Disease severity index in normal subjects ranged from 0.100 to 0.203; in patients with mild/moderate disease, it fell between 0.204 and 0.346; and in those with severe disease, it ranged from 0.347 to 0.664. Of interest, none of the subjects was entirely negative across all clinical measures. As such, no subject registered a score of 0. Similarly, patients with the most severe disease did not test the upper limits of the index, which would have required a 0 mm Schirmer strip, 0 second TBUT, complete staining of the cornea and conjunctiva, and a score of 100 on the OSDI.
The average results for each measurement, broken down by quartile-derived severity, are shown in
Table 2. Normal values for osmolarity determined by this method (302.2 ± 8.3 mOsm/L) matched those given by earlier studies. Specifically, 9 of the 13 studies cited in the meta-analysis by Tomlinson et al.
13 reported values within 2 mOsm/L of this mean, and the combined average of those studies reported a value of 302 ± 9.7 mOsm/L. A more recent study reported the average in 25 normal control subjects to be 302 ± 18.2 mOsm/L with TearLab osmolarity. (Jacobi C, et al.
IOVS 2010;51:ARVO E-Abstract 3381). Similar concordance between normal referent values in the literature and those found in this study was observed for other signs: TBUT (11.8 ± 6.4 seconds vs. 12.8 ± 1.3 seconds),
23 OSDI (5.5 ± 7.4 vs. 4.5 ± 6.6),
18 and Schirmer test (19.3 ± 10.4 mm vs. 20.2 ± 11.3).
24
The average osmolarity in all dry eye subjects in this study, including mild/moderate and severe (322.2 ± 18.8 mOsm/L), was similar, although it was lower than that in Tomlinson et al.
13 (326.9 ± 22.1 mOsm/L), indicating that sample in the present study was most likely from a population with less severe disease than the samples in past studies. TBUT values for severe dry eye (2.7 ± 1.5 seconds) were concordant with those reported in Abelson et al.
25 (2.2 seconds, range 0.9–5.2), and the TBUT average for all dry eye subjects (5.0 ± 4.4 seconds) compared favorably with the 5 second clinical threshold reported for microquantity instillations.
5,25 A recent study by Miller et al.,
26 evaluated symptoms segregated by disease severity and reported an average OSDI in all mild/moderate subjects across baseline and follow-up (20.1 ± 8.4) that was comparable to the average in all mild/moderate subjects in this study (21.0 ± 19.2). Averages across baseline and follow-up for subjects with severe disease in the Miller study (43.1 ± 19.8) were similarly close to the severe group in this study (41.2 ± 21.6).
26 These results confirm that the composite index provided an unbiased method for classifying dry eye patients.
Figure 1 displays the relationship between each of the clinical signs and the composite disease severity index. Each sign is plotted with disease severity on the
x-axis and the raw clinical data on the
y-axis. The correlation coefficient of each sign is as follows: osmolarity (
r 2 = 0.55), TBUT (
r 2 = 0.30), Schirmer (
r 2 = 0.17), corneal staining (
r 2 = 0.43), conjunctival staining (
r 2 = 0.47), meibomian score (
r 2 = 0.37), and OSDI (
r 2 = 0.41).
The resulting average correlation coefficients for the random control dataset were: osmolarity (r 2 = 0.10), TBUT (r 2 = 0.15), Schirmer (r 2 = 0.08), corneal staining (r 2 = 0.09), conjunctival staining (r 2 = 0.10), meibomian score (r 2 = 0.09), and OSDI (r 2 = 0.24). Therefore, high correlation against the index is not guaranteed, simply because the individual measurements are part of the composite. The one exception was the mapping used for OSDI, which showed a small correlation with the index, even when random noise replaced the clinical values. Removal of OSDI from the composite did not alter the interpretation of the results. Without OSDI as part of the index, the average osmolarity across the three severity grades was 300.8 ± 7.8, 315.5 ± 10.4, and 336.7 ± 22.2 mOsm/L, whereas the correlation coefficients for osmolarity (r 2 = 0.63), TBUT (r 2 = 0.28), Schirmer test (r 2 = 0.17), corneal staining (r 2 = 0.44), conjunctival staining (r 2 = 0.49), and meibomian score (r 2 = 0.34) were essentially unchanged.
Figure 2 exhibits histograms of the composite severity index for the normal and dry eye groups defined by the threshold-based prospective selection criteria. Prospective normal subjects exhibited severities from 0.10 to 0.34, and prospective dry eye patients showed severities ranging from 0.16 to 0.66. Fully 63% of the subjects fell within the overlapping area between severities of 0.16 and 0.34. Examples of prospectively defined normal individuals with clear evidence of disease, as well as prospectively defined dry eye subjects with low disease severities, are shown in
Table 3. These data suggest that threshold-based selection criteria failed to properly classify most mild/moderate dry eye subjects.