The validation of surrogate end points by using data from randomized clinical trials: a case-study in advanced colorectal cancer

Summary.  In many therapeutic areas, the identification and validation of surrogate end points is of prime interest to reduce the duration and/or size of clinical trials. Buyse and co-workers and Burzykowski and co-workers have proposed a validation strategy for end points that are either normally distributed or (possibly censored) failure times. In this paper, we address the problem of validating an ordinal categorical or binary end point as a surrogate for a failure time true end point. In particular, we investigate the validity of tumour response as a surrogate for survival time in evaluating fluoropyrimidine-based experimental therapies for advanced colorectal cancer. Our analysis is performed on data from 28 randomized trials in advanced colorectal cancer, which are available through the Meta-Analysis Group in Cancer.     

Using quantile plots of the prediction variance for comparing designs for a constrained mixture region: an application involving a fertilizer experiment

Summary. Vining and co-workers have used plots of the prediction variance trace (PVT) along the so-called prediction rays to compare mixture designs in a constrained region R . In the present paper, we propose a method for describing the distribution of the prediction variance within the region R by using quantile plots. More comprehensive comparisons between mixture designs are possible through the proposed plots than with the PVT plots. The utility of the quantile plots is illustrated with a four-component fertilizer experiment that was initiated in São Paulo, Brazil.     

Two-step estimation of functional linear models with applications to longitudinal data

Functional linear models are useful in longitudinal data analysis. They include many classical and recently proposed statistical models for longitudinal data and other functional data. Recently, smoothing spline and kernel methods have been proposed for estimating their coefficient functions nonparametrically but these methods are either intensive in computation or inefficient in performance. To overcome these drawbacks, in this paper, a simple and powerful two-step alternative is proposed. In particular, the implementation of the proposed approach via local polynomial smoothing is discussed. Methods for estimating standard deviations of estimated coefficient functions are also proposed. Some asymptotic results for the local polynomial estimators are established. Two longitudinal data sets, one of which involves time-dependent covariates, are used to demonstrate the approach proposed. Simulation studies show that our two-step approach improves the kernel method proposed by Hoover and co-workers in several aspects such as accuracy, computational time and visual appeal of the estimators.     

Validation of surrogate end points in multiple randomized clinical trials with failure time end points

Before a surrogate end point can replace a final (true) end point in the evaluation of an experimental treatment, it must be formally 'validated'. The validation will typically require large numbers of observations. It is therefore useful to consider situations in which data are available from several randomized experiments. For two normally distributed end points Buyse and co-workers suggested a new definition of validity in terms of the quality of both trial level and individual level associations between the surrogate and true end points. This paper extends this approach to the important case of two failure time end points, using bivariate survival modelling. The method is illustrated by using two actual sets of data from cancer clinical trials.     

Nonparametric estimation of the sojourn time distributions for a multipath model

Summary. We use a multipath (multistate) model to describe data with multiple end points. Statistical inference based on the intermediate end point is challenging because of the problems of nonidentifiability and dependent censoring. We study nonparametric estimation for the path probability and the sojourn time distributions between the states. The methodology proposed can be applied to analyse cure models which account for the competing risk of death. Asymptotic properties of the estimators proposed are derived. Simulation shows that the methods proposed have good finite sample performance. The methodology is applied to two data sets.     

Parametric and semiparametric models for recapture and removal studies: a likelihood approach

Capture–recapture processes are biased samplings of recurrent event processes, which can be modelled by the Andersen–Gill intensity model. The intensity function is assumed to be a function of time, covariates and a parameter. We derive the maximum likelihood estimators of both the parameter and the population size and show the consistency and asymptotic normality of the estimators for both recapture and removal studies. The estimators are asymptotically efficient and their theoretical asymptotic relative efficiencies with respect to the existing estimators of Yip and co-workers can be as large as ∞. The variance estimation and a numerical example are also presented.     

Estimation of the cumulative baseline hazard function for dependently right-censored failure time data

In this paper, we study the properties of a special class of frailty models when the frailty is common to several failure times. The models are closely linked to Archimedean copula models. We establish a useful formula for cumulative baseline hazard functions and develop a new estimator for cumulative baseline hazard functions in bivariate frailty regression models. Based on our proposed estimator, we present a graphical model checking procedure. We fit a leukemia data set using our model and end our paper with some discussions.     

