Modeling Unequally Spaced Bivariate Growth Curve Data Using a Kalman Filter Approach

ABSTRACT

In many clinical studies, patients are followed over time with their responses measured longitudinally. Using mixed model theory, one can characterize these data using a wide array of across subject models. A state-space representation of the mixed effects model and use of the Kalman filter allows one to have great flexibility in choosing the within error correlation structure even in the presence of missing or unequally spaced observations. Furthermore, using the state-space approach, one can avoid inverting large matrices resulting in efficient computation. The approach also allows one to make detailed inference about the error correlation structure. We consider a bivariate situation where the longitudinal responses are unequally spaced and assume that the within subject errors follows a continuous first-order autoregressive (CAR(1)) structure. Since a large number of nonlinear parameters need to be estimated, the modeling strategy and numerical techniques are critical in the process. We developed both a Visual Fortran^® and a SAS^® program for modeling such data. A simulation study was conducted to investigate the robustness of the model assumptions. We also use data from a psychiatric study to demonstrate our model fitting procedure.     

Regularization in dynamic random-intercepts models for analysis of longitudinal data

This paper addresses the problem of simultaneous variable selection and estimation in the random-intercepts model with the first-order lag response. This type of model is commonly used for analyzing longitudinal data obtained through repeated measurements on individuals over time. This model uses random effects to cover the intra-class correlation, and the first lagged response to address the serial correlation, which are two common sources of dependency in longitudinal data. We demonstrate that the conditional likelihood approach by ignoring correlation among random effects and initial responses can lead to biased regularized estimates. Furthermore, we demonstrate that joint modeling of initial responses and subsequent observations in the structure of dynamic random-intercepts models leads to both consistency and Oracle properties of regularized estimators. We present theoretical results in both low- and high-dimensional settings and evaluate regularized estimators' performances by conducting simulation studies and analyzing a real dataset. Supporting information is available online.     

Non-penalty shrinkage estimation of random effect models for longitudinal data with AR(1) errors

In this paper, we consider the non-penalty shrinkage estimation method of random effect models with autoregressive errors for longitudinal data when there are many covariates and some of them may not be active for the response variable. In observational studies, subjects are followed over equally or unequally spaced visits to determine the continuous response and whether the response is associated with the risk factors/covariates. Measurements from the same subject are usually more similar to each other and thus are correlated with each other but not with observations of other subjects. To analyse this data, we consider a linear model that contains both random effects across subjects and within-subject errors that follows autoregressive structure of order 1 (AR(1)). Considering the subject-specific random effect as a nuisance parameter, we use two competing models, one includes all the covariates and the other restricts the coefficients based on the auxiliary information. We consider the non-penalty shrinkage estimation strategy that shrinks the unrestricted estimator in the direction of the restricted estimator. We discuss the asymptotic properties of the shrinkage estimators using the notion of asymptotic biases and risks. A Monte Carlo simulation study is conducted to examine the relative performance of the shrinkage estimators with the unrestricted estimator when the shrinkage dimension exceeds two. We also numerically compare the performance of the shrinkage estimators to that of the LASSO estimator. A longitudinal CD4 cell count data set will be used to illustrate the usefulness of shrinkage and LASSO estimators.     

A monte carlo comparison of the smoothing,scoring and em algorithms for dispersion matrix estimation with incomplete growth curve data

Incomplete growth curve data often result from missing or mistimed observations in a repeated measures design. Virtually all methods of analysis rely on the dispersion matrix estimates. A Monte Carlo simulation was used to compare three methods of estimation of dispersion matrices for incomplete growth curve data. The three methods were: 1) maximum likelihood estimation with a smoothing algorithm, which finds the closest positive semidefinite estimate of the pairwise estimated dispersion matrix; 2) a mixed effects model using the EM (estimation maximization) algorithm; and 3) a mixed effects model with the scoring algorithm. The simulation included 5 dispersion structures, 20 or 40 subjects with 4 or 8 observations per subject and 10 or 30% missing data. In all the simulations, the smoothing algorithm was the poorest estimator of the dispersion matrix. In most cases, there were no significant differences between the scoring and EM algorithms. The EM algorithm tended to be better than the scoring algorithm when the variances of the random effects were close to zero, especially for the simulations with 4 observations per subject and two random effects.     

