대한진단검사의학회지제 29 권제 5 호 29 Korean J Lab Med 29;29:423-9 DOI 1.3343/kjlm.29.29.5.423 Original Article Clinical Chemistry ISO15197 에따른혈당측정기의분석적수행능평가 안동희 정희정 이혜원 이우창 전사일 민원기 울산의대서울아산병원진단검사의학과 Analytical Performance Evaluation of Glucose Monitoring System Following ISO15197 Dongheui An, M.D., Hee-Jung Chung, M.D., Hye-Won Lee, Woochang Lee, M.D., Sail Chun, M.D., and Won-Ki Min, M.D. Department of Laboratory Medicine, University of Ulsan College of Medicine and Asan Medical Center, Seoul, Korea Background : We have evaluated the analytical performance of SureStep Flexx (Johnson and Johnson, USA) which can report the plasma equivalent glucose test results and be connected to the hospital information networks, following ISO15197 analytic procedure for glucometer for the first time. Methods : Adopting the guidelines of ISO15197, we measured the precision of ten glucometers from their repeatability and intermediate precision, and determined the accuracies of the glucometer, comparing to those of GEM Premier 4 (Instrumentation Laboratory, USA). In addition, the guidelines of CLSI EP9-A2 and EP6-A were applied to correlate between data of glucometer and those of laboratory reference method by TBA-2FR (Toshiba Medical Systems, Japan) and to examine its linearity of glucose concentrations measured by SureStep Flexx. We used the clinical specimens and commercial control materials. Results : Repeatabilities and intermediate precisions of those glucometers were 4.-7.3%, and 4.3-6.2%, respectively. When glucose levels are under 75 mg/dl, the difference between results of those meters and the reference values were within ±6 mg/dl. However when glucose levels are over 75 mg/dl, those differences were within ±12.7%. These results were acceptable for the ISO15197 criteria in all glucose concentrations. The glucose concentrations showed the clinically relevant linearity in the range from 36 mg/dl to 491 mg/dl. Moreover, Error Grid Analysis showed that all glucose results were in zone A, which means that these values were clinically accurate. Conclusions : This study showed that SureStep Flexx can provide reliable results for patients and clinicians to manage the diabetes mellitus, satisfying the ISO15197 criteria. (Korean J Lab Med 29; 29:423-9) Key Words : SureStep Flexx, Networked glucometer, ISO15197, Evaluation, POCT 서 론 Received : May 8, 29 Manuscript No : KJLM9-6 Revision received : July 15, 29 Accepted : August 31, 29 Corresponding author : Sail Chun, M.D. Department of Laboratory Medicine, University of Ulsan College of Medicine and Asan Medical Center, 388-1 Pungnap 2-dong, Songpa-gu, Seoul 138-736, Korea Tel : +82-2-31-4513, Fax : +82-2-478-884 E-mail : sailchun@amc.seoul.kr 혈당측정기를통한혈당관리는저혈당을예방하고당뇨병의악화와합병증발생을지연시키는데필수적이다 [1]. 