BESTish: A Diffusion-Approximation Framework for Inferring Selection and Mutation in Clonal Hematopoiesis

Clonal hematopoiesis (CH) arises when hematopoietic stem cells (HSCs) gain a fitness advantage from somatic mutations and expand, resulting in an increase in variant allele frequency (VAF) over time. To analyze CH trajectories, we develop a state-dependent stochastic model of wild-type and mutant HSCs, in which an environmental parameter <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>α</mml:mi> <mml:mspace></mml:mspace> <mml:mo>∈</mml:mo> <mml:mspace></mml:mspace> <mml:mo>[</mml:mo> <mml:mn>0</mml:mn> <mml:mo>,</mml:mo> <mml:mspace></mml:mspace> <mml:mn>1</mml:mn> <mml:mo>]</mml:mo></mml:math> regulates death rates and interpolates between homeostatic (Moran-like, <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>α</mml:mi> <mml:mspace></mml:mspace> <mml:mo>=</mml:mo> <mml:mspace></mml:mspace> <mml:mn>1</mml:mn></mml:math> ) and growth-facilitating ( <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>α</mml:mi> <mml:mspace></mml:mspace> <mml:mo><</mml:mo> <mml:mspace></mml:mspace> <mml:mn>1</mml:mn></mml:math> ) regimes. Using functional law of large numbers and central limit theorems, we derive explicit mean-field dynamics and a Gaussian-Markov approximation for VAF fluctuations. We show that the mean VAF trajectory has an explicit logistic form determined by selective advantage, while environmental effects affect only the variance and autocovariance structure. Building on these results, we introduce BESTish (Bayesian estimate for selection incorporating scaling-limit to detect mutant heterogeneity), a novel, efficient and accurate Bayesian inference method that can be applied to analyze both cohort-level and longitudinal VAF datasets. BESTish implements the closed-form finite-dimensional distributions that we derive to estimate mutation fitness, mutation rate, and environmental strength for individual CH drivers. When applied to existing CH datasets, BESTish produces consistent mutation fitness inferences across different studies, and estimates CH driver mutation rates in agreement with independent experimental studies. Furthermore, BESTish reveals patient-specific heterogeneity in the selective behavior of recurrent mutations, and identifies variants whose dynamics are compatible with non-homeostatic, growth-facilitating environments. BESTish provides a unified and mechanistic framework for quantifying CH evolution, with potential applications for other biological systems where clonal expansions can be measured.