scholarly journals Deaminase associated single nucleotide variants in blood and saliva-derived exomes from healthy subjects

2019 ◽  
Author(s):  
Nathan E. Hall ◽  
Jared Mamrot ◽  
Christopher M.A. Frampton ◽  
Prue Read ◽  
Edward J. Steele ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Healthy Subjects ◽  
Intraclass Correlation ◽  
Correlation Coefficients ◽  
Healthy Individuals ◽  
Intraclass Correlation Coefficients ◽  
Whole Exome ◽  
The Impact ◽  
Group 1

AbstractBackgroundDeaminases play an important role in shaping inherited and somatic variants. Disease related SNVs are associated with deaminase mutagenesis and genome instability. Here, we investigate the reproducibility and variance of whole exome SNV calls in blood and saliva of healthy subjects and analyze variants associated with AID, ADAR, APOBEC3G and APOBEC3B deaminase sequence motifs.MethodsSamples from twenty-four healthy Caucasian volunteers, allocated into two groups, underwent whole exome sequencing. Group 1 (n=12) analysis involved one blood and four saliva replicates. A single saliva sample was sequenced for Group 2 subjects (n=12). Overall, a total of 72 whole exome datasets were analyzed. Biological (Group 1 & 2) and technical (Group 1) variance of SNV calls and deaminase metrics were calculated and analyzed using intraclass correlation coefficients. Candidate somatic SNVs were identified and evaluated.ResultsWe report high blood-saliva concordance in germline SNVs from whole exome sequencing. Concordant SNVs, found in all subject replicates, accounted for 97% of SNVs located within the protein coding sequence of genes. Discordant SNVs have a 30% overlap with variants that fail gnomAD quality filters and are less likely to be found in dbSNP. SNV calls and deaminase-associated metrics were found to be reproducible and robust (intraclass correlation coefficients >0.95). No somatic SNVs were conclusively identified when comparing blood and saliva samples.ConclusionsSaliva and blood both provide high quality sources of DNA for whole exome sequencing, with no difference in ability to resolve SNVs and deaminase-associated metrics. We did not identify somatic SNVs when comparing blood and saliva of healthy individuals, and we conclude that more specialized investigative methods are required to comprehensively assess the impact of deaminase activity on genome stability in healthy individuals.

scholarly journals Maximum phonation time in the pulmonary function assessment

Revista CEFAC ◽  
2021 ◽  
Vol 23 (4) ◽  
Author(s):  
Edvania Gomes Henrique Moreno ◽  
Bianca Teixeira Calassa ◽  
Daniela Vitoria Silva Oliveira ◽  
Maylanne Iris Nascimento Silva ◽  
Laienne Carla Barbosa de Barros Albuquerque ◽  
...  
Keyword(s):  
Vital Capacity ◽  
Intraclass Correlation ◽  
Correlation Coefficients ◽  
Descriptive Statistics ◽  
Healthy Individuals ◽  
Reliability Study ◽  
Maximum Phonation Time ◽  
Intraclass Correlation Coefficients ◽  
Single Breath ◽  
Examiner Agreement

ABSTRACT Purpose: to evaluate the reliability of the maximum phonation time (MPT) and Vital Capacity intra and inter-examiner, by means of the single-breath counting test (CT) and the sustained /a/ phoneme, and the slow vital capacity (SVC). Methods: a reliability study carried out in three groups of healthy individuals, each group with 30 volunteers, allocated according to age. SVC was measured using a spirometer, while the MPT was assessed by the phoneme /a/ and CT. The data were analyzed using SPSS version 20.0. Initially, descriptive statistics were used and for data reliability, the intraclass correlation coefficient (ICC). Results: the Intraclass Correlation Coefficients (ICC) were considered excellent, with significant results above 0.92 for SVC and greater than 0.79 for CT and phoneme /a/. Regarding the inter-examiner evaluation, the ICCs were also significant for both SVC with values greater than 0.96, and for CT and the phoneme /a/ with values greater than 0.85. The error inherent in the technique was assessed using the standard error of the measurement for intra and inter-examiner analyses with values ranging from 1.79 to 3.29 for phoneme /a/, 3.20 to 6.58 for CT and 65, 05 to 206.73 for SVCml. Conclusion: phonation techniques with the phoneme /a/ and CT, as well as SVC, have an excellent reliability, due to intra and inter-examiner agreement measures.

scholarly journals Multiple Variant Calling Pipelines in Wheat Whole Exome Sequencing

