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While the classic off-policy evaluation (OPE) literature commonly assumes decision time points to be evenly spaced for simplicity, in many real-world scenarios, such as those involving user-initiated visits, decisions are made at irregularly-spaced and potentially outcome-dependent time points. For a more principled evaluation of the dynamic policies, this paper constructs a novel OPE framework, which concerns not only the state-action process but also an observation process dictating the time points at which decisions are made. The framework is closely connected to the Markov decision process in computer science and with the renewal process in the statistical literature. Within the framework, two distinct value functions, derived from cumulative reward and integrated reward respectively, are considered, and statistical inference for each value function is developed under revised Markov and time-homogeneous assumptions. The validity of the proposed method is further supported by theoretical results, simulation studies, and a real-world application from electronic health records (EHR) evaluating periodontal disease treatments.

Joint modelling of longitudinal observations and event times continues to remain a topic of considerable interest in biomedical research. For example, in HIV studies, the longitudinal bio-marker such as CD4 cell count in a patient's blood over follow up months is jointly modelled with the time to disease progression, death or dropout via a random intercept term mostly assumed to be Gaussian. However, longitudinal observations in these kinds of studies often exhibit non-Gaussian behavior (due to high degree of skewness), and parameter estimation is often compromised under violations of the Gaussian assumptions. In linear mixed-effects model assumptions, the distributional assumption for the subject-specific random-effects is taken as Gaussian which may not be true in many situations. Further, this assumption makes the model extremely sensitive to outlying observations. We address these issues in this work by devising a joint model which uses a robust distribution in a parametric setup along with a conditional distributional assumption that ensures dependency of two processes in case the subject-specific random effects is given.

Observations of groundwater pollutants, such as arsenic or Perfluorooctane sulfonate (PFOS), are riddled with left censoring. These measurements have impact on the health and lifestyle of the populace. Left censoring of these spatially correlated observations are usually addressed by applying Gaussian processes (GPs), which have theoretical advantages. However, this comes with a challenging computational complexity of $\mathcal{O}(n^3)$, which is impractical for large datasets. Additionally, a sizable proportion of the data being left-censored creates further bottlenecks, since the likelihood computation now involves an intractable high-dimensional integral of the multivariate Gaussian density. In this article, we tackle these two problems simultaneously by approximating the GP with a Gaussian Markov random field (GMRF) approach that exploits an explicit link between a GP with Mat\'ern correlation function and a GMRF using stochastic partial differential equations (SPDEs). We introduce a GMRF-based measurement error into the model, which alleviates the likelihood computation for the censored data, drastically improving the speed of the model while maintaining admirable accuracy. Our approach demonstrates robustness and substantial computational scalability, compared to state-of-the-art methods for censored spatial responses across various simulation settings. Finally, the fit of this fully Bayesian model to the concentration of PFOS in groundwater available at 24,959 sites across California, where 46.62\% responses are censored, produces prediction surface and uncertainty quantification in real time, thereby substantiating the applicability and scalability of the proposed method. Code for implementation is made available via GitHub.

Multistate current status (CS) data presents a more severe form of censoring due to the single observation of study participants transitioning through a sequence of well-defined disease states at random inspection times. Moreover, these data may be clustered within specified groups, and informativeness of the cluster sizes may arise due to the existing latent relationship between the transition outcomes and the cluster sizes. Failure to adjust for this informativeness may lead to a biased inference. Motivated by a clinical study of periodontal disease (PD), we propose an extension of the pseudo-value approach to estimate covariate effects on the state occupation probabilities (SOP) for these clustered multistate CS data with informative cluster or intra-cluster group sizes. In our approach, the proposed pseudo-value technique initially computes marginal estimators of the SOP utilizing nonparametric regression. Next, the estimating equations based on the corresponding pseudo-values are reweighted by functions of the cluster sizes to adjust for informativeness. We perform a variety of simulation studies to study the properties of our pseudo-value regression based on the nonparametric marginal estimators under different scenarios of informativeness. For illustration, the method is applied to the motivating PD dataset, which encapsulates the complex data-generation mechanism., Comment: 36 pages, 3 figures, 5 tables

In contrast to the popular Cox model which presents a multiplicative covariate effect specification on the time to event hazards, the semiparametric additive risks model (ARM) offers an attractive additive specification, allowing for direct assessment of the changes or the differences in the hazard function for changing value of the covariates. The ARM is a flexible model, allowing the estimation of both time-independent and time-varying covariates. It has a nonparametric component and a regression component identified by a finite-dimensional parameter. This chapter presents an efficient approach for maximum-likelihood (ML) estimation of the nonparametric and the finite-dimensional components of the model via the minorize-maximize (MM) algorithm for case-II interval-censored data. The operating characteristics of our proposed MM approach are assessed via simulation studies, with illustration on a breast cancer dataset via the R package MMIntAdd. It is expected that the proposed computational approach will not only provide scalability to the ML estimation scenario but may also simplify the computational burden of other complex likelihoods or models.

