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1 Korean J Gastroenterol Vol. 68 No. 2, pissn eissn ORIGINAL ARTICLE 단일 2 차종합병원에서출혈성소화성궤양환자의임상양상과빅데이터분석을위한조작적정의에관한연구 이재원 1, 김현기 1, 우용식 1, 장재훈 1, 진영란 2, 박종헌 3, 김용성 1,5, 정훈용 4,5 원광대학교의과대학산본병원내과학교실및원광소화기질환연구소 1, 의무기록실 2, 국민건강보험공단빅데이터운영실 3, 울산대학교의과대학서울아산병원내과학교실 4, 대한상부위장관ㆍ헬리코박터학회학술위원회 5 Optimal Operational Definition of Patient with Peptic Ulcer Bleeding for Big Data Analysis Using Combination of Clinical Characteristics in a Secondary General Hospital Jae Won Lee 1, Hyun Ki Kim 1, Yong Sik Woo 1, Jaehoon Jahng 1, Young Ran Jin 2, Jong Heon Park 3, Yong Sung Kim 1,5, and Hwoon-Yong Jung 4,5 Department of Internal Medicine and Wonkwang Digestive Disease Research Institute 1, Department of Medical Record 2, Wonkwang University Sanbon Hospital, Wonkwang University College of Medicine, Gunpo, Big Data Steering Department, National Health Insurance Service, Wonju 3, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul 4, Scientific Committee of the Korean College of Helicobacter and Upper Gastrointestinal Research, Seoul 5, Korea Background/Aims: Peptic ulcer bleeding (PUB) is the most common cause of upper gastrointestinal bleeding in Korea but there has been no research done using big data. This study evaluates the optimal operational definition (OD) for big data research by analyzing clinical characteristics of PUB. Methods: We reviewed the clinical characteristics of 92 patients with PUB confirmed on endoscopy in Wonkwang University Sanbon Hospital (January 2013 to December 2014). We calculated sensitivity and positive predictive value (PPV) to detect confirmed PUB patients using ODs developed by combining clinical features of patients with PUB. Results: The mean patient age was 63 years. Men had higher prevalence of PUB than women. Bleeding gastric ulcer was proportionately common in the age range of 40s to 60s in men, while a significantly higher rate of bleeding occurred in women older than 70s. The rate of drug-induced ulcer was 28.2%, whereas the prevalence of Helicobacter pylori was 47.8%. Among the hospitalized patients with diagnostic code of PUB, we ruled out patients with endoscopic removal of gastric adenoma or peritonitis, and selected patients who had been administered intravenous proton pump inhibitor. The sensitivity in this setting was 82.6%, and PPV was 88.4%. Conclusions: PUB was more common in older patients, and there was a clear gender difference in gastric ulcer bleeding by age. With a proper OD using PUB diagnostic codes, we can identify true patients with sufficiently high sensitivity and PPV. (Korean J Gastroenterol 2016;68:77-86) Key Words: Peptic ulcer hemorrhage; Big data; Operational definition; Sensitivity and specificity; Predictive value of tests 서 론 급성상부위장관출혈은연간인구 100,000 명당 건 정도로발생하며소화성궤양이가장흔한출혈의원인이다. 1,2 서양및대만의대규모인구집단을대상으로한연구에서는 Helicobacter pylori 제균치료및양성자펌프억제제등의궤 Received June 15, Revised August 3, Accepted August 3, CC This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Copyright Korean Society of Gastroenterology. 교신저자 : 김용성, 15865, 군포시산본로 321, 원광대학교의과대학산본병원소화기내과 Correspondence to: Yong Sung Kim, Division of Gastroenterology, Department of Internal Medicine, Wonkwang University Sanbon Hospital, Sanbon-ro 321, Gunpo 15865, Korea. Tel: , Fax: , wms89@hanmail.net Financial support: None. Conflict of interest: None. Korean J Gastroenterol, Vol. 68 No. 2, August