Covariate Decomposition Methods for Longitudinal Missing‐at‐Random Data and Predictors Associated with Subject‐Specific Effects

Investigators often gather longitudinal data to assess changes in responses over time within subjects and to relate these changes to within‐subject changes in predictors. Missing data are common in such studies and predictors can be correlated with subject‐specific effects. Maximum likelihood methods for generalized linear mixed models provide consistent estimates when the data are ‘missing at random’ (MAR) but can produce inconsistent estimates in settings where the random effects are correlated with one of the predictors. On the other hand, conditional maximum likelihood methods (and closely related maximum likelihood methods that partition covariates into between‐ and within‐cluster components) provide consistent estimation when random effects are correlated with predictors but can produce inconsistent covariate effect estimates when data are MAR. Using theory, simulation studies, and fits to example data this paper shows that decomposition methods using complete covariate information produce consistent estimates. In some practical cases these methods, that ostensibly require complete covariate information, actually only involve the observed covariates. These results offer an easy‐to‐use approach to simultaneously protect against bias from both cluster‐level confounding and MAR missingness in assessments of change.     

Stochastic Differential Mixed-Effects Models

Abstract.  Stochastic differential equations have been shown useful in describing random continuous time processes. Biomedical experiments often imply repeated measurements on a series of experimental units and differences between units can be represented by incorporating random effects into the model. When both system noise and random effects are considered, stochastic differential mixed-effects models ensue. This class of models enables the simultaneous representation of randomness in the dynamics of the phenomena being considered and variability between experimental units, thus providing a powerful modelling tool with immediate applications in biomedicine and pharmacokinetic/pharmacodynamic studies. In most cases the likelihood function is not available, and thus maximum likelihood estimation of the unknown parameters is not possible. Here we propose a computationally fast approximated maximum likelihood procedure for the estimation of the non-random parameters and the random effects. The method is evaluated on simulations from some famous diffusion processes and on real data sets.     

A Bayesian approach of joint models for clustered zero-inflated count data with skewness and measurement errors

Count data with excess zeros are widely encountered in the fields of biomedical, medical, public health and social survey, etc. Zero-inflated Poisson (ZIP) regression models with mixed effects are useful tools for analyzing such data, in which covariates are usually incorporated in the model to explain inter-subject variation and normal distribution is assumed for both random effects and random errors. However, in many practical applications, such assumptions may be violated as the data often exhibit skewness and some covariates may be measured with measurement errors. In this paper, we deal with these issues simultaneously by developing a Bayesian joint hierarchical modeling approach. Specifically, by treating intercepts and slopes in logistic and Poisson regression as random, a flexible two-level ZIP regression model is proposed, where a covariate process with measurement errors is established and a skew-t-distribution is considered for both random errors and random effects. Under the Bayesian framework, model selection is carried out using deviance information criterion (DIC) and a goodness-of-fit statistics is also developed for assessing the plausibility of the posited model. The main advantage of our method is that it allows for more robustness and correctness for investigating heterogeneity from different levels, while accommodating the skewness and measurement errors simultaneously. An application to Shanghai Youth Fitness Survey is used as an illustrate example. Through this real example, it is showed that our approach is of interest and usefulness for applications.     

Simulated maximum likelihood estimation in joint models for multiple longitudinal markers and recurrent events of multiple types,in the presence of a terminal event

In medical studies we are often confronted with complex longitudinal data. During the follow-up period, which can be ended prematurely by a terminal event (e.g. death), a subject can experience recurrent events of multiple types. In addition, we collect repeated measurements from multiple markers. An adverse health status, represented by ‘bad’ marker values and an abnormal number of recurrent events, is often associated with the risk of experiencing the terminal event. In this situation, the missingness of the data is not at random and, to avoid bias, it is necessary to model all data simultaneously using a joint model. The correlations between the repeated observations of a marker or an event type within an individual are captured by normally distributed random effects. Because the joint likelihood contains an analytically intractable integral, Bayesian approaches or quadrature approximation techniques are necessary to evaluate the likelihood. However, when the number of recurrent event types and markers is large, the dimensionality of the integral is high and these methods are too computationally expensive. As an alternative, we propose a simulated maximum-likelihood approach based on quasi-Monte Carlo integration to evaluate the likelihood of joint models with multiple recurrent event types and markers.     

