Deep Learning for Multiclass Classification, Predictive Modeling and Segmentation of Disease Prone Regions in Alzheimer’s Disease

One of the challenges facing accurate diagnosis and prognosis of Alzheimer’s Disease (AD) is identifying the subtle changes that define the early onset of the disease. This dissertation investigates three of the main challenges confronted when such subtle changes are to be identified in the most meaningful way. These are (1) the missing data challenge, (2) longitudinal modeling of disease progression, and (3) the segmentation and volumetric calculation of disease-prone brain areas in medical images. The scarcity of sufficient data compounded by the missing data challenge in many longitudinal samples exacerbates the problem as we seek statistical meaningfulness in multiclass classification and regression analysis. Although there are many participants in the AD Neuroimaging Initiative (ADNI) study, many of the observations have a lot of missing features which often lead to the exclusion of potentially valuable data points that could add significant meaning in many ongoing experiments. Motivated by the necessity of examining all participants, even those with missing tests or imaging modalities, multiple techniques of handling missing data in this domain have been explored. Specific attention was drawn to the Gradient Boosting (GB) algorithm which has an inherent capability of addressing missing values. Prior to applying state-of-the-art classifiers such as Support Vector Machine (SVM) and Random Forest (RF), the impact of imputing data in common datasets with numerical techniques has been also investigated and compared with the GB algorithm. Furthermore, to discriminate AD subjects from healthy control individuals, and Mild Cognitive Impairment (MCI), longitudinal multimodal heterogeneous data was modeled using recurring neural networks (RNNs). In the segmentation and volumetric calculation challenge, this dissertation places its focus on one of the most relevant disease-prone areas in many neurological and neurodegenerative diseases, the hippocampus region. Changes in hippocampus shape and volume are considered significant biomarkers for AD diagnosis and prognosis. Thus, a two-stage model based on integrating the Vision Transformer and Convolutional Neural Network (CNN) is developed to automatically locate, segment, and estimate the hippocampus volume from the brain 3D MRI. The proposed architecture was trained and tested on a dataset containing 195 brain MRIs from the 2019 Medical Segmentation Decathlon Challenge against the manually segmented regions provided therein and was deployed on 326 MRI from our own data collected through Mount Sinai Medical Center as part of the 1Florida Alzheimer Disease Research Center (ADRC)

View-aligned hypergraph learning for Alzheimer’s disease diagnosis with incomplete multi-modality data

AbstractEffectively utilizing incomplete multi-modality data for the diagnosis of Alzheimer's disease (AD) and its prodrome (i.e., mild cognitive impairment, MCI) remains an active area of research. Several multi-view learning methods have been recently developed for AD/MCI diagnosis by using incomplete multi-modality data, with each view corresponding to a specific modality or a combination of several modalities. However, existing methods usually ignore the underlying coherence among views, which may lead to sub-optimal learning performance. In this paper, we propose a view-aligned hypergraph learning (VAHL) method to explicitly model the coherence among views. Specifically, we first divide the original data into several views based on the availability of different modalities and then construct a hypergraph in each view space based on sparse representation. A view-aligned hypergraph classification (VAHC) model is then proposed, by using a view-aligned regularizer to capture coherence among views. We further assemble the class probability scores generated from VAHC, via a multi-view label fusion method for making a final classification decision. We evaluate our method on the baseline ADNI-1 database with 807 subjects and three modalities (i.e., MRI, PET, and CSF). Experimental results demonstrate that our method outperforms state-of-the-art methods that use incomplete multi-modality data for AD/MCI diagnosis

Diagnosing Alzheimer's Disease using Early-Late Multimodal Data Fusion with Jacobian Maps

Alzheimer's disease (AD) is a prevalent and debilitating neurodegenerative disorder impacting a large aging population. Detecting AD in all its presymptomatic and symptomatic stages is crucial for early intervention and treatment. An active research direction is to explore machine learning methods that harness multimodal data fusion to outperform human inspection of medical scans. However, existing multimodal fusion models have limitations, including redundant computation, complex architecture, and simplistic handling of missing data. Moreover, the preprocessing pipelines of medical scans remain inadequately detailed and are seldom optimized for individual subjects. In this paper, we propose an efficient early-late fusion (ELF) approach, which leverages a convolutional neural network for automated feature extraction and random forests for their competitive performance on small datasets. Additionally, we introduce a robust preprocessing pipeline that adapts to the unique characteristics of individual subjects and makes use of whole brain images rather than slices or patches. Moreover, to tackle the challenge of detecting subtle changes in brain volume, we transform images into the Jacobian domain (JD) to enhance both accuracy and robustness in our classification. Using MRI and CT images from the OASIS-3 dataset, our experiments demonstrate the effectiveness of the ELF approach in classifying AD into four stages with an accuracy of 97.19%.Comment: To be published in Proceedings of 2023 IEEE Healthcom, December 202

