Analysis of histopathological images is critical in cancer diagnosis and treatment. Due to the huge size of histopathological images and the varied number of imaging records per patient, many existing works analyze the Whole Slide Image (WSI) as a bag in which its patches are instances. However, these approaches are limited to analyzing the patches in a fixed shape, while the malignant lesions can form varied shapes. To address this challenge, in this article we propose a Multi-Instance Multi-Shape Support Vector Machine (MIMSSVM) to analyze the multiple images (instances) jointly where each instance consists of multiple patches in various shapes. In our approach, we can identify the different morphologic abnormalities of nuclei shapes from the multiple images. In addition to the multi-instance multi-shape learning capability, we derive an efficient solution algorithm to optimize the proposed model that scales well to a large number of features. Our experimental results show our new method outperforms the existing SVMs and deep learning models in histopathological classification. The proposed model also identifies the tissue segments in an image exhibiting an indication of an abnormality which provides utility in the early detection of malignant tumors. All these promising experimental results have demonstrated the effectiveness of our new method. We anticipate that our new method is of interest to biomedical engineering communities beyond WSI research and have open sourced the code of our method online. The implementation of our proposed MIMSSVM model is publicly available at https://github.com/hoonseo0409/MIMSSVM .

MOTIVATION: Breast cancer is a type of cancer that develops in breast tissues, and, after skin cancer, it is the most commonly diagnosed cancer in women in the United States. Given that an early diagnosis is imperative to prevent breast cancer progression, many machine learning models have been developed in recent years to automate the histopathological classification of the different types of carcinomas. However, many of them are not scalable to large-scale datasets. RESULTS: In this study, we propose the novel Primal-Dual Multi-Instance Support Vector Machine to determine which tissue segments in an image exhibit an indication of an abnormality. We derive an efficient optimization algorithm for the proposed objective by bypassing the quadratic programming and least-squares problems, which are commonly employed to optimize Support Vector Machine models. The proposed method is computationally efficient, thereby it is scalable to large-scale datasets. We applied our method to the public BreaKHis dataset and achieved promising prediction performance and scalability for histopathological classification. AVAILABILITY AND IMPLEMENTATION: Software is publicly available at: https://1drv.ms/u/s!AiFpD21bgf2wgRLbQq08ixD0SgRD?e=OpqEmY. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Alzheimer’s Disease (AD) is a chronic neurodegenerative disease that causes severe problems in patients’ thinking, memory, and behavior. An early diagnosis is crucial to prevent AD progression; to this end, many algorithmic approaches have recently been proposed to predict cognitive decline. However, these predictive models often fail to integrate heterogeneous genetic and neuroimaging biomarkers and struggle to handle missing data. In this work we propose a novel objective function and an associated optimization algorithm to identify cognitive decline related to AD. Our approach is designed to incorporate dynamic neuroimaging data by way of a participant-specific augmentation combined with multimodal data integration aligned via a regression task. Our approach, in order to incorporate additional side-information, utilizes structured regularization techniques popularized in recent AD literature. Armed with the fixed-length vector representation learned from the multimodal dynamic and static modalities, conventional machine learning methods can be used to predict the clinical outcomes associated with AD. Our experimental results show that the proposed augmentation model improves the prediction performance on cognitive assessment scores for a collection of popular machine learning algorithms. The results of our approach are interpreted to validate existing genetic and neuroimaging biomarkers that have been shown to be predictive of cognitive decline.

Multi-instance learning (MIL) is an area of machine learning that handles data that is organized into sets of instances known as bags. Traditionally, MIL is used in the supervised-learning setting and is able to classify bags which can contain any number of instances. This property allows MIL to be naturally applied to solve the problems in a wide variety of real-world applications from computer vision to healthcare. However, many traditional MIL algorithms do not scale efficiently to large datasets. In this paper we present a novel Primal-Dual Multi-Instance Support Vector Machine (pdMISVM) derivation and implementation that can operate efficiently on large scale data. Our method relies on an algorithm derived using a multi-block variation of the alternating direction method of multipliers (ADMM). The approach presented in this work is able to scale to large-scale data since it avoids iteratively solving quadratic programming problems which are generally used to optimize MIL algorithms based on SVMs. In addition, we modify our derivation to include an additional optimization designed to avoid solving a least-squares problem during our algorithm; this optimization increases the utility of our approach to handle a large number of features as well as bags. Finally, we apply our approach to synthetic and real-world multi-instance datasets to illustrate the scalability, promising predictive performance, and interpretability of our proposed method. We end our discussion with an extension of our approach to handle non-linear decision boundaries. Code and data for our methods are available online at: https://github.com/minds-mines/pdMISVM.jl.

