Dataset Information

Executable pathway analysis using ensemble discrete-state modeling for large-scale data.

ABSTRACT: Pathway analysis is widely used to gain mechanistic insights from high-throughput omics data. However, most existing methods do not consider signal integration represented by pathway topology, resulting in enrichment of convergent pathways when downstream genes are modulated. Incorporation of signal flow and integration in pathway analysis could rank the pathways based on modulation in key regulatory genes. This implementation can be facilitated for large-scale data by discrete state network modeling due to simplicity in parameterization. Here, we model cellular heterogeneity using discrete state dynamics and measure pathway activities in cross-sectional data. We introduce a new algorithm, Boolean Omics Network Invariant-Time Analysis (BONITA), for signal propagation, signal integration, and pathway analysis. Our signal propagation approach models heterogeneity in transcriptomic data as arising from intercellular heterogeneity rather than intracellular stochasticity, and propagates binary signals repeatedly across networks. Logic rules defining signal integration are inferred by genetic algorithm and are refined by local search. The rules determine the impact of each node in a pathway, which is used to score the probability of the pathway's modulation by chance. We have comprehensively tested BONITA for application to transcriptomics data from translational studies. Comparison with state-of-the-art pathway analysis methods shows that BONITA has higher sensitivity at lower levels of source node modulation and similar sensitivity at higher levels of source node modulation. Application of BONITA pathway analysis to previously validated RNA-sequencing studies identifies additional relevant pathways in in-vitro human cell line experiments and in-vivo infant studies. Additionally, BONITA successfully detected modulation of disease specific pathways when comparing relevant RNA-sequencing data with healthy controls. Most interestingly, the two highest impact score nodes identified by BONITA included known drug targets. Thus, BONITA is a powerful approach to prioritize not only pathways but also specific mechanistic role of genes compared to existing methods. BONITA is available at: https://github.com/thakar-lab/BONITA.

SUBMITTER: Palli R

PROVIDER: S-EPMC6743792 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:Most biological processes are orchestrated by large-scale molecular networks which are described in large-scale model repositories and whose dynamics are extremely complex. An observed phenotype is a state of this system that results from control mechanisms whose identification is key to its understanding. The Biological Pathway Exchange (BioPAX) format is widely used to standardize the biological information relative to regulatory processes. However, few modeling approaches developed so far enable for computing the events that control a phenotype in large-scale networks. Here we developed an integrated approach to build large-scale dynamic networks from BioPAX knowledge databases in order to analyse trajectories and to identify sets of biological entities that control a phenotype. The Cadbiom approach relies on the guarded transitions formalism, a discrete modeling approach which models a system dynamics by taking into account competition and cooperation events in chains of reactions. The method can be applied to every BioPAX (large-scale) model thanks to a specific package which automatically generates Cadbiom models from BioPAX files. The Cadbiom framework was applied to the BioPAX version of two resources (PID, KEGG) of the Pathway Commons database and to the Atlas of Cancer Signalling Network (ACSN). As a case-study, it was used to characterize sets of biological entities implicated in the epithelial-mesenchymal transition. Our results highlight the similarities between the PID and ACSN resources in terms of biological content, and underline the heterogeneity of usage of the BioPAX semantics limiting the fusion of models that require curation. Causality analyses demonstrate the smart complementarity of the databases in terms of combinatorics of controllers that explain a phenotype. From a biological perspective, our results show the specificity of controllers for epithelial and mesenchymal phenotypes that are consistent with the literature and identify a novel signature for intermediate states.

