Analyzing survival data in conjunction with time-dependent surrogate endpoints in clinical trials

Current survival techniques do not provide a good method for handling clinical trials with a large percent of censored observations. This research proposes using time-dependent surrogates of survival as outcome variables, in conjunction with observed survival time, to improve the precision in comparing the relative effects of two treatments on the distribution of survival time. This is in contrast to the standard method used today which uses the marginal density of survival time, T. only, or the marginal density of a surrogate, X, only, therefore, ignoring some available information. The surrogate measure, X, may be a fixed value or a time-dependent variable, X(t). X is a summary measure of some of the covariates measured throughout the trial that provide additional information on a subject's survival time. It is possible to model these time-dependent covariate values and relate the parameters in the model to the parameters in the distribution of T given X. The result is that three new models are available for the analysis of clinical trials. All three models use the joint density of survival time and a surrogate measure. Given one of three different assumed mechanisms of the potential treatment effect, each of the three methods improves the precision of the treatment estimate.     

Location estimators based on linear combinations of modified order statistics

Let Xj,…, X be i.i.d random variables with common distribution function F(x-0), and let a(u) be a function defined on [0,1], For each t$$$R define the t-order statistics as: X. (t) = X. if there in k exist exactly (i- 1) X. !s such that |X.-t|greater|X.-t| and define the variable T (t) = n 2. , a(i/n) X, (t) . We consider estimates of 8 defined as solutions of the eauaticn T (8) =6 , and     

Uniform Representation of Product-Limit Integrals with Applications

Abstract.  Let X be a d -variate random vector that is completely observed, and let Y be a random variable that is subject to right censoring and left truncation. For arbitrary functions φ we consider expectations of the form E [ φ ( X ,  Y )], which appear in many statistical problems, and we estimate these expectations by using a product-limit estimator for censored and truncated data, extended to the context where covariates are present. An almost sure representation for these estimators is obtained, with a remainder term that is of a certain negligible order, uniformly over a class of φ -functions. This uniformity is important for the application to goodness-of-fit testing in regression and to inference for the regression depth, which we consider in more detail.     

Latent Variable Models for Mixed Discrete and Continuous Outcomes

We propose a latent variable model for mixed discrete and continuous outcomes. The model accommodates any mixture of outcomes from an exponential family and allows for arbitrary covariate effects, as well as direct modelling of covariates on the latent variable. An EM algorithm is proposed for parameter estimation and estimates of the latent variables are produced as a by-product of the analysis. A generalized likelihood ratio test can be used to test the significance of covariates affecting the latent outcomes. This method is applied to birth defects data, where the outcomes of interest are continuous measures of size and binary indicators of minor physical anomalies. Infants who were exposed in utero to anticonvulsant medications are compared with controls.     

Weighting for item non-response in attitude scales by using latent variable models with covariates

We discuss the use of latent variable models with observed covariates for computing response propensities for sample respondents. A response propensity score is often used to weight item and unit responders to account for item and unit non-response and to obtain adjusted means and proportions. In the context of attitude scaling, we discuss computing response propensity scores by using latent variable models for binary or nominal polytomous manifest items with covariates. Our models allow the response propensity scores to be found for several different items without refitting. They allow any pattern of missing responses for the items. If one prefers, it is possible to estimate population proportions directly from the latent variable models, so avoiding the use of propensity scores. Artificial data sets and a real data set extracted from the 1996 British Social Attitudes Survey are used to compare the various methods proposed.     

A characterization of and new consistent tests for symmetry

Let X and Y be independent and identically distributed random variables having a continuous distribution function. We study new consistent tests for symmetry around a known median based on the fact that the distribution of X is symmetric around 0 if, and only if, |X| and |max(X,Y)| have the same distribution.     

Identification of Multivariate Responders/Non-Responders Using Bayesian Growth Curve Latent Class Models

In this paper, we propose a multivariate growth curve mixture model that groups subjects based on multiple symptoms measured repeatedly over time. Our model synthesizes features of two models. First, we follow Roy and Lin (2000) in relating the multiple symptoms at each time point to a single latent variable. Second, we use the growth mixture model of Muthén and Shedden (1999) to group subjects based on distinctive longitudinal profiles of this latent variable. The mean growth curve for the latent variable in each class defines that class's features. For example, a class of "responders" would have a decline in the latent symptom summary variable over time. A Bayesian approach to estimation is employed where the methods of Elliott et al (2005) are extended to simultaneously estimate the posterior distributions of the parameters from the latent variable and growth curve mixture portions of the model. We apply our model to data from a randomized clinical trial evaluating the efficacy of Bacillus Calmette-Guerin (BCG) in treating symptoms of Interstitial Cystitis. In contrast to conventional approaches using a single subjective Global Response Assessment, we use the multivariate symptom data to identify a class of subjects where treatment demonstrates effectiveness. Simulations are used to confirm identifiability results and evaluate the performance of our algorithm. The definitive version of this paper is available at onlinelibrary.wiley.com.     

