Individual reference intervals for personalised interpretation of clinical and metabolomics measurements

The Population Reference Interval (PRI) refers to the range of outcomes that are expected in a healthy population for a clinical or a diagnostic measurement. It is widely used in daily clinical practice and is essential for assisting clinical decision-making in diagnostics and treatment. In this manuscript, we start from the observation that each healthy individual has its own range for a given variable, depending on personal biological traits. This Individual Reference Interval (IRI) can be calculated and be utilised in clinical practice, in combination with the PRI for improved decision making. Nonparametric estimation of IRIs would require quite long time series. To circumvent this problem, we propose methods based on quantile models in combination with penalised parameter estimation methods that allow for information-sharing among the subjects. Our approach considers the calculation of an IRI as a prediction problem rather than an estimation problem. We perform a simulation study designed to benchmark the methods under different assumptions. From the simulation study we conclude that the new methods are robust and provide empirical coverages close to the nominal level. Finally, we evaluate the methods on real-life data consisting of eleven clinical tests and metabolomics measurements from the VITO IAM Frontier study.