A Practical Approach to Curate Clonal Hematopoiesis of Indeterminate Potential in Human Genetic Data Sets

Details

• Personal Author:
  Bick AG ; Ebert BL ; Gibson C ; Heimlich JB ; Jaiswal S ; Lanktree MB ; Mack T ; Natarajan P ; Niroula A ; Rauh MJ ; Savona M ; Sharber B ; Silver AJ ; Uddin MM ; Vlasschaert C ; Weinstock J ; Xu Y
• Description:
  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 approximately 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. [Description provided by NIOSH]
• Subjects:
  Age Factors Blood Epidemiology Genetics Hematologic Tests Neoplasms Occupational Health Safety
• Keywords:
  Age Factors Bioinformatics Blood Samples Genes Hematopoiesis Malignancy Myeloid Tissue Statistical Analysis
• ISSN:
  0006-4971
• Document Type:
  Text
• Funding:
  Cooperative Agreement
• Genre:
  Journal Article
• Place as Subject:
  California ; Massachusetts ; Michigan ; New York ; OSHA Region 1 ; OSHA Region 2 ; OSHA Region 4 ; OSHA Region 5 ; OSHA Region 9 ; Tennessee
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Volume:
  141
• Issue:
  18
• NIOSHTIC Number:
  nn:20067547
• Citation:
  Blood 2023 May; 141(18):2214-2223
• Contact Point Address:
  Alexander Bick, Robinson Research Building 550, 2200 Pierce Ave, Nashville TN 37232
• Email:
  alexander.bick@vumc.org
• Federal Fiscal Year:
  2023
• Performing Organization:
  Albert Einstein College of Medicine, Bronx, New York
• Peer Reviewed:
  True
• Start Date:
  20210701
• Source Full Name:
  Blood
• End Date:
  20240630
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:d05f11aea6f4adbd9903b997794b6a5f1b7a65509d4f7c4b6ff4a7be0b72547cf7656a3e30dc0702383d55a896ad0f62770f6de27b96bd26deac44feb0951262
• Download URL:
  https://stacks.cdc.gov/view/cdc/231491/cdc_231491_DS1.pdf
• File Type:
  [PDF - 1.11 MB ]