Nonnegative Matrix Factorization (NMF) is broadly used to determine class membership in a variety of clustering applications. From movie recommendations and image clustering to visual feature extractions, NMF has applications to solve a large number of knowledge discovery and data mining problems. Traditional optimization methods, such as the Multiplicative Updating Algorithm (MUA), solves the NMF problem by utilizing an auxiliary function to ensure that the objective monotonically decreases. Although the objective in MUA converges, there exists no proof to show that the learned matrix factors converge as well. Without this rigorous analysis, the clustering performance and stability of the NMF algorithms cannot be guaranteed. To address this knowledge gap, in this article, we study the factor-bounded NMF problem and provide a solution algorithm with proven convergence by rigorous mathematical analysis, which ensures that both the objective and matrix factors converge. In addition, we show the relationship between MUA and our solution followed by an analysis of the convergence of MUA. Experiments on both toy data and real-world datasets validate the correctness of our proposed method and its utility as an effective clustering algorithm.

The social and financial costs associated with Alzheimer's disease (AD) result in significant burdens on our society. In order to understand the causes of this disease, public-private partnerships such as the Alzheimer's Disease Neuroimaging Initiative (ADNI) release data into the scientific community. These data are organized into various modalities (genetic, brain-imaging, cognitive scores, diagnoses, etc.) for analysis. Many statistical learning approaches used in medical image analysis do not explicitly take advantage of this multimodal data structure. In this work we propose a novel objective function and optimization algorithm that is designed to handle multimodal information for the prediction and analysis of AD. Our approach relies on robust matrix-factorization and row-wise sparsity provided by the ℓ2,1- norm in order to integrate multimodal data provided by the ADNI. These techniques are jointly optimized with a classification task to guide the feature selection in our proposed Task Balanced Multimodal Feature Selection method. Our results, when compared against some widely used machine learning algorithms, show improved balanced accuracies, precision, and Matthew's correlation coefficients for identifying cognitive decline. In addition to the improved prediction performance, our method is able to identify brain and genetic biomarkers that are of interest to the clinical research community. Our experiments validate existing brain biomarkers and single nucleotide polymorphisms located on chromosome 11 and detail novel polymorphisms on chromosome 10 that, to the best of the authors' knowledge, have not previously been reported. We anticipate that our method will be of interest to the greater research community and have released our method's code online.11Code is provided at: https://github.com/minds-mines/TBMFSjl

Alzheimer's Disease (AD) is a progressive memory disorder that causes irreversible cognitive decline. Recently, many statistical learning methods have been presented to predict cognitive declines by using longitudinal imaging data. However, missing records that broadly exist in the longitudinal neuroimaging data have posed a critical challenge for effectively using these data in machine learning models. To tackle this difficulty, in this paper we propose a novel approach to integrate longitudinal (dynamic) phenotypic data and static genetic data to learn a fixed-length biomarker representation using the enrichment learned from the temporal data in multiple imaging modalities. Armed with this enriched biomarker representation, as a fixed-length vector per participant, conventional machine learning models can be used to predict clinical outcomes associated with AD. We have applied our new method on the Alzheimer's Disease Neruoimaging Initiative (ADNI) cohort and achieved promising experimental results that validate its effectiveness.

Alzheimer's disease (AD) is a serious neurodegenerative condition that affects millions of individuals across the world. As the average age of individuals in the United States and the world increases, the prevalence of AD will continue to grow. To address this public health problem, the research community has developed computational approaches to sift through various aspects of clinical data and uncover their insights, among which one of the most challenging problem is to determine the biological mechanisms that cause AD to develop. To study this problem, in this paper we present a novel Joint Multi-Modal Longitudinal Regression and Classification method and show how it can be used to identify the cognitive status of the participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort and the underlying biological mechanisms. By intelligently combining clinical data of various modalities (i.e., genetic information and brain scans) using a variety of regularizations that can identify AD-relevant biomarkers, we perform the regression and classification tasks simultaneously. Because the proposed objective is a non-smooth optimization problem that is difficult to solve in general, we derive an efficient iterative algorithm and rigorously prove its convergence. To validate our new method in predicting the cognitive scores of patients and their clinical diagnosis, we conduct comprehensive experiments on the ADNI cohort. Our promising results demonstrate the benefits and flexibility of the proposed method. We anticipate that our new method is of interest to clinical communities beyond AD research and have open-sourced the code of our method online.11 The code package for the proposed Joint Multi-Modal Longitudinal Regression and Classification model have been made publicly available online at https://github.com/minds-mines/jmmlrc.

Metric Learning, which aims at learning a distance metric for a given data set, plays an important role in measuring the distance or similarity between data objects. Due to its broad usefulness, it has attracted a lot of interest in machine learning and related areas in the past few decades. This paper proposes to learn the distance metric from the side information in the forms of must-links and cannot-links. Given the pairwise constraints, our goal is to learn a Mahalanobis distance that minimizes the ratio of the distances of the data pairs in the must-links to those in the cannot-links. Different from many existing papers that use the traditional squared L2-norm distance, we develop a robust model that is less sensitive to data noise or outliers by using the not-squared L2-norm distance. In our objective, the orthonormal constraint is enforced to avoid degenerate solutions. To solve our objective, we have derived an efficient iterative solution algorithm. We have conducted extensive experiments, which demonstrated the superiority of our method over state-of-the-art.