Martin Bendszus

Sarthak Pati, Ujjwal Baid, Brandon Edwards et al.

Although machine learning (ML) has shown promise in numerous domains, there are concerns about generalizability to out-of-sample data. This is currently addressed by centrally sharing ample, and importantly diverse, data from multiple sites. However, such centralization is challenging to scale (or even not feasible) due to various limitations. Federated ML (FL) provides an alternative to train accurate and generalizable ML models, by only sharing numerical model updates. Here we present findings from the largest FL study to-date, involving data from 71 healthcare institutions across 6 continents, to generate an automatic tumor boundary detector for the rare disease of glioblastoma, utilizing the largest dataset of such patients ever used in the literature (25,256 MRI scans from 6,314 patients). We demonstrate a 33% improvement over a publicly trained model to delineate the surgically targetable tumor, and 23% improvement over the tumor's entire extent. We anticipate our study to: 1) enable more studies in healthcare informed by large and diverse data, ensuring meaningful results for rare diseases and underrepresented populations, 2) facilitate further quantitative analyses for glioblastoma via performance optimization of our consensus model for eventual public release, and 3) demonstrate the effectiveness of FL at such scale and task complexity as a paradigm shift for multi-site collaborations, alleviating the need for data sharing.

Hui Min Wong, Philip Heesen, Pascal Janetzky et al.

Large language models (LLMs) are increasingly used for diagnostic tasks in medicine. In clinical practice, the correct diagnosis can rarely be immediately inferred from the initial patient presentation alone. Rather, reaching a diagnosis often involves systematic history taking, during which clinicians reason over multiple potential conditions through iterative questioning to resolve uncertainty. This process requires considering differential diagnoses and actively excluding emergencies that demand immediate intervention. Yet, the ability of medical LLMs to generate informative follow-up questions and thus reason over differential diagnoses remains underexplored. Here, we introduce MedClarify, an AI agent for information-seeking that can generate follow-up questions for iterative reasoning to support diagnostic decision-making. Specifically, MedClarify computes a list of candidate diagnoses analogous to a differential diagnosis, and then proactively generates follow-up questions aimed at reducing diagnostic uncertainty. By selecting the question with the highest expected information gain, MedClarify enables targeted, uncertainty-aware reasoning to improve diagnostic performance. In our experiments, we first demonstrate the limitations of current LLMs in medical reasoning, which often yield multiple, similarly likely diagnoses, especially when patient cases are incomplete or relevant information for diagnosis is missing. We then show that our information-theoretic reasoning approach can generate effective follow-up questioning and thereby reduces diagnostic errors by ~27 percentage points (p.p.) compared to a standard single-shot LLM baseline. Altogether, MedClarify offers a path to improve medical LLMs through agentic information-seeking and to thus promote effective dialogues with medical LLMs that reflect the iterative and uncertain nature of real-world clinical reasoning.

Jun Ma, Feifei Li, Sumin Kim et al.

Promptable segmentation foundation models have emerged as a transformative approach to addressing the diverse needs in medical images, but most existing models require expensive computing, posing a big barrier to their adoption in clinical practice. In this work, we organized the first international competition dedicated to promptable medical image segmentation, featuring a large-scale dataset spanning nine common imaging modalities from over 20 different institutions. The top teams developed lightweight segmentation foundation models and implemented an efficient inference pipeline that substantially reduced computational requirements while maintaining state-of-the-art segmentation accuracy. Moreover, the post-challenge phase advanced the algorithms through the design of performance booster and reproducibility tasks, resulting in improved algorithms and validated reproducibility of the winning solution. Furthermore, the best-performing algorithms have been incorporated into the open-source software with a user-friendly interface to facilitate clinical adoption. The data and code are publicly available to foster the further development of medical image segmentation foundation models and pave the way for impactful real-world applications.

Hao Li, Jianan Liu, Marianne Schell et al.

