Hidden Markov models (HMMs) are commonly used for disease progression modeling when the true patient health state is not fully known. Since HMMs typically have multiple local optima, incorporating additional patient covariates can improve parameter estimation and predictive performance. To allow for this, we develop hidden Markov recurrent neural networks (HMRNNs), a special case of recurrent neural networks that combine neural networks' flexibility with HMMs' interpretability. The HMRNN can be reduced to a standard HMM, with an identical likelihood function and parameter interpretations, but it can also combine an HMM with other predictive neural networks that take patient information as input. The HMRNN estimates all parameters simultaneously via gradient descent. Using a dataset of Alzheimer's disease patients, we demonstrate how the HMRNN can combine an HMM with other predictive neural networks to improve disease forecasting and to offer a novel clinical interpretation compared with a standard HMM trained via expectation-maximization.
While a large body of research has formally identified apolipoprotein E (APOE) as a major genetic risk marker for Alzheimer disease, accumulating evidence supports the notion that other risk markers may exist. The traditional Alzheimer-specific signature analysis methods, however, have not been able to make full use of rich protein expression data, especially the interaction between attributes. This paper develops a novel feature selection method to identify pathogenic factors of Alzheimer disease using the proteomic and clinical data. This approach has taken the weights of network nodes as th…
Institute for Applied Computational Science, Harvard John A. Paulson School of Engineering and Applied Sciences（哈佛大学约翰·A·保尔森工程与应用科学学院应用计算科学研究所）
Alzheimer's Disease (AD) ravages the cognitive ability of more than 5 million Americans and creates an enormous strain on the health care system. This paper proposes a machine learning predictive model for AD development without medical imaging and with fewer clinical visits and tests, in hopes of earlier and cheaper diagnoses. That earlier diagnoses could be critical in the effectiveness of any drug or medical treatment to cure this disease. Our model is trained and validated using demographic, biomarker and cognitive test data from two prominent research studies: Alzheimer's Disease Neuroima…
Imperial College London（帝国理工学院）；King’s College London（伦敦国王学院）
Pattern recognition methods using neuroimaging data for the diagnosis of Alzheimer's disease have been the subject of extensive research in recent years. In this paper, we use deep learning methods, and in particular sparse autoencoders and 3D convolutional neural networks, to build an algorithm that can predict the disease status of a patient, based on an MRI scan of the brain. We report on experiments using the ADNI data set involving 2,265 historical scans. We demonstrate that 3D convolutional neural networks outperform several other classifiers reported in the literature and produce state-…
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, …
We develop three efficient approaches for generating visual explanations from 3D convolutional neural networks (3D-CNNs) for Alzheimer's disease classification. One approach conducts sensitivity analysis on hierarchical 3D image segmentation, and the other two visualize network activations on a spatial map. Visual checks and a quantitative localization benchmark indicate that all approaches identify important brain parts for Alzheimer's disease diagnosis. Comparative analysis show that the sensitivity analysis based approach has difficulty handling loosely distributed cerebral cortex, and appr…
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…
Simulators make unique benchmarks for causal effect estimation since they do not rely on unverifiable assumptions or the ability to intervene on real-world systems, but are often too simple to capture important aspects of real applications. We propose a simulator of Alzheimer's disease aimed at modeling intricacies of healthcare data while enabling benchmarking of causal effect and policy estimators. We fit the system to the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset and ground hand-crafted components in results from comparative treatment trials and observational treatment patt…
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…
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…
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…
Univ. Bordeaux（波尔多大学）；CNRS（法国国家科学研究中心）；Bordeaux INP（波尔多国立高等物理、数学与信息技术学院）；Universitat Politècnia de València（瓦伦西亚理工大学）
