Inferring causal molecular networks: empirical assessment through a community-based effort.
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ABSTRACT:
SUBMITTER: Hill SM
PROVIDER: S-EPMC4854847 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundGenetic variation influences both chromatin accessibility, assessed in chromatin accessibility quantitative trait loci (caQTL) studies, and gene expression, assessed in expression QTL (eQTL) studies. Genetic variants can impact either nearby genes (cis-eQTLs) or distal genes (trans-eQTLs). Colocalization between caQTL and eQTL, or cis- and trans-eQTLs suggests that they share causal variants. However, pairwise colocalization between these molecular QTLs does not guarantee a causal relationship. Mediation analysis can be applied to assess the evidence supporting causality versus independence between molecular QTLs. Given that the function of QTLs can be cell-type-specific, we performed mediation analyses to find epigenetic and distal regulatory causal pathways for genes within two major cell types of the developing human cortex, progenitors and neurons.ResultsWe find that the expression of 168 and 38 genes is mediated by chromatin accessibility in progenitors and neurons, respectively. We also find that the expression of 11 and 12 downstream genes is mediated by upstream genes in progenitors and neurons. Moreover, we discover that a genetic locus associated with inter-individual differences in brain structure shows evidence for mediation of SLC26A7 through chromatin accessibility, identifying molecular mechanisms of a common variant association to a brain trait.ConclusionsIn this study, we identify cell-type-specific causal gene regulatory networks whereby the impacts of variants on gene expression were mediated by chromatin accessibility or distal gene expression. Identification of these causal paths will enable identifying and prioritizing actionable regulatory targets perturbing these key processes during neurodevelopment.
| S-EPMC10230710 | biostudies-literature
Project description:We use phosphorylation sites to quantify the enrichment of kinase-kinase relationships in response to diferent kinase inhibitors, from which we construct weighted kinase networks, and assess whether the application of community detection algorithms to such networks can provide new insights on the inner workings of canonical signalling pathways
2023-06-07 | PXD026039 | Pride
Project description:Here, we present Scribe (https://github.com/aristoteleo/Scribe-py), a toolkit for detecting and visualizing causal regulatory interactions between genes and explore the potential for single-cell experiments to power network reconstruction. Scribe employs restricted directed information to determine causality by estimating the strength of information transferred from a potential regulator to its downstream target. We apply Scribe and other leading approaches for causal network reconstruction to several types of single-cell measurements and show that there is a dramatic drop in performance for "pseudotime"-ordered single-cell data compared with true time-series data. We demonstrate that performing causal inference requires temporal coupling between measurements. We show that methods such as "RNA velocity" restore some degree of coupling through an analysis of chromaffin cell fate commitment. These analyses highlight a shortcoming in experimental and computational methods for analyzing gene regulation at single-cell resolution and suggest ways of overcoming it.
| S-EPMC7223477 | biostudies-literature
Project description:Reverse-engineering of biological networks is a central problem in systems biology. The use of intervention data, such as gene knockouts or knockdowns, is typically used for teasing apart causal relationships among genes. Under time or resource constraints, one needs to carefully choose which intervention experiments to carry out. Previous approaches for selecting most informative interventions have largely been focused on discrete Bayesian networks. However, continuous Bayesian networks are of great practical interest, especially in the study of complex biological systems and their quantitative properties. In this work, we present an efficient, information-theoretic active learning algorithm for Gaussian Bayesian networks (GBNs), which serve as important models for gene regulatory networks. In addition to providing linear-algebraic insights unique to GBNs, leading to significant runtime improvements, we demonstrate the effectiveness of our method on data simulated with GBNs and the DREAM4 network inference challenge data sets. Our method generally leads to faster recovery of underlying network structure and faster convergence to final distribution of confidence scores over candidate graph structures using the full data, in comparison to random selection of intervention experiments.