2021 ◽  
Vol 22 (19) ◽  
pp. 10400
Author(s):  
H. Busra Cagirici ◽  
Bala Ani Akpinar ◽  
Taner Z. Sen ◽  
Hikmet Budak
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Variant Calling ◽  
High Sensitivity ◽  
Whole Exome ◽  
The Impact ◽  
Multiple Reference ◽  
Reference Genomes ◽  
Selection Of ◽  
Variant Identification

The highly challenging hexaploid wheat (Triticum aestivum) genome is becoming ever more accessible due to the continued development of multiple reference genomes, a factor which aids in the plight to better understand variation in important traits. Although the process of variant calling is relatively straightforward, selection of the best combination of the computational tools for read alignment and variant calling stages of the analysis and efficient filtering of the false variant calls are not always easy tasks. Previous studies have analyzed the impact of methods on the quality metrics in diploid organisms. Given that variant identification in wheat largely relies on accurate mining of exome data, there is a critical need to better understand how different methods affect the analysis of whole exome sequencing (WES) data in polyploid species. This study aims to address this by performing whole exome sequencing of 48 wheat cultivars and assessing the performance of various variant calling pipelines at their suggested settings. The results show that all the pipelines require filtering to eliminate false-positive calls. The high consensus among the reference SNPs called by the best-performing pipelines suggests that filtering provides accurate and reproducible results. This study also provides detailed comparisons for high sensitivity and precision at individual and population levels for the raw and filtered SNP calls.

scholarly journals IMPACT: a whole-exome sequencing analysis pipeline for integrating molecular profiles with actionable therapeutics in clinical samples

2016 ◽  
Vol 23 (4) ◽  
pp. 721-730 ◽  
Author(s):  
Jennifer Hintzsche ◽  
Jihye Kim ◽  
Vinod Yadav ◽  
Carol Amato ◽  
Steven E Robinson ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Impact Analysis ◽  
Resistance Mutation ◽  
Braf Inhibitor ◽  
Egfr Mutations ◽  
Analysis Pipeline ◽  
Whole Exome ◽  
The Impact ◽  
Inhibitor Treatment

Abstract Objective Currently, there is a disconnect between finding a patient’s relevant molecular profile and predicting actionable therapeutics. Here we develop and implement the Integrating Molecular Profiles with Actionable Therapeutics (IMPACT) analysis pipeline, linking variants detected from whole-exome sequencing (WES) to actionable therapeutics. Methods and materials The IMPACT pipeline contains 4 analytical modules: detecting somatic variants, calling copy number alterations, predicting drugs against deleterious variants, and analyzing tumor heterogeneity. We tested the IMPACT pipeline on whole-exome sequencing data in The Cancer Genome Atlas (TCGA) lung adenocarcinoma samples with known EGFR mutations. We also used IMPACT to analyze melanoma patient tumor samples before treatment, after BRAF-inhibitor treatment, and after BRAF- and MEK-inhibitor treatment. Results IMPACT Food and Drug Administration (FDA) correctly identified known EGFR mutations in the TCGA lung adenocarcinoma samples. IMPACT linked these EGFR mutations to the appropriate FDA-approved EGFR inhibitors. For the melanoma patient samples, we identified NRAS p.Q61K as an acquired resistance mutation to BRAF-inhibitor treatment. We also identified CDKN2A deletion as a novel acquired resistance mutation to BRAFi/MEKi inhibition. The IMPACT analysis pipeline predicts these somatic variants to actionable therapeutics. We observed the clonal dynamic in the tumor samples after various treatments. We showed that IMPACT not only helped in successful prioritization of clinically relevant variants but also linked these variations to possible targeted therapies. Conclusion IMPACT provides a new bioinformatics strategy to delineate candidate somatic variants and actionable therapies. This approach can be applied to other patient tumor samples to discover effective drug targets for personalized medicine. IMPACT is publicly available at http://tanlab.ucdenver.edu/IMPACT.

