Early Treatment Diabetic Retinopathy Study Charts

The ETDRS charts are based on a design by Bailey and Lovie, and are commonly used in clinical research.^66,71–74 ETDRS charts present a series of five letters of equal difficulty on each row with standardized spacing between letters and rows, for a total of 14 lines (70 letters). ETDRS letters score can be calculated when 20 or more letters are read correctly at 4.0 metres; the visual acuity letter score is equal to the total number of letters read correctly at 4.0 metres plus 30. If less than 20 letters are read correctly at 4.0 metres, the visual acuity letter score is equal to the total number of letters read correctly at 4.0 metres (number of letters recorded on line 1.0), plus the total number of letters read correctly at 1.0 metre in the first six lines. Therefore, the ETDRS letter score could result in a maximum score of 100.^75,76

Charts are used in a standard light box with a background illumination of approximately 150 cd/m². Standard chart testing distance is four metres; however, shorter distances may be used when vision is severely impaired.^66,77 ETDRS results can be converted to Snellen fractions, another common measure of visual acuity, in which the numerator indicates the distance at which the chart was read, and the denominator the distance at which a person may discern letters of a particular size. A larger denominator indicates worsening vision. For example a person with 20/100 vision can read letters at 20 feet that a person with 20/20 vision could read at 100 feet.^66,78 ETDRS letters range from 58.18 mm to 2.92 mm in height corresponding to Snellen visual acuity fractions of 20/200 to 20/10 respectively. Further, letter size increases geometrically and equivalently in every line by a factor of 1.2589 (or 0.1 log unit) moving up the chart. Scoring for ETDRS charts is designed to produce a logarithmic score (logMAR) suitable for statistical analysis in which individual letters score 0.02 log units.

ETDRS charts may reliably identify changes in visual acuity of two lines (10 letters) or more, but not changes of one line (five letters) or less.⁵⁴ The reliability of ETDRS charts depends on the baseline visual acuity. For eyes with acuity better than 20/100, a change in visual acuity of five or more letters has a greater than 90% probability of being a real change, while for eyes worse than 20/100, a change of 10 or more letters is required for the same reliability.⁵⁵ A loss or gain of three lines (15 letters) is considered a moderate degree of change and is commonly used as a outcome in clinical trials.⁷⁹ For macular edema, the FDA recommends a mean change of 15 letters or more on an ETDRS chart, or a statistically significant difference in the proportion of patients with greater than or equal to 15-letter change in visual acuity, as clinically relevant outcome measures in trials of interventions.⁵²

With regards to the relationship between visual acuity measurement and visual function, a loss of three or more lines (greater than or equal to 15 letters) on an ETDRS chart corresponds to a doubling of the visual angle and is considered moderate visual loss, while a loss of six or more lines (greater than or equal to 30 letters) corresponds to a quadrupling of the visual angle and is considered severe. However, visual acuity is only one component contributing to overall visual function and the ability to perform everyday visual tasks (e.g., reading, recognizing faces, driving, and using the telephone). Overall visual function also depends upon variables such as contrast sensitivity, near vision, colour vision, and sensitivity to glare.⁸⁰ The various components of visual function will affect the performance of different vision-related tasks by varying degrees. For example, the use of distance acuity to measure the success of treatments for age-related macular degeneration is not optimal given that distance vision is usually two ETDRS lines better than reading vision,⁷⁹ and difficulties with reading is a common complaint among persons with eye disease.⁶⁸ Rather, contrast sensitivity is a more important contributor to reading performance.^79,81

Optical Coherence Tomography

Optical coherence tomography (OCT) is a fast, non-invasive technique used to create cross sectional maps of the retinal structures and to quantify retinal thickness in patients with macular edema.⁴³ OCT uses lasers centred on infrared wavelengths to record light reflected from interfaces between materials with different refractive indices, and from materials that scatter light. OCT3 machines are able to differentiate three reflecting layers thought to be the vitreous/retina, inner/outer photoreceptor segments and the retinal pigment epithelium/choriocapillaris interfaces. Ultra-high resolution machines can differentiate a fourth layer. During the OCT scan, a series of intersecting, radial cross sections of the retina are measured. Resolution depends on the software as well as the hardware used and is better around the central axis than lateral areas.^43,82 A recent advancement in OCT device technology has been the shift from time domain (TD-OCT) to spectral domain OCT (SD-OCT), as the latter can acquire data at a higher speed with better image resolution and reduced motion artifact.⁸³

In a previous meta-analysis analyzing the discriminatory power of foveal thickness for the diagnosis of DME, the sensitivity, specificity, positive likelihood ratio and negative likelihood ration of OCT were 0.81, 0.85, 5.4 and 0.22, respectively.⁸⁴ Intra-device repeatability and inter-device reproducibility of measurements depend on a number of factors including retinal pathology, retinal region, region size, OCT model, equipment settings, manual or automated analysis, and operator experience.⁴³ In eyes with DME, a comparison of measurements with four different OCT devices found good intra-device repeatability, but statistically significant differences in retinal thickness values across different devices.⁸⁵ Another study which compared the reproducibility of retinal thickness measurements from OCT images of eyes with DME obtained by TD-OCT and SD-OCT instruments found that SD-OCT devices demonstrated less test-retest variability.⁸³ Inter-device differences in retinal thickness were also reported in this study, though they were expected due to the different algorithms used by SD-OCT and TD-OCT machines that define the anatomical structures serving as the boundaries for measurement. Additionally, the presence of macular edema can influence OCT measurement precision. In one study, the 95% limits of agreement (the scale of which an instrument can detect changes in a patient) for average foveal thickness in healthy eyes was 8 µm, while in patients with DME it was 36 µm.⁸⁶

In patients with DME, the association between OCT measured retinal thickness and BCVA has been evaluated. A moderate correlation between visual acuity and OCT center-point thickness has been observed (r = 0.52).⁵⁶ For every 100 µm decrease in center-point thickness, visual acuity increased by 4.4 letters (95% CI, 3.5 to 5.3).⁵⁶ Other studies have shown similarly modest correlations between visual acuity and CRT determined by OCT.^57,58 In eyes with DME treated by laser photocoagulation, changes in center-point thickness were associated with changes in visual acuity, with correlation coefficients of 0.44, 0.30 and 0.43 at 3.5, 8, and 12 months respectively.⁵⁶ Retinal thickness, measured using OCT, may be a useful clinical tool to monitor macular edema and retinal changes in DME but is modestly correlated with changes in vision and cannot be used as a substitute for visual acuity or other patient reported outcomes.

National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25)

The NEI-VFQ was developed as a means to measure vision-targeted quality of life. The original 51-item questionnaire was developed based on focus groups comprised of persons with a number of common eye conditions (e.g., age-related cataracts, age-related macular degeneration, and diabetic retinopathy), and thus may be used to assess quality of life in a broad range of eye conditions.⁶⁸ The original 51-item questionnaire is comprised of 12 subscales related to general vision, ocular pain, near vision, distance vision, social functioning, mental health, role functioning, dependency, driving, peripheral vision, colour vision, and expectations for future vision. In addition, the questionnaire includes one general health subscale.⁸⁷

A shorter version of the original instrument, the NEI-VFQ-25, was subsequently developed, which retained the multidimensional nature of the original, and is more practical and efficient to administer.⁶⁹ With the exception of the expectations for future vision, all the constructs listed above were retained in the shortened version, with a reduced number of items within each subscale. Thus, the NEI-VFQ-25 includes 25 items relevant to 11 vision-related constructs, in addition to a single-item general health component. Responses for each item are converted to a 0 to 100 scale, with 0 representing the worst, and 100 the best visual functioning. Items within each construct, or subscale, are averaged to create 12 subscale scores, and averaging of the subscale scores produces the overall composite score. Different scoring approaches for the NEI-VFQ-25 have been proposed.⁷⁰ Rasch modelling is used to obtain measurements from categorical data. When comparing standard scoring to Rasch analysis and an algorithm to approximate Rasch scores, all methods were highly correlated.⁷⁰ However, standard scoring is subject to floor and ceiling effects whereby the ability of the least visually able is overestimated and the ability of the most visually able is underestimated.⁷⁰

Determination of what constitutes a clinically meaningful change in the NEI-VFQ-25 appears to be linked to its correlation with visual acuity. A three-line (15 letters) change in visual acuity has been used as the outcome of interest in clinical trials, and corresponding changes in the NEI-VFQ-25 are suggested as clinically meaningful end points. For patients with neovascular age-related macular degeneration (AMD) and specifically for the study eye, which is typically the worse seeing eye, a 15-letter change in visual acuity corresponds to a four-point change in overall NEI-VFQ-25 score.⁸⁸ For the better-seeing eye, the clinically relevant difference for NEI-VFQ-25 scores based on a three-line change is seven to eight for overall score. Other studies in patients with subfoveal choroidal neovascularization have shown similar estimated clinically relevant differences.⁸⁹ The instrument showed weaker correlation or was not responsive to changes in the visual acuity of the worse eye in patients with AMD.^90,91 This may have implications when evaluating patients with unilateral disease. A psychometric validation study of the NEI-VFQ-25 specifically in patients with DME has more recently been conducted, and two distribution-based methods were employed to determine a minimal clinically important difference (MCID) from baseline to week 54.²⁰ Using a ½ standard deviation-based approach, the MCID for each NEI-VFQ-25 domain ranged from 8.80 (general vision) to 14.40 (role difficulties) and produced a composite score MCID of 6.13 points. The MCID for the near vision and distance vision subscales were 10.24 and 11.07, respectively. A standard error of measurement (SEM) approach yielded similar MCID estimates from 8.79 (driving) to 14.04 (role difficulties), with a composite score MCID estimate of 3.33 points. This technique lowered the MCID estimates for the near and distance vision domains, which were reported as 9.17 and 10.19, respectively.

Both versions of the NEI-VFQ were reported to be valid and reliable measures of health-related quality of life among patients with a wide range of eye conditions, including DME^20,69,87,90 and all but two subscale scores (general health, and ocular pain) have been shown to be responsive to changes in visual acuity in the better-seeing eye.^90,91 However, some assessments of the psychometric validity of the NEI-VFQ-25 using Rasch scoring and principal component analysis in patients with various eye conditions have identified issues with multidimensionality (measurement of more than one construct) and poor performance of the subscales.^59,60,91 The NEI-VFQ-25 subscales were found to have too few items and were unable to discriminate among the population under measurement, and thus were not valid.^59,60 Re-engineering the NEI-VFQ-25 into two constructs (visual functioning and socio-emotional factors) and removing misfit items (e.g., pain around eyes, general health and driving in difficult conditions) improved the psychometric validity of the scale in individuals with low vision.^59,60 Considering the evidence of multidimensionality, the validity of the single composite score of the NEI-VFQ-25 may be questioned.

Limitations of internal consistency due to the presence of single-item domains were also noted in a validation study specific for DME population.²⁰ The near vision and distance vision subscales are 3-item domains on the NEI-VFQ-25; their internal reliability as represented by Cronbach’s alpha was reported as 0.73 and 0.58, respectively. Convergent validity analysis to examine the relationship between NEI-VFQ-25 scores and other disease-related variables provided mixed results, and the NEI-VFQ-25 domains collectively showed low to moderate correlations with ETDRS visual acuity score for both the study and untreated eyes. The Pearson correlation with ETDRS total letters in the study eye was reported as 0.35 for the near vision subscale and 0.34 for the distance vision subscale. A slightly stronger correlation was observed between the NEI-VFQ-25 and the EQ-5D Visual Analogue Scale (VAS), and the EQ-5D VAS along with ETDRS was a significant predictor of near and distance vision subscale scores, suggesting that general health-related quality of life was captured by the NEI-VFQ-25 more so than strictly vision-related information. However, in support of known group validity, patients who saw more ETDRS letters also scored higher on the NEI-VFQ-25 near and distance subscales as well as on the NEI-VFQ-25 composite. Overall, the authors concluded that despite its documented limitations and the need for an improved instrument, the NEI-VFQ-25 demonstrated a degree of validity to measure health-related quality of life in patients with DME.²⁰