On the analysis of long-term experiments

Summary.  Long-term experiments are commonly used tools in agronomy, soil science and other disciplines for comparing the effects of different treatment regimes over an extended length of time. Periodic measurements, typically annual, are taken on experimental units and are often analysed by using customary tools and models for repeated measures. These models contain nothing that accounts for the random environmental variations that typically affect all experimental units simultaneously and can alter treatment effects. This added variability can dominate that from all other sources and can adversely influence the results of a statistical analysis and interfere with its interpretation. The effect that this has on the standard repeated measures analysis is quantified by using an alternative model that allows for random variations over time. This model, however, is not useful for analysis because the random effects are confounded with fixed effects that are already in the repeated measures model. Possible solutions are reviewed and recommendations are made for improving statistical analysis and interpretation in the presence of these extra random variations.     

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.     

M-quantile models with application to poverty mapping

Over the last decade there has been growing demand for estimates of population characteristics at small area level. Unfortunately, cost constraints in the design of sample surveys lead to small sample sizes within these areas and as a result direct estimation, using only the survey data, is inappropriate since it yields estimates with unacceptable levels of precision. Small area models are designed to tackle the small sample size problem. The most popular class of models for small area estimation is random effects models that include random area effects to account for between area variations. However, such models also depend on strong distributional assumptions, require a formal specification of the random part of the model and do not easily allow for outlier robust inference. An alternative approach to small area estimation that is based on the use of M-quantile models was recently proposed by Chambers and Tzavidis (Biometrika 93(2):255–268, 2006) and Tzavidis and Chambers (Robust prediction of small area means and distributions. Working paper, 2007). Unlike traditional random effects models, M-quantile models do not depend on strong distributional assumption and automatically provide outlier robust inference. In this paper we illustrate for the first time how M-quantile models can be practically employed for deriving small area estimates of poverty and inequality. The methodology we propose improves the traditional poverty mapping methods in the following ways: (a) it enables the estimation of the distribution function of the study variable within the small area of interest both under an M-quantile and a random effects model, (b) it provides analytical, instead of empirical, estimation of the mean squared error of the M-quantile small area mean estimates and (c) it employs a robust to outliers estimation method. The methodology is applied to data from the 2002 Living Standards Measurement Survey (LSMS) in Albania for estimating (a) district level estimates of the incidence of poverty in Albania, (b) district level inequality measures and (c) the distribution function of household per-capita consumption expenditure in each district. Small area estimates of poverty and inequality show that the poorest Albanian districts are in the mountainous regions (north and north east) with the wealthiest districts, which are also linked with high levels of inequality, in the coastal (south west) and southern part of country. We discuss the practical advantages of our methodology and note the consistency of our results with results from previous studies. We further demonstrate the usefulness of the M-quantile estimation framework through design-based simulations based on two realistic survey data sets containing small area information and show that the M-quantile approach may be preferable when the aim is to estimate the small area distribution function.     

Mean-Squared errors of small area estimators under a multivariate linear model for repeated measures data

In this paper, we discuss the derivation of the first and second moments for the proposed small area estimators under a multivariate linear model for repeated measures data. The aim is to use these moments to estimate the mean-squared errors (MSE) for the predicted small area means as a measure of precision. At the first stage, we derive the MSE when the covariance matrices are known. At the second stage, a method based on parametric bootstrap is proposed for bias correction and for prediction error that reflects the uncertainty when the unknown covariance is replaced by its suitable estimator.     

Small area estimation of mean price of habitation transaction using time-series and cross-sectional area-level models

In this paper, a new small domain estimator for area-level data is proposed. The proposed estimator is driven by a real problem of estimating the mean price of habitation transaction at a regional level in a European country, using data collected from a longitudinal survey conducted by a national statistical office. At the desired level of inference, it is not possible to provide accurate direct estimates because the sample sizes in these domains are very small. An area-level model with a heterogeneous covariance structure of random effects assists the proposed combined estimator. This model is an extension of a model due to Fay and Herriot [5], but it integrates information across domains and over several periods of time. In addition, a modified method of estimation of variance components for time-series and cross-sectional area-level models is proposed by including the design weights. A Monte Carlo simulation, based on real data, is conducted to investigate the performance of the proposed estimators in comparison with other estimators frequently used in small area estimation problems. In particular, we compare the performance of these estimators with the estimator based on the Rao–Yu model [23]. The simulation study also accesses the performance of the modified variance component estimators in comparison with the traditional ANOVA method. Simulation results show that the estimators proposed perform better than the other estimators in terms of both precision and bias.     

