Henning Müller

Lena Maier-Hein, Annika Reinke, Patrick Godau et al. · utoronto

Increasing evidence shows that flaws in machine learning (ML) algorithm validation are an underestimated global problem. Particularly in automatic biomedical image analysis, chosen performance metrics often do not reflect the domain interest, thus failing to adequately measure scientific progress and hindering translation of ML techniques into practice. To overcome this, our large international expert consortium created Metrics Reloaded, a comprehensive framework guiding researchers in the problem-aware selection of metrics. Following the convergence of ML methodology across application domains, Metrics Reloaded fosters the convergence of validation methodology. The framework was developed in a multi-stage Delphi process and is based on the novel concept of a problem fingerprint - a structured representation of the given problem that captures all aspects that are relevant for metric selection, from the domain interest to the properties of the target structure(s), data set and algorithm output. Based on the problem fingerprint, users are guided through the process of choosing and applying appropriate validation metrics while being made aware of potential pitfalls. Metrics Reloaded targets image analysis problems that can be interpreted as a classification task at image, object or pixel level, namely image-level classification, object detection, semantic segmentation, and instance segmentation tasks. To improve the user experience, we implemented the framework in the Metrics Reloaded online tool, which also provides a point of access to explore weaknesses, strengths and specific recommendations for the most common validation metrics. The broad applicability of our framework across domains is demonstrated by an instantiation for various biological and medical image analysis use cases.

Annika Reinke, Minu D. Tizabi, Michael Baumgartner et al.

Validation metrics are key for the reliable tracking of scientific progress and for bridging the current chasm between artificial intelligence (AI) research and its translation into practice. However, increasing evidence shows that particularly in image analysis, metrics are often chosen inadequately in relation to the underlying research problem. This could be attributed to a lack of accessibility of metric-related knowledge: While taking into account the individual strengths, weaknesses, and limitations of validation metrics is a critical prerequisite to making educated choices, the relevant knowledge is currently scattered and poorly accessible to individual researchers. Based on a multi-stage Delphi process conducted by a multidisciplinary expert consortium as well as extensive community feedback, the present work provides the first reliable and comprehensive common point of access to information on pitfalls related to validation metrics in image analysis. Focusing on biomedical image analysis but with the potential of transfer to other fields, the addressed pitfalls generalize across application domains and are categorized according to a newly created, domain-agnostic taxonomy. To facilitate comprehension, illustrations and specific examples accompany each pitfall. As a structured body of information accessible to researchers of all levels of expertise, this work enhances global comprehension of a key topic in image analysis validation.

Zhuxian Guo, Qitong Wang, Henning Müller et al. · harvard

In digital histopathology, entire neoplasm segmentation on Whole Slide Image (WSI) of Hepatocellular Carcinoma (HCC) plays an important role, especially as a preprocessing filter to automatically exclude healthy tissue, in histological molecular correlations mining and other downstream histopathological tasks. The segmentation task remains challenging due to HCC's inherent high-heterogeneity and the lack of dependency learning in large field of view. In this article, we propose a novel deep learning architecture with a hierarchical Transformer encoder, HiTrans, to learn the global dependencies within expanded 4096$\times$4096 WSI patches. HiTrans is designed to encode and decode the patches with larger reception fields and the learned global dependencies, compared to the state-of-the-art Fully Convolutional Neural networks (FCNN). Empirical evaluations verified that HiTrans leads to better segmentation performance by taking into account regional and global dependency information.

Nataliia Molchanova, Alessandro Cagol, Pedro M. Gordaliza et al.

Uncertainty quantification (UQ) has become critical for evaluating the reliability of artificial intelligence systems, especially in medical image segmentation. This study addresses the interpretability of instance-wise uncertainty values in deep learning models for focal lesion segmentation in magnetic resonance imaging, specifically cortical lesion (CL) segmentation in multiple sclerosis. CL segmentation presents several challenges, including the complexity of manual segmentation, high variability in annotation, data scarcity, and class imbalance, all of which contribute to aleatoric and epistemic uncertainty. We explore how UQ can be used not only to assess prediction reliability but also to provide insights into model behavior, detect biases, and verify the accuracy of UQ methods. Our research demonstrates the potential of instance-wise uncertainty values to offer post hoc global model explanations, serving as a sanity check for the model. The implementation is available at https://github.com/NataliiaMolch/interpret-lesion-unc.

Mara Graziani, Niccolò Marini, Nicolas Deutschmann et al.

