Semiparametric Bayesian hierarchical models for heterogeneous population in nonlinear mixed effect model: application to gastric emptying studies

Gastric emptying studies are frequently used in medical research, both human and animal, when evaluating the effectiveness and determining the unintended side-effects of new and existing medications, diets, and procedures or interventions. It is essential that gastric emptying data be appropriately summarized before making comparisons between study groups of interest and to allow study the comparisons. Since gastric emptying data have a nonlinear emptying curve and are longitudinal data, nonlinear mixed effect (NLME) models can accommodate both the variation among measurements within individuals and the individual-to-individual variation. However, the NLME model requires strong assumptions that are often not satisfied in real applications that involve a relatively small number of subjects, have heterogeneous measurement errors, or have large variation among subjects. Therefore, we propose three semiparametric Bayesian NLMEs constructed with Dirichlet process priors, which automatically cluster sub-populations and estimate heterogeneous measurement errors. To compare three semiparametric models with the parametric model we propose a penalized posterior Bayes factor. We compare the performance of our semiparametric hierarchical Bayesian approaches with that of the parametric Bayesian hierarchical approach. Simulation results suggest that our semiparametric approaches are more robust and flexible. Our gastric emptying studies from equine medicine are used to demonstrate the advantage of our approaches.     

A parameter expansion version of the SAEM algorithm

The EM algorithm and its extensions are very popular tools for maximum likelihood estimation in incomplete data setting. However, one of the limitations of these methods is their slow convergence. The PX-EM (parameter-expanded EM) algorithm was proposed by Liu, Rubin and Wu to make EM much faster. On the other hand, stochastic versions of EM are powerful alternatives of EM when the E-step is untractable in a closed form. In this paper we propose the PX-SAEM which is a parameter expansion version of the so-called SAEM (Stochastic Approximation version of EM). PX-SAEM is shown to accelerate SAEM and improve convergence toward the maximum likelihood estimate in a parametric framework. Numerical examples illustrate the behavior of PX-SAEM in linear and nonlinear mixed effects models.     

General partially linear additive transformation model with right-censored data

We propose a class of general partially linear additive transformation models (GPLATM) with right-censored survival data in this work. The class of models are flexible enough to cover many commonly used parametric and nonparametric survival analysis models as its special cases. Based on the B spline interpolation technique, we estimate the unknown regression parameters and functions by the maximum marginal likelihood estimation method. One important feature of the estimation procedure is that it does not need the baseline and censoring cumulative density distributions. Some numerical studies illustrate that this procedure can work very well for the moderate sample size.     

A flexible parametric survival model for fitting time to event data in clinical trials

Time‐to‐event data are common in clinical trials to evaluate survival benefit of a new drug, biological product, or device. The commonly used parametric models including exponential, Weibull, Gompertz, log‐logistic, log‐normal, are simply not flexible enough to capture complex survival curves observed in clinical and medical research studies. On the other hand, the nonparametric Kaplan Meier (KM) method is very flexible and successful on catching the various shapes in the survival curves but lacks ability in predicting the future events such as the time for certain number of events and the number of events at certain time and predicting the risk of events (eg, death) over time beyond the span of the available data from clinical trials. It is obvious that neither the nonparametric KM method nor the current parametric distributions can fulfill the needs in fitting survival curves with the useful characteristics for predicting. In this paper, a full parametric distribution constructed as a mixture of three components of Weibull distribution is explored and recommended to fit the survival data, which is as flexible as KM for the observed data but have the nice features beyond the trial time, such as predicting future events, survival probability, and hazard function.     

Nonparametric Bayes Stochastically Ordered Latent Class Models

Latent class models (LCMs) are used increasingly for addressing a broad variety of problems, including sparse modeling of multivariate and longitudinal data, model-based clustering, and flexible inferences on predictor effects. Typical frequentist LCMs require estimation of a single finite number of classes, which does not increase with the sample size, and have a well-known sensitivity to parametric assumptions on the distributions within a class. Bayesian nonparametric methods have been developed to allow an infinite number of classes in the general population, with the number represented in a sample increasing with sample size. In this article, we propose a new nonparametric Bayes model that allows predictors to flexibly impact the allocation to latent classes, while limiting sensitivity to parametric assumptions by allowing class-specific distributions to be unknown subject to a stochastic ordering constraint. An efficient MCMC algorithm is developed for posterior computation. The methods are validated using simulation studies and applied to the problem of ranking medical procedures in terms of the distribution of patient morbidity.     

