**Purpose**:
To model between subject variability of corneal swelling (CS) and deswelling after overnight wear of silicone hydrogel (SiHy) contact lenses.

**Methods**:
A total of 29 neophyte subjects wore 12 SiHy lenses with central transmissibility range of 31 to 211 Dk/t units on separate nights, in random order, and on one eye only. The contralateral eye served as the control. Central corneal thickness was measured using digital optical pachymetry before lens insertion, immediately after lens removal on waking, then 20, 40 minutes, 1, 2, and 3 hours later. Mixed modelling was conducted for simultaneous analysis of group and between-subject effects of CS and deswelling.

**Results**:
The best model for overnight CS versus Dk/t was linear with a random intercept showing constant between-subject differences in CS for different Dk/t values. The best fit for corneal deswelling versus time was a curvilinear random intercept and random slope model. About 90% of the total between-subject deswelling variance in either lens or control eyes was due to the intercept variability with much less (∼10%) being due to the variability of the individual deswelling rate (slope). Subject age, sex, and ametropia were not predictors of individual corneal swelling in the swelling versus Dk/t analysis. Age, however, was a significant (inverse) predictor of the rate of corneal deswelling, only in lens-wearing eyes.

**Conclusions**:
A large proportion of variability in corneal swelling is because of subject-specific differences in corneal response to hypoxia. This shows that “low swellers” and “high swellers” actually do exist.

^{1,2}The postlens tear oxygen tension in soft lenses is dependent on the oxygen diffusion through the lens material

^{3,4}and the effect of the tear pump on tear mixing to equilibrate the oxygen tension under a soft lens is insignificant.

^{5,6}Therefore, oxygen diffusion through contact lenses plays a vital role in maintaining corneal health and normal physiology in soft lens wear.

^{7,8}Corneal oxygen deprivation may lead to corneal swelling (thickening) from water absorption by the corneal stroma. This is believed to primarily be from the increased stromal osmotic gradient resulting from the accumulation of lactic acid from anaerobic metabolism in the cornea.

^{9}It would appear self-evident, therefore, that the level of lens induced corneal swelling is inversely related to the oxygen transmissibility of the contact lens.

^{10}

^{11}in nonlens wearers

^{12–15}and sleeping with a contact lens on the eye, further deprives the cornea of the oxygen supply from the palpebral vasculature, maximizing the hypoxic stress and potentially leading to increased corneal edema.

^{16}Even silicone hydrogel (SiHy) lenses with high oxygen transmissibility do not limit the overnight corneal swelling to the level of no lens wear

^{17}and so some subjects may reach potentially unsafe levels of overnight corneal swelling while wearing these highly oxygen permeable lenses.

^{18}

^{19,20}but it has been mentioned in others.

^{19,21,22}It appears that the between-subject variability in corneal swelling is not dependent on lens oxygen transmissibility (Dk/t) because there is a similarly wide range of swelling response while wearing SiHy lenses

^{18}and, interestingly, has been demonstrated with anoxia in the absence of any CL wear.

^{20}These findings suggest that differences in the amount of corneal swelling between individuals (with similar oxygen supply) can be attributed to individual differences in corneal physiologic response to hypoxia (a random effect of subject) rather than the CL wear itself.

^{10,13,17,23–25}This approach compares group mean outcomes as fixed effects and is mathematically unable to address the structure of the underlying subject variability (i.e., the random effects or the individual specific responses). This random structure of corneal swelling or deswelling has never been reported. In our experiment, we conducted a “standard” corneal swelling experiment: Corneal thickness was measured with and without, and before and after overnight lens wear to examine swelling response and its recovery. The novel aspect of our report is to NOT be limited in what we are able to analyze about our predictor variables by only using averages: This is the first report about simultaneously controlling for both fixed (average) and random (subject) effects in SiHy lens induced overnight corneal swelling (CS) and deswelling analyses compared to no lens wear in the contralateral eye. We therefore took a ‘traditional' experimental/analytical route to assess overnight corneal swelling when wearing contact lenses.

^{25}However, the current study was also designed to measure the magnitude of the between-subject variability of CS and the magnitude of between-subject variability in deswelling after lens removal. In addition, we attempted to examine the association of between-subject variability of CS itself (intercept of the deswelling over time regression) and the individual recovery (variability in the slope of the recovery). Analysis of the whole range of CS and deswelling using this statistical approach can provide evidence for the presence of people in the sample who might be clinically referred to as “high-” and “low-swellers”, and also whether the course of recovery (within the study 3-hour limit) in high-swellers is the same or different than low-swellers. We also simultaneously examined the influence of the independent variables of age, sex, and the refractive error (auto-refraction spherical equivalent) in addition to the lens related independent variable of Dk/t on corneal swelling and deswelling over the 3-hour period after eye opening and lens removal.

