Diabetes mellitus is the seventh major cause of mortality worldwide  and is characterized by hyperglycemia. Hyperglycemia favors non-enzymatic glycation, a slow process that affects all proteins in the blood and tissues and alters their conformation and function, ultimately participating in micro- and macrovascular complications , . Hemoglobin is particularly prone to non-enzymatic glycation and HbA1c, the major form of glycated hemoglobin, is a well-known biomarker of diabetes mellitus , . As it reflects the mean glycemia over erythrocyte lifetime (approx. 120 days), HbA1c testing is widely used to ensure treatment adequacy and observance of patients with diabetes. Since 2009, HbA1c is also recommended as a diagnostic marker of diabetes , .
Given the prevalence of diabetes and the role of HbA1c measurements in patient care, evaluating the trueness of HbA1c assays is of prime importance. In addition to internal quality controls, participation in external quality assessments schemes (EQAS) helps to verify on a recurring basis that laboratory results meet quality requirements . As a measure of accuracy, a pair-wise comparison of individual laboratory results with the consensus mean of its peers or all participants, is very often used. It has been recommended that, if a reference measurement procedure (RMP) exists, method trueness should be estimated against the target value determined by the RMP . However, a prerequisite to evaluate trueness is that materials must be commutable for the concerned assay , , , .
Commutability is defined as the equivalence of mathematical relationships between the results obtained with different measurement procedures for a reference material or an EQA material and for representative samples from healthy and diseased individuals . It thus reflects the ability of the material to mimic clinical specimens (CSs). Although guidelines to produce commutable materials exist for cholesterol in serum , following CLSI C-37A guidelines does not per se guarantee the commutability of the material for other parameters and matrices. In the case of HbA1c, EQA materials generally consist in lyophilized hemolysates or stabilized whole blood. As commutability is a property of a material for a given measurement procedure, it cannot be predicted, and a material found commutable for one assay may not be commutable for another one.
This article presents the results of a commutability study performed on 26 processed quality control materials for 17 of the most frequently used HbA1c assays and the impact of materials commutability on trueness assessment and between-methods comparability . Trueness of frequently used HbA1c assays against the IFCC RMP is additionally presented.
Materials and methods
Commutability of processed EQA materials was assessed against a set of CSs consisting of fresh whole blood. Twenty-four diabetic and non-diabetic donors were selected to achieve a wide range of HbA1c concentrations so as to bracket the HbA1c concentrations of the EQA materials under investigation. CSs were collected at Solomon Park Research Laboratories (Kirkland, WA, USA) in EDTA tubes (Becton Dickinson, NJ, USA). Blood collection was performed in agreement with human subject protection laws and following IRB approved protocol. Freshly collected CSs were divided in two parts. A first half was kept fresh and stored at +4 °C until analysis. The second half was frozen immediately after collection and stored at −80 °C. HbA1c concentrations of the 24 CSs ranged from 30 mmol/mol (4.9% National Glycohemoglobin Standardization Program; NGSP) to 120 mmol/mol (13.1% NGSP), with a mean concentration of 55 mmol/mol (7.2% NGSP). Fresh CSs were collected from 23rd to 26th May 2017 and were shipped to participating laboratories on the 27th, in insulated boxes, on ice packs and under controlled temperature conditions (+4 °C). They were delivered on 30th May to European laboratories and on 31st May to US laboratories. Samples were assayed between 31st May and 2nd June. Concentrations of HbS, HbA2, HbC, HbE and HbF were measured in all single donations (Supplementary Data S1) . Elevated concentrations of HbS were detected in CSs 012 and 013 and these samples were excluded from data analysis.
EQA materials in which commutability was evaluated consisted of frozen stabilized whole blood or lyophilized whole blood. EQA materials were obtained from different EQA providers that did not all agree to disclose from which manufacturers samples were sourced but it can be expected that the different materials were produced using different manufacturing procedures. According to the information obtained from some EQA providers, there were sometimes different lots from the same producer, but this information could not be obtained for all the materials involved in this study. It should be noted that none of the EQA materials have indications for use as a trueness control or to evaluate accuracy.