The Identifiability of Dependent Competing Risks Models Induced by Bivariate Frailty Models

In this paper, we propose to use a special class of bivariate frailty models to study dependent censored data. The proposed models are closely linked to Archimedean copula models. We give sufficient conditions for the identifiability of this type of competing risks models. The proposed conditions are derived based on a property shared by Archimedean copula models and satisfied by several well‐known bivariate frailty models. Compared with the models studied by Heckman and Honoré and Abbring and van den Berg, our models are more restrictive but can be identified with a discrete (even finite) covariate. Under our identifiability conditions, expectation–maximization (EM) algorithm provides us with consistent estimates of the unknown parameters. Simulation studies have shown that our estimation procedure works quite well. We fit a dependent censored leukaemia data set using the Clayton copula model and end our paper with some discussions. © 2014 Board of the Foundation of the Scandinavian Journal of Statistics     

Semiparametric regression for the mean and rate functions of recurrent events

The counting process with the Cox-type intensity function has been commonly used to analyse recurrent event data. This model essentially assumes that the underlying counting process is a time-transformed Poisson process and that the covariates have multiplicative effects on the mean and rate function of the counting process. Recently, Pepe and Cai, and Lawless and co-workers have proposed semiparametric procedures for making inferences about the mean and rate function of the counting process without the Poisson-type assumption. In this paper, we provide a rigorous justification of such robust procedures through modern empirical process theory. Furthermore, we present an approach to constructing simultaneous confidence bands for the mean function and describe a class of graphical and numerical techniques for checking the adequacy of the fitted mean–rate model. The advantages of the robust procedures are demonstrated through simulation studies. An illustration with multiple-infection data taken from a clinical study on chronic granulomatous disease is also provided.     

Generalized additive models with unknown link function including variable selection

The generalized additive model is a well established and strong tool that allows modelling smooth effects of predictors on the response. However, if the link function, which is typically chosen as the canonical link, is misspecified, estimates can be biased. A procedure is proposed that simultaneously estimates the form of the link function and the unknown form of the predictor functions including selection of predictors. The procedure is based on boosting methodology, which obtains estimates by using a sequence of weak learners. It strongly dominates fitting procedures that are unable to modify a given link function if the true link function deviates from the fixed function. The performance of the procedure is shown in simulation studies and illustrated by real world examples.     

Testing in semiparametric models with interaction, with applications to gene–environment interactions

Summary.  Motivated from the problem of testing for genetic effects on complex traits in the presence of gene–environment interaction, we develop score tests in general semiparametric regression problems that involves Tukey style 1 degree-of-freedom form of interaction between parametrically and non-parametrically modelled covariates. We find that the score test in this type of model, as recently developed by Chatterjee and co-workers in the fully parametric setting, is biased and requires undersmoothing to be valid in the presence of non-parametric components. Moreover, in the presence of repeated outcomes, the asymptotic distribution of the score test depends on the estimation of functions which are defined as solutions of integral equations, making implementation difficult and computationally taxing. We develop profiled score statistics which are unbiased and asymptotically efficient and can be performed by using standard bandwidth selection methods. In addition, to overcome the difficulty of solving functional equations, we give easy interpretations of the target functions, which in turn allow us to develop estimation procedures that can be easily implemented by using standard computational methods. We present simulation studies to evaluate type I error and power of the method proposed compared with a naive test that does not consider interaction. Finally, we illustrate our methodology by analysing data from a case–control study of colorectal adenoma that was designed to investigate the association between colorectal adenoma and the candidate gene NAT2 in relation to smoking history.     

Network-based genomic discovery: application and comparison of Markov random field models

Summary.  As biological knowledge accumulates rapidly, gene networks encoding genomewide gene–gene interactions have been constructed. As an improvement over the standard mixture model that tests all the genes identically and independently distributed a priori , Wei and co-workers have proposed modelling a gene network as a discrete or Gaussian Markov random field (MRF) in a mixture model to analyse genomic data. However, how these methods compare in practical applications is not well understood and this is the aim here. We also propose two novel constraints in prior specifications for the Gaussian MRF model and a fully Bayesian approach to the discrete MRF model. We assess the accuracy of estimating the false discovery rate by posterior probabilities in the context of MRF models. Applications to a chromatin immuno-precipitation–chip data set and simulated data show that the modified Gaussian MRF models have superior performance compared with other models, and both MRF-based mixture models, with reasonable robustness to misspecified gene networks, outperform the standard mixture model.     

Looking for max-semistability: A new test for the extreme value condition

To test the extreme value condition, Cramér-Von Mises type tests were recently proposed by Drees et al. (2006) and Dietrich et al. (2002). Hüsler and Li (2006) presented a simulation study on the behavior of these tests and verified that they are not robust for models in the domain of attraction of a max-semistable distribution function. In this work we develop a test statistic that distinguishes quite well distribution functions which belong to a max-stable domain of attraction from those in a max-semistable one. The limit law is deduced and the results from a numerical simulation study are presented.     

Robust Variable Selection in Linear Mixed Models

In this article, we develop a robust variable selection procedure jointly for fixed and random effects in linear mixed models for longitudinal data. We propose a penalized robust estimator for both the regression coefficients and the variance of random effects based on a re-parametrization of the linear mixed models. Under some regularity conditions, we show the oracle properties of the proposed robust variable selection method. Simulation study shows the robustness of the proposed method against outliers. In the end, the proposed methods is illustrated in the analysis of a real data set.     

Model selection for the localized mixture of experts models

In this paper, we propose a penalized likelihood method to simultaneous select covariate, and mixing component and obtain parameter estimation in the localized mixture of experts models. We develop an expectation maximization algorithm to solve the proposed penalized likelihood procedure, and introduce a data-driven procedure to select the tuning parameters. Extensive numerical studies are carried out to compare the finite sample performances of our proposed method and other existing methods. Finally, we apply the proposed methodology to analyze the Boston housing price data set and the baseball salaries data set.     

Ordered multivariate extremes

Multivariate extreme value models and associated statistical methods are developed for vector observations whose components are subject to an order restriction. The approach extends the multivariate threshold methodology of Coles and Tawn, Joe and co-workers and Smith and co-workers. The results are illustrated by an analysis of extreme rainfalls of different durations, and by a study of the problem of linking a long series of daily rainfall extremes with a partially overlapping shorter series of hourly extremes.     

Latent class models for longitudinal studies of the elderly with data missing at random

The elderly population in the USA is expected to double in size by the year 2025, making longitudinal health studies of this population of increasing importance. The degree of loss to follow-up in studies of the elderly, which is often because elderly people cannot remain in the study, enter a nursing home or die, make longitudinal studies of this population problematic. We propose a latent class model for analysing multiple longitudinal binary health outcomes with multiple-cause non-response when the data are missing at random and a non-likelihood-based analysis is performed. We extend the estimating equations approach of Robins and co-workers to latent class models by reweighting the multiple binary longitudinal outcomes by the inverse probability of being observed. This results in consistent parameter estimates when the probability of non-response depends on observed outcomes and covariates (missing at random) assuming that the model for non-response is correctly specified. We extend the non-response model so that institutionalization, death and missingness due to failure to locate, refusal or incomplete data each have their own set of non-response probabilities. Robust variance estimates are derived which account for the use of a possibly misspecified covariance matrix, estimation of missing data weights and estimation of latent class measurement parameters. This approach is then applied to a study of lower body function among a subsample of the elderly participating in the 6-year Longitudinal Study of Aging.     

Optimal estimating function for estimation and prediction in semi-parametric models

In a seminal paper, Godambe [1985. The foundations of finite sample estimation in stochastic processes. Biometrika 72, 419–428.] introduced the ‘estimating function’ approach to estimation of parameters in semi-parametric models under a filtering associated with a martingale structure. Later, Godambe [1987. The foundations of finite sample estimation in stochastic processes II. Bernoulli, Vol. 2. V.N.V. Science Press, 49–54.] and Godambe and Thompson [1989. An extension of quasi-likelihood Estimation. J. Statist. Plann. Inference 22, 137–172.] replaced this filtering by a more flexible conditioning. Abraham et al. [1997. On the prediction for some nonlinear time-series models using estimating functions. In: Basawa, I.V., et al. (Eds.), IMS Selected Proceedings of the Symposium on Estimating Functions, Vol. 32. pp. 259–268.] and Thavaneswaran and Heyde [1999. Prediction via estimating functions. J. Statist. Plann. Inference 77, 89–101.] invoked the theory of estimating functions for one-step ahead prediction in time-series models. This paper addresses the problem of simultaneous estimation of parameters and multi-step ahead prediction of a vector of future random variables in semi-parametric models by extending the inimitable approach of 13 and 14. The proposed technique is in conformity with the paradigm of the modern theory of estimating functions leading to finite sample optimality within a chosen class of estimating functions, which in turn are used to get the predictors. Particular applications of the technique give predictors that enjoy optimality properties with respect to other well-known criteria.     

A consistent simulation-based estimator in generalized linear mixed models

We propose a strongly root-n consistent simulation-based estimator for the generalized linear mixed models. This estimator is constructed based on the first two marginal moments of the response variables, and it allows the random effects to have any parametric distribution (not necessarily normal). Consistency and asymptotic normality for the proposed estimator are derived under fairly general regularity conditions. We also demonstrate that this estimator has a bounded influence function and that it is robust against data outliers. A bias correction technique is proposed to reduce the finite sample bias in the estimation of variance components. The methodology is illustrated through an application to the famed seizure count data and some simulation studies.     

Efficient Bayesian sampling plans for exponential distributions with random censoring

This paper considers Bayesian sampling plans for exponential distribution with random censoring. The efficient Bayesian sampling plan for a general loss function is derived. This sampling plan possesses the property that it may make decisions prior to the end of the life test experiment, and its decision function is the same as the Bayes decision function which makes decisions based on data collected at the end of the life test experiment. Compared with the optimal Bayesian sampling plan of Chen et al. (2004), the efficient Bayesian sampling plan has the smaller Bayes risk due to the less duration time of life test experiment. Computations of the efficient Bayes risks for the conjugate prior are given. Numerical comparisons between the proposed efficient Bayesian sampling plan and the optimal Bayesian sampling plan of Chen et al. (2004) under two special decision losses, including the quadratic decision loss, are provided. Numerical results also demonstrate that the performance of the proposed efficient sampling plan is superior to that of the optimal sampling plan by Chen et al. (2004).