Incorporating diagnostic accuracy into the estimation of discrete survival function

Empirical distribution function (EDF) is a commonly used estimator of population cumulative distribution function. Survival function is estimated as the complement of EDF. However, clinical diagnosis of an event is often subjected to misclassification, by which the outcome is given with some uncertainty. In the presence of such errors, the true distribution of the time to first event is unknown. We develop a method to estimate the true survival distribution by incorporating negative predictive values and positive predictive values of the prediction process into a product-limit style construction. This will allow us to quantify the bias of the EDF estimates due to the presence of misclassified events in the observed data. We present an unbiased estimator of the true survival rates and its variance. Asymptotic properties of the proposed estimators are provided and these properties are examined through simulations. We evaluate our methods using data from the VIRAHEP-C study.     

Estimation in autoregressive models with surrogate data and validation data

Time-series data are often subject to measurement error, usually the result of needing to estimate the variable of interest. Generally, however, the relationship between the surrogate variables and the true variables can be rather complicated compared to the classical additive error structure usually assumed. In this article, we address the estimation of the parameters in autoregressive models in the presence of function measurement errors. We first develop a parameter estimation method with the help of validation data; this estimation method does not depend on functional form and the distribution of the measurement error. The proposed estimator is proved to be consistent. Moreover, the asymptotic representation and the asymptotic normality of the estimator are also derived, respectively. Simulation results indicate that the proposed method works well for practical situation.     

A Bezier curve method in interval-censored data

In this paper we propose a Bezier curve method to estimate the survival function and the median survival time in interval-censored data. We compare the proposed estimator with other existing methods such as the parametric method, the single point imputation method, and the nonparametric maximum likelihood estimator through extensive numerical studies, and it is shown that the proposed estimator performs better than others in the sense of mean squared error and mean integrated squared error. An illustrative example based on a real data set is given.     

A flexible parametric survival model for fitting time to event data in clinical trials

Time‐to‐event data are common in clinical trials to evaluate survival benefit of a new drug, biological product, or device. The commonly used parametric models including exponential, Weibull, Gompertz, log‐logistic, log‐normal, are simply not flexible enough to capture complex survival curves observed in clinical and medical research studies. On the other hand, the nonparametric Kaplan Meier (KM) method is very flexible and successful on catching the various shapes in the survival curves but lacks ability in predicting the future events such as the time for certain number of events and the number of events at certain time and predicting the risk of events (eg, death) over time beyond the span of the available data from clinical trials. It is obvious that neither the nonparametric KM method nor the current parametric distributions can fulfill the needs in fitting survival curves with the useful characteristics for predicting. In this paper, a full parametric distribution constructed as a mixture of three components of Weibull distribution is explored and recommended to fit the survival data, which is as flexible as KM for the observed data but have the nice features beyond the trial time, such as predicting future events, survival probability, and hazard function.     

An empirical saddlepoint approximation based method for smoothing survival functions under right censoring

The Kaplan–Meier (KM) estimator is ubiquitously used for estimating survival functions, but it provides only a discrete approximation at the observation times and does not deliver a proper distribution if the largest observation is censored. Using KM as a starting point, we devise an empirical saddlepoint approximation‐based method for producing a smooth survival function that is unencumbered by choice of tuning parameters. The procedure inverts the moment generating function (MGF) defined through a Riemann–Stieltjes integral with respect to an underlying mixed probability measure consisting of the discrete KM mass function weights and an absolutely continuous exponential right‐tail completion. Uniform consistency, and weak and strong convergence results are established for the resulting MGF and its derivatives, thus validating their usage as inputs into the saddlepoint routines. Relevant asymptotic results are also derived for the density and distribution function estimates. The performance of the resulting survival approximations is examined in simulation studies, which demonstrate a favourable comparison with the log spline method (Kooperberg & Stone, 1992) in small sample settings. For smoothing survival functions we argue that the methodology has no immediate competitors in its class, and we illustrate its application on several real data sets. The Canadian Journal of Statistics 47: 238–261; 2019 © 2019 Statistical Society of Canada     

A New Regression Model: Modal Linear Regression

The mode of a distribution provides an important summary of data and is often estimated on the basis of some non‐parametric kernel density estimator. This article develops a new data analysis tool called modal linear regression in order to explore high‐dimensional data. Modal linear regression models the conditional mode of a response Y given a set of predictors x as a linear function of x . Modal linear regression differs from standard linear regression in that standard linear regression models the conditional mean (as opposed to mode) of Y as a linear function of x . We propose an expectation–maximization algorithm in order to estimate the regression coefficients of modal linear regression. We also provide asymptotic properties for the proposed estimator without the symmetric assumption of the error density. Our empirical studies with simulated data and real data demonstrate that the proposed modal regression gives shorter predictive intervals than mean linear regression, median linear regression and MM‐estimators.     

