HbA1c and the Prediction of Type 2Diabetes in Children and AdultsDiabetes Care 2017;40:16–21 | DOI: 10.2337/dc16-1358

OBJECTIVE

Long-termdata validating glycated hemoglobin (HbA1c) in assessing the risk of type 2diabetes in children are limited. HbA1c, fasting plasma glucose (FPG), and 2-h post-load plasma glucose (2hPG) concentrationsweremeasured in a longitudinal study ofAmerican Indians to determine their utility in predicting incident diabetes, all ofwhich is thought to be type 2 in this population.

RESEARCH DESIGN AND METHODS

Incident diabetes (FPG ‡126 mg/dL [7.0 mmol/L], 2hPG ‡200 mg/dL [11.1 mmol/L],HbA1c ‡6.5% [8 mmol/mol], or clinical diagnosis) was determined in 2,095 childrenwithout diabetes ages 10–19 years monitored through age 39, and in 2,005 adultsages 20–39 monitored through age 59. Areas under the receiver operating charac-teristic (ROC) curve for HbA1c, FPG, and 2hPG in predicting diabetes within 10 yearswere compared.

RESULTS

During long-term follow-up of children and adolescents who did not initially havediabetes, the incidence rate of subsequent diabetes was fourfold (in boys) as highandmore than sevenfold (in girls) as high in those with HbA1c ‡5.7% as in those withHbA1c £5.3%dgreater rate ratios than experienced by adults in the same HbA1c

categories. Analyses of ROCs revealed no significant differences between HbA1c,FPG, and 2hPG in sensitivity and specificity for identifying children and adolescentswho later developed diabetes.

CONCLUSIONS

HbA1c is a useful predictor of diabetes risk in children and can be used to identifyprediabetes in childrenwithother type2diabetes risk factorswith the samepredictivevalue as FPG and 2hPG.

The prevalence of type 2 diabetes has increased among youth in the U.S.; between2001 and 2009, therewas a 30.5% rise in the overall prevalence of diagnosed diabetes(1,2). Many youth diagnosed with type 2 diabetes have poor glycemic control (2,3)and experience higher rates of cardiovascular disease riskmarkers, fatty liver disease,and early evidence ofmicrovascular complications (2,4,5). This highlights the need forearly detection of prediabetes to prevent the increase in diabetes and its associatedcardiometabolic risk factors.The American Diabetes Association (ADA) recommends glycated hemoglobin

(HbA1c) as a diagnostic test for diabetes. This guideline is based on adult epidemiolog-ical studies that show an association between increased HbA1c and the risk for micro-vascular complications (6–8). Longitudinal studies investigating the relationshipbetweenHbA1c in childhoodand the risk of developing diabetes are lacking. In addition,

Diabetes Epidemiology and Clinical ResearchSection, National Institute of Diabetes and Di-gestive and Kidney Diseases, National Institutesof Health, Phoenix, AZ

Corresponding author: Madhumita Sinha,madhumita.sinha@nih.gov.

Received 24 June 2016 and accepted 13 October2016.

This article contains Supplementary Data onlineat http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc16-1358/-/DC1.

© 2017 by the American Diabetes Association.Readers may use this article as long as the workis properly cited, the use is educational and notfor profit, and the work is not altered. More infor-mation is available at http://www.diabetesjournals.org/content/license.

Pavithra Vijayakumar, Robert G. Nelson,

Robert L. Hanson, William C. Knowler, and

Madhumita Sinha

16 Diabetes Care Volume 40, January 2017

CLINCARE/ED

UCATION/N

UTR

ITION/PSY

CHOSO

CIAL

few pediatric studies have comparedHbA1c with other measures of glycemiasuch as fasting plasma glucose (FPG) and2-h postload plasma glucose (2hPG).In the 2016 Standards of Medical Care

in Diabetes, the ADA recognized that datasupporting HbA1c as a diagnosticmeasurefor diabetes are limited in children andadolescents (9) while noting that pastshort-term studies did not address themore pertinent relationship betweenHbA1c and long-term health outcomes.The ADA recommends screening fortype 2 diabetes or prediabetes usingHbA1c in asymptomatic children and ado-lescents aged$10 yearswith aBMI$85thpercentile for age and sex, based on Cen-ters for Disease Control and Preventiongrowth charts (10), and at least two addi-tional type 2 diabetes risk factors (9). Riskfactors include type 2 diabetes in a first- orsecond-degree relative, minority race orethnicity, signs of insulin resistance, or ma-ternal history of diabetes or gestationaldiabetes during the child’s gestation (9).Measuring HbA1c is convenient in chil-

dren because it does not require fasting,and a single test can be used to both di-agnose and monitor glycemic control,thereby facilitating sample collection andcompliance in children. In addition, HbA1creflects chronic glycemia and has less pre-analytical and analytical variability thanFPG and 2hPG (9,11).In our current study, HbA1c, FPG, and

