Open and reusable deep learning for pathology with WSInfer and QuPath

The field of digital pathology has seen a proliferation of deep learning models in recent years. Despite substantial progress, it remains rare for other researchers and pathologists to be able to access models published in the literature and apply them to their own images. This is due to difficulties in both sharing and running models. To address these concerns, we introduce WSInfer: a new, open-source software ecosystem designed to make deep learning for pathology more streamlined and accessible. WSInfer comprises three main elements: 1) a Python package and command line tool to efficiently apply patch-based deep learning inference to whole slide images; 2) a QuPath extension that provides an alternative inference engine through user-friendly and interactive software, and 3) a model zoo, which enables pathology models and metadata to be easily shared in a standardized form. Together, these contributions aim to encourage wider reuse, exploration, and interrogation of deep learning models for research purposes, by putting them into the hands of pathologists and eliminating a need for coding experience when accessed through QuPath. The WSInfer source code is hosted on GitHub and documentation is available at https://wsinfer.readthedocs.io

Tissue Cross-Section and Pen Marking Segmentation in Whole Slide Images

Tissue segmentation is a routine preprocessing step to reduce the computational cost of whole slide image (WSI) analysis by excluding background regions. Traditional image processing techniques are commonly used for tissue segmentation, but often require manual adjustments to parameter values for atypical cases, fail to exclude all slide and scanning artifacts from the background, and are unable to segment adipose tissue. Pen marking artifacts in particular can be a potential source of bias for subsequent analyses if not removed. In addition, several applications require the separation of individual cross-sections, which can be challenging due to tissue fragmentation and adjacent positioning. To address these problems, we develop a convolutional neural network for tissue and pen marking segmentation using a dataset of 200 H&E stained WSIs. For separating tissue cross-sections, we propose a novel post-processing method based on clustering predicted centroid locations of the cross-sections in a 2D histogram. On an independent test set, the model achieved a mean Dice score of 0.981$\pm$0.033 for tissue segmentation and a mean Dice score of 0.912$\pm$0.090 for pen marking segmentation. The mean absolute difference between the number of annotated and separated cross-sections was 0.075$\pm$0.350. Our results demonstrate that the proposed model can accurately segment H&E stained tissue cross-sections and pen markings in WSIs while being robust to many common slide and scanning artifacts. The model with trained model parameters and post-processing method are made publicly available as a Python package called SlideSegmenter.Comment: 6 pages, 3 figure

On the calibration of neural networks for histological slide-level classification

Deep Neural Networks have shown promising classification performance when predicting certain biomarkers from Whole Slide Images in digital pathology. However, the calibration of the networks' output probabilities is often not evaluated. Communicating uncertainty by providing reliable confidence scores is of high relevance in the medical context. In this work, we compare three neural network architectures that combine feature representations on patch-level to a slide-level prediction with respect to their classification performance and evaluate their calibration. As slide-level classification task, we choose the prediction of Microsatellite Instability from Colorectal Cancer tissue sections. We observe that Transformers lead to good results in terms of classification performance and calibration. When evaluating the classification performance on a separate dataset, we observe that Transformers generalize best. The investigation of reliability diagrams provides additional insights to the Expected Calibration Error metric and we observe that especially Transformers push the output probabilities to extreme values, which results in overconfident predictions.Comment: 7 pages, 2 figures, 2 table

Active data enrichment by learning what to annotate in digital pathology

Our work aims to link pathology with radiology with the goal to improve the early detection of lung cancer. Rather than utilising a set of predefined radiomics features, we propose to learn a new set of features from histology. Generating a comprehensive lung histology report is the first vital step toward this goal. Deep learning has revolutionised the computational assessment of digital pathology images. Today, we have mature algorithms for assessing morphological features at the cellular and tissue levels. In addition, there are promising efforts that link morphological features with biologically relevant information. While promising, these efforts mostly focus on narrow, well-defined questions. Developing a comprehensive report that is required in our setting requires an annotation strategy that captures all clinically relevant patterns specified in the WHO guidelines. Here, we propose and compare approaches aimed to balance the dataset and mitigate the biases in learning by automatically prioritising regions with clinical patterns underrepresented in the dataset. Our study demonstrates the opportunities active data enrichment can provide and results in a new lung-cancer dataset annotated to a degree that is not readily available in the public domain

