Esther E. Bron

Marawan Elbatel, Mohamed Ghonim, Jiaji Mao et al.

Automated segmentation of liver lesions on non-contrast computed tomography (NCCT) is clinically important but fundamentally challenging, particularly in low-resource settings across Africa and Asia where contrast agents are frequently unavailable. Progress has been limited by the absence of annotated NCCT benchmarks. Here we describe the TriALS challenge for automated liver lesion segmentation under contrast-limited conditions, supported by a multi-centre dataset of 150 cases with four-phase CT acquisitions (600 volumes) from Egyptian and Chinese institutions. Algorithms were evaluated on 70 cases from three institutions, including an independent external cohort. The top-performing method achieved a mean venous-phase Dice of 0.754, consistent with human-level performance, yet dropped to 0.57 on NCCT. On external validation, the leading method outperformed off-the-shelf models by up to 28% in Dice on NCCT. Algorithm performance was most strongly predicted by training data scale and pre-training strategy. A cross-year comparison exposed a persistent perceptual barrier on NCCT that scaling pre-training alone cannot overcome. Data, annotations, and code are available at https://github.com/xmed-lab/TriALS.

Sterre de Jonge, Elisabeth J. Vinke, Meike W. Vernooij et al.

Disease progression modeling provides a robust framework to identify long-term disease trajectories from short-term biomarker data. It is a valuable tool to gain a deeper understanding of diseases with a long disease trajectory, such as Alzheimer's disease. A key limitation of most disease progression models is that they are specific to a single data type (e.g., continuous data), thereby limiting their applicability to heterogeneous, real-world datasets. To address this limitation, we propose the Mixed Events model, a novel disease progression model that handles both discrete and continuous data types. This model is implemented within the Subtype and Stage Inference (SuStaIn) framework, resulting in Mixed-SuStaIn, enabling subtype and progression modeling. We demonstrate the effectiveness of Mixed-SuStaIn through simulation experiments and real-world data from the Alzheimer's Disease Neuroimaging Initiative, showing that it performs well on mixed datasets. The code is available at: https://github.com/ucl-pond/pySuStaIn.

Kaouther Mouheb, Marawan Elbatel, Stefan Klein et al.

Deep learning has achieved impressive performance across various medical imaging tasks. However, its inherent bias against specific groups hinders its clinical applicability in equitable healthcare systems. A recently discovered phenomenon, Neural Collapse (NC), has shown potential in improving the generalization of state-of-the-art deep learning models. Nonetheless, its implications on bias in medical imaging remain unexplored. Our study investigates deep learning fairness through the lens of NC. We analyze the training dynamics of models as they approach NC when training using biased datasets, and examine the subsequent impact on test performance, specifically focusing on label bias. We find that biased training initially results in different NC configurations across subgroups, before converging to a final NC solution by memorizing all data samples. Through extensive experiments on three medical imaging datasets -- PAPILA, HAM10000, and CheXpert -- we find that in biased settings, NC can lead to a significant drop in F1 score across all subgroups. Our code is available at https://gitlab.com/radiology/neuro/neural-collapse-fairness

Wenjie Kang, Bo Li, Janne M. Papma et al.

Machine learning methods have shown large potential for the automatic early diagnosis of Alzheimer's Disease (AD). However, some machine learning methods based on imaging data have poor interpretability because it is usually unclear how they make their decisions. Explainable Boosting Machines (EBMs) are interpretable machine learning models based on the statistical framework of generalized additive modeling, but have so far only been used for tabular data. Therefore, we propose a framework that combines the strength of EBM with high-dimensional imaging data using deep learning-based feature extraction. The proposed framework is interpretable because it provides the importance of each feature. We validated the proposed framework on the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset, achieving accuracy of 0.883 and area-under-the-curve (AUC) of 0.970 on AD and control classification. Furthermore, we validated the proposed framework on an external testing set, achieving accuracy of 0.778 and AUC of 0.887 on AD and subjective cognitive decline (SCD) classification. The proposed framework significantly outperformed an EBM model using volume biomarkers instead of deep learning-based features, as well as an end-to-end convolutional neural network (CNN) with optimized architecture.

