Joakim Lindblad

Axel Andersson, Nadezhda Koriakina, Nataša Sladoje et al.

Being able to learn on weakly labeled data, and provide interpretability, are two of the main reasons why attention-based deep multiple instance learning (ABMIL) methods have become particularly popular for classification of histopathological images. Such image data usually come in the form of gigapixel-sized whole-slide-images (WSI) that are cropped into smaller patches (instances). However, the sheer size of the data makes training of ABMIL models challenging. All the instances from one WSI cannot be processed at once by conventional GPUs. Existing solutions compromise training by relying on pre-trained models, strategic sampling or selection of instances, or self-supervised learning. We propose a training strategy based on gradient accumulation that enables direct end-to-end training of ABMIL models without being limited by GPU memory. We conduct experiments on both QMNIST and Imagenette to investigate the performance and training time, and compare with the conventional memory-expensive baseline and a recent sampled-based approach. This memory-efficient approach, although slower, reaches performance indistinguishable from the memory-expensive baseline.

Wenyi Lian, Joakim Lindblad, Christina Runow Stark et al.

Oral cancer is a global health challenge. It is treatable if detected early, but it is often fatal in late stages. There is a shift from the invasive and time-consuming tissue sampling and histological examination, toward non-invasive brush biopsies and cytological examination. Reliable computer-assisted methods are essential for cost-effective and accurate cytological analysis, but the lack of detailed cell-level annotations impairs model effectiveness. This study aims to improve AI-based oral cancer detection using multimodal imaging and deep fusion. We combine brightfield and fluorescence whole slide microscopy imaging to analyze Papanicolaou-stained liquid-based cytology slides of brush biopsies collected from both healthy and cancer patients. Due to limited cytological annotations, we utilize a weakly supervised deep learning approach using only patient-level labels. We evaluate various multimodal fusion strategies, including early, late, and three recent intermediate fusion methods. Our results show: (i) fluorescence imaging of Papanicolaou-stained samples provides substantial diagnostic information; (ii) multimodal fusion enhances classification and cancer detection accuracy over single-modality methods. Intermediate fusion is the leading method among the studied approaches. Specifically, the Co-Attention Fusion Network (CAFNet) model excels with an F1 score of 83.34% and accuracy of 91.79%, surpassing human performance on the task. Additional tests highlight the need for precise image registration to optimize multimodal analysis benefits. This study advances cytopathology by combining deep learning and multimodal imaging to enhance early, non-invasive detection of oral cancer, improving diagnostic accuracy and streamlining clinical workflows. The developed pipeline is also applicable in other cytological settings. Our codes and dataset are available online for further research.

Elisabeth Wetzer, Joakim Lindblad, Nataša Sladoje

Multimodal imaging and correlative analysis typically require image alignment. Contrastive learning can generate representations of multimodal images, reducing the challenging task of multimodal image registration to a monomodal one. Previously, additional supervision on intermediate layers in contrastive learning has improved biomedical image classification. We evaluate if a similar approach improves representations learned for registration to boost registration performance. We explore three approaches to add contrastive supervision to the latent features of the bottleneck layer in the U-Nets encoding the multimodal images and evaluate three different critic functions. Our results show that representations learned without additional supervision on latent features perform best in the downstream task of registration on two public biomedical datasets. We investigate the performance drop by exploiting recent insights in contrastive learning in classification and self-supervised learning. We visualize the spatial relations of the learned representations by means of multidimensional scaling, and show that additional supervision on the bottleneck layer can lead to partial dimensional collapse of the intermediate embedding space.

Marc Fraile, Natalia Calvo-Barajas, Anastasia Sophia Apeiron et al.