Commutability of the 26 EQA materials was assessed for 17 HbA1c assays: immunoassays from Roche (Cobas C513), Beckman Coulter (DxC700AU B00389) and Siemens (DCA Vantage), enzymatic assay from Abbott (Architect C-4000), ion-exchange HPLC assays from Bio-Rad (D10, D100, Variant II NU and Variant II Turbo), Tosoh (G8, G11 and Gx) and Arkray (HA-8180T), affinity assay from Abbott (Abbott Afinion AS-100), boronate affinity HPLC assay from Trinity Biotech (Premier Hb9210) and capillary electrophoresis assays from Sebia (Capillarys 2, Capillarys 3 and Minicap). Detailed information on analyzers, reagent lots, calibrators and laboratories involved in the commutability study are provided in Supplementary Data S2. All samples (EQA materials, fresh CSs and frozen CSs) were analyzed in triplicates by all participants, altogether in a unique sequence. Measurements were performed in manufacturers’ quality control or R&D laboratories, except for Arkray, Trinity Biotech, Abbott and Siemens (measurements performed in expert laboratories are listed in Supplementary Data S2). All measurements were performed according to manufacturers’ instructions. To ensure that methods performed according to specifications, the calibration of each system was verified by measuring quality control (QC) materials provided by assay manufacturers 5 times during the analytical sequence.
Trueness was assessed using four trueness control materials consisting of single donations of fresh whole blood. Four donors were selected in order to obtain four materials at three concentration levels: low HbA1c (34 mmol/mol, i.e. 5.3% NGSP), medium HbA1c close to the clinical decision limit (49 and 58 mmol/mol, i.e. 6.6% and 7.4% NGSP, respectively) and high HbA1c (90 mmol/mol, i.e. 10.3% NGSP). Samples were collected at Queen Beatrix Hospital (Winterswijk, The Netherlands) in EDTA tubes and stored at +4 °C until shipment.
Three campaigns were organized: January (one sample), March (two samples) and June 2017 (one sample). Each time, blood was drawn from volunteers on Monday and stored at +4 °C until shipping to study participants on Tuesday. Participants performed and reported measurements no later than Friday. Homogeneity and stability of the materials were tested according to the requirements of ISO 17043 and ISO 13528 standards.
For each campaign, samples were analyzed once in approximately 450 medical laboratories participating to the Instand e.V. EQA scheme . Involved assays were partitioned in 11 peer groups including different combinations of analyzers and reagents for which calibration was identical: Abbott Architect, Abbott-Afinion System, Beckman AU, Beckman Unicel DxC, Bio-Rad Variant II, Menarini, Roche, Sebia Capillarys, Siemens DCA 2000, Siemens Dimension+ and Tosoh.
Reference method value assignment
All samples (EQA materials, trueness verifiers, fresh and frozen CSs) were analyzed with the LC-MS IFCC RMP for HbA1c quantification , . Measurements were conducted at the Instand reference laboratory (Düsseldorf, Germany), a member of the IFCC reference network for HbA1c that is accredited according to ISO 17025 and ISO 15195 standards for HbA1c measurement. Assays were performed in two duplicates (two independent digestions, four values). Accuracy of the IFCC RMP was verified using QC materials obtained from the IFCC network. No significant deviation from the target value of the IFCC reference laboratory network was observed (see Supplementary Data S3).
HbA1c results reported in NGSP units in % were converted into IFCC units in mmol/mol using the master equation NGSP=[0.09148×IFCC]+2.152 .
Commutability of the 26 EQA materials was assessed according to the difference in bias approach described in the IFCC recommendations on commutability assessment , . Briefly, this approach consists in calculating, for each assay, the difference between the bias of the assay against the IFCC RMP for the EQA material under investigation, and the mean bias against the IFCC RMP of the same assay for a panel of fresh CSs. This bias difference is then compared with a commutability acceptance criterion that corresponds to the maximum bias allowed to meet medical needs . The results were categorized as commutable, inconclusive and non-commutable , . In this study, HbA1c concentrations were ln-transformed and a fixed acceptance criterion of 6% was used .
The effect of freeze-thawing was evaluated by calculating the mean relative difference between HbA1c concentrations measured in the 22 fresh CSs and the corresponding frozen CSs.
Trueness was assessed by calculating the mean relative bias of the different peer groups against the IFCC RMP for each of the four trueness verifiers. Between-method imprecision was additionally evaluated by calculating the relative standard deviation across HbA1c concentrations measured with the 17 routine assays for the 26 EQA materials, as well as the fresh and frozen CSs involved in the commutability study. The mean of all the RSDs was then reported. Assay performance was additionally characterized using the model described by Weykamp et al. that consists in combining the biological variation  and the sigma metrics models . All the research meets the ethical guidelines and comply with the World Medical Association Declaration of Helsinki regarding ethical conduct of research involving human subjects.
