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임상검사와정도관리 : 제 28 권제 1 호 2006 J Lab Med Qual Assur 2006:28:213-217 213 외부정도관리물질을이용한내부정도관리시행의유용성 김윤희 보령아산병원진단검사의학과 The Usefulness of Internal Quality Control Procedure Using External Quality Control Materials Yun-Hee Kim Department of Laboratory Medicine, Boryeong Asan Hospital, Boryeong, Korea Background : It is very important to keep the quality of the process of clinical tests and for that internal & extenal quality control procedures are performed in many clinical laboratorys. With the simultaneous use of external quality control materials for internal and external quality control procedures, not only precision but also bias presumed to be systematic error can be assessed. Also the control limits for internal quality control procedure can be obtained. It is the aim of this study to investigate the useful aspects of the integration of internal and extenal quality control procedures. Methods : The Korean Association of Quality Assurance for Clinical Laboratory 2006-CC-01 quality control materials for external quality control survey were tested on 19 general chemistry items with Hitachi 7180 (Hitachi, Tokyo, Japan) autoanlyzer once a day for 20 days. Current means and standard deviations (sd) were obtained from internal quality control results for 20 days and were used to calculate the biases with target means from external quality control survey results. Bias, sigma (TEa/sd), method sigma (TEa- bias /sd) and total error (TE) of each the 19 items were calculated and the calculated total errors of 19 items were compared with the CLIA'88 allowable total errors (TEa). Contol limits for internal quality control procedures were established according to the method sigma levels and probability for false rejection (Pfr), probability for error detection (Ped), average run length for false rejection (ARLfr) and average run length for error detection (ARLed) according to the control limit levels were estimated. Results : Out of total 19 items, 8 items such as albumin, glucose, triglyceride, total cholesterol, uric acid, total bilirubin, GGT and LDH satisfied the CLIA'88 TEa criteria and 11 items such as total protein, total calcium, inorganic phosphorus, BUN, creatinine, AST, ALT, ALP, sodium, potassium and chloride didn't satisfied. In the 11 items not satisfying CLIA'88 TEa criteria, 6 items such as BUN, creatinine, AST, ALT, sodium and chloride had the method sigma below 1.65 and control limits for internal quality control procedure could not be established. Control limits of the other 13 items were established according to the method sigma leves. In case of 6 method sigma level, Pfr were estimated to be 0.000007 and Ped to be 1.0000 and ARLfr to be 146910 and ARLed to be 1.00. Conclusion : The integrated data from both the internal and external quality control results were very useful in assessment of the quality status of the tests and in designing and planning the internal quality control procedures such as control limits. Key Words:External quality control, Internal quality control, Total error, Bias, Sigma 교신저자 : 김윤희우 ) 365-120 충남보령시죽정동 1 보령아산병원진단검사의학과전화 :041)930-5114, FAX:041)934-3292 E-mail:elimyh@naver.com 서론산업계에서사용되던정도관리의이론과방법이 1950 년대에 Levey 와 Jennings 에의해검사실에도입된후, 정도

