Personalised simulation of hemodynamics in cerebrovascular disease: lessons learned from a study of diagnostic accuracy.

Intracranial atherosclerotic disease (ICAD) poses a significant risk of subsequent stroke but current prevention strategies are limited. Mechanistic simulations of brain hemodynamics offer an alternative precision medicine approach by utilising individual patient characteristics. For clinical use, however, current simulation frameworks have insufficient validation. In this study, we performed the first quantitative validation of a simulation-based precision medicine framework to assess cerebral hemodynamics in patients with ICAD against clinical standard perfusion imaging. In a retrospective analysis, we used a 0-dimensional simulation model to detect brain areas that are hemodynamically vulnerable to subsequent stroke. The main outcome measures were sensitivity, specificity, and area under the receiver operating characteristics curve (ROC AUC) of the simulation to identify brain areas vulnerable to subsequent stroke as defined by quantitative measurements of relative mean transit time (relMTT) from dynamic susceptibility contrast MRI (DSC-MRI). In 68 subjects with unilateral stenosis >70% of the internal carotid artery (ICA) or middle cerebral artery (MCA), the sensitivity and specificity of the simulation were 0.65 and 0.67, respectively. The ROC AUC was 0.68. The low-to-moderate accuracy of the simulation may be attributed to assumptions of Newtonian blood flow, rigid vessel walls, and the use of time-of-flight MRI for geometric representation of subject vasculature. Future simulation approaches should focus on integrating additional patient data, increasing accessibility of precision medicine tools to clinicians, addressing disease burden disparities amongst different populations, and quantifying patient benefit. Our results underscore the need for further improvement of mechanistic simulations of brain hemodynamics to foster the translation of the technology to clinical practice.

Enhancing the prediction for shunt-dependent hydrocephalus after aneurysmal subarachnoid hemorrhage using a machine learning approach.

Early and reliable prediction of shunt-dependent hydrocephalus (SDHC) after aneurysmal subarachnoid hemorrhage (aSAH) may decrease the duration of in-hospital stay and reduce the risk of catheter-associated meningitis. Machine learning (ML) may improve predictions of SDHC in comparison to traditional non-ML methods. ML models were trained for CHESS and SDASH and two combined individual feature sets with clinical, radiographic, and laboratory variables. Seven different algorithms were used including three types of generalized linear models (GLM) as well as a tree boosting (CatBoost) algorithm, a Naive Bayes (NB) classifier, and a multilayer perceptron (MLP) artificial neural net. The discrimination of the area under the curve (AUC) was classified (0.7 ≤ AUC < 0.8, acceptable; 0.8 ≤ AUC < 0.9, excellent; AUC ≥ 0.9, outstanding). Of the 292 patients included with aSAH, 28.8% (n = 84) developed SDHC. Non-ML-based prediction of SDHC produced an acceptable performance with AUC values of 0.77 (CHESS) and 0.78 (SDASH). Using combined feature sets with more complex variables included than those incorporated in the scores, the ML models NB and MLP reached excellent performances, with an AUC of 0.80, respectively. After adding the amount of CSF drained within the first 14 days as a late feature to ML-based prediction, excellent performances were reached in the MLP (AUC 0.81), NB (AUC 0.80), and tree boosting model (AUC 0.81). ML models may enable clinicians to reliably predict the risk of SDHC after aSAH based exclusively on admission data. Future ML models may help optimize the management of SDHC in aSAH by avoiding delays in clinical decision-making.

Two-Stage Deep Learning Model for Automated Segmentation and Classification of Splenomegaly.

Splenomegaly is a common cross-sectional imaging finding with a variety of differential diagnoses. This study aimed to evaluate whether a deep learning model could automatically segment the spleen and identify the cause of splenomegaly in patients with cirrhotic portal hypertension versus patients with lymphoma disease. This retrospective study included 149 patients with splenomegaly on computed tomography (CT) images (77 patients with cirrhotic portal hypertension, 72 patients with lymphoma) who underwent a CT scan between October 2020 and July 2021. The dataset was divided into a training (n = 99), a validation (n = 25) and a test cohort (n = 25). In the first stage, the spleen was automatically segmented using a modified U-Net architecture. In the second stage, the CT images were classified into two groups using a 3D DenseNet to discriminate between the causes of splenomegaly, first using the whole abdominal CT, and second using only the spleen segmentation mask. The classification performances were evaluated using the area under the receiver operating characteristic curve (AUC), accuracy (ACC), sensitivity (SEN), and specificity (SPE). Occlusion sensitivity maps were applied to the whole abdominal CT images, to illustrate which regions were important for the prediction. When trained on the whole abdominal CT volume, the DenseNet was able to differentiate between the lymphoma and liver cirrhosis in the test cohort with an AUC of 0.88 and an ACC of 0.88. When the model was trained on the spleen segmentation mask, the performance decreased (AUC = 0.81, ACC = 0.76). Our model was able to accurately segment splenomegaly and recognize the underlying cause. Training on whole abdomen scans outperformed training using the segmentation mask. Nonetheless, considering the performance, a broader and more general application to differentiate other causes for splenomegaly is also conceivable.

