Test-Retest Reliability of the Impact of Vision Impairment-Very Low Vision Questionnaire.

Purpose: Most patient-reported outcome measures used in ophthalmology show floor effects in a very low vision population, which limits their use in vision restoration trials. The Impact of Vision Impairment-Very Low Vision scale (IVI-VLV) was developed to specifically target a very low vision population, but its test-retest reliability has not been investigated yet. Methods: The German version of the IVI-VLV was administered twice to patients with stable disease of a low vision clinic. Test and retest person measures of the IVI-VLV subscales were obtained from Rasch analysis. Test-retest reliability was investigated by intraclass correlation coefficients and Bland-Altman plots. Results: We included 134 patients (72 women, 62 men) at a mean age of 62 ± 15 years. The intraclass correlation coefficients were 0.920 (95% confidence interval, 0.888-0.944) for the activities of daily living and mobility subscale of the IVI-VLV and 0.929 (95% confidence interval, 0.899-0.949) for the emotional well-being subscale. Bland-Altman plots did not indicate any systematic bias. In linear regression analysis, test-retest differences were not significantly associated with visual acuity or administration interval. Conclusions: Both subscales of the IVI-VLV showed excellent repeatability independent of visual acuity and length of repeat interval. Further validation steps including an assessment of the patient-reported outcome measure's responsiveness are required for use in vision restoration trials. Translational Relevance: The results support repeated use of the IVI-VLV as a patient-reported end point in future studies in very low and ultralow vision populations.

Disease-specific assessment of Vision Impairment in Low Luminance in age-related macular degeneration - a MACUSTAR study report.

BACKGROUND/AIMS: To further validate the Vision Impairment in Low Luminance (VILL) questionnaire, which captures visual functioning and vision-related quality of life (VRQoL) under low luminance, low-contrast conditions relevant to age-related macular degeneration (AMD). METHODS: The VILL was translated from German into English (UK), Danish, Dutch, French, Italian and Portuguese. Rasch analysis was used to assess psychometric characteristics of 716 participants (65% female, mean age 72±7 years, 82% intermediate AMD) from the baseline visit of the MACUSTAR study. In a subset of participants (n=301), test-retest reliability (intraclass correlation coefficient (ICC) and coefficient of repeatability (CoR)) and construct validity were assessed. RESULTS: Four items were removed from the VILL with 37 items due to misfit. The resulting Vision Impairment in Low Luminance with 33 items (VILL-33) has three subscales with no disordered thresholds and no misfitting items. No differential item functioning and no multidimensionality were observed. Person reliability and person separation index were 0.91 and 3.27 for the Vision Impairment in Low Luminance Reading Subscale (VILL-R), 0.87 and 2.58 for the Vision Impairment in Low Luminance Mobility Subscale (VILL-M), and 0.78 and 1.90 for the Vision Impairment in Low Luminance Emotional Subscale (VILL-E). ICC and CoR were 0.92 and 1.9 for VILL-R, 0.93 and 1.8 for VILL-M and 0.82 and 5.0 for VILL-E. Reported VRQoL decreased with advanced AMD stage (p<0.0001) and was lower in the intermediate AMD group than in the no AMD group (p≤0.0053). CONCLUSION: The VILL is a psychometrically sound patient-reported outcome instrument, and the results further support its reliability and validity across all AMD stages. We recommend the shortened version of the questionnaire with three subscales (VILL-33) for future use. TRIAL REGISTRATION NUMBER: NCT03349801.

Instrumental Activities of Daily Living Tools in Very-Low Vision: Ready for Use in Trials?

Traditional endpoints assessing visual function are limited by their responsiveness to interventions restoring or maintaining vision. An alternative concept is assessing instrumental activities of daily living (IADL). Herein, we review all available vision-specific IADL instruments relevant for vision restoration trials and report data for the most promising instrument. Six relevant instruments exist: The Low Vision Functional Status Evaluation (LVFSE), Timed IADL (TIADL), Melbourne Low-Vision Activities of Daily Living Index (MLVAI), Assessment of Disability Related to Vision (ADREV), Functional Low-Vision Observer Rated Assessment (FLORA), and Very Low Vision IADL (IADL-VLV). Both internal consistency and test-retest data were available for the LVFSE, MLVAI, and IADL-VLV. In a sample from a low-vision clinic (n = 51; age 57 ± 16 years), we report additional validation data on the IVI-VLV including test-retest reliability (intraclass correlation coefficient 0.981 [0.961; 0.991]). The LVSFE was noticeably less reliable than the MLVAI and the IADL-VLV. Content and construct validity data were available for the LVFSE, TIADL, MLVAI, ADREV, and IADL-VLV, but only the MLVAI and IADL-VLV were developed for an ultra-low vision context. Ceiling effects were present across instruments. Thus, of all appropriate IADL instruments related to vision, the IADL-VLV and MLVAI best meet existing requirements for use in vision restoration trials, e.g., in gene therapies or visual prostheses in inherited retinal diseases, but require further validation.

