Christoph Lippert

Josafat-Mattias Burmeister, Marcel Fernandez Rosas, Johannes Hagemann et al.

Since labeling medical image data is a costly and labor-intensive process, active learning has gained much popularity in the medical image segmentation domain in recent years. A variety of active learning strategies have been proposed in the literature, but their effectiveness is highly dependent on the dataset and training scenario. To facilitate the comparison of existing strategies and provide a baseline for evaluating novel strategies, we evaluate the performance of several well-known active learning strategies on three datasets from the Medical Segmentation Decathlon. Additionally, we consider a strided sampling strategy specifically tailored to 3D image data. We demonstrate that both random and strided sampling act as strong baselines and discuss the advantages and disadvantages of the studied methods. To allow other researchers to compare their work to our results, we provide an open-source framework for benchmarking active learning strategies on a variety of medical segmentation datasets.

Alexander Rakowski, Christoph Lippert

We consider the problem of identifying the signal shared between two one-dimensional target variables, in the presence of additional multivariate observations. Canonical Correlation Analysis (CCA)-based methods have traditionally been used to identify shared variables, however, they were designed for multivariate targets and only offer trivial solutions for univariate cases. In the context of Multi-Task Learning (MTL), various models were postulated to learn features that are sparse and shared across multiple tasks. However, these methods were typically evaluated by their predictive performance. To the best of our knowledge, no prior studies systematically evaluated models in terms of correctly recovering the shared signal. Here, we formalize the setting of univariate shared information retrieval, and propose ICM, an evaluation metric which can be used in the presence of ground-truth labels, quantifying 3 aspects of the learned shared features. We further propose Deep Canonical Information Decomposition (DCID) - a simple, yet effective approach for learning the shared variables. We benchmark the models on a range of scenarios on synthetic data with known ground-truths and observe DCID outperforming the baselines in a wide range of settings. Finally, we demonstrate a real-life application of DCID on brain Magnetic Resonance Imaging (MRI) data, where we are able to extract more accurate predictors of changes in brain regions and obesity. The code for our experiments as well as the supplementary materials are available at https://github.com/alexrakowski/dcid

Wei-Cheng Lai, Marco Simnacher, Christoph Lippert

Two-sample testing is a fundamental tool for detecting distributional differences across scientific domains, but classical tests (including kernel-based tests) can be ineffective on high-dimensional structured data such as images. Recent deep two-sample tests improve sensitivity in these settings by learning informative representations, yet they provide limited insight into which data features drive rejection of the null hypothesis $H_0$. To address this issue, we propose a counterfactual explanation framework for deep two-sample testing that generates sample-level edits moving observations from a source group toward a target group while explicitly reducing the discrepancy measured by the test. Our method combines a diffusion autoencoder with a pretrained deep two-sample test model and optimizes a maximum mean discrepancy (MMD) objective in the test model's representation space to produce plausible counterfactuals. We quantify distribution-level effects through changes in the test statistic and the resulting two-sample p-values. We evaluate the method on synthetic 2D shape datasets and two MRI cohorts. Across both settings, the counterfactual transformations consistently increase p-values relative to the original samples, indicating that the edited source set becomes statistically closer to the target distribution under the test. We measure minimality using LPIPS to ensure the counterfactuals remain close to the original samples. The resulting edits provide interpretable evidence of the features associated with the detected group differences. On MRI, the localized changes are consistent with known anatomical differences between cohorts.

Benjamin Bergner, Christoph Lippert, Aravindh Mahendran

High-resolution images are prevalent in various applications, such as autonomous driving and computer-aided diagnosis. However, training neural networks on such images is computationally challenging and easily leads to out-of-memory errors even on modern GPUs. We propose a simple method, Iterative Patch Selection (IPS), which decouples the memory usage from the input size and thus enables the processing of arbitrarily large images under tight hardware constraints. IPS achieves this by selecting only the most salient patches, which are then aggregated into a global representation for image recognition. For both patch selection and aggregation, a cross-attention based transformer is introduced, which exhibits a close connection to Multiple Instance Learning. Our method demonstrates strong performance and has wide applicability across different domains, training regimes and image sizes while using minimal accelerator memory. For example, we are able to finetune our model on whole-slide images consisting of up to 250k patches (>16 gigapixels) with only 5 GB of GPU VRAM at a batch size of 16.

