Quality of Life in Keratoconus: Evaluation With Keratoconus Outcomes Specic Questionnaire (KORQ)

Purpose: To assess quality of life in keratoconus patients using the Keratoconus Outcomes Research Questionnaire (KORQ) translated and validated to Portuguese language. KORQ is the only validated keratoconus specic questionnaire and has high rating for psychometric properties. Methods: In this cross-sectional study enrolled 100 patients with keratoconus from a tertiary referral eye hospital, from April 2018 to June 2019. Associations between age, gender, allergic conjunctivitis, keratoconus stage, best-corrected visual acuity (BCVA), maximum simulated keratometry (Kmax), steep keratometry (K2), pachymetry, treatments performed, hydrops and KORQ scores were evaluated with univariate (Wilcoxon test and the Kruskal Wallis test) and multivariate linear regression with stepwise backward modeling. Lower scores of KORQ are associated with better quality of life, as well as higher scores are associated with greater impairment of functional activities and symptoms. Results: Out of the 100 patients, mild, moderate and severe keratoconus, was observed in 15%, 46% and 39% of participants, respectively. Univariate analysis showed lower values for function scores with male gender (p<0.05) and both functional and symptoms scores statistically associated with BCVA<0.3 (LogMAR) (p<0.05). Multivariate analysis indicated signicantly lower functional scores in individuals with BCVA<0.3 (p<0.001) and those with history of crosslinking treatment (p=0.022), while symptom scores were only statistically associated with BCVA<0.3 (p<0.001). Conclusions: In patients with keratoconus, BCVA in the better eye and history of crosslinkig are factors were associated with better quality of life scores using KORQ.


Introduction
Keratoconus it is a progressive corneal disease with typical onset in adolescence or early adulthood, although cases of severe keratoconus have been reported in children as young as 4 years of age. 1 It is a progressive asymmetric corneal disease characterized by steepening and distortion, apical thinning, and central scarring of the cornea. 2 After onset, keratoconus can progress steepening and increasing irregularity of corneal parameters, as worsening vision. 3 Treatment of keratoconus consists of spectacles, contact lenses, intrastromal corneal ring implants and corneal collagen crosslinking 4 , and when these treatment options are no longer effective for vision rehabilitation, lamellar or penetrating keratoplasty. 5 Increasing attention has been given to the assessment of health-related quality-of-life (QoL) outcome measures in clinical trials during the past 3 decades. Vision-related quality-of-life (VQRL) is a person's satisfaction with visual function and how visual ability affects life. 6 Keratoconus signi cantly impacts on VRQL with a substantial number of patients experiencing a decline in their VRQL over time. 6,7 Even the simplest rehabilitation methods such as spectacles or contact lenses t can affect QoL due to negative effects on cosmesis and/or inconvenience in handling. [8][9][10] Questionnaires have been increasingly implemented as a tool to assess the QoL related to a speci c disease, quantify symptoms, evaluate disease natural course and determine the impact of treatment strategies. Generic or ophthalmic patient-reported outcome (PRO) measures that are not speci c to keratoconus may not include essential items that capture unique, keratoconus-speci c QoL issues 3,11 , and studies that have investigated the QoL impact of keratoconus have used PRO instruments developed for other conditions, such as cataract or refractive error 12 , once there was no keratoconus-speci c PRO instrument. An accurate measurement of QoL requires high-quality PRO measures. Recent study evaluating QoL in keratoconus using existing questionnaires concluded that this aspect of the disease would be better evaluated by using quality of life questionnaire speci cally designed to keratoconus. 13 However, only recently a psychometrically robust and valid instrument to assess the impact of keratoconus on activity limitation and symptoms was created, called Keratoconus Outcomes Research Questionnaire (KORQ). 14 A recent study evaluated psychometric properties of the KORQ by using both classical test theory and Rasch analysis and concluded that KORQ is a psychometrically robust PRO measure to evaluate QoL parameters in individuals with keratoconus, it is appropriate for clinical use and research settings. 15 In addition, another study comparing the quality of life questionnaires already used for keratoconus concluded that KORQ was the only validated keratoconus speci c questionnaire and had the highest rating for psychometric properties among all the questionnaires. 16 Thus, KORQ is the recommended "gold standard" method for development and validation of a patient-reported outcome measure. 17 Important issues regarding to QoL and disease impact remain to be accessed: (1) there is no previous study evaluating QoL in keratoconus with the application of KORQ in a group of patients and (2) misuse of QoL questionnaires can lead to misleading results, adding confusion and causing the negative contribution to the understanding of the impact of keratoconus. Thus, the aim of the present study is to evaluate the QoL in keratoconus patients, using KORQ.