Shortening acquisition time and reducing motion artifacts are the most critical challenges in magnetic resonance imaging (MRI). Deep learning-based image restoration has emerged as a promising solution capable of generating high-resolution and motion-artifact-free MRI images from low-resolution images acquired with shortened acquisition times or from motion-artifact-corrupted images. To facilitate clinical integration, a time- and GPU-efficient network with reliable accuracy is essential. In this study, we adopted a unified 2D deep learning framework for pseudo-3D MRI image super-resolution reconstruction (SRR) and motion artifact reduction (MAR). The optimal down-sampling factors to optimize the acquisition time in SRR were identified. Training for MAR was performed using publicly available in vivo data, employing a novel standardized method to induce motion artifacts of varying severity in a controlled way. The accuracy of the network was evaluated through a pixel-wise uncertainty map, and performance was benchmarked against state-of-the-art methods. The results demonstrated that the down-sampling factor of 1x1x2 for x2 acceleration and 2x2x2 for x4 acceleration was optimal. For SRR, the proposed TS-RCAN outperformed the 3D networks of mDCSRN and ReCNN, with an improvement of more than 0.01 in SSIM and 1.5 dB in PSNR while reducing GPU load by up to and inference time by up to 90%. For MAR, TS-RCAN exceeded UNet's performance by up to 0.014 in SSIM and 1.48 dB in PSNR. Additionally, TS-RCAN provided uncertainty information, which can be used to estimate the quality of the reconstructed images. TS-RCAN has potential use for SRR and MAR in the clinical setting.

Jens Petersen, Fabian Isensee, Gregor Köhler et al.

The ability to estimate how a tumor might evolve in the future could have tremendous clinical benefits, from improved treatment decisions to better dose distribution in radiation therapy. Recent work has approached the glioma growth modeling problem via deep learning and variational inference, thus learning growth dynamics entirely from a real patient data distribution. So far, this approach was constrained to predefined image acquisition intervals and sequences of fixed length, which limits its applicability in more realistic scenarios. We overcome these limitations by extending Neural Processes, a class of conditional generative models for stochastic time series, with a hierarchical multi-scale representation encoding including a spatio-temporal attention mechanism. The result is a learned growth model that can be conditioned on an arbitrary number of observations, and that can produce a distribution of temporally consistent growth trajectories on a continuous time axis. On a dataset of 379 patients, the approach successfully captures both global and finer-grained variations in the images, exhibiting superior performance compared to other learned growth models.

Jens Petersen, Paul F. Jäger, Fabian Isensee et al.

Existing approaches to modeling the dynamics of brain tumor growth, specifically glioma, employ biologically inspired models of cell diffusion, using image data to estimate the associated parameters. In this work, we propose an alternative approach based on recent advances in probabilistic segmentation and representation learning that implicitly learns growth dynamics directly from data without an underlying explicit model. We present evidence that our approach is able to learn a distribution of plausible future tumor appearances conditioned on past observations of the same tumor.

Fabian Isensee, Marianne Schell, Irada Tursunova et al.

Brain extraction is a critical preprocessing step in the analysis of MRI neuroimaging studies and influences the accuracy of downstream analyses. The majority of brain extraction algorithms are, however, optimized for processing healthy brains and thus frequently fail in the presence of pathologically altered brain or when applied to heterogeneous MRI datasets. Here we introduce a new, rigorously validated algorithm (termed HD-BET) relying on artificial neural networks that aims to overcome these limitations. We demonstrate that HD-BET outperforms six popular, publicly available brain extraction algorithms in several large-scale neuroimaging datasets, including one from a prospective multicentric trial in neuro-oncology, yielding state-of-the-art performance with median improvements of +1.16 to +2.11 points for the DICE coefficient and -0.66 to -2.51 mm for the Hausdorff distance. Importantly, the HD-BET algorithm shows robust performance in the presence of pathology or treatment-induced tissue alterations, is applicable to a broad range of MRI sequence types and is not influenced by variations in MRI hardware and acquisition parameters encountered in both research and clinical practice. For broader accessibility our HD-BET prediction algorithm is made freely available (http://www.neuroAI-HD.org) and may become an essential component for robust, automated, high-throughput processing of MRI neuroimaging data.

