Metabolomics and proteomics generate large, complex datasets that reflect the state of a biological system. Multi-omics is the integration of these disparate methods and data to gain a clearer picture of the biological state. Multi-omic studies of the proteome and metabolome are becoming more common as mass spectrometry technology continues to be democratized. However, knowledge extraction through integration of these data remains challenging. Here we show that connections between these omic layers can be discovered through a combination of machine learning and model interpretation. We find that SHAP values connecting proteins to metabolites are valid experimentally, and reveal also largely new connections. Further, clustering the magnitudes of protein control over all metabolites enabled prediction of gene five gene functions, each of which was validated experimentally. We accurately predicted that two uncharacterized genes in yeast modulate mitochondrial translation, YJR120W and YLD157C.We also predict and validate functions for several incompletely characterized genes, including SDH9, ISC1, and FMP52. Our work demonstrates that multi-omic analysis with machine learning (MIMaL) is a new lens that reveals new insight from multi-omic data that would not be possible using any omic layer alone.

Technologies for profiling samples using different omics platforms have been at the forefront since the human genome project. Large-scale multi-omics data hold the promise of deciphering different regulatory layers. Yet, while there is a myriad of bioinformatics tools, each multi-omics analysis appears to start from scratch with an arbitrary decision over which tools to use and how to combine them. Therefore, it is an unmet need to conceptualize how to integrate such data and implement and validate pipelines in different cases. We have designed a conceptual framework (STATegra), aiming it to be as generic as possible for multi-omics analysis, combining available multi-omic anlaysis tools (machine learning component analysis, non-parametric data combination, and a multi-omics exploratory analysis) in a step-wise manner. While in several studies, we have previously combined those integrative tools, here, we provide a systematic description of the STATegra framework and its validation using two The Cancer Genome Atlas (TCGA) case studies. For both, the Glioblastoma and the Skin Cutaneous Melanoma (SKCM) cases, we demonstrate an enhanced capacity of the framework (and beyond the individual tools) to identify features and pathways compared to single-omics analysis. Such an integrative multi-omics analysis framework for identifying features and components facilitates the discovery of new biology. Finally, we provide several options for applying the STATegra framework when parametric assumptions are fulfilled and for the case when not all the samples are profiled for all omics. The STATegra framework is built using several tools, which are being integrated step-by-step as OpenSource in the STATegRa Bioconductor package.1

Multi-Omics Data Integration SaaS Market Outlook

According to the latest research, the global Multi-Omics Data Integration SaaS market size reached USD 1.42 billion in 2024, reflecting a robust momentum driven by technological advancements and increasing adoption across life sciences. The market is expected to expand at a CAGR of 17.6% during the forecast period, with projections indicating a value of USD 6.13 billion by 2033. This remarkable growth is primarily fueled by the rising demand for integrated omics solutions in drug discovery, precision medicine, and clinical diagnostics, as organizations seek to leverage data-driven insights for improved outcomes and operational efficiencies.

A key driver behind the expansion of the Multi-Omics Data Integration SaaS market is the surging volume and complexity of biological data generated through next-generation sequencing (NGS) and high-throughput omics technologies. Researchers and clinical practitioners are increasingly reliant on advanced SaaS platforms to unify genomics, proteomics, transcriptomics, and metabolomics data for comprehensive analysis. The integration of these diverse datasets enables a holistic understanding of biological systems, facilitating breakthroughs in disease characterization, biomarker discovery, and therapeutic target identification. As the need for cross-omics data analysis intensifies, SaaS-based solutions offer scalable, flexible, and cost-effective approaches, eliminating the constraints of traditional on-premises infrastructures.

Another significant growth factor is the ongoing digital transformation in healthcare and life sciences, which has accelerated the adoption of cloud-based platforms for data management and analytics. SaaS solutions for multi-omics data integration provide seamless collaboration, secure data sharing, and real-time analytics, empowering interdisciplinary teams to drive innovation at scale. The COVID-19 pandemic further underscored the importance of rapid data integration and remote accessibility, catalyzing investments in digital infrastructure and cloud-native applications. As regulatory frameworks evolve to support data privacy and interoperability, organizations are increasingly confident in leveraging SaaS platforms for sensitive multi-omics research and clinical workflows.

