Artificial Intelligence (AI) has found many applications in medicine [15] and, more specifically, in cancer research [32] in the form of predictive models for diagnosis [14], prognosis [6] and therapy planning [12]. As a subfield of AI, Machine Learning (ML) and in particular Deep Learning (DL) has achieved significant results, especially in image processing [3]. Nonetheless, ML and DL models have limited explainability [13] because of their black-box design, which limits their adoption in the clinical field: clinicians and physicians are reluctant to include models that are not transparent in their decision process [24]. While recent research on Explainable AI (XAI) [11] has attacked this problem, DL models are still opaque and difficult to interpret. In contrast, in Probabilistic Graphical Models (PGMs) the interactions between different variables are encoded explicitly: the joint probability distribution P of the variables of interest factorizes according to a graph G, hence the "graphical" connotation. Bayesian Networks (BNs) [23], which we will describe in Section 3.1, are an instance of PGMs that can be used as causal models. In turn, this makes them ideal to use as decision support systems and overcome the limitations of the predictions based on probabilistic associations produced by other ML models [1, 19].

In clinical practice, many diagnosis tasks rely on the identification of cells in histopathology images. While supervised machine learning techniques require labels, providing manual cell annotations is time-consuming due to the large number of cells. In this paper, we propose a self-supervised framework (VOLTA) for cell representation learning in histopathology images using a novel technique that accounts for the cell's mutual relationship with its environment for improved cell representations. We subjected our model to extensive experiments on the data collected from multiple institutions around the world comprising of over 700,000 cells, four cancer types, and cell types ranging from three to six categories for each dataset. The results show that our model outperforms the state-of-the-art models in cell representation learning. To showcase the potential power of our proposed framework, we applied VOLTA to ovarian and endometrial cancers with very small sample sizes (10-20 samples) and demonstrated that our cell representations can be utilized to identify the known histotypes of ovarian cancer and provide novel insights that link histopathology and molecular subtypes of endometrial cancer. Unlike supervised deep learning models that require large sample sizes for training, we provide a framework that can empower new discoveries without any annotation data in situations where sample sizes are limited.

Research at the Leiden University Medical Center (LUMC) Department of Pathology shows the power of artificial intelligence (AI) applied to endometrial carcinoma microscopy images. The group of Dr Tjalling Bosse offers insights that could improve diagnosis and treatment of uterine cancer. Their findings have been published in The Lancet Digital Health. Endometrial carcinoma is the most common cancer of the gynaecologic tract. At the LUMC both clinical trials and translational research is conducted to improve the care for these patients.

Research at the Leiden University Medical Center (LUMC) Department of Pathology shows the power of artificial intelligence (AI) applied to endometrial carcinoma microscopy images. The group of Dr. Tjalling Bosse offers novel insights that could improve diagnosis and treatment of uterine cancer. Their findings have been published in The Lancet Digital Health. Endometrial carcinoma is the most common cancer of the gynecologic tract. At the LUMC both clinical trials and translational research are conducted to improve the care for these patients.

Randomized controlled trials (RCTs) are considered as the gold standard for testing causal hypotheses in the clinical domain. However, the investigation of prognostic variables of patient outcome in a hypothesized cause-effect route is not feasible using standard statistical methods. Here, we propose a new automated causal inference method (AutoCI) built upon the invariant causal prediction (ICP) framework for the causal re-interpretation of clinical trial data. Compared to existing methods, we show that the proposed AutoCI allows to efficiently determine the causal variables with a clear differentiation on two real-world RCTs of endometrial cancer patients with mature outcome and extensive clinicopathological and molecular data. This is achieved via suppressing the causal probability of non-causal variables by a wide margin. In ablation studies, we further demonstrate that the assignment of causal probabilities by AutoCI remain consistent in the presence of confounders. In conclusion, these results confirm the robustness and feasibility of AutoCI for future applications in real-world clinical analysis.