Clinically Plausible Pathology-Anatomy Disentanglement in Patient Brain MRI with Structured Variational Priors

We propose a hierarchically structured variational inference model for accurately disentangling observable evidence of disease (e.g. brain lesions or atrophy) from subject-specific anatomy in brain MRIs. With flexible, partially autoregressive priors, our model (1) addresses the subtle and fine-grained dependencies that typically exist between anatomical and pathological generating factors of an MRI to ensure the clinical validity of generated samples; (2) preserves and disentangles finer pathological details pertaining to a patient's disease state. Additionally, we experiment with an alternative training configuration where we provide supervision to a subset of latent units. It is shown that (1) a partially supervised latent space achieves a higher degree of disentanglement between evidence of disease and subject-specific anatomy; (2) when the prior is formulated with an autoregressive structure, knowledge from the supervision can propagate to the unsupervised latent units, resulting in more informative latent representations capable of modelling anatomy-pathology interdependencies.

Rethinking Generalization: The Impact of Annotation Style on Medical Image Segmentation

Generalization is an important attribute of machine learning models, particularly for those that are to be deployed in a medical context, where unreliable predictions can have real world consequences. While the failure of models to generalize across datasets is typically attributed to a mismatch in the data distributions, performance gaps are often a consequence of biases in the ``ground-truth" label annotations. This is particularly important in the context of medical image segmentation of pathological structures (e.g. lesions), where the annotation process is much more subjective, and affected by a number underlying factors, including the annotation protocol, rater education/experience, and clinical aims, among others. In this paper, we show that modeling annotation biases, rather than ignoring them, poses a promising way of accounting for differences in annotation style across datasets. To this end, we propose a generalized conditioning framework to (1) learn and account for different annotation styles across multiple datasets using a single model, (2) identify similar annotation styles across different datasets in order to permit their effective aggregation, and (3) fine-tune a fully trained model to a new annotation style with just a few samples. Next, we present an image-conditioning approach to model annotation styles that correlate with specific image features, potentially enabling detection biases to be more easily identified.

On Learning Fairness and Accuracy on Multiple Subgroups

We propose an analysis in fair learning that preserves the utility of the data while reducing prediction disparities under the criteria of group sufficiency. We focus on the scenario where the data contains multiple or even many subgroups, each with limited number of samples. As a result, we present a principled method for learning a fair predictor for all subgroups via formulating it as a bilevel objective. Specifically, the subgroup specific predictors are learned in the lower-level through a small amount of data and the fair predictor. In the upper-level, the fair predictor is updated to be close to all subgroup specific predictors. We further prove that such a bilevel objective can effectively control the group sufficiency and generalization error. We evaluate the proposed framework on real-world datasets. Empirical evidence suggests the consistently improved fair predictions, as well as the comparable accuracy to the baselines.

Heatmap Regression for Lesion Detection using Pointwise Annotations

In many clinical contexts, detecting all lesions is imperative for evaluating disease activity. Standard approaches pose lesion detection as a segmentation problem despite the time-consuming nature of acquiring segmentation labels. In this paper, we present a lesion detection method which relies only on point labels. Our model, which is trained via heatmap regression, can detect a variable number of lesions in a probabilistic manner. In fact, our proposed post-processing method offers a reliable way of directly estimating the lesion existence uncertainty. Experimental results on Gad lesion detection show our point-based method performs competitively compared to training on expensive segmentation labels. Finally, our detection model provides a suitable pre-training for segmentation. When fine-tuning on only 17 segmentation samples, we achieve comparable performance to training with the full dataset.

Counterfactual Image Synthesis for Discovery of Personalized Predictive Image Markers

The discovery of patient-specific imaging markers that are predictive of future disease outcomes can help us better understand individual-level heterogeneity of disease evolution. In fact, deep learning models that can provide data-driven personalized markers are much more likely to be adopted in medical practice. In this work, we demonstrate that data-driven biomarker discovery can be achieved through a counterfactual synthesis process. We show how a deep conditional generative model can be used to perturb local imaging features in baseline images that are pertinent to subject-specific future disease evolution and result in a counterfactual image that is expected to have a different future outcome. Candidate biomarkers, therefore, result from examining the set of features that are perturbed in this process. Through several experiments on a large-scale, multi-scanner, multi-center multiple sclerosis (MS) clinical trial magnetic resonance imaging (MRI) dataset of relapsing-remitting (RRMS) patients, we demonstrate that our model produces counterfactuals with changes in imaging features that reflect established clinical markers predictive of future MRI lesional activity at the population level. Additional qualitative results illustrate that our model has the potential to discover novel and subject-specific predictive markers of future activity.

Information Gain Sampling for Active Learning in Medical Image Classification

Large, annotated datasets are not widely available in medical image analysis due to the prohibitive time, costs, and challenges associated with labelling large datasets. Unlabelled datasets are easier to obtain, and in many contexts, it would be feasible for an expert to provide labels for a small subset of images. This work presents an information-theoretic active learning framework that guides the optimal selection of images from the unlabelled pool to be labeled based on maximizing the expected information gain (EIG) on an evaluation dataset. Experiments are performed on two different medical image classification datasets: multi-class diabetic retinopathy disease scale classification and multi-class skin lesion classification. Results indicate that by adapting EIG to account for class-imbalances, our proposed Adapted Expected Information Gain (AEIG) outperforms several popular baselines including the diversity based CoreSet and uncertainty based maximum entropy sampling. Specifically, AEIG achieves ~95% of overall performance with only 19% of the training data, while other active learning approaches require around 25%. We show that, by careful design choices, our model can be integrated into existing deep learning classifiers.