2hPG were measured in a longitudinalstudy of American Indian children, adoles-cents, and adults to assess the ability ofthese measurements to predict the devel-opment of diabetes, as defined by theADA. This study examined the extent towhich the ADA-recommended definitionsof prediabetes in children and adolescentspredicted who would develop diabetesand compared the sensitivity and specific-ity of HbA1c, FPG, and 2hPG in predictingfuture diabetes.

RESEARCH DESIGN AND METHODS

A longitudinal study of diabetes and re-lated conditions was conducted amongresidents of an American Indian commu-nity in the southwestern U.S. from 1965to 2007. Children$5 years and adults un-derwent comprehensive clinical examina-tions, which included detailed medicalhistories, anthropometric measurements,and biochemical tests. These children andadults were invited to return for researchexaminations every 2 years. All laboratory

tests during the study period were per-formed at the National Institute of Diabe-tes and Digestive and Kidney Diseaseslaboratory located in Phoenix. HbA1c wasmeasured from 1989 to 2000 by high-performance liquid chromatographyusingthe Bio-Rad MDMS system; from 2001 to2007, we used the A1C 2.2 Plus Glycohe-moglobin Analyzer (TosohMedics, Inc.). ABland-Altman analysis of 252 samplesmeasured with each instrument indicatedsmall systematic differences. Therefore, alinear regressionequationwasused to con-vert the older assay results to the newerassay: HbA1c new method = 20.1916 +(0.9829 3 HbA1c old method). Our labo-ratory has followed the National Glycohe-moglobin Standardization Program assaystandardization recommendations sinceits inception. At each research examina-tion, FPG and HbA1c were measured infasting venous blood, and 2hPG was mea-sured after a 75-g oral glucose tolerancetest (OGTT).

The National Institute of Diabetes andDigestive andKidneyDiseases InstitutionalReview Board approved the study. Writ-ten informed consent was obtained fromadults and fromparents of theminors, andassent was obtained from the minors.

Criteria for inclusion in this analysiswere HbA1c, FPG, and 2hPGmeasures per-formed when the participant was 10through 19 years of age at his or her first

examination without diabetes, and atleast one follow-up examination beforethe 40th birthday, which yielded 2,095children and adolescents. The adult com-parison cohort consisted of those with afirst baseline examination when they didnot have diabetes from age 20 through39 years with all three glycemic measuresand a follow-up examination before the60th birthday, which yielded 2,005 adults.A person could be counted in each cohort ifseen at the appropriate ages. Subjects whogave a history of possibly takingmetforminat baseline were excluded. Diabetes wasdefined at baseline and follow-up by thecurrent ADA criteria: FPG $126 mg/dL(7.0 mmol/L), 2hPG $200 mg/dL(11.1 mmol/L), HbA1c $6.5% (48 mmol/mol) (9), or a previous clinical diagnosis.Prediabetes was defined as HbA1c levelsbetween 5.7 and 6.4%, FPG between100 and 125 mg/dL, or 2hPG between140 and 199 mg/dL (9).

Statistical analyses were conducted us-ing SAS 9.4 software (SAS Institute, Inc.,Cary, NC). Diabetes incidence per 1,000person-years was calculated using thenumber of incident cases of diabetes andperson-years of follow-up through age39 for the child cohort and through age59 for the adult cohort. Sex-stratified areasunder the receiver operating characteristic(ROC) curve (AUC) and standard errors forHbA1c, FPG, and 2hPG predicting diabetes

Table 1—Baseline characteristics of child and adult cohorts, stratified by HbA1c level

HbA1c (%)

