Thematic review series: Patient-Oriented Research.Design and analysis of lipoprotein tracer kinetics studies in humans

P. Hugh R. Barrett, Dick C. Chan, Gerald F. Watts
2006 Journal of Lipid Research  
Lipoprotein tracer kinetics studies have for many years provided new and important knowledge of the metabolism of lipoproteins. Our understanding of kinetics defects in lipoprotein metabolism has resulted from the use of tracer kinetics studies and mathematical modeling. This review discusses all aspects of the performance of kinetics studies, including the development of hypotheses, experimental design, statistical considerations, tracer administration and sampling schedule, and the
more » ... of compartmental models for the interpretation of tracer data. In addition to providing insight into new metabolic pathways, such models provide quantitative information on the effect of interventions on lipoprotein metabolism. Compartment models are useful tools to describe experimental data but can also be used to aid in experimental design and hypothesis generation. The SAAM II program provides an easy-to-use interface with which to develop and test compartmental models against experimental models. The development of a model requires that certain checks be performed to ensure that the model describes the experimental data and that the model parameters can be estimated with precision. In addition to methodologic aspects, several compartment models of apoprotein and lipid metabolism are reviewed.-Barrett, P. H. R., D. C. Chan, and G. F. Watts. Design and analysis of lipoprotein tracer kinetics studies in humans. J. Lipid Res. 2006. 47: 1607-1619. Supplementary key words stable isotopes . compartment models . kinetics analysis . modeling . apolipoproteins . lipids Years of clinical investigation have provided valuable insight into the complexity of human lipoprotein metabolism. The measurement of plasma lipoprotein concentrations provides useful information, but from a functional viewpoint these concentrations reflect the balance between input and output in the lipoprotein system in plasma. The only way to quantify input and output in this system is by undertaking kinetics studies, typically using tracer methodology. These studies, however, are time-consuming and dif-ficult to perform. Nevertheless, they are important to characterize the pathways that result in dyslipidemic states and to describe the in vivo mechanisms of action of treatments designed to regulate dyslipidemia and cardiovascular disease risk in clinical practice. There are many steps to consider when planning such metabolic studies. This review touches on all aspects of the design and analysis of lipoprotein kinetics studies, including philosophical angles, tracer methodology, mathematical modeling, and statistical considerations related to experimental design and analysis. With the advent of commercial stable isotopes and endogenous labeling protocols, some aspects of performing kinetics studies are now easier than when radioactive tracers and laborious exogenous labeling of lipoproteins were required. However, the number of laboratories and research groups undertaking these types of metabolic studies has changed little, highlighting the complexity of the methods involved. In addition to the design and modeling aspects of lipoprotein kinetics studies, what we have learned from apolipoprotein B (apoB) and HDL apoA-I and apoA-II tracer kinetics studies is covered in the present series of reviews by Parhofer and Barrett (1) and Rashid, Patterson, and Lewis (2). Other recent reviews of the present field of investigation and its applications include those by Marsh et al. (3, 4) and Barrett, and Watts (5). For basic definitions of terms used in kinetics modeling, the reader is referred to these and other reviews (6, 7).
doi:10.1194/jlr.r600017-jlr200 pmid:16728729 fatcat:my3qh2fxjjhwli7e6zqlg3grai