2 78 이재원등. 출혈성소화성궤양의임상양상과조작적정의 양예방약제사용이증가함에따라 1990년대이후부터 2000 년대에들어오면서소화성궤양의발생이전연령층에서감소하는것으로나타났다. 3,4 이와함께출혈성소화성궤양의빈도도감소하고있으나, 고령인구층의증가와함께소화성궤양과출혈을유발할수있는아스피린, 비스테로이드소염제및항혈소판제의사용이증가하면서궤양으로인한치사율은별차이없이유지되고있다. 4,5 서양및대만의보고와는대조적으로국내및일본의단일기관연구에서는소화성궤양의발생이나출혈성궤양의발생도과거와큰차이가없는것으로보고되었다. 6,7 이러한차이는지역또는인종의차이나연구대상의규모가다른것이원인으로생각된다. 서양과대만의연구가전국민의료데이터를이용한빅데이터연구인것에비해국내에서는노령층과같은일부환자들만을대상으로하거나단일기관에국한된연구결과가주로보고되었다. 6,8-10 또한국내에서는 2000년대중반의소화성궤양에대한연구이후최근의역학적자료는보고되지않고있다. 그러므로국내에서도대규모인구집단을대상으로한빅데이터연구가필요한시점이며, 최근국민건강보험공단의자료와건강보험심사평가원자료를이용한연구들이시작되고있다. 의료빅데이터연구를위해서는대규모의료정보에서연구대상질환환자를먼저선별해낸후분석해야하는데각환자에부여된상병을이용해대상질환환자를추출해낼수있다. 그러나국민건강보험공단자료의경우청구를위해상병을부여하게되므로, 진료행위나약제를세세히설명하기위한목적으로실제진단과다른상병이붙거나상병입력오류등으로상병이실제그환자를정확하게반영하지못하는경우가많다. 11 또한국민건강보험공단자료에서는내시경검사판독지와같은환자의검사결과를직접검색할수없기때문에빅데이터내에서이용가능한기초정보, 상병, 검사및시술시행코드, 사용된약제등의정보를모두이용해환자를선별해내야한다. 이렇게자료내의여러변수를조합하여특정질환환자를가장잘추출하게하는조건을 조작적정의 라고하며, 설정된조작적정의가얼마나실제대상환자를잘찾아내는지가빅데이터연구의신뢰도를결정하는결정적요인이될수있다. 국내에서는의료빅데이터를이용하여상부위장관출혈성소화성궤양에대해시행한연구는매우적다. Bae 등 12 이 2005년심사평가원자료를이용하여시행한연구에서는입원또는응급실을내원한환자를대상으로하여소화성궤양상병이주상병혹은부상병으로부여된환자를모두선정하고, 그환자들중에서상부위장관출혈지혈술청구코드가단독으로있는경우, 또는상부위장관내시경청구코드와함께비위관삽입술청구코드혹은위세척청구코드가동시에있는조합으 로검색을하였다. 이방식으로실제출혈이있었던소화성궤양환자를찾아낼수있는민감도와양성예측도는각각 94% 와 54% 였다. 이결과를다시 H 2 수용체길항제와양성자펌프억제제가처방된경우로제한하면민감도와양성예측도가각각 89% 와 88% 였다. 그러나같은질환이라하더라도시간이지남에따라새로운연구결과를근거로진료의행태가달라질수있고, 또보험기준의변화에따라약제처방패턴이달라지기때문에 10여년전의과거의기준을그대로이용하기는어렵다. 이번연구의목적은경기도의단일의료기관에서최근 2년동안경험한출혈성소화성궤양의임상양상을알아보고, 의무기록에반영된임상조건을바탕으로의료빅데이터연구에서출혈성소화성궤양환자를가장적절하게검색해낼수있는조작적정의의조건을찾고자하였다. 대상및방법 1. 대상 2013년 1월 1일부터 2014년 12월 31일까지원광대학교의과대학산본병원에입원했던환자중상부위장관내시경을시행받고출혈성소화성궤양으로확진된 92명의환자를대상으로하여후향적인방법으로내시경검사결과와의무기록을조사하였다. 내시경에서상부위장관출혈이있었으나암성출혈이나 Mallory-Weiss 증후군이원인이었던경우는궤양출혈상병이같이부여되어있더라도출혈성소화성궤양확진환자에서는제외하였다. 이연구는원광대학교의과대학산본병원연구윤리위원회의승인을받았다 (IRB No ). 2. 방법 2년간소화성궤양출혈환자의임상양상을파악하기위해확진환자들의연령, 성별, 동반병력및약제사용력, H. pylori 감염의검사방법과그결과를조사하였다. 내시경소견에서출혈궤양의위치를위와십이지장으로나누어 Forrest 분류법에따라출혈정도를분류하였고, 내시경지혈술을시행한경우지혈방법을조사하였다. 빅데이터연구에서출혈성소화성궤양환자를찾아낼수있는최적의조작적정의를알아내기위해먼저기존 Bae 등 12 의연구에서사용된정의가이번연구의확진환자를얼마나찾아낼수있는지알아보았다. 그리고새로운조작적정의를만들기위해한국표준질병사인분류 6차개정안 (Korean Standard Classification of Disease 6th revision, KCD-6) 을이용하여출혈이포함된소화성궤양상병과출혈이나천공의합병증이없는소화성궤양상병으로나누어검색조건을만들었다 (Table 1). 출혈성소화성궤양상병은의무기록에상병이 The Korean Journal of Gastroenterology

3 Lee JW, et al. Clinical Characteristics and Operational Definition of Peptic Ulcer Bleeding 79 Table 1. Diagnostic Codes for Peptic Ulcer Disease Used in This Study Code a Disease Diagnostic codes for peptic ulcer disease including hemorrhage K25.0 Acute gastric ulcer with hemorrhage K25.2 Acute gastric ulcer with both hemorrhage and perforation K25.4 Chronic or unspecified gastric ulcer with hemorrhage K25.6 Chronic or unspecified gastric ulcer with both hemorrhage and perforation K26.0 Acute duodenal ulcer with hemorrhage