Project description:To conserve habitat for disturbance specialist species, ecologists must identify where individuals will likely settle in newly disturbed areas. Habitat suitability models can predict which sites at new disturbances will most likely attract specialists. Without validation data from newly disturbed areas, however, the best approach for maximizing predictive accuracy can be unclear (Northwestern U.S.A.). We predicted habitat suitability for nesting Black-backed Woodpeckers (Picoides arcticus; a burned-forest specialist) at 20 recently (?6 years postwildfire) burned locations in Montana using models calibrated with data from three locations in Washington, Oregon, and Idaho. We developed 8 models using three techniques (weighted logistic regression, Maxent, and Mahalanobis D (2) models) and various combinations of four environmental variables describing burn severity, the north-south orientation of topographic slope, and prefire canopy cover. After translating model predictions into binary classifications (0 = low suitability to unsuitable, 1 = high to moderate suitability), we compiled "ensemble predictions," consisting of the number of models (0-8) predicting any given site as highly suitable. The suitability status for 40% of the area burned by eastside Montana wildfires was consistent across models and therefore robust to uncertainty in the relative accuracy of particular models and in alternative ecological hypotheses they described. Ensemble predictions exhibited two desirable properties: (1) a positive relationship with apparent rates of nest occurrence at calibration locations and (2) declining model agreement outside surveyed environments consistent with our reduced confidence in novel (i.e., "no-analogue") environments. Areas of disagreement among models suggested where future surveys could help validate and refine models for an improved understanding of Black-backed Woodpecker nesting habitat relationships. Ensemble predictions presented here can help guide managers attempting to balance salvage logging with habitat conservation in burned-forest landscapes where black-backed woodpecker nest location data are not immediately available. Ensemble modeling represents a promising tool for guiding conservation of large-scale disturbance specialists.

Project description:Revealing the tertiary structure of proteins holds huge significance as it unveils their vital properties and functions. These intricate three-dimensional configurations comprise diverse interactions including ionic, hydrophobic, and disulfide forces. In certain instances, these structures exhibit missing regions, necessitating the reconstruction of specific segments, thereby resulting in challenges in protein design, which encompasses loop modeling, circular permutation, and interface prediction. To address this problem, we present two pioneering models: pix2pix generative adversarial network (GAN) and PLM-GAN. The pix2pix GAN model is adept at generating and inpainting distance matrices of protein structures, whereas the PLM-GAN model incorporates residual blocks into the U-Net network of the GAN, building upon the foundation of the pix2pix GAN model. To bolster the models' performance, we introduce a novel loss function named the "missing to real regions loss" (LMTR) within the GAN framework. Additionally, we introduce a distinctive approach of pairing two different distance matrices: one representing the native protein structure and the other representing the same structure with a missing region that undergoes changes in each successive epoch. Moreover, we extend the reconstruction of missing regions, encompassing up to 30 amino acids and increase the protein length by 128 amino acids. The evaluation of our pix2pix GAN and PLM-GAN models on a random selection of natural proteins (4ZCB, 3FJB, and 2REZ) demonstrated promising experimental results. Our models constitute significant contributions to addressing intricate challenges in protein structure design. These contributions hold immense potential to propel advancements in protein-protein interactions, drug design, and further innovations in protein engineering. Data, code, trained models, examples, and measurements are available on https://github.com/mena01/PLM-GAN-A-Large-Scale-Protein-Loop-Modeling-Using-pix2pix-GAN_.

Project description:Large-scale observational data from citizen science efforts are becoming increasingly common in ecology, and researchers often choose between these and data from intensive local-scale studies for their analyses. This choice has potential trade-offs related to spatial scale, observer variance, and interannual variability. Here we explored this issue with phenology by comparing models built using data from the large-scale, citizen science USA National Phenology Network (USA-NPN) effort with models built using data from more intensive studies at Long Term Ecological Research (LTER) sites. We built statistical and process based phenology models for species common to each data set. From these models, we compared parameter estimates, estimates of phenological events, and out-of-sample errors between models derived from both USA-NPN and LTER data. We found that model parameter estimates for the same species were most similar between the two data sets when using simple models, but parameter estimates varied widely as model complexity increased. Despite this, estimates for the date of phenological events and out-of-sample errors were similar, regardless of the model chosen. Predictions for USA-NPN data had the lowest error when using models built from the USA-NPN data, while LTER predictions were best made using LTER-derived models, confirming that models perform best when applied at the same scale they were built. This difference in the cross-scale model comparison is likely due to variation in phenological requirements within species. Models using the USA-NPN data set can integrate parameters over a large spatial scale while those using an LTER data set can only estimate parameters for a single location. Accordingly, the choice of data set depends on the research question. Inferences about species-specific phenological requirements are best made with LTER data, and if USA-NPN or similar data are all that is available, then analyses should be limited to simple models. Large-scale predictive modeling is best done with the larger-scale USA-NPN data, which has high spatial representation and a large regional species pool. LTER data sets, on the other hand, have high site fidelity and thus characterize inter-annual variability extremely well. Future research aimed at forecasting phenology events for particular species over larger scales should develop models that integrate the strengths of both data sets.

Dataset Information

Executable pathway analysis using ensemble discrete-state modeling for large-scale data.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets