Recent advancements in computational pathology have greatly improved automated histopathological analysis. A compelling question in the field is how morphological traits are associated with genetic characteristics or molecular phenotypes. Here we propose TEMI, a novel framework for molecular subtype classification of cancers using whole-slide images (WSIs), augmented with transcriptomic data during training. TEMI aims to extract molecular-level signals from WSIs and make efficient use of available multimodal data. To this end, TEMI introduces a patch fusion network that captures dependencies among local patches of gigapixel WSIs to produce global representations and aligns them with transcriptomic embeddings attained from a masked transcriptomic autoencoder. TEMI achieves superior performance compared with existing methods in molecular subtype classification, owing to its effective integration of transcriptomic information achieved by the two developed alignment strategies. Guided by discriminative transcriptomic data, TEMI learns invariant WSI representations, while morphological features also enhance gene expression prediction. These findings suggest that histological features encode latent molecular signals, highlighting the interplay between the tumor microenvironment and cancer transcriptomics. Our study demonstrates how multimodal learning can bridge morphology and molecular biology, providing an effective tool to advance precision medicine.

Invariant risk minimization (IRM) is an arising approach to generalize invariant features to different environments in machine learning. While most related works focus on new IRM settings or new application scenarios, the mathematical essence of IRM remains to be properly explained. We verify that IRM is essentially a total variation based on $L^2$ norm (TV-$\ell_2$) of the learning risk with respect to the classifier variable. Moreover, we propose a novel IRM framework based on the TV-$\ell_1$ model. It not only expands the classes of functions that can be used as the learning risk and the feature extractor, but also has robust performance in denoising and invariant feature preservation based on the coarea formula. We also illustrate some requirements for IRM-TV-$\ell_1$ to achieve out-of-distribution generalization. Experimental results show that the proposed framework achieves competitive performance in several benchmark machine learning scenarios.

MOTIVATION: Cell-type annotation is fundamental in revealing cell heterogeneity for single-cell data analysis. Although a host of works have been developed, the low signal-to-noise-ratio single-cell RNA-sequencing data that suffers from batch effects and dropout still poses obstacles in discovering grouped patterns for cell types by unsupervised learning and its alternative-semi-supervised learning that utilizes a few labeled cells as guidance for cell-type annotation. RESULTS: We propose a robust cell-type annotation method scSemiGCN based on graph convolutional networks. Built upon a denoised network structure that characterizes reliable cell-to-cell connections, scSemiGCN generates pseudo labels for unannotated cells. Then supervised contrastive learning follows to refine the noisy single-cell data. Finally, message passing with the refined features over the denoised network structure is conducted for semi-supervised cell-type annotation. Comparison over several datasets with six methods under extremely limited supervision validates the effectiveness and efficiency of scSemiGCN for cell-type annotation. AVAILABILITY AND IMPLEMENTATION: Implementation of scSemiGCN is available at https://github.com/Jane9898/scSemiGCN.

The discovery of cancer subtypes has become much-researched topic in oncology. Dividing cancer patients into subtypes can provide personalized treatments for heterogeneous patients. High-throughput technologies provide multiple omics data for cancer subtyping. Integration of multi-view data is used to identify cancer subtypes in many computational methods, which obtain different subtypes for the same cancer, even using the same multi-omics data. To a certain extent, these subtypes from distinct methods are related, which may have certain guiding significance for cancer subtyping. It is a challenge to effectively utilize the valuable information of distinct subtypes to produce more accurate and reliable subtypes. A weighted ensemble sparse latent representation (subtype-WESLR) is proposed to detect cancer subtypes on heterogeneous omics data. Using a weighted ensemble strategy to fuse base clustering obtained by distinct methods as prior knowledge, subtype-WESLR projects each sample feature profile from each data type to a common latent subspace while maintaining the local structure of the original sample feature space and consistency with the weighted ensemble and optimizes the common subspace by an iterative method to identify cancer subtypes. We conduct experiments on various synthetic datasets and eight public multi-view datasets from The Cancer Genome Atlas. The results demonstrate that subtype-WESLR is better than competing methods by utilizing the integration of base clustering of exist methods for more precise subtypes.

