Multimodality or multiconstruct data arise increasingly in functional neuroimaging studies to characterize brain activity under different cognitive states. Relying on those high-resolution imaging collections, it is of great interest to identify predictive imaging markers and intermodality interactions with respect to behavior outcomes. Currently, most of the existing variable selection models do not consider predictive effects from interactions, and the desired higher-order terms can only be included in the predictive mechanism following a two-step procedure, suffering from potential misspecification. In this paper, we propose a unified Bayesian prior model to simultaneously identify main effect features and intermodality interactions within the same inference platform in the presence of high-dimensional data. To accommodate the brain topological information and correlation between modalities, our prior is designed by compiling the intermediate selection status of sequential partitions in light of the data structure and brain anatomical architecture, so that we can improve posterior inference and enhance biological plausibility. Through extensive simulations, we show the superiority of our approach in main and interaction effects selection, and prediction under multimodality data. Applying the method to the Adolescent Brain Cognitive Development (ABCD) study, we characterize the brain functional underpinnings with respect to general cognitive ability under different memory load conditions.

One key challenge encountered in single-cell data clustering is to combine clustering results of data sets acquired from multiple sources. We propose to represent the clustering result of each data set by a Gaussian mixture model (GMM) and produce an integrated result based on the notion of Wasserstein barycenter. However, the precise barycenter of GMMs, a distribution on the same sample space, is computationally infeasible to solve. Importantly, the barycenter of GMMs may not be a GMM containing a reasonable number of components. We thus propose to use the minimized aggregated Wasserstein (MAW) distance to approximate the Wasserstein metric and develop a new algorithm for computing the barycenter of GMMs under MAW. Recent theoretical advances further justify using the MAW distance as an approximation for the Wasserstein metric between GMMs. We also prove that the MAW barycenter of GMMs has the same expectation as the Wasserstein barycenter. Our proposed algorithm for clustering integration scales well with the data dimension and the number of mixture components, with complexity independent of data size. We demonstrate that the new method achieves better clustering results on several single-cell RNA-seq data sets than some other popular methods.

Sample sizes vary substantially across tissues in the Genotype-Tissue Expression (GTEx) project, where considerably fewer samples are available from certain inaccessible tissues, such as the substantia nigra (SSN), than from accessible tissues, such as blood. This severely limits power for identifying tissue-specific expression quantitative trait loci (eQTL) in undersampled tissues. Here we propose Surrogate Phenotype Regression Analysis (Spray) for leveraging information from a correlated surrogate outcome (eg, expression in blood) to improve inference on a partially missing target outcome (eg, expression in SSN). Rather than regarding the surrogate outcome as a proxy for the target outcome, Spray jointly models the target and surrogate outcomes within a bivariate regression framework. Unobserved values of either outcome are treated as missing data. We describe and implement an expectation conditional maximization algorithm for performing estimation in the presence of bilateral outcome missingness. Spray estimates the same association parameter estimated by standard eQTL mapping and controls the type I error even when the target and surrogate outcomes are truly uncorrelated. We demonstrate analytically and empirically, using simulations and GTEx data, that in comparison with marginally modeling the target outcome, jointly modeling the target and surrogate outcomes increases estimation precision and improves power.

Microarray studies, in order to identify genes associated with an outcome of interest, usually produce noisy measurements for a large number of gene expression features from a small number of subjects. One common approach to analyzing such high-dimensional data is to use linear errors-in-variables (EIV) models; however, current methods for fitting such models are computationally expensive. In this paper, we present two efficient screening procedures, namely, corrected penalized marginal screening (PMSc) and corrected sure independence screening (SISc), to reduce the number of variables for final model building. Both screening procedures are based on fitting corrected marginal regression models relating the outcome to each contaminated covariate separately, which can be computed efficiently even with a large number of features. Under mild conditions, we show that these procedures achieve screening consistency and reduce the number of features substantially, even when the number of covariates grows exponentially with sample size. In addition, if the true covariates are weakly correlated, we show that PMSc can achieve full variable selection consistency. Through a simulation study and an analysis of gene expression data for bone mineral density of Norwegian women, we demonstrate that the two new screening procedures make estimation of linear EIV models computationally scalable in high-dimensional settings, and improve finite sample estimation and selection performance compared with estimators that do not employ a screening stage.

