A practical approach to curate clonal hematopoiesis of indeterminate potential in human genetic datasets

Abstract

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 sequenced using approaches that cover the whole genome, whole exome or targeted genetic regions; however, differentiating true CHIP mutations from sequencing artifacts and germline variants is a considerable bioinformatic challenge. We present a stepwise method that combines filtering based on sequencing metrics, variant annotation, and novel 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 prior 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%/year, which increases to 0.5%/year amongst 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.

Competing Interest Statement

M.S.: Membership on a Board or Advisory Committee: Abbvie, Bristol Myers Squibb, CTI, Forma, Geron, Karyopharm, Novartis, Ryvu, Sierra Oncology, Taiho, Takeda, TG Therapeutics; Patents and Royalties: Boehringer Ingelheim; Research Funding: ALX Oncology, Astex, Incyte, Takeda, TG Therapeutics; Equity Ownership: Karyopharm, Ryvu; Consultancy: Forma, Karyopharm, Ryvu S. Jaiswal is a paid consultant to Novartis, AVRO Bio, Roche Genentech, GSK, and Foresite Labs and is on the scientific advisory board to Bitterroot Bio. S. Jaiswal, A. Bick, and P. Natarajan are co-founders, equity holders, and on the scientific advisory board of TenSixteen Bio.

Funding Statement

This work was supported by NIH Early Independence Award grant DP5 OD029586, a Burroughs Wellcome Fund Career Award for Medical Scientists, the E.P. Evans Foundation, RUNX1 Research Program, a Pew-Stewart Scholar for Cancer Research award, supported by the Pew Charitable Trusts and the Alexander and Margaret Stewart Trust and the Vanderbilt University Medical Center Brock Family Endowment and Young Ambassador Award to Dr. Bick.

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

We have obtained institutional approval to perform research using the All of Us and UK Biobank datasets at Vanderbilt University Medical Center.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.

Yes

Data Availability

The UK Biobank calls and All of Us calls are in the process of being returned to the respective datasets and will be available to all registered researchers of the respective platforms upon publication.

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