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 characteristics, generating both predictions and their confidence intervals. Our unsupervised model predicts changes in total ADAS-Cog scores with the same accuracy as specifically trained supervised models and identifies sub-components associated with word recall as predictive of progression. The ability to simultaneously simulate dozens of patient characteristics is a crucial step towards personalized medicine for Alzheimer's Disease.
Alzheimer's disease (AD) is the most common neurodegenerative disease in older people. Despite considerable efforts to find a cure for AD, there is a 99.6% failure rate of clinical trials for AD drugs, likely because AD patients cannot easily be identified at early stages. This project investigated machine learning approaches to predict the clinical state of patients in future years to benefit AD research. Clinical data from 1737 patients was obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database and was processed using the "All-Pairs" technique, a novel methodology crea…
University of Oxford（牛津大学）；Alan Turing Institute（艾伦·图灵研究所）
Joint models for longitudinal and time-to-event data are commonly used in longitudinal studies to forecast disease trajectories over time. Despite the many advantages of joint modeling, the standard forms suffer from limitations that arise from a fixed model specification and computational difficulties when applied to large datasets. We adopt a deep learning approach to address these limitations, enhancing existing methods with the flexibility and scalability of deep neural networks while retaining the benefits of joint modeling. Using data from the Alzheimer's Disease Neuroimaging Institute, …
Universidad Carlos III de Madrid（马德里卡洛斯三世大学）；University of Eastern Finland（东芬兰大学）
Machine learning techniques typically applied to dementia forecasting lack in their capabilities to jointly learn several tasks, handle time dependent heterogeneous data and missing values. In this paper, we propose a framework using the recently presented SSHIBA model for jointly learning different tasks on longitudinal data with missing values. The method uses Bayesian variational inference to impute missing values and combine information of several views. This way, we can combine different data-views from different time-points in a common latent space and learn the relations between each ti…
Forecasting Medium-Horizon Alzheimer's Disease Progression: Residual Gap-Aware Transformers for 24-Month CDR-SB Change from ADNI Clinical and Biomarker Histories
Department of Mathematical Sciences, University of Texas at Dallas（德克萨斯大学达拉斯分校数学科学系）；Department of Plant Science and Landscape Architecture, University of Connecticut（康奈尔大学植物科学与景观建筑系）；Naveen Jindal School of Management, University of Texas at Dallas（德克萨斯大学达拉斯分校纳文·金达管理学院）；Zhejiang Provincial People’s Hospital（浙江省人民医院）
Biomediq A/S（Biomediq公司）；Cerebriu A/S（Cerebriu公司）；University of Copenhagen（哥本哈根大学）；University College London（伦敦大学学院）；King’s College London（伦敦国王学院）
Quantitative characterization of disease progression using longitudinal data can provide long-term predictions for the pathological stages of individuals. This work studies the robust modeling of Alzheimer's disease progression using parametric methods. The proposed method linearly maps the individual's age to a disease progression score (DPS) and jointly fits constrained generalized logistic functions to the longitudinal dynamics of biomarkers as functions of the DPS using M-estimation. Robustness of the estimates is quantified using bootstrapping via Monte Carlo resampling, and the estimated…
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…
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 …
Università Sapienza（罗马大学）；Centro Ricerche Enrico Fermi（恩里科·费米研究中心）；Joint Research Centre（联合研究中心）；Istituto dei Sistemi Complessi - CNR（意大利国家研究委员会复杂系统研究所）
Economic complexity methods, and in particular relatedness measures, lack a systematic evaluation and comparison framework. We argue that out-of-sample forecast exercises should play this role, and we compare various machine learning models to set the prediction benchmark. We find that the key object to forecast is the activation of new products, and that tree-based algorithms clearly overperform both the quite strong auto-correlation benchmark and the other supervised algorithms. Interestingly, we find that the best results are obtained in a cross-validation setting, when data about the predi…
