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Predicting survival in Amyotrophic Lateral Sclerosis (ALS) is a challenging task. Magnetic resonance imaging (MRI) data provide in vivo insight into brain health, but the low prevalence of the condition and resultant data scarcity limit training set sizes for prediction models. Survival models are further hindered by the subtle and often highly localised profile of ALS-related neurodegeneration. Normative models present a solution as they increase statistical power by leveraging large healthy cohorts. Separately, diffusion models excel in capturing the semantics embedded within images including subtle signs of accelerated brain ageing, which may help predict survival in ALS. Here, we combine the benefits of generative and normative modelling by introducing the normative diffusion autoencoder framework. To our knowledge, this is the first use of normative modelling within a diffusion autoencoder, as well as the first application of normative modelling to ALS. Our approach outperforms generative and non-generative normative modelling benchmarks in ALS prognostication, demonstrating enhanced predictive accuracy in the context of ALS survival prediction and normative modelling in general.

Purpose: Most studies evaluating artificial intelligence (AI) models that detect abnormalities in neuroimaging are either tested on unrepresentative patient cohorts or are insufficiently well-validated, leading to poor generalisability to real-world tasks. The aim was to determine the diagnostic test accuracy and summarise the evidence supporting the use of AI models performing first-line, high-volume neuroimaging tasks. Methods: Medline, Embase, Cochrane library and Web of Science were searched until September 2021 for studies that temporally or externally validated AI capable of detecting abnormalities in first-line CT or MR neuroimaging. A bivariate random-effects model was used for meta-analysis where appropriate. PROSPERO: CRD42021269563. Results: Only 16 studies were eligible for inclusion. Included studies were not compromised by unrepresentative datasets or inadequate validation methodology. Direct comparison with radiologists was available in 4/16 studies. 15/16 had a high risk of bias. Meta-analysis was only suitable for intracranial haemorrhage detection in CT imaging (10/16 studies), where AI systems had a pooled sensitivity and specificity 0.90 (95% CI 0.85 - 0.94) and 0.90 (95% CI 0.83 - 0.95) respectively. Other AI studies using CT and MRI detected target conditions other than haemorrhage (2/16), or multiple target conditions (4/16). Only 3/16 studies implemented AI in clinical pathways, either for pre-read triage or as post-read discrepancy identifiers. Conclusion: The paucity of eligible studies reflects that most abnormality detection AI studies were not adequately validated in representative clinical cohorts. The few studies describing how abnormality detection AI could impact patients and clinicians did not explore the full ramifications of clinical implementation.

Artificial neural networks trained on large, expert-labelled datasets are considered state-of-the-art for a range of medical image recognition tasks. However, categorically labelled datasets are time-consuming to generate and constrain classification to a pre-defined, fixed set of classes. For neuroradiological applications in particular, this represents a barrier to clinical adoption. To address these challenges, we present a self-supervised text-vision framework that learns to detect clinically relevant abnormalities in brain MRI scans by directly leveraging the rich information contained in accompanying free-text neuroradiology reports. Our training approach consisted of two-steps. First, a dedicated neuroradiological language model - NeuroBERT - was trained to generate fixed-dimensional vector representations of neuroradiology reports (N = 50,523) via domain-specific self-supervised learning tasks. Next, convolutional neural networks (one per MRI sequence) learnt to map individual brain scans to their corresponding text vector representations by optimising a mean square error loss. Once trained, our text-vision framework can be used to detect abnormalities in unreported brain MRI examinations by scoring scans against suitable query sentences (e.g., 'there is an acute stroke', 'there is hydrocephalus' etc.), enabling a range of classification-based applications including automated triage. Potentially, our framework could also serve as a clinical decision support tool, not only by suggesting findings to radiologists and detecting errors in provisional reports, but also by retrieving and displaying examples of pathologies from historical examinations that could be relevant to the current case based on textual descriptors., Comment: Under Review

Brain age prediction models have succeeded in predicting clinical outcomes in neurodegenerative diseases, but can struggle with tasks involving faster progressing diseases and low quality data. To enhance their performance, we employ a semi-supervised diffusion model, obtaining a 0.83(p<0.01) correlation between chronological and predicted age on low quality T1w MR images. This was competitive with state-of-the-art non-generative methods. Furthermore, the predictions produced by our model were significantly associated with survival length (r=0.24, p<0.05) in Amyotrophic Lateral Sclerosis. Thus, our approach demonstrates the value of diffusion-based architectures for the task of brain age prediction.

