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Structural and mechanical differences between cancerous and healthy tissue give rise to variations in macroscopic properties such as visual appearance and elastic modulus that show promise as signatures for early cancer detection. Atomic force microscopy (AFM) has been used to measure significant differences in stiffness between cancerous and healthy cells owing to its high force sensitivity and spatial resolution, however due to absorption and scattering of light, it is often challenging to accurately locate where AFM measurements have been made on a bulk tissue sample. In this paper we describe an image registration method that localizes AFM elastic stiffness measurements with high-resolution images of haematoxylin and eosin (H&E)-stained tissue to within 1.5 microns. Color RGB images are segmented into three structure types (lumen, cells and stroma) by a neural network classifier trained on ground-truth pixel data obtained through k-means clustering in HSV color space. Using the localized stiffness maps and corresponding structural information, a whole-sample stiffness map is generated with a region matching and interpolation algorithm that associates similar structures with measured stiffness values. We present results showing significant differences in stiffness between healthy and cancerous liver tissue and discuss potential applications of this technique.
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Magnetic resonance Fingerprinting (MRF) is a relatively new multi-parametric quantitative imaging method that involves a two-step process: (i) reconstructing a series of time frames from highly-undersampled non-Cartesian spiral k-space data and (ii) pattern matching using the time frames to infer tissue properties (e.g., T1 and T2 relaxation times). In this paper, we introduce a novel end-to-end deep learning framework to seamlessly map the tissue properties directly from spiral k-space MRF data, thereby avoiding time-consuming processing such as the nonuniform fast Fourier transform (NUFFT) and the dictionary-based Fingerprint matching. Our method directly consumes the non-Cartesian k- space data, performs adaptive density compensation, and predicts multiple tissue property maps in one forward pass. Experiments on both 2D and 3D MRF data demonstrate that quantification accuracy comparable to state-of-the-art methods can be accomplished within 0.5 second, which is 1100 to 7700 times faster than the original MRF framework. The proposed method is thus promising for facilitating the adoption of MRF in clinical settings.
Deep learning based analysis of histopathology images shows promise in advancing the understanding of tumor progression, tumor micro-environment, and their underpinning biological processes. So far, these approaches have focused on extracting information associated with annotations. In this work, we ask how much information can be learned from the tissue architecture itself. We present an adversarial learning model to extract feature representations of cancer tissue, without the need for manual annotations. We show that these representations are able to identify a variety of morphological characteristics across three cancer types: Breast, colon, and lung. This is supported by 1) the separation of morphologic characteristics in the latent space; 2) the ability to classify tissue type with logistic regression using latent representations, with an AUC of 0.97 and 85% accuracy, comparable to supervised deep models; 3) the ability to predict the presence of tumor in Whole Slide Images (WSIs) using multiple instance learning (MIL), achieving an AUC of 0.98 and 94% accuracy. Our results show that our model captures distinct phenotypic characteristics of real tissue samples, paving the way for further understanding of tumor progression and tumor micro-environment, and ultimately refining histopathological classification for diagnosis and treatment. The code and pretrained models are available at: https://github.com/AdalbertoCq/Adversarial-learning-of-cancer-tissue-representations
In neuroimaging, MRI tissue properties characterize underlying neurobiology, provide quantitative biomarkers for neurological disease detection and analysis, and can be used to synthesize arbitrary MRI contrasts. Estimating tissue properties from a single scan session using a protocol available on all clinical scanners promises to reduce scan time and cost, enable quantitative analysis in routine clinical scans and provide scan-independent biomarkers of disease. However, existing tissue properties estimation methods - most often $mathbf{T_1}$ relaxation, $mathbf{T_2^*}$ relaxation, and proton density ($mathbf{PD}$) - require data from multiple scan sessions and cannot estimate all properties from a single clinically available MRI protocol such as the multiecho MRI scan. In addition, the widespread use of non-standard acquisition parameters across clinical imaging sites require estimation methods that can generalize across varying scanner parameters. However, existing learning methods are acquisition protocol specific and cannot estimate from heterogenous clinical data from different imaging sites. In this work we propose an unsupervised deep-learning strategy that employs MRI physics to estimate all three tissue properties from a single multiecho MRI scan session, and generalizes across varying acquisition parameters. The proposed strategy optimizes accurate synthesis of new MRI contrasts from estimated latent tissue properties, enabling unsupervised training, we also employ random acquisition parameters during training to achieve acquisition generalization. We provide the first demonstration of estimating all tissue properties from a single multiecho scan session. We demonstrate improved accuracy and generalizability for tissue property estimation and MRI synthesis.
The rapidly emerging field of computational pathology has the potential to enable objective diagnosis, therapeutic response prediction and identification of new morphological features of clinical relevance. However, deep learning-based computational pathology approaches either require manual annotation of gigapixel whole slide images (WSIs) in fully-supervised settings or thousands of WSIs with slide-level labels in a weakly-supervised setting. Moreover, whole slide level computational pathology methods also suffer from domain adaptation and interpretability issues. These challenges have prevented the broad adaptation of computational pathology for clinical and research purposes. Here we present CLAM - Clustering-constrained attention multiple instance learning, an easy-to-use, high-throughput, and interpretable WSI-level processing and learning method that only requires slide-level labels while being data efficient, adaptable and capable of handling multi-class subtyping problems. CLAM is a deep-learning-based weakly-supervised method that uses attention-based learning to automatically identify sub-regions of high diagnostic value in order to accurately classify the whole slide, while also utilizing instance-level clustering over the representative regions identified to constrain and refine the feature space. In three separate analyses, we demonstrate the data efficiency and adaptability of CLAM and its superior performance over standard weakly-supervised classification. We demonstrate that CLAM models are interpretable and can be used to identify well-known and new morphological features. We further show that models trained using CLAM are adaptable to independent test cohorts, cell phone microscopy images, and biopsies. CLAM is a general-purpose and adaptable method that can be used for a variety of different computational pathology tasks in both clinical and research settings.
Deep Learning-based computational pathology algorithms have demonstrated profound ability to excel in a wide array of tasks that range from characterization of well known morphological phenotypes to predicting non-human-identifiable features from histology such as molecular alterations. However, the development of robust, adaptable, and accurate deep learning-based models often rely on the collection and time-costly curation large high-quality annotated training data that should ideally come from diverse sources and patient populations to cater for the heterogeneity that exists in such datasets. Multi-centric and collaborative integration of medical data across multiple institutions can naturally help overcome this challenge and boost the model performance but is limited by privacy concerns amongst other difficulties that may arise in the complex data sharing process as models scale towards using hundreds of thousands of gigapixel whole slide images. In this paper, we introduce privacy-preserving federated learning for gigapixel whole slide images in computational pathology using weakly-supervised attention multiple instance learning and differential privacy. We evaluated our approach on two different diagnostic problems using thousands of histology whole slide images with only slide-level labels. Additionally, we present a weakly-supervised learning framework for survival prediction and patient stratification from whole slide images and demonstrate its effectiveness in a federated setting. Our results show that using federated learning, we can effectively develop accurate weakly supervised deep learning models from distributed data silos without direct data sharing and its associated complexities, while also preserving differential privacy using randomized noise generation.
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