Commutability assessment of 26 EQA materials
Commutability results of the 26 processed EQA materials for the 17 HbA1c assays are presented in Figure 1 (see also Supplementary Data S4A). It shows that commutability of EQA materials is highly heterogeneous. Only a few EQA materials were commutable for most assays and some materials were found non-commutable for most HbA1c assays, suggesting that commutability of processed EQA materials cannot be assumed a priori. Results additionally show that commutability of EQA materials was globally better for some assays than for others (see Supplementary Data S4B). For some assays like Abbott enzymatic, Siemens DCA Vantage and Bio-Rad Variant II NU, very few of the 26 EQA materials were found to be commutable. On the contrary, a larger fraction of EQA materials was found to be commutable for Tosoh, Arkray HA-8180T, Sebia Capillarys 3 and Roche Cobas C-513 assays. None of the EQA materials investigated were found to be commutable for the Abbott Afinion assay as it does not allow the measurement of coagulated or hemolyzed samples. As comparison point, the 22 fresh and frozen CSs were first examined as if they were processed materials. Altogether, the 22 fresh CSs were commutable in 87% of the pairwise comparisons and 13% of the statistical analyses were inconclusive (see Supplementary Data S4C). Altogether, the 22 frozen CSs were found to be commutable in 67% of the pairwise comparisons, non-commutable in 12% of them and 21% of statistical assessments were inconclusive (Supplementary Data S4D).
Impact of EQA materials commutability on between-method imprecision
As shown in Figure 2, the between-method imprecision was better with fresh and frozen CSs (between-methods RSD of 3.2±1.1% and 3.9±1.4%, respectively) than with processed EQA materials (RSD of 8.0±5.8%). This means that the non-commutability of processed EQA materials leads to underestimating how well the different HbA1c assays agree with each other. In addition, the agreement between HbA1c assays greatly varies across the different EQA materials, confirming that the heterogeneity in commutability levels results in highly discrepant and underestimated between-methods agreement . This observation confirms that processed materials are not adequate to evaluate comparability between methods.
Impact of EQA materials commutability on trueness assessment
Relative deviations of results provided by the different assays against the IFCC RMP are detailed in Figure 3 depending on the commutability of the control materials. Results show that non-commutability of EQA materials greatly affects the trueness assessment of HbA1c assays. For most assays, a larger deviation against the IFCC RMP was almost always observed when non-commutable EQA materials were used. Interestingly, for some assays like Siemens DCA Vantage, Bio-Rad D100 and Sebia, non-commutability of EQA materials consistently resulted in a positive shift in bias, i.e. in overestimating bias. For example, for the Sebia Capillarys 3 assay, using non-commutable materials resulted in observing a mean bias of +17.1% while a bias of only +1.8% was observed when using commutable materials. On the contrary, for other assays like the Abbott enzymatic, non-commutability resulted in a negative shift in bias (+3.0% bias with commutable materials and −17.8% with non-commutable materials). These results show that non-commutability of EQA materials skews trueness assessment differently depending on the assay. Even though some assays are more affected than others by the matrix effects, using non-commutable materials consistently leads to measuring an erroneously large bias.
The fact that results obtained using frozen CSs are globally close to those obtained with fresh CSs was confirmed and was supported by the absence of the freeze-thawing effect. The mean relative difference between HbA1c concentrations measured in fresh and frozen CSs with eight assays and the IFCC RMP was −0.0±0.9% (Supplementary Data S5). It is noteworthy that most of the frozen CSs received by Sebia and Bio-Rad were partly or fully degraded during shipment. Analysis of the electrophoretic and chromatographic profiles showed that these samples were compromised and the corresponding data were excluded from the study, implying that the freeze-thawing effect could not be evaluated for Sebia and Bio-Rad assays.
