慢性病在患者间进展差异显著，而非随机变化。Subtype and Stage Inference Event-Based Model (SuStaIn) 通过估计亚型数量、每个亚型的疾病进展顺序及将患者分配到亚型来捕捉这种结构异质性。然而，其性能的鲁棒性如何？本文提出贝叶斯事件基于模型(BEBMS)，在不同模型失配程度的合成数据实验中，BEBMS在排序、分期和亚型分配任务中均优于SuStaIn。进一步，BEBMS和SuStaIn被应用于阿尔茨海默病真实数据集，发现BEBMS的结果更符合阿尔茨海默病进展的科学共识。
英文摘要：
Chronic diseases often progress differently across patients. Rather than randomly varying, there are typically a small number of subtypes for how a disease progresses across patients. To capture this structured heterogeneity, the Subtype and Stage Inference Event-Based Model (SuStaIn) estimates the number of subtypes, the order of disease progression for each subtype, and assigns each patient to a subtype from primarily cross-sectional data. It has been widely applied to uncover the subtypes of many diseases and inform our understanding of them. But how robust is its performance? In this paper, we develop a principled Bayesian subtype variant of the event-based model (BEBMS) and compare its performance to SuStaIn in a variety of synthetic data experiments with varied levels of model misspecification. BEBMS substantially outperforms SuStaIn across ordering, staging, and subtype assignment tasks. Further, we apply BEBMS and SuStaIn to a real-world Alzheimer's data set. We find BEBMS has results that are more consistent with the scientific consensus of Alzheimer's disease progression than SuStaIn.
Disease subtype identification (clustering) is an important problem in biomedical research. Gene expression profiles are commonly utilized to infer disease subtypes, which often lead to biologically meaningful insights into disease. Despite many successes, existing clustering methods may not perform well when genes are highly correlated and many uninformative genes are included for clustering due to the high dimensionality. In this article, we introduce a novel subtype identification method in the Bayesian setting based on gene expression profiles. This method, called BCSub, adopts an innovati…
Texas A&M University（德州农工大学）；University of Texas at Austin（德克萨斯大学奥斯汀分校）
Precision medicine aims for personalized prognosis and therapeutics by utilizing recent genome-scale high-throughput profiling techniques, including next-generation sequencing (NGS). However, translating NGS data faces several challenges. First, NGS count data are often overdispersed, requiring appropriate modeling. Second, compared to the number of involved molecules and system complexity, the number of available samples for studying complex disease, such as cancer, is often limited, especially considering disease heterogeneity. The key question is whether we may integrate available data from…
University of Warwick（华威大学）；The Netherlands Cancer Institute（荷兰癌症研究所）
In many applications, multivariate samples may harbor previously unrecognized heterogeneity at the level of conditional independence or network structure. For example, in cancer biology, disease subtypes may differ with respect to subtype-specific interplay between molecular components. Then, both subtype discovery and estimation of subtype-specific networks present important and related challenges. To enable such analyses, we put forward a mixture model whose components are sparse Gaussian graphical models. This brings together model-based clustering and graphical modeling to permit simultane…
Converging evidence indicates that the heterogeneity of cognitive profiles may arise through detectable alternations in brain functions. Particularly, brain functional connectivity, measured under resting and cognitive states, characterizes the unique neuronal interconnections across large-scale brain networks. Despite an unprecedented opportunity to uncover neurobiological subtypes through clustering or subtyping analyses on multi-state functional connectivity, few existing approaches are applicable here to accommodate the network topology and unique biological architecture of functional conn…
Patient subtyping based on temporal observations can lead to significantly nuanced subtyping that acknowledges the dynamic characteristics of diseases. Existing methods for subtyping trajectories treat the evolution of clinical observations as a homogeneous process or employ data available at regular intervals. In reality, diseases may have transient underlying states and a state-dependent observation pattern. In our paper, we present an approach to subtype irregular patient data while acknowledging the underlying progression of disease states. Our approach consists of two components: a probab…
Big Bayes is the computationally intensive co-application of big data and large, expressive Bayesian models for the analysis of complex phenomena in scientific inference and statistical learning. Standing as an example, Bayesian multidimensional scaling (MDS) can help scientists learn viral trajectories through space-time, but its computational burden prevents its wider use. Crucial MDS model calculations scale quadratically in the number of observations. We partially mitigate this limitation through massive parallelization using multi-core central processing units, instruction-level vectoriza…
Accurate diagnosis of disease is of great importance in clinical practice and medical research. The receiver operating characteristic (ROC) surface is a popular tool for evaluating the discriminatory ability of continuous diagnostic test outcomes when there exist three ordered disease classes (e.g., no disease, mild disease, advanced disease). We propose the Bayesian bootstrap, a fully nonparametric method, for conducting inference about the ROC surface and its functionals, such as the volume under the surface. The proposed method is based on a simple, yet interesting, representation of the RO…
