Semiparametric normal transformation joint model of multivariate longitudinal and bivariate time-to-event data.

Joint models for longitudinal and survival data (JMLSs) are widely used to investigate the relationship between longitudinal and survival data in clinical trials in recent years. But, the existing studies mainly focus on independent survival data. In many clinical trials, survival data may be bivariately correlated. To this end, this paper proposes a novel JMLS accommodating multivariate longitudinal and bivariate correlated time-to-event data. Nonparametric marginal survival hazard functions are transformed to bivariate normal random variables. Bayesian penalized splines are employed to approximate unknown baseline hazard functions. Incorporating the Metropolis-Hastings algorithm into the Gibbs sampler, we develop a Bayesian adaptive Lasso method to simultaneously estimate parameters and baseline hazard functions, and select important predictors in the considered JMLS. Simulation studies and an example taken from the International Breast Cancer Study Group are used to illustrate the proposed methodologies.

Bayesian semiparametric joint model of multivariate longitudinal and survival data with dependent censoring.

We consider a novel class of semiparametric joint models for multivariate longitudinal and survival data with dependent censoring. In these models, unknown-fashion cumulative baseline hazard functions are fitted by a novel class of penalized-splines (P-splines) with linear constraints. The dependence between the failure time of interest and censoring time is accommodated by a normal transformation model, where both nonparametric marginal survival function and censoring function are transformed to standard normal random variables with bivariate normal joint distribution. Based on a hybrid algorithm together with the Metropolis-Hastings algorithm within the Gibbs sampler, we propose a feasible Bayesian method to simultaneously estimate unknown parameters of interest, and to fit baseline survival and censoring functions. Intensive simulation studies are conducted to assess the performance of the proposed method. The use of the proposed method is also illustrated in the analysis of a data set from the International Breast Cancer Study Group.

scDLC: a deep learning framework to classify large sample single-cell RNA-seq data.

BACKGROUND: Using single-cell RNA sequencing (scRNA-seq) data to diagnose disease is an effective technique in medical research. Several statistical methods have been developed for the classification of RNA sequencing (RNA-seq) data, including, for example, Poisson linear discriminant analysis (PLDA), negative binomial linear discriminant analysis (NBLDA), and zero-inflated Poisson logistic discriminant analysis (ZIPLDA). Nevertheless, few existing methods perform well for large sample scRNA-seq data, in particular when the distribution assumption is also violated. RESULTS: We propose a deep learning classifier (scDLC) for large sample scRNA-seq data, based on the long short-term memory recurrent neural networks (LSTMs). Our new scDLC does not require a prior knowledge on the data distribution, but instead, it takes into account the dependency of the most outstanding feature genes in the LSTMs model. LSTMs is a special recurrent neural network, which can learn long-term dependencies of a sequence. CONCLUSIONS: Simulation studies show that our new scDLC performs consistently better than the existing methods in a wide range of settings with large sample sizes. Four real scRNA-seq datasets are also analyzed, and they coincide with the simulation results that our new scDLC always performs the best. The code named "scDLC" is publicly available at https://github.com/scDLC-code/code .

Simultaneous variable selection and estimation for joint models of longitudinal and failure time data with interval censoring.

This paper discusses variable selection in the context of joint analysis of longitudinal data and failure time data. A large literature has been developed for either variable selection or the joint analysis but there exists only limited literature for variable selection in the context of the joint analysis when failure time data are right censored. Corresponding to this, we will consider the situation where instead of right-censored data, one observes interval-censored failure time data, a more general and commonly occurring form of failure time data. For the problem, a class of penalized likelihood-based procedures will be developed for simultaneous variable selection and estimation of relevant covariate effects for both longitudinal and failure time variables of interest. In particular, a Monte Carlo EM (MCEM) algorithm is presented for the implementation of the proposed approach. The proposed method allows for the number of covariates to be diverging with the sample size and is shown to have the oracle property. An extensive simulation study is conducted to assess the finite sample performance of the proposed approach and indicates that it works well in practical situations. An application is also provided.