Trueness assessment of HbA1c assays
Trueness assessment of HbA1c assays was performed via the Instand accuracy-based EQA program and the results are presented in Figure 4. The mean bias against the IFCC RMP across the 11 peer groups was −0.1 mmol/mol for the low HbA1c sample (34 mmol/mol, i.e. 5.3% NGSP), +1.3 mmol/mol and +1.0 mmol/mol, for the two medium HbA1c samples, respectively (49 and 58 mmol/mol, i.e. 6.6% and 7.4% NGSP) and +1.2 mmol/mol for the high HbA1c sample (90 mmol/mol, i.e. 10.3% NGSP). The mean bias across the four trueness verifiers ranged from −0.53 mmol/mol for the Siemens Dimension+ peer group to +2.15 mmol/mol for the Siemens DCA 2000 peer group. The TAE quality target of 5 mmol/mol (0.46% NGSP) suggested by Weykamp et al. was met for all methods except for the Siemens DCA 2000 peer group for the high trueness verifier (mean bias of +5.2 mmol/mol) and for the Siemens Dimension+ peer group for the high trueness verifier (mean bias of −5.1 mmol/mol) (Figure 4).
Each assay’s performance estimated using the model proposed by Weykamp et al. are presented in Figure 5. Using the Sigma Metrics model, four assays met the 4σ criterion (Abbott-Afinion System by affinity, Siemens Dimension+ by immunoassay, Menarini HA8160 and Sebia assays by capillary electrophoresis). All other assays met the 2σ criterion (TAE<5 mmol/mol). Using the biological variation model, four assays did not meet the minimum performance criterion (Beckman AU B00389, Beckman UniCel DxC, Siemens DCA 2000 immunoassays and Bio-Rad Variant II assays by ion-exchange HPLC) while the other assays met the minimum performance criterion. The Abbott-Afinion System was the only assay to meet the desirable performance criterion. No method met the optimal performance criterion.
Performance of individual laboratories
While the evaluation of assays performance according to the sigma metrics model shown in Figure 5 describes global performance of all laboratories from a given peer group, the Youden plot shown in Figure 6 provides further insights on the performance of individual laboratories. The results show that 86% of the laboratories met the 6% acceptance criterion for bias (data not shown). Ninety-nine percent and 86% of laboratories met the 5 mmol/mol acceptance criterion for TAE at low and high HbA1c concentration, respectively. For the high control (90 mmol/mol, i.e. 10.3% NGSP), only 2% of the participants reported results below the acceptance limit while 11% exceeded the upper acceptance limit. This result confirms that accuracy of HbA1c assays is globally better for low and medium HbA1c concentrations than for high concentrations.
In this study, we assessed the commutability of 26 processed EQA materials for 17 of the most frequently used HbA1c assays. Our results show that the materials’ commutability was highly heterogeneous and generally low. Although some of the processed materials were shown to be more commutable than others, it was not possible to identify any unique features for the more commutable materials. Additional work is needed to gather extensive information on the materials’ properties, composition and manufacturing process so as to better understand what the parameters affecting commutability are. This would make it possible to select the most appropriate manufacturing process leading to the highest commutability levels and ultimately be able to predict the commutability of materials.
Although the 26 processed EQA materials involved in this study were used in various EQA schemes and were expected to be representative of the usual behavior of other similar EQA materials, the conclusions of this study may not be extended to other processed EQA materials. It should be noted that none of the EQA providers who participated in the study claimed, nor were anticipated to have, full commutability across all platforms. The fact that fresh CSs were not all found to be commutable when examined as if they were processed materials was unexpected and could be due to samples aging and/or degradation during shipment. This could cause either matrix effects or an alteration of samples homogeneity that would affect measurements precision and result in a higher rate of inconclusive statistical assessments. Still, our study clearly demonstrates that the commutability of EQA materials is very heterogeneous and cannot be taken for granted without conducting a formal commutability assessment.
In addition to selecting the study materials, a critical step in assessing commutability with the difference in bias approach is the choice of an appropriate commutability acceptance criterion . If this criterion is too wide, it could be concluded that a material is suitable to assess trueness and/or between-methods comparability, when it might not be. On the contrary, a criterion that would be too stringent would result in a high rate of inconclusive results and the inability to make a conclusion , . A consensus in commutability assessment of a trueness verifier is that it should correspond to a fraction of the TAE , . Recently, Weykamp et al. recommended a 5 mmol/mol (0.46% NGSP) TAE for a sample of 50 mmol/mol (6.7% NGSP) HbA1c . However, the use of this criterion in our study resulted in finding almost all EQA materials to be commutable (data not shown), even though strong discrepancies could be observed between different materials in terms of bias and between-method agreement, suggesting that this criterion was not sufficiently stringent. Besides, in France, a 7% TAE is used in the national mandatory EQA program  and the NGSP and the College of American Pathologists (CAP) both recommend a 6% TAE for HbA1c concentrations between 31 and 86 mmol/mol (5.0% and 10.0% NGSP) . Similarly, in Germany, a change of TAE from 18% to 8% has been suggested for the national EQAS . As the non-commutability of an EQA material is supposed to consume only a reasonable part of the TAE, a 6% criterion appeared a reasonable choice. Although it can be considered very stringent, only 12% of the statistical analyses were inconclusive and the fresh CSs were never found to be non-commutable.
