Summer 2010 Meetings
Clinical Advisory Committee | NGSP Steering Committee | Manufacturer Forum
2010 NGSP Steering Committee Meeting
American Association for Clinical Chemistry Annual Exposition, July 2010
Below is a summary of the issues discussed.
NGSP Progress Report: Randie Little, NGSP Network Coordinator
The NGSP network laboratories continue to demonstrate excellent comparability; monthly between-lab CVs were all <2.5% over the past year. The number of certified methods and laboratories continues to increase. CAP results show much improvement in the comparability of HbA1c results since 1993. On the CAP 2010A survey a few methods still show significant bias and/or imprecision, but the biases for 23 of 30 methods were <0.3% HbA1c, and 93% of laboratories are using methods with between-lab CVs<5%, at all three HbA1c levels. Overall pass rates at the current CAP limits of +/-8% HbA1c were >95%. The NGSP certification criteria for the 95% CI of the differences between a method and the NGSP were tightened from +/- 0.85% HbA1c to +/- 0.75% in January 2010. The CAP began accuracy-based grading for HbA1c using NGSP-assigned target values in 2007 with an acceptable limit of +/-15%; this was subsequently reduced to +/- 12%, +/- 10% and +/- 8% in 2008, 2009 and 2010, respectively. The CAP acceptable limit will be further reduced to +/- 7% for 2011 and 2012. It is difficult to directly compare the CAP and NGSP criteria since the former is based on a single sample while the latter is based on 40 samples, but the CAP criteria are clearly tighter in the normal range while the two are comparable at ~9.5% HbA1c.
Discussion: The committee decided not to tighten the NGSP certification criteria at this time even though they are less stringent than the CAP criteria in the low and middle HbA1c range. The subject will be reconsidered next year, the NGSP may consider using criteria based on % bias in order to be more consistent with the CAP acceptance limits.
Uncertainty of CAP Value Assignments: Curtis Parvin, NGSP Steering Committee
Dr. Parvin calculated the uncertainty of both the NGSP target value assignments for the CAP survey (based on 2009 data) and IFCC value assignments for the secondary reference materials used by manufacturers. The combined total CV estimates (incorporating both the NGSP and most recent IFCC value assignments) was 0.75%. These estimates were then used to calculate the performance requirements for a manufacturer’s assay method to pass the current (+/-8%) and future (+/-7%) CAP criteria with 95 and 99% probability after accounting for value assignment uncertainty. For example, at a true HbA1c value of 7, a between-lab method CV of ~3.5% or less is required to pass the future +/-7% CAP criterion with 95% probability (99% probability requires a CV of ~2.5% or less) if there is no bias. If there is a bias of 0.1% HbA1c a CV of ~3% or less is required for 95% probability.
Discussion: Performance requirements should be based on clinical needs; unfortunately it is very difficult to precisely define clinical needs for HbA1c, it depends to some extent upon exactly how the test is utilized. CAP had planned to tighten the acceptance limits to +/-6% for 2011 but they have now decided on +/-7% for 2011 and 2012 due to concerns about failing too may laboratories. The goal is still to eventually tighten the limits to +/-6%. The recent recommendation to use HbA1c for the diagnosis of diabetes and pre-diabetes makes continual improvement of HbA1c assays even more important.
Hemoglobin Variant Interference Update: Randie Little
The NGSP regularly evaluates new assay methods for potential interference from the four most common hemoglobin variants (HbAS, HbAC, HbAE and HbAD). This information is updated on the NGSP web site. Currently 4.2%, 21% and 6.5% of labs are using methods that show clinically significant interference (defined as ≥10% difference at 6 or 9% HbA1c) from HbAS and/or HbAC, HbAE and HbD, respectively. HbAE and HbAD interferences occur with ion-exchange HPLC methods and the interfering variant can generally be detected on the chromatogram prior to a result being reported. The ≥10% limit used to defining interference will likely be tightened in future studies.
Update on the Clinical Advisory Committee Meeting: David Sacks, NGSP Steering Committee Chair
The NGSP CAC met at the American Diabetes Association Annual Scientific Sessions in June. The CAC serves as an interface between major clinical organizations and the NGSP as well as manufacturers. There was much discussion regarding the recent recommendation to use HbA1c for diagnosing diabetes and pre-diabetes. It was suggested that HbA1c values should be reported as a range based on 95% confidence intervals. There was also much discussion regarding the performance and use of point-of-care HbA1c methods.
Discussion: The recommendation to use HbA1c for diagnosis has proven to be controversial, mainly because there is some discordance between individuals diagnosed using HbA1c versus glucose. However, glucose has some analytical variability comparable to that of HbA1c and there are additional pre-analytical issues with glucose. WHO may endorse the use of HbA1c for diagnosis. If so it will likely be added to the current glucose criteria and not replace glucose, there are concerns about costs of HbA1c testing in developing nations. Reporting of HbA1c results as a range might be helpful in getting across to healthcare providers that the number reported is not exact; however, there are potential pitfalls. Labs might not all report confidence intervals in the same way, and other analytes are not reported in this way, this could result in confusion when interpreting results. Perhaps the NGSP could publish a discourse on this topic on the NGSP web site, but physicians generally do not look at the NGSP site.
IFCC Reference System Report: Cas Weykamp, IFCC Network Coordinator
The IFCC Working Group on HbA1c Standardization has been disbanded by the IFCC Scientific Division, having fulfilled its mission to develop a reference method and materials for HbA1c. The network will continue and will be overseen by the IFCC Committee on Traceability in Laboratory Medicine. Educational work will be intensified via a new IFCC Integrated Project chaired by Garry John. The IFCC network continues to re-approve network laboratories annually, there are currently two candidate laboratories. The master equations between the IFCC and NGSP as well as the IFCC and Swedish system have remained stable. There has been some deviation between the IFCC and JDS systems in the upper range of HbA1c values, this continues to be investigated. A modification of the IFCC HPLC/MS reference method has been tested and approved. There was an issue with the manufacturing of calibrators for the IFCC reference method, this has now been resolved. The use of isotope-labeled hexapeptides for the HPLC/MS reference method is being investigated.
HbA1c Standardisation-- the Current Situation: Garry John, Chair, IFCC Integrated Project for HbA1c
A 2010 update to the 2007 Worldwide Consensus Statement has been published. It reiterates that HbA1c results should be standardized worldwide and that the IFCC reference system represents the only valid anchor for worldwide HbA1c standardization. Estimated average glucose (eAG) is not mentioned, the number of decimal places for reporting results is specified (none for IFCC mmol/mol, one for NGSP%), and there is a recommendation that conversion tables listing both IFCC and NGSP units be made easily accessible to the diabetes community. Other recommendations are that editors of journals and other materials should require that manscripts report both units, and HbA1c should be the official term for the analyte although other abbreviations (e.g. A1C) can be used in guidelines and educational materials. The aim of the new Integrated Project for HbA1c is to establish an interface between the IFCC and clinical users of HbA1c to enable implementation of a scientifically sound reporting structure for HbA1c standardized to the IFCC Reference Method. It will consist of approximately five members; objectives will include advising the Reference Lab network and manufacturers, establishing links with scientific and clinical bodies, assist with implementation of the Consensus Statement, and develop quality targets for HbA1c measurement. Currently many countries in Europe, as well as New Zealand and Australia, are reporting IFCC and NGSP/DCCT units but not eAG. The U.S. is reporting DCCT/NGSP and eAG.