A mixture model using likelihood‐based and Bayesian approaches for identifying responders and non‐responders in longitudinal clinical trials

A longitudinal mixture model for classifying patients into responders and non‐responders is established using both likelihood‐based and Bayesian approaches. The model takes into consideration responders in the control group. Therefore, it is especially useful in situations where the placebo response is strong, or in equivalence trials where the drug in development is compared with a standard treatment. Under our model, a treatment shows evidence of being effective if it increases the proportion of responders or increases the response rate among responders in the treated group compared with the control group. Therefore, the model has flexibility to accommodate different situations. The proposed method is illustrated using simulation and a depression clinical trial dataset for the likelihood‐based approach, and the same depression clinical trial dataset for the Bayesian approach. The likelihood‐based and Bayesian approaches generated consistent results for the depression trial data. In both the placebo group and the treated group, patients are classified into two components with distinct response rate. The proportion of responders is shown to be significantly higher in the treated group compared with the control group, suggesting the treatment paroxetine is effective. Copyright © 2014 John Wiley & Sons, Ltd.     

A Markov regime‐switching model for crude‐oil markets: Comparison of composite likelihood and full likelihood

We use the two‐state Markov regime‐switching model to explain the behaviour of the WTI crude‐oil spot prices from January 1986 to February 2012. We investigated the use of methods based on the composite likelihood and the full likelihood. We found that the composite‐likelihood approach can better capture the general structural changes in world oil prices. The two‐state Markov regime‐switching model based on the composite‐likelihood approach closely depicts the cycles of the two postulated states: fall and rise. These two states persist for on average 8 and 15 months, which matches the observed cycles during the period. According to the fitted model, drops in oil prices are more volatile than rises. We believe that this information can be useful for financial officers working in related areas. The model based on the full‐likelihood approach was less satisfactory. We attribute its failure to the fact that the two‐state Markov regime‐switching model is too rigid and overly simplistic. In comparison, the composite likelihood requires only that the model correctly specifies the joint distribution of two adjacent price changes. Thus, model violations in other areas do not invalidate the results. The Canadian Journal of Statistics 41: 353–367; 2013 © 2013 Statistical Society of Canada     

Empirical likelihood for the varying‐coefficient single‐index model

In this article the author investigates the application of the empirical‐likelihood‐based inference for the parameters of varying‐coefficient single‐index model (VCSIM). Unlike the usual cases, if there is no bias correction the asymptotic distribution of the empirical likelihood ratio cannot achieve the standard chi‐squared distribution. To this end, a bias‐corrected empirical likelihood method is employed to construct the confidence regions (intervals) of regression parameters, which have two advantages, compared with those based on normal approximation, that is, (1) they do not impose prior constraints on the shape of the regions; (2) they do not require the construction of a pivotal quantity and the regions are range preserving and transformation respecting. A simulation study is undertaken to compare the empirical likelihood with the normal approximation in terms of coverage accuracies and average areas/lengths of confidence regions/intervals. A real data example is given to illustrate the proposed approach. The Canadian Journal of Statistics 38: 434–452; 2010 © 2010 Statistical Society of Canada     

A two‐step proximal‐point algorithm for the calculus of divergence‐based estimators in finite mixture models

Estimators derived from the expectation‐maximization (EM) algorithm are not robust since they are based on the maximization of the likelihood function. We propose an iterative proximal‐point algorithm based on the EM algorithm to minimize a divergence criterion between a mixture model and the unknown distribution that generates the data. The algorithm estimates in each iteration the proportions and the parameters of the mixture components in two separate steps. Resulting estimators are generally robust against outliers and misspecification of the model. Convergence properties of our algorithm are studied. The convergence of the introduced algorithm is discussed on a two‐component Weibull mixture entailing a condition on the initialization of the EM algorithm in order for the latter to converge. Simulations on Gaussian and Weibull mixture models using different statistical divergences are provided to confirm the validity of our work and the robustness of the resulting estimators against outliers in comparison to the EM algorithm. An application to a dataset of velocities of galaxies is also presented. The Canadian Journal of Statistics 47: 392–408; 2019 © 2019 Statistical Society of Canada     

Asymptotic properties of likelihood ratio test statistics in affected‐sib‐pair analysis

