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Register a new userData Efficient and Weakly Supervised Computational Pathology on Whole Slide Images
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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.
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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.
The application of deep learning to pathology assumes the existence of digital whole slide images of pathology slides. However, slide digitization is bottlenecked by the high cost of precise motor stages in slide scanners that are needed for position information used for slide stitching. We propose GloFlow, a two-stage method for creating a whole slide image using optical flow-based image registration with global alignment using a computationally tractable graph-pruning approach. In the first stage, we train an optical flow predictor to predict pairwise translations between successive video frames to approximate a stitch. In the second stage, this approximate stitch is used to create a neighborhood graph to produce a corrected stitch. On a simulated dataset of video scans of WSIs, we find that our method outperforms known approaches to slide-stitching, and stitches WSIs resembling those produced by slide scanners.
Ovarian cancer is the most lethal cancer of the female reproductive organs. There are $5$ major histological subtypes of epithelial ovarian cancer, each with distinct morphological, genetic, and clinical features. Currently, these histotypes are determined by a pathologists microscopic examination of tumor whole-slide images (WSI). This process has been hampered by poor inter-observer agreement (Cohens kappa $0.54$-$0.67$). We utilized a textit{two}-stage deep transfer learning algorithm based on convolutional neural networks (CNN) and progressive resizing for automatic classification of epithelial ovarian carcinoma WSIs. The proposed algorithm achieved a mean accuracy of $87.54%$ and Cohens kappa of $0.8106$ in the slide-level classification of $305$ WSIs; performing better than a standard CNN and pathologists without gynecology-specific training.
One of the challenges facing the adoption of digital pathology workflows for clinical use is the need for automated quality control. As the scanners sometimes determine focus inaccurately, the resultant image blur deteriorates the scanned slide to the point of being unusable. Also, the scanned slide images tend to be extremely large when scanned at greater or equal 20X image resolution. Hence, for digital pathology to be clinically useful, it is necessary to use computational tools to quickly and accurately quantify the image focus quality and determine whether an image needs to be re-scanned. We propose a no-reference focus quality assessment metric specifically for digital pathology images, that operates by using a sum of even-derivative filter bases to synthesize a human visual system-like kernel, which is modeled as the inverse of the lens point spread function. This kernel is then applied to a digital pathology image to modify high-frequency image information deteriorated by the scanners optics and quantify the focus quality at the patch level. We show in several experiments that our method correlates better with ground-truth $z$-level data than other methods, and is more computationally efficient. We also extend our method to generate a local slide-level focus quality heatmap, which can be used for automated slide quality control, and demonstrate the utility of our method for clinical scan quality control by comparison with subjective slide quality scores.
Obtaining a large amount of labeled data in medical imaging is laborious and time-consuming, especially for histopathology. However, it is much easier and cheaper to get unlabeled data from whole-slide images (WSIs). Semi-supervised learning (SSL) is an effective way to utilize unlabeled data and alleviate the need for labeled data. For this reason, we proposed a framework that employs an SSL method to accurately detect cancerous regions with a novel annotation method called Minimal Point-Based annotation, and then utilize the predicted results with an innovative hybrid loss to train a classification model for subtyping. The annotator only needs to mark a few points and label them are cancer or not in each WSI. Experiments on three significant subtypes of renal cell carcinoma (RCC) proved that the performance of the classifier trained with the Min-Point annotated dataset is comparable to a classifier trained with the segmentation annotated dataset for cancer region detection. And the subtyping model outperforms a model trained with only diagnostic labels by 12% in terms of f1-score for testing WSIs.
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