Clinical progression of clonal hematopoiesis is determined by a combination of mutation timing, clonal fitness, and structure

Clonal hematopoiesis (CH) is characterized by expanding blood cell clones carrying somatic mutations in healthy aged individuals and is associated with various age-related diseases and all-cause mortality. While CH mutations affect diverse genes associated with myeloid malignancies, their mechanisms of expansion and disease associations remain poorly understood. We investigate the relationship between clonal fitness and clinical outcomes by integrating data from three longitudinal aging cohorts (n=713). We demonstrate pathway-specific fitness advantage and clonal composition significantly influence clonal dynamics. Further, the timing of mutation acquisition is necessary to determine the extent of clonal expansion reached during the host individual's lifetime. We introduce MAC120, a metric combining mutation context, timing, and variant fitness to predict future clonal growth, outperforming traditional variant allele frequency measurements in predicting clinical outcomes. Our unified analytical framework enables standardized clonal dynamics inference across cohorts, advancing our ability to predict and potentially intervene in CH-related pathologies. Our expanded cohort longitudinally sampled from the LBC1936 was processed as per our previous work. Briefly, DNA was extracted from whole blood with Ethylenediaminetetraacetic acid (EDTA) using the Nucleon BACC3 kit (Sigma-Aldrich, GERPN8512), according to the manufacturer’s protocol. Libraries were generated from 200 ng of each DNA sample using the Invitea/Archer VariantPlex® 75 Myeloid gene panel and the VariantPlex® Somatic Protocol for Illumina sequencing (Invitae, AB0108, and the VariantPlex®-HCG Myeloid Kit; see Supplementary Table 2), with adaptations for detecting low variant allele frequencies. Sequencing was performed on the NextSeq 550 platform (Illumina) using the NextSeq 500/550 High-Output version 2.5 kit (300 cycles). Two ‘Genome in a Bottle’ (GIAB) DNA samples (NA12878, Coriell Institute) were included in each sequencing batch to ensure reproducibility and support background error modeling and batch correction.