Concordance Probability and Discriminatory Power in Proportional Hazards Regression

The concordance probability is used to evaluate the discriminatory power and the predictive accuracy of nonlinear statistical models. We derive an analytic expression for the concordance probability in the Cox proportional hazards model. The proposed estimator is a function of the regression parameters and the covariate distribution only and does not use the observed event and censoring times. For this reason it is asymptotically unbiased, unlike Harrell's c-index based on informative pairs. The asymptotic distribution of the concordance probability estimate is derived using U-statistic theory and the methodology is applied to a predictive model in lung cancer.

Monotone Constrained Tensor-product B-spline with application to screening studies

When different markers are responsive to different aspects of a disease, combination of multiple markers could provide a better screening test for early detection. It is also resonable to assume that the risk of disease changes smoothly as the biomarker values change and the change in risk is monotone with respect to each biomarker. In this paper, we propose a boundary constrained tensor-product B-spline method to estimate the risk of disease by maximizing a penalized likelihood. To choose the optimal amount of smoothing, two scores are proposed which are extensions of the GCV score (O'Sullivan et al. (1986)) and the GACV score (Ziang and Wahba (1996)) to incorporate linear constraints. Simulation studies are carried out to investigate the performance of the proposed estimator and the selection scores. In addidtion, sensitivities and specificities based ona pproximate leave-one-out estimates are proposed to generate more realisitc ROC curves. Data from a pancreatic cancer study is used for illustration.

Tests for Comparing Mark-Specific Hazards and Cumulative Incidence Functions

It is of interest in some applications to determine whether there is a relationship between a hazard rate function (or a cumulative incidence function) and a mark variable which is only observed at uncensored failure times. We develop nonparametric tests for this problem when the mark variable is continuous. Tests are developed for the null hypothesis that the mark-specific hazard rate is independent of the mark versus ordered and two-sided alternatives expressed in terms of mark-specific hazard functions and mark-specific cumulative incidence functions. The test statistics are based on functionals of a bivariate test process equal to a weighted average of differences between a Nelson--Aalen-type estimator of the mark-specific cumulative hazard function and a nonparametric estimator of this function under the null hypothesis. The weight function in the test process can be chosen so that the test statistics are asymptotically distribution-free.Asymptotically correct critical values are obtained through a simple simulation procedure. The testing procedures are shown to perform well in numerical studies, and are illustrated with an AIDS clinical trial example. Specifically, the tests are used to assess if the instantaneous or absolute risk of treatment failure depends on the amount of accumulation of drug resistance mutations in a subject's HIV virus. This assessment helps guide development of anti-HIV therapies that surmount the problem of drug resistance.

Asymptotics for Marginal Generalized Linear Models With Sparse Correlations

Marginal generalized linear models can be used for clustered and longitudinal data by fitting a model as if the data were independent and using an empirical estimator of parameter standard errors. We extend this approach to data where the number of observations correlated with a given one grows with sample size and show that parameter estimates are consistent and asymptotically Normal with a slower convergence rate than for independent data, and that an information sandwich variance estimator is consistent. We present two problems that motivated this work, the modelling of patterns of HIV genetic variation and the behavior of clustered data estimators when clusters are large.

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.

Efficient and Ad Hoc Estimation in the Bivariate Censoring Model

A large number of proposals for estimating the bivariate survival function under random censoring has been made. In this paper we discuss nonparametric maximum likelihood estimation and the bivariate Kaplan-Meier estimator of Dabrowska. We show how these estimators are computed, present their intuitive background and compare their practical performance under different levels of dependence and censoring, based on extensive simulation results, which leads to a practical advise.

A Note on the Asymptotic Variance of Survival Function in the Semi-Markov Model

In Malani and Neilsen (1992) we have proposed alternative estimates of survival function (for time to disease) using a simple marker that describes time to some intermediate stage in a disease process. In this paper we derive the asymptotic variance of one such proposed estimator using two different methods and compare terms of order 1/n when there is no censoring. In the absence of censoring the asymptotic variance obtained using the Greenwood type approach converges to exact variance up to terms involving 1/n. But the asymptotic variance obtained using the theory of the counting process and results from Voelkel and Crowley (1984) on semi-Markov processes has a different term of order 1/n. It is not clear to us at this point why the variance formulae using the latter approach give different results.

