Retinol Isotope Dilution Is Applied during Restriction of Vitamin A Intake to Predict Individual Subject Total Body Vitamin A Stores at Isotopic Equilibrium

Green, Michael H.; Ford, Jennifer Lynn; Green, Joanne Balmer

doi:10.3945/jn.116.238899

Cited by 18 publications

(7 citation statements)

References 7 publications

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“…As an overview and as described in the next section and in Supplemental Methods , we first used model-based compartmental analysis to generate a database that included 50 theoretical children with a wide range of known values for whole-body retinol kinetic parameters and specified state variables such as vitamin A TBS, plasma retinol pool size, and dietary vitamin A intake. We use the term “known values” as it is understood in pharmacokinetics ( 15 ) to describe information that is assigned or calculated a priori for many theoretical individuals and then used for validation of population data sets (see references 22 and 23 for applications in the vitamin A field). Next, we used the known values for model parameters as inputs into a compartmental model for vitamin A metabolism and used WinSAAM to simulate plasma retinol kinetic response data for each individual.…”

Section: Methodsmentioning

confidence: 99%

A Population-Based (Super-Child) Approach for Predicting Vitamin A Total Body Stores and Retinol Kinetics in Children Is Validated by the Application of Model-Based Compartmental Analysis to Theoretical Data

Ford

Green

2018

Current Developments in Nutrition

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BackgroundPublic health nutritionists need accurate and feasible methods to assess vitamin A status and to evaluate efficacy of interventions, especially in children. The application of population-based designs to tracer kinetic data is an effective approach that reduces sample burden for each child.ObjectivesObjectives of the study were to use theoretical data to validate a population-based (super-child) approach for estimating group mean vitamin A total body stores (TBS) and retinol kinetics in children and to use population-based data to improve individual TBS predictions using retinol isotope dilution (RID).MethodsWe generated plasma retinol kinetic data from 6 h to 56 d for 50 theoretical children with high vitamin A intakes, assigning values within physiologically reasonable ranges for state variables and kinetic parameters (“known values”). Mean data sets for all subjects at extensive (n = 36) and reduced (n = 11) sampling times, plus 5 data sets for reduced numbers (5/time, except all at 4 d) and times, were analyzed using Simulation, Analysis and Modeling software. Results were compared with known values; population RID coefficients were used to calculate TBS for individuals.ResultsFor extensive and reduced data sets including all subjects, population TBS predictions were within 1% of the known value. For 5 data sets reflecting numbers and times being used in ongoing super-child studies, predictions were within 1–17% of the known group value. Using RID equation coefficients from population modeling, TBS predictions at 4 d were within 25% of the known value for 66–80% of subjects and reflected the range of assigned values; when ranked, predicted and assigned values were significantly correlated (Rs = 0.93, P < 0.0001). Results indicate that 7 d may be better than 4 d for applying RID in children. For all data sets, predictions for kinetic parameters reflected the range of known values.ConclusionThe population-based (super-child) approach provides a feasible experimental design for quantifying retinol kinetics, accurately estimating group mean TBS, and predicting TBS for individuals reasonably well.

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Section: Methodsmentioning

confidence: 99%

A Population-Based (Super-Child) Approach for Predicting Vitamin A Total Body Stores and Retinol Kinetics in Children Is Validated by the Application of Model-Based Compartmental Analysis to Theoretical Data

Ford

Green

2018

Current Developments in Nutrition

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“…By using modeling to generate theoretical data, and then adding error to the data so data would be comparable to those collected in retinol kinetic studies in humans and calculating reference values for the parameters of interest, we established a “gold standard” for evaluating accuracy of predictions and were thus able to test our hypotheses. Theoretical data are used to test methods and evaluate protocols in pharmacokinetics (31), and we have previously used this approach to test other methods in the vitamin A field (11–14).…”

Section: Discussionmentioning

confidence: 99%

“…Here, we asked whether inclusion of dietary vitamin A intake data as an additional input during compartmental modeling would improve the accuracy of model predictions of TBS and other state variables as well as retinol kinetic parameters and whether the additional data would impact the study duration required to obtain accurate predictions. To evaluate these hypotheses, we generated data for 12 theoretical human subjects with a range of values for age, state variables (including dietary vitamin A intake and TBS), and retinol kinetic parameters to use as reference values—an approach we have previously used to validate other methods in the vitamin A field (11–14). Our current results indicate that addition of vitamin A intake as a modeling input allows for accurate prediction of state variables, including TBS, and retinol kinetic parameters in studies of reasonable duration.…”

Section: Introductionmentioning

confidence: 99%

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

Ford

Green

2019

The Journal of Nutrition

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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.