Modelling forces of infection by using monotone local polynomials

Summary. On the basis of serological data from prevalence studies of rubella, mumps and hepatitis A, the paper describes a flexible local maximum likelihood method for the estimation of the rate at which susceptible individuals acquire infection at different ages. In contrast with parametric models that have been used before in the literature, the local polynomial likelihood method allows this age-dependent force of infection to be modelled without making any assumptions about the parametric structure. Moreover, this method allows for simultaneous nonparametric estimation of age-specific incidence and prevalence. Unconstrained models may lead to negative estimates for the force of infection at certain ages. To overcome this problem and to guarantee maximal flexibility, the local smoother can be constrained to be monotone. It turns out that different parametric and nonparametric estimates of the force of infection can exhibit considerably different qualitative features like location and the number of maxima, emphasizing the importance of a well-chosen flexible statistical model.     

A flexible semiparametric regression model for bimodal,asymmetric and censored data

In this paper, we propose a new semiparametric heteroscedastic regression model allowing for positive and negative skewness and bimodal shapes using the B-spline basis for nonlinear effects. The proposed distribution is based on the generalized additive models for location, scale and shape framework in order to model any or all parameters of the distribution using parametric linear and/or nonparametric smooth functions of explanatory variables. We motivate the new model by means of Monte Carlo simulations, thus ignoring the skewness and bimodality of the random errors in semiparametric regression models, which may introduce biases on the parameter estimates and/or on the estimation of the associated variability measures. An iterative estimation process and some diagnostic methods are investigated. Applications to two real data sets are presented and the method is compared to the usual regression methods.     

Simulation-Extrapolation via the Bezier Curve in Measurement Error Models

Simulation-extrapolation (SIMEX) is a method for correcting for bias in measurement error models, and parametric SIMEX estimates are often used. In this paper, we propose a nonparametric method for computing the SIMEX estimate via the Bezier curve, which is a popular smoothing technique in the computer graphics area. Comparisons are done for the bias of the limit values of parametric SIMEX estimates and the Bezier estimate in the various nonlinear measurement error models.     

Kernel-based semiparametric multinomial logit modelling of political party preferences

Conventional, parametric multinomial logit models are in general not sufficient for capturing the complex structures of electorates. In this paper, we use a semiparametric multinomial logit model to give an analysis of party preferences along individuals’ characteristics using a sample of the German electorate in 2006. Germany is a particularly strong case for more flexible nonparametric approaches in this context, since due to the reunification and the preceding different political histories the composition of the electorate is very complex and nuanced. Our analysis reveals strong interactions of the covariates age and income, and highly nonlinear shapes of the factor impacts for each party’s likelihood to be supported. Notably, we develop and provide a smoothed likelihood estimator for semiparametric multinomial logit models, which can be applied also in other application fields, such as, e.g., marketing.     

Functional convergence of quantile-type frontiers with application to parametric approximations

Nonparametric estimators of the upper boundary of the support of a multivariate distribution are very appealing because they rely on very few assumptions. But in productivity and efficiency analysis, this upper boundary is a production (or a cost) frontier and a parametric form for it allows for a richer economic interpretation of the production process under analysis. On the other hand, most of the parametric approaches rely on often too restrictive assumptions on the stochastic part of the model and are based on standard regression techniques fitting the shape of the center of the cloud of points rather than its boundary. To overcome these limitations, Florens and Simar [2005. Parametric approximations of nonparametric frontiers. J. Econometrics 124 (1), 91–116] propose a two-stage approach which tries to capture the shape of the cloud of points near its frontier by providing parametric approximations of a nonparametric frontier. In this paper we propose an alternative method using the nonparametric quantile-type frontiers introduced in Aragon, Daouia and Thomas-Agnan [2005. Nonparametric frontier estimation: a conditional quantile-based approach. Econometric Theory 21, 358–389] for the nonparametric part of our model. These quantile-type frontiers have the superiority of being more robust to extremes. Our main result concerns the functional convergence of the quantile-type frontier process. Then we provide convergence and asymptotic normality of the resulting estimators of the parametric approximation. The approach is illustrated through simulated and real data sets.     