In an affected‐sib‐pair genetic linkage analysis, identical by descent data for affected sib pairs are routinely collected at a large number of markers along chromosomes. Under very general genetic assumptions, the IBD distribution at each marker satisfies the possible triangle constraint. Statistical analysis of IBD data should thus utilize this information to improve efficiency. At the same time, this constraint renders the usual regularity conditions for likelihood‐based statistical methods unsatisfied. In this paper, the authors study the asymptotic properties of the likelihood ratio test (LRT) under the possible triangle constraint. They derive the limiting distribution of the LRT statistic based on data from a single locus. They investigate the precision of the asymptotic distribution and the power of the test by simulation. They also study the test based on the supremum of the LRT statistics over the markers distributed throughout a chromosome. Instead of deriving a limiting distribution for this test, they use a mixture of chi‐squared distributions to approximate its true distribution. Their simulation results show that this approach has desirable simplicity and satisfactory precision.     

Smooth Semi‐nonparametric Analysis for Mixture Cure Models and Its Application to Breast Cancer

Mixture cure models are widely used when a proportion of patients are cured. The proportional hazards mixture cure model and the accelerated failure time mixture cure model are the most popular models in practice. Usually the expectation–maximisation (EM) algorithm is applied to both models for parameter estimation. Bootstrap methods are used for variance estimation. In this paper we propose a smooth semi‐nonparametric (SNP) approach in which maximum likelihood is applied directly to mixture cure models for parameter estimation. The variance can be estimated by the inverse of the second derivative of the SNP likelihood. A comprehensive simulation study indicates good performance of the proposed method. We investigate stage effects in breast cancer by applying the proposed method to breast cancer data from the South Carolina Cancer Registry.     

Generalised quasi‐likelihood inference in a semi‐parametric binary dynamic mixed logit model

There exists a recent study where dynamic mixed‐effects regression models for count data have been extended to a semi‐parametric context. However, when one deals with other discrete data such as binary responses, the results based on count data models are not directly applicable. In this paper, we therefore begin with existing binary dynamic mixed models and generalise them to the semi‐parametric context. For inference, we use a new semi‐parametric conditional quasi‐likelihood (SCQL) approach for the estimation of the non‐parametric function involved in the semi‐parametric model, and a semi‐parametric generalised quasi‐likelihood (SGQL) approach for the estimation of the main regression, dynamic dependence and random effects variance parameters. A semi‐parametric maximum likelihood (SML) approach is also used as a comparison to the SGQL approach. The properties of the estimators are examined both asymptotically and empirically. More specifically, the consistency of the estimators is established and finite sample performances of the estimators are examined through an intensive simulation study.     

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.     

Model‐based linear clustering

The authors propose a profile likelihood approach to linear clustering which explores potential linear clusters in a data set. For each linear cluster, an errors‐in‐variables model is assumed. The optimization of the derived profile likelihood can be achieved by an EM algorithm. Its asymptotic properties and its relationships with several existing clustering methods are discussed. Methods to determine the number of components in a data set are adapted to this linear clustering setting. Several simulated and real data sets are analyzed for comparison and illustration purposes. The Canadian Journal of Statistics 38: 716–737; 2010 © 2010 Statistical Society of Canada     

Impact of missing data on type 1 error rates in non‐inferiority trials

In this paper, a simulation study is conducted to systematically investigate the impact of different types of missing data on six different statistical analyses: four different likelihood‐based linear mixed effects models and analysis of covariance (ANCOVA) using two different data sets, in non‐inferiority trial settings for the analysis of longitudinal continuous data. ANCOVA is valid when the missing data are completely at random. Likelihood‐based linear mixed effects model approaches are valid when the missing data are at random. Pattern‐mixture model (PMM) was developed to incorporate non‐random missing mechanism. Our simulations suggest that two linear mixed effects models using unstructured covariance matrix for within‐subject correlation with no random effects or first‐order autoregressive covariance matrix for within‐subject correlation with random coefficient effects provide well control of type 1 error (T1E) rate when the missing data are completely at random or at random. ANCOVA using last observation carried forward imputed data set is the worst method in terms of bias and T1E rate. PMM does not show much improvement on controlling T1E rate compared with other linear mixed effects models when the missing data are not at random but is markedly inferior when the missing data are at random. Copyright © 2009 John Wiley & Sons, Ltd.     