Abundance estimation with a categorical covariate subject to missing in continuous-time capture-recapture studies

Abstract

In continuous-time capture-recapture experiments, individual heterogeneity has a large effect on the capture probability. To account for the heterogeneity, we consider an individual covariate, which is categorical and subject to missing. In this article, we develop a general model to summarize three kinds of missing mechanisms, and propose a maximum likelihood estimator of the abundance. A likelihood ratio confidence interval of the abundance is also proposed. We illustrate the proposed methods by simulation studies and a real data example of a bird species prinia subflava in Hong Kong.     

Approximate bounded influence estimation for longitudinal data with outliers and measurement errors

Mixed effects models or random effects models are popular for the analysis of longitudinal data. In practice, longitudinal data are often complex since there may be outliers in both the response and the covariates and there may be measurement errors. The likelihood method is a common approach for these problems but it can be computationally very intensive and sometimes may even be computationally infeasible. In this article, we consider approximate robust methods for nonlinear mixed effects models to simultaneously address outliers and measurement errors. The approximate methods are computationally very efficient. We show the consistency and asymptotic normality of the approximate estimates. The methods can also be extended to missing data problems. An example is used to illustrate the methods and a simulation is conducted to evaluate the methods.     

A Bayesian semiparametric method for analyzing length-biased data

Survival data obtained from prevalent cohort study designs are often subject to length-biased sampling. Frequentist methods including estimating equation approaches, as well as full likelihood methods, are available for assessing covariate effects on survival from such data. Bayesian methods allow a perspective of probability interpretation for the parameters of interest, and may easily provide the predictive distribution for future observations while incorporating weak prior knowledge on the baseline hazard function. There is lack of Bayesian methods for analyzing length-biased data. In this paper, we propose Bayesian methods for analyzing length-biased data under a proportional hazards model. The prior distribution for the cumulative hazard function is specified semiparametrically using I-Splines. Bayesian conditional and full likelihood approaches are developed for analyzing simulated and real data.     

Additive mixed models with Dirichlet process mixture and P-spline priors

Longitudinal data often require a combination of flexible time trends and individual-specific random effects. For example, our methodological developments are motivated by a study on longitudinal body mass index profiles of children collected with the aim to gain a better understanding of factors driving childhood obesity. The high amount of nonlinearity and heterogeneity in these data and the complexity of the data set with a large number of observations, long longitudinal profiles and clusters of observations with specific deviations from the population model make the application challenging and prevent the application of standard growth curve models. We propose a fully Bayesian approach based on Markov chain Monte Carlo simulation techniques that allows for the semiparametric specification of both the trend function and the random effects distribution. Bayesian penalized splines are considered for the former, while a Dirichlet process mixture (DPM) specification allows for an adaptive amount of deviations from normality for the latter. The advantages of such DPM prior structures for random effects are investigated in terms of a simulation study to improve the understanding of the model specification before analyzing the childhood obesity data.     

Empirical Bayes estimates for correlated hierarchical data with overdispersion

An extension of the generalized linear mixed model was constructed to simultaneously accommodate overdispersion and hierarchies present in longitudinal or clustered data. This so‐called combined model includes conjugate random effects at observation level for overdispersion and normal random effects at subject level to handle correlation, respectively. A variety of data types can be handled in this way, using different members of the exponential family. Both maximum likelihood and Bayesian estimation for covariate effects and variance components were proposed. The focus of this paper is the development of an estimation procedure for the two sets of random effects. These are necessary when making predictions for future responses or their associated probabilities. Such (empirical) Bayes estimates will also be helpful in model diagnosis, both when checking the fit of the model as well as when investigating outlying observations. The proposed procedure is applied to three datasets of different outcome types. Copyright © 2014 John Wiley & Sons, Ltd.     