Quantile regression estimation of partially linear additive models

In this paper, we consider the estimation of partially linear additive quantile regression models where the conditional quantile function comprises a linear parametric component and a nonparametric additive component. We propose a two-step estimation approach: in the first step, we approximate the conditional quantile function using a series estimation method. In the second step, the nonparametric additive component is recovered using either a local polynomial estimator or a weighted Nadaraya–Watson estimator. Both consistency and asymptotic normality of the proposed estimators are established. Particularly, we show that the first-stage estimator for the finite-dimensional parameters attains the semiparametric efficiency bound under homoskedasticity, and that the second-stage estimators for the nonparametric additive component have an oracle efficiency property. Monte Carlo experiments are conducted to assess the finite sample performance of the proposed estimators. An application to a real data set is also illustrated.     

Outlier Resistant Estimation in Difference-Based Semiparametric Partially Linear Models

Partially linear models are extensions of linear models that include a nonparametric function of some covariate allowing an adequate and more flexible handling of explanatory variables than in linear models. The difference-based estimation in partially linear models is an approach designed to estimate parametric component by using the ordinary least squares estimator after removing the nonparametric component from the model by differencing. However, it is known that least squares estimates do not provide useful information for the majority of data when the error distribution is not normal, particularly when the errors are heavy-tailed and when outliers are present in the dataset. This paper aims to find an outlier-resistant fit that represents the information in the majority of the data by robustly estimating the parametric and the nonparametric components of the partially linear model. Simulations and a real data example are used to illustrate the feasibility of the proposed methodology and to compare it with the classical difference-based estimator when outliers exist.     

Estimating Optimal Dynamic Regimes: Correcting Bias under the Null

Abstract.  A dynamic regime provides a sequence of treatments that are tailored to patient-specific characteristics and outcomes. In 2004, James Robins proposed g –estimation using structural nested mean models (SNMMs) for making inference about the optimal dynamic regime in a multi-interval trial. The method provides clear advantages over traditional parametric approaches. Robins' g –estimation method always yields consistent estimators, but these can be asymptotically biased under a given SNMM for certain longitudinal distributions of the treatments and covariates, termed exceptional laws. In fact, under the null hypothesis of no treatment effect, every distribution constitutes an exceptional law under SNMMs which allow for interaction of current treatment with past treatments or covariates. This paper provides an explanation of exceptional laws and describes a new approach to g –estimation which we call Zeroing Instead of Plugging In (ZIPI). ZIPI provides nearly identical estimators to recursive g -estimators at non-exceptional laws while providing substantial reduction in the bias at an exceptional law when decision rule parameters are not shared across intervals.     

Estimating curves and derivatives with parametric penalized spline smoothing

Accurate estimation of an underlying function and its derivatives is one of the central problems in statistics. Parametric forms are often proposed based on the expert opinion or prior knowledge of the underlying function. However, these strict parametric assumptions may result in biased estimates when they are not completely accurate. Meanwhile, nonparametric smoothing methods, which do not impose any parametric form, are quite flexible. We propose a parametric penalized spline smoothing method, which has the same flexibility as the nonparametric smoothing methods. It also uses the prior knowledge of the underlying function by defining an additional penalty term using the distance of the fitted function to the assumed parametric function. Our simulation studies show that the parametric penalized spline smoothing method can obtain more accurate estimates of the function and its derivatives than the penalized spline smoothing method. The parametric penalized spline smoothing method is also demonstrated by estimating the human height function and its derivatives from the real data.     

Nonparametric causal effects based on marginal structural models

A parametric marginal structural model (PMSM) approach to Causal Inference has been favored since the introduction of MSMs by Robins [1998a. Marginal structural models. In: 1997 Proceedings of the American Statistical Association. American Statistical Association, Alexandria, VA, pp. 1–10]. We propose an alternative, nonparametric MSM (NPMSM) approach that extends the definition of causal parameters of interest and causal effects. This approach is appealing in practice as it does not require correct specification of a parametric model but instead relies on a working model which can be willingly misspecified. We propose a methodology for longitudinal data to generate and estimate so-called NPMSM parameters describing so-called nonparametric causal effects and provide insight on how to interpret these parameters causally in practice. Results are illustrated with a point treatment simulation study. The proposed NPMSM approach to Causal Inference is compared to the more typical PMSM approach and we contribute to the general understanding of PMSM estimation by addressing the issue of PMSM misspecification.     

