Best practice guidelines on reference interval harmonization in Canada: Evidence-based recommendations from the CSCC working group on reference interval harmonization (CSCC WG-hRI)

Unnecessary variation in reference intervals across clinical laboratories increases the risk of inconsistent or misinformed clinical decision-making. Development of harmonized or common reference intervals for assays that demonstrate minimal bias across measurement procedures and laboratories is an important step towards standardized quality healthcare. The aim of this document is to recommend evidence-based harmonized reference intervals for routine clinical laboratory tests that can be implemented in hospital and community settings across Canada. The approach that was taken for these recommendations included several important steps. Candidate analytes for harmonization were selected based on documented traceability and external quality assessment performance. Two years of patient test result data for 16 routine clinical chemistry analytes were extracted from four provincial community laboratories across Canada. A robust indirect statistical algorithm was applied to assess the feasibility of harmonization and harmonized reference intervals were established for appropriate analytes. Derived harmonized reference intervals were compared to existing data from healthy individuals from Canadian and international studies. All recommended harmonized reference intervals were verified across nine Canadian laboratories that included all main manufacturers using serum and plasma samples collected from 60 healthy volunteers. Based on our findings, evidence-based harmonized reference intervals are recommended for 13 analytes, including: albumin (bromocresol green method only), alanine aminotransferase (ALT) with and without pyridoxal 5'-phosphate, alkaline phosphatase (ALP), calcium, carbon dioxide (total), chloride, creatinine, lactate dehydrogenase (LDH), phosphate, potassium (serum only), magnesium, total protein, and thyroid stimulating hormone (TSH). These recommendations will support national harmonization of laboratory reference intervals with the goal of improving and standardizing clinical decision-making and patient care across Canada.