MODEL‐BASED DIRECT ESTIMATION OF SMALL‐AREA DISTRIBUTIONS

Much of the small‐area estimation literature focuses on population totals and means. However, users of survey data are often interested in the finite‐population distribution of a survey variable and in the measures (e.g. medians, quartiles, percentiles) that characterize the shape of this distribution at the small‐area level. In this paper we propose a model‐based direct estimator (MBDE, Chandra and Chambers) of the small‐area distribution function. The MBDE is defined as a weighted sum of sample data from the area of interest, with weights derived from the calibrated spline‐based estimate of the finite‐population distribution function introduced by Harms and Duchesne, under an appropriately specified regression model with random area effects. We also discuss the mean squared error estimation of the MBDE. Monte Carlo simulations based on both simulated and real data sets show that the proposed MBDE and its associated mean squared error estimator perform well when compared with alternative estimators of the area‐specific finite‐population distribution function.     

A Spline‐Based Semiparametric Maximum Likelihood Estimation Method for the Cox Model with Interval‐Censored Data

Abstract. We propose a spline‐based semiparametric maximum likelihood approach to analysing the Cox model with interval‐censored data. With this approach, the baseline cumulative hazard function is approximated by a monotone B‐spline function. We extend the generalized Rosen algorithm to compute the maximum likelihood estimate. We show that the estimator of the regression parameter is asymptotically normal and semiparametrically efficient, although the estimator of the baseline cumulative hazard function converges at a rate slower than root‐n. We also develop an easy‐to‐implement method for consistently estimating the standard error of the estimated regression parameter, which facilitates the proposed inference procedure for the Cox model with interval‐censored data. The proposed method is evaluated by simulation studies regarding its finite sample performance and is illustrated using data from a breast cosmesis study.     

Estimation with Interval Censored Data and 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 C, then the data conforms to the well understood singly-censored current status model, also known as interval censored data, case I. Additional covariates can be used to allow for dependent censoring and to improve estimation of the marginal distribution of T. Assuming a wrong model for the conditional distribution of T, given the covariates, will lead to an inconsistent estimator of the marginal distribution. On the other hand, the nonparametric maximum likelihood estimator of FT requires splitting up the sample in several subsamples corresponding with a particular value of the covariates, computing the NPMLE for every subsample and then taking an average. With a few continuous covariates the performance of the resulting estimator is typically miserable. In van der Laan, Robins (1996) a locally efficient one-step estimator is proposed for smooth functionals of the distribution of T, assuming nothing about the conditional distribution of T, given the covariates, but assuming a model for censoring, given the covariates. The estimators are asymptotically linear if the censoring mechanism is estimated correctly. The estimator also uses an estimator of the conditional distribution of T, given the covariates. If this estimate is consistent, then the estimator is efficient and if it is inconsistent, then the estimator is still consistent and asymptotically normal. In this paper we show that the estimators can also be used to estimate the distribution function in a locally optimal way. Moreover, we show that the proposed estimator can be used to estimate the distribution based on interval censored data (T is now known to lie between two observed points) in the presence of covariates. The resulting estimator also has a known influence curve so that asymptotic confidence intervals are directly available. In particular, one can apply our proposal to the interval censored data without covariates. In Geskus (1992) the information bound for interval censored data with two uniformly distributed monitoring times at the uniform distribution (for T has been computed. We show that the relative efficiency of our proposal w.r.t. this optimal bound equals 0.994, which is also reflected in finite sample simulations. Finally, the good practical performance of the estimator is shown in a simulation study. This revised version was published online in July 2006 with corrections to the Cover Date.     

Locally Efficient Semiparametric Estimators for Proportional Hazards Models with Measurement Error

We propose a new class of semiparametric estimators for proportional hazards models in the presence of measurement error in the covariates, where the baseline hazard function, the hazard function for the censoring time, and the distribution of the true covariates are considered as unknown infinite dimensional parameters. We estimate the model components by solving estimating equations based on the semiparametric efficient scores under a sequence of restricted models where the logarithm of the hazard functions are approximated by reduced rank regression splines. The proposed estimators are locally efficient in the sense that the estimators are semiparametrically efficient if the distribution of the error‐prone covariates is specified correctly and are still consistent and asymptotically normal if the distribution is misspecified. Our simulation studies show that the proposed estimators have smaller biases and variances than competing methods. We further illustrate the new method with a real application in an HIV clinical trial.     

