Robust Bayesian nonlinear mixed‐effects modeling of time to positivity in tuberculosis trials

Early phase 2 tuberculosis (TB) trials are conducted to characterize the early bactericidal activity (EBA) of anti‐TB drugs. The EBA of anti‐TB drugs has conventionally been calculated as the rate of decline in colony forming unit (CFU) count during the first 14 days of treatment. The measurement of CFU count, however, is expensive and prone to contamination. Alternatively to CFU count, time to positivity (TTP), which is a potential biomarker for long‐term efficacy of anti‐TB drugs, can be used to characterize EBA. The current Bayesian nonlinear mixed‐effects (NLME) regression model for TTP data, however, lacks robustness to gross outliers that often are present in the data. The conventional way of handling such outliers involves their identification by visual inspection and subsequent exclusion from the analysis. However, this process can be questioned because of its subjective nature. For this reason, we fitted robust versions of the Bayesian nonlinear mixed‐effects regression model to a wide range of TTP datasets. The performance of the explored models was assessed through model comparison statistics and a simulation study. We conclude that fitting a robust model to TTP data obviates the need for explicit identification and subsequent “deletion” of outliers but ensures that gross outliers exert no undue influence on model fits. We recommend that the current practice of fitting conventional normal theory models be abandoned in favor of fitting robust models to TTP data.     

Campylobacter QMRA: A Bayesian Estimation of Prevalence and Concentration in Retail Foods Under Clustering and Heavy Censoring

A Bayesian statistical temporal‐prevalence‐concentration model (TPCM) was built to assess the prevalence and concentration of pathogenic campylobacter species in batches of fresh chicken and turkey meat at retail. The data set was collected from Finnish grocery stores in all the seasons of the year. Observations at low concentration levels are often censored due to the limit of determination of the microbiological methods. This model utilized the potential of Bayesian methods to borrow strength from related samples in order to perform under heavy censoring. In this extreme case the majority of the observed batch‐specific concentrations was below the limit of determination. The hierarchical structure was included in the model in order to take into account the within‐batch and between‐batch variability, which may have a significant impact on the sample outcome depending on the sampling plan. Temporal changes in the prevalence of campylobacter were modeled using a Markovian time series. The proposed model is adaptable for other pathogens if the same type of data set is available. The computation of the model was performed using OpenBUGS software.     

Bayesian penalized B-spline estimation approach for epidemic models

Ordinary differential equations (ODEs) are normally used to model dynamic processes in applied sciences such as biology, engineering, physics, and many other areas. In these models, the parameters are usually unknown, and thus they are often specified artificially or empirically. Alternatively, a feasible method is to estimate the parameters based on observed data. In this study, we propose a Bayesian penalized B-spline approach to estimate the parameters and initial values for ODEs used in epidemiology. We evaluated the efficiency of the proposed method based on simulations using the Markov chain Monte Carlo algorithm for the Kermack–McKendrick model. The proposed approach is also illustrated based on a real application to the transmission dynamics of hepatitis C virus in mainland China.     

Bayesian optimal sequential design for nonparametric regression via inhomogeneous evolutionary MCMC

We develop a novel computational methodology for Bayesian optimal sequential design for nonparametric regression. This computational methodology, that we call inhomogeneous evolutionary Markov chain Monte Carlo, combines ideas of simulated annealing, genetic or evolutionary algorithms, and Markov chain Monte Carlo. Our framework allows optimality criteria with general utility functions and general classes of priors for the underlying regression function. We illustrate the usefulness of our novel methodology with applications to experimental design for nonparametric function estimation using Gaussian process priors and free-knot cubic splines priors.     

Generating synthetic data to produce public-use microdata for small geographic areas based on complex sample survey data with application to the National Health Interview Survey

Small area statistics obtained from sample survey data provide a critical source of information used to study health, economic, and sociological trends. However, most large-scale sample surveys are not designed for the purpose of producing small area statistics. Moreover, data disseminators are prevented from releasing public-use microdata for small geographic areas for disclosure reasons; thus, limiting the utility of the data they collect. This research evaluates a synthetic data method, intended for data disseminators, for releasing public-use microdata for small geographic areas based on complex sample survey data. The method replaces all observed survey values with synthetic (or imputed) values generated from a hierarchical Bayesian model that explicitly accounts for complex sample design features, including stratification, clustering, and sampling weights. The method is applied to restricted microdata from the National Health Interview Survey and synthetic data are generated for both sampled and non-sampled small areas. The analytic validity of the resulting small area inferences is assessed by direct comparison with the actual data, a simulation study, and a cross-validation study.     

Model averaging for treatment effect estimation in subgroups

In many clinical trials, biological, pharmacological, or clinical information is used to define candidate subgroups of patients that might have a differential treatment effect. Once the trial results are available, interest will focus on subgroups with an increased treatment effect. Estimating a treatment effect for these groups, together with an adequate uncertainty statement is challenging, owing to the resulting “random high” / selection bias. In this paper, we will investigate Bayesian model averaging to address this problem. The general motivation for the use of model averaging is to realize that subgroup selection can be viewed as model selection, so that methods to deal with model selection uncertainty, such as model averaging, can be used also in this setting. Simulations are used to evaluate the performance of the proposed approach. We illustrate it on an example early‐phase clinical trial.     