214 김윤희 관리는임상검사실에서점차그중요성이강조 [1-3] 되어, 현재국내 500 여병원검사실에서외부및내부정도관리가시행되고있다. 최근같은내부정도관리물질을사용하는검사실간의전산망구축에의한외부및내부정도관리의통합이일부정도관리물질제조사에의해시도된바있으나, 비용적인측면과가입검사실의숫자가적은점등의문제로실제임상검사실에서외부정도관리의결과를분석하여이에따라내부정도관리의규칙을고안하고, 이규칙에의하여내부정도관리검사결과를처리하기가어려운실정이다. 현재대한임상검사정도관리협회임상화학분과에서는일반화학검사 19종목에대해정도관리가가능한물질 12검체를매년전국 500 여검사실에발송하여매월 1회씩의외부정도관리의시행이가능하게하고있다. 또한, 최근개발되는자동화학분석기는검체요구량이약 150 μl 정도로극히적기때문에, 자동화학분석기 1대를운용하고있는중소병원검사실의경우, 대한임상검사정도관리협회에서발송한외부정도관리물질을이용하여동시에내부정도관리를시행하는것이가능하다. 본연구에서는검사의질평가및관리를위하여외부정도관리결과자료를분석시외부정도관리물질을이용한내부정도관리를시행하여얻어진결과자료를함께분석함으로써, 검사공정의정확도및정밀도를평가하고내부정도관리의규칙을고안하고계획하는데, 어떻게활용될수있는지분석해보고자한다. to pyruvate법 (LDH), vanadate oxidation 법 (total bilirubin), enzymatic 법 (total cholesterol), enzymatic-hd- AOS with glycerol blank 법 (triglyceride), biuret법 (total protein), uricase 법 (uric acid), direct ISE 법 (sodium, potassium 및 chloride) 등이었다. 20일간의내부정도관리결과의평균 (current mean) 및표준편차 (standard deviation, sd) 와외부정도관리조사결과의 method mean 및 all method mean 을가지고, 각검사종목들의편차 (bias), sigma(tea/sd), method sigma(tea- bias /sd), 총오차 (total error, TE) 를구하여, CLIA'88 allowable total error(tea) 의기준에부합되는지평가하였다 [4-7]. CLIA'88 TEa 의기준을만족시킨검사종목들에대해서는이후검사실내부정도관리에적용될규칙 (control limit, rejection rule) 을설정하였고, 이렇게설정된규칙을실제내부정도관리에적용할때예측되는 probability for false rejection(pfr), probability for error detection(ped), average run length for false rejection(arlfr), 및 average run length for error detection(arled) 을분석하였다 [6]. 결과 1. 외부및내부정도관리결과에의해계산된총오차 (total error, TE) 의평가 (Table 1) 대상및방법대한임상검사정도관리협회일반화학검사용외부정도관리검체 2006-CC-01을이용하여 albumin, alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (B- UN), total calcium, inorganic phosphorus, creatinine, gamma glutamyl transferase (GGT), glucose, lactate dehydrogenase (LDH), total biliruin, total cholesterol, triglyceride, total protein, uric acid, sodium, potassium 및 chloride 등의 19 가지검사종목에대하여본원검사실에설치된 Hitachi 7180 (Hitachi, Tokyo, Japan) 자동화학분석기에 Wako 시약 (Wako pure chemical industries, Ltd., Tokyo, Japan) 을장착한후 Wako calibrator (Wako pure chemical industries, Ltd., Tokyo, Japan) 로보정하여 1일 1회시행간격으로 20 일간내부정도관리를시행하였다. 