Clonal hematopoiesis of indeterminate potential (CHIP) occurs when at least 4% of blood cells harbor somatic mutations in leukemogenic genes and is associated with increased risk for cardiovascular disease, malignancy, and mortality. While deep sequencing (>1,000x coverage) is the gold standard for CHIP detection, most large-scale studies rely on shallow genome/exome sequencing (∼35x coverage) from biobanks. However, the sensitivity and specificity of genome-based CHIP detection remain unknown, raising concerns about the accuracy of reported disease associations. We performed both deep targeted sequencing and genome sequencing on identical DNA samples from 9,925 participants to characterize genome-based CHIP detection performance. Genome sequencing showed poor sensitivity (28%) and positive predictive value (44%) compared to deep sequencing, with performance highly dependent on clone size. Simulation studies revealed that these ascertainment errors dramatically reduce statistical power and underestimate true effect sizes by >80%. These findings indicate that genome-based studies profoundly underestimate CHIP-disease associations, necessitating targeted deep sequencing for accurate clinical risk assessment.

M.R.S. has received honoraria for advisory board membership or consultancy from Bristol Myers Squibb, CTI, Forma, Geron, GlaxoSmithKline/Sierra Oncology, Karyopharm, Ryvu Therapeutics, and Taiho Pharmaceutical; has received research funding from ALX Oncology, Astex Pharmaceuticals, Incyte Corporation, Takeda, and TG Therapeutics; holds equity in Empath Biosciences, Karyopharm, and Ryvu Therapeutics; and has been reimbursed for travel expenses by Astex.

Vanderbilt University Medical Center BioVU projects are supported by numerous sources: institutional funding, private agencies, and federal grants. These include NIH funded Shared Instrumentation Grants S10OD017985, S10RR025141, and S10OD025092; and CTSA grants UL1TR002243, UL1TR000445, and UL1RR024975. Genomic data are also supported by investigator-led projects that include U01HG004798, R01NS032830, RC2GM092618, P50GM115305, U01HG006378, U19HL065962, R01HD074711. The sequencing of 250,000 WGS individuals from BioVU, including the 10,310 described here, has been funded by the Alliance for Genomic Discovery consisting of NashBio, Illumina and industry partners Amgen, AbbVie, AstraZeneca, Bayer, BMS, GSK, Merck, and Novo. DNA sequencing was performed at deCODE genetics using Illumina sequencing technology.

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:

The Institutional Review Board of Vanderbilt University Medical Center oversees BioVU and gave ethical approval for this work (IRB #201783).

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, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

↵* RWC and YP (second listed author) are co–first authors. The authorship order reflects that the study was initiated by RWC, who was joined by YP (second listed author) in leading the project.

Conflict of Interest: M.R.S. has received honoraria for advisory board membership or consultancy from Bristol Myers Squibb, CTI, Forma, Geron, GlaxoSmithKline/Sierra Oncology, Karyopharm, Ryvu Therapeutics, and Taiho Pharmaceutical; has received research funding from ALX Oncology, Astex Pharmaceuticals, Incyte Corporation, Takeda, and TG Therapeutics; holds equity in Empath Biosciences, Karyopharm, and Ryvu Therapeutics; and has been reimbursed for travel expenses by Astex.