Recent advancements in miniaturized fluorescence microscopy have made it possible to investigate neuronal responses to external stimuli in awake behaving animals through the analysis of intracellular calcium signals. An ongoing challenge is deconvolving the temporal signals to extract the spike trains from the noisy calcium signals' time series. In this article, we propose a nested Bayesian finite mixture specification that allows the estimation of spiking activity and, simultaneously, reconstructing the distributions of the calcium transient spikes' amplitudes under different experimental conditions. The proposed model leverages two nested layers of random discrete mixture priors to borrow information between experiments and discover similarities in the distributional patterns of neuronal responses to different stimuli. Furthermore, the spikes' intensity values are also clustered within and between experimental conditions to determine the existence of common (recurring) response amplitudes. Simulation studies and the analysis of a dataset from the Allen Brain Observatory show the effectiveness of the method in clustering and detecting neuronal activities.

In functional data analysis for longitudinal data, the observation process is typically assumed to be noninformative, which is often violated in real applications. Thus, methods that fail to account for the dependence between observation times and longitudinal outcomes may result in biased estimation. For longitudinal data with informative observation times, we find that under a general class of shared random effect models, a commonly used functional data method may lead to inconsistent model estimation while another functional data method results in consistent and even rate-optimal estimation. Indeed, we show that the mean function can be estimated appropriately via penalized splines and that the covariance function can be estimated appropriately via penalized tensor-product splines, both with specific choices of parameters. For the proposed method, theoretical results are provided, and simulation studies and a real data analysis are conducted to demonstrate its performance.

Passive surveillance systems are widely used to monitor diseases occurrence over wide spatial areas due to their cost-effectiveness and integration into broadly distributed healthcare systems. However, such systems are generally associated with imperfect ascertainment of disease cases and with heterogeneous capture probabilities arising from factors such as differential access to care. Augmenting passive surveillance systems with other surveillance efforts provides a way to estimate the true number of incident cases. We develop a hierarchical modeling framework for analyzing data from multiple surveillance systems that allows for individual-level covariate-dependent heterogeneous capture probabilities, and borrows information across surveillance sites to improve estimation of the true number of incident cases. Inference is carried out via a two-stage Bayesian procedure. Simulation studies illustrated superior performance of the proposed approach with respect to bias, root mean square error, and coverage compared to a model that does not borrow information across sites. We applied the proposed model to data from three surveillance systems reporting pulmonary tuberculosis (PTB) cases in a major center of ongoing transmission in China. The analysis yielded bias-corrected estimates of PTB cases from the passive system and led to the identification of risk factors associated with PTB rates, as well as factors influencing the operating characteristics of the implemented surveillance systems.

In contrast to differential gene expression analysis at the single-gene level, gene regulatory network (GRN) analysis depicts complex transcriptomic interactions among genes for better understandings of underlying genetic architectures of human diseases and traits. Recent advances in single-cell RNA sequencing (scRNA-seq) allow constructing GRNs at a much finer resolution than bulk RNA-seq and microarray data. However, scRNA-seq data are inherently sparse, which hinders the direct application of the popular Gaussian graphical models (GGMs). Furthermore, most existing approaches for constructing GRNs with scRNA-seq data only consider gene networks under one condition. To better understand GRNs across different but related conditions at single-cell resolution, we propose to construct Joint Gene Networks with scRNA-seq data (JGNsc) under the GGMs framework. To facilitate the use of GGMs, JGNsc first proposes a hybrid imputation procedure that combines a Bayesian zero-inflated Poisson model with an iterative low-rank matrix completion step to efficiently impute zero-inflated counts resulted from technical artifacts. JGNsc then transforms the imputed data via a nonparanormal transformation, based on which joint GGMs are constructed. We demonstrate JGNsc and assess its performance using synthetic data. The application of JGNsc on two cancer clinical studies of medulloblastoma and glioblastoma gains novel insights in addition to confirming well-known biological results.

Combining dependent tests of significance has broad applications but the related p-value calculation is challenging. For Fisher's combination test, current p-value calculation methods (eg, Brown's approximation) tend to inflate the type I error rate when the desired significance level is substantially less than 0.05. The problem could lead to significant false discoveries in big data analyses. This paper provides two main contributions. First, it presents a general family of Fisher type statistics, referred to as the GFisher, which covers many classic statistics, such as Fisher's combination, Good's statistic, Lancaster's statistic, weighted Z-score combination, and so forth. The GFisher allows a flexible weighting scheme, as well as an omnibus procedure that automatically adapts proper weights and the statistic-defining parameters to a given data. Second, the paper presents several new p-value calculation methods based on two novel ideas: moment-ratio matching and joint-distribution surrogating. Systematic simulations show that the new calculation methods are more accurate under multivariate Gaussian, and more robust under the generalized linear model and the multivariate t-distribution. The applications of the GFisher and the new p-value calculation methods are demonstrated by a gene-based single nucleotide polymorphism (SNP)-set association study. Relevant computation has been implemented to an R package GFisher available on the Comprehensive R Archive Network.