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 Bayesian Hierarchical Model for Multiple Comparisons in Mixed Models

We propose a Bayesian hierarchical model for multiple comparisons in mixed models where the repeated measures on subjects are described with the subject random effects. The model facilitates inferences in parameterizing the successive differences of the population means, and for them, we choose independent prior distributions that are mixtures of a normal distribution and a discrete distribution with its entire mass at zero. For the other parameters, we choose conjugate or vague priors. The performance of the proposed hierarchical model is investigated in the simulated and two real data sets, and the results illustrate that the proposed hierarchical model can effectively conduct a global test and pairwise comparisons using the posterior probability that any two means are equal. A simulation study is performed to analyze the type I error rate, the familywise error rate, and the test power. The Gibbs sampler procedure is used to estimate the parameters and to calculate the posterior probabilities.     

Copula-based predictions in small area estimation

Unit-level regression models are commonly used in small area estimation (SAE) to obtain an empirical best linear unbiased prediction of small area characteristics. The underlying assumptions of these models, however, may be unrealistic in some applications. Previous work developed a copula-based SAE model where the empirical Kendall's tau was used to estimate the dependence between two units from the same area. In this article, we propose a likelihood framework to estimate the intra-class dependence of the multivariate exchangeable copula for the empirical best unbiased prediction (EBUP) of small area means. One appeal of the proposed approach lies in its accommodation of both parametric and semi-parametric estimation approaches. Under each estimation method, we further propose a bootstrap approach to obtain a nearly unbiased estimator of the mean squared prediction error of the EBUP of small area means. The performance of the proposed methods is evaluated through simulation studies and also by a real data application.     

Small area estimation under unit-level temporal linear mixed models

Data from past time periods and temporal correlation are rich sources of information for estimating small area parameters at the current period. This paper investigates the use of unit-level temporal linear mixed models for estimating linear parameters. Two models are considered, with domain and domain-time random effects. The first model assumes time independency and the second one AR(1)-type time correlation. They are fitted by a Fisher-scoring algorithm that calculates the residual maximum likelihood estimators of the model parameters. Based on the introduced models, empirical best linear unbiased predictors of small area linear parameters are studied, and analytic estimators for evaluating the performance of their mean squared errors are proposed. Three simulation experiments are carried out to study the behaviour of the fitting algorithm, the small area predictors and the estimators of the mean squared error. By using data of the Spanish surveys of income and living conditions of 2004–2008, an application to the estimation of 2008 average normalized net annual incomes in Spanish provinces by sex is given.     

Hierarchical Bayes estimation in small area estimation using cross-sectional and time-series data

Bayesian methods have been extensively used in small area estimation. A linear model incorporating autocorrelated random effects and sampling errors was previously proposed in small area estimation using both cross-sectional and time-series data in the Bayesian paradigm. There are, however, many situations that we have time-related counts or proportions in small area estimation; for example, monthly dataset on the number of incidence in small areas. This article considers hierarchical Bayes generalized linear models for a unified analysis of both discrete and continuous data with incorporating cross-sectional and time-series data. The performance of the proposed approach is evaluated through several simulation studies and also by a real dataset.     

A generalized linear mixed model for longitudinal binary data with a marginal logit link function

Longitudinal studies of a binary outcome are common in the health, social, and behavioral sciences. In general, a feature of random effects logistic regression models for longitudinal binary data is that the marginal functional form, when integrated over the distribution of the random effects, is no longer of logistic form. Recently, Wang and Louis (2003) proposed a random intercept model in the clustered binary data setting where the marginal model has a logistic form. An acknowledged limitation of their model is that it allows only a single random effect that varies from cluster to cluster. In this paper, we propose a modification of their model to handle longitudinal data, allowing separate, but correlated, random intercepts at each measurement occasion. The proposed model allows for a flexible correlation structure among the random intercepts, where the correlations can be interpreted in terms of Kendall's τ. For example, the marginal correlations among the repeated binary outcomes can decline with increasing time separation, while the model retains the property of having matching conditional and marginal logit link functions. Finally, the proposed method is used to analyze data from a longitudinal study designed to monitor cardiac abnormalities in children born to HIV-infected women.     

