Добірка наукової літератури з теми "Omic network inference"

Abstract Microbial association networks are frequently used for understanding and comparing community dynamics from microbiome datasets. Inferring microbial correlations for such networks and obtaining meaningful biological insights, however, requires a lengthy data management workflow, choice of appropriate methods, statistical computations, followed by a different pipeline for suitably visualizing, reporting and comparing the associations. The complexity is further increased with the added dimension of multi-group ‘meta-data’ and ‘inter-omic’ functional profiles that are often associated with microbiome studies. This not only necessitates the need for categorical networks, but also integrated and bi-partite networks. Multiple options of network inference algorithms further add to the efforts required for performing correlation-based microbiome interaction studies. We present MetagenoNets, a web-based application, which accepts multi-environment microbial abundance as well as functional profiles, intelligently segregates ‘continuous and categorical’ meta-data and allows inference as well as visualization of categorical, integrated (inter-omic) and bi-partite networks. Modular structure of MetagenoNets ensures logical flow of analysis (inference, integration, exploration and comparison) in an intuitive and interactive personalized dashboard driven framework. Dynamic choice of filtration, normalization, data transformation and correlation algorithms ensures, that end-users get a one-stop solution for microbial network analysis. MetagenoNets is freely available at https://web.rniapps.net/metagenonets.

Advances in high-throughput sequencing have ushered in a new era of research into the gut microbiome and its role in human health and disease. However, due to the unique characteristics of microbiome survey data, their use for the detection of ecological interaction networks remains a considerable challenge, and a field of active methodological development. In this review, we discuss the landscape of existing statistical and experimental methods for detecting and characterizing microbial interactions, as well as the role that host and environmental metabolic signals play in mediating the behavior of these networks. Numerous statistical tools for microbiome network inference have been developed. Yet due to tool-specific biases, the networks identified by these methods are often discordant, motivating a need for the development of more general tools, the use of ensemble approaches, and the incorporation of prior knowledge into prediction. By elucidating the complex dynamics of the microbial interactome, we will enhance our understanding of the microbiome’s role in disease, more precisely predict the microbiome’s response to perturbation, and inform the development of future therapeutic strategies for microbiome-related disease. Impact statement This review provides a comprehensive description of experimental and statistical tools used for network analyses of the human gut microbiome. Understanding the system dynamics of microbial interactions may lead to the improvement of therapeutic approaches for managing microbiome-associated diseases. Microbiome network inference tools have been developed and applied to both cross-sectional and longitudinal experimental designs, as well as to multi-omic datasets, with the goal of untangling the complex web of microbe-host, microbe-environmental, and metabolism-mediated microbial interactions. The characterization of these interaction networks may lead to a better understanding of the systems dynamics of the human gut microbiome, augmenting our knowledge of the microbiome’s role in human health, and guiding the optimization of effective, precise, and rational therapeutic strategies for managing microbiome-associated disease.

Abstract Recent studies have demonstrated that, despite their nomenclature, gliomas recapitulate an interneuron progenitor-like state that drives tumor progression. During human neurodevelopment, interneurons arise from the subcortical ganglionic eminences and migrate tangentially into the neocortex, settling in the cortical plate where they integrate local neurocircuitry. Analogously, malignant glioblastoma (GBM) cells migrate from the tumor core into the surrounding healthy tissue. This innate infiltrative property renders these malignant cells elusive to surgical resection, leading to tumor recurrence. To understand the regulatory networks that drive tumor infiltration from a neurodevelopmental perspective, we generated a single-nucleus Assay for Transposase-Accessible Chromatin sequencing (snATAC-seq) dataset of 41,000 nuclei from the core and infiltrative edge of surgically resected GBM specimens (n = 4). Concurrently, we sequenced 46,000 nuclei from non-pathological, postmortem samples of second- and third-trimester neocortices (n = 17). We integrated these datasets with paired single-nucleus RNA sequencing (snRNA-seq) data and identified candidate regulatory TFs that exhibit high correlation between motif enrichment and TF expression. Using single-trajectory inference and pseudo-time analyses, we identified TCF12 as a potential driver of interneuron lineage fate in developing cortical progenitors. Given its implication in projection neuron migration, we were intrigued to find that TCF12 activity is highest in GBM cells with a migratory interneuron signature, hinting at its putative role in tumor infiltration. To understand the significance of these findings, we will interrogate other genes in the TCF12 regulatory network with the ultimate goal of identifying therapeutic targets that inhibit GBM infiltration.