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.

Smooth Estimation of a Monotone Density

We investigate the interplay of smoothness and monotonicity assumptions when estimating a density from a sample of observations. The nonparametric maximum likelihood estimator of a decreasing density on the positive half line attains a rate of convergence at a fixed point if the density has a negative derivative. The same rate is obtained by a kernel estimator, but the limit distributions are different. If the density is both differentiable and known to be monotone, then a third estimator is obtained by isotonization of a kernel estimator. We show that this again attains the rate of convergence and compare the limit distributors of the three types of estimators. It is shown that both isotonization and smoothing lead to a more concentrated limit distribution and we study the dependence on the proportionality constant in the bandwidth. We also show that isotonization does not change the limit behavior of a kernel estimator with a larger bandwidth, in the case that the density is known to have more than one derivative.

Locally Efficient Estimation with Bivariate Right Censored Data

Estimation for bivariate right censored data is a problem that has had much study over the past 15 years. In this paper we propose a new class of estimators for the bivariate survival function based on locally efficient estimation. We introduce the locally efficient estimator for bivariate right censored data, present an asymptotic theorem, present the results of simulation studies and perform a brief data analysis illustrating the use of the locally efficient estimator.

Locally Efficient Estimation in Censored Data Models: Theory and Examples

In many applications the observed data can be viewed as a censored high dimensional full data random variable X. By the curve of dimensionality it is typically not possible to construct estimators that are asymptotically efficient at every probability distribution in a semiparametric censored data model of such a high dimensional censored data structure. We provide a general method for construction of one-step estimators that are efficient at a chosen submodel of the full-data model, are still well behaved off this submodel and can be chosen to always improve on a given initial estimator. These one-step estimators rely on good estimators of the censoring mechanism and thus will require a parametric or semiparametric model for the censoring mechanism. We present a general theorem that provides a template for proving the desired asymptotic results. We illustrate the general one-step estimation methods by constructing locally efficient one-step estimators of marginal distributions and regression parameters with right-censored data, current status data and bivariate right-censored data, in all models allowing the presence of time-dependent covariates. The conditions of the asymptotics theorem are rigorously verified in one of the examples and the key condition of the general theorem is verified for all examples.

Semiparametric Methods for Semi-competing Risks Problem with Censoring and Truncation

Studies of chronic life-threatening diseases often involve both mortality and morbidity. In observational studies, the data may also be subject to administrative left truncation and right censoring. Since mortality and morbidity may be correlated and mortality may censor morbidity, the Lynden-Bell estimator for left truncated and right censored data may be biased for estimating the marginal survival function of the non-terminal event. We propose a semiparametric estimator for this survival function based on a joint model for the two time-to-event variables, which utilizes the gamma frailty specification in the region of the observable data. Firstly, we develop a novel estimator for the gamma frailty parameter under left truncation. Using this estimator, we then derive a closed form estimator for the marginal distribution of the non-terminal event. The large sample properties of the estimators are established via asymptotic theory. The methodology performs well with moderate sample sizes, both in simulations and in an analysis of data from a diabetes registry.

On the Accelerated Failure Time Model for Current Status and Interval Censored Data

This paper introduces a novel approach to making inference about the regression parameters in the accelerated failure time (AFT) model for current status and interval censored data. The estimator is constructed by inverting a Wald type test for testing a null proportional hazards model. A numerically efficient Markov chain Monte Carlo (MCMC) based resampling method is proposed to simultaneously obtain the point estimator and a consistent estimator of its variance-covariance matrix. We illustrate our approach with interval censored data sets from two clinical studies. Extensive numerical studies are conducted to evaluate the finite sample performance of the new estimators.