Josien P. W. Pluim

Ishaan Bhat, Josien P. W. Pluim, Max A. Viergever et al.

We propose the Generalized Probabilistic U-Net, which extends the Probabilistic U-Net by allowing more general forms of the Gaussian distribution as the latent space distribution that can better approximate the uncertainty in the reference segmentations. We study the effect the choice of latent space distribution has on capturing the variation in the reference segmentations for lung tumors and white matter hyperintensities in the brain. We show that the choice of distribution affects the sample diversity of the predictions and their overlap with respect to the reference segmentations. We have made our implementation available at https://github.com/ishaanb92/GeneralizedProbabilisticUNet

Ishaan Bhat, Josien P. W. Pluim, Max A. Viergever et al.

Deep learning techniques show success in detecting objects in medical images, but still suffer from false-positive predictions that may hinder accurate diagnosis. The estimated uncertainty of the neural network output has been used to flag incorrect predictions. We study the role played by features computed from neural network uncertainty estimates and shape-based features computed from binary predictions in reducing false positives in liver lesion detection by developing a classification-based post-processing step for different uncertainty estimation methods. We demonstrate an improvement in the lesion detection performance of the neural network (with respect to F1-score) for all uncertainty estimation methods on two datasets, comprising abdominal MR and CT images, respectively. We show that features computed from neural network uncertainty estimates tend not to contribute much toward reducing false positives. Our results show that factors like class imbalance (true over false positive ratio) and shape-based features extracted from uncertainty maps play an important role in distinguishing false positive from true positive predictions. Our code can be found at https://github.com/ishaanb92/FPCPipeline.

Ishaan Bhat, Josien P. W. Pluim, Hugo J. Kuijf

We propose the Generalized Probabilistic U-Net, which extends the Probabilistic U-Net by allowing more general forms of the Gaussian distribution as the latent space distribution that can better approximate the uncertainty in the reference segmentations. We study the effect the choice of latent space distribution has on capturing the uncertainty in the reference segmentations using the LIDC-IDRI dataset. We show that the choice of distribution affects the sample diversity of the predictions and their overlap with respect to the reference segmentations. For the LIDC-IDRI dataset, we show that using a mixture of Gaussians results in a statistically significant improvement in the generalized energy distance (GED) metric with respect to the standard Probabilistic U-Net. We have made our implementation available at https://github.com/ishaanb92/GeneralizedProbabilisticUNet

Sina Amirrajab, Cristian Lorenz, Juergen Weese et al.

We propose a method for synthesizing cardiac magnetic resonance (MR) images with plausible heart pathologies and realistic appearances for the purpose of generating labeled data for the application of supervised deep-learning (DL) training. The image synthesis consists of label deformation and label-to-image translation tasks. The former is achieved via latent space interpolation in a VAE model, while the latter is accomplished via a label-conditional GAN model. We devise three approaches for label manipulation in the latent space of the trained VAE model; i) \textbf{intra-subject synthesis} aiming to interpolate the intermediate slices of a subject to increase the through-plane resolution, ii) \textbf{inter-subject synthesis} aiming to interpolate the geometry and appearance of intermediate images between two dissimilar subjects acquired with different scanner vendors, and iii) \textbf{pathology synthesis} aiming to synthesize a series of pseudo-pathological synthetic subjects with characteristics of a desired heart disease. Furthermore, we propose to model the relationship between 2D slices in the latent space of the VAE prior to reconstruction for generating 3D-consistent subjects from stacking up 2D slice-by-slice generations. We demonstrate that such an approach could provide a solution to diversify and enrich an available database of cardiac MR images and to pave the way for the development of generalizable DL-based image analysis algorithms. We quantitatively evaluate the quality of the synthesized data in an augmentation scenario to achieve generalization and robustness to multi-vendor and multi-disease data for image segmentation. Our code is available at https://github.com/sinaamirrajab/CardiacPathologySynthesis.

Yiping Jiao, Jeroen van der Laak, Shadi Albarqouni et al. · eth-zurich

We introduce LYSTO, the Lymphocyte Assessment Hackathon, which was held in conjunction with the MICCAI 2019 Conference in Shenzen (China). The competition required participants to automatically assess the number of lymphocytes, in particular T-cells, in histopathological images of colon, breast, and prostate cancer stained with CD3 and CD8 immunohistochemistry. Differently from other challenges setup in medical image analysis, LYSTO participants were solely given a few hours to address this problem. In this paper, we describe the goal and the multi-phase organization of the hackathon; we describe the proposed methods and the on-site results. Additionally, we present post-competition results where we show how the presented methods perform on an independent set of lung cancer slides, which was not part of the initial competition, as well as a comparison on lymphocyte assessment between presented methods and a panel of pathologists. We show that some of the participants were capable to achieve pathologist-level performance at lymphocyte assessment. After the hackathon, LYSTO was left as a lightweight plug-and-play benchmark dataset on grand-challenge website, together with an automatic evaluation platform. LYSTO has supported a number of research in lymphocyte assessment in oncology. LYSTO will be a long-lasting educational challenge for deep learning and digital pathology, it is available at https://lysto.grand-challenge.org/.

