Cost effective sequencing enables longitudinal profiling of clonal hematopoiesis

Clonal hematopoiesis of indeterminate potential (CHIP), the age-related expansion of mutant hematopoietic stem cells, confers risk for multiple diseases of aging including hematologic cancer and cardiovascular disease. Whole-exome or genome sequencing can detect CHIP, but due to its high cost, most population studies have been cross-sectional, sequencing only a single timepoint. Here we describe a cost-effective sequencing assay for detecting CHIP. We validate this technology on a set of 548 longitudinal and multi-timepoint samples from 182 participants in the Womens Health Initiative cohort over median 16 years, including 85 participants with [≥]3 timepoints assayed. The majority (52.1%) of clonal mutations expanded over time (with a median doubling period of 7.43 years), with the others remaining static or decreasing in size in the absence of any cytotoxic therapy. This assay provides a cost-effective and sensitive platform for investigating the associations between CHIP dynamics and health outcomes at a biobank scale.