scholarly journals BitEpi: A Fast and Accurate Exhaustive Higher-Order Epistasis Search

2019 ◽  
Author(s):  
Arash Bayat ◽  
Brendan Hosking ◽  
Yatish Jain ◽  
Cameron Hosking ◽  
Milindi Kodikara ◽  
...  
Keyword(s):  
Genetic Diseases ◽  
Accurate Method ◽  
Higher Order ◽  
P Value ◽  
The Novel ◽  
Single Nucleotide ◽  
Epistatic Interactions ◽  
Genomic Variants ◽  
Visual Elements ◽  
Complex Genetic Diseases

Motivation: Complex genetic diseases may be modulated by a large number of epistatic interactions affecting a polygenic phenotype. Identifying these interactions is difficult due to computational complexity, especially in the case of higher-order interactions were more than two genomic variants are involved. Results: In this paper, we present BitEpi, a fast and accurate method to test all possible combinations of up to four bi-allelic variants (i.e. Single Nucleotide Variant or SNV for short). BitEpi introduces a novel bitwise algorithm that is 2.1 and 56 times faster for 3-SNV and 4-SNV search, respectively. The novel entropy statistic used in BitEpi is 44% more accurate to identify interactive SNVs, incorporating a p-value based significance testing. We also present EpiExplorer to visualize the potentially large number of individual and interacting SNVs in an interactive Cytoscape graph. EpiExplorer uses various visual elements to facilitate the discovery of true biological events in a complex polygenic environment.

scholarly journals Fast and accurate exhaustive higher-order epistasis search with BitEpi

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Arash Bayat ◽  
Brendan Hosking ◽  
Yatish Jain ◽  
Cameron Hosking ◽  
Milindi Kodikara ◽  
...  
Keyword(s):  
Genetic Diseases ◽  
Accurate Method ◽  
Higher Order ◽  
The Novel ◽  
Real World Data ◽  
Single Nucleotide ◽  
Epistatic Interactions ◽  
Genomic Variants ◽  
Visual Elements ◽  
Complex Genetic Diseases

AbstractComplex genetic diseases may be modulated by a large number of epistatic interactions affecting a polygenic phenotype. Identifying these interactions is difficult due to computational complexity, especially in the case of higher-order interactions where more than two genomic variants are involved. In this paper, we present BitEpi, a fast and accurate method to test all possible combinations of up to four bi-allelic variants (i.e. Single Nucleotide Variant or SNV for short). BitEpi introduces a novel bitwise algorithm that is 1.7 and 56 times faster for 3-SNV and 4-SNV search, than established software. The novel entropy statistic used in BitEpi is 44% more accurate to identify interactive SNVs, incorporating a p-value-based significance testing. We demonstrate BitEpi on real world data of 4900 samples and 87,000 SNPs. We also present EpiExplorer to visualize the potentially large number of individual and interacting SNVs in an interactive Cytoscape graph. EpiExplorer uses various visual elements to facilitate the discovery of true biological events in a complex polygenic environment.

Direct Read and Quantify Damage Nucleotide from an Oligonucleotide Using a Single Molecule Interface

2019 ◽  
Author(s):  
Jiajun Wang ◽  
Meng-Yin Li ◽  
Jie Yang ◽  
Ya-Qian Wang ◽  
Xue-Yuan Wu ◽  
...  
Keyword(s):  
Dna Sequencing ◽  
Single Molecule ◽  
Genetic Diseases ◽  
High Sensitivity ◽  
Dna Lesions ◽  
Lesion Detection ◽  
The Novel ◽  
Structural Variations ◽  
Dna Lesion ◽  
Base Lesion

DNA lesion such as metholcytosine(<sup>m</sup>C), 8-OXO-guanine(<sup>O</sup>G), inosine(I) <i>etc</i> could cause the genetic diseases. Identification of the varieties of lesion bases are usually beyond the capability of conventional DNA sequencing which is mainly designed to discriminate four bases only. Therefore, lesion detection remain challenge due to the massive varieties and less distinguishable readouts for minor structural variations. Moreover, standard amplification and labelling hardly works in DNA lesions detection. Herein, we designed a single molecule interface from the mutant K238Q Aerolysin, whose confined sensing region shows the high compatible to capture and then directly convert each base lesion into distinguishable current readouts. Compared with previous single molecule sensing interface, the resolution of the K238Q Aerolysin nanopore is enhanced by 2-order. The novel K238Q could direct discriminate at least 3 types (<sup>m</sup>C, <sup>O</sup>G, I) lesions without lableing and quantify modification sites under mixed hetero-composition condition of oligonucleotide. Such nanopore could be further applied to diagnose genetic diseases at high sensitivity.