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…
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…
ImageFlowNet: Forecasting Multiscale Image-Level Trajectories of Disease Progression with Irregularly-Sampled Longitudinal Medical Images
Yale University（耶鲁大学）；University of California, San Francisco（加州大学旧金山分校）；Mila - Quebec AI Institute（魁北克AI研究所）；Université de Montréal（蒙特利尔大学）；McGill University（麦吉尔大学）；Northern California Retina Vitreous Associates（北加州视网膜与玻璃体协会）
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…
Uncovering the heterogeneity in the disease progression of Alzheimer's is a key factor to disease understanding and treatment development, so that interventions can be tailored to target the subgroups that will benefit most from the treatment, which is an important goal of precision medicine. However, in practice, one top methodological challenge hindering the heterogeneity investigation is that the true subgroup membership of each individual is often unknown. In this article, we aim to identify latent subgroups of individuals who share a common disorder progress over time, to predict latent s…
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…
McGovern Institute for Brain Research, Massachusetts Institute of Technology（麻省理工学院麦戈文脑研究所）；Complutense University of Madrid（马德里康普顿斯大学）；Harvard Medical School（哈佛医学院）
Characterizing the subtle changes of functional brain networks associated with the pathological cascade of Alzheimer's disease (AD) is important for early diagnosis and prediction of disease progression prior to clinical symptoms. We developed a new deep learning method, termed multiple graph Gaussian embedding model (MG2G), which can learn highly informative network features by mapping high-dimensional resting-state brain networks into a low-dimensional latent space. These latent distribution-based embeddings enable a quantitative characterization of subtle and heterogeneous brain connectivit…
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…
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…
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））
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…
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 …
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）
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…
PROMISE-AD: Progression-aware Multi-horizon Survival Estimation for Alzheimer's Disease Progression and Dynamic Tracking
Department of Radiology and Biomedical Imaging, Yale School of Medicine（放射科与生物医学成像系，耶鲁医学院）；Department of Radiology Oncology, Wake Forest University School of Medicine（放射肿瘤科，沃杰福大学医学院）；Department of Applied Mathematics & Statistics and Department of Computer Science, Stony Brook University（应用数学与统计系和计算机科学系，史泰文布鲁克大学）
Flexible Multimodal Neuroimaging Fusion for Alzheimer's Disease Progression Prediction
Department of Computer Science and Engineering（计算机科学与工程系）；Department of Biomedical Informatics（生物医学信息学系）；Department of Neurology（神经病学系）；Translational Data Analytics Institute（转化数据分析研究所）
Northwestern University（西北大学）；University of Florida（佛罗里达大学）；Weill Cornell Medicine（威尔康奈尔医学院）；Mayo Clinic（梅奥诊所）
Objective: We develop a deep learning framework based on the pre-trained Bidirectional Encoder Representations from Transformers (BERT) model using unstructured clinical notes from electronic health records (EHRs) to predict the risk of disease progression from Mild Cognitive Impairment (MCI) to Alzheimer's Disease (AD). Materials and Methods: We identified 3657 patients diagnosed with MCI together with their progress notes from Northwestern Medicine Enterprise Data Warehouse (NMEDW) between 2000-2020. The progress notes no later than the first MCI diagnosis were used for the prediction. We fi…
Biomediq A/S（Biomediq公司）；Cerebriu A/S（Cerebriu公司）；University of Copenhagen（哥本哈根大学）；University College London（伦敦大学学院）；King’s College London（伦敦国王学院）
Disease progression modeling (DPM) using longitudinal data is a challenging machine learning task. Existing DPM algorithms neglect temporal dependencies among measurements, make parametric assumptions about biomarker trajectories, do not model multiple biomarkers jointly, and need an alignment of 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 hinders the application of standard RNNs and requires a pre-processing step such as imputation of the missing values…