The emergence of artificial intelligence (AI) and machine learning (ML) technologies is also transforming the Multi-Omics Data Integration SaaS market. By harnessing advanced algorithms, SaaS platforms can automate complex data integration, normalization, and interpretation tasks, uncovering hidden patterns and actionable insights from vast multi-omics datasets. This capability is particularly valuable in precision medicine, where individualized patient profiles require sophisticated analytics to inform diagnosis, prognosis, and treatment selection. As AI-powered multi-omics platforms become more accessible and user-friendly, their adoption is expected to proliferate across academic, clinical, and commercial settings, further propelling market growth.

From a regional perspective, North America currently dominates the global Multi-Omics Data Integration SaaS market, accounting for the largest revenue share in 2024. This leadership is attributed to the region’s advanced healthcare infrastructure, significant R&D investments, and a strong presence of leading SaaS providers. Europe and Asia Pacific are also experiencing rapid growth, driven by expanding genomics research initiatives, government funding, and increasing collaborations between academic institutions and industry stakeholders. As emerging markets in Latin America and the Middle East & Africa invest in digital health infrastructure, the global footprint of multi-omics SaaS solutions is expected to broaden, fostering greater accessibility and innovation worldwide.

Component Analysis

The Component segment of the Multi-Omics Data Integration SaaS market is bifurcated into software and services, each playing a pivotal role in enabling seamless integration and analysis of multi-omics datasets. Software solutions form the backbone of this segment, offering robust platforms for data ingestion, harmonization, visualization, and advanced analytics. These solutions are designed to handle the complexity and heterogeneity of omics data, providing researchers with intuitive interfaces and customizable workflows. The increasing sophistication of analytical tools, including AI-

Spatial Multi-Omics Data Integration Software Market Outlook

According to our latest research, the global spatial multi-omics data integration software market size reached USD 392.5 million in 2024, demonstrating robust growth fueled by increasing adoption of multi-omics technologies in biomedical research and clinical practice. The market is projected to expand at a remarkable CAGR of 13.7% during the forecast period, with the value expected to reach approximately USD 1,162.8 million by 2033. This accelerated growth is primarily driven by the surging demand for integrated data solutions to unravel complex biological mechanisms, enhance drug discovery, and enable precision medicine initiatives. As per our latest research, the market’s momentum is underpinned by technological advancements, rising R&D investments, and the growing prevalence of chronic diseases necessitating advanced diagnostic and therapeutic strategies.

One of the primary growth factors propelling the spatial multi-omics data integration software market is the increasing need for comprehensive biological insights at the cellular and tissue levels. The convergence of genomics, transcriptomics, proteomics, metabolomics, and epigenomics data enables researchers and clinicians to capture a multidimensional view of biological systems. This holistic approach is essential for understanding disease heterogeneity, tumor microenvironments, and cellular interactions, particularly in oncology and immunology. The rapid evolution of spatial omics technologies, coupled with the availability of high-throughput sequencing platforms, has generated massive datasets that require sophisticated integration and analysis tools. Consequently, the demand for advanced software solutions capable of harmonizing and interpreting complex multi-omics data is experiencing a significant uptick across both academic and industrial settings.

Another critical driver for the market is the accelerating pace of drug discovery and development, which increasingly relies on spatial multi-omics data integration to identify novel therapeutic targets and biomarkers. Pharmaceutical and biotechnology companies are leveraging these software platforms to streamline the drug development pipeline, reduce attrition rates, and personalize treatment regimens based on patient-specific molecular profiles. The integration of spatial and multi-omics data enhances the ability to predict drug responses, monitor disease progression, and assess therapeutic efficacy in real time. Furthermore, collaborations between software providers, academic institutions, and life science companies are fostering the development of user-friendly, scalable, and interoperable solutions that cater to the evolving needs of end users. This collaborative ecosystem is expected to sustain market growth by facilitating knowledge transfer, standardization, and innovation.

