Reference Intervals in Clinical Chemistry — ISO 15189 Requirements

Reference intervals (also called reference ranges or normal ranges) are fundamental to medical laboratory reporting. ISO 15189:2022 has specific requirements for how reference intervals are established, verified, and maintained.

A reference interval defines the values expected in a healthy reference population. When a patient’s result falls outside this range, it flags potential disease. Incorrect reference intervals lead to misdiagnosis — making this a critical quality element.

Types of Reference Intervals

• Established reference intervals: Published in scientific literature or provided by reagent/instrument manufacturers
• Verified reference intervals: Established intervals confirmed to be appropriate for your laboratory’s population and methodology
• Locally established reference intervals: Derived from your own population study

ISO 15189:2022 Requirements

ISO 15189:2022 requires that laboratories:

• Define and document all reference intervals
• Verify reference intervals for their population when using manufacturer-supplied ranges
• Periodically review reference intervals when methodology, instrumentation, or population changes
• Communicate reference intervals clearly on reports
• Apply age- and sex-specific intervals where appropriate

Reference Interval Verification — A Practical Approach

For most labs, a simplified verification using 20 healthy subjects is acceptable:

1. Select 20 apparently healthy subjects from your patient population
2. Test them under standard conditions
3. If 18 out of 20 values fall within the stated reference interval, the interval is verified as appropriate
4. Document the verification study