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This Article Full Text Full Text (PDF) All Versions of this Article: 289/5/E915    most recent 00503.2003v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via ISI Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Panunzi, S. Articles by Mingrone, G. Search for Related Content PubMed PubMed Citation Articles by Panunzi, S. Articles by Mingrone, G.

Approximate linear confidence and curvature of a kinetic model of dodecanedioic acid in humans

¹Laboratorio di Biomatematica, Centro Nazionale delle Ricerche, Istituto di Analisi dei Sistemi ed Informatica "A. Ruberti"; and ²Universita' Cattolica, Cattedra di Medicina Interna II, Rome, Italy

Submitted 7 November 2003 ; accepted in final form 15 June 2005

Dicarboxylic acids with an even number of carbon atoms have been proposed as an alternate energy substrate for enteral or parenteral nutrition in the acutely ill patient, due to their water solubility and their yielding TCA cycle intermediates upon -oxidation. In the present work, a nonlinear compartmental model of the kinetics of dodecanedioic acid is developed, and its parameters are estimated from time concentration experimental observations obtained from six healthy volunteers undergoing a per os administration of 3 g of the substance. Although the model is linear in the transfer of the free substance from plasma to the tissues, the exchange between gut and plasma compartments is represented as a saturable function. Albumin binding is then incorporated to obtain the final model in terms of the measured total concentrations. Estimates of the model's structural parameters were computed for each experimental subject, and the usual single-subject approximate confidence regions for the parameters were derived by inversion of the Hessian at the optimum. To verify the applicability of this approximation, the nonlinearity of the expectation surface at the optimum was measured by computing the normal (intrinsic) component of curvature. Because the model curvature was excessive in all subjects, the usual approximation could not be trusted to provide acceptable approximations to the parameter confidence regions. A suitable Monte Carlo simulation yielded empirical joint parameter distributions from which the approximate parameter variances could finally be obtained.

mathematical models; metabolism; kinetics; nonlinear parameter estimation; confidence regions