Perbandingan Expanded Curb-65 Terhadap Curb-65 dan Psi Dalam Memprediksi Luaran Pasien Cap

2019 ◽  
Vol 4 (3) ◽  
pp. 608
Author(s):  
Suyastri Suyastri ◽  
Irvan Medison ◽  
Deddy Herman ◽  
Russilawati Russilawati
Keyword(s):  
Logistic Regression ◽  
Multivariate Analysis ◽  
Prospective Study ◽  
Pneumonia Severity Index ◽  
Severity Index ◽  
Accurate Method ◽  
P Value ◽  
Pneumonia Severity ◽  
Advantages And Disadvantages ◽  
Care Decision

<p><em>Tingkat keparahan CAP adalah poin penting pengambilan keputusan perawatan pasien. Beberapa metode telah digunakan untuk menilai tingkat keparahan pneumonia seperti Pneumonia Severity Index (PSI), CURB-65, SMART-COP dan Expanded CURB-65. Metode tersebut memiliki kelebihan dan kekurangan. Expanded CURB 65 diusulkan menjadi metode yang lebih akurat untuk mengevaluasi keparahan pneumonia dan memprediksi kematian pasien CAP. Tujuan penelitian ini memprediksi keakuratan Expanded CURB  65 dibandingkan CURB 65 dan PSI. Penelitian kohort prospektif pada pasien CAP yang dirawat di RSUP Dr. M.Djamil Padang dari April sampai Oktober 2019. Tingkat keparahan CAP pada pasien dinilai menggunakan PSI, CURB 65, Expanded CURB 65, kemudian hasilnya dievaluasi berdasarkan keparahan. Data dianalisis menggunakan regresi logistik dengan CI 95% dan nilai p &lt;0,05 dianggap signifikan. Hasil penelitian pada 90 pasien sebagian besar laki-laki usia 53 tahun dengan komorbiditas terbanyak keganasan. Uji Pearson Chi aquare menunjukkan tidak ada hubungan antara tingkat keparahan berdasarkan CURB 65 dan luaran pengobatan (CI 95%, nilai p = 0,104). Sementara, PSI dan Expanded CURB 65 memiliki hubungan yang signifikan antara tingkat keparahan dan luaran (CI 95%, p=0,081 dan CI 95%, p= 0,046, masing-masing). Analisis multivariat menemukan Expanded CURB 65 lebih akurat dalam memprediksi luaran pasien CAP rawat inap (kappa =0,108 dan AUC=0,422).</em></p><p><em><br /></em></p><p><em><em>Severity of CAP is very important for site care decision inpatients. Several methods have been used to assess the severity of pneumonia such as Pneumonia Severity Index (PSI), CURB-65, SMART-COP and Expanded CURB-65. Those methods have advantages and disadvantages. Expanded CURB 65 is proposed to be more accurate method for evaluating pneumonia severity and predicting mortality in CAP. The aim of this study was to investigate the accuracy of Expanded CURB 65 compare to CURB 65 and PSI. Cohort prospective study was conducted for CAP patients who were hospitalized at RSUP Dr. M.Djamil Padang from April to October 2019. Patients was assesed for severity using PSI, CURB 65, Expanded CURB 65, then we evaluated it’s outcome. The data were analyzed by logistic regression with CI 95% and p value &lt;0,05 considered as statistically significant. We found 90 patients that predominantly males with an average age of 53 years, and the most common comorbidity is malignancy. There was no relationship between pneumonia severity by CURB 65 and outcome (CI 95%, p=0.104). PSI and Expanded CURB 65 had significant relationship between severity and outcome (CI 95%, p=0.081and CI 95%, p=0.046, respectively). Multivariate analysis showed the expanded CURB 65 was more accurate for predicting the outcome of CAP inpatients (kappa=0.108 and AUC= 0.422).</em></em></p>

EpiPen: An R Package to Investigate Two-Locus Epistatic Models

2014 ◽  
Vol 17 (4) ◽  
Author(s):  
Raymond K. Walters ◽  
Charles Laurin ◽  
Gitta H. Lubke
Keyword(s):  
Power Analysis ◽  
R Package ◽  
Simulation Studies ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Epistatic Interactions ◽  
Model Interpretation ◽  
Genome Wide ◽  
Using Data ◽  
Power Analyses

