Standardization and harmonization of analytical examination results

Background

The purpose of a clinical laboratory test is to provide information on the pathophysiologic condition of an individual patient to assist with diagnosis, to guide or monitor therapy, or to assess risk for a disease. Results for the same measurand must be equivalent when measured using different measurement procedures (MPs) to avoid medical errors when using clinical decision values to interpret those results. Standardization or harmonization of results is accomplished by metrological traceability of calibration to the same reference system and by MPs having adequate selectivity for the measurand being measured.

Content

The purpose of a clinical laboratory test is to provide information on the pathophysiologic condition of an individual patient to assist with diagnosis, to guide or monitor therapy, or to assess risk for a disease. Results for the same measurand must be equivalent when measured using different MPs to avoid medical errors when using clinical decision values to interpret those results. Standardization or harmonization of results is accomplished by metrological traceability of calibration to the same reference system and by MPs having adequate selectivity for the measurand being measured.

The International Organization for Standardization (ISO) has published a series of standards that describe requirements for metrological traceability of results for patients’ samples to higher-order references, including a harmonization protocol, for reference materials (RMs) and reference MPs used in metrological traceability, and for calibration laboratories that offer reference measurement services. The Joint Committee for Traceability in Laboratory Medicine reviews and approves RMs and reference MPs that conform to the ISO standards.

In vitro diagnostic manufacturers of end-user MPs used in clinical laboratories, including clinical laboratories that develop test procedures, establish metrological traceability to the available higher-order reference system for a measurand. When metrological traceability is successful, results for patients’ samples agree among different MPs. Important limitations in achieving harmonized results are that higher-order references are available for only a little over 100 measurands and some matrix-based RMs in use are not commutable with patients’ samples, which causes disagreement among results from different MPs. External quality assessment or proficiency testing using commutable samples is an important procedure to monitor the success of harmonization and provide feedback to identify measurands that need better harmonization of results.

Regulations

Although standardization and harmonization of test results have been important goals in laboratory medicine for many decades, there have been few regulations requiring calibration of clinical laboratory MPs to be traceable to higher-order references. One of the first regulations was a directive passed by the European Commission in 1998 that by 2003 all in vitro diagnostic (IVD) devices sold in the European Union were required whenever possible to have calibration traceable to a higher-order reference system. The directive was replaced by a regulation in 2017, effective 2022, with essentially the same requirements but adding a formal review and approval process. In response to the European Commission directive, the International Organization for Standardization (ISO) developed standards for higher-order reference system components and the Joint Committee for Traceability in Laboratory Medicine (JCTLM) was formed to approve reference system components for use by IVD medical device manufacturers. Other countries are introducing regulations requiring calibration hierarchies that are metrologically traceable to higher-order reference systems. In addition, many countries have regulations and a regulatory review agency that approve all medical devices including clinical laboratory MPs as safe and effective before they can be sold. Unfortunately, not all regulatory agencies require metrological traceability to approved reference systems when available. Consequently, harmonization of regulatory approval procedures in different countries would contribute to improved harmonization of results among different MPs for the same measurand.

Terminology

The term analyte refers to the name of the substance being analyzed or measured. The term “measurand” refers to the quantity intended to be measured or the quantity subject to measurement in a stated matrix where quantity means the property of the molecular substance being measured. For example, in the phrase “mass of creatinine in blood serum,” the analyte is creatinine, the measurand is creatinine in blood serum, and the quantity being measured is the mass of creatinine. If we measured the mass of creatinine in urine, the analyte and quantity are the same, but the measurand is different because the sample matrix is now urine rather than blood serum. The measurand can be difficult to specify for complex molecules such as proteins. For example, when measuring the “mass of albumin in urine” using a mass spectrometry MP after trypsin digestion, the analyte is albumin, the measurand defined as the quantity intended to be measured is albumin in urine, but the quantity actually measured is a specific trypsin amino acid fragment presumably derived only from the intact albumin in the urine. In clinical laboratory medicine, we frequently use the terms analyte and measurand colloquially and the reader or listener must infer what is the correct measurand from the context of the usage.

Various terms are used to describe a measurement procedure in different contexts. An MP is a written description of a measurement process including reagents, calibrators, equipment, software, procedure for calibration, calibration hierarchy, etc., and how measurements are made on specified samples using these items. A measuring system is the physical embodiment of an MP that is used by a laboratory to make measurements on a physical sample. A measuring system is also called an IVD medical device developed by an IVD manufacturer for use by a clinical laboratory. Note that an IVD measuring system may be produced by a commercial manufacturer or by a clinical laboratory for its own use when it is also called a laboratory developed test. In this chapter, the abbreviation MP is used to refer to a written description of a MP or to a measuring system used to make measurements on samples. The intended meaning is clear from the context.

The term method is typically used to describe the technology or measurement principle used in an MP; examples include ion-selective electrode, kinetic spectrophotometry, mass spectrometry. The term method is sometimes used to mean a specific MP or physical measuring system based on that MP used in a laboratory. The term assay is used similarly to method to mean either a type of measurement principle or a specific MP or physical measuring system used in a laboratory. The terms assay and method are vague and not used in this chapter.

The terms standardization and harmonization (or standardized and harmonized ) are frequently used interchangeably to refer to achieving equivalent results, within clinically acceptable limits, for patients’ samples measured using different clinical laboratory MPs. The term standardization has traditionally been used when calibration is metrologically traceable to a certified reference material (CRM) and/or a reference measurement procedure (RMP) as described later. The ISO standard 17511:2020 uses the term harmonization in the context of an international harmonization protocol to achieve equivalent results based on a consensus approach for metrological traceability to harmonization reference materials (RMs) as described later.