Interpretability of deep learning is widely used to evaluate the reliability of medical imaging models and reduce the risks of inaccurate patient recommendations. For models exceeding human performance, e.g. predicting RNA structure from microscopy images, interpretable modelling can be further used to uncover highly non-trivial patterns which are otherwise imperceptible to the human eye. We show that interpretability can reveal connections between the microscopic appearance of cancer tissue and its gene expression profiling. While exhaustive profiling of all genes from the histology images is still challenging, we estimate the expression values of a well-known subset of genes that is indicative of cancer molecular subtype, survival, and treatment response in colorectal cancer. Our approach successfully identifies meaningful information from the image slides, highlighting hotspots of high gene expression. Our method can help characterise how gene expression shapes tissue morphology and this may be beneficial for patient stratification in the pathology unit. The code is available on GitHub.

Mara Graziani, Laura O' Mahony, An-Phi Nguyen et al.

Interpreting the inner workings of deep learning models is crucial for establishing trust and ensuring model safety. Concept-based explanations have emerged as a superior approach that is more interpretable than feature attribution estimates such as pixel saliency. However, defining the concepts for the interpretability analysis biases the explanations by the user's expectations on the concepts. To address this, we propose a novel post-hoc unsupervised method that automatically uncovers the concepts learned by deep models during training. By decomposing the latent space of a layer in singular vectors and refining them by unsupervised clustering, we uncover concept vectors aligned with directions of high variance that are relevant to the model prediction, and that point to semantically distinct concepts. Our extensive experiments reveal that the majority of our concepts are readily understandable to humans, exhibit coherency, and bear relevance to the task at hand. Moreover, we showcase the practical utility of our method in dataset exploration, where our concept vectors successfully identify outlier training samples affected by various confounding factors. This novel exploration technique has remarkable versatility to data types and model architectures and it will facilitate the identification of biases and the discovery of sources of error within training data.

Mario Martínez-Zarzuela, Javier González-Alonso, Míriam Antón-Rodríguez et al.

Human activity recognition and clinical biomechanics are challenging problems in physical telerehabilitation medicine. However, most publicly available datasets on human body movements cannot be used to study both problems in an out-of-the-lab movement acquisition setting. The objective of the VIDIMU dataset is to pave the way towards affordable patient gross motor tracking solutions for daily life activities recognition and kinematic analysis. The dataset includes 13 activities registered using a commodity camera and five inertial sensors. The video recordings were acquired in 54 subjects, of which 16 also had simultaneous recordings of inertial sensors. The novelty of dataset lies in: (i) the clinical relevance of the chosen movements, (ii) the combined utilization of affordable video and custom sensors, and (iii) the implementation of state-of-the-art tools for multimodal data processing of 3D body pose tracking and motion reconstruction in a musculoskeletal model from inertial data. The validation confirms that a minimally disturbing acquisition protocol, performed according to real-life conditions can provide a comprehensive picture of human joint angles during daily life activities.

Marek Wodzinski, Henning Müller

Automatic aorta segmentation from 3-D medical volumes is an important yet difficult task. Several factors make the problem challenging, e.g. the possibility of aortic dissection or the difficulty with segmenting and annotating the small branches. This work presents a contribution by the MedGIFT team to the SEG.A challenge organized during the MICCAI 2023 conference. We propose a fully automated algorithm based on deep encoder-decoder architecture. The main assumption behind our work is that data preprocessing and augmentation are much more important than the deep architecture, especially in low data regimes. Therefore, the solution is based on a variant of traditional convolutional U-Net. The proposed solution achieved a Dice score above 0.9 for all testing cases with the highest stability among all participants. The method scored 1st, 4th, and 3rd in terms of the clinical evaluation, quantitative results, and volumetric meshing quality, respectively. We freely release the source code, pretrained model, and provide access to the algorithm on the Grand-Challenge platform.

Marek Wodzinski, Henning Müller

The automatic registration of noninvasive second-harmonic generation microscopy to hematoxylin and eosin slides is a highly desired, yet still unsolved problem. The task is challenging because the second-harmonic images contain only partial information, in contrast to the stained H&E slides that provide more information about the tissue morphology. Moreover, both imaging methods have different intensity distributions. Therefore, the task can be formulated as a multi-modal registration problem with missing data. In this work, we propose a method based on automatic keypoint matching followed by deformable registration based on instance optimization. The method does not require any training and is evaluated using the dataset provided in the Learn2Reg challenge by the COMULIS organization. The method achieved relatively good generalizability resulting in 88% of success rate in the initial alignment and average target registration error equal to 2.48 on the external validation set. We openly release the source code and incorporate it in the DeeperHistReg image registration framework.

Sina Raeisadigh, Myles Joshua Toledo Tan, Henning Müller et al.

This study compares baseline (J0) and 24-hour (J1) diffusion magnetic resonance imaging (MRI) for predicting three-month functional outcomes after acute ischemic stroke (AIS). Seventy-four AIS patients with paired apparent diffusion coefficient (ADC) scans and clinical data were analyzed. Three-dimensional ResNet-50 embeddings were fused with structured clinical variables, reduced via principal component analysis (<=12 components), and classified using linear support vector machines with eight-fold stratified group cross-validation. J1 multimodal models achieved the highest predictive performance (AUC = 0.923 +/- 0.085), outperforming J0-based configurations (AUC <= 0.86). Incorporating lesion-volume features further improved model stability and interpretability. These findings demonstrate that early post-treatment diffusion MRI provides superior prognostic value to pre-treatment imaging and that combining MRI, clinical, and lesion-volume features produces a robust and interpretable framework for predicting three-month functional outcomes in AIS patients.

Mohammadreza Amirian, Michael Bach, Oscar Jimenez-del-Toro et al.

Artificial intelligence (AI) has introduced numerous opportunities for human assistance and task automation in medicine. However, it suffers from poor generalization in the presence of shifts in the data distribution. In the context of AI-based computed tomography (CT) analysis, significant data distribution shifts can be caused by changes in scanner manufacturer, reconstruction technique or dose. AI harmonization techniques can address this problem by reducing distribution shifts caused by various acquisition settings. This paper presents an open-source benchmark dataset containing CT scans of an anthropomorphic phantom acquired with various scanners and settings, which purpose is to foster the development of AI harmonization techniques. Using a phantom allows fixing variations attributed to inter- and intra-patient variations. The dataset includes 1378 image series acquired with 13 scanners from 4 manufacturers across 8 institutions using a harmonized protocol as well as several acquisition doses. Additionally, we present a methodology, baseline results and open-source code to assess image- and feature-level stability and liver tissue classification, promoting the development of AI harmonization strategies.

Dimitrios Markonis, Roger Schaer, Alba García Seco de Herrera et al.

Image retrieval is a complex task that differs according to the context and the user requirements in any specific field, for example in a medical environment. Search by text is often not possible or optimal and retrieval by the visual content does not always succeed in modelling high-level concepts that a user is looking for. Modern image retrieval techniques consist of multiple steps and aim to retrieve information from large--scale datasets and not only based on global image appearance but local features and if possible in a connection between visual features and text or semantics. This paper presents the Parallel Distributed Image Search Engine (ParaDISE), an image retrieval system that combines visual search with text--based retrieval and that is available as open source and free of charge. The main design concepts of ParaDISE are flexibility, expandability, scalability and interoperability. These concepts constitute the system, able to be used both in real-world applications and as an image retrieval research platform. Apart from the architecture and the implementation of the system, two use cases are described, an application of ParaDISE in retrieval of images from the medical literature and a visual feature evaluation for medical image retrieval. Future steps include the creation of an open source community that will contribute and expand this platform based on the existing parts.

Johannes Rückert, Louise Bloch, Raphael Brüngel et al.

Automated medical image analysis systems often require large amounts of training data with high quality labels, which are difficult and time consuming to generate. This paper introduces Radiology Object in COntext version 2 (ROCOv2), a multimodal dataset consisting of radiological images and associated medical concepts and captions extracted from the PMC Open Access subset. It is an updated version of the ROCO dataset published in 2018, and adds 35,705 new images added to PMC since 2018. It further provides manually curated concepts for imaging modalities with additional anatomical and directional concepts for X-rays. The dataset consists of 79,789 images and has been used, with minor modifications, in the concept detection and caption prediction tasks of ImageCLEFmedical Caption 2023. The dataset is suitable for training image annotation models based on image-caption pairs, or for multi-label image classification using Unified Medical Language System (UMLS) concepts provided with each image. In addition, it can serve for pre-training of medical domain models, and evaluation of deep learning models for multi-task learning.

Zhuxian Guo, Amine Marzouki, Jean-François Emile et al.

Lymphoid infiltration at tumor margins is a key prognostic marker in solid tumors, playing a crucial role in guiding immunotherapy decisions. Current assessment methods, heavily reliant on immunohistochemistry (IHC), face challenges in tumor margin delineation and are affected by tissue preservation conditions. In contrast, we propose a Hematoxylin and Eosin (H&E) staining-based approach, underpinned by an advanced lymphocyte segmentation model trained on a public dataset for the precise detection of CD3+ and CD20+ lymphocytes. In our colorectal cancer study, we demonstrate that our H&E-based method offers a compelling alternative to traditional IHC, achieving comparable results in many cases. Our method's validity is further explored through a Turing test, involving blinded assessments by a pathologist of anonymized curves from H&E and IHC slides. This approach invites the medical community to consider Turing tests as a standard for evaluating medical applications involving expert human evaluation, thereby opening new avenues for enhancing cancer management and immunotherapy planning.

Kaiyuan Yang, Fabio Musio, Yihui Ma et al.

The Circle of Willis (CoW) is an important network of arteries connecting major circulations of the brain. Its vascular architecture is believed to affect the risk, severity, and clinical outcome of serious neurovascular diseases. However, characterizing the highly variable CoW anatomy is still a manual and time-consuming expert task. The CoW is usually imaged by two non-invasive angiographic imaging modalities, magnetic resonance angiography (MRA) and computed tomography angiography (CTA), but there exist limited datasets with annotations on CoW anatomy, especially for CTA. Therefore, we organized the TopCoW challenge with the release of an annotated CoW dataset. The TopCoW dataset is the first public dataset with voxel-level annotations for 13 CoW vessel components, enabled by virtual reality technology. It is also the first large dataset using 200 pairs of MRA and CTA from the same patients. As part of the benchmark, we invited submissions worldwide and attracted over 250 registered participants from six continents. The submissions were evaluated on both internal and external test datasets of 226 scans from over five centers. The top performing teams achieved over 90% Dice scores at segmenting the CoW components, over 80% F1 scores at detecting key CoW components, and over 70% balanced accuracy at classifying CoW variants for nearly all test sets. The best algorithms also showed clinical potential in classifying fetal-type posterior cerebral artery and locating aneurysms with CoW anatomy. TopCoW demonstrated the utility and versatility of CoW segmentation algorithms for a wide range of downstream clinical applications with explainability. The annotated datasets and best performing algorithms have been released as public Zenodo records to foster further methodological development and clinical tool building.

Marek Wodzinski, Niccolò Marini, Manfredo Atzori et al.

The automatic registration of differently stained whole slide images (WSIs) is crucial for improving diagnosis and prognosis by fusing complementary information emerging from different visible structures. It is also useful to quickly transfer annotations between consecutive or restained slides, thus significantly reducing the annotation time and associated costs. Nevertheless, the slide preparation is different for each stain and the tissue undergoes complex and large deformations. Therefore, a robust, efficient, and accurate registration method is highly desired by the scientific community and hospitals specializing in digital pathology. We propose a two-step hybrid method consisting of (i) deep learning- and feature-based initial alignment algorithm, and (ii) intensity-based nonrigid registration using the instance optimization. The proposed method does not require any fine-tuning to a particular dataset and can be used directly for any desired tissue type and stain. The method scored 1st place in the ACROBAT 2023 challenge. We evaluated using three open datasets: (i) ANHIR, (ii) ACROBAT, and (iii) HyReCo, and performed several ablation studies concerning the resolution used for registration and the initial alignment robustness and stability. The method achieves the most accurate results for the ACROBAT dataset, the cell-level registration accuracy for the restained slides from the HyReCo dataset, and is among the best methods evaluated on the ANHIR dataset. The method does not require any fine-tuning to a new datasets and can be used out-of-the-box for other types of microscopic images. The method is incorporated into the DeeperHistReg framework, allowing others to directly use it to register, transform, and save the WSIs at any desired pyramid level. The proposed method is a significant contribution to the WSI registration, thus advancing the field of digital pathology.

Marek Wodzinski, Niccolò Marini, Manfredo Atzori et al.

DeeperHistReg is a software framework dedicated to registering whole slide images (WSIs) acquired using multiple stains. It allows one to perform the preprocessing, initial alignment, and nonrigid registration of WSIs acquired using multiple stains (e.g. hematoxylin \& eosin, immunochemistry). The framework implements several state-of-the-art registration algorithms and provides an interface to operate on arbitrary resolution of the WSIs (up to 200k x 200k). The framework is extensible and new algorithms can be easily integrated by other researchers. The framework is available both as a PyPI package and as a Docker container.

Yuan Jin, Antonio Pepe, Gian Marco Melito et al.