| S-EPMC4773135 | biostudies-literature
Project description:Signaling pathways represent parts of the global biological molecular network which connects them into a seamless whole through complex direct and indirect (hidden) crosstalk whose structure can change during development or in pathological conditions. We suggest a novel methodology, called Googlomics, for the structural analysis of directed biological networks using spectral analysis of their Google matrices, using parallels with quantum scattering theory, developed for nuclear and mesoscopic physics and quantum chaos. We introduce analytical "reduced Google matrix" method for the analysis of biological network structure. The method allows inferring hidden causal relations between the members of a signaling pathway or a functionally related group of genes. We investigate how the structure of hidden causal relations can be reprogrammed as a result of changes in the transcriptional network layer during cancerogenesis. The suggested Googlomics approach rigorously characterizes complex systemic changes in the wiring of large causal biological networks in a computationally efficient way.
| S-EPMC5784915 | biostudies-literature
Project description:BackgroundThe inference of gene regulatory networks (GRNs) from experimental observations is at the heart of systems biology. This includes the inference of both the network topology and its dynamics. While there are many algorithms available to infer the network topology from experimental data, less emphasis has been placed on methods that infer network dynamics. Furthermore, since the network inference problem is typically underdetermined, it is essential to have the option of incorporating into the inference process, prior knowledge about the network, along with an effective description of the search space of dynamic models. Finally, it is also important to have an understanding of how a given inference method is affected by experimental and other noise in the data used.ResultsThis paper contains a novel inference algorithm using the algebraic framework of Boolean polynomial dynamical systems (BPDS), meeting all these requirements. The algorithm takes as input time series data, including those from network perturbations, such as knock-out mutant strains and RNAi experiments. It allows for the incorporation of prior biological knowledge while being robust to significant levels of noise in the data used for inference. It uses an evolutionary algorithm for local optimization with an encoding of the mathematical models as BPDS. The BPDS framework allows an effective representation of the search space for algebraic dynamic models that improves computational performance. The algorithm is validated with both simulated and experimental microarray expression profile data. Robustness to noise is tested using a published mathematical model of the segment polarity gene network in Drosophila melanogaster. Benchmarking of the algorithm is done by comparison with a spectrum of state-of-the-art network inference methods on data from the synthetic IRMA network to demonstrate that our method has good precision and recall for the network reconstruction task, while also predicting several of the dynamic patterns present in the network.ConclusionsBoolean polynomial dynamical systems provide a powerful modeling framework for the reverse engineering of gene regulatory networks, that enables a rich mathematical structure on the model search space. A C++ implementation of the method, distributed under LPGL license, is available, together with the source code, at http://www.paola-vera-licona.net/Software/EARevEng/REACT.html.
| S-EPMC4022379 | biostudies-literature
Project description:The spread of pathogens fundamentally depends on the underlying contacts between individuals. Modeling the dynamics of infectious disease spread through contact networks, however, can be challenging due to limited knowledge of how an infectious disease spreads and its transmission rate. We developed a novel statistical tool, INoDS (Identifying contact Networks of infectious Disease Spread) that estimates the transmission rate of an infectious disease outbreak, establishes epidemiological relevance of a contact network in explaining the observed pattern of infectious disease spread and enables model comparison between different contact network hypotheses. We show that our tool is robust to incomplete data and can be easily applied to datasets where infection timings of individuals are unknown. We tested the reliability of INoDS using simulation experiments of disease spread on a synthetic contact network and find that it is robust to incomplete data and is reliable under different settings of network dynamics and disease contagiousness compared with previous approaches. We demonstrate the applicability of our method in two host-pathogen systems: Crithidia bombi in bumblebee colonies and Salmonella in wild Australian sleepy lizard populations. INoDS thus provides a novel and reliable statistical tool for identifying transmission pathways of infectious disease spread. In addition, application of INoDS extends to understanding the spread of novel or emerging infectious disease, an alternative approach to laboratory transmission experiments, and overcoming common data-collection constraints.
