Nonlinear mixed‐effects models with misspecified random‐effects distribution

Nonlinear mixed‐effects models are being widely used for the analysis of longitudinal data, especially from pharmaceutical research. They use random effects which are latent and unobservable variables so the random‐effects distribution is subject to misspecification in practice. In this paper, we first study the consequences of misspecifying the random‐effects distribution in nonlinear mixed‐effects models. Our study is focused on Gauss‐Hermite quadrature, which is now the routine method for calculation of the marginal likelihood in mixed models. We then present a formal diagnostic test to check the appropriateness of the assumed random‐effects distribution in nonlinear mixed‐effects models, which is very useful for real data analysis. Our findings show that the estimates of fixed‐effects parameters in nonlinear mixed‐effects models are generally robust to deviations from normality of the random‐effects distribution, but the estimates of variance components are very sensitive to the distributional assumption of random effects. Furthermore, a misspecified random‐effects distribution will either overestimate or underestimate the predictions of random effects. We illustrate the results using a real data application from an intensive pharmacokinetic study.     

A new estimation procedure for a partially nonlinear model via a mixed‐effects approach

The authors consider the estimation of the parametric component of a partially nonlinear semiparametric regression model whose nonparametric component is viewed as a nuisance parameter. They show how estimation can proceed through a nonlinear mixed‐effects model approach. They prove that under certain regularity conditions, the proposed estimate is consistent and asymptotically Gaussian. They investigate its finite‐sample properties through simulations and illustrate its use with data on the relation between the photosynthetically active radiation and the net ecosystem‐atmosphere exchange of carbon dioxide.     

Goodness-of-fit measures of R 2 for repeated measures mixed effect models

Linear mixed effects model (LMEM) is efficient in modeling repeated measures longitudinal data. However, little research has been done in developing goodness-of-fit measures that can evaluate the models, particularly those that can be interpreted in an absolute sense without referencing a null model. This paper proposes three coefficient of determination (R ²) as goodness-of-fit measures for LMEM with repeated measures longitudinal data. Theorems are presented describing the properties of R ² and relationships between the R ² statistics. A simulation study was conducted to evaluate and compare the R ² along with other criteria from literature. Finally, we applied the proposed R ² to a real virologic response data of an HIV-patient cohort. We conclude that our proposed R ² statistics have more advantages than other goodness-of-fit measures in the literature, in terms of robustness to sample size, intuitive interpretation, well-defined range, and unnecessary to determine a null model.     

A novel quantification of information for longitudinal data analyzed by mixed‐effects modeling

Nonlinear mixed‐effects (NLME) modeling is one of the most powerful tools for analyzing longitudinal data especially under the sparse sampling design. The determinant of the Fisher information matrix is a commonly used global metric of the information that can be provided by the data under a given model. However, in clinical studies, it is also important to measure how much information the data provide for a certain parameter of interest under the assumed model, for example, the clearance in population pharmacokinetic models. This paper proposes a new, easy‐to‐interpret information metric, the “relative information” (RI), which is designed for specific parameters of a model and takes a value between 0% and 100%. We establish the relationship between interindividual variability for a specific parameter and the variance of the associated parameter estimator, demonstrating that, under a “perfect” experiment (eg, infinite samples or/and minimum experimental error), the RI and the variance of the model parameter estimator converge, respectively, to 100% and the ratio of the interindividual variability for that parameter and the number of subjects. Extensive simulation experiments and analyses of three real datasets show that our proposed RI metric can accurately characterize the information for parameters of interest for NLME models. The new information metric can be readily used to facilitate study designs and model diagnosis.     

A comparison of bootstrap approaches for estimating uncertainty of parameters in linear mixed‐effects models

A version of the nonparametric bootstrap, which resamples the entire subjects from original data, called the case bootstrap, has been increasingly used for estimating uncertainty of parameters in mixed‐effects models. It is usually applied to obtain more robust estimates of the parameters and more realistic confidence intervals (CIs). Alternative bootstrap methods, such as residual bootstrap and parametric bootstrap that resample both random effects and residuals, have been proposed to better take into account the hierarchical structure of multi‐level and longitudinal data. However, few studies have been performed to compare these different approaches. In this study, we used simulation to evaluate bootstrap methods proposed for linear mixed‐effect models. We also compared the results obtained by maximum likelihood (ML) and restricted maximum likelihood (REML). Our simulation studies evidenced the good performance of the case bootstrap as well as the bootstraps of both random effects and residuals. On the other hand, the bootstrap methods that resample only the residuals and the bootstraps combining case and residuals performed poorly. REML and ML provided similar bootstrap estimates of uncertainty, but there was slightly more bias and poorer coverage rate for variance parameters with ML in the sparse design. We applied the proposed methods to a real dataset from a study investigating the natural evolution of Parkinson's disease and were able to confirm that the methods provide plausible estimates of uncertainty. Given that most real‐life datasets tend to exhibit heterogeneity in sampling schedules, the residual bootstraps would be expected to perform better than the case bootstrap. Copyright © 2013 John Wiley & Sons, Ltd.     