K26.2 Acute duodenal ulcer with both hemorrhage and perforation K26.4 Chronic or unspecified duodenal ulcer with hemorrhage K26.6 Chronic or unspecified duodenal ulcer with both hemorrhage and perforation K27.0 Acute peptic ulcer, site unspecified with hemorrhage K27.2 Acute peptic ulcer, site unspecified with both hemorrhage and perforation K27.4 Chronic or unspecified peptic ulcer, site unspecified with hemorrhage K27.6 Chronic or unspecified peptic ulcer, site unspecified with both hemorrhage and perforation Diagnostic codes for peptic ulcer disease without complication K25 Gastric ulcer K25.3 Acute gastric ulcer without hemorrhage or perforation K25.7 Chronic gastric ulcer without hemorrhage or perforation K25.9 Unspecified as acute or chronic gastric ulcer without hemorrhage or perforation K26 Duodenal ulcer K26.3 Acute duodenal ulcer without hemorrhage or perforation K26.7 Chronic duodenal ulcer without hemorrhage or perforation K26.9 Unspecified as acute or chronic duodenal ulcer without hemorrhage or perforation K27 Peptic ulcer, site unspecified K27.3 Acute peptic ulcer, site unspecified without hemorrhage or perforation K27.7 Chronic peptic ulcer, site unspecified without hemorrhage or perforation K27.9 Unspecified as acute or chronic peptic ulcer, site unspecified without hemorrhage or perforation a Korean Standard Classification of Disease 6th revision (KCD-6). 부여된시점에따라입원전, 입원기간, 그리고입원후로나누었고, 검색된환자들에게동시에부여된다른상병을모두조사하였다. 이와함께상부위장관출혈지혈술시행여부, 비위관삽관시행여부를조사하였다. 항궤양약제사용여부에대한조사에서는과거에비해양성자펌프억제제의경구사용범위가늘어났기때문에양성자펌프억제제주사제로한정하였다. 환자들이응급실로내원하여소화성궤양출혈이의심되는경우양성자펌프억제제를먼저사용하고다음날입원하게되는경우가있으므로, 약제사용기간은입원 1일전부터퇴원일까지를조사기간으로정하였다. 이러한모든자료를바탕으로상병과임상조건이포함된다양한조작적정의의조합을만들고, 각각의조합으로 년동안입원했던모든환자의의무기록을검색했을때출혈성소화성궤양확진환자를얼마나찾아낼수있는지민감도와양성예측도를구하였다. 3. 통계통계분석은 SPSS program version 13.0 (SPSS Inc., Chicago, IL, USA) 을이용하였다. 두군간의분석에서연속변수는독립표본 t 검정 (independent samples t-test) 을, 범주형변수는 chi-square test, Fisher s exact test를사용하 여비교분석하였고, 자료는평균 ± 표준편차, 혹은비율 (%) 로표시하였다. 모든통계에서 p값이 0.05 미만일때유의하다고판정하였다. 결과 1. 출혈성소화성궤양환자의임상양상 2년간출혈성소화성궤양환자로확진된 92명의환자중남자환자 1예가 2013년과 2014년에각각한번의출혈이발생하여 2예로계산되었다. 환자들의성별은남자 60명 (65.2%), 여자 32명 (34.8%) 이었다 (Table 2). 환자들의평균나이는 63±16.7세였고, 남녀각각 58±14.7세및 73±15.7세로여자환자들의연령이유의하게더높았다 (p<0.001) 연령별분포를 20세부터 10세간격으로나누어보면 40대-80대에궤양발생빈도가높았으며, 십이지장궤양출혈이전연령층에서발생하는것에비해위궤양출혈은나이가많은환자에서주로발생하였다 (Fig. 1A). 발생빈도를성별에따라분석했을때출혈성위궤양은남자의경우 40대-60대환자들이많은반면여자의경우 70대이상의환자들이많아분명한성별차이를보였다 (p<0.001). 출혈성십이지장궤양의경우성별 Vol. 68 No. 2, August 2016

4 80 이재원등. 출혈성소화성궤양의임상양상과조작적정의 Table 2. Demographic Data of Patients with Bleeding Peptic Ulcer Disease Total Male Female p-value c Number of patients 92 (100) 60 (65.2) 32 (34.8) Age (yr) 63± ± ±15.7 <0.001 d Location of ulcer NS e GU 64 (69.6) 38 a (63.3) 26 (81.3) DU 19 (20.7) 16 (26.7) 3 (9.4) GU+DU 9 (9.8) 6 (10.0) 3 (9.4) Bleeding site NS f GU 67 (72.8) 40 (66.7) 27 (84.4) DU 25 (27.2) 20 (33.3) 5 (15.6) Stage of ulcer NS f A1 32 (34.8) 24 (40.0) 8 (25.0) A2 46 (50.0) 30 (50.0) 16 (50.0) H1 12 (13.0) 5 (8.3) 7 (21.9) H2 2 (2.2) 1 (1.7) 1 (3.1) Forrest classification <0.01 f IA 5 (5.4) 4 (6.7) 1 (3.1) IB 