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In oncology clinical trials, tumor burden (TB) stands as a crucial longitudinal biomarker, reflecting the toll a tumor takes on a patient's prognosis. With certain treatments, the disease's natural progression shows the tumor burden initially receding before rising once more. Biologically, the point of change may be different between individuals and must have occurred between the baseline measurement and progression time of the patient, implying a random effects model obeying a bound constraint. However, in practice, patients may drop out of the study due to progression or death, presenting a non-ignorable missing data problem. In this paper, we introduce a novel joint model that combines time-to-event data and longitudinal data, where the latter is parameterized by a random change point augmented by random pre-slope and post-slope dynamics. Importantly, the model is equipped to incorporate covariates across for the longitudinal and survival models, adding significant flexibility. Adopting a Bayesian approach, we propose an efficient Hamiltonian Monte Carlo algorithm for parameter inference. We demonstrate the superiority of our approach compared to a longitudinal-only model via simulations and apply our method to a data set in oncology.

With the robust uptick in the applications of Bayesian external data borrowing, eliciting a prior distribution with the proper amount of information becomes increasingly critical. The prior effective sample size (ESS) is an intuitive and efficient measure for this purpose. The majority of ESS definitions have been proposed in the context of borrowing control information. While many Bayesian models can be naturally extended to leveraging external information on the treatment effect scale, very little attention has been directed to computing the prior ESS in this setting. In this research, we bridge this methodological gap by extending the popular ELIR ESS definition. We lay out the general framework, and derive the prior ESS for various types of endpoints and treatment effect measures. The posterior distribution and the predictive consistency property of ESS are also examined. The methods are implemented in R programs available on GitHub: https://github.com/squallteo/TrtEffESS.

The BayesPPDSurv (Bayesian Power Prior Design for Survival Data) R package supports Bayesian power and type I error calculations and model fitting using the power and normalized power priors incorporating historical data with for the analysis of time-to-event outcomes. The package implements the stratified proportional hazards regression model with piecewise constant hazard within each stratum. The package allows the historical data to inform the treatment effect parameter, parameter effects for other covariates in the regression model, as well as the baseline hazard parameters. The use of multiple historical datasets is supported. A novel algorithm is developed for computationally efficient use of the normalized power prior. In addition, the package supports the use of arbitrary sampling priors for computing Bayesian power and type I error rates, and has built-in features that semi-automatically generate sampling priors from the historical data. We demonstrate the use of BayesPPDSurv in a comprehensive case study for a melanoma clinical trial design.

The power prior is a popular class of informative priors for incorporating information from historical data. It involves raising the likelihood for the historical data to a power, which acts as a discounting parameter. When the discounting parameter is modeled as random, the normalized power prior is recommended. Bayesian hierarchical modeling is a widely used method for synthesizing information from different sources, including historical data. In this work, we examine the analytical relationship between the normalized power prior (NPP) and Bayesian hierarchical models (BHM) for \emph{i.i.d.} normal data. We establish a direct relationship between the prior for the discounting parameter of the NPP and the prior for the variance parameter of the BHM. Such a relationship is first established for the case of a single historical dataset, and then extended to the case with multiple historical datasets with dataset-specific discounting parameters. For multiple historical datasets, we develop and establish theory for the BHM-matching NPP (BNPP) which establishes dependence between the dataset-specific discounting parameters leading to inferences that are identical to the BHM. Establishing this relationship not only justifies the NPP from the perspective of hierarchical modeling, but also provides insight on prior elicitation for the NPP. We present strategies on inducing priors on the discounting parameter based on hierarchical models, and investigate the borrowing properties of the BNPP.

Generalized linear mixed models (GLMMs) are widely used in research for their ability to model correlated outcomes with non-Gaussian conditional distributions. The proper selection of fixed and random effects is a critical part of the modeling process since model misspecification may lead to significant bias. However, the joint selection of fixed and random effects has historically been limited to lower-dimensional GLMMs, largely due to the use of criterion-based model selection strategies. Here we present the R package glmmPen, one of the first to select fixed and random effects in higher dimension using a penalized GLMM modeling framework. Model parameters are estimated using a Monte Carlo Expectation Conditional Minimization (MCECM) algorithm, which leverages Stan and RcppArmadillo for increased computational efficiency. Our package supports the Binomial, Gaussian, and Poisson families and multiple penalty functions. In this manuscript we discuss the modeling procedure, estimation scheme, and software implementation through application to a pancreatic cancer subtyping study. Simulation results show our method has good performance in selecting both the fixed and random effects in high dimensional GLMMs.