Methods
The KORQ comprises 2 scales tool, 18 items "Activity Limitation" scale (Table 1) and 11 items "Symptoms" scale ( Table 2). Each item has a 4-point rating scale with an additional "not applicable" option. The patient's score is obtained through a ready-to-use Microsoft excel scoring (available at http://links.lww.com/OPX/A287 and http://links.lww.com/OPX/A288) spreadsheets for the two scales of the KORQ. These spreadsheets can be used to convert respondents' raw scores into person measures in logits without having to run Rasch analysis when the study sample is similar to the original study. Each spreadsheet consists of three sheets labeled as ''rawdata,'' ''raschscore,'' and ''raw to Rasch conversion.'' Users are required to register respondents' responses to items in numerical label (i.e. 1 to 4) in the ''rawdata'' sheet, and the corresponding Rasch scores automatically appears in the ''raw to rasch conversion''. 14 Person measure data were rescaled from the original logit scale, with values from 0 to 100, to better understand its meaning. Lower scores are associated with better quality of life, as well as higher scores are associated with greater impairment of functional activities and symptoms. The inclusion criteria encompassed participants aged 18 years and older with a previous diagnosis of keratoconus or those who underwent penetrating keratoplasty for keratoconus. Participants with other ocular comorbidities, signi cant systemic disease, or inability to read Portuguese and understand the questionnaire were excluded. The KORQ was applied in its Portuguese version, after proper translation and validation process of the original questionnaire. 18   The psychometric properties of the KORQ were evaluated by WINSTEPS (version 3.92.1) in a Rasch model using in t and out t item statistics. According to our analysis, we found that items Q10 from the "Activity Limitation" scale and items Q2, Q4, Q5 and Q9 from the Symptoms scale were mis tted ( Table 4). After excluding items that were mis tted, we conducted a principal components analysis of the residuals (difference between the observed and expected responses) to investigate unidimensionality. Data were considered unidimensional if most of the variance is explained by the principal component and there is no signi cant explanation of the residual variance by the contrasts to the principal component. The raw variance explained by measures was 66.6% and 56.9% in the Activity Limitation and Symptoms scales, respectively. We found that the unexplained variance in 1st contrast was 2.17 and 2.27 eigenvalues in the Activity Limitation and Symptoms scales, respectively. Despite that, we found that the disattenuated person-measure correlation in the rst contrast was > 0.50, suggesting that clusters belonged to random noise whether than multidimensionality issue. The person separation index is the ratio of the variance in the person measures for the sample to the average error in estimating these measures. It is a measure of how broadly the persons could be distinguished into statistically distinct levels. The person separation reliability coe cient describes the reliability of the scale to discriminate between the persons of different abilities. A person separation index of ≥ 2.0 or a reliability value of ≥ 0.8 represents the minimum acceptable level of separation. 22 We found a person separation index of 3.84 and 2.46 in the Activity Limitation and Symptoms scales, respectively. We found a person reliability value of 0.94 and 0.86 for the Activity Limitation and Symptoms scales, respectively. This analysis provides information that the Portuguese translated version of the KORQ is unidimensional and a psychometrically valid tool to access QoL in patients with keratoconus. We used the nal score obtained from the activity limitation and symptom questionnaire after excluding mis tted items, according to our Rasch analysis.  CXL: corneal collagen cross-linking; RGP: rigid permeable gas; ICRS: intraestromal corneal rings; PKP: penetrating keratoplasty; K: keratometry; Data are mean ± standard deviation, unless otherwise indicated Table 6 shows the result of multiple linear regression for functional and symptoms scores. A statistically signi cant association between functional score, visual acuity and history of crosslinking was observed.
Individuals with BCVA < 0.3 LogMAR have an average score of 18.39 lower than those with BCVA ≥ 0.3 LogMAR and individuals with a history of crosslinking have an average score of 9.12 lower than those without a history. Regarding symptoms score, only visual acuity was associated with the nal score with individuals with BCVA < 0.3 LogMAR showing an average score 14.29 lower than those with BCVA ≥ 0.3 LogMAR. The results are represented by boxplot in Fig. 1. ---0.468 functional (r = 0.4934, p < 0.0001) and symptoms (r = 0.4457, p < 0.0001) scores. Figure 2 illustrates these results.

