ICTNet2: integrating heterogeneous biological interactions to understand complex traits.
Ontology highlight
ABSTRACT:
SUBMITTER: Wang L
PROVIDER: S-EPMC4706053 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Background It often takes more than 10 years and costs more than 1 billion dollars to develop a new drug for a particular disease and bring it to the market. Drug repositioning can significantly reduce costs and time in drug development. Recently, computational drug repositioning attracted a considerable amount of attention among researchers, and a plethora of computational drug repositioning methods have been proposed. This methodology has widely been used in order to address various medical challenges, including cancer treatment. The most common cancers are lung and breast cancers. Thus, suggesting FDA-approved drugs via drug repositioning for breast cancer would help us to circumvent the approval process and subsequently save money as well as time. Methods In this study, we propose a novel network-based method, named RepCOOL, for drug repositioning. RepCOOL integrates various heterogeneous biological networks to suggest new drug candidates for a given disease. Results The proposed method showed a promising performance on benchmark datasets via rigorous cross-validation. The final drug repositioning model has been built based on a random forest classifier after examining various machine learning algorithms. Finally, in a case study, four FDA approved drugs were suggested for breast cancer stage II. Conclusion Results show the potency of the proposed method in detecting true drug-disease relationships. RepCOOL suggested four new drugs for breast cancer stage II namely Doxorubicin, Paclitaxel, Trastuzumab, and Tamoxifen.
| S-EPMC7532104 | biostudies-literature
Project description:BackgroundPrioritization schemes usually highlight species-rich areas, where many species are at imminent risk of extinction. To be ecologically relevant these schemes should also include species biological traits into area-setting methods. Furthermore, in a world of limited funds for conservation, conservation action is constrained by land acquisition costs. Hence, including economic costs into conservation priorities can substantially improve their conservation cost-effectiveness.Methodology/principal findingsWe examined four global conservation scenarios for carnivores based on the joint mapping of economic costs and species biological traits. These scenarios identify the most cost-effective priority sets of ecoregions, indicating best investment opportunities for safeguarding every carnivore species, and also establish priority sets that can maximize species representation in areas harboring highly vulnerable species. We compared these results with a scenario that minimizes the total number of ecoregions required for conserving all species, irrespective of other factors. We found that cost-effective conservation investments should focus on 41 ecoregions highlighted in the scenario that consider simultaneously both ecoregion vulnerability and economic costs of land acquisition. Ecoregions included in priority sets under these criteria should yield best returns of investments since they harbor species with high extinction risk and have lower mean land cost.Conclusions/significanceOur study highlights ecoregions of particular importance for the conservation of the world's carnivores defining global conservation priorities in analyses that encompass socioeconomic and life-history factors. We consider the identification of a comprehensive priority-set of areas as a first step towards an in-situ biodiversity maintenance strategy.
| S-EPMC2728536 | biostudies-literature
Project description:BackgroundProtein-protein interactions (PPIs) play important roles in various cellular processes. However, the low quality of current PPI data detected from high-throughput screening techniques has diminished the potential usefulness of the data. We need to develop a method to address the high data noise and incompleteness of PPI data, namely, to filter out inaccurate protein interactions (false positives) and predict putative protein interactions (false negatives).ResultsIn this paper, we proposed a novel two-step method to integrate diverse biological and computational sources of supporting evidence for reliable PPIs. The first step, interaction binning or InterBIN, groups PPIs together to more accurately estimate the likelihood (Bin-Confidence score) that the protein pairs interact for each biological or computational evidence source. The second step, interaction classification or InterCLASS, integrates the collected Bin-Confidence scores to build classifiers and identify reliable interactions.ConclusionsWe performed comprehensive experiments on two benchmark yeast PPI datasets. The experimental results showed that our proposed method can effectively eliminate false positives in detected PPIs and identify false negatives by predicting novel yet reliable PPIs. Our proposed method also performed significantly better than merely using each of individual evidence sources, illustrating the importance of integrating various biological and computational sources of data and evidence.
| S-EPMC2957691 | biostudies-literature
Project description:Despite the growing constellation of genetic loci linked to common traits, these loci have yet to account for most heritable variation, and most act through poorly understood mechanisms. Recent machine learning (ML) systems have used hierarchical biological knowledge to associate genetic mutations with phenotypic outcomes, yielding substantial predictive power and mechanistic insight. Here, we use an ontology-guided ML system to map single nucleotide variants (SNVs) focusing on 6 classic phenotypic traits in natural yeast populations. The 29 identified loci are largely novel and account for ~17% of the phenotypic variance, versus <3% for standard genetic analysis. Representative results show that sensitivity to hydroxyurea is linked to SNVs in two alternative purine biosynthesis pathways, and that sensitivity to copper arises through failure to detoxify reactive oxygen species in fatty acid metabolism. This work demonstrates a knowledge-based approach to amplifying and interpreting signals in population genetic studies.
| S-EPMC8480841 | biostudies-literature
Project description:Local genetic correlation quantifies the genetic similarity of complex traits in specific genomic regions. However, accurate estimation of local genetic correlation remains challenging, due to linkage disequilibrium in local genomic regions and sample overlap across studies. We introduce SUPERGNOVA, a statistical framework to estimate local genetic correlations using summary statistics from genome-wide association studies. We demonstrate that SUPERGNOVA outperforms existing methods through simulations and analyses of 30 complex traits. In particular, we show that the positive yet paradoxical genetic correlation between autism spectrum disorder and cognitive performance could be explained by two etiologically distinct genetic signatures with bidirectional local genetic correlations.
