Figure Legends
Figure 1. Schematic structure of the semi-mechanistic model of
Henrich et al. and our comprehensive mechanistic model of
thrombocytopoiesis compared in this work. We present major compartments
as boxes and cell or TPO fluxes as black arrows. Actions are depicted as
thick lines with arrows (stimulation) respectively orthogonal lines
(suppression). Different colors correspond to different kinds of
actions.
Figure 2. Distribution of degrees of thrombocytopenia observed
at different treatment cycles (primary data set of 135 patients from
NHL-B trial). Percentages of patients with thrombocytopenia degree 0 is
continuously decreasing from cycle to cylce. Percentages of patients
with degrees 3 or 4 increase continuously. In particular, degree 4
thrombocytopenias only occur from cycle 3 and increase up to 10.1% at
cycle 6.
Figure 3. Comparisons of model predictions and data for the
mechanistic and semi-mechanistic model for four selected patients from
the NHL-B trial with either nearly periodic behavior (patient #69) or
with strong cumulative platelet toxicity during the course of the
therapy (patients #814, #1678, #1261). Model performances are
comparable for these cases. Compared to the semi-mechanistic model, the
mechanistic model performs slightly inferior at the first cycle but
better at later cycles 5 and 6).
Figure 4. Comparisons of model predictions and data for the
mechanistic and the semi-mechanistic model for eight patients from NHL-B
study with irregular platelet dynamics during the course of the therapy
with (patients #37, #398, #489) or without clear cumulative toxicity
(patients#14, #15 and #677, #1017, #1428). Both models fail to fit
the degree of thrombocytopenia correctly. The mechanistic model performs
better for patients #14, #15, #398 and #1017.
Figure 5. Comparison of the predictive powers of the
mechanistic and the semi-mechanistic model. Models are either calibrated
on a prescribed number of previous cycles (x-axis) or used parameter
settings obtained from regression models of baseline covariates from the
validation data set (no calibration cycles, yellow). We present the
average of the absolute differences between predicted and observed
degrees of thrombocytopenia for future cycles (DD characteristics,
y-axis). Color-coding corresponds to the predicted cycle. The
mechanistic model outperforms the semi-mechanistic model in all
situations except for the parameters derived from the regression model
showing similar predictive power. The mechanistic model calibrated on
the first cycle even outperforms the semi-mechanistic model calibrated
on a higher number of cycles.
Figure 6. Comparison of the predictive powers of the
mechanistic and the semi-mechanistic model. Models are calibrated on a
prescribed number of cycles (x-axis) or used parameter settings obtained
from regression models of baseline covariates from the validation data
set (no calibration cycles, yellow). We present the average of the
absolute differences between predicted and observed degrees of
thrombocytopenia for future cycles, but compared to Figure 5, only
differences of more than one degree are counted (LDD characteristics,
y-axis). Color-coding corresponds to the predicted cycle. The
mechanistic model outperforms the semi-mechanistic model in all
situations except for the parameters derived from the regression model
showing similar predictive power. The mechanistic model calibrated on
the first cycle even outperforms the semi-mechanistic model calibrated
on a higher number of cycles for most of the cases. The advantage of the
mechanistic model is more pronounced than in Figure 5.
Figure 7. Comparison of sensitivities regarding grade III/IV
toxicity of the mechanistic and the semi-mechanistic model. Models are
calibrated on a prescribed number of cycles (x-axis). The sensitivity of
the mechanistic model is higher.
Figure 8. Comparison of Youden’s J statistics regarding grade
III/IV toxicity of the mechanistic and the semi-mechanistic model.
Models are calibrated on a prescribed number of cycles (x-axis).
Youden’s J statistics are higher throughout indicating higher predictive
power.