Vikram Venkatraghavan, Sebastian R. van der Voort, Daniel Bos et al.

Computer-aided methods have shown added value for diagnosing and predicting brain disorders and can thus support decision making in clinical care and treatment planning. This chapter will provide insight into the type of methods, their working, their input data - such as cognitive tests, imaging and genetic data - and the types of output they provide. We will focus on specific use cases for diagnosis, i.e. estimating the current 'condition' of the patient, such as early detection and diagnosis of dementia, differential diagnosis of brain tumours, and decision making in stroke. Regarding prediction, i.e. estimation of the future 'condition' of the patient, we will zoom in on use cases such as predicting the disease course in multiple sclerosis and predicting patient outcomes after treatment in brain cancer. Furthermore, based on these use cases, we will assess the current state-of-the-art methodology and highlight current efforts on benchmarking of these methods and the importance of open science therein. Finally, we assess the current clinical impact of computer-aided methods and discuss the required next steps to increase clinical impact.

Bo Li, Jeroen de Bresser, Wiro Niessen et al.

Lacunes of presumed vascular origin, also referred to as lacunar infarcts, are important to assess cerebral small vessel disease and cognitive diseases such as dementia. However, visual rating of lacunes from imaging data is challenging, time-consuming, and rater-dependent, owing to their small size, sparsity, and mimics. Whereas recent developments in automatic algorithms have shown to make the detection of lacunes faster while preserving sensitivity, they also showed a large number of false positives, which makes them impractical for use in clinical practice or large-scale studies. Here, we develop a novel framework that, in addition to lacune detection, outputs a categorical burden score. This score could provide a more practical estimate of lacune presence that simplifies and effectively accelerates the imaging assessment of lacunes. We hypothesize that the combination of detection and the categorical score makes the procedure less sensitive to noisy labels.

Claudia Chinea Hammecher, Karin van Garderen, Marion Smits et al.

Glioma growth may be quantified with longitudinal image registration. However, the large mass-effects and tissue changes across images pose an added challenge. Here, we propose a longitudinal, learning-based, and groupwise registration method for the accurate and unbiased registration of glioma MRI. We evaluate on a dataset from the Glioma Longitudinal AnalySiS consortium and compare it to classical registration methods. We achieve comparable Dice coefficients, with more detailed registrations, while significantly reducing the runtime to under a minute. The proposed methods may serve as an alternative to classical toolboxes, to provide further insight into glioma growth.

Pedro Mateus, Swier Garst, Jing Yu et al.

Biological age scores are an emerging tool to characterize aging by estimating chronological age based on physiological biomarkers. Various scores have shown associations with aging-related outcomes. This study assessed the relation between an age score based on brain MRI images (BrainAge) and an age score based on metabolomic biomarkers (MetaboAge). We trained a federated deep learning model to estimate BrainAge in three cohorts. The federated BrainAge model yielded significantly lower error for age prediction across the cohorts than locally trained models. Harmonizing the age interval between cohorts further improved BrainAge accuracy. Subsequently, we compared BrainAge with MetaboAge using federated association and survival analyses. The results showed a small association between BrainAge and MetaboAge as well as a higher predictive value for the time to mortality of both scores combined than for the individual scores. Hence, our study suggests that both aging scores capture different aspects of the aging process.

Kaouther Mouheb, Amos Pomp, Antoine Manenti et al.