현재혈당측정기의종류는매우다양하나, 모두표준화된방법으로수행능평가가시행된것이아니다. 대부분의혈당측정기의수행능평가는전문인력에의해행해지는단일장비에대한평가지침인 Clinical and Laboratory Standards Institute (CLSI) 지 423
424 안동희 정희정 이혜원외 3 인 침에따라시행되었으나, 비전문가가사용하는혈당측정기의평가는검사실에서사용하는장비와다른표준화방법으로정확도및정밀도를평가할필요성이있다 [2]. 이에따라 International Organization for Standardization (ISO) Technical Committee ISO/TC 212에서는 23년에 1대이상의장비를사용하여 3단계혹은 5단계의혈당농도에서혈당측정기의정밀도와정확도를평가하는 당뇨병관리를위한자가시험용혈당측정기의요건 (In vitro diagnostic test systems-requirements for blood-glucose monitoring systems for self-testing in managing diabetes mellitus [23e]: ISO15197) 을발표하였으나, 아직이규정을전적으로만족하는혈당측정기평가는없었다. 또한국내식품의약품안정청 (Korea Food & Drug Administration, KFDA) 에서도 ISO15197을기초로한 혈당측정기성능평가가이드라인 을 27년 11 월발표하여국내에서사용되는혈당측정기의수행능평가에필요한최소지침을규정하였다. SureStep Flexx (SureStep Flexx, Johnson and Johnson, New Brunswick, NJ, USA) 는전혈의혈당값을혈장값으로환산하여결과값을보고하고, 병원전산망과연결하여실시간으로자료전송이가능한혈당측정기이다. 본연구에서는 Sure- Step Flexx의정밀도및정확도를 ISO15197와 혈당측정기성능평가가이드라인 에따라수행능평가를하고자하였다. 대상및방법 1. 대상장비및검체전혈을사용하여 SureStep Flexx의정확도, 정밀도, 직선성등의수행능을평가하였다. SureStep Flexx는 glucose oxidase 법으로전혈의혈당을측정하여전혈의혈당값에 1.12를곱해혈장값으로환산하여보고한다 [3]. 정밀도와직선성평가에는혈당측정기용정도관리물질 Meter Trax Control (Bio-Rad, Irvine, CA, USA) 을사용하였다. Meter Trax Control의 SureStep Flexx에대한 3가지농도의대조물질의농도값은각각저농도 : 89±12 mg/dl, 중간농도 : 21±2 mg/dl, 고농도 : 4 mg/dl 이상의범위였으며, 이들을혼합하여평가항목에따라제시된대로농도를제조하였다. 정확도평가에는환자검체를이용하였다. 29년 1월 5일부터 16일까지서울아산병원진단검사의학과에일반화학검사가의뢰된환자들의혈청과전혈을수집하였다. 각평가항목에따 라필요한농도군은 glucose oxidase-peroxidase법으로혈당을측정하는 TBA-2FR 자동화학분석기 (TBA-2FR, Toshiba Medical Systems, Tokyo, Japan) 의값을기초로선택되었다. 본연구는환자의다른검사결과를사용하지않는다는조건으로임상연구심의위원회의심의를통과하였다 ( 심의번호 28-418). 2. 평가방법실험은 ISO15197에따라기온 23±5 에서이루어졌고, 실험을마칠때까지실험시작시기온의 ±2 범위로유지되었다. 실험에사용된모든시약과시험지는단일로트제품이었고, 1회검사시검체량은피펫으로 7.5 μl 씩동량을사용하였다. 정도관리와시약보관은제조사의권고에따랐다. 1) 정밀도평가 ISO15197에따라정밀도는반복성 (repeatability) 과중간정밀도 (intermediate precision) 두가지로평가하였다. 반복성평가는 24시간이내에이루어졌고, 1개의혈당측정기로각농도별로 1번씩반복측정하였다. 검체의농도는 3-5 mg/dl, 51-11 mg/dl, 111-15 mg/dl, 151-25 mg/dl, 251-4 mg/dl 범위의 5가지 ( 농도 1-농도 5) 로제조하였다. 농도 1과농도 2는생리식염수와저농도정도관리물질을 1:1, :2 비율로, 농도 3과농도 4는저농도와중간농도물질을 1:1, :2 비율로, 5번물질은중간농도와고농도물질을 1:1로혼합하여제조하였다. 중간정밀도평가는 1개의혈당측정기로하루에각농도별로한회씩총 1일간반복측정하였다. 검체의농도는 3-5 mg/ dl, 96-144 mg/dl, 28-42 mg/dl 범위의 3가지 ( 농도 1- 농도 3) 로제조하였다. 농도 1-농도 3은각각생리식염수와저농도, 저농도와중간농도, 중간농도와고농도정도관리물질을 1:1 로혼합하여제조하였다. 각농도물질을 1개로분주하여냉장보관하였고매일 1개씩실온에서해동후사용하였다. 2) 정확도평가 ISO15197에따라일반화학검사가의뢰된환자의정맥혈검체 개를 1일에걸쳐측정하였다. Glucose dehydrogenase with nicotinamide-adenine dinucleotide (GDH-NAD) 법으로전혈의혈당을측정하는 GEM Premier 4 (GEM Premier 4, Instrumentation Laboratory, Lexington, MA, USA) 의측정치를기준으로하였다. GEM Premier 4은정
