대한안과학회지 2016 년제 57 권제 9 호 J Korean Ophthalmol Soc 2016;57(9):1354-1360 ISSN 0378-6471 (Print) ISSN 2092-9374 (Online) http://dx.doi.org/10.3341/jkos.2016.57.9.1354 Original Article 각막지형도를이용한새로운비침습적눈물막파괴시간검사의신뢰도평가 Reliability of a New Non-invasive Tear Film Break-up Time Measurement Using a Keratograph 정성용 이상범 Seongyong Jeong, MD, Sang Bumm Lee, MD, PhD 영남대학교의과대학안과학교실 Department of Ophthalmology, Yeungnam University College of Medicine, Daegu, Korea Purpose: To evaluate the repeatability of non-invasive tear film break-up time and identify its relationships with dry eye parameters. Methods: A total of 100 participants (50 with dry eye, and 50 in the control group) were enrolled prospectively. Non-invasive keratograph first (NIKf-BUT) and average (NIKav-BUT) break-up times were evaluated 2 times using Keratograph 4 (Oculus, Wetzler, Germany), and then tear film break-up time with fluorescein (FBUT) was measured. The correlation analyses were performed between non-invasive parameters (NIKf-BUT and NIKav-BUT) and FBUT. Intra-observer agreements of NIKf-BUT and NIKav-BUT were assessed using intraclass correlation coefficients (ICC). The receiver operating characteristic (ROC) curve technique was used to evaluate the non-invasive method in the diagnosis of dry eye. Results: The correlation analyses revealed positive correlation between NIKav-BUT and FBUT in both groups (dry eye; r = 0.66, p < 0.001 and control group; r = 0.77, p < 0.001). The ICCs of NIKf-BUT and NIKav-BUT were 0.72 and 0.94 in the dry eye, respectively, and 0.70 and 0.91 in the control group. NIKav-BUT was not different from FBUT in either group. The areas under the ROC curves of NIKf-BUT and NIKav-BUT were 0.917 and 0.980, respectively. Conclusions: The high ICCs verified the repeatability of NIKf-BUT and NIKav-BUT. NIKav-BUT showed no difference from FBUT and positive correlation with FBUT. NIK-BUT showed high diagnostic power and can be considered a new parameter to evaluate dry eye syndrome. J Korean Ophthalmol Soc 2016;57(9):1354-1360 Keywords: Correlation, Dry eye, Keratograph 4, Non-invasive tear film break-up time, Repeatability 안구건조증은눈물과안구표면의다양한요인에의해발생하는질환으로안구불편감과시각장애, 눈물막이상을초 Received: 2016. 4. 21. Revised: 2016. 5. 25. Accepted: 2016. 6. 27. Address reprint requests to Sang Bumm Lee, MD, PhD Department of Ophthalmology, Yeungnam University Hospital, #170 Hyeonchung-ro, Nam-gu, Daegu 42415, Korea Tel: 82-53-620-3445, Fax: 82-53-626-5936 E-mail: sbummlee@ynu.ac.kr 래한다. 1 안구건조증은일반적으로환자의주관적증상과눈물생성, 눈물막안정성, 각결막손상정도로평가한다. 