Toward Sharing Brain Images: Differentially Private TOF-MRA Images With Segmentation Labels Using Generative Adversarial Networks.

Sharing labeled data is crucial to acquire large datasets for various Deep Learning applications. In medical imaging, this is often not feasible due to privacy regulations. Whereas anonymization would be a solution, standard techniques have been shown to be partially reversible. Here, synthetic data using a Generative Adversarial Network (GAN) with differential privacy guarantees could be a solution to ensure the patient's privacy while maintaining the predictive properties of the data. In this study, we implemented a Wasserstein GAN (WGAN) with and without differential privacy guarantees to generate privacy-preserving labeled Time-of-Flight Magnetic Resonance Angiography (TOF-MRA) image patches for brain vessel segmentation. The synthesized image-label pairs were used to train a U-net which was evaluated in terms of the segmentation performance on real patient images from two different datasets. Additionally, the Fréchet Inception Distance (FID) was calculated between the generated images and the real images to assess their similarity. During the evaluation using the U-Net and the FID, we explored the effect of different levels of privacy which was represented by the parameter ϵ. With stricter privacy guarantees, the segmentation performance and the similarity to the real patient images in terms of FID decreased. Our best segmentation model, trained on synthetic and private data, achieved a Dice Similarity Coefficient (DSC) of 0.75 for ϵ = 7.4 compared to 0.84 for ϵ = ∞ in a brain vessel segmentation paradigm (DSC of 0.69 and 0.88 on the second test set, respectively). We identified a threshold of ϵ <5 for which the performance (DSC <0.61) became unstable and not usable. Our synthesized labeled TOF-MRA images with strict privacy guarantees retained predictive properties necessary for segmenting the brain vessels. Although further research is warranted regarding generalizability to other imaging modalities and performance improvement, our results mark an encouraging first step for privacy-preserving data sharing in medical imaging.

Generating 3D TOF-MRA volumes and segmentation labels using generative adversarial networks.

Deep learning requires large labeled datasets that are difficult to gather in medical imaging due to data privacy issues and time-consuming manual labeling. Generative Adversarial Networks (GANs) can alleviate these challenges enabling synthesis of shareable data. While 2D GANs have been used to generate 2D images with their corresponding labels, they cannot capture the volumetric information of 3D medical imaging. 3D GANs are more suitable for this and have been used to generate 3D volumes but not their corresponding labels. One reason might be that synthesizing 3D volumes is challenging owing to computational limitations. In this work, we present 3D GANs for the generation of 3D medical image volumes with corresponding labels applying mixed precision to alleviate computational constraints. We generated 3D Time-of-Flight Magnetic Resonance Angiography (TOF-MRA) patches with their corresponding brain blood vessel segmentation labels. We used four variants of 3D Wasserstein GAN (WGAN) with: 1) gradient penalty (GP), 2) GP with spectral normalization (SN), 3) SN with mixed precision (SN-MP), and 4) SN-MP with double filters per layer (c-SN-MP). The generated patches were quantitatively evaluated using the Fréchet Inception Distance (FID) and Precision and Recall of Distributions (PRD). Further, 3D U-Nets were trained with patch-label pairs from different WGAN models and their performance was compared to the performance of a benchmark U-Net trained on real data. The segmentation performance of all U-Net models was assessed using Dice Similarity Coefficient (DSC) and balanced Average Hausdorff Distance (bAVD) for a) all vessels, and b) intracranial vessels only. Our results show that patches generated with WGAN models using mixed precision (SN-MP and c-SN-MP) yielded the lowest FID scores and the best PRD curves. Among the 3D U-Nets trained with synthetic patch-label pairs, c-SN-MP pairs achieved the highest DSC (0.841) and lowest bAVD (0.508) compared to the benchmark U-Net trained on real data (DSC 0.901; bAVD 0.294) for intracranial vessels. In conclusion, our solution generates realistic 3D TOF-MRA patches and labels for brain vessel segmentation. We demonstrate the benefit of using mixed precision for computational efficiency resulting in the best-performing GAN-architecture. Our work paves the way towards sharing of labeled 3D medical data which would increase generalizability of deep learning models for clinical use.

