Diabetes mellitus is a chronic disorder characterized by insulin deficiency, hyperglycemia, and high risk for development of complications of the eyes, kidneys, peripheral nerves, heart and blood vessels. The disease is highly prevalent, affecting as many as 16 million people in the U.S. (1,2). The disease is also expensive, in terms of both human suffering and dollars; it is estimated that approximately 1 in every 7 health care dollars spent in the U.S. goes to diabetes care, mostly for treatment of the chronic complications. In the U.S., diabetes is the most common cause of blindness in young adults, kidney failure, and nontraumatic limb amputation (3,4).
The landmark nine-year Diabetes Control and Complications Trial (DCCT), completed in 1993, showed that the risk for development and progression of the chronic complications of diabetes is closely related to the degree of glycemic control, as measured by glycated hemoglobin (GHB) determinations (5). The DCCT also provided a large body of data relating GHB values to mean blood glucose. Thus, the DCCT results have set the stage for establishing specific diabetes treatment goals using GHB as an index of mean blood glucose. However, the fact that GHB assay methods have not been standardized among laboratories has prevented optimal use of the test. Recent studies (6-10) have shown the advantages and feasibility of standardizing GHB assays, and a candidate reference method for GHB has been proposed (9,12).
Because of the positive impact standardization of GHB determinations would have on the care of diabetic patients, the American Association for Clinical Chemistry (AACC) Standards Committee established a GHB Standardization Subcommittee in April 1993. The goal of the subcommittee was to develop a plan for GHB standardization that would ultimately allow individual clinical laboratories to relate their GHB assay results to those of large-scale studies such as the DCCT, where relationships of GHB values to mean blood glucose and to risks for developing chronic diabetic complications have been established.
Although the DCCT was completed in 1993, the GHB assay systems from the study (13) are still in place as part of another National Institutes-sponsored long-term diabetes study called the Epidemiology of Diabetes Interventions and Complications (EDIC). In order to initiate a standardization program in a timely fashion, the subcommittee has recommended that the DCCT assay method be used as an interim reference method while studies are being performed to evaluate candidate definitive and reference methods and to develop purified GHB standards. Standardizing GHB results to DCCT values would allow individual clinical laboratories to provide diabetic patients and their health-care providers with test results that could be related directly to both mean blood glucose values and risks for development and/or progression of diabetic chronic complications.
Early efforts to standardize GHB values among clinical laboratories by using a "universal calibrator" (6) proved feasible with some assay methods. Later studies (9) showed, however, that such an approach, although relatively simple, did not work for a number of existing methods. It was found that materials prepared for use as calibrators, quality control materials, and proficiency-testing samples are often subjected to preparative processes that may cause them to yield results that differ appreciably from those of patient specimens, i.e., matrix effects. Therefore, since an important goal was to allow standardization of most existing and future assay methods, it was proposed that, for most assay methods, standardization to the DCCT reference could be performed best at the manufacturing level, where the most appropriate materials and standardization format for each method could be determined. It was also proposed that verification of method standardization should be based on fresh sample comparisons with the Reference Method [In this document, the interim reference method, which is the DCCT reference method, will be referred to as the "Primary Reference Method," although it is technically a "designated comparison method." (14)]
The approach to GHB assay standardization described here, and
which has been recommended by the Subcommittee on GHB Standardization,
is modeled after the Cholesterol Reference Method Laboratory Network
program (15). The Cholesterol program is based on performing
split-sample comparisons with the cholesterol reference method
and thus provides a means for manufacturers to establish traceability
to the National Reference System for Cholesterol. For GHB standardization,
a network of reference laboratories is calibrated to the DCCT
Reference values. A Central Primary Reference Laboratory (CPRL)
sets the initial calibration and is responsible for monitoring
back-up Primary Reference Laboratories (PRLs) and Secondary Reference
Laboratories (SRLs). The SRLs work directly with manufacturers
to standardize their methods and provide comparison data for method
certification, in order to achieve the desired end result of comparability
of fresh sample results with the DCCT Reference. Proficiency
testing (PT) data (from fresh sample surveys) is used to assess
the effectiveness of method standardization.
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