Gene-SGAN: a method for discovering disease subtypes with imaging and genetic signatures via multi-view weakly-supervised deep clustering

Disease heterogeneity has been a critical challenge for precision diagnosis and treatment, especially in neurologic and neuropsychiatric diseases. Many diseases can display multiple distinct brain phenotypes across individuals, potentially reflecting disease subtypes that can be captured using MRI and machine learning methods. However, biological interpretability and treatment relevance are limited if the derived subtypes are not associated with genetic drivers or susceptibility factors. Herein, we describe Gene-SGAN - a multi-view, weakly-supervised deep clustering method - which dissects disease heterogeneity by jointly considering phenotypic and genetic data, thereby conferring genetic correlations to the disease subtypes and associated endophenotypic signatures. We first validate the generalizability, interpretability, and robustness of Gene-SGAN in semi-synthetic experiments. We then demonstrate its application to real multi-site datasets from 28,858 individuals, deriving subtypes of Alzheimer's disease and brain endophenotypes associated with hypertension, from MRI and SNP data. Derived brain phenotypes displayed significant differences in neuroanatomical patterns, genetic determinants, biological and clinical biomarkers, indicating potentially distinct underlying neuropathologic processes, genetic drivers, and susceptibility factors. Overall, Gene-SGAN is broadly applicable to disease subtyping and endophenotype discovery, and is herein tested on disease-related, genetically-driven neuroimaging phenotypes

Integrated Graph Theoretic, Radiomics, and Deep Learning Framework for Personalized Clinical Diagnosis, Prognosis, and Treatment Response Assessment of Body Tumors

Purpose: A new paradigm is beginning to emerge in radiology with the advent of increased computational capabilities and algorithms. The future of radiological reading rooms is heading towards a unique collaboration between computer scientists and radiologists. The goal of computational radiology is to probe the underlying tissue using advanced algorithms and imaging parameters and produce a personalized diagnosis that can be correlated to pathology. This thesis presents a complete computational radiology framework (I GRAD) for personalized clinical diagnosis, prognosis and treatment planning using an integration of graph theory, radiomics, and deep learning. Methods: There are three major components of the I GRAD framework–image segmentation, feature extraction, and clinical decision support. Image Segmentation: I developed the multiparametric deep learning (MPDL) tissue signature model for segmentation of normal and abnormal tissue from multiparametric (mp) radiological images. The segmentation MPDL network was constructed from stacked sparse autoencoders (SSAE) with five hidden layers. The MPDL network parameters were optimized using k-fold cross-validation. In addition, the MPDL segmentation network was tested on an independent dataset. Feature Extraction: I developed the radiomic feature mapping (RFM) and contribution scattergram (CSg) methods for characterization of spatial and inter-parametric relationships in multiparametric imaging datasets. The radiomic feature maps were created by filtering radiological images with first and second order statistical texture filters followed by the development of standardized features for radiological correlation to biology and clinical decision support. The contribution scattergram was constructed to visualize and understand the inter-parametric relationships of the breast MRI as a complex network. This multiparametric imaging complex network was modeled using manifold learning and evaluated using graph theoretic analysis. Feature Integration: The different clinical and radiological features extracted from multiparametric radiological images and clinical records were integrated using a hybrid multiview manifold learning technique termed the Informatics Radiomics Integration System (IRIS). IRIS uses hierarchical clustering in combination with manifold learning to visualize the high-dimensional patient space on a two-dimensional heatmap. The heatmap highlights the similarity and dissimilarity between different patients and variables. Results: All the algorithms and techniques presented in this dissertation were developed and validated using breast cancer as a model for diagnosis and prognosis using multiparametric breast magnetic resonance imaging (MRI). The deep learning MPDL method demonstrated excellent dice similarity of 0.87±0.05 and 0.84±0.07 for segmentation of lesions on malignant and benign breast patients, respectively. Furthermore, each of the methods, MPDL, RFM, and CSg demonstrated excellent results for breast cancer diagnosis with area under the receiver (AUC) operating characteristic (ROC) curve of 0.85, 0.91, and 0.87, respectively. Furthermore, IRIS classified patients with low risk of breast cancer recurrence from patients with medium and high risk with an AUC of 0.93 compared to OncotypeDX, a 21 gene assay for breast cancer recurrence. Conclusion: By integrating advanced computer science methods into the radiological setting, the I-GRAD framework presented in this thesis can be used to model radiological imaging data in combination with clinical and histopathological data and produce new tools for personalized diagnosis, prognosis or treatment planning by physicians

Deep Learning in Breast Cancer Imaging: A Decade of Progress and Future Directions

Breast cancer has reached the highest incidence rate worldwide among all malignancies since 2020. Breast imaging plays a significant role in early diagnosis and intervention to improve the outcome of breast cancer patients. In the past decade, deep learning has shown remarkable progress in breast cancer imaging analysis, holding great promise in interpreting the rich information and complex context of breast imaging modalities. Considering the rapid improvement in the deep learning technology and the increasing severity of breast cancer, it is critical to summarize past progress and identify future challenges to be addressed. In this paper, we provide an extensive survey of deep learning-based breast cancer imaging research, covering studies on mammogram, ultrasound, magnetic resonance imaging, and digital pathology images over the past decade. The major deep learning methods, publicly available datasets, and applications on imaging-based screening, diagnosis, treatment response prediction, and prognosis are described in detail. Drawn from the findings of this survey, we present a comprehensive discussion of the challenges and potential avenues for future research in deep learning-based breast cancer imaging.Comment: Survey, 41 page

