Search

Multiple imputation by chained equations (MICE) has emerged as a leading strategy for imputing missing epidemiological data due to its ease of implementation and ability to maintain unbiased effect estimates and valid inference. Within the MICE algorithm, imputation can be performed using a variety of parametric or nonparametric methods. Literature has suggested that nonparametric tree-based imputation methods outperform parametric methods in terms of bias and coverage when there are interactions or other nonlinear effects among the variables. However, these studies fail to provide a fair comparison as they do not follow the well-established recommendation that any effects in the final analysis model (including interactions) should be included in the parametric imputation model. We show via simulation that properly incorporating interactions in the parametric imputation model leads to much better performance. In fact, correctly specified parametric imputation and tree-based random forest imputation perform similarly when estimating the interaction effect. Parametric imputation leads to slightly higher coverage for the interaction effect, but it has wider confidence intervals than random forest imputation and requires correct specification of the imputation model. Epidemiologists should take care in specifying MICE imputation models, and this paper assists in that task by providing a fair comparison of parametric and tree-based imputation in MICE. [ABSTRACT FROM AUTHOR]

This paper develops object-oriented data analysis (OODA) statistical methods that are novel and complementary to existing methods of analysis of human brain scan connectomes, defined as graphs representing brain anatomical or functional connectivity. OODA is an emerging field where classical statistical approaches (e.g., hypothesis testing, regression, estimation, and confidence intervals) are applied to data objects such as graphs or functions. By analyzing data objects directly we avoid loss of information that occurs when data objects are transformed into numerical summary statistics. By providing statistical tools that analyze sets of connectomes without loss of information, new insights into neurology and medicine may be achieved. In this paper we derive the formula for statistical model fitting, regression, and mixture models; test their performance in simulation experiments; and apply them to connectomes from fMRI brain scans collected during a serial reaction time task study. Software for fitting graphical object-oriented data analysis is provided. [ABSTRACT FROM AUTHOR]

Drug-drug interactions (DDIs) are a common cause of adverse drug events (ADEs). The electronic medical record (EMR) database and the FDA's adverse event reporting system (FAERS) database are the major data sources for mining and testing the ADE associated DDI signals. Most DDI data mining methods focus on pair-wise drug interactions, and methods to detect high-dimensional DDIs in medical databases are lacking. In this paper, we propose 2 novel mixture drug-count response models for detecting high-dimensional drug combinations that induce myopathy. The "count" indicates the number of drugs in a combination. One model is called fixed probability mixture drug-count response model with a maximum risk threshold (FMDRM-MRT). The other model is called count-dependent probability mixture drug-count response model with a maximum risk threshold (CMDRM-MRT), in which the mixture probability is count dependent. Compared with the previous mixture drug-count response model (MDRM) developed by our group, these 2 new models show a better likelihood in detecting high-dimensional drug combinatory effects on myopathy. CMDRM-MRT identified and validated (54; 374; 637; 442; 131) 2-way to 6-way drug interactions, respectively, which induce myopathy in both EMR and FAERS databases. We further demonstrate FAERS data capture much higher maximum myopathy risk than EMR data do. The consistency of 2 mixture models' parameters and local false discovery rate estimates are evaluated through statistical simulation studies. [ABSTRACT FROM AUTHOR]

Many disease diagnoses involve subjective judgments by qualified raters. For example, through the inspection of a mammogram, MRI, or ultrasound image, the clinician himself becomes part of the measuring instrument. To reduce diagnostic errors and improve the quality of diagnoses, it is necessary to assess raters' diagnostic skills and to improve their skills over time. This paper focuses on a subjective binary classification process, proposing a hierarchical model linking data on rater opinions with patient true disease-development outcomes. The model allows for the quantification of the effects of rater diagnostic skills (bias and magnifier) and patient latent disease severity on the rating results. A Bayesian Markov chain Monte Carlo (MCMC) algorithm is developed to estimate these parameters. Linking to patient true disease outcomes, the rater-specific sensitivity and specificity can be estimated using MCMC samples. Cost theory is used to identify poor- and strong-performing raters and to guide adjustment of rater bias and diagnostic magnifier to improve the rating performance. Furthermore, diagnostic magnifier is shown as a key parameter to present a rater's diagnostic ability because a rater with a larger diagnostic magnifier has a uniformly better receiver operating characteristic (ROC) curve when varying the value of diagnostic bias. A simulation study is conducted to evaluate the proposed methods, and the methods are illustrated with a mammography example. [ABSTRACT FROM AUTHOR]

