mixture model using the Maximum likelihood method, the mixture model is modeled to approximate the empirical cumulative distribution function using the computational intelligence algorithms. The Probability Density Function is obtained by differentiating the estimate of the Cumulative Distribution Function. The proposed technique estimates the Cumulative Distribution Function of different benchmark distributions. Also, the performance of the proposed technique is compared with the state-of-the-art kernel density estimator and the Gaussian Mixture Model. Experimental results on κ−μ distribution show that the proposed technique performs equally well in estimating the probability density function. In contrast, the proposed technique outperforms in estimating the cumulative distribution function. Also, it is evident from the experimental results that the proposed technique outperforms the state-of-the-art Gaussian Mixture model and kernel density estimation techniques with less training data.

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 events of interest in any survival analysis study are regularly subject to censoring. There are various censoring schemes, including right or left censoring, and interval censoring. The most frequent censoring scheme is the right censoring, where subjects might drop out of the study or simply because not all events of interest occur before the end of the study. Moreover, for each subject, additional information referred to as covariates is registered at the beginning or throughout the study, such as age, sex, undergoing treatment, etc. The classical model to study the distribution of the events of interest, while accounting for additional information, is the Cox model. The Cox model expresses the hazard function of a subject given a set of covariates in terms of a baseline hazard, for which all covariates are zero, and an exponential function of the covariates and corresponding regression parameters. The baseline hazard can be left completely unspecified while estimating the regression parameters. Nonetheless, in practice, there are numerous studies in which the baseline hazard appears to be monotone. Time to death or to the onset of a disease are observed to have a nondecreasing baseline hazard, while the survival or recovery time after a successful medical treatment usually exhibit a nonincreasing baseline hazard. The aim of this thesis is to study the behavior of nonparametric baseline hazard and baseline density estimators in the Cox model under monotonicity constraints. The event times are assumed to be right censored and the censoring mechanism is assumed to be independent of the event of interest and non-informative. The covariates are assumed to be time-independent, usually recorded at the beginning of the study. In addition to point estimates, interval estimates of a monotone baseline hazard will be provided, based on a likelihood ratio method, along with testing at a fixed point. Furthermore, kernel smoothed estimates of a monotone baseline hazard will be defined and their behavior will be investigated. In Chapter 2, we propose several nonparametric monotone estimators of a baseline hazard or a baseline density within the Cox model. We derive the nonparametric maximum likelihood estimator of a nondecreasing baseline hazard and we consider a Grenander-type estimator, defined as the left-hand slope of the greatest convex minorant of the Breslow estimator. The two estimators are then shown to be strongly consistent and asymptotically equivalent. Moreover, we derive their common limit distribution at a fixed point. The two equivalent estimators of a nonincreasing baseline hazard and their asymptotic properties are acquired similarly. Furthermore, we introduce a Grenander-type estimator of a nonincreasing baseline density, defined as the left-hand slope of the least concave majorant of an estimator of the baseline cumulative distribution function derived from the Breslow estimator. This estimator is proven to be strongly consistent and its asymptotic distribution at a fixed point is derived. Chapter 3 provides an asymptotic linear representation of the Breslow estimator of the baseline cumulative hazard function in the Cox model. This representation can be used to derive the asymptotic distribution of the Grenander type estimator of a monotone baseline hazard estimator. The representation consists of an average of independent random variables and a term involving the difference between the maximum partial likelihood estimator and the underlying regression parameter. The order of the remainder term is arbitrarily close to n^-1. Chapter 4 focuses on interval estimation and on testing whether a monotone baseline hazard function in the Cox model has a particular value at a fixed point, via a likelihood ratio method. Nonparametric maximum likelihood estimators under the null hypothesis are defined for both nondecreasing and nonincreasing baseline hazard functions. These characterizations, along with those of the monotone nonparametric maximum likelihood estimators provide the asymptotic distribution of the likelihood ratio test. This asymptotic distribution enables, via inversion, the construction of pointwise confidence intervals. This method of constructing confidence intervals avoids the issue of estimating the nuisance parameters, as in the case of confidence intervals based on the asymptotic distribution of the estimators. Simulations indicate that the two methods yield confidence intervals with comparable coverage probabilities. Nonetheless, the confidence intervals based on the likelihood ratio are smaller, on average. Finally, in chapter 5 we consider smooth baseline hazard estimators. The estimators are obtained by kernel smoothing the maximum likelihood and Grenander-type estimators of a monotone baseline hazard function. Three different estimators are proposed for a nondecreasing baseline hazard, which are provided by the interchange of the smoothing and isotonization step. With this respect, we define a smoothed maximum likelihood estimator (SMLE), as well as a smoothed Grenander type (SG) estimator and a Grenander type smoothed (GS) estimator. All estimators are shown to be strongly pointwise or uniformly consistent.

This paper describes evaluation procedures and experimental results for the estimation of Cumulative Distribution Functions (CDF) giving best-fit to the sample data in the Probability based risk Evaluation Techniques (PET) which is to assess the risks of a small-sized sea floater. The CDF in the PET is to provide the reference values of risk acceptance criteria which are to evaluate the risk level of the floater and, it can be estimated from sample data sets of motion response functions such as Roll, Pitch and Heave in the floater model. Using Maximum Likelihood Estimates and with the eight kinds of regulated distribution functions, the evaluation tests for the CDF having maximum likelihood to the sample data are carried out in this work. Throughout goodness-of-fit tests to the distribution functions, it is shown that the Beta distribution is best-fit to the Roll and Pitch sample data with smallest averaged probability errors of 0.024 and 0.022, respectively and, Gamma distribution is best-fit to the Heave sample data with smallest of 0.027. The proposed method in this paper can be expected to adopt in various application areas estimating best-fit distributions to the sample data.

Suppose that in a carcinogenicity experiment with animals where the tumour is not palpable, we observe only the time of death of the animal, the cause of death (the tumour or another independent cause, as sacrifice) and whether the tumour was present at the time of death. These last two indicator variables are evaluated after an autopsy. We can estimate the cumulative distribution function F 2 of the time of death from the disease using the Kaplan–Meier estimator and then calculate the non-parametric maximum pseudo-likelihood estimator (NPMPLE) of the cumulative distribution function F 1 of the time of onset of the disease. After a brief review of some past works on the estimation of F 1 and F 2, we demonstrate the strong uniform consistency of the NPMPLE of F 1.

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.

ABSTRACTIn this paper we consider the uniform strong consistency, along with a rate, of the cumulative distribution function (CDF) estimator. We extend the extended Glivenko–Cantelli lemma (for empirical distribution function) in Fabian and Hannan (1985, pp. 80–83) to the kernel estimator of the CDF.

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.

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 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.