2 이중에서눈물막안정성을평가하는눈물막파괴시간은 1969 년처음소개된이후안구건조증진단에임상지표로널리이용되었다. 3 플루오레신염색약을이용하는눈물막파괴시간 (fluorescein tear film break-up time, FBUT) 은침습적검사법에해당한다. 플루오레신은눈물막을염색하여코발트블루광원에서눈물막결손을쉽게찾아낼수있게해주지만, 눈물막안정 c2016 The Korean Ophthalmological Society This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. 1354
- 정성용 이상범 : 비침습적눈물막파괴시간검사의신뢰도 - 성을감소시켜눈물막파괴시간에영향을미칠수있으며, 4,5 검사자의주관적판단에의한측정방법이라는단점이있다. 플루오레신이눈물막에미치는영향을배제하기위해 Mengher et al 6 은비침습눈물막파괴시간 (non-invasive tear film breakup time, NIBUT) 을고안하였다. 이검사는원형의투사장치를이용하여각막에방사형직선들과원들로구성된격자모양의무늬를투사하여눈물막의안정성을측정하는방법으로, 투사된선에왜곡이나타낼때를눈물막파괴시간으로정의하였다. 한편, 검사자의주관을배제하기위해실시간영상하에서소프트웨어를이용하는눈물막파괴시간측정법들이고안되었으며, 그중하나로 Keratograph 4 (Oculus, Wetzlar, Germany) 는객관적이고일관된눈물막파괴시간평가가가능하다. 그러나그재현성과검사신뢰도, 기존안구건조증지표와의관계를밝히는연구는부족한실정이다. 7-9 이에본연구에서는한국인에서 Keratograph 4를이용한비침습눈물막파괴시간의신뢰도와재현성을평가하고자하였으며, 그값을기존의안구건조증지표와비교분석해보고자하였다. 대상과방법 본연구는 2015년 4월부터 10월까지영남대학교병원안과를방문한환자를대상으로하였다. 한국안구건조증진단기준 2 에따라안구건조증의주관적증상이있으면서눈물막파괴시간이 10초미만이며, 플루오레신염색으로각결막미란이있는경우를안구건조증으로진단하였다. 위의기준에따라안구건조증군 50명 50안과정상대조군 50명 50안을전향적으로선정하였다. 안구건조증군은증상호소가더심한눈으로, 정상대조군은무작위로대상안을선정하였다. 콘택트렌즈를사용하고있는환자와눈물점마개를시행한환자, 안수술력이있는환자, 심한안구불편감 으로눈을뜨고있기힘들어검사가불가능한환자, 한국안구건조증진단기준 level 3 이상인환자는대상에서제외하였다. 본연구는대상환자로부터연구참여에대한동의서를받았고, 헬싱키선언 (Declaration of Helsinki) 을준수하였으며영남대학교병원임상연구윤리위원회 (institutional review board, IRB) 의승인을얻었다 (No. 2016-05-003). 대상자에게다음의순서대로일련의검사를시행하였다. 먼저, 문진을통해대상자의나이와성별, 병력을조사하였으며, 안구불편감의주관적평가를위해안구표면질환지수 (ocular surface disease index, OSDI) 를사용하였다. 10 OSDI 는 12개의문항으로구성되며각문항에 0점에서 4점까지의점수가할당된다. OSDI 점수계산은 [( 문항별점수의총합 ) 100]/[( 대상자가응답한문항의수 ) 4] 로하였으며총점은 0점에서 100점까지분포한다. 비침습적인눈물막파괴시간검사를위해 Keratograph 4를사용하였다. Keratograph 4는각막지형도를이용하여비침습눈물막파괴시간 (non-invasive keratograph tear film break-up time, NIK-BUT) 을측정하는장비이다. Keratograph 4는각막위에 22개의동심원 (placido ring) 을투사한후, 내장된소프트웨어를이용하여각막을 8개의원과 24개의방사형직선으로구분된 192개의영역으로분획한다 (Fig. 1). 분획된각영역은투사된동심원이일그러질때눈물막파괴시간이기록된다. 첫번째로눈물막이파괴되는시간은비침습첫눈물막파괴시간 (non-invasive keratograph first break-up time, NIKf-BUT) 으로제시되며, 검사종료시까지발생한모든지점의눈물막파괴시간의평균값으로비침습평균눈물막파괴시간 (non-invasive keratograph average break-up time, NIKav-BUT) 이제시된다. NIK-BUT는각환자마다 30분간격으로 2회시행하였다. 한명의숙련된검사자가환자의턱과머리를고정하고정면을주시하게한후눈을깜박거리도록하였다. 