#5.3 5.4–5.6 5.7–6.4

ChildrenTotal (n) 1,795 238 62Male (n) 831 97 13Female (n) 964 141 49Age (years) 14.1 (12.5–16.1) 13.8 (12–16) 14 (11.8–15.3)Follow-up (years) 6.0 (3–10) 3.1 (2–6.1) 2.3 (1.9–4)BMI (kg/m2) 26.0 (22.0–31.0) 30.0 (25.0–35.0) 32.0 (28.0–38.0)BMI (percentile) 94.9 (79.6–98.4) 98.2 (94.6–99.2) 98.7 (97–99.3)HbA1c (%) 4.9 (4.6–5.1) 5.5 (5.4–5.5) 5.7 (5.7–5.9)FPG (mg/dL) 89 (85–94) 91 (86–96) 93.5 (88–98)2hPG (mg/dL) 101 (87–116) 107 (92–125) 116.5 (103–149)

AdultsTotal (n) 1,466 371 168Male (n) 587 141 72Female (n) 879 230 96Age (years) 29.0 (24.1–33.3) 28.4 (23.6–34.1) 29.9 (23.8–34.2)Follow-up (years) 5.2 (3.1–8.4) 3.6 (2.2–6.3) 3.2 (2.0–5.4)BMI (kg/m2) 33.0 (28.7–38.0) 36.6 (32.7–42.0) 39.1 (34.3–45.2)HbA1c (%) 4.9 (4.7–5.1) 5.5 (5.4–5.6) 5.8 (5.7–5.9)FPG (mg/dL) 90.0 (85.0–97.0) 95.0 (89.0–101.0) 98.0 (91.0–105.0)2hPG (mg/dL) 106.0 (88.0–124.0) 114 (93–141.0) 120.0 (102.0–148.0)

Data are shown as median (interquartile range) or as indicated.

care.diabetesjournals.org Vijayakumar and Associates 17

were calculated by the method of Pencinaand D’Agostino (12); the AUCs were com-pared by themethod of DeLong et al. (13).AUCs allow for a quantitative compari-son of the discriminatory power of thedifferent tests. For graphical purposes,ROC curveswere derived for each variable,based on predicting the cumulative inci-dence at 10 years. In brief, ROC curvesfor each testmeasureweredrawnbymod-eling the survival probability with thePHREG procedure in SAS using successivedetection thresholds for HbA1c (incre-mented by 0.1%), FPG (incremented by2 mg/dL), or 2hPG (incremented by5 mg/dL) and calculating the 10-year cu-mulative incidence of diabetes in thoseabove and below the threshold from thebaseline hazard and the hazard ratio asso-ciated with being above the threshold.Sensitivity, specificity, positive predictivevalue (PPV), and negative predictive value(NPV) at each threshold (at 10 years offollow-up) were calculated from these cu-mulative incidence values and the propor-tion exceeding the threshold at baseline.

RESULTS

Baseline CharacteristicsAmong 2,095 children and adolescents atbaseline, 588 (28.1%) were categorized asnormal weight (BMI ,85th percentile forage and sex), 394 (18.8%) were overweight(BMI $85th to ,95th percentile), and1,113 (53.1%) were obese. In the adultcohort at baseline, 143 (7.1%) hadBMI ,25 kg/m2, 383 (19.1%) had a BMIbetween 25 and 30 kg/m2, and 1,479(73.8%)wereobesewithaBMI$30kg/m2.Adult and pediatric participants were

classified into prediabetes (5.7–6.4%), in-termediate (5.4–5.6%), or lower (#5.3%)baselineHbA1c categories. The prevalenceof prediabetes by HbA1c$5.7% was 3.0%in the children and adolescents and 8.4%in theadults, andby FPG$100mg/dL, theprevalence was 9.2% in children and ado-lescents and 21.1% in adults. The preva-lence of impaired glucose tolerance(2hPG$140 mg/dL) was 8.1% in childrenand adolescents and 17.3% in adults.Baseline characteristics are reported inTable 1 for the pediatric and adult cohorts,stratified by HbA1c. FPG, 2hPG, and BMIvalues increased with HbA1c strata in chil-dren and adults. Supplementary Table 1lists the Spearman correlation coeffi-cients between HbA1c, FPG, and 2hPG inchildren and adults. Age-sex stratifiedVenn diagrams representing the overlap

in prediabetes definitions at baseline byHbA1c, FPG,and2hPGarepresented inSup-plementary Figs. 1 and 2.