On nonlinear random effects models for repeated measurements

Linear random effects models for longitudinal data discussed by Laird and Ware (1982), Jennrich and Schluchter (1986), Lange and Laird (1989), and others are extended in a straight forward manner to nonlinear random effects models. This results in a simple computational approach which accommodates patterned covariance matrices and data insufficient for fitting each subject separately. The technique is demonstrated with an interesting medical data set, and a short, simple SAS PROC IML program based on the EM algorithm is presented.     

Computation aspects of the parameter estimates of linear mixed effects model in multivariate repeated measures set-up

The number of parameters mushrooms in a linear mixed effects (LME) model in the case of multivariate repeated measures data. Computation of these parameters is a real problem with the increase in the number of response variables or with the increase in the number of time points. The problem becomes more intricate and involved with the addition of additional random effects. A multivariate analysis is not possible in a small sample setting. We propose a method to estimate these many parameters in bits and pieces from baby models, by taking a subset of response variables at a time, and finally using these bits and pieces at the end to get the parameter estimates for the mother model, with all variables taken together. Applying this method one can calculate the fixed effects, the best linear unbiased predictions (BLUPs) for the random effects in the model, and also the BLUPs at each time of observation for each response variable, to monitor the effectiveness of the treatment for each subject. The proposed method is illustrated with an example of multiple response variables measured over multiple time points arising from a clinical trial in osteoporosis.     

A generalized Bayesian nonlinear mixed‐effects regression model for zero‐inflated longitudinal count data in tuberculosis trials

In this paper, we investigate Bayesian generalized nonlinear mixed‐effects (NLME) regression models for zero‐inflated longitudinal count data. The methodology is motivated by and applied to colony forming unit (CFU) counts in extended bactericidal activity tuberculosis (TB) trials. Furthermore, for model comparisons, we present a generalized method for calculating the marginal likelihoods required to determine Bayes factors. A simulation study shows that the proposed zero‐inflated negative binomial regression model has good accuracy, precision, and credibility interval coverage. In contrast, conventional normal NLME regression models applied to log‐transformed count data, which handle zero counts as left censored values, may yield credibility intervals that undercover the true bactericidal activity of anti‐TB drugs. We therefore recommend that zero‐inflated NLME regression models should be fitted to CFU count on the original scale, as an alternative to conventional normal NLME regression models on the logarithmic scale.     

Short notes on maximum likelihood inference for control‐based pattern‐mixture models

A likelihood‐based analytical approach has been proposed for the control‐based pattern‐mixture model and its extension. In this note, we derive equivalent but simpler analytical expressions for the treatment effect and its variance for these control‐based pattern mixture models. Our formulae are easier to use and interpret. An application of our formulae to an antidepressant trial is provided, in which the likelihood‐based analysis is compared with the multiple imputation approach. Copyright © 2015 John Wiley & Sons, Ltd.     

Estimation of treatment effects for heterogeneous matched‐pairs data with probit models

Estimating the effect of medical treatments on subject responses is one of the crucial problems in medical research. Matched‐pairs designs are commonly implemented in the field of medical research to eliminate confounding and improve efficiency. In this article, new estimators of treatment effects for heterogeneous matched‐pairs data are proposed. Asymptotic properties of the proposed estimators are derived. Simulation studies show that the proposed estimators have some advantages over the famous Heckman's estimator, the conditional maximum likelihood estimator, and the inverse probability weighted estimator. We apply the proposed methodology to a data set from a study of low‐birth‐weight infants.     

Robust transformation mixed‐effects models for longitudinal continuous proportional data

The authors propose a robust transformation linear mixed‐effects model for longitudinal continuous proportional data when some of the subjects exhibit outlying trajectories over time. It becomes troublesome when including or excluding such subjects in the data analysis results in different statistical conclusions. To robustify the longitudinal analysis using the mixed‐effects model, they utilize the multivariate t distribution for random effects or/and error terms. Estimation and inference in the proposed model are established and illustrated by a real data example from an ophthalmology study. Simulation studies show a substantial robustness gain by the proposed model in comparison to the mixed‐effects model based on Aitchison's logit‐normal approach. As a result, the data analysis benefits from the robustness of making consistent conclusions in the presence of influential outliers. The Canadian Journal of Statistics © 2009 Statistical Society of Canada     

Type I error rates from likelihood‐based repeated measures analyses of incomplete longitudinal data

