scholarly journals Precision Medicine Advancements Using Whole Genome Sequencing, Noninvasive Whole Body Imaging, and Functional Diagnostics

2018 ◽  
Author(s):  
Ying-Chen Claire Hou ◽  
Hung-Chun Yu ◽  
Rick Martin ◽  
Natalie M. Schenker-Ahmed ◽  
Michael Hicks ◽  
...  
Keyword(s):  
Coronary Artery ◽  
Whole Genome Sequencing ◽  
Precision Medicine ◽  
Genome Sequencing ◽  
Coronary Artery Calcium ◽  
Whole Body ◽  
Whole Genome ◽  
Calcium Scoring ◽  
Coronary Artery Calcium Scoring ◽  
Precision Health

ABSTRACTWe report the results of a three-year precision medicine study that enrolled 1190 presumed healthy participants at a single research clinic. To enable a better assessment of disease risk and improve diagnosis, a precision health platform that integrates non-invasive functional measurements and clinical tests combined with whole genome sequencing (WGS) was developed. The platform included WGS, comprehensive quantitative non-contrast whole body (WB) and brain magnetic resonance imaging/angiography (MRI/MRA), computed tomography (CT) coronary artery calcium scoring, electrocardiogram, echocardiogram, continuous cardiac monitoring, clinical laboratory tests, and metabolomics. In our cohort, 24.3% had medically significant genetic findings (MSF) which may contribute to increased risk of disease. A total of 206 unique medically significant variants in 111 genes were identified, and forty individuals (3.4%) had more than one MSF. Phenotypic testing revealed: 34.2% of our cohort had a metabolomics profile suggestive of insulin resistance, 29.2% had elevated liver fat identified by MRI, 16.4% had clinically important cardiac structure or cardiac function abnormalities on cardiac MRI or ECHO, 8.8% had a high cardiovascular risk on CT coronary artery calcium scoring (Agatston calcium score > 400, Relative Risk of 7.2), 8.0% had arrhythmia found on continuous rhythm monitoring, 6.5% had cardiac conduction disorders found on EKG, 2% had previously undetected tumors detected by WB MRI, and 2.5% had previously undetected aneurysms detected by non-contrast MRI/MRA. Using family histories, personal histories, and test results, clinical and phenotypic findings were correlated with genomic findings in 130 study participants (63.1%) with high to moderate penetrance variants, suggesting the precision health platform improves the diagnostic process in asymptomatic individuals who were at risk. Cardiovascular and endocrine diseases achieved considerable clinical associations between MSFs and clinical phenotypes (89% and 72%, respectively). These findings demonstrate the value of integrating WGS and noninvasive clinical assessments for a rapid and integrated point-of-care clinical diagnosis of age-related diseases that contribute to premature mortality.

Coronary Artery Calcium Scoring for Adults at Borderline 10-Year ASCVD Risk

2021 ◽  
Vol 78 (5) ◽  
pp. 537-538
Author(s):  
S.M. Iftekhar Uddin ◽  
Albert D. Osei ◽  
Olufunmilayo Obisesan ◽  
Omar Dzaye ◽  
Zeina Dardari ◽  
...  
Keyword(s):  
Coronary Artery ◽  
Coronary Artery Calcium ◽  
Calcium Scoring ◽  
Coronary Artery Calcium Scoring ◽  
Ascvd Risk

scholarly journals Novel BMD loci identified by whole genome sequencing and CRISPR editing in zebrafish: The NHLBI Trans-Omics for Precision Medicine (TOPMED) study

Bone Reports ◽  
2021 ◽  
Vol 14 ◽  
pp. 100765
Author(s):  
Yi-Hsiang Hsu ◽  
Joyce W. Tang ◽  
Hanfei Xu ◽  
Cecily Choy ◽  
May Montasser ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Precision Medicine ◽  
Genome Sequencing ◽  
Whole Genome

scholarly journals Genetic variant at coronary artery disease and ischemic stroke locus 1p32.2 regulates endothelial responses to hemodynamics

2018 ◽  
Vol 115 (48) ◽  
pp. E11349-E11358 ◽  
Author(s):  
Matthew D. Krause ◽  
Ru-Ting Huang ◽  
David Wu ◽  
Tzu-Pin Shentu ◽  
Devin L. Harrison ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Ischemic Stroke ◽  
Coronary Artery ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Whole Genome ◽  
Enhancer Activity ◽  
Protective Allele ◽  
Unidirectional Flow ◽  
Artery Disease