Evaluation of Glucose Monitoring System 425 밀도의경우검사내정밀도변이계수는 1.-1.4%, 검사일간정밀도변이계수는 1.9-2.7% 의범위를나타내었고, 이외직선성, 간섭인자등의수행능에대해서도검사실에사용하기에충분한것으로검증된바있다 [4]. 채취후 3 분이내의전혈을선택하였고, 검체분포는각각 5 mg/dl 미만 5%, 5-8 mg/dl 15%, 81-12 mg/dl 2%, 121-2 mg/dl 3%, 21-3 mg/dl 15%, 31-4 mg/dl 1%, 4 mg/dl 초과 5% 였다. Sure- Step Flexx는전혈혈당값을혈장값으로보고하므로, 전혈값으로측정되는 GEM Premier 4 값도 1.12를곱하여혈장값으로환산하여정확도평가를하였다 [3]. GEM Premier 4에서 2회씩반복측정하였고, SureStep Flexx 두대의장비에서각각 1회씩측정하였다. 동일검체로두장비에서측정한평균값으로회귀식, 기준치 (GEM Premier 4측정치의평균 ) 와의차이, % 기준치와의차이를구하였다. 또한혈당측정기의값을검사실측정값과비교하여임상적정확도를평가하는 Error Grid 분석을실시하였고, Parked 등 [5] 의방법대로 A, B, C, D, E의 5개영역으로표시하였다. 3) 중앙검사실장비측정치와상관성분석 CLSI EP9-A2에준하여 5개의임상검체에서 TBA-2FR 측정치와비교하였다 [6]. TBA-2FR에의해측정된값을기준으로다양한농도의혈당치가고루분포하도록동일시점에채취한전혈과혈장을선택하였다. TBA-2FR에서는혈장으로, SureStep Flexx에서는전혈로 2회씩반복측정하여평균값을비교하였다. 혈당측정기의값을중앙검사실측정값과비교하여 Error Grid 분석과 Modified Bland-Altman plot을도시하였다. 4) 직선성평가 CLSI EP6-A에따라 7개농도물질을각각 1회반복측정하여직선성을평가하였다 [7]. 검체분포는 <5 mg/dl, 5-8 mg/dl, 81-12 mg/dl, 121-2 mg/dl, 21-3 mg/dl, 31-4 mg/dl, >4 mg/dl였다. 7개농도물질 ( 농도 1- 농도 7) 은세농도의 Meter Trax Control을혼합하여제조하였다. 농도 1, 2는생리식염수와저농도정도관리물질을 2:2, 1:3으로, 농도 3-5는저농도와중간농도정도관리물질을 5:2, 2:5, :7 로, 농도 6, 7은중간농도와고농도정도관리물질을 1:1, 1:4로혼합하여제조하였다. 4. 통계분석통계분석에는 EP Evaluator Release 8 (David G. Rhoads Assoc., Kennett square, PA, USA) 과 SPSS version 13. (SPSS Inc., Chicago, IL, USA) 소프트웨어를이용하였다. EP Evaluator Release 8을이용한 Error Grid 분석으로 Clarke diagram과 Consensus diagram을얻었다. 결과 1. 정밀도반복성과중간정밀도평가결과각농도에서의평균, 표준편차, 변이계수를 Table 1에나타내었다. 반복성변이계수는농도 1부터농도 5에대하여각각 7.3%, 7.1%, 4.5%, 5.6%, 4.% 이었다. 1일에걸친중간정밀도변이계수는농도 1부터농도 3에대하여각각 6.2%, 4.3%, 4.5% 이었다 (Table 1). 이는모두 CLIA Table 1. Precision of the SureStep Flexx Repeatability Intermediate precision Level 1 Level 2 Level 3 Level 4 Level 5 Level 1 Level 2 Level 3 Mean (mg/dl) 34.1 85.7 135.1 189. 353.8 34.1 139.2 373.5 SD (mg/dl) 2.5 6.1 6.1 1.6 14. 2.1 6. 16.8 CV (%) 7.3 7.1 4.5 5.6 4. 6.2 4.3 4.5 Table 2. Accuracy of the SureStep Flexx by ISO Standard Criteria Glucose concentration of reference method <75 mg/dl 75 mg/dl Interval Within±5 mg/dl Within±1 mg/dl Within±15 mg/dl Within±5% Within±1% Within±15% Within±2% N (%) 15/16 (93.8) 16/16 (.) 16/16 (.) 49/84 (58.3) 77/84 (91.7) 84/84 (.) 84/84 (.) Abbreviation: ISO, International Organization for Standardization.