Matthias Kirchler, Christoph Lippert, Marius Kloft

Normalizing flows are powerful non-parametric statistical models that function as a hybrid between density estimators and generative models. Current learning algorithms for normalizing flows assume that data points are sampled independently, an assumption that is frequently violated in practice, which may lead to erroneous density estimation and data generation. We propose a likelihood objective of normalizing flows incorporating dependencies between the data points, for which we derive a flexible and efficient learning algorithm suitable for different dependency structures. We show that respecting dependencies between observations can improve empirical results on both synthetic and real-world data, and leads to higher statistical power in a downstream application to genome-wide association studies.

Masoumeh Javanbakhat, Christoph Lippert

In this paper we present a practical Bayesian self-supervised learning method with Cyclical Stochastic Gradient Hamiltonian Monte Carlo (cSGHMC). Within this framework, we place a prior over the parameters of a self-supervised learning model and use cSGHMC to approximate the high dimensional and multimodal posterior distribution over the embeddings. By exploring an expressive posterior over the embeddings, Bayesian self-supervised learning produces interpretable and diverse representations. Marginalizing over these representations yields a significant gain in performance, calibration and out-of-distribution detection on a variety of downstream classification tasks. We provide experimental results on multiple classification tasks on four challenging datasets. Moreover, we demonstrate the effectiveness of the proposed method in out-of-distribution detection using the SVHN and CIFAR-10 datasets.

Eshant English, Eliot Wong-Toi, Matteo Fontana et al.

Conformal prediction provides machine learning models with prediction sets that offer theoretical guarantees, but the underlying assumption of exchangeability limits its applicability to time series data. Furthermore, existing approaches struggle to handle multi-step ahead prediction tasks, where uncertainty estimates across multiple future time points are crucial. We propose JANET (Joint Adaptive predictioN-region Estimation for Time-series), a novel framework for constructing conformal prediction regions that are valid for both univariate and multivariate time series. JANET generalises the inductive conformal framework and efficiently produces joint prediction regions with controlled K-familywise error rates, enabling flexible adaptation to specific application needs. Our empirical evaluation demonstrates JANET's superior performance in multi-step prediction tasks across diverse time series datasets, highlighting its potential for reliable and interpretable uncertainty quantification in sequential data.

Eshant English, Matthias Kirchler, Christoph Lippert

Normalising Flows are non-parametric statistical models characterised by their dual capabilities of density estimation and generation. This duality requires an inherently invertible architecture. However, the requirement of invertibility imposes constraints on their expressiveness, necessitating a large number of parameters and innovative architectural designs to achieve good results. Whilst flow-based models predominantly rely on neural-network-based transformations for expressive designs, alternative transformation methods have received limited attention. In this work, we present Ferumal flow, a novel kernelised normalising flow paradigm that integrates kernels into the framework. Our results demonstrate that a kernelised flow can yield competitive or superior results compared to neural network-based flows whilst maintaining parameter efficiency. Kernelised flows excel especially in the low-data regime, enabling flexible non-parametric density estimation in applications with sparse data availability.

Anees Ur Rehman Hashmi, Numan Saeed, Christoph Lippert

Multimodal medical large language models have shown substantial progress in chest X-ray interpretation but continue to face challenges in spatial reasoning and anatomical understanding. Although existing grounding techniques improve overall performance, they often fail to establish a true anatomical correspondence, resulting in incorrect anatomical understanding in the medical domain. To address this gap, we introduce AnatomiX, a multitask multimodal large language model for anatomically grounded chest X-ray interpretation. Inspired by the radiological workflow, AnatomiX adopts a two stage approach: first, it identifies anatomical structures and extracts their features, and then leverages a large language model to perform diverse downstream tasks such as phrase grounding, report generation, visual question answering, and image understanding. Extensive experiments across multiple benchmarks demonstrate that AnatomiX achieves superior anatomical reasoning and delivers over 25% improvement in performance on anatomy grounding, phrase grounding, grounded diagnosis and grounded captioning tasks compared to existing approaches. Code and pretrained model are available at github.com/aneesurhashmi/anatomix.

