Enhancing predictive imaging biomarker discovery through treatment effect analysis

Identifying predictive biomarkers, which forecast individual treatment effectiveness, is crucial for personalized medicine and informs decision-making across diverse disciplines. These biomarkers are extracted from pre-treatment data, often within randomized controlled trials, and have to be distinguished from prognostic biomarkers, which are independent of treatment assignment. Our study focuses on the discovery of predictive imaging biomarkers, aiming to leverage pre-treatment images to unveil new causal relationships. Previous approaches relied on labor-intensive handcrafted or manually derived features, which may introduce biases. In response, we present a new task of discovering predictive imaging biomarkers directly from the pre-treatment images to learn relevant image features. We propose an evaluation protocol for this task to assess a model's ability to identify predictive imaging biomarkers and differentiate them from prognostic ones. It employs statistical testing and a comprehensive analysis of image feature attribution. We explore the suitability of deep learning models originally designed for estimating the conditional average treatment effect (CATE) for this task, which previously have been primarily assessed for the precision of CATE estimation, overlooking the evaluation of imaging biomarker discovery. Our proof-of-concept analysis demonstrates promising results in discovering and validating predictive imaging biomarkers from synthetic outcomes and real-world image datasets.

nnU-Net Revisited: A Call for Rigorous Validation in 3D Medical Image Segmentation

The release of nnU-Net marked a paradigm shift in 3D medical image segmentation, demonstrating that a properly configured U-Net architecture could still achieve state-of-the-art results. Despite this, the pursuit of novel architectures, and the respective claims of superior performance over the U-Net baseline, continued. In this study, we demonstrate that many of these recent claims fail to hold up when scrutinized for common validation shortcomings, such as the use of inadequate baselines, insufficient datasets, and neglected computational resources. By meticulously avoiding these pitfalls, we conduct a thorough and comprehensive benchmarking of current segmentation methods including CNN-based, Transformer-based, and Mamba-based approaches. In contrast to current beliefs, we find that the recipe for state-of-the-art performance is 1) employing CNN-based U-Net models, including ResNet and ConvNeXt variants, 2) using the nnU-Net framework, and 3) scaling models to modern hardware resources. These results indicate an ongoing innovation bias towards novel architectures in the field and underscore the need for more stringent validation standards in the quest for scientific progress.

ValUES: A Framework for Systematic Validation of Uncertainty Estimation in Semantic Segmentation

Uncertainty estimation is an essential and heavily-studied component for the reliable application of semantic segmentation methods. While various studies exist claiming methodological advances on the one hand, and successful application on the other hand, the field is currently hampered by a gap between theory and practice leaving fundamental questions unanswered: Can data-related and model-related uncertainty really be separated in practice? Which components of an uncertainty method are essential for real-world performance? Which uncertainty method works well for which application? In this work, we link this research gap to a lack of systematic and comprehensive evaluation of uncertainty methods. Specifically, we identify three key pitfalls in current literature and present an evaluation framework that bridges the research gap by providing 1) a controlled environment for studying data ambiguities as well as distribution shifts, 2) systematic ablations of relevant method components, and 3) test-beds for the five predominant uncertainty applications: OoD-detection, active learning, failure detection, calibration, and ambiguity modeling. Empirical results on simulated as well as real-world data demonstrate how the proposed framework is able to answer the predominant questions in the field revealing for instance that 1) separation of uncertainty types works on simulated data but does not necessarily translate to real-world data, 2) aggregation of scores is a crucial but currently neglected component of uncertainty methods, 3) While ensembles are performing most robustly across the different downstream tasks and settings, test-time augmentation often constitutes a light-weight alternative. Code is at: https://github.com/IML-DKFZ/values

Application-driven Validation of Posteriors in Inverse Problems

Current deep learning-based solutions for image analysis tasks are commonly incapable of handling problems to which multiple different plausible solutions exist. In response, posterior-based methods such as conditional Diffusion Models and Invertible Neural Networks have emerged; however, their translation is hampered by a lack of research on adequate validation. In other words, the way progress is measured often does not reflect the needs of the driving practical application. Closing this gap in the literature, we present the first systematic framework for the application-driven validation of posterior-based methods in inverse problems. As a methodological novelty, it adopts key principles from the field of object detection validation, which has a long history of addressing the question of how to locate and match multiple object instances in an image. Treating modes as instances enables us to perform mode-centric validation, using well-interpretable metrics from the application perspective. We demonstrate the value of our framework through instantiations for a synthetic toy example and two medical vision use cases: pose estimation in surgery and imaging-based quantification of functional tissue parameters for diagnostics. Our framework offers key advantages over common approaches to posterior validation in all three examples and could thus revolutionize performance assessment in inverse problems.

RecycleNet: Latent Feature Recycling Leads to Iterative Decision Refinement

Despite the remarkable success of deep learning systems over the last decade, a key difference still remains between neural network and human decision-making: As humans, we cannot only form a decision on the spot, but also ponder, revisiting an initial guess from different angles, distilling relevant information, arriving at a better decision. Here, we propose RecycleNet, a latent feature recycling method, instilling the pondering capability for neural networks to refine initial decisions over a number of recycling steps, where outputs are fed back into earlier network layers in an iterative fashion. This approach makes minimal assumptions about the neural network architecture and thus can be implemented in a wide variety of contexts. Using medical image segmentation as the evaluation environment, we show that latent feature recycling enables the network to iteratively refine initial predictions even beyond the iterations seen during training, converging towards an improved decision. We evaluate this across a variety of segmentation benchmarks and show consistent improvements even compared with top-performing segmentation methods. This allows trading increased computation time for improved performance, which can be beneficial, especially for safety-critical applications.

