UKIN Combines New and Prior Information with Guided Network Propagation to Accurately Identify Disease Genes.
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ABSTRACT:
SUBMITTER: Hristov BH
PROVIDER: S-EPMC7821437 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Many inborn errors of metabolism (IEMs) are amenable to treatment, therefore early diagnosis is imperative. Whole-exome sequencing (WES) variant prioritization coupled with phenotype-guided clinical and bioinformatics expertise is typically used to identify disease-causing variants; however, it can be challenging to identify the causal candidate gene when a large number of rare and potentially pathogenic variants are detected. Here, we present a network-based approach, metPropagate, that uses untargeted metabolomics (UM) data from a single patient and a group of controls to prioritize candidate genes in patients with suspected IEMs. We validate metPropagate on 107 patients with IEMs diagnosed in Miller et al. (2015) and 11 patients with both CNS and metabolic abnormalities. The metPropagate method ranks candidate genes by label propagation, a graph-smoothing algorithm that considers each gene's metabolic perturbation in addition to the network of interactions between neighbors. metPropagate was able to prioritize at least one causative gene in the top 20th percentile of candidate genes for 92% of patients with known IEMs. Applied to patients with suspected neurometabolic disease, metPropagate placed at least one causative gene in the top 20th percentile in 9/11 patients, and ranked the causative gene more highly than Exomiser's phenotype-based ranking in 6/11 patients. Interestingly, ranking by a weighted combination of metPropagate and Exomiser scores resulted in improved prioritization. The results of this study indicate that network-based analysis of UM data can provide an additional mode of evidence to prioritize causal genes in patients with suspected IEMs.
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Project description:BackgroundA gene network's capacity to process information, so as to bind past events to future actions, depends on its structure and logic. From previous and new microarray measurements in Saccharomyces cerevisiae following gene deletions and overexpressions, we identify a core gene regulatory network (GRN) of functional interactions between 328 genes and the transfer functions of each gene. Inferred connections are verified by gene enrichment.ResultsWe find that this core network has a generalized clustering coefficient that is much higher than chance. The inferred Boolean transfer functions have a mean p-bias of 0.41, and thus similar amounts of activation and repression interactions. However, the distribution of p-biases differs significantly from what is expected by chance that, along with the high mean connectivity, is found to cause the core GRN of S. cerevisiae's to have an overall sensitivity similar to critical Boolean networks. In agreement, we find that the amount of information propagated between nodes in finite time series is much higher in the inferred core GRN of S. cerevisiae than what is expected by chance.ConclusionsWe suggest that S. cerevisiae is likely to have evolved a core GRN with enhanced information propagation among its genes.
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Project description:BackgroundGenome-wide association studies have identified many individual genes associated with complex traits. However, pathway and network information have not been fully exploited in searches for genetic determinants, and including this information may increase our understanding of the underlying biology of common diseases.ResultsIn this study, we propose a framework to address this problem in a principled way, with the underlying hypothesis that complex disease operates through multiple connected genes. Associations inferred from GWAS are translated into prior scores for vertices in a protein-protein interaction network, and these scores are propagated through the network. Permutation is used to select genes that are guilty-by-association and thus consistently obtain high scores after network propagation. We apply the approach to data of Crohn's disease and call candidate genes that have been reported by other independent GWAS, but not in the analysed data set. A prediction model based on these candidate genes show good predictive power as measured by Area Under the Receiver Operating Curve (AUC) in 10 fold cross-validations.ConclusionsOur network propagation method applied to a genome-wide association study increases association findings over other approaches.
