Type 1 diabetes (T1DM) is a lifelong disease affecting children and adolescents that ultimately can lead to significant morbidity. Measuring the hemoglobin A1c (HbA1c) is the standard of care for assessing long-term glycemic control of patients with diabetes, describing the average glycemic level. Lowering HbA1c levels to below or around 7% (53 mmol/mol) has been shown to reduce microvascular and macrovascular complications of diabetes [1], thus HbA1c measurement also provides a treatment goal. According to the guidelines of the International Society of Pediatrics and Adolescents (ISPAD) treatment of T1DM should target HbA1c level of <7.5% (<58 mmol/mol), if achieved without severe episodes of hypoglycemia [2]. The American Diabetes Association (ADA) recommend a target values for HbA1c in relation to age as follows: HbA1c<8.5% (<69 mmol/mol) at age <6 years, <8 (<64 mmol/mol) % at 6 to 12 years, <7.5% (<58 mmol/mol) at 13 to 18 years and <7% (<53 mmol/mol) in adults [3].

Nevertheless, current studies show that only minority of the subjects achieve the goals of ISPAD [4]. HbA1c levels above 9.5% (<80 mmol/mol), reflecting poor glycemic control, were found in 17% of youth in the SEARCH for diabetes in Youth Study conducted in the United States among 3,947 individuals with T1DM [5]. The average HbA1c in the Hvidore study of 2,873 children from 18 countries in Europe was 8.6 (70 mmol/mol) [6]. Results from the Type 1 Diabetes Exchange Clinic Network, including 13,316 participants revealed that overall, only 32% met the ADA targets for their age group and 25% met the ISPAD goals. The proportions meeting the ADA goals were 64% for the under-6-year age group, 43% for 6- to 12-year-olds, and 21% for the 13- to 19-year-olds [7].

Despite recent advances in diabetes therapy including the new insulin analogs, insulin intensification strategies and newest therapeutic technologies such as continuous glucose monitoring system (CGMS) many patients fail to reach or maintain target HbA1c [8]. Persistent poor glycemic control has been documented also in adults with T1DM [9]. During a 4 year follow-up, 30% of subjects from the selected cohort of the Diabetes Control and Complications trial (DCCT) had average HbA1c levels above 8.5% (<69 mmol/mol) [10].

HbA1c levels in children and adolescents are associated with age, duration of diabetes and gender [11], [12], [13]. The aim of the present study was to describe the distribution of HbA1c levels among patients with T1DM, and to develop age dependent percentile curves for HbA1c levels hence visual representation of the of HbA1c levels according to age in individual patients compared with a reference patient population.

We have constructed curves of HbA1c levels using quantile regression. These curves demonstrate the distribution of HbA1c levels among T1DM patients, and can serve as a new tool to graphically illustrate an individual patient's measurements longitudinally compared with age-matched patients.

The ADA recommends a less-stringent targetfor children younger than 6 years [18], since highly variable eating and activity patterns, together with frequent illness, impose difficulties on glycemic control in this age group [19]. As ADA targets are higher, 75% of our measurements in this age group were within the recommendations. This is similar to the Type 1 Diabetes Exchange Clinic Network results where 64% of the under-6-year age group met the ADA goals [7]. At adolescence ADA recommendations are more stringent aiming to lower HbA1c levels, however our data show that during this period HbA1c levels increase to peak levels, therefore 75% of the measurement were above the ADA recommendations [18]. These findings reflect the challenge in achieving glycemic control during pubertal years. Similarly, worsening of glycemic control during puberty was observed in a longitudinal study; [20] and 60% of adolescents aged between 13 and 18 years receiving multidisciplinary care reportedly had glycemic control outside the ADA recommended target [21]. After age 18 years the distribution curves show improvement in all percentiles. Similar to our findings, mean levels of HbA1c from 117 subjects decreased from age 18 to 24 years [22]. Despite this improvement in HbA1c levels, since the target recommended HbA1c after age 18 is 7% (<53 mmol/mol), only 25% of the measurements were within the target.

Comparison between the female and male HbA1c curves demonstrated that females had higher HbA1c levels in all percentiles except in the outliers, however the difference was only 0.1%. Similar findings were observed in other large studies such as the DPV-Wiss [11], SEARCH for diabetes in youth study [5] an international multicenter study and [23] a Swedish childhood diabetes registry [24] showing that for all age groups, girls and women had higher HbA1c values compared to boys.

The distribution curves presented in this study may be helpful for several purposes. For clinicians, use of these curves may enable classification of an individual glycemic control relative to similar age group as depicted in Fig. 4. Furthermore, plotting individual's data may demonstrate response to therapeutic interventions as well as identifying an abnormal clinical course. We have recently demonstrated that adolescent girls with insulin omission eating disorder have a different pattern of HbA1c levels compared with girls with simple poor glycemic control and on this basis have proposed an algorithm for the identification of insulin omission [25].

For patients and their families, the curves may also prove useful as an educational tool. Knowledge was found to independent predictor of glycemic control among patients with T1DM, and improvement in patients' understanding of HbA1c was associated with improvement in glycemic control. [26], [27]. Strategies to convey data has been previously studied and visual explanatory cues were found to be important for people's comprehension [28]. We therefore created color codes in the percentiles such as blue and green suggest acceptable range and orange and red call for attention and alert to danger.

In assessing the results of this study a number of limitations should be considered. Firstly, the curves are based on HbA1c levels from different patients at different ages, a similarly known limitation in building longitudinal height, weight and BMI curves. In addition treatment modalities and interventions were not taken into account in our analysis. Finally, different HbA1c assays were used over the course of the study which ran from 1995 to 2010. However, analytical variation between assays or within assays over time can be expected to be equally distributed across age groups.

The strength of this study is that it provides new and simple graphs for clinicians as well as patients to use as a basis to assess and follow their glycemic control compared to other patients of the same age group and to upper ADA recommended HbA1c levels. The current graphs do however reflect our own experience in our specific population. Additional studies in different national and ethnic groups are needed, yet the novelty of the current paper is the creation of HbA1c reference curves.

In summary, we have constructed age specific reference curves for HbA1c levels for patients with T1DM to give an indication of the distribution of HbA1c values. These curves provide a comprehensive demonstration of HbA1c levels in the real world of children from infancy to young adulthood over the years following diagnosis. Using the age-based curves will give the clinician a better understanding of the likely variability of HbA1c levels in patients at specific age. In addition the curves can be used as an educational tool to graphically illustrate the patient's glycemic control both in relation to a population of patients with T1DM, as well as in relation to their own longitudinal measures.