Abstract Delayed diagnosis and rapid progression are major drivers of poor survival outcomes for pancreatic ductal adenocarcinoma (PDAC). PDAC is expected to be the second leading cause of cancer death and has a dismal 5 year survival rate of 10%. There is an urgent unmet need to detect the disease at an early stage and stratify patients into more effective treatment regimens within clinically meaningful timeframes. To accomplish this, robust quality controlled OMIC molecular profiling platforms and analytic solutions need to be deployed into precision medicine protocols to discover actionable biomarkers. Project Survival® is a multicenter (n=6), prospective biomarker study (NCT 02781012) of PDAC and relevant controls combining high-fidelity longitudinal phenotypic characterization, multi-omic profiling (proteomics, signaling lipidomics, structural lipidomics, and metabolomics), and agnostic Bayesian artificial intelligence network inference (bAIcis®) to discover biomarkers with diagnostic and therapeutic utility. This study utilizes a systems medicine approach for translational biomarker discovery by performing analysis of matched subject sera, plasma, buffy coat, saliva, urine, and tumor/adjacent normal tissues and integrating them with the respective full clinical annotation using the BERG Interrogative Biology® platform. Multiple longitudinal time points were taken over the course of the six-year timeline enabling dynamic modeling. Utilizing the Project Survival® molecular and clinical data, we have analyzed and integrated baseline samples from 121 at risk patients and 279 patients with PDAC. Samples were randomized and analyzed over the course of recruitment allowing for agnostic discovery and integration to determine diagnostic utility. Discovery analysis identified 123 potential molecular markers, of which, four demonstrated a combined AUC of 0.85, PPV 0.83, NPV 0.72, and OR 13.1. In parallel, 4 non-canonical clinical measurements were assessed for diagnostic utility providing an AUC 0.79, PPV 0.84, NPV 0.72 and OR 13.2. Combining molecular and clinical features demonstrated an AUC of 0.9, PPV 0.9, NPV 0.77, OR 29.2, and p-value 1.4 E-40. Molecular markers revealed no treatment associated expression effects. Taken together, these marker panels demonstrate diagnostic utility to detect PDAC and will be further validated using robust bioanalysis methods as well as in an independent cohort of samples to provide enhanced insight into their positioning in the diagnostic landscape for PDAC. Citation Format: Eric M. Grund, A. James Moser, Corinne L. DeCicco, Nischal M. Chand, Genesis L. Perez-Melara, Gregory M. Miller, Punit Shah, Valarie Bussberg, Vladimir Tolstikov, Rangaprasad Sarangarajan, Elder Granger, Niven Narian, Michael A. Kiebish. Project Survival®: Discovery of a molecular-clinical phenome biomarker panel to detect pancreatic ductal adenocarcinoma among at risk populations using high-fidelity longitudinal phenotypic and multi-omic analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5145.

Abstract Recent advances in artificial intelligence (AI) and availability of multimodal patient datasets have enabled the construction of complex network models to derive disease molecular mechanisms and predict the impact of therapeutic intervention. However, observational datasets are commonly affected by confounding factors making causal interpretation challenging. Causal inference network methods are particularly suited to facilitate therapeutic intervention studies by inferring the causal structure from sufficiently detailed multi-omic molecular data. The learned models enable in-silico loss-of-function screening experiments on patient data by using counterfactual simulation to reveal the impact of a gene loss in a disease model. These models enhance gene dependency characterization and the design of advanced therapeutic interventions. In this study, we developed an in-silico multiple myeloma (MM) patient causal model of overall survival (OS) based on transcriptomic expression, clinical, and genomic alteration data from Multiple Myeloma Research Foundation (MMRF) CoMMpass dataset (IA19). After filtering for data quality and availability, we included 516 patients, with 60% being hyperdiploid. We sampled Bayesian networks using Markov Chain Monte Carlo simulation to infer probabilistic causal relationships between network components that influence overall survival. We then simulated synthetic knock downs of those genes where a path exists to overall survival with posterior probability of at least 0.25. Next, we compared CRISPR-SpCas9 cancer dependency data from DepMap (version 22Q2) for multiple myeloma cell lines against genes predicted to be causal (causal genes) for overall survival. Last, we examined the causal genes that are non-dependent in MM cell lines for upstream genomic alterations to determine if specific patient genomic contexts are affecting the results. We identified 102 causal genes, including non-coding RNA genes (n=23), driving overall survival. Among them, 70% (56/79, p=2.2e-16, OR=9.5) of the coding genes were found to be MM-dependent in DepMap, with 44 common essential, 7 strongly selective and 5 weakly selective genes. From 23 genes identified as causal and not known to be MM-dependent, 20 (87%) were selective in other cancer lineages and all of them (23/23) had consistent upstream genomic alterations driving their expression. Causal genes identified from AI-driven in-silico experiments to predict overall survival were strongly enriched for known dependent genes from DepMap. Furthermore, we identified causal genes that may be dependent in unique patient genomic contexts. This demonstrates in-silico AI causal modelling is a powerful tool for exploring cancer cell vulnerability directly from patient data to advance target discovery. Citation Format: Brandon Nathasingh, Derek Walkama, Laurel Mayhew, Kendall Loh, Jeanne Latourelle, Bruce W. Church, Yaoyu E. Wang. Infer cancer cell gene dependency in multiple myeloma using causal AI in-silico patient model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB181.