이어서눈 A B C Figure 1. Representative image of non-invasive keratograph tear film break-up time (NIK-BUT) using Oculus Keratograph 4 (Oculus, Wetzler, Germany). (A) A real time image recorded the entire course of break up process. Placido rings were reflected from surface of cornea and their distortions were recorded as the red-framed rectangular break-up units. (B) The final report was summarized as tear film break-up colour-code map. (C) Non-invasive keratograph first break-up time (NIKf-BUT), non-invasive keratograph average break-up time (NIKav-BUT) and break-up progress of break-up units were provided. 1355
- 대한안과학회지 2016 년제 57 권제 9 호 - 을감게한다음다시눈을크게뜨게하면검사가자동으로시작되었다. 검사자는환자에게계속눈을뜨고있도록독려하였으며환자가눈을감을때측정이자동으로종료되었다. 검사를통해자동으로첫번째 NIKf-BUT (1st NIKf-BUT) 와 NIKav-BUT (1st NIKav-BUT) 가기록되었다. 30분후에동일한검사자가동일한방법으로검사를반복하여두번째로측정한 2nd NIKf-BUT 와 2nd NIKav-BUT 가산출되었다. Keratograph에의해측정된 NIK-BUT는소수둘째자리까지제시되며, 결과분석은소수첫째자리까지값으로처리하였다. 2nd NIK-BUT 검사를마치고 30분후, 플루오레신염색을통해코발트블루광원하세극등에서눈물막파괴시간을확인하였다. 각결막의염색은 fluorescein strip으로대상자의아래쪽결막에플루오레신을묻히고환자에게눈을깜박거리게하여각결막에골고루퍼지게하였다. 플루오레신염색을이용한눈물막파괴시간 (fluorescein tear film break-up time, FBUT) 은환자에게눈을깜박거리게한후눈을감았다가뜨게하여첫결손이생길때까지의시간으로정의하였으며, 디지털초시계를이용하여측정하였다. 각결막염색을확인하여한국안구건조증진단기준에따른중증도를분류하였다. 쉬르머검사를통해눈물분비기능을평가하였다. 검사지 (Schirmer strip; Madhu instruments Pvt. Ltd, New Delhi, India) 를환자의아래쪽결막이측부에위치하게한후환자가눈을감도록하였다. 5분이경과한후검사지를회수하였으며검사지가젖은부분까지의눈금을읽어서기록하였다. 통계학적분석으로두군의연령과 FBUT, NIKf-BUT, NIKav-BUT, 쉬르머검사, OSDI 점수를 independent samples t-test 또는 paired samples t-test를이용하여비교하였으며, 두군간의성별은카이제곱검정을시행하여비교하였다. NIK-BUT의재현성을평가하기위해급내상관계수 (Intra-class correlation coefficients, ICC) 를이용한신뢰도분석을시행하였다. Box and whisker plot을이용하여 NIK-BUT 와 FBUT의분포를표현하였다. FBUT 와 NIKf-BUT, NIKav- BUT, 쉬르머검사, OSDI 점수간의상관관계를평가하기위해피어슨상관계수 (Pearson s correlation coefficients) 를구하였다. Receiver operating characteristic (ROC) curve를이용하여곡선아래면적 (area under the curve, AUC) 및 cut-off value를분석하였다. 통계분석프로그램은 SPSS 20.0 for Windows (IBM Corp., Armonk, NY, USA) 와 MedCalc (MedCalc software bvba, Ostend, Belgium) 를사용하였고통계분석결과 p값이 0.05 미만인경우를통계적유의성이있다고해석하였다. 결 과 총 100명 100안중정상대조군은 50명 50안, 안구건조증군은 50명 50안 (level 1 30안, level 2 20안 ) 이었다. 안구건조증군의평균나이는 54.6세였으며그중남자는 18명, 여자는 32명이었다. 정상대조군의평균나이는 52.8세였으며남자는 23명, 여자는 27명이었다. 두군간의연령과성별분포에는유의한차이가없었다. 안구건조증군과정상대조군별로 FBUT, 1st NIKf-BUT, 1st NIKav-BUT, 2nd NIKf-BUT, 2nd NIKav-BUT, 쉬르머검사는각 5.7초와 13.1초, 4.1초와 10.8초, 5.8초와 13.5초, 4.3초와 10.8초, 5.8초와 13.6초, 7.0 mm와 13.2 mm였고모두안구건조증군에서유의하게짧았다. OSDI는두군에서각 40.1점, 25.1점으로안구건조증군에서유의하게높았다 (Table 1). NIKf-BUT와 NIKav-BUT 의 ICC는정상대조군에서각 0.700과 0.912이었고, 안구건조증군에서각 0.717과 0.943을나타내어높은재현성을보였으며, 통계적으로유의하였다 (p<0.001 in all parameters; Table 1). NIK-BUT와 FBUT의분포를 Box and whisker plot을이용하여확인한결과, NIK-BUT 는두군모두에서첫번째검사와두번째검사간에유사한분포를보였다. 