1040-5488/14/9112-1412/0 VOL. 91, NO. 12, PP. 1412Y1418 OPTOMETRY AND VISION SCIENCE Copyright * 2014 American Academy of Optometry

ORIGINAL ARTICLE

Automatic Noninvasive Tear Breakup Time (TBUT) and Conventional Fluorescent TBUT Weizhong Lan*, Lixia Lin*, Xiao Yang†, and Minbin Yu†

ABSTRACT Purpose. To compare the effects of different volumes of fluorescein on tear breakup time (FTBUT) and to investigate if and to what extent the tear breakup time determined by an automated noninvasive instrument (NITBUT) differs from FTBUT. Methods. Twenty-four healthy volunteers were recruited to the study. Fluorescent tear breakup time was measured with different volumes of fluorescein solution delivered by either glass rod or objective directly by fluorescein strip. Noninvasive tear breakup time was measured with a noninvasive instrument (Oculus Keratograph 5M, Germany; K5). The average levels of the tear breakup times (TBUTs) and the variability of the successive recordings for each measurement were compared. Results. Increasing the volume of fluorescein delivered from 1 to 7 Kl lengthened FTBUT by a mean ratio of 1.26-fold (p = 0.019) for the glass rod technique. No significant difference was detected in the FTBUT measured by the fluorescein strip technique when the delivered volume was increased from 4.5 to 7 Kl. The variability of successive recordings was stable across the tested volumes for both techniques. Noninvasive tear breakup time determined by K5 was significantly longer than FTBUTs (mean difference: 3.90 seconds, p = 0.003 and 4.12 seconds, p = 0.002, respectively). Although no significant difference was detected in the average SD for successive recordings among K5 and the other two invasive techniques (p = 0.325), the variability of NITBUT was found significantly dependent on the observed TBUT (r = 0.532, p = 0.007). Conclusions. The Oculus Keratograph 5M usually produced substantially longer TBUT compared with invasive techniques tested. The variability of readings by this novel method increased with the values of NITBUT. Given the small sample size in the current experiment, however, these findings need to be confirmed in a larger study. (Optom Vis Sci 2014;91:1412Y1418) Key Words: tear breakup time (TBUT), tear film, invasive, noninvasive, Oculus Keratograph 5M

T

he parameter of tear breakup time (TBUT) is important in the evaluation of tear film stability, and it is an essential criterion for the diagnosis of dry eye.1 It is defined as the time interval between a complete blink and the first occurrence of a dry spot in the tear film.2,3 Clinically, it can be measured invasively by instilling fluorescein dye to make the tear film observable and subsequently detecting its first break (FTBUT). Alternatively, it can also be measured noninvasively (i.e., without preinstilled fluorescein [NITBUT]) by special instruments such as the Tearscope.4Y6 Because it is simple and does not require expensive instruments, FTBUT is more commonly used in clinical practice. However, its reliability and repeatability have been questioned,7,8 because its

*MD † MD, PhD State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China (all authors).

results have been reported to be influenced by many factors, such as the method of instillation (e.g., with a glass rod [GR], which is commonly used in Asia,9 or directly with a fluorescein strip [FS]8,10,11) and the instilled volume of fluorescein solution.10,11 Theoretically, noninvasive techniques are superior to the more commonly used invasive ones, because it does not require the addition of fluorescein solution and therefore does not alter the volume or the physicochemical properties of the tear layer.12 However, most of these techniques are subjective and request the examiner to detect the break of the tear film, which results in considerable interexaminer variability.13,14 Recently, an examiner-independent device, the Oculus Keratograph 5M (hereinafter called K5), was released, thus offering the first automated, objective technique for measuring NITBUT. Despite numerous studies done on FTBUT and NITBUT, the exact relation between this novel technique and conventional fluorescein-applied techniques is unclear. Accordingly, the purpose

Optometry and Vision Science, Vol. 91, No. 12, December 2014

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Noninvasive Tear Breakup Time and Conventional Fluorescent TBUTVLan et al.

of this study was to compare the NITBUT measured by K5 and its variability with the FTBUT determined by GR and FS techniques. Given that FTBUT is readily affected by the volume of instilled fluorescein solution,10,11 this influential factor was quantified by determining the volume with a micropipette, and for a quantitative comparison, several volumes of fluorescein solution have been tested in the current study.