Purpose: Previous quantitative MR imaging studies using self-supervised deep learning have reported biased parameter estimates at low SNR. Such systematic errors arise from the choice of Mean Squared Error (MSE) loss function for network training, which is incompatible with Rician-distributed MR magnitude signals. To address this issue, we introduce the negative log Rician likelihood (NLR) loss. Methods: A numerically stable and accurate implementation of the NLR loss was developed to estimate quantitative parameters of the apparent diffusion coefficient (ADC) model and intra-voxel incoherent motion (IVIM) model. Parameter estimation accuracy, precision and overall error were evaluated in terms of bias, variance and root mean squared error and compared against the MSE loss over a range of SNRs (5 - 30). Results: Networks trained with NLR loss show higher estimation accuracy than MSE for the ADC and IVIM diffusion coefficients as SNR decreases, with minimal loss of precision or total error. At high effective SNR (high SNR and small diffusion coefficients), both losses show comparable accuracy and precision for all parameters of both models. Conclusion: The proposed NLR loss is numerically stable and accurate across the full range of tested SNRs and improves parameter estimation accuracy of diffusion coefficients using self-supervised deep learning. We expect the development to benefit quantitative MR imaging techniques broadly, enabling more accurate parameter estimation from noisy data., Comment: 16 pages, 6 figures

In visual object classification, humans often justify their choices by comparing objects to prototypical examples within that class. We may therefore increase the interpretability of deep learning models by imbuing them with a similar style of reasoning. In this work, we apply this principle by classifying Alzheimer's Disease based on the similarity of images to training examples within the latent space. We use a contrastive loss combined with a diffusion autoencoder backbone, to produce a semantically meaningful latent space, such that neighbouring latents have similar image-level features. We achieve a classification accuracy comparable to black box approaches on a dataset of 2D MRI images, whilst producing human interpretable model explanations. Therefore, this work stands as a contribution to the pertinent development of accurate and interpretable deep learning within medical imaging.

Machine learning models deployed on medical imaging tasks must be equipped with out-of-distribution detection capabilities in order to avoid erroneous predictions. It is unsure whether out-of-distribution detection models reliant on deep neural networks are suitable for detecting domain shifts in medical imaging. Gaussian Processes can reliably separate in-distribution data points from out-of-distribution data points via their mathematical construction. Hence, we propose a parameter efficient Bayesian layer for hierarchical convolutional Gaussian Processes that incorporates Gaussian Processes operating in Wasserstein-2 space to reliably propagate uncertainty. This directly replaces convolving Gaussian Processes with a distance-preserving affine operator on distributions. Our experiments on brain tissue-segmentation show that the resulting architecture approaches the performance of well-established deterministic segmentation algorithms (U-Net), which has not been achieved with previous hierarchical Gaussian Processes. Moreover, by applying the same segmentation model to out-of-distribution data (i.e., images with pathology such as brain tumors), we show that our uncertainty estimates result in out-of-distribution detection that outperforms the capabilities of previous Bayesian networks and reconstruction-based approaches that learn normative distributions. To facilitate future work our code is publicly available., Comment: Published in Journal of Machine Learning for Biomedical Imaging: Special Issue: Information Processing in Medical Imaging (IPMI) 2021

The deviation between chronological age and age predicted from neuroimaging data has been identified as a sensitive risk-marker of cross-disorder brain changes, growing into a cornerstone of biological age-research. However, Machine Learning models underlying the field do not consider uncertainty, thereby confounding results with training data density and variability. Also, existing models are commonly based on homogeneous training sets, often not independently validated, and cannot be shared due to data protection issues. Here, we introduce an uncertainty-aware, shareable, and transparent Monte-Carlo Dropout Composite-Quantile-Regression (MCCQR) Neural Network trained on N=10,691 datasets from the German National Cohort. The MCCQR model provides robust, distribution-free uncertainty quantification in high-dimensional neuroimaging data, achieving lower error rates compared to existing models across ten recruitment centers and in three independent validation samples (N=4,004). In two examples, we demonstrate that it prevents spurious associations and increases power to detect accelerated brain-aging. We make the pre-trained model publicly available.

The growing demand for head magnetic resonance imaging (MRI) examinations, along with a global shortage of radiologists, has led to an increase in the time taken to report head MRI scans around the world. For many neurological conditions, this delay can result in increased morbidity and mortality. An automated triaging tool could reduce reporting times for abnormal examinations by identifying abnormalities at the time of imaging and prioritizing the reporting of these scans. In this work, we present a convolutional neural network for detecting clinically-relevant abnormalities in $\text{T}_2$-weighted head MRI scans. Using a validated neuroradiology report classifier, we generated a labelled dataset of 43,754 scans from two large UK hospitals for model training, and demonstrate accurate classification (area under the receiver operating curve (AUC) = 0.943) on a test set of 800 scans labelled by a team of neuroradiologists. Importantly, when trained on scans from only a single hospital the model generalized to scans from the other hospital ($\Delta$AUC $\leq$ 0.02). A simulation study demonstrated that our model would reduce the mean reporting time for abnormal examinations from 28 days to 14 days and from 9 days to 5 days at the two hospitals, demonstrating feasibility for use in a clinical triage environment., Comment: Accepted as an oral presentation at Medical Imaging with Deep Learning (MIDL) 2021

We propose a parameter efficient Bayesian layer for hierarchical convolutional Gaussian Processes that incorporates Gaussian Processes operating in Wasserstein-2 space to reliably propagate uncertainty. This directly replaces convolving Gaussian Processes with a distance-preserving affine operator on distributions. Our experiments on brain tissue-segmentation show that the resulting architecture approaches the performance of well-established deterministic segmentation algorithms (U-Net), which has never been achieved with previous hierarchical Gaussian Processes. Moreover, by applying the same segmentation model to out-of-distribution data (i.e., images with pathology such as brain tumors), we show that our uncertainty estimates result in out-of-distribution detection that outperforms the capabilities of previous Bayesian networks and reconstruction-based approaches that learn normative distributions.