Objectives: Automatic data extraction from free-text radiology reports enables large-scale research, but few studies assessed the performance of large language models (LLMs) on Dutch neuroradiology reports. Methods: We analyzed 947 brain MRI reports from a tertiary memory clinic (2016-2021), authored by consultant neuroradiologists. Trained medical students annotated thirty variables; 100 reports were double-annotated to assess inter-rater reliability. We evaluated the performance of the open-weight LLM LLaMA 3.1 using different languages (Dutch vs. English translation) and few-shot prompting with different example selection strategies. Performance was evaluated using balanced accuracy for categorical variables, accuracy and mean absolute error for counts, and text similarity for free-text. Metrics were computed across 10 random splits of the 947 reports. Results: LLaMA 3.1 demonstrated high zero-shot performance for visual rating scores (mean [95%-CI]): Medial Temporal Atrophy: 90% [77-100%] on the left and 96% [94-99%] on the right, Global Cortical Atrophy: 87% [83-91%], and Fazekas: 94% [93-96%]. Microbleed mentions were detected with 93% accuracy [92-95%] and infarct mentions with 82% [80-84%]. Text similarity for lesion location reached 0.95 [0.95-0.96]. Performance was lower for numerical variables: 80% [78-82%] for the number of microbleeds and 66% [63-68%] for infarcts. English translation yielded comparable results. Few-shot prompting improved performance for numerical variables, achieving 92% [90-93%] for microbleeds and 81% [77-85%] for infarcts using structural similarity-based selection. Conclusion: LLaMA 3.1 shows strong potential for extracting data from Dutch neuroradiology reports. Few-shot prompting enhances performance for numerical variables, whereas challenges remain for location-specific variables.

Xianjing Liu, Bo Li, Meike W. Vernooij et al.

This study addresses the challenges of confounding effects and interpretability in artificial-intelligence-based medical image analysis. Whereas existing literature often resolves confounding by removing confounder-related information from latent representations, this strategy risks affecting image reconstruction quality in generative models, thus limiting their applicability in feature visualization. To tackle this, we propose a different strategy that retains confounder-related information in latent representations while finding an alternative confounder-free representation of the image data. Our approach views the latent space of an autoencoder as a vector space, where imaging-related variables, such as the learning target (t) and confounder (c), have a vector capturing their variability. The confounding problem is addressed by searching a confounder-free vector which is orthogonal to the confounder-related vector but maximally collinear to the target-related vector. To achieve this, we introduce a novel correlation-based loss that not only performs vector searching in the latent space, but also encourages the encoder to generate latent representations linearly correlated with the variables. Subsequently, we interpret the confounder-free representation by sampling and reconstructing images along the confounder-free vector. The efficacy and flexibility of our proposed method are demonstrated across three applications, accommodating multiple confounders and utilizing diverse image modalities. Results affirm the method's effectiveness in reducing confounder influences, preventing wrong or misleading associations, and offering a unique visual interpretation for in-depth investigations by clinical and epidemiological researchers. The code is released in the following GitLab repository: https://gitlab.com/radiology/compopbio/ai_based_association_analysis}

Douwe J. Spaanderman, Karthik Prathaban, Petr Zelina et al.

Large language models (LLMs) are increasingly used to extract structured information from free-text clinical records, but prior work often focuses on single tasks, limited models, and English-language reports. We evaluated 15 open-weight LLMs on pathology and radiology reports across six use cases, colorectal liver metastases, liver tumours, neurodegenerative diseases, soft-tissue tumours, melanomas, and sarcomas, at three institutes in the Netherlands, UK, and Czech Republic. Models included general-purpose and medical-specialised LLMs of various sizes, and six prompting strategies were compared: zero-shot, one-shot, few-shot, chain-of-thought, self-consistency, and prompt graph. Performance was assessed using task-appropriate metrics, with consensus rank aggregation and linear mixed-effects models quantifying variance. Top-ranked models achieved macro-average scores close to inter-rater agreement across tasks. Small-to-medium general-purpose models performed comparably to large models, while tiny and specialised models performed worse. Prompt graph and few-shot prompting improved performance by ~13%. Task-specific factors, including variable complexity and annotation variability, influenced results more than model size or prompting strategy. These findings show that open-weight LLMs can extract structured data from clinical reports across diseases, languages, and institutions, offering a scalable approach for clinical data curation.

Hyunho Mo, Djura Smits, Mahlet A. Birhanu et al.

