Multi-domain stain normalization for digital pathology: A cycle-consistent adversarial network for whole slide images

The variation in histologic staining between different medical centers is one of the most profound challenges in the field of computer-aided diagnosis. The appearance disparity of pathological whole slide images causes algorithms to become less reliable, which in turn impedes the wide-spread applicability of downstream tasks like cancer diagnosis. Furthermore, different stainings lead to biases in the training which in case of domain shifts negatively affect the test performance. Therefore, in this paper we propose MultiStain-CycleGAN, a multi-domain approach to stain normalization based on CycleGAN. Our modifications to CycleGAN allow us to normalize images of different origins without retraining or using different models. We perform an extensive evaluation of our method using various metrics and compare it to commonly used methods that are multi-domain capable. First, we evaluate how well our method fools a domain classifier that tries to assign a medical center to an image. Then, we test our normalization on the tumor classification performance of a downstream classifier. Furthermore, we evaluate the image quality of the normalized images using the Structural similarity index and the ability to reduce the domain shift using the Fr\'echet inception distance. We show that our method proves to be multi-domain capable, provides the highest image quality among the compared methods, and can most reliably fool the domain classifier while keeping the tumor classifier performance high. By reducing the domain influence, biases in the data can be removed on the one hand and the origin of the whole slide image can be disguised on the other, thus enhancing patient data privacy.Comment: 19 pages, 11 figures, 3 table

Domain shifts in dermoscopic skin cancer datasets: Evaluation of essential limitations for clinical translation

The limited ability of Convolutional Neural Networks to generalize to images from previously unseen domains is a major limitation, in particular, for safety-critical clinical tasks such as dermoscopic skin cancer classification. In order to translate CNN-based applications into the clinic, it is essential that they are able to adapt to domain shifts. Such new conditions can arise through the use of different image acquisition systems or varying lighting conditions. In dermoscopy, shifts can also occur as a change in patient age or occurence of rare lesion localizations (e.g. palms). These are not prominently represented in most training datasets and can therefore lead to a decrease in performance. In order to verify the generalizability of classification models in real world clinical settings it is crucial to have access to data which mimics such domain shifts. To our knowledge no dermoscopic image dataset exists where such domain shifts are properly described and quantified. We therefore grouped publicly available images from ISIC archive based on their metadata (e.g. acquisition location, lesion localization, patient age) to generate meaningful domains. To verify that these domains are in fact distinct, we used multiple quantification measures to estimate the presence and intensity of domain shifts. Additionally, we analyzed the performance on these domains with and without an unsupervised domain adaptation technique. We observed that in most of our grouped domains, domain shifts in fact exist. Based on our results, we believe these datasets to be helpful for testing the generalization capabilities of dermoscopic skin cancer classifiers

Mitigating the influence of domain shift in skin lesion classification: A benchmark study of unsupervised domain adaptation methods

The potential of deep neural networks in skin lesion classification has already been demonstrated to be on-par if not superior to the dermatologists' diagnosis in experimental settings. However, the performance of these models usually deteriorates in real-world scenarios, where the test data differs significantly from the training data (i.e. domain shift). This concerning limitation for models intended to be used in real-world skin lesion classification tasks poses a risk to patients. For example, different image acquisition systems or previously unseen anatomical sites on the patient can suffice to cause such domain shifts. Mitigating the negative effect of such shifts is therefore crucial, but developing effective methods to address domain shift has proven to be challenging. In this study, we carry out a comparative analysis of eight different unsupervised domain adaptation methods to analyze their effectiveness in improving generalization for dermoscopic datasets. To ensure robustness of our findings, we test each method on a total of ten derived datasets, thereby covering a variety of possible domain shifts. In addition, we investigated which factors in the domain shifted datasets have an impact on the effectiveness of domain adaptation methods. Our findings show that all of the eight domain adaptation methods result in improved AUPRC for the majority of analyzed datasets. Altogether, these results indicate that unsupervised domain adaptations generally lead to performance improvements for the binary melanoma-nevus classification task regardless of the nature of the domain shift. However, small or heavily imbalanced datasets lead to a reduced conformity of the results due to the influence of these factors on the methods' performance

