Biostatistics最新文献

In basket trials a single therapeutic treatment is tested on several patient populations simultaneously, each of which forming a basket, where patients across all baskets on the trial share a common genetic aberration. These trials allow testing of treatments on small groups of patients, however, limited basket sample sizes can result in inadequate precision and power of estimates. It is well known that Bayesian information borrowing models such as the exchangeability-nonexchangeability (EXNEX) model can be implemented to tackle such a problem, drawing on information from one basket when making inference in another. An alternative approach to improve power of estimates, is to incorporate any historical or external information available. This paper considers models that amalgamate both forms of information borrowing, allowing borrowing between baskets in the ongoing trial whilst also drawing on response data from historical sources, with the aim to further improve treatment effect estimates. We propose several Bayesian information borrowing approaches that incorporate historical information into the model. These methods are data-driven, updating the degree of borrowing based on the level of homogeneity between information sources. A thorough simulation study is presented to draw comparisons between the proposed approaches, whilst also comparing to the standard EXNEX model in which no historical information is utilized. The models are also applied to a real-life trial example to demonstrate their performance in practice. We show that the incorporation of historic data under the novel approaches can lead to a substantial improvement in precision and power of treatment effect estimates when such data is homogeneous to the responses in the ongoing trial. Under some approaches, this came alongside an inflation in type I error rate in cases of heterogeneity. However, the use of a power prior in the EXNEX model is shown to increase power and precision, whilst maintaining similar error rates to the standard EXNEX model.

Object-oriented data analysis is a fascinating and evolving field in modern statistical science, with the potential to make significant contributions to biomedical applications. This statistical framework facilitates the development of new methods to analyze complex data objects that capture more information than traditional clinical biomarkers. This paper applies the object-oriented framework to analyze physical activity levels, measured by accelerometers, as response objects in a regression model. Unlike traditional summary metrics, we utilize a recently proposed representation of physical activity data as a distributional object, providing a more nuanced and complete profile of individual energy expenditure across all ranges of monitoring intensity. A novel hybrid Fréchet regression model is proposed and applied to US population accelerometer data from National Health and Nutrition Examination Survey (NHANES) 2011 to 2014. The semi-parametric nature of the model allows for the inclusion of nonlinear effects for critical variables, such as age, which are biologically known to have subtle impacts on physical activity. Simultaneously, the inclusion of linear effects preserves interpretability for other variables, particularly categorical covariates such as ethnicity and sex. The results obtained are valuable from a public health perspective and could lead to new strategies for optimizing physical activity interventions in specific American subpopulations.

We develop a stochastic epidemic model progressing over dynamic networks, where infection rates are heterogeneous and may vary with individual-level covariates. The joint dynamics are modeled as a continuous-time Markov chain such that disease transmission is constrained by the contact network structure, and network evolution is in turn influenced by individual disease statuses. To accommodate partial epidemic observations commonly seen in real-world data, we propose a stochastic EM algorithm for inference, introducing key innovations that include efficient conditional samplers for imputing missing infection and recovery times which respect the dynamic contact network. Experiments on both synthetic and real datasets demonstrate that our inference method can accurately and efficiently recover model parameters and provide valuable insight at the presence of unobserved disease episodes in epidemic data.

Accounting for exposure measurement errors has been recognized as a crucial problem in environmental epidemiology for over two decades. Bayesian hierarchical models offer a coherent probabilistic framework for evaluating associations between environmental exposures and health effects, which take into account exposure measurement errors introduced by uncertainty in the estimated exposure as well as spatial misalignment between the exposure and health outcome data. While two-stage Bayesian analyses are often regarded as a good alternative to fully Bayesian analyses when joint estimation is not feasible, there has been minimal research on how to properly propagate uncertainty from the first-stage exposure model to the second-stage health model, especially in the case of a large number of participant locations along with spatially correlated exposures. We propose a scalable two-stage Bayesian approach, called a sparse multivariate normal (sparse MVN) prior approach, based on the Vecchia approximation for assessing associations between exposure and health outcomes in environmental epidemiology. We compare its performance with existing approaches through simulation. Our sparse MVN prior approach shows comparable performance with the fully Bayesian approach, which is a gold standard but is impossible to implement in some cases. We investigate the association between source-specific exposures and pollutant (nitrogen dioxide [NO2])-specific exposures and birth weight of full-term infants born in 2012 in Harris County, Texas, using several approaches, including the newly developed method.

The winner's curse is a form of selection bias that arises when estimates are obtained for a large number of features, but only a subset of most extreme estimates is reported. It occurs in large scale significance testing as well as in rank-based selection, and imperils reproducibility of findings and follow-up study design. Several methods correcting for this selection bias have been proposed, but questions remain on their susceptibility to dependence between features since theoretical analyses and comparative studies are few. We prove that estimation through Tweedie's formula is biased in presence of strong dependence, and propose a convolution of its density estimator to restore its competitive performance, which also aids other empirical Bayes methods. Furthermore, we perform a comprehensive simulation study comparing different classes of winner's curse correction methods for point estimates as well as confidence intervals under dependence. We find a bootstrap method and empirical Bayes methods with density convolution to perform best at correcting the selection bias, although this correction generally does not improve the feature ranking. Finally, we apply the methods to a comparison of single-feature versus multi-feature prediction models in predicting Brassica napus phenotypes from gene expression data, demonstrating that the superiority of the best single-feature model may be illusory.