A general quantile residual life model for length‐biased right‐censored data

The quantile residual lifetime function provides comprehensive quantitative measures for residual life, especially when the distribution of the latter is skewed or heavy‐tailed and/or when the data contain outliers. In this paper, we propose a general class of semiparametric quantile residual life models for length‐biased right‐censored data. We use the inverse probability weighted method to correct the bias due to length‐biased sampling and informative censoring. Two estimating equations corresponding to the quantile regressions are constructed in two separate steps to obtain an efficient estimator. Consistency and asymptotic normality of the estimator are established. The main difficulty in implementing our proposed method is that the estimating equations associated with the quantiles are nondifferentiable, and we apply the majorize–minimize algorithm and estimate the asymptotic covariance using an efficient resampling method. We use simulation studies to evaluate the proposed method and illustrate its application by a real‐data example.     

Inverse probability of censoring weighting for visual predictive checks of time-to-event models with time-varying covariates

When constructing models to summarize clinical data to be used for simulations, it is good practice to evaluate the models for their capacity to reproduce the data. This can be done by means of Visual Predictive Checks (VPC), which consist of several reproductions of the original study by simulation from the model under evaluation, calculating estimates of interest for each simulated study and comparing the distribution of those estimates with the estimate from the original study. This procedure is a generic method that is straightforward to apply, in general. Here we consider the application of the method to time-to-event data and consider the special case when a time-varying covariate is not known or cannot be approximated after event time. In this case, simulations cannot be conducted beyond the end of the follow-up time (event or censoring time) in the original study. Thus, the simulations must be censored at the end of the follow-up time. Since this censoring is not random, the standard KM estimates from the simulated studies and the resulting VPC will be biased. We propose to use inverse probability of censoring weighting (IPoC) method to correct the KM estimator for the simulated studies and obtain unbiased VPCs. For analyzing the Cantos study, the IPoC weighting as described here proved valuable and enabled the generation of VPCs to qualify PKPD models for simulations. Here, we use a generated data set, which allows illustration of the different situations and evaluation against the known truth.     

A robust and efficient estimation method for nonparametric models with jump points

Nonparametric models with jump points have been considered by many researchers. However, most existing methods based on least squares or likelihood are sensitive when there are outliers or the error distribution is heavy tailed. In this article, a local piecewise-modal method is proposed to estimate the regression function with jump points in nonparametric models, and a piecewise-modal EM algorithm is introduced to estimate the proposed estimator. Under some regular conditions, the large-sample theory is established for the proposed estimators. Several simulations are presented to evaluate the performances of the proposed method, which shows that the proposed estimator is more efficient than the local piecewise-polynomial regression estimator in the presence of outliers or heavy tail error distribution. What is more, the proposed procedure is asymptotically equivalent to the local piecewise-polynomial regression estimator under the assumption that the error distribution is a Gaussian distribution. The proposed method is further illustrated via the sea-level pressures.     

The least concave majorant of the empirical distribution function

The author compares two estimators of a continuous, concave distribution function having support on the positive half line. In terms of samples from uniform distributions, he gives stochastic bounds for the pointwise and sup‐norm differences between the least concave majorant of the empirical distribution function and the underlying distribution function. He also offers evidence demonstrating the almost paradoxical result that the empirical distribution function is not as good an estimator as its least concave majorant in terms of sup‐norm error but a better pointwise estimator of the true distribution function in terms of mean squared error.     

Estimation Under Inequality Constraints: Semiparametric Estimation of Conditional Duration Models

This article proposes a semiparametric estimator of the parameter in a conditional duration model when there are inequality constraints on some parameters and the error distribution may be unknown. We propose to estimate the parameter by a constrained version of an unrestricted semiparametrically efficient estimator. The main requirement for applying this method is that the initial unrestricted estimator converges in distribution. Apart from this, additional regularity conditions on the data generating process or the likelihood function, are not required. Hence the method is applicable to a broad range of models where the parameter space is constrained by inequality constraints, such as the conditional duration models. In a simulation study involving conditional duration models, the overall performance of the constrained estimator was better than its competitors, in terms of mean squared error. A data example is used to illustrate the method.     

