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Merging concepts - coupling an agent-based model of hematopoietic stem cells with an ODE model of granulopoiesis.

Krinner A, Roeder I, Loeffler M, Scholz M - BMC Syst Biol (2013)

Bottom Line: A combination of complementary models promises to provide their mutual confirmation and to explain a broader range of scenarios.ABM and ODE model proved to be compatible and were combined without altering the structure of both models.Therefore, it promises to serve as a valuable tool for studies in a broader range of clinical applications, in particular where stem cell activation and proliferation are involved.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institute for Medical Informatics and Biometry, TU Dresden, Blasewitzer str, 86, D-01307 Dresden, Germany. axel.krinner@tu-dresden.de.

ABSTRACT

Background: Hematopoiesis is a complex process involving different cell types and feedback mechanisms mediated by cytokines. This complexity stimulated various models with different scopes and applications. A combination of complementary models promises to provide their mutual confirmation and to explain a broader range of scenarios. Here we propose a combination of an ordinary differential equation (ODE) model of human granulopoiesis and an agent-based model (ABM) of hematopoietic stem cell (HSC) organization. The first describes the dynamics of bone marrow cell stages and circulating cells under various perturbations such as G-CSF treatment or chemotherapy. In contrast to the ODE model describing cell numbers, our ABM focuses on the organization of individual cells in the stem population.

Results: We combined the two models by replacing the HSC compartment of the ODE model by a difference equation formulation of the ABM. In this hybrid model, regulatory mechanisms and parameters of the original models were kept unchanged except for a few specific improvements: (i) Effect of chemotherapy was restricted to proliferating HSC and (ii) HSC regulation in the ODE model was replaced by the intrinsic regulation of the ABM. Model simulations of bleeding, chronic irradiation and stem cell transplantation revealed that the dynamics of hybrid and ODE model differ markedly in scenarios with stem cell damage. Despite these differences in response to stem cell damage, both models explain clinical data of leukocyte dynamics under four chemotherapy regimens.

Conclusions: ABM and ODE model proved to be compatible and were combined without altering the structure of both models. The new hybrid model introduces model improvements by considering the proliferative state of stem cells and enabling a cell cycle-dependent effect of chemotherapy. We demonstrated that it is able to explain and predict granulopoietic dynamics for a large variety of scenarios such as irradiation, bone marrow transplantation, chemotherapy and growth factor applications. Therefore, it promises to serve as a valuable tool for studies in a broader range of clinical applications, in particular where stem cell activation and proliferation are involved.

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Comparison of the predictions of the hybrid model with clinical data on leukocyte dynamics in peripheral blood during chemotherapy without G-CSF. Clinical data of a) CHOP-21 and b) CHOEP-21 administration (Blue: median of patients, black: 25 and 75 percentiles) are compared with corresponding simulation results of the hybrid model (red). Simulation results fit well to clinical data in the sense that they lie in the interquartile range of data for almost all time points. Cell numbers are normalized with respect to the average WBC/leukocyte count value of healthy individuals (7000 cells/μl).
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Figure 6: Comparison of the predictions of the hybrid model with clinical data on leukocyte dynamics in peripheral blood during chemotherapy without G-CSF. Clinical data of a) CHOP-21 and b) CHOEP-21 administration (Blue: median of patients, black: 25 and 75 percentiles) are compared with corresponding simulation results of the hybrid model (red). Simulation results fit well to clinical data in the sense that they lie in the interquartile range of data for almost all time points. Cell numbers are normalized with respect to the average WBC/leukocyte count value of healthy individuals (7000 cells/μl).

Mentions: The hybrid model distinguishes between proliferative and quiescent stem cells. For the mitosis-related effect of the applied drugs we restrict their toxic effect on proliferating stem cells. The effect of the three cytotoxic drugs applied in the CHOP regimen is modeled by a single set of toxicity parameters, one parameter for each compartment Ω, CG, PGB and MGB. Toxicity parameters were taken from [17]. In particular, we used the same parameter value for toxicity in Ω as for our former stem cell toxicity. The effect of prednisone is modeled as a prolongation of granulocyte half-life according to Bishop et al. [42] and Dale et al. [43]. The results of the simulation of CHOP-21 in comparison to clinical data are shown in Figure 6a. After an initial increase of leukocytes due to prednisone application, the cell counts decrease to about 10% of their normal value until day 11, followed by a recovery phase until the start of the next cycle. Model results fit well to the clinical data in the sense that the model prediction is in the interquartile range of the clinical data for almost all time points. For the CHOEP regimen, an additional set of toxicity parameters representing the toxicity of the drug etoposide is used. Again, model predictions fit well to clinical data applying the same toxicity parameters as used in Scholz et al. [17] (Figure 6b).