METHODS Twenty-four volunteer staff at Zhongshan Ophthalmic Center (Guangzhou, China) were recruited for this cross-sectional crossover study. The mean (TSD) age was 24 (T2.2) years (range, 20 to 32 years), and 46% of the sample was female. None had selfreported dry eye symptoms or eye discomfort. Other ocular diseases were excluded as well through slit-lamp microscopy and ophthalmoscopy. All had no history of wearing contact lenses. No subjects were taking medications known to affect TBUT.2 None had previous ocular surgeries (e.g., corneal refractive surgery). Informed consent was obtained before the study and the possible consequences of participation were explained. The study conformed to the Declaration of Helsinki and was approved by the institutional research ethics committee.

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after the alignment of the instrument head with the center of the pupil and after subjects were asked to blink. Each recording did not stop until the subject blinked (subjects were encouraged to blink if they felt discomfort to avoid reflex tearing). Then, the first TBUT, denoted as NITBUT, and the average TBUT (i.e., the average value of the intervals after blinking across the observed area on the cornea) were produced automatically (Fig. 1). This procedure was repeated three times. Only the values of NITBUT were used for further analysis. The TBUT and the variability of the measurement were calculated as the mean and the SD of the three readings for each subject, respectively. All six measurements (i.e., three volumes for the GR technique, two volumes for the FS technique, and one measurement for K5) were done randomly from 1:00 PM to 3:00 PM on two consecutive days (i.e., three measurements each day) to exclude the influence of diurnal variation. The interval between every two measurements was about 20 minutes to ensure complete tear turnover.15 The ambient air temperature and relative humidity of the examination room were relatively constant at 23 to 26-C and 45 to 50%, respectively. Because of the similar nature of the two eyes, in the present study, only right eyes were measured.

Statistics

Fluorescent Tear Breakup Time Fluorescent tear breakup time was measured in subjects after the fluorescein was transferred by using one of two techniques. 1. Glass rod technique: Determined by micropipette (Eppendorf Research Plus, Eppendorf, Germany), 1, 4.5, or 7 Kl of 1% fluorescein solution was dropped onto a GR and then applied on the inferior temporal bulbar conjunctiva. These volumes were selected because we found that 1 Kl of fluorescein is the minimum volume necessary to make the tear film observable by a slit-lamp microscope with a cobalt blue filter and because the average tear volume was reportedly to be about 7 Kl previously.15 2. Fluorescein strip technique: 4.5 or 7 Kl of 0.9% saline was applied to FSs (Fluorets 1 mg; Bausch + Lomb, UK), which were then lightly applied to the superior-temporal bulbar conjunctiva while the subjects looked inferior-nasally. The volume of 1 Kl was not tested for this technique, because it was not sufficient to wet the strip. After the fluorescein dye was instilled, the subjects were asked to blink naturally three to four times to distribute the fluorescein evenly over the cornea. The subjects were then asked to cease blinking until instructed. Fluorescent tear breakup time was measured using the full aperture method14 with the cobalt blue filter in place so that the whole cornea was illuminated. Tear break was recorded with a video camera mounted in the slit lamp. The recordings of each subject were later played back and reviewed by one experienced ophthalmologist. Only the first three FTBUTs were used for further analysis. If blinking occurred before tear breakup, the next FTBUT was adopted instead.

As determined by the Shapiro-Wilk W test, the mean TBUT and the SD of the repeated readings for each subject were often nonnormally distributed. Thus, besides the mean, the median was also used for statistical description. In agreement with previous reports,10,12 in this study, the geometric mean was used to describe the average level for each technique, expressed as mean T SD. Given the multiple measurements taken from each subject, a repeatedmeasures analysis of variance (ANOVA) and a Student unpaired t test with Bonferroni correction for multiple testing were used to determine whether the differences between the average values for techniques were statistically significant. Because only two volumes were tested for the FS technique, a paired t test was used instead to compare the difference. Because a normal distribution of the data is required for these parametric analyses, natural logarithmical transformations of these data were attempted when necessary. If this requirement was still unmet after the transformation, the Friedman test was then applied for comparison. For this nonparametric analysis, Wilcoxon signed rank tests with Bonferroni correction were used for post hoc analysis if an overall comparison was found significant. Pearson correlation was applied to analyze the relationship between variables. All the analyses were performed with commercial SPSS ver. 16.0 software (SPSS, Chicago, IL). The significance level was set at two-tailed 0.05.

