Likelihood‐based inferences about the mean area under a longitudinal curve in the presence of observations subject to limits of detection

Comparison of groups in longitudinal studies is often conducted using the area under the outcome versus time curve. However, outcomes may be subject to censoring due to a limit of detection and specific methods that take informative missingness into account need to be applied. In this article, we present a unified model‐based method that accounts for both the within‐subject variability in the estimation of the area under the curve as well as the missingness mechanism in the event of censoring. Simulation results demonstrate that our proposed method has a significant advantage over traditionally implemented methods with regards to its inferential properties. A working example from an AIDS study is presented to demonstrate the applicability of our approach. Copyright © 2015 John Wiley & Sons, Ltd.     

Sequential imputation for models with latent variables assuming latent ignorability

Models that involve an outcome variable, covariates, and latent variables are frequently the target for estimation and inference. The presence of missing covariate or outcome data presents a challenge, particularly when missingness depends on the latent variables. This missingness mechanism is called latent ignorable or latent missing at random and is a generalisation of missing at random. Several authors have previously proposed approaches for handling latent ignorable missingness, but these methods rely on prior specification of the joint distribution for the complete data. In practice, specifying the joint distribution can be difficult and/or restrictive. We develop a novel sequential imputation procedure for imputing covariate and outcome data for models with latent variables under latent ignorable missingness. The proposed method does not require a joint model; rather, we use results under a joint model to inform imputation with less restrictive modelling assumptions. We discuss identifiability and convergence‐related issues, and simulation results are presented in several modelling settings. The method is motivated and illustrated by a study of head and neck cancer recurrence. Imputing missing data for models with latent variables under latent‐dependent missingness without specifying a full joint model.     

Regression analysis under non-standard situations: a pairwise pseudolikelihood approach

Regression analysis is one of the most used statistical methods for data analysis. There are, however, many situations in which one cannot base inference solely on f ( y ∣ x ; β), the conditional probability (density) function for the response variable Y , given x , the covariates. Examples include missing data where the missingness is non-ignorable, sampling surveys in which subjects are selected on the basis of the Y -values and meta-analysis where published studies are subject to 'selection bias'. The conventional approaches require the correct specification of the missingness mechanism, sampling probability and probability for being published respectively. In this paper, we propose an alternative estimating procedure for β based on an idea originated by Kalbfleisch. The novelty of this method is that no assumption on the missingness probability mechanisms etc. mentioned above is required to be specified. Asymptotic efficiency calculations and simulation studies were conducted to compare the method proposed with the two existing methods: the conditional likelihood and the weighted estimating function approaches.     

A general approach to heteroscedastic linear regression

Our article presents a general treatment of the linear regression model, in which the error distribution is modelled nonparametrically and the error variances may be heteroscedastic, thus eliminating the need to transform the dependent variable in many data sets. The mean and variance components of the model may be either parametric or nonparametric, with parsimony achieved through variable selection and model averaging. A Bayesian approach is used for inference with priors that are data-based so that estimation can be carried out automatically with minimal input by the user. A Dirichlet process mixture prior is used to model the error distribution nonparametrically; when there are no regressors in the model, the method reduces to Bayesian density estimation, and we show that in this case the estimator compares favourably with a well-regarded plug-in density estimator. We also consider a method for checking the fit of the full model. The methodology is applied to a number of simulated and real examples and is shown to work well.     

Likelihood-based and Bayesian methods for Tweedie compound Poisson linear mixed models

