Simulation of mutations yielding a replication advantage. Example realizations of simulated human hematopoiesis under HSC mutation. Optimized values for λ (once per 40 weeks), α (once per 285 weeks), ν (once per 56 weeks), and μ (10 weeks) were used for the normal HSCs,⁴  and are preset in the simulation tool. Each simulation begins with 1 mutant HSC that self-renews on average twice as frequently (on average once every 20 weeks) as the 20 000 normal HSCs (which renew on average once every 40 weeks). In this thought experiment, the maximum numbers of normal HSCs plus mutant HSCs is set at 25 000. Mutant cells are represented as type a cells and appear as blue circles above. In roughly one-quarter of simulations, mutant HSC replicates but never contributes to hematopoiesis (enters compartment 2), or its clones transiently appear in compartment 2 at very low levels. (A) An example of this. At other times, the mutant clone very slowly expands in the stem cell reserve and then contributing compartments (B). Conceptually, these simulations provide a virtual representation of clonal hematopoiesis of indeterminate significance.^28,29  (A) The clonal contribution reaches roughly 1% of compartment 2 (STRCs), decreases to near zero, and then reaches 1.8% after 400 weeks. (B) An example where the mutant clone persists, reaching a population of 411 mutant STRCs (of 2486 compartment 2 cells or 14.1%) after 400 weeks. In this simulation, the number of mutant HSC (compartment 1 cells) increases to 3911, or 15.6% of total HSCs. Expansions to 10 or more percent of HSCs occurs in roughly one-quarter of the simulations. In contrast, this rarely ever occurs when decreasing the replicative advantage of the mutant cell to once every 30 weeks. Varying the parameter values enables simulating hematopoiesis with different behaviors for a single mutant HSC, allowing for visualization of the differing physiologies under which clonal hematopoiesis could emerge or progress.