When test results fall outside the reference intervals in healthy individuals, it often leads to frustration and unnecessary investigations for potential diseases. These anomalies can be attributed to matrix effects or lack of selectivity but more commonly are due to the strict criteria we use when designing reference intervals that ultimately could be narrow for some tests (1–3).

The central question we raise here is whether it is time to reevaluate and redesign our approach to creating reference intervals to reduce the occurrence of false positives while minimizing false negatives. Here we provide a condensed overview of the history, theory, and practical considerations regarding reference intervals and why we firmly believe we need to update our approach for some tests.