Analyzing associations and higher-order effects in multi-omics data with double machine learning

Host-microbiome interactions are crucial in maintaining physiological homeostasis and influencing disease progression. While traditional microbiome research, focused on microbial diversity and abundance, provided essential frameworks, the integration of multi-omics approaches established a far more comprehensive, systems-level understanding of microbiome functionality. However, significant methodological challenges in multi-omics data integration remain, including inconsistent sample coverage, heterogeneous data formats, and complex downstream analytical workflows. These challenges impact the reproducibility and reliability of results and underscore the critical requirement for developing standardized, systematic workflows. Thus, we developed the EasyMultiProfiler (EMP) workflow, a streamlined and efficient analytical framework for multi-omics data analysis. EMP provides a comprehensive infrastructure based on the SummarizedExperiment and MultiAssayExperiment classes, creating a unified framework for storing and analyzing omics data. The framework's architecture comprises five interconnected functional modules: data extraction, preparation, support, analysis, and visualization. These modules are smoothly integrated into natural language-style analytical workflows, offering users an efficient and standardized solution for multi-omics analysis. EMP addresses critical challenges in multi-omics data analysis, including data integration, workflow standardization, and result reproducibility. The platform's modular architecture and intuitive interface provide researchers and clinicians with a robust, flexible workflow to systematically extract biologically relevant insights from complex multi-omics datasets.

Pharmacogenomics is the study of how genes affect a person's response to drugs. Thus, understanding the effect of drug at the molecular level can be helpful in both drug discovery and personalized medicine. Over the years, transcriptome data upon drug treatment has been collected and several databases compiled before drug treatment cancer cell multi-omics data with drug sensitivity (IC50, AUC) or time-series transcriptomic data after drug treatment. However, analyzing transcriptome data upon drug treatment is challenging since more than 20,000 genes interact in complex ways. In addition, due to the difficulty of both time-series analysis and multi-omics integration, current methods can hardly perform analysis of databases with different data characteristics. One effective way is to interpret transcriptome data in terms of well-characterized biological pathways. Another way is to leverage state-of-the-art methods for multi-omics data integration. In this paper, we developed Drug Response analysis Integrating Multi-omics and time-series data (DRIM), an integrative multi-omics and time-series data analysis framework that identifies perturbed sub-pathways and regulation mechanisms upon drug treatment. The system takes drug name and cell line identification numbers or user's drug control/treat time-series gene expression data as input. Then, analysis of multi-omics data upon drug treatment is performed in two perspectives. For the multi-omics perspective analysis, IC50-related multi-omics potential mediator genes are determined by embedding multi-omics data to gene-centric vector space using a tensor decomposition method and an autoencoder deep learning model. Then, perturbed pathway analysis of potential mediator genes is performed. For the time-series perspective analysis, time-varying perturbed sub-pathways upon drug treatment are constructed. Additionally, a network involving transcription factors (TFs), multi-omics potential mediator genes, and perturbed sub-pathways is constructed, and paths to perturbed pathways from TFs are determined by an influence maximization method. To demonstrate the utility of our system, we provide analysis results of sub-pathway regulatory mechanisms in breast cancer cell lines of different drug sensitivity. DRIM is available at: http://biohealth.snu.ac.kr/software/DRIM/.

During the past two decades, computational analysis has become paramount for biological research. Advancements in high-throughput methods and computational tools resulted in the generation of large amounts of data from different omics fields (multi-omics), such as genomics, epigenomics, transcriptomics, and metabolomics. This plethora of large scale and diverse omics data is being driven by the understanding that a single-omic type does not provide adequate information and integrative analysis of multi-omics data is optimal to gain sufficiently meaningful insights into the actual biological mechanisms. Although various open-source tools have been developed for this purpose, multi-omics data integration and analysis are still beset by a number of problems, including software compatibility, complex parameter selection and creation of functional pipelines with multiple steps of analyses. In this work we present GenOptics, a novel visual analytics platform that aims to facilitate the integration and subsequent analysis of diverse multi-omics datasets as well as meta-data (e.g., clinical data), through a fully interactive environment. The platform comprises of two separate parts. The first incorporates asynchronous analyses of Next-Generation Sequencing raw data, including RNA-, Whole exome-, and ChIP-Seq, using workflows implemented with the Common Workflow Language (doi:10.6084/m9.figshare.3115156.v2) and Docker containers to automate software installation and confer cross-platform portability. The second part constitutes the analytical platform itself, designed to facilitate the execution of robust bioinformatics analyses by life scientists with minimal or no knowledge of programming. GenOptics constitutes an open source (https://genoptics.github.io/), computational biology platform for novel pattern and biomarker detection.