Modern biomedical datasets are increasingly high dimensional and exhibit complex correlation structures. Generalized Linear Mixed Models (GLMMs) have long been employed to account for such dependencies. However, proper specification of the fixed and random effects in GLMMs is increasingly difficult in high dimensions, and computational complexity grows with increasing dimension of the random effects. We present a novel reformulation of the GLMM using a factor model decomposition of the random effects, enabling scalable computation of GLMMs in high dimensions by reducing the latent space from a large number of random effects to a smaller set of latent factors. We also extend our prior work to estimate model parameters using a modified Monte Carlo Expectation Conditional Minimization algorithm, allowing us to perform variable selection on both the fixed and random effects simultaneously. We show through simulation that through this factor model decomposition, our method can fit high dimensional penalized GLMMs faster than comparable methods and more easily scale to larger dimensions not previously seen in existing approaches.

It is becoming increasingly popular to elicit informative priors on the basis of historical data. Popular existing priors, including the power prior, commensurate prior, and robust meta-analytic prior provide blanket discounting. Thus, if only a subset of participants in the historical data are exchangeable with the current data, these priors may not be appropriate. In order to combat this issue, propensity score (PS) approaches have been proposed. However, PS approaches are only concerned with the covariate distribution, whereas exchangeability is typically assessed with parameters pertaining to the outcome. In this paper, we introduce the latent exchangeability prior (LEAP), where observations in the historical data are classified into exchangeable and non-exchangeable groups. The LEAP discounts the historical data by identifying the most relevant subjects from the historical data. We compare our proposed approach against alternative approaches in simulations and present a case study using our proposed prior to augment a control arm in a phase 3 clinical trial in plaque psoriasis with an unbalanced randomization scheme.

The power prior is a popular class of informative priors for incorporating information from historical data. It involves raising the likelihood for the historical data to a power, which acts as discounting parameter. When the discounting parameter is modelled as random, the normalized power prior is recommended. In this work, we prove that the marginal posterior for the discounting parameter for generalized linear models converges to a point mass at zero if there is any discrepancy between the historical and current data, and that it does not converge to a point mass at one when they are fully compatible. In addition, we explore the construction of optimal priors for the discounting parameter in a normalized power prior. In particular, we are interested in achieving the dual objectives of encouraging borrowing when the historical and current data are compatible and limiting borrowing when they are in conflict. We propose intuitive procedures for eliciting the shape parameters of a beta prior for the discounting parameter based on two minimization criteria, the Kullback-Leibler divergence and the mean squared error. Based on the proposed criteria, the optimal priors derived are often quite different from commonly used priors such as the uniform prior.

Deep Learning (DL) methods have dramatically increased in popularity in recent years, with significant growth in their application to supervised learning problems in the biomedical sciences. However, the greater prevalence and complexity of missing data in modern biomedical datasets present significant challenges for DL methods. Here, we provide a formal treatment of missing data in the context of deeply learned generalized linear models, a supervised DL architecture for regression and classification problems. We propose a new architecture, \textit{dlglm}, that is one of the first to be able to flexibly account for both ignorable and non-ignorable patterns of missingness in input features and response at training time. We demonstrate through statistical simulation that our method outperforms existing approaches for supervised learning tasks in the presence of missing not at random (MNAR) missingness. We conclude with a case study of a Bank Marketing dataset from the UCI Machine Learning Repository, in which we predict whether clients subscribed to a product based on phone survey data. Supplementary materials for this article are available online.

The R package BayesPPD (Bayesian Power Prior Design) supports Bayesian power and type I error calculation and model fitting after incorporating historical data with the power prior and the normalized power prior for generalized linear models (GLM). The package accommodates summary level data or subject level data with covariate information. It supports use of multiple historical datasets as well as design without historical data. Supported distributions for responses include normal, binary (Bernoulli/binomial), Poisson and exponential. The power parameter $a_0$ can be fixed or modeled as random using a normalized power prior for each of these distributions. In addition, the package supports the use of arbitrary sampling priors for computing Bayesian power and type I error rates, and has specific features for GLMs that semi-automatically generate sampling priors from historical data. Since sample size determination (SSD) for GLMs is computationally intensive, an approximation method based on asymptotic theory has been implemented to support applications using the power prior. In addition to describing the statistical methodology and functions implemented in the package to enable SSD, we also demonstrate the use of BayesPPD in two comprehensive case studies., Comment: 28 pages, 1 figure