Rob A. J. de Mooij, Josien P. W. Pluim, Cian M. Scannell

Self-supervised pretraining (SSP) has shown promising results in learning from large unlabeled datasets and, thus, could be useful for automated cardiovascular magnetic resonance (CMR) short-axis cine segmentation. However, inconsistent reports of the benefits of SSP for segmentation have made it difficult to apply SSP to CMR. Therefore, this study aimed to evaluate SSP methods for CMR cine segmentation. To this end, short-axis cine stacks of 296 subjects (90618 2D slices) were used for unlabeled pretraining with four SSP methods; SimCLR, positional contrastive learning, DINO, and masked image modeling (MIM). Subsets of varying numbers of subjects were used for supervised fine-tuning of 2D models for each SSP method, as well as to train a 2D baseline model from scratch. The fine-tuned models were compared to the baseline using the 3D Dice similarity coefficient (DSC) in a test dataset of 140 subjects. The SSP methods showed no performance gains with the largest supervised fine-tuning subset compared to the baseline (DSC = 0.89). When only 10 subjects (231 2D slices) are available for supervised training, SSP using MIM (DSC = 0.86) improves over training from scratch (DSC = 0.82). This study found that SSP is valuable for CMR cine segmentation when labeled training data is scarce, but does not aid state-of-the-art deep learning methods when ample labeled data is available. Moreover, the choice of SSP method is important. The code is publicly available at: https://github.com/q-cardIA/ssp-cmr-cine-segmentation

Seyed Mostafa Kia, Nastaran Mohammadian Rad, Daniel van Opstal et al.

While data are the primary fuel for machine learning models, they often suffer from missing values, especially when collected in real-world scenarios. However, many off-the-shelf machine learning models, including artificial neural network models, are unable to handle these missing values directly. Therefore, extra data preprocessing and curation steps, such as data imputation, are inevitable before learning and prediction processes. In this study, we propose a simple and intuitive yet effective method for pruning missing values (PROMISSING) during learning and inference steps in neural networks. In this method, there is no need to remove or impute the missing values; instead, the missing values are treated as a new source of information (representing what we do not know). Our experiments on simulated data, several classification and regression benchmarks, and a multi-modal clinical dataset show that PROMISSING results in similar prediction performance compared to various imputation techniques. In addition, our experiments show models trained using PROMISSING techniques are becoming less decisive in their predictions when facing incomplete samples with many unknowns. This finding hopefully advances machine learning models from being pure predicting machines to more realistic thinkers that can also say "I do not know" when facing incomplete sources of information.

Evi M. C. Huijben, Sina Amirrajab, Josien P. W. Pluim

Out-of-distribution (OOD) detection is crucial for the safety and reliability of artificial intelligence algorithms, especially in the medical domain. In the context of the Medical OOD (MOOD) detection challenge 2023, we propose a pipeline that combines a histogram-based method and a diffusion-based method. The histogram-based method is designed to accurately detect homogeneous anomalies in the toy examples of the challenge, such as blobs with constant intensity values. The diffusion-based method is based on one of the latest methods for unsupervised anomaly detection, called DDPM-OOD. We explore this method and propose extensive post-processing steps for pixel-level and sample-level anomaly detection on brain MRI and abdominal CT data provided by the challenge. Our results show that the proposed DDPM method is sensitive to blur and bias field samples, but faces challenges with anatomical deformation, black slice, and swapped patches. These findings suggest that further research is needed to improve the performance of DDPM for OOD detection in medical images.

Ralf Raumanns, Gerard Schouten, Josien P. W. Pluim et al.

The influence of bias in datasets on the fairness of model predictions is a topic of ongoing research in various fields. We evaluate the performance of skin lesion classification using ResNet-based CNNs, focusing on patient sex variations in training data and three different learning strategies. We present a linear programming method for generating datasets with varying patient sex and class labels, taking into account the correlations between these variables. We evaluated the model performance using three different learning strategies: a single-task model, a reinforcing multi-task model, and an adversarial learning scheme. Our observations include: 1) sex-specific training data yields better results, 2) single-task models exhibit sex bias, 3) the reinforcement approach does not remove sex bias, 4) the adversarial model eliminates sex bias in cases involving only female patients, and 5) datasets that include male patients enhance model performance for the male subgroup, even when female patients are the majority. To generalise these findings, in future research, we will examine more demographic attributes, like age, and other possibly confounding factors, such as skin colour and artefacts in the skin lesions. We make all data and models available on GitHub.

Sina Amirrajab, Yasmina Al Khalil, Cristian Lorenz et al.

There has been considerable interest in the MR physics-based simulation of a database of virtual cardiac MR images for the development of deep-learning analysis networks. However, the employment of such a database is limited or shows suboptimal performance due to the realism gap, missing textures, and the simplified appearance of simulated images. In this work we 1) provide image simulation on virtual XCAT subjects with varying anatomies, and 2) propose sim2real translation network to improve image realism. Our usability experiments suggest that sim2real data exhibits a good potential to augment training data and boost the performance of a segmentation algorithm.

Hassan Keshvarikhojasteh, Josien Pluim, Mitko Veta

This paper introduces MAD-MIL, a Multi-head Attention-based Deep Multiple Instance Learning model, designed for weakly supervised Whole Slide Images (WSIs) classification in digital pathology. Inspired by the multi-head attention mechanism of the Transformer, MAD-MIL simplifies model complexity while achieving competitive results against advanced models like CLAM and DS-MIL. Evaluated on the MNIST-BAGS and public datasets, including TUPAC16, TCGA BRCA, TCGA LUNG, and TCGA KIDNEY, MAD-MIL consistently outperforms ABMIL. This demonstrates enhanced information diversity, interpretability, and efficiency in slide representation. The model's effectiveness, coupled with fewer trainable parameters and lower computational complexity makes it a promising solution for automated pathology workflows. Our code is available at https://github.com/tueimage/MAD-MIL.

Tim J. M. Jaspers, Ronald L. P. D. de Jong, Yiping Li et al.