Detection and analysis of cerebral aneurysms based on X-ray rotational angiography - the CADA 2020 challenge.

The Cerebral Aneurysm Detection and Analysis (CADA) challenge was organized to support the development and benchmarking of algorithms for detecting, analyzing, and risk assessment of cerebral aneurysms in X-ray rotational angiography (3DRA) images. 109 anonymized 3DRA datasets were provided for training, and 22 additional datasets were used to test the algorithmic solutions. Cerebral aneurysm detection was assessed using the F2 score based on recall and precision, and the fit of the delivered bounding box was assessed using the distance to the aneurysm. The segmentation quality was measured using the Jaccard index and a combination of different surface distance measures. Systematic errors were analyzed using volume correlation and bias. Rupture risk assessment was evaluated using the F2 score. 158 participants from 22 countries registered for the CADA challenge. The U-Net-based detection solutions presented by the community show similar accuracy compared to experts (F2 score 0.92), with a small number of missed aneurysms with diameters smaller than 3.5 mm. In addition, the delineation of these structures, based on U-Net variations, is excellent, with a Jaccard score of 0.92. The rupture risk estimation methods achieved an F2 score of 0.71. The performance of the detection and segmentation solutions is equivalent to that of human experts. The best results are obtained in rupture risk estimation by combining different image-based, morphological, and computational fluid dynamic parameters using machine learning methods. Furthermore, we evaluated the best methods pipeline, from detecting and delineating the vessel dilations to estimating the risk of rupture. The chain of these methods achieves an F2-score of 0.70, which is comparable to applying the risk prediction to the ground-truth delineation (0.71).

Image-to-image generative adversarial networks for synthesizing perfusion parameter maps from DSC-MR images in cerebrovascular disease.

Stroke is a major cause of death or disability. As imaging-based patient stratification improves acute stroke therapy, dynamic susceptibility contrast magnetic resonance imaging (DSC-MRI) is of major interest in image brain perfusion. However, expert-level perfusion maps require a manual or semi-manual post-processing by a medical expert making the procedure time-consuming and less-standardized. Modern machine learning methods such as generative adversarial networks (GANs) have the potential to automate the perfusion map generation on an expert level without manual validation. We propose a modified pix2pix GAN with a temporal component (temp-pix2pix-GAN) that generates perfusion maps in an end-to-end fashion. We train our model on perfusion maps infused with expert knowledge to encode it into the GANs. The performance was trained and evaluated using the structural similarity index measure (SSIM) on two datasets including patients with acute stroke and the steno-occlusive disease. Our temp-pix2pix architecture showed high performance on the acute stroke dataset for all perfusion maps (mean SSIM 0.92-0.99) and good performance on data including patients with the steno-occlusive disease (mean SSIM 0.84-0.99). While clinical validation is still necessary for future studies, our results mark an important step toward automated expert-level perfusion maps and thus fast patient stratification.

Evaluation of a Deep Learning Algorithm for Automated Spleen Segmentation in Patients with Conditions Directly or Indirectly Affecting the Spleen.

The aim of this study was to develop a deep learning-based algorithm for fully automated spleen segmentation using CT images and to evaluate the performance in conditions directly or indirectly affecting the spleen (e.g., splenomegaly, ascites). For this, a 3D U-Net was trained on an in-house dataset (n = 61) including diseases with and without splenic involvement (in-house U-Net), and an open-source dataset from the Medical Segmentation Decathlon (open dataset, n = 61) without splenic abnormalities (open U-Net). Both datasets were split into a training (n = 32.52%), a validation (n = 9.15%) and a testing dataset (n = 20.33%). The segmentation performances of the two models were measured using four established metrics, including the Dice Similarity Coefficient (DSC). On the open test dataset, the in-house and open U-Net achieved a mean DSC of 0.906 and 0.897 respectively (p = 0.526). On the in-house test dataset, the in-house U-Net achieved a mean DSC of 0.941, whereas the open U-Net obtained a mean DSC of 0.648 (p < 0.001), showing very poor segmentation results in patients with abnormalities in or surrounding the spleen. Thus, for reliable, fully automated spleen segmentation in clinical routine, the training dataset of a deep learning-based algorithm should include conditions that directly or indirectly affect the spleen.

Synthesizing anonymized and labeled TOF-MRA patches for brain vessel segmentation using generative adversarial networks.