Alzheimer's disease (AD) is known as one of the major causes of dementia and is characterized by slow progression over several years, with no treatments or available medicines. In this regard, there have been efforts to identify the risk of developing AD in its earliest time. While many of the previous works considered cross-sectional analysis, more recent studies have focused on the diagnosis and prognosis of AD with longitudinal or time series data in a way of disease progression modeling (DPM). Under the same problem settings, in this work, we propose a novel computational framework that ca…
Multi-Task Learning with Feature-Similarity Laplacian Graphs for Predicting Alzheimer's Disease Progression
School of Software（软件学院）；Yunnan University（云南大学）；Department of Computer Science（计算机科学系）；The University of Sheffield（谢菲尔德大学）；Department of Computing（计算系）；Xi’an JiaoTong-Liverpool University（西安交通大学利物浦大学）；School of Medical Technology（医学技术学院）；Beijing Institute of Technology（北京理工大学）
Identification of Causal Relationship between Amyloid-beta Accumulation and Alzheimer's Disease Progression via Counterfactual Inference
University of Georgia（佐治亚大学）；Beijing Normal University（北京师范大学）；The University of Texas at Arlington（德克萨斯大学阿灵顿分校）；Massachusetts General Hospital（麻省总医院）；Harvard Medical School（哈佛医学院）；Brigham and Women’s Hospital（布莱根妇女医院）；Shanghai Jiao Tong University（上海交通大学）；The University of Virginia（弗吉尼亚大学）
Platform of Bioinformatics (PBI), University Lausanne Hospital (CHUV) and Faculty of Biology and Medicine (FBM), University of Lausanne (UNIL)（生物信息平台（PBI）、日内瓦大学医院（CHUV）和生物医学学院（FBM）、日内瓦大学（UNIL））；PBI, CHUV and FBM, UNIL（PBI、CHUV和FBM、UNIL）；Department of Biomedical Engineering, University of Basel（生物医学工程系、巴塞尔大学）；Roche Diagnostics International Ltd.（罗氏诊断国际有限公司）；F. Hoffmann - La Roche Ltd., Roche Information Solutions（F. Hoffmann-La Roche有限公司、罗氏信息解决方案）
Longitudinal Bayesian Learning of Continuous Disease Position across the Alzheimer's Disease Continuum
University of Texas Rio Grande Valley（德克萨斯大学里奥格兰德河谷分校）；University of Pittsburgh（匹兹堡大学）；Eli and Lilly Company（礼来公司）；Washington University in St. Louis（圣路易斯华盛顿大学）
Massachusetts Institute of Technology（麻省理工学院）；Imperial College London（伦敦帝国理工学院）
In this paper, we introduce the use of a personalized Gaussian Process model (pGP) to predict per-patient changes in ADAS-Cog13 -- a significant predictor of Alzheimer's Disease (AD) in the cognitive domain -- using data from each patient's previous visits, and testing on future (held-out) data. We start by learning a population-level model using multi-modal data from previously seen patients using a base Gaussian Process (GP) regression. The personalized GP (pGP) is formed by adapting the base GP sequentially over time to a new (target) patient using domain adaptive GPs. We extend this person…
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…
Cornell（康奈尔大学）；Electrical and Computer Eng, Cornell（康奈尔大学电气与计算机工程学院）
In this work, we consider the problem of predicting the course of a progressive disease, such as cancer or Alzheimer's. Progressive diseases often start with mild symptoms that might precede a diagnosis, and each patient follows their own trajectory. Patient trajectories exhibit wild variability, which can be associated with many factors such as genotype, age, or sex. An additional layer of complexity is that, in real life, the amount and type of data available for each patient can differ significantly. For example, for one patient we might have no prior history, whereas for another patient we…
Alzheimer's Disease (AD) is a progressive neurodegenerative disease and the leading cause of dementia. Early diagnosis is critical for patients to benefit from potential intervention and treatment. The retina has been hypothesized as a diagnostic site for AD detection owing to its anatomical connection with the brain. Developed AI models for this purpose have yet to provide a rational explanation about the decision and neither infer the stage of disease's progression. Along this direction, we propose a novel model-agnostic explainable-AI framework, called Granular Neuron-level Explainer (LAVA)…
Artificial Intelligence for Personalized Prediction of Alzheimer's Disease Progression: A Survey of Methods, Data Challenges, and Future Directions
Department of Industrial Engineering and Management Systems University of Central Florida（工业工程与管理系统系 佛罗里达中央大学）；Institute for Simulation and Training University of Central Florida（模拟与培训研究所 佛罗里达中央大学）；Department of Internal Medicine University of Central Florida（内科医学系 佛罗里达中央大学）；Department of Statistics and Data Science University of Central Florida（统计学与数据科学系 佛罗里达中央大学）