RESULTS Table 1 shows the TBUT for each technique and the SD of three individual readings for each measurement.

Noninvasive Tear Breakup Time

Influence of Volume on FTBUT for the GR Technique

Noninvasive tear breakup time determined by K5 was also measured in the same subjects. With no preinstillation of fluorescein dye, the dynamics of the tear film were recorded by the device,

As expected, instilling an increased volume of liquid fluorescein lengthened TBUT. Specifically, the average geometric means of FTBUT after 1, 4.5, and 7 Kl of fluorescein solution delivered by

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1414 Noninvasive Tear Breakup Time and Conventional Fluorescent TBUTVLan et al.

FIGURE 1. Screenshot of the output window of K5 for one sample subject. The first TBUT (i.e., the time interval between blinking and the first dry spot in the tear film) and the average TBUT (i.e., the average value of the intervals between blinking and individual dry spots across all the observed area on the cornea) are automatically shown in the right inferior area. A color version of this figure is available online at www.optvissci.com.

GR were 5.67 T 1.64, 6.64 T 1.70, and 6.97 T 1.42 seconds, respectively. Significant difference in the mean LnFTBUT (natural logarithm of FTBUT) was found among these three volumes of instilled fluorescein solution (F = 5.236, p = 0.009, repeatedmeasures ANOVA; Fig. 2A). Post hoc tests using a Student unpaired t test with Bonferroni correction revealed that the difference was derived from the comparison between LnFTBUT1Kl and LnFTBUT7Kl (p = 0.019, t test). The 95% confidence interval (CI) for the average difference between LnFTBUT7Kl and LnFTBUT1Kl was 0.03 to 0.43 seconds (mean, 0.23 seconds; p = 0.019). The antilogs of these values were 1.03 to 1.54, and 1.26, which corresponded to estimates of the ratio of their geometric means. This means that for the subjects with extreme FTBUT, such as the minimum (2.45 seconds) and the maximum (9.00 seconds) in the current study, the average difference between 1 and 7 Kl ranged from 0.64 to 2.34 seconds. The mean SDs of FTBUT for 1, 4.5, and 7 Kl fluorescein solution were 2.12 T 1.20, 1.91 T 0.84, and 2.69 T 1.17 seconds,

respectively. No significant difference in the SDs of FTBUT was found among different volumes of fluorescein solution used in this technique (F = 3.082, p = 0.055, repeated-measures ANOVA; Fig. 2B). No significant correlation was found between the SD and the FTBUT for every specific volume (Pearson correlation: r = 0.274, 0.16, and j0.272, respectively; all p 9 0.05).

Influence of Volume on FTBUT for the FS Technique The average geometric means of FTBUT after the instillation of 4.5 and 7 Kl fluorescein by the FS technique were 6.24 T 1.64 and 6.17 T 1.62 seconds, respectively. The difference between these two volumes was not significant (t = 0.188, p = 0.853, paired t test; Fig. 3A). The 95% CI for the average difference between TBUT4.5Kl and TBUT7Kl was j0.63 to 0.76 seconds (mean, 0.06 seconds). The mean SDs for these two volumes were 2.33 T 1.13 and 2.48 T 0.93 seconds, respectively, which was not statistically significant (t = j0.454, p = 0.654, paired t test; Fig. 3B). The 95% CI

TABLE 1.