A Comparative Study of Observation- and Parameter-driven Zero-inflated Poisson Models for Longitudinal Count Data

Longitudinal count data with excessive zeros frequently occur in social, biological, medical, and health research. To model such data, zero-inflated Poisson (ZIP) models are commonly used, after separating zero and positive responses. As longitudinal count responses are likely to be serially correlated, such separation may destroy the underlying serial correlation structure. To overcome this problem recently observation- and parameter-driven modelling approaches have been proposed. In the observation-driven model, the response at a specific time point is modelled through the responses at previous time points after incorporating serial correlation. One limitation of the observation-driven model is that it fails to accommodate the presence of any possible over-dispersion, which frequently occurs in the count responses. This limitation is overcome in a parameter-driven model, where the serial correlation is captured through the latent process using random effects. We compare the results obtained by the two models. A quasi-likelihood approach has been developed to estimate the model parameters. The methodology is illustrated with analysis of two real life datasets. To examine model performance the models are also compared through a simulation study.     

A robust regression model for a first-order autoregressive time series with unequal spacing: application to water monitoring

Summary.  Time series arise often in environmental monitoring settings, which typically involve measuring processes repeatedly over time. In many such applications, observations are irregularly spaced and, additionally, are not distributed normally. An example is water monitoring data collected in Boston Harbor by the Massachusetts Water Resources Authority. We describe a simple robust approach for estimating regression parameters and a first-order autocorrelation parameter in a time series where the observations are irregularly spaced. Estimates are obtained from an estimating equation that is constructed as a linear combination of estimated innovation errors, suitably made robust by symmetric and possibly bounded functions. Under an assumption of data missing completely at random and mild regularity conditions, the proposed estimating equation yields consistent and asymptotically normal estimates. Simulations suggest that our estimator performs well in moderate sample sizes. We demonstrate our method on Secchi depth data collected from Boston Harbor.     

Slashed generalized exponential distribution

In this paper, we introduce an extension of the generalized exponential (GE) distribution, making it more robust against possible influential observations. The new model is defined as the quotient between a GE random variable and a beta-distributed random variable with one unknown parameter. The resulting distribution is a distribution with greater kurtosis than the GE distribution. Probability properties of the distribution such as moments and asymmetry and kurtosis are studied. Likewise, statistical properties are investigated using the method of moments and the maximum likelihood approach. Two real data analyses are reported illustrating better performance of the new model over the GE model.     

Small sample distribution of the likelihood ratio test in the random effects model

In this paper we examine the small sample distribution of the likelihood ratio test in the random effects model which is often recommended for meta-analyses. We find that this distribution depends strongly on the true value of the heterogeneity parameter (between-study variance) of the model, and that the correct p-value may be quite different from its large sample approximation. We recommend that the dependence of the heterogeneity parameter be examined for the data at hand and suggest a (simulation) method for this. Our setup allows for explanatory variables on the study level (meta-regression) and we discuss other possible applications, too. Two data sets are analyzed and two simulation studies are performed for illustration.     

A flexible approach for multivariate mixed-effects models with non-ignorable missing values

We propose a flexible model approach for the distribution of random effects when both response variables and covariates have non-ignorable missing values in a longitudinal study. A Bayesian approach is developed with a choice of nonparametric prior for the distribution of random effects. We apply the proposed method to a real data example from a national long-term survey by Statistics Canada. We also design simulation studies to further check the performance of the proposed approach. The result of simulation studies indicates that the proposed approach outperforms the conventional approach with normality assumption when the heterogeneity in random effects distribution is salient.     

Empirical likelihood-based serial correlation testing in partially varying coefficient single-index models

ABSTRACT

Partially varying coefficient single-index models (PVCSIM) are a class of semiparametric regression models. One important assumption is that the model error is independently and identically distributed, which may contradict with the reality in many applications. For example, in the economical and financial applications, the observations may be serially correlated over time. Based on the empirical likelihood technique, we propose a procedure for testing the serial correlation of random error in PVCSIM. Under some regular conditions, we show that the proposed empirical likelihood ratio statistic asymptotically follows a standard χ² distribution. We also present some numerical studies to illustrate the performance of our proposed testing procedure.     

Flexible estimation of serial correlation in nonlinear mixed models

In the conventional linear mixed-effects model, four structures can be distinguished: fixed effects, random effects, measurement error and serial correlation. The latter captures the phenomenon that the correlation structure within a subject depends on the time lag between two measurements. While the general linear mixed model is rather flexible, the need has arisen to further increase flexibility. In addition to work done in the area, we propose the use of spline-based modeling of the serial correlation function, so as to allow for additional flexibility. This approach is applied to data from a pre-clinical experiment in dementia which studied the eating and drinking behavior in mice.