Domain shifts in dermoscopic skin cancer datasets: Evaluation of essential limitations for clinical translation

he limited ability of Convolutional Neural Networks to generalize to images from previously unseen domains is a major limitation, in particular, for safety-critical clinical tasks such as dermoscopic skin cancer classification. In order to translate CNN-based applications into the clinic, it is essential that they are able to adapt to domain shifts. Such new conditions can arise through the use of different image acquisition systems or varying lighting conditions. In dermoscopy, shifts can also occur as a change in patient age or occurrence of rare lesion localizations (e.g. palms). These are not prominently represented in most training datasets and can therefore lead to a decrease in performance. In order to verify the generalizability of classification models in real world clinical settings it is crucial to have access to data which mimics such domain shifts. To our knowledge no dermoscopic image dataset exists where such domain shifts are properly described and quantified. We therefore grouped publicly available images from ISIC archive based on their metadata (e.g. acquisition location, lesion localization, patient age) to generate meaningful domains. To verify that these domains are in fact distinct, we used multiple quantification measures to estimate the presence and intensity of domain shifts. Additionally, we analyzed the performance on these domains with and without an unsupervised domain adaptation technique. We observed that in most of our grouped domains, domain shifts in fact exist. Based on our results, we believe these datasets to be helpful for testing the generalization capabilities of dermoscopic skin cancer classifiers

Evaluating Deep Learning-based Melanoma Classification using Immunohistochemistry and Routine Histology: A Three Center Study

Pathologists routinely use immunohistochemical (IHC)-stained tissue slides against MelanA in addition to hematoxylin and eosin (H&E)-stained slides to improve their accuracy in diagnosing melanomas. The use of diagnostic Deep Learning (DL)-based support systems for automated examination of tissue morphology and cellular composition has been well studied in standard H&E-stained tissue slides. In contrast, there are few studies that analyze IHC slides using DL. Therefore, we investigated the separate and joint performance of ResNets trained on MelanA and corresponding H&E-stained slides. The MelanA classifier achieved an area under receiver operating characteristics curve (AUROC) of 0.82 and 0.74 on out of distribution (OOD)-datasets, similar to the H&E-based benchmark classification of 0.81 and 0.75, respectively. A combined classifier using MelanA and H&E achieved AUROCs of 0.85 and 0.81 on the OOD datasets. DL MelanA-based assistance systems show the same performance as the benchmark H&E classification and may be improved by multi stain classification to assist pathologists in their clinical routine

Benchmarking weakly-supervised deep learning pipelines for whole slide classification in computational pathology.

Artificial intelligence (AI) can extract visual information from histopathological slides and yield biological insight and clinical biomarkers. Whole slide images are cut into thousands of tiles and classification problems are often weakly-supervised: the ground truth is only known for the slide, not for every single tile. In classical weakly-supervised analysis pipelines, all tiles inherit the slide label while in multiple-instance learning (MIL), only bags of tiles inherit the label. However, it is still unclear how these widely used but markedly different approaches perform relative to each other. We implemented and systematically compared six methods in six clinically relevant end-to-end prediction tasks using data from N=2980 patients for training with rigorous external validation. We tested three classical weakly-supervised approaches with convolutional neural networks and vision transformers (ViT) and three MIL-based approaches with and without an additional attention module. Our results empirically demonstrate that histological tumor subtyping of renal cell carcinoma is an easy task in which all approaches achieve an area under the receiver operating curve (AUROC) of above 0.9. In contrast, we report significant performance differences for clinically relevant tasks of mutation prediction in colorectal, gastric, and bladder cancer. In these mutation prediction tasks, classical weakly-supervised workflows outperformed MIL-based weakly-supervised methods for mutation prediction, which is surprising given their simplicity. This shows that new end-to-end image analysis pipelines in computational pathology should be compared to classical weakly-supervised methods. Also, these findings motivate the development of new methods which combine the elegant assumptions of MIL with the empirically observed higher performance of classical weakly-supervised approaches. We make all source codes publicly available at https://github.com/KatherLab/HIA, allowing easy application of all methods to any similar task

Facial-aging mobile apps for smoking prevention in secondary schools in Brazil : appearance-focused interventional study.

