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A Guide to Estimating the Reference Range From a Meta-Analysis Using Aggregate or Individual Participant Data.


Clinicians frequently must decide whether a patient's measurement reflects that of a healthy "normal" individual. Thus, the reference range is defined as the interval in which some proportion (frequently 95%) of measurements from a healthy population is expected to fall. One can estimate it from a single study or preferably from a meta-analysis of multiple studies to increase generalizability. This range differs from the confidence interval for the pooled mean and the prediction interval for a new study mean in a meta-analysis, which do not capture natural variation across healthy individuals. Methods for estimating the reference range from a meta-analysis of aggregate data that incorporates both within- and between-study variations were recently proposed. In this guide, we present 3 approaches for estimating the reference range: one frequentist, one Bayesian, and one empirical. Each method can be applied to either aggregate or individual-participant data meta-analysis, with the latter being the gold standard when available. We illustrate the application of these approaches to data from a previously published individual-participant data meta-analysis of studies measuring liver stiffness by transient elastography in healthy individuals between 2006 and 2016.

Acceptance Date Jan 21, 2022
Publication Date May 1, 2022
Journal American Journal of Epidemiology
Print ISSN 0002-9262
Publisher Oxford University Press
Pages 948 - 956
Publisher URL


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