Inference in Semi‐Parametric Dynamic Models for Repeated Count Data

This paper deals with a longitudinal semi‐parametric regression model in a generalised linear model setup for repeated count data collected from a large number of independent individuals. To accommodate the longitudinal correlations, we consider a dynamic model for repeated counts which has decaying auto‐correlations as the time lag increases between the repeated responses. The semi‐parametric regression function involved in the model contains a specified regression function in some suitable time‐dependent covariates and a non‐parametric function in some other time‐dependent covariates. As far as the inference is concerned, because the non‐parametric function is of secondary interest, we estimate this function consistently using the independence assumption‐based well‐known quasi‐likelihood approach. Next, the proposed longitudinal correlation structure and the estimate of the non‐parametric function are used to develop a semi‐parametric generalised quasi‐likelihood approach for consistent and efficient estimation of the regression effects in the parametric regression function. The finite sample performance of the proposed estimation approach is examined through an intensive simulation study based on both large and small samples. Both balanced and unbalanced cluster sizes are incorporated in the simulation study. The asymptotic performances of the estimators are given. The estimation methodology is illustrated by reanalysing the well‐known health care utilisation data consisting of counts of yearly visits to a physician by 180 individuals for four years and several important primary and secondary covariates.     

Empirical Uncertain Bayes Methods in Area‐level Models

Random effects model can account for the lack of fitting a regression model and increase precision of estimating area‐level means. However, in case that the synthetic mean provides accurate estimates, the prior distribution may inflate an estimation error. Thus, it is desirable to consider the uncertain prior distribution, which is expressed as the mixture of a one‐point distribution and a proper prior distribution. In this paper, we develop an empirical Bayes approach for estimating area‐level means, using the uncertain prior distribution in the context of a natural exponential family, which we call the empirical uncertain Bayes (EUB) method. The regression model considered in this paper includes the Poisson‐gamma and the binomial‐beta, and the normal‐normal (Fay–Herriot) model, which are typically used in small area estimation. We obtain the estimators of hyperparameters based on the marginal likelihood by using a well‐known expectation‐maximization algorithm and propose the EUB estimators of area means. For risk evaluation of the EUB estimator, we derive a second‐order unbiased estimator of a conditional mean squared error by using some techniques of numerical calculation. Through simulation studies and real data applications, we evaluate a performance of the EUB estimator and compare it with the usual empirical Bayes estimator.     

Robust Estimation for Zero‐Inflated Poisson Regression

Abstract. The zero‐inflated Poisson regression model is a special case of finite mixture models that is useful for count data containing many zeros. Typically, maximum likelihood (ML) estimation is used for fitting such models. However, it is well known that the ML estimator is highly sensitive to the presence of outliers and can become unstable when mixture components are poorly separated. In this paper, we propose an alternative robust estimation approach, robust expectation‐solution (RES) estimation. We compare the RES approach with an existing robust approach, minimum Hellinger distance (MHD) estimation. Simulation results indicate that both methods improve on ML when outliers are present and/or when the mixture components are poorly separated. However, the RES approach is more efficient in all the scenarios we considered. In addition, the RES method is shown to yield consistent and asymptotically normal estimators and, in contrast to MHD, can be applied quite generally.     

PARAMETRIC FRACTIONAL IMPUTATION FOR NON‐IGNORABLE CATEGORICAL MISSING DATA WITH FOLLOW‐UP

Incomplete data subject to non‐ignorable non‐response are often encountered in practice and have a non‐identifiability problem. A follow‐up sample is randomly selected from the set of non‐respondents to avoid the non‐identifiability problem and get complete responses. Glynn, Laird, & Rubin analyzed non‐ignorable missing data with a follow‐up sample under a pattern mixture model. In this article, maximum likelihood estimation of parameters of the categorical missing data is considered with a follow‐up sample under a selection model. To estimate the parameters with non‐ignorable missing data, the EM algorithm with weighting, proposed by Ibrahim, is used. That is, in the E‐step, the weighted mean is calculated using the fractional weights for imputed data. Variances are estimated using the approximated jacknife method. Simulation results are presented to compare the proposed method with previously presented methods.     

Building and Fitting Non‐Gaussian Latent Variable Models via the Moment‐Generating Function

Abstract. For certain classes of hierarchical models, it is easy to derive an expression for the joint moment‐generating function (MGF) of data, whereas the joint probability density has an intractable form which typically involves an integral. The most important example is the class of linear models with non‐Gaussian latent variables. Parameters in the model can be estimated by approximate maximum likelihood, using a saddlepoint‐type approximation to invert the MGF. We focus on modelling heavy‐tailed latent variables, and suggest a family of mixture distributions that behaves well under the saddlepoint approximation (SPA). It is shown that the well‐known normalization issue renders the ordinary SPA useless in the present context. As a solution we extend the non‐Gaussian leading term SPA to a multivariate setting, and introduce a general rule for choosing the leading term density. The approach is applied to mixed‐effects regression, time‐series models and stochastic networks and it is shown that the modified SPA is very accurate.     

