Bart Liefers

Jose D. Vargas Quiros, Michael J. Beyeler, Sofia Ortin Vela et al.

The automatic extraction of retinal vascular biomarkers from color fundus images (CFI) is essential for large-scale studies of the retinal vasculature. We present VascX, an open-source Python toolbox designed for the automated extraction of biomarkers from artery and vein segmentations. The VascX workflow processes vessel segmentation masks into skeletons to build undirected and directed vessel graphs, which are then used to resolve segments into continuous vessels. This architecture enables the calculation of a comprehensive suite of biomarkers, including vascular density, bifurcation angles, central retinal equivalents (CREs), tortuosity, and temporal angles, alongside image quality metrics. A distinguishing feature of VascX is its region awareness; by utilizing the fovea, optic disc, and CFI boundaries as anatomical landmarks, the tool ensures spatially standardized measurements and identifies when specific biomarkers are not computable. Spatially localized biomarkers are calculated over grids relative to these landmarks, facilitating precise clinical analysis. Released via GitHub and PyPI, VascX provides an explainable and modifiable framework that supports reproducible vascular research through integrated visualizations. By enabling the rapid extraction of established biomarkers and the development of new ones, VascX advances the field of oculomics, offering a robust, computationally efficient solution for scalable deployment in large-scale clinical and epidemiological databases.

Jose Vargas Quiros, Bart Liefers, Karin van Garderen et al.

We introduce VascX models, a comprehensive set of model ensembles for analyzing retinal vasculature from color fundus images (CFIs). Annotated CFIs were aggregated from public datasets . Additional CFIs, mainly from the population-based Rotterdam Study were annotated by graders for arteries and veins at pixel level, resulting in a dataset diverse in patient demographics and imaging conditions. VascX models demonstrated superior segmentation performance across datasets, image quality levels, and anatomic regions when compared to existing, publicly available models, likely due to the increased size and variety of our training set. Important improvements were observed in artery-vein and disc segmentation performance, particularly in segmentations of these structures on CFIs of intermediate quality, common in large cohorts and clinical datasets. Importantly, these improvements translated into significantly more accurate vascular features when we compared features extracted from VascX segmentation masks with features extracted from segmentation masks generated by previous models. With VascX models we provide a robust, ready-to-use set of model ensembles and inference code aimed at simplifying the implementation and enhancing the quality of automated retinal vasculature analyses. The precise vessel parameters generated by the model can serve as starting points for the identification of disease patterns in and outside of the eye.

Mohammad Mohaiminul Islam, Coen de Vente, Bart Liefers et al.

In this paper, we present a new approach for uncertainty-aware retinal layer segmentation in Optical Coherence Tomography (OCT) scans using probabilistic signed distance functions (SDF). Traditional pixel-wise and regression-based methods primarily encounter difficulties in precise segmentation and lack of geometrical grounding respectively. To address these shortcomings, our methodology refines the segmentation by predicting a signed distance function (SDF) that effectively parameterizes the retinal layer shape via level set. We further enhance the framework by integrating probabilistic modeling, applying Gaussian distributions to encapsulate the uncertainty in the shape parameterization. This ensures a robust representation of the retinal layer morphology even in the presence of ambiguous input, imaging noise, and unreliable segmentations. Both quantitative and qualitative evaluations demonstrate superior performance when compared to other methods. Additionally, we conducted experiments on artificially distorted datasets with various noise types-shadowing, blinking, speckle, and motion-common in OCT scans to showcase the effectiveness of our uncertainty estimation. Our findings demonstrate the possibility to obtain reliable segmentation of retinal layers, as well as an initial step towards the characterization of layer integrity, a key biomarker for disease progression. Our code is available at \url{https://github.com/niazoys/RLS_PSDF}.

Jose Vargas Quiros, Bart Liefers, Karin van Garderen et al.

Purpose: To provide a diverse, high-quality dataset of color fundus images (CFIs) with detailed artery-vein (A/V) segmentation annotations, supporting the development and evaluation of machine learning algorithms for vascular analysis in ophthalmology. Methods: CFIs were sampled from the longitudinal Rotterdam Study (RS), encompassing a wide range of ages, devices, and capture conditions. Images were annotated using a custom interface that allowed graders to label arteries, veins, and unknown vessels on separate layers, starting from an initial vessel segmentation mask. Connectivity was explicitly verified and corrected using connected component visualization tools. Results: The dataset includes 1024x1024-pixel PNG images in three modalities: original RGB fundus images, contrast-enhanced versions, and RGB-encoded A/V masks. Image quality varied widely, including challenging samples typically excluded by automated quality assessment systems, but judged to contain valuable vascular information. Conclusion: This dataset offers a rich and heterogeneous source of CFIs with high-quality segmentations. It supports robust benchmarking and training of machine learning models under real-world variability in image quality and acquisition settings. Translational Relevance: By including connectivity-validated A/V masks and diverse image conditions, this dataset enables the development of clinically applicable, generalizable machine learning tools for retinal vascular analysis, potentially improving automated screening and diagnosis of systemic and ocular diseases.

