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Stochastic Evolutionary Control in Heterogeneous Populations.

Peng Chen1,2, Jonathan Asher Pachter1,2, Jacob G Scott1,2,3

  • 1Department of Physics, Case Western Reserve University, Cleveland, OH 44106.

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Summary
This summary is machine-generated.

SHEPHERD (Stochastic Heterogeneity-informed Evolutionary Policy Hampering the Expansion of Resistance to Drugs) optimizes adaptive drug policies to reduce disease fitness and mitigate resistance. This approach effectively models heterogeneous populations, outperforming traditional methods for controlling evolving diseases.

Keywords:
Markov Decision ProcessWright–Fisher dynamicsdrug resistanceevolutionary control

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Area of Science:

  • Evolutionary biology
  • Computational biology
  • Mathematical modeling

Background:

  • Therapeutic resistance is a major challenge in treating cancer and infectious diseases.
  • Existing methods often rely on the strong-selection, weak-mutation assumption, limiting their applicability to homogeneous populations.
  • Understanding the evolutionary dynamics of heterogeneous populations is crucial for developing effective resistance-mitigation strategies.

Purpose of the Study:

  • To introduce SHEPHERD (Stochastic Heterogeneity-informed Evolutionary Policy Hampering the Expansion of Resistance to Drugs), a novel framework for designing adaptive drug policies.
  • To move beyond the strong-selection, weak-mutation assumption by incorporating stochastic heterogeneity in evolutionary modeling.
  • To reduce the fitness of evolving diseases and mitigate therapeutic resistance.

Main Methods:

  • Integration of Wright-Fisher (WF) population genetics modeling with Markov Decision Processes (MDPs).
  • Development of a computational framework (SHEPHERD) to capture full stochastic dynamics of genetically heterogeneous populations.
  • Simulation using synthetic multi-drug fitness landscapes with varying numbers of genotypes.

Main Results:

  • The optimized SHEPHERD protocol significantly reduced long-term mean disease fitness compared to single-drug or periodic two-drug regimens in silico.
  • Demonstrated robustness of SHEPHERD strategies across different levels of genotypic frequency discretization and temporal resolution.
  • Highlighted strong dependence of strategy effectiveness on the timing of drug updates.

Conclusions:

  • SHEPHERD provides a foundation for applying MDP optimization to control a broad class of evolving populations beyond the strong-selection, weak-mutation regime.
  • The approach offers a promising strategy for mitigating therapeutic resistance in complex, heterogeneous disease systems.
  • Acknowledged the need for empirical multi-genotype, multi-drug measurements to further validate and refine the models.