Tear breakup time of each technique and the SD of three individual readings of each measurement TBUT of each technique, s Technique GR

FS K5

SD of each measurement, s

Volume

Min

Max

Mean

SD

Median

Min

Max

Mean

SD

Median

1 Kl 4.5 Kl 7 Kl 4.5 Kl 7 Kl

2.45 4.16 5.13 3.00 3.48 3.67

9.00 9.11 10.18 8.88 9.21 22.73

5.67 6.64 6.97 6.24 6.17 10.33

1.64 1.70 1.42 1.64 1.62 5.24

5.64 6.80 6.33 6.21 5.56 8.97

0.58 0.58 0.58 0.58 0.58 0.39

5.66 3.51 5.00 4.73 4.58 11.35

2.12 1.91 2.69 2.33 2.48 4.11

1.20 0.84 1.17 1.13 0.93 3.46

2.00 2.00 2.52 2.08 2.52 2.76

Data from the MeanGR4.5Kl, SDGR1Kl, and SDK5 were found to be nonnormally distributed, as verified by the Shapiro-Wilk W test. Optometry and Vision Science, Vol. 91, No. 12, December 2014

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Noninvasive Tear Breakup Time and Conventional Fluorescent TBUTVLan et al.

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FIGURE 2. Boxplots for the FTBUTs determined by the GR technique with three different volumes (A) and the SDs of the three individual recordings for each FTBUT measurement (B). Data were natural logarithmically transformed as the distributions were nonnormal. Significant difference in the LnFTBUT was found among the tested volumes (F = 5.236, p = 0.009, repeated-measures ANOVA) and the difference derived from the comparison between LnFTBUT1Kl and LnFTBUT7Kl (p = 0.019, t test). There was no significant difference in the SDs of FTBUT among the three volumes (F = 3.082, p = 0.055, repeated-measures ANOVA).

for the difference of mean SD between TBUT4.5Kl and TBUT7Kl was j0.84 to 0.54 seconds (mean, 0.65 seconds). Similar with the GR technique, the SD did not vary with the FTBUT for each specific volume (Pearson correlation: r = j0.270 and 0.118, respectively; both p 9 0.05). Comparison of the results of these two techniques of transferring fluorescein solution found no significant difference in FTBUT for each level of volume (4.5 Kl: t = 0.845, p = 0.407; 7 Kl: t = 1.783, p = 0.088; paired t test). No significant difference was found in the comparisons of SDs either (4.5 Kl: t = j1.486, p = 0.151; 7 Kl: t = 0.431, p = 0.670; paired t test).

Comparison of NITBUT and FTBUTs Although there was a statistically significant difference between FTBUT1Kl and FTBUT7Kl for the GR technique, the difference was clinically minor. Additionally, no significant difference was

detected between FTBUT4.5Kl and FTBUT7Kl for the FS technique. Thus, the average data of all volumes of the two invasive techniques for each subject (i.e., mean of the data for 1, 4.5, and 7 Kl for the GR technique and that for 4.5 and 7 Kl for the FS technique) were used to facilitate the comparison between the results of NITBUT and FTBUTs. The average geometric mean of NITBUT determined by K5 was 10.33 T 5.24 seconds (range, 3.67 to 22.73 seconds), which differed significantly from the FTBUTs determined by the two invasive techniques (F = 14.146, p = 0.001; repeated-measures ANOVA). Post hoc tests revealed that the NITBUT determined by K5 was significantly longer than that by the GR technique (p = 0.003, t test) and that by the FS technique (p = 0.002, t test). The 95% CIs for the average difference of these multiple testing were from 1.23 to 6.57 seconds (mean, 3.90 seconds; p = 0.003) and from 1.40 to 6.85 seconds (mean, 4.12 seconds; p = 0.002), respectively.

FIGURE 3. Boxplots for the FTBUTs determined by the FS technique with two different volumes (A) and the SDs of the three individual recordings for each FTBUT measurement (B). The difference in the mean FTBUTs was not significant (t = 0.188, p = 0.853, paired t test), neither for the SDs for these two volumes (t = j0.454, p = 0.654, paired t test). Optometry and Vision Science, Vol. 91, No. 12, December 2014

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1416 Noninvasive Tear Breakup Time and Conventional Fluorescent TBUTVLan et al.