The automated analysis of the aortic vessel tree (AVT) from computed tomography angiography (CTA) holds immense clinical potential, but its development has been impeded by a lack of shared, high-quality data. We launched the SEG.A. challenge to catalyze progress in this field by introducing a large, publicly available, multi-institutional dataset for AVT segmentation. The challenge benchmarked automated algorithms on a hidden test set, with subsequent optional tasks in surface meshing for computational simulations. Our findings reveal a clear convergence on deep learning methodologies, with 3D U-Net architectures dominating the top submissions. A key result was that an ensemble of the highest-ranking algorithms significantly outperformed individual models, highlighting the benefits of model fusion. Performance was strongly linked to algorithmic design, particularly the use of customized post-processing steps, and the characteristics of the training data. This initiative not only establishes a new performance benchmark but also provides a lasting resource to drive future innovation toward robust, clinically translatable tools.

Lasse Hansen, Wiebke Heyer, Christoph Großbröhmer et al.

Medical image registration is critical for clinical applications, and fair benchmarking of different methods is essential for monitoring ongoing progress. To date, the Learn2Reg 2020-2023 challenges have released several complementary datasets and established metrics for evaluations. However, these editions did not capture all aspects of the registration problem, particularly in terms of modality diversity and task complexity. To address these limitations, the 2024 edition introduces three new tasks, including large-scale multi-modal registration and unsupervised inter-subject brain registration, as well as the first microscopy-focused benchmark within Learn2Reg. The new datasets also inspired new method developments, including invertibility constraints, pyramid features, keypoints alignment and instance optimisation.

Federico Del Pup, Riccardo Brun, Filippo Iotti et al.

Electroencephalography (EEG) is establishing itself as an important, low-cost, noninvasive diagnostic tool for the early detection of Parkinson's Disease (PD). In this context, EEG-based Deep Learning (DL) models have shown promising results due to their ability to discover highly nonlinear patterns within the signal. However, current state-of-the-art DL models suffer from poor generalizability caused by high inter-subject variability. This high variability underscores the need for enhancing model generalizability by developing new architectures better tailored to EEG data. This paper introduces TransformEEG, a hybrid Convolutional-Transformer designed for Parkinson's disease detection using EEG data. Unlike transformer models based on the EEGNet structure, TransformEEG incorporates a depthwise convolutional tokenizer. This tokenizer is specialized in generating tokens composed by channel-specific features, which enables more effective feature mixing within the self-attention layers of the transformer encoder. To evaluate the proposed model, four public datasets comprising 290 subjects (140 PD patients, 150 healthy controls) were harmonized and aggregated. A 10-outer, 10-inner Nested-Leave-N-Subjects-Out (N-LNSO) cross-validation was performed to provide an unbiased comparison against seven other consolidated EEG deep learning models. TransformEEG achieved the highest balanced accuracy's median (78.45%) as well as the lowest interquartile range (6.37%) across all the N-LNSO partitions. When combined with data augmentation and threshold correction, median accuracy increased to 80.10%, with an interquartile range of 5.74%. In conclusion, TransformEEG produces more consistent and less skewed results. It demonstrates a substantial reduction in variability and more reliable PD detection using EEG data compared to the other investigated models.

Nataliia Molchanova, Pedro M. Gordaliza, Alessandro Cagol et al.

Trustworthy artificial intelligence (AI) is essential in healthcare, particularly for high-stakes tasks like medical image segmentation. Explainable AI and uncertainty quantification significantly enhance AI reliability by addressing key attributes such as robustness, usability, and explainability. Despite extensive technical advances in uncertainty quantification for medical imaging, understanding the clinical informativeness and interpretability of uncertainty remains limited. This study introduces a novel framework to explain the potential sources of predictive uncertainty, specifically in cortical lesion segmentation in multiple sclerosis using deep ensembles. The proposed analysis shifts the focus from the uncertainty-error relationship towards relevant medical and engineering factors. Our findings reveal that instance-wise uncertainty is strongly related to lesion size, shape, and cortical involvement. Expert rater feedback confirms that similar factors impede annotator confidence. Evaluations conducted on two datasets (206 patients, almost 2000 lesions) under both in-domain and distribution-shift conditions highlight the utility of the framework in different scenarios.