Masoumeh Javanbakhat, Piotr Komorowski, Dilyara Bareeva et al.

Deep neural two-sample tests have recently shown strong power for detecting distributional differences between groups, yet their black-box nature limits interpretability and practical adoption in biomedical analysis. Moreover, most existing post-hoc explainability methods rely on class labels, making them unsuitable for label-free statistical testing settings. We propose an explainable deep statistical testing framework that augments deep two-sample tests with sample-level and feature-level explanations, revealing which individual samples and which input features drive statistically significant group differences. Our method highlights which image regions and which individual samples contribute most to the detected group difference, providing spatial and instance-wise insight into the test's decision. Applied to biomedical imaging data, the proposed framework identifies influential samples and highlights anatomically meaningful regions associated with disease-related variation. This work bridges statistical inference and explainable AI, enabling interpretable, label-free population analysis in medical imaging.

Eshant English, Matthias Kirchler, Christoph Lippert

Normalising flows are generative models that transform a complex density into a simpler density through the use of bijective transformations enabling both density estimation and data generation from a single model. %However, the requirement for bijectivity imposes the use of specialised architectures. In the context of image modelling, the predominant choice has been the Glow-based architecture, whereas alternative architectures remain largely unexplored in the research community. In this work, we propose a novel architecture called MixerFlow, based on the MLP-Mixer architecture, further unifying the generative and discriminative modelling architectures. MixerFlow offers an efficient mechanism for weight sharing for flow-based models. Our results demonstrate comparative or superior density estimation on image datasets and good scaling as the image resolution increases, making MixerFlow a simple yet powerful alternative to the Glow-based architectures. We also show that MixerFlow provides more informative embeddings than Glow-based architectures and can integrate many structured transformations such as splines or Kolmogorov-Arnold Networks.

Aiham Taleb, Winfried Loetzsch, Noel Danz et al.

Self-supervised learning methods have witnessed a recent surge of interest after proving successful in multiple application fields. In this work, we leverage these techniques, and we propose 3D versions for five different self-supervised methods, in the form of proxy tasks. Our methods facilitate neural network feature learning from unlabeled 3D images, aiming to reduce the required cost for expert annotation. The developed algorithms are 3D Contrastive Predictive Coding, 3D Rotation prediction, 3D Jigsaw puzzles, Relative 3D patch location, and 3D Exemplar networks. Our experiments show that pretraining models with our 3D tasks yields more powerful semantic representations, and enables solving downstream tasks more accurately and efficiently, compared to training the models from scratch and to pretraining them on 2D slices. We demonstrate the effectiveness of our methods on three downstream tasks from the medical imaging domain: i) Brain Tumor Segmentation from 3D MRI, ii) Pancreas Tumor Segmentation from 3D CT, and iii) Diabetic Retinopathy Detection from 2D Fundus images. In each task, we assess the gains in data-efficiency, performance, and speed of convergence. Interestingly, we also find gains when transferring the learned representations, by our methods, from a large unlabeled 3D corpus to a small downstream-specific dataset. We achieve results competitive to state-of-the-art solutions at a fraction of the computational expense. We publish our implementations for the developed algorithms (both 3D and 2D versions) as an open-source library, in an effort to allow other researchers to apply and extend our methods on their datasets.

Laura Manduchi, Clara Meister, Kushagra Pandey et al.

The field of deep generative modeling has grown rapidly in the last few years. With the availability of massive amounts of training data coupled with advances in scalable unsupervised learning paradigms, recent large-scale generative models show tremendous promise in synthesizing high-resolution images and text, as well as structured data such as videos and molecules. However, we argue that current large-scale generative AI models exhibit several fundamental shortcomings that hinder their widespread adoption across domains. In this work, our objective is to identify these issues and highlight key unresolved challenges in modern generative AI paradigms that should be addressed to further enhance their capabilities, versatility, and reliability. By identifying these challenges, we aim to provide researchers with insights for exploring fruitful research directions, thus fostering the development of more robust and accessible generative AI solutions.