FIGURE 4. Bland-Altman plots to analyze the agreement between NITBUT by K5 and FTBUT by the GR technique (A) and between the NITBUT and FTBUT by the FS technique (B). Abscissa: average of the two methods, ordinate: differences of the two methods. The average difference for either comparison was 3.90 seconds (p = 0.003) and 4.12 seconds (p = 0.002), respectively. The 95% limit of the difference (mean T 1.96 SD) for both comparisons was j6.04 to 13.84 seconds and j6.01 to 14.25 seconds, respectively. The difference between the two methods was significantly correlated with the average of the two methods in both cases (Pearson correlation: r = 0.935, p G0.001 and r = 0.869, p G0.001, respectively), indicating that the longer TBUT, the bigger discrepancy between NITBUT and FTBUTs. Also shown are the fitted regression lines: Difference between NITBUT and FTBUTGR = j10.336 + 1.699  mean of NITBUT and FTBUTGR (A, solid line); difference between NITBUT and FTBUTFS = j8.991 + 1.587  mean of NITBUT and FTBUTFS (B, solid line), and their 95% CIs (thin dashed lines) and 95% prediction intervals (thick dashed lines).

As shown in the Bland-Altman plots addressing the agreement between the methods tested, the difference between NITBUT by K5 and FTBUT by the GR technique (Fig. 4A) and the FS technique (Fig. 4B) both had considerable range: the 95% limit of the difference (mean T 1.96 SD) for both comparisons was j6.04 to 13.84 seconds and j6.01 to 14.25 seconds, respectively. More importantly, the intermethod difference was positively correlated with the average of the two methods in both cases (Pearson correlation: r = 0.935, p G0.001 and r = 0.869, p G0.001, respectively), indicating that the longer TBUT, the bigger discrepancy between NITBUT and FTBUTs. The SDs of the recordings of K5 ranged from 0.39 to 11.35 seconds, with a mean of 4.11 seconds (median, 2.76). No significant difference was found in the SDs between K5 and the two invasive techniques (W2 = 2.250, p = 0.325; Friedman test). Different with them, however, the SD of K5 was found to increase with longer TBUT (Pearson correlation: r = 0.532 for the correlation between LnSD [natural logarithm of SD] and LnNITBUT [natural logarithm of NITBUT], p = 0.007; Fig. 5). Linear regression analysis further revealed how the variability of this technique changed with the detected NITBUT (LnSD = j1.36 + 1.06  LnNITBUT). The antilog for this coefficient was 2.89, indicating that the variability increased 2.08-fold if the detected NITBUT doubled.

temperature and humidity,16 methodology of measurement,14 concentration,17 and volume11 of the delivered fluorescein, which makes it difficult to compare the absolute values found in different studies.18 Given a good control of these influential factors for each individual methodology tested in the present study, in the following discussion, we will focus on the reliability (i.e., the change in value influenced by the volume) and the repeatability of each method, and we will compare them for consistency.

DISCUSSION

FIGURE 5.

Tear breakup time, despite its widespread use and clinical significance in assisting the diagnosis of dry eye, is often criticized for its reliability and repeatability.7,8 It has been reported that TBUT is influenced by multiple factors, including the ambient

Variations in the SD of the three individual recordings of each NITBUT measured by K5. Data were natural logarithmically transformed because the data were not derived from normal distributions. Also shown is the fitted regression line: LnSD = j1.36 + 1.06  LnNITBUT (Pearson correlation: r = 0.532, p = 0.007).

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Noninvasive Tear Breakup Time and Conventional Fluorescent TBUTVLan et al.