검사종목별측정방법은 dye binding-bcg 법 (albumin), PPNP, DEA buffer 법 (ALP), UV without P5P 법 (AST 및 ALT), urease with GLDH 법 (BUN), cresolphthalein complexone 법 (total calcium), phosphomolydate with any reduction 법 (inorganic phosphorus), kinetic alkaline picrate 법 (creatinine), gamma-glutamyl-carboxy-nitroanilide 법 (GGT), hexokinase 법 (glucose), lactate 19검사종목중 albumin, glucose, triglyceride, total cholesterol, uric acid, total bilirubin, GGT 및 LDH 의 8종목의 TE 가 CLIA'88 TEa 의기준을만족시켰고, total protein, total calcium, inorganic phosphorus, BUN, creatinine, AST, ALT, ALP, sodium, potassium 및 chloride 의 11종목의 TE 는 CLIA'88 TEa 의기준을만족시키지못하였다. CLIA'88 TEa의기준을만족시키지못한 11종목중 BUN, creatinine, AST, ALT, sodium 및 chloride 의 6종목은 method sigma 가 1.65 미만이었다. Total protein, total calcium, inorganic phosphorus, BUN, creatinine, ALP 및 potassium 의 7종목은 sigma 가 4이상, AST, ALT, sodium 및 chloride 의 4종목은 sigma 가 4미만이었다. 2. 내부정도관리규칙 (control limit) 의설정 (Table 2) Method sigma가 1.65 이상인 13종목중 6 method sigma 이상의 process 를보인 6종목은 6 method sigma 에서의 critical systematic error(sec) 인 4.35sd 를내부정도관리의규칙 (control limit, rejection rule) 으로설정하였고, 6 method sigma 미만의 process 를보인 7종목에대해서는각종목의 SEc 를 control limit 으로설정하였다. Control limit 이 4.35sd 인 6종목의경우 Pfr 은

외부정도관리물질을이용한내부정도관리시행의유용성 215 Table 1. Total error determined by internal & external QC results on 19 chemisty items Bias Sigma Method sigma TE by method mean TE by all method mean CLIA'88 TEa Total protein 0.1 4.0 3.7 0.7 0.7 0.6 Albumin 0.1 7.5 6.7 0.3 0.3 0.4 Glucose -0.6 6.1 5.5 4.5 4.9 6.0 Triglyceride 2.9 29.4 27.6 9 9 47 Total cholesterol 2.8 6.5 5.8 18 18 25 Total calcium 0.4 6.6 3.9 1.0 1.0 1.0 Inorganic phosphorus -0.1 5.4 3.8 0.4 0.5 0.3 Uric acid -0.1 12.1 10.6 0.3 0.3 0.7 Blood urea nitrogen 2.0 5.4-0.8 3.2 3.2 1.7 Creatinine 0.3 7.8 0.5 0.4 0.5 0.3 Total bilirubin -0.1 17.0 12.1 0.2 0.3 0.4 Aspartate aminotransferase -5.1 2.8 0.7 14.9 15.1 6.8 Alanine aminotransferase -4.7 3.5 0.5 11.0 11.1 5.5 Alkaline phosphatase 6.0 4.2 3.6 49 63 46 Gamma glutamyl transferase 9.2 23.4 7.4 12 12 13 Lactate dehydrogenase 3.2 9.5 8.6 17 137 32 Sodium -0.6 1.9 1.6 9.2 9.1 4.0 Potassium 0.1 4.3 3.6 0.6 0.6 0.5 Chloride 2.2 2.3 1.3 11.4 11.9 5.2 Abbreviations: QC, quality control; TE, total error; TEa, allowable total error. Table 2. Establishment of control limit on 13 items with 1.65 and up method sigma SEc Control limit Pfr Ped ARLfr ARLed Total protein 2.1 2.1 0.017864 0.9821 56 1.02 Albumin 5.0 4.35 0.000007 1.0000 146910 1.00 Glucose 3.9 3.9 0.000048 1.0000 20792 1.00 Triglyceride 25.9 4.35 0.000007 1.0000 146910 1.00 Total cholesterol 4.1 4.1 0.000021 1.0000 48409 1.00 Total calcium 2.2 2.2 0.013903 0.9861 72 1.01 Inorganic phosphorus 2.2 2.2 0.013903 0.9861 72 1.01 Uric acid 9.0 4.35 0.000007 1.0000 146910 1.00 Total bilirubin 10.5 4.35 0.000007 1.0000 146910 1.00 Alkaline phosphatase 2.0 2.0 0.022750 0.9772 44 1.02 Gamma glutamyl transferase 5.8 4.35 0.000007 1.0000 146910 1.00 Lactate dehydrogenase 6.9 4.35 0.000007 1.0000 146910 1.00 Potassium 1.9 1.9 0.028717 0.9713 35 1.03 Abbreviations:SEc, critical systematic error; Pfr, probability for false rejection; Ped, probability for error detection; ARLfr, average run length for false rejection; ARLed, average run length for error detection.

