From Population to Subject-Specific Reference Intervals

In clinical practice, normal values or reference intervals are the main point of reference for interpreting a wide array of measurements, including biochemical laboratory tests, anthropometrical measurements, physiological or physical ability tests. They are historically defined to separate a healthy population from unhealthy and therefore serve a diagnostic purpose. Numerous cross-sectional studies use various classical parametric and nonparametric approaches to calculate reference intervals. Based on a large cross-sectional study (N = 60,799), we compute reference intervals for subpopulations (e.g. males and females) which illustrate that subpopulations may have their own specific and more narrow reference intervals. We further argue that each healthy subject may actually have its own reference interval (subject-specific reference intervals or SSRIs). However, for estimating such SSRIs longitudinal data are required, for which the traditional reference interval estimating methods cannot be used. In this study, a linear quantile mixed model (LQMM) is proposed for estimating SSRIs from longitudinal data. The SSRIs can help clinicians to give a more accurate diagnosis as they provide an interval for each individual patient. We conclude that it is worthwhile to develop a dedicated methodology to bring the idea of subject-specific reference intervals to the preventive healthcare landscape.