Distance-to-optimum biological drift as a new framework for interpreting routine laboratory results: a benchmark against Reference Change Values across 62 routine biomarkers

Background: We propose the biological drift framework for the interpretation of biological test results: a z-score-like framework based on optimized and personalized reference populations and a distance-to-optimum drift metric for longitudinal interpretation relative to an estimated individual optimum. We benchmarked biological drifts against Reference Change Values (RCVs), which are used to interpret serial laboratory results by defining the minimum change expected to exceed normal within-subject biological variation CVi. Objectives: To benchmark biological drifts against the classical biological-variation framework and assess their consistency with RCV thresholds across routine biomarkers. Methods: For 62 routine biomarkers, biological drift levels were compared with RCVs after transformation to test the consistency between the two frameworks. Results: Severe biological drifts mostly exceeded the 95% RCV threshold, indicating changes unlikely to be explained by short-term biological variation alone. In contrast, moderate drifts reached the 95% RCV threshold for approximately one in two biomarkers, suggesting that many moderate distance-to-optimum deviations may remain within expected variability, particularly for biomarkers with large within-subject variation CVi. Results are particularly interesting for the follow-up of people with diabetes and for the management of thyroid and hepatic disorders. Conclusions: Biological drifts derived from optimized personalized reference populations are broadly consistent with the RCV framework for identifying biologically meaningful deviations from the optimum and may therefore be relevant for the monitoring of certain biomarkers across several medical conditions in clinical practice.