Ann-Margret Ervin

Evidence gaps and ethical review of multicenter studies

Empirical research is needed to guide federal policy Large, multicenter clinical studies are the backbone of evidence-based prevention and health care. Ethical review of multicenter research is usually conducted by the institutional review board (IRB) of each participating institution. However, variation in interpretation of regulations by IRBs is common and can have ethical and scientific implications (1, 2). Recent mandates in the United States aim to reduce the administrative burden and to expedite multicenter research by conducting ethical review with a single, central IRB of record (CIRB). Yet the quality of ethical review must not suffer. We characterize current models of ethical review in the United States and identify research gaps that must be addressed before such policies are instituted.

Visual Acuity Change Over 24 Months and its Association With Foveal Phenotype and Genotype in Individuals With Stargardt Disease: ProgStar Study Report No. 10

Importance Limited data from prospective studies are available to understand the natural history of ABCA4-related Stargardt disease (STGD1). Such data are important for determining appropriate outcome measures for future STGD1 trials. Objective To estimate the rate of loss of best-corrected visual acuity (BCVA) during 2 years and to estimate the associations of BCVA loss with foveal phenotype and genotype in patients with STGD1. Design, Setting, and Participants This multicenter prospective cohort study included 259 participants (489 study eyes) with molecularly confirmed STGD1 who were 6 years or older. The participants were enrolled at 9 centers in the United States and Europe and were followed up every 6 months for 2 years. Exposures Baseline BCVA and presence and type of foveal lesion (determined via fundus autofluorescence images) and genotype (classified into 4 groups based on the number and pathogenicity of ABCA4 mutations). Main Outcomes and Measures Rate of BCVA change per year. Results The mean (SD) age was 33 (15) years. Of 259 the participants, 141 (54%) were female, and 222 (85%) were white. The overall rate of BCVA loss was 0.55 (95% CI, 0.20-0.90) letters per year during the 2 years. Eyes with baseline BCVA worse than 20/200 showed an improvement of 0.65 (95% CI, 0.1-1.2) letters per year. At baseline, the mean BCVA for eyes without foveal lesion was 20/32, and their BCVA change rate over time was 0.1 (95% CI, −1.2 to 1.35) letters per year (P = .89). Eyes with a foveal lesion but having BCVA of 20/70 or better at baseline lost BCVA at a rate of 3 (95% CI, 1.5-4.4) letters per year (P < .001). Genotype was neither associated with baseline BCVA nor with the rate of BCVA change during the follow-up. Conclusions and Relevance A clinically small BCVA loss was observed during 2 years, and the change rate varied depending on baseline BCVA. Eyes without lesion in the fovea had better BCVA at baseline and showed minimal change of BCVA throughout 2 years. Eyes with no or modest acuity impairment but with a foveal lesion at baseline had the fastest loss rate. For trials of STGD1 with 2 years of duration, it may be difficult to show efficacy using BCVA as an end point owing to its slow rate of change over this time.

RESEARCH ETHICS. Evidence gaps and ethical review of multicenter studies.

Empirical research is needed to guide federal policy Large, multicenter clinical studies are the backbone of evidence-based prevention and health care. Ethical review of multicenter research is usually conducted by the institutional review board (IRB) of each participating institution. However, variation in interpretation of regulations by IRBs is common and can have ethical and scientific implications (1, 2). Recent mandates in the United States aim to reduce the administrative burden and to expedite multicenter research by conducting ethical review with a single, central IRB of record (CIRB). Yet the quality of ethical review must not suffer. We characterize current models of ethical review in the United States and identify research gaps that must be addressed before such policies are instituted.

Scotopic Microperimetric Assessment of Rod Function in Stargardt Disease (SMART) Study: Design and Baseline Characteristics (Report No. 1)

Purpose: To describe the study design and characteristics at first visit of participants in the longitudinal Scotopic Microperimetric Assessment of Rod Function in Stargardt Disease (SMART) study. Methods: Scotopic microperimetry (sMP) was performed in one designated study eye in a subset of participants with molecularly proven ABCA4-associated Stargardt disease (STGD1) enrolled in a multicenter natural history study (ProgStar). Study visits were every 6 months over a period ranging from 6 to 24 months, and also included fundus autofluorescence (FAF). Results: SMART enrolled 118 participants (118 eyes). At the first visit of SMART, the mean sensitivity in mesopic microperimetry was 11.48 (±5.05; range 0.00–19.88) dB and in sMP 11.25 (±5.26; 0–19.25) dB. For FAF, all eyes had a lesion of decreased autofluorescence (mean lesion size 3.62 [±3.48; 0.10–21.46] mm2), and a total of 76 eyes (65.5%) had a lesion of definitely decreased autofluorescence with a mean lesion size of 3.46 (±3.60; 0.21–21.46) mm2. Conclusions: Rod function is impaired in STGD1 and can be assessed by sMP. Testing rod function may serve as a potential outcome measure for future clinical treatment trials. This is evaluated in the SMART study.

