The Use of Datasets for Theoretical Subjects to Validate Vitamin A–Related Methods and Experimental Designs

Abstract

We review recent work in which model-based compartmental analysis has been applied to data for theoretical human subjects in order to study questions related to vitamin A kinetics and metabolism. Using model simulations in this way, one can validate experimental designs, evaluate or improve vitamin A assessment methods, study the influence of perturbations on assessment methods, and/or advance information related to retinol kinetics. We also provide some information on the rationale for assigning physiologically-appropriate values for specified characteristics [e.g., plasma retinol concentration, vitamin A total body stores (TBS), vitamin A intake] to hypothetical individuals; and in addition, we outline how one might first select an appropriate compartmental model for whole-body vitamin A metabolism and then specify physiologically-reasonable values for the associated retinol kinetic parameters. In the studies discussed here, the Simulation, Analysis and Modeling software was used to simulate responses in key model compartments for hypothetical subjects so that model predictions could be compared to assigned values or projected outcomes. For example, in the case of the retinol isotope dilution (RID) method that is used to assess vitamin A status, application of this approach has provided a way to evaluate the accuracy of TBS predictions under different steady state and non-steady state conditions, thus increasing confidence about the validity of RID results obtained in the field. Although datasets for theoretical subjects have been used to evaluate protocols in pharmacokinetics, to our knowledge, other nutrition researchers have not previously used approaches like those described here. Our results to date indicate that this strategy has the potential to provide useful information related not only to vitamin A but perhaps to other nutrients as well.

Use of Compartmental Modeling and Retinol Isotope Dilution to Determine Vitamin A Stores in Young People with Sickle Cell Disease Before and After Vitamin A Supplementation

“…Also of interest, among the 11 subjects with SCD-HbSS for whom data were available on both day 3 and day 28 postdosing, RID predictions of TBS were not significantly different. Although studies in theoretical subjects [ 16 ] indicate that later sampling times (>14 d in adults and >10 d in children) provide the most accurate RID predictions of TBS for the largest number of individuals, predictions for a group will be the same at all times if correct values for the composite coefficient FaS are used in the RID equation, along with the geometric mean SA p [ 18 ].…”

“…That is, since we did not obtain extensive retinol kinetic data after vitamin A supplementation in subjects with SCD-HbSS or in the healthy volunteers, we could not determine their group-specific values for FaS . Ideally, investigators should obtain group-specific values for the composite coefficient to ensure that the most accurate RID predictions of TBS for individuals will be calculated; when that is not possible, they should use values that were determined for a group that is as similar as possible to the one under study [ 16 ]. For example, if we had used 2.0, the d 3 value for FaS determined by Green and Green [ 47 ] for 20 theoretical healthy children who had a relatively low mean assigned value for TBS (284 μmol) rather than 2.4, the value for current subjects with SCD-HbSS, RID-predicted TBS for the healthy peer group would have been within 20% of the 406 μmol shown in Table 2 .…”

“…Although plasma retinol is often used as an indicator of vitamin A status, its sensitivity is limited because concentrations are homeostatically controlled over a wide range of vitamin A stores [ 3 , 12 ]. At present, retinol isotope dilution (RID) is considered the best available method for estimating vitamin A status (ie, vitamin A total body stores [TBS]) in groups, and it is also used to estimate TBS in individuals; see, for example, [ 2 , [13] , [14] , [15] , [16] ]. For an RID study, subjects ingest a dose of a vitamin A stable isotope, and a single blood sample is collected from each individual at a predetermined time; retinol specific activity in plasma (SA p ) is determined and then used in an RID equation, along with coefficients that reflect assumptions related to dose absorption, catabolism, and mixing, to predict TBS; see, for example, [ 2 , 13 , [17] , [18] , [19] ] for more details.…”