Domain generalization across tumor types, laboratories, and species -- insights from the 2022 edition of the Mitosis Domain Generalization Challenge

Recognition of mitotic figures in histologic tumor specimens is highly relevant to patient outcome assessment. This task is challenging for algorithms and human experts alike, with deterioration of algorithmic performance under shifts in image representations. Considerable covariate shifts occur when assessment is performed on different tumor types, images are acquired using different digitization devices, or specimens are produced in different laboratories. This observation motivated the inception of the 2022 challenge on MItosis Domain Generalization (MIDOG 2022). The challenge provided annotated histologic tumor images from six different domains and evaluated the algorithmic approaches for mitotic figure detection provided by nine challenge participants on ten independent domains. Ground truth for mitotic figure detection was established in two ways: a three-expert consensus and an independent, immunohistochemistry-assisted set of labels. This work represents an overview of the challenge tasks, the algorithmic strategies employed by the participants, and potential factors contributing to their success. With an $F_1$ score of 0.764 for the top-performing team, we summarize that domain generalization across various tumor domains is possible with today's deep learning-based recognition pipelines. When assessed against the immunohistochemistry-assisted reference standard, all methods resulted in reduced recall scores, but with only minor changes in the order of participants in the ranking.

Why is the winner the best?

International benchmarking competitions have become fundamental for the comparative performance assessment of image analysis methods. However, little attention has been given to investigating what can be learnt from these competitions. Do they really generate scientific progress? What are common and successful participation strategies? What makes a solution superior to a competing method? To address this gap in the literature, we performed a multi-center study with all 80 competitions that were conducted in the scope of IEEE ISBI 2021 and MICCAI 2021. Statistical analyses performed based on comprehensive descriptions of the submitted algorithms linked to their rank as well as the underlying participation strategies revealed common characteristics of winning solutions. These typically include the use of multi-task learning (63%) and/or multi-stage pipelines (61%), and a focus on augmentation (100%), image preprocessing (97%), data curation (79%), and postprocessing (66%). The "typical" lead of a winning team is a computer scientist with a doctoral degree, five years of experience in biomedical image analysis, and four years of experience in deep learning. Two core general development strategies stood out for highly-ranked teams: the reflection of the metrics in the method design and the focus on analyzing and handling failure cases. According to the organizers, 43% of the winning algorithms exceeded the state of the art but only 11% completely solved the respective domain problem. The insights of our study could help researchers (1) improve algorithm development strategies when approaching new problems, and (2) focus on open research questions revealed by this work.

CoNIC Challenge: Pushing the Frontiers of Nuclear Detection, Segmentation, Classification and Counting

Nuclear detection, segmentation and morphometric profiling are essential in helping us further understand the relationship between histology and patient outcome. To drive innovation in this area, we setup a community-wide challenge using the largest available dataset of its kind to assess nuclear segmentation and cellular composition. Our challenge, named CoNIC, stimulated the development of reproducible algorithms for cellular recognition with real-time result inspection on public leaderboards. We conducted an extensive post-challenge analysis based on the top-performing models using 1,658 whole-slide images of colon tissue. With around 700 million detected nuclei per model, associated features were used for dysplasia grading and survival analysis, where we demonstrated that the challenge's improvement over the previous state-of-the-art led to significant boosts in downstream performance. Our findings also suggest that eosinophils and neutrophils play an important role in the tumour microevironment. We release challenge models and WSI-level results to foster the development of further methods for biomarker discovery.

Federated contrastive learning models for prostate cancer diagnosis and Gleason grading

The application effect of artificial intelligence (AI) in the field of medical imaging is remarkable. Robust AI model training requires large datasets, but data collection faces communication, ethics, and privacy protection constraints. Fortunately, federated learning can solve the above problems by coordinating multiple clients to train the model without sharing the original data. In this study, we design a federated contrastive learning framework (FCL) for large-scale pathology images and the heterogeneity challenges. It enhances the model's generalization ability by maximizing the attention consistency between the local client and server models. To alleviate the privacy leakage problem when transferring parameters and verify the robustness of FCL, we use differential privacy to further protect the model by adding noise. We evaluate the effectiveness of FCL on the cancer diagnosis task and Gleason grading task on 19,635 prostate cancer WSIs from multiple clients. In the diagnosis task, the average AUC of 7 clients is 95% when the categories are relatively balanced, and our FCL achieves 97%. In the Gleason grading task, the average Kappa of 6 clients is 0.74, and the Kappa of FCL reaches 0.84. Furthermore, we also validate the robustness of the model on external datasets(one public dataset and two private datasets). In addition, to better explain the classification effect of the model, we show whether the model focuses on the lesion area by drawing a heatmap. Finally, FCL brings a robust, accurate, low-cost AI training model to biomedical research, effectively protecting medical data privacy.

Artificial intelligence for diagnosing and predicting survival of patients with renal cell carcinoma: Retrospective multi-center study