The Tweedie compound Poisson distribution is a subclass of the exponential dispersion family with a power variance function, in which the value of the power index lies in the interval (1,2). It is well known that the Tweedie compound Poisson density function is not analytically tractable, and numerical procedures that allow the density to be accurately and fast evaluated did not appear until fairly recently. Unsurprisingly, there has been little statistical literature devoted to full maximum likelihood inference for Tweedie compound Poisson mixed models. To date, the focus has been on estimation methods in the quasi-likelihood framework. Further, Tweedie compound Poisson mixed models involve an unknown variance function, which has a significant impact on hypothesis tests and predictive uncertainty measures. The estimation of the unknown variance function is thus of independent interest in many applications. However, quasi-likelihood-based methods are not well suited to this task. This paper presents several likelihood-based inferential methods for the Tweedie compound Poisson mixed model that enable estimation of the variance function from the data. These algorithms include the likelihood approximation method, in which both the integral over the random effects and the compound Poisson density function are evaluated numerically; and the latent variable approach, in which maximum likelihood estimation is carried out via the Monte Carlo EM algorithm, without the need for approximating the density function. In addition, we derive the corresponding Markov Chain Monte Carlo algorithm for a Bayesian formulation of the mixed model. We demonstrate the use of the various methods through a numerical example, and conduct an array of simulation studies to evaluate the statistical properties of the proposed estimators.     

Density Approximation by Summary Statistics: An Information-theoretic Approach

In the case of exponential families, it is a straightforward matter to approximate a density function by use of summary statistics; however, an appropriate approach to such approximation is far less clear when an exponential family is not assumed. In this paper, a maximin argument based on information theory is used to derive a new approach to density approximation from summary statistics which is not restricted by the assumption of validity of an underlying exponential family. Information-theoretic criteria are developed to assess loss of predictive power of summary statistics under such minimal knowledge. Under these criteria, optimal density approximations in the maximin sense are obtained and shown to be related to exponential families. Conditions for existence of optimal density approximations are developed. Applications of the proposed approach are illustrated, and methods for estimation of densities are provided in the case of simple random sampling. Large-sample theory for estimates is developed.     

A unified approach to minimum variance unbiased estimation of a probability function belonging to an exponential family

The problem of minimum variance unbiased estimation of the probability density function of a random variable belonging to an exponential family is considered. The method of estimation proposed in this paper requires the solution of a certain integral equation. For many probability distributions the solution of this equation is given by a known result in integral transform theory.     

Bayesian semiparametric models for nonignorable missing mechanisms in generalized linear models

Semiparametric models provide a more flexible form for modeling the relationship between the response and the explanatory variables. On the other hand in the literature of modeling for the missing variables, canonical form of the probability of the variable being missing (p) is modeled taking a fully parametric approach. Here we consider a regression spline based semiparametric approach to model the missingness mechanism of nonignorably missing covariates. In this model the relationship between the suitable canonical form of p (e.g. probit p) and the missing covariate is modeled through several splines. A Bayesian procedure is developed to efficiently estimate the parameters. A computationally advantageous prior construction is proposed for the parameters of the semiparametric part. A WinBUGS code is constructed to apply Gibbs sampling to obtain the posterior distributions. We show through an extensive Monte Carlo simulation experiment that response model coefficent estimators maintain better (when the true missingness mechanism is nonlinear) or equivalent (when the true missingness mechanism is linear) bias and efficiency properties with the use of proposed semiparametric missingness model compared to the conventional model.     

Penalised spline estimation for generalised partially linear single-index models

Generalised linear models are frequently used in modeling the relationship of the response variable from the general exponential family with a set of predictor variables, where a linear combination of predictors is linked to the mean of the response variable. We propose a penalised spline (P-spline) estimation for generalised partially linear single-index models, which extend the generalised linear models to include nonlinear effect for some predictors. The proposed models can allow flexible dependence on some predictors while overcome the “curse of dimensionality”. We investigate the P-spline profile likelihood estimation using the readily available R package mgcv, leading to straightforward computation. Simulation studies are considered under various link functions. In addition, we examine different choices of smoothing parameters. Simulation results and real data applications show effectiveness of the proposed approach. Finally, some large sample properties are established.     

On approximating distribution of the quadratic discriminant function

The quadratic discriminant function (QDF) with known parameters has been represented in terms of a weighted sum of independent noncentral chi-square variables. To approximate the density function of the QDF as m-dimensional exponential family, its moments in each order have been calculated. This is done using the recursive formula for the moments via the Stein's identity in the exponential family. We validate the performance of our method using simulation study and compare with other methods in the literature based on the real data. The finding results reveal better estimation of misclassification probabilities, and less computation time with our method.     