^{23}

^{17,24}26 subjects were required to detect an 0.8% ± 1.2% difference in central corneal swelling with a power of 0.90 at α = 0.05. In this study 37 neophytes were enrolled and 29 completed the study (14 female, 15 male). The mean age of the subjects was 27.1 ± 7.9 years (median: 25 years; range: 17–50 years). Eight subjects chose to discontinue their participation in the study for nonlens related, personal reasons (relocation, finding a new job, etc.) before completing all follow-up visits: There is no reason to suppose that these participants would have added anything different to the data set. Only the data from the subjects who completed all study visits were included for data analysis. Table 1 summarizes the refractive characteristics of the study subjects.

^{26}and its calibration was verified and maintained throughout the study period.

- Analysis of corneal swelling (%) over the range of Dk/t of study lenses controlling for subjects' age, and refractive error (autorefraction spherical equivalent) as covariates, sex as a fixed factor, and subject (intercept and/or slope) as a random factor(s). The intercept represents the level of CS with eye closure (with or without a lens) and the slope represents the rate of corneal swelling as a function of lens Dk/t.
- Analysis of corneal deswelling (%) during the 3-hour period after lens removal, controlling for oxygen transmissibility, subjects' age and refractive error as covariates, sex as a fixed factor, and subject (intercept and/or slope) as a random factor(s). The intercept represents the level of CS following eye closure (with or without a lens) and the slope represents the rate of corneal deswelling per hour.

*χ*

^{2}distribution (Accepting the null hypothesis,

*H*

_{0}, indicates that the added complexity does not improve the model fit; rejecting the null hypothesis indicates the converse). In addition, generally a parsimony criterion was used when model log likelihood ratios did not show a statistical difference; in these instances, the simplest model was accepted. The model fit was similarly evaluated for inclusion of 2- or 3-way interactions of the fixed effects. For the selected “best” models, the models were re-run to generate restricted −2log likelihood values with Hurvich and Tsai's (AICc) criterion (which accounts for bias in log likelihood estimations with small sample sizes) to optimize the estimate of the variance of the random effects for the fitted model.

^{27}The estimates from this model are those that are reported in the “Results” section.

*P*= 0.01 for both).

^{28–31}we suggest adding individual measures of corneal oxygen demand (corneal metabolic activity) and a measure of individual endothelial morphologic variability (endothelial function) in a future mixed model analysis to investigate other biologically plausible predictors of between-subject differences in corneal swelling.

^{2}) in the curvilinear model were close to zero, contributing to only 0.25% and 0.37% of the total between-subject variance in lens-wearing and control eyes, respectively (Table 9). This indicates that this random effect (between-subject variability in the rate of deswelling), in either lens wearing or control eyes, was largely linear. Therefore, the between-subject variability of corneal deswelling can similarly be described by the between-subject variances of the linear function in either linear or curvilinear models of corneal deswelling. This confirms sufficiency of the linear term for explaining the random effects in corneal deswelling, and that it could be considered as a parsimonious substitute for the more complex curvilinear model of corneal deswelling. The main advantage of using the more complex curvilinear model would be its improved intercept and slope estimates.

*P*= 0.008). Our finding of slower recovery from corneal swelling in older age is in line with findings from previous studies,

^{32,33}with statistically significantly slower recovery of corneal swelling in older compared to younger groups after 2 hours of closed eye CL wear. It is also worth noting that these previous studies

^{32,33}did not control for any no-lens wear. The slower corneal deswelling rate in older individuals might be attributed (among other things) to lower endothelial pump function in older individuals

^{32}by endothelial morphologic changes

^{34}with older age. An association between endothelial morphological changes and endothelial pump function (recovery from swelling) was found in both normal

^{32}and diseased

^{35,36}corneal endothelium in the past.

^{25}Furthermore, the average analysis is prone to measurement errors from Simpson's paradox

^{37–41}and that by averaging among the study clusters (in this context, high-swellers and low-swellers and their rate of deswelling), other relationships within the data may be masked or reversed. In addition, the mixed model analysis can concurrently investigate the impact of other factors or covariates that might explain why some individuals behave differently (such as the effect of age on corneal deswelling). This analysis enabling the combination of random and fixed effects provides novel insights into, and therefore examination of testable theories of how, subject variability contributes to the outcome in ways not possible using more “traditional” methods.

*IOVS*2016;57:ARVO E-Abstract 1491).

**A.M. Moezzi**, CORE (E), Advanced Vision Research (F), Alcon (F), Allergan (F), CIBA Vision (F), Contamac USA (F), CooperVision (F), Essilor (F), Inflamax Research (F), J&J Vision Care (F), Ocular Dynamics (F), Oculus (F), Safilens (F), TearLab (F), TearScience (F);

**N. Hutchings**, None;

**D. Fonn**, CooperVision, Inc. (C);

**T.L. Simpson**, None

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