5 (5.4) 5 (8.3) 0 (0.0) IIA 16 (17.4) 14 (23.3) 2 (6.3) IIB 6 (6.5) 4 (6.7) 2 (6.3) IIC 40 (43.5) 26 (43.3) 14 (43.8) III 20 (21.7) 7 (11.7) 13 (40.6) Drug history b 26 (28.2) 17 (28.3) 9 (28.1) NS f NSAIDS 15 (16.3) 10 (16.7) 5 (15.6) Aspirin 5 (5.4) 2 (3.3) 3 (9.4) Steroid 5 (5.4) 2 (3.3) 3 (9.4) Anti-platelet agent 9 (9.8) 7 (11.7) 2 (6.3) Values are presented as n (%) or mean±sd. GU, gastric ulcer; DU, duodenal ulcer. a One male patient who had two separate ulcer bleeding events at 2013 and 2014 was counted as two cases; b Some patients were exposed to multiple drugs. c Male vs. female; d Independent samples t-test; e chi-square test; f Fisher s exact test. 에따른유의한차이는없었다 (Fig. 1B, C). 아스피린, 비스테로이드소염제, 스테로이드나혈소판저해제등의궤양유발약제를복용한경우가남자 17명 (28.3%), 여자 9명 (28.1%) 으로총 26명이었으며이중비스테로이드소염제가 15명으로가장많았다. 약제에노출된환자의평균나이는남녀각각 59 세와 78세로유의하게여자환자의나이가많았다 (p<0.01). 2. 출혈성소화성궤양의내시경적특징궤양을발생한위치로분류해보면위궤양 64명 (69.6%), 십이지장궤양 19명 (20.7%), 위궤양과십이지장궤양이동반된경우 9명 (9.8%) 이었고, 이중출혈이발생한부위는위궤양이월등하게많았다 (67명 vs. 25명, Table 2). 소화성궤양출혈로확진된환자들중비위관삽입술은 30명에서만시행되었다. 92명의확진환자중일반적으로내시경지혈술이필요하다고권고되는 Forrest 분류 I-IIA의궤양은 26명이었고, 남자환자의경우여자환자에비해지혈술이필요한출혈성궤양이유의하게더많았다 (Table 2, p<0.01). 내시경지혈술은 32명에게시행되었고, 에피네프린주입과클립을이용한지 혈술을가장많이이용하였다 (Table 3). 3. H. pylori 감염률출혈성소화성궤양환자로확진된 92명중 27.2% 의환자에서 H. pylori 검사가시행되지않았으며, H. pylori 감염에대한검사를시행한환자는 67명으로이중 32명이양성으로확인되어감염률은 47.8% 로나타났다 (Table 4). 67명의 H. pylori를검사했던환자중양성의비율은남녀각각 26명과 6명으로남자에서유의하게많았으나 (59.1% vs. 26.1%, p<0.05), 감염된환자들의평균나이는남녀각각 56.1세와 60.8세로차이가없었다. H. pylori 감염과약제노출력에따라환자군을분류해보면 92명중 H. pylori 감염만있었던경우는 22명, 궤양유발약제노출만있었던환자는 16명, H. pylori 감염과궤양유발약제노출이동시에있었던환자는 10명이었고, 두가지위험인자가모두없었던경우가 44명이었다. The Korean Journal of Gastroenterology

5 Lee JW, et al. Clinical Characteristics and Operational Definition of Peptic Ulcer Bleeding 81 Fig. 1. Distribution by age and sex. (A) Patients with peptic ulcer bleeding were evenly distributed over the forties age decade. (B) In gender analysis of gastric ulcer (GU) bleeding, the proportions of patients with bleeding gastric ulcer was high in the age range of 40s to 60s in men, while higher rate of bleeding occurred at age older than 70s in female (p<0.001, Fisher s exact test). (C) There was no significant gender difference in duodenal ulcer (DU) bleeding. Table 3. Hemostasis Method Hemostasis method n (%) Epinephrine injection 8 (8.7) Endoclip 4 (4.3) Coagrasper 2 (2.2) Epinephrine injection+endoclip 11 (12.0) Epinephrine injection+cosagrasper 4 (4.3) Epinephrine injection+endoclip+cosagrasper 1 (1.1) Epinephrine injection+apc 1 (1.1) Coagrasper+APC 1 (1.1) None 60 (65.2) APC, argon plasma coagulation. Table 4. Infection Rate and Diagnostic Method for Helicobacter pylori Variable Total Positive Negative Untested Total patients (34.8) 35 (38.0) 25 (27.2) Tested patients (47.8) 35 (52.2) Sex (male:female) 44:23 26:6 (59.1:26.1) 18:17 (40.9:73.9) Diagnostic method Rapid urease test (45.2) 23 (54.8) Rapid urease test+ 1 0 (0) 1 (100) Giemsa Giemsa 8 3 (37.5) 5 (62.5) Urea breath test 3 3 (100) 0 (0) Serology 13 7 (53.8) 6 (46.2) Not done 25 Values are presented as n only or n (%). 4. 조작적정의의조건내시경지혈술과비위관삽입술이각각확진환자의약 1/3 에서만시행되었기때문에기존에 Bae 등 12 이보고한방법에따라소화성궤양상병전체와지혈술, 상부위장관내시경, 비위관삽입술및위세척청구코드를이용해검색할경우 년사이에발생한출혈성소화성궤양확진환자를찾아낼수있는민감도와양성예측도가 40.2% 및 62.7% 로 매우낮았다 (Table 5, Combination A). 이에이번연구에서는소화성궤양상병전체를사용하는대신출혈이포함된궤양상병을중심으로새로운조작적정의를만들어검색하였다. 내시경으로확진된 92명의환자중출혈성소화성궤양상병이부여된환자는 76명이었는데, 이중 8명은퇴원후한달이내에부여되었고, 3명은출혈성소화성궤양의과거력이 Vol. 68 No. 2, August 2016