Improved sensitivity of microperimetric outcomes for clinical studies in age-related macular degeneration.

To investigate sensitive outcome measures based exclusively on abnormal points in microperimetry testing of eyes with intermediate age-related macular degeneration (iAMD). 25 eyes of 25 subjects with iAMD had undergone 2 successive tests of mesopic microperimetry with the Macular Integrity Assessment Microperimeter (MAIA), using a custom grid of 33 points spanning the central 14 degrees of the macula. Each point was defined as abnormal if its threshold sensitivity was lower than 1.65 standard deviations (SD) (5%) or 2 SD (2.5%) than the expected threshold in healthy eyes according to the MAIA internal database. Among the 25 eyes there were 11.8 ± 9 and 8.4 ± 8.2 abnormal points at < 5% and < 2.5%, with mean deviation of thresholds from normal - 4.9 ± 1.2 dB and - 5.8 ± 1.5 dB, respectively. These deviations were greater, and their SD smaller, compared with the complete microperimetry grid, - 2.3 ± 2.0 dB. The 95% limits of agreement for average threshold between the 2 successive tests were smaller when only abnormal points were included. Analyzing only abnormal grid points yields an outcome parameter with a greater deviation from normal, a more homogenous dataset, and better test-retest variability, compared with analysis of all grid points. This parameter may thus be more sensitive to change, while moderately limiting the number of potential recruits. The proposed outcome measures should be further investigated as potential endpoints in clinical trials in iAMD.

Development of the Vision Impairment in Low Luminance Questionnaire.

Purpose: The purpose of this study was to design and evaluate an instrument for assessing vision-related quality of life appropriate for the specific visual impairment characteristic for all stages of age-related macular degeneration (AMD), with a focus on the low luminance deficit in early/intermediate stages. Methods: A standardized questionnaire was developed in three steps with participants with early, intermediate, and late AMD: (1) based on in-depth interviews (n = 19) and two focus group discussions (n = 5 each), content was developed followed by 2. (2) The questionnaire development using cognitive debriefing interviews (n = 3) and leading to a preliminary version of the questionnaire. (3) This version was then administered to 127 participants with early, intermediate, and late AMD. Psychometric properties, such as response category functioning (floor and ceiling effects) and targeting of item difficulty to patient ability of the pilot Vision Impairment in Low Luminance (VILL) questionnaire were evaluated using Rasch analysis. Results: The preliminary VILL questionnaire consisted of 68 items with a 5-step response scale. Several items were removed based on floor/ceiling effects or misfit and a final pool of 37 items remained. The response scale was collapsed to four categories as one category was underutilized. The targeting of the instrument was good with minimal difference in person and item means (0.52 logits). Precision was also good with a person separation index of 3.55 and reliability of 0.93. There was evidence of multidimensionality (eigenvalue of the first contrast = 5.95) in the scale, which could be resolved by splitting the items into subscales including a reading, mobility, and emotional well-being subscale. Conclusions: Individuals with AMD report difficulties with vision-related activities and functioning under visually challenging conditions at all stages of the disease. These aspects were considered when developing the 37-item VILL, which demonstrates promising psychometric characteristics. Further assessments of reliability and validity are warranted. Translational Relevance: The VILL questionnaire is a new patient-reported outcome (PRO) measure developed for future use in AMD studies.

Association of Visual Function Measures with Drusen Volume in Early Stages of Age-Related Macular Degeneration.

Purpose: To assess which visual function measures are most strongly associated with overall retinal drusen volume in age-related macular degeneration (AMD). Methods: A total of 100 eyes (16 eyes with early AMD, 62 eyes with intermediate AMD, and 22 eyes from healthy controls) were recruited in this cross-sectional study. All subjects underwent several functional assessments: best-corrected visual acuity (BCVA), low-luminance visual acuity (LLVA), visual acuity (VA) measured with the Moorfields Acuity Chart (MAC-VA), contrast sensitivity with the Pelli-Robson test, reading speed using the International Reading Speed texts, and mesopic and dark-adapted microperimetry. Drusen volume was automatically determined based on optical coherence tomography using an approach based on convolutional neural networks. The relationship between drusen volume and visual function was assessed with linear regressions controlling for confounders. Results: Mean drusen volume and MAC-VA differed significantly among all AMD stages and controls (P < 0.001). In univariate linear regression, LLVA, MAC-VA, contrast sensitivity, and mesopic and dark-adapted microperimetry were significantly negatively associated with the overall drusen volume (all P < 0.006). After controlling for AMD stage, age, and the presence of subretinal drusenoid deposits, MAC-VA and mesopic and dark-adapted microperimetry were still significantly associated with drusen volume (P = 0.008, P = 0.023, and P = 0.022, respectively). Conclusions: Our results suggest that MAC-VA, as well as mesopic and dark-adapted microperimetry, might indicate structural changes related to drusen volume in early stages of AMD.