Friendship and rapport play an important role in the formation of constructive social interactions, and have been widely studied in educational settings due to their impact on student outcomes. Given the growing interest in automating the analysis of such phenomena through Machine Learning (ML), access to annotated interaction datasets is highly valuable. However, no dataset on dyadic child-child interactions explicitly capturing rapport currently exists. Moreover, despite advances in the automatic analysis of human behaviour, no previous work has addressed the prediction of rapport in child-child dyadic interactions in educational settings. We present UpStory -- the Uppsala Storytelling dataset: a novel dataset of naturalistic dyadic interactions between primary school aged children, with an experimental manipulation of rapport. Pairs of children aged 8-10 participate in a task-oriented activity: designing a story together, while being allowed free movement within the play area. We promote balanced collection of different levels of rapport by using a within-subjects design: self-reported friendships are used to pair each child twice, either minimizing or maximizing pair separation in the friendship network. The dataset contains data for 35 pairs, totalling 3h 40m of audio and video recordings. It includes two video sources covering the play area, as well as separate voice recordings for each child. An anonymized version of the dataset is made publicly available, containing per-frame head pose, body pose, and face features; as well as per-pair information, including the level of rapport. Finally, we provide ML baselines for the prediction of rapport.

Olle Edgren Schüllerqvist, Jens Baumann, Joakim Lindblad et al.

The tumor microenvironment (TME) has emerged as a promising source of prognostic biomarkers. To fully leverage its potential, analysis methods must capture complex interactions between different cell types. We propose HiGINE -- a hierarchical graph-based approach to predict patient survival (short vs. long) from TME characterization in multiplex immunofluorescence (mIF) images and enhance risk stratification in lung cancer. Our model encodes both local and global inter-relations in cell neighborhoods, incorporating information about cell types and morphology. Multimodal fusion, aggregating cancer stage with mIF-derived features, further boosts performance. We validate HiGINE on two public datasets, demonstrating improved risk stratification, robustness, and generalizability.

Wenyi Lian, Patrick Micke, Joakim Lindblad et al.

Vision Transformers (ViTs) have achieved remarkable success in standard RGB image processing tasks. However, applying ViTs to multi-channel imaging (MCI) data, e.g., for medical and remote sensing applications, remains a challenge. In particular, MCI data often consist of layers acquired from different modalities. Directly training ViTs on such data can obscure complementary information and impair the performance. In this paper, we introduce a simple yet effective pretraining framework for large-scale MCI datasets. Our method, named Isolated Channel ViT (IC-ViT), patchifies image channels individually and thereby enables pretraining for multimodal multi-channel tasks. We show that this channel-wise patchifying is a key technique for MCI processing. More importantly, one can pretrain the IC-ViT on single channels and finetune it on downstream multi-channel datasets. This pretraining framework captures dependencies between patches as well as channels and produces robust feature representation. Experiments on various tasks and benchmarks, including JUMP-CP and CHAMMI for cell microscopy imaging, and So2Sat-LCZ42 for satellite imaging, show that the proposed IC-ViT delivers 4-14 percentage points of performance improvement over existing channel-adaptive approaches. Further, its efficient training makes it a suitable candidate for large-scale pretraining of foundation models on heterogeneous data. Our code is available at https://github.com/shermanlian/IC-ViT.

Swarnadip Chatterjee, Vladimir Basic, Arrigo Capitanio et al.

In computational cytology, detecting malignancy on whole-slide images is difficult because malignant cells are morphologically diverse yet vanishingly rare amid a vast background of normal cells. Accurate detection of these extremely rare malignant cells remains challenging due to large class imbalance and limited annotations. Conventional weakly supervised approaches, such as multiple instance learning (MIL), often fail to generalize at the instance level, especially when the fraction of malignant cells (witness rate) is exceedingly low. In this study, we explore the use of one-class representation learning techniques for detecting malignant cells in low-witness-rate scenarios. These methods are trained exclusively on slide-negative patches, without requiring any instance-level supervision. Specifically, we evaluate two OCC approaches, DSVDD and DROC, and compare them with FS-SIL, WS-SIL, and the recent ItS2CLR method. The one-class methods learn compact representations of normality and detect deviations at test time. Experiments on a publicly available bone marrow cytomorphology dataset (TCIA) and an in-house oral cancer cytology dataset show that DSVDD achieves state-of-the-art performance in instance-level abnormality ranking, particularly in ultra-low witness-rate regimes ($\leq 1\%$) and, in some cases, even outperforming fully supervised learning, which is typically not a practical option in whole-slide cytology due to the infeasibility of exhaustive instance-level annotations. DROC is also competitive under extreme rarity, benefiting from distribution-augmented contrastive learning. These findings highlight one-class representation learning as a robust and interpretable superior choice to MIL for malignant cell detection under extreme rarity.