Stacking Gaussian Processes severely diminishes the model's ability to detect outliers, which when combined with non-zero mean functions, further extrapolates low non-parametric variance to low training data density regions. We propose a hybrid kernel inspired from Varifold theory, operating in both Euclidean and Wasserstein space. We posit that directly taking into account the variance in the computation of Wasserstein-2 distances is of key importance towards maintaining outlier status throughout the hierarchy. We show improved performance on medium and large scale datasets and enhanced out-of-distribution detection on both toy and real data.

Natural language processing (NLP) shows promise as a means to automate the labelling of hospital-scale neuroradiology magnetic resonance imaging (MRI) datasets for computer vision applications. To date, however, there has been no thorough investigation into the validity of this approach, including determining the accuracy of report labels compared to image labels as well as examining the performance of non-specialist labellers. In this work, we draw on the experience of a team of neuroradiologists who labelled over 5000 MRI neuroradiology reports as part of a project to build a dedicated deep learning-based neuroradiology report classifier. We show that, in our experience, assigning binary labels (i.e. normal vs abnormal) to images from reports alone is highly accurate. In contrast to the binary labels, however, the accuracy of more granular labelling is dependent on the category, and we highlight reasons for this discrepancy. We also show that downstream model performance is reduced when labelling of training reports is performed by a non-specialist. To allow other researchers to accelerate their research, we make our refined abnormality definitions and labelling rules available, as well as our easy-to-use radiology report labelling app which helps streamline this process.

Labelling large datasets for training high-capacity neural networks is a major obstacle to the development of deep learning-based medical imaging applications. Here we present a transformer-based network for magnetic resonance imaging (MRI) radiology report classification which automates this task by assigning image labels on the basis of free-text expert radiology reports. Our model's performance is comparable to that of an expert radiologist, and better than that of an expert physician, demonstrating the feasibility of this approach. We make code available online for researchers to label their own MRI datasets for medical imaging applications.

Deep learning is attracting significant interest in the neuroimaging community as a means to diagnose psychiatric and neurological disorders from structural magnetic resonance images. However, there is a tendency amongst researchers to adopt architectures optimized for traditional computer vision tasks, rather than design networks customized for neuroimaging data. We address this by introducing NEURO-DRAM, a 3D recurrent visual attention model tailored for neuroimaging classification. The model comprises an agent which, trained by reinforcement learning, learns to navigate through volumetric images, selectively attending to the most informative regions for a given task. When applied to Alzheimer's disease prediction, NEURODRAM achieves state-of-the-art classification accuracy on an out-of-sample dataset, significantly outperforming a baseline convolutional neural network. When further applied to the task of predicting which patients with mild cognitive impairment will be diagnosed with Alzheimer's disease within two years, the model achieves state-of-the-art accuracy with no additional training. Encouragingly, the agent learns, without explicit instruction, a search policy in agreement with standardized radiological hallmarks of Alzheimer's disease, suggesting a route to automated biomarker discovery for more poorly understood disorders., Comment: Improved network figure

The use of machine learning (ML) algorithms has significantly increased in neuroscience. However, from the vast extent of possible ML algorithms, which one is the optimal model to predict the target variable? What are the hyperparameters for such a model? Given the plethora of possible answers to these questions, in the last years, automated machine learning (autoML) has been gaining attention. Here, we apply an autoML library called TPOT which uses a tree-based representation of machine learning pipelines and conducts a genetic-programming based approach to find the model and its hyperparameters that more closely predicts the subject's true age. To explore autoML and evaluate its efficacy within neuroimaging datasets, we chose a problem that has been the focus of previous extensive study: brain age prediction. Without any prior knowledge, TPOT was able to scan through the model space and create pipelines that outperformed the state-of-the-art accuracy for Freesurfer-based models using only thickness and volume information for anatomical structure. In particular, we compared the performance of TPOT (mean accuracy error (MAE): $4.612 \pm .124$ years) and a Relevance Vector Regression (MAE $5.474 \pm .140$ years). TPOT also suggested interesting combinations of models that do not match the current most used models for brain prediction but generalise well to unseen data. AutoML showed promising results as a data-driven approach to find optimal models for neuroimaging applications.