Variable selection for semiparametric regression models with iterated penalization

Semiparametric regression models with multiple covariates are commonly encountered. When there are covariates not associated with response variable, variable selection may lead to sparser models, more lucid interpretations and more accurate estimation. In this study, we adopt a sieve approach for the estimation of nonparametric covariate effects in semiparametric regression models. We adopt a two-step iterated penalization approach for variable selection. In the first step, a mixture of the Lasso and group Lasso penalties are employed to conduct the first-round variable selection and obtain the initial estimate. In the second step, a mixture of the weighted Lasso and weighted group Lasso penalties, with weights constructed using the initial estimate, are employed for variable selection. We show that the proposed iterated approach has the variable selection consistency property, even when number of unknown parameters diverges with sample size. Numerical studies, including simulation and analysis of a diabetes dataset, show satisfactory performance of the proposed approach.     

Estimation and variable selection in partial linear single index models with error-prone linear covariates

We study the estimation and variable selection for a partial linear single index model (PLSIM) when some linear covariates are not observed, but their ancillary variables are available. We use the semiparametric profile least-square based estimation procedure to estimate the parameters in the PLSIM after the calibrated error-prone covariates are obtained. Asymptotic normality for the estimators are established. We also employ the smoothly clipped absolute deviation (SCAD) penalty to select the relevant variables in the PLSIM. The resulting SCAD estimators are shown to be asymptotically normal and have the oracle property. Performance of our estimation procedure is illustrated through numerous simulations. The approach is further applied to a real data example.     

Logistic regression with a partially observed covariate

We present results of a Monte Carlo study comparing four methods of estimating the parameters of the logistic model logit (pr (Y = 1 | X, Z)) = α₀ + α ₁ X + α ₂ Z where X and Z are continuous covariates and X is always observed but Z is sometimes missing. The four methods examined are 1) logistic regression using complete cases, 2) logistic regression with filled-in values of Z obtained from the regression of Z on X and Y, 3) logistic regression with filled-in values of Z and random error added, and 4) maximum likelihood estimation assuming the distribution of Z given X and Y is normal. Effects of different percent missing for Z and different missing value mechanisms on the bias and mean absolute deviation of the estimators are examined for data sets of N = 200 and N = 400.     

Symmetrically distributed and unbiased estimators in linear models

Let Y be distributed symmetrically about Xβ. Natural generalizations of odd location statistics, say T‘Y’, and even location-free statistics, say W‘Y’, that were used by Hogg ‘1960, 1967)’ are introduced. We show that T‘Y’ is distributed symmetrically about β and thus E[T‘Y’] = β and that each element of T‘Y’ is uncorrelated with each element of W‘Y’. Applications of this result are made to R-estiraators and the result is extended to a multivariate linear model situation.     

Likelihood Ratio Confidence Bands in Non–parametric Regression with Censored Data

Let ( X , Y ) be a random vector, where Y denotes the variable of interest possibly subject to random right censoring, and X is a covariate. We construct confidence intervals and bands for the conditional survival and quantile function of Y given X using a non-parametric likelihood ratio approach. This approach was introduced by Thomas & Grunkemeier (1975 ), who estimated confidence intervals of survival probabilities based on right censored data. The method is appealing for several reasons: it always produces intervals inside [0, 1], it does not involve variance estimation, and can produce asymmetric intervals. Asymptotic results for the confidence intervals and bands are obtained, as well as simulation results, in which the performance of the likelihood ratio intervals and bands is compared with that of the normal approximation method. We also propose a bandwidth selection procedure based on the bootstrap and apply the technique on a real data set.     

Test of Association Between Two Ordinal Variables While Adjusting for Covariates

We propose a new set of test statistics to examine the association between two ordinal categorical variables X and Y after adjusting for continuous and/or categorical covariates Z. Our approach first fits multinomial (e.g., proportional odds) models of X and Y, separately, on Z. For each subject, we then compute the conditional distributions of X and Y given Z. If there is no relationship between X and Y after adjusting for Z, then these conditional distributions will be independent, and the observed value of (X, Y) for a subject is expected to follow the product distribution of these conditional distributions. We consider two simple ways of testing the null of conditional independence, both of which treat X and Y equally, in the sense that they do not require specifying an outcome and a predictor variable. The first approach adds these product distributions across all subjects to obtain the expected distribution of (X, Y) under the null and then contrasts it with the observed unconditional distribution of (X, Y). Our second approach computes "residuals" from the two multinomial models and then tests for correlation between these residuals; we define a new individual-level residual for models with ordinal outcomes. We present methods for computing p-values using either the empirical or asymptotic distributions of our test statistics. Through simulations, we demonstrate that our test statistics perform well in terms of power and Type I error rate when compared to proportional odds models which treat X as either a continuous or categorical predictor. We apply our methods to data from a study of visual impairment in children and to a study of cervical abnormalities in human immunodeficiency virus (HIV)-infected women. Supplemental materials for the article are available online.     