There has been increased interest in using prior information in statistical analyses. For example, in rare diseases, it can be difficult to establish treatment efficacy based solely on data from a prospective study due to low sample sizes. To overcome this issue, an informative prior for the treatment effect may be elicited. We develop a novel extension of the conjugate prior of Chen and Ibrahim (2003) that enables practitioners to elicit a prior prediction for the mean response for generalized linear models, treating the prediction as random. We refer to the hierarchical prior as the hierarchical prediction prior. For i.i.d. settings and the normal linear model, we derive cases for which the hyperprior is a conjugate prior. We also develop an extension of the HPP in situations where summary statistics from a previous study are available, drawing comparisons with the power prior. The HPP allows for discounting based on the quality of individual level predictions, having the potential to provide efficiency gains (e.g., lower MSE) where predictions are incompatible with the data. An efficient Markov chain Monte Carlo algorithm is developed. Applications illustrate that inferences under the HPP are more robust to prior-data conflict compared to selected non-hierarchical priors.

We develop the scale transformed power prior for settings where historical and current data involve different data types, such as binary and continuous data, respectively. This situation arises often in clinical trials, for example, when historical data involve binary responses and the current data involve time-to-event or some other type of continuous or discrete outcome. The power prior proposed by Ibrahim and Chen (2000) does not address the issue of different data types. Herein, we develop a new type of power prior, which we call the scale transformed power prior (straPP). The straPP is constructed by transforming the power prior for the historical data by rescaling the parameter using a function of the Fisher information matrices for the historical and current data models, thereby shifting the scale of the parameter vector from that of the historical to that of the current data. Examples are presented to motivate the need for a scale transformation and simulation studies are presented to illustrate the performance advantages of the straPP over the power prior and other informative and non-informative priors. A real dataset from a clinical trial undertaken to study a novel transitional care model for stroke survivors is used to illustrate the methodology., Comment: 21 pages, 5 figures, 5 tables

Deep Learning (DL) methods have dramatically increased in popularity in recent years. While its initial success was demonstrated in the classification and manipulation of image data, there has been significant growth in the application of DL methods to problems in the biomedical sciences. However, the greater prevalence and complexity of missing data in biomedical datasets present significant challenges for DL methods. Here, we provide a formal treatment of missing data in the context of Variational Autoencoders (VAEs), a popular unsupervised DL architecture commonly utilized for dimension reduction, imputation, and learning latent representations of complex data. We propose a new VAE architecture, NIMIWAE, that is one of the first to flexibly account for both ignorable and non-ignorable patterns of missingness in input features at training time. Following training, samples can be drawn from the approximate posterior distribution of the missing data can be used for multiple imputation, facilitating downstream analyses on high dimensional incomplete datasets. We demonstrate through statistical simulation that our method outperforms existing approaches for unsupervised learning tasks and imputation accuracy. We conclude with a case study of an EHR dataset pertaining to 12,000 ICU patients containing a large number of diagnostic measurements and clinical outcomes, where many features are only partially observed., Comment: 31 pages, 4 figures, 2 tables, under review (Biometrics Methodology)

Given the cost and duration of phase III and phase IV clinical trials, the development of statistical methods for go/no-go decisions is vital. In this paper, we introduce a Bayesian methodology to compute the probability of success based on the current data of a treatment regimen for the multivariate linear model. Our approach utilizes a Bayesian seemingly unrelated regression model, which allows for multiple endpoints to be modeled jointly even if the covariates between the endpoints are different. Correlations between endpoints are explicitly modeled. This Bayesian joint modeling approach unifies single and multiple testing procedures under a single framework. We develop an approach to multiple testing that asymptotically guarantees strict family-wise error rate control, and is more powerful than frequentist approaches to multiplicity. The method effectively yields those of Ibrahim et al. and Chuang-Stein as special cases, and, to our knowledge, is the only method that allows for robust sample size determination for multiple endpoints and/or hypotheses and the only method that provides strict family-wise type I error control in the presence of multiplicity.

The power prior is a popular tool for constructing informative prior distributions based on historical data. The method consists of raising the likelihood to a discounting factor in order to control the amount of information borrowed from the historical data. It is customary to perform a sensitivity analysis reporting results for a range of values of the discounting factor. However, one often wishes to assign it a prior distribution and estimate it jointly with the parameters, which in turn necessitates the computation of a normalising constant. In this paper we are concerned with how to recycle computations from a sensitivity analysis in order to approximately sample from joint posterior of the parameters and the discounting factor. We first show a few important properties of the normalising constant and then use these results to motivate a bisection-type algorithm for computing it on a fixed budget of evaluations. We give a large array of illustrations and discuss cases where the normalising constant is known in closed-form and where it is not. We show that the proposed method produces approximate posteriors that are very close to the exact distributions when those are available and also produces posteriors that cover the data-generating parameters with higher probability in the intractable case. Our results show that proper inclusion the normalising constant is crucial to the correct quantification of uncertainty and that the proposed method is an accurate and easy to implement technique to include this normalisation, being applicable to a large class of models. Key-words: Doubly-intractable; elicitation; historical data; normalisation; power prior; sensitivity analysis., Comment: Code available at https://github.com/maxbiostat/propriety_power_priors

