Comment on: Wilson et al. Persistence of Individual Variations in Glycated Hemoglobin: Analysis of Data From the Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Randomized Trial. Diabetes Care 2011;34:1315–1317

Wilson et al. (1) recently used continuous glucose monitoring (CGM) to estimate mean blood glucose (MG) and calculate an MG-to-HbA_1c ratio to assess biological variation in HbA_1c in pediatric type 1 diabetic patients. The authors reported that patients with relatively low or high ratios at one clinic visit tended to have similarly low or high ratios at subsequent visits. The same group previously used CGM-derived MG to calculate the hemoglobin glycation index (HGI) as a measure of biological variation in HbA_1c (2). Their results showed that HGI was quantitatively consistent within individuals at baseline and at follow-up clinic visits. This observation confirmed prior reports of HGI consistency within patients over time where MG was estimated using less advanced technologies such as patient blood glucose meter data or timed glucose profile sets (3,4). Because CGM is widely accepted as the gold standard for directly estimating MG, the studies by Wilson et al. both strongly suggest that interindividual variation in HGI is not an artifact of interindividual bias in blood glucose measurement.

Although their MG-to-HbA_1c ratio results provide further evidence of phenotypic consistency within individuals over time, the authors did not explain why they switched from HGI to the ratio. When our group first developed the HGI (3), we considered but decided against the use of ratios for assessing biological variation in HbA_1c for the following reasons: First, ratios subsume all effects into one statistic which makes it more difficult to inherently grasp the relationship between the two directly measured metrics, especially if the relationship is nonlinear as is the case for MG-to-HbA_1c ratio versus MG or HbA_1c. It is also more difficult to statistically work with variances of ratios than variances of the metrics that make up the ratio. Without a reference range, the ratio is relatively uninformative. In contrast, glycation indices such as HGI and the glycation gap (GG) of Cohen et al. (5) automatically provide clinicians with a meaningful and easily remembered reference point because both are approximately normally distributed in human populations with a mean of zero (3–5). HGI and GG are calculated as the difference between an individual's observed HbA_1c and a predicted HbA_1c calculated by inserting either the subject's date-matched MG (for HGI) or fructosamine (for GG) into the population linear regression equation for HbA_1c versus MG or fructosamine. Because of how they are calculated, HGI and GG measure HbA_1c controlled for MG or fructosamine, respectively. HGI and GG not only provide an immediately recognizable reference point, they also reflect the relative direction (negative or positive) and magnitude of each individual's HbA_1c response. An HGI or GG greater than zero indicates a tendency for higher than average HbA_1c independent of the effects of MG or fructosamine. Values lower than zero indicate a tendency for lower than average HbA_1c. Ratios do not provide these same inherent advantages. We suggest that compared with ratios, HGI and GG are superior metrics of biological variation in HbA_1c and recommend their use in future studies of this phenomenon and its impact on diabetes diagnosis and management.

• © 2011 by the American Diabetes Association.