In a recent study, Liu et al. used both the CLSI EP30-A guidelines  and the difference in bias approach to characterize the commutability of three certified reference materials consisting of frozen hemolyzed whole blood . Using a similar study design and acceptance criteria, the authors found that the three materials were commutable for the main HbA1c assays except one. This confirms that producing materials that are commutable for all assays remains challenging and that commutability should be assessed for all assays for which trueness is evaluated, as was demonstrated in our study.
Due to the insufficient commutability of the processed EQA materials involved in our study, assay trueness could not be evaluated with these materials. Although the 22 fresh CSs used to evaluate commutability of the processed materials were also measured with the IFCC RMP, measurements were conducted in only one laboratory at the manufacturer sites (except for Abbott, Siemens, Trinity Biotech and Arkray assays). In order to better reflect “real” assay performances, it was decided to evaluate the trueness of HbA1c assays using fresh whole blood samples that were assayed in a large number of medical laboratories even though these did not necessarily use the same assays as those involved in the commutability study (e.g. Siemens DCA Vantage and DCA 2000). Biases observed during this study were in good agreement with those reported in previously published studies. Indeed, in a study involving 526 laboratories, Kaiser et al. reported a mean +1.3 mmol/mol bias for a sample at 71 mmol/mol (8.6% NGSP) . Similarly, Weykamp et al. in a study involving the 3277 laboratories of the CAP 2014 survey, reported a mean bias of +1.3 mmol/mol (0.11% NGSP) for a material at 48 mmol/mol HbA1c (6.5% NGSP) . More recently, the EurA1c Trial Group reported a +0.2 mmol/mol bias over 1517 laboratories using a fresh whole blood material and a −0.5 mmol/mol bias across 649 laboratories using a lyophilized material . While biases reported in our study and in the EurA1c trial are consistent, it should be noted that in our study, peer groups gathered different analyzers and reagents, potentially shifting up the between-laboratory imprecision component. Despite this, the EurA1c Trial still showed a larger proportion of assays not meeting the 2σ performance criterion, supporting the fact that efforts are needed to further reduce between-laboratory variation . Results of the EurA1c study also confirm our findings that for some assays, bias estimated using lyophilized materials were substantially larger than with fresh samples, especially the Abbott enzymatic assay .
Although processed EQA materials can still be used to evaluate assay precision and compare individual laboratory results with its peers, our study shows that the commutability of processed EQA materials is highly heterogeneous and generally insufficient to properly estimate between-method agreement and trueness of HbA1c assays. As commutability cannot be assumed or predicted, accuracy-based EQA programs should preferably rely on processed materials of proven commutability or fresh whole blood.
Even though it proved to be feasible, the use of fresh whole blood in the context of large EQA schemes remains challenging as it requires large blood volumes, ethical authorizations and optimal logistics due to the limited stability of materials , , , . Using frozen materials could be a viable option as it would reduce the risks associated with the stability of samples. However, it should be kept in mind that frozen samples are not commutable for all assays. Especially, more and more POCT instruments are coming onto the market and many of these instruments can only work with fresh whole blood.
Finally, this study demonstrates the overall good analytical performances of HbA1c assays. Even though the accuracy is still perfectible at elevated HbA1c concentrations, most HbA1c assays meet the quality target of 5 mmol/mol TAE and demonstrate good comparability when evaluated with fresh blood samples or commutable materials.
We thank EQA providers and manufacturers of quality control materials having shared the materials which commutability was assessed in this study.
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The online version of this article offers supplementary material (https://doi.org/10.1515/cclm-2019-0219).
About the article
Published Online: 2019-05-14
Published in Print: 2019-09-25
Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Research funding: None declared.
Employment or leadership: None declared.
Honorarium: None declared.
Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.