We study possible relations between the structure of the connectome, white matter connecting different regions of brain, and Alzheimer disease. Regression models in covariates including age, gender and disease status for the extent of white matter connecting each pair of regions of brain are proposed. Subject We study possible relations between the Alzheimer's disease progression and the structure of the connectome, white matter connecting different regions of brain. Regression models in covariates including age, gender and disease status for the extent of white matter connecting each pair of …
Cardiovascular diseases (CVD), including atherosclerosis CVD (ASCVD), are multifactorial diseases that present a major economic and social burden worldwide. Tremendous efforts have been made to understand traditional risk factors for ASCVD, but these risk factors account for only about half of all cases of ASCVD. It remains a critical need to identify nontraditional risk factors (e.g., genetic variants, genes) contributing to ASCVD. Further, incorporating functional knowledge in prediction models have the potential to reveal pathways associated with disease risk. We propose Bayesian hierarchic…
Clustering is commonly performed as an initial analysis step for uncovering structure in 'omics datasets, e.g. to discover molecular subtypes of disease. The high-throughput, high-dimensional nature of these datasets means that they provide information on a diverse array of different biomolecular processes and pathways. Different groups of variables (e.g. genes or proteins) will be implicated in different biomolecular processes, and hence undertaking analyses that are limited to identifying just a single clustering partition of the whole dataset is therefore liable to conflate the multiple clu…
Characterization of long-term disease dynamics, from disease-free to end-stage, is integral to understanding the course of neurodegenerative diseases such as Parkinson's and Alzheimer's; and ultimately, how best to intervene. Natural history studies typically recruit multiple cohorts at different stages of disease and follow them longitudinally for a relatively short period of time. We propose a latent time joint mixed effects model to characterize long-term disease dynamics using this short-term data. Markov chain Monte Carlo methods are proposed for estimation, model selection, and inference…
Spatial connectivity is an important consideration when modelling infectious disease data across a geographical region. Connectivity can arise for many reasons, including shared characteristics between regions, and human or vector movement. Bayesian hierarchical models include structured random effects to account for spatial connectivity. However, conventional approaches require the spatial structure to be fully defined prior to model fitting. By applying penalised smoothing splines to coordinates, we create 2-dimensional smooth surfaces describing the spatial structure of the data whilst maki…
Background. Conventional phylogenetic clustering approaches rely on arbitrary cutpoints applied a posteriori to phylogenetic estimates. Although in practice, Bayesian and bootstrap-based clustering tend to lead to similar estimates, they often produce conflicting measures of confidence in clusters. The current study proposes a new Bayesian phylogenetic clustering algorithm, which we refer to as DM-PhyClus, that identifies sets of sequences resulting from quick transmission chains, thus yielding easily-interpretable clusters, without using any ad hoc distance or confidence requirement. Results.…
McCombs School of Business（麦库姆斯商学院）；The University of Texas at Austin（德克萨斯大学奥斯汀分校）
Combining Bayesian nonparametrics and a forward model selection strategy, we construct parsimonious Bayesian deep networks (PBDNs) that infer capacity-regularized network architectures from the data and require neither cross-validation nor fine-tuning when training the model. One of the two essential components of a PBDN is the development of a special infinite-wide single-hidden-layer neural network, whose number of active hidden units can be inferred from the data. The other one is the construction of a greedy layer-wise learning algorithm that uses a forward model selection criterion to det…
RWTH Aachen University（亚琛工业大学）；University of Edinburgh（爱丁堡大学）；QuantumBlack；McGill University（麦吉尔大学）
Identification of disease subtypes and corresponding biomarkers can substantially improve clinical diagnosis and treatment selection. Discovering these subtypes in noisy, high dimensional biomedical data is often impossible for humans and challenging for machines. We introduce a new approach to facilitate the discovery of disease subtypes: Instead of analyzing the original data, we train a diagnostic classifier (healthy vs. diseased) and extract instance-wise explanations for the classifier's decisions. The distribution of instances in the explanation space of our diagnostic classifier amplifi…
Background. Health economic evaluations of interventions against infectious diseases are commonly based on the predictions of ordinary differential equation (ODE) systems or Markov models (MMs). Standard MMs are static, whereas ODE systems are usually dynamic and account for herd immunity which is crucial to prevent overestimation of infection prevalence. Complex ODE systems including probabilistic model parameters are computationally intensive. Thus, mainly ODE-based models including deterministic parameters are presented in the literature. These do not account for parameter uncertainty. As a…
The vast majority of models for the spread of communicable diseases are parametric in nature and involve underlying assumptions about how the disease spreads through a population. In this article we consider the use of Bayesian nonparametric approaches to analysing data from disease outbreaks. Specifically we focus on methods for estimating the infection process in simple models under the assumption that this process has an explicit time-dependence.
