Quantifying the Scanner-Induced Domain Gap in Mitosis Detection

Automated detection of mitotic figures in histopathology images has seen vast improvements, thanks to modern deep learning-based pipelines. Application of these methods, however, is in practice limited by strong variability of images between labs. This results in a domain shift of the images, which causes a performance drop of the models. Hypothesizing that the scanner device plays a decisive role in this effect, we evaluated the susceptibility of a standard mitosis detection approach to the domain shift introduced by using a different whole slide scanner. Our work is based on the MICCAI-MIDOG challenge 2021 data set, which includes 200 tumor cases of human breast cancer and four scanners. Our work indicates that the domain shift induced not by biochemical variability but purely by the choice of acquisition device is underestimated so far. Models trained on images of the same scanner yielded an average F1 score of 0.683, while models trained on a single other scanner only yielded an average F1 score of 0.325. Training on another multi-domain mitosis dataset led to mean F1 scores of 0.52. We found this not to be reflected by domain-shifts measured as proxy A distance-derived metric.

Corneal Pachymetry by AS-OCT after Descemet's Membrane Endothelial Keratoplasty

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 68 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.

Physics-informed neural networks for myocardial perfusion MRI quantification

Tracer-kinetic models allow for the quantification of kinetic parameters such as blood flow from dynamic contrast-enhanced magnetic resonance (MR) images. Fitting the observed data with multi-compartment exchange models is desirable, as they are physiologically plausible and resolve directly for blood flow and microvascular function. However, the reliability of model fitting is limited by the low signal-to-noise ratio, temporal resolution, and acquisition length. This may result in inaccurate parameter estimates. This study introduces physics-informed neural networks (PINNs) as a means to perform myocardial perfusion MR quantification, which provides a versatile scheme for the inference of kinetic parameters. These neural networks can be trained to fit the observed perfusion MR data while respecting the underlying physical conservation laws described by a multi-compartment exchange model. Here, we provide a framework for the implementation of PINNs in myocardial perfusion MR. The approach is validated both in silico and in vivo. In the in silico study, an overall reduction in mean-squared error with the ground-truth parameters was observed compared to a standard non-linear least squares fitting approach. The in vivo study demonstrates that the method produces parameter values comparable to those previously found in literature, as well as providing parameter maps which match the clinical diagnosis of patients.

Deep Learning-Based Grading of Ductal Carcinoma In Situ in Breast Histopathology Images

Ductal carcinoma in situ (DCIS) is a non-invasive breast cancer that can progress into invasive ductal carcinoma (IDC). Studies suggest DCIS is often overtreated since a considerable part of DCIS lesions may never progress into IDC. Lower grade lesions have a lower progression speed and risk, possibly allowing treatment de-escalation. However, studies show significant inter-observer variation in DCIS grading. Automated image analysis may provide an objective solution to address high subjectivity of DCIS grading by pathologists. In this study, we developed a deep learning-based DCIS grading system. It was developed using the consensus DCIS grade of three expert observers on a dataset of 1186 DCIS lesions from 59 patients. The inter-observer agreement, measured by quadratic weighted Cohen's kappa, was used to evaluate the system and compare its performance to that of expert observers. We present an analysis of the lesion-level and patient-level inter-observer agreement on an independent test set of 1001 lesions from 50 patients. The deep learning system (dl) achieved on average slightly higher inter-observer agreement to the observers (o1, o2 and o3) ($\kappa_{o1,dl}=0.81, \kappa_{o2,dl}=0.53, \kappa_{o3,dl}=0.40$) than the observers amongst each other ($\kappa_{o1,o2}=0.58, \kappa_{o1,o3}=0.50, \kappa_{o2,o3}=0.42$) at the lesion-level. At the patient-level, the deep learning system achieved similar agreement to the observers ($\kappa_{o1,dl}=0.77, \kappa_{o2,dl}=0.75, \kappa_{o3,dl}=0.70$) as the observers amongst each other ($\kappa_{o1,o2}=0.77, \kappa_{o1,o3}=0.75, \kappa_{o2,o3}=0.72$). In conclusion, we developed a deep learning-based DCIS grading system that achieved a performance similar to expert observers. We believe this is the first automated system that could assist pathologists by providing robust and reproducible second opinions on DCIS grade.