Marco Acerbis, Swarnadip Chatterjee, Christophe Avenel et al.

Computational cytology faces two major challenges: i) instance-level labels are unreliable and prohibitively costly to obtain, ii) witness rates are extremely low. We propose SLAM-AGS, a Slide-Label-Aware Multitask pretraining framework that jointly optimizes (i) a weakly supervised similarity objective on slide-negative patches and (ii) a self-supervised contrastive objective on slide-positive patches, yielding stronger performance on downstream tasks. To stabilize learning, we apply Adaptive Gradient Surgery to tackle conflicting task gradients and prevent model collapse. We integrate the pretrained encoder into an attention-based Multiple Instance Learning aggregator for bag-level prediction and attention-guided retrieval of the most abnormal instances in a bag. On a publicly available bone-marrow cytology dataset, with simulated witness rates from 10% down to 0.5%, SLAM-AGS improves bag-level F1-Score and Top 400 positive cell retrieval over other pretraining methods, with the largest gains at low witness rates, showing that resolving gradient interference enables stable pretraining and better performance on downstream tasks. To facilitate reproducibility, we share our complete implementation and evaluation framework as open source: https://github.com/Ace95/SLAM-AGS.

Nadezhda Koriakina, Nataša Sladoje, Vladimir Bašić et al.

The current medical standard for setting an oral cancer (OC) diagnosis is histological examination of a tissue sample from the oral cavity. This process is time consuming and more invasive than an alternative approach of acquiring a brush sample followed by cytological analysis. Skilled cytotechnologists are able to detect changes due to malignancy, however, to introduce this approach into clinical routine is associated with challenges such as a lack of experts and labour-intensive work. To design a trustworthy OC detection system that would assist cytotechnologists, we are interested in AI-based methods that reliably can detect cancer given only per-patient labels (minimizing annotation bias), and also provide information on which cells are most relevant for the diagnosis (enabling supervision and understanding). We, therefore, perform a comparison of a conventional single instance learning (SIL) approach and a modern multiple instance learning (MIL) method suitable for OC detection and interpretation, utilizing three different neural network architectures. To facilitate systematic evaluation of the considered approaches, we introduce a synthetic PAP-QMNIST dataset, that serves as a model of OC data, while offering access to per-instance ground truth. Our study indicates that on PAP-QMNIST, the SIL performs better, on average, than the MIL approach. Performance at the bag level on real-world cytological data is similar for both methods, yet the single instance approach performs better on average. Visual examination by cytotechnologist indicates that the methods manage to identify cells which deviate from normality, including malignant cells as well as those suspicious for dysplasia. We share the code as open source at https://github.com/MIDA-group/OralCancerMILvsSIL

Eva Breznik, Elisabeth Wetzer, Joakim Lindblad et al.