| S-EPMC8758098 | biostudies-literature
Project description:Proposed molecular classifiers may be overfit to idiosyncrasies of noisy genomic and proteomic data. Cross-validation methods are often used to obtain estimates of classification accuracy, but both simulations and case studies suggest that, when inappropriate methods are used, bias may ensue. Bias can be bypassed and generalizability can be tested by external (independent) validation. We evaluated 35 studies that have reported on external validation of a molecular classifier. We extracted information on study design and methodological features, and compared the performance of molecular classifiers in internal cross-validation versus external validation for 28 studies where both had been performed. We demonstrate that the majority of studies pursued cross-validation practices that are likely to overestimate classifier performance. Most studies were markedly underpowered to detect a 20% decrease in sensitivity or specificity between internal cross-validation and external validation [median power was 36% (IQR, 21-61%) and 29% (IQR, 15-65%), respectively]. The median reported classification performance for sensitivity and specificity was 94% and 98%, respectively, in cross-validation and 88% and 81% for independent validation. The relative diagnostic odds ratio was 3.26 (95% CI 2.04-5.21) for cross-validation versus independent validation. Finally, we reviewed all studies (n = 758) which cited those in our study sample, and identified only one instance of additional subsequent independent validation of these classifiers. In conclusion, these results document that many cross-validation practices employed in the literature are potentially biased and genuine progress in this field will require adoption of routine external validation of molecular classifiers, preferably in much larger studies than in current practice.
| S-EPMC3088312 | biostudies-literature
Project description:One of the pressing open problems of computational systems biology is the elucidation of the topology of genetic regulatory networks (GRNs) using high throughput genomic data, in particular microarray gene expression data. The Dialogue for Reverse Engineering Assessments and Methods (DREAM) challenge aims to evaluate the success of GRN inference algorithms on benchmarks of simulated data. In this article, we present GENIE3, a new algorithm for the inference of GRNs that was best performer in the DREAM4 In Silico Multifactorial challenge. GENIE3 decomposes the prediction of a regulatory network between p genes into p different regression problems. In each of the regression problems, the expression pattern of one of the genes (target gene) is predicted from the expression patterns of all the other genes (input genes), using tree-based ensemble methods Random Forests or Extra-Trees. The importance of an input gene in the prediction of the target gene expression pattern is taken as an indication of a putative regulatory link. Putative regulatory links are then aggregated over all genes to provide a ranking of interactions from which the whole network is reconstructed. In addition to performing well on the DREAM4 In Silico Multifactorial challenge simulated data, we show that GENIE3 compares favorably with existing algorithms to decipher the genetic regulatory network of Escherichia coli. It doesn't make any assumption about the nature of gene regulation, can deal with combinatorial and non-linear interactions, produces directed GRNs, and is fast and scalable. In conclusion, we propose a new algorithm for GRN inference that performs well on both synthetic and real gene expression data. The algorithm, based on feature selection with tree-based ensemble methods, is simple and generic, making it adaptable to other types of genomic data and interactions.
| S-EPMC2946910 | biostudies-literature
Project description:Background: Resolving causal genes for type 2 diabetes at loci implicated by genome-wide association studies (GWAS) requires integrating functional genomic data from relevant cell types. Chromatin features in endocrine cells of the pancreatic islet are particularly informative and recent studies leveraging chromosome conformation capture (3C) with Hi-C based methods have elucidated regulatory mechanisms in human islets. However, these genome-wide approaches are less sensitive and afford lower resolution than methods that target specific loci. Methods: To gauge the extent to which targeted 3C further resolves chromatin-mediated regulatory mechanisms at GWAS loci, we generated interaction profiles at 23 loci using next-generation (NG) capture-C in a human beta cell model (EndoC-βH1) and contrasted these maps with Hi-C maps in EndoC-βH1 cells and human islets and a promoter capture Hi-C map in human islets. Results: We found improvements in assay sensitivity of up to 33-fold and resolved ~3.6X more chromatin interactions. At a subset of 18 loci with 25 co-localised GWAS and eQTL signals, NG Capture-C interactions implicated effector transcripts at five additional genetic signals relative to promoter capture Hi-C through physical contact with gene promoters. Conclusions: High resolution chromatin interaction profiles at selectively targeted loci can complement genome- and promoter-wide maps.
| S-EPMC10509606 | biostudies-literature