Nonparametric Covariate-Adjusted Association Tests Based on the Generalized Kendall's Tau()

Identifying the risk factors for comorbidity is important in psychiatric research. Empirically, studies have shown that testing multiple, correlated traits simultaneously is more powerful than testing a single trait at a time in association analysis. Furthermore, for complex diseases, especially mental illnesses and behavioral disorders, the traits are often recorded in different scales such as dichotomous, ordinal and quantitative. In the absence of covariates, nonparametric association tests have been developed for multiple complex traits to study comorbidity. However, genetic studies generally contain measurements of some covariates that may affect the relationship between the risk factors of major interest (such as genes) and the outcomes. While it is relatively easy to adjust these covariates in a parametric model for quantitative traits, it is challenging for multiple complex traits with possibly different scales. In this article, we propose a nonparametric test for multiple complex traits that can adjust for covariate effects. The test aims to achieve an optimal scheme of adjustment by using a maximum statistic calculated from multiple adjusted test statistics. We derive the asymptotic null distribution of the maximum test statistic, and also propose a resampling approach, both of which can be used to assess the significance of our test. Simulations are conducted to compare the type I error and power of the nonparametric adjusted test to the unadjusted test and other existing adjusted tests. The empirical results suggest that our proposed test increases the power through adjustment for covariates when there exist environmental effects, and is more robust to model misspecifications than some existing parametric adjusted tests. We further demonstrate the advantage of our test by analyzing a data set on genetics of alcoholism.     

Kernel partial correlation: a novel approach to capturing conditional independence in graphical models for noisy data

Graphical models capture the conditional independence structure among random variables via existence of edges among vertices. One way of inferring a graph is to identify zero partial correlation coefficients, which is an effective way of finding conditional independence under a multivariate Gaussian setting. For more general settings, we propose kernel partial correlation which extends partial correlation with a combination of two kernel methods. First, a nonparametric function estimation is employed to remove effects from other variables, and then the dependence between remaining random components is assessed through a nonparametric association measure. The proposed approach is not only flexible but also robust under high levels of noise owing to the robustness of the nonparametric approaches.     

Testing the Significance of Categorical Predictor Variables in Nonparametric Regression Models

In this paper we propose a test for the significance of categorical predictors in nonparametric regression models. The test is fully data-driven and employs cross-validated smoothing parameter selection while the null distribution of the test is obtained via bootstrapping. The proposed approach allows applied researchers to test hypotheses concerning categorical variables in a fully nonparametric and robust framework, thereby deflecting potential criticism that a particular finding is driven by an arbitrary parametric specification. Simulations reveal that the test performs well, having significantly better power than a conventional frequency-based nonparametric test. The test is applied to determine whether OECD and non-OECD countries follow the same growth rate model or not. Our test suggests that OECD and non-OECD countries follow different growth rate models, while the tests based on a popular parametric specification and the conventional frequency-based nonparametric estimation method fail to detect any significant difference.     

Flexible semiparametric analysis of longitudinal genetic studies by reduced rank smoothing

In family-based longitudinal genetic studies, investigators collect repeated measurements on a trait that changes with time along with genetic markers. Since repeated measurements are nested within subjects and subjects are nested within families, both the subject-level and measurement-level correlations must be taken into account in the statistical analysis to achieve more accurate estimation. In such studies, the primary interests include to test for quantitative trait locus (QTL) effect, and to estimate age-specific QTL effect and residual polygenic heritability function. We propose flexible semiparametric models along with their statistical estimation and hypothesis testing procedures for longitudinal genetic designs. We employ penalized splines to estimate nonparametric functions in the models. We find that misspecifying the baseline function or the genetic effect function in a parametric analysis may lead to substantially inflated or highly conservative type I error rate on testing and large mean squared error on estimation. We apply the proposed approaches to examine age-specific effects of genetic variants reported in a recent genome-wide association study of blood pressure collected in the Framingham Heart Study.     

Estimation for semiparametric varying coefficient models with different smoothing variables under random right censoring

In this paper we study a semiparametric varying coefficient model when the response is subject to random right censoring. The model gives an easy interpretation due to its direct connectivity to the classical linear model and is very flexible since nonparametric functions which accommodates various nonlinear interaction effects between covariates are admitted in the model. We propose estimators for this model using mean-preserving transformation and establish their asymptotic properties. The estimation procedure is based on the profiling and the smooth backfitting techniques. A simulation study is presented to show the reliability of the proposed estimators and an automatic bandwidth selector is given in a data-driven way.