Table 1.
Equations for calculating elementary effects.
Table 2.
The conditions on various model parameters that were used to ensure that the virtual person remained “alive” during a simulation, based on definitions from the Common Terminology Criteria for Adverse Events v4.03 (CTCAE) [41].
Table 3.
Parameters for building the virtual population.
Figure 1.
Probability density of mean arterial pressure (MAP) in the virtual population.
The vertical line marks the threshold of hypertension (), and both gamma and chi-squared distributions have been fitted.
Table 4.
Categorization of the virtual individuals into normotensive and hypertensive populations, based on mean arterial pressure (MAP).
Figure 2.
The most significant elementary effects on three key output variables at each time .
A: The effects on mean arterial pressure (MAP), cardiac output (QAO) and rate of urine production (VUD) are plotted (at after the perturbations) as
. B: The most significant elementary effects when HYL is ignored. The complete tables of elementary effects are included in the supplementary material.
Figure 3.
The largest elementary effects on three key output variables at and
.
The effects on mean arterial pressure (MAP), cardiac output (QAO) and rate of urine production (VUD) are plotted as . Elementary effects were sorted by the magnitude of their largest effect on the three output variables. A: The elementary effects at
(excluding HYL). B: The elementary effects at
.
Figure 4.
Significant correlations between model parameters and the elementary effects of HYL at .
Correlations () are shown for the elementary effect of HYL on mean arterial pressure (MAP), cardiac output (QAO) and rate of urine production (VUD).
Figure 5.
Significant correlations between model parameters and three key output variables.
Correlations are shown for mean arterial pressure (MAP), cardiac output (QAO) and rate of urine production (VUD), where and
.
Figure 6.
Probability densities of model variables in the normotensive and hypertensive virtual sub-populations.
Probability densities are shown for AAR (the afferent arteriolar resistance), POR (the reference value of capillary pressure in non-muscle tissue) and CPR (the critical plasma protein concentration for protein destruction).
Figure 7.
Comparison of correlations between parameters and variables in the normotensive and hypertensive virtual sub-populations.
For a given variable, the correlations with each parameter are plotted against the x-axis for the normotensive population, and against the y-axis for the hypertensive population (only correlations are shown). A: Mean arterial pressure (MAP). B: Cardiac output (QAO). C: Blood volume (VB). D: Rate of urine production (VUD).
Figure 8.
Evaluation of linear classifiers for identifying hypertensive virtual individuals.
Each classifier (binomial GLM) was fitted to a random sample of the virtual population and then evaluated on the remaining
. A: ROC curves for several classifiers; the optimal (30-parameter) classifier has an area under curve (AUC) of
, demonstrating high predictive power. The 6-parameter “Renal+Liver” classifier performs nearly as well (AUC = 0.948). B: The parameter sensitivity of the optimal classifier. The y-axis measures the variation in the prediction over the range of values for each parameter.
Table 5.
The coefficients of each classifier (GLM) presented in Figure 8a.
Table 6.
The parameters used to predict hypertension in the reduced-parameter GLMs (“Renal”, “Liver” and “Renal+Liver”).
Figure 9.
The effects of ingestion of hypotonic and hypertonic solutions on urine flow.
These simulations reproduced the conditions shown in Figures 3 and 4 of Uttamsingh et al. [74], which include experimental from Baldes and Smirk [93] and Dean and McCance [75]. A: Urine flow following ingestion of 1 L of water. B: Urine flow following ingestion of hypertonic saline (normalized wrt. the urine flow rate prior to ingestion).
Figure 10.
The effects of aldosterone loading on the human body.
This simulation reproduced the conditions shown in Figure 5 of Uttamsingh et al. [74], which inclues experimental data from Davis and Howell [94] and Relman and Schwartz [76]. A: Extra-cellular fluid volume. B: Mean arterial pressure. C: Serum aldosterone (normalized). D: Sodium excretion rate.