The rising adoption of personalized medicine and precision diagnostics is further fueling the spatial multi-omics data integration software market. As healthcare systems worldwide shift toward individualized care paradigms, there is a growing emphasis on leveraging multi-layered molecular data to inform clinical decision-making. Spatial multi-omics integration software enables clinicians to correlate genetic, transcriptomic, proteomic, and metabolic alterations with spatial context, thereby improving the accuracy of disease classification, prognosis, and therapeutic selection. This paradigm shift is particularly evident in oncology, neurology, and rare disease management, where spatially resolved molecular insights can guide targeted interventions. The increasing prevalence of chronic diseases, aging populations, and the need for early disease detection are expected to drive sustained investments in multi-omics data integration capabilities across healthcare and research institutions.

Regionally, North America continues to dominate the spatial multi-omics data integration software market, accounting for the largest revenue share in 2024. This leadership position is attributed to the presence of leading life science companies, advanced healthcare infrastructure, and substantial government funding for multi-omics research. Europe follows closely, benefiting from strong academic networks and growing investments in precision medicine initiatives. The Asia Pacific region is emerging as a high-growth market, driven by expanding genomics research, increasing healthcare expenditure, and rising awareness of the benefits of integrated omics analyses.

Genetic background is a major driver of the phenotypic variability observed across pluripotent stem cells (PSCs), and studies addressing it have relied on transcript abundance as the primary molecular readout of cell state. However, little is known about how proteins, the functional units in the cell, vary across genetically diverse PSCs and how this relates to variation in other measures of gene output. Here we present the first comprehensive genetic study characterizing the pluripotent proteome using 190 unique mouse embryonic stem cell lines derived from highly heterogeneous Diversity Outbred mice. Moreover, we integrated the proteome with chromatin accessibility and transcript abundance in 163 cell lines with matching genotypes using multi-omics factor analysis to distinguish shared and unique drivers of variability across molecular layers. Our findings highlight the power of multi-omics data integration in revealing the distal impacts of genetic variation. We show that limitations in mapping of individual molecular traits may be overcome by utilizing data integration to consolidate the influence of genetic signals shared across molecular traits and increase detection power.

Triple negative breast cancer is an aggressive type of breast cancer with very little treatment options. TNBC is very heterogeneous with large alterations in the genomic, transcriptomic, and proteomic landscapes leading to various subtypes with differing responses to therapeutic treatments. We applied a multi-omics data integration method to evaluate the correlation of important regulatory features in TNBC BRCA1 wild-type MDA-MB-231 and TNBC BRCA1 5382insC mutated HCC1937 cells compared with normal epithelial breast MCF10A cells. The data includes DNA methylation, RNAseq, protein, phosphoproteomics, and histone post-translational modification. Data integration methods identified regulatory features from each omics method had greater than 80% positive correlation within each TNBC subtype. Key regulatory features at each omics level were identified distinguishing the three cell lines and were involved in important cancer related pathways such as TGFbeta signaling, PI3K/AKT/mTOR, and Wnt/beta-catenin signaling.

Additional file6: ORA with Reactome Pathways and AMEND Module from OGT-KO Data. Complete list of significant Reactome pathways from ORA on the AMEND module from the OGT-KO data analysis. Significance level was set to 0.05 after adjustment for multiple testing using the Benjamini-Hochberg method