Foundation models have revolutionized computer vision by achieving vastly superior performance across diverse tasks through large-scale pretraining on extensive datasets. However, their application in surgical computer vision has been limited. This study addresses this gap by introducing SurgeNetXL, a novel surgical foundation model that sets a new benchmark in surgical computer vision. Trained on the largest reported surgical dataset to date, comprising over 4.7 million video frames, SurgeNetXL achieves consistent top-tier performance across six datasets spanning four surgical procedures and three tasks, including semantic segmentation, phase recognition, and critical view of safety (CVS) classification. Compared with the best-performing surgical foundation models, SurgeNetXL shows mean improvements of 2.4, 9.0, and 12.6 percent for semantic segmentation, phase recognition, and CVS classification, respectively. Additionally, SurgeNetXL outperforms the best-performing ImageNet-based variants by 14.4, 4.0, and 1.6 percent in the respective tasks. In addition to advancing model performance, this study provides key insights into scaling pretraining datasets, extending training durations, and optimizing model architectures specifically for surgical computer vision. These findings pave the way for improved generalizability and robustness in data-scarce scenarios, offering a comprehensive framework for future research in this domain. All models and a subset of the SurgeNetXL dataset, including over 2 million video frames, are publicly available at: https://github.com/TimJaspers0801/SurgeNet.

Hassan Keshvarikhojasteh, Mihail Tifrea, Sibylle Hess et al.

Multiple instance learning (MIL) is a promising approach for weakly supervised classification in pathology using whole slide images (WSIs). However, conventional MIL methods such as Attention-Based Deep Multiple Instance Learning (ABMIL) typically disregard spatial interactions among patches that are crucial to pathological diagnosis. Recent advancements, such as Transformer based MIL (TransMIL), have incorporated spatial context and inter-patch relationships. However, it remains unclear whether explicitly modeling patch relationships yields similar performance gains in ABMIL, which relies solely on Multi-Layer Perceptrons (MLPs). In contrast, TransMIL employs Transformer-based layers, introducing a fundamental architectural shift at the cost of substantially increased computational complexity. In this work, we enhance the ABMIL framework by integrating interaction-aware representations to address this question. Our proposed model, Global ABMIL (GABMIL), explicitly captures inter-instance dependencies while preserving computational efficiency. Experimental results on two publicly available datasets for tumor subtyping in breast and lung cancers demonstrate that GABMIL achieves up to a 7 percentage point improvement in AUPRC and a 5 percentage point increase in the Kappa score over ABMIL, with minimal or no additional computational overhead. These findings underscore the importance of incorporating patch interactions within MIL frameworks. Our code is available at \href{https://github.com/tueimage/GABMIL}{\texttt{GABMIL}}.

Hong Liu, Haosen Yang, Federica Eduati et al.

Leveraging multimodal data, particularly the integration of whole-slide histology images (WSIs) and transcriptomic profiles, holds great promise for improving cancer survival prediction. However, excessive redundancy in multimodal data can degrade model performance. In this paper, we propose Adaptive Prototype Learning (APL), a novel and effective approach for multimodal cancer survival analysis. APL adaptively learns representative prototypes in a data-driven manner, reducing redundancy while preserving critical information. Our method employs two sets of learnable query vectors that serve as a bridge between high-dimensional representations and survival prediction, capturing task-relevant features. Additionally, we introduce a multimodal mixed self-attention mechanism to enable cross-modal interactions, further enhancing information fusion. Extensive experiments on five benchmark cancer datasets demonstrate the superiority of our approach over existing methods. The code is available at https://github.com/HongLiuuuuu/APL.

Hong Liu, Haosen Yang, Paul J. van Diest et al.

The Segment Anything Model (SAM) marks a significant advancement in segmentation models, offering robust zero-shot abilities and dynamic prompting. However, existing medical SAMs are not suitable for the multi-scale nature of whole-slide images (WSIs), restricting their effectiveness. To resolve this drawback, we present WSI-SAM, enhancing SAM with precise object segmentation capabilities for histopathology images using multi-resolution patches, while preserving its efficient, prompt-driven design, and zero-shot abilities. To fully exploit pretrained knowledge while minimizing training overhead, we keep SAM frozen, introducing only minimal extra parameters and computational overhead. In particular, we introduce High-Resolution (HR) token, Low-Resolution (LR) token and dual mask decoder. This decoder integrates the original SAM mask decoder with a lightweight fusion module that integrates features at multiple scales. Instead of predicting a mask independently, we integrate HR and LR token at intermediate layer to jointly learn features of the same object across multiple resolutions. Experiments show that our WSI-SAM outperforms state-of-the-art SAM and its variants. In particular, our model outperforms SAM by 4.1 and 2.5 percent points on a ductal carcinoma in situ (DCIS) segmentation tasks and breast cancer metastasis segmentation task (CAMELYON16 dataset). The code will be available at https://github.com/HongLiuuuuu/WSI-SAM.

Ralf Raumanns, Gerard Schouten, Max Joosten et al.

We present ENHANCE, an open dataset with multiple annotations to complement the existing ISIC and PH2 skin lesion classification datasets. This dataset contains annotations of visual ABC (asymmetry, border, colour) features from non-expert annotation sources: undergraduate students, crowd workers from Amazon MTurk and classic image processing algorithms. In this paper we first analyse the correlations between the annotations and the diagnostic label of the lesion, as well as study the agreement between different annotation sources. Overall we find weak correlations of non-expert annotations with the diagnostic label, and low agreement between different annotation sources. We then study multi-task learning (MTL) with the annotations as additional labels, and show that non-expert annotations can improve (ensembles of) state-of-the-art convolutional neural networks via MTL. We hope that our dataset can be used in further research into multiple annotations and/or MTL. All data and models are available on Github: https://github.com/raumannsr/ENHANCE.

Linde S. Hesse, Pim A. de Jong, Josien P. W. Pluim et al.

Early detection of lung cancer has been proven to decrease mortality significantly. A recent development in computed tomography (CT), spectral CT, can potentially improve diagnostic accuracy, as it yields more information per scan than regular CT. However, the shear workload involved with analyzing a large number of scans drives the need for automated diagnosis methods. Therefore, we propose a detection and classification system for lung nodules in CT scans. Furthermore, we want to observe whether spectral images can increase classifier performance. For the detection of nodules we trained a VGG-like 3D convolutional neural net (CNN). To obtain a primary tumor classifier for our dataset we pre-trained a 3D CNN with similar architecture on nodule malignancies of a large publicly available dataset, the LIDC-IDRI dataset. Subsequently we used this pre-trained network as feature extractor for the nodules in our dataset. The resulting feature vectors were classified into two (benign/malignant) and three (benign/primary lung cancer/metastases) classes using support vector machine (SVM). This classification was performed both on nodule- and scan-level. We obtained state-of-the art performance for detection and malignancy regression on the LIDC-IDRI database. Classification performance on our own dataset was higher for scan- than for nodule-level predictions. For the three-class scan-level classification we obtained an accuracy of 78\%. Spectral features did increase classifier performance, but not significantly. Our work suggests that a pre-trained feature extractor can be used as primary tumor origin classifier for lung nodules, eliminating the need for elaborate fine-tuning of a new network and large datasets. Code is available at \url{https://github.com/tueimage/lung-nodule-msc-2018}.

Evi M. C. Huijben, Sina Amirrajab, Josien P. W. Pluim

Out-of-distribution (OOD) detection is crucial for safely deploying automated medical image analysis systems, as abnormal patterns in images could hamper their performance. However, OOD detection in medical imaging remains an open challenge, and we address three gaps: the underexplored potential of a simple OOD detection model, the lack of optimization of deep learning strategies specifically for OOD detection, and the selection of appropriate reconstruction metrics. In this study, we investigated the effectiveness of a reconstruction-based autoencoder for unsupervised detection of synthetic artifacts in brain MRI. We evaluated the general reconstruction capability of the model, analyzed the impact of the selected training epoch and reconstruction metrics, assessed the potential of model and/or metric ensembles, and tested the model on a dataset containing a diverse range of artifacts. Among the metrics assessed, the contrast component of SSIM and LPIPS consistently outperformed others in detecting homogeneous circular anomalies. By combining two well-converged models and using LPIPS and contrast as reconstruction metrics, we achieved a pixel-level area under the Precision-Recall curve of 0.66. Furthermore, with the more realistic OOD dataset, we observed that the detection performance varied between artifact types; local artifacts were more difficult to detect, while global artifacts showed better detection results. These findings underscore the importance of carefully selecting metrics and model configurations, and highlight the need for tailored approaches, as standard deep learning approaches do not always align with the unique needs of OOD detection.

H. Keshvarikhojasteh, J. P. W. Pluim, M. Veta

In computational pathology, random sampling of patches during training of Multiple Instance Learning (MIL) methods is computationally efficient and serves as a regularization strategy. Despite its promising benefits, questions concerning performance trends for varying sample sizes and its influence on model interpretability remain. Addressing these, we reach an optimal performance enhancement of 1.7% using thirty percent of patches on the CAMELYON16 dataset, and 3.7% with only eight samples on the TUPAC16 dataset. We also find interpretability effects are strongly dataset-dependent, with interpretability impacted on CAMELYON16, while remaining unaffected on TUPAC16. This reinforces that both the performance and interpretability relationships with sampling are closely task-specific. End-to-end training with 1024 samples reveals improvements across both datasets compared to pre-extracted features, further highlighting the potential of this efficient approach.

Noortje I. P. Schueler, Nathan C. K. Wong, Richard J. Crawley et al.

Background: Quantitative stress perfusion cardiovascular magnetic resonance (CMR) is a powerful tool for assessing myocardial ischemia. Motion correction is essential for accurate pixel-wise mapping but traditional registration-based methods are slow and sensitive to acquisition variability, limiting robustness and scalability. Methods: We developed an unsupervised deep learning-based motion correction pipeline that replaces iterative registration with efficient one-shot estimation. The method corrects motion in three steps and uses robust principal component analysis to reduce contrast-related effects. It aligns the perfusion series and auxiliary images (arterial input function and proton density-weighted series). Models were trained and validated on multivendor data from 201 patients, with 38 held out for testing. Performance was assessed via temporal alignment and quantitative perfusion values, compared to a previously published registration-based method. Results: The deep learning approach significantly improved temporal smoothness of time-intensity curves (p<0.001). Myocardial alignment (Dice = 0.92 (0.04) and 0.91 (0.05)) was comparable to the baseline and superior to before registration (Dice = 0.80 (0.09), p<0.001). Perfusion maps showed reduced motion, with lower standard deviation in the myocardium (0.52 (0.39) ml/min/g) compared to baseline (0.55 (0.44) ml/min/g). Processing time was reduced 15-fold. Conclusion: This deep learning pipeline enables fast, robust motion correction for stress perfusion CMR, improving accuracy across dynamic and auxiliary images. Trained on multivendor data, it generalizes across sequences and may facilitate broader clinical adoption of quantitative perfusion imaging.

Mahmoud Ibrahim, Yasmina Al Khalil, Sina Amirrajab et al.

This paper presents a comprehensive systematic review of generative models (GANs, VAEs, DMs, and LLMs) used to synthesize various medical data types, including imaging (dermoscopic, mammographic, ultrasound, CT, MRI, and X-ray), text, time-series, and tabular data (EHR). Unlike previous narrowly focused reviews, our study encompasses a broad array of medical data modalities and explores various generative models. Our search strategy queries databases such as Scopus, PubMed, and ArXiv, focusing on recent works from January 2021 to November 2023, excluding reviews and perspectives. This period emphasizes recent advancements beyond GANs, which have been extensively covered previously. The survey reveals insights from three key aspects: (1) Synthesis applications and purpose of synthesis, (2) generation techniques, and (3) evaluation methods. It highlights clinically valid synthesis applications, demonstrating the potential of synthetic data to tackle diverse clinical requirements. While conditional models incorporating class labels, segmentation masks and image translations are prevalent, there is a gap in utilizing prior clinical knowledge and patient-specific context, suggesting a need for more personalized synthesis approaches and emphasizing the importance of tailoring generative approaches to the unique characteristics of medical data. Additionally, there is a significant gap in using synthetic data beyond augmentation, such as for validation and evaluation of downstream medical AI models. The survey uncovers that the lack of standardized evaluation methodologies tailored to medical images is a barrier to clinical application, underscoring the need for in-depth evaluation approaches, benchmarking, and comparative studies to promote openness and collaboration.

Juul P. A. van Boxtel, Vincent R. J. Vousten, Josien Pluim et al.

Ultrasound-guided regional anesthesia (UGRA) can replace general anesthesia (GA), improving pain control and recovery time. This method can be applied on the brachial plexus (BP) after clavicular surgeries. However, identification of the BP from ultrasound (US) images is difficult, even for trained professionals. To address this problem, convolutional neural networks (CNNs) and more advanced deep neural networks (DNNs) can be used for identification and segmentation of the BP nerve region. In this paper, we propose a hybrid model consisting of a classification model followed by a segmentation model to segment BP nerve regions in ultrasound images. A CNN model is employed as a classifier to precisely select the images with the BP region. Then, a U-net or M-net model is used for the segmentation. Our experimental results indicate that the proposed hybrid model significantly improves the segmentation performance over a single segmentation model.

Friso G. Heslinga, Ruben T. Lucassen, Myrthe A. van den Berg et al.

Corneal thickness (pachymetry) maps can be used to monitor restoration of corneal endothelial function, for example after Descemet's membrane endothelial keratoplasty (DMEK). Automated delineation of the corneal interfaces in anterior segment optical coherence tomography (AS-OCT) can be challenging for corneas that are irregularly shaped due to pathology, or as a consequence of surgery, leading to incorrect thickness measurements. In this research, deep learning is used to automatically delineate the corneal interfaces and measure corneal thickness with high accuracy in post-DMEK AS-OCT B-scans. Three different deep learning strategies were developed based on 960 B-scans from 50 patients. On an independent test set of 320 B-scans, corneal thickness could be measured with an error of 13.98 to 15.50 micrometer for the central 9 mm range, which is less than 3% of the average corneal thickness. The accurate thickness measurements were used to construct detailed pachymetry maps. Moreover, follow-up scans could be registered based on anatomical landmarks to obtain differential pachymetry maps. These maps may enable a more comprehensive understanding of the restoration of the endothelial function after DMEK, where thickness often varies throughout different regions of the cornea, and subsequently contribute to a standardized postoperative regime.

Ishaan Bhat, Hugo J. Kuijf, Veronika Cheplygina et al.

Despite the successes of deep learning techniques at detecting objects in medical images, false positive detections occur which may hinder an accurate diagnosis. We propose a technique to reduce false positive detections made by a neural network using an SVM classifier trained with features derived from the uncertainty map of the neural network prediction. We demonstrate the effectiveness of this method for the detection of liver lesions on a dataset of abdominal MR images. We find that the use of a dropout rate of 0.5 produces the least number of false positives in the neural network predictions and the trained classifier filters out approximately 90% of these false positives detections in the test-set.

Maxime W. Lafarge, Josien P. W. Pluim, Mitko Veta

Unsupervised learning enables modeling complex images without the need for annotations. The representation learned by such models can facilitate any subsequent analysis of large image datasets. However, some generative factors that cause irrelevant variations in images can potentially get entangled in such a learned representation causing the risk of negatively affecting any subsequent use. The orientation of imaged objects, for instance, is often arbitrary/irrelevant, thus it can be desired to learn a representation in which the orientation information is disentangled from all other factors. Here, we propose to extend the Variational Auto-Encoder framework by leveraging the group structure of rotation-equivariant convolutional networks to learn orientation-wise disentangled generative factors of histopathology images. This way, we enforce a novel partitioning of the latent space, such that oriented and isotropic components get separated. We evaluated this structured representation on a dataset that consists of tissue regions for which nuclear pleomorphism and mitotic activity was assessed by expert pathologists. We show that the trained models efficiently disentangle the inherent orientation information of single-cell images. In comparison to classical approaches, the resulting aggregated representation of sub-populations of cells produces higher performances in subsequent tasks.

Sina Amirrajab, Samaneh Abbasi-Sureshjani, Yasmina Al Khalil et al.

Generative adversarial networks (GANs) have provided promising data enrichment solutions by synthesizing high-fidelity images. However, generating large sets of labeled images with new anatomical variations remains unexplored. We propose a novel method for synthesizing cardiac magnetic resonance (CMR) images on a population of virtual subjects with a large anatomical variation, introduced using the 4D eXtended Cardiac and Torso (XCAT) computerized human phantom. We investigate two conditional image synthesis approaches grounded on a semantically-consistent mask-guided image generation technique: 4-class and 8-class XCAT-GANs. The 4-class technique relies on only the annotations of the heart; while the 8-class technique employs a predicted multi-tissue label map of the heart-surrounding organs and provides better guidance for our conditional image synthesis. For both techniques, we train our conditional XCAT-GAN with real images paired with corresponding labels and subsequently at the inference time, we substitute the labels with the XCAT derived ones. Therefore, the trained network accurately transfers the tissue-specific textures to the new label maps. By creating 33 virtual subjects of synthetic CMR images at the end-diastolic and end-systolic phases, we evaluate the usefulness of such data in the downstream cardiac cavity segmentation task under different augmentation strategies. Results demonstrate that even with only 20% of real images (40 volumes) seen during training, segmentation performance is retained with the addition of synthetic CMR images. Moreover, the improvement in utilizing synthetic images for augmenting the real data is evident through the reduction of Hausdorff distance up to 28% and an increase in the Dice score up to 5%, indicating a higher similarity to the ground truth in all dimensions.

Friso G. Heslinga, Mark Alberti, Josien P. W. Pluim et al.

Purpose: We developed a method to automatically locate and quantify graft detachment after Descemet's Membrane Endothelial Keratoplasty (DMEK) in Anterior Segment Optical Coherence Tomography (AS-OCT) scans. Methods: 1280 AS-OCT B-scans were annotated by a DMEK expert. Using the annotations, a deep learning pipeline was developed to localize scleral spur, center the AS-OCT B-scans and segment the detached graft sections. Detachment segmentation model performance was evaluated per B-scan by comparing (1) length of detachment and (2) horizontal projection of the detached sections with the expert annotations. Horizontal projections were used to construct graft detachment maps. All final evaluations were done on a test set that was set apart during training of the models. A second DMEK expert annotated the test set to determine inter-rater performance. Results: Mean scleral spur localization error was 0.155 mm, whereas the inter-rater difference was 0.090 mm. The estimated graft detachment lengths were in 69% of the cases within a 10-pixel (~150μm) difference from the ground truth (77% for the second DMEK expert). Dice scores for the horizontal projections of all B-scans with detachments were 0.896 and 0.880 for our model and the second DMEK expert respectively. Conclusion: Our deep learning model can be used to automatically and instantly localize graft detachment in AS-OCT B-scans. Horizontal detachment projections can be determined with the same accuracy as a human DMEK expert, allowing for the construction of accurate graft detachment maps. Translational Relevance: Automated localization and quantification of graft detachment can support DMEK research and standardize clinical decision making.

Maxime W. Lafarge, Erik J. Bekkers, Josien P. W. Pluim et al.

Rotation-invariance is a desired property of machine-learning models for medical image analysis and in particular for computational pathology applications. We propose a framework to encode the geometric structure of the special Euclidean motion group SE(2) in convolutional networks to yield translation and rotation equivariance via the introduction of SE(2)-group convolution layers. This structure enables models to learn feature representations with a discretized orientation dimension that guarantees that their outputs are invariant under a discrete set of rotations. Conventional approaches for rotation invariance rely mostly on data augmentation, but this does not guarantee the robustness of the output when the input is rotated. At that, trained conventional CNNs may require test-time rotation augmentation to reach their full capability. This study is focused on histopathology image analysis applications for which it is desirable that the arbitrary global orientation information of the imaged tissues is not captured by the machine learning models. The proposed framework is evaluated on three different histopathology image analysis tasks (mitosis detection, nuclei segmentation and tumor classification). We present a comparative analysis for each problem and show that consistent increase of performances can be achieved when using the proposed framework.

Samaneh Abbasi-Sureshjani, Sina Amirrajab, Cristian Lorenz et al.

We propose a hybrid controllable image generation method to synthesize anatomically meaningful 3D+t labeled Cardiac Magnetic Resonance (CMR) images. Our hybrid method takes the mechanistic 4D eXtended CArdiac Torso (XCAT) heart model as the anatomical ground truth and synthesizes CMR images via a data-driven Generative Adversarial Network (GAN). We employ the state-of-the-art SPatially Adaptive De-normalization (SPADE) technique for conditional image synthesis to preserve the semantic spatial information of ground truth anatomy. Using the parameterized motion model of the XCAT heart, we generate labels for 25 time frames of the heart for one cardiac cycle at 18 locations for the short axis view. Subsequently, realistic images are generated from these labels, with modality-specific features that are learned from real CMR image data. We demonstrate that style transfer from another cardiac image can be accomplished by using a style encoder network. Due to the flexibility of XCAT in creating new heart models, this approach can result in a realistic virtual population to address different challenges the medical image analysis research community is facing such as expensive data collection. Our proposed method has a great potential to synthesize 4D controllable CMR images with annotations and adaptable styles to be used in various supervised multi-site, multi-vendor applications in medical image analysis.

Friso G. Heslinga, Josien P. W. Pluim, A. J. H. M. Houben et al.

Type 2 Diabetes (T2D) is a chronic metabolic disorder that can lead to blindness and cardiovascular disease. Information about early stage T2D might be present in retinal fundus images, but to what extent these images can be used for a screening setting is still unknown. In this study, deep neural networks were employed to differentiate between fundus images from individuals with and without T2D. We investigated three methods to achieve high classification performance, measured by the area under the receiver operating curve (ROC-AUC). A multi-target learning approach to simultaneously output retinal biomarkers as well as T2D works best (AUC = 0.746 [$\pm$0.001]). Furthermore, the classification performance can be improved when images with high prediction uncertainty are referred to a specialist. We also show that the combination of images of the left and right eye per individual can further improve the classification performance (AUC = 0.758 [$\pm$0.003]), using a simple averaging approach. The results are promising, suggesting the feasibility of screening for T2D from retinal fundus images.

Suzanne C Wetstein, Allison M Onken, Christina Luffman et al.

Terminal ductal lobular unit (TDLU) involution is the regression of milk-producing structures in the breast. Women with less TDLU involution are more likely to develop breast cancer. A major bottleneck in studying TDLU involution in large cohort studies is the need for labor-intensive manual assessment of TDLUs. We developed a computational pathology solution to automatically capture TDLU involution measures. Whole slide images (WSIs) of benign breast biopsies were obtained from the Nurses' Health Study (NHS). A first set of 92 WSIs was annotated for TDLUs, acini and adipose tissue to train deep convolutional neural network (CNN) models for detection of acini, and segmentation of TDLUs and adipose tissue. These networks were integrated into a single computational method to capture TDLU involution measures including number of TDLUs per tissue area, median TDLU span and median number of acini per TDLU. We validated our method on 40 additional WSIs by comparing with manually acquired measures. Our CNN models detected acini with an F1 score of 0.73$\pm$0.09, and segmented TDLUs and adipose tissue with Dice scores of 0.86$\pm$0.11 and 0.86$\pm$0.04, respectively. The inter-observer ICC scores for manual assessments on 40 WSIs of number of TDLUs per tissue area, median TDLU span, and median acini count per TDLU were 0.71, 95% CI [0.51, 0.83], 0.81, 95% CI [0.67, 0.90], and 0.73, 95% CI [0.54, 0.85], respectively. Intra-observer reliability was evaluated on 10/40 WSIs with ICC scores of >0.8. Inter-observer ICC scores between automated results and the mean of the two observers were: 0.80, 95% CI [0.63, 0.90] for number of TDLUs per tissue area, 0.57, 95% CI [0.19, 0.77] for median TDLU span, and 0.80, 95% CI [0.62, 0.89] for median acini count per TDLU. TDLU involution measures evaluated by manual and automated assessment were inversely associated with age and menopausal status.

Mariëlle J. A. Jansen, Wouter B. Veldhuis, Maarten S. van Leeuwen et al.

Motion correction of dynamic contrast enhanced magnetic resonance images (DCE-MRI) is a challenging task, due to changes in image appearance. In this study a groupwise registration, using a principle component analysis (PCA) based metric,1 is evaluated for clinical DCE MRI of the liver. The groupwise registration transforms the images to a common space, rather than to a reference volume as conventional pairwise methods do, and computes the similarity metric on all volumes simultaneously. This groupwise registration method is compared to a pairwise approach using a mutual information metric. Clinical DCE MRI of the abdomen of eight patients were included. Per patient one lesion in the liver was manually segmented in all temporal images (N=16). The registered images were compared for accuracy, spatial and temporal smoothness after transformation, and lesion volume change. Compared to a pairwise method or no registration, groupwise registration provided better alignment. In our recently started clinical study groupwise registered clinical DCE MRI of the abdomen of nine patients were scored by three radiologists. Groupwise registration increased the assessed quality of alignment. The gain in reading time for the radiologist was estimated to vary from no difference to almost a minute. A slight increase in reader confidence was also observed. Registration had no added value for images with little motion. In conclusion, the groupwise registration of DCE MR images results in better alignment than achieved by pairwise registration, which is beneficial for clinical assessment.

Mitko Veta, Yujing J. Heng, Nikolas Stathonikos et al.

Tumor proliferation is an important biomarker indicative of the prognosis of breast cancer patients. Assessment of tumor proliferation in a clinical setting is highly subjective and labor-intensive task. Previous efforts to automate tumor proliferation assessment by image analysis only focused on mitosis detection in predefined tumor regions. However, in a real-world scenario, automatic mitosis detection should be performed in whole-slide images (WSIs) and an automatic method should be able to produce a tumor proliferation score given a WSI as input. To address this, we organized the TUmor Proliferation Assessment Challenge 2016 (TUPAC16) on prediction of tumor proliferation scores from WSIs. The challenge dataset consisted of 500 training and 321 testing breast cancer histopathology WSIs. In order to ensure fair and independent evaluation, only the ground truth for the training dataset was provided to the challenge participants. The first task of the challenge was to predict mitotic scores, i.e., to reproduce the manual method of assessing tumor proliferation by a pathologist. The second task was to predict the gene expression based PAM50 proliferation scores from the WSI. The best performing automatic method for the first task achieved a quadratic-weighted Cohen's kappa score of $κ$ = 0.567, 95% CI [0.464, 0.671] between the predicted scores and the ground truth. For the second task, the predictions of the top method had a Spearman's correlation coefficient of r = 0.617, 95% CI [0.581 0.651] with the ground truth. This was the first study that investigated tumor proliferation assessment from WSIs. The achieved results are promising given the difficulty of the tasks and weakly-labelled nature of the ground truth. However, further research is needed to improve the practical utility of image analysis methods for this task.

Veronika Cheplygina, Josien P. W. Pluim

Classifiers for medical image analysis are often trained with a single consensus label, based on combining labels given by experts or crowds. However, disagreement between annotators may be informative, and thus removing it may not be the best strategy. As a proof of concept, we predict whether a skin lesion from the ISIC 2017 dataset is a melanoma or not, based on crowd annotations of visual characteristics of that lesion. We compare using the mean annotations, illustrating consensus, to standard deviations and other distribution moments, illustrating disagreement. We show that the mean annotations perform best, but that the disagreement measures are still informative. We also make the crowd annotations used in this paper available at \url{https://figshare.com/s/5cbbce14647b66286544}.

Veronika Cheplygina, Marleen de Bruijne, Josien P. W. Pluim

Machine learning (ML) algorithms have made a tremendous impact in the field of medical imaging. While medical imaging datasets have been growing in size, a challenge for supervised ML algorithms that is frequently mentioned is the lack of annotated data. As a result, various methods which can learn with less/other types of supervision, have been proposed. We review semi-supervised, multiple instance, and transfer learning in medical imaging, both in diagnosis/detection or segmentation tasks. We also discuss connections between these learning scenarios, and opportunities for future research.

Maxime W. Lafarge, Josien P. W. Pluim, Koen A. J. Eppenhof et al.

Histological images are obtained by transmitting light through a tissue specimen that has been stained in order to produce contrast. This process results in 2D images of the specimen that has a three-dimensional structure. In this paper, we propose a method to infer how the stains are distributed in the direction perpendicular to the surface of the slide for a given 2D image in order to obtain a 3D representation of the tissue. This inference is achieved by decomposition of the staining concentration maps under constraints that ensure realistic decomposition and reconstruction of the original 2D images. Our study shows that it is possible to generate realistic 3D images making this method a potential tool for data augmentation when training deep learning models.

Pim Moeskops, Josien P. W. Pluim

Quantitative analysis of brain MRI at the age of 6 months is difficult because of the limited contrast between white matter and gray matter. In this study, we use a dilated triplanar convolutional neural network in combination with a non-dilated 3D convolutional neural network for the segmentation of white matter, gray matter and cerebrospinal fluid in infant brain MR images, as provided by the MICCAI grand challenge on 6-month infant brain MRI segmentation.

