Regression analysis of zero-inflated time-series counts: application to air pollution related emergency room visit data

Time-series count data with excessive zeros frequently occur in environmental, medical and biological studies. These data have been traditionally handled by conditional and marginal modeling approaches separately in the literature. The conditional modeling approaches are computationally much simpler, whereas marginal modeling approaches can link the overall mean with covariates directly. In this paper, we propose new models that can have conditional and marginal modeling interpretations for zero-inflated time-series counts using compound Poisson distributed random effects. We also develop a computationally efficient estimation method for our models using a quasi-likelihood approach. The proposed method is illustrated with an application to air pollution-related emergency room visits. We also evaluate the performance of our method through simulation studies.     

An omnibus two-sample test for ranked-set sampling data

We develop an omnibus two-sample test for ranked-set sampling (RSS) data. The test statistic is the conditional probability of seeing the observed sequence of ranks in the combined sample, given the observed sequences within the separate samples. We compare the test to existing tests under perfect rankings, finding that it can outperform existing tests in terms of power, particularly when the set size is large. The test does not maintain its level under imperfect rankings. However, one can create a permutation version of the test that is comparable in power to the basic test under perfect rankings and also maintains its level under imperfect rankings. Both tests extend naturally to judgment post-stratification, unbalanced RSS, and even RSS with multiple set sizes. Interestingly, the tests have no simple random sampling analog.     

A unified approach to estimation of nonlinear mixed effects and Berkson measurement error models

Mixed effects models and Berkson measurement error models are widely used. They share features which the author uses to develop a unified estimation framework. He deals with models in which the random effects (or measurement errors) have a general parametric distribution, whereas the random regression coefficients (or unobserved predictor variables) and error terms have nonparametric distributions. He proposes a second-order least squares estimator and a simulation-based estimator based on the first two moments of the conditional response variable given the observed covariates. He shows that both estimators are consistent and asymptotically normally distributed under fairly general conditions. The author also reports Monte Carlo simulation studies showing that the proposed estimators perform satisfactorily for relatively small sample sizes. Compared to the likelihood approach, the proposed methods are computationally feasible and do not rely on the normality assumption for random effects or other variables in the model.     

Moment-based estimation of nonlinear regression models with boundary outcomes and endogeneity,with applications to nonnegative and fractional responses

In this article, we suggest simple moment-based estimators to deal with unobserved heterogeneity in a special class of nonlinear regression models that includes as main particular cases exponential models for nonnegative responses and logit and complementary loglog models for fractional responses. The proposed estimators: (i) treat observed and omitted covariates in a similar manner; (ii) can deal with boundary outcomes; (iii) accommodate endogenous explanatory variables without requiring knowledge on the reduced form model, although such information may be easily incorporated in the estimation process; (iv) do not require distributional assumptions on the unobservables, a conditional mean assumption being enough for consistent estimation of the structural parameters; and (v) under the additional assumption that the dependence between observables and unobservables is restricted to the conditional mean, produce consistent estimators of partial effects conditional only on observables.     

A shared parameter model of longitudinal measurements and survival time with heterogeneous random-effects distribution

Typical joint modeling of longitudinal measurements and time to event data assumes that two models share a common set of random effects with a normal distribution assumption. But, sometimes the underlying population that the sample is extracted from is a heterogeneous population and detecting homogeneous subsamples of it is an important scientific question. In this paper, a finite mixture of normal distributions for the shared random effects is proposed for considering the heterogeneity in the population. For detecting whether the unobserved heterogeneity exits or not, we use a simple graphical exploratory diagnostic tool proposed by Verbeke and Molenberghs [34] to assess whether the traditional normality assumption for the random effects in the mixed model is adequate. In the joint modeling setting, in the case of evidence against normality (homogeneity), a finite mixture of normals is used for the shared random-effects distribution. A Bayesian MCMC procedure is developed for parameter estimation and inference. The methodology is illustrated using some simulation studies. Also, the proposed approach is used for analyzing a real HIV data set, using the heterogeneous joint model for this data set, the individuals are classified into two groups: a group with high risk and a group with moderate risk.     