426 안동희 정희정 이혜원외 3 인 88의기준인 1% 를충족하였다 [8]. 2. 정확도혈당농도 75 mg/dl 이상인검체에서는 58.3% (49/84) 가 ±5% 범위내에, 91.7% (77/84) 가 ±1% 범위내에,.% (84/84) 가 ±12.7% 범위내에분포하여 ISO15197 기준인 2% 를만족하였다. 혈당농도가 75 mg/dl 미만인검체에서는 93.8% (15/16) 가참고치와의 ±5 mg/dl 범위내에, % (16/16) 모두 ±6 mg/dl 범위내에분포하여 ISO15197 기준인 ±15 mg/dl 를만족하였다 (Table 2). GEM Premier 4과 SureStep Flexx에서측정한평균값의회귀식, Error Grid 분석, Modified Bland-Altman plot은 Fig. 1과같다. GEM Premier 4 측정값을기준으로상관 SureStep flexx (mg/dl) 5 4 3 2 A % B % C % D % E % Consensus grid y=.9268x+5.6219 r=.9969 2 3 4 5 Gem premier 4 (mg/dl) A SureStep flexx-gem premier 4 (mg/dl) 12. 11.. 9. 8. 7. 6. 5. 4. 3. 2. 1. -1. -2. -3. -4. -5. -6. -7. -8. -9. -. -11. -12. 2 3 4 5 6 Gem premier 4 (mg/dl) B Fig. 1. Accuracy of the SureStep Flexx compared with GEM Premier 4 (A) Error Grid Analysis showed that all glucose measurements by SureStep Flexx were included in zone A. Dotted line represents regression analysis. Zone A represents no effect on clinical action; zone B represents altered clinical action-little or no effect on clinical outcome; zone C represents altered clinical action-likely to affect clinical outcome; zone D represents altered clinical action-could have significant medical risk; and zone E represents altered clinical action-could have dangerous consequences [5]. (B) Modified Bland-Altman plots with superimposed ISO15197 tolerance band. SureStep flexx (mg/dl) 5 4 3 2 A % B % C % D % E % Consensus grid 2 3 4 5 TBA-2FR (mg/dl) y=1.21x-5.2435 r=.9965 A SureStep flexx-tba-2fr (mg/dl) 9 8 7 6 5 4 3 2 1-1 -2-3 -4-5 -6-7 -8-9 - 2 3 4 5 TBA-2FR (mg/dl) B Fig. 2. Correlation of glucose concentrations measured by SureStep Flexx versus TBA-2FR (A) Error Grid Analysis of the SureStep Flexx glucose measurements compared with TBA-2FR. All glucose results by the SureStep Flexx were included in zone A (See Fig. 1.). Dotted line represents regression analysis. (B) Modified Bland-Altman plots with superimposed ISO15197 tolerance band.
Evaluation of Glucose Monitoring System 427 계수 (r) 는.975 이상의우수한상관관계를보였다 (Fig. 1, y=.9268x+5.6219, r=.9969, P<.1). SureStep Flexx 측정치는 GEM Premier 4 측정치보다평균 7.5 mg/dl (95% 신뢰구간 : 4.97-1.1 mg/dl), 3.43% (2.54-4.32 mg/dl) 낮게측정되었다. Error Grid 분석결과모든결과는임상적으로정확하다고판단할수있는 A 영역에속하였다 [5]. 3. 중앙검사실장비측정치와상관성분석 Error Grid 분석을통한 SureStep Flexx 측정치와 TBA- 2FR 측정치비교는 Fig. 2와같다. 분석결과모든측정치는 A영역에속하였고, 두값의차이는 ±11.3% 이내였다. Sure- Step Flexx 측정치는 TBA-2FR 측정치보다평균 1.7 mg/dl (95% 신뢰구간 : -1.-4.4 mg/dl), 1.6% (.1-3.1%) 낮게측정되었다 (Fig. 2). 4. 직선성 36-491 mg/dl 농도범위에서 lack of fit 검사를통과하여직선성을보였고, 상관계수는.9993 (P<.1) 이었다 (Fig. 3). 고 미국 FDA는혈당측정기의수행능평가를할때정밀도와정확도평가는 ISO15197에따라수행하고, 직선성등은 CLSI 지 SureStep flexx glucose value (mg/dl) 5 4 3 2 Fig. 3. Analytical measuring range of the SureStep Flexx was 36-491 mg/dl. The straight line was determined by a linear regression of the measured glucose concentrations with those of the expected glucose concentrations. 찰 y=1.46x+3.23 r=.9993 (P<.1) 2 3 4 5 Expected glucose value (mg/dl) 침을따를것을권고하였다 [9]. 그러나 ISO의혈당측정기평가지침은까다로워평가기준을차용한문헌들은있었지만, ISO- 15197 방법을엄격하게따라혈당측정기의수행능평가를한보고는없었다 [1-12]. 정밀도나정확도평가시사용하는 CLSI 지침은단일장비에대한평가방법이다 [6, 7, 13]. 이에반하여, ISO15197은혈당측정기만을위하여고안된지침이며, 평가항목별농도범위와장비의숫자도구체적으로제시하고있다. 이번연구에서의정밀도평가에서는단일장비의 CV는 1.- 4.9% 로기존에보고된 SureStep Flexx를포함한다른혈당측정기의정밀도보고들과차이가없었다 [14-17]. 그러나 ISO- 15197 지침에따라 1대를평가한반복성변이계수와중간정밀도변이계수는각각 4.-7.3%, 4.3-6.2% 로 CLIA 88의혈당측정기에대한정밀도기준인 1% 이내에모두포함되었다 [8]. 저자들의 CV는기존보고보다높게나타났는데, 이는 1대의장비간의오차가누적되어나타나는것으로추론된다. ISO15197은반복성측정시혈당의불안정성을최소화하기위하여시간을하루이내로규정하였다고한다. 그러나, 실제수행결과는시간적으로뒤에평가된혈당치가더높았고, 변이계수도증가하는경향을보였다. 이는실험진행에따른시약의증발등의영향으로생각된다. ISO15197에서정한정확도의기준은혈당측정기에관한지침인 CLSI C3-A2에제시된중앙검사실장비와의비교기준과같다 [18]. 기존의보고들에서는정확도평가를위하여혈당측정을위한참고장비로혈액가스분석장비 Yellow Springs Instrument (Yellow Springs, OH, USA) 측정치와주로비교하였으며, 이에따라이번연구에서도혈액가스분석장비인 GEM Premier 4 측정치와비교하였다. 또한, CLSI EP9-A2지침에따라중앙검사실장비와의상관성분석을위하여 TBA- 2FR 측정치와비교하였다. GEM premier 4을중앙검사실장비와의상관성을비교한결과 (n=56) 상관계수 (r) 는.975 이상의우수한상관성을보였다 (y=1.753x-11.511, r=.994). 정확도평가결과 SureStep Flexx는다른연구들과비교해볼때, ISO15197 기준을충분히만족하였다 [1, 11, 19, 2]. Hoedemaekers 등 [2] 은 3대의혈당측정기를참고법과비교했을때모든검체의 2.5-13.4% 가 ISO15197에서제시한정확도기준에서벗어났다고보고하였으나, 본연구에서는모든검체가 ISO15197의정확도기준을만족시켰다. 저자들은검체량을 7.5 μl 로최소검체요구량인 5 μl 보다는충분한양을사용했지만, 검체량에따라참고법과오차가달라진다는문헌도있어서검체량에따른오차도배제할수없을것
428 안동희 정희정 이혜원외 3 인 으로생각된다 [21]. 이번연구에서 SureStep Flexx는 36-491 mg/dl 농도범위에서직선성을보여임상적으로환자의관리및치료를위한혈당범위를충분히포함하였다 [15]. International Federation of Clinical Chemistry에서는혈당치를혈장값으로보고할것을권장하고있는데, SureStep Flexx는기계내에서전혈혈당값에 1.12를곱하여자동으로혈장값으로환산하여보고하는기능이있다 [3]. 또한, SureStep Flexx는현장검사장비이면서병원전산망및검사정보시스템과연결하여실시간으로전자의무기록에자료를전송할수있을뿐아니라, 임상의로하여금즉각적인조치를취할수있게하고, 수기입력과정과관련된사무적오류를감소시킬수있어효율적인자료관리를가능하게한다. 또한, 현장검사장비의정도관리결과를중앙검사실에서관리할수있어현장검사장비의신뢰성향상에도움이될것으로생각된다 [22, 23]. 이번연구에서는최초로 ISO15197 지침에따라 SureStep Flexx의정밀도와정확도를평가하였다. SureStep Flexx는 ISO15197의정확도기준을충족하였고, 정밀도, 직선성에서우수한수행능을보였으며, 중앙검사실장비와만족스러운상관성을보였다. 또한, 결과값을혈장값으로환산하여보고하므로중앙검사실의결과와연속적으로비교가가능하다는장점이있다. 궁극적으로 SureStep Flexx는현장검사장비로사용함으로써효과적인당뇨병관리와치료계획및결정에도움을줄것으로기대된다. 요약배경 : 저자들은결과값을혈장값으로환산하여보고하고병원전산망과연결가능한 SureStep Flexx (Johnson and Johnson, USA) 의분석적수행능을혈당측정기평가지침인 ISO- 15197에따라최초로평가하였다. 방법 : ISO15197에따라정밀도와정확도를평가하였다. 정밀도는 1대장비로반복성과중간정밀도를평가하였고, 정확도는 GEM Premier 4 (Instrumentation Laboratory, USA) 을혈당측정참고법으로사용하였다. 또한, CLSI 지침에따라중앙장비측정치와상관성및직선성평가를하였다. 중앙장비측정치와상관성평가를위하여혈당측정참고법으로 TBA- 2FR 자동화학분석기 (Toshiba Medical Systems, Japan) 를사용하였다. 이를위하여환자검체와시판되는대조물질을사용하였다. 결과 : SureStep Flex의반복성변이계수는 4.-7.3% 였고, 중간정밀도변이계수는 4.3-6.2% 였다. 정확도는 75 mg/dl 미만인검체와 75 mg/dl 이상인검체는모두참고법에의한혈당값차이가각각 ±6 mg/dl, ±12.7% 범위내에분포하여 ISO- 15197 기준을만족하였다. 농도범위 36-491 mg/dl에서직선성을보였다. 또한, Error Grid 방법으로분석한결과, GEM Premier 4 및 TBA-2FR 값과비교한모든측정치는임상적으로정확한범위인 A영역에포함되었다. 결론 : SureStep Flexx는 ISO1597 기준을충족하는신뢰성있는검사값을제공함으로써, 효과적인당뇨병관리에도움을줄수있을것으로사료된다. 참고문헌 1. Welschen LM, Bloemendal E, Nijpels G, Dekker JM, Heine RJ, Stalman WA, et al. Self-monitoring of blood glucose in patients with type 2 diabetes who are not using insulin: a systematic review. Diabetes Care 25;28:151-7. 2. The International Organization for Standardization. In vitro diagnostic test systems-requirements for blood glucose monitoring systems for self-testing in managing diabetes mellitus. ISO/TC 212/SC. International Standard ISO 15197. Geneva, Switzerland: ISO, 23. 3. Burnett RW, D Orazio P, Fogh-Andersen N, Kuwa K, Kulpmann WR, Larsson L, et al. IFCC recommendation on reporting results for blood glucose. Clin Chim Acta 21;37:25-9. 4. Beneteau-Burnat B, Pernet P, Pilon A, Latour D, Goujon S, Feuillu A, et al. Evaluation of the GEM Premier 4: a compact blood gas CO-Oximeter and electrolyte analyzer for point-of-care and laboratory testing. Clin Chem Lab Med 28;46:271-9. 5. Parkes JL, Slatin SL, Pardo S, Ginsberg BH. A new consensus error grid to evaluate the clinical significance of inaccuracies in the measurement of blood glucose. Diabetes Care 2;23:1143-8. 6. Clinical and Laboratory Standards Institute. Method comparison and bias estimation using patient samples; Approved guideline-2nd ed. Document EP9-A2. Wayne, PA: Clinical and Laboratory Standards Institute, 22. 7. Clinical and Laboratory Standards Institute. Evaluation of the linearity of quantitative measurement procedures; A statistical approach; Approved guideline. Document EP6-A. Wayne, PA: Clinical and Laboratory Standards Institute 23. 8. Medicare, Medicaid and CLIA programs; regulations implementing the Clinical Laboratory Improvement Amendments of 1988 (CLIA)-
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