Detecting vision loss in intermediate age-related macular degeneration: A comparison of visual function tests.

The purpose of the study was to evaluate the diagnostic accuracy of visual function tests in intermediate age-related macular degeneration (iAMD). A total of 62 subjects (38 patients with iAMD and 24 controls) were included and underwent several functional assessments: Best-corrected visual acuity (BCVA), low luminance visual acuity (LLVA), visual acuity (VA) measured with the Moorfields Vanishing Optotypes Acuity Charts (MAC), contrast sensitivity with the Pelli-Robson test, reading speed using the International Reading Speed texts (IReST) and mesopic and dark-adapted microperimetry (S-MAIA, CenterVue, Padova, Italy). Groups were compared using non-parametric Wilcoxon rank sum tests and ROC analyses. Linear regression was used to control for confounding. Results showed that all visual function test performances except the IReST were significantly reduced in iAMD patients compared to controls (p < 0.05). These effects did not alter after controlling for age and sex. Best discrimination between iAMD and controls yield the combination of LLVA and contrast sensitivity as well as MAC-VA and contrast sensitivity (ROC area under the curve 0.95 and 0.93, respectively). Our results suggest that LLVA, MAC-VA, contrast sensitivity and mesopic and dark-adapted microperimetry can capture visual impairment characteristic for iAMD. Best discrimination against iAMD is achieved with a combination of two tests.

Risk estimation for air travel-induced malaria transmission in central Europe - A mathematical modelling study.

BACKGROUND: Aim of our study was to identify conditions under which malaria transmission caused by imported infectious mosquitoes or travellers could occur at large central European airports, and if such transmission could be sustained by indigenous mosquitoes. METHODS: We developed a deterministic and a stochastic compartmental Susceptible-Exposed-Infectious-Recovered-Susceptible (humans)/Susceptible-Exposed-Infectious (mosquitoes) model with two mosquito (imported Anopheles gambiae, indigenous A. plumbeus) and three human (travellers, airport personnel exposed/not exposed to imported A. gambiae) populations. We assessed various scenarios to identify combinations of model parameters leading to ongoing malaria transmission at the airport. RESULTS: The number of infected airport personnel was low (five infected employees/six months) under assumptions reflecting possible future climatic conditions, current passenger mobility and no desinsection of airports/aircraft. Almost all infections among airport personnel were directly due to bites by imported A. gambiae. Indigenous mosquitoes would need to have comparable transmission parameters to A. gambiae to sustain disease transmission. Incoming infectious passengers play only a minor role in malaria transmission. Use of aircraft/airport desinsection led to no transmission events in the model. CONCLUSION: Our study shows that sustainable air travel-induced malaria transmission in central Europe is unlikely under current conditions or conditions which might become realistic in the next century.

Association of Vision-related Quality of Life with Visual Function in Age-Related Macular Degeneration.

The purpose of this study was to assess which visual function measures are most strongly associated with vision-related quality of life (VRQoL) in age-related macular degeneration (AMD). A cross-sectional study of subjects with early AMD (n = 10), intermediate AMD (n = 42) and late AMD (n = 38) was conducted. Subjects were interviewed with the Impact of Vision Impairment (IVI) questionnaire. Functional tests performed included best-corrected visual acuity (BCVA), low luminance visual acuity (LLVA), visual acuity measured with the Moorfields Acuity Charts (MAC), contrast sensitivity, reading speed, mesopic and dark-adapted microperimetry. The relationship between VRQoL and visual function was assessed with multiple regressions controlling for confounders. Rasch analysis demonstrated the validity of the IVI to assess VRQoL through three subscales: reading and accessing information, mobility and independence, and emotional well-being. Subjects with late AMD had significant lower IVI scores on all subscales compared with intermediate and early AMD (p < 0.011). In the overall cohort, IVI subscales were associated with BCVA, LLVA, MAC-VA and contrast sensitivity (all p < 0.001). Among the subgroup of early and intermediate AMD subjects, reading and mobility subscales were significantly associated with MAC-VA (p < 0.013). These results suggest that MAC-VA is a useful, patient-relevant measure of visual impairment in AMD.