특히 NIKav-BUT의 Interquartile range (IQR) 는검사간차이가거의없었다. NIKf-BUT의 IQR은안구건조증군이정상대 Table 1. Demographics and ocular parameters of the study subjects Dry eye Control group group p-value Eyes (n) 50 50 Age (years) 54.6 ± 10.9 52.8 ± 11.8 0.347 * Gender (male:female) 18:32 23:27 0.309 FBUT (seconds) 5.7 ± 1.7 13.1 ± 2.9 <0.001 * 1st NIKf-BUT (sec) 4.1 ± 1.3 10.8 ± 4.9 <0.001 * 1st NIKav-BUT (sec) 5.8 ± 2.0 13.5 ± 3.7 <0.001 * 2nd NIKf-BUT (sec) 4.3 ± 1.5 10.8 ± 4.2 <0.001 * 2nd NIKav-BUT (sec) 5.8 ± 2.1 13.6 ± 2.9 <0.001 * Schirmer test (mm/5 min) 7.0 ± 3.6 13.2 ± 5.6 <0.001 * OSDI score 40.1 ± 14.2 25.1 ± 13.3 <0.001 * Values are presented as mean ± SD unless otherwise indicated. For the NIKf-BUT, the intraclass correlation coefficient between first and second examination was 0.717 in the dry eye and 0.700 in the control group. For the NIKav-BUT, the intraclass correlation coefficient between first and second examination was 0.943 in the dry eye and 0.912 in the control group. FBUT = fluorescein tear film break-up time; NIKf-BUT = non-invasive keratograph first break-up time; NIKav-BUT = non-invasive keratograph average break-up time; OSDI = ocular surface disease index. * p-value based on independent sample t-test; p-value based on chi-square test. 1356
- 정성용 이상범 : 비침습적눈물막파괴시간검사의신뢰도 - Figure 2. Distribution of non-invasive keratograph tear film break-up time (NIK-BUT) and tear film break-up time with fluorecein (FBUT) using box and whisker plot in the dry eye and control groups. The boxes include 50% of the measured values between 1st and 3rd quartiles and the median (horizontal line). The upper and lower fences indicate 1.5 times the interquartile range (IQR) from 3rd and 1st quartiles. The outliers which are more than 1.5 IQR from the box are shown as circles. The mean of each parameter are shown as diamond. Comparison between FBUT and NIK-BUTs was performed by paired sample t-test. NIKf-BUT = non-invasive keratograph first break-up time; NIKav-BUT = non-invasive keratograph average break-up time. * p-value < 0.05 by paired sample t-test. Table 2. Pearson s correlation coefficients for all reference methods FBUT 1st NIKf 1st NIKav 2nd NIKf 2nd NIKav Schirmer OSDI FBUT 1 0.440 0.660 0.592 0.689 0.289 * -0.046 1st NIKf 0.612 1 0.687 0.567 0.601 0.111-0.118 1st NIKav 0.768 0.832 1 0.638 0.893 0.228 0.003 2nd NIKf 0.503 0.545 