6 82 이재원등. 출혈성소화성궤양의임상양상과조작적정의 Table 5. Operational Definition Combinations Combinations Total patients (n) Confirmed (n) Not confirmed (n) Sensitivity a (%) PPV (%) Combination A (operational definition used in previous study 12 ) 1. All PUD code AND [Hemostasis code or EGD with L-tube insertion code] All PUD code AND [Hemostasis code or EGD with L-tube insertion code] AND IV PPI Combination B (coding during admission period only for new onset and recurrent cases) 1. PUD code including hemorrhage PUD code including hemorrhage AND Exclusion of EMR/ESD/peritonitis code PUD code including hemorrhage AND Exclusion of EMR/ESD/peritonitis code AND IV PPI Combination C (coding during admission period and within 1 month after discharge b for new onset and recurrent cases) 1. PUD code including hemorrhage PUD code including hemorrhage AND Exclusion of EMR/ESD/peritonitis code PUD code including hemorrhage AND Exclusion of EMR/ESD/peritonitis code AND IV PPI Combination D (coding before, during admission period, and within 1 month after discharge for new onset and recurrent cases) 1. PUD code including hemorrhage PUD code including hemorrhage AND Exclusion of EMR/ESD/peritonitis code PUD code including hemorrhage AND Exclusion of EMR/ESD/peritonitis code AND IV PPI Combination E (add combinations using codes of PUD without complication to combination D for new onset and recurrent cases) 1. Combination D-3+[PUD code without complication AND Hemostasis code AND Exclusion of EMR/ESD code] 2. Combination D-3+[PUD code without complication AND Hemostasis code with Exclusion of EMR/ESD code]+[pud code without complication AND EGD with L-tube insertion/iv PPI] Combination F (coding during admission period and within 1month after discharge for new onset cases only) 1. PUD code including hemorrhage AND Exclusion of EMR/ESD/peritonitis code AND IV PPI Combination F-1+[PUD code without complication AND Hemostasis code AND Exclusion of EMR/ESD code] 3. Combination F-1+[PUD code without complication AND Hemostasis code with Exclusion of EMR/ESD code]+[pud code without complication AND EGD with L-tube insertion/iv PPI] PUD, peptic ulcer disease; EGD, esophagogastroduodenoscopy; IV, intravenous; PPI, proton pump inhibitor; PPV, positive predictive value; EMR, endoscopic mucosal resection; ESD, endoscopic submucosal dissection. a Validation is on the basis of a cohort of 92 true patients with bleeding PUD who were confirmed by upper endoscopy in Wonkwang University Sanbon Hospital during For sensitivity calculation, the number of true patients was 92 for new onset and recurrent bleeding PUD cases and 89 for new onset bleeding PUD cases only; b coding for bleeding PUD was completed until 11 days after discharge in patients with bleeding PUD code. 