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“…This pseudoequilibrium, in which the dose is preferentially retained in the liver due to new, incoming unlabeled VA in the diet and/or sequestration of a large dose, has been seen Sheftel et al Swine as a model for infants and lactation 583 in earlier RID studies, leading to the inclusion of a specific activity factor of 0.65-0.80 in RID equations when these factors are present. 7,11,34 In the absence of either of those two factors, it has been predicted 11,35 and shown in rats and monkeys 6,31 that complete equilibrium (specific activity of 1) can be achieved. In this study, feed was used that contained a small amount of b-cryptoxanthin but was otherwise VA-deficient, which resulted in deficiency (liver VA stores 0.043 lmol/g) in these piglets.…”

Section: Discussionmentioning

confidence: 99%

Retinol isotope dilution accurately predicts liver reserves in piglets but overestimates reserves in lactating sows

Sheftel

Surles

Tanumihardjo

2019

Exp Biol Med (Maywood)

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Retinol isotope dilution (RID) is used to estimate total body vitamin A (VA) stores in groups to assess VA status. Metabolic differences during lactation may affect RID calculations as currently applied. We evaluated the time required for isotopic equilibration between serum and liver retinol in piglets, and the utility of milk retinol isotopic enrichment as a proxy for serum in lactating sows. Piglets ( n = 24) and sows ( n = 6) were fed 1.75 or 20 µmol 13 C2-retinyl acetate, respectively. Piglets ( n = 5 or 7) were killed on d 0, 4, 7, or 14. Blood and milk were collected at d 0, 0.5, 1, 2, 4, 7, 10, 14, and 21 before the sows were killed to collect liver. Retinol 13 C-enrichment was determined by gas chromatography-combustion-isotope ratio mass spectrometry. Equilibration time and RID-predicted liver VA reserves were calculated. In piglets, serum and liver retinol 13 C-enrichment differed significantly in individuals at d 4 and 7 ( P = 0.008, 0.03) but not d 14 ( P = 0.06); however, mean values were not different by d 4 ( P = 0.62). Current RID equations accurately predicted VA deficiency (means ≤0.027 µmol/g liver) in the piglets. In sows, milk and serum retinol 13 C-enrichment reached equilibrium between 2 and 7 d post-dose. After correcting for dose lost to milk, RID equations predicted higher liver stores than measured values even though the serum to liver atom % was 1.00 ± 0.01 at kill. In VA deficient infants, a shorter period may be accurate in population-level RID studies when using appropriate assumptions. In lactating women, the RID may have decreased accuracy due to variable losses of tracer in milk. Furthermore, assumptions about storage and loss of the dose in milk must be evaluated in lactating women considering the observed discrepancy between predicted and measured stores. Impact statement Vitamin A (VA) deficiency and hypervitaminosis A have been reported in groups of people worldwide. Conventional biomarkers of VA deficiency (e.g. serum retinol concentration, dose response tests) are not able to distinguish between sufficiency and hypervitaminosis A. Retinol isotope dilution (RID) predictions of VA status have been validated in humans and animal models from deficiency through toxicity; however, RID during life stages with unique issues related to isotopic tracing, such as infancy and lactation, requires further evaluation. This study investigated RID in piglets and lactating sows as models for human infants and women. In piglets, RID successfully determined VA deficiency (confirmed with liver analysis), and that the tracer mixes quickly. Conversely, in lactating sows, although serum and milk enrichments were similar, traditional RID equations overestimated VA stores, likely due to losses of tracer and higher extrahepatic VA storage than predictions. These data inform researchers about the challenges of using RID during lactation.

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Retinol Isotope Dilution Is Applied during Restriction of Vitamin A Intake to Predict Individual Subject Total Body Vitamin A Stores at Isotopic Equilibrium

Abstract: By eliminating or strictly limiting vitamin A input, isotopic equilibrium was reached by 5 d. At isotopic equilibrium, SA is the same as that in the body's exchangeable vitamin A pools; under these conditions, SA may be measured at any time from 5 d on and used to calculate TBS.

Cited by 18 publications

References 7 publications

A Population-Based (Super-Child) Approach for Predicting Vitamin A Total Body Stores and Retinol Kinetics in Children Is Validated by the Application of Model-Based Compartmental Analysis to Theoretical Data

A Population-Based (Super-Child) Approach for Predicting Vitamin A Total Body Stores and Retinol Kinetics in Children Is Validated by the Application of Model-Based Compartmental Analysis to Theoretical Data

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

Retinol isotope dilution accurately predicts liver reserves in piglets but overestimates reserves in lactating sows

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