Cardiovascular disease risk prediction models often rely on data from a single institution or centrally pooled datasets. Extending these models across institutions could be limited by privacy regulations and constraints on sharing patient-level data. Federated learning enables collaborative model development without transferring sensitive patient data, but its application in healthcare remains challenging because datasets often differ in size, population characteristics, and outcome definitions. In this study, we present a federated deep learning approach for privacy-preserving cardiovascular disease risk prediction that integrates two population-based cohorts with different characteristics: Lifelines, including 148,230 participants meeting the study inclusion criteria with self-reported outcomes, and the Rotterdam Study, including a smaller cohort of 10,155 participants with digitally linked clinical outcomes. Model performance was primarily evaluated on the Rotterdam Study because of its complete follow-up. Deep survival models trained using federated learning achieved higher predictive performance than models trained locally without federation. For the Rotterdam Study, the C-statistic increased from 0.728 (95% CI: 0.717-0.739) to 0.739 (95% CI: 0.728-0.749). For Lifelines, the C-statistic increased from 0.783 (95% CI: 0.775-0.791) to 0.787 (95% CI: 0.780-0.792). These findings suggest that federated deep learning across heterogeneous cohorts can improve cardiovascular disease risk prediction while preserving the privacy of individual-level patient data.

Wenjie Kang, Lize Jiskoot, Peter De Deyn et al.

Deep learning methods based on Convolutional Neural Networks (CNNs) have shown great potential to improve early and accurate diagnosis of Alzheimer's disease (AD) dementia based on imaging data. However, these methods have yet to be widely adopted in clinical practice, possibly due to the limited interpretability of deep learning models. The Explainable Boosting Machine (EBM) is a glass-box model but cannot learn features directly from input imaging data. In this study, we propose a novel interpretable model that combines CNNs and EBMs for the diagnosis and prediction of AD. We develop an innovative training strategy that alternatingly trains the CNN component as a feature extractor and the EBM component as the output block to form an end-to-end model. The model takes imaging data as input and provides both predictions and interpretable feature importance measures. We validated the proposed model on the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset and the Health-RI Parelsnoer Neurodegenerative Diseases Biobank (PND) as an external testing set. The proposed model achieved an area-under-the-curve (AUC) of 0.956 for AD and control classification, and 0.694 for the prediction of conversion of mild cognitive impairment (MCI) to AD on the ADNI cohort. The proposed model is a glass-box model that achieves a comparable performance with other state-of-the-art black-box models. Our code is publicly available at: https://anonymous.4open.science/r/GL-ICNN.

Héctor Cadavid, Hyunho Mo, Bauke Arends et al.

Cardiovascular disease (CVD) remains a leading cause of death, and primary prevention through personalized interventions is crucial. This paper introduces MyDigiTwin, a framework that integrates health digital twins with personal health environments to empower patients in exploring personalized health scenarios while ensuring data privacy. MyDigiTwin uses federated learning to train predictive models across distributed datasets without transferring raw data, and a novel data harmonization framework addresses semantic and format inconsistencies in health data. A proof-of-concept demonstrates the feasibility of harmonizing and using cohort data to train privacy-preserving CVD prediction models. This framework offers a scalable solution for proactive, personalized cardiovascular care and sets the stage for future applications in real-world healthcare settings.

Esther E. Bron, Stefan Klein, Annika Reinke et al.

Machine learning methods exploiting multi-parametric biomarkers, especially based on neuroimaging, have huge potential to improve early diagnosis of dementia and to predict which individuals are at-risk of developing dementia. To benchmark algorithms in the field of machine learning and neuroimaging in dementia and assess their potential for use in clinical practice and clinical trials, seven grand challenges have been organized in the last decade. The seven grand challenges addressed questions related to screening, clinical status estimation, prediction and monitoring in (pre-clinical) dementia. There was little overlap in clinical questions, tasks and performance metrics. Whereas this aids providing insight on a broad range of questions, it also limits the validation of results across challenges. The validation process itself was mostly comparable between challenges, using similar methods for ensuring objective comparison, uncertainty estimation and statistical testing. In general, winning algorithms performed rigorous data preprocessing and combined a wide range of input features. Despite high state-of-the-art performances, most of the methods evaluated by the challenges are not clinically used. To increase impact, future challenges could pay more attention to statistical analysis of which factors relate to higher performance, to clinical questions beyond Alzheimer's disease, and to using testing data beyond the Alzheimer's Disease Neuroimaging Initiative. Grand challenges would be an ideal venue for assessing the generalizability of algorithm performance to unseen data of other cohorts. Key for increasing impact in this way are larger testing data sizes, which could be reached by sharing algorithms rather than data to exploit data that cannot be shared.