The last observation carried forward (LOCF) approach is commonly utilized to handle missing values in the primary analysis of clinical trials. However, recent evidence suggests that likelihood‐based analyses developed under the missing at random (MAR) framework are sensible alternatives. The objective of this study was to assess the Type I error rates from a likelihood‐based MAR approach – mixed‐model repeated measures (MMRM) – compared with LOCF when estimating treatment contrasts for mean change from baseline to endpoint (Δ). Data emulating neuropsychiatric clinical trials were simulated in a 4 × 4 factorial arrangement of scenarios, using four patterns of mean changes over time and four strategies for deleting data to generate subject dropout via an MAR mechanism. In data with no dropout, estimates of Δ and SE_Δ from MMRM and LOCF were identical. In data with dropout, the Type I error rates (averaged across all scenarios) for MMRM and LOCF were 5.49% and 16.76%, respectively. In 11 of the 16 scenarios, the Type I error rate from MMRM was at least 1.00% closer to the expected rate of 5.00% than the corresponding rate from LOCF. In no scenario did LOCF yield a Type I error rate that was at least 1.00% closer to the expected rate than the corresponding rate from MMRM. The average estimate of SE_Δ from MMRM was greater in data with dropout than in complete data, whereas the average estimate of SE_Δ from LOCF was smaller in data with dropout than in complete data, suggesting that standard errors from MMRM better reflected the uncertainty in the data. The results from this investigation support those from previous studies, which found that MMRM provided reasonable control of Type I error even in the presence of MNAR missingness. No universally best approach to analysis of longitudinal data exists. However, likelihood‐based MAR approaches have been shown to perform well in a variety of situations and are a sensible alternative to the LOCF approach. MNAR methods can be used within a sensitivity analysis framework to test the potential presence and impact of MNAR data, thereby assessing robustness of results from an MAR method. Copyright © 2004 John Wiley & Sons, Ltd.     

Robust Bayesian nonlinear mixed‐effects modeling of time to positivity in tuberculosis trials

Early phase 2 tuberculosis (TB) trials are conducted to characterize the early bactericidal activity (EBA) of anti‐TB drugs. The EBA of anti‐TB drugs has conventionally been calculated as the rate of decline in colony forming unit (CFU) count during the first 14 days of treatment. The measurement of CFU count, however, is expensive and prone to contamination. Alternatively to CFU count, time to positivity (TTP), which is a potential biomarker for long‐term efficacy of anti‐TB drugs, can be used to characterize EBA. The current Bayesian nonlinear mixed‐effects (NLME) regression model for TTP data, however, lacks robustness to gross outliers that often are present in the data. The conventional way of handling such outliers involves their identification by visual inspection and subsequent exclusion from the analysis. However, this process can be questioned because of its subjective nature. For this reason, we fitted robust versions of the Bayesian nonlinear mixed‐effects regression model to a wide range of TTP datasets. The performance of the explored models was assessed through model comparison statistics and a simulation study. We conclude that fitting a robust model to TTP data obviates the need for explicit identification and subsequent “deletion” of outliers but ensures that gross outliers exert no undue influence on model fits. We recommend that the current practice of fitting conventional normal theory models be abandoned in favor of fitting robust models to TTP data.     

Estimating the reliability of repeatedly measured endpoints based on linear mixed‐effects models. A tutorial

There are various settings in which researchers are interested in the assessment of the correlation between repeated measurements that are taken within the same subject (i.e., reliability). For example, the same rating scale may be used to assess the symptom severity of the same patients by multiple physicians, or the same outcome may be measured repeatedly over time in the same patients. Reliability can be estimated in various ways, for example, using the classical Pearson correlation or the intra‐class correlation in clustered data. However, contemporary data often have a complex structure that goes well beyond the restrictive assumptions that are needed with the more conventional methods to estimate reliability. In the current paper, we propose a general and flexible modeling approach that allows for the derivation of reliability estimates, standard errors, and confidence intervals – appropriately taking hierarchies and covariates in the data into account. Our methodology is developed for continuous outcomes together with covariates of an arbitrary type. The methodology is illustrated in a case study, and a Web Appendix is provided which details the computations using the R package CorrMixed and the SAS software. Copyright © 2016 John Wiley & Sons, Ltd.     

Robust estimation for order of hidden Markov models based on density power divergences

In this paper, we study the robust estimation for the order of hidden Markov model (HMM) based on a penalized minimum density power divergence estimator, which is obtained by utilizing the finite mixture marginal distribution of HMM. For this task, we adopt the locally conic parametrization method used in [D. Dacunha-Castelle and E. Gassiate, Testing in locally conic models and application to mixture models. ESAIM Probab. Stat. (1997), pp. 285–317; D. Dacunha-Castelle and E. Gassiate, Testing the order of a model using locally conic parametrization: population mixtures and stationary arma processes, Ann. Statist. 27 (1999), pp. 1178–1209; T. Lee and S. Lee, Robust and consistent estimation of the order of finite mixture models based on the minimizing a density power divergence estimator, Metrika 68 (2008), pp. 365–390] to avoid the difficulties that arise in handling mixture marginal models, such as the non-identifiability of the parameter space and the singularity problem with the asymptotic variance. We verify that the estimated order is consistent and simulation results are provided for illustration.     