| S-EPMC8422619 | biostudies-literature
Project description:Supplemental food provided to wildlife by human activities can be more abundant and predictable than natural resources, and subsequent changes in wildlife ecology can have profound impacts on host-parasite interactions. Identifying traits of species associated with increases or decreases in infection outcomes with resource provisioning could improve assessments of wildlife most prone to disease risks in changing environments. We conducted a phylogenetic meta-analysis of 342 host-parasite interactions across 56 wildlife species and three broad taxonomic groups of parasites to identify host-level traits that influence whether provisioning is associated with increases or decreases in infection. We predicted dietary generalists that capitalize on novel food would show greater infection in provisioned habitats owing to population growth and food-borne exposure to contaminants and parasite infectious stages. Similarly, species with fast life histories could experience stronger demographic and immunological benefits from provisioning that affect parasite transmission. We also predicted that wide-ranging and migratory behaviours could increase infection risks with provisioning if concentrated and non-seasonal foods promote dense aggregations that increase exposure to parasites. We found that provisioning increased infection with bacteria, viruses, fungi and protozoa (i.e. microparasites) most for wide-ranging, dietary generalist host species. Effect sizes for ectoparasites were also highest for host species with large home ranges but were instead lowest for dietary generalists. In contrast, the type of provisioning was a stronger correlate of infection outcomes for helminths than host species traits. Our analysis highlights host traits related to movement and feeding behaviour as important determinants of whether species experience greater infection with supplemental feeding. These results could help prioritize monitoring wildlife with particular trait profiles in anthropogenic habitats to reduce infectious disease risks in provisioned populations.
| S-EPMC5836909 | biostudies-literature
Project description:There is increasing evidence that many risk loci found using genome-wide association studies are molecular quantitative trait loci (QTLs). Here we introduce a new set of functional annotations based on causal posterior probabilities of fine-mapped molecular cis-QTLs, using data from the Genotype-Tissue Expression (GTEx) and BLUEPRINT consortia. We show that these annotations are more strongly enriched for heritability (5.84× for eQTLs; P?=?1.19?×?10-31) across 41 diseases and complex traits than annotations containing all significant molecular QTLs (1.80× for expression (e)QTLs). eQTL annotations obtained by meta-analyzing all GTEx tissues generally performed best, whereas tissue-specific eQTL annotations produced stronger enrichments for blood- and brain-related diseases and traits. eQTL annotations restricted to loss-of-function intolerant genes were even more enriched for heritability (17.06×; P?=?1.20?×?10-35). All molecular QTLs except splicing QTLs remained significantly enriched in joint analysis, indicating that each of these annotations is uniquely informative for disease and complex trait architectures.
| S-EPMC6030458 | biostudies-literature
Project description:The study of genetic architecture of complex traits has been dramatically influenced by implementing genome-wide analytical approaches during recent years. Of particular interest are genomic prediction strategies which make use of genomic information for predicting phenotypic responses instead of detecting trait-associated loci. In this work, we present the results of a simulation study to improve our understanding of the statistical properties of estimation of genetic variance components of complex traits, and of additive, dominance, and genetic effects through best linear unbiased prediction methodology. Simulated dense marker information was used to construct genomic additive and dominance matrices, and multiple alternative pedigree- and marker-based models were compared to determine if including a dominance term into the analysis may improve the genetic analysis of complex traits. Our results showed that a model containing a pedigree- or marker-based additive relationship matrix along with a pedigree-based dominance matrix provided the best partitioning of genetic variance into its components, especially when some degree of true dominance effects was expected to exist. Also, we noted that the use of a marker-based additive relationship matrix along with a pedigree-based dominance matrix had the best performance in terms of accuracy of correlations between true and estimated additive, dominance, and genetic effects.
| S-EPMC4892418 | biostudies-literature
Project description:The conformational dynamism of proteins is well established. Rather than having a single structure, proteins are more accurately described as a conformational ensemble that exists across a rugged energy landscape, where different conformational sub-states interconvert. The interaction between ?? T cell receptors (TCR) and cognate peptide-MHC (pMHC) is no exception, and is a dynamic process that involves substantial conformational change. This review focuses on technological advances that have begun to establish the role of conformational dynamics and dynamic allostery in TCR recognition of the pMHC and the early stages of signaling. We discuss how the marriage of molecular dynamics (MD) simulations with experimental techniques provides us with new ways to dissect and interpret the process of TCR ligation. Notably, application of simulation techniques lags behind other fields, but is predicted to make substantial contributions. Finally, we highlight integrated approaches that are being used to shed light on some of the key outstanding questions in the early events leading to TCR signaling.
| S-EPMC6293202 | biostudies-literature
Project description:In genetic mapping of complex traits, scored haplotypes are likely to represent only a subset of all causal polymorphisms. At the extreme of this scenario, observed polymorphisms are not themselves functional, and only linked to causal ones via linkage disequilibrium (LD). We will demonstrate that due to such incomplete knowledge regarding the underlying genetic mechanism, the variance of a trait may become different between the scored haplotypes. Thus, unequal variances between haplotypes may be indicative of additional functional polymorphisms affecting the trait. Methods accounting for such haplotype-specific variance may also provide an increased power to detect complex associations. We suggest ways to estimate and test these haplotypic variance contrasts, and incorporate them into the haplotypic tests for association. We further extend this approach to data with unknown gametic phase via likelihood-based simultaneous estimation of haplotypic effects and their frequencies. We find our approach to provide additional power, especially under the following types of models: (a) where scored and unobserved variants are epistatically interacting with each other; and (b) under heterogeneity models, where multiple unobserved mutations are linked to non-functional observed polymorphisms via LD. An illustrative example of usefulness of the method is discussed, utilizing analysis of multilocus effects within the catechol-O-methyltransferase gene.
| S-EPMC2700858 | biostudies-literature