Domain-Adversarial Learning for Multi-Centre, Multi-Vendor, and Multi-Disease Cardiac MR Image Segmentation

Cine cardiac magnetic resonance (CMR) has become the gold standard for the non-invasive evaluation of cardiac function. In particular, it allows the accurate quantification of functional parameters including the chamber volumes and ejection fraction. Deep learning has shown the potential to automate the requisite cardiac structure segmentation. However, the lack of robustness of deep learning models has hindered their widespread clinical adoption. Due to differences in the data characteristics, neural networks trained on data from a specific scanner are not guaranteed to generalise well to data acquired at a different centre or with a different scanner. In this work, we propose a principled solution to the problem of this domain shift. Domain-adversarial learning is used to train a domain-invariant 2D U-Net using labelled and unlabelled data. This approach is evaluated on both seen and unseen domains from the M\&Ms challenge dataset and the domain-adversarial approach shows improved performance as compared to standard training. Additionally, we show that the domain information cannot be recovered from the learned features.

Orientation-Disentangled Unsupervised Representation Learning for Computational Pathology

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.

Are pathologist-defined labels reproducible? Comparison of the TUPAC16 mitotic figure dataset with an alternative set of labels

Pathologist-defined labels are the gold standard for histopathological data sets, regardless of well-known limitations in consistency for some tasks. To date, some datasets on mitotic figures are available and were used for development of promising deep learning-based algorithms. In order to assess robustness of those algorithms and reproducibility of their methods it is necessary to test on several independent datasets. The influence of different labeling methods of these available datasets is currently unknown. To tackle this, we present an alternative set of labels for the images of the auxiliary mitosis dataset of the TUPAC16 challenge. Additional to manual mitotic figure screening, we used a novel, algorithm-aided labeling process, that allowed to minimize the risk of missing rare mitotic figures in the images. All potential mitotic figures were independently assessed by two pathologists. The novel, publicly available set of labels contains 1,999 mitotic figures (+28.80%) and additionally includes 10,483 labels of cells with high similarities to mitotic figures (hard examples). We found significant difference comparing F_1 scores between the original label set (0.549) and the new alternative label set (0.735) using a standard deep learning object detection architecture. The models trained on the alternative set showed higher overall confidence values, suggesting a higher overall label consistency. Findings of the present study show that pathologists-defined labels may vary significantly resulting in notable difference in the model performance. Comparison of deep learning-based algorithms between independent datasets with different labeling methods should be done with caution.

Adversarial Attack Vulnerability of Medical Image Analysis Systems: Unexplored Factors

Adversarial attacks are considered a potentially serious security threat for machine learning systems. Medical image analysis (MedIA) systems have recently been argued to be particularly vulnerable to adversarial attacks due to strong financial incentives. In this paper, we study several previously unexplored factors affecting adversarial attack vulnerability of deep learning MedIA systems in three medical domains: ophthalmology, radiology and pathology. Firstly, we study the effect of varying the degree of adversarial perturbation on the attack performance and its visual perceptibility. Secondly, we study how pre-training on a public dataset (ImageNet) affects the models' vulnerability to attacks. Thirdly, we study the influence of data and model architecture disparity between target and attacker models. Our experiments show that the degree of perturbation significantly affects both performance and human perceptibility of attacks. Pre-training may dramatically increase the transfer of adversarial examples; the larger the performance gain achieved by pre-training, the larger the transfer. Finally, disparity in data and/or model architecture between target and attacker models substantially decreases the success of attacks. We believe that these factors should be considered when designing cybersecurity-critical MedIA systems, as well as kept in mind when evaluating their vulnerability to adversarial attacks.