Unsupervised Anomaly Detection using Aggregated Normative Diffusion

Early detection of anomalies in medical images such as brain MRI is highly relevant for diagnosis and treatment of many conditions. Supervised machine learning methods are limited to a small number of pathologies where there is good availability of labeled data. In contrast, unsupervised anomaly detection (UAD) has the potential to identify a broader spectrum of anomalies by spotting deviations from normal patterns. Our research demonstrates that existing state-of-the-art UAD approaches do not generalise well to diverse types of anomalies in realistic multi-modal MR data. To overcome this, we introduce a new UAD method named Aggregated Normative Diffusion (ANDi). ANDi operates by aggregating differences between predicted denoising steps and ground truth backwards transitions in Denoising Diffusion Probabilistic Models (DDPMs) that have been trained on pyramidal Gaussian noise. We validate ANDi against three recent UAD baselines, and across three diverse brain MRI datasets. We show that ANDi, in some cases, substantially surpasses these baselines and shows increased robustness to varying types of anomalies. Particularly in detecting multiple sclerosis (MS) lesions, ANDi achieves improvements of up to 178% in terms of AUPRC.

Right for the Wrong Reason: Can Interpretable ML Techniques Detect Spurious Correlations?

While deep neural network models offer unmatched classification performance, they are prone to learning spurious correlations in the data. Such dependencies on confounding information can be difficult to detect using performance metrics if the test data comes from the same distribution as the training data. Interpretable ML methods such as post-hoc explanations or inherently interpretable classifiers promise to identify faulty model reasoning. However, there is mixed evidence whether many of these techniques are actually able to do so. In this paper, we propose a rigorous evaluation strategy to assess an explanation technique's ability to correctly identify spurious correlations. Using this strategy, we evaluate five post-hoc explanation techniques and one inherently interpretable method for their ability to detect three types of artificially added confounders in a chest x-ray diagnosis task. We find that the post-hoc technique SHAP, as well as the inherently interpretable Attri-Net provide the best performance and can be used to reliably identify faulty model behavior.

Uncertainty Estimation and Propagation in Accelerated MRI Reconstruction

MRI reconstruction techniques based on deep learning have led to unprecedented reconstruction quality especially in highly accelerated settings. However, deep learning techniques are also known to fail unexpectedly and hallucinate structures. This is particularly problematic if reconstructions are directly used for downstream tasks such as real-time treatment guidance or automated extraction of clinical paramters (e.g. via segmentation). Well-calibrated uncertainty quantification will be a key ingredient for safe use of this technology in clinical practice. In this paper we propose a novel probabilistic reconstruction technique (PHiRec) building on the idea of conditional hierarchical variational autoencoders. We demonstrate that our proposed method produces high-quality reconstructions as well as uncertainty quantification that is substantially better calibrated than several strong baselines. We furthermore demonstrate how uncertainties arising in the MR econstruction can be propagated to a downstream segmentation task, and show that PHiRec also allows well-calibrated estimation of segmentation uncertainties that originated in the MR reconstruction process.

Deep Hypothesis Tests Detect Clinically Relevant Subgroup Shifts in Medical Images

Distribution shifts remain a fundamental problem for the safe application of machine learning systems. If undetected, they may impact the real-world performance of such systems or will at least render original performance claims invalid. In this paper, we focus on the detection of subgroup shifts, a type of distribution shift that can occur when subgroups have a different prevalence during validation compared to the deployment setting. For example, algorithms developed on data from various acquisition settings may be predominantly applied in hospitals with lower quality data acquisition, leading to an inadvertent performance drop. We formulate subgroup shift detection in the framework of statistical hypothesis testing and show that recent state-of-the-art statistical tests can be effectively applied to subgroup shift detection on medical imaging data. We provide synthetic experiments as well as extensive evaluation on clinically meaningful subgroup shifts on histopathology as well as retinal fundus images. We conclude that classifier-based subgroup shift detection tests could be a particularly useful tool for post-market surveillance of deployed ML systems.

Inherently Interpretable Multi-Label Classification Using Class-Specific Counterfactuals

Interpretability is essential for machine learning algorithms in high-stakes application fields such as medical image analysis. However, high-performing black-box neural networks do not provide explanations for their predictions, which can lead to mistrust and suboptimal human-ML collaboration. Post-hoc explanation techniques, which are widely used in practice, have been shown to suffer from severe conceptual problems. Furthermore, as we show in this paper, current explanation techniques do not perform adequately in the multi-label scenario, in which multiple medical findings may co-occur in a single image. We propose Attri-Net, an inherently interpretable model for multi-label classification. Attri-Net is a powerful classifier that provides transparent, trustworthy, and human-understandable explanations. The model first generates class-specific attribution maps based on counterfactuals to identify which image regions correspond to certain medical findings. Then a simple logistic regression classifier is used to make predictions based solely on these attribution maps. We compare Attri-Net to five post-hoc explanation techniques and one inherently interpretable classifier on three chest X-ray datasets. We find that Attri-Net produces high-quality multi-label explanations consistent with clinical knowledge and has comparable classification performance to state-of-the-art classification models.

Studying Therapy Effects and Disease Outcomes in Silico using Artificial Counterfactual Tissue Samples

Understanding the interactions of different cell types inside the immune tumor microenvironment (iTME) is crucial for the development of immunotherapy treatments as well as for predicting their outcomes. Highly multiplexed tissue imaging (HMTI) technologies offer a tool which can capture cell properties of tissue samples by measuring expression of various proteins and storing them in separate image channels. HMTI technologies can be used to gain insights into the iTME and in particular how the iTME differs for different patient outcome groups of interest (e.g., treatment responders vs. non-responders). Understanding the systematic differences in the iTME of different patient outcome groups is crucial for developing better treatments and personalising existing treatments. However, such analyses are inherently limited by the fact that any two tissue samples vary due to a large number of factors unrelated to the outcome. Here, we present CF-HistoGAN, a machine learning framework that employs generative adversarial networks (GANs) to create artificial counterfactual tissue samples that resemble the original tissue samples as closely as possible but capture the characteristics of a different patient outcome group. Specifically, we learn to "translate" HMTI samples from one patient group to create artificial paired samples. We show that this approach allows to directly study the effects of different patient outcomes on the iTMEs of individual tissue samples. We demonstrate that CF-HistoGAN can be employed as an explorative tool for understanding iTME effects on the pixel level. Moreover, we show that our method can be used to identify statistically significant differences in the expression of different proteins between patient groups with greater sensitivity compared to conventional approaches.

Multiscale Metamorphic VAE for 3D Brain MRI Synthesis

Generative modeling of 3D brain MRIs presents difficulties in achieving high visual fidelity while ensuring sufficient coverage of the data distribution. In this work, we propose to address this challenge with composable, multiscale morphological transformations in a variational autoencoder (VAE) framework. These transformations are applied to a chosen reference brain image to generate MRI volumes, equipping the model with strong anatomical inductive biases. We structure the VAE latent space in a way such that the model covers the data distribution sufficiently well. We show substantial performance improvements in FID while retaining comparable, or superior, reconstruction quality compared to prior work based on VAEs and generative adversarial networks (GANs).

Adversarial Robustness of MR Image Reconstruction under Realistic Perturbations

Deep Learning (DL) methods have shown promising results for solving ill-posed inverse problems such as MR image reconstruction from undersampled $k$-space data. However, these approaches currently have no guarantees for reconstruction quality and the reliability of such algorithms is only poorly understood. Adversarial attacks offer a valuable tool to understand possible failure modes and worst case performance of DL-based reconstruction algorithms. In this paper we describe adversarial attacks on multi-coil $k$-space measurements and evaluate them on the recently proposed E2E-VarNet and a simpler UNet-based model. In contrast to prior work, the attacks are targeted to specifically alter diagnostically relevant regions. Using two realistic attack models (adversarial $k$-space noise and adversarial rotations) we are able to show that current state-of-the-art DL-based reconstruction algorithms are indeed sensitive to such perturbations to a degree where relevant diagnostic information may be lost. Surprisingly, in our experiments the UNet and the more sophisticated E2E-VarNet were similarly sensitive to such attacks. Our findings add further to the evidence that caution must be exercised as DL-based methods move closer to clinical practice.