Addition of Vitamin A Intake Data during Compartmental Modeling of Retinol Kinetics in Theoretical Humans Leads to Accurate Prediction of Vitamin A Total Body Stores and Kinetic Parameters in Studies of Reasonable Duration

Abstract

Background Mathematical modeling of theoretical data has been used to validate experimental protocols and methods in several fields. Objectives We hypothesized that adding dietary vitamin A intake data as an input during compartmental modeling of retinol kinetics would lead to accurate prediction of vitamin A total body stores (TBS) at 2 specified study lengths and would reduce study duration required to accurately define the system. Methods We generated reference values for state variables (including TBS and intake) and kinetic parameters for 12 theoretical individuals (4 each of children, younger adults, and older adults) based on modeling plasma retinol tracer data for 365 d. We compared TBS predictions using data to 28 d (children) or 56 d (adults) without and with intake included in the model to reference values for each subject. Then, by truncating data sets from 365 d, we determined the shortest study duration required to accurately define the system without and with inclusion of vitamin A intake. Results Reference values for TBS ranged from 30 to 3023 µmol. Study durations of 28 and 56 d were sufficient to accurately predict TBS for 6 of the 12 subjects without intake; adding intake resulted in accurate predictions of TBS for all individuals. When intake was not included as a modeling input, durations of 35–310 d were required to define the system; inclusion of intake data substantially reduced the time required to 10–42 d. Conclusions Inclusion of vitamin A intake as additional data input when modeling vitamin A kinetics allows investigators to accurately predict TBS and define the vitamin A system in studies of reasonable length (4 wk in children and 8 wk in adults). Because it is generally possible to obtain estimates/measures of intake, including such data increases confidence in model predictions while also making studies more feasible.

Vitamin A Absorption Efficiency Determined by Compartmental Analysis of Postprandial Plasma Retinyl Ester Kinetics in Theoretical Humans

“…To further investigate our observation (see Introduction) that plasma retinol tracer data alone are not sufficient to determine a unique value for vitamin A absorption, we assumed, as has been done in our previous retinol modeling studies in adults ( 18 , 19 , 25 ), that absorption efficiency was 75% and then we modeled each individual's plasma retinol data. Figure 2 A shows simulated data for subjects 1 and 12, who had the lowest (55%) and highest assigned values (90%), respectively, for vitamin A absorption efficiency and values of 159 and 1448 μmol for TBS.…”

“…Using an approach similar to that presented by Ford et al ( 18 ), we hypothesized 12 theoretical adults, assigning a range of values ( Supplemental Table 1 ) for vitamin A absorption efficiency, kinetic parameters, and state variables including vitamin A total body stores (TBS). Parameters and state variables were assigned for each subject based on published values ( 18–20 ); specifically, we designated a range for each parameter and then randomly assigned a value within that range for each subject, except that subjects with higher vitamin A absorption efficiencies were assigned values for TBS that were at the upper end of the range and vice versa.…”

“…Using an approach similar to that presented by Ford et al ( 18 ), we hypothesized 12 theoretical adults, assigning a range of values ( Supplemental Table 1 ) for vitamin A absorption efficiency, kinetic parameters, and state variables including vitamin A total body stores (TBS). Parameters and state variables were assigned for each subject based on published values ( 18–20 ); specifically, we designated a range for each parameter and then randomly assigned a value within that range for each subject, except that subjects with higher vitamin A absorption efficiencies were assigned values for TBS that were at the upper end of the range and vice versa. Parameters were assigned in light of a previously published ( 21 ) 7-component compartmental model describing whole-body vitamin A metabolism that we adapted to include 2 components related to vitamin A absorption: compartment 10 to represent chylomicron REs and component 15 to represent chylomicron remnant processing in hepatocytes ( Figure 1 ).…”

“…First, we used WinSAAM to find a best fit to the simulated retinol and RE data for each subject in order to confirm that the model accurately predicted the assigned values for vitamin A absorption, kinetic parameters, and state variables. Second, to more systematically explore our observation (see Introduction) that plasma retinol tracer data versus time are not sufficient to determine a unique value for vitamin A absorption, we modeled retinol data versus time for each subject, assuming an absorption efficiency of 75%, the value we have used in previous studies in adults ( 18 , 19 , 25 ); we then compared model-predicted vitamin A absorption efficiencies and TBS with the assigned values.…”

Development of a Compartmental Model to Investigate the Influence of Inflammation on Predictions of Vitamin A Total Body Stores by Retinol Isotope Dilution in Theoretical Humans

“…In light of concerns that inflammation might compromise the accuracy of RID predictions of TBS, we sought to advance our previously published compartmental models for vitamin A kinetics ( 13 , 17 , 18 ) by incorporating simulations reflecting responses to inflammation, specifically focusing on the influence of inflammation on RBP production and RID-predicted TBS. To accomplish this, we applied model-based compartmental analysis to data for several previously studied theoretical subjects ( 18 , 19 ) and simulated the generalized impacts of chronic and acute inflammation—as well as the timing of administration of the tracer dose versus the onset of inflammation—on the kinetics of plasma retinol (tracer and tracee), on hepatic RBP input, and on the estimates of vitamin A status obtained by RID. In previous work ( 19 – 21 ), we have shown that by analyzing simulated data for hypothetical subjects, we can confirm the accuracy of the RID method for estimating TBS; we were thus confident that this approach would provide useful information related to generalized examples of inflammation.…”