0.558 1 0.685 0.374-0.052 2nd NIKav 0.724 0.654 0.860 0.730 1 0.206 0.063 Schirmer 0.377 0.230 0.311 * 0.247 0.337 * 1-0.112 OSDI -0.162-0.309 * -0.265-0.270-0.233-0.045 1 Values in light gray background area represent correlation in the normal control group, and the other values represent correlation in the dry eye group. FBUT = fluorescein tear film break-up time; NIKf = non-invasive keratograph first break-up time; NIKav = non-invasive keratograph average break-up time; OSDI = ocular surface disease index. * p-value < 0.05; p-value < 0.01. 조군보다더좁은분포를보였다. 안구건조증군에서 1st NIKf-BUT (p<0.001) 와 2nd NIKf-BUT (p<0.001) 는 FBUT 보다짧았으며, 1st NIKav-BUT (p=0.624) 와 2nd NIKav- BUT (p=0.537) 는 FUBT와유의한차이가없었다. 정상대조군에서도 1st NIKf-BUT (p<0.001) 와 2nd NIKf-BUT (p<0.001) 는 FBUT보다짧았으며, 1st NIKav-BUT (p=0.260) 와 2nd NIKav-BUT (p=0.098) 는 FBUT와유의한차이가없었다 (Fig. 2). 각지표들간의상관관계를평가하였다. FBUT와 NIKf- BUT 간에는안구건조증군 (r=0.440, p<0.001 between FBUT and 1st NIKf-BUT & r=0.592, p<0.001 between FBUT and 2nd NIKf-BUT) 과정상대조군 (r=0.612, p<0.001 between FBUT and 1st NIKf-BUT & r=0.503, p<0.001 between FBUT and 2nd NIKf-BUT) 에서모두중등도양의상관관계를보였고, FBUT와 NIKav-BUT 간에는안구건조증군 (r=0.660, p<0.001 between FBUT and 1st NIKav-BUT & r=0.689, p<0.001 between FBUT and 2nd NIKav-BUT) 과 정상대조군 (r=0.768, p<0.001 between FBUT and 1st NIKav-BUT & r=0.724, p<0.001 between FBUT and 2nd NIKav-BUT) 에서모두강한양의상관관계를보였다. OSDI와나머지지표들간에는전반적으로음의상관관계를보였으나통계적으로유의하지않았다 (Table 2). NIK-BUT의 ROC curve 를 Fig. 3에나타내었다. NIKav- BUT의 AUC는 0.980으로 NIKf-BUT의 0.917보다높았으며, 유의한차이를보였다 (p=0.032). 각지표의 cut-off value 는 1st NIKf-BUT 5.2초 (sensitivity 90%, specificity 80%), 1st NIKav-BUT 8.9초 (sensitivity 94%, specificity 92%) 이었다 (Fig. 3). 고찰 플루오레신을이용한눈물막파괴시간검사는안구건조증의진단과경과관찰에널리사용되고있다. 11 그러나플루오레신이눈물막의안정성을감소시키며검사자가주관 1357
- 대한안과학회지 2016 년제 57 권제 9 호 - Figure 3. Receiver operating characteristic curve (ROC) of non-invasive keratograph tear film break-up time (NIK-BUT). The area under the curve (AUC) is 0.917 in 1st non-invasive keratograph first break-up time (NIKf-BUT) and 0.980 in 1st non-invasive keratograph average break-up time (NIKav-BUT). The cut-off value derived from ROC curve was provided. The difference of AUC between NIKf-BUT and NIKav-BUT was 0.063 and was significant (p = 0.032). 적으로측정한다는단점이있다. 4,5 또한동일검사자가시행하더라도 0.6-0.7 정도의중등도재현성을보이는것으로보고되었다. 12,13 한편, Mengher et al 6 이 1985년비침습눈물막파괴시간검사를제안한이후 tear film lipid layer interferometry 14, tearscope 15 등의비침습검사방법들이개발되었다. Mengher et al 6 은격자무늬를각막에투사하여반사된상의일그러짐을측정하는비침습눈물막파괴시간검사를고안하였다. 