Automated identification and quantification of myocardial inflammatory infiltration in digital histological images to diagnose myocarditis

This study aims to develop a new computational pathology approach that automates the identification and quantification of myocardial inflammatory infiltration in digital HE-stained images to provide a quantitative histological diagnosis of myocarditis.898 HE-stained whole slide images (WSIs) of myocardium from 154 heart transplant patients diagnosed with myocarditis or dilated cardiomyopathy (DCM) were included in this study. An automated DL-based computational pathology approach was developed to identify nuclei and detect myocardial inflammatory infiltration, enabling the quantification of the lymphocyte nuclear density (LND) on myocardial WSIs. A cutoff value based on the quantification of LND was proposed to determine if the myocardial inflammatory infiltration was present. The performance of our approach was evaluated with a five-fold cross-validation experiment, tested with an internal test set from the myocarditis group, and confirmed by an external test from a double-blind trial group. An LND of 1.02/mm2 could distinguish WSIs with myocarditis from those without. The accuracy, sensitivity, specificity, and area under the receiver operating characteristic curve (AUC) in the five-fold cross-validation experiment were 0.899 plus or minus 0.035, 0.971 plus or minus 0.017, 0.728 plus or minus 0.073 and 0.849 plus or minus 0.044, respectively. For the internal test set, the accuracy, sensitivity, specificity, and AUC were 0.887, 0.971, 0.737, and 0.854, respectively. The accuracy, sensitivity, specificity, and AUC for the external test set reached 0.853, 0.846, 0.858, and 0.852, respectively. Our new approach provides accurate and reliable quantification of the LND of myocardial WSIs, facilitating automated quantitative diagnosis of myocarditis with HE-stained images.Comment: 21 pages,5 figures,6 Tables, 25 reference

Segmentation of diagnostic tissue compartments on whole slide images with renal thrombotic microangiopathies (TMAs)

The thrombotic microangiopathies (TMAs) manifest in renal biopsy histology with a broad spectrum of acute and chronic findings. Precise diagnostic criteria for a renal biopsy diagnosis of TMA are missing. As a first step towards a machine learning- and computer vision-based analysis of wholes slide images from renal biopsies, we trained a segmentation model for the decisive diagnostic kidney tissue compartments artery, arteriole, glomerulus on a set of whole slide images from renal biopsies with TMAs and Mimickers (distinct diseases with a similar nephropathological appearance as TMA like severe benign nephrosclerosis, various vasculitides, Bevacizumab-plug glomerulopathy, arteriolar light chain deposition disease). Our segmentation model combines a U-Net-based tissue detection with a Shifted windows-transformer architecture to reach excellent segmentation results for even the most severely altered glomeruli, arterioles and arteries, even on unseen staining domains from a different nephropathology lab. With accurate automatic segmentation of the decisive renal biopsy compartments in human renal vasculopathies, we have laid the foundation for large-scale compartment-specific machine learning and computer vision analysis of renal biopsy repositories with TMAs.Comment: 12 pages, 3 figure

Detection of acute promyelocytic leukemia in peripheral blood and bone marrow with annotation-free deep learning

While optical microscopy inspection of blood films and bone marrow aspirates by a hematologist is a crucial step in establishing diagnosis of acute leukemia, especially in low-resource settings where other diagnostic modalities are not available, the task remains time-consuming and prone to human inconsistencies. This has an impact especially in cases of Acute Promyelocytic Leukemia (APL) that require urgent treatment. Integration of automated computational hematopathology into clinical workflows can improve the throughput of these services and reduce cognitive human error. However, a major bottleneck in deploying such systems is a lack of sufficient cell morphological object-labels annotations to train deep learning models. We overcome this by leveraging patient diagnostic labels to train weakly-supervised models that detect different types of acute leukemia. We introduce a deep learning approach, Multiple Instance Learning for Leukocyte Identification (MILLIE), able to perform automated reliable analysis of blood films with minimal supervision. Without being trained to classify individual cells, MILLIE differentiates between acute lymphoblastic and myeloblastic leukemia in blood films. More importantly, MILLIE detects APL in blood films (AUC 0.94 ± 0.04) and in bone marrow aspirates (AUC 0.99 ± 0.01). MILLIE is a viable solution to augment the throughput of clinical pathways that require assessment of blood film microscopy