On population‐based measures of agreement for binary classifications

The authors describe a model‐based kappa statistic for binary classifications which is interpretable in the same manner as Scott's pi and Cohen's kappa, yet does not suffer from the same flaws. They compare this statistic with the data‐driven and population‐based forms of Scott's pi in a population‐based setting where many raters and subjects are involved, and inference regarding the underlying diagnostic procedure is of interest. The authors show that Cohen's kappa and Scott's pi seriously underestimate agreement between experts classifying subjects for a rare disease; in contrast, the new statistic is robust to changes in prevalence. The performance of the three statistics is illustrated with simulations and prostate cancer data.     

Bias‐reduced marginal Akaike information criteria based on a Monte Carlo method for linear mixed‐effects models

In linear mixed‐effects (LME) models, if a fitted model has more random‐effect terms than the true model, a regularity condition required in the asymptotic theory may not hold. In such cases, the marginal Akaike information criterion (AIC) is positively biased for (?2) times the expected log‐likelihood. The asymptotic bias of the maximum log‐likelihood as an estimator of the expected log‐likelihood is evaluated for LME models with balanced design in the context of parameter‐constrained models. Moreover, bias‐reduced marginal AICs for LME models based on a Monte Carlo method are proposed. The performance of the proposed criteria is compared with existing criteria by using example data and by a simulation study. It was found that the bias of the proposed criteria was smaller than that of the existing marginal AIC when a larger model was fitted and that the probability of choosing a smaller model incorrectly was decreased.     

Non‐stationary Cross‐Covariance Models for Multivariate Processes on a Globe

Abstract. In geophysical and environmental problems, it is common to have multiple variables of interest measured at the same location and time. These multiple variables typically have dependence over space (and/or time). As a consequence, there is a growing interest in developing models for multivariate spatial processes, in particular, the cross‐covariance models. On the other hand, many data sets these days cover a large portion of the Earth such as satellite data, which require valid covariance models on a globe. We present a class of parametric covariance models for multivariate processes on a globe. The covariance models are flexible in capturing non‐stationarity in the data yet computationally feasible and require moderate numbers of parameters. We apply our covariance model to surface temperature and precipitation data from an NCAR climate model output. We compare our model to the multivariate version of the Matérn cross‐covariance function and models based on coregionalization and demonstrate the superior performance of our model in terms of AIC (and/or maximum loglikelihood values) and predictive skill. We also present some challenges in modelling the cross‐covariance structure of the temperature and precipitation data. Based on the fitted results using full data, we give the estimated cross‐correlation structure between the two variables.     

The effects of missing serial effects and/or heteroscedastic errors on mixed models using repeated growth data

When a two-level multilevel model (MLM) is used for repeated growth data, the individuals constitute level 2 and the successive measurements constitute level 1, which is nested within the individuals that make up level 2. The heterogeneity among individuals is represented by either the random-intercept or random-coefficient (slope) model. The variance components at level 1 involve serial effects and measurement errors under constant variance or heteroscedasticity. This study hypothesizes that missing serial effects or/and heteroscedasticity may bias the results obtained from two-level models. To illustrate this effect, we conducted two simulation studies, where the simulated data were based on the characteristics of an empirical mouse tumour data set. The results suggest that for repeated growth data with constant variance (measurement error) and misspecified serial effects (ρ > 0.3), the proportion of level-2 variation (intra-class correlation coefficient) increases with ρ and the two-level random-coefficient model is the minimum AIC (or AIC_c) model when compared with the fixed model, heteroscedasticity model, and random-intercept model. In addition, the serial effect (ρ > 0.1) and heteroscedasticity are both misspecified, implying that the two-level random-coefficient model is the minimum AIC (or AIC_c) model when compared with the fixed model and random-intercept model. This study demonstrates that missing serial effects and/or heteroscedasticity may indicate heterogeneity among individuals in repeated growth data (mixed or two-level MLM). This issue is critical in biomedical research.     

Score tests for heterogeneity and overdispersion in zero‐inflated Poisson and binomial regression models

Hall (2000) has described zero‐inflated Poisson and binomial regression models that include random effects to account for excess zeros and additional sources of heterogeneity in the data. The authors of the present paper propose a general score test for the null hypothesis that variance components associated with these random effects are zero. For a zero‐inflated Poisson model with random intercept, the new test reduces to an alternative to the overdispersion test of Ridout, Demério & Hinde (2001). The authors also examine their general test in the special case of the zero‐inflated binomial model with random intercept and propose an overdispersion test in that context which is based on a beta‐binomial alternative.