Alzheimer's disease is the most common neurodegenerative disease. The aim of this study is to infer structural changes in brain connectivity resulting from disease progression using cortical thickness measurements from a cohort of participants who were either healthy control, or with mild cognitive impairment, or Alzheimer's disease patients. For this purpose, we develop a novel approach for inference of multiple networks with related edge values across groups. Specifically, we infer a Gaussian graphical model for each group within a joint framework, where we rely on Bayesian hierarchical prio…
We propose a framework for Bayesian non-parametric estimation of the rate at which new infections occur assuming that the epidemic is partially observed. The developed methodology relies on modelling the rate at which new infections occur as a function which only depends on time. Two different types of prior distributions are proposed namely using step-functions and B-splines. The methodology is illustrated using both simulated and real datasets and we show that certain aspects of the epidemic such as seasonality and super-spreading events are picked up without having to explicitly incorporate…
This article introduces epidemia, an R package for Bayesian, regression-oriented modeling of infectious diseases. The implemented models define a likelihood for all observed data while also explicitly modeling transmission dynamics: an approach often termed as semi-mechanistic. Infections are propagated over time using renewal equations. This approach is inspired by self-exciting, continuous-time point processes such as the Hawkes process. A variety of inferential tasks can be performed using the package. Key epidemiological quantities, including reproduction numbers and latent infections, may…
Disease Progression and Subtype Modeling for Combined Discrete and Continuous Input Data
Department of Radiology and Nuclear Medicine, Erasmus MC, Rotterdam, The Netherlands（埃因霍温麦斯特大学放射学与核医学系）；Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands（埃因霍温麦斯特大学流行病学系）；Hawkes Institute, Department of Computer Science, University College London, London, United Kingdom（伦敦大学学院霍克斯研究所）
University of Illinois at Urbana-Champaign（伊利诺伊大学厄巴纳-香槟分校）；National Institutes of Health（美国国立卫生研究院）
Alzheimer's disease (AD) is a degenerative brain disease impairing a person's ability to perform day to day activities. The clinical manifestations of Alzheimer's disease are characterized by heterogeneity in age, disease span, progression rate, impairment of memory and cognitive abilities. Due to these variabilities, personalized care and treatment planning, as well as patient counseling about their individual progression is limited. Recent developments in machine learning to detect hidden patterns in complex, multi-dimensional datasets provides significant opportunities to address this criti…
Early, reliable detection of disease outbreaks is a critical problem today. This paper reports an investigation of the use of causal Bayesian networks to model spatio-temporal patterns of a non-contagious disease (respiratory anthrax infection) in a population of people. The number of parameters in such a network can become enormous, if not carefully managed. Also, inference needs to be performed in real time as population data stream in. We describe techniques we have applied to address both the modeling and inference challenges. A key contribution of this paper is the explication of assumpti…
We consider the joint inference of regression coefficients and the inverse covariance matrix for covariates in high-dimensional probit regression, where the predictors are both relevant to the binary response and functionally related to one another. A hierarchical model with spike and slab priors over regression coefficients and the elements in the inverse covariance matrix is employed to simultaneously perform variable and graph selection. We establish joint selection consistency for both the variable and the underlying graph when the dimension of predictors is allowed to grow much larger tha…
GeSubNet: Gene Interaction Inference for Disease Subtype Network Generation
Bioinformatics Center, Kyoto University（京都大学生物信息学中心）；SANKEN, Osaka University（大阪大学SANKEN（大阪大学蛋白质研究所））；National Institute of Advanced Industrial Science and Technology (AIST)（日本国立先进工业科学技术研究所）；RIKEN Center for Computational Science（理化学研究所计算科学中心）；University of Illinois Urbana-Champaign（伊利诺伊大学厄巴纳-香槟分校）
Medical University of Vienna（维也纳医科大学）；University of Oxford（牛津大学）；Medical University of Innsbruck（因斯布鲁克医科大学）；Kepler University Hospital（开普勒大学医院）