Bayesian sample size determination in a three-arm non-inferiority trial with binary endpoints.

A three-arm non-inferiority trial including a test treatment, a reference treatment, and a placebo is recommended to assess the assay sensitivity and internal validity of a trial when applicable. Existing methods for designing and analyzing three-arm trials with binary endpoints are mainly developed from a frequentist viewpoint. However, these methods largely depend on large sample theories. To alleviate this problem, we propose two fully Bayesian approaches, the posterior variance approach and Bayes factor approach, to determine sample size required in a three-arm non-inferiority trial with binary endpoints. Simulation studies are conducted to investigate the performance of the proposed Bayesian methods. An example is illustrated by the proposed methodologies. Bayes factor method always leads to smaller sample sizes than the posterior variance method, utilizing the historical data can reduce the required sample size, simultaneous test requires more sample size to achieve the desired power than the non-inferiority test, the selection of the hyperparameters has a relatively large effect on the required sample size. When only controlling the posterior variance, the posterior variance criterion is a simple and effective option for obtaining a rough outcome. When conducting a previous clinical trial, it is recommended to use the Bayes factor criterion in practical applications.

A new approach to estimation of the proportional hazards model based on interval-censored data with missing covariates.

This paper discusses the fitting of the proportional hazards model to interval-censored failure time data with missing covariates. Many authors have discussed the problem when complete covariate information is available or the missing is completely at random. In contrast to this, we will focus on the situation where the missing is at random. For the problem, a sieve maximum likelihood estimation approach is proposed with the use of I-spline functions to approximate the unknown cumulative baseline hazard function in the model. For the implementation of the proposed method, we develop an EM algorithm based on a two-stage data augmentation. Furthermore, we show that the proposed estimators of regression parameters are consistent and asymptotically normal. The proposed approach is then applied to a set of the data concerning Alzheimer Disease that motivated this study.

Variational Bayesian partially linear mean shift models for high-dimensional Alzheimer's disease neuroimaging data.

Alzheimer's disease can be diagnosed by analyzing brain images (eg, magnetic resonance imaging, MRI) and neuropsychological tests (eg, mini-mental state examination, MMSE). A partially linear mean shift model (PLMSM) is here proposed to investigate the relationship between MMSE score and high-dimensional regions of interest in MRI, and detect the outliers. In the presence of high-dimensional data, existing Bayesian approaches (eg, Markov chain Monte Carlo) to analyze a PLMSM take intensive computational cost and require huge memory, and have low convergence rate. To address these issues, a variational Bayesian inference is developed to simultaneously estimate parameters and nonparametric functions and identify outliers in a PLMSM. A Bayesian P-splines method is presented to approximate nonparametric functions, a Bayesian adaptive Lasso approach is employed to select predictors, and outliers are detected by the classification variable. Two simulation studies are conducted to assess the finite sample performance of the proposed method. An MRI dataset with elderly cognitive ability is provided to corroborate the proposed method.

Confidence intervals of the difference between areas under two ROC curves in matched-pair experiments.

In a matched-pair study, when outcomes of two diagnostic tests are ordinal/continuous, the difference between two correlated areas under ROC curves (AUCs) is usually used to compare the overall discriminatory ability of two diagnostic tests. This article considers confidence interval (CI) construction problems of difference between two correlated AUCs in a matched-pair experiment, and proposes 13 hybrid CIs based on variance estimates recovery with the maximum likelihood estimation, Delong's statistic, Wilson score statistic (WS) and WS with continuity correction, the modified Wald statistic (MW) and MW with continuity correction and Agresti-Coull statistic, and three Bootstrap-resampling-based CIs. For comparison, we present traditional parametric and nonparametric CIs. Simulation studies are conducted to assess the performance of the proposed CIs in terms of empirical coverage probabilities, empirical interval widths, and ratios of the mesial noncoverage probabilities to the noncoverage probabilities. Two examples from clinical studies are illustrated by the proposed methodologies. Empirical results evidence that the hybrid Agresti-Coull CI with the empirical estimation (EAC) behaved most satisfactorily because its coverage probability was quite close to the prespecified confidence level with short interval width. Hence, we recommend the usage of the EAC CI in applications.