N. Khalili, P. Moeskops, N. H. P. Claessens et al.

MR images of the fetus allow non-invasive analysis of the fetal brain. Quantitative analysis of fetal brain development requires automatic brain tissue segmentation that is typically preceded by segmentation of the intracranial volume (ICV). This is challenging because fetal MR images visualize the whole moving fetus and in addition partially visualize the maternal body. This paper presents an automatic method for segmentation of the ICV in fetal MR images. The method employs a multi-scale convolutional neural network in 2D slices to enable learning spatial information from larger context as well as detailed local information. The method is developed and evaluated with 30 fetal T2-weighted MRI scans (average age $33.2\pm1.2$ weeks postmenstrual age). The set contains $10$ scans acquired in axial, $10$ in coronal and $10$ in sagittal imaging planes. A reference standard was defined in all images by manual annotation of the intracranial volume in $10$ equidistantly distributed slices. The automatic analysis was performed by training and testing the network using scans acquired in the representative imaging plane as well as combining the training data from all imaging planes. On average, the automatic method achieved Dice coefficients of 0.90 for the axial images, 0.90 for the coronal images and 0.92 for the sagittal images. Combining the training sets resulted in average Dice coefficients of 0.91 for the axial images, 0.95 for the coronal images, and 0.92 for the sagittal images. The results demonstrate that the evaluated method achieved good performance in extracting ICV in fetal MR scans regardless of the imaging plane.

Maxime W. Lafarge, Josien P. W. Pluim, Koen A. J. Eppenhof et al.

Preparing and scanning histopathology slides consists of several steps, each with a multitude of parameters. The parameters can vary between pathology labs and within the same lab over time, resulting in significant variability of the tissue appearance that hampers the generalization of automatic image analysis methods. Typically, this is addressed with ad-hoc approaches such as staining normalization that aim to reduce the appearance variability. In this paper, we propose a systematic solution based on domain-adversarial neural networks. We hypothesize that removing the domain information from the model representation leads to better generalization. We tested our hypothesis for the problem of mitosis detection in breast cancer histopathology images and made a comparative analysis with two other approaches. We show that combining color augmentation with domain-adversarial training is a better alternative than standard approaches to improve the generalization of deep learning methods.

Pim Moeskops, Mitko Veta, Maxime W. Lafarge et al.

Convolutional neural networks (CNNs) have been applied to various automatic image segmentation tasks in medical image analysis, including brain MRI segmentation. Generative adversarial networks have recently gained popularity because of their power in generating images that are difficult to distinguish from real images. In this study we use an adversarial training approach to improve CNN-based brain MRI segmentation. To this end, we include an additional loss function that motivates the network to generate segmentations that are difficult to distinguish from manual segmentations. During training, this loss function is optimised together with the conventional average per-voxel cross entropy loss. The results show improved segmentation performance using this adversarial training procedure for segmentation of two different sets of images and using two different network architectures, both visually and in terms of Dice coefficients.

Veronika Cheplygina, Pim Moeskops, Mitko Veta et al.

Supervised learning is ubiquitous in medical image analysis. In this paper we consider the problem of meta-learning -- predicting which methods will perform well in an unseen classification problem, given previous experience with other classification problems. We investigate the first step of such an approach: how to quantify the similarity of different classification problems. We characterize datasets sampled from six classification problems by performance ranks of simple classifiers, and define the similarity by the inverse of Euclidean distance in this meta-feature space. We visualize the similarities in a 2D space, where meaningful clusters start to emerge, and show that the proposed representation can be used to classify datasets according to their origin with 89.3\% accuracy. These findings, together with the observations of recent trends in machine learning, suggest that meta-learning could be a valuable tool for the medical imaging community.

Mitko Veta, Paul J. van Diest, Josien P. W. Pluim

The size of nuclei in histological preparations from excised breast tumors is predictive of patient outcome (large nuclei indicate poor outcome). Pathologists take into account nuclear size when performing breast cancer grading. In addition, the mean nuclear area (MNA) has been shown to have independent prognostic value. The straightforward approach to measuring nuclear size is by performing nuclei segmentation. We hypothesize that given an image of a tumor region with known nuclei locations, the area of the individual nuclei and region statistics such as the MNA can be reliably computed directly from the image data by employing a machine learning model, without the intermediate step of nuclei segmentation. Towards this goal, we train a deep convolutional neural network model that is applied locally at each nucleus location, and can reliably measure the area of the individual nuclei and the MNA. Furthermore, we show how such an approach can be extended to perform combined nuclei detection and measurement, which is reminiscent of granulometry.

Korsuk Sirinukunwattana, Josien P. W. Pluim, Hao Chen et al.

Colorectal adenocarcinoma originating in intestinal glandular structures is the most common form of colon cancer. In clinical practice, the morphology of intestinal glands, including architectural appearance and glandular formation, is used by pathologists to inform prognosis and plan the treatment of individual patients. However, achieving good inter-observer as well as intra-observer reproducibility of cancer grading is still a major challenge in modern pathology. An automated approach which quantifies the morphology of glands is a solution to the problem. This paper provides an overview to the Gland Segmentation in Colon Histology Images Challenge Contest (GlaS) held at MICCAI'2015. Details of the challenge, including organization, dataset and evaluation criteria, are presented, along with the method descriptions and evaluation results from the top performing methods.

Mitko Veta, Paul J. van Diest, Stefan M. Willems et al.

The proliferative activity of breast tumors, which is routinely estimated by counting of mitotic figures in hematoxylin and eosin stained histology sections, is considered to be one of the most important prognostic markers. However, mitosis counting is laborious, subjective and may suffer from low inter-observer agreement. With the wider acceptance of whole slide images in pathology labs, automatic image analysis has been proposed as a potential solution for these issues. In this paper, the results from the Assessment of Mitosis Detection Algorithms 2013 (AMIDA13) challenge are described. The challenge was based on a data set consisting of 12 training and 11 testing subjects, with more than one thousand annotated mitotic figures by multiple observers. Short descriptions and results from the evaluation of eleven methods are presented. The top performing method has an error rate that is comparable to the inter-observer agreement among pathologists.