Non-parametric Regression with Dependent Censored Data

Abstract.  Let ( X _i , Y _i ) ( i = 1 ,…, n ) be n replications of a random vector ( X , Y  ), where Y is supposed to be subject to random right censoring. The data ( X _i , Y _i ) are assumed to come from a stationary α -mixing process. We consider the problem of estimating the function m ( x ) = E ( φ ( Y ) |  X = x ), for some known transformation φ . This problem is approached in the following way: first, we introduce a transformed variable     , that is not subject to censoring and satisfies the relation     , and then we estimate m ( x ) by applying local linear regression techniques. As a by-product, we obtain a general result on the uniform rate of convergence of kernel type estimators of functionals of an unknown distribution function, under strong mixing assumptions.     

State-space models for multivariate longitudinal data of mixed types

We propose a class of state-space models for multivariate longitudinal data where the components of the response vector may have different distributions. The approach is based on the class of Tweedie exponential dispersion models, which accommodates a wide variety of discrete, continuous and mixed data. The latent process is assumed to be a Markov process, and the observations are conditionally independent given the latent process, over time as well as over the components of the response vector. This provides a fully parametric alternative to the quasilikelihood approach of Liang and Zeger. We estimate the regression parameters for time-varying covariates entering either via the observation model or via the latent process, based on an estimating equation derived from the Kalman smoother. We also consider analysis of residuals from both the observation model and the latent process.     

Bayesian Estimation of Survival Functions under Stochastic Precedence

When estimating the distributions of two random variables, X and Y, investigators often have prior information that Y tends to be bigger than X. To formalize this prior belief, one could potentially assume stochastic ordering between X and Y, which implies Pr(X < or = z) > or = Pr(Y < or = z) for all z in the domain of X and Y. Stochastic ordering is quite restrictive, though, and this article focuses instead on Bayesian estimation of the distribution functions of X and Y under the weaker stochastic precedence constraint, Pr(X < or = Y) > or = 0.5. We consider the case where both X and Y are categorical variables with common support and develop a Gibbs sampling algorithm for posterior computation. The method is then generalized to the case where X and Y are survival times. The proposed approach is illustrated using data on survival after tumor removal for patients with malignant melanoma.     

Computing Marginal Likelihoods via Posterior Sampling

This article presents a novel and simple approach to the estimation of a marginal likelihood, in a Bayesian context. The estimate is based on a Markov chain output which provides samples from the posterior distribution and an additional latent variable. It is the mean of this latent variable which provides the estimate for the value of the marginal likelihood.     

Modified SEE variable selection for varying coefficient instrumental variable models

We consider the problem of variable selection for a class of varying coefficient models with instrumental variables. We focus on the case that some covariates are endogenous variables, and some auxiliary instrumental variables are available. An instrumental variable based variable selection procedure is proposed by using modified smooth-threshold estimating equations (SEEs). The proposed procedure can automatically eliminate the irrelevant covariates by setting the corresponding coefficient functions as zero, and simultaneously estimate the nonzero regression coefficients by solving the smooth-threshold estimating equations. The proposed variable selection procedure avoids the convex optimization problem, and is flexible and easy to implement. Simulation studies are carried out to assess the performance of the proposed variable selection method.     

Gamma variates of fractional shape as functioials of a homogeneous multidimensional poisson process

If events are scattered in Rⁿ in accordance with a homogeneous Poisson process and if X is the location of the event with minimal [d]l^P norm, then in the case p = n the n^th absolute powers of the coordinates of X form a sample of size n from a gamma distribution with shape parameter 1/n. In an age of parallel computing, this fact may lead to some attractive simulation methods. One possibility is to generate R = [d]X[d] and U = Y/[d]X[d] independently, perhaps by setting U = Y/[d]Y[d] where Y has any p.d.f. which is a function only of ¦Y¦. We consider for example Y having the uniform distribution in an l^P ball.     

Penalized inverse probability weighted estimators for weighted rank regression with missing covariates

Abstract

In this article, we study the variable selection and estimation for linear regression models with missing covariates. The proposed estimation method is almost as efficient as the popular least-squares-based estimation method for normal random errors and empirically shown to be much more efficient and robust with respect to heavy tailed errors or outliers in the responses and covariates. To achieve sparsity, a variable selection procedure based on SCAD is proposed to conduct estimation and variable selection simultaneously. The procedure is shown to possess the oracle property. To deal with the covariates missing, we consider the inverse probability weighted estimators for the linear model when the selection probability is known or unknown. It is shown that the estimator by using estimated selection probability has a smaller asymptotic variance than that with true selection probability, thus is more efficient. Therefore, the important Horvitz-Thompson property is verified for penalized rank estimator with the covariates missing in the linear model. Some numerical examples are provided to demonstrate the performance of the estimators.