Joint modeling of survival time and longitudinal outcomes with flexible random effects

Joint models with shared Gaussian random effects have been conventionally used in analysis of longitudinal outcome and survival endpoint in biomedical or public health research. However, misspecifying the normality assumption of random effects can lead to serious bias in parameter estimation and future prediction. In this paper, we study joint models of general longitudinal outcomes and survival endpoint but allow the underlying distribution of shared random effect to be completely unknown. For inference, we propose to use a mixture of Gaussian distributions as an approximation to this unknown distribution and adopt an Expectation–Maximization (EM) algorithm for computation. Either AIC and BIC criteria are adopted for selecting the number of mixtures. We demonstrate the proposed method via a number of simulation studies. We illustrate our approach with the data from the Carolina Head and Neck Cancer Study (CHANCE).     

Conditional Akaike Information Criteria for a Class of Poisson Mixture Models with Random Effects

Focusing on the model selection problems in the family of Poisson mixture models (including the Poisson mixture regression model with random effects and zero‐inflated Poisson regression model with random effects), the current paper derives two conditional Akaike information criteria. The criteria are the unbiased estimators of the conditional Akaike information based on the conditional log‐likelihood and the conditional Akaike information based on the joint log‐likelihood, respectively. The derivation is free from the specific parametric assumptions about the conditional mean of the true data‐generating model and applies to different types of estimation methods. Additionally, the derivation is not based on the asymptotic argument. Simulations show that the proposed criteria have promising estimation accuracy. In addition, it is found that the criterion based on the conditional log‐likelihood demonstrates good model selection performance under different scenarios. Two sets of real data are used to illustrate the proposed method.     

Regression models for binary longitudinal responses

Some conditional models to deal with binary longitudinal responses are proposed, extending random effects models to include serial dependence of Markovian form, and hence allowing for quite general association structures between repeated observations recorded on the same individual. The presence of both these components implies a form of dependence between them, and so a complicated expression for the resulting likelihood. To handle this problem, we introduce, as a first instance, what Follmann and Wu (1995) called, in a different setting, an approximate conditional model, which represents an optimal choice for the general framework of categorical longitudinal responses. Then we define two more formally correct models for the binary case, with no assumption about the distribution of the random effect. All of the discussed models are estimated by means of an EM algorithm for nonparametric maximum likelihood. The algorithm, an adaptation of that used by Aitkin (1996) for the analysis of overdispersed generalized linear models, is initially derived as a form of Gaussian quadrature, and then extended to a completely unknown mixing distribution. A large scale simulation work is described to explore the behaviour of the proposed approaches in a number of different situations.     

Conditional mix-GEE models for longitudinal data with unspecified random-effects distributions

In the longitudinal studies, the mixture generalized estimation equation (mix-GEE) was proposed to improve the efficiency of the fixed-effects estimator for addressing the working correlation structure misspecification. When the subject-specific effect is one of interests, mixed-effects models were widely used to analyze longitudinal data. However, most of the existing approaches assume a normal distribution for the random effects, and this could affect the efficiency of the fixed-effects estimator. In this article, a conditional mixture generalized estimating equation (cmix-GEE) approach based on the advantage of mix-GEE and conditional quadratic inference function (CQIF) method is developed. The advantage of our new approach is that it does not require the normality assumption for random effects and can accommodate the serial correlation between observations within the same cluster. The feature of our proposed approach is that the estimators of the regression parameters are more efficient than CQIF even if the working correlation structure is not correctly specified. In addition, according to the estimates of some mixture proportions, the true working correlation matrix can be identified. We establish the asymptotic results for the fixed-effects parameter estimators. Simulation studies were conducted to evaluate our proposed method.     

A new method for the estimation of variance matrix with prescribed zeros in nonlinear mixed effects models

We propose a new method for the Maximum Likelihood Estimator (MLE) of nonlinear mixed effects models when the variance matrix of Gaussian random effects has a prescribed pattern of zeros (PPZ). The method consists of coupling the recently developed Iterative Conditional Fitting (ICF) algorithm with the Expectation Maximization (EM) algorithm. It provides positive definite estimates for any sample size, and does not rely on any structural assumption concerning the PPZ. It can be easily adapted to many versions of EM.     