We analyze adolescent BMI and middle-age systolic blood pressure (SBP) repeatedly measured on women enrolled in the Fels longitudinal study (FLS) between 1929 and 2010 to address three questions: Do adolescent-specific growth rates in BMI and menarche affect middle-age SBP? Do they moderate the aging effect on middle-age SBP? Have the effects changed over historical time? To address the questions, we propose analyzing a growth curve model (GCM) that controls for age, birth-year cohort and historical time. However, several complications in the data make the GCM analysis non-standard. First, the person-specific adolescent BMI and middle-age SBP trajectories are unobservable. Second, missing data are substantial on BMI, SBP and menarche. Finally, modeling the latent trajectories for BMI and SBP, repeatedly measured on two distinct sets of unbalanced time points, are computationally intensive. We adopt a bivariate GCM for BMI and SBP with correlated random coefficients. To efficiently handle missing values of BMI, SBP and menarche assumed missing at random, we estimate their joint distribution by maximum likelihood via the EM algorithm where the correlated random coefficients and menarche are multivariate normal. The estimated distribution will be transformed to the desired GCM for SBP that includes the random coefficients of BMI and menarche as covariates. We demonstrate unbiased estimation by simulation. We find that adolescent growth rates in BMI and menarche are positively associated with and moderate the aging effect on SBP in middle age, controlling for age, cohort and historical time, but the effect sizes are at most modest. The aging effect is significant on SBP, controlling for cohort and historical time, but not vice versa. [This paper was published in "Biometrical Journal" v62 n7 p1702-1716 2020.]

Spatial confounding is how is called the confounding between fixed and spatial random effects. It has been widely studied and it gained attention in the past years in the spatial statistics literature, as it may generate unexpected results in modeling. The projection-based approach, also known as restricted models, appears as a good alternative to overcome the spatial confounding in generalized linear mixed models. However, when the support of fixed effects is different from the spatial effect one, this approach can no longer be applied directly. In this work, we introduce a method to alleviate the spatial confounding for the spatial frailty models family. This class of models can incorporate spatially structured effects and it is usual to observe more than one sample unit per area which means that the support of fixed and spatial effects differs. In this case, we introduce a two folded projection-based approach projecting the design matrix to the dimension of the space and then projecting the random effect to the orthogonal space of the new design matrix. To provide fast inference in our analysis we employ the integrated nested Laplace approximation methodology. The method is illustrated with an application with lung and bronchus cancer in California - US that confirms that the methodology efficiency., Comment: 21 pages, 5 figures, 4 tables

Current status data abounds in the field of epidemiology and public health, where the only observable data for a subject is the random inspection time and the event status at inspection. Motivated by such a current status data from a periodontal study where data are inherently clustered, we propose a unified methodology to analyze such complex data. We allow the time-to-event to follow the semiparametric GOR model with a cure fraction, and develop a unified estimation scheme powered by the EM algorithm. The within-subject correlation is accounted for by a random (frailty) effect, and the non-parametric component of the GOR model is approximated via penalized splines, with a set of knot points that increases with the sample size. Proposed methodology is accompanied by a rigorous asymptotic theory, and the related semiparametric efficiency. The finite sample performance of our model parameters are assessed via simulation studies. Furthermore, the proposed methodology is illustrated via application to the oral health data, accompanied by diagnostic checks to identify influential observations. An easy to use R package CRFCSD is also available for implementation., Comment: Unstable EM algorithm due to limited information in current status data

Geostatistical modeling for continuous point-referenced data has been extensively applied to neuroimaging because it produces efficient and valid statistical inference. However, diffusion tensor imaging (DTI), a neuroimaging characterizing the brain structure produces a positive definite (p.d.) matrix for each voxel. Current geostatistical modeling has not been extended to p.d. matrices because introducing spatial dependence among positive definite matrices properly is challenging. In this paper, we use the spatial Wishart process, a spatial stochastic process (random field) where each p.d. matrix-variate marginally follows a Wishart distribution, and spatial dependence between random matrices is induced by latent Gaussian processes. This process is valid on an uncountable collection of spatial locations and is almost surely continuous, leading to a reasonable means of modeling spatial dependence. Motivated by a DTI dataset of cocaine users, we propose a spatial matrix-variate regression model based on the spatial Wishart process. A problematic issue is that the spatial Wishart process has no closed-form density function. Hence, we propose approximation methods to obtain a feasible working model. A local likelihood approximation method is also applied to achieve fast computation. The simulation studies and real data analysis demonstrate that the working model produces reliable inference and improved performance compared to other methods.