Epistasis is a growing area of research in genome-wide studies, but the differences between alternative definitions of epistasis remain a source of confusion for many researchers. One problem is that models for epistasis are presented in a number of formats, some of which have difficult-to-interpret parameters. In addition, the relation between the different models is rarely explained. Existing software for testing epistatic interactions between single-nucleotide polymorphisms (SNPs) does not provide the flexibility to compare the available model parameterizations. For that reason we have developed an R package for investigating epistatic and penetrance models, EpiPen, to aid users who wish to easily compare, interpret, and utilize models for two-locus epistatic interactions. EpiPen facilitates research on SNP-SNP interactions by allowing the R user to easily convert between common parametric forms for two-locus interactions, generate data for simulation studies, and perform power analyses for the selected model with a continuous or dichotomous phenotype. The usefulness of the package for model interpretation and power analysis is illustrated using data on rheumatoid arthritis.

scholarly journals Red panda: a novel method for detecting variants in single-cell RNA sequencing

BMC Genomics ◽  
2020 ◽  
Vol 21 (S11) ◽  
Author(s):  
Adam Cornish ◽  
Shrabasti Roychoudhury ◽  
Krishna Sarma ◽  
Suravi Pramanik ◽  
Kishor Bhakat ◽  
...  
Keyword(s):  
Single Cell ◽  
Rna Sequencing ◽  
Articular Chondrocytes ◽  
Genetic Diseases ◽  
Simulated Data ◽  
Single Nucleotide ◽  
Single Cell Rna Sequencing ◽  
Red Panda ◽  
Novel Method ◽  
Rare Cells

Abstract Background Single-cell sequencing enables us to better understand genetic diseases, such as cancer or autoimmune disorders, which are often affected by changes in rare cells. Currently, no existing software is aimed at identifying single nucleotide variations or micro (1-50 bp) insertions and deletions in single-cell RNA sequencing (scRNA-seq) data. Generating high-quality variant data is vital to the study of the aforementioned diseases, among others. Results In this study, we report the design and implementation of Red Panda, a novel method to accurately identify variants in scRNA-seq data. Variants were called on scRNA-seq data from human articular chondrocytes, mouse embryonic fibroblasts (MEFs), and simulated data stemming from the MEF alignments. Red Panda had the highest Positive Predictive Value at 45.0%, while other tools—FreeBayes, GATK HaplotypeCaller, GATK UnifiedGenotyper, Monovar, and Platypus—ranged from 5.8–41.53%. From the simulated data, Red Panda had the highest sensitivity at 72.44%. Conclusions We show that our method provides a novel and improved mechanism to identify variants in scRNA-seq as compared to currently existing software. However, methods for identification of genomic variants using scRNA-seq data can be still improved.

scholarly journals Age by Single Nucleotide Polymorphism Interactions on Bronchodilator Response in Asthmatics

2021 ◽  
Vol 11 (1) ◽  
pp. 59
Author(s):  
Kirsten Voorhies ◽  
Joanne E. Sordillo ◽  
Michael McGeachie ◽  
Elizabeth Ampleford ◽  
Alberta L. Wang ◽  
...  
Keyword(s):  
Candidate Genes ◽  
P Value ◽  
Genome Wide Association Studies ◽  
Genetic Associations ◽  
Single Nucleotide ◽  
Significance Level ◽  
Bronchodilator Response ◽  
Genome Wide ◽  
A Genome ◽  
Β2 Agonists

An unaddressed and important issue is the role age plays in modulating response to short acting β2-agonists in individuals with asthma. The objective of this study was to identify whether age modifies genetic associations of single nucleotide polymorphisms (SNPs) with bronchodilator response (BDR) to β2-agonists. Using three cohorts with a total of 892 subjects, we ran a genome wide interaction study (GWIS) for each cohort to examine SNP by age interactions with BDR. A fixed effect meta-analysis was used to combine the results. In order to determine if previously identified BDR SNPs had an age interaction, we also examined 16 polymorphisms in candidate genes from two published genome wide association studies (GWAS) of BDR. There were no significant SNP by age interactions on BDR using the genome wide significance level of 5 × 10−8. Using a suggestive significance level of 5 × 10−6, three interactions, including one for a SNP within PRAG1 (rs4840337), were significant and replicated at the significance level of 0.05. Considering candidate genes from two previous GWAS of BDR, three SNPs (rs10476900 (near ADRB2) [p-value = 0.009], rs10827492 (CREM) [p-value = 0.02], and rs72646209 (NCOA3) [p-value = 0.02]) had a marginally significant interaction with age on BDR (p < 0.05). Our results suggest age may be an important modifier of genetic associations for BDR in asthma.

scholarly journals Sex Differences in Circadian Clock Genes and Myocardial Infarction Susceptibility

2021 ◽  
Vol 8 (5) ◽  
pp. 53
Author(s):  
Ivana Škrlec ◽  
Jasminka Talapko ◽  
Martina Juzbašić ◽  
Robert Steiner
Keyword(s):  
Myocardial Infarction ◽  
Cardiovascular Disease ◽  
Circadian Rhythm ◽  
Single Nucleotide Polymorphisms ◽  
Clock Genes ◽  
P Value ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Biological Sex ◽  
Significant Difference

The growing body of evidence shows a significant difference in the circadian rhythm of cardiovascular disease based on biological sex. The incidence of cardiovascular disease varies between women and men. Additionally, biological sex is vital for the timely application of therapy—chronotherapy, which benefits both sexes. This study aimed to examine the potential difference of single nucleotide polymorphisms (SNPs) of the circadian rhythm genes ARNTL, CLOCK, CRY2 and PER2 in women and men with myocardial infarction. A cross-sectional study was conducted, including 200 patients with myocardial infarction. Altogether, ten single nucleotide polymorphisms in the ARNTL, CLOCK, CRY2 and PER2 genes were analyzed. The Chi-square test yielded statistically significant differences in CLOCK gene rs11932595 polymorphism in a recessive genotype model between women and men with a p-value of 0.03 and an odds ratio 2.66, and a corresponding 95% confidence interval of 1.07 to 6.66. Other analyzed polymorphisms of the circadian rhythm genes ARNTL, CRY2, and PER2 did not significantly differ between the sexes. According to the study’s current results, the CLOCK gene’s genetic variability might affect myocardial infarction concerning biological sex.

scholarly journals Synergistic effect of genetic polymorphisms in TLR6 and TLR10 genes on the risk of pulmonary tuberculosis in a Moldavian population

2021 ◽  
pp. 175342592110299
Author(s):  
Alexander Varzari ◽  
Igor V. Deyneko ◽  
Elena Tudor ◽  
Harald Grallert ◽  
Thomas Illig
Keyword(s):  
Pulmonary Tuberculosis ◽  
Interaction Analysis ◽  
P Value ◽  
Fisher Exact Test ◽  
Snp Analysis ◽  
Nucleotide Polymorphism ◽  
Single Nucleotide ◽  
Exact Test ◽  
Pulmonary Tb ◽  
The Republic

Polymorphisms in genes that control immune function and regulation may influence susceptibility to pulmonary tuberculosis (TB). In this study, 14 polymorphisms in 12 key genes involved in the immune response ( VDR, MR1, TLR1, TLR2, TLR10, SLC11A1, IL1B, IL10, IFNG, TNF, IRAK1, and FOXP3) were tested for their association with pulmonary TB in 271 patients with TB and 251 community-matched controls from the Republic of Moldova. In addition, gene–gene interactions involved in TB susceptibility were analyzed for a total of 43 genetic loci. Single nucleotide polymorphism (SNP) analysis revealed a nominal association between TNF rs1800629 and pulmonary TB (Fisher exact test P = 0.01843). In the pairwise interaction analysis, the combination of the genotypes TLR6 rs5743810 GA and TLR10 rs11096957 GT was significantly associated with an increased genetic risk of pulmonary TB (OR = 2.48, 95% CI = 1.62–3.85; Fisher exact test P value = 1.5 × 10−5, significant after Bonferroni correction). In conclusion, the TLR6 rs5743810 and TLR10 rs11096957 two-locus interaction confers a significantly higher risk for pulmonary TB; due to its high frequency in the population, this SNP combination may serve as a novel biomarker for predicting TB susceptibility.

scholarly journals A gain-of-function single nucleotide variant creates a new promoter which acts as an orientation-dependent enhancer-blocker

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yavor K. Bozhilov ◽  
Damien J. Downes ◽  
Jelena Telenius ◽  
A. Marieke Oudelaar ◽  
Emmanuel N. Olivier ◽  
...  
Keyword(s):  
Gene Expression ◽  
Genetic Diseases ◽  
Regulatory Elements ◽  
Base Change ◽  
Dependent Manner ◽  
Globin Genes ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Super Enhancer ◽  
Single Base Change

AbstractMany single nucleotide variants (SNVs) associated with human traits and genetic diseases are thought to alter the activity of existing regulatory elements. Some SNVs may also create entirely new regulatory elements which change gene expression, but the mechanism by which they do so is largely unknown. Here we show that a single base change in an otherwise unremarkable region of the human α-globin cluster creates an entirely new promoter and an associated unidirectional transcript. This SNV downregulates α-globin expression causing α-thalassaemia. Of note, the new promoter lying between the α-globin genes and their associated super-enhancer disrupts their interaction in an orientation-dependent manner. Together these observations show how both the order and orientation of the fundamental elements of the genome determine patterns of gene expression and support the concept that active genes may act to disrupt enhancer-promoter interactions in mammals as in Drosophila. Finally, these findings should prompt others to fully evaluate SNVs lying outside of known regulatory elements as causing changes in gene expression by creating new regulatory elements.

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