Causal inference, social networks and chain graphs.
Ontology highlight
ABSTRACT:
SUBMITTER: Ogburn EL
PROVIDER: S-EPMC8313030 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Understanding the causal relationships between variables is a central goal of many scientific inquiries. Causal relationships may be represented by directed edges in a graph (or equivalently, a network). In biology, for example, gene regulatory networks may be viewed as a type of causal networks, where X→Y represents gene X regulating (i.e., being causal to) gene Y. However, existing general-purpose graph inference methods often result in a high number of false edges, whereas current causal inference methods developed for observational data in genomics can handle only limited types of causal relationships. We present MRPC (a PC algorithm with the principle of Mendelian Randomization), an R package that learns causal graphs with improved accuracy over existing methods. Our algorithm builds on the powerful PC algorithm (named after its developers Peter Spirtes and Clark Glymour), a canonical algorithm in computer science for learning directed acyclic graphs. The improvements in MRPC result in increased accuracy in identifying v-structures (i.e., X→Y←Z), and robustness to how the nodes are arranged in the input data. In the special case of genomic data that contain genotypes and phenotypes (e.g., gene expression) at the individual level, MRPC incorporates the principle of Mendelian randomization as constraints on edge direction to help orient the edges. MRPC allows for inference of causal graphs not only for general purposes, but also for biomedical data where multiple types of data may be input to provide evidence for causality. The R package is available on CRAN and is a free open-source software package under a GPL (≥2) license.
| S-EPMC8120292 | biostudies-literature
Project description:Single-cell RNA and protein concentrations dynamically fluctuate because of stochastic ("noisy") regulation. Consequently, biological signaling and genetic networks not only translate stimuli with functional response but also random fluctuations. Intuitively, this feature manifests as the accumulation of fluctuations from the network source to the target. Taking advantage of the fact that noise propagates directionally, we developed a method for causation prediction that does not require time-lagged observations and therefore can be applied to data generated by destructive assays such as immunohistochemistry. Our method for causation prediction, "Inference of Network Directionality Using Covariance Elements (INDUCE)," exploits the theoretical relationship between a change in the strength of a causal interaction and the associated changes in the single cell measured entries of the covariance matrix of protein concentrations. We validated our method for causation prediction in two experimental systems where causation is well established: in an E. coli synthetic gene network, and in MEK to ERK signaling in mammalian cells. We report the first analysis of covariance elements documenting noise propagation from a kinase to a phosphorylated substrate in an endogenous mammalian signaling network.
| S-EPMC4452541 | biostudies-literature
Project description:Inferring causal relationships among molecular and higher order phenotypes is a critical step in elucidating the complexity of living systems. Here we propose a novel method for inferring causality that is no longer constrained by the conditional dependency arguments that limit the ability of statistical causal inference methods to resolve causal relationships within sets of graphical models that are Markov equivalent. Our method utilizes Bayesian belief propagation to infer the responses of perturbation events on molecular traits given a hypothesized graph structure. A distance measure between the inferred response distribution and the observed data is defined to assess the 'fitness' of the hypothesized causal relationships. To test our algorithm, we infer causal relationships within equivalence classes of gene networks in which the form of the functional interactions that are possible are assumed to be nonlinear, given synthetic microarray and RNA sequencing data. We also apply our method to infer causality in real metabolic network with v-structure and feedback loop. We show that our method can recapitulate the causal structure and recover the feedback loop only from steady-state data which conventional method cannot.
| S-EPMC4299932 | biostudies-literature
Project description:Gene regulatory networks (GRNs) play a central role in systems biology, especially in the study of mammalian organ development. One key question remains largely unanswered: Is it possible to infer mammalian causal GRNs using observable gene co-expression patterns alone? We assembled two mouse GRN datasets (embryonic tooth and heart) and matching microarray gene expression profiles to systematically investigate the difficulties of mammalian causal GRN inference. The GRNs were assembled based on > 2,000 pieces of experimental genetic perturbation evidence from manually reading > 150 primary research articles. Each piece of perturbation evidence records the qualitative change of the expression of one gene following knock-down or over-expression of another gene. Our data have thorough annotation of tissue types and embryonic stages, as well as the type of regulation (activation, inhibition and no effect), which uniquely allows us to estimate both sensitivity and specificity of the inference of tissue specific causal GRN edges. Using these unprecedented datasets, we found that gene co-expression does not reliably distinguish true positive from false positive interactions, making inference of GRN in mammalian development very difficult. Nonetheless, if we have expression profiling data from genetic or molecular perturbation experiments, such as gene knock-out or signalling stimulation, it is possible to use the set of differentially expressed genes to recover causal regulatory relationships with good sensitivity and specificity. Our result supports the importance of using perturbation experimental data in causal network reconstruction. Furthermore, we showed that causal gene regulatory relationship can be highly cell type or developmental stage specific, suggesting the importance of employing expression profiles from homogeneous cell populations. This study provides essential datasets and empirical evidence to guide the development of new GRN inference methods for mammalian organ development.