Background: Most smokers start smoking during their early adolescence, often with the idea that smoking is glamorous. Interventions that harness the broad availability of mobile phones as well as adolescents' interest in their appearance may be a novel way to improve school-based prevention. A recent study conducted in Germany showed promising results. However, the transfer to other cultural contexts, effects on different genders, and implementability remains unknown. Objective: In this observational study, we aimed to test the perception and implementability of facial-aging apps to prevent smoking in secondary schools in Brazil in accordance with the theory of planned behavior and with respect to different genders. Methods: We used a free facial-aging mobile phone app (?Smokerface?) in three Brazilian secondary schools via a novel method called mirroring. The students? altered three-dimensional selfies on mobile phones or tablets and images were ?mirrored? via a projector in front of their whole grade. Using an anonymous questionnaire, we then measured on a 5-point Likert scale the perceptions of the intervention among 306 Brazilian secondary school students of both genders in the seventh grade (average age 12.97 years). A second questionnaire captured perceptions of medical students who conducted the intervention and its conduction per protocol. Results: The majority of students perceived the intervention as fun (304/306, 99.3%), claimed the intervention motivated them not to smoke (289/306, 94.4%), and stated that they learned new benefits of not smoking (300/306, 98.0%). Only a minority of students disagreed or fully disagreed that they learned new benefits of nonsmoking (4/306, 1.3%) or that they themselves were motivated not to smoke (5/306, 1.6%). All of the protocol was delivered by volunteer medical students. Conclusions: Our data indicate the potential for facial-aging interventions to reduce smoking prevalence in Brazilian secondary schools in accordance with the theory of planned behavior. Volunteer medical students enjoyed the intervention and are capable of complete implementation per protocol

Test Time Augmentation Meets Post-hoc Calibration: Uncertainty Quantification under Real-World Conditions

Communicating the predictive uncertainty of deep neural networks transparently and reliably is important in many safety-critical applications such as medicine. However, modern neural networks tend to be poorly calibrated, resulting in wrong predictions made with a high confidence. While existing post-hoc calibration methods like temperature scaling or isotonic regression yield strongly calibrated predictions in artificial experimental settings, their efficiency can significantly reduce in real-world applications, where scarcity of labeled data or domain drifts are commonly present. In this paper, we first investigate the impact of these characteristics on post-hoc calibration and introduce an easy-to-implement extension of common post-hoc calibration methods based on test time augmentation. In extensive experiments, we demonstrate that our approach results in substantially better calibration on various architectures. We demonstrate the robustness of our proposed approach on a real-world application for skin cancer classification and show that it facilitates safe decision-making under real-world uncertainties

Enhanced classifier training to improve precision of a convolutional neural network to identify images of skin lesions.

BackgroundIn recent months, multiple publications have demonstrated the use of convolutional neural networks (CNN) to classify images of skin cancer as precisely as dermatologists. However, these CNNs failed to outperform the International Symposium on Biomedical Imaging (ISBI) 2016 challenge which ranked the average precision for classification of dermoscopic melanoma images. Accordingly, the technical progress represented by these studies is limited. In addition, the available reports are impossible to reproduce, due to incomplete descriptions of training procedures and the use of proprietary image databases or non-disclosure of used images. These factors prevent the comparison of various CNN classifiers in equal terms.ObjectiveTo demonstrate the training of an image-classifier CNN that outperforms the winner of the ISBI 2016 CNNs challenge by using open source images exclusively.MethodsA detailed description of the training procedure is reported while the used images and test sets are disclosed fully, to insure the reproducibility of our work.ResultsOur CNN classifier outperforms all recent attempts to classify the original ISBI 2016 challenge test data (full set of 379 test images), with an average precision of 0.709 (vs. 0.637 of the ISBI winner) and with an area under the receiver operating curve of 0.85.ConclusionThis work illustrates the potential for improving skin cancer classification with enhanced training procedures for CNNs, while avoiding the use of costly equipment or proprietary image data