Year: 2022
Type: article
Abstract: Clinical laboratory measurements that are accurate and comparable across measurement systems and over time are critical for patient care and public health systems. Evidence-based clinical practice guidelines recommend specific decision points to guide clinical decisions. Electronic health records include patient laboratory data, transferrable across healthcare systems, that inform physicians about a patient’s health history. Laboratory data generated within and across healthcare systems are used to characterize patient populations, identify public health concerns, and track outcomes. Patients access their laboratory results, compare them with publicly available information, and discuss them with healthcare providers. These recent developments have advanced the roles of the clinical laboratory and introduced opportunities for laboratories to provide valuable new information to the patient and the healthcare team. However, these advancements and opportunities require accurate and reliable laboratory measurements. Reliability, in this context, comprises characteristics such as analytical sensitivity, specificity, precision, and consistency over time. Harmonization of laboratory measurement results and standardization, a more specific way of harmonizing results, can help to achieve this. Harmonization creates laboratory measurements that are applicable to practice guidelines, comparable, and interoperable across health systems and over time. Inadequately harmonized measurements prevent efficient and appropriate healthcare delivery and impact the clinical laboratory’s ability to contribute to the healthcare team effectively and successfully. The clinical impacts of poor result harmonization have been described for many years. For example, in 2010, the Institute of Medicine recognized that “a single individual might be deemed deficient or sufficient [for vitamin D], depending on the laboratory where the blood is tested” (1). Clinical practice guidelines, such as the 2013 Endocrine Society Guideline on the Diagnosis and Treatment of Polycystic Ovary Syndrome, pointed out that “given variability in testosterone (T) levels and the poor standardization of assays, it is difficult to define an absolute level that is diagnostic of PCOS or other causes of hyperandrogenism” (2). Additionally, research studies found that estradiol assays lack the accuracy to measure the very low serum estradiol levels in patients treated with aromatase inhibitors (3). The need for accurate and reliable assays is also reflected by the publication of analyte standardization priority lists by major stakeholders, such as the Partnership for the Accurate Testing of Hormones and the International Consortium for Harmonization of Clinical Laboratory Results. The CDC started standardizing traditional blood lipids over 60 years ago and achieved assay measurement comparability globally. The success of this CDC program inspired the establishment of the National Glycohemoglobin Standardization Program, which is modeled after the CDC Cholesterol Reference Method Laboratory Network program (4). Hemoglobin A1c measurements are now highly harmonized and comparable globally. The CDC only recently received congressional funding to support its standardization and harmonization programs. This crucial funding enabled the CDC to: (a) maintain and expand standardization programs to include new and emerging cardiovascular disease biomarkers, such as lipoproteins; (b) broaden its scope from 4 traditional blood lipids (total cholesterol, triglycerides, and high- and low-density lipoprotein-cholesterol) to 26 analytes relevant to endocrine and other chronic diseases; and (c) strengthen technical support of other organizations, such as the College of American Pathologists, the National Institute of Standards and Technology, the UK National Institute for Biological Standards and Control, and the French Laboratoire national de métrologie et d’essais. Funding further enabled the CDC to establish projects for new reference interval development to facilitate harmonized measurements use and to assess point-of-care testing devices. The CDC’s Clinical Standardization Program (CSP) is comprised of comprehensive programs, focused projects, and technical support. These activities enable thousands of laboratories to obtain analytical performance information about their assays. The CDC CSP helps laboratories and assay manufacturers to improve assay accuracy and reliability through thorough, independent, and transparent assessments, and certifies program participants that meet performance criteria established by clinical stakeholders. The CDC CSP lists over 200 successful program participants on its website (https://www.cdc.gov/labstandards/hs.html). Through CDC CSP’s work, laboratories and assay manufacturers have a comprehensive range of tools available to appropriately assess and improve analytical performance. It creates and supplies high-quality, single-donor reference materials, supports the development of certified reference materials available at metrological organizations, and conducts and supports accuracy-based longitudinal and cross-sectional surveys available through the CDC CSP and External Quality Assessment providers. Laboratories and assay manufacturers that successfully participate in the CDC CSP show a higher level of accuracy and reliability compared to other laboratories and manufacturers (5, 6). Furthermore, continuous participation in these programs leads to continued improvements in accuracy (7). The benefits of using accurate and reliable assays are well recognized by stakeholders. Organizations such as Partnership for the Accurate Testing of Hormones, which includes the AACC and College of American Pathologists, promote the use of standardized tests. Researchers use assays that are standardized by the CDC CSP and include quality control materials characterized by the CDC’s reference laboratories in their studies, such as the National Health and Nutrition Examination Survey (8), VITamin D and OmegA-3 TriaL (VITAL) (9), and T-trials (10). Organizations such as the Endocrine Society develop guidelines with clinical decision points established with standardized assays (11) and develop educational materials focused on assay quality and standardization. Additionally, device manufacturers provide information about traceability to the CDC CSP in their package inserts, and payers recognize the importance of using standardized assays (12). Despite considerable progress, challenges to improve the accuracy and reliability of assays used in patient care remain. Standardization program participation is voluntary. As a result, standardized and nonstandardized assays are used in patient care without any distinction. For example, even though the CDC’s Vitamin D Standardization-Certification Program has been in place for 9 years, nonstandardized assays without sufficient accuracy are still utilized; thus, the potential of misclassifying patients persists, as pointed out in a recent College of American Pathologists report. Clinical applications change, along with the analytical performance requirements. Low-density lipoprotein-cholesterol targets, for example, are much lower in recent guidelines than in the previous National Cholesterol Education Program guidelines. Therefore, analytical performance requirements and assessments developed for the National Cholesterol Education Program guidelines need to change accordingly. With harmonization of assay calibration, other sample-specific factors affecting measurement accuracy and reliability, such as those related to analytical specificity, become more apparent and can be addressed more effectively. As a first step, CDC CSP is providing information about the accuracy observed in individual samples for certified assays on its website, and is assisting researchers in investigating the impacts of different molecular structures of biomarkers on measurement accuracy. It is also important to note that as technologies, instruments, and reagents evolve and change, the analytical performance can change. Thus, assays need to be harmonized continuously, meaning reference methods and materials need to be maintained constantly using approaches that are sensitive enough to detect and address concerning changes before they affect patient care. The CDC CSP continues the work, together with partners, to provide unique harmonization services to the clinical and public health communities by assisting with reference measurements, materials, and technical support to national and international laboratories, assay manufacturers, and clinical organizations. Author Contributions:All authors confirmed they have contributed to the intellectual content of this paper and have met the following 4 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; (c) final approval of the published article; and (d) agreement to be accountable for all aspects of the article thus ensuring that questions related to the accuracy or integrity of any part of the article are appropriately investigated and resolved. Employment or Leadership: H.W. Vesper is Chair of the IFCC Committee for Standardizing Thyroid Function Tests and co-Chair of the Partnership for the Accurate Testing of Hormones. Consultant or Advisory Role: None declared. Stock Ownership: None declared. Honoraria: None declared. Research Funding: None declared. Expert Testimony: None declared. Patents: None declared. Disclaimer: The findings and conclusions in this report are those of the author(s) and do not necessarily represent the official position of the Centers for Disease Control and Prevention/the Agency for Toxic Substances and Disease Registry. Use of trade names is for identification only and does not imply endorsement by the Centers for Disease Control and Prevention, the Public Health Service, and the US Department of Health and Human Services.
DOI: 10.1093/jalm/jfac061
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $3,857
OpenAlex ID: W4288080463