MODEL‐BASED DIRECT ESTIMATION OF SMALL‐AREA DISTRIBUTIONS

Much of the small‐area estimation literature focuses on population totals and means. However, users of survey data are often interested in the finite‐population distribution of a survey variable and in the measures (e.g. medians, quartiles, percentiles) that characterize the shape of this distribution at the small‐area level. In this paper we propose a model‐based direct estimator (MBDE, Chandra and Chambers) of the small‐area distribution function. The MBDE is defined as a weighted sum of sample data from the area of interest, with weights derived from the calibrated spline‐based estimate of the finite‐population distribution function introduced by Harms and Duchesne, under an appropriately specified regression model with random area effects. We also discuss the mean squared error estimation of the MBDE. Monte Carlo simulations based on both simulated and real data sets show that the proposed MBDE and its associated mean squared error estimator perform well when compared with alternative estimators of the area‐specific finite‐population distribution function.     

ROBUST ESTIMATION OF SMALL‐AREA MEANS AND QUANTILES

Small‐area estimation techniques have typically relied on plug‐in estimation based on models containing random area effects. More recently, regression M‐quantiles have been suggested for this purpose, thus avoiding conventional Gaussian assumptions, as well as problems associated with the specification of random effects. However, the plug‐in M‐quantile estimator for the small‐area mean can be shown to be the expected value of this mean with respect to a generally biased estimator of the small‐area cumulative distribution function of the characteristic of interest. To correct this problem, we propose a general framework for robust small‐area estimation, based on representing a small‐area estimator as a functional of a predictor of this small‐area cumulative distribution function. Key advantages of this framework are that it naturally leads to integrated estimation of small‐area means and quantiles and is not restricted to M‐quantile models. We also discuss mean squared error estimation for the resulting estimators, and demonstrate the advantages of our approach through model‐based and design‐based simulations, with the latter using economic data collected in an Australian farm survey.     

Mixed models for data from thorough QT studies: part 1. assessment of marginal QT prolongation

We investigate mixed models for repeated measures data from cross-over studies in general, but in particular for data from thorough QT studies. We extend both the conventional random effects model and the saturated covariance model for univariate cross-over data to repeated measures cross-over (RMC) data; the resulting models we call the RMC model and Saturated model, respectively. Furthermore, we consider a random effects model for repeated measures cross-over data previously proposed in the literature. We assess the standard errors of point estimates and the coverage properties of confidence intervals for treatment contrasts under the various models. Our findings suggest: (i) Point estimates of treatment contrasts from all models considered are similar; (ii) Confidence intervals for treatment contrasts under the random effects model previously proposed in the literature do not have adequate coverage properties; the model therefore cannot be recommended for analysis of marginal QT prolongation; (iii) The RMC model and the Saturated model have similar precision and coverage properties; both models are suitable for assessment of marginal QT prolongation; and (iv) The Akaike Information Criterion (AIC) is not a reliable criterion for selecting a covariance model for RMC data in the following sense: the model with the smallest AIC is not necessarily associated with the highest precision for the treatment contrasts, even if the model with the smallest AIC value is also the most parsimonious model.     

A semiparametric stochastic mixed effects model for bivariate cyclic longitudinal data

We propose a flexible semiparametric stochastic mixed effects model for bivariate cyclic longitudinal data. The model can handle either single cycle or, more generally, multiple consecutive cycle data. The approach models the mean of responses by parametric fixed effects and a smooth nonparametric function for the underlying time effects, and the relationship across the bivariate responses by a bivariate Gaussian random field and a joint distribution of random effects. The proposed model not only can model complicated individual profiles, but also allows for more flexible within-subject and between-response correlations. The fixed effects regression coefficients and the nonparametric time functions are estimated using maximum penalized likelihood, where the resulting estimator for the nonparametric time function is a cubic smoothing spline. The smoothing parameters and variance components are estimated simultaneously using restricted maximum likelihood. Simulation results show that the parameter estimates are close to the true values. The fit of the proposed model on a real bivariate longitudinal dataset of pre-menopausal women also performs well, both for a single cycle analysis and for a multiple consecutive cycle analysis. The Canadian Journal of Statistics 48: 471–498; 2020 © 2020 Statistical Society of Canada     

Mixed-Poisson Point Process with Partially-Observed Covariates: Ecological Momentary Assessment of Smoking