Imaging biomarkers extraction and classification for Prion disease

Prion diseases are a group of rare neurodegenerative conditions characterised by a high rate of progression and highly heterogeneous phenotypes. Whilst the most common form of prion disease occurs sporadically (sporadic Creutzfeldt-Jakob disease, sCJD), other forms are caused by inheritance of prion protein gene mutations or exposure to prions. To date, there are no accurate imaging biomarkers that can be used to predict the future diagnosis of a subject or to quantify the progression of symptoms over time. Besides, CJD is commonly mistaken for other forms of dementia. Due to the large heterogeneity of phenotypes of prion disease and the lack of a consistent spatial pattern of disease progression, the approaches used to study other types of neurodegenerative diseases are not satisfactory to capture the progression of the human form of prion disease. Using a tailored framework, I extracted quantitative imaging biomarkers for characterisation of patients with Prion diseases. Following the extraction of patient-specific imaging biomarkers from multiple images, I implemented a Gaussian Process approach to correlated symptoms with disease types and stages. The model was used on three different tasks: diagnosis, differential diagnosis and stratification, addressing an unmet need to automatically identify patients with or at risk of developing Prion disease. The work presented in this thesis has been extensively validated in a unique Prion disease cohort, comprising both the inherited and sporadic forms of the disease. The model has shown to be effective in the prediction of this illness. Furthermore, this approach may have used in other disorders with heterogeneous imaging features, being an added value for the understanding of neurodegenerative diseases. Lastly, given the rarity of this disease, I also addressed the issue of missing data and the limitations raised by it. Overall, this work presents progress towards modelling of Prion diseases and which computational methodologies are potentially suitable for its characterisation

Novel Statistical Learning Methods for Multi-Modality Heterogeneous Data Fusion in Health Care Applications

abstract: With the development of computer and sensing technology, rich datasets have become available in many fields such as health care, manufacturing, transportation, just to name a few. Also, data come from multiple heterogeneous sources or modalities. This is a common phenomenon in health care systems. While multi-modality data fusion is a promising research area, there are several special challenges in health care applications. (1) The integration of biological and statistical model is a big challenge; (2) It is commonplace that data from various modalities is not available for every patient due to cost, accessibility, and other reasons. This results in a special missing data structure in which different modalities may be missed in “blocks”. Therefore, how to train a predictive model using such a dataset poses a significant challenge to statistical learning. (3) It is well known that different modality data may contain different aspects of information about the response. The current studies cannot afford to solve this problem. My dissertation includes new statistical learning model development to address each of the aforementioned challenges as well as application case studies using real health care datasets, included in three chapters (Chapter 2, 3, and 4), respectively. Collectively, it is expected that my dissertation could provide a new sets of statistical learning models, algorithms, and theory contributed to multi-modality heterogeneous data fusion driven by the unique challenges in this area. Also, application of these new methods to important medical problems using real-world datasets is expected to provide solutions to these problems, and therefore contributing to the application domains.Dissertation/ThesisDoctoral Dissertation Industrial Engineering 201

Multi-Task Linear Programming Discriminant Analysis for the Identification of Progressive MCI Individuals

