When the International Expert Committee recommended using HbA1c to diagnose diabetes in the pediatric population as in adults, it did so without considering the test performance of HbA1c in adolescents. We found that at the recommended HbA1c threshold of 6.5% for diagnosis of diabetes according to FPG in adolescents, the sensitivity estimate (75%) was highly unstable with wide confidence intervals (95% CI (30.1–95.4)). This instability is due, in large part, to the low prevalence of diabetes in the pediatric population. Moreover, our ROC curves for predicting diabetes demonstrate that HbA1c does not appear to have the same level of discrimination for adolescents compared with adults. Taken together, these findings highlight that extrapolation of adult HbA1c testing recommendations to the pediatric population is likely premature.
Alternative HbA1c thresholds to those used in adults may be useful for the pediatric population. The ROC curve for predicting diabetes in adolescents was based on a limited number of individuals, therefore additional analyses with sufficient numbers of adolescents with diabetes are necessary before any firm recommendation can be made as to what constitutes an appropriate HbA1c level for diagnosis of diabetes in this age group. However, we speculate that a lower HbA1c threshold should be explored for adolescents, given that studies have shown that HbA1c increases with age in the population.18
In fact, the committee’s choice of an HbA1c threshold of 6.5% for adults was in part based on the fact that an HbA1c of 6.5% represents just 3 standard deviations above the mean for US adults, as well as the high specificity (99.6%) and reasonable sensitivity (43–44%) at this threshold based on NHANES III and NHANES 1999–2004 data.3
The notion of a lower threshold for adolescents is supported by the findings of one recent study based on the Bogalusa Heart Study, albeit based on FPG criteria. Nguyen et al found that children with an FPG of 86 to 99 mg/dL had a greater than 2-fold risk of developing adult prediabetes and type 2 diabetes compared with children with an FPG less than 86 mg/dL, even after controlling for other traditional cardiometabolic risk factors.19
As a result, ranges that are considered “normal” for adults may in fact be abnormal for children and adolescents. However, we do acknowledge that the majority of the Bogalusa Heart Study participants with elevated FPG in childhood did not continue with prediabetes nor develop diabetes by approximately age 32 years. Therefore, some elevations in FPG in childhood may be explained by the transient insulin resistance that occurs during Tanner stages 2–4 of puberty.20
We also evaluated the performance of the recommended HbA1c thresholds of ≥5.7% or ≥6.0% for detecting individuals with prediabetes based either on a FPG or a 2-hr PG. We found that HbA1c had a much lower sensitivity for adolescents compared with adults using either of the measures. Moreover, HbA1c for predicting prediabetes in adolescents had poor sensitivity over a range of values and was generally a poor marker for detecting adolescents with prediabetes compared with adults, whether diagnosed by FPG (AUC 0.61 (adolescents) vs. 0.74 (adults) or 2-hr PG (0.53 for adolescents vs. 0.73 for adults). Even though HbA1c may be useful for detecting adults with prediabetes, it may not adequately serve as a diagnostic tool for identifying adolescents with prediabetes, given the poor concordance with 2-hr PG and FPG. Even more concerning is that by following the Committee recommendations of phasing out glucose measurements for detecting prediabetes and using HbA1c in its place, a majority of adolescents with prediabetes would be missed.
We acknowledge the practical appeal of using HbA1c over plasma glucose levels for detecting diabetes, especially in the pediatric population. Compared with HbA1c levels, plasma glucose levels are not perfectly stable and are subject to diurnal21
as well as laboratory variation.22
In contrast, the HbA1c test can be obtained non-fasting, is stable at room temperature, and has less day-to-day and within person variability. Furthermore, there has been standardization of HbA1c assays across laboratories,3
and a variety of epidemiologic studies have demonstrated a link between HbA1c levels ≥6.5% and increased rates of diabetic retinopathy among adult populations.23, 24
We also note that because of the high negative predictive values of HbA1c for predicting diabetes and prediabetes, HbA1c may be a clinically useful test to exclude a diagnosis of prediabetes or diabetes for at-risk adolescents.
However, there are disadvantages regarding the use of HbA1c such as racial/ethnic variation in HbA1c levels (i.e. higher levels of HbA1c by 0.4%–0.7% for African-Americans compared with Caucasians)25
and medical conditions that can affect HbA1c levels independent of glucose levels. For example, hemolytic anemia and active bleeding can lead to decreases in erythrocyte age, which lowers HbA1c; this glucose-independent lowering of HbA1c could possibly lead to a missed diagnosis of diabetes. In contrast, iron-deficiency anemia, splenectomy, or aplastic anemia can lead to higher HbA1c levels; this glucose-independent increase in HbA1c could possibly lead to an erroneous diagnosis of diabetes.3
Although the Committee recommends that providers perform glucose tests (FPG or 2-hr PG) rather than HbA1c for patients with these conditions, most pediatric providers in the primary care setting are not familiar with these limitations of HbA1c, potentially leading to diagnostic errors.
Our findings contrast with a recent study suggesting that HbA1c could be a useful marker for identifying adolescents with prediabetes and diabetes.26
They found that optimal sensitivity and specificity to detect type 2 diabetes were, respectively, 99% and 96% at an HbA1c ≥ 6.0%. Their reported levels of sensitivity and specificity were notably higher than our estimates. However, their population of obese adolescents and subgroup of obese insulin-resistant adolescents were referred to an obesity clinic and may have had symptoms of diabetes. Therefore these results are not generalizable to an asymptomatic population-based sample of adolescents in the pediatric primary care setting. Furthermore, their estimates were based on a total of 4 cases of type 2 diabetes out of 468 children. They do not report confidence intervals for their estimates of sensitivity and specificity, but based on the low number of cases, it is likely that the confidence intervals, similar to our study, were quite high.
We do acknowledge limitations to our study. We note that our findings relate to HbA1c testing of asymptomatic, rather than symptomatic, overweight and obese children. We recognize that previous studies have used NHANES data to evaluate the performance of HbA1c for predicting diabetes in adults,5, 6
but we are unaware of studies that have systematically compared its performance for adults compared with children. Despite the fact that FPG was measured in the morning, which maximizes the prevalence of diabetes detected,21
the number of individuals with diabetes in the sample was low, which is related to the overall low prevalence of diabetes among US children and adolescents compared with adults.27
The findings of our study highlight the dilemma of screening for diabetes in adolescents. The prevalence of undiagnosed diabetes in the pediatric population is only 0.02%,27
As a result, any test, not just HbA1c, will have a low positive predictive value for detecting diabetes. The ADA guidelines were published in 2000, when there was believed to be an epidemic of type 2 diabetes in children. However, more recent studies suggest that the epidemic is not as large as was initially anticipated.27–29
Our ability to diagnose undiagnosed diabetes and prediabetes was limited due to the absence of repeat testing of FPG or 2-hr PG on a different day in NHANES. Without a repeat measure, some adolescents or adults who would not have had a confirmatory FPG or 2-hr PG may have been erroneously diagnosed with diabetes or prediabetes. Despite this lack of repeat testing, studies of diabetes prevalence using NHANES have employed similar methods for identifying undiagnosed diabetes and prediabetes.30
Furthermore, studies in both adolescents9
suggest that FPG has better reproducibility compared with a 2-hr PG. We do however recognize that one abnormal measurement of HbA1c is not sufficient for diagnosis of diabetes, as additional testing in the clinical setting would likely be needed to confirm the clinical diagnosis.