The challenge in controlling stochastic systems in which random events can set the system on catastrophic trajectories is to develop a robust ability to respond to such events without significantly compromising the optimality of the baseline control policy.  Drug resistance can emerge from random and variable mutations in targeted cell populations; in the absence of an appropriate dosing policy, emergent resistant subpopulations can proliferate and lead to treatment failure. Dynamic feedback dosage control holds promise in combatting this phenomenon, but cell population evolutionary dynamics are complex, stochastic, and often high-dimensional, posing significant challenges to system control. This paper presents CelluDose, a deep reinforcement learning closed-loop dynamic control prototype for automated precision drug dosing targeting stochastic and heterogeneous cell proliferation. Developing optimal dosing schedules for preventing therapy-induced drug resistance involves a tradeoff between the effective suppression of emergent resistant cell subpopulations and the use of conservative dosages and a preference for first-line drugs. CelluDose is trained on model simulations of cell population evolutionary dynamics that combine a system of stochastic differential equations and the additional occurrence of random perturbing events. Both the single-drug and combination therapy policies obtained in training exhibit a 100\% success rate at suppressing simulated heterogeneous harmful cell growth and responding to diverse system fluctuations and perturbations within the alloted time and using conservative dosing. The policies obtained were found to be highly robust to model parameter changes and fluctuations not introduced during training .
The challenge in controlling stochastic systems in which low-probability events can set the system on catastrophic trajectories is to develop a robust ability to respond to such events without significantly compromising the optimality of the baseline control policy. This paper presents CelluDose, a stochastic simulation-trained deep reinforcement learning adaptive feedback control prototype for automated precision drug dosing targeting stochastic and heterogeneous cell proliferation. Drug resistance can emerge from random and variable mutations in targeted cell populations; in the absence of an appropriate dosing policy, emergent resistant subpopulations can proliferate and lead to treatment failure. Dynamic feedback dosage control holds promise in combatting this phenomenon, but the application of traditional control approaches to such systems is fraught with challenges due to the complexity of cell dynamics, uncertainty in model parameters, and the need in medical applications for a robust controller that can be trusted to properly handle unexpected outcomes. Here, training on a sample biological scenario identified single-drug and combination therapy policies that exhibit a 100\% success rate at suppressing cell proliferation and responding to diverse system perturbations while establishing low-dose no-event baselines. These policies were found to be highly robust to variations in a key model parameter subject to significant uncertainty and unpredictable dynamical changes .
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random
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This paper presents CelluDose, a stochastic simulation-trained deep reinforcement learning adaptive feedback control prototype for automated precision drug dosing targeting stochastic and heterogeneous cell proliferation.
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cell population evolutionary dynamics are complex, stochastic, and often high-dimensional, posing significant challenges to system control. This paper presents CelluDose, a deep reinforcement learning closed-loop dynamic control prototype for automated precision drug dosing targeting stochastic and heterogeneous cell proliferation. Developing optimal dosing schedules for preventing therapy-induced drug resistance involves a tradeoff between the effective suppression of emergent resistant cell subpopulations and the use of conservative dosages and a preference for first-line drugs. CelluDose is trained on model simulations of cell population evolutionary dynamics that combine a system of stochastic differential equations and the additional occurrence of random perturbing events. Both the
the application of traditional control approaches to such systems is fraught with challenges due to the complexity of cell dynamics, uncertainty in model parameters, and the need in medical applications for a robust controller that can be trusted to properly handle unexpected outcomes. Here, training on a sample biological scenario identified
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obtained in training
that
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simulated heterogeneous harmful cell growth
cell proliferation
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fluctuations and perturbations within the alloted time and using conservative dosing. The policies obtained
perturbations while establishing low-dose no-event baselines. These policies
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model parameter changes and fluctuations not introduced during training
variations in a key model parameter subject to significant uncertainty and unpredictable dynamical changes