Marek Wodzinski, Henning Müller

Lightsheet microscopy is a powerful 3-D imaging technique that addresses limitations of traditional optical and confocal microscopy but suffers from a low penetration depth and reduced image quality at greater depths. Multiview lightsheet microscopy improves 3-D resolution by combining multiple views but simultaneously increasing the complexity and the photon budget, leading to potential photobleaching and phototoxicity. The FuseMyCells challenge, organized in conjunction with the IEEE ISBI 2025 conference, aims to benchmark deep learning-based solutions for fusing high-quality 3-D volumes from single 3-D views, potentially simplifying procedures and conserving the photon budget. In this work, we propose a contribution to the FuseMyCells challenge based on a two-step procedure. The first step processes a downsampled version of the image to capture the entire region of interest, while the second step uses a patch-based approach for high-resolution inference, incorporating adversarial loss to enhance visual outcomes. This method addresses challenges related to high data resolution, the necessity of global context, and the preservation of high-frequency details. Experimental results demonstrate the effectiveness of our approach, highlighting its potential to improve 3-D image fusion quality and extend the capabilities of lightsheet microscopy. The average SSIM for the nucleus and membranes is greater than 0.85 and 0.91, respectively.

Niccolò Marini, Stefano Marchesin, Lluis Borras Ferris et al.

The increasing availability of biomedical data is helping to design more robust deep learning (DL) algorithms to analyze biomedical samples. Currently, one of the main limitations to train DL algorithms to perform a specific task is the need for medical experts to label data. Automatic methods to label data exist, however automatic labels can be noisy and it is not completely clear when automatic labels can be adopted to train DL models. This paper aims to investigate under which circumstances automatic labels can be adopted to train a DL model on the classification of Whole Slide Images (WSI). The analysis involves multiple architectures, such as Convolutional Neural Networks (CNN) and Vision Transformer (ViT), and over 10000 WSIs, collected from three use cases: celiac disease, lung cancer and colon cancer, which one including respectively binary, multiclass and multilabel data. The results allow identifying 10% as the percentage of noisy labels that lead to train competitive models for the classification of WSIs. Therefore, an algorithm generating automatic labels needs to fit this criterion to be adopted. The application of the Semantic Knowledge Extractor Tool (SKET) algorithm to generate automatic labels leads to performance comparable to the one obtained with manual labels, since it generates a percentage of noisy labels between 2-5%. Automatic labels are as effective as manual ones, reaching solid performance comparable to the one obtained training models with manual labels.

Artur Jurgas, Marek Wodzinski, Marina D'Amato et al.

The problem of artifacts in whole slide image acquisition, prevalent in both clinical workflows and research-oriented settings, necessitates human intervention and re-scanning. Overcoming this challenge requires developing quality control algorithms, that are hindered by the limited availability of relevant annotated data in histopathology. The manual annotation of ground-truth for artifact detection methods is expensive and time-consuming. This work addresses the issue by proposing a method dedicated to augmenting whole slide images with artifacts. The tool seamlessly generates and blends artifacts from an external library to a given histopathology dataset. The augmented datasets are then utilized to train artifact classification methods. The evaluation shows their usefulness in classification of the artifacts, where they show an improvement from 0.10 to 0.01 AUROC depending on the artifact type. The framework, model, weights, and ground-truth annotations are freely released to facilitate open science and reproducible research.

Marek Wodzinski, Henning Müller

Automatic prediction of fluorescently labeled organelles from label-free transmitted light input images is an important, yet difficult task. The traditional way to obtain fluorescence images is related to performing biochemical labeling which is time-consuming and costly. Therefore, an automatic algorithm to perform the task based on the label-free transmitted light microscopy could be strongly beneficial. The importance of the task motivated researchers from the France-BioImaging to organize the LightMyCells challenge where the goal is to propose an algorithm that automatically predicts the fluorescently labeled nucleus, mitochondria, tubulin, and actin, based on the input consisting of bright field, phase contrast, or differential interference contrast microscopic images. In this work, we present the contribution of the AGHSSO team based on a carefully prepared and trained encoder-decoder deep neural network that achieves a considerable score in the challenge, being placed among the best-performing teams.

Mario Martínez-Zarzuela, David González-Ortega, Míriam Antón-Rodríguez et al.

The use of a wide range of computer vision solutions, and more recently high-end Inertial Measurement Units (IMU) have become increasingly popular for assessing human physical activity in clinical and research settings. Nevertheless, to increase the feasibility of patient tracking in out-of-the-lab settings, it is necessary to use a reduced number of devices for movement acquisition. Promising solutions in this context are IMU-based wearables and single camera systems. Additionally, the development of machine learning systems able to recognize and digest clinically relevant data in-the-wild is needed, and therefore determining the ideal input to those is crucial.

Philippe Weitz, Masi Valkonen, Leslie Solorzano et al.