Benjamin Bergner, Christoph Lippert, Aravindh Mahendran

The adoption of Vision Transformers (ViTs) in resource-constrained applications necessitates improvements in inference throughput. To this end several token pruning and merging approaches have been proposed that improve efficiency by successively reducing the number of tokens. However, it remains an open problem to design a token reduction method that is fast, maintains high performance, and is applicable to various vision tasks. In this work, we present a token pruner that uses auxiliary prediction heads that learn to select tokens end-to-end based on task relevance. These auxiliary heads can be removed after training, leading to throughput close to that of a random pruner. We evaluate our method on image classification, semantic segmentation, object detection, and instance segmentation, and show speedups of 1.5 to 4x with small drops in performance. As a best case, on the ADE20k semantic segmentation benchmark, we observe a 2x speedup relative to the no-pruning baseline, with a negligible performance penalty of 0.1 median mIoU across 5 seeds.

Eshant English, Christoph Lippert

Conformal Prediction offers a powerful framework for quantifying uncertainty in machine learning models, enabling the construction of prediction sets with finite-sample validity guarantees. While easily adaptable to non-probabilistic models, applying conformal prediction to probabilistic generative models, such as Normalising Flows is not straightforward. This work proposes a novel method to conformalise conditional normalising flows, specifically addressing the problem of obtaining prediction regions for multi-step time series forecasting. Our approach leverages the flexibility of normalising flows to generate potentially disjoint prediction regions, leading to improved predictive efficiency in the presence of potential multimodal predictive distributions.

Eshant English, Christoph Lippert

Conformal prediction provides a model-agnostic framework for uncertainty quantification with finite-sample validity guarantees, making it an attractive tool for constructing reliable prediction sets. However, existing approaches commonly rely on residual-based conformity scores, which impose geometric constraints and struggle when the underlying distribution is multimodal. In particular, they tend to produce overly conservative prediction areas centred around the mean, often failing to capture the true shape of complex predictive distributions. In this work, we introduce JAPAN (Joint Adaptive Prediction Areas with Normalising-Flows), a conformal prediction framework that uses density-based conformity scores. By leveraging flow-based models, JAPAN estimates the (predictive) density and constructs prediction areas by thresholding on the estimated density scores, enabling compact, potentially disjoint, and context-adaptive regions that retain finite-sample coverage guarantees. We theoretically motivate the efficiency of JAPAN and empirically validate it across multivariate regression and forecasting tasks, demonstrating good calibration and tighter prediction areas compared to existing baselines. We also provide several \emph{extensions} adding flexibility to our proposed framework.

Marco Simnacher, Xiangnan Xu, Hani Park et al.

Conditional independence tests (CITs) test for conditional dependence between random variables. As existing CITs are limited in their applicability to complex, high-dimensional variables such as images, we introduce deep nonparametric CITs (DNCITs). The DNCITs combine embedding maps, which extract feature representations of high-dimensional variables, with nonparametric CITs applicable to these feature representations. For the embedding maps, we derive general properties on their parameter estimators to obtain valid DNCITs and show that these properties include embedding maps learned through (conditional) unsupervised or transfer learning. For the nonparametric CITs, appropriate tests are selected and adapted to be applicable to feature representations. Through simulations, we investigate the performance of the DNCITs for different embedding maps and nonparametric CITs under varying confounder dimensions and confounder relationships. We apply the DNCITs to brain MRI scans and behavioral traits, given confounders, of healthy individuals from the UK Biobank (UKB), confirming null results from a number of ambiguous personality neuroscience studies with a larger data set and with our more powerful tests. In addition, in a confounder control study, we apply the DNCITs to brain MRI scans and a confounder set to test for sufficient confounder control, leading to a potential reduction in the confounder dimension under improved confounder control compared to existing state-of-the-art confounder control studies for the UKB. Finally, we provide an R package implementing the DNCITs.

Benjamin Bergner, Csaba Rohrer, Aiham Taleb et al.

We propose a simple and efficient image classification architecture based on deep multiple instance learning, and apply it to the challenging task of caries detection in dental radiographs. Technically, our approach contributes in two ways: First, it outputs a heatmap of local patch classification probabilities despite being trained with weak image-level labels. Second, it is amenable to learning from segmentation labels to guide training. In contrast to existing methods, the human user can faithfully interpret predictions and interact with the model to decide which regions to attend to. Experiments are conducted on a large clinical dataset of $\sim$38k bitewings ($\sim$316k teeth), where we achieve competitive performance compared to various baselines. When guided by an external caries segmentation model, a significant improvement in classification and localization performance is observed.