Metrics reloaded: Pitfalls and recommendations for image analysis validation

The field of automatic biomedical image analysis crucially depends on robust and meaningful performance metrics for algorithm validation. Current metric usage, however, is often ill-informed and does not reflect the underlying domain interest. Here, we present a comprehensive framework that guides researchers towards choosing performance metrics in a problem-aware manner. Specifically, we focus on biomedical image analysis problems that can be interpreted as a classification task at image, object or pixel level. The framework first compiles domain interest-, target structure-, data set- and algorithm output-related properties of a given problem into a problem fingerprint, while also mapping it to the appropriate problem category, namely image-level classification, semantic segmentation, instance segmentation, or object detection. It then guides users through the process of selecting and applying a set of appropriate validation metrics while making them aware of potential pitfalls related to individual choices. In this paper, we describe the current status of the Metrics Reloaded recommendation framework, with the goal of obtaining constructive feedback from the image analysis community. The current version has been developed within an international consortium of more than 60 image analysis experts and will be made openly available as a user-friendly toolkit after community-driven optimization.

Segmentation-Consistent Probabilistic Lesion Counting

Lesion counts are important indicators of disease severity, patient prognosis, and treatment efficacy, yet counting as a task in medical imaging is often overlooked in favor of segmentation. This work introduces a novel continuously differentiable function that maps lesion segmentation predictions to lesion count probability distributions in a consistent manner. The proposed end-to-end approach--which consists of voxel clustering, lesion-level voxel probability aggregation, and Poisson-binomial counting--is non-parametric and thus offers a robust and consistent way to augment lesion segmentation models with post hoc counting capabilities. Experiments on Gadolinium-enhancing lesion counting demonstrate that our method outputs accurate and well-calibrated count distributions that capture meaningful uncertainty information. They also reveal that our model is suitable for multi-task learning of lesion segmentation, is efficient in low data regimes, and is robust to adversarial attacks.

Personalized Prediction of Future Lesion Activity and Treatment Effect in Multiple Sclerosis from Baseline MRI

Precision medicine for chronic diseases such as multiple sclerosis (MS) involves choosing a treatment which best balances efficacy and side effects/preferences for individual patients. Making this choice as early as possible is important, as delays in finding an effective therapy can lead to irreversible disability accrual. To this end, we present the first deep neural network model for individualized treatment decisions from baseline magnetic resonance imaging (MRI) (with clinical information if available) for MS patients. Our model (a) predicts future new and enlarging T2 weighted (NE-T2) lesion counts on follow-up MRI on multiple treatments and (b) estimates the conditional average treatment effect (CATE), as defined by the predicted future suppression of NE-T2 lesions, between different treatment options relative to placebo. Our model is validated on a proprietary federated dataset of 1817 multi-sequence MRIs acquired from MS patients during four multi-centre randomized clinical trials. Our framework achieves high average precision in the binarized regression of future NE-T2 lesions on five different treatments, identifies heterogeneous treatment effects, and provides a personalized treatment recommendation that accounts for treatment-associated risk (e.g. side effects, patient preference, administration difficulties).

QU-BraTS: MICCAI BraTS 2020 Challenge on Quantifying Uncertainty in Brain Tumor Segmentation -- Analysis of Ranking Metrics and Benchmarking Results

Deep learning (DL) models have provided the state-of-the-art performance in a wide variety of medical imaging benchmarking challenges, including the Brain Tumor Segmentation (BraTS) challenges. However, the task of focal pathology multi-compartment segmentation (e.g., tumor and lesion sub-regions) is particularly challenging, and potential errors hinder the translation of DL models into clinical workflows. Quantifying the reliability of DL model predictions in the form of uncertainties, could enable clinical review of the most uncertain regions, thereby building trust and paving the way towards clinical translation. Recently, a number of uncertainty estimation methods have been introduced for DL medical image segmentation tasks. Developing metrics to evaluate and compare the performance of uncertainty measures will assist the end-user in making more informed decisions. In this study, we explore and evaluate a metric developed during the BraTS 2019-2020 task on uncertainty quantification (QU-BraTS), and designed to assess and rank uncertainty estimates for brain tumor multi-compartment segmentation. This metric (1) rewards uncertainty estimates that produce high confidence in correct assertions, and those that assign low confidence levels at incorrect assertions, and (2) penalizes uncertainty measures that lead to a higher percentages of under-confident correct assertions. We further benchmark the segmentation uncertainties generated by 14 independent participating teams of QU-BraTS 2020, all of which also participated in the main BraTS segmentation task. Overall, our findings confirm the importance and complementary value that uncertainty estimates provide to segmentation algorithms, and hence highlight the need for uncertainty quantification in medical image analyses. Our evaluation code is made publicly available at https://github.com/RagMeh11/QU-BraTS.