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Project description:One influential theory on object knowledge is feature-based model, which proposes that the object knowledge is organized by different feature types, such as sensory/perceptual and motor/functional ones. Previous studies have shown that prior knowledge enhances the processes of acquiring and remembering relevant information. However, whether the effect of prior knowledge is applied to different types of conceptual information over time remains unclear. In this study, we addressed this question by testing memory of different types of object features at various retention intervals. The level of prior knowledge was manipulated as object features from familiar and unfamiliar categories. In Experiments 1 and 2, sentences that described the perceptual and functional features of new words were presented. Sentences with episodic features were additionally presented in Experiment 2. The participants were then tested with recognition (Experiment 1) and recall (Experiment 2) tasks at different retention intervals. The results showed that prior knowledge enhanced memory for perceptual features but not for functional and episodic features. Such enhancement depended on the recollection process. In addition, the effect of prior knowledge on perceptual features remained stable over time. This study clarified how different types of new factual information were acquired and maintained and highlighted the importance of prior knowledge in acquiring new conceptual knowledge with the passage of time.
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Project description:Expression quantitative trait loci (eQTL) mapping is often used to identify genetic loci and candidate genes correlated with traits. Although usually a group of genes affect complex traits, genes in most eQTL mapping methods are considered as independent. Recently, some eQTL mapping methods have accounted for correlated genes, used biological prior knowledge and applied these in model species such as yeast or mouse. However, biological prior knowledge might be very limited for most species.We proposed a data-driven prior knowledge guided eQTL mapping for identifying candidate genes. At first, quantitative trait loci (QTL) analysis was used to identify single nucleotide polymorphisms (SNP) markers that are associated with traits. Then co-expressed gene modules were generated and gene modules significantly associated with traits were selected. Prior knowledge from QTL mapping was used for eQTL mapping on the selected modules. We tested and compared prior knowledge guided eQTL mapping to the eQTL mapping with no prior knowledge in a simulation study and two barley stem rust resistance case studies. The results in simulation study and real barley case studies show that models using prior knowledge outperform models without prior knowledge. In the first case study, three gene modules were selected and one of the gene modules was enriched with defense response Gene Ontology (GO) terms. Also, one probe in the gene module is mapped to Rpg1, previously identified as resistance gene to stem rust. In the second case study, four gene modules are identified, one gene module is significantly enriched with defense response to fungus and bacterium.Prior knowledge guided eQTL mapping is an effective method for identifying candidate genes. The case studies in stem rust show that this approach is robust, and outperforms methods with no prior knowledge in identifying candidate genes.
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Project description:A stimulus predicting reinforcement can trigger emotional responses, such as arousal, and cognitive ones, such as increased attention toward the stimulus. Neuroscientists have long appreciated that the amygdala mediates spatially nonspecific emotional responses, but it remains unclear whether the amygdala links motivational and spatial representations. To test whether amygdala neurons encode spatial and motivational information, we presented reward-predictive cues in different spatial configurations to monkeys and assessed how these cues influenced spatial attention. Cue configuration and predicted reward magnitude modulated amygdala neural activity in a coordinated fashion. Moreover, fluctuations in activity were correlated with trial-to-trial variability in spatial attention. Thus, the amygdala integrates spatial and motivational information, which may influence the spatial allocation of cognitive resources. These results suggest that amygdala dysfunction may contribute to deficits in cognitive processes normally coordinated with emotional responses, such as the directing of attention toward the location of emotionally relevant stimuli.
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Project description:In 2003, we developed an ab initio program, ZCURVE 1.0, to find genes in bacterial and archaeal genomes. In this work, we present the updated version (i.e. ZCURVE 3.0). Using 422 prokaryotic genomes, the average accuracy was 93.7% with the updated version, compared with 88.7% with the original version. Such results also demonstrate that ZCURVE 3.0 is comparable with Glimmer 3.02 and may provide complementary predictions to it. In fact, the joint application of the two programs generated better results by correctly finding more annotated genes while also containing fewer false-positive predictions. As the exclusive function, ZCURVE 3.0 contains one post-processing program that can identify essential genes with high accuracy (generally >90%). We hope ZCURVE 3.0 will receive wide use with the web-based running mode. The updated ZCURVE can be freely accessed from http://cefg.uestc.edu.cn/zcurve/ or http://tubic.tju.edu.cn/zcurveb/ without any restrictions.