Reversible jump MCMC to identify dropout mechanism in longitudinal data

Existence of missing values is an inseparable part of longitudinal studies in epidemiology, medical and clinical studies. Usually researchers, for simplicity, ignore the missingness mechanism while, ignoring a not at random mechanism may lead to misleading results. In this paper, we use a Bayesian paradigm for fitting selection model of Heckman, which allows the non-ignorable missingness for longitudinal data. Also, we use reversible-jump Markov chain Monte Carlo to allow the model to choose between non-ignorable and ignorable structures for missingness mechanism, and show how the selection can be incorporated. Some simulation studies are performed for illustration of the proposed approach. The approach is also used for analyzing two real data sets.     

A Bayesian Shrinkage Model for Incomplete Longitudinal Binary Data with Application to the Breast Cancer Prevention Trial

We consider inference in randomized longitudinal studies with missing data that is generated by skipped clinic visits and loss to follow-up. In this setting, it is well known that full data estimands are not identified unless unverified assumptions are imposed. We assume a non-future dependence model for the drop-out mechanism and partial ignorability for the intermittent missingness. We posit an exponential tilt model that links non-identifiable distributions and distributions identified under partial ignorability. This exponential tilt model is indexed by non-identified parameters, which are assumed to have an informative prior distribution, elicited from subject-matter experts. Under this model, full data estimands are shown to be expressed as functionals of the distribution of the observed data. To avoid the curse of dimensionality, we model the distribution of the observed data using a Bayesian shrinkage model. In a simulation study, we compare our approach to a fully parametric and a fully saturated model for the distribution of the observed data. Our methodology is motivated by, and applied to, data from the Breast Cancer Prevention Trial.     

Influence Function Based Variance Estimation and Missing Data Issues in Case-Cohort Studies

Recognizing that the efficiency in relative risk estimation for the Cox proportional hazards model is largely constrained by the total number of cases, Prentice (1986) proposed the case-cohort design in which covariates are measured on all cases and on a random sample of the cohort. Subsequent to Prentice, other methods of estimation and sampling have been proposed for these designs. We formalize an approach to variance estimation suggested by Barlow (1994), and derive a robust variance estimator based on the influence function. We consider the applicability of the variance estimator to all the proposed case-cohort estimators, and derive the influence function when known sampling probabilities in the estimators are replaced by observed sampling fractions. We discuss the modifications required when cases are missing covariate information. The missingness may occur by chance, and be completely at random; or may occur as part of the sampling design, and depend upon other observed covariates. We provide an adaptation of S-plus code that allows estimating influence function variances in the presence of such missing covariates. Using examples from our current case-cohort studies on esophageal and gastric cancer, we illustrate how our results our useful in solving design and analytic issues that arise in practice.     

Joint generalized estimating equations for multivariate longitudinal binary outcomes with missing data: an application to acquired immune deficiency syndrome data

Summary.  In a large, prospective longitudinal study designed to monitor cardiac abnormalities in children born to women who are infected with the human immunodeficiency virus, instead of a single outcome variable, there are multiple binary outcomes (e.g. abnormal heart rate, abnormal blood pressure and abnormal heart wall thickness) considered as joint measures of heart function over time. In the presence of missing responses at some time points, longitudinal marginal models for these multiple outcomes can be estimated by using generalized estimating equations (GEEs), and consistent estimates can be obtained under the assumption of a missingness completely at random mechanism. When the missing data mechanism is missingness at random, i.e. the probability of missing a particular outcome at a time point depends on observed values of that outcome and the remaining outcomes at other time points, we propose joint estimation of the marginal models by using a single modified GEE based on an EM-type algorithm. The method proposed is motivated by the longitudinal study of cardiac abnormalities in children who were born to women infected with the human immunodeficiency virus, and analyses of these data are presented to illustrate the application of the method. Further, in an asymptotic study of bias, we show that, under a missingness at random mechanism in which missingness depends on all observed outcome variables, our joint estimation via the modified GEE produces almost unbiased estimates, provided that the correlation model has been correctly specified, whereas estimates from standard GEEs can lead to substantial bias.     

A protective estimator for longitudinal binary data subject to non-ignorable non-monotone missingness

Summary.  In longitudinal studies missing data are the rule not the exception. We consider the analysis of longitudinal binary data with non-monotone missingness that is thought to be non-ignorable. In this setting a full likelihood approach is complicated algebraically and can be computationally prohibitive when there are many measurement occasions. We propose a 'protective' estimator that assumes that the probability that a response is missing at any occasion depends, in a completely unspecified way, on the value of that variable alone. Relying on this 'protectiveness' assumption, we describe a pseudolikelihood estimator of the regression parameters under non-ignorable missingness, without having to model the missing data mechanism directly. The method proposed is applied to CD4 cell count data from two longitudinal clinical trials of patients infected with the human immunodeficiency virus.     

An Exponential Model for Damage Accumulation

In this article, we present a general model for predicting the fatigue behavior for any stress level and amplitude using the exponential model. Based on the Wöhler field for fixed stress level, a compatibility functional equation enables us to derive the general model with eight parameters. The problem of parameter estimation is then discussed and some methods are described. Some examples are finally presented to illustrate the derived model and the proposed methods of estimation.     

A finite sample comparison of nonparametric estimates of the effective dose in quantal bioassay

To estimate the effective dose level ED_α in the common binary response model, several parametric and nonparametric estimators have been proposed in the literature. In the present article, we focus on nonparametric methods and present a detailed numerical comparison of four different approaches to estimate the ED_α nonparametrically. The methods are briefly reviewed and their finite sample properties are studied by means of a detailed simulation study. Moreover, a data example is presented to illustrate the different concepts.     

Joint models for a GLM-type longitudinal response and a time-to-event with smooth random effects

ABSTRACT

Longitudinal studies often entail non-Gaussian primary responses. When dropout occurs, potential non-ignorability of the missingness process may occur, and a joint model for the primary response and a time-to-event may represent an appealing tool to account for dependence between the two processes. As an extension to the GLMJM, recently proposed, and based on Gaussian latent effects, we assume that the random effects follow a smooth, P-spline based density. To estimate model parameters, we adopt a two-step conditional Newton–Raphson algorithm. Since the maximization of the penalized log-likelihood requires numerical integration over the random effect, which is often cumbersome, we opt for a pseudo-adaptive Gaussian quadrature rule to approximate the model likelihood. We discuss the proposed model by analyzing an original dataset on dilated cardiomyopathies and through a simulation study.     

Linear Increments with Non‐monotone Missing Data and Measurement Error

Linear increments (LI) are used to analyse repeated outcome data with missing values. Previously, two LI methods have been proposed, one allowing non‐monotone missingness but not independent measurement error and one allowing independent measurement error but only monotone missingness. In both, it was suggested that the expected increment could depend on current outcome. We show that LI can allow non‐monotone missingness and either independent measurement error of unknown variance or dependence of expected increment on current outcome but not both. A popular alternative to LI is a multivariate normal model ignoring the missingness pattern. This gives consistent estimation when data are normally distributed and missing at random (MAR). We clarify the relation between MAR and the assumptions of LI and show that for continuous outcomes multivariate normal estimators are also consistent under (non‐MAR and non‐normal) assumptions not much stronger than those of LI. Moreover, when missingness is non‐monotone, they are typically more efficient.     

Series evaluation of Tweedie exponential dispersion model densities

Exponential dispersion models, which are linear exponential families with a dispersion parameter, are the prototype response distributions for generalized linear models. The Tweedie family comprises those exponential dispersion models with power mean-variance relationships. The normal, Poisson, gamma and inverse Gaussian distributions belong to theTweedie family. Apart from these special cases, Tweedie distributions do not have density functions which can be written in closed form. Instead, the densities can be represented as infinite summations derived from series expansions. This article describes how the series expansions can be summed in an numerically efficient fashion. The usefulness of the approach is demonstrated, but full machine accuracy is shown not to be obtainable using the series expansion method for all parameter values. Derivatives of the density with respect to the dispersion parameter are also derived to facilitate maximum likelihood estimation. The methods are demonstrated on two data examples and compared with with Box-Cox transformations and extended quasi-likelihoood.