The alignment of tissue between histopathological whole-slide-images (WSI) is crucial for research and clinical applications. Advances in computing, deep learning, and availability of large WSI datasets have revolutionised WSI analysis. Therefore, the current state-of-the-art in WSI registration is unclear. To address this, we conducted the ACROBAT challenge, based on the largest WSI registration dataset to date, including 4,212 WSIs from 1,152 breast cancer patients. The challenge objective was to align WSIs of tissue that was stained with routine diagnostic immunohistochemistry to its H&E-stained counterpart. We compare the performance of eight WSI registration algorithms, including an investigation of the impact of different WSI properties and clinical covariates. We find that conceptually distinct WSI registration methods can lead to highly accurate registration performances and identify covariates that impact performances across methods. These results establish the current state-of-the-art in WSI registration and guide researchers in selecting and developing methods.

José Pereira Amorim, Pedro Henriques Abreu, João Santos et al.

Despite Convolutional Neural Networks having reached human-level performance in some medical tasks, their clinical use has been hindered by their lack of interpretability. Two major interpretability strategies have been proposed to tackle this problem: post-hoc methods and intrinsic methods. Although there are several post-hoc methods to interpret DL models, there is significant variation between the explanations provided by each method, and it a difficult to validate them due to the lack of ground-truth. To address this challenge, we adapted the intrinsical interpretable ProtoPNet for the context of histopathology imaging and compared the attribution maps produced by it and the saliency maps made by post-hoc methods. To evaluate the similarity between saliency map methods and attribution maps we adapted 10 saliency metrics from the saliency model literature, and used the breast cancer metastases detection dataset PatchCamelyon with 327,680 patches of histopathological images of sentinel lymph node sections to validate the proposed approach. Overall, SmoothGrad and Occlusion were found to have a statistically bigger overlap with ProtoPNet while Deconvolution and Lime have been found to have the least.

Niccoló Marini, Manfredo Atzori, Sebastian Otálora et al.

Computational pathology is a domain that aims to develop algorithms to automatically analyze large digitized histopathology images, called whole slide images (WSI). WSIs are produced scanning thin tissue samples that are stained to make specific structures visible. They show stain colour heterogeneity due to different preparation and scanning settings applied across medical centers. Stain colour heterogeneity is a problem to train convolutional neural networks (CNN), the state-of-the-art algorithms for most computational pathology tasks, since CNNs usually underperform when tested on images including different stain variations than those within data used to train the CNN. Despite several methods that were developed, stain colour heterogeneity is still an unsolved challenge that limits the development of CNNs that can generalize on data from several medical centers. This paper aims to present a novel method to train CNNs that better generalize on data including several colour variations. The method, called H&E-adversarial CNN, exploits H&E matrix information to learn stain-invariant features during the training. The method is evaluated on the classification of colon and prostate histopathology images, involving eleven heterogeneous datasets, and compared with five other techniques used to handle stain colour heterogeneity. H&E-adversarial CNNs show an improvement in performance compared to the other algorithms, demonstrating that it can help to better deal with stain colour heterogeneous images.

Annika Reinke, Minu D. Tizabi, Carole H. Sudre et al.

While the importance of automatic image analysis is continuously increasing, recent meta-research revealed major flaws with respect to algorithm validation. Performance metrics are particularly key for meaningful, objective, and transparent performance assessment and validation of the used automatic algorithms, but relatively little attention has been given to the practical pitfalls when using specific metrics for a given image analysis task. These are typically related to (1) the disregard of inherent metric properties, such as the behaviour in the presence of class imbalance or small target structures, (2) the disregard of inherent data set properties, such as the non-independence of the test cases, and (3) the disregard of the actual biomedical domain interest that the metrics should reflect. This living dynamically document has the purpose to illustrate important limitations of performance metrics commonly applied in the field of image analysis. In this context, it focuses on biomedical image analysis problems that can be phrased as image-level classification, semantic segmentation, instance segmentation, or object detection task. The current version is based on a Delphi process on metrics conducted by an international consortium of image analysis experts from more than 60 institutions worldwide.

Adrien Depeursinge, Vincent Andrearczyk, Philip Whybra et al.

The Image Biomarker Standardisation Initiative (IBSI) aims to improve reproducibility of radiomics studies by standardising the computational process of extracting image biomarkers (features) from images. We have previously established reference values for 169 commonly used features, created a standard radiomics image processing scheme, and developed reporting guidelines for radiomic studies. However, several aspects are not standardised. Here we present a complete version of a reference manual on the use of convolutional filters in radiomics and quantitative image analysis. Filters, such as wavelets or Laplacian of Gaussian filters, play an important part in emphasising specific image characteristics such as edges and blobs. Features derived from filter response maps were found to be poorly reproducible. This reference manual provides definitions for convolutional filters, parameters that should be reported, reference feature values, and tests to verify software compliance with the reference standard.