있어입원전부터이미부여되어있었다. 입원기간중출혈성소화성궤양상병이부여된환자만대상으로하거나퇴원후상병이부여된환자까지포함해서검색한경우도확진환자를찾아낼민감도가 80% 미만이었다 (Table 5, Combination B, C). 부여시기에관계없이출혈성소화성궤양상병이있는환자를모두검색한경우민감도가 80% 이상으로상승하였으나여전히위양성환자가많아양성예측도가 70% 미만이었다. 위양성의주된이유는세가지로, 1 위선종의제거를위해점막절제술 (endoscopic mucosal resection, EMR) 이나점막하박리절제술 (endoscopic submucosal dissection, ESD) 을시행하고나서출혈성위궤양상병을부여한경우, 2 이번연구에서는출혈과천공이동시에포함된상병도출혈성소화성궤양상병에포함하여검색하였는데이환자들중실제천공으로수술을시행했던경우, 3 단순소화성궤양이나다른상부위장관질환에출혈성소화성궤양상병을잘못입력한경우였다. 이러한위양성경우를배제하기위해 내시경상부소화관종양수술-점막절제술및점막하종양절제술 (Q7652, EMR) 또는 내시경상부소화관종양수술-점막하박리절제술 (QZ933, ESD) 시술코드가같이있는환자나급성복막염 (K65.0) 또는상세불명의복막염 (K65.9) 상병이같이있는환자를제외하면양성예측도가상승하였지만, 여전히 80% 미만이었다. 상병입력오류가있었던위양성예를배제하기위해입원기간중양성자펌프억제제를정맥주사로사용했던환자만으로제한하면민감도가약간감소하는대신양성예측도가올라가각각 82.6% 와 88.4% 로확진환자를찾아낼수있었다 (Table 5, Combination D-3). 확진환자를더찾아민감도를올리기위해출혈이나천공의합병증이동반되지않은소화성궤양상병만붙은환자를따로검색하여추가하였다. 합병증이없는소화성궤양상병이있는환자들중에서상부위장관지혈술을시행했지만, EMR/ESD 시술코드가없는경우나상부위장관내시경과비위관삽입술을동시에시행하고양성자펌프억제제주사제를투여받은경우를추출하면추가적으로실제출혈성소화성궤양환자를 3명더검색할수있었으나위양성환자가 5명더늘어났다. 이결과를출혈성소화성궤양상병을이용한결과에더하면민감도와양성예측도는각각 85.9% 와 84.0% 였다 The Korean Journal of Gastroenterology

7 Lee JW, et al. Clinical Characteristics and Operational Definition of Peptic Ulcer Bleeding 83 (Table 5, Combination E-2). 재발성환자를제외하고 년사이에처음출혈성소화성궤양이진단된환자는 89명이었다. 이환자들만을찾고자하는경우는확진환자수는 89명으로하고, 입원기간및퇴원후에상병이부여된환자만을추출하여같은조건의조작적정의를적용하면민감도와양성예측도가각각 82.0% 와 88.0% 로검색가능하였다. 또한합병증이없는소화성궤양상병을이용한결과를추가하면민감도와양성예측도가각각 85.4% 와 83.5% 였다 (Table 5, Combination F). 고찰 이번연구의첫번째목적은 년사이에단일 2차의료기관에서진료한출혈성소화성궤양환자의임상양상을조사하는것으로, 위궤양이십이지장궤양보다더많았고남녀간의발생률과중증도의차이가있었다. 이러한결과들은기존에보고된소화성궤양의임상양상에대한연구들과일치한다. 9 국내소화성궤양환자를대상으로한연구에서는 65세이하의저연령군에서남성이많았다 10,13 이번연구에서는출혈성소화성궤양의경우에서도분명한남녀차이가있다는점을확인하였는데, 남자의경우상대적으로젊은 40-60대에주로발생한것에비해여자의경우 70대이상의고령에서주로발생하였다. 십이지장궤양의경우는환자의수가적어분석이어려웠지만전연령층에서비슷하게발생하는것으로보인다. 과거에보고된소화성궤양의위험인자에대한국내연구에서흡연및음주가남자환자와더연관이많았기때문에 9 아마도이러한남녀간의차이는생물학적인성별의차이보다는생활습관의차이와고령에서의약제복용의차이에의해나타났을가능성이높다. 이번연구에서는후향적연구의제한점때문에남녀의나이에따른유병률의차이를보이는원인을정확히분석하기어려웠지만, 의무기록에서조사가능한환자만을대상으로궤양발생의중요인자인비스테로이드성소염제와 H. pylori의 14 영향을추정해볼수있었다. 이번연구에서출혈성궤양으로확진된환자의약 30% 가아스피린이나비스테로이드소염제와같은궤양유발약제를복용했는데, 의무기록에만의존하여약물복용력을정확하게파악하기어려웠고처방없이약국에서구입하여복용한경우는조사되지않았기때문에실제이보다더많은환자들이약제원인일가능성이높다. 궤양유발약제에노출된것으로확인된환자들만을대상으로분석해보면약제노출빈도는남녀간에차이가없었지만, 약제에노출된여자환자의평균나이가 78세로남자환자에비해유의하게많았다. 이와는반대로 H. pylori에감염된환자의비율은남자에서유의하게많았으나감염된환자의평균나이는각각 56세와 61세로남 녀간의차이가없었다. 이런결과는 50대-60대의남자환자의경우 H. pylori와생활습관이주된원인으로작용하며, 70 대이상의여자환자의경우비스테로이드소염제와같은약제가더연관이있다는것을시사한다. 그러나이분석에이용된환자수가너무작기때문에이두가지요인이출혈성궤양의남녀차이에영향을미치는지알기위해서는대규모전향적연구가필요하다. 또한건강보험심사평가원정보를이용해전국민을대상으로한연구 12 에서는모든연령대에서남성이많아, 향후빅테이터연구를통해서나이에따른남녀차이를다시검증할필요가있다. 국내에서는그동안제균치료를꾸준히시행한결과 H. pylori 감염률이 1998년 66.9% 에서 2011년 54.4% 로낮아졌다. 15 그러나이번연구에서는소화성궤양환자에서 H. pylori 감염률이높았던기존의보고와는달리 H. pylori 검사를시행한 67명중 32명 (47.8%) 만이양성으로나타나, 국내유병률의변화를감안하더라도상대적으로낮은감염률을보였다. 10 단일기관의연구로판단하기는어려우나감염률이낮은이유는출혈이있는궤양이라는대상환자군의특성때문으로추정되는데, 기전은명확하지않지만출혈성궤양환자에서 H. pylori 검사의위음성이높다는것은잘알려져있다. 16 출혈환자에서위음성이높은기전으로는출혈환자의경우검사전에이미양성자펌프억제제를사용하고있는경우가많고, 출혈로인한혈장의직접적인효과또는알부민의완충효과 (buffering effect), 비위관삽입후공기주입으로인해 H. pylori 생존에필요한환경이변하는것등이제시되고있다. 