Self-Supervision Enhances Instance-based Multiple Instance Learning Methods in Digital Pathology: A Benchmark Study

Multiple Instance Learning (MIL) has emerged as the best solution for Whole Slide Image (WSI) classification. It consists of dividing each slide into patches, which are treated as a bag of instances labeled with a global label. MIL includes two main approaches: instance-based and embedding-based. In the former, each patch is classified independently, and then the patch scores are aggregated to predict the bag label. In the latter, bag classification is performed after aggregating patch embeddings. Even if instance-based methods are naturally more interpretable, embedding-based MILs have usually been preferred in the past due to their robustness to poor feature extractors. However, recently, the quality of feature embeddings has drastically increased using self-supervised learning (SSL). Nevertheless, many authors continue to endorse the superiority of embedding-based MIL. To investigate this further, we conduct 710 experiments across 4 datasets, comparing 10 MIL strategies, 6 self-supervised methods with 4 backbones, 4 foundation models, and various pathology-adapted techniques. Furthermore, we introduce 4 instance-based MIL methods never used before in the pathology domain. Through these extensive experiments, we show that with a good SSL feature extractor, simple instance-based MILs, with very few parameters, obtain similar or better performance than complex, state-of-the-art (SOTA) embedding-based MIL methods, setting new SOTA results on the BRACS and Camelyon16 datasets. Since simple instance-based MIL methods are naturally more interpretable and explainable to clinicians, our results suggest that more effort should be put into well-adapted SSL methods for WSI rather than into complex embedding-based MIL methods.

First Order Logic with Fuzzy Semantics for Describing and Recognizing Nerves in Medical Images

This article deals with the description and recognition of fiber bundles, in particular nerves, in medical images, based on the anatomical description of the fiber trajectories. To this end, we propose a logical formalization of this anatomical knowledge. The intrinsically imprecise description of nerves, as found in anatomical textbooks, leads us to propose fuzzy semantics combined with first-order logic. We define a language representing spatial entities, relations between these entities and quantifiers. A formula in this language is then a formalization of the natural language description. The semantics are given by fuzzy representations in a concrete domain and satisfaction degrees of relations. Based on this formalization, a spatial reasoning algorithm is proposed for segmentation and recognition of nerves from anatomical and diffusion magnetic resonance images, which is illustrated on pelvic nerves in pediatric imaging, enabling surgeons to plan surgery.

Separating common from salient patterns with Contrastive Representation Learning

Contrastive Analysis is a sub-field of Representation Learning that aims at separating common factors of variation between two datasets, a background (i.e., healthy subjects) and a target (i.e., diseased subjects), from the salient factors of variation, only present in the target dataset. Despite their relevance, current models based on Variational Auto-Encoders have shown poor performance in learning semantically-expressive representations. On the other hand, Contrastive Representation Learning has shown tremendous performance leaps in various applications (classification, clustering, etc.). In this work, we propose to leverage the ability of Contrastive Learning to learn semantically expressive representations well adapted for Contrastive Analysis. We reformulate it under the lens of the InfoMax Principle and identify two Mutual Information terms to maximize and one to minimize. We decompose the first two terms into an Alignment and a Uniformity term, as commonly done in Contrastive Learning. Then, we motivate a novel Mutual Information minimization strategy to prevent information leakage between common and salient distributions. We validate our method, called SepCLR, on three visual datasets and three medical datasets, specifically conceived to assess the pattern separation capability in Contrastive Analysis. Code available at https://github.com/neurospin-projects/2024_rlouiset_sep_clr.

Double InfoGAN for Contrastive Analysis

Contrastive Analysis (CA) deals with the discovery of what is common and what is distinctive of a target domain compared to a background one. This is of great interest in many applications, such as medical imaging. Current state-of-the-art (SOTA) methods are latent variable models based on VAE (CA-VAEs). However, they all either ignore important constraints or they don't enforce fundamental assumptions. This may lead to sub-optimal solutions where distinctive factors are mistaken for common ones (or viceversa). Furthermore, the generated images have a rather poor quality, typical of VAEs, decreasing their interpretability and usefulness. Here, we propose Double InfoGAN, the first GAN based method for CA that leverages the high-quality synthesis of GAN and the separation power of InfoGAN. Experimental results on four visual datasets, from simple synthetic examples to complex medical images, show that the proposed method outperforms SOTA CA-VAEs in terms of latent separation and image quality. Datasets and code are available online.

Non-Redundant Combination of Hand-Crafted and Deep Learning Radiomics: Application to the Early Detection of Pancreatic Cancer

We address the problem of learning Deep Learning Radiomics (DLR) that are not redundant with Hand-Crafted Radiomics (HCR). To do so, we extract DLR features using a VAE while enforcing their independence with HCR features by minimizing their mutual information. The resulting DLR features can be combined with hand-crafted ones and leveraged by a classifier to predict early markers of cancer. We illustrate our method on four early markers of pancreatic cancer and validate it on a large independent test set. Our results highlight the value of combining non-redundant DLR and HCR features, as evidenced by an improvement in the Area Under the Curve compared to baseline methods that do not address redundancy or solely rely on HCR features.