Lena Maier-Hein, Annika Reinke, Michal Kozubek et al.

The number of biomedical image analysis challenges organized per year is steadily increasing. These international competitions have the purpose of benchmarking algorithms on common data sets, typically to identify the best method for a given problem. Recent research, however, revealed that common practice related to challenge reporting does not allow for adequate interpretation and reproducibility of results. To address the discrepancy between the impact of challenges and the quality (control), the Biomedical I mage Analysis ChallengeS (BIAS) initiative developed a set of recommendations for the reporting of challenges. The BIAS statement aims to improve the transparency of the reporting of a biomedical image analysis challenge regardless of field of application, image modality or task category assessed. This article describes how the BIAS statement was developed and presents a checklist which authors of biomedical image analysis challenges are encouraged to include in their submission when giving a paper on a challenge into review. The purpose of the checklist is to standardize and facilitate the review process and raise interpretability and reproducibility of challenge results by making relevant information explicit.

Mara Graziani, Vincent Andrearczyk, Henning Müller

Explanations for deep neural network predictions in terms of domain-related concepts can be valuable in medical applications, where justifications are important for confidence in the decision-making. In this work, we propose a methodology to exploit continuous concept measures as Regression Concept Vectors (RCVs) in the activation space of a layer. The directional derivative of the decision function along the RCVs represents the network sensitivity to increasing values of a given concept measure. When applied to breast cancer grading, nuclei texture emerges as a relevant concept in the detection of tumor tissue in breast lymph node samples. We evaluate score robustness and consistency by statistical analysis.

Lena Maier-Hein, Matthias Eisenmann, Annika Reinke et al.

International challenges have become the standard for validation of biomedical image analysis methods. Given their scientific impact, it is surprising that a critical analysis of common practices related to the organization of challenges has not yet been performed. In this paper, we present a comprehensive analysis of biomedical image analysis challenges conducted up to now. We demonstrate the importance of challenges and show that the lack of quality control has critical consequences. First, reproducibility and interpretation of the results is often hampered as only a fraction of relevant information is typically provided. Second, the rank of an algorithm is generally not robust to a number of variables such as the test data used for validation, the ranking scheme applied and the observers that make the reference annotations. To overcome these problems, we recommend best practice guidelines and define open research questions to be addressed in the future.

Antonio Foncubierta-Rodríguez, Henning Müller, Adrien Depeursinge

The Bag--of--Visual--Words (BoVW) is a visual description technique that aims at shortening the semantic gap by partitioning a low--level feature space into regions of the feature space that potentially correspond to visual concepts and by giving more value to this space. In this paper we present a conceptual analysis of three major properties of language grammar and how they can be adapted to the computer vision and image understanding domain based on the bag of visual words paradigm. Evaluation of the visual grammar shows that a positive impact on classification accuracy and/or descriptor size is obtained when the technique are applied when the proposed techniques are applied.

Allan Hanbury, Henning Müller, Krisztian Balog et al.

Evaluation in empirical computer science is essential to show progress and assess technologies developed. Several research domains such as information retrieval have long relied on systematic evaluation to measure progress: here, the Cranfield paradigm of creating shared test collections, defining search tasks, and collecting ground truth for these tasks has persisted up until now. In recent years, however, several new challenges have emerged that do not fit this paradigm very well: extremely large data sets, confidential data sets as found in the medical domain, and rapidly changing data sets as often encountered in industry. Also, crowdsourcing has changed the way that industry approaches problem-solving with companies now organizing challenges and handing out monetary awards to incentivize people to work on their challenges, particularly in the field of machine learning. This white paper is based on discussions at a workshop on Evaluation-as-a-Service (EaaS). EaaS is the paradigm of not providing data sets to participants and have them work on the data locally, but keeping the data central and allowing access via Application Programming Interfaces (API), Virtual Machines (VM) or other possibilities to ship executables. The objective of this white paper are to summarize and compare the current approaches and consolidate the experiences of these approaches to outline the next steps of EaaS, particularly towards sustainable research infrastructures. This white paper summarizes several existing approaches to EaaS and analyzes their usage scenarios and also the advantages and disadvantages. The many factors influencing EaaS are overviewed, and the environment in terms of motivations for the various stakeholders, from funding agencies to challenge organizers, researchers and participants, to industry interested in supplying real-world problems for which they require solutions.