216 김윤희 0.000007, Ped 1.0000, ARLfr 146910, ARLed 1.00 으로예측되었으며, 이외의 7종목각각의 control limit 에서예측되는 Pfr, Ped, ARLfr 및 ARLed 는표2와같았다. 고찰국내대부분의검사실에서자가제조또는상품화된정도관리물질을이용하여내부정도관리를시행하고있으나, 외부정도관리를통하여평가된 method sigma 수준에따라 control limit을적절히설정하여내부정도관리를시행하기보다는자동화학분석기에적용되어있는 Levey-Jennings control limit 또는 Westgard multirule의 screening limit인 2sd를 control limit으로하여내부정도관리를시행하는것이일반적이다 [8]. 모든일반화학검사종목에 2sd control limit을적용할경우, 오차의절대값은크더라도임상적허용오차한계를고려할경우, 무시될수있는오차들이불필요하게관리되고, 오차의절대값은작더라도임상적허용오차의관점에서는관리되어야할오차들이무시될수있는문제가있다. 본연구에서는외부정도관리에사용된물질을이용하여내부정도관리를시행함으로써, 19개의일반화학검사종목에대하여각각의참고법과비교측정하지않고도총오차 (total error, TE) 를분석할수있었다. 분석된총오차를 CLIA'88 의 TEa 를기준으로평가시 albumin, glucose, triglyceride, total cholesterol, uric acid, total bilirubin, GGT 및 LDH 의 8종목은 CLIA'88 TEa 의기준을만족시켰고, total protein, total calcium, inorganic phosphorus, BUN, creatinine, AST, ALT, ALP, sodium, potassium 및 chloride 의 11종목은 CLIA'88 TEa 의기준을만족시키지못하였다. Method mean 을 target mean 으로간주한경우의총오차와 all method mean 을 target mean 으로간주한경우의총오차각각을 CLIA'88 TEa 의기준과비교평가시 LDH 를제외하고는모두동일한비교평가결과를보여주었는데, LDH 의경우 lactate to pyryvate 법과 pyruvate to lactate 법에따른검사결과의차이가커서 all method mean 에의한총오차가증가했기때문이다. CLIA'88 TEa 의기준을만족시키지못한 11종목중특히 BUN, creatinine, AST, ALT, sodium 및 chloride 의 6종목은 method sigma가 1.65 미만을보여관리의대상이되는오차의범위가 0으로검사의시행을지속시키기전에먼저오차의원인을조사하고해결하는일이요구되었다. BUN, creatinine 은 sigma 가 5.4, 7.8 로정밀도는적절하였으나, bias 가 2.0, 0.28 을보여계통적오차의원인조사및해결이요구되었다. AST, ALT, sodium 및 chloride 는 4 미만의 sigma 를보여우선정밀도의개선이 시급한것으로판단되었다. CLIA'88 TEa 의기준을만족시킨 8종목중 albumin, triglyceride, uric acid, total bilirubin, GGT 및 LDH 는 method sigma가 6이상을보여 4.35sd 를 control limit으로설정하였고, glucose 는 SEc 인 3.9sd 를, total cholesterol 은 SEc 인 4.1sd 를 contol limit으로설정하였다. 이와같이통상적인 2sd 보다 control limit 을크게설정하더라도, Ped 는 1.0000 으로예측되었다. CLIA'88 TEa 의기준을만족시키지는못하였으나, method sigma 가 1.65 이상이어서 control limit의설정이가능했던 5종목 total protein, total calcium, inorganic phosphorus, ALP 및 potassium의 control limit 은각각 2.1sd, 2.2sd, 2.2sd, 2.0sd 및 1.9sd 로통상적 control limit인 2sd 와유사한결과를보였다. 이때의 Ped 는각각 0.9821, 0.9861, 0.9861, 0.9772 및 0.9713이었으며, ARLfr 은각각 56, 72, 72, 44 및 35이었다. 각검사종목에따라내부정도관리의규칙 (control limit) 을다르게설정할뿐아니라시행횟수의조절을포함하는계획을세울수있는데, 예를들어 CLIA'88 TEa 의기준을만족시킨 albumin, triglyceride, uric acid, total bilirubin, GGT, LDH, glucose 및 total cholesterol 의 8종목에대해서는매일이상의간격으로정도관리를시행하도록하고, CLIA'88 TEa 의기준을만족시키지못한 total protein, total calcium, inorganic phosphorus, ALP 및 potassium 의 5종목에대해서는매일의간격보다좀더자주정도관리를시행하도록계획할수있을것이다. 외부정도관리물질을이용하여일반화학 19검사종목에대하여내부정도관리를시행한결과, 본원검사실의경우 BUN 및 Creatinine 은계통적오차의제거가, AST, A- LT, sodium 및 chloride 는정밀도의개선이요구되는것을알수있었고, 나머지 13종목중 albumin, triglyceride, uric acid, total bilirubin, GGT, LDH, glucose 및 total cholesterol 은약 4sd 를 control limit 으로, total protein, total calcium, inorganic phosphorus, ALP 및 potassium 은약 2sd를 control limit 으로설정할수있었다. 요약배경 : 일반화학외부정도관리물질을이용하여내부정도관리를시행하여얻어진통합된외부및내부정도관리의결과자료가검사공정의정확도및정밀도를평가하고내부정도관리의규칙을고안하고계획하는데, 어떻게활용될수있는지알아보고자한다. 방법 : 대한임상검사정도관리협회일반화학검사용외부정도관리검체 2006-CC-01 을이용하여 Hitachi 7180 (Hitachi, Tokyo, Japan) 자동화학분석기로 20일간 19