Accurately identifying mild cognitive impairment (MCI) individuals who will progress to Alzheimer's disease (AD) is very important for making early interventions. Many classification methods focus on integrating multiple imaging modalities such as magnetic resonance imaging (MRI) and fluorodeoxyglucose positron emission tomography (FDG-PET). However, the main challenge for MCI classification using multiple imaging modalities is the existence of a lot of missing data in many subjects. For example, in the Alzheimer's Disease Neuroimaging Initiative (ADNI) study, almost half of the subjects do not have PET images. In this paper, we propose a new and flexible binary classification method, namely Multi-task Linear Programming Discriminant (MLPD) analysis, for the incomplete multi-source feature learning. Specifically, we decompose the classification problem into different classification tasks, i.e., one for each combination of available data sources. To solve all different classification tasks jointly, our proposed MLPD method links them together by constraining them to achieve the similar estimated mean difference between the two classes (under classification) for those shared features. Compared with the state-of-the-art incomplete Multi-Source Feature (iMSF) learning method, instead of constraining different classification tasks to choose a common feature subset for those shared features, MLPD can flexibly and adaptively choose different feature subsets for different classification tasks. Furthermore, our proposed MLPD method can be efficiently implemented by linear programming. To validate our MLPD method, we perform experiments on the ADNI baseline dataset with the incomplete MRI and PET images from 167 progressive MCI (pMCI) subjects and 226 stable MCI (sMCI) subjects. We further compared our method with the iMSF method (using incomplete MRI and PET images) and also the single-task classification method (using only MRI or only subjects with both MRI and PET images). Experimental results show very promising performance of our proposed MLPD method

Combining Multi-Task Learning and Multi-Channel Variational Auto-Encoders to Exploit Datasets with Missing Observations -Application to Multi-Modal Neuroimaging Studies in Dementia

The joint modeling of neuroimaging data across multiple datasets requires to consistently analyze high-dimensional and heterogeneous information in presence of often non-overlapping sets of views across data samples (e.g. imaging data, clinical scores, biological measurements). This analysis is associated with the problem of missing information across datasets, which can happen in two forms: missing at random (MAR), when the absence of a view is unpredictable and does not depend on the dataset (e.g. due to data corruption); missing not at random (MNAR), when a specific view is absent by design for a specific dataset. In order to take advantage of the increased variability and sample size when pooling together observations from many cohorts and at the same time cope with the ubiquitous problem of missing information, we propose here a multi-task generative latent-variable model where the common variability across datasets stems from the estimation of a shared latent representation across views. Our formulation allows to retrieve a consistent latent representation common to all views and datasets, even in the presence of missing information. Simulations on synthetic data show that our method is able to identify a common latent representation of multi-view datasets, even when the compatibility across datasets is minimal. When jointly analyzing multi-modal neuroimaging and clinical data from real independent dementia studies, our model is able to mitigate the absence of modalities without having to discard any available information. Moreover, the common latent representation inferred with our model can be used to define robust classifiers gathering the combined information across different datasets. To conclude, both on synthetic and real data experiments, our model compared favorably to state of the art benchmark methods, providing a more powerful exploitation of multi-modal observations with missing views

Machine Learning for Multiclass Classification and Prediction of Alzheimer\u27s Disease

Alzheimer\u27s disease (AD) is an irreversible neurodegenerative disorder and a common form of dementia. This research aims to develop machine learning algorithms that diagnose and predict the progression of AD from multimodal heterogonous biomarkers with a focus placed on the early diagnosis. To meet this goal, several machine learning-based methods with their unique characteristics for feature extraction and automated classification, prediction, and visualization have been developed to discern subtle progression trends and predict the trajectory of disease progression. The methodology envisioned aims to enhance both the multiclass classification accuracy and prediction outcomes by effectively modeling the interplay between the multimodal biomarkers, handle the missing data challenge, and adequately extract all the relevant features that will be fed into the machine learning framework, all in order to understand the subtle changes that happen in the different stages of the disease. This research will also investigate the notion of multitasking to discover how the two processes of multiclass classification and prediction relate to one another in terms of the features they share and whether they could learn from one another for optimizing multiclass classification and prediction accuracy. This research work also delves into predicting cognitive scores of specific tests over time, using multimodal longitudinal data. The intent is to augment our prospects for analyzing the interplay between the different multimodal features used in the input space to the predicted cognitive scores. Moreover, the power of modality fusion, kernelization, and tensorization have also been investigated to efficiently extract important features hidden in the lower-dimensional feature space without being distracted by those deemed as irrelevant. With the adage that a picture is worth a thousand words, this dissertation introduces a unique color-coded visualization system with a fully integrated machine learning model for the enhanced diagnosis and prognosis of Alzheimer\u27s disease. The incentive here is to show that through visualization, the challenges imposed by both the variability and interrelatedness of the multimodal features could be overcome. Ultimately, this form of visualization via machine learning informs on the challenges faced with multiclass classification and adds insight into the decision-making process for a diagnosis and prognosis