Learning node representation is a fundamental problem in biological network analysis, as compact representation features reveal complicated network structures and carry useful information for downstream tasks such as link prediction and node classification. Recently, multiple networks that profile objects from different aspects are increasingly accumulated, providing the opportunity to learn objects from multiple perspectives. However, the complex common and specific information across different networks pose challenges to node representation methods. Moreover, ubiquitous noise in networks calls for more robust representation. To deal with these problems, we present a representation learning method for multiple biological networks. First, we accommodate the noise and spurious edges in networks using denoised diffusion, providing robust connectivity structures for the subsequent representation learning. Then, we introduce a graph regularized integration model to combine refined networks and compute common representation features. By using the regularized decomposition technique, the proposed model can effectively preserve the common structural property of different networks and simultaneously accommodate their specific information, leading to a consistent representation. A simulation study shows the superiority of the proposed method on different levels of noisy networks. Three network-based inference tasks, including drug-target interaction prediction, gene function identification and fine-grained species categorization, are conducted using representation features learned from our method. Biological networks at different scales and levels of sparsity are involved. Experimental results on real-world data show that the proposed method has robust performance compared with alternatives. Overall, by eliminating noise and integrating effectively, the proposed method is able to learn useful representations from multiple biological networks.

MOTIVATION: Drug repositioning that aims to find new indications for existing drugs has been an efficient strategy for drug discovery. In the scenario where we only have confirmed disease-drug associations as positive pairs, a negative set of disease-drug pairs is usually constructed from the unknown disease-drug pairs in previous studies, where we do not know whether drugs and diseases can be associated, to train a model for disease-drug association prediction (drug repositioning). Drugs and diseases in these negative pairs can potentially be associated, but most studies have ignored them. RESULTS: We present a method, springD2A, to capture the uncertainty in the negative pairs, and to discriminate between positive and unknown pairs because the former are more reliable. In springD2A, we introduce a spring-like penalty for the loss of negative pairs, which is strong if they are too close in a unit sphere, but mild if they are at a moderate distance. We also design a sequential sampling in which the probability of an unknown disease-drug pair sampled as negative is proportional to its score predicted as positive. Multiple models are learned during sequential sampling, and we adopt parameter- and feature-based ensemble schemes to boost performance. Experiments show springD2A is an effective tool for drug-repositioning. AVAILABILITY AND IMPLEMENTATION: A python implementation of springD2A and datasets used in this study are available at https://github.com/wangyuanhao/springD2A. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

With diverse types of omics data widely available, many computational methods have been recently developed to integrate these heterogeneous data, providing a comprehensive understanding of diseases and biological mechanisms. But most of them hardly take noise effects into account. Data-specific patterns unique to data types also make it challenging to uncover the consistent patterns and learn a compact representation of multi-omics data. Here we present a multi-omics integration method considering these issues. We explicitly model the error term in data reconstruction and simultaneously consider noise effects and data-specific patterns. We utilize a denoised network regularization in which we build a fused network using a denoising procedure to suppress noise effects and data-specific patterns. The error term collaborates with the denoised network regularization to capture data-specific patterns. We solve the optimization problem via an inexact alternating minimization algorithm. A comparative simulation study shows the method's superiority at discovering common patterns among data types at three noise levels. Transcriptomics-and-epigenomics integration, in seven cancer cohorts from The Cancer Genome Atlas, demonstrates that the learned integrative representation extracted in an unsupervised manner can depict survival information. Specially in liver hepatocellular carcinoma, the learned integrative representation attains average Harrell's C-index of 0.78 in 10 times 3-fold cross-validation for survival prediction, which far exceeds competing methods, and we discover an aggressive subtype in liver hepatocellular carcinoma with this latent representation, which is validated by an external dataset GSE14520. We also show that DeFusion is applicable to the integration of other omics types.