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2.  Expert Prior Elicitation and Bayesian Analysis of the Mycotic Ulcer Treatment Trial I 
Purpose.
To perform a Bayesian analysis of the Mycotic Ulcer Treatment Trial I (MUTT I) using expert opinion as a prior belief.
Methods.
MUTT I was a randomized clinical trial comparing topical natamycin or voriconazole for treating filamentous fungal keratitis. A questionnaire elicited expert opinion on the best treatment of fungal keratitis before MUTT I results were available. A Bayesian analysis was performed using the questionnaire data as a prior belief and the MUTT I primary outcome (3-month visual acuity) by frequentist analysis as a likelihood.
Results.
Corneal experts had a 41.1% prior belief that natamycin improved 3-month visual acuity compared with voriconazole. The Bayesian analysis found a 98.4% belief for natamycin treatment compared with voriconazole treatment for filamentous cases as a group (mean improvement 1.1 Snellen lines, 95% credible interval 0.1–2.1). The Bayesian analysis estimated a smaller treatment effect than the MUTT I frequentist analysis result of 1.8-line improvement with natamycin versus voriconazole (95% confidence interval 0.5–3.0, P = 0.006). For Fusarium cases, the posterior demonstrated a 99.7% belief for natamycin treatment, whereas non-Fusarium cases had a 57.3% belief.
Conclusions.
The Bayesian analysis suggests that natamycin is superior to voriconazole when filamentous cases are analyzed as a group. Subgroup analysis of Fusarium cases found improvement with natamycin compared with voriconazole, whereas there was almost no difference between treatments for non-Fusarium cases. These results were consistent with, though smaller in effect size than, the MUTT I primary outcome by frequentist analysis. The accordance between analyses further validates the trial results. (ClinicalTrials.gov number, NCT00996736.)
We elicited the opinions of corneal specialists on treating filamentous fungal keratitis, to perform a Bayesian analysis of the Mycotic Ulcer Treatment Trial I. The Bayesian analysis result was consistent with, but suggested a smaller treatment effect than, the frequentist result.
doi:10.1167/iovs.13-11716
PMCID: PMC3684218  PMID: 23702779
fungal keratitis; corneal ulceration; clinical trial; Bayesian; statistics
5.  Comparison of Natamycin and Voriconazole for the Treatment of Fungal Keratitis 
Archives of ophthalmology  2010;128(6):672-678.
Objective
To conduct a therapeutic exploratory clinical trial comparing clinical outcomes of treatment with topical natamycin vs topical voriconazole for fungal keratitis.
Methods
The multicenter, double-masked, clinical trial included 120 patients with fungal keratitis at Aravind Eye Hospital in India who were randomized to receive either topical natamycin or topical voriconazole and either had repeated scraping of the epithelium or not.
Main Outcome Measures
The primary outcome was best spectacle-corrected visual acuity (BSCVA) at 3 months. Other outcomes included scar size, perforations, and a sub-analysis of BSCVA at 3 months in patients with an enrollment visual acuity of 20/40 to 20/400.
Results
Compared with those who received natamycin, voriconazole-treated patients had an approximately 1-line improvement in BSCVA at 3 months after adjusting for scraping in a multivariate regression model but the difference was not statistically significant (P=.29). Scar size at 3 months was slightly greater with voriconazole after adjusting for scraping (P=.48). Corneal perforations in the voriconazole group (10 of 60 patients) were not significantly different than in the natamycin-treated group (9 of 60 patients) (P>.99). Scraping was associated with worse BSCVA at 3 months after adjusting for drug (P=.06). Patients with baseline BSCVA of 20/40 to 20/400 showed a trend toward a 2-line improvement in visual acuity with voriconazole (P=.07).
Conclusions
Overall, there were no significant differences in visual acuity, scar size, and perforations between voriconazole- and natamycin-treated patients. There was a trend toward scraping being associated with worse outcomes.
Application to Clinical Practice
The benefit seen with voriconazole in the subgroup of patients with baseline visual acuity of 20/40 to 20/400 needs to be validated in a confirmatory clinical trial.
Trial Registration
clinicaltrials.gov Identifier: NCT00557362
doi:10.1001/archophthalmol.2010.102
PMCID: PMC3774126  PMID: 20547942
6.  The Mycotic Ulcer Treatment Trial 
JAMA ophthalmology  2013;131(4):422-429.