A popular design for clinical trials assessing targeted therapies is the two-stage adaptive enrichment design with recruitment in stage 2 limited to a biomarker-defined subgroup chosen based on data from stage 1. The data-dependent selection leads to statistical challenges if data from both stages are used to draw inference on treatment effects in the selected subgroup. If subgroups considered are nested, as when defined by a continuous biomarker, treatment effect estimates in different subgroups follow the same distribution as estimates in a group-sequential trial. This result is used to obtain tests controlling the familywise type I error rate (FWER) for six simple subgroup selection rules, one of which also controls the FWER for any selection rule. Two approaches are proposed: one based on multivariate normal distributions suitable if the number of possible subgroups, k, is small, and one based on Brownian motion approximations suitable for large k. The methods, applicable in the wide range of settings with asymptotically normal test statistics, are illustrated using survival data from a breast cancer trial.

An important experimental design problem in early-stage drug discovery is how to prioritize available compounds for testing when very little is known about the target protein. Informer-based ranking (IBR) methods address the prioritization problem when the compounds have provided bioactivity data on other potentially relevant targets. An IBR method selects an informer set of compounds, and then prioritizes the remaining compounds on the basis of new bioactivity experiments performed with the informer set on the target. We formalize the problem as a two-stage decision problem and introduce the Bayes Optimal Informer SEt (BOISE) method for its solution. BOISE leverages a flexible model of the initial bioactivity data, a relevant loss function, and effective computational schemes to resolve the two-step design problem. We evaluate BOISE and compare it to other IBR strategies in two retrospective studies, one on protein-kinase inhibition and the other on anticancer drug sensitivity. In both empirical settings BOISE exhibits better predictive performance than available methods. It also behaves well with missing data, where methods that use matrix completion show worse predictive performance.

The rapid acceleration of genetic data collection in biomedical settings has recently resulted in the rise of genetic compendiums filled with rich longitudinal disease data. One common feature of these data sets is their plethora of interval-censored outcomes. However, very few tools are available for the analysis of genetic data sets with interval-censored outcomes, and in particular, there is a lack of methodology available for set-based inference. Set-based inference is used to associate a gene, biological pathway, or other genetic construct with outcomes and is one of the most popular strategies in genetics research. This work develops three such tests for interval-censored settings beginning with a variance components test for interval-censored outcomes, the interval-censored sequence kernel association test (ICSKAT). We also provide the interval-censored version of the Burden test, and then we integrate ICSKAT and Burden to construct the interval censored sequence kernel association test-optimal (ICSKATO) combination. These tests unlock set-based analysis of interval-censored data sets with analogs of three highly popular set-based tools commonly applied to continuous and binary outcomes. Simulation studies illustrate the advantages of the developed methods over ad hoc alternatives, including protection of the type I error rate at very low levels and increased power. The proposed approaches are applied to the investigation that motivated this study, an examination of the genes associated with bone mineral density deficiency and fracture risk.

An estimated quadratic inference function method is proposed for correlated failure time data with auxiliary covariates. The proposed method makes efficient use of the auxiliary information for the incomplete exposure covariates and preserves the property of the quadratic inference function method that requires the covariates to be completely observed. It can improve the estimation efficiency and easily deal with the situation when the cluster size is large. The proposed estimator which minimizes the estimated quadratic inference function is shown to be consistent and asymptotically normal. A chi-squared test based on the estimated quadratic inference function is proposed to test hypotheses about the regression parameters. The small-sample performance of the proposed method is investigated through extensive simulation studies. The proposed method is then applied to analyze the Study of Left Ventricular Dysfunction (SOLVD) data as an illustration.

We propose a model-based approach that combines Bayesian variable selection tools, a novel spatial kernel convolution structure, and autoregressive processes for detecting a subject's brain activation at the voxel level in complex-valued functional magnetic resonance imaging (CV-fMRI) data. A computationally efficient Markov chain Monte Carlo algorithm for posterior inference is developed by taking advantage of the dimension reduction of the kernel-based structure. The proposed spatiotemporal model leads to more accurate posterior probability activation maps and less false positives than alternative spatial approaches based on Gaussian process models, and other complex-valued models that do not incorporate spatial and/or temporal structure. This is illustrated in the analysis of simulated data and human task-related CV-fMRI data. In addition, we show that complex-valued approaches dominate magnitude-only approaches and that the kernel structure in our proposed model considerably improves sensitivity rates when detecting activation at the voxel level.

Update of ArXiv. 2021 May 10;: