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Finite mixture models have been used to model population heterogeneity and to relax distributional assumptions. These models are also convenient tools for clustering and classification of complex data such as, for example, repeated-measurements data. The performance of model-based clustering algorithms is sensitive to influential and outlying observations. Methods for identifying outliers in a finite mixture model have been described in the literature. Approaches to identify influential observations are less common. In this paper, we apply local-influence diagnostics to a finite mixture model with known number of components. The methodology is illustrated on real-life data.

In longitudinal studies, continuous, binary, categorical, and survival outcomes are often jointly collected, possibly with some observations missing. However, when it comes to modeling responses, the ordinal ones have received less attention in the literature. In a longitudinal or hierarchical context, the univariate proportional odds mixed model (POMM) can be regarded as an instance of the generalized linear mixed model (GLMM). When the response of the joint multivariate model encompass ordinal responses, the complexity further increases. An additional problem of model fitting is the size of the collected data. Pseudo-likelihood based methods for pairwise fitting, for partitioned samples and, as introduced in this paper, pairwise fitting within partitioned samples allow joint modeling of even larger numbers of responses. We show that that pseudo-likelihood methodology allows for highly efficient and fast inferences in high-dimensional large datasets.

In this paper, we develop a simple diagnostic test for the random-effects distribution in mixed models. The test is based on the gradient function, a graphical tool proposed by Verbeke and Molenberghs to check the impact of assumptions about the random-effects distribution in mixed models on inferences. Inference is conducted through the bootstrap. The proposed test is easy to implement and applicable in a general class of mixed models. The operating characteristics of the test are evaluated in a simulation study, and the method is further illustrated using two real data analyses.

We combine conjugate and normal random effects in a joint model for outcomes, at least one of which is non-Gaussian, with particular emphasis on cases in which one of the outcomes is of survival type. Conjugate random effects are used to relax the often-restrictive mean-variance prescription in the non-Gaussian outcome, while normal random effects account for not only the correlation induced by repeated measurements from the same subject but also the association between the different outcomes. Using a case study in chronic heart failure, we show that model fit can be improved, even resulting in impact on significance tests, by switching to our extended framework. By first taking advantage of the ease of analytical integration over conjugate random effects, we easily estimate our framework, by maximum likelihood, in standard software., (© The Author(s) 2013.)

This paper presents, extends, and studies a model for repeated, overdispersed time-to-event outcomes, subject to censoring. Building upon work by Molenberghs, Verbeke, and Demétrio (2007) and Molenberghs et al. (2010), gamma and normal random effects are included in a Weibull model, to account for overdispersion and between-subject effects, respectively. Unlike these authors, censoring is allowed for, and two estimation methods are presented. The partial marginalization approach to full maximum likelihood of Molenberghs et al. (2010) is contrasted with pseudo-likelihood estimation. A limited simulation study is conducted to examine the relative merits of these estimation methods. The modeling framework is employed to analyze data on recurrent asthma attacks in children on the one hand and on survival in cancer patients on the other., (© The Author(s) 2014.)

Longitudinal experiments often involve multiple outcomes measured repeatedly within a set of study participants. While many questions can be answered by modeling the various outcomes separately, some questions can only be answered in a joint analysis of all of them. In this article, we will present a review of the many approaches proposed in the statistical literature. Four main model families will be presented, discussed and compared. Focus will be on presenting advantages and disadvantages of the different models rather than on the mathematical or computational details.

The vast majority of settings for which frequentist statistical properties are derived assume a fixed, a priori known sample size. Familiar properties then follow, such as, for example, the consistency, asymptotic normality, and efficiency of the sample average for the mean parameter, under a wide range of conditions. We are concerned here with the alternative situation in which the sample size is itself a random variable which may depend on the data being collected. Further, the rule governing this may be deterministic or probabilistic. There are many important practical examples of such settings, including missing data, sequential trials, and informative cluster size. It is well known that special issues can arise when evaluating the properties of statistical procedures under such sampling schemes, and much has been written about specific areas (Grambsch P. Sequential sampling based on the observed Fisher information to guarantee the accuracy of the maximum likelihood estimator. Ann Stat 1983; 11: 68-77; Barndorff-Nielsen O and Cox DR. The effect of sampling rules on likelihood statistics. Int Stat Rev 1984; 52: 309-326). Our aim is to place these various related examples into a single framework derived from the joint modeling of the outcomes and sampling process and so derive generic results that in turn provide insight, and in some cases practical consequences, for different settings. It is shown that, even in the simplest case of estimating a mean, some of the results appear counterintuitive. In many examples, the sample average may exhibit small sample bias and, even when it is unbiased, may not be optimal. Indeed, there may be no minimum variance unbiased estimator for the mean. Such results follow directly from key attributes such as non-ancillarity of the sample size and incompleteness of the minimal sufficient statistic of the sample size and sample sum. Although our results have direct and obvious implications for estimation following group sequential trials, there are also ramifications for a range of other settings, such as random cluster sizes, censored time-to-event data, and the joint modeling of longitudinal and time-to-event data. Here, we use the simplest group sequential setting to develop and explicate the main results. Some implications for random sample sizes and missing data are also considered. Consequences for other related settings will be considered elsewhere.

Background: Constraint-induced movement therapy (CIMT) has gained emerging evidence and popularity in children with unilateral cerebral palsy (CP). However, many issues remain unanswered regarding the best approach., Objective: This study investigated the additional effects of an intensive therapy program to promote hand function combined with home-based modified CIMT (m-CIMT)., Methods: . Fifty-one children (mean age 8 years 9 months) were randomized to m-CIMT alone or m-CIMT with intensive therapy (IT). All children had to wear a constraint on the unaffected hand for 1 hour, 5 days/week for 10 weeks. Children in the m-CIMT + IT group also received 3 sessions of 45 minutes weekly of intensive therapy for distal muscle strengthening and hand function, using unimanual and bimanual activities. The Assisting Hand Assessment (AHA) was the primary outcome measure. Secondary outcome measures were muscle tone, strength, Melbourne Assessment, Jebsen-Taylor test, and ABILHAND-Kids questionnaire. Assessments were administered at baseline, after intervention, and at 10-week follow-up., Results: Significant between-group differences in AHA were in favor of the m-CIMT + IT group (P = .04). Both groups demonstrated comparable improvements in muscle tone (P = .002), strength (P < .0001), grip strength (P = .02), and unimanual capacity (Melbourne Assessment and Jebsen-Taylor, P < .0001). Younger children and children with poorer hand function benefited from both interventions, whereas older children and children with better hand function only benefited from the combined approach., Conclusions: The combination of m-CIMT with an intensive therapy program on distal hand function and strength enhances the effects of m-CIMT alone for improving bimanual performance.

This article reviews various recently suggested approaches to estimate the random effects distribution in a linear mixed model, i.e. (1) the smoothing by roughening approach of Shen and Louis,(1) (2) the semi-non-parametric approach of Zhang and Davidian,(2) (3) the heterogeneity model of Verbeke and Lesaffre( 3) and (4) a flexible approach of Ghidey et al. (4) These four approaches are compared via an extensive simulation study. We conclude that for the considered cases, the approach of Ghidey et al. (4) often shows to have the smallest integrated mean squared error for estimating the random effects distribution. An analysis of a longitudinal dental data set illustrates the performance of the methods in a practical example.

Mixed models are widely used for the analysis of one repeatedly measured outcome. If more than one outcome is present, a mixed model can be used for each one. These separate models can be tied together into a multivariate mixed model by specifying a joint distribution for their random effects. This strategy has been used for joining multivariate longitudinal profiles or other types of multivariate repeated data. However, computational problems are likely to occur when the number of outcomes increases. A pairwise modeling approach, in which all possible bivariate mixed models are fitted and where inference follows from pseudo-likelihood arguments, has been proposed to circumvent the dimensional limitations in multivariate mixed models. An analysis on 22-variate longitudinal measurements of hearing thresholds illustrates the performance of the pairwise approach in the context of multivariate linear mixed models. For generalized linear mixed models, a data set containing repeated measurements of seven aspects of psycho-cognitive functioning will be analyzed.

The researcher collecting hierarchical data is frequently confronted with incompleteness. Since the processes governing missingness are often outside the investigator's control, no matter how well the experiment has been designed, careful attention is needed when analyzing such data.We sketch a standard framework and taxonomy largely based on Rubin's work. After briefly touching upon (overly) simple methods,we turn to a number of viable candidates for a standard analysis, including direct likelihood, multiple imputation and versions of generalized estimating equations. Many of these require so-called ignorability. With the latter condition not necessarily satisfied, we also review flexible models for the outcome and missingnessprocesses at the same time. Finally, we illustrate how such methods can be very sensitive to modeling assumptions and then conclude with a number of routes for sensitivity analysis. Attention will be given to the feasibility of the proposed modes of analysis within a regulatory environment.