Objective
To compare topical natamycin vs voriconazole in the treatment of filamentous fungal keratitis.
Methods
This phase 3, double-masked, multicenter trial was designed to randomize 368 patients to voriconazole (1%) or natamycin (5%), applied topically every hour while awake until reepithelialization, then 4 times daily for at least 3 weeks. Eligibility included smear-positive filamentous fungal ulcer and visual acuity of 20/40 to 20/400.
Main Outcome Measures
The primary outcome was best spectacle-corrected visual acuity at 3 months; secondary outcomes included corneal perforation and/or therapeutic penetrating keratoplasty.
Results
A total of 940 patients were screened and 323 were enrolled. Causative organisms included Fusarium (128 patients [40%]), Aspergillus (54 patients [17%]), and other filamentous fungi (141 patients [43%]). Natamycin-treated cases had significantly better 3-month best spectacle-corrected visual acuity than voriconazole-treated cases (regression coefficient=−0.18 logMAR; 95% CI, −0.30 to −0.05; P=.006). Natamycin-treated cases were less likely to have perforation or require therapeutic penetrating keratoplasty (odds ratio=0.42; 95% CI, 0.22 to 0.80; P=.009). Fusarium cases fared better with natamycin than with voriconazole (regression coefficient=−0.41 logMAR; 95% CI, −0.61 to −0.20; P<.001; odds ratio for perforation=0.06; 95% CI, 0.01 to 0.28; P<.001), while non-Fusarium cases fared similarly (regression coefficient=−0.02 logMAR; 95% CI, −0.17 to 0.13; P=.81; odds ratio for perforation=1.08; 95% CI, 0.48 to 2.43; P=.86).
Conclusions
Natamycin treatment was associated with significantly better clinical and microbiological outcomes than voriconazole treatment for smear-positive filamentous fungal keratitis, with much of the difference attributable to improved results in Fusarium cases.
Application to Clinical Practice
Voriconazole should not be used as monotherapy in filamentous keratitis.
Trial Registration
clinicaltrials.gov Identifier: NCT00996736
PMCID: PMC3769211  PMID: 23710492
8.  Organism, MIC, and Outcome in a Fungal Corneal Ulcer Clinical Trial 
Cornea  2012;31(6):662-667.
Purpose
To analyze the minimum inhibitory concentration (MIC) of isolates from fungal keratitis to natamycin and voriconazole, and to assess the relationship between organism, MIC, and clinical outcome.
Methods
Data were collected as part of a randomized, controlled, double-masked clinical trial. Main outcome measures included best spectacle-corrected visual acuity (BSCVA), infiltrate/scar size, time to re-epithelialization, and perforation. Speciation and analysis of MIC to natamycin and voriconazole was done according to NCCLS standards. The relationship between MIC and organism, organism and outcome measure, and each outcome measure and MIC was assessed.
Results
Of 120 samples obtained in the trial, 84 isolates had an identifiable organism and were available for further analyses. Fusarium spp and Aspergillus spp were the most commonly-isolated organisms. MIC was significantly different across the groups of organisms (P=0.0001). A higher MIC was significantly associated with an increased likelihood of perforation (OR 2.03, 95%CI 1.02 to 4.04, P=0.04). There was no significant association between MIC and 3-week visual acuity (0.058, 95%CI -0.01 to 0.13, P=0.11), 3-month visual acuity (0.01, 95%CI -0.08 to 1.04, P=0.79), 3-week infiltrate/scar size (0.12, 95% CI -0.02 to 0.27, P=0.10), 3-month infiltrate/scar size (0.12, 95%CI -0.02 to 0.25, P=0.09), or time to re-epithelialization (HR 1.19, 95%CI 0.98 to 1.45, P=0.08).
Conclusion
A higher MIC was associated with an increased odds of perforation. The results of this study suggest that resistance to antifungal medication may be associated with worse outcomes in fungal keratitis.
doi:10.1097/ICO.0b013e31823f8ae0
PMCID: PMC3695737  PMID: 22333662
fungus; keratitis; susceptibility; voriconazole; natamycin
9.  Prevalence of Early and Late Age-Related Macular Degeneration in India: The INDEYE Study 
This large, two-center, population-based study provides estimates of the prevalence of age-related macular degeneration in India.
Purpose.
To estimate the prevalence of early and late age-related macular degeneration (AMD) in India.
Methods.
Of 7518