Background: Clear cell renal cell carcinoma (ccRCC) is the most common renal-related tumor with high heterogeneity. There is still an urgent need for novel diagnostic and prognostic biomarkers for ccRCC. Methods: We proposed a weakly-supervised deep learning strategy using conventional histology of 1752 whole slide images from multiple centers. Our study was demonstrated through internal cross-validation and external validations for the deep learning-based models. Results: Automatic diagnosis for ccRCC through intelligent subtyping of renal cell carcinoma was proved in this study. Our graderisk achieved aera the curve (AUC) of 0.840 (95% confidence interval: 0.805-0.871) in the TCGA cohort, 0.840 (0.805-0.871) in the General cohort, and 0.840 (0.805-0.871) in the CPTAC cohort for the recognition of high-grade tumor. The OSrisk for the prediction of 5-year survival status achieved AUC of 0.784 (0.746-0.819) in the TCGA cohort, which was further verified in the independent General cohort and the CPTAC cohort, with AUC of 0.774 (0.723-0.820) and 0.702 (0.632-0.765), respectively. Cox regression analysis indicated that graderisk, OSrisk, tumor grade, and tumor stage were found to be independent prognostic factors, which were further incorporated into the competing-risk nomogram (CRN). Kaplan-Meier survival analyses further illustrated that our CRN could significantly distinguish patients with high survival risk, with hazard ratio of 5.664 (3.893-8.239, p < 0.0001) in the TCGA cohort, 35.740 (5.889-216.900, p < 0.0001) in the General cohort and 6.107 (1.815 to 20.540, p < 0.0001) in the CPTAC cohort. Comparison analyses conformed that our CRN outperformed current prognosis indicators in the prediction of survival status, with higher concordance index for clinical prognosis.

DeepNoise: Disentanglement of Experimental Noise from Real Biological Signals based on Fluorescent Microscopy Image Classification via Deep Learning

The high-content image-based assay is commonly leveraged for identifying the phenotypic impact of genetic perturbations in biology field. However, a persistent issue remains unsolved during experiments: the interferential technical noise caused by systematic errors (e.g., temperature, reagent concentration, and well location) is always mixed up with the real biological signals, leading to misinterpretation of any conclusion drawn. Here, we show a mean teacher based deep learning model (DeepNoise) that can disentangle biological signals from the experimental noise. Specifically, we aim to classify the phenotypic impact of 1,108 different genetic perturbations screened from 125,510 fluorescent microscopy images, which are totally unrecognizable by human eye. We validate our model by participating in the Recursion Cellular Image Classification Challenge, and our proposed method achieves an extremely high classification score (Acc: 99.596%), ranking the 2nd place among 866 participating groups. This promising result indicates the successful separation of biological and technical factors, which might help decrease the cost of treatment development and expedite the drug discovery process.

Dual Skipping Guidance for Document Retrieval with Learned Sparse Representations

This paper proposes a dual skipping guidance scheme with hybrid scoring to accelerate document retrieval that uses learned sparse representations while still delivering a good relevance. This scheme uses both lexical BM25 and learned neural term weights to bound and compose the rank score of a candidate document separately for skipping and final ranking, and maintains two top-k thresholds during inverted index traversal. This paper evaluates time efficiency and ranking relevance of the proposed scheme in searching MS MARCO TREC datasets.

Pan-cancer computational histopathology reveals tumor mutational burden status through weakly-supervised deep learning

Tumor mutational burden (TMB) is a potential genomic biomarker that can help identify patients who will benefit from immunotherapy across a variety of cancers. We included whole slide images (WSIs) of 3228 diagnostic slides from the Cancer Genome Atlas and 531 WSIs from the Clinical Proteomic Tumor Analysis Consortium for the development and verification of a pan-cancer TMB prediction model (PC-TMB). We proposed a multiscale weakly-supervised deep learning framework for predicting TMB of seven types of tumors based only on routinely used hematoxylin-eosin (H&E)-stained WSIs. PC-TMB achieved a mean area under curve (AUC) of 0.818 (0.804-0.831) in the cross-validation cohort, which was superior to the best single-scale model. In comparison with the state-of-the-art TMB prediction model from previous publications, our multiscale model achieved better performance over previously reported models. In addition, the improvements of PC-TMB over the single-tumor models were also confirmed by the ablation tests on 10x magnification. The PC-TMB algorithm also exhibited good generalization on external validation cohort with AUC of 0.732 (0.683-0.761). PC-TMB possessed a comparable survival-risk stratification performance to the TMB measured by whole exome sequencing, but with low cost and being time-efficient for providing a prognostic biomarker of multiple solid tumors. Moreover, spatial heterogeneity of TMB within tumors was also identified through our PC-TMB, which might enable image-based screening for molecular biomarkers with spatial variation and potential exploring for genotype-spatial heterogeneity relationships.

Mitosis domain generalization in histopathology images -- The MIDOG challenge

The density of mitotic figures within tumor tissue is known to be highly correlated with tumor proliferation and thus is an important marker in tumor grading. Recognition of mitotic figures by pathologists is known to be subject to a strong inter-rater bias, which limits the prognostic value. State-of-the-art deep learning methods can support the expert in this assessment but are known to strongly deteriorate when applied in a different clinical environment than was used for training. One decisive component in the underlying domain shift has been identified as the variability caused by using different whole slide scanners. The goal of the MICCAI MIDOG 2021 challenge has been to propose and evaluate methods that counter this domain shift and derive scanner-agnostic mitosis detection algorithms. The challenge used a training set of 200 cases, split across four scanning systems. As a test set, an additional 100 cases split across four scanning systems, including two previously unseen scanners, were given. The best approaches performed on an expert level, with the winning algorithm yielding an F_1 score of 0.748 (CI95: 0.704-0.781). In this paper, we evaluate and compare the approaches that were submitted to the challenge and identify methodological factors contributing to better performance.

A Deep Learning Framework for Nuclear Segmentation and Classification in Histopathological Images

Nucleus segmentation and classification are the prerequisites in the workflow of digital pathology processing. However, it is very challenging due to its high-level heterogeneity and wide variations. This work proposes a deep neural network to simultaneously achieve nuclear classification and segmentation, which is designed using a unified framework with three different branches, including segmentation, HoVer mapping, and classification. The segmentation branch aims to generate the boundaries of each nucleus. The HoVer branch calculates the horizontal and vertical distances of nuclear pixels to their centres of mass. The nuclear classification branch is used to distinguish the class of pixels inside the nucleus obtained from segmentation.