Velocity of the center of pressure during walking

2000 ◽  
Vol 90 (7) ◽  
pp. 334-338 ◽  
Author(s):  
MW Cornwall ◽  
TG McPoil
Keyword(s):  
Stance Phase ◽  
Center Of Pressure ◽  
Intraclass Correlation ◽  
Correlation Coefficients ◽  
Healthy Individuals ◽  
Intraclass Correlation Coefficients ◽  
Study Results ◽  
Predictable Pattern

The purpose of this study was to describe the velocity of the center of pressure during walking in a sample of young, healthy individuals. The velocity of the center of pressure was recorded in 60 subjects while they walked barefoot over a floor-mounted pressure platform. The results of this study indicate that the velocity of the center of pressure follows a predictable pattern during the stance phase of walking. Intraclass correlation coefficients calculated to measure between-trial reliability for specific parameters of the velocity of the center of pressure ranged from 0.361 to 0.912. These study results suggest that velocity of the center of pressure may be a useful measurement in future gait research.

scholarly journals Ultrasonography Method of Deep Cervical Muscles and Thickness Measurement Reliability in Cervicogenic Headache and Healthy Subjects:APilot Study

2021 ◽  
Author(s):  
Omolbanin Abaspour ◽  
Mohammad Akbari ◽  
Asghar Rezasoltani
Keyword(s):  
Healthy Subjects ◽  
Intraclass Correlation ◽  
Correlation Coefficients ◽  
Muscle Thickness ◽  
Cervicogenic Headache ◽  
Thickness Measurement ◽  
Neck Muscle ◽  
Ultrasound Images ◽  
Intraclass Correlation Coefficients ◽  
Linear Probe

Introduction: In Cervicogenic Headache (CGH), motor control of muscles is impaired and deep upper neck muscles (extensor and flexor muscles) become atrophied. In this research, thickness measurement of Longus Capitis (LCap), Rectus Capitis Posterior Major (RCPM), and Obliquus Capitis Superior (OCS) muscles were conducted and intra-rater reliability of the thickness measurement of these muscles was assessed in CGH and healthy subjects. Materials and Methods: Twenty subjects, including 10 healthy subjects (19-32 years old) and 10 CGH patients (20-35 years old) participated in this study. LCap thickness was measured at the level of C3-C4 in the supine position and posterior muscles (RCPM and OCS) thickness at the C1-C2 level in the sitting position. All ultrasound images were captured by a linear probe with a 50-mm footprint in B mode option and frequency range of 9-12 Hz. Intraclass Correlation Coefficients (ICC), Standard Error Of Measurement (SEM), and the Smallest Detectable Difference (SDD) were calculated for data analysis. Results: The ICC for thickness measurement of LCap was from 0.70 to 0.91 (good to excellent), for RCPM thickness was from 0.69 to 0.94 and for OCS muscle thickness was from 0.87 to 0.98. SEM values for LCap were between 0.08 and 0.25 and the SDD values between 0.22 and 0.71. SEM values for RCPM were between 0.22 and 0.43 and these values were reported for OCS muscle between 0.19 and 0.45. Conclusion: The results indicated that the presented position and the level of ultrasonography in this study are appropriate and ultrasound is a reliable tool to measure the deep upper neck muscle thickness in CGH and healthy subjects.

Clinical correlates and implications of the reliability of the frailty index in the Canadian Longitudinal Study on Aging

2021 ◽  
Author(s):  
Quoc Dinh Nguyen ◽  
Erica M Moodie ◽  
Mark R Keezer ◽  
Christina Wolfson
Keyword(s):  
Odds Ratio ◽  
Frailty Index ◽  
Intraclass Correlation ◽  
Correlation Coefficients ◽  
Community Dwelling ◽  
Deficit Accumulation ◽  
Intraclass Correlation Coefficients ◽  
Reliability Estimates ◽  
Predicted Probability ◽  
The Impact

Abstract Background Deficit-accumulation frailty indices (FIs) are widely used to characterize frailty. FIs vary in number and composition of items; the impact of this variation on reliability and clinical applicability is unknown. Methods We simulated 12,000 studies using a set of 70 candidate deficits in 12,080 community-dwelling participants 65 years and older. For each study, we varied the number (5, 10, 15, 25, 35, 45) and composition (random selection) of items defining the FI and calculated descriptive and predictive estimates: frailty score, prevalence, frailty cut-off, mortality odds ratio, predicted probability of mortality for FI=0.28 (prevalence threshold), and FI cut-off predicting 10% mortality over the follow-up. We summarized the estimates’ medians and spreads (0.025-0.975 quantiles) by number of items and calculated intraclass correlation coefficients (ICC). Results Medians of frailty scores were 0.11-0.12 with decreasing spreads from 0.04-0.24 to 0.10-0.14 for 5-item and 45-item FIs. The median cut-offs identifying 15% as frail was 0.19-0.20 and stable; the spreads decreased with more items. However, medians and spreads for the prevalence of frailty (medians: 11% to 3%), mortality odds ratio (medians:1.24 to 2.19), predicted probability of mortality (medians: 8% to 17%), and FI cut-off predicting 10% mortality (medians: 0.38 to 0.20) varied markedly. ICC increased from 0.19 (5-item FIs) to 0.84 (45-item FIs). Conclusions Variability in the number and composition of items of individual FIs strongly influences their reliability. Estimates using FIs may not be sufficiently stable for generalizing results or direct application. We propose avenues to improve the development, reporting, and interpretation of FIs.