Discussion
Most of the existing questionnaires are rst generation questionnaires based on classical test theory, which uses summary scoring. This type of scoring is an over simplistic method once assumes that all items in a scale or a questionnaire have an equal weight, and the response options are located at equal distance from each other. It falsely assumes categorical ordinal data as interval-level data 17 . Modern psychometric methods such as Rasch analysis, on the other hand, can convert categorical data into interval-level data using logarithmic transformation. 23 Rasch analysis can use Andrich rating-scale and Partial-credit models to obtain the estimates of the required ability of each item, perceived ability of each subject, and the thresholds for each response category. 23 In this study we evaluated the psychometric properties of KORQ using an Andrich rating scale model, corroborating previous studies showing that KORQ is a psychometrically robust PRO measure to evaluate QoL parameters in individuals with keratoconus. 15,16 In this study, a validated version of the KORQ was applied in a large sample of keratoconus patients. The data presented herein represents the rst cohort of patients evaluated by the KORQ tool.
In this sample, there was less impact in activity limitation and symptoms in those patients with better vision (visual acuity < 0.3 LogMAR). We used the BCVA of the best-seeing eye based on previous studies that observed that ability to perform vision-related activities of daily living seems to be primarily a function of the vision in the best eye. 24 There are several potential implications of our study. This is the rst study that applied KORQ to a group of keratoconus patients. We have shown that better visual acuity is the main variable associated with quality of life scores, which is in agreement with ndings from other large case series, using distinct tools. 3,24,27 With this in mind, improving visual acuity should be a constant goal in the treatment of keratoconus, through any currently available option, according to disease stage and improvement rate.
Corneal CXL is a well-known procedure to stabilize keratoconus progression and we observed that CXL may have a signi cant impact on patient's quality of life. We also found few patients under medication for allergic conjunctivitis (31%), despite of higher number of related symptoms report (67%). Considering that continuous corneal micro trauma is an important and well-known risk factor for disease progression, it is mandatory that all patients receive education about allergy signs and symptoms to prompt recognize and treat acute episodes and to incorporate preventive measurements in daily life.
Our ndings show that BCVA in the better eye and history of crosslinkig were factors associated with higher quality of life scores using KORQ. Strategies to prevent keratoconus from reaching severe stages, and consequently worse visual acuity, must be warranted to maintain QoL. Rehabilitation strategies are needed to improve QoL in those already managing severe disease and should focus on reading and mobility issues.

Declarations
Data availability The data that support the ndings of this study are available from the corresponding author, RDPP, upon request.
Authors contributions: Roberto Damian Pacheco Pinto: Conceived and designed the analysis, collected the data, performed the analysis, wrote the paper Figures Figure 1 Above, Boxplots Functional Score according to Sex (p>0.05), BCVA (p<0.001) and Crosslinking (p=0.02).