BackgroundMulti-omics experimental approaches are becoming common practice in biological and medical sciences underlining the need to design new integrative techniques and applications to enable the multi-scale characterization of biological systems. The integrative analysis of heterogeneous datasets generally allows to acquire additional insights and generate novel hypotheses about a given biological system. However, it can become challenging given the often-large size of omics datasets and the diversity of existing techniques. Moreover, visualization tools for interpretation are usually non-accessible to biologists without programming skills.ResultsHere, we present MiBiOmics, a web-based and standalone application that facilitates multi-omics data visualization, exploration, integration, and analysis by providing easy access to dedicated and interactive protocols. It implements classical ordination techniques and the inference of omics-based (multilayer) networks to mine complex biological systems, and identify robust biomarkers linked to specific contextual parameters or biological states.ConclusionsMiBiOmics provides easy-access to exploratory ordination techniques and to a network-based approach for integrative multi-omics analyses through an intuitive and interactive interface. MiBiOmics is currently available as a Shiny app at https://shiny-bird.univ-nantes.fr/app/Mibiomics and as a standalone application at https://gitlab.univ-nantes.fr/combi-ls2n/mibiomics.

Multi-omics data integration and drug screening of AML cancer using Generative Adversarial Network

MotivationIsoforms spliced from the same gene may carry distinct biological functions. Therefore, annotating functions at the isoform level provides valuable insights into the functional diversity of genomes. Since experimental approaches for determining isoform functions are time- and cost-demanding, computational methods have been proposed. In this case, multi-omics data integration helps enhance the model performance, providing complementary insights for isoform functions. However, current methods underperform in leveraging diverse omics data, primarily due to the limited power to integrate the heterogeneous feature domains. Besides, among the multi-omics data, isoform-isoform interactions (IIIs) are a key data source, as isoforms interact with each other to perform functions. Unfortunately, IIIs remain largely underutilized in isoform function predictions until now.ResultsWe introduce CrossIsoFun, a multi-omics data analysis framework for isoform function prediction. CrossIsoFun combines omics-specific and cross-omics learning for data integration and function prediction. In detail, CrossIsoFun uses a graph convolutional network (GCN) as the omics-specific classifier for each data source. The initial label predictions from GCNs are forwarded to the View Correlation Discovery Network (VCDN) and processed as a cross-omics integrative representation. The representation is then used to produce final predictions of isoform functions. In addition, an antoencoder within a cycle-consistency generative adversarial network (cycleGAN) is designed to generate IIIs from PPIs and thereby enrich the interactomics data. Our method outperforms the state-of-the-art methods on three tissue-naive datasets and 15 tissue-specific datasets with mRNA expression, sequence, and PPI data. The prediction of CrossIsoFun is further validated by its consistency with subcellular localization and isoform-level annotations with literature support.Availability and implementationCrossIsoFun is freely available at https://github.com/genemine/CrossIsoFun.

Breast cancer (BC) is the second leading cause of cancer-related death among women in the United States. Previous studies have shown that African American (AA) women have disproportionately high mortality rate in BC compared to European American (EA) women in the United States. Existing studies have suggested that transfer learning could reduce health disparities in BC by transferring information from a majority group (e.g., EA women) to a minority group (e.g., AA women). However, their performance may be decreased due to limited training patient samples and using single-omics data only. We recently presented a transfer learning method by integrating two multi-omics data for reducing cancer disparities. However, the integration model was not optimized, and its performance in reducing disparities was not robust. To address these concerns, we propose a novel weighted multi-modal transfer learning model that can optimize the integration of multi-omics data to alleviate racial disparities in BC. Specifically, we first calculated the patient-patient similarity by using the Pearson Correlation Coefficient (PCC), based on which we performed weighted integration of multi-omics data. Then, we performed a nested grid search method to find the optimal weights for each type of omics data, which were subsequently fed into a transfer learning model. To demonstrate the effectiveness of our model, we performed the tasks of predicting Disease-Specific Survival (DSS) prognosis for the 1098 female BC patient samples from The Cancer Genome Atlas (TCGA) database. Results suggested that our model with optimized weighted integration of three multi-omics (including mRNA, miRNA and methylation) data significantly outperformed previous multi-omics transfer learning models in terms of AUC. In addition, our multi-modal transfer learning model performed remarkably better than single-omics and two-omics-integration transfer learning models, suggesting that the inclusion of more diverse omics data contributes to a better reduction of racial disparities in BC. Furthermore, the performance of our transfer learning model was also superior to that of conventional mixed models and independent models. In summary, our proposed weighted multi-modal transfer learning model achieves far better performance than existing state-of-the-art methods for reducing health disparities in BC. We expect that our proposed model will provide a new way to reduce health disparities in BC diagnosis, prognosis, and treatment, and it can be extensible to alleviate health disparities in other types of cancer. Citation Format: Min-jeong Baek, Lusheng Li, Jieqiong Wang, Vimla Band, Shibiao Wan. A weighted multi-modal transfer learning model for alleviating racial disparities in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3620.

ABSTRACTA key challenge in the analysis of longitudinal microbiome data is the inference of temporal interactions between microbial taxa, their genes, the metabolites that they consume and produce, and host genes. To address these challenges, we developed a computational pipeline, a pipeline for the analysis of longitudinal multi-omics data (PALM), that first aligns multi-omics data and then uses dynamic Bayesian networks (DBNs) to reconstruct a unified model. Our approach overcomes differences in sampling and progression rates, utilizes a biologically inspired multi-omic framework, reduces the large number of entities and parameters in the DBNs, and validates the learned network. Applying PALM to data collected from inflammatory bowel disease patients, we show that it accurately identifies known and novel interactions. Targeted experimental validations further support a number of the predicted novel metabolite-taxon interactions.IMPORTANCE While a number of large consortia collect and profile several different types of microbiome and genomic time series data, very few methods exist for joint modeling of multi-omics data sets. We developed a new computational pipeline, PALM, which uses dynamic Bayesian networks (DBNs) and is designed to integrate multi-omics data from longitudinal microbiome studies. When used to integrate sequence, expression, and metabolomics data from microbiome samples along with host expression data, the resulting models identify interactions between taxa, their genes, and the metabolites that they produce and consume, as well as their impact on host expression. We tested the models both by using them to predict future changes in microbiome levels and by comparing the learned interactions to known interactions in the literature. Finally, we performed experimental validations for a few of the predicted interactions to demonstrate the ability of the method to identify novel relationships and their impact.

BackgroundStudies on multiple modalities of omics data such as transcriptomics, genomics and proteomics are growing in popularity, since they allow us to investigate complex mechanisms across molecular layers. It is widely recognized that integrative omics analysis holds the promise to unlock novel and actionable biological insights into health and disease. Integration of multi-omics data remains challenging, however, and requires combination of several software tools and extensive technical expertise to account for the properties of heterogeneous data.ResultsThis paper presents the miodin R package, which provides a streamlined workflow-based syntax for multi-omics data analysis. The package allows users to perform analysis of omics data either across experiments on the same samples (vertical integration), or across studies on the same variables (horizontal integration). Workflows have been designed to promote transparent data analysis and reduce the technical expertise required to perform low-level data import and processing.ConclusionsThe miodin package is implemented in R and is freely available for use and extension under the GPL-3 license. Package source, reference documentation and user manual are available at https://gitlab.com/algoromics/miodin.

Integration of incomplete multi-omics data using Knowledge Distillation and Supervised Variational Autoencoders for disease progression prediction

Big data, integrative omics and network biology.

Multi-omics data are increasingly being gathered for investigations of complex diseases such as cancer. However, high dimensionality, small sample size, and heterogeneity of different omics types pose huge challenges to integrated analysis. In this paper, we evaluate two network-based approaches for integration of multi-omics data in an application of clinical outcome prediction of neuroblastoma. We derive Patient Similarity Networks (PSN) as the first step for individual omics data by computing distances among patients from omics features. The fusion of different omics can be investigated in two ways: the network-level fusion is achieved using Similarity Network Fusion algorithm for fusing the PSNs derived for individual omics types; and the feature-level fusion is achieved by fusing the network features obtained from individual PSNs. We demonstrate our methods on two high-risk neuroblastoma datasets from SEQC project and TARGET project. We propose Deep Neural Network and Machine Learning methods with Recursive Feature Elimination as the predictor of survival status of neuroblastoma patients. Our results indicate that network-level fusion outperformed feature-level fusion for integration of different omics data whereas feature-level fusion is more suitable incorporating different feature types derived from same omics type. We conclude that the network-based methods are capable of handling heterogeneity and high dimensionality well in the integration of multi-omics.

The integration of multi-omic data is pivotal for understanding complex diseases, but its high dimensionality and noise present significant challenges. Graph Neural Networks (GNNs) offer a robust framework for analyzing large-scale signaling pathways and protein-protein interaction networks, yet they face limitations in expressivity when capturing intricate biological relationships. To address this, we propose Graph Sequence Language Model (GraphSeqLM), a framework that enhances GNNs with biological sequence embeddings generated by Large Language Models (LLMs). These embeddings encode structural and biological properties of DNA, RNA, and proteins, augmenting GNNs with enriched features for analyzing sample-specific multi-omic data. By integrating topological, sequence-derived, and biological information, GraphSeqLM demonstrates superior predictive accuracy and outperforms existing methods, paving the way for more effective multi-omic data integration in precision medicine https://github.com/FuhaiLiAiLab/GraphSeqLM.

The formation of complex traits is the consequence of genotype and activities at multiple molecular levels. However, connecting genotypes and these activities to complex traits remains challenging. Here, we investigate whether integrating genomic, transcriptomic, and methylomic data can improve prediction for six Arabidopsis traits. We find that transcriptome- and methylome-based models have performances comparable to those of genome-based models. However, models built for flowering time using different omics data identify different benchmark genes. Nine additional genes identified as important for flowering time from our models are experimentally validated as regulating flowering. Gene contributions to flowering time prediction are accession-dependent and distinct genes contribute to trait prediction in different genotypes. Models integrating multi-omics data perform best and reveal known and additional gene interactions, extending knowledge about existing regulatory networks underlying flowering time determination. These results demonstrate the feasibility of revealing molecular mechanisms underlying complex traits through multi-omics data integration.

Cancer is one of the leading causes of mortality worldwide, and its inherent diversity and heterogeneity pose significant challenges in early diagnosis, drug development, and prognosis. Accurate identification of cancer subtypes has therefore become a critical aspect of personalized cancer treatment. With the advancement of omics technologies, multi-omics data offer a more comprehensive understanding of cancer's underlying mechanisms. However, effectively integrating such diverse datasets to identify cancer subtypes remains a significant challenge. In this study, we introduce a novel approach, termed HRAGNN, for cancer subtype identification through the integration of multi-omics data. HRAGNN first constructs an integrated graph and then leverages Relational Attention Mechanism (RAM) and Graph Neural Network (GNN) to capture complex features across these multi-omics layers. Subsequently, the Multi-view Fusion Network (MVFN) is employed to fuse the features derived from the different omics data. We evaluated the performance of HRAGNN on three datasets, comparing it with other existing methods. The experimental results demonstrate that HRAGNN outperforms other approaches in terms of several key evaluation metrics.