Progressive diseases worsen over time and are characterised by monotonic change in features that track disease progression. Here we connect ideas from two formerly separate methodologies -- event-based and hidden Markov modelling -- to derive a new generative model of disease progression. Our model can uniquely infer the most likely group-level sequence and timing of events (natural history) from limited datasets. Moreover, it can infer and predict individual-level trajectories (prognosis) even when data are missing, giving it high clinical utility. Here we derive the model and provide an inference scheme based on the expectation maximisation algorithm. We use clinical, imaging and biofluid data from the Alzheimer's Disease Neuroimaging Initiative to demonstrate the validity and utility of our model. First, we train our model to uncover a new group-level sequence of feature changes in Alzheimer's disease over a period of ${\sim}17.3$ years. Next, we demonstrate that our model provides improved utility over a continuous time hidden Markov model by area under the receiver operator characteristic curve ${\sim}0.23$. Finally, we demonstrate that our model maintains predictive accuracy with up to $50\%$ missing data. These results support the clinical validity of our model and its broader utility in resource-limited medical applications.
IBM Research（IBM研究院）；Helmholtz Zentrum München（慕尼黑亥姆霍兹中心）；JDRF；University of Washington（华盛顿大学）；Lund University（隆德大学）；University of Oulu（奥卢大学）；University of Colorado（科罗拉多大学）
Analyzing disease progression patterns can provide useful insights into the disease processes of many chronic conditions. These analyses may help inform recruitment for prevention trials or the development and personalization of treatments for those affected. We learn disease progression patterns using Hidden Markov Models (HMM) and distill them into distinct trajectories using visualization methods. We apply it to the domain of Type 1 Diabetes (T1D) using large longitudinal observational data from the T1DI study group. Our method discovers distinct disease progression trajectories that corrob…
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）
We model Alzheimer's disease (AD) progression by combining differential equations (DEs) and reinforcement learning (RL) with domain knowledge. DEs provide relationships between some, but not all, factors relevant to AD. We assume that the missing relationships must satisfy general criteria about the working of the brain, for e.g., maximizing cognition while minimizing the cost of supporting cognition. This allows us to extract the missing relationships by using RL to optimize an objective (reward) function that captures the above criteria. We use our model consisting of DEs (as a simulator) an…
Unscrambling disease progression at scale: fast inference of event permutations with optimal transport
Sussex AI Centre Department of Informatics University of Sussex（苏塞克斯大学人工智能中心信息学院）；Hawkes Institute Department of Computer Science University College London（霍克斯研究所计算机科学学院）
A particular challenge for disease progression modeling is the heterogeneity of a disease and its manifestations in the patients. Existing approaches often assume the presence of a single disease progression characteristics which is unlikely for neurodegenerative disorders such as Parkinson's disease. In this paper, we propose a hierarchical time-series model that can discover multiple disease progression dynamics. The proposed model is an extension of an input-output hidden Markov model that takes into account the clinical assessments of patients' health status and prescribed medications. We …
Disease progression modeling (DPM) involves using mathematical frameworks to quantitatively measure the severity of how certain disease progresses. DPM is useful in many ways such as predicting health state, categorizing disease stages, and assessing patients disease trajectory etc. Recently, with wider availability of electronic health records (EHR) and the broad application of data-driven machine learning method, DPM has attracted much attention yet remains two major challenges: (i) Due to the existence of irregularity, heterogeneity and long-term dependency in EHRs, most existing DPM method…
Conditional Neural ODE for Longitudinal Parkinson's Disease Progression Forecasting
Emory University（埃默里大学）；University of California, Los Angeles（加州大学洛杉矶分校）；Illinois Institute of Technology（伊利诺伊理工学院）；Lehigh University（莱斯大学）；University of Pittsburgh（匹兹堡大学）；University of Wisconsin–Madison（威斯康星大学麦迪逊分校）
Unifying Interpretability and Explainability for Alzheimer's Disease Progression Prediction
Kansas State University（堪萨斯州立大学）；Carnegie Mellon University（卡内基梅隆大学）；University of Kansas Medical Center（堪萨斯大学医学中心）；Alzheimer’s Disease Research Center（阿尔茨海默病研究中心）
Longitudinal Progression Prediction of Alzheimer's Disease with Tabular Foundation Model