As societies around the world are ageing, the number of Alzheimer's disease (AD) patients is rapidly increasing. To date, no low-cost, non-invasive biomarkers have been established to advance the objectivization of AD diagnosis and progression assessment. Here, we utilize Bayesian neural networks to develop a multivariate predictor for AD severity using a wide range of quantitative EEG (QEEG) markers. The Bayesian treatment of neural networks both automatically controls model complexity and provides a predictive distribution over the target function, giving uncertainty bounds for our regressio…
Disease mapping is the field of spatial epidemiology interested in estimating the spatial pattern in disease risk across $n$ areal units. One aim is to identify units exhibiting elevated disease risks, so that public health interventions can be made. Bayesian hierarchical models with a spatially smooth conditional autoregressive prior are used for this purpose, but they cannot identify the spatial extent of high-risk clusters. Therefore we propose a two stage solution to this problem, with the first stage being a spatially adjusted hierarchical agglomerative clustering algorithm. This algorith…
Alzheimer's disease is a neurodegenerative condition that accelerates cognitive decline relative to normal aging. It is of critical scientific importance to gain a better understanding of early disease mechanisms in the brain to facilitate effective, targeted therapies. The volume of the hippocampus is often used in diagnosis and monitoring of the disease. Measuring this volume via neuroimaging is difficult since each hippocampus must either be manually identified or automatically delineated, a task referred to as segmentation. Automatic hippocampal segmentation often involves mapping a previo…
We present a probabilistic programmed deep kernel learning approach to personalized, predictive modeling of neurodegenerative diseases. Our analysis considers a spectrum of neural and symbolic machine learning approaches, which we assess for predictive performance and important medical AI properties such as interpretability, uncertainty reasoning, data-efficiency, and leveraging domain knowledge. Our Bayesian approach combines the flexibility of Gaussian processes with the structural power of neural networks to model biomarker progressions, without needing clinical labels for training. We run …
Duke University Medical Center（杜克大学医学中心）；Duke University（杜克大学）
The task of clustering a set of objects based on multiple sources of data arises in several modern applications. We propose an integrative statistical model that permits a separate clustering of the objects for each data source. These separate clusterings adhere loosely to an overall consensus clustering, and hence they are not independent. We describe a computationally scalable Bayesian framework for simultaneous estimation of both the consensus clustering and the source-specific clusterings. We demonstrate that this flexible approach is more robust than joint clustering of all data sources, …
University of Pennsylvania（宾夕法尼亚大学）；University of Southern California（南加州大学）；Lausanne University Hospital (CHUV) and University of Lausanne（洛桑大学医院（CHUV）和洛桑大学）；University of Texas San Antonio Health Science Center（德克萨斯大学圣安东尼奥健康科学中心）；The University of Melbourne（墨尔本大学）；CSIRO（澳大利亚联邦科学与工业研究组织）；National Institute on Aging, National Institutes of Health（美国国立卫生研究院国家老龄化研究所）；Johns Hopkins University（约翰霍普金斯大学）；University of Wisconsin（威斯康星大学）；Washington University in St. Louis（圣路易斯华盛顿大学）；National Institute on Aging（国家老龄化研究所）
Disease heterogeneity has been a critical challenge for precision diagnosis and treatment, especially in neurologic and neuropsychiatric diseases. Many diseases can display multiple distinct brain phenotypes across individuals, potentially reflecting disease subtypes that can be captured using MRI and machine learning methods. However, biological interpretability and treatment relevance are limited if the derived subtypes are not associated with genetic drivers or susceptibility factors. Herein, we describe Gene-SGAN - a multi-view, weakly-supervised deep clustering method - which dissects dis…
The joint modeling of longitudinal and time-to-event data is an important tool of growing popularity to gain insights into the association between a biomarker and an event process. We develop a general framework of flexible additive joint models that allows the specification of a variety of effects, such as smooth nonlinear, time-varying and random effects, in the longitudinal and survival parts of the models. Our extensions are motivated by the investigation of the relationship between fluctuating disease-specific markers, in this case autoantibodies, and the progression to the autoimmune dis…