There are insufficient accurate biomarkers and effective therapeutic targets in current cancer treatment. Multi-omics regulatory networks in patient bulk tumors and single cells can shed light on molecular disease mechanisms. Integration of multi-omics data with large-scale patient electronic medical records (EMRs) can lead to the discovery of biomarkers and therapeutic targets. In this review, multi-omics data harmonization methods were introduced, and common approaches to molecular network inference were summarized. Our Prediction Logic Boolean Implication Networks (PLBINs) have advantages over other methods in constructing genome-scale multi-omics networks in bulk tumors and single cells in terms of computational efficiency, scalability, and accuracy. Based on the constructed multi-modal regulatory networks, graph theory network centrality metrics can be used in the prioritization of candidates for discovering biomarkers and therapeutic targets. Our approach to integrating multi-omics profiles in a patient cohort with large-scale patient EMRs such as the SEER-Medicare cancer registry combined with extensive external validation can identify potential biomarkers applicable in large patient populations. These methodologies form a conceptually innovative framework to analyze various available information from research laboratories and healthcare systems, accelerating the discovery of biomarkers and therapeutic targets to ultimately improve cancer patient survival outcomes.

Recent advances in single-cell omics have transformed characterisation of cell types in challenging-to-study biological contexts. In contexts with limited single-cell samples, such as the early human embryo inference of transcription factor-gene regulatory network (GRN) interactions is especially difficult. Here, we assessed application of different linear or non-linear GRN predictions to single-cell simulated and human embryo transcriptome datasets. We also compared how expression normalisation impacts on GRN predictions, finding that transcripts per million reads outperformed alternative methods. GRN inferences were more reproducible using a non-linear method based on mutual information (MI) applied to single-cell transcriptome datasets refined with chromatin accessibility (CA) (called MICA), compared with alternative network prediction methods tested. MICA captures complex non-monotonic dependencies and feedback loops. Using MICA, we generated the first GRN inferences in early human development. MICA predicted co-localisation of the AP-1 transcription factor subunit proto-oncogene JUND and the TFAP2C transcription factor AP-2γ in early human embryos. Overall, our comparative analysis of GRN prediction methods defines a pipeline that can be applied to single-cell multi-omics datasets in especially challenging contexts to infer interactions between transcription factor expression and target gene regulation.

Biological networks have garnered widespread attention. The development of biological networks has spawned the birth of a new interdisciplinary field – network biology. Network biology involves the exploration of complex biological systems through biological networks for better understanding of biological functions. This paper reviews some of the recent development of network biology. On the one hand, various approaches to constructing different types of biological networks are reviewed, and the pros and cons of each approach are discussed; on the other hand, the recent advances of information mining in biological networks are reviewed. The principles of guilt-by-association and guilt-by-rewiring in network biology and their applications are discussed. Although great advances have been achieved in the field of network biology over the past decades, there are still many challenging issues. First, efficient and reliable network inference algorithms for high-dimensional and highly noisy omics data are still in great demand. Second, the research focus will be on multilayer biological network theory. This plays a critical role in the exploration of the multi-scale or dynamical characteristics of complex biomolecular networks by integrating multi-source heterogeneous omics data. Third, a close cooperation among biologists, medical workers, and researchers from network science is still a prerequisite in the applications of network biology. The rapid development of network biology will undoubtedly raise important clues for understanding complex phenotypes in biological systems.

One of the key challenges in systems biology and molecular sciences is how to infer regulatory relationships between genes and proteins using high-throughout omics datasets. Although a wide range of methods have been designed to reverse engineer the regulatory networks, recent studies show that the inferred network may depend on the variable order in the dataset. In this work, we develop a new algorithm, called the statistical path-consistency algorithm (SPCA), to solve the problem of the dependence of variable order. This method generates a number of different variable orders using random samples, and then infers a network by using the path-consistent algorithm based on each variable order. We propose measures to determine the edge weights using the corresponding edge weights in the inferred networks, and choose the edges with the largest weights as the putative regulations between genes or proteins. The developed method is rigorously assessed by the six benchmark networks in DREAM challenges, the mitogen-activated protein (MAP) kinase pathway, and a cancer-specific gene regulatory network. The inferred networks are compared with those obtained by using two up-to-date inference methods. The accuracy of the inferred networks shows that the developed method is effective for discovering molecular regulatory systems.