Decoupled conditional contrastive learning with variable metadata for prostate lesion detection

Early diagnosis of prostate cancer is crucial for efficient treatment. Multi-parametric Magnetic Resonance Images (mp-MRI) are widely used for lesion detection. The Prostate Imaging Reporting and Data System (PI-RADS) has standardized interpretation of prostate MRI by defining a score for lesion malignancy. PI-RADS data is readily available from radiology reports but is subject to high inter-reports variability. We propose a new contrastive loss function that leverages weak metadata with multiple annotators per sample and takes advantage of inter-reports variability by defining metadata confidence. By combining metadata of varying confidence with unannotated data into a single conditional contrastive loss function, we report a 3% AUC increase on lesion detection on the public PI-CAI challenge dataset. Code is available at: https://github.com/camilleruppli/decoupled_ccl

SepVAE: a contrastive VAE to separate pathological patterns from healthy ones

Contrastive Analysis VAE (CA-VAEs) is a family of Variational auto-encoders (VAEs) that aims at separating the common factors of variation between a background dataset (BG) (i.e., healthy subjects) and a target dataset (TG) (i.e., patients) from the ones that only exist in the target dataset. To do so, these methods separate the latent space into a set of salient features (i.e., proper to the target dataset) and a set of common features (i.e., exist in both datasets). Currently, all models fail to prevent the sharing of information between latent spaces effectively and to capture all salient factors of variation. To this end, we introduce two crucial regularization losses: a disentangling term between common and salient representations and a classification term between background and target samples in the salient space. We show a better performance than previous CA-VAEs methods on three medical applications and a natural images dataset (CelebA). Code and datasets are available on GitHub https://github.com/neurospin-projects/2023_rlouiset_sepvae.

Weakly-supervised positional contrastive learning: application to cirrhosis classification

Large medical imaging datasets can be cheaply and quickly annotated with low-confidence, weak labels (e.g., radiological scores). Access to high-confidence labels, such as histology-based diagnoses, is rare and costly. Pretraining strategies, like contrastive learning (CL) methods, can leverage unlabeled or weakly-annotated datasets. These methods typically require large batch sizes, which poses a difficulty in the case of large 3D images at full resolution, due to limited GPU memory. Nevertheless, volumetric positional information about the spatial context of each 2D slice can be very important for some medical applications. In this work, we propose an efficient weakly-supervised positional (WSP) contrastive learning strategy where we integrate both the spatial context of each 2D slice and a weak label via a generic kernel-based loss function. We illustrate our method on cirrhosis prediction using a large volume of weakly-labeled images, namely radiological low-confidence annotations, and small strongly-labeled (i.e., high-confidence) datasets. The proposed model improves the classification AUC by 5% with respect to a baseline model on our internal dataset, and by 26% on the public LIHC dataset from the Cancer Genome Atlas. The code is available at: https://github.com/Guerbet-AI/wsp-contrastive.

Learning to diagnose cirrhosis from radiological and histological labels with joint self and weakly-supervised pretraining strategies

Identifying cirrhosis is key to correctly assess the health of the liver. However, the gold standard diagnosis of the cirrhosis needs a medical intervention to obtain the histological confirmation, e.g. the METAVIR score, as the radiological presentation can be equivocal. In this work, we propose to leverage transfer learning from large datasets annotated by radiologists, which we consider as a weak annotation, to predict the histological score available on a small annex dataset. To this end, we propose to compare different pretraining methods, namely weakly-supervised and self-supervised ones, to improve the prediction of the cirrhosis. Finally, we introduce a loss function combining both supervised and self-supervised frameworks for pretraining. This method outperforms the baseline classification of the METAVIR score, reaching an AUC of 0.84 and a balanced accuracy of 0.75, compared to 0.77 and 0.72 for a baseline classifier.

Contrastive learning for regression in multi-site brain age prediction

Building accurate Deep Learning (DL) models for brain age prediction is a very relevant topic in neuroimaging, as it could help better understand neurodegenerative disorders and find new biomarkers. To estimate accurate and generalizable models, large datasets have been collected, which are often multi-site and multi-scanner. This large heterogeneity negatively affects the generalization performance of DL models since they are prone to overfit site-related noise. Recently, contrastive learning approaches have been shown to be more robust against noise in data or labels. For this reason, we propose a novel contrastive learning regression loss for robust brain age prediction using MRI scans. Our method achieves state-of-the-art performance on the OpenBHB challenge, yielding the best generalization capability and robustness to site-related noise.