Mixed models for data from thorough QT studies: part 2. One-step assessment of conditional QT prolongation

We investigate mixed analysis of covariance models for the 'one-step' assessment of conditional QT prolongation. Initially, we consider three different covariance structures for the data, where between-treatment covariance of repeated measures is modelled respectively through random effects, random coefficients, and through a combination of random effects and random coefficients. In all three of those models, an unstructured covariance pattern is used to model within-treatment covariance. In a fourth model, proposed earlier in the literature, between-treatment covariance is modelled through random coefficients but the residuals are assumed to be independent identically distributed (i.i.d.). Finally, we consider a mixed model with saturated covariance structure. We investigate the precision and robustness of those models by fitting them to a large group of real data sets from thorough QT studies. Our findings suggest: (i) Point estimates of treatment contrasts from all five models are similar. (ii) The random coefficients model with i.i.d. residuals is not robust; the model potentially leads to both under- and overestimation of standard errors of treatment contrasts and therefore cannot be recommended for the analysis of conditional QT prolongation. (iii) The combined random effects/random coefficients model does not always converge; in the cases where it converges, its precision is generally inferior to the other models considered. (iv) Both the random effects and the random coefficients model are robust. (v) The random effects, the random coefficients, and the saturated model have similar precision and all three models are suitable for the one-step assessment of conditional QT prolongation.     

Evaluation of incomplete multiple diagnostic tests,with an application in the colon cancer family registry study

Accurate diagnosis of a molecularly defined subtype of cancer is often an important step toward its effective control and treatment. For the diagnosis of some subtypes of a cancer, a gold standard with perfect sensitivity and specificity may be unavailable. In those scenarios, tumor subtype status is commonly measured by multiple imperfect diagnostic markers. Additionally, in many such studies, some subjects are only measured by a subset of diagnostic tests and the missing probabilities may depend on the unknown disease status. In this paper, we present statistical methods based on the EM algorithm to evaluate incomplete multiple imperfect diagnostic tests under a missing at random assumption and one missing not at random scenario. We apply the proposed methods to a real data set from the National Cancer Institute (NCI) colon cancer family registry on diagnosing microsatellite instability for hereditary non-polyposis colorectal cancer to estimate diagnostic accuracy parameters (i.e. sensitivities and specificities), prevalence, and potential differential missing probabilities for 11 biomarker tests. Simulations are also conducted to evaluate the small-sample performance of our methods.     

An alternative approach for compatibility of two discrete conditional distributions

ABSTRACT

Conditional specification of distributions is a developing area with increasing applications. In the finite discrete case, a variety of compatible conditions can be derived. In this paper, we propose an alternative approach to study the compatibility of two conditional probability distributions under the finite discrete setup. A technique based on rank-based criterion is shown to be particularly convenient for identifying compatible distributions corresponding to complete conditional specification including the case with zeros.The proposed methods are illustrated with several examples.     

Modelling Survival Events with Longitudinal Covariates Measured with Error

In survival analysis, time-dependent covariates are usually present as longitudinal data collected periodically and measured with error. The longitudinal data can be assumed to follow a linear mixed effect model and Cox regression models may be used for modelling of survival events. The hazard rate of survival times depends on the underlying time-dependent covariate measured with error, which may be described by random effects. Most existing methods proposed for such models assume a parametric distribution assumption on the random effects and specify a normally distributed error term for the linear mixed effect model. These assumptions may not be always valid in practice. In this article, we propose a new likelihood method for Cox regression models with error-contaminated time-dependent covariates. The proposed method does not require any parametric distribution assumption on random effects and random errors. Asymptotic properties for parameter estimators are provided. Simulation results show that under certain situations the proposed methods are more efficient than the existing methods.     

An efficient model-free estimation of multiclass conditional probability

Conventional multiclass conditional probability estimation methods, such as Fisher's discriminate analysis and logistic regression, often require restrictive distributional model assumption. In this paper, a model-free estimation method is proposed to estimate multiclass conditional probability through a series of conditional quantile regression functions. Specifically, the conditional class probability is formulated as a difference of corresponding cumulative distribution functions, where the cumulative distribution functions can be converted from the estimated conditional quantile regression functions. The proposed estimation method is also efficient as its computation cost does not increase exponentially with the number of classes. The theoretical and numerical studies demonstrate that the proposed estimation method is highly competitive against the existing competitors, especially when the number of classes is relatively large.     

Count data and treatment heterogeneity in 2×2 crossover trials

Count data are routinely assumed to have a Poisson distribution, especially when there are no straightforward diagnostic procedures for checking this assumption. We reanalyse two data sets from crossover trials of treatments for angina pectoris , in which the outcomes are counts of anginal attacks. Standard analyses focus on treatment effects, averaged over subjects; we are also interested in the dispersion of these effects (treatment heterogeneity). We set up a log-Poisson model with random coefficients to estimate the distribution of the treatment effects and show that the analysis is very sensitive to the distributional assumption; the population variance of the treatment effects is confounded with the (variance) function that relates the conditional variance of the outcomes, given the subject's rate of attacks, to the conditional mean. Diagnostic model checks based on resampling from the fitted distribution indicate that the default choice of the Poisson distribution for the analysed data sets is poorly supported. We propose to augment the data sets with observations of the counts, made possibly outside the clinical setting, so that the conditional distribution of the counts could be established.     

Response prediction in mixed effects models

Although prediction in mixed effects models usually concerns the random effects, in this paper we deal with the problem of prediction of a future, or yet unobserved, response random variable, belonging to a given cluster. In particular, the aim is to define computationally tractable prediction intervals, with conditional and unconditional coverage probability close to the target nominal value. This solution involves the conditional density of the future response random variable given the observed data, or a suitable high-order approximation based on the Laplace method. We prove that, unless the amount of data is very limited, the estimative or naive predictive procedure gives a relatively simple, feasible solution for response prediction. An application to generalized linear mixed models is presented.     

Quantile estimation in ultra-high frequency financial data: a comparison between parametric and semiparametric approach

In the context of ACD models for ultra-high frequency data different specifications are available to estimate the conditional mean of intertrade durations, while quantiles estimation has been completely neglected by literature, even if to trading extent it can be more informative. The main problem arising with quantiles estimation is the correct specification of durations probability law: the usual assumption of Exponentially distributed residuals, is very robust for the estimation of parameters of the conditional mean, but dramatically fails the distributional fit. In this paper a semiparametric approach is formalized, and compared with the parametric one, deriving from Exponential assumption. Empirical evidence for a stock of Italian financial market strongly supports the former approach.Paola Zuccolotto: The author wishes to thank Prof. A. Mazzali, Dott. G. De Luca, Dott. M. Sandri for valuable comments.     

A biomedical application of latent class models with random effects

Traditional latent class modelling has been used in many biomedical settings. Unfortunately, many of these applications assume that the diagnostic tests are independent given the true disease status, an assumption that is often violated in practice. Qu, Tan and Kutner developed general latent class models with random effects to model the conditional dependence among multiple diagnostic tests. In this paper latent class modelling with random effects is used to estimate the sensitivity and specificity of six screening tests for detecting Chlamydia trachomatis in endocervical specimens from women attending family planning clinics.     

Maximum-likelihood estimation and influence analysis in multivariate skew-normal reproductive dispersion mixed models for longitudinal data

Various mixed models were developed to capture the features of between- and within-individual variation for longitudinal data under the normality assumption of the random effect and the within-individual random error. However, the normality assumption may be violated in some applications. To this end, this article assumes that the random effect follows a skew-normal distribution and the within-individual error is distributed as a reproductive dispersion model. An expectation conditional maximization (ECME) algorithm together with the Metropolis-Hastings (MH) algorithm within the Gibbs sampler is presented to simultaneously obtain estimates of parameters and random effects. Several diagnostic measures are developed to identify the potentially influential cases and assess the effect of minor perturbation to model assumptions via the case-deletion method and local influence analysis. To reduce the computational burden, we derive the first-order approximations to case-deletion diagnostics. Several simulation studies and a real data example are presented to illustrate the newly developed methodologies.