This Scientific Short is an update to What is the current state of reference intervals in Canada? A need for harmonization provided by the original author.

Harmonization of the total testing process in laboratory medicine is of utmost importance to ensure high quality and consistent patient care. While great attention has been given to harmonizing and standardizing the analytical phase, there has been a lack of harmonization in the post-analytical phase, specifically of reference intervals. A survey published in 2017 by the Canadian Society of Clinical Chemists (CSCC) Reference Interval Harmonization Working Group (hRI-WG) showed the vast variation in reference intervals for routine blood tests across Canadian laboratories, even across laboratories using the same analytical instrument (1). Reference interval differences were evident despite great comparability in laboratory results using commutable reference samples. These findings support the notion that reference interval variation across laboratories cannot be merely explained by analytical differences between assays, but may be due to the limited availability of evidence-based reference intervals. This consequently leads to laboratories implementing reference intervals from different sources over time (e.g. manufacturer package inserts, literature, in-house studies, etc.). To address this critical harmonization gap, the CSCC hRI-WG, formed in 2015, aims to develop evidence-based harmonized reference intervals and support their implementation in clinical laboratories across Canada.

Harmonized reference intervals are only appropriate for assays that exhibit minimal variation across methods, permitting common interpretation. Several initiatives have worked to establish harmonized reference intervals for clinical implementation, using data-driven and/or consensus-based approaches. Such initiatives include Nordic Reference Interval Project (NORIP), the Australasian Harmonized Reference Intervals for Paediatrics (AHRIP) and Australasian Harmonized Reference Intervals for Adults (AHRIA), and the UK Pathology Harmony project supported by the Association of Clinical Biochemistry (ACB). The CSCC hRI-WG took an evidence-based, big data approach to establish harmonized reference intervals, intended for use in Canadian clinical laboratories.

Phase I of the CSCC hRI-WG initiative assessed 16 analytes, ultimately recommending harmonized reference intervals for all but one of them (i.e., free thyroxine (FT4)) (2). Briefly, the approach taken by the CSCC hRI-WG began by extracting 2 years of retrospective adult outpatient data from four community laboratories across Canada with different analytical instruments. Differences between age, sex, geographical location, and analytical instrument were assessed. The refineR algorithm was used to calculate harmonized reference intervals, when appropriate (i.e., no difference between geographical location/analytical instrument). Harmonized reference intervals were then verified for serum and plasma across nine Canadian clinical laboratories using different analytical instruments. Reference interval harmonization exhibited limitations for some analytes, including recommendations to harmonize potassium reference intervals for serum only and to harmonize albumin reference intervals for bromocresol green methods only. The CSCC hRI-WG recommends clinical laboratories perform a local verification of the proposed harmonized reference intervals prior to implementation.

The CSCC hRI-WG encourages all Canadian clinical laboratories to adopt their proposed evidence-based harmonized reference intervals and plans to support their national implementation. This will ultimately reduce inter-laboratory reference interval variation to improve test result interpretation and patient care across Canada.

References

  1. Adeli K, Higgins V, Seccombe D, Collier CP, Balion CM, Cembrowski G, et al. National Survey of Adult and Pediatric Reference Intervals in Clinical Laboratories across Canada: A Report of the CSCC Working Group on Reference Interval Harmonization. Clin Biochem. 2017 Jun 21
  2. Bohn MK, Bailey D, Balion C, Cembrowski G, Collier C, De Guire V, Higgins V, Jung B, Mohammed Ali Z, Seccombe D, Taher J, Tsui AKY, Venner A, Adeli K. Reference Interval Harmonization: Harnessing the Power of Big Data Analytics to Derive Common Reference Intervals Across Populations and Testing Platforms. Clin Chem. September 2023, Volume 69, No. 9