When modeling longitudinal data, the true values of time-varying covariates may be unknown because of detection-limit censoring or measurement error. A common approach in the literature is to empirically model the covariate process based on observed data and then predict the censored values or mismeasured values based on this empirical model. Such an empirical model can be misleading, especially for censored values since the (unobserved) censored values may behave very differently than observed values due to the underlying data-generation mechanisms or disease status. In this paper, we propose a mechanistic nonlinear covariate model based on the underlying data-generation mechanisms to address censored values and mismeasured values. Such a mechanistic model is based on solid scientific or biological arguments, so the predicted censored or mismeasured values are more reasonable. We use a Monte Carlo EM algorithm for likelihood inference and apply the methods to an AIDS dataset, where viral load is censored by a lower detection limit. Simulation results confirm that the proposed models and methods offer substantial advantages over existing empirical covariate models for censored and mismeasured covariates. [ABSTRACT FROM AUTHOR]

In clinical trials and biomedical studies, treatments are compared to determine which one is effective against illness; however, individuals can react to the same treatment very differently. We propose a complete process for longitudinal data that identifies subgroups of the population that would benefit from a specific treatment. A random effects linear model is used to evaluate individual treatment effects longitudinally where the random effects identify a positive or negative reaction to the treatment over time. With the individual treatment effects and characteristics of the patients, various classification algorithms are applied to build prediction models for subgrouping. While many subgrouping approaches have been developed recently, most of them do not check its validity. In this paper, we further propose a simple validation approach which not only determines if the subgroups used are appropriate and beneficial but also compares methods to predict individual treatment effects. This entire procedure is readily implemented by existing packages in statistical software. The effectiveness of the proposed method is confirmed with simulation studies and analysis of data from the Women Entering Care study on depression. [ABSTRACT FROM AUTHOR]

Traditional Chinese medicine (TCM) is a very complex mixture containing many different ingredients. Thus, statistical analysis of traditional Chinese medicine data becomes challenging, as one needs to handle the association among the observed data across different time points and across different ingredients of the multivariate response. This paper builds a 3-stage Bayesian hierarchical model for analyzing multivariate response pharmacokinetic data. Usually, the dimensionality of the parameter space is very huge, which leads to the parameter-estimation difficulty. So we take the hybrid Markov chain Monte Carlo algorithms to obtain the posterior Bayesian estimation of corresponding parameters in our model. Both simulation study and real-data analysis show that our theoretical model and Markov chain Monte Carlo algorithms perform well, and especially the correlation among different ingredients can be calculated very accurately. [ABSTRACT FROM AUTHOR]

Interval-censored data, in which the event time is only known to lie in some time interval, arise commonly in practice, for example, in a medical study in which patients visit clinics or hospitals at prescheduled times and the events of interest occur between visits. Such data are appropriately analyzed using methods that account for this uncertainty in event time measurement. In this paper, we propose a survival tree method for interval-censored data based on the conditional inference framework. Using Monte Carlo simulations, we find that the tree is effective in uncovering underlying tree structure, performs similarly to an interval-censored Cox proportional hazards model fit when the true relationship is linear, and performs at least as well as (and in the presence of right-censoring outperforms) the Cox model when the true relationship is not linear. Further, the interval-censored tree outperforms survival trees based on imputing the event time as an endpoint or the midpoint of the censoring interval. We illustrate the application of the method on tooth emergence data. [ABSTRACT FROM AUTHOR]

Identification of treatment selection biomarkers has become very important in cancer drug development. Adaptive enrichment designs have been developed for situations where a unique treatment selection biomarker is not apparent based on the mechanism of action of the drug. With such designs, the eligibility rules may be adaptively modified at interim analysis times to exclude patients who are unlikely to benefit from the test treatment.We consider a recently proposed, particularly flexible approach that permits development of model-based multifeature predictive classifiers as well as optimized cut-points for continuous biomarkers. A single significance test, including all randomized patients, is performed at the end of the trial of the strong null hypothesis that the expected outcome on the test treatment is no better than control for any of the subset populations of patients accrued in the K stages of the clinical trial. In this paper, we address 2 issues involving inference following an adaptive enrichment design as described above. The first is specification of the intended use population and estimation of treatment effect for that population following rejection of the strong null hypothesis. The second issue is defining conditions in which rejection of the strong null hypothesis implies rejection of the null hypothesis for the intended use population. [ABSTRACT FROM AUTHOR]

This paper presents a novel approach to estimation of the cumulative incidence function in the presence of competing risks. The underlying statistical model is specified via a mixture factorization of the joint distribution of the event type and the time to the event. The time to event distributions conditional on the event type are modeled using smooth semi-nonparametric densities. One strength of this approach is that it can handle arbitrary censoring and truncation while relying on mild parametric assumptions. A stepwise forward algorithm for model estimation and adaptive selection of smooth semi-nonparametric polynomial degrees is presented, implemented in the statistical software R, evaluated in a sequence of simulation studies, and applied to data from a clinical trial in cryptococcal meningitis. The simulations demonstrate that the proposed method frequently outperforms both parametric and nonparametric alternatives. They also support the use of 'ad hoc' asymptotic inference to derive confidence intervals. An extension to regression modeling is also presented, and its potential and challenges are discussed. © 2017 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd. [ABSTRACT FROM AUTHOR]