In tissue characterization and cancer diagnostics, multimodal imaging has emerged as a powerful technique. Thanks to computational advances, large datasets can be exploited to discover patterns in pathologies and improve diagnosis. However, this requires efficient and scalable image retrieval methods. Cross-modality image retrieval is particularly challenging, since images of similar (or even the same) content captured by different modalities might share few common structures. We propose a new application-independent content-based image retrieval (CBIR) system for reverse (sub-)image search across modalities, which combines deep learning to generate representations (embedding the different modalities in a common space) with classical feature extraction and bag-of-words models for efficient and reliable retrieval. We illustrate its advantages through a replacement study, exploring a number of feature extractors and learned representations, as well as through comparison to recent (cross-modality) CBIR methods. For the task of (sub-)image retrieval on a (publicly available) dataset of brightfield and second harmonic generation microscopy images, the results show that our approach is superior to all tested alternatives. We discuss the shortcomings of the compared methods and observe the importance of equivariance and invariance properties of the learned representations and feature extractors in the CBIR pipeline. Code is available at: \url{https://github.com/MIDA-group/CrossModal_ImgRetrieval}.

Johan Öfverstedt, Joakim Lindblad, Nataša Sladoje

Multimodal image alignment involves finding spatial correspondences between volumes varying in appearance and structure. Automated alignment methods are often based on local optimization that can be highly sensitive to their initialization. We propose a global optimization method for rigid multimodal 3D image alignment, based on a novel efficient algorithm for computing similarity of normalized gradient fields (NGF) in the frequency domain. We validate the method experimentally on a dataset comprised of 20 brain volumes acquired in four modalities (T1w, Flair, CT, [18F] FDG PET), synthetically displaced with known transformations. The proposed method exhibits excellent performance on all six possible modality combinations, and outperforms all four reference methods by a large margin. The method is fast; a 3.4Mvoxel global rigid alignment requires approximately 40 seconds of computation, and the proposed algorithm outperforms a direct algorithm for the same task by more than three orders of magnitude. Open-source implementation is provided.

Johan Öfverstedt, Joakim Lindblad, Nataša Sladoje

Multimodal image alignment is the process of finding spatial correspondences between images formed by different imaging techniques or under different conditions, to facilitate heterogeneous data fusion and correlative analysis. The information-theoretic concept of mutual information (MI) is widely used as a similarity measure to guide multimodal alignment processes, where most works have focused on local maximization of MI that typically works well only for small displacements; this points to a need for global maximization of MI, which has previously been computationally infeasible due to the high run-time complexity of existing algorithms. We propose an efficient algorithm for computing MI for all discrete displacements (formalized as the cross-mutual information function (CMIF)), which is based on cross-correlation computed in the frequency domain. We show that the algorithm is equivalent to a direct method while asymptotically superior in terms of run-time. Furthermore, we propose a method for multimodal image alignment for transformation models with few degrees of freedom (e.g. rigid) based on the proposed CMIF-algorithm. We evaluate the efficacy of the proposed method on three distinct benchmark datasets, of aerial images, cytological images, and histological images, and we observe excellent success-rates (in recovering known rigid transformations), overall outperforming alternative methods, including local optimization of MI as well as several recent deep learning-based approaches. We also evaluate the run-times of a GPU implementation of the proposed algorithm and observe speed-ups from 100 to more than 10,000 times for realistic image sizes compared to a GPU implementation of a direct method. Code is shared as open-source at \url{github.com/MIDA-group/globalign}.

Jiahao Lu, Johan Öfverstedt, Joakim Lindblad et al.

Despite current advancement in the field of biomedical image processing, propelled by the deep learning revolution, multimodal image registration, due to its several challenges, is still often performed manually by specialists. The recent success of image-to-image (I2I) translation in computer vision applications and its growing use in biomedical areas provide a tempting possibility of transforming the multimodal registration problem into a, potentially easier, monomodal one. We conduct an empirical study of the applicability of modern I2I translation methods for the task of rigid registration of multimodal biomedical and medical 2D and 3D images. We compare the performance of four Generative Adversarial Network (GAN)-based I2I translation methods and one contrastive representation learning method, subsequently combined with two representative monomodal registration methods, to judge the effectiveness of modality translation for multimodal image registration. We evaluate these method combinations on four publicly available multimodal (2D and 3D) datasets and compare them with the performance of registration achieved by several well-known approaches acting directly on multimodal image data. Our results suggest that, although I2I translation may be helpful when the modalities to register are clearly correlated, registration of modalities which express distinctly different properties of the sample is not well handled by the I2I translation approach. The evaluated representation learning method, which aims to find abstract image-like representations of the information shared between the modalities, manages better, and so does the Mutual Information maximisation approach, acting directly on the original multimodal images. We share our complete experimental setup as open-source (https://github.com/MIDA-group/MultiRegEval).

