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A practical approac...
A practical approach to curate clonal hematopoiesis of indeterminate potential in human genetic data sets
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- Vlasschaert, Caitlyn (author)
- Queen's University at Kingston
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- Mack, Taralynn (author)
- Vanderbilt University Medical Center
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- Heimlich, J. Brett (author)
- Vanderbilt University Medical Center
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- Niroula, Abhishek (author)
- Lund University,Lunds universitet,Hematogenomics,Forskargrupper vid Lunds universitet,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Lund University Research Groups,LUCC: Lund University Cancer Centre,Other Strong Research Environments,Broad Institute,Dana-Farber Cancer Institute
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- Uddin, Md Mesbah (author)
- Massachusetts General Hospital,Broad Institute
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- Weinstock, Joshua (author)
- University of Michigan
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- Sharber, Brian (author)
- Vanderbilt University Medical Center
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- Silver, Alexander J. (author)
- Vanderbilt University
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- Xu, Yaomin (author)
- Vanderbilt University
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- Savona, Michael (author)
- Vanderbilt University
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- Gibson, Christopher (author)
- Harvard Medical School
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- Lanktree, Matthew B. (author)
- St Joseph’s Healthcare Hamilton,McMaster University
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Rauh, Michael J. (author)
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- Ebert, Benjamin L. (author)
- Broad Institute,Harvard Medical School,Howard Hughes Medical Institute
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- Natarajan, Pradeep (author)
- Massachusetts General Hospital,Harvard Medical School,Broad Institute
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- Jaiswal, Siddhartha (author)
- Stanford University
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- Bick, Alexander G. (author)
- Vanderbilt University Medical Center,Vanderbilt University
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(creator_code:org_t)
- 2023-01-18
- 2023
- English 10 s.
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In: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 141:18, s. 2214-2223
- Related links:
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http://dx.doi.org/10...
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https://lup.lub.lu.s...
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Abstract
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- Clonal hematopoiesis of indeterminate potential (CHIP) is a common form of age-related somatic mosaicism that is associated with significant morbidity and mortality. CHIP mutations can be identified in peripheral blood samples that are sequenced using approaches that cover the whole genome, the whole exome, or targeted genetic regions; however, differentiating true CHIP mutations from sequencing artifacts and germ line variants is a considerable bioinformatic challenge. We present a stepwise method that combines filtering based on sequencing metrics, variant annotation, and population-based associations to increase the accuracy of CHIP calls. We apply this approach to ascertain CHIP in ∼550 000 individuals in the UK Biobank complete whole exome cohort and the All of Us Research Program initial whole genome release cohort. CHIP ascertainment on this scale unmasks recurrent artifactual variants and highlights the importance of specialized filtering approaches for several genes, including TET2 and ASXL1. We show how small changes in filtering parameters can considerably increase CHIP misclassification and reduce the effect size of epidemiological associations. Our high-fidelity call set refines previous population-based associations of CHIP with incident outcomes. For example, the annualized incidence of myeloid malignancy in individuals with small CHIP clones is 0.03% per year, which increases to 0.5% per year among individuals with very large CHIP clones. We also find a significantly lower prevalence of CHIP in individuals of self-reported Latino or Hispanic ethnicity in All of Us, highlighting the importance of including diverse populations. The standardization of CHIP calling will increase the fidelity of CHIP epidemiological work and is required for clinical CHIP diagnostic assays.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Medicinsk genetik (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medical Genetics (hsv//eng)
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- ref (subject category)
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Blood
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- By the author/editor
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Vlasschaert, Cai ...
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Mack, Taralynn
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Heimlich, J. Bre ...
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Niroula, Abhishe ...
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Uddin, Md Mesbah
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Weinstock, Joshu ...
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show more...
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Sharber, Brian
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Silver, Alexande ...
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Xu, Yaomin
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Savona, Michael
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Gibson, Christop ...
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Lanktree, Matthe ...
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Rauh, Michael J.
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Ebert, Benjamin ...
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Natarajan, Prade ...
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Jaiswal, Siddhar ...
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Bick, Alexander ...
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Medical Genetics
- Articles in the publication
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Blood
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Lund University