Recent publications from the Alzheimer's Disease Neuroimaging Initiative: Reviewing progress toward improved AD clinical trials

INTRODUCTION: The Alzheimer's Disease Neuroimaging Initiative (ADNI) has continued development and standardization of methodologies for biomarkers and has provided an increased depth and breadth of data available to qualified researchers. This review summarizes the over 400 publications using ADNI data during 2014 and 2015. METHODS: We used standard searches to find publications using ADNI data. RESULTS: (1) Structural and functional changes, including subtle changes to hippocampal shape and texture, atrophy in areas outside of hippocampus, and disruption to functional networks, are detectable in presymptomatic subjects before hippocampal atrophy; (2) In subjects with abnormal β-amyloid deposition (Aβ+), biomarkers become abnormal in the order predicted by the amyloid cascade hypothesis; (3) Cognitive decline is more closely linked to tau than Aβ deposition; (4) Cerebrovascular risk factors may interact with Aβ to increase white-matter (WM) abnormalities which may accelerate Alzheimer's disease (AD) progression in conjunction with tau abnormalities; (5) Different patterns of atrophy are associated with impairment of memory and executive function and may underlie psychiatric symptoms; (6) Structural, functional, and metabolic network connectivities are disrupted as AD progresses. Models of prion-like spreading of Aβ pathology along WM tracts predict known patterns of cortical Aβ deposition and declines in glucose metabolism; (7) New AD risk and protective gene loci have been identified using biologically informed approaches; (8) Cognitively normal and mild cognitive impairment (MCI) subjects are heterogeneous and include groups typified not only by "classic" AD pathology but also by normal biomarkers, accelerated decline, and suspected non-Alzheimer's pathology; (9) Selection of subjects at risk of imminent decline on the basis of one or more pathologies improves the power of clinical trials; (10) Sensitivity of cognitive outcome measures to early changes in cognition has been improved and surrogate outcome measures using longitudinal structural magnetic resonance imaging may further reduce clinical trial cost and duration; (11) Advances in machine learning techniques such as neural networks have improved diagnostic and prognostic accuracy especially in challenges involving MCI subjects; and (12) Network connectivity measures and genetic variants show promise in multimodal classification and some classifiers using single modalities are rivaling multimodal classifiers. DISCUSSION: Taken together, these studies fundamentally deepen our understanding of AD progression and its underlying genetic basis, which in turn informs and improves clinical trial desig

Dataset shift in land-use classification for optical remote sensing

Multimodal dataset shifts consisting of both concept and covariate shifts are addressed in this study to improve texture-based land-use classification accuracy for optical panchromatic and multispectral remote sensing. Multitemporal and multisensor variances between train and test data are caused by atmospheric, phenological, sensor, illumination and viewing geometry differences, which cause supervised classification inaccuracies. The first dataset shift reduction strategy involves input modification through shadow removal before feature extraction with gray-level co-occurrence matrix and local binary pattern features. Components of a Rayleigh quotient-based manifold alignment framework is investigated to reduce multimodal dataset shift at the input level of the classifier through unsupervised classification, followed by manifold matching to transfer classification labels by finding across-domain cluster correspondences. The ability of weighted hierarchical agglomerative clustering to partition poorly separated feature spaces is explored and weight-generalized internal validation is used for unsupervised cardinality determination. Manifold matching solves the Hungarian algorithm with a cost matrix featuring geometric similarity measurements that assume the preservation of intrinsic structure across the dataset shift. Local neighborhood geometric co-occurrence frequency information is recovered and a novel integration thereof is shown to improve matching accuracy. A final strategy for addressing multimodal dataset shift is multiscale feature learning, which is used within a convolutional neural network to obtain optimal hierarchical feature representations instead of engineered texture features that may be sub-optimal. Feature learning is shown to produce features that are robust against multimodal acquisition differences in a benchmark land-use classification dataset. A novel multiscale input strategy is proposed for an optimized convolutional neural network that improves classification accuracy to a competitive level for the UC Merced benchmark dataset and outperforms single-scale input methods. All the proposed strategies for addressing multimodal dataset shift in land-use image classification have resulted in significant accuracy improvements for various multitemporal and multimodal datasets.Thesis (PhD)--University of Pretoria, 2016.National Research Foundation (NRF)University of Pretoria (UP)Electrical, Electronic and Computer EngineeringPhDUnrestricte

An overview of clustering methods with guidelines for application in mental health research

Cluster analyzes have been widely used in mental health research to decompose inter-individual heterogeneity by identifying more homogeneous subgroups of individuals. However, despite advances in new algorithms and increasing popularity, there is little guidance on model choice, analytical framework and reporting requirements. In this paper, we aimed to address this gap by introducing the philosophy, design, advantages/disadvantages and implementation of major algorithms that are particularly relevant in mental health research. Extensions of basic models, such as kernel methods, deep learning, semi-supervised clustering, and clustering ensembles are subsequently introduced. How to choose algorithms to address common issues as well as methods for pre-clustering data processing, clustering evaluation and validation are then discussed. Importantly, we also provide general guidance on clustering workflow and reporting requirements. To facilitate the implementation of different algorithms, we provide information on R functions and librarie