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

Dick C Chan,P Hugh R Barrett,Gerald F Watts

doi:10.1194/jlr.r600017-jlr200

Abstract

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 development 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.

Highlights

Lipoprotein tracer kinetics studies have for many years provided new and important knowledge of the metabolism of lipoproteins
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
In addition to the design and modeling aspects of lipoprotein kinetics studies, what we have learned from apolipoprotein B 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]

Summary

DESIGN OF TRACER STUDIES

Before launching into the details of the analysis and modeling of tracer data, it is important to stress some funda-. The concept of balancing feedback can help explain why, for example, the effect of a primary change in catabolism is balanced by other changes in the whole system, including production rate Statistical methods, such as general linear modeling, mixed models, and multiple regression methods, are the preferred tools for end point analysis [17]. Cross-sectional comparisons without a priori hypotheses require similar adjustments to P values This approach guards against inappropriate statistical inferences drawn from poorly designed studies with small sample sizes. In as much as it uses a mathematical tool to understand the natural world (e.g., lipoprotein metabolism), mathematical modeling is a special form of “instrumentalist” science [18] This implies that, in contrast with a “realist” approach, it does not deal directly with observable entities, providing data that only approximate reality. There are a number of issues related to analysis and modeling that need to be considered in more detail below

LABELING METHODS

LABORATORY METHODS

CONCLUSION