Johan Öfverstedt, Joakim Lindblad, Nataša Sladoje

We present INSPIRE, a top-performing general-purpose method for deformable image registration. INSPIRE brings distance measures which combine intensity and spatial information into an elastic B-splines-based transformation model and incorporates an inverse inconsistency penalization supporting symmetric registration performance. We introduce several theoretical and algorithmic solutions which provide high computational efficiency and thereby applicability of the proposed framework in a wide range of real scenarios. We show that INSPIRE delivers highly accurate, as well as stable and robust registration results. We evaluate the method on a 2D dataset created from retinal images, characterized by presence of networks of thin structures. Here INSPIRE exhibits excellent performance, substantially outperforming the widely used reference methods. {We also evaluate INSPIRE on the Fundus Image Registration Dataset (FIRE), which consists of 134 pairs of separately acquired retinal images. INSPIRE exhibits excellent performance on the FIRE dataset, substantially outperforming several domain-specific methods.} We also evaluate the method on four benchmark datasets of 3D magnetic resonance images of brains, for a total of 2088 pairwise registrations. A comparison with 17 other state-of-the-art methods reveals that INSPIRE provides the best overall performance. Code is available at http://github.com/MIDA-group/inspire

Nicolas Pielawski, Elisabeth Wetzer, Johan Öfverstedt et al.

We propose contrastive coding to learn shared, dense image representations, referred to as CoMIRs (Contrastive Multimodal Image Representations). CoMIRs enable the registration of multimodal images where existing registration methods often fail due to a lack of sufficiently similar image structures. CoMIRs reduce the multimodal registration problem to a monomodal one, in which general intensity-based, as well as feature-based, registration algorithms can be applied. The method involves training one neural network per modality on aligned images, using a contrastive loss based on noise-contrastive estimation (InfoNCE). Unlike other contrastive coding methods, used for, e.g., classification, our approach generates image-like representations that contain the information shared between modalities. We introduce a novel, hyperparameter-free modification to InfoNCE, to enforce rotational equivariance of the learnt representations, a property essential to the registration task. We assess the extent of achieved rotational equivariance and the stability of the representations with respect to weight initialization, training set, and hyperparameter settings, on a remote sensing dataset of RGB and near-infrared images. We evaluate the learnt representations through registration of a biomedical dataset of bright-field and second-harmonic generation microscopy images; two modalities with very little apparent correlation. The proposed approach based on CoMIRs significantly outperforms registration of representations created by GAN-based image-to-image translation, as well as a state-of-the-art, application-specific method which takes additional knowledge about the data into account. Code is available at: https://github.com/MIDA-group/CoMIR.

Jiahao Lu, Nataša Sladoje, Christina Runow Stark et al.

Oral cancer incidence is rapidly increasing worldwide. The most important determinant factor in cancer survival is early diagnosis. To facilitate large scale screening, we propose a fully automated pipeline for oral cancer detection on whole slide cytology images. The pipeline consists of fully convolutional regression-based nucleus detection, followed by per-cell focus selection, and CNN based classification. Our novel focus selection step provides fast per-cell focus decisions at human-level accuracy. We demonstrate that the pipeline provides efficient cancer classification of whole slide cytology images, improving over previous results both in terms of accuracy and feasibility. The complete source code is available at https://github.com/MIDA-group/OralScreen.