Consistent with a study by Johnson and Murphy,10 we found that the volume of fluorescein delivered to the tear film affected the FTBUT values and that larger amounts of fluorescein instilled generally tended to lengthen its duration. Specifically, an increase of volume from 1 to 7 Kl lengthened the TBUT by 1.26-fold (95% CI, 1.03 to 1.54) in the GR technique. However, there was no significant difference in the FTBUT between these two extreme volumes and the intermediate volume (4.5 Kl), which suggests a linear correlation between the increase in volume and the change in FTBUT for the range of volumes tested in the study. This is confirmed by the statistical analysis (Pearson correlation: r = 0.351, p = 0.002). Interestingly, in the study by Johnson and Murphy,10 this correlation was found to be nonlinear, with a plateau starting at the volume of 2.7 Kl. This discrepancy was likely caused by differences in the ambient environmental factors (e.g., air temperature and relative humidity) between these two studies.16 Similar with the case of the GR technique, no significant influence in TBUT was detected between the 4.5- and 7-Kl fluorescent delivered by paper strip. This might be attributed to the limited difference between the volumes tested, which is especially true for the FS technique. It is likely that the saline used to wet the paper strip was rapidly absorbed by the strip itself and the difference in the amount of fluorescein that was really transferred to the ocular surface might be further less than expected. The mean SD ranged from 1.91 to 2.69 seconds for the three volumes delivered by GR and from 2.33 to 2.48 seconds for the two volumes by the FS technique. Given that 30% of the generally accepted norm of tear film instability (10 seconds)10,19 is regarded as the cutoff value to produce clinical significance,10 the repeatability of both invasive methods was found satisfactory. In clinical practice, a common way to moisten the FS is to wet the strip with one drop of saline. However, the amount of fluorescein delivered to the ocular surface through this manipulation was found unpredictable, even after the excess fluid was removed by shaking the strip,10 which compromises the reliability of this technique.11 Indeed, the volume of the instilled fluorescein was often considerably larger than the total tear volume,20 which probably led to a falsely higher TBUT, and therefore dry eye might be overlooked. In contrast, we applied a micropipette to quantify the instilled liquid used to moisten the FS, which obviously improved the repeatability of this technique greatly in the present study. Alternatively, if a micropipette is not available in clinical practice, specifically designed narrower strips (Dry Eye Test, Akorn Inc, Buffalo Grove, IL) might be used to minimize the variance in the instilled volume of fluorescein, which has been shown to achieve consistent results.11,19 Different with FTBUT, K5 does not require instillation of fluorescein solution before the measurement. The Oculus Keratograph 5M determines NITBUT by projecting ring pattern in the form of a Placido disk onto the cornea, with an invisible infrared illumination (wavelength, 880 nm), and detecting the first disruption of the reflected image by the imbedded software. Because the ocular surface environment is very sensitive to any external stimulus and the results of the invasive TBUT can be easily interrupted by the tests themselves,21,22 NITBUT was usually found longer than FTBUT.13,14 This is also the case for K5, whose values were often found longer than the FTBUTs in the present study (Fig. 4). Because of the lack of the stimulation by

1417

instilling fluorescein solution and of the glare-related reflex secretion by using infrared illumination, the TBUT determined by this device therefore was more likely to reflect the ‘‘real’’ stability of the tear film. It should be pointed out that, however, as with other objective assessments, there must be a default threshold regarding the sensitivity to the size of the breakup area in the software of K5, which might lead to an internal bias. Indeed, this has been noted by a recent study, in which the results measured with K5 were found significantly shorter than that recorded with the Tearscope (by 12.35 T 7.45 seconds).22 Nevertheless, provided that the sensitivity of the software in interpreting a tear break is unlikely to be adjusted in clinical practice, this potential internal bias should not be inconsistent among subjects or visits and therefore has no impact on the diagnosis of tear film instability or on monitoring the change of the disease. The variability of successive measurements of K5 was found better, compared with other traditional noninvasive methods.13,22,23 This is because the detection of any disruption of the reflected image is completely conducted by the computer of K5, whereas traditional NITBUT techniques require the examiner to accomplish the process subjectively. This examiner-independent nature has increased the overall repeatability of this method to a level that is comparable to those of the two invasive techniques using precise determination of instilled fluorescein. Nevertheless, different with the tested invasive techniques, the SD of K5 was found to increase with TBUT, indicating that the repeatability in successive recordings dropped with the increased NITBUT. Specifically, a borderline appeared at LnNITBUT = 2.1 seconds (the antilog is ~8 seconds), which classified the subjects into two groups with two levels of NITBUT (Fig. 5). If we take this as a cutoff value, albeit somewhat arbitrary, the variability in these two groups differs remarkably: the median of SD is 0.77 seconds for those with NITBUT shorter than 8 seconds and 5.68 seconds for those with NITBUT longer than 8 seconds. Accordingly, it is suggested to increase the repetition of recordings for subjects with long TBUT (e.g., greater than 8 seconds), so as to increase the reliability of this objective noninvasive method. Nevertheless, from a clinical point of view, this might not be necessary, as those that have very long TBUT are usually considered ‘‘normal’’ and there is no need to spend extra time to confirm normal findings. Dry eye disease is one of the most common ocular disorders and TBUT is among the top tests used to assess for dry eye. Although there are already several lines of techniques to measure the TBUT in practice, K5, given its objective and noninvasive nature, might represent a new direction in this respect. The systematic bias of K5 found in the 24 volunteers in the present study suggests that NITBUT and FTBUT are not interchangeable tests and caution should be paid to compare results determined by these two methods. It should be pointed out, however, that all these results were derived only from healthy subjects and it is not clear whether these results also apply to patients with dry eye symptoms. In addition, all our analysis was based on a small sample size. Thus, our findings, especially those obtained by using nonparametric tests, need to be confirmed in a larger study.

