Spatial transcriptomics (ST) is a novel technology that enables the observation of gene expression at the resolution of individual spots within pathological tissues. ST quantifies the expression of tens of thousands of genes in a tissue section; however, heavy observational noise is often introduced during measurement. In prior studies, to ensure meaningful assessment, both training and evaluation have been restricted to only a small subset of highly variable genes, and genes outside this subset have also been excluded from the training process. However, since there are likely co-expression relationships between genes, low-expression genes may still contribute to the estimation of the evaluation target. In this paper, we propose Auxiliary Gene Learning (AGL) that utilizes the benefit of the ignored genes by reformulating their expression estimation as auxiliary tasks and training them jointly with the primary tasks. To effectively leverage auxiliary genes, we must select a subset of auxiliary genes that positively influence the prediction of the target genes. However, this is a challenging optimization problem due to the vast number of possible combinations. To overcome this challenge, we propose Prior-Knowledge-Based Differentiable Top-k Gene Selection via Bi-level Optimization (DkGSB), a method that ranks genes by leveraging prior knowledge and relaxes the combinatorial selection problem into a differentiable top-k selection problem. The experiments confirm the effectiveness of incorporating auxiliary genes and show that the proposed method outperforms conventional auxiliary task learning approaches.

Gene expression estimation from pathology images has the potential to reduce the RNA sequencing cost. Point-wise loss functions have been widely used to minimize the discrepancy between predicted and absolute gene expression values. However, due to the complexity of the sequencing techniques and intrinsic variability across cells, the observed gene expression contains stochastic noise and batch effects, and estimating the absolute expression values accurately remains a significant challenge. To mitigate this, we propose a novel objective of learning relative expression patterns rather than absolute levels. We assume that the relative expression levels of genes exhibit consistent patterns across independent experiments, even when absolute expression values are affected by batch effects and stochastic noise in tissue samples. Based on the assumption, we model the relation and propose a novel loss function called STRank that is robust to noise and batch effects. Experiments using synthetic datasets and real datasets demonstrate the effectiveness of the proposed method. The code is available at https://github.com/naivete5656/STRank.

Patient-level diagnosis of severity in ulcerative colitis (UC) is common in clinical practice, where the most severe score for a patient is typically recorded as the diagnosis result. However, previous UC classification methods (i.e., image-level estimation) mainly assumed the input was a single image. Thus, these methods can not utilize severity labels recorded in real clinical settings. In this paper, we propose a patient-level severity estimation method by a transformer with selective aggregator tokens, where a severity label is estimated from multiple images taken from a patient, similar to a clinical setting. Our method can effectively aggregate features of severe parts from a set of images captured in each patient, and it facilitates improving the discriminative ability between adjacent severity classes. Experiments demonstrate the effectiveness of the proposed method on two datasets compared with the state-of-the-art MIL methods. Moreover, we evaluated our method using real clinical data and confirmed that our method outperformed the previous image-level methods. The code is publicly available at https://github.com/Shiku-Kaito/Ordinal-Multiple-instance-Learning-for-Ulcerative-Colitis-Severity-Estimation.

The paper proposes a novel problem in multi-class Multiple-Instance Learning (MIL) called Learning from the Majority Label (LML). In LML, the majority class of instances in a bag is assigned as the bag’s label. LML aims to classify instances using bag-level majority classes. This problem is valuable in various applications. Existing MIL methods are unsuitable for LML due to aggregating confidences, which may lead to inconsistency between the bag-level label and the label obtained by counting the number of instances for each class. This may lead to incorrect instance-level classification. We propose a counting network trained to produce the bag-level majority labels estimated by counting the number of instances for each class. This led to the consistency of the majority class between the network outputs and one obtained by counting the number of instances. Experimental results show that our counting network outperforms conventional MIL methods on four datasets1.