Biomechanical cues dynamically control major cellular processes, but whether genetic variants actively participate in mechanosensing mechanisms remains unexplored. Vascular homeostasis is tightly regulated by hemodynamics. Exposure to disturbed blood flow at arterial sites of branching and bifurcation causes constitutive activation of vascular endothelium contributing to atherosclerosis, the major cause of coronary artery disease (CAD) and ischemic stroke (IS). Conversely, unidirectional flow promotes quiescent endothelium. Genome-wide association studies (GWAS) have identified chromosome 1p32.2 as strongly associated with CAD/IS; however, the causal mechanism related to this locus remains unknown. Using statistical analyses, assay of transposase accessible chromatin with whole-genome sequencing (ATAC-seq), H3K27ac/H3K4me2 ChIP with whole-genome sequencing (ChIP-seq), and CRISPR interference in human aortic endothelial cells (HAECs), our results demonstrate that rs17114036, a common noncoding polymorphism at 1p32.2, is located in an endothelial enhancer dynamically regulated by hemodynamics. CRISPR-Cas9–based genome editing shows that rs17114036-containing region promotes endothelial quiescence under unidirectional shear stress by regulating phospholipid phosphatase 3 (PLPP3). Chromatin accessibility quantitative trait locus (caQTL) mapping using HAECs from 56 donors, allelic imbalance assay from 7 donors, and luciferase assays demonstrate that CAD/IS-protective allele at rs17114036 in PLPP3 intron 5 confers increased endothelial enhancer activity. ChIP-PCR and luciferase assays show that CAD/IS-protective allele at rs17114036 creates a binding site for transcription factor Krüppel-like factor 2 (KLF2), which increases the enhancer activity under unidirectional flow. These results demonstrate that a human SNP contributes to critical endothelial mechanotransduction mechanisms and suggest that human haplotypes and related cis-regulatory elements provide a previously unappreciated layer of regulatory control in cellular mechanosensing mechanisms.

Half-dose Coronary Artery Calcium Scoring

2019 ◽  
Vol 34 (1) ◽  
pp. 18-25 ◽  
Author(s):  
Damiano Caruso ◽  
Domenico De Santis ◽  
Tommaso Biondi ◽  
Nicola Panvini ◽  
Marta Zerunian ◽  
...  
Keyword(s):  
Coronary Artery ◽  
Coronary Artery Calcium ◽  
Calcium Scoring ◽  
Coronary Artery Calcium Scoring ◽  
Half Dose

scholarly journals Evaluation of a Deep Learning–Based Automated CT Coronary Artery Calcium Scoring Algorithm

2020 ◽  
Vol 13 (2) ◽  
pp. 524-526 ◽  
Author(s):  
Simon S. Martin ◽  
Marly van Assen ◽  
Saikiran Rapaka ◽  
H. Todd Hudson ◽  
Andreas M. Fischer ◽  
...  
Keyword(s):  
Deep Learning ◽  
Coronary Artery ◽  
Coronary Artery Calcium ◽  
Calcium Scoring ◽  
Coronary Artery Calcium Scoring ◽  
Scoring Algorithm

scholarly journals Precision medicine integrating whole-genome sequencing, comprehensive metabolomics, and advanced imaging

2020 ◽  
Vol 117 (6) ◽  
pp. 3053-3062 ◽  
Author(s):  
Ying-Chen Claire Hou ◽  
Hung-Chun Yu ◽  
Rick Martin ◽  
Elizabeth T. Cirulli ◽  
Natalie M. Schenker-Ahmed ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Precision Medicine ◽  
Genome Sequencing ◽  
Clinical Laboratory ◽  
Descriptive Analysis ◽  
Disease Diagnosis ◽  
Whole Genome ◽  
Advanced Imaging ◽  
Family Medical History ◽  
Deep Phenotyping

Genome sequencing has established clinical utility for rare disease diagnosis. While increasing numbers of individuals have undergone elective genome sequencing, a comprehensive study surveying genome-wide disease-associated genes in adults with deep phenotyping has not been reported. Here we report the results of a 3-y precision medicine study with a goal to integrate whole-genome sequencing with deep phenotyping. A cohort of 1,190 adult participants (402 female [33.8%]; mean age, 54 y [range 20 to 89+]; 70.6% European) had whole-genome sequencing, and were deeply phenotyped using metabolomics, advanced imaging, and clinical laboratory tests in addition to family/medical history. Of 1,190 adults, 206 (17.3%) had at least 1 genetic variant with pathogenic (P) or likely pathogenic (LP) assessment that suggests a predisposition of genetic risk. A multidisciplinary clinical team reviewed all reportable findings for the assessment of genotype and phenotype associations, and 137 (11.5%) had genotype and phenotype associations. A high percentage of genotype and phenotype associations (>75%) was observed for dyslipidemia (n = 24), cardiomyopathy, arrhythmia, and other cardiac diseases (n = 42), and diabetes and endocrine diseases (n = 17). A lack of genotype and phenotype associations, a potential burden for patient care, was observed in 69 (5.8%) individuals with P/LP variants. Genomics and metabolomics associations identified 61 (5.1%) heterozygotes with phenotype manifestations affecting serum metabolite levels in amino acid, lipid and cofactor, and vitamin pathways. Our descriptive analysis provides results on the integration of whole-genome sequencing and deep phenotyping for clinical assessments in adults.

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