Aiham Taleb, Matthias Kirchler, Remo Monti et al.

High annotation costs are a substantial bottleneck in applying modern deep learning architectures to clinically relevant medical use cases, substantiating the need for novel algorithms to learn from unlabeled data. In this work, we propose ContIG, a self-supervised method that can learn from large datasets of unlabeled medical images and genetic data. Our approach aligns images and several genetic modalities in the feature space using a contrastive loss. We design our method to integrate multiple modalities of each individual person in the same model end-to-end, even when the available modalities vary across individuals. Our procedure outperforms state-of-the-art self-supervised methods on all evaluated downstream benchmark tasks. We also adapt gradient-based explainability algorithms to better understand the learned cross-modal associations between the images and genetic modalities. Finally, we perform genome-wide association studies on the features learned by our models, uncovering interesting relationships between images and genetic data.

Yamen Ali, Aiham Taleb, Marina M. -C. Höhne et al.

Self-supervised learning methods can be used to learn meaningful representations from unlabeled data that can be transferred to supervised downstream tasks to reduce the need for labeled data. In this paper, we propose a 3D self-supervised method that is based on the contrastive (SimCLR) method. Additionally, we show that employing Bayesian neural networks (with Monte-Carlo Dropout) during the inference phase can further enhance the results on the downstream tasks. We showcase our models on two medical imaging segmentation tasks: i) Brain Tumor Segmentation from 3D MRI, ii) Pancreas Tumor Segmentation from 3D CT. Our experimental results demonstrate the benefits of our proposed methods in both downstream data-efficiency and performance.

Matthias Kirchler, Martin Graf, Marius Kloft et al.

When explaining the decisions of deep neural networks, simple stories are tempting but dangerous. Especially in computer vision, the most popular explanation approaches give a false sense of comprehension to its users and provide an overly simplistic picture. We introduce an interactive framework to understand the highly complex decision boundaries of modern vision models. It allows the user to exhaustively inspect, probe, and test a network's decisions. Across a range of case studies, we compare the power of our interactive approach to static explanation methods, showing how these can lead a user astray, with potentially severe consequences.

Jakob Lindinger, David Reeb, Christoph Lippert et al.

Deep Gaussian Processes learn probabilistic data representations for supervised learning by cascading multiple Gaussian Processes. While this model family promises flexible predictive distributions, exact inference is not tractable. Approximate inference techniques trade off the ability to closely resemble the posterior distribution against speed of convergence and computational efficiency. We propose a novel Gaussian variational family that allows for retaining covariances between latent processes while achieving fast convergence by marginalising out all global latent variables. After providing a proof of how this marginalisation can be done for general covariances, we restrict them to the ones we empirically found to be most important in order to also achieve computational efficiency. We provide an efficient implementation of our new approach and apply it to several benchmark datasets. It yields excellent results and strikes a better balance between accuracy and calibrated uncertainty estimates than its state-of-the-art alternatives.

Aiham Taleb, Christoph Lippert, Tassilo Klein et al.

Self-supervised learning approaches leverage unlabeled samples to acquire generic knowledge about different concepts, hence allowing for annotation-efficient downstream task learning. In this paper, we propose a novel self-supervised method that leverages multiple imaging modalities. We introduce the multimodal puzzle task, which facilitates rich representation learning from multiple image modalities. The learned representations allow for subsequent fine-tuning on different downstream tasks. To achieve that, we learn a modality-agnostic feature embedding by confusing image modalities at the data-level. Together with the Sinkhorn operator, with which we formulate the puzzle solving optimization as permutation matrix inference instead of classification, they allow for efficient solving of multimodal puzzles with varying levels of complexity. In addition, we also propose to utilize cross-modal generation techniques for multimodal data augmentation used for training self-supervised tasks. In other words, we exploit synthetic images for self-supervised pretraining, instead of downstream tasks directly, in order to circumvent quality issues associated with synthetic images, while improving data-efficiency and representations quality. Our experimental results, which assess the gains in downstream performance and data-efficiency, show that solving our multimodal puzzles yields better semantic representations, compared to treating each modality independently. Our results also highlight the benefits of exploiting synthetic images for self-supervised pretraining. We showcase our approach on four downstream tasks: Brain tumor segmentation and survival days prediction using four MRI modalities, Prostate segmentation using two MRI modalities, and Liver segmentation using unregistered CT and MRI modalities. We outperform many previous solutions, and achieve results competitive to state-of-the-art.