In this paper, we introduce a flexible family of cure rate models, mainly motivated by the biological derivation of the classical promotion time cure rate model and assuming that a metastasis-competent tumor cell produces a detectable-tumor mass only when a specific number of distinct biological factors affect the cell. Special cases of the new model are, among others, the promotion time (proportional hazards), the geometric (proportional odds), and the negative binomial cure rate model. In addition, our model generalizes specific families of transformation cure rate models and some well-studied destructive cure rate models. Exact likelihood inference is carried out by the aid of the expectationŰmaximization algorithm; a profile likelihood approach is exploited for estimating the parameters of the model while model discrimination problem is analyzed by the aid of the likelihood ratio test. A simulation study demonstrates the accuracy of the proposed inferential method. Finally, as an illustration, we fit the proposed model to a cutaneous melanoma data-set. Copyright © 2017 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

The generalized odds-rate model is a class of semiparametric regression models, which includes the proportional hazards and proportional odds models as special cases. There are few works on estimation of the generalized odds-rate model with interval censored data because of the challenges in maximizing the complex likelihood function. In this paper, we propose a gamma-Poisson data augmentation approach to develop an Expectation Maximization algorithm, which can be used to fit the generalized odds-rate model to interval censored data. The proposed Expectation Maximization algorithm is easy to implement and is computationally efficient. The performance of the proposed method is evaluated by comprehensive simulation studies and illustrated through applications to datasets from breast cancer and hemophilia studies. In order to make the proposed method easy to use in practice, an R package 'ICGOR' was developed. Copyright © 2016 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

The Bayesian model averaging continual reassessment method (CRM) is a Bayesian dose-finding design. It improves the robustness and overall performance of the continual reassessment method (CRM) by specifying multiple skeletons (or models) and then using Bayesian model averaging to automatically favor the best-fitting model for better decision making. Specifying multiple skeletons, however, can be challenging for practitioners. In this paper, we propose a default way to specify skeletons for the Bayesian model averaging CRM. We show that skeletons that appear rather different may actually lead to equivalent models. Motivated by this, we define a nonequivalence measure to index the difference among skeletons. Using this measure, we extend the model calibration method of Lee and Cheung (2009) to choose the optimal skeletons that maximize the average percentage of correct selection of the maximum tolerated dose and ensure sufficient nonequivalence among the skeletons. Our simulation study shows that the proposed method has desirable operating characteristics. We provide software to implement the proposed method. Copyright © 2016 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

In many medical applications, combining information from multiple biomarkers could yield a better diagnosis than any single one on its own. When there is a lack of a gold standard, an algorithm of classifying subjects into the case and non-case status is necessary for combining multiple markers. The aim of this paper is to develop a method to construct a composite test from multiple applicable tests and derive an optimal classification rule under the absence of a gold standard. Rather than combining the tests, we treat the tests as a sequence. This sequential composite test is based on a mixture of two multivariate normal latent models for the distribution of the test results in case and non-case groups, and the optimal classification rule is derived returning the greatest sensitivity at a given specificity. This method is applied to a real-data example and simulation studies have been carried out to assess the statistical properties and predictive accuracy of the proposed composite test. This method is also attainable to implement nonparametrically. [ABSTRACT FROM AUTHOR]

The frailty model, an extension of the proportional hazards model, is often used to model clustered survival data. However, some extension of the ordinary frailty model is required when there exist competing risks within a cluster. Under competing risks, the underlying processes affecting the events of interest and competing events could be different but correlated. In this paper, the hierarchical likelihood method is proposed to infer the cause-specific hazard frailty model for clustered competing risks data. The hierarchical likelihood incorporates fixed effects as well as random effects into an extended likelihood function, so that the method does not require intensive numerical methods to find the marginal distribution. Simulation studies are performed to assess the behavior of the estimators for the regression coefficients and the correlation structure among the bivariate frailty distribution for competing events. The proposed method is illustrated with a breast cancer dataset. [ABSTRACT FROM AUTHOR]

This paper develops a model for cancer screening and cancer incidence data, accommodating the partially unobserved disease status, clustered data structures, general covariate effects, and dependence between exams. The true unobserved cancer and detection status of screening participants are treated as latent variables, and a Markov Chain Monte Carlo algorithm is used to estimate the Bayesian posterior distributions of the diagnostic error rates and disease prevalence. We show how the Bayesian approach can be used to draw inferences about screening exam properties and disease prevalence while allowing for the possibility of conditional dependence between two exams. The techniques are applied to the estimation of the diagnostic accuracy of mammography and clinical breast examination using data from the Ontario Breast Screening Program in Canada. [ABSTRACT FROM AUTHOR]