Rheumatoid arthritis clinical trials are strategically designed to collect the disease activity score of each patient over multiple clinical visits, meanwhile a patient may drop out before their intended completion due to various reasons. The dropout terminates the longitudinal data collection on the patients activity score. In the presence of informative dropout, that is, the dropout depends on latent variables from the longitudinal process, simply applying a model to analyze the longitudinal outcomes may lead to biased results because the assumption of random dropout is violated. In this paper we develop a data driven Bayesian joint model for modeling DAS28 scores and competing risk informative drop out. The motivating example is a clinical trial of Etanercept and Methotrexate with radiographic Patient Outcomes (TEMPO, Keystone et.al).

In the genomic era, the identification of gene signatures associated with disease is of significant interest. Such signatures are often used to predict clinical outcomes in new patients and aid clinical decision-making. However, recent studies have shown that gene signatures are often not replicable. This occurrence has practical implications regarding the generalizability and clinical applicability of such signatures. To improve replicability, we introduce a novel approach to select gene signatures from multiple datasets whose effects are consistently non-zero and account for between-study heterogeneity. We build our model upon some rank-based quantities, facilitating integration over different genomic datasets. A high dimensional penalized Generalized Linear Mixed Model (pGLMM) is used to select gene signatures and address data heterogeneity. We compare our method to some commonly used strategies that select gene signatures ignoring between-study heterogeneity. We provide asymptotic results justifying the performance of our method and demonstrate its advantage in the presence of heterogeneity through thorough simulation studies. Lastly, we motivate our method through a case study subtyping pancreatic cancer patients from four gene expression studies.

The aim of this paper is to develop a class of spatial transformation models (STM) to spatially model the varying association between imaging measures in a three-dimensional (3D) volume (or 2D surface) and a set of covariates. Our STMs include a varying Box-Cox transformation model for dealing with the issue of non-Gaussian distributed imaging data and a Gaussian Markov Random Field model for incorporating spatial smoothness of the imaging data. Posterior computation proceeds via an efficient Markov chain Monte Carlo algorithm. Simulations and real data analysis demonstrate that the STM significantly outperforms the voxel-wise linear model with Gaussian noise in recovering meaningful geometric patterns. Our STM is able to reveal important brain regions with morphological changes in children with attention deficit hyperactivity disorder.

Medical imaging studies have collected high dimensional imaging data to identify imaging biomarkers for diagnosis, screening, and prognosis, among many others. These imaging data are often represented in the form of a multi-dimensional array, called a tensor. The aim of this paper is to develop a tensor partition regression modeling (TPRM) framework to establish a relationship between low-dimensional clinical outcomes (e.g., diagnosis) and high dimensional tensor covariates. Our TPRM is a hierarchical model and efficiently integrates four components: (i) a partition model, (ii) a canonical polyadic decomposition model, (iii) a principal components model, and (iv) a generalized linear model with a sparse inducing normal mixture prior. This framework not only reduces ultra-high dimensionality to a manageable level, resulting in efficient estimation, but also optimizes prediction accuracy in the search for informative sub-tensors. Posterior computation proceeds via an efficient Markov chain Monte Carlo algorithm. Simulation shows that TPRM outperforms several other competing methods. We apply TPRM to predict disease status (Alzheimer versus control) by using structural magnetic resonance imaging data obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) study.

Cook's distance [Technometrics 19 (1977) 15-18] is one of the most important diagnostic tools for detecting influential individual or subsets of observations in linear regression for cross-sectional data. However, for many complex data structures (e.g., longitudinal data), no rigorous approach has been developed to address a fundamental issue: deleting subsets with different numbers of observations introduces different degrees of perturbation to the current model fitted to the data, and the magnitude of Cook's distance is associated with the degree of the perturbation. The aim of this paper is to address this issue in general parametric models with complex data structures. We propose a new quantity for measuring the degree of the perturbation introduced by deleting a subset. We use stochastic ordering to quantify the stochastic relationship between the degree of the perturbation and the magnitude of Cook's distance. We develop several scaled Cook's distances to resolve the comparison of Cook's distance for different subset deletions. Theoretical and numerical examples are examined to highlight the broad spectrum of applications of these scaled Cook's distances in a formal influence analysis., Comment: Published in at http://dx.doi.org/10.1214/12-AOS978 the Annals of Statistics (http://www.imstat.org/aos/) by the Institute of Mathematical Statistics (http://www.imstat.org)