그들의연구에이용된검사의원리는 Keratograph 4와유사하지만, 검사자가주관적으로평가한다는점에서는 FBUT 와유사하다. 그리고 Keratograph 4는각막지형도를이용하여비침습눈물막파괴시간측정이가능하며, 검사자의주관적오류와플루오레신에의한눈물막영향이없어임상적으로유용성이높다. 본연구는안구건조증환자와정상인을대상으로 Keratograph 4를이용한비침습눈물막파괴시간검사를측정하여, 재현성과진단력및기존안구건조증지표와의관계를분석하였다. NIKav-BUT의 ICC는안구건조증군과정상대조군에서각 0.943, 0.912로높은재현성을보였으며, NIKf-BUT 의 ICC는 0.717, 0.700으로비교적높은재현성을보였다. 본연구에서확인된 ICC는 Hong et al 8 의연구에서 85명을대상으로 0.8 이상을보인것과유사하였다. 다만임상적 해석에서, 그들의연구는 2일간격으로시행한 inter-visit ICC로습도를포함한환경적요인과환자상태등이반영된결과로유추되며, 본연구의 ICC는같은날에 30분간격으로두번측정하여얻은결과임을고려하여야할것으로생각된다. 또한, Cox et al 7 은 60명의환자들을대상으로 NIKf-BUT, NIKav-BUT 및 FBUT를 1주일간격으로측정하여, 각검사값들의방문간급내상관계수 (inter-visit ICC) 가유사하게나타남을확인한바있다. 따라서 NIK-BUT의 intra-observer ICC가높음을본연구를통해확인할수있었고, 또한 inter-visit ICC도 Cox et al 7 의연구를통해높음이확인되어 NIK-BUT는 FBUT를대체하여임상적으로유용하게사용할수있을것으로판단된다. NIKf-BUT와 NIKav-BUT의 ICC는안구건조증군 (0.717, 0.943) 이정상대조군 (0.700, 0.912) 보다다소높았다. 이는안구건조증군에서눈물막파괴시간변화범위가상대적으로짧은것과정상대조군에서반사눈물분비가영향을미친것으로설명할수있다. NIK-BUT는본질적으로미세한눈물막의일그러짐에도영향을받을수있으며, 16 특히눈을오래뜨고있으면반사눈물분비발생확률이높아져눈물막변동과함께 NIK-BUT에영향을미칠수있다. 이와같이 NIK-BUT 값자체가상대적으로길어질경우그변동성도같이커지는경향에대하여이전의연구 7 에서도밝혀진바있다. 이에따라비침습눈물막파괴시간이안구건조증환자들에서상대적으로높은재현성을보인다는점을설명할수있을것으로생각된다. 실제로이러한경향은본연구의 NIKf-BUT 분포에서도나타나는데, Fig. 2의 Box and whisker plot에서 FBUT와비교한 NIKf-BUT의 IQR이정상대조군에서안구건조증군보다넓게분포함을보여주는것으로설명이가능하다. 본연구에서 NIKf-BUT는두군모두 FBUT보다유의하게짧았으며, Jiang et al 9 의연구에서도동일한결과가보고된바있다. 이같은결과의설명으로, 우선눈물막결손 (tear break) 을측정하는 FBUT와달리 NIK-BUT는이미지소프트웨어를이용하여눈물막에투영된플라시도링의일그러짐을측정하며또한육안으로구별할수없는수준의눈물막불안정영역까지측정이가능하기때문인것으로생각된다. 그리고 Keratograph 4를이용한측정방법이 0.01 초단위로측정된다는점과 light emitting diode (LED) 광원에서방출되는미약한열또한 NIKf-BUT가짧아지는결과에영향을미쳤을것으로생각된다. 16 Keratograph 4는 NIKav-BUT라는또다른지표를제시하고있다. NIKav-BUT는검사시작과종료사이에서발생하는눈물막파괴시간의평균값이다. 24개의방사형직선과 8개의원으로나누어진 192개의영역은일그러짐이발생할 1358
- 정성용 이상범 : 비침습적눈물막파괴시간검사의신뢰도 - 때마다각영역의시간이측정되고, 검사종료후자동으로평균눈물막파괴시간이산출된다. 본연구에서 NIKav-BUT 는두군모두에서 FBUT와통계적으로유의한차이를보이지않았으며, NIKav-BUT와 FBUT 간에는차이가없다는것이 Jiang et al 9 의연구에서도동일하게확인된바있다. 따라서본연구를통해 NIKav-BUT는, 임상적으로흔히이용되는 FBUT를대체하여적용할수있을것으로보인다. 본연구의상관관계분석에서, NIKf-BUT와 FBUT 간에는중등도의양의상관관계를보였으며, NIKav-BUT와 FBUT 간에는강한양의상관관계를보였다. 본연구와유사하게 Keratograph를이용한 Jiang et al 9 의연구와 Hong et al 8 의연구에서 NIK-BUT와 FBUT 간에중등도의양의상관관계가있음이보고된바있다. 반면, 1995년이루어진비침습눈물막파괴시간에대한과거의연구에서 Cho and Douthwaite 17 는 Mengher et al 6 이제안한 NIBUT의측정값이 FBUT와유의한상관관계를보이지않음을보고하였다. 이러한상관관계의불일치는그당시연구에서 NIBUT 측정시검사자의주관성이개입되었을가능성과, 각연구에서사용한 NIBUT 검사장비의차이에의한것으로생각된다. 