Incidence of Diabetes by HbA1c

Median follow-up time to the diagnosis ofdiabetes or the last examination beforediabetes developed in the pediatric co-hort was 5.2 years (interquartile range[IQR] 2.7–9.6). Median follow-up was4.6 years (IQR 2.8–7.9) in the adults. Totalperson-years of follow-up were 13,528 inchildren and 11,520 in adults. The sex-stratified incidence of diabetes by base-line HbA1c category in children and adultsis shown in Fig. 1A. The incidence ratesexhibited a similar pattern of risk increasein the higher HbA1c categories in childrenand adolescents and in adults (Fig. 1A).Although the incidence rates were higherin adults, the rate ratios comparing higherHbA1c categories with the lowest cate-gory of HbA1c were the same or higherin children (Fig. 1B). Male children andadolescents in the highest HbA1c category(5.7–6.4%) at baseline had a fourfoldhigher incidence of diabetes, and female

children and adolescents in the sameHbA1c range at baseline had a sevenfoldhigher incidence of diabetes during follow-up than their counterparts in the lowestHbA1c category (Fig. 1B).

HbA1c, FPG, and 2hPG PredictingDiabetes in Children and AdultsFigure 2 shows the incidence of diabetesby different glycemic measures at base-line stratified by age and sex. Amongchildren and adolescents in both sexes,all three glycemic measures were simi-larly predictive.

Supplementary Table 2 lists the AUCsfor each of the three tests in boys, girls,men, and women. In boys, girls, andmen,the AUC for HbA1c did not differ signifi-cantly from that of FPG or 2hPG. Only inwomen did the HbA1c have a lower AUCthan 2hPG (0.63 vs. 0.70, P = 0.0012).Supplementary Table 3 reports the sensi-tivities and specificities from which theseAUCs were derived. The lack of a signifi-cant difference in AUC between HbA1cand the glucose measures suggests thatall three tests have the potential to offer

Figure 1—Incidence of type 2 diabetes by HbA1c category stratified by sex. Data are presented asincidence rates (cases/1,000 person-years) (A) and as incidence rate ratios (using the incidencein the lowest HbA1c category as the reference rate) (B).

18 Glycated Hemoglobin Predicts Type 2 Diabetes Diabetes Care Volume 40, January 2017

the same level of sensitivity and specific-ity, depending on the threshold chosen.

Clinical Utility of HbA1c

Although adults may undergo HbA1c

screening regardless of weight, theADA recommends testing children andadolescents $10 years only if their BMIis in the overweight or obese range andif they have two additional risk factors.All children and adolescents in this studyhad at least one risk factor, American In-dian ethnicity. We classified the pediatricsubjects as having parental diabetes if atleast one parent was diagnosed with dia-betes before the age of 45 years. The ROCcurves in Fig. 3A represent the sensitivity

and specificity of HbA1c, FPG, and 2hPGwithin this already higher-risk populationof American Indian children and adoles-cents who were overweight or obese andhad at least one parent with diabetes. Fig-ure 3B depicts the same curves for the fullchild cohort. Among the children and ad-olescents who met the recommendedscreening criteria (overweight or obesewith two additional risk factors), the esti-mated 10-year cumulative incidence of di-abetes in those with HbA1c $5.7% was78% (i.e., PPV) and the 10-year cumulativeincidence in those with HbA1c,5.7% was23% (i.e., NPV = 100% – 23% = 77%). ForFPG $100 mg/dL, the PPV was 36% andtheNPVwas78%,andfor2hPG$140mg/dL,

the PPV was 52% and the NPV was 80%.Differences among these values generallyreflect that the specific thresholds for eachtest differ in specificity and sensitivity;comparable PPV and NPV could be ob-tained by changing the thresholds.

The current ADA thresholds for predia-betes for each of the three tests have beendepicted using circular points on the ROCcurves in Fig. 3, and their proximity to eachother indicates that these thresholdsoffer a similar sensitivity and specificity.Thus, the testing method used does notaffect the sensitivity and specificity withwhich we are able to predict diabetes inchildren and adolescents. An arbitraryHbA1c threshold of 5.4% is marked with adiamond point in Fig. 3, with a higher sen-sitivity (40% in the high-risk group) but alower specificity (89% in the high-riskgroup). Thesquarepoints inFig. 3 representthe sensitivity and specificity offered by dif-ferent combinations of current ADA thresh-olds. These combinations do offer a highersensitivity than any one ADA thresholdalone at the expense of lower specificity.