Ecological Momentary Assessment is an emerging method of data collection in behavioral research that may be used to capture the times of repeated behavioral events on electronic devices, and information on subjects' psychological states through the electronic administration of questionnaires at times selected from a probability-based design as well as the event times. A method for fitting a mixed Poisson point process model is proposed for the impact of partially-observed, time-varying covariates on the timing of repeated behavioral events. A random frailty is included in the point-process intensity to describe variation among subjects in baseline rates of event occurrence. Covariate coefficients are estimated using estimating equations constructed by replacing the integrated intensity in the Poisson score equations with a design-unbiased estimator. An estimator is also proposed for the variance of the random frailties. Our estimators are robust in the sense that no model assumptions are made regarding the distribution of the time-varying covariates or the distribution of the random effects. However, subject effects are estimated under gamma frailties using an approximate hierarchical likelihood. The proposed approach is illustrated using smoking data.     

Binary Time Series Modeling with Application to Adhesion Frequency Experiments

Repeated adhesion frequency assay is the only published method for measuring the kinetic rates of cell adhesion. Cell adhesion plays an important role in many physiological and pathological processes. Traditional analysis of adhesion frequency experiments assumes that the adhesion test cycles are independent Bernoulli trials. This assumption can often be violated in practice. Motivated by the analysis of repeated adhesion tests, a binary time series model incorporating random effects is developed in this paper. A goodness-of-fit statistic is introduced to assess the adequacy of distribution assumptions on the dependent binary data with random effects. The asymptotic distribution of the goodness-of-fit statistic is derived and its finite-sample performance is examined via a simulation study. Application of the proposed methodology to real data from a T-cell experiment reveals some interesting information, including the dependency between repeated adhesion tests.     

Optimal Prediction in Stochastic Regression Models with Application to the Analysis of Repeated Surveys

Several results relating to the optimal prediction of regression coefficients and random variables under a general linear model with stochastic coefficients are presented. These results are then applied to the analysis of repeated sample surveys over time. In particular, if the finite population can be modelled by a superpopulation model, a fully efficient method for the analysis of repeated surveys is proposed.     

Estimated estimating equations: semiparametric inference for clustered and longitudinal data

Summary.  We introduce a flexible marginal modelling approach for statistical inference for clustered and longitudinal data under minimal assumptions. This estimated estimating equations approach is semiparametric and the proposed models are fitted by quasi-likelihood regression, where the unknown marginal means are a function of the fixed effects linear predictor with unknown smooth link, and variance–covariance is an unknown smooth function of the marginal means. We propose to estimate the nonparametric link and variance–covariance functions via smoothing methods, whereas the regression parameters are obtained via the estimated estimating equations. These are score equations that contain nonparametric function estimates. The proposed estimated estimating equations approach is motivated by its flexibility and easy implementation. Moreover, if data follow a generalized linear mixed model, with either a specified or an unspecified distribution of random effects and link function, the model proposed emerges as the corresponding marginal (population-average) version and can be used to obtain inference for the fixed effects in the underlying generalized linear mixed model, without the need to specify any other components of this generalized linear mixed model. Among marginal models, the estimated estimating equations approach provides a flexible alternative to modelling with generalized estimating equations. Applications of estimated estimating equations include diagnostics and link selection. The asymptotic distribution of the proposed estimators for the model parameters is derived, enabling statistical inference. Practical illustrations include Poisson modelling of repeated epileptic seizure counts and simulations for clustered binomial responses.     

On efficient inferences in familial-longitudinal binary models with two variance components

When a generalized linear mixed model (GLMM) with multiple (two or more) sources of random effects is considered, the inferences may vary depending on the nature of the random effects. For example, the inference in GLMMs with two independent random effects with two distinct components of dispersion will be different from the inference in GLMMs with two random effects in a two factor factorial design set-up. In this paper, we consider a familial-longitudinal model for repeated binary data where the binary response of an individual member of a family at a given time point is assumed to be influenced by the past responses of the member as well as two but independent sources of random family effects. For the estimation of the parameters of the proposed model, we discuss the well-known maximum-likelihood (ML) method as well as a generalized quasi-likelihood (GQL) approach. The main objective of the paper is to examine the relative asymptotic efficiency performance of the ML and GQL estimators for the regression effects, dynamic (longitudinal) dependence and variance parameters of the random family effects from two sources.