The Progression of the Stargardt Disease Type 4 (ProgStar-4) Study: Design and Baseline Characteristics (ProgStar-4 Report No. 1)

Background/Aims: To describe the design and baseline characteristics of patients enrolled in the multicenter, prospective natural history study of Stargardt disease type 4. Methods: Fifteen eligible patients aged 6 years and older at baseline, harboring disease-causing variants in the PROM1 gene, and with specified ocular lesions were enrolled. They were examined at baseline using a standard protocol, with 6 monthly follow-up visits for a 2-year period including best-corrected ETDRS visual acuity, spectral-domain optical coherence tomography, fundus autofluorescence (FAF), mesopic and scotopic microperimetry (MP). Areas of definitely decreased FAF (DDAF) and questionably decreased FAF were outlined and quantified on FAF images. Results: Amongst the 15 patients (29 eyes) that were enrolled at 5 centers in the USA and Europe, 10 eyes (34.5%) had areas of DDAF with an average lesion area of 3.2 ± 3.5 mm2 (range 0.36–10.39 mm2) at baseline. The mean retinal sensitivity of the posterior pole derived from mesopic MP was 8.8 ± 5.8 dB. Conclusions: Data on disease progression in PROM1-related retinopathy from this study will contribute to the characterization of the natural history of disease and the exploration of the utility of several modalities to track progression and therefore to potentially be used in future interventional clinical trials.

Punctal occlusion for dry eye syndrome: summary of a Cochrane systematic review

Dry eye disease is a disorder of the tear film associated with ocular signs and symptoms. Punctal occlusion aids the preservation of natural tears. We conducted a Cochrane systematic review to assess the effectiveness of punctal plugs for managing dry eye. Randomised and quasi-randomised trials were included. The primary outcome was symptomatic improvement (SI) at 2–12 months. Nine databases were searched with no date or language restrictions. Two authors assessed trial quality and extracted data. Summary risk ratios and mean differences were calculated. Ten trials were included. In two trials of punctal plugs versus observation, there was less dryness with punctal plugs. The mean difference (MD) in the dry eye symptom score at 2 months was −28.20 points (95% CI –33.61 to −22.79, range 0 to 105, one trial). Three trials compared punctal plugs with artificial tears. In a pooled analysis of two trials, punctal plug participants reported more SI at 3 months than artificial tear participants (MD −4.20 points, 95%  CI −5.87 to −2.53, scales varied from 0 to 6). In the remaining five trials comparing punctal plug placement, acrylic and silicone plugs, or comparing plugs with cyclosporine or pilocarpine, none of the investigators reported a clinically or statistically meaningful difference in symptomatic improvement at 2–12 months. The effectiveness of punctal plugs for treating dry eye symptoms and common signs are inconclusive. Heterogeneity in the type of punctal plug, type and severity of dry eye being treated, and trial methodology confounds the ability to make decisive statements regarding the effectiveness of punctal plugs.

Detailed genetic characteristics of an international large cohort of patients with Stargardt disease: ProgStar study report 8

Background/aims To describe the genetic characteristics of the cohort enrolled in the international multicentre progression of Stargardt disease 1 (STGD1) studies (ProgStar) and to determine geographic differences based on the allele frequency. Methods 345 participants with a clinical diagnosis of STGD1 and harbouring at least one disease-causing ABCA4 variant were enrolled from 9 centres in the USA and Europe. All variants were reviewed and in silico analysis was performed including allele frequency in public databases and pathogenicity predictions. Participants with multiple likely pathogenic variants were classified into four national subgroups (USA, UK, France, Germany), with subsequent comparison analysis of the allele frequency for each prevalent allele. Results 211 likely pathogenic variants were identified in the total cohort, including missense (63%), splice site alteration (18%), stop (9%) and others. 50 variants were novel. Exclusively missense variants were detected in 139 (50%) of 279 patients with multiple pathogenic variants. The three most prevalent variants of these patients with multiple pathogenic variants were p.G1961E (15%), p.G863A (7%) and c.5461-10 T>C (5%). Subgroup analysis revealed a statistically significant difference between the four recruiting nations in the allele frequency of nine variants. Conclusions There is a large spectrum of ABCA4 sequence variants, including 50 novel variants, in a well-characterised cohort thereby further adding to the unique allelic heterogeneity in STGD1. Approximately half of the cohort harbours missense variants only, indicating a relatively mild phenotype of the ProgStar cohort. There are significant differences in allele frequencies between nations, although the three most prevalent variants are shared as frequent variants.

Visual Disability in the Elderly: Implications for Visual Rehabilitation

When visual system disorders result in bilateral visual impairments, patients have difficulty performing their customary activities and experience a diminished quality of life (West et al. 2002). Visual impairments increase patients’ risk of falling (Ivers et al. 1998), injury (Salive et al. 1994), poor general health (Crews and Campbell 2001), depression (Casten et al. 2004), and even death (Pedula et al. 2006). Activity-limiting chronic visual impairments, collectively called “low vision,” most often are caused by age-related visual system disorders, with age-related macular degeneration, glaucoma, diabetic retinopathy, and cataract leading the list (Congdon et al. 2004). Some visual system disorders, such as diabetic retinopathy, are manifestations of more general disorders that frequently produce co-disabilities. But most low vision patients are elderly, so comorbidities and co-disabilities from diseases unrelated to their visual system disorders are common (Ahmadian and Massof 2008). Thus, for a large portion of the low vision population, activity limitations from visual impairments are superimposed on and worsen activity limitations from comorbidities (Langelaan et al. 2009).