Derivation of level-specific reference change values (RCV) from a health screening database and optimization of their thresholds based on clinical utility

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Reference change values (RCV) are used for judging the significance of changes between any two measurements. Based on the within-individual CV (CVI), RCV is conventionally computed as the 95% confidence limit (CL) of the changes: Symbol However, the appropriateness of assuming a constant CVI and using the 95% CL for RCV remains controversial.


The level-specific CVI and RCV were estimated for 20 screening tests using a database composed of results from 13,545 health-screening attendees over a 17-year period, after preliminary exclusion of individuals taking medications or having unusual changes in body mass index (BMI). A rational CL for RCV was explored in reference to a clinical score for the metabolic syndrome, sMS, which was derived based on a logistic regression model consisting of tests related to metabolic syndrome. The effect of adjusting CL for the RCV on diagnostic efficacies of detecting between-year change in sMS was evaluated.


Test level dependency of CVI was apparent for some screening tests which have distributions with prominent skewing. The use of level-specific RCV was thus essential for them. The sensitivity for detecting a critical change in sMS based on the RCV set at 95%CL was extremely low in the majority of tests. However, by lowering CL stepwise from 95 to 75%, the sensitivity improved greatly without much change in specificity and positive predictive value. Loss-and-gain analysis showed that CL for RCV set around 80% gave the lowest loss, assuming a policy of reducing false negative judgment.


Level specific CVI and RCV were necessary in tests with skewed distributions. RCV using 80%-90% CL is suitable in health screening for diseases that require early intervention for changes.

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