Many problems in life sciences can be brought back to a comparison of graphs. Even though a multitude of such techniques exist, often, these assume prior knowledge about the partitioning or the number of clusters and fail to provide statistical significance of observed between-network heterogeneity. Addressing these issues, we developed an unsupervised workflow to identify groups of graphs from reliable network-based statistics. In particular, we first compute the similarity between networks via appropriate distance measures between graphs and use them in an unsupervised hierarchical algorithm to identify classes of similar networks. Then, to determine the optimal number of clusters, we recursively test for distances between two groups of networks. The test itself finds its inspiration in distance-wise ANOVA algorithms. Finally, we assess significance via the permutation of between-object distance matrices. Notably, the approach, which we will call netANOVA, is flexible since users can choose multiple options to adapt to specific contexts and network types. We demonstrate the benefits and pitfalls of our approach via extensive simulations and an application to two real-life datasets. NetANOVA achieved high performance in many simulation scenarios while controlling type I error. On non-synthetic data, comparison against state-of-the-art methods showed that netANOVA is often among the top performers. There are many application fields, including precision medicine, for which identifying disease subtypes via individual-level biological networks improves prevention programs, diagnosis and disease monitoring.

MOTIVATION: Large-scale clinical proteomics datasets of infectious pathogens, combined with antimicrobial resistance outcomes, have recently opened the door for machine learning models which aim to improve clinical treatment by predicting resistance early. However, existing prediction frameworks typically train a separate model for each antimicrobial and species in order to predict a pathogen's resistance outcome, resulting in missed opportunities for chemical knowledge transfer and generalizability. RESULTS: We demonstrate the effectiveness of multimodal learning over proteomic and chemical features by exploring two clinically relevant tasks for our proposed deep learning models: drug recommendation and generalized resistance prediction. By adopting this multi-view representation of the pathogenic samples and leveraging the scale of the available datasets, our models outperformed the previous single-drug and single-species predictive models by statistically significant margins. We extensively validated the multi-drug setting, highlighting the challenges in generalizing beyond the training data distribution, and quantitatively demonstrate how suitable representations of antimicrobial drugs constitute a crucial tool in the development of clinically relevant predictive models. AVAILABILITY AND IMPLEMENTATION: The code used to produce the results presented in this article is available at https://github.com/BorgwardtLab/MultimodalAMR.

Genes and gene products do not function in isolation but as components of complex networks of macromolecules through physical or biochemical interactions. Dependencies of gene mutations on genetic background (i.e., epistasis) are believed to play a role in understanding molecular underpinnings of complex diseases such as inflammatory bowel disease (IBD). However, the process of identifying such interactions is complex due to for instance the curse of high dimensionality, dependencies in the data and non-linearity. Here, we propose a novel approach for robust and computationally efficient epistasis detection. We do so by first reducing dimensionality, per gene via diffusion kernel principal components (kpc). Subsequently, kpc gene summaries are used for downstream analysis including the construction of a gene-based epistasis network. We show that our approach is not only able to recover known IBD associated genes but also additional genes of interest linked to this difficult gastrointestinal disease.