본연구를포함하여최근에보고된 Keratograph를사용한연구 8,9 에서는상관관계에대해유사한결과를보였으며, 본연구에서는안구건조증군과정상대조군의상관관계를나누어분석하였으므로그임상적가치가더크다고할수있다. 따라서본연구는 NIKav-BUT가 FBUT를대체하여적용할수있음을상관관계분석에서도확인하는의미를지닌다. ROC 분석에서본연구의 NIKf-BUT와 NIKav-BUT의 cut-off value는각 5.2초와 8.9초였으며, Hong et al 8 의연구에서 NIKf-BUT의 cut-off value는 2.65초로제시되었다. 안구건조증의진단기준 2 에서 FBUT의 cut-off value는일반적으로알려진 10초로적용되었으나, 본연구의결과를포함하여 Keratograph 를이용한연구들의 NIK-BUT cut-off value 와는차이를나타내었다. 이에따라 NIK-BUT의 cut-off value 는 FBUT의 cut-off value와구별되어적용되어야할것이며, 더큰표본과모든안구건조증 level을포함하는추가적인연구를통해밝혀져야할부분으로생각된다. 또한, 본연구에서 NIK-BUT의 AUC는 0.9 이상이었고, 특히 NIKav-BUT 는 0.98의높은 AUC를보였다. Hong et al 8 의연구에서도 NIK-BUT의 AUC가 0.8 이상임이보고된바있어 NIK- BUT의진단력이높음을확인할수있었다. 본연구에서제시된 NIK-BUT의 cut-off value에서민감도는 90% 이상, 특이도는 80% 이상으로우수한결과를보였으며, Hong et al 8 의연구에서제시된민감도 84%, 특이도 76% 와유사하였다. 따라서본연구의결과를토대로 NIK-BUT는높은 재현성과진단력을가지고, FBUT와양의상관관계를만족하는검사법이라고할수있다. 현재까지 FBUT와 NIK-BUT의관계를밝히는연구들이부족한실정을감안하고, 본연구를통해제시된 FBUT와 NIKf-BUT, NIKav-BUT 의기초적인관계를토대로할때 NIK-BUT는임상적으로안구건조증의유용한지표로간편하게이용될수있을것으로생각된다. 앞으로충분한환자수와중등도이상의안구건조증을대상으로한다각적인연구가진행된다면보다유용하고실제적인임상지표로서의해석이가능할것이다. 본연구는 Keratograph 4를이용한비침습눈물막파괴시간의재현성을평가하였으나, 한국안구건조증진단기준에서 level 1, 2만을포함하였으며눈물막검사의반복시행이결과에미치는영향을고려하지않았다는제한점을가진다. 그리고, 본연구에서는안구건조증군과정상대조군으로구분하여안구건조증지표들을비교하였지만, 안구건조증의중증도에따라분석하지는않았다. 안구건조증의중증도에따라 NIK-BUT의평균에차이가있는지, 다른안구건조증지표와상관관계를보이는지에대해서는향후질병중증도를포함한추가적인연구가필요할것이다. 결론적으로비침습눈물막파괴시간은검사자의주관을배제한객관적인검사로, 검사간의재현성이확인되었으며 ROC curve에서높은진단력을보였다. 또한 NIKav-BUT 는 FBUT 와유의한차이가없었으며중등도이상의양의상관관계를보였다. 따라서비침습눈물막파괴시간은직관적이면서도임상적으로간편하게안구건조증정도를평가하는새로운지표로유용하게이용될수있을것으로생각된다. REFERENCES 1) The definition and classification of dry eye disease: report of the Definition and Classification Subcommittee of the International Dry Eye WorkShop (2007). Ocul Surf 2007;5:75-92. 2) Hyon JY, Kim HM, Lee D, et al. Korean guidelines for the diagnosis and management of dry eye: development and validation of clinical efficacy. Korean J Ophthalmol 2014;28:197-206. 3) Norn MS. Desiccation of the precorneal film. I. Corneal wetting-time. Acta Ophthalmol (Copenh) 1969;47:865-80. 4) Mengher LS, Bron AJ, Tonge SR, Gilbert DJ. Effect of fluorescein instillation on the pre-corneal tear film stability. Curr Eye Res 1985;4:9-12. 5) Patel S, Murray D, McKenzie A, et al. Effects of fluorescein on tear breakup time and on tear thinning time. Am J Optom Physiol Opt 1985;62:188-90. 6) Mengher LS, Bron AJ, Tonge SR, Gilbert DJ. A non-invasive instrument for clinical assessment of the pre-corneal tear film stability. Curr Eye Res 1985;4:1-7. 7) Cox SM, Nichols KK, Nichols JJ. Agreement between automated 1359