Merging concepts - coupling an agent-based model of hematopoietic stem cells with an ODE model of granulopoiesis.

Krinner A, Roeder I, Loeffler M, Scholz M - BMC Syst Biol (2013)

Comparison of the predictions of the hybrid model with clinical data on leukocyte dynamics in peripheral blood during chemotherapy without G-CSF. Clinical data of a) CHOP-21 and b) CHOEP-21 administration (Blue: median of patients, black: 25 and 75 percentiles) are compared with corresponding simulation results of the hybrid model (red). Simulation results fit well to clinical data in the sense that they lie in the interquartile range of data for almost all time points. Cell numbers are normalized with respect to the average WBC/leukocyte count value of healthy individuals (7000 cells/μl).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4228322&req=5

Figure 6: Comparison of the predictions of the hybrid model with clinical data on leukocyte dynamics in peripheral blood during chemotherapy without G-CSF. Clinical data of a) CHOP-21 and b) CHOEP-21 administration (Blue: median of patients, black: 25 and 75 percentiles) are compared with corresponding simulation results of the hybrid model (red). Simulation results fit well to clinical data in the sense that they lie in the interquartile range of data for almost all time points. Cell numbers are normalized with respect to the average WBC/leukocyte count value of healthy individuals (7000 cells/μl).
Mentions: The hybrid model distinguishes between proliferative and quiescent stem cells. For the mitosis-related effect of the applied drugs we restrict their toxic effect on proliferating stem cells. The effect of the three cytotoxic drugs applied in the CHOP regimen is modeled by a single set of toxicity parameters, one parameter for each compartment Ω, CG, PGB and MGB. Toxicity parameters were taken from [17]. In particular, we used the same parameter value for toxicity in Ω as for our former stem cell toxicity. The effect of prednisone is modeled as a prolongation of granulocyte half-life according to Bishop et al. [42] and Dale et al. [43]. The results of the simulation of CHOP-21 in comparison to clinical data are shown in Figure 6a. After an initial increase of leukocytes due to prednisone application, the cell counts decrease to about 10% of their normal value until day 11, followed by a recovery phase until the start of the next cycle. Model results fit well to the clinical data in the sense that the model prediction is in the interquartile range of the clinical data for almost all time points. For the CHOEP regimen, an additional set of toxicity parameters representing the toxicity of the drug etoposide is used. Again, model predictions fit well to clinical data applying the same toxicity parameters as used in Scholz et al. [17] (Figure 6b).

Bottom Line: A combination of complementary models promises to provide their mutual confirmation and to explain a broader range of scenarios.ABM and ODE model proved to be compatible and were combined without altering the structure of both models.Therefore, it promises to serve as a valuable tool for studies in a broader range of clinical applications, in particular where stem cell activation and proliferation are involved.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institute for Medical Informatics and Biometry, TU Dresden, Blasewitzer str, 86, D-01307 Dresden, Germany. axel.krinner@tu-dresden.de.

ABSTRACT

Background: Hematopoiesis is a complex process involving different cell types and feedback mechanisms mediated by cytokines. This complexity stimulated various models with different scopes and applications. A combination of complementary models promises to provide their mutual confirmation and to explain a broader range of scenarios. Here we propose a combination of an ordinary differential equation (ODE) model of human granulopoiesis and an agent-based model (ABM) of hematopoietic stem cell (HSC) organization. The first describes the dynamics of bone marrow cell stages and circulating cells under various perturbations such as G-CSF treatment or chemotherapy. In contrast to the ODE model describing cell numbers, our ABM focuses on the organization of individual cells in the stem population.

Results: We combined the two models by replacing the HSC compartment of the ODE model by a difference equation formulation of the ABM. In this hybrid model, regulatory mechanisms and parameters of the original models were kept unchanged except for a few specific improvements: (i) Effect of chemotherapy was restricted to proliferating HSC and (ii) HSC regulation in the ODE model was replaced by the intrinsic regulation of the ABM. Model simulations of bleeding, chronic irradiation and stem cell transplantation revealed that the dynamics of hybrid and ODE model differ markedly in scenarios with stem cell damage. Despite these differences in response to stem cell damage, both models explain clinical data of leukocyte dynamics under four chemotherapy regimens.

Conclusions: ABM and ODE model proved to be compatible and were combined without altering the structure of both models. The new hybrid model introduces model improvements by considering the proliferative state of stem cells and enabling a cell cycle-dependent effect of chemotherapy. We demonstrated that it is able to explain and predict granulopoietic dynamics for a large variety of scenarios such as irradiation, bone marrow transplantation, chemotherapy and growth factor applications. Therefore, it promises to serve as a valuable tool for studies in a broader range of clinical applications, in particular where stem cell activation and proliferation are involved.

Show MeSH
Related in: MedlinePlus