16 고려해야할점은이번연구에서는검사자체가시행되지않은경우가 27% 로비교적높았다는점인데, 응급상황에서 H. pylori 검사없이내시경만시행한후추적검사가안되는경우가많았으며, 특히소화기내과가아닌타과입원중출혈성궤양이발생한환자의경우출혈이멈추고안정되면서추적관찰이되지않는경우가있었다. 외국의한보고에의하면출혈성궤양환자의 1차 H. pylori 검사에서음성이나온환자를대상으로시간을두고 2차검사를시행한경우초기음성이었던환자중 79% 가양성으로확인되어, 출혈이있는환자의경우첫검사에서음성이라하더라도추적검사를반드시고려해야할것으로생각된다. 이번연구의두번째목적은의무기록을이용한빅데이터연구에서가장필수적인최선의조작적정의가무엇인지실제출혈성궤양환자의임상정보를이용해알아보고자하는것이다. 대규모역학연구를위한기존의연구및조사방법 ( 대규모다기관임상연구, 코호트연구등 ) 의경우비용및시간이많이소모되거나일반화가능성이낮다는한계점이있다. 17 이에대한보완책및대체방법으로이미축적되어있는대규모전산화의료자료들을사용하는빅데이터연구가최근주목을 Vol. 68 No. 2, August 2016

8 84 이재원등. 출혈성소화성궤양의임상양상과조작적정의 받고있다. 영국, 미국, 캐나다, 호주등의료선진국에서는보건의료분야연구에빅데이터자료를활발히활용하고있는데, 미국의 SEER (Surveillance, Epidemiology, and End Results)-Medicare data와호주의 Western Australian Data Linkage System 등이그예이다. 18 국내에서도국민건강보험공단이 2014년부터건강보험의진료내역, 건강검진, 거주지및보험료, 요양기관정보등의정보를연구자들이이용할수있도록 100만명의 표본코호트DB 를구축하여제공하고있다. 또한전국민을대상으로한국민건강보험공단자료도이용이가능한데전국민의주민등록번호로관리되는단일건강보험체계를운영하고있기때문에질병에대한전국적인현황파악과연구결과를효율적으로얻어낼수있는장점이있다. 이런빅데이터연구시실제그질환을가지고있는정확한환자를얼마나찾아내느냐하는것이연구결과의신뢰성을결정짓는요소인데아직까지국내에서빅데이터연구에서조작적정의조건에대해서연구된것은없다. 기존의임상연구에서사용되는대상환자선정기준을빅데이터연구에적용하기어렵고, 또과거에만들어진조작적정의의기준은시간이지나면서민감도와특이도가떨어질가능성이있다 년건강보험심사평가원자료를이용한 Bae 등 12 의연구에서는당시에는소화성궤양의상병중합병증유무를알수있는 4자리수상병사용이의무사항이아니었기때문에기본적인 3자리수소화성궤양상병 (K25, K26, K27, K28) 과상부위장관내시경시행, 비위관삽입술, 위장관지혈술청구코드를이용하여출혈성소화성궤양의조작적정의를만들었다. 이조작적정의를이용하여본병원의 년의무기록자료에서환자를추출해보았을때실제출혈성소화성궤양의검색률이너무낮았는데, 92명의확진환자중 37명만찾아낼수있어민감도와양성예측도가각각 40.2% 와 60.7% 에불과하였다 년자료에서는 80% 후반으로매우높았던조작적정의의민감도가 10년사이에이렇게낮아진것은출혈성소화성궤양환자의진료에대한근거가달라진것이주요원인으로생각된다. 과거상부위장관출혈이의심이되는경우생리식염수세척을모든환자에서시행하였으나최근에는그진단적또는치료적효과가의문시되고있고, 국내의경우응급내시경의시행이비교적빠른시간내에이루어지므로흑색변과같은상부위장관출혈의증상이있는경우바로내시경을시행하는경우가많다. 19,20 또한위산억제약물사용에대한조건도 2000년대후반이후양성자펌프억제제사용의보험조건이완화되면서궤양이아닌위식도역류질환에서도흔히사용되므로경구약제까지포함하는경우그특이성이떨어진다. 기존에보고된 Bae 등 12 의조작적정의가얼마나유용한지알아보는과정에서는이런약물처방기준의변화를고려하여과거보다엄격히양성자펌프억제제를주사 제로제한했음에도불구하고확진환자검색률이낮았고위양성환자가많았다. 이러한이유로새로운조작적정의의기준이필요하다고판단하였고, 궤양상병전체를사용하는것보다는출혈이동반된소화성궤양상병을사용하면위양성을낮출것으로예상하였다. 출혈이동반된상병중에는천공이같이포함된경우가있는데, 궤양출혈환자나궤양천공환자가이상병을같이사용할수있기때문에우선포함시키고실제천공으로수술한환자를배제하는조건을설정하였다. 확진환자의검색률을높이기위해상병이부여된시점을어디까지로제한할것인가에대해서도고려가필요하다. 출혈성소화성궤양상병이입원기간중에부여되지않고첫번째외래추적시에부여된경우가종종있었고, 이경우는대개 2주내에외래방문을하여최장퇴원후 11일이내에모두상병이부여되었기때문에상병부여기간을퇴원후한달까지로설정하였다. 출혈발생시점이전에이미출혈성소화성궤양상병이붙어있는환자는실제로이전에출혈성궤양의과거력이있는환자이거나아니면단순궤양이진단된후출혈성궤양상병을잘못부여했던경우이다. 그러므로특정기간에발생한모든출혈성궤양환자를찾아낼지아니면재발성이아닌새로발생한출혈환자만을찾아낼지연구의목적에따라환자의상병이부여된시기를제한하여검색할수있다. 이번연구에서특이한점은최근위선종치료를위해내시경치료가늘어나면서시술후출혈이발생했거나출혈의예방을위해양성자펌프억제제를사용하고출혈성위궤양상병을붙이는경우가많았기때문에위선종절제환자를배제하는것이위양성환자수를줄이는데매우중요하였다는점이다. 이러한사실은향후새로운시술이도입되면이를배제할수있는제한조건이더필요할수있음을의미하고, 국민건강보험공단자료의이용의효율성을높이기위해서는정확한상병을입력하는의료진의노력과함께불필요한상병을부여하지않도록현실적인보험기준이수립되어야한다는점을시사한다. 국내에서는아직빅데이터연구가당뇨병과같은대사성질환에대해주로이루어지고있어소화기질환에적용하는것이시급하다. 이런의미에서이번연구는소화기영역의대표적질환중하나인출혈성소화성궤양환자에대한조작적정의를처음으로연구한것에의의가있다. 이번연구의제한점은 1) 단일 2차기관의환자들을대상으로한연구로서이번연구에서제시된출혈성궤양의임상양상이환자군의특성이나입원에대한역치가다른 1차및 3차의료기관환자들의임상양상을모두반영하지못하고, 2) 대상환자수가작은후향적연구이기때문에이번연구에서제시된조작적정의의민감도와양성예측도가다른연구에서는달라질가능성이있으며, 3) 약제사용력에대한조사와 H. pylori 감염에대한 The Korean Journal of Gastroenterology