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Project description:Most tissue collections of neoplasms are composed of formalin-fixed and paraffin-embedded (FFPE) excised tumor samples used for routine diagnostics. DNA sequencing is becoming increasingly important in cancer research and clinical management; however it is difficult to accurately sequence DNA from FFPE samples. We developed and validated a new bioinformatic pipeline to use existing variant-calling strategies to robustly identify somatic single nucleotide variants (SNVs) from whole exome sequencing using small amounts of DNA extracted from archival FFPE samples of breast cancers. We optimized this strategy using 28 pairs of technical replicates. After optimization, the mean similarity between replicates increased 5-fold, reaching 88% (range 0-100%), with a mean of 21.4 SNVs (range 1-68) per sample, representing a markedly superior performance to existing tools. We found that the SNV-identification accuracy declined when there was less than 40 ng of DNA available and that insertion-deletion variant calls are less reliable than single base substitutions. As the first application of the new algorithm, we compared samples of ductal carcinoma in situ of the breast to their adjacent invasive ductal carcinoma samples. We observed an increased number of mutations (paired-samples sign test, P < 0.05), and a higher genetic divergence in the invasive samples (paired-samples sign test, P < 0.01). Our method provides a significant improvement in detecting SNVs in FFPE samples over previous approaches.
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Project description:A fundamental challenge in human health is the identification of disease-causing genes. Recently, several studies have tackled this challenge via a network-based approach, motivated by the observation that genes causing the same or similar diseases tend to lie close to one another in a network of protein-protein or functional interactions. However, most of these approaches use only local network information in the inference process and are restricted to inferring single gene associations. Here, we provide a global, network-based method for prioritizing disease genes and inferring protein complex associations, which we call PRINCE. The method is based on formulating constraints on the prioritization function that relate to its smoothness over the network and usage of prior information. We exploit this function to predict not only genes but also protein complex associations with a disease of interest. We test our method on gene-disease association data, evaluating both the prioritization achieved and the protein complexes inferred. We show that our method outperforms extant approaches in both tasks. Using data on 1,369 diseases from the OMIM knowledgebase, our method is able (in a cross validation setting) to rank the true causal gene first for 34% of the diseases, and infer 139 disease-related complexes that are highly coherent in terms of the function, expression and conservation of their member proteins. Importantly, we apply our method to study three multi-factorial diseases for which some causal genes have been found already: prostate cancer, alzheimer and type 2 diabetes mellitus. PRINCE's predictions for these diseases highly match the known literature, suggesting several novel causal genes and protein complexes for further investigation.
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Project description:OBJECTIVE:To reduce the danger for firefighters and ensure the safety of firefighters as much as possible, based on the back propagation neural network (BPNN) the fire sensor multi-sensor information fusion detection system is investigated. METHOD:According to previous studies, the information sources and information processing methods for the design of this study are first explained. Then, the basic structure and flowchart of the research object in this study are designed. Based on the structure diagram and flowchart, the BPNN is selected to fuse the feature layers in this study, and the fuzzy control is selected to fuse the decision layers in this study. The multi-sensor information fusion detection system collects information for the sensors first, processes the collected information, and sends it to the processor of the robot. The processor analyzes and processes the received signal, and transmits the obtained information to the control terminal through the wireless communication system. RESULTS:Through the tests in this study, it is found that when the number of hidden layer nodes of the BPNN is 7, the optimal training result is obtained. On this basis, the test of BPNN in this study is performed. The test results show that after 127 iterations, the error of the BPNN reaches the lowest target value, indicating that the BPNN achieves an excellent level of accuracy. The trained BPNN has a running time of 0.0276 s and a mean square error of 0.0013. The smaller the mean square error value is, the higher the accuracy of the BPNN is, which shows that the BPNN meets the high precision requirements of this study. CONCLUSION:The research on the multi-sensor information fusion detection system of fire robots in this study can provide theoretical support for the research on forest fire detection in China. Since the proposed BPNN-based robot is applied to the inspection and processing of forest remaining fire, the results are applicable to the forests of various countries, with a wide range of applications.
| S-EPMC7380588 | biostudies-literature