Martijn P. A. Starmans, Sebastian R. van der Voort, Thomas Phil et al.

Predicting clinical outcomes from medical images using quantitative features (``radiomics'') requires many method design choices, Currently, in new clinical applications, finding the optimal radiomics method out of the wide range of methods relies on a manual, heuristic trial-and-error process. We introduce a novel automated framework that optimizes radiomics workflow construction per application by standardizing the radiomics workflow in modular components, including a large collection of algorithms for each component, and formulating a combined algorithm selection and hyperparameter optimization problem. To solve it, we employ automated machine learning through two strategies (random search and Bayesian optimization) and three ensembling approaches. Results show that a medium-sized random search and straight-forward ensembling perform similar to more advanced methods while being more efficient. Validated across twelve clinical applications, our approach outperforms both a radiomics baseline and human experts. Concluding, our framework improves and streamlines radiomics research by fully automatically optimizing radiomics workflow construction. To facilitate reproducibility, we publicly release six datasets, software of the method, and code to reproduce this study.

Xianjing Liu, Bo Li, Esther Bron et al.

Confounding bias is a crucial problem when applying machine learning to practice, especially in clinical practice. We consider the problem of learning representations independent to multiple biases. In literature, this is mostly solved by purging the bias information from learned representations. We however expect this strategy to harm the diversity of information in the representation, and thus limiting its prospective usage (e.g., interpretation). Therefore, we propose to mitigate the bias while keeping almost all information in the latent representations, which enables us to observe and interpret them as well. To achieve this, we project latent features onto a learned vector direction, and enforce the independence between biases and projected features rather than all learned features. To interpret the mapping between projected features and input data, we propose projection-wise disentangling: a sampling and reconstruction along the learned vector direction. The proposed method was evaluated on the analysis of 3D facial shape and patient characteristics (N=5011). Experiments showed that this conceptually simple method achieved state-of-the-art fair prediction performance and interpretability, showing its great potential for clinical applications.

Bo Li, Wiro J. Niessen, Stefan Klein et al.

This work presents a single-step deep-learning framework for longitudinal image analysis, coined Segis-Net. To optimally exploit information available in longitudinal data, this method concurrently learns a multi-class segmentation and nonlinear registration. Segmentation and registration are modeled using a convolutional neural network and optimized simultaneously for their mutual benefit. An objective function that optimizes spatial correspondence for the segmented structures across time-points is proposed. We applied Segis-Net to the analysis of white matter tracts from N=8045 longitudinal brain MRI datasets of 3249 elderly individuals. Segis-Net approach showed a significant increase in registration accuracy, spatio-temporal segmentation consistency, and reproducibility comparing with two multistage pipelines. This also led to a significant reduction in the sample-size that would be required to achieve the same statistical power in analyzing tract-specific measures. Thus, we expect that Segis-Net can serve as a new reliable tool to support longitudinal imaging studies to investigate macro- and microstructural brain changes over time.

Esther E. Bron, Stefan Klein, Janne M. Papma et al.

This work validates the generalizability of MRI-based classification of Alzheimer's disease (AD) patients and controls (CN) to an external data set and to the task of prediction of conversion to AD in individuals with mild cognitive impairment (MCI). We used a conventional support vector machine (SVM) and a deep convolutional neural network (CNN) approach based on structural MRI scans that underwent either minimal pre-processing or more extensive pre-processing into modulated gray matter (GM) maps. Classifiers were optimized and evaluated using cross-validation in the ADNI (334 AD, 520 CN). Trained classifiers were subsequently applied to predict conversion to AD in ADNI MCI patients (231 converters, 628 non-converters) and in the independent Health-RI Parelsnoer data set. From this multi-center study representing a tertiary memory clinic population, we included 199 AD patients, 139 participants with subjective cognitive decline, 48 MCI patients converting to dementia, and 91 MCI patients who did not convert to dementia. AD-CN classification based on modulated GM maps resulted in a similar AUC for SVM (0.940) and CNN (0.933). Application to conversion prediction in MCI yielded significantly higher performance for SVM (0.756) than for CNN (0.742). In external validation, performance was slightly decreased. For AD-CN, it again gave similar AUCs for SVM (0.896) and CNN (0.876). For prediction in MCI, performances decreased for both SVM (0.665) and CNN (0.702). Both with SVM and CNN, classification based on modulated GM maps significantly outperformed classification based on minimally processed images. Deep and conventional classifiers performed equally well for AD classification and their performance decreased only slightly when applied to the external cohort. We expect that this work on external validation contributes towards translation of machine learning to clinical practice.

Bo Li, Wiro J. Niessen, Stefan Klein et al.

Analysis of longitudinal changes in imaging studies often involves both segmentation of structures of interest and registration of multiple timeframes. The accuracy of such analysis could benefit from a tailored framework that jointly optimizes both tasks to fully exploit the information available in the longitudinal data. Most learning-based registration algorithms, including joint optimization approaches, currently suffer from bias due to selection of a fixed reference frame and only support pairwise transformations. We here propose an analytical framework based on an unbiased learning strategy for group-wise registration that simultaneously registers images to the mean space of a group to obtain consistent segmentations. We evaluate the proposed method on longitudinal analysis of a white matter tract in a brain MRI dataset with 2-3 time-points for 3249 individuals, i.e., 8045 images in total. The reproducibility of the method is evaluated on test-retest data from 97 individuals. The results confirm that the implicit reference image is an average of the input image. In addition, the proposed framework leads to consistent segmentations and significantly lower processing bias than that of a pair-wise fixed-reference approach. This processing bias is even smaller than those obtained when translating segmentations by only one voxel, which can be attributed to subtle numerical instabilities and interpolation. Therefore, we postulate that the proposed mean-space learning strategy could be widely applied to learning-based registration tasks. In addition, this group-wise framework introduces a novel way for learning-based longitudinal studies by direct construction of an unbiased within-subject template and allowing reliable and efficient analysis of spatio-temporal imaging biomarkers.

Vikram Venkatraghavan, Stefan Klein, Lana Fani et al.

Alzheimer's disease (AD) is the most common form of dementia and is phenotypically heterogeneous. APOE is a triallelic gene which correlates with phenotypic heterogeneity in AD. In this work, we determined the effect of APOE alleles on the disease progression timeline of AD using a discriminative event-based model (DEBM). Since DEBM is a data-driven model, stratification into smaller disease subgroups would lead to more inaccurate models as compared to fitting the model on the entire dataset. Hence our secondary aim is to propose and evaluate novel approaches in which we split the different steps of DEBM into group-aspecific and group-specific parts, where the entire dataset is used to train the group-aspecific parts and only the data from a specific group is used to train the group-specific parts of the DEBM. We performed simulation experiments to benchmark the accuracy of the proposed approaches and to select the optimal approach. Subsequently, the chosen approach was applied to the baseline data of 417 cognitively normal, 235 mild cognitively impaired who convert to AD within 3 years, and 342 AD patients from the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset to gain new insights into the effect of APOE carriership on the disease progression timeline of AD. The presented models could aid understanding of the disease, and in selecting homogeneous group of presymptomatic subjects at-risk of developing symptoms for clinical trials.

Bo Li, Marius de Groot, Rebecca M. E. Steketee et al.