- 대한안과학회지 2016 년제 57 권제 9 호 - and traditional measures of tear film breakup. Optom Vis Sci 2015;92:e257-63. 8) Hong J, Sun X, Wei A, et al. Assessment of tear film stability in dry eye with a newly developed keratograph. Cornea 2013;32:716-21. 9) Jiang Y, Ye H, Xu J, Lu Y. Noninvasive Keratograph assessment of tear film break-up time and location in patients with age-related cataracts and dry eye syndrome. J Int Med Res 2014;42:494-502. 10) Schiffman RM, Christianson MD, Jacobsen G, et al. Reliability and validity of the Ocular Surface Disease Index. Arch Ophthalmol 2000;118:615-21. 11) Korb DR. Survey of preferred tests for diagnosis of the tear film and dry eye. Cornea 2000;19:483-6. 12) Nichols KK, Mitchell GL, Zadnik K. The repeatability of clinical measurements of dry eye. Cornea 2004;23:272-85. 13) Lee JH, Kee CW. The significance of tear film break-up time in the diagnosis of dry eye syndrome. Korean J Ophthalmol 1988;2: 69-71. 14) Goto E, Tseng SC. Differentiation of lipid tear deficiency dry eye by kinetic analysis of tear interference images. Arch Ophthalmol 2003;121:173-80. 15) Guillon JP. Use of the Tearscope Plus and attachments in the routine examination of the marginal dry eye contact lens patient. Adv Exp Med Biol 1998;438:859-67. 16) Best N, Drury L, Wolffsohn JS. Clinical evaluation of the Oculus Keratograph. Cont Lens Anterior Eye 2012;35:171-4. 17) Cho P, Douthwaite W. The relation between invasive and noninvasive tear break-up time. Optom Vis Sci 1995;72:17-22. = 국문초록 = 각막지형도를이용한새로운비침습적눈물막파괴시간검사의신뢰도평가 목적 : 비침습눈물막파괴시간검사의재현성을평가하고기존안구건조증지표와의관계를분석해보고자하였다. 대상과방법 : 안구건조증군 50 명과정상대조군 50 명을전향적으로모집하였다. Keratograph 4 (Oculus, Wetzler, Germany) 를이용하여눈물막첫파괴시간 (non-invasive keratograph first break-up time, NIKf-BUT) 과평균파괴시간 (non-invasive keratograph average break-up time, NIKav-BUT) 을 2 회반복측정후, 플루오레신눈물막파괴시간 (tear film break-up time with fluorescein, FBUT) 을측정하고지표간상관관계를분석하였다. NIKf-BUT 와 NIKav-BUT 의급내상관계수와곡선아래면적을이용한진단력을평가하였다. 결과 : NIKav-BUT 는두군모두 FBUT 와양의상관관계를보였다 (dry eye; r=0.66, p<0.001 and control group; r=0.77, p<0.001). NIKf-BUT 와 NIKav-BUT 의급내상관계수는안구건조증군에서각 0.72 와 0.94 였고, 대조군에서는각 0.70 과 0.91 이었다. NIKav-BUT 와 FBUT 는유의한차이가없었다. 곡선아래면적은 NIKf-BUT 에서 0.917, NIKav-BUT 에서 0.980 이었다. 결론 : NIKf-BUT 와 NIKav-BUT 는재현성이확인되었다. NIKav-BUT 는 FBUT 와유의한차이가없었으며, 양의상관관계를만족하였다. 높은진단력을보인 NIK-BUT 는안구건조증정도를나타내는새로운지표로유용하게이용될수있을것으로생각된다. < 대한안과학회지 2016;57(9):1354-1360> 1360