Department of Computer Science Emory University Atlanta GA USA（埃默里大学计算机科学系）；Center for Data Science Nell Hodgson Woodruff School of Nursing Emory University Atlanta GA USA（埃默里大学数据科学中心）；Department of Computer Science Georgia State University Atlanta GA USA（佐治亚州立大学计算机科学系）；Tri-Institutional Center for Translational Research in Neuroimaging and Data Science (TReNDS) Atlanta GA USA（神经影像与数据科学转化研究三机构中心（TReNDS））
Erasmus MC, University Medical Center Rotterdam（鹿特丹伊拉斯姆斯医学中心（鹿特丹大学医学中心））；Delft University of Technology（代尔夫特理工大学）
Alzheimer's Disease (AD) is characterized by a cascade of biomarkers becoming abnormal, the pathophysiology of which is very complex and largely unknown. Event-based modeling (EBM) is a data-driven technique to estimate the sequence in which biomarkers for a disease become abnormal based on cross-sectional data. It can help in understanding the dynamics of disease progression and facilitate early diagnosis and prognosis. In this work we propose a novel discriminative approach to EBM, which is shown to be more accurate than existing state-of-the-art EBM methods. The method first estimates for e…
Intense debate in the Neurology community before 2010 culminated in hypothetical models of Alzheimer's disease progression: a pathophysiological cascade of biomarkers, each dynamic for only a segment of the full disease timeline. Inspired by this, data-driven disease progression modelling emerged from the computer science community with the aim to reconstruct neurodegenerative disease timelines using data from large cohorts of patients, healthy controls, and prodromal/at-risk individuals. This chapter describes selected highlights from the field, with a focus on utility for understanding and f…
Temporally Detailed Hypergraph Neural ODEs for Disease Progression Modeling
Department of Computer and Information Science and Engineering, University of Florida（佛罗里达大学计算机与信息科学与工程系）；Regenstrief Institute（Regenstrief研究所）；Department of Biostatistics and Health Data Science, Indiana University（印第安纳大学生物统计学与健康数据科学系）；Department of Pharmacy Practice, Purdue University（普渡大学药学实践系）
In this thesis the aim is to work on optimizing the modern machine learning models for personalized forecasting of Alzheimer Disease (AD) Progression from clinical trial data. The data comes from the TADPOLE challenge, which is one of the largest publicly available datasets for AD research (ADNI dataset). The goal of the project is to develop machine learning models that can be used to perform personalized forecasts of the participants cognitive changes (e.g., ADAS-Cog13 scores) over the time period of 6,12, 18 and 24 months in the future and the change in Clinical Status (CS) i.e., whether a …
IBM Research（IBM研究院）；University of Colorado Denver（科罗拉多大学丹佛分校）；Lund University（隆德大学）
Clinical researchers use disease progression models to understand patient status and characterize progression patterns from longitudinal health records. One approach for disease progression modeling is to describe patient status using a small number of states that represent distinctive distributions over a set of observed measures. Hidden Markov models (HMMs) and its variants are a class of models that both discover these states and make inferences of health states for patients. Despite the advantages of using the algorithms for discovering interesting patterns, it still remains challenging fo…
University of Texas at Arlington（德克萨斯大学阿灵顿分校）；The University of Georgia（佐治亚大学）
For decades, a variety of predictive approaches have been proposed and evaluated in terms of their prediction capability for Alzheimer's Disease (AD) and its precursor - mild cognitive impairment (MCI). Most of them focused on prediction or identification of statistical differences among different clinical groups or phases (e.g., longitudinal studies). The continuous nature of AD development and transition states between successive AD related stages have been overlooked, especially in binary or multi-class classification. Though a few progression models of AD have been studied recently, they w…
Alzheimer's Disease (AD), as the most devastating neurodegenerative disease worldwide, has reached nearly 10 million new cases annually. Current technology provides unprecedented opportunities to study the progression and etiology of this disease with the advanced in imaging techniques. With the recent emergence of a society driven by big data and machine learning (ML), researchers have exerted considerable effort to summarize recent advances in ML-based AD diagnosis. Here, we outline some of the most prevalent and recent ML models for assessing the progression of AD and provide insights on th…
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…
Modeling disease progression in healthcare administrative databases is complicated by the fact that patients are observed only at irregular intervals when they seek healthcare services. In a longitudinal cohort of 76,888 patients with chronic obstructive pulmonary disease (COPD), we used a continuous-time hidden Markov model with a generalized linear model to model healthcare utilization events. We found that the fitted model provides interpretable results suitable for summarization and hypothesis generation.