Johan Öfverstedt, Joakim Lindblad, Nataša Sladoje

Intensity-based image registration approaches rely on similarity measures to guide the search for geometric correspondences with high affinity between images. The properties of the used measure are vital for the robustness and accuracy of the registration. In this study a symmetric, intensity interpolation-free, affine registration framework based on a combination of intensity and spatial information is proposed. The excellent performance of the framework is demonstrated on a combination of synthetic tests, recovering known transformations in the presence of noise, and real applications in biomedical and medical image registration, for both 2D and 3D images. The method exhibits greater robustness and higher accuracy than similarity measures in common use, when inserted into a standard gradient-based registration framework available as part of the open source Insight Segmentation and Registration Toolkit (ITK). The method is also empirically shown to have a low computational cost, making it practical for real applications. Source code is available.

Lasse Hansen, Wiebke Heyer, Christoph Großbröhmer et al.

Medical image registration is critical for clinical applications, and fair benchmarking of different methods is essential for monitoring ongoing progress. To date, the Learn2Reg 2020-2023 challenges have released several complementary datasets and established metrics for evaluations. However, these editions did not capture all aspects of the registration problem, particularly in terms of modality diversity and task complexity. To address these limitations, the 2024 edition introduces three new tasks, including large-scale multi-modal registration and unsupervised inter-subject brain registration, as well as the first microscopy-focused benchmark within Learn2Reg. The new datasets also inspired new method developments, including invertibility constraints, pyramid features, keypoints alignment and instance optimisation.

Marco Acerbis, Nataša Sladoje, Joakim Lindblad

Accurate and efficient cell detection is crucial in many biomedical image analysis tasks. We evaluate the performance of several Deep Learning (DL) methods for cell detection in Papanicolaou-stained cytological Whole Slide Images (WSIs), focusing on accuracy of predictions and computational efficiency. We examine recentoff-the-shelf algorithms as well as custom-designed detectors, applying them to two datasets: the CNSeg Dataset and the Oral Cancer (OC) Dataset. Our comparison includes well-established segmentation methods such as StarDist, Cellpose, and the Segment Anything Model 2 (SAM2), alongside centroid-based Fully Convolutional Regression Network (FCRN) approaches. We introduce a suitable evaluation metric to assess the accuracy of predictions based on the distance from ground truth positions. We also explore the impact of dataset size and data augmentation techniques on model performance. Results show that centroid-based methods, particularly the Improved Fully Convolutional Regression Network (IFCRN) method, outperform segmentation-based methods in terms of both detection accuracy and computational efficiency. This study highlights the potential of centroid-based detectors as a preferred option for cell detection in resource-limited environments, offering faster processing times and lower GPU memory usage without compromising accuracy.

Johan Öfverstedt, Joakim Lindblad, Nataša Sladoje

The distance transform (DT) and its many variations are ubiquitous tools for image processing and analysis. In many imaging scenarios, the images of interest are corrupted by noise. This has a strong negative impact on the accuracy of the DT, which is highly sensitive to spurious noise points. In this study, we consider images represented as discrete random sets and observe statistics of DT computed on such representations. We, thus, define a stochastic distance transform (SDT), which has an adjustable robustness to noise. Both a stochastic Monte Carlo method and a deterministic method for computing the SDT are proposed and compared. Through a series of empirical tests, we demonstrate that the SDT is effective not only in improving the accuracy of the computed distances in the presence of noise, but also in improving the performance of template matching and watershed segmentation of partially overlapping objects, which are examples of typical applications where DTs are utilized.

Tomáš Majtner, Buda Bajić, Sule Yildirim et al.

In this report, we are presenting our automated prediction system for disease classification within dermoscopic images. The proposed solution is based on deep learning, where we employed transfer learning strategy on VGG16 and GoogLeNet architectures. The key feature of our solution is preprocessing based primarily on image augmentation and colour normalization. The solution was evaluated on Task 3: Lesion Diagnosis of the ISIC 2018: Skin Lesion Analysis Towards Melanoma Detection.