| S-EPMC4219746 | biostudies-literature
Project description:Accurate inference of regulatory networks from experimental data facilitates the rapid characterization and understanding of biological systems. High-throughput technologies can provide a wealth of time-series data to better interrogate the complex regulatory dynamics inherent to organisms, but many network inference strategies do not effectively use temporal information. We address this limitation by introducing Sliding Window Inference for Network Generation (SWING), a generalized framework that incorporates multivariate Granger causality to infer network structure from time-series data. SWING moves beyond existing Granger methods by generating windowed models that simultaneously evaluate multiple upstream regulators at several potential time delays. We demonstrate that SWING elucidates network structure with greater accuracy in both in silico and experimentally validated in vitro systems. We estimate the apparent time delays present in each system and demonstrate that SWING infers time-delayed, gene-gene interactions that are distinct from baseline methods. By providing a temporal framework to infer the underlying directed network topology, SWING generates testable hypotheses for gene-gene influences.
| S-EPMC5834671 | biostudies-literature
Project description:A central question in neuroscience is how self-organizing dynamic interactions in the brain emerge on their relatively static structural backbone. Due to the complexity of spatial and temporal dependencies between different brain areas, fully comprehending the interplay between structure and function is still challenging and an area of intense research. In this paper we present a graph neural network (GNN) framework, to describe functional interactions based on the structural anatomical layout. A GNN allows us to process graph-structured spatio-temporal signals, providing a possibility to combine structural information derived from diffusion tensor imaging (DTI) with temporal neural activity profiles, like that observed in functional magnetic resonance imaging (fMRI). Moreover, dynamic interactions between different brain regions discovered by this data-driven approach can provide a multi-modal measure of causal connectivity strength. We assess the proposed model's accuracy by evaluating its capabilities to replicate empirically observed neural activation profiles, and compare the performance to those of a vector auto regression (VAR), like that typically used in Granger causality. We show that GNNs are able to capture long-term dependencies in data and also computationally scale up to the analysis of large-scale networks. Finally we confirm that features learned by a GNN can generalize across MRI scanner types and acquisition protocols, by demonstrating that the performance on small datasets can be improved by pre-training the GNN on data from an earlier study. We conclude that the proposed multi-modal GNN framework can provide a novel perspective on the structure-function relationship in the brain. Accordingly this approach appears to be promising for the characterization of the information flow in brain networks.
| S-EPMC8044149 | biostudies-literature
Project description:BackgroundInference of active regulatory cascades under specific molecular and environmental perturbations is a recurring task in transcriptional data analysis. Commercial tools based on large, manually curated networks of causal relationships offering such functionality have been used in thousands of articles in the biomedical literature. The adoption and extension of such methods in the academic community has been hampered by the lack of freely available, efficient algorithms and an accompanying demonstration of their applicability using current public networks.ResultsIn this article, we propose a new statistical method that will infer likely upstream regulators based on observed patterns of up- and down-regulated transcripts. The method is suitable for use with public interaction networks with a mix of signed and unsigned causal edges. It subsumes and extends two previously published approaches and we provide a novel algorithmic method for efficient statistical inference. Notably, we demonstrate the feasibility of using the approach to generate biological insights given current public networks in the context of controlled in-vitro overexpression experiments, stem-cell differentiation data and animal disease models. We also provide an efficient implementation of our method in the R package QuaternaryProd available to download from Bioconductor.ConclusionsIn this work, we have closed an important gap in utilizing causal networks to analyze differentially expressed genes. Our proposed Quaternary test statistic incorporates all available evidence on the potential relevance of an upstream regulator. The new approach broadens the use of these types of statistics for highly curated signed networks in which ambiguities arise but also enables the use of networks with unsigned edges. We design and implement a novel computational method that can efficiently estimate p-values for upstream regulators in current biological settings. We demonstrate the ready applicability of the implemented method to analyze differentially expressed genes using the publicly available networks.