In this work we introduce Disease Progression Modeling workbench 360 (DPM360) opensource clinical informatics framework for collaborative research and delivery of healthcare AI. DPM360, when fully developed, will manage the entire modeling life cycle, from data analysis (e.g., cohort identification) to machine learning algorithm development and prototyping. DPM360 augments the advantages of data model standardization and tooling (OMOP-CDM, Athena, ATLAS) provided by the widely-adopted OHDSI initiative with a powerful machine learning training framework, and a mechanism for rapid prototyping th…
Ability to quantify and predict progression of a disease is fundamental for selecting an appropriate treatment. Many clinical metrics cannot be acquired frequently either because of their cost (e.g. MRI, gait analysis) or because they are inconvenient or harmful to a patient (e.g. biopsy, x-ray). In such scenarios, in order to estimate individual trajectories of disease progression, it is advantageous to leverage similarities between patients, i.e. the covariance of trajectories, and find a latent representation of progression. Most of existing methods for estimating trajectories do not accoun…
Alzheimer's Disease (AD) is a neurodegenerative disease that affects subjects in a broad range of severity and is assessed in clinical trials with multiple cognitive and functional instruments. As clinical trials in AD increasingly focus on earlier stages of the disease, especially Mild Cognitive Impairment (MCI), the ability to model subject outcomes across the disease spectrum is extremely important. We use unsupervised machine learning models called Conditional Restricted Boltzmann Machines (CRBMs) to create Digital Twins of AD subjects. Digital Twins are simulated clinical records that sha…
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…
Most approaches to machine learning from electronic health data can only predict a single endpoint. Here, we present an alternative that uses unsupervised deep learning to simulate detailed patient trajectories. We use data comprising 18-month trajectories of 44 clinical variables from 1908 patients with Mild Cognitive Impairment or Alzheimer's Disease to train a model for personalized forecasting of disease progression. We simulate synthetic patient data including the evolution of each sub-component of cognitive exams, laboratory tests, and their associations with baseline clinical characteri…
TransFair: Transferring Fairness from Ocular Disease Classification to Progression Prediction
School of Computing and Informatics, University of Louisiana at Lafayette（路易斯安那大学拉斐特分校计算与信息学院）；Informatics Research Institute, University of Louisiana at Lafayette（路易斯安那大学拉斐特分校信息学研究所）；College of Engineering and Computer Science, Florida Atlantic University（佛罗里达大西洋大学工程与计算机科学学院）；Harvard Medical School（哈佛医学院）
Erasmus MC, University Medical Center Rotterdam（鹿特丹大学医学中心伊拉斯谟医学中心）；Delft University of Technology（代尔夫特理工大学）
Alzheimer's disease (AD) is the most common form of dementia and is phenotypically heterogeneous. APOE is a triallelic gene which correlates with phenotypic heterogeneity in AD. In this work, we determined the effect of APOE alleles on the disease progression timeline of AD using a discriminative event-based model (DEBM). Since DEBM is a data-driven model, stratification into smaller disease subgroups would lead to more inaccurate models as compared to fitting the model on the entire dataset. Hence our secondary aim is to propose and evaluate novel approaches in which we split the different st…
In this policy paper, we implement the epidemiological SIR to estimate the basic reproduction number $\mathcal{R}_0$ at national and state level. We also developed the statistical machine learning model to predict the cases ahead of time. Our analysis indicates that the situation of Punjab ($\mathcal{R}_0\approx 16$) is not good. It requires immediate aggressive attention. We see the $\mathcal{R}_0$ for Madhya Pradesh (3.37) , Maharastra (3.25) and Tamil Nadu (3.09) are more than 3. The $\mathcal{R}_0$ of Andhra Pradesh (2.96), Delhi (2.82) and West Bengal (2.77) is more than the India's $\mat…
PIE: Simulating Disease Progression via Progressive Image Editing
The University of Texas at Austin（德克萨斯大学奥斯汀分校）；University of Illinois Urbana-Champaign（伊利诺伊大学厄巴纳-香槟分校）；University of California San Diego（加利福尼亚大学圣迭戈分校）；University of California, Berkeley（加利福尼亚大学伯克利分校）；University of Virginia（弗吉尼亚大学）；PediaMed AI；Northwestern University（西北大学）；Carnegie Mellon University（卡内基梅隆大学）
We introduce a probabilistic generative model for disentangling spatio-temporal disease trajectories from series of high-dimensional brain images. The model is based on spatio-temporal matrix factorization, where inference on the sources is constrained by anatomically plausible statistical priors. To model realistic trajectories, the temporal sources are defined as monotonic and time-reparametrized Gaussian Processes. To account for the non-stationarity of brain images, we model the spatial sources as sparse codes convolved at multiple scales. The method was tested on synthetic data favourably…
Learning Disease Progression Models That Capture Health Disparities
Cornell Tech Cornell University（康奈尔科技 康奈尔大学）；NewYork-Presbyterian Weill Cornell Medical College（纽约- Presbyterian 威廉斯堡康奈尔医学学院）；NewYork-Presbyterian Columbia University Irving Medical Center（纽约- Presbyterian 哥伦比亚大学伊文思医疗中心）；University of California Berkeley（加州大学伯克利分校）
Memorial Sloan Kettering Cancer Center（纪念斯隆凯特琳癌症中心）；Indian Institute of Technology Madras（印度理工学院马德拉斯分校）