Pseudo-empirical Bayes estimation of small area means under a nested error linear regression model with functional measurement errors

Small area estimation is studied under a nested error linear regression model with area level covariate subject to measurement error. Ghosh and Sinha (2007) obtained a pseudo-Bayes (PB) predictor of a small area mean and a corresponding pseudo-empirical Bayes (PEB) predictor, using the sample means of the observed covariate values to estimate the true covariate values. In this paper, we first derive an efficient PB predictor by using all the available data to estimate true covariate values. We then obtain a corresponding PEB predictor and show that it is asymptotically “optimal”. In addition, we employ a jackknife method to estimate the mean squared prediction error (MSPE) of the PEB predictor. Finally, we report the results of a simulation study on the performance of our PEB predictor and associated jackknife MSPE estimator. Our results show that the proposed PEB predictor can lead to significant gain in efficiency over the previously proposed PEB predictor. Area level models are also studied.     

Composite Estimation for Single‐Index Models with Responses Subject to Detection Limits

We propose a semiparametric estimator for single‐index models with censored responses due to detection limits. In the presence of left censoring, the mean function cannot be identified without any parametric distributional assumptions, but the quantile function is still identifiable at upper quantile levels. To avoid parametric distributional assumption, we propose to fit censored quantile regression and combine information across quantile levels to estimate the unknown smooth link function and the index parameter. Under some regularity conditions, we show that the estimated link function achieves the non‐parametric optimal convergence rate, and the estimated index parameter is asymptotically normal. The simulation study shows that the proposed estimator is competitive with the omniscient least squares estimator based on the latent uncensored responses for data with normal errors but much more efficient for heavy‐tailed data under light and moderate censoring. The practical value of the proposed method is demonstrated through the analysis of a human immunodeficiency virus antibody data set.     

The Poisson Generalized Linear Failure Rate Model

We formulate a new cure rate survival model by assuming that the number of competing causes of the event of interest has the Poisson distribution, and the time to this event has the generalized linear failure rate distribution. A new distribution to analyze lifetime data is defined from the proposed cure rate model, and its quantile function as well as a general expansion for the moments is derived. We estimate the parameters of the model with cure rate in the presence of covariates for censored observations using maximum likelihood and derive the observed information matrix. We obtain the appropriate matrices for assessing local influence on the parameter estimates under different perturbation schemes and present some ways to perform global influence analysis. The usefulness of the proposed cure rate survival model is illustrated in an application to real data.     

A Semi‐parametric Transformation Frailty Model for Semi‐competing Risks Survival Data

In the analysis of semi‐competing risks data interest lies in estimation and inference with respect to a so‐called non‐terminal event, the observation of which is subject to a terminal event. Multi‐state models are commonly used to analyse such data, with covariate effects on the transition/intensity functions typically specified via the Cox model and dependence between the non‐terminal and terminal events specified, in part, by a unit‐specific shared frailty term. To ensure identifiability, the frailties are typically assumed to arise from a parametric distribution, specifically a Gamma distribution with mean 1.0 and variance, say, σ². When the frailty distribution is misspecified, however, the resulting estimator is not guaranteed to be consistent, with the extent of asymptotic bias depending on the discrepancy between the assumed and true frailty distributions. In this paper, we propose a novel class of transformation models for semi‐competing risks analysis that permit the non‐parametric specification of the frailty distribution. To ensure identifiability, the class restricts to parametric specifications of the transformation and the error distribution; the latter are flexible, however, and cover a broad range of possible specifications. We also derive the semi‐parametric efficient score under the complete data setting and propose a non‐parametric score imputation method to handle right censoring; consistency and asymptotic normality of the resulting estimators is derived and small‐sample operating characteristics evaluated via simulation. Although the proposed semi‐parametric transformation model and non‐parametric score imputation method are motivated by the analysis of semi‐competing risks data, they are broadly applicable to any analysis of multivariate time‐to‐event outcomes in which a unit‐specific shared frailty is used to account for correlation. Finally, the proposed model and estimation procedures are applied to a study of hospital readmission among patients diagnosed with pancreatic cancer.     

Fitting Cox Models with Doubly Censored Data Using Spline‐Based Sieve Marginal Likelihood

In some applications, the failure time of interest is the time from an originating event to a failure event while both event times are interval censored. We propose fitting Cox proportional hazards models to this type of data using a spline‐based sieve maximum marginal likelihood, where the time to the originating event is integrated out in the empirical likelihood function of the failure time of interest. This greatly reduces the complexity of the objective function compared with the fully semiparametric likelihood. The dependence of the time of interest on time to the originating event is induced by including the latter as a covariate in the proportional hazards model for the failure time of interest. The use of splines results in a higher rate of convergence of the estimator of the baseline hazard function compared with the usual non‐parametric estimator. The computation of the estimator is facilitated by a multiple imputation approach. Asymptotic theory is established and a simulation study is conducted to assess its finite sample performance. It is also applied to analyzing a real data set on AIDS incubation time.