Simultaneous confidence interval for assessing non-inferiority with assay sensitivity in a three-arm trial with binary endpoints.

A three-arm trial including an experimental treatment, an active reference treatment and a placebo is often used to assess the non-inferiority (NI) with assay sensitivity of an experimental treatment. Various hypothesis-test-based approaches via a fraction or pre-specified margin have been proposed to assess the NI with assay sensitivity in a three-arm trial. There is little work done on confidence interval in a three-arm trial. This paper develops a hybrid approach to construct simultaneous confidence interval for assessing NI and assay sensitivity in a three-arm trial. For comparison, we present normal-approximation-based and bootstrap-resampling-based simultaneous confidence intervals. Simulation studies evidence that the hybrid approach with the Wilson score statistic performs better than other approaches in terms of empirical coverage probability and mesial-non-coverage probability. An example is used to illustrate the proposed approaches.

Smoothed empirical likelihood inference for ROC curve in the presence of missing biomarker values.

This paper considers statistical inference for the receiver operating characteristic (ROC) curve in the presence of missing biomarker values by utilizing estimating equations (EEs) together with smoothed empirical likelihood (SEL). Three approaches are developed to estimate ROC curve and construct its SEL-based confidence intervals based on the kernel-assisted EE imputation, multiple imputation, and hybrid imputation combining the inverse probability weighted imputation and multiple imputation. Under some regularity conditions, we show asymptotic properties of the proposed maximum SEL estimators for ROC curve. Simulation studies are conducted to investigate the performance of the proposed SEL approaches. An example is illustrated by the proposed methodologies. Empirical results show that the hybrid imputation method behaves better than the kernel-assisted and multiple imputation methods, and the proposed three SEL methods outperform existing nonparametric method.

Sparse Multicategory Generalized Distance Weighted Discrimination in Ultra-High Dimensions.

Distance weighted discrimination (DWD) is an appealing classification method that is capable of overcoming data piling problems in high-dimensional settings. Especially when various sparsity structures are assumed in these settings, variable selection in multicategory classification poses great challenges. In this paper, we propose a multicategory generalized DWD (MgDWD) method that maintains intrinsic variable group structures during selection using a sparse group lasso penalty. Theoretically, we derive minimizer uniqueness for the penalized MgDWD loss function and consistency properties for the proposed classifier. We further develop an efficient algorithm based on the proximal operator to solve the optimization problem. The performance of MgDWD is evaluated using finite sample simulations and miRNA data from an HIV study.

A nonparametric Bayesian continual reassessment method in single-agent dose-finding studies.

BACKGROUND: The main purpose of dose-finding studies in Phase I trial is to estimate maximum tolerated dose (MTD), which is the maximum test dose that can be assigned with an acceptable level of toxicity. Existing methods developed for single-agent dose-finding assume that the dose-toxicity relationship follows a specific parametric potency curve. This assumption may lead to bias and unsafe dose escalations due to the misspecification of parametric curve. METHODS: This paper relaxes the parametric assumption of dose-toxicity relationship by imposing a Dirichlet process prior on unknown dose-toxicity curve. A hybrid algorithm combining the Gibbs sampler and adaptive rejection Metropolis sampling (ARMS) algorithm is developed to estimate the dose-toxicity curve, and a two-stage Bayesian nonparametric adaptive design is presented to estimate MTD. RESULTS: For comparison, we consider two classical continual reassessment methods (CRMs) (i.e., logistic and power models). Numerical results show the flexibility of the proposed method for single-agent dose-finding trials, and the proposed method behaves better than two classical CRMs under our considered scenarios. CONCLUSIONS: The proposed dose-finding procedure is model-free and robust, and behaves satisfactorily even in small sample cases.

Influence analysis for skew-normal semiparametric joint models of multivariate longitudinal and multivariate survival data.