ACKNOWLEDGMENTS Weizhong Lan and Lixia Lin contributed equally to this work and are considered cofirst authors.

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1418 Noninvasive Tear Breakup Time and Conventional Fluorescent TBUTVLan et al. This study was supported by the National Natural Science Foundation of China, Beijing, China (grant no. 81200714). No conflicting relationship exists for any author. Received March 13, 2014; accepted July 30, 2014.

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12. Brown B, Cho P. Inter- and intra-individual variability of non-invasive tear break-up time in Hong Kong Chinese. Clin Exper Optom 1994;77:15Y23. 13. Nichols JJ, Nichols KK, Puent B, Saracino M, Mitchell GL. Evaluation of tear film interference patterns and measures of tear break-up time. Optom Vis Sci 2002;79:363Y9. 14. Cho P, Douthwaite W. The relation between invasive and noninvasive tear break-up time. Optom Vis Sci 1995;72:17Y22. 15. Mishima S, Gasset A, Klyce SD, Jr., Baum JL. Determination of tear volume and tear flow. Invest Ophthalmol 1966;5:264Y76. 16. Maruyama K, Yokoi N, Takamata A, Kinoshita S. Effect of environmental conditions on tear dynamics in soft contact lens wearers. Invest Ophthalmol Vis Sci 2004;45:2563Y8. 17. King-Smith PE, Ramamoorthy P, Braun RJ, Nichols JJ. Tear film images and breakup analyzed using fluorescent quenching. Invest Ophthalmol Vis Sci 2013;54:6003Y11. 18. Foulks GN. Challenges and pitfalls in clinical trials of treatments for dry eye. Ocul Surf 2003;1:20Y30. 19. Savini G, Prabhawasat P, Kojima T, Grueterich M, Espana E, Goto E. The challenge of dry eye diagnosis. Clin Ophthalmol 2008; 2:31Y55. 20. Snyder C, Paugh JR. Rose bengal dye concentration and volume delivered via dye-impregnated paper strips. Optom Vis Sci 1998; 75:339Y41. 21. Ishibashi T, Mori K, Adachi W, Naruse S, Hino Y, Komuro A, Yokoi N, Kinoshita S. Effect of latanoprost on the barrier function of corneal epithelium. Nihon Ganka Gakkai Zasshi 2001;105:333Y7. 22. Best N, Drury L, Wolffsohn JS. Clinical evaluation of the Oculus Keratograph. Cont Lens Anterior Eye 2012;35:171Y4. 23. Cho P. Reliability of a portable noninvasive tear break-up time test on Hong Kong-Chinese. Optom Vis Sci 1993;70:1049Y54.

Minbin Yu State Key Laboratory of Ophthalmology Zhongshan Ophthalmic Center Sun Yat-sen University 54 South Xianlie Road Guangzhou, Guangdong China e-mail: [email protected]

Optometry and Vision Science, Vol. 91, No. 12, December 2014

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Automatic noninvasive tear breakup time (TBUT) and conventional fluorescent TBUT.

To compare the effects of different volumes of fluorescein on tear breakup time (FTBUT) and to investigate if and to what extent the tear breakup time...
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