This repository contains the input and output files necessary to reproduce the case studies reported in the manuscript "MUUMI: an R package for statistical and network-based meta-analysis for MUlti-omics data Integration". MUUMI is an R package implementing network-based data integration and statistical meta-analysis within a single analytical framework. MUUMI allows the identification of robust molecular signatures through multiple meta-analytic methods, inference and analysis of molecular interactomes and the integration of multiple omics layers. The functionalities of MUUMI are showcased in two case studies in which we analysed 17 transcriptomic datasets on idiopathic pulmonary fibrosis (IPF) from both microarray and RNA-Seq platforms and multi-omics data of THP-1 macrophages exposed to different polarising stimuli. Part of the data reported in this repository derive from the Zenodo entry https://doi.org/10.5281/zenodo.10692129 (Curated and harmonised transcriptomics datasets of interstitial lung disease patients). Other data derive from the following publication: Migliaccio G, Morikka J, del Giudice G, Vaani M, Möbus L, Serra A, Federico A, Greco D. Methylation and transcriptomic profiling reveals short term and long term regulatory responses in polarized macrophages, Comp and Struct Biotech J, 2024(25), 143-152. doi: 10.1016/j.csbj.2024.08.018.

We proposed DCCA for accurately dissecting the cellular heterogeneity on joint-profiling multi-omics data from the same individual cell by transferring representation between each other.

The mechanisms responsible for weight loss-induced improvement in insulin sensitivity are partially understood. Greater insight can now be achieved through deep phenotyping and data integration. Here, we used an integrative approach to investigate associations between changes in insulin sensitivity and variations in lifestyle factors (diet and physical activity), subcutaneous adipose tissue (sAT) gene expression, metabolomics in serum, urine and feces, and gut microbiota composition after a 6-week calorie restriction period in overweight and obese adults. A spectrum of variables from lifestyle factors, gut microbiota and host multi-omics most associated with insulin sensitivity was identified. These analyses highlight associations between variations in insulin sensitivity, serum branched chain amino acids, sAT genes involved in endoplasmic reticulum stress and ubiquitination, and gut metagenomic species. This work has enhanced previous knowledge on mechanistic links between host glucose homeostasis, lifestyle factors and microbiota, and has identified modifiable factors and biomarkers that may be used to predict and improve individual response to weight loss interventions.

Cloud-Based Multi-Omics Data Warehouse Market Outlook

According to our latest research, the global market size for the Cloud-Based Multi-Omics Data Warehouse Market reached USD 2.47 billion in 2024. The market is witnessing a robust expansion, registering a CAGR of 18.2% from 2025 to 2033, and is forecasted to achieve a value of USD 12.55 billion by 2033. This remarkable growth is primarily driven by the escalating adoption of cloud technologies in life sciences and healthcare, combined with the surging demand for integrated omics data analysis to accelerate drug discovery and personalized medicine initiatives.

The rapid proliferation of high-throughput sequencing technologies and the exponential rise in multi-omics data generation are pivotal growth factors for the Cloud-Based Multi-Omics Data Warehouse Market. As research organizations and healthcare providers increasingly focus on precision medicine, the need for scalable, secure, and interoperable platforms to store, manage, and analyze diverse datasets is more critical than ever. Cloud-based solutions offer unparalleled scalability and computational power, enabling seamless integration and real-time analysis of genomics, proteomics, transcriptomics, metabolomics, and epigenomics data. This capability is essential for uncovering novel biomarkers, understanding disease mechanisms, and tailoring therapeutic interventions, thereby fueling market expansion.

Another significant driver is the growing collaboration between pharmaceutical companies, academic institutions, and technology providers to develop advanced analytics platforms. These partnerships are fostering the development of comprehensive multi-omics data warehouses that support artificial intelligence (AI) and machine learning (ML) algorithms for predictive analytics and hypothesis generation. The increasing emphasis on reducing time-to-market for new drugs and improving clinical outcomes is compelling stakeholders to invest in cloud-based multi-omics solutions. Additionally, the adoption of regulatory-compliant cloud infrastructures is mitigating concerns related to data privacy and security, further accelerating market adoption across regulated sectors such as healthcare and pharmaceuticals.