Alzheimer's disease is the most common dementia leading to an irreversible neurodegenerative process. To date, subject revealed advanced brain structural alterations when the diagnosis is established. Therefore, an earlier diagnosis of this dementia is crucial although it is a challenging task. Recently, many studies have proposed biomarkers to perform early detection of Alzheimer's disease. Some of them have proposed methods based on inter-subject similarity while other approaches have investigated framework using intra-subject variability. In this work, we propose a novel framework combining…
Instituto Superior Técnico, Universidade de Lisboa（里斯本大学高等技术学院）
Most machine learning classifiers give predictions for new examples accurately, yet without indicating how trustworthy predictions are. In the medical domain, this hampers their integration in decision support systems, which could be useful in the clinical practice. We use a supervised learning approach that combines Ensemble learning with Conformal Predictors to predict conversion from Mild Cognitive Impairment to Alzheimer's Disease. Our goal is to enhance the classification performance (Ensemble learning) and complement each prediction with a measure of credibility (Conformal Predictors). O…
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 …
ETH Zurich（苏黎世联邦理工学院）；SIB Swiss Institute of Bioinformatics（瑞士生物信息学研究所）
Alzheimer's disease (AD) is associated with local (e.g. brain tissue atrophy) and global brain changes (loss of cerebral connectivity), which can be detected by high-resolution structural magnetic resonance imaging. Conventionally, these changes and their relation to AD are investigated independently. Here, we introduce a novel, highly-scalable approach that simultaneously captures $\textit{local}$ and $\textit{global}$ changes in the diseased brain. It is based on a neural network architecture that combines patch-based, high-resolution 3D-CNNs with global topological features, evaluating mult…
Deep Learning Approaches with Explainable AI for Differentiating Alzheimer Disease and Mild Cognitive Impairment
School of Mathematical and Natural Sciences（数学与自然科学学院）；Arizona State University（亚利桑那州立大学）；Department of Mathematics（数学系）；Florida Gulf Coast University（佛罗里达海岸大学）；Department of Public Health（公共卫生系）；Julia Jones Matthews School of Population and Public Health（朱莉亚·琼斯·马修斯人口与公共卫生学院）；Texas Tech University Health Sciences Center（德克萨斯农工大学健康科学中心）
Introduction: Alzheimer's disease is a type of dementia in which early diagnosis plays a major rule in the quality of treatment. Among new works in the diagnosis of Alzheimer's disease, there are many of them analyzing the voice stream acoustically, syntactically or both. The mostly used tools to perform these analysis usually include machine learning techniques. Objective: Designing an automatic machine learning based diagnosis system will help in the procedure of early detection. Also, systems, using noninvasive data are preferable. Methods: We used are classification system based on spoken …
Hasso Plattner Institute（哈索·普拉特纳研究所）；Universität Potsdam（波茨坦大学）；Max Delbrück Center for Molecular Medicine（马克斯·德尔布吕克分子医学中心）
For precision medicine and personalized treatment, we need to identify predictive markers of disease. We focus on Alzheimer's disease (AD), where magnetic resonance imaging scans provide information about the disease status. By combining imaging with genome sequencing, we aim at identifying rare genetic markers associated with quantitative traits predicted from convolutional neural networks (CNNs), which traditionally have been derived manually by experts. Kernel-based tests are a powerful tool for associating sets of genetic variants, but how to optimally model rare genetic variants is still …
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…
We propose a method to predict the subject-specific longitudinal progression of brain structures extracted from baseline MRI, and evaluate its performance on Alzheimer's disease data. The disease progression is modeled as a trajectory on a group of diffeomorphisms in the context of large deformation diffeomorphic metric mapping (LDDMM). We first exhibit the limited predictive abilities of geodesic regression extrapolation on this group. Building on the recent concept of parallel curves in shape manifolds, we then introduce a second predictive protocol which personalizes previously learned traj…
New York University（纽约大学）；New York University Langone Medical Center（纽约大学朗格尼医学中心）
Early detection is a crucial goal in the study of Alzheimer's Disease (AD). In this work, we describe several techniques to boost the performance of 3D deep convolutional neural networks (CNNs) trained to detect AD using structural brain MRI scans. Specifically, we provide evidence that (1) instance normalization outperforms batch normalization, (2) early spatial downsampling negatively affects performance, (3) widening the model brings consistent gains while increasing the depth does not, and (4) incorporating age information yields moderate improvement. Together, these insights yield an incr…