Small area estimation strategies for large population surveys: a comparison of design and model-based methods

Small area estimation (SAE) concerns with how to reliably estimate population quantities of interest when some areas or domains have very limited samples. This is an important issue in large population surveys, because the geographical areas or groups with only small samples or even no samples are often of interest to researchers and policy-makers. For example, large population health surveys, such as Behavioural Risk Factor Surveillance System and Ohio Mecaid Assessment Survey (OMAS), are regularly conducted for monitoring insurance coverage and healthcare utilization. Classic approaches usually provide accurate estimators at the state level or large geographical region level, but they fail to provide reliable estimators for many rural counties where the samples are sparse. Moreover, a systematic evaluation of the performances of the SAE methods in real-world setting is lacking in the literature. In this paper, we propose a Bayesian hierarchical model with constraints on the parameter space and show that it provides superior estimators for county-level adult uninsured rates in Ohio based on the 2012 OMAS data. Furthermore, we perform extensive simulation studies to compare our methods with a collection of common SAE strategies, including direct estimators, synthetic estimators, composite estimators, and Datta GS, Ghosh M, Steorts R, Maples J.'s [Bayesian benchmarking with applications to small area estimation. Test 2011;20(3):574–588] Bayesian hierarchical model-based estimators. To set a fair basis for comparison, we generate our simulation data with characteristics mimicking the real OMAS data, so that neither model-based nor design-based strategies use the true model specification. The estimators based on our proposed model are shown to outperform other estimators for small areas in both simulation study and real data analysis.     

Bayesian Classifiers Applied to the Tennessee Eastman Process

Fault diagnosis includes the main task of classification. Bayesian networks (BNs) present several advantages in the classification task, and previous works have suggested their use as classifiers. Because a classifier is often only one part of a larger decision process, this article proposes, for industrial process diagnosis, the use of a Bayesian method called dynamic Markov blanket classifier that has as its main goal the induction of accurate Bayesian classifiers having dependable probability estimates and revealing actual relationships among the most relevant variables. In addition, a new method, named variable ordering multiple offspring sampling capable of inducing a BN to be used as a classifier, is presented. The performance of these methods is assessed on the data of a benchmark problem known as the Tennessee Eastman process. The obtained results are compared with naive Bayes and tree augmented network classifiers, and confirm that both proposed algorithms can provide good classification accuracies as well as knowledge about relevant variables.     

Bivariate versus univariate ordinal categorical data with reference to an ophthalmologic study

The Wisconsin Epidemiologic Study of Diabetic Retinopathy is a population-based epidemiological study carried out in Southern Wisconsin during the 1980s. The resulting data were analysed by different statisticians and ophthalmologists during the last two decades. Most of the analyses were carried out on the baseline data, although there were two follow-up studies on the same population. A Bayesian analysis of the first follow-up data, taken four years after the baseline study, was carried out by Angers and Biswas [Angers, J.-F. and Biswas, A., 2004, A Bayesian analysis of the four-year follow-up data of theWisconsin epidemiologic study of diabetic retinopathy. Statistics in Medicine, 23, 601–615.], where the choice of the best model in terms of the covariate inclusion is done, and estimates of the associated covariate effects were obtained using the baseline data to set the prior for the parameters. In the present article we consider an univariate transformation of the bivariate ordinal data, and a parallel analysis with the much simpler univariate data is carried out. The results are then compared with the results of Angers and Biswas (2004). In conclusion, our analyses suggest that the univariate analysis fails to detect features of the data found by the bivariate analysis. Even an univariate transformation of our data with quite high correlation with both left and right eyes is inadequate.     

Bayesian adaptive dose‐escalation designs for simultaneously estimating the optimal and maximum safe dose based on safety and efficacy

The main purpose of dose‐escalation trials is to identify the dose(s) that is/are safe and efficacious for further investigations in later studies. In this paper, we introduce dose‐escalation designs that incorporate both the dose‐limiting events and dose‐limiting toxicities (DLTs) and indicative responses of efficacy into the procedure. A flexible nonparametric model is used for modelling the continuous efficacy responses while a logistic model is used for the binary DLTs. Escalation decisions are based on the combination of the probabilities of DLTs and expected efficacy through a gain function. On the basis of this setup, we then introduce 2 types of Bayesian adaptive dose‐escalation strategies. The first type of procedures, called “single objective,” aims to identify and recommend a single dose, either the maximum tolerated dose, the highest dose that is considered as safe, or the optimal dose, a safe dose that gives optimum benefit risk. The second type, called “dual objective,” aims to jointly estimate both the maximum tolerated dose and the optimal dose accurately. The recommended doses obtained under these dose‐escalation procedures provide information about the safety and efficacy profile of the novel drug to facilitate later studies. We evaluate different strategies via simulations based on an example constructed from a real trial on patients with type 2 diabetes, and the use of stopping rules is assessed. We find that the nonparametric model estimates the efficacy responses well for different underlying true shapes. The dual‐objective designs give better results in terms of identifying the 2 real target doses compared to the single‐objective designs.