| S-EPMC4995651 | biostudies-literature
Project description:Temporal analysis of genome-wide data can provide insights into the underlying mechanism of the biological processes in two ways. First, grouping the temporal data provides a richer, more robust representation of the underlying processes that are co-regulated. The net result is a significant dimensional reduction of the genome-wide array data into a smaller set of vocabularies for bioinformatics analysis. Second, the computed set of time-course vocabularies can be interrogated for a potential causal network that can shed light on the underlying interactions. The method is coupled with an experiment for investigating responses to high doses of ionizing radiation with and without a small priming dose. From a computational perspective, inference of a causal network can rapidly become computationally intractable with the increasing number of variables. Additionally, from a bioinformatics perspective, larger networks always hinder interpretation. Therefore, our method focuses on inferring the simplest network that is computationally tractable and interpretable. The method first reduces the number of temporal variables through consensus clustering to reveal a small set of temporal templates. It then enforces simplicity in the network configuration through the sparsity constraint, which is further regularized by requiring continuity between consecutive time points. We present intermediate results for each computational step, and apply our method to a time-course transcriptome dataset for a cell line receiving a challenge dose of ionizing radiation with and without a prior priming dose. Our analyses indicate that (i) the priming dose increases the diversity of the computed templates (e.g., diversity of transcriptome signatures); thus, increasing the network complexity; (ii) as a result of the priming dose, there are a number of unique templates with delayed and oscillatory profiles; and (iii) radiation-induced stress responses are enriched through pathway and subnetwork studies.
| S-EPMC3423420 | biostudies-literature
Project description:Causal graphs are an increasingly popular tool for the analysis of biological datasets. In particular, signed causal graphs--directed graphs whose edges additionally have a sign denoting upregulation or downregulation--can be used to model regulatory networks within a cell. Such models allow prediction of downstream effects of regulation of biological entities; conversely, they also enable inference of causative agents behind observed expression changes. However, due to their complex nature, signed causal graph models present special challenges with respect to assessing statistical significance. In this paper we frame and solve two fundamental computational problems that arise in practice when computing appropriate null distributions for hypothesis testing.First, we show how to compute a p-value for agreement between observed and model-predicted classifications of gene transcripts as upregulated, downregulated, or neither. Specifically, how likely are the classifications to agree to the same extent under the null distribution of the observed classification being randomized? This problem, which we call "Ternary Dot Product Distribution" owing to its mathematical form, can be viewed as a generalization of Fisher's exact test to ternary variables. We present two computationally efficient algorithms for computing the Ternary Dot Product Distribution and investigate its combinatorial structure analytically and numerically to establish computational complexity bounds.Second, we develop an algorithm for efficiently performing random sampling of causal graphs. This enables p-value computation under a different, equally important null distribution obtained by randomizing the graph topology but keeping fixed its basic structure: connectedness and the positive and negative in- and out-degrees of each vertex. We provide an algorithm for sampling a graph from this distribution uniformly at random. We also highlight theoretical challenges unique to signed causal graphs; previous work on graph randomization has studied undirected graphs and directed but unsigned graphs.We present algorithmic solutions to two statistical significance questions necessary to apply the causal graph methodology, a powerful tool for biological network analysis. The algorithms we present are both fast and provably correct. Our work may be of independent interest in non-biological contexts as well, as it generalizes mathematical results that have been studied extensively in other fields.
| S-EPMC3307026 | biostudies-literature
Project description:Social networks emerge as a result of actors' linking decisions. We propose a game-theoretical model of socio-strategic network formation on directed weighted graphs, in which every actors' benefit is a parametric trade-off between centrality measure, brokerage opportunities, clustering coefficient, and sociological network patterns. We use two different stability definitions to infer individual behavior of homogeneous, rational agents from network structure, and to quantify the impact of cooperation. Our theoretical analysis confirms results known for specific network motifs studied previously in isolation, yet enables us to precisely quantify the trade-offs in the space of user preferences. To deal with complex networks of heterogeneous and irrational actors, we construct a statistical behavior estimation method using Nash equilibrium conditions. We provide evidence that our results are consistent with empirical, historical, and sociological observations on real-world data-sets. Furthermore, our method offers sociological and strategic interpretations of random networks models, such as preferential attachment and small-world networks.
| S-EPMC6890725 | biostudies-literature