To Err Is Human

Harmonization of laboratory test results is one of the most pressing issues in laboratory medicine. The landmark 1999 report from the US Institute of Medicine “To Err Is Human: Building a Safer Health System” emphasized the importance of clinical practice guidelines to standardize decisions and treatments. Using guidelines was not new in 1999 but has assumed increasing importance in the practice of medicine. A 2015 follow up report from the Institute “Improving Diagnosis in Health Care” again emphasized the importance of guidelines and stressed that cooperation among the healthcare team, including laboratory professionals is essential to reduce diagnostic errors.

Neither of these reports recognized that laboratory test results frequently vary depending on the measurement procedure or laboratory performing the test. Consequently, diagnostic errors are possible when non-harmonized laboratory test results are interpreted using fixed decision values in clinical practice guidelines. For example, parathyroid hormone results varied four-fold across different laboratory measurement procedures, yet a guideline recommended the drug Cinacalcet to treat calcium and phosphate imbalance in chronic kidney disease when the parathyroid hormone exceeded a fixed value (1). Urine albumin to creatinine ratios of 30 mg/g (3.4 mg/mmol) and 300 mg/g (34 mg/mmol) are almost universally used in guidelines to identify micro- and macro-albuminuria in diabetes or hypertension, despite a 45 percent difference in median results among different laboratory measurement procedures for urine albumin (2). Steroid hormone measurements such as testosterone and estradiol have 100 percent or more variability among different measurement procedures making clinical guidelines difficult to develop or apply (3).

A substantial infrastructure has been developed to provide tools and procedures for harmonization of laboratory test results (4). The International Standards Organization (ISO), for example, has standards for reference materials, reference measurement procedures, and reference laboratory services. The Joint Committee for Traceability in Laboratory Medicine (JCTLM) reviews specific components of reference systems that conform to one of the ISO standards and lists those that meet the criteria. Measurement procedure producers use these approved reference systems to establish calibration traceability for the measurement procedures used in medical laboratories. At present, the JCTLM lists reference methods for 79 analytes and reference materials for 162 analytes. However, no reference system exists for most of the 1,000-plus medical laboratory tests. Clearly, our profession has a challenge to fill this gap so that more test results can be harmonized.

In principle, calibration traceability to reference systems should produce harmonized results among different measurement procedures. Unfortunately, some analytes with reference system components remain non-harmonized. One of the main reasons for ineffective harmonization is lack of commutability of reference materials with authentic clinical samples (4). Commutable reference materials are those that have the same relationship for results between different measurement procedures as do clinical samples. Calibration traceability to commutable reference materials effectively harmonizes results for clinical samples. Unfortunately, a number of older JCTLM listed and other international reference materials are not commutable, so when they are used for calibration traceability the results for clinical samples do not agree among different measurement procedures (4). JCTLM now requires commutability validation for reference materials intended to be used as calibrators for medical laboratory tests. Therefore, all providers of reference materials should ensure commutability for new reference materials.

Another challenge for harmonization is the large number of analytes for which there are no reference system components available. This problem was addressed at a conference in 2010 (5) and mechanisms are now being developed by the International Federation of Clinical Chemistry and Laboratory Medicine, the International Consortium for Harmonization of Clinical Laboratory Results and ISO to use international consensus harmonization protocols to achieve agreement for clinical sample results among different measurement procedures.

An interesting challenge for implementing new calibration schemes to achieve harmonized test results is conformance to regulatory requirements. Many countries have regulations that require measurement procedure manufacturers to resubmit for approval when a test has been recalibrated to conform to international harmonization recommendations. Our profession needs to collaborate with regulatory agencies to streamline and lower the cost for approval of harmonized measurement procedures – such realignment of calibration is clearly in the best interest of good medical care. New measurement procedures should be required to demonstrate calibration traceability to approved reference systems, when they exist, rather than simply demonstrating agreement with another measurement procedure already on the market.