Anonymization and data sharing are crucial for privacy protection and acquisition of large datasets for medical image analysis. This is a big challenge, especially for neuroimaging. Here, the brain's unique structure allows for re-identification and thus requires non-conventional anonymization. Generative adversarial networks (GANs) have the potential to provide anonymous images while preserving predictive properties. Analyzing brain vessel segmentation, we trained 3 GANs on time-of-flight (TOF) magnetic resonance angiography (MRA) patches for image-label generation: 1) Deep convolutional GAN, 2) Wasserstein-GAN with gradient penalty (WGAN-GP) and 3) WGAN-GP with spectral normalization (WGAN-GP-SN). The generated image-labels from each GAN were used to train a U-net for segmentation and tested on real data. Moreover, we applied our synthetic patches using transfer learning on a second dataset. For an increasing number of up to 15 patients we evaluated the model performance on real data with and without pre-training. The performance for all models was assessed by the Dice Similarity Coefficient (DSC) and the 95th percentile of the Hausdorff Distance (95HD). Comparing the 3 GANs, the U-net trained on synthetic data generated by the WGAN-GP-SN showed the highest performance to predict vessels (DSC/95HD 0.85/30.00) benchmarked by the U-net trained on real data (0.89/26.57). The transfer learning approach showed superior performance for the same GAN compared to no pre-training, especially for one patient only (0.91/24.66 vs. 0.84/27.36). In this work, synthetic image-label pairs retained generalizable information and showed good performance for vessel segmentation. Besides, we showed that synthetic patches can be used in a transfer learning approach with independent data. This paves the way to overcome the challenges of scarce data and anonymization in medical imaging.

A U-Net Deep Learning Framework for High Performance Vessel Segmentation in Patients With Cerebrovascular Disease.

Brain vessel status is a promising biomarker for better prevention and treatment in cerebrovascular disease. However, classic rule-based vessel segmentation algorithms need to be hand-crafted and are insufficiently validated. A specialized deep learning method-the U-net-is a promising alternative. Using labeled data from 66 patients with cerebrovascular disease, the U-net framework was optimized and evaluated with three metrics: Dice coefficient, 95% Hausdorff distance (95HD) and average Hausdorff distance (AVD). The model performance was compared with the traditional segmentation method of graph-cuts. Training and reconstruction was performed using 2D patches. A full and a reduced architecture with less parameters were trained. We performed both quantitative and qualitative analyses. The U-net models yielded high performance for both the full and the reduced architecture: A Dice value of ~0.88, a 95HD of ~47 voxels and an AVD of ~0.4 voxels. The visual analysis revealed excellent performance in large vessels and sufficient performance in small vessels. Pathologies like cortical laminar necrosis and a rete mirabile led to limited segmentation performance in few patients. The U-net outperfomed the traditional graph-cuts method (Dice ~0.76, 95HD ~59, AVD ~1.97). Our work highly encourages the development of clinically applicable segmentation tools based on deep learning. Future works should focus on improved segmentation of small vessels and methodologies to deal with specific pathologies.

Multiparametric Model for Penumbral Flow Prediction in Acute Stroke.

BACKGROUND AND PURPOSE: Identification of salvageable penumbra tissue by dynamic susceptibility contrast magnetic resonance imaging is a valuable tool for acute stroke patient stratification for treatment. However, prior studies have not attempted to combine the different perfusion maps into a predictive model. In this study, we established a multiparametric perfusion imaging model and cross-validated it using positron emission tomography perfusion for detection of penumbral flow. METHODS: In a retrospective analysis of 17 subacute stroke patients with consecutive magnetic resonance imaging and H2O15 positron emission tomography scans, perfusion maps of cerebral blood flow, cerebral blood volume, mean transit time, time-to-maximum, and time-to-peak were constructed and combined using a generalized linear model (GLM). Both the GLM maps and the single perfusion maps alone were cross-validated with positron emission tomography-cerebral blood flow scans to predict penumbral flow on a voxel-wise level. Performance was tested by receiver-operating characteristics curve analysis, that is, the area under the curve, and the models' fits were compared using the likelihood ratio test. RESULTS: The GLM demonstrated significantly improved model fit compared with each of the single perfusion maps (P<1×e-5) and demonstrated higher performance, with an area under the curve of 0.91. However, the absolute difference between the performance of GLM and the best-performing single perfusion parameter (time-to-maximum) was relatively low (area under the curve difference =0.04). CONCLUSIONS: Our results support a dynamic susceptibility contrast magnetic resonance imaging-based GLM as an improved model for penumbral flow prediction in stroke patients. With given perfusion maps, this model is a straightforward and observer-independent alternative for therapy stratification.