Model‐based Prediction In Ecological Surveys Including Those with Incomplete Detection

This paper explores and develops model‐based predictors for surveys of plants and wildlife including those with incomplete detection. The methodology allows for estimating a detection function to account for objects which were not detected at the time of the survey. The model‐based theory utilises generalized linear models (GLMs) and is either new or adapted from other areas of sampling. A simulation study is used to validate the estimators and comparisons are made with an integrated likelihood approach. An aerial survey of kangaroos in western New South Wales is used to illustrate the theory. The area within 50m of the aircraft is treated as a strip transect and mark‐recapture methods are used to estimate the detection function.     

Addressing potential prior‐data conflict when using informative priors in proof‐of‐concept studies

Bayesian methods are increasingly used in proof‐of‐concept studies. An important benefit of these methods is the potential to use informative priors, thereby reducing sample size. This is particularly relevant for treatment arms where there is a substantial amount of historical information such as placebo and active comparators. One issue with using an informative prior is the possibility of a mismatch between the informative prior and the observed data, referred to as prior‐data conflict. We focus on two methods for dealing with this: a testing approach and a mixture prior approach. The testing approach assesses prior‐data conflict by comparing the observed data to the prior predictive distribution and resorting to a non‐informative prior if prior‐data conflict is declared. The mixture prior approach uses a prior with a precise and diffuse component. We assess these approaches for the normal case via simulation and show they have some attractive features as compared with the standard one‐component informative prior. For example, when the discrepancy between the prior and the data is sufficiently marked, and intuitively, one feels less certain about the results, both the testing and mixture approaches typically yield wider posterior‐credible intervals than when there is no discrepancy. In contrast, when there is no discrepancy, the results of these approaches are typically similar to the standard approach. Whilst for any specific study, the operating characteristics of any selected approach should be assessed and agreed at the design stage; we believe these two approaches are each worthy of consideration. Copyright © 2015 John Wiley & Sons, Ltd.     

New estimation and feature selection methods in mixture‐of‐experts models

We study estimation and feature selection problems in mixture‐of‐experts models. An $l_2$ ‐penalized maximum likelihood estimator is proposed as an alternative to the ordinary maximum likelihood estimator. The estimator is particularly advantageous when fitting a mixture‐of‐experts model to data with many correlated features. It is shown that the proposed estimator is root‐$n$ consistent, and simulations show its superior finite sample behaviour compared to that of the maximum likelihood estimator. For feature selection, two extra penalty functions are applied to the $l_2$ ‐penalized log‐likelihood function. The proposed feature selection method is computationally much more efficient than the popular all‐subset selection methods. Theoretically it is shown that the method is consistent in feature selection, and simulations support our theoretical results. A real‐data example is presented to demonstrate the method. The Canadian Journal of Statistics 38: 519–539; 2010 © 2010 Statistical Society of Canada     

Estimating the variance for heterogeneity in arm‐based network meta‐analysis

Network meta‐analysis can be implemented by using arm‐based or contrast‐based models. Here we focus on arm‐based models and fit them using generalized linear mixed model procedures. Full maximum likelihood (ML) estimation leads to biased trial‐by‐treatment interaction variance estimates for heterogeneity. Thus, our objective is to investigate alternative approaches to variance estimation that reduce bias compared with full ML. Specifically, we use penalized quasi‐likelihood/pseudo‐likelihood and hierarchical (h) likelihood approaches. In addition, we consider a novel model modification that yields estimators akin to the residual maximum likelihood estimator for linear mixed models. The proposed methods are compared by simulation, and 2 real datasets are used for illustration. Simulations show that penalized quasi‐likelihood/pseudo‐likelihood and h‐likelihood reduce bias and yield satisfactory coverage rates. Sum‐to‐zero restriction and baseline contrasts for random trial‐by‐treatment interaction effects, as well as a residual ML‐like adjustment, also reduce bias compared with an unconstrained model when ML is used, but coverage rates are not quite as good. Penalized quasi‐likelihood/pseudo‐likelihood and h‐likelihood are therefore recommended.