Subtle changes in white matter (WM) microstructure have been associated with normal aging and neurodegeneration. To study these associations in more detail, it is highly important that the WM tracts can be accurately and reproducibly characterized from brain diffusion MRI. In addition, to enable analysis of WM tracts in large datasets and in clinical practice it is essential to have methodology that is fast and easy to apply. This work therefore presents a new approach for WM tract segmentation: Neuro4Neuro, that is capable of direct extraction of WM tracts from diffusion tensor images using convolutional neural network (CNN). This 3D end-to-end method is trained to segment 25 WM tracts in aging individuals from a large population-based study (N=9752, 1.5T MRI). The proposed method showed good segmentation performance and high reproducibility, i.e., a high spatial agreement (Cohen's kappa, k = 0.72 ~ 0.83) and a low scan-rescan error in tract-specific diffusion measures (e.g., fractional anisotropy: error = 1% ~ 5%). The reproducibility of the proposed method was higher than that of a tractography-based segmentation algorithm, while being orders of magnitude faster (0.5s to segment one tract). In addition, we showed that the method successfully generalizes to diffusion scans from an external dementia dataset (N=58, 3T MRI). In two proof-of-principle experiments, we associated WM microstructure obtained using the proposed method with age in a normal elderly population, and with disease subtypes in a dementia cohort. In concordance with the literature, results showed a widespread reduction of microstructural organization with aging and substantial group-wise microstructure differences between dementia subtypes. In conclusion, we presented a highly reproducible and fast method for WM tract segmentation that has the potential of being used in large-scale studies and clinical practice.

Bo Li, Marius de Groot, Meike Vernooij et al.

Tract-specific diffusion measures, as derived from brain diffusion MRI, have been linked to white matter tract structural integrity and neurodegeneration. As a consequence, there is a large interest in the automatic segmentation of white matter tract in diffusion tensor MRI data. Methods based on the tractography are popular for white matter tract segmentation. However, because of the limited consistency and long processing time, such methods may not be suitable for clinical practice. We therefore developed a novel convolutional neural network based method to directly segment white matter tract trained on a low-resolution dataset of 9149 DTI images. The method is optimized on input, loss function and network architecture selections. We evaluated both segmentation accuracy and reproducibility, and reproducibility of determining tract-specific diffusion measures. The reproducibility of the method is higher than that of the reference standard and the determined diffusion measures are consistent. Therefore, we expect our method to be applicable in clinical practice and in longitudinal analysis of white matter microstructure.

Bo Li, Wiro Niessen, Stefan Klein et al.

To accurately analyze changes of anatomical structures in longitudinal imaging studies, consistent segmentation across multiple time-points is required. Existing solutions often involve independent registration and segmentation components. Registration between time-points is used either as a prior for segmentation in a subsequent time point or to perform segmentation in a common space. In this work, we propose a novel hybrid convolutional neural network (CNN) that integrates segmentation and registration into a single procedure. We hypothesize that the joint optimization leads to increased performance on both tasks. The hybrid CNN is trained by minimizing an integrated loss function composed of four different terms, measuring segmentation accuracy, similarity between registered images, deformation field smoothness, and segmentation consistency. We applied this method to the segmentation of white matter tracts, describing functionally grouped axonal fibers, using N=8045 longitudinal brain MRI data of 3249 individuals. The proposed method was compared with two multistage pipelines using two existing segmentation methods combined with a conventional deformable registration algorithm. In addition, we assessed the added value of the joint optimization for segmentation and registration separately. The hybrid CNN yielded significantly higher accuracy, consistency and reproducibility of segmentation than the multistage pipelines, and was orders of magnitude faster. Therefore, we expect it can serve as a novel tool to support clinical and epidemiological analyses on understanding microstructural brain changes over time.

Vikram Venkatraghavan, Florian Dubost, Esther E. Bron et al.