9 Lee JW, et al. Clinical Characteristics and Operational Definition of Peptic Ulcer Bleeding 85 검사가완전히이루어지지않아서이두가지요인이출혈성궤양에미치는영향을명확하게파악하지못했다는점이다. 이러한이유로추후전향적연구나 1차및 3차기관이참여하는다기관연구를통해임상양상을파악하고조작적정의를규정하는연구가필요할것으로생각된다. 그러나다른환자집단을대상으로할때민감도나양성예측도가달라질수는있더라도이번연구에서제시한조작적정의의기준자체는크게달라지지않을것이므로국민건강보험공단자료와같은빅데이터연구에서도이용될수있으리라생각된다. 소화성궤양은상부위장관출혈의가장흔한원인으로새로운치료약제와내시경을통한조기진단에의해발생률및재발률은감소하고있으나출혈성소화성궤양의사망률은큰변화가없는실정이다. 5,21 그러나국내전반의출혈성소화성궤양에대한발생현황및임상양상에대한데이터는부족한상태이며, 향후국내에서도국민건강보험공단등의빅데이터를이용하여궤양발생률의추이나합병증으로인한입원및의료비용의변화를확인할필요가있다. 또한약제사용패턴의변화가소화성궤양의역학에어떤영향을미치는지빅데이터연구를통해파악하고외국과다른국내환자들의특성을파악하는것이향후국내의출혈성소화성궤양치료및예후개선을위해도움이될것으로예상된다. 요약 목적 : 출혈성소화성궤양은상부위장관출혈의가장흔한원인으로아직국내에빅데이터를이용한연구는없는실정이다. 이번연구에서 년사이의단일 2차병원에서나타난출혈성소화성궤양의임상양상을분석하고이를이용하여빅데이터연구시필요한최선의조작적정의를알아보고자하였다. 대상및방법 : 2013년 1월 1일부터 2014년 12월 31일까지원광대학교산본병원에서내시경검사로출혈성소화성궤양이확진된 92명을대상으로후향적의무기록을통해환자의연령, 성별, 내시경소견, H. pylori 양성률, 복용중인약물을조사하여그특성을알아보았다. 출혈이포함된소화성궤양상병과동반된임상양상의조합으로다양한조작적정의를만들고이를이용해확진된환자를검색할수있는민감도와양성예측도를구하였다. 결과 : 전체출혈성소화성궤양환자의평균연령은 63세였으며남성의비율이 65.2% 로여성보다높았다. 출혈성위궤양의경우 40대-60대에서는남성이많았고 70대이상에서는여성이통계적으로많아차이를보였다. 비스테로이드소염제와같은궤양유발약제를복용한경우는 28.2% 였으며 H. pylori 감염률은 47.8% 였다. 출혈성소화성궤양상병을가진환자들 중에서내시경선종제거술을시행한경우와복막염상병을가진환자를제외하고, 입원기간중양성자펌프억제제를주사제로사용한경우만검색하면출혈성소화성궤양으로확진된환자를찾아낼수있는민감도와양성예측도는각각 82.6% 와 88.4% 였다. 결론 : 출혈성소화성궤양환자는 40대이상에서호발하였으며출혈성위궤양의경우분명한남녀차이를보였다. 출혈이포함되어있는상병명을중심으로조작적정의를설정한경우충분히높은민감도와양성예측도로확진환자가검색되어, 향후빅데이터연구에사용할수있을것으로생각한다. 색인단어 : 소화성궤양출혈, 빅데이터, 조작적정의, 민감도, 예측도 REFERENCES 1. Kurien M, Lobo AJ. Acute upper gastrointestinal bleeding. Clin Med (Lond) 2015;15: Sung JK. Diagnosis and management of peptic ulcer bleeding. Korean J Med 2015;88: Wu CY, Wu CH, Wu MS, et al. A nationwide population-based cohort study shows reduced hospitalization for peptic ulcer disease associated with H pylori eradication and proton pump inhibitor use. Clin Gastroenterol Hepatol 2009;7: Ahsberg K, Ye W, Lu Y, Zheng Z, Staël von Holstein C. Hospitalisation of and mortality from bleeding peptic ulcer in Sweden: a nationwide time-trend analysis. Aliment Pharmacol Ther 2011;33: Theocharis GJ, Thomopoulos KC, Sakellaropoulos G, Katsakoulis E, Nikolopoulou V. Changing trends in the epidemiology and clinical outcome of acute upper gastrointestinal bleeding in a defined geographical area in Greece. J Clin Gastroenterol 2008;42: Kwon JH, Choi MG, Lee SW, et al. Trends of gastrointestinal diseases at a single institution in Korea over the past two decades. Gut Liver 2009;3: Nagasue T, Nakamura S, Kochi S, et al. Time trends of the impact of Helicobacter pylori infection and nonsteroidal anti-inflammatory drugs on peptic ulcer bleeding in Japanese patients. Digestion 2015;91: Choi JW, Kim HY, Kim KH, et al. Has any improvement been made in the clinical outcome of patients with bleeding peptic ulcer in the part 10 years? Korean J Gastrointest Endosc 2005;30: Kim JJ, Kim N, Lee BH, et al. Risk factors for development and recurrence of peptic ulcer disease. Korean J Gastroenterol 2010;56: Na YJ, Shim KN, Kang MJ, et al. Comparison of clinical characteristics and outcomes between geriatric and non-geriatric patients in peptic ulcer bleeding. Korean J Gastroenterol 2009;53: Bae SO, Kang GW. A comparative study of the disease codes be- Vol. 68 No. 2, August 2016

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