Gerda Bortsova, Cristina González-Gonzalo, Suzanne C. Wetstein et al.

Adversarial attacks are considered a potentially serious security threat for machine learning systems. Medical image analysis (MedIA) systems have recently been argued to be vulnerable to adversarial attacks due to strong financial incentives and the associated technological infrastructure. In this paper, we study previously unexplored factors affecting adversarial attack vulnerability of deep learning MedIA systems in three medical domains: ophthalmology, radiology, and pathology. We focus on adversarial black-box settings, in which the attacker does not have full access to the target model and usually uses another model, commonly referred to as surrogate model, to craft adversarial examples. We consider this to be the most realistic scenario for MedIA systems. Firstly, we study the effect of weight initialization (ImageNet vs. random) on the transferability of adversarial attacks from the surrogate model to the target model. Secondly, we study the influence of differences in development data between target and surrogate models. We further study the interaction of weight initialization and data differences with differences in model architecture. All experiments were done with a perturbation degree tuned to ensure maximal transferability at minimal visual perceptibility of the attacks. Our experiments show that pre-training may dramatically increase the transferability of adversarial examples, even when the target and surrogate's architectures are different: the larger the performance gain using pre-training, the larger the transferability. Differences in the development data between target and surrogate models considerably decrease the performance of the attack; this decrease is further amplified by difference in the model architecture. We believe these factors should be considered when developing security-critical MedIA systems planned to be deployed in clinical practice.

Cristina González-Gonzalo, Bart Liefers, Bram van Ginneken et al.

Interpretability of deep learning (DL) systems is gaining attention in medical imaging to increase experts' trust in the obtained predictions and facilitate their integration in clinical settings. We propose a deep visualization method to generate interpretability of DL classification tasks in medical imaging by means of visual evidence augmentation. The proposed method iteratively unveils abnormalities based on the prediction of a classifier trained only with image-level labels. For each image, initial visual evidence of the prediction is extracted with a given visual attribution technique. This provides localization of abnormalities that are then removed through selective inpainting. We iteratively apply this procedure until the system considers the image as normal. This yields augmented visual evidence, including less discriminative lesions which were not detected at first but should be considered for final diagnosis. We apply the method to grading of two retinal diseases in color fundus images: diabetic retinopathy (DR) and age-related macular degeneration (AMD). We evaluate the generated visual evidence and the performance of weakly-supervised localization of different types of DR and AMD abnormalities, both qualitatively and quantitatively. We show that the augmented visual evidence of the predictions highlights the biomarkers considered by experts for diagnosis and improves the final localization performance. It results in a relative increase of 11.2+/-2.0% per image regarding sensitivity averaged at 10 false positives/image on average, when applied to different classification tasks, visual attribution techniques and network architectures. This makes the proposed method a useful tool for exhaustive visual support of DL classifiers in medical imaging.

Bart Liefers, Johanna M. Colijn, Cristina González-Gonzalo et al.

Purpose: To develop and validate a deep learning model for automatic segmentation of geographic atrophy (GA) in color fundus images (CFIs) and its application to study growth rate of GA. Participants: 409 CFIs of 238 eyes with GA from the Rotterdam Study (RS) and the Blue Mountain Eye Study (BMES) for model development, and 5,379 CFIs of 625 eyes from the Age-Related Eye Disease Study (AREDS) for analysis of GA growth rate. Methods: A deep learning model based on an ensemble of encoder-decoder architectures was implemented and optimized for the segmentation of GA in CFIs. Four experienced graders delineated GA in CFIs from RS and BMES. These manual delineations were used to evaluate the segmentation model using 5-fold cross-validation. The model was further applied to CFIs from the AREDS to study the growth rate of GA. Linear regression analysis was used to study associations between structural biomarkers at baseline and GA growth rate. A general estimate of the progression of GA area over time was made by combining growth rates of all eyes with GA from the AREDS set. Results: The model obtained an average Dice coefficient of 0.72 $\pm$ 0.26 on the BMES and RS. An intraclass correlation coefficient of 0.83 was reached between the automatically estimated GA area and the graders' consensus measures. Eight automatically calculated structural biomarkers (area, filled area, convex area, convex solidity, eccentricity, roundness, foveal involvement and perimeter) were significantly associated with growth rate. Combining all growth rates indicated that GA area grows quadratically up to an area of around 12 mm$^{2}$, after which growth rate stabilizes or decreases. Conclusion: The presented deep learning model allowed for fully automatic and robust segmentation of GA in CFIs. These segmentations can be used to extract structural characteristics of GA that predict its growth rate.