Epidemiological investigations of regionally aggregated spatial data often involve detecting spatial health disparities among neighboring regions on a map of disease mortality or incidence rates. Analyzing such data introduces spatial dependence among health outcomes and seeks to report statistically significant spatial disparities by delineating boundaries that separate neighboring regions with disparate health outcomes. However, there are statistical challenges to appropriately define what constitutes a spatial disparity and to construct robust probabilistic inferences for spatial disparities. We enrich the familiar Bayesian linear regression framework to introduce spatial autoregression and offer model-based detection of spatial disparities. We derive exploitable analytical tractability that considerably accelerates computation. Simulation experiments conducted on a county map of the entire United States demonstrate the effectiveness of our method, and we apply our method to a data set from the Institute of Health Metrics and Evaluation (IHME) on age-standardized US county-level estimates of lung cancer mortality rates.

Causal mediation analysis of observational data is an important tool for investigating the potential causal effects of medications on disease-related risk factors, and on time-to-death (or disease progression) through these risk factors. However, when analyzing data from a cohort study, such analyses are complicated by the longitudinal structure of the risk factors and the presence of time-varying confounders. Leveraging data from the Atherosclerosis Risk in Communities (ARIC) cohort study, we develop a causal mediation approach, using (semi-parametric) Bayesian Additive Regression Tree (BART) models for the longitudinal and survival data. Our framework is developed using static longitudinal exposure regimes and allows for time-varying confounders and mediators, both of which can be either continuous or binary. We also identify and estimate direct and indirect causal effects in the presence of a competing event. We apply our methods to assess how medication, prescribed to target cardiovascular disease (CVD) risk factors, affects the time-to-CVD death.

Bayesian graphical models are powerful tools to infer complex relationships in high dimension, yet are often fraught with computational and statistical challenges. If exploited in a principled way, the increasing information collected alongside the data of primary interest constitutes an opportunity to mitigate these difficulties by guiding the detection of dependence structures. For instance, gene network inference may be informed by the use of publicly available summary statistics on the regulation of genes by genetic variants. Here we present a novel Gaussian graphical modeling framework to identify and leverage information on the centrality of nodes in conditional independence graphs. Specifically, we consider a fully joint hierarchical model to simultaneously infer (i) sparse precision matrices and (ii) the relevance of node-level information for uncovering the sought-after network structure. We encode such information as candidate auxiliary variables using a spike-and-slab submodel on the propensity of nodes to be hubs, which allows hypothesis-free selection and interpretation of a sparse subset of relevant variables. As efficient exploration of large posterior spaces is needed for real-world applications, we develop a variational expectation conditional maximization algorithm that scales inference to hundreds of samples, nodes and auxiliary variables. We illustrate and exploit the advantages of our approach in simulations and in a gene network study which identifies hub genes involved in biological pathways relevant to immune-mediated diseases.

Assessing how brain functional connectivity networks vary across individuals promises to uncover important scientific questions such as patterns of healthy brain aging through the lifespan or dysconnectivity associated with disease. In this article, we introduce a general regression framework, Connectivity Regression (ConnReg), for regressing subject-specific functional connectivity networks on covariates while accounting for within-network inter-edge dependence. ConnReg utilizes a multivariate generalization of Fisher's transformation to project network objects into an alternative space where Gaussian assumptions are justified and positive semidefinite constraints are automatically satisfied. Penalized multivariate regression is fit in the transformed space to simultaneously induce sparsity in regression coefficients and in covariance elements, which capture within network inter-edge dependence. We use permutation tests to perform multiplicity-adjusted inference to identify covariates associated with connectivity, and stability selection scores to identify network edges that vary with selected covariates. Simulation studies validate the inferential properties of our proposed method and demonstrate how estimating and accounting for within-network inter-edge dependence leads to more efficient estimation, more powerful inference, and more accurate selection of covariate-dependent network edges. We apply ConnReg to the Human Connectome Project Young Adult study, revealing insights into how connectivity varies with language processing covariates and structural brain features.

Making causal inferences from observational studies can be challenging when confounders are missing not at random. In such cases, identifying causal effects is often not guaranteed. Motivated by a real example, we consider a treatment-independent missingness assumption under which we establish the identification of causal effects when confounders are missing not at random. We propose a weighted estimating equation approach for estimating model parameters and introduce three estimators for the average causal effect, based on regression, propensity score weighting, and doubly robust estimation. We evaluate the performance of these estimators through simulations, and provide a real data analysis to illustrate our proposed method.