외부정도관리물질을이용한내부정도관리시행의유용성 217 가지일반화학검사종목에대한내부정도관리를시행하여평균 (current mean) 및표준편차 (standard deviation, sd) 를구하고, 외부정도관리결과의 method mean 및 all method mean 을가지고, 각검사종목들의편차 (bias), s- igma (TEa/sd), method sigma (TEa- bias /sd), 총오차 (total error, TE) 를구하여, CLIA'88 allowable total error (TEa) 의기준에부합되는지평가하였다. CLI- A'88 TEa 의기준을만족시킨검사종목들에대해서는이후검사실내부정도관리에적용될규칙 (control limit, rejection rule) 을설정하였고, 이렇게설정된규칙을실제내부정도관리에적용시예측되는 probability for false rejection(pfr), probability for error detection(ped), average run length for false rejection (ARLfr), 및 average run length for error detection (ARLed) 을분석하였다. 결과 : 19 검사종목중 albumin, glucose, triglyceride, total cholesterol, uric acid, total bilirubin, GGT 및 LDH 의 8종목은 CLIA'88 TEa 의기준을만족시켰고, total protein, total calcium, inorganic phosphorus, BUN, creatinine, AST, ALT, ALP, sodium, potassium 및 chloride 의 11종목은 CLIA'88 TEa 의기준을만족시키지못하였다. CLIA'88 TEa의기준을만족시키지못한 11종목중 BUN, creatinine, AST, ALT, sodium 및 chloride 의 6종목은 method sigma가 1.65 미만이었다. Method sigma 가 1.65 이상인 13종목중 6 m- ethod sigma 이상의 process 를보인 6종목은 6 method sigma 에서의 critical systematic error(sec) 인 4.35sd 를내부정도관리의규칙 (control limit, rejection rule) 으로설정하였고, 6 method sigma 미만의 process 를보인 7종목에대해서는각종목의 SEc 를 control limit 으로설정하였다. Control limit 이 4.35sd 인 6종목의경우 Pfr 은 0.000007, Ped 1.0000, ARLfr 146910, ARLed 1.00 으로예측되었다. 결론 : 외부정도관리물질을이용하여일반화학 19검사종목에대하여내부정도관리를시행한결과를분석한결과, 본원검사실의경우 BUN 및 Creatinine 은계통적오차의제거가, AST, ALT, sodium 및 chloride 는정밀도의개선이요구되는것을알수있었고, 나머지 13종목중 albumin, triglyceride, uric acid, total bilirubin, GGT, LDH, glucose 및 total cholesterol 은약 4sd를 control limit 으로, total protein, total calcium, inorganic phosphorus, ALP 및 potassium 은약 2sd 를 control limit으로설정할수있었다. 참고문헌 1. Buttner J, Borth R, Broughton PMG, et al. International Federation of Clinical Chemistry approved recommendation (1983) on quality control in clinical chemistry IV Internal quality control. J Clin Chem Clin Biochem 1983;21:877-884. 2. Waid ME, Hoffmann RG. The quality control of laboratory precision. Am J Clin Path 1955; 25:585-594. 3. Sax SM, Dorman L, Libenson DD, et al. Design and operation of an expanded system of quality control. Clin Chem 1967;13:825-833. 4. Burnett L, Hegedus G, Chesher D, Burnett J, Costagnanna G. Application of process capability indices to quality control in a clinical chemistry laboratory. Clin Chem 1996;42: 2035-7. 5. Westgard JO, Seehafer JJ, Barry PL. European specifications for imprecision and inaccuracy compared with operating specifications that assure the quality required by US CLIA proficiency-testing criteria. Clin Chem 1994;40:1228-32. 6. Westgard JO. Internal quality control: planning and implementation strategies. Ann Clin Biochem 2003;40:593-611. 7. www. westgard. com 8. Burtis CA and Ashwood ER. Quality management. In: Burtis CA, ed. Tietz testbook of clinical chemistry. 3rd ed. Phildelphia: WB Saunders, 1999:384-420.