Cadence, Age, and Weight as Determinants of Forefoot Plantar Pressures Using the Biofoot In-shoe System

2008 ◽  
Vol 98 (4) ◽  
pp. 302-310 ◽  
Author(s):  
Alfonso Martínez-Nova ◽  
Javier Pascual Huerta ◽  
Raquel Sánchez-Rodríguez
Keyword(s):  
Healthy Subjects ◽  
Intraclass Correlation ◽  
Correlation Coefficients ◽  
Metatarsal Head ◽  
Multiple Regression Model ◽  
Good Reliability ◽  
Intraclass Correlation Coefficients ◽  
Plantar Pressures ◽  
Foot Biomechanics ◽  
Peak Plantar Pressure

Background: We evaluated normal plantar pressures and studied the effect of weight, cadence, and age on forefoot plantar pressures in healthy subjects by using the Biofoot (Instituto de Biomecánica de Valencia, Valencia, Spain) in-shoe measurement system. Methods: The feet of 45 healthy subjects with no evident foot or lower-limb diseases were measured with the Biofoot in-shoe system. The forefoot was divided into seven areas: the first through fifth metatarsal heads, the hallux, and the second through fifth lesser toes. Three trials of 8 sec each were recorded twice in each subject, and the mean was used to analyze peak and mean plantar pressures. A multiple regression model including weight, age, and cadence was run for each metatarsal head, the hallux, and the lesser toes. Intraclass correlation coefficients and coefficients of variation were also calculated to assess reliability. Results: The second metatarsal head had the greatest peak (960 kPa) and mean (585.1 kPa) pressures, followed by the third metatarsal head. Weight and cadence combined explained 18% and 23% of peak plantar pressure at the second and third metatarsal heads, respectively (P < .001). The intraclass correlation coefficient varied from 0.76 to 0.96 for all variables. The coefficient of variation between sessions ranged from 5.8% to 9.0%. Conclusion: The highest peak and mean plantar pressures were found at the second and third metatarsal heads in healthy subjects. Weight, cadence, and age explained a low variability of this pressure pattern. The Biofoot in-shoe system has good reliability to measure plantar pressures. These data will have implications for the understanding of normal foot biomechanics and its determinants. (J Am Podiatr Med Assoc 98(4): 302–310, 2008)

scholarly journals Categorized Genetic Analysis in Childhood-Onset Cardiomyopathy

2020 ◽  
Vol 13 (5) ◽  
pp. 504-514
Author(s):  
Zuhair N. Al-Hassnan ◽  
Abdulrahman Almesned ◽  
Sahar Tulbah ◽  
Ali Alakhfash ◽  
Faten Alhadeq ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Genome Sequencing ◽  
Founder Mutation ◽  
Genetic Test ◽  
Whole Genome ◽  
Childhood Onset ◽  
Whole Exome ◽  
The Impact

Background: Childhood-onset cardiomyopathy is a heterogeneous group of conditions the cause of which is largely unknown. The influence of consanguinity on the genetics of cardiomyopathy has not been addressed at a large scale. Methods: To unravel the genetic cause of childhood-onset cardiomyopathy in a consanguineous population, a categorized approach was adopted. Cases with childhood-onset cardiomyopathy were consecutively recruited. Based on the likelihood of founder mutation and on the clinical diagnosis, genetic test was categorized to either (1) targeted genetic test with targeted mutation test, single-gene test, or multigene panel for Noonan syndrome, or (2) untargeted genetic test with whole-exome sequencing or whole-genome sequencing. Several bioinformatics tools were used to filter the variants. Results: Two-hundred five unrelated probands with various forms of cardiomyopathy were evaluated. The median age of presentation was 10 months. In 30.2% (n=62), targeted genetic test had a yield of 82.7% compared with 33.6% for whole-exome sequencing/whole-genome sequencing (n=143) giving an overall yield of 53.7%. Strikingly, 96.4% of the variants were homozygous, 9% of which were found in 4 dominant genes. Homozygous variants were also detected in 7 novel candidates ( ACACB, AASDH, CASZ1, FLII, RHBDF1, RPL3L, ULK1 ). Conclusions: Our work demonstrates the impact of consanguinity on the genetics of childhood-onset cardiomyopathy, the value of adopting a categorized population-sensitive genetic approach, and the opportunity of uncovering novel genes. Our data suggest that if a founder mutation is not suspected, adopting whole-exome sequencing/whole-genome sequencing as a first-line test should be considered.

Postmortem Whole Exome Sequencing Identifies Novel EIF2B3 Mutation With Prenatal Phenotype in 2 Siblings

2017 ◽  
Vol 32 (10) ◽  
pp. 867-870 ◽  
Author(s):  
Hannah Song ◽  
Sina Haeri ◽  
Hannes Vogel ◽  
Marjo van der Knaap ◽  
Keith Van Haren
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Clinical Care ◽  
Mutation Screening ◽  
Medical Decision ◽  
Homozygous Mutation ◽  
Vitro Fertilization ◽  
Whole Exome ◽  
The Impact

Objective: We describe 2 male siblings with a severe, prenatal phenotype of vanishing white matter disease and the impact of whole exome sequencing on their diagnosis and clinical care. Methods: The 2 children underwent detailed clinical characterization, through clinical and laboratory testing, as well as prenatal and postnatal imaging. Biobanked blood from the 2 siblings was submitted for whole exome sequencing at Baylor Laboratories. Results: Both male children had abnormal prenatal neuroimaging and suffered precipitous, fatal neurologic decline. Neuropathologic findings included subependymal pseudocysts, microcalcifications, and profound lack of brain myelin and sparing of peripheral nerve myelin. A novel homozygous mutation in the EIF2B3 gene (c.97A>G [p.Lys33Glu]) was found in both children; both parents were heterozygous carriers. The family subsequently conceived a healthy child via in vitro fertilization with preimplantation mutation screening. Conclusion: These histories expand the prenatal phenotype of eIF2b-related disorders and poignantly illustrate the impact that unbiased genomic sequencing can have on the diagnosis and medical decision making for families affected by childhood neurodegenerative disorders.

scholarly journals Whole Exome Sequencing Identifies a Novel COL1A1 Missense Mutation Causing Dentinogenesis Imperfecta Type I Without Skeletal Abnormalities

2021 ◽  
Author(s):  
Yuting Zeng ◽  
Yuhua Pan ◽  
Jiayao Mo ◽  
Zhiting Ling ◽  
Lifang Jiang ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Missense Mutation ◽  
Whole Exome Sequencing ◽  
Blue Staining ◽  
Nanoindentation Test ◽  
Type I ◽  
Dentinogenesis Imperfecta ◽  
Whole Exome ◽  
Blue Sclerae ◽  
The Impact

Abstract Background：Osteogenesis imperfecta (OI) is a genetic disorder characterized by bone fragility, blue sclerae and dentinogenesis imperfecta (DGI), which are mainly caused by a mutation of the COL1A1 or COL1A2 genes that encode type I procollagen.Methods: The ultrastructure of dentin was analyzed by micro-CT, scanning electron microscopy, energy-dispersive spectroscopy analysis, nanoindentation test and Toluidine Blue Staining. Whole-exome sequencing (WES) was performed to identify the pathogenic gene. The function of the mutant COL1A1 was studied by real-time PCR, western blotting, subcellular localization. Functional analysis in dental pulp stem cells (DPSCs) was also performed to explore the impact of the identified mutation on this phenotype. Results: WES identified a missense mutation (c.1463G > C) in exon 22 of the COL1A1 gene. However, the cases reported herein only exhibited DGI-I in the clinical phenotype, there is no bone disease and any other common abnormal symptom caused by COL1A1 mutation. In addition, ultrastructural analysis of the tooth affected with non-syndromic DGI-I showed that the abnormal dentin was accompanied by disruption of odontoblast polarization, reduced numbers of odontoblasts, loss of dentinal tubules, and reduction in hardness and elasticity, suggesting severe developmental disturbance. What’s more, the odontoblast differentiation ability based on DPSCs that were isolated and cultured from the DGI-I patient was enhanced compared with those from an age-matched, healthy control.Conclusion: This study helped the family members to understand the disease progression and provided new insights into the phenotype-genotype association in collagen-associated diseases and improve clinical diagnosis of OI/DGI-I.

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