Longitudinal imaging studies are essential to understanding the neural development of neuropsychiatric disorders, substance use disorders, and the normal brain. The main objective of this paper is to develop a two-stage adjusted exponentially tilted empirical likelihood (TETEL) for the spatial analysis of neuroimaging data from longitudinal studies. The TETEL method as a frequentist approach allows us to efficiently analyze longitudinal data without modeling temporal correlation and to classify different time-dependent covariate types. To account for spatial dependence, the TETEL method developed here specifically combines all the data in the closest neighborhood of each voxel (or pixel) on a 3-dimensional (3D) volume (or 2D surface) with appropriate weights to calculate adaptive parameter estimates and adaptive test statistics. Simulation studies are used to examine the finite sample performance of the adjusted exponential tilted likelihood ratio statistic and TETEL. We demonstrate the application of our statistical methods to the detection of the difference in the morphological changes of the hippocampus across time between schizophrenia patients and healthy subjects in a longitudinal schizophrenia study., Comment: Published in at http://dx.doi.org/10.1214/11-AOAS480 the Annals of Applied Statistics (http://www.imstat.org/aoas/) by the Institute of Mathematical Statistics (http://www.imstat.org)

Longitudinal studies of a binary outcome are common in the health, social, and behavioral sciences. In general, a feature of random effects logistic regression models for longitudinal binary data is that the marginal functional form, when integrated over the distribution of the random effects, is no longer of logistic form. Recently, Wang and Louis [Biometrika 90 (2003) 765--775] proposed a random intercept model in the clustered binary data setting where the marginal model has a logistic form. An acknowledged limitation of their model is that it allows only a single random effect that varies from cluster to cluster. In this paper we propose a modification of their model to handle longitudinal data, allowing separate, but correlated, random intercepts at each measurement occasion. The proposed model allows for a flexible correlation structure among the random intercepts, where the correlations can be interpreted in terms of Kendall's $\tau$. For example, the marginal correlations among the repeated binary outcomes can decline with increasing time separation, while the model retains the property of having matching conditional and marginal logit link functions. Finally, the proposed method is used to analyze data from a longitudinal study designed to monitor cardiac abnormalities in children born to HIV-infected women., Comment: Published in at http://dx.doi.org/10.1214/10-AOAS390 the Annals of Applied Statistics (http://www.imstat.org/aoas/) by the Institute of Mathematical Statistics (http://www.imstat.org)

Cook's [J. Roy. Statist. Soc. Ser. B 48 (1986) 133--169] local influence approach based on normal curvature is an important diagnostic tool for assessing local influence of minor perturbations to a statistical model. However, no rigorous approach has been developed to address two fundamental issues: the selection of an appropriate perturbation and the development of influence measures for objective functions at a point with a nonzero first derivative. The aim of this paper is to develop a differential--geometrical framework of a perturbation model (called the perturbation manifold) and utilize associated metric tensor and affine curvatures to resolve these issues. We will show that the metric tensor of the perturbation manifold provides important information about selecting an appropriate perturbation of a model. Moreover, we will introduce new influence measures that are applicable to objective functions at any point. Examples including linear regression models and linear mixed models are examined to demonstrate the effectiveness of using new influence measures for the identification of influential observations., Comment: Published in at http://dx.doi.org/10.1214/009053607000000343 the Annals of Statistics (http://www.imstat.org/aos/) by the Institute of Mathematical Statistics (http://www.imstat.org)

We propose a class of transformation hazard models for right-censored failure time data. It includes the proportional hazards model (Cox) and the additive hazards model (Lin and Ying) as special cases. Due to the requirement of a nonnegative hazard function, multidimensional parameter constraints must be imposed in the model formulation. In the Bayesian paradigm, the nonlinear parameter constraint introduces many new computational challenges. We propose a prior through a conditional-marginal specification, in which the conditional distribution is univariate, and absorbs all of the nonlinear parameter constraints. The marginal part of the prior specification is free of any constraints. This class of prior distributions allows us to easily compute the full conditionals needed for Gibbs sampling, and hence implement the Markov chain Monte Carlo algorithm in a relatively straightforward fashion. Model comparison is based on the conditional predictive ordinate and the deviance information criterion. This new class of models is illustrated with a simulation study and a real dataset from a melanoma clinical trial., Comment: Published at http://dx.doi.org/10.1214/074921706000000446 in the IMS Lecture Notes--Monograph Series (http://www.imstat.org/publications/lecnotes.htm) by the Institute of Mathematical Statistics (http://www.imstat.org)