CONCLUSIONS

Few large longitudinal studies haveassessed the predictive value of HbA1cmeasured in childhood and adolescencein predicting incident diabetes. Theprevalence of prediabetes defined byimpaired fasting glucose (IFG) and IGTamong 12–19 year old adolescents in theU.S. based on the 2005–2006 NationalHealth and Nutrition Examination Survey(NHANES) was 12.7% and 3.4% respec-tively (14). In our current study amongsubjects aged 10 to 19 years, the IFG prev-alence at baseline was 9.2%, and the IGTprevalence, 8.1%, was higher than inNHANES. In the current study, HbA1cwas a useful predictor of future diabetesin all age and sex categories, performing aswell as or better than other measures ofglycemia, except in adult women, amongwhom2hPG had a significantly higher AUCthanHbA1c. HbA1c, FPG, and 2hPGalsohadvery similar discriminatory power withinthe subset of high-risk children identifiedby ADA criteria.

The reason for the poorer performanceof HbA1c in adult women is uncertain.Women participants were not pregnantat baseline but of reproductive age. Irondeficiency is common in women of repro-ductive age, and depleted iron stores af-fect glycation rates and elevate HbA1c.A study from the NHANES (1999–2006)

Figure 2—Incidence of type 2 diabetes by various glycemicmeasures at baseline stratified by ageand sex. PG, plasma glucose. Data are presented as incidence rates (cases/1,000 person-years)

care.diabetesjournals.org Vijayakumar and Associates 19

showed iron deficiency was commonamongwomen (13.7%) andwas associatedwith higher HbA1c primarily at the lowerend of the HbA1c distribution (15). In theabsence of iron studies in our cohort, weare unable to evaluate whether iron defi-ciency altered the HbA1c at baseline amongthe women.Some recent studies have expressed

skepticism about using adult HbA1c thresh-old values for diagnosing prediabetes anddiabetes in children andadolescents. Thesestudies tend to rely on cross-sectional com-parisons of HbA1c with previously estab-lished measures of glycemia and showedpoor correlation of HbA1c with FPG or2hPG. Our current study differs, however,becauseweexamined the valueofHbA1c inpredicting diabetes, not in associating with

IFG or IGT. Clearly, there is little overlapamong the three categorical definitions ofprediabetes based on HbA1c, FPG, and2hPG, as is well recognized in adults andas we found in children and adolescents aswell as in adults (Supplementary Figs. 1 and2). We suggest the goal of screening is toidentify those at high risk of developing di-abetes (or who already have it) rather thandetecting those who have prediabetes bydifferent criteria. In this respect, the HbA1cperforms as well as the other tests.

The ADA includes HbA1c as a diagnosticmeasure for diabetes because of its associ-ationwith long-termmicrovascular compli-cations in adults, including retinopathy anddiabetic nephropathy. This recommenda-tion included adult participants from thesame study population we describe here,

andwe reported previously that HbA1c andFPG measurements in adults were just asuseful as 2hPG in predicting the risk of mi-crovascular complications (16). Anotherstudy in this population found that a sharprise in incidence of these complications oc-curred at the same level of glycemia inyouth and adult cohorts; however, thatstudy compared only FPG and 2hPG (17).

In the current study, we also stratifiedby ADA-recommended risk factors (9). Allof the subjects had at least one risk factor,American Indian ethnicity. We furtherstratified the cohort based on those whohad at least one parent with diabetes on-set before age 45 years, those who wereoverweight or obese, or both.Weused theparental onset age of 45 years becausewepreviously showed that the prevalence oftype 2 diabetes is particularly high in off-spring whose parents both had diabetesbefore age 45 in this population (18). Wefind that the current prediabetes defini-tion of HbA1c $5.7% had a sensitivity of;13% and a specificity of ;99% in over-weight children with two additional riskfactors (one risk factor unique to our studybeing American Indian ethnicity) for pre-dicting the 10-year incidence of diabetes.Of course, the sensitivity would be in-creased by using a lower threshold; forexample, sensitivity was 39% and specific-ity 88% at an HbA1c $5.4% (Fig. 3).

Our study was conducted in a specificpopulation group with a high prevalenceof diabetes that is almost exclusivelytype 2 diabetes (18). Past studies have es-tablished that mutations in the maturity-onset diabetes of the young genes arenot a major cause of diabetes amongyouth in this population (19). Though var-iation inHbA1c reliability hasbeen reportedamongAfrican,Mediterranean, and South-east Asian populations, hemoglobinopa-thies prevalent in these populations thatcould interfere with the HbA1c interpreta-tion have not been commonly reported inAmerican Indians (20). HbA1c results alsovary with red cell dynamics and assaymethods (21–23). Thus, the generalizabil-ity of our results to populations with alower prevalence of type 2 diabetes, ahigher prevalence of type 1 diabetes,or a higher prevalence of hemoglobinop-athies or disorders affecting hemoglobinturnover is uncertain.

The strengths of our study includeboth a large pediatric and adult cohort,examinations with all three glycemia testsperformed at the same time, and an

Figure 3—Sensitivity and specificity of HbA1c, FPG, and 2hPG in identifying persons who de-veloped diabetes within 10 years of screening among children and adolescents meeting ADArecommended criteria for screening (A) and among all children and adolescents in the study (B).The black circles indicate the current ADA thresholds for prediabetes for each of the three tests.The squares represent the sensitivity and specificity offered by different combinations of currentADA thresholds. The diamond indicates the arbitrary HbA1c threshold of 5.4%.

20 Glycated Hemoglobin Predicts Type 2 Diabetes Diabetes Care Volume 40, January 2017

extensive longitudinal follow-up period.Also, all of our laboratory tests, includingHbA1c assays,wereperformedat the samelaboratory using standardized methods.In summary, higher HbA1c at baseline

predicted a higher incidence of diabetesin both children and adults. Although theabsolute incidence rates were greater inadults, the incidence rate ratios were thesame or greater in children. When inci-dence rates were compared with variousabnormalities in glycemic measures (HbA1c,FPG, and 2hPG) at baseline, individually orcombined, HbA1c performed as well as FPGand 2hPG in boys, girls, andmen, but not aswell as 2hPG in adult women.We thereforeconclude that HbA1c can be used to assessrisk for diabetes in children or to identifychildren with prediabetes with the sameconfidence as FPG or 2hPG.

Acknowledgments. The authors thank theparticipants and their parents for participationin the study.Funding. This research was supported by theIntramural Research Program of the NationalInstitute of Diabetes and Digestive and KidneyDiseases.Duality of Interest. No potential conflicts ofinterest relevant to this article were reported.Author Contributions. P.V. designed the study,performed the analyses, andassisted indrafting themanuscript. R.G.N. assisted in study design, ob-tained study data, and critically reviewed the man-uscript. R.L.H. obtained study data and assisted instudydesign,dataanalysis, andcritical reviewof themanuscript. W.C.K. obtained study data, conceptu-alized the study, assisted in study design and dataanalysis, and drafted the initial manuscript. M.S.conceptualized the study, assisted in study designanddataanalysis,draftedthe initialmanuscript,andhad final responsibility for the decision to submitfor publication. All authors approved the final man-uscript as submitted. M.S. is the guarantor of thiswork and, as such, had full access to all the data inthe study and takes responsibility for the integrity ofthe data and the accuracy of the data analysis.Prior Presentation. Parts of this study werepresented in abstract formas anoral presentation

at the 76th Scientific Sessions of the AmericanDiabetes Association, New Orleans, LA, 10–14June, 2016.

References1. Dabelea D, Mayer-Davis EJ, Saydah S, et al.;SEARCH for Diabetes in Youth Study. Prevalenceof type 1 and type 2 diabetes among childrenand adolescents from 2001 to 2009. JAMA 2014;311:1778–17862. Hamman RF, Bell RA, Dabelea D, et al.;SEARCH for Diabetes in Youth Study Group.The SEARCH for Diabetes in Youth study: ratio-nale, findings, and future directions. DiabetesCare 2014;37:3336–33443. Petitti DB, Klingensmith GJ, Bell RA, et al.;SEARCH for Diabetes in Youth Study Group. Gly-cemic control in youth with diabetes: theSEARCH for Diabetes in Youth Study. J Pediatr2009;155:668–672 e1-34. Rodriguez BL, Fujimoto WY, Mayer-Davis EJ,et al. Prevalence of cardiovascular disease riskfactors in U.S. children and adolescents with di-abetes: the SEARCH for Diabetes in Youth study.Diabetes Care 2006;29:1891–18965. Kershnar AK, Daniels SR, Imperatore G, et al.Lipid abnormalities are prevalent in youth withtype 1 and type 2 diabetes: the SEARCH for Di-abetes in YouthStudy. J Pediatr 2006;149:314–3196. American Diabetes Association. Diagnosisand classification of diabetes mellitus. DiabetesCare 2010;33(Suppl. 1):S62–S697. International Expert Committee. Interna-tional Expert Committee report on the role ofthe A1C assay in the diagnosis of diabetes. Di-abetes Care 2009;32:1327–13348. Expert Committee on the Diagnosis and Clas-sification of Diabetes Mellitus. Report of theExpert Committee on the Diagnosis and Classi-fication of Diabetes Mellitus. Diabetes Care1997;20:1183–11979. American Diabetes Association. Sec. 2. Clas-sification and diagnosis of diabetes. In Standardsof Medical Care in Diabetesd2016. DiabetesCare 2016;39(Suppl. 1):S13–S2210. Centers for Disease Control and Prevention.Defining Childhood Obesity. Available at http://www.cdc.gov/obesity/childhood/defining.html.Accessed 9 June 201611. Lippi G, Targher G. A laboratory standpointon the role of hemoglobin A1c for the diagnosisof diabetes in childhood: more doubts than cer-tainties? Pediatr Diabetes 2011;12:183–186

12. Pencina MJ, D’Agostino RB. Overall C as ameasure of discrimination in survival analysis:model specific population value and confidenceinterval estimation. StatMed 2004;23:2109–212313. DeLong ER, DeLong DM, Clarke-Pearson DL.Comparing theareas under twoormore correlatedreceiver operating characteristic curves: a non-parametric approach. Biometrics 1988;44:837–84514. Cowie CC, Rust KF, Ford ES, et al. Full ac-counting of diabetes and pre-diabetes in theU.S. population in 1988-1994 and 2005-2006.Diabetes Care 2009;32:287–29415. Kim C, Bullard KM, HermanWH, Beckles GL.Association between iron deficiency and A1Clevels among adults without diabetes in the Na-tional Health and Nutrition Examination Survey,1999-2006. Diabetes Care 2010;33:780–78516. McCance DR, Hanson RL, Charles MA, et al.Comparison of tests for glycated haemoglobinand fasting and two hour plasma glucose con-centrations as diagnostic methods for diabetes.BMJ 1994;308:1323–132817. Krakoff J, Hanson RL, Kobes S, Knowler WC.Comparison of the effect of plasma glucose con-centrations on microvascular disease betweenPima Indian youths and adults. Diabetes Care2001;24:1023–102818. Knowler WC, Pettitt DJ, Saad MF, BennettPH. Diabetes mellitus in the Pima Indians: inci-dence, risk factors and pathogenesis. DiabetesMetab Rev 1990;6:1–2719. Baier LJ, Permana PA, Traurig M, et al. Mu-tations in the genes for hepatocyte nuclear fac-tor (HNF)-1alpha, -4alpha, -1beta, and -3beta;the dimerization cofactor of HNF-1; and insulinpromoter factor 1 are not common causes ofearly-onset type 2 diabetes in Pima Indians.Diabetes Care 2000;23:302–30420. ACOG Committee on Obstetrics. ACOG Prac-tice Bulletin No. 78: hemoglobinopathies in preg-nancy. Obstet Gynecol 2007;109:229–23721. Cohen RM, Franco RS, Khera PK, et al. Redcell life span heterogeneity in hematologicallynormal people is sufficient to alter HbA1c. Blood2008;112:4284–429122. Cohen RM, Snieder H, Lindsell CJ, et al. Ev-idence for independent heritability of the glyca-tion gap (glycosylation gap) fraction of HbA1c innondiabetic twins. Diabetes Care 2006;29:1739–174323. Chan CL, McFann K, Newnes L, Nadeau KJ,Zeitler PS, Kelsey M. Hemoglobin A1c assay vari-ations and implications for diabetes screening inobese youth. Pediatr Diabetes 2014;15:557–563

care.diabetesjournals.org Vijayakumar and Associates 21