Accuracy of a New Real-Time Continuous Glucose Monitoring Algorithm

Transcription

1 Journl of Dibetes Science nd Technology Volume 4, Issue 1, Jnury 2010 Dibetes Technology Society ORIGINAL ARTICLES Accurcy of New Rel-Time Continuous Glucose Monitoring Algorithm D. Brry, Ph.D., Rymond Crty, B.Sc., nd John J. Mstrototro, Ph.D. Abstrct Bckground: Through minimlly invsive sensor-bsed continuous glucose monitoring (CGM), individuls cn mnge their blood glucose (BG) levels more ggressively, thereby improving their hemoglobin A1c level, while reducing the risk of hypoglycemi. Tighter glycemic control through CGM, however, requires n ccurte glucose sensor nd clibrtion lgorithm with incresed performnce t lower BG levels. Methods: Sensor nd BG mesurements for 72 dult nd dolescent subjects were obtined during the course of 26-week multicenter study evluting the efficcy of the Prdigm REAL-Time (PRT) sensor-ugmented pump system (Medtronic Dibetes, Northridge, CA) in n outptient setting. Subjects in the study rm performed t lest four dily finger stick mesurements. A retrospective nlysis of the dt set ws performed to evlute new clibrtion lgorithm utilized in the Prdigm Veo insulin pump (Medtronic Dibetes) nd to compre these results to performnce metrics clculted for the PRT. Results: A totl of N = 7193 PRT sensor downlods for 3 dys of use, s well s 90,472 temporlly nd nonuniformly pired dt points (sensor nd meter vlues), were evluted, with 5841 hypoglycemic nd 15,851 hyperglycemic events detected through finger stick mesurements. The Veo clibrtion lgorithm decresed the overll men bsolute reltive difference by greter thn 0.25 to 15.89%, with hypoglycemi sensitivity incresed from 54.9% in the PRT to 82.3% in the Veo (90.5% with predictive lerts); however, hyperglycemi sensitivity ws decresed only mrginlly from 86% in the PRT to 81.7% in the Veo. Conclusions: The Veo clibrtion lgorithm, with sensor error reduced significntly in the 40- to 120-mg/dl rnge, improves hypoglycemi detection, while retining ccurcy t high glucose levels. J Dibetes Sci Technol 2010;4(1): Author Affilition: Medtronic MiniMed, Northridge, Cliforni Abbrevitions: (BG) blood glucose, (CLSI) Clinicl nd Lbortory Stndrds Institute, (CGM) continuous glucose monitoring, (DCCT) Dibetes Control nd Complictions Tril, (FoH) fer of hypoglycemi, (HbA1c) hemoglobin A1c, (MARD) men bsolute reltive difference, (PRT) Prdigm REAL-Time, (SMBG) self-monitoring of blood glucose Keywords: continuous glucose monitoring, hypoglycemi, insulin pump, sensor Corresponding Author: D. Brry, Ph.D., Medtronic MiniMed, Devonshire Street, Northridge, CA 91325; emil ddress brry.keenn@medtronic.com 111

2 Introduction The lndmrk Dibetes Control nd Complictions Tril (DCCT) 1,2 clerly demonstrted the benefits of treting to trget hemoglobin A1c (HbA1c) of 7. or less fter reporting vst decrese in morbidity nd slowed onset, or progression, of severe complictions in type 1 dibetes popultion. This outcome ws ttributed to reduced blood glucose (BG) levels through the use of intensive insulin therpy, which required self-monitoring of blood glucose (SMBG) levels t lest four times dy. However, fer of hypoglycemi (FoH) deters insulindependent ptients from more ggressive mngement of their BG levels. In fct, before home blood glucose monitoring, physicins encourged ptients to im for higher-thn-norml BG level phenomenon tht hs been reviewed extensively by Wild nd collegues. 3 In contrst, it hs been demonstrted tht ptients who perform only SMBG with customry BG meter with four dily finger stick mesurements could miss up to 71% of hypoglycemic events, wheres testing up to seven times dily could miss 58% of events when compred to continuous glucose monitoring (CGM). 4 Additionlly, the bility of CGM to reduce HbA1c hs been demonstrted, t lest under clinicl supervision. 5,6 The introduction of glucose sensors, therefore, hs provided evidence indicting tht CGM cn indeed further reduce HbA1c levels nd glycemic vribility, with incresed wreness to hypoglycemi, when compred to stndrd SMBG. Also, becuse the gol of intensive therpy dibetes mngement is to reduce HbA1c levels without incresing the incidence of hypoglycemi, then it is evident tht CGM therpy cn be very beneficil. This rticle focuses on the ccurcy of CGM specificlly the ccurcy of new clibrtion lgorithm. The motivtion for improved ccurcy is to enhnce further the efficcy of CGM in lowering HbA1c, s lredy seen in severl clinicl studies. To dte, the lrgest of these studies included 322 ptients in multicenter rndomized control tril sponsored by the Juvenile Dibetes Reserch Foundtion, which compred the efficcy of CGM to tht of SMBG. 7 Overll, results demonstrted tht CGM significntly improves glycemi over stndrd SMBG with reduction of 0.5% in HbA1c, lthough results were not sttisticlly significnt in the dolescent popultion, likely due to poor dherence. Similrly, the Europen GurdControl Tril 8 evluted the efficcy of CGM in multicenter study tht included 156 ptients wering the Gurdin RT monitor (Medtronic Dibetes, Northridge, CA). The outcome showed tht subjects in the tretment rm decresed their HbA1c levels by n verge of 1% 0.6% improvement over the control group using trditionl SMBG nd HbA1c levels were reduced by 2% in over 26% of subjects. In 2006, the first sensor-ugmented insulin pump, Medtronic s Prdigm REAL-Time (PRT) system, ws lunched, introducing the first pltform with ll of the required components communicting together, necessry for n mbultory closed-loop rtificil pncres product. 9 The system is composed of Prdigm 522/722 insulin pump enhnced with the rel-time CGM component, which utilizes the sme clibrtion lgorithm s the Gurdin RT, Prdigm REAL-Time Revel system, nd Gurdin REAL-Time system. An erly prototype of this system ws tested in 20 type 1 dibetes subjects who wore the device for up to 2 yers. 10 Study results demonstrted tht prticipnts chieved men reduction in HbA1c of 1.1% nd tht those subjects with levels greter thn 7% hd 0.67 probbility of reducing their level below this vlue in the first 3 months of use. The STAR 1 study, sponsored by Medtronic Dibetes nd conducted cross seven centers, investigted the efficcy of the PRT system. 11 The primry objective of this study ws to demonstrte greter reduction of HbA1c levels in subjects plced on the PRT system. In the control group, the overll chnge in HbA1c from bseline ws 0.58 ± 0.73%, wheres the chnge ws 0.72 ± 0.69% in the PRT group, representing 7% decrese for the control group nd n 8.3% decrese for the PRT group. Compred to the 8.2% verge HbA1c outcome from 30 university hospitl centers 12 nd the 8. DCCT HbA1c results, 13 subjects in the study chieved n verge HbA1c of 7.68%. Finl results reveled tht 38% of ptients in the CGM sensor-ugmented group reched the 7% (or below) HbA1c trget versus 19% in the control insulin pump group. Additionlly, the PRT group showed significnt decrese in hypoglycemi re under the curve when compred to the control group, nd the PRT group lso included higher percentge of dult nd dolescent subjects reching trget HbA1c vlue of less thn 7.. This development is cliniclly meningful becuse previous ttempts to reduce HbA1c levels below the 7% mrk in n dolescent popultion 112

3 hve been unsuccessful due to n incresed risk for hypoglycemi. 14,15 Furthermore, becuse the control group ws not ble to chieve this reduction, the lowered HbA1c levels ttined by dults nd dolescents in the PRT group were, in ll probbility, due to sensor usge. From the previously detiled studies, it is evident tht through CGM therpy ptients cn more effectively mnge their BG levels nd chieve n improvement in HbA1c, while reducing the risk of hypoglycemi nd, possibly, nxiety ssocited with FoH. However, it is lso evident tht improved control through CGM requires relible nd ccurte glucose sensor with n effective clibrtion lgorithm coupled with ptient complince. Current commercilly vilble CGM devices re progressively demonstrting greter ccurcies. 16,17 In multicenter study tht included 58 subjects to evlute the performnce of the FreeStyle Nvigtor (Abbott Dibetes Cre, Almed, CA), men bsolute reltive difference (MARD) of 12.8% ws chieved over 5 dys of sensor use with 8 sensitivity to hypoglycemi (<70 mg/dl). In more recent study tht included 72 insulin-dependent dibetic subjects wering the SEVEN system (DexCom, Sn Diego, CA), ccurcy ws evluted over 7 dys of sensor use, clibrting with cpillry finger stick mesurements. An overll MARD of 16.7% ws chieved with 13.3% on dy 7, which demonstrtes tht the DexCom 7-dy system shows significnt improvement over the 3-dy system, development tht is credited to new lgorithm enhncements. Similrly, this investigtion evlutes the performnce of new glucose sensor clibrtion lgorithm, now utilized in the Prdigm Veo insulin pump recently lunched in Europe. The Veo clibrtion lgorithm with enhncements is compred to tht of the PRT by retrospective nlysis of dt collected during the STAR 1 clinicl tril, with rnge of performnce metrics clculted for ech system. Methods In the previously discussed STAR 1 tril rndomized multicenter tret-to-trget 6-month study in which continuous subcutneous insulin infusion therpy, ugmented with rel-time CGM, ws compred with stndrd SMBG nd insulin pump therpy ptients were enrolled cross seven study centers. Ninety-six subjects were dults, of whom 57% were femle, while 6 of the dolescent subjects were femle. Ptients were rndomized into either control rm wering the Prdigm 715 insulin pump or tretment group wering the PRT sensor-ugmented insulin pump. The primry end point of HbA1c reduction over 26-week period ws the helthy glycemic control gol for dibetes ptients of below 7%. Subjects hd to be insulin pump users for period greter thn 6 months nd hve HbA1c levels greter thn or equl to 7.5%. Subjects in the study group were required to perform t lest four finger stick mesurements dily, uploding with the Prdigm Link blood glucose monitor (Medtronic Dibetes) for the durtion of the study. Subjects wore two sensors per week nd tested HbA1c five times during the study. Insulin pump nd glucose sensor dt were uploded every 2 weeks over the Internet vi the CreLink Clinicl ppliction (Medtronic Dibetes). This investigtion utilized BG nd rw glucose sensor dt cquired from the CGM rm of the study. The ccurcy of two clibrtion lgorithms ws compred by retrospective nlysis of rw dt. As the difference between clibrtion lgorithms is purely mthemticl, in tht ech lgorithm uses the sme dt points with the sme timing, true point-to-point nlysis cn be performed between the two routines. Consequently, the PRT lgorithm is pplied retrospectively to rw dt to ensure this consistency. As the commercil PRT lgorithm does not hve the benefit of predictive lerts, this retrospective nlysis uses predictive lerts tht re prt of the Prdigm REAL-Time Revel system nd Gurdin REAL-Time system devices not yet lunched in the United Sttes. However, ll three devices hve the sme clibrtion lgorithm. The predictive lerts utilize Svitzky Goly finite impulse response derivtive filter to estimte the sensor glucose rte of chnge, which is multiplied by prediction horizon of 5 30 minutes. Sensors were worn for up to 3 dys of use by 72 subjects in the study rm of the STAR 1 tril. A totl of 7193 sensor downlods provided 90,472 pired BG nd sensor mesurements for retrospective nlysis. Performnce metrics were clculted for ech glucose sensor clibrtion lgorithm bsed on guidelines set forth by the Interntionl Orgniztion for Stndrdiztion 18 nd the Clinicl nd Lbortory Stndrds Institute (CLSI) 19 for continuous interstitil fluid glucose monitoring. Sensitivity nd specificity were clculted for hypo- nd hyperglycemi, defined s single BG mesurement below 70 mg/dl nd bove 240 mg/dl, respectively. Additionlly, consensus 20 nd Clrke 21 error grid nlyses were performed for ech lgorithm. 113

4 Results The performnce of ech clibrtion lgorithm is presented in Tbles 1 6 for the rnge of metrics described previously. The PRT clibrtion lgorithm is represented s bold following results of the Veo clibrtion lgorithm. The ggregted error is shown in Tble 1, with the error strtified by rnge in Tble 2. The Veo lgorithm outperforms the PRT lgorithm, with the overll men ± SD decresed by 0.25 ± 0.6 to ± 16.89%, with reduction in medin error of 0.1 to 11.56%. The error is reduced further by 5.3 to 19.5% nd 0.4 to 17.31% in the 40- to 80- nd 80- to 120-mg/dl rnges. A slight error increse exists in the mid to upper rnges, with 0.7% increse from 120 to 240 nd 0.6% bove this threshold. Tble 3 provides the number of points within 20 nd 3 of their respective pired BG vlues, or 20 mg/dl for BG vlues below 80 mg/dl. For the Veo lgorithm, more thn 8% dditionl points reside within both boundries in the 40- to 80-mg/dl rnge with n insignificnt difference between the two lgorithms in ll other rnges nd the number of points processed by this new lgorithm decreses t higher rnges. The number of observed hypo- nd hyperglycemic events, bsed on criteri for home-monitoring use, is reported Tble 1. Aggregted Error Sensors Pirs MARD (SD) Medin , (16.86) (17.46) The PRT clibrtion lgorithm is represented s bold following results of the Veo clibrtion lgorithm. in Tble 4. The Veo lgorithm detected 82.28% of the 5841 hypoglycemic episodes nd 81.67% of the 15,851 hyperglycemic episodes. In contrst, the PRT lgorithm detected nd 86.26% of ll hypo- nd hyperglycemic events, respectively. The new lgorithm hd slightly lower specificity ( %) for hypoglycemi nd comprble specificity (~98%) for hyperglycemi. Sensitivity nd specificity nlyses for the Veo nd Revel lgorithms re illustrted with pie chrts in Figures 1 nd 2, respectively, for hypo- nd hyperglycemic events. The pie chrts re color coded to specify the percentge of events flling within prticulr limits. An dditionl ctegory ccurte glucose shows the percentge of events tht fll within the error tolernce of the mesuring reference Tble 3. Number of Points within 20 nd 3 of Their Respective Pired BG Vlues Comprtive glucose (mg/dl) Totl number pired of redings , , , ,742 Overll 90,472 Within 2 or 20 mg/dl 8,635 (81.04%) 7,765 (73%) 13,132 (71.29%) 12,960 (7) 34,274 (75.07%) 35,291 (77%) 11,731 (74.52%) 12,074 (77%) 67,772 (74.91%) 68,090 (75%) Within 3 or 20 mg/dl 8,849 (83.05%) 8,016 (75%) 15,451 (83.88%) 15,491 (84%) 40,254 (88.17%) 41,043 (9) 13,933 (88.51%) 14,176 (9) 78,487 (86.75%) 78,726 (87%) The PRT clibrtion lgorithm is represented s bold following results of the Veo clibrtion lgorithm. Tble 2. Error Strtified by Rnge mg/dl > mg/dl > mg/dl >240 mg/dl Tble 4. Number of Observed Hypo- nd Hyperglycemic Events Bsed on Criteri for Home-Monitoring Use Hypo events Hyper events Number of redings MARD (SD) Medin 10,655 18,420 45,655 15, (23.78) 24.8 (27.65) (18.84) (19.02) (14.92) (14.15) (13.17) (12.64) Number of redings ,851 Sensitivity Specificity Flse positive rte The PRT clibrtion lgorithm is represented s bold following results of the Veo clibrtion lgorithm. The PRT clibrtion lgorithm is represented s bold following results of the Veo clibrtion lgorithm. 114

5 device, which, in this cse, is home-monitoring BG meter. This error boundry for hypoglycemi is mg/dl nd 2 for hyperglycemi bsed on CLSI guidelines. 17 The chrts illustrte the sensitivities reported previously, including the percentge of both threshold nd predicted lerts for 15-minute prediction horizon. Likewise, the specificities re shown for true nd flse threshold lerts. As the PRT lgorithm does not include predictive lerts, but hs the sme clibrtion lgorithm s the Revel nd Gurdin devices, its performnce cn be derived from Figure 2 by only including threshold lerts in the clcultions. In the following lrm ctegories threshold, threshold nd projected, projected, no lrm ccurte glucose, nd flse negtive when pplying 30-minute prediction horizon for hypoglycemi detection, the Veo lgorithm generted ccurcies of 2.62, 79.7, 11.4, 4.02, nd 2.29%, respectively. Applying the sme 30-minute prediction horizon to Gurdin nd Revel lgorithms produced ccurcies of 7.29, 47.6, 20.1, 13.8, nd 11.3%, respectively. Figure 1. Veo lgorithm sensitivity nd specificity nlyses for hypond hyperglycemic events. Over 14 hours of dt is illustrted in Figure 3 for rtes of chnge in excess of 1 mg/dl/min, nd greter rtes on the decline. The 330-mg/dl clibrtion smple before hour 28 resulted in the PRT lgorithm overreding proceeding low glucose levels nd consequently filing to detect the 59-mg/dl (PRT = 81 mg/dl) hypoglycemic event t hour 34, wheres the Veo lgorithm detected the event severl hours before the meter indicted hypoglycemic episode. Clrke nd consensus error grid nlyses re presented in Tbles 5 nd 6. Results re comprble with greter thn 97% of ll redings in the A + B zones of the consensus error grid for both lgorithms nd in ll rnges, with the exception of the PRT lgorithm in the 40- to 80-mg/dl rnge. In this rnge, the new lgorithm shows 4% improvement. No points reside within the E zone of the consensus error grid for either lgorithm. Similrly, results re comprble throughout most rnges for Clrke error grid nlysis, with the exception of low Figure 2. Revel nd Gurdin REAL-Time lgorithm sensitivity nd specificity nlyses for hypo- nd hyperglycemic events. Figure 3. Sensor trcings for PRT nd Veo clibrtion lgorithms. 115

6 BG levels in the 40- to 80-mg/dl rnge. In this instnce, the new lgorithm hs more thn 13% improvement with 89.81% of pired points in the A + B zones. Both lgorithms hve pproximtely 96% of ll vlues in the cliniclly ccurte nd benign (A + B) zones for the complete rnge. Overll, there re only 0.18 nd 0.12% points in the E zone of the Clrke error grid for Veo nd PRT lgorithms, respectively, which could led to erroneous tretment of hypo- or hyperglycemi. Discussion The Prdigm Veo clibrtion lgorithm is more ccurte in the 40- to 80- nd 81- to 120-mg/dl rnges, nd it consequently detected significntly more hypoglycemic events. Sensitivity nlysis of hypoglycemic events produced ccurcies of 82.3% compred to the 54.9% detected by the PRT lgorithm. Predictive lerts, with 30-minute prediction horizon, detected 94% of ll hypoglycemic events. It would, thus, be expected tht n increse in sensitivity in the lower glucose rnges would result in blnced decrese in ccurcy t higher glucose rnges. However, ccurcy t higher glucose rnges ws ffected only mrginlly n expected development, s the new lgorithm ttempts to produce n even error distribution cross the dynmic rnge of the sensor, reflective of the insignificnt sensitivity difference for hypo- nd hyperglycemi. Incresing ccurcy t low blood glucose levels, therefore, while mintining ccurcy t high glucose levels, essentilly brodens the dynmic rnge of the glucose sensor system; this is evident in Figure 3. Tble 5. Consensus Error Grid Anlysis Comprtive glucose (mg/dl) Overll Totl sensor redings 10,655 (11.78%) 18,420 (20.36%) 45,655 (50.46%) 15,985 (17.67%) 90,472 (10) Consensus error grid zones A + B A B C D E 97.13% 93.15% 99.08% 98.76% 98.96% 99.24% 97.94% 98.21% 98.59% 98.24% 84.21% % 76.83% % 76.87% 78.47% 75.35% 76.66% 12.91% 15.25% 23.32% 21.93% 26.36% 23.55% 21.08% 19.74% 23.24% 21.58% 2.52% 6.35% 0.85% 1.17% 1.04% 0.76% % 1.67% 0.36% % 0.07% 0.16% 0.09% 0.08% 0.09% The PRT clibrtion lgorithm is represented s bold following results of the Veo clibrtion lgorithm. Tble 6. Clrke Error Grid Anlysis Clrke error grid zones Comprtive glucose (mg/dl) Overll Totl sensor redings 10,655 (11.78%) 18,420 (20.36%) 45,655 (50.46%) 15,985 (17.67%) 90,472 (10) A + B A B C D E 89.81% 76.53% 99.47% 99.48% 98.96% 99.18% 92.78% 93.58% 96.89% 95.57% % 69.06% 67.77% 75.07% 77.05% 74.56% 76.24% 73.72% 72.92% 15.01% 17.24% 30.41% 31.71% 23.89% 22.13% 18.22% 17.34% 23.17% 22.66% 0.09% 0.14% 0.53% 0.52% 0.83% 0.69% 0.53% % 0.54% 9.91% 23.05% 6.43% 5.86% % 0.19% 0.28% 0.21% 0.13% 0.27% 0.16% 0.18% 0.12% The PRT clibrtion lgorithm is represented s bold following results of the Veo clibrtion lgorithm. 116

7 The Veo lgorithm is more sensitive to fst glucose excursions, with decresed filter dely ( 5 minutes), reducing the overll signl processing dely to 3.5 minutes nd providing much fster response time to rpid glucose excursions. The rnge of intrinsic delys for other CGM devices currently on the mrket ws reported previously by the uthors. 22 It should be noted tht STAR 1 dt used in this investigtion were cquired in n outptient setting nd evluted retrospectively using stndrds for home monitoring. In this setting, ccurcies re generlly lower s error mesurements re generlly mde t the mximum time durtion following clibrtion. In contrst, evluting sensor performnce from frequent smpled in-clinic studies with lbortory reference mesurements tken every 15 minutes, the sensor error is generlly 3 4% lower with more ccurte smples cquired by professionls. Conclusion Fer of hypoglycemi is common emotion experienced by people with type 1 dibetes, often discourging greter intensive mngement of their BG levels in order to chieve better glycemic control. Fetures vilble with the Prdigm Veo, such s lerts nd the low glucose suspend function, cn help mitigte serious hypoglycemi, where insulin delivery is suspended beyond predetermined threshold. While most CGM devices provide threshold nd predictive lrms to wrn the user of impending or occurring hypo- or hyperglycemic episodes, widespred doption of these fetures is often hmpered by low ccurcy nd flse lerts. Therefore, incresed ccurcy, specificlly t low blood glucose levels, is dvntgeous. The Prdigm Veo clibrtion lgorithm demonstrtes performnce improvement over the current PRT system, with ccurcy improved in nerly ll performnce ctegories. Hypoglycemi sensitivity is incresed by greter thn 5, with 90.5 nd 94% of ll hypoglycemic events detected for prediction horizons of 15 nd 30 minutes, respectively. The men error in the low glucose rnge is decresed by pproximtely 5%, nd the sensor signl is more rective to fst glucose excursions. Furthermore, sensor signl processing delys re reduced considerbly in the Veo lgorithm. This reduction in time dely provides erlier nd more ccurte lerts, where hypoglycemi cn be detected nd predicted sooner, thereby enhncing ptient sfety nd ffording more time to self-tret potentil rections. Disclosure: D. Brry, Rymond Crty, nd John J. Mstrototro re employees of Medtronic MiniMed. References: 1. The Dibetes Control nd Complictions Tril Reserch Group. The effect of intensive tretment of dibetes on the development nd progression of long-term complictions in insulin-dependent dibetes mellitus. N Engl J Med. 1993;329(14): The Dibetes Control nd Complictions Tril Reserch Group. Implementtion of tretment protocols in the Dibetes Control nd Complictions Tril. Dibetes Cre. 1995;18(3): Wild D, von Mltzhn R, Brohn E, Christensen T, Cluson P, Gonder-Frederick L. A criticl review of the literture on fer of hypoglycemi in dibetes: implictions for dibetes mngement nd ptient eduction. Ptient Educ Couns. 2007;68(1): Jungheim K, Wientjes KJ, Heinemnn L, Lodwig V, Koschinsky T, Schoonen AJ; Glucose Monitoring Study Group. Subcutneous continuous glucose monitoring: fesibility of new microdilysisbsed glucose sensor system. Dibetes Cre. 2001;24(9): Bode BW, Gross TM, Thornton KR, Mstrototro JJ. Continuous glucose monitoring used to djust dibetes therpy improves glycosylted hemoglobin: pilot study. Dibetes Res Clin Prct. 1999;46(3): Gross TM, Bode BW, Einhorn D, Kyne DM, Reed JH, White NH, Mstrototro JJ. Performnce evlution of the MiniMed continuous glucose monitoring system during ptient home use. Dibetes Technol Ther. 2000;2(1): Juvenile Dibetes Reserch Foundtion Continuous Glucose Monitoring Study Group, Tmborlne WV, Beck RW, Bode BW, Buckinghm B, Chse HP, Clemons R, Fillo-Schrer R, Fox LA, Gillim LK, Hirsch IB, Hung ES, Kollmn C, Kowlski AJ, Lffel L, Lwrence JM, Lee J, Murs N, O Grdy M, Ruedy KJ, Tnsey M, Tslikin E, Weinzimer S, Wilson DM, Wolpert H, Wysocki T, Xing D. Continuous glucose monitoring nd intensive tretment of type 1 dibetes. N Engl J Med. 2008;359(14): Deiss D, Bolinder J, Riveline JP, Bttelino T, Bosi E, Tubin-Rufi N, Kerr D, Phillip M. Improved glycemic control in poorly controlled ptients with type 1 dibetes using rel time continuous glucose monitoring. Dibetes Cre. 2006;29(12): Hovork R, Wilinsk ME, Chssin LJ, Acerini CL, Dunger DB. The rtificil pncres: mking hedwy. Prcticl Dibetes Int. 2007;24(2): Mstrototro JJ, Cooper KW, Soundrrjn G, Snder JB, Shh RV. Clinicl experience with n integrted continuous glucose sensor/insulin pump pltform: fesibility study. Adv Ther. 2006;23(5): Hirsch IB, Abelseth J, Bode BW, Fischer JS, Kufmn FR, Mstrototro J, Prkin CG, Wolpert HA, Buckinghm BA. Sensorugmented insulin pump therpy: results from the first rndomized tret-to-trget study. Dibetes Technol Ther. 2008;10(5): Writing Tem for the Dibetes Control nd Complictions Tril/ Epidemiology of Dibetes Interventions nd Complictions Reserch Group. Sustined effect of intensive tretment of type 1 dibetes mellitus on development nd progression of dibetic nephropthy. JAMA. 2003;290(16): Allen C, Zccro DJ, Plt M, Klein R, Duck SC, D Alessio DJ. Glycemic control in erly IDDM. The Wisconsin Dibetes Registry. Dibetes Cre. 1992;15(8): Amiel SA, Sherwin RS, Simonson DC, Luritno AA, Tmborlne WV. Impired insulin ction in puberty. A contributing fctor to poor glycemic control in dolescents with dibetes. N Engl J Med. 1986;315(4):

8 15. Grnt RW, Buse JB, Meigs JB; University HelthSystem Consortium (UHC) Dibetes Benchmrking Project Tem. Qulity of dibetes cre in U.S. cdemic medicl centers. Dibetes Cre. 2005;28(2): Weinstein RL, Schwrtz SL, Brzg RL, Bugler JR, Peyser TA, McGrrugh GV. Accurcy of the 5-dy FreeStyle Nvigtor Continuous Glucose Monitoring System: comprison with frequent lbortory reference mesurements. Dibetes Cre. 2007;30(5): Zisser H, Biley TS, Schwrtz S, Rtner RE, Wise J. Accurcy of the SEVEN continuous glucose monitoring system: comprison with frequently smpled venous glucose mesurements. J Dibetes Sci Technol. 2009;3(5): Interntionl Orgniztion for Stndrdiztion: ISO In vitro dignostic test systems requirements for blood glucose monitoring systems for self testing in mnging dibetes mellitus. Interntionl Orgniztion for Stndrdiztion (ISO), Genev; Clinicl nd Lbortory Stndrds Institute. Performnce metrics for continuous interstitil glucose monitoring; pproved guideline. Clinicl nd Lbortory Stndrds Institute document POCT05-A. Wyne: Clinicl nd Lbortory Stndrds Institute; Prkes JL, Sltin SL, Prdo S, Ginsberg BH. A new consensus error grid to evlute the clinicl significnce of inccurcies in the mesurement of blood glucose. Dibetes Cre. 2000;23(8): Clrke WL, Cox D, Gonder-Frederick LA, Crter W, Pohl SL. Evluting clinicl ccurcy of systems for self-monitoring of blood glucose. Dibetes Cre. 1987;10(5): DB, Vosknyn G, Mstrototro JJ, Steil GM. Delys in minimlly invsive continuous glucose monitoring devices: review of current technology. J Dibetes Sci Technol. 2009;3(5):