Spyridon Bakas, Mauricio Reyes, Andras Jakab et al.

Gliomas are the most common primary brain malignancies, with different degrees of aggressiveness, variable prognosis and various heterogeneous histologic sub-regions, i.e., peritumoral edematous/invaded tissue, necrotic core, active and non-enhancing core. This intrinsic heterogeneity is also portrayed in their radio-phenotype, as their sub-regions are depicted by varying intensity profiles disseminated across multi-parametric magnetic resonance imaging (mpMRI) scans, reflecting varying biological properties. Their heterogeneous shape, extent, and location are some of the factors that make these tumors difficult to resect, and in some cases inoperable. The amount of resected tumor is a factor also considered in longitudinal scans, when evaluating the apparent tumor for potential diagnosis of progression. Furthermore, there is mounting evidence that accurate segmentation of the various tumor sub-regions can offer the basis for quantitative image analysis towards prediction of patient overall survival. This study assesses the state-of-the-art machine learning (ML) methods used for brain tumor image analysis in mpMRI scans, during the last seven instances of the International Brain Tumor Segmentation (BraTS) challenge, i.e., 2012-2018. Specifically, we focus on i) evaluating segmentations of the various glioma sub-regions in pre-operative mpMRI scans, ii) assessing potential tumor progression by virtue of longitudinal growth of tumor sub-regions, beyond use of the RECIST/RANO criteria, and iii) predicting the overall survival from pre-operative mpMRI scans of patients that underwent gross total resection. Finally, we investigate the challenge of identifying the best ML algorithms for each of these tasks, considering that apart from being diverse on each instance of the challenge, the multi-institutional mpMRI BraTS dataset has also been a continuously evolving/growing dataset.

Fabian Isensee, Philipp Kickingereder, Wolfgang Wick et al.

In this paper we demonstrate the effectiveness of a well trained U-Net in the context of the BraTS 2018 challenge. This endeavour is particularly interesting given that researchers are currently besting each other with architectural modifications that are intended to improve the segmentation performance. We instead focus on the training process arguing that a well trained U-Net is hard to beat. Our baseline U-Net, which has only minor modifications and is trained with a large patch size and a Dice loss function indeed achieved competitive Dice scores on the BraTS2018 validation data. By incorporating additional measures such as region based training, additional training data, a simple postprocessing technique and a combination of loss functions, we obtain Dice scores of 77.88, 87.81 and 80.62, and Hausdorff Distances (95th percentile) of 2.90, 6.03 and 5.08 for the enhancing tumor, whole tumor and tumor core, respectively on the test data. This setup achieved rank two in BraTS2018, with more than 60 teams participating in the challenge.

Fabian Isensee, Philipp Kickingereder, Wolfgang Wick et al.

Quantitative analysis of brain tumors is critical for clinical decision making. While manual segmentation is tedious, time consuming and subjective, this task is at the same time very challenging to solve for automatic segmentation methods. In this paper we present our most recent effort on developing a robust segmentation algorithm in the form of a convolutional neural network. Our network architecture was inspired by the popular U-Net and has been carefully modified to maximize brain tumor segmentation performance. We use a dice loss function to cope with class imbalances and use extensive data augmentation to successfully prevent overfitting. Our method beats the current state of the art on BraTS 2015, is one of the leading methods on the BraTS 2017 validation set (dice scores of 0.896, 0.797 and 0.732 for whole tumor, tumor core and enhancing tumor, respectively) and achieves very good Dice scores on the test set (0.858 for whole, 0.775 for core and 0.647 for enhancing tumor). We furthermore take part in the survival prediction subchallenge by training an ensemble of a random forest regressor and multilayer perceptrons on shape features describing the tumor subregions. Our approach achieves 52.6% accuracy, a Spearman correlation coefficient of 0.496 and a mean square error of 209607 on the test set.