The market is also benefiting from the rising prevalence of chronic diseases and the subsequent demand for personalized healthcare solutions. Multi-omics data integration enables clinicians to make informed decisions regarding disease diagnosis, prognosis, and treatment selection. Cloud-based platforms facilitate the aggregation and harmonization of large-scale omics datasets from diverse sources, supporting translational research and clinical applications. Furthermore, advancements in data interoperability standards and API-driven architectures are enhancing the accessibility and usability of multi-omics data warehouses, making them indispensable tools for researchers and clinicians alike.

Regionally, North America continues to dominate the Cloud-Based Multi-Omics Data Warehouse Market, accounting for the largest revenue share in 2024, followed by Europe and Asia Pacific. The presence of leading biotechnology firms, robust healthcare infrastructure, and significant investments in genomics research are key contributors to North America's leadership. Europe is witnessing steady growth owing to supportive regulatory frameworks and increasing funding for omics research. Meanwhile, Asia Pacific is emerging as a lucrative market, driven by expanding healthcare digitization, government initiatives to promote precision medicine, and rising adoption of cloud computing in research and clinical settings.

Component Analysis

The Cloud-Based Multi-Omics Data Warehouse Market is segmented by component into software and services, each playing a distinct yet complementary role in the ecosystem. The software segment encompasses platforms and tools designed for data integration, management, analysis, and visualization of multi-omics datasets. These solutions are engineered to

During evolution, plants have developed the ability to produce a vast array of specialized metabolites, which play crucial roles in helping plants adapt to different environmental niches. However, their biosynthetic pathways remain largely elusive. In the past decades, increasing numbers of plant biosynthetic pathways have been elucidated based on approaches utilizing genomics, transcriptomics, and metabolomics. These efforts, however, are limited by the fact that they typically adopt a target-based approach, requiring prior knowledge. Here, we present MEANtools, a systematic and unsupervised computational integrative omics workflow to predict candidate metabolic pathways de novo by leveraging knowledge of general reaction rules and metabolic structures stored in public databases. In our approach, possible connections between metabolites and transcripts that show correlated abundance across samples are identified using reaction rules linked to the transcript-encoded enzyme families. MEANtools thus assesses whether these reactions can connect transcript-correlated mass features within a candidate metabolic pathway. We validate MEANtools using a paired transcriptomic-metabolomic dataset recently generated to reconstruct the falcarindiol biosynthetic pathway in tomato. MEANtools correctly anticipated five out of seven steps of the characterized pathway and also identified other candidate pathways involved in specialized metabolism, which demonstrates its potential for hypothesis generation. Altogether, MEANtools represents a significant advancement to integrate multi-omics data for the elucidation of biochemical pathways in plants and beyond.

Additional file4: ORA with GO Terms and AMEND Module from TCGA-KIRC Data. Complete list of significant Gene Ontologyterms from ORA on the AMEND module from the TCGA-KIRC data analysis. Significance level was set to 0.01 after adjustment for multiple testing using the Benjamini-Hochberg method

Multi-omics has the promise to provide a detailed molecular picture for biological systems. Although obtaining multi-omics data is relatively easy, methods that analyze such data have been lagging. In this paper, we present an algorithm that uses probabilistic graph representations and external knowledge to perform optimum structure learning and deduce a multifarious interaction network for multi-omics data from a bacterial community. Kefir grain, a microbial community that ferments milk and creates kefir, represents a self-renewing, stable, natural microbial community. Kefir has been shown to associate with a wide range of health benefits. We obtained a controlled bacterial community using the two most abundant and well-studied species in kefir grains: Lentilactobacillus kefiri and Lactobacillus kefiranofaciens. We applied growth temperatures of 30°C and 37°C, and obtained transcriptomic, metabolomic, and proteomic data for the same 20 samples (10 samples per temperature). We obtained a multi-omics interaction network, which generated insights that would not have been possible with single-omics analysis. We identified interactions among transcripts, proteins, and metabolites suggesting active toxin/antitoxin systems. We also observed multifarious interactions that involved the shikimate pathway. These observations helped explain bacterial adaptation to different stress conditions, co-aggregation, and increased activation of L. kefiranofaciens at 37°C.

ZIP file contains the HTML files which are referred to as the "Additional file 1" in the IMP manuscript.

Glioblastoma multiforme (GBM) is one of the most aggressive types of cancer and exhibits profound genetic and epigenetic heterogeneity, making the development of an effective treatment a major challenge. The recent incorporation of molecular features into the diagnosis of GBM patients has led to an improved categorisation into various tumour subtypes with different prognoses and disease management. In this work, we have exploited the benefits of genome-wide multi-omic approaches to identify potential molecular vulnerabilities existing in GBM patients. Integration of gene expression and DNA methylation data from both bulk GBM and patient-derived GBM stem cell lines has revealed the presence of major sources of GBM variability, pinpointing subtype-specific tumour vulnerabilities amenable to pharmacological interventions. In this sense, inhibition of the AP1, SMAD3 and RUNX1 / RUNX2 pathways, in combination or not with the chemotherapeutic agent temozolomide, led to the subtype-specific impairment of tumour growth, particularly in the context of the aggressive, mesenchymal-like subtype. These results emphasize the involvement of these molecular pathways in the development of GBM and have potential implications for the development of personalized therapeutic approaches.

Single Cell Multi-Omics Market Outlook

As of 2023, the global single cell multi-omics market size is valued at approximately USD 2.5 billion, with a robust projected CAGR of 20.1% forecasted to propel the market to USD 9.8 billion by 2032. This remarkable growth is driven by several key factors, including technological advancements in single-cell analysis techniques, increased funding for omics research, and a growing emphasis on personalized medicine. The market is experiencing a surge in demand as researchers and healthcare providers seek more precise and comprehensive insights into cellular behavior, disease mechanisms, and therapeutic responses. The integration of multi-omics data at a single-cell level offers unparalleled resolution and depth, enabling a transformative understanding of complex biological systems.

One of the primary growth drivers of the single cell multi-omics market is the rapid advancement of technology, particularly in sequencing and analytical tools. Innovations in microfluidics, next-generation sequencing, and enhanced bioinformatics capabilities have significantly lowered the cost and increased the efficiency of single-cell analysis. These technological advancements allow researchers to dissect the heterogeneity of cellular populations with unprecedented precision, facilitating breakthroughs in understanding disease pathology and developing targeted therapeutics. Moreover, the continuous evolution of these technologies fosters their adoption across various fields, further expanding the market's scope and application.

Another significant factor contributing to market growth is the escalating demand for personalized medicine. As the healthcare industry shifts towards more individualized treatment approaches, the need for comprehensive insights at a cellular level becomes paramount. Single cell multi-omics provides a holistic view of cellular function by integrating genomic, transcriptomic, proteomic, and metabolomic data. This integrated approach not only enhances the understanding of disease mechanisms but also aids in the development of personalized therapeutic strategies, thereby driving the adoption of single cell multi-omics in clinical settings. The ability to tailor treatments based on unique cellular profiles is expected to significantly boost market demand over the forecast period.

Additionally, increasing funding and investments in life sciences research is acting as a catalyst for the growth of the single cell multi-omics market. Governments, academic institutions, and private entities are investing heavily in omics research to unlock new scientific insights and address pressing healthcare challenges. This influx of funding is facilitating the establishment of state-of-the-art research facilities and fostering collaborations between academic institutions and industry players. The enhanced research infrastructure and collaborative efforts are expected to accelerate scientific discoveries and propel the market's expansion, as researchers strive to unravel the complexities of biological systems at a single-cell level.

From a regional perspective, North America currently dominates the single cell multi-omics market, owing to its robust research infrastructure, presence of leading biotechnology firms, and substantial government funding for genomics and precision medicine initiatives. However, the Asia Pacific region is anticipated to exhibit the highest growth rate over the forecast period, driven by increasing investments in healthcare research, the rising prevalence of chronic diseases, and the burgeoning biotechnology sector. European countries are also witnessing a growing adoption of single cell multi-omics technologies, supported by collaborative research initiatives and favorable regulatory frameworks. These regional dynamics underscore the diverse growth opportunities within the global market, as stakeholders capitalize on regional strengths and address specific healthcare needs.