Purpose: A core component of advancing cancer treatment research is assessing response to therapy. Doing so by hand, for example as per RECIST or RANO criteria, is tedious, time-consuming, and can miss important tumor response information; most notably, they exclude non-target lesions. We wish to assess change in a holistic fashion that includes all lesions, obtaining simple, informative, and automated assessments of tumor progression or regression. Due to often low patient enrolments in clinical trials, we wish to make response assessments with small training sets. Deep neuroevolution (DNE) c…
Massachusetts Institute of Technology（麻省理工学院）；Imperial College London（伦敦帝国学院）
In this paper, we introduce the use of a personalized Gaussian Process model (pGP) to predict the key metrics of Alzheimer's Disease progression (MMSE, ADAS-Cog13, CDRSB and CS) based on each patient's previous visits. We start by learning a population-level model using multi-modal data from previously seen patients using the base Gaussian Process (GP) regression. Then, this model is adapted sequentially over time to a new patient using domain adaptive GPs to form the patient's pGP. We show that this new approach, together with an auto-regressive formulation, leads to significant improvements …
Disease progression models are instrumental in predicting individual-level health trajectories and understanding disease dynamics. Existing models are capable of providing either accurate predictions of patients prognoses or clinically interpretable representations of disease pathophysiology, but not both. In this paper, we develop the phased attentive state space (PASS) model of disease progression, a deep probabilistic model that captures complex representations for disease progression while maintaining clinical interpretability. Unlike Markovian state space models which assume memoryless dy…
The University of Texas Southwestern Medical Center（德克萨斯大学西南医学中心）；The University of Texas at Dallas（德克萨斯大学达拉斯分校）
Parkinson's disease (PD) is a common neurological disorder characterized by gait impairment. PD has no cure, and an impediment to developing a treatment is the lack of any accepted method to predict disease progression rate. The primary aim of this study was to develop a model using clinical measures and biomechanical measures of gait and postural stability to predict an individual's PD progression over two years. Data from 160 PD subjects were utilized. Machine learning models, including XGBoost and Feed Forward Neural Networks, were developed using extensive model optimization and cross-vali…
Biomediq A/S（Biomediq公司）；University of Copenhagen（哥本哈根大学）；University College London（伦敦大学学院）
Disease progression modeling (DPM) using longitudinal data is a challenging task in machine learning for healthcare that can provide clinicians with better tools for diagnosis and monitoring of disease. Existing DPM algorithms neglect temporal dependencies among measurements and make parametric assumptions about biomarker trajectories. In addition, they do not model multiple biomarkers jointly and need to align subjects' trajectories. In this paper, recurrent neural networks (RNNs) are utilized to address these issues. However, in many cases, longitudinal cohorts contain incomplete data, which…
Robust forecasting of the future anatomical changes inflicted by an ongoing disease is an extremely challenging task that is out of grasp even for experienced healthcare professionals. Such a capability, however, is of great importance since it can improve patient management by providing information on the speed of disease progression already at the admission stage, or it can enrich the clinical trials with fast progressors and avoid the need for control arms by the means of digital twins. In this work, we develop a deep learning method that models the evolution of age-related disease by proce…
The Mind Research Network（心智研究网络）；University of New Mexico（新墨西哥大学）；Microsoft Research（微软研究院）；Montreal Institute for Learning Algorithms（蒙特利尔学习算法研究所）；University of Montreal（蒙特利尔大学）；Shanxi University（山西大学）
Arguably, unsupervised learning plays a crucial role in the majority of algorithms for processing brain imaging. A recently introduced unsupervised approach Deep InfoMax (DIM) is a promising tool for exploring brain structure in a flexible non-linear way. In this paper, we investigate the use of variants of DIM in a setting of progression to Alzheimer's disease in comparison with supervised AlexNet and ResNet inspired convolutional neural networks. As a benchmark, we use a classification task between four groups: patients with stable, and progressive mild cognitive impairment (MCI), with Alzhe…
Washington University School of Medicine（华盛顿大学医学院）
Objective Alzheimer disease (AD) is the most common cause of dementia, a syndrome characterized by cognitive impairment severe enough to interfere with activities of daily life. We aimed to conduct a systematic literature review (SLR) of studies that applied machine learning (ML) methods to clinical data derived from electronic health records in order to model risk for progression of AD dementia. Materials and Methods: We searched for articles published between January 1, 2010, and May 31, 2020, in PubMed, Scopus, ScienceDirect, IEEE Explore Digital Library, Association for Computing Machinery…
LaTiM: Longitudinal representation learning in continuous-time models to predict disease progression
LaTIM UMR 1101；Inserm（法国国家健康与医学研究院）；University of Western Brittany（西布列塔尼大学）；IMT Atlantique（大西洋电信学院）；Lariboisière Hospital（拉里布瓦西耶尔医院）；AP-HP（巴黎公共医疗援助局）；CHRU Brest（布雷斯特大学医院中心）