Event-based models (EBM) are a class of disease progression models that can be used to estimate temporal ordering of neuropathological changes from cross-sectional data. Current EBMs only handle scalar biomarkers, such as regional volumes, as inputs. However, regional aggregates are a crude summary of the underlying high-resolution images, potentially limiting the accuracy of EBM. Therefore, we propose a novel method that exploits high-dimensional voxel-wise imaging biomarkers: n-dimensional discriminative EBM (nDEBM). nDEBM is based on an insight that mixture modeling, which is a key element of conventional EBMs, can be replaced by a more scalable semi-supervised support vector machine (SVM) approach. This SVM is used to estimate the degree of abnormality of each region which is then used to obtain subject-specific disease progression patterns. These patterns are in turn used for estimating the mean ordering by fitting a generalized Mallows model. In order to validate the biomarker ordering obtained using nDEBM, we also present a framework for Simulation of Imaging Biomarkers' Temporal Evolution (SImBioTE) that mimics neurodegeneration in brain regions. SImBioTE trains variational auto-encoders (VAE) in different brain regions independently to simulate images at varying stages of disease progression. We also validate nDEBM clinically using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI). In both experiments, nDEBM using high-dimensional features gave better performance than state-of-the-art EBM methods using regional volume biomarkers. This suggests that nDEBM is a promising approach for disease progression modeling.

Vikram Venkatraghavan, Esther E. Bron, Wiro J. Niessen et al.

Alzheimer's Disease (AD) is characterized by a cascade of biomarkers becoming abnormal, the pathophysiology of which is very complex and largely unknown. Event-based modeling (EBM) is a data-driven technique to estimate the sequence in which biomarkers for a disease become abnormal based on cross-sectional data. It can help in understanding the dynamics of disease progression and facilitate early diagnosis and prognosis. In this work we propose a novel discriminative approach to EBM, which is shown to be more accurate than existing state-of-the-art EBM methods. The method first estimates for each subject an approximate ordering of events. Subsequently, the central ordering over all subjects is estimated by fitting a generalized Mallows model to these approximate subject-specific orderings. We also introduce the concept of relative distance between events which helps in creating a disease progression timeline. Subsequently, we propose a method to stage subjects by placing them on the estimated disease progression timeline. We evaluated the proposed method on Alzheimer's Disease Neuroimaging Initiative (ADNI) data and compared the results with existing state-of-the-art EBM methods. We also performed extensive experiments on synthetic data simulating the progression of Alzheimer's disease. The event orderings obtained on ADNI data seem plausible and are in agreement with the current understanding of progression of AD. The proposed patient staging algorithm performed consistently better than that of state-of-the-art EBM methods. Event orderings obtained in simulation experiments were more accurate than those of other EBM methods and the estimated disease progression timeline was observed to correlate with the timeline of actual disease progression. The results of these experiments are encouraging and suggest that discriminative EBM is a promising approach to disease progression modeling.

Vikram Venkatraghavan, Esther Bron, Wiro Niessen et al.

The event-based model (EBM) for data-driven disease progression modeling estimates the sequence in which biomarkers for a disease become abnormal. This helps in understanding the dynamics of disease progression and facilitates early diagnosis by staging patients on a disease progression timeline. Existing EBM methods are all generative in nature. In this work we propose a novel discriminative approach to EBM, which is shown to be more accurate as well as computationally more efficient than existing state-of-the art EBM methods. The method first estimates for each subject an approximate ordering of events, by ranking the posterior probabilities of individual biomarkers being abnormal. Subsequently, the central ordering over all subjects is estimated by fitting a generalized Mallows model to these approximate subject-specific orderings based on a novel probabilistic Kendall's Tau distance. To evaluate the accuracy, we performed extensive experiments on synthetic data simulating the progression of Alzheimer's disease. Subsequently, the method was applied to the Alzheimer's Disease Neuroimaging Initiative (ADNI) data to estimate the central event ordering in the dataset. The experiments benchmark the accuracy of the new model under various conditions and compare it with existing state-of-the-art EBM methods. The results indicate that discriminative EBM could be a simple and elegant approach to disease progression modeling.