Technology Analysis

The technology segment within the single cell multi-omics market is predominantly categorized into single cell genomics, single cell transcriptomics, single cell proteomics, and single cell metabolomics. Each of these sub-segments plays a crucial role in providing comprehensive insights into cellular functions and interactions. Single cell genomics, which involves the analysis of DNA at a single-cell level, has become a cornerstone technology in this market. It enables researchers to investigate genetic variations, mutations, and chromosomal aberrations with unprecedented accuracy. This technology is pivotal in advancing our understanding of genetic predisposit

The Multiomics Market offers a range of products, including instruments, consumables, software, and services. Instruments include sequencing systems, mass spectrometers, and flow cytometers. Consumables encompass reagents, kits, and microarrays. Software solutions provide data analysis and visualization capabilities. Services include sample preparation, data analysis, and interpretation. Recent developments include: September 2023: The chromium single-cell gene expression flex assay manufactured by 10x Genomics Inc. now offers high throughput multi-omic cellular profiling as a commercially available capability thanks to the introduction of a new kit. Researchers and their options may detect simultaneous gene and protein expression, which can be expanded at a greater scale thanks to the new kit, which makes the multi-omic characterization of cell populations simple and efficient. The company's product portfolio was able to grow due to this technique., February 2023: Becton, Dickinson, and Company introduced the Rhapsody HT Xpress System, a high-throughput single-cell multiomics platform, to broaden the field of scientific research. With up to eight times more cells per sample than previous BD single-cell analyzers, this innovative technology allows scientists to extract, label, and analyze individual cells at a high sample throughput. This plan should assist the business in expanding its product's uses and serving more clients.. Notable trends are: Rising integration of multi-omics data is driving the market growth.

Omics data integration is becoming necessary to investigate the still unknown genomic mechanisms of complex diseases. During the integration process, many challenges arise such as data heterogeneity, the smaller number of individuals in comparison to the number of parameters, multicollinearity, and interpretation and validation of results due to their complexity and lack of knowledge about biological mechanisms. To overcome some of these issues, innovative statistical approaches are being developed. In this work, we applied penalized regression methods (LASSO and ENET) to explore relationships between common genetic variants, DNA methylation and gene expression measured in bladder tumor samples and have proposed a permutation-based method to concomitantly assess significance and correct by multiple testing with the MaxT algorithm. The overall analysis flow consisted of three steps: (1) SNPs/CpGs were selected per each gene probe within 1Mb window upstream and downstream the gene; (2) LASSO and ENET were applied to assess the association between each expression probe and the selected SNPs/CpGs in three multivariable models (SNP, CPG, and Global models, the latter integrating SNPs and CPGs); and (3) the significance of each model was assessed using the permutation-based MaxT method. We identified 48 genes whom expression levels were associated with both SNPs and GPGs. Importantly, we replicated results for 36 (75%) of them in an independent data set (TCGA). We checked the performance of the proposed method with a simulation study and further supported our results with a biological interpretation based on an enrichment analysis. The approach we propose allows reducing computational time and is flexibly and easy to implement when analyzing several omics data. Our results highlight the importance of integrating omics data by applying appropriate statistical strategies to discover new insights into the complexity of disease genetic mechanisms. Overall design: Gene expression data were obtained from 44 tumor samples using the Affymetrix DNA Microarray Human Gene 1.0 ST Array with 32,321 probes.

Datasets for protein, mRNA, and microRNAThe file contains four datasets. Three with differentially expressed protein, mRNA, and microRNA, respectively. The last dataset contain data on all proteins detected in all TMT sets. Information about the sample names is included in the readme file.Datasets.xlsx