Diffusion tensor imaging (DTI) is a popular magnetic resonance imaging technique used to characterize microstructural changes in the brain. DTI studies quantify the diffusion of water molecules in a voxel using an estimated 3x3 symmetric positive definite diffusion tensor matrix. Statistical analysis of DTI data is challenging because the data are positive definite matrices. Matrix-variate information is often summarized by a univariate quantity, such as the fractional anisotropy (FA), leading to a loss of information. Furthermore, DTI analyses often ignore the spatial association of neighboring voxels, which can lead to imprecise estimates. Although the spatial modeling literature is abundant, modeling spatially dependent positive definite matrices is challenging. To mitigate these issues, we propose a matrix-variate Bayesian semiparametric mixture model, where the positive definite matrices are distributed as a mixture of inverse Wishart distributions with the spatial dependence captured by a Markov model for the mixture component labels. Conjugacy and the double Metropolis-Hastings algorithm result in fast and elegant Bayesian computing. Our simulation study shows that the proposed method is more powerful than non-spatial methods. We also apply the proposed method to investigate the effect of cocaine use on brain structure. The contribution of our work is to provide a novel statistical inference tool for DTI analysis by extending spatial statistics to matrix-variate data.

This paper proposes dynamic treatment regimes for choosing individualized effective treatment strategies of chronic periodontal disease. R codes for implementing the proposed sample size formula are available in GitHub.

Preventing periodontal diseases (PD) and maintaining the structure and function of teeth are important goals for personal oral care. To understand the heterogeneity in patients with diverse PD patterns, we develop BAREB, a Bayesian repulsive biclustering method that can simultaneously cluster the PD patients and their tooth sites after taking the patient- and site- level covariates into consideration. BAREB uses the determinantal point process (DPP) prior to induce diversity among different biclusters to facilitate parsimony and interpretability. Since PD progression is hypothesized to be spatially-referenced, BAREB factors in the spatial dependence among tooth sites. In addition, since PD is the leading cause for tooth loss, the missing data mechanism is non-ignorable. Such nonrandom missingness is incorporated into BAREB. For the posterior inference, we design an efficient reversible jump Markov chain Monte Carlo sampler. Simulation studies show that BAREB is able to accurately estimate the biclusters, and compares favorably to alternatives. For real world application, we apply BAREB to a dataset from a clinical PD study, and obtain desirable and interpretable results. A major contribution of this paper is the Rcpp implementation of BAREB, available at https://github.com/YanxunXu/ BAREB.

We introduce a Bayesian nonparametric regression model for data with multiway (tensor) structure, motivated by an application to periodontal disease (PD) data. Our outcome is the number of diseased sites measured over four different tooth types for each subject, with subject-specific covariates available as predictors. The outcomes are not well-characterized by simple parametric models, so we use a nonparametric approach with a binomial likelihood wherein the latent probabilities are drawn from a mixture with an arbitrary number of components, analogous to a Dirichlet Process (DP). We use a flexible probit stick-breaking formulation for the component weights that allows for covariate dependence and clustering structure in the outcomes. The parameter space for this model is large and multiway: patients $\times$ tooth types $\times$ covariates $\times$ components. We reduce its effective dimensionality, and account for the multiway structure, via low-rank assumptions. We illustrate how this can improve performance, and simplify interpretation, while still providing sufficient flexibility. We describe a general and efficient Gibbs sampling algorithm for posterior computation. The resulting fit to the PD data outperforms competitors, and is interpretable and well-calibrated. An interactive visual of the predictive model is available at http://ericfrazerlock.com/toothdata/ToothDisplay.html , and the code is available at https://github.com/lockEF/NonparametricMultiway ., Comment: 20 pages, 5 figures

Tooth loss from periodontal disease is a major public health burden in the United States. Standard clinical practice is to recommend a dental visit every six months; however, this practice is not evidence-based, and poor dental outcomes and increasing dental insurance premiums indicate room for improvement. We consider a tailored approach that recommends recall time based on patient characteristics and medical history to minimize disease progression without increasing resource expenditures. We formalize this method as a dynamic treatment regime which comprises a sequence of decisions, one per stage of intervention, that follow a decision rule which maps current patient information to a recommendation for their next visit time. The dynamics of periodontal health, visit frequency, and patient compliance are complex, yet the estimated optimal regime must be interpretable to domain experts if it is to be integrated into clinical practice. We combine non-parametric Bayesian dynamics modeling with policy-search algorithms to estimate the optimal dynamic treatment regime within an interpretable class of regimes. Both simulation experiments and application to a rich database of electronic dental records from the HealthPartners HMO shows that our proposed method leads to better dental health without increasing the average recommended recall time relative to competing methods.