The normality assumption of measurement error is a widely used distribution in joint models of longitudinal and survival data, but it may lead to unreasonable or even misleading results when longitudinal data reveal skewness feature. This paper proposes a new joint model for multivariate longitudinal and multivariate survival data by incorporating a nonparametric function into the trajectory function and hazard function and assuming that measurement errors in longitudinal measurement models follow a skew-normal distribution. A Monte Carlo Expectation-Maximization (EM) algorithm together with the penalized-splines technique and the Metropolis-Hastings algorithm within the Gibbs sampler is developed to estimate parameters and nonparametric functions in the considered joint models. Case deletion diagnostic measures are proposed to identify the potential influential observations, and an extended local influence method is presented to assess local influence of minor perturbations. Simulation studies and a real example from a clinical trial are presented to illustrate the proposed methodologies. Copyright © 2017 John Wiley & Sons, Ltd.

Bayesian variable selection and estimation in semiparametric joint models of multivariate longitudinal and survival data.

This paper presents a novel semiparametric joint model for multivariate longitudinal and survival data (SJMLS) by relaxing the normality assumption of the longitudinal outcomes, leaving the baseline hazard functions unspecified and allowing the history of the longitudinal response having an effect on the risk of dropout. Using Bayesian penalized splines to approximate the unspecified baseline hazard function and combining the Gibbs sampler and the Metropolis-Hastings algorithm, we propose a Bayesian Lasso (BLasso) method to simultaneously estimate unknown parameters and select important covariates in SJMLS. Simulation studies are conducted to investigate the finite sample performance of the proposed techniques. An example from the International Breast Cancer Study Group (IBCSG) is used to illustrate the proposed methodologies.

Confidence intervals construction for difference of two means with incomplete correlated data.

BACKGROUND: Incomplete data often arise in various clinical trials such as crossover trials, equivalence trials, and pre and post-test comparative studies. Various methods have been developed to construct confidence interval (CI) of risk difference or risk ratio for incomplete paired binary data. But, there is little works done on incomplete continuous correlated data. To this end, this manuscript aims to develop several approaches to construct CI of the difference of two means for incomplete continuous correlated data. METHODS: Large sample method, hybrid method, simple Bootstrap-resampling method based on the maximum likelihood estimates (B 1) and Ekbohm's unbiased estimator (B 2), and percentile Bootstrap-resampling method based on the maximum likelihood estimates (B 3) and Ekbohm's unbiased estimator (B 4) are presented to construct CI of the difference of two means for incomplete continuous correlated data. Simulation studies are conducted to evaluate the performance of the proposed CIs in terms of empirical coverage probability, expected interval width, and mesial and distal non-coverage probabilities. RESULTS: Empirical results show that the Bootstrap-resampling-based CIs B 1, B 2, B 4 behave satisfactorily for small to moderate sample sizes in the sense that their coverage probabilities could be well controlled around the pre-specified nominal confidence level and the ratio of their mesial non-coverage probabilities to the non-coverage probabilities could be well controlled in the interval [0.4, 0.6]. CONCLUSIONS: If one would like a CI with the shortest interval width, the Bootstrap-resampling-based CIs B 1 is the optimal choice.

Confidence interval construction for the difference between two correlated proportions with missing observations.

Under the assumption of missing at random, eight confidence intervals (CIs) for the difference between two correlated proportions in the presence of incomplete paired binary data are constructed on the basis of the likelihood ratio statistic, the score statistic, the Wald-type statistic, the hybrid method incorporated with the Wilson score and Agresti-Coull (AC) intervals, and the Bootstrap-resampling method. Extensive simulation studies are conducted to evaluate the performance of the presented CIs in terms of coverage probability and expected interval width. Our empirical results evidence that the Wilson-score-based hybrid CI and the Wald-type CI together with the constrained maximum likelihood estimates perform well for small-to-moderate sample sizes in the sense that (i) their empirical coverage probabilities are quite close to the prespecified confidence level, (ii) their expected interval widths are shorter, and (iii) their ratios of the mesial non-coverage to non-coverage probabilities lie in interval [0.4, 0.6]. An example from a neurological study is used to illustrate the proposed methodologies.

Semiparametric Bayesian inference on skew-normal joint modeling of multivariate longitudinal and survival data.

We propose a semiparametric multivariate skew-normal joint model for multivariate longitudinal and multivariate survival data. One main feature of the posited model is that we relax the commonly used normality assumption for random effects and within-subject error by using a centered Dirichlet process prior to specify the random effects distribution and using a multivariate skew-normal distribution to specify the within-subject error distribution and model trajectory functions of longitudinal responses semiparametrically. A Bayesian approach is proposed to simultaneously obtain Bayesian estimates of unknown parameters, random effects and nonparametric functions by combining the Gibbs sampler and the Metropolis-Hastings algorithm. Particularly, a Bayesian local influence approach is developed to assess the effect of minor perturbations to within-subject measurement error and random effects. Several simulation studies and an example are presented to illustrate the proposed methodologies.

Testing non-inferiority of a new treatment in three-arm clinical trials with binary endpoints.

BACKGROUND: A two-arm non-inferiority trial without a placebo is usually adopted to demonstrate that an experimental treatment is not worse than a reference treatment by a small pre-specified non-inferiority margin due to ethical concerns. Selection of the non-inferiority margin and establishment of assay sensitivity are two major issues in the design, analysis and interpretation for two-arm non-inferiority trials. Alternatively, a three-arm non-inferiority clinical trial including a placebo is usually conducted to assess the assay sensitivity and internal validity of a trial. Recently, some large-sample approaches have been developed to assess the non-inferiority of a new treatment based on the three-arm trial design. However, these methods behave badly with small sample sizes in the three arms. This manuscript aims to develop some reliable small-sample methods to test three-arm non-inferiority. METHODS: Saddlepoint approximation, exact and approximate unconditional, and bootstrap-resampling methods are developed to calculate p-values of the Wald-type, score and likelihood ratio tests. Simulation studies are conducted to evaluate their performance in terms of type I error rate and power. RESULTS: Our empirical results show that the saddlepoint approximation method generally behaves better than the asymptotic method based on the Wald-type test statistic. For small sample sizes, approximate unconditional and bootstrap-resampling methods based on the score test statistic perform better in the sense that their corresponding type I error rates are generally closer to the prespecified nominal level than those of other test procedures. CONCLUSIONS: Both approximate unconditional and bootstrap-resampling test procedures based on the score test statistic are generally recommended for three-arm non-inferiority trials with binary outcomes.

Confidence-interval construction for rate ratio in matched-pair studies with incomplete data.

Matched-pair design is often used in clinical trials to increase the efficiency of establishing equivalence between two treatments with binary outcomes. In this article, we consider such a design based on rate ratio in the presence of incomplete data. The rate ratio is one of the most frequently used indices in comparing efficiency of two treatments in clinical trials. In this article, we propose 10 confidence-interval estimators for the rate ratio in incomplete matched-pair designs. A hybrid method that recovers variance estimates required for the rate ratio from the confidence limits for single proportions is proposed. It is noteworthy that confidence intervals based on this hybrid method have closed-form solution. The performance of the proposed confidence intervals is evaluated with respect to their exact coverage probability, expected confidence interval width, and distal and mesial noncoverage probability. The results show that the hybrid Agresti-Coull confidence interval based on Fieller's theorem performs satisfactorily for small to moderate sample sizes. Two real examples from clinical trials are used to illustrate the proposed confidence intervals.

Empirical Likelihood for Estimating Equations with Nonignorably Missing Data.

We develop an empirical likelihood (EL) inference on parameters in generalized estimating equations with nonignorably missing response data. We consider an exponential tilting model for the nonignorably missing mechanism, and propose modified estimating equations by imputing missing data through a kernel regression method. We establish some asymptotic properties of the EL estimators of the unknown parameters under different scenarios. With the use of auxiliary information, the EL estimators are statistically more efficient. Simulation studies are used to assess the finite sample performance of our proposed EL estimators. We apply our EL estimators to investigate a data set on earnings obtained from the New York Social Indicators Survey.