Matthias Kirchler, Shahryar Khorasani, Marius Kloft et al.

We propose a two-sample testing procedure based on learned deep neural network representations. To this end, we define two test statistics that perform an asymptotic location test on data samples mapped onto a hidden layer. The tests are consistent and asymptotically control the type-1 error rate. Their test statistics can be evaluated in linear time (in the sample size). Suitable data representations are obtained in a data-driven way, by solving a supervised or unsupervised transfer-learning task on an auxiliary (potentially distinct) data set. If no auxiliary data is available, we split the data into two chunks: one for learning representations and one for computing the test statistic. In experiments on audio samples, natural images and three-dimensional neuroimaging data our tests yield significant decreases in type-2 error rate (up to 35 percentage points) compared to state-of-the-art two-sample tests such as kernel-methods and classifier two-sample tests.

Stefan Konigorski, Shahryar Khorasani, Christoph Lippert

For precision medicine and personalized treatment, we need to identify predictive markers of disease. We focus on Alzheimer's disease (AD), where magnetic resonance imaging scans provide information about the disease status. By combining imaging with genome sequencing, we aim at identifying rare genetic markers associated with quantitative traits predicted from convolutional neural networks (CNNs), which traditionally have been derived manually by experts. Kernel-based tests are a powerful tool for associating sets of genetic variants, but how to optimally model rare genetic variants is still an open research question. We propose a generalized set of kernels that incorporate prior information from various annotations and multi-omics data. In the analysis of data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), we evaluate whether (i) CNNs yield precise and reliable brain traits, and (ii) the novel kernel-based tests can help to identify loci associated with AD. The results indicate that CNNs provide a fast, scalable and precise tool to derive quantitative AD traits and that new kernels integrating domain knowledge can yield higher power in association tests of very rare variants.

Stephan Mandt, Florian Wenzel, Shinichi Nakajima et al.

Linear Mixed Models (LMMs) are important tools in statistical genetics. When used for feature selection, they allow to find a sparse set of genetic traits that best predict a continuous phenotype of interest, while simultaneously correcting for various confounding factors such as age, ethnicity and population structure. Formulated as models for linear regression, LMMs have been restricted to continuous phenotypes. We introduce the Sparse Probit Linear Mixed Model (Probit-LMM), where we generalize the LMM modeling paradigm to binary phenotypes. As a technical challenge, the model no longer possesses a closed-form likelihood function. In this paper, we present a scalable approximate inference algorithm that lets us fit the model to high-dimensional data sets. We show on three real-world examples from different domains that in the setup of binary labels, our algorithm leads to better prediction accuracies and also selects features which show less correlation with the confounding factors.

Jennifer Listgarten, Christoph Lippert, Eun Yong Kang et al.

Approaches for testing sets of variants, such as a set of rare or common variants within a gene or pathway, for association with complex traits are important. In particular, set tests allow for aggregation of weak signal within a set, can capture interplay among variants, and reduce the burden of multiple hypothesis testing. Until now, these approaches did not address confounding by family relatedness and population structure, a problem that is becoming more important as larger data sets are used to increase power. Results: We introduce a new approach for set tests that handles confounders. Our model is based on the linear mixed model and uses two random effects-one to capture the set association signal and one to capture confounders. We also introduce a computational speedup for two-random-effects models that makes this approach feasible even for extremely large cohorts. Using this model with both the likelihood ratio test and score test, we find that the former yields more power while controlling type I error. Application of our approach to richly structured GAW14 data demonstrates that our method successfully corrects for population structure and family relatedness, while application of our method to a 15,000 individual Crohn's disease case-control cohort demonstrates that it additionally recovers genes not recoverable by univariate analysis. Availability: A Python-based library implementing our approach is available at http://mscompbio.codeplex.com