Anatomy-informed Data Augmentation for Enhanced Prostate Cancer Detection

Data augmentation (DA) is a key factor in medical image analysis, such as in prostate cancer (PCa) detection on magnetic resonance images. State-of-the-art computer-aided diagnosis systems still rely on simplistic spatial transformations to preserve the pathological label post transformation. However, such augmentations do not substantially increase the organ as well as tumor shape variability in the training set, limiting the model's ability to generalize to unseen cases with more diverse localized soft-tissue deformations. We propose a new anatomy-informed transformation that leverages information from adjacent organs to simulate typical physiological deformations of the prostate and generates unique lesion shapes without altering their label. Due to its lightweight computational requirements, it can be easily integrated into common DA frameworks. We demonstrate the effectiveness of our augmentation on a dataset of 774 biopsy-confirmed examinations, by evaluating a state-of-the-art method for PCa detection with different augmentation settings.

Understanding Silent Failures in Medical Image Classification

To ensure the reliable use of classification systems in medical applications, it is crucial to prevent silent failures. This can be achieved by either designing classifiers that are robust enough to avoid failures in the first place, or by detecting remaining failures using confidence scoring functions (CSFs). A predominant source of failures in image classification is distribution shifts between training data and deployment data. To understand the current state of silent failure prevention in medical imaging, we conduct the first comprehensive analysis comparing various CSFs in four biomedical tasks and a diverse range of distribution shifts. Based on the result that none of the benchmarked CSFs can reliably prevent silent failures, we conclude that a deeper understanding of the root causes of failures in the data is required. To facilitate this, we introduce SF-Visuals, an interactive analysis tool that uses latent space clustering to visualize shifts and failures. On the basis of various examples, we demonstrate how this tool can help researchers gain insight into the requirements for safe application of classification systems in the medical domain. The open-source benchmark and tool are at: https://github.com/IML-DKFZ/sf-visuals.

cOOpD: Reformulating COPD classification on chest CT scans as anomaly detection using contrastive representations

Classification of heterogeneous diseases is challenging due to their complexity, variability of symptoms and imaging findings. Chronic Obstructive Pulmonary Disease (COPD) is a prime example, being underdiagnosed despite being the third leading cause of death. Its sparse, diffuse and heterogeneous appearance on computed tomography challenges supervised binary classification. We reformulate COPD binary classification as an anomaly detection task, proposing cOOpD: heterogeneous pathological regions are detected as Out-of-Distribution (OOD) from normal homogeneous lung regions. To this end, we learn representations of unlabeled lung regions employing a self-supervised contrastive pretext model, potentially capturing specific characteristics of diseased and healthy unlabeled regions. A generative model then learns the distribution of healthy representations and identifies abnormalities (stemming from COPD) as deviations. Patient-level scores are obtained by aggregating region OOD scores. We show that cOOpD achieves the best performance on two public datasets, with an increase of 8.2% and 7.7% in terms of AUROC compared to the previous supervised state-of-the-art. Additionally, cOOpD yields well-interpretable spatial anomaly maps and patient-level scores which we show to be of additional value in identifying individuals in the early stage of progression. Experiments in artificially designed real-world prevalence settings further support that anomaly detection is a powerful way of tackling COPD classification.

Improving Explainability of Disentangled Representations using Multipath-Attribution Mappings

Explainable AI aims to render model behavior understandable by humans, which can be seen as an intermediate step in extracting causal relations from correlative patterns. Due to the high risk of possible fatal decisions in image-based clinical diagnostics, it is necessary to integrate explainable AI into these safety-critical systems. Current explanatory methods typically assign attribution scores to pixel regions in the input image, indicating their importance for a model's decision. However, they fall short when explaining why a visual feature is used. We propose a framework that utilizes interpretable disentangled representations for downstream-task prediction. Through visualizing the disentangled representations, we enable experts to investigate possible causation effects by leveraging their domain knowledge. Additionally, we deploy a multi-path attribution mapping for enriching and validating explanations. We demonstrate the effectiveness of our approach on a synthetic benchmark suite and two medical datasets. We show that the framework not only acts as a catalyst for causal relation extraction but also enhances model robustness by enabling shortcut detection without the need for testing under distribution shifts.

MedNeXt: Transformer-driven Scaling of ConvNets for Medical Image Segmentation

There has been exploding interest in embracing Transformer-based architectures for medical image segmentation. However, the lack of large-scale annotated medical datasets make achieving performances equivalent to those in natural images challenging. Convolutional networks, in contrast, have higher inductive biases and consequently, are easily trainable to high performance. Recently, the ConvNeXt architecture attempted to modernize the standard ConvNet by mirroring Transformer blocks. In this work, we improve upon this to design a modernized and scalable convolutional architecture customized to challenges of data-scarce medical settings. We introduce MedNeXt, a Transformer-inspired large kernel segmentation network which introduces - 1) A fully ConvNeXt 3D Encoder-Decoder Network for medical image segmentation, 2) Residual ConvNeXt up and downsampling blocks to preserve semantic richness across scales, 3) A novel technique to iteratively increase kernel sizes by upsampling small kernel networks, to prevent performance saturation on limited medical data, 4) Compound scaling at multiple levels (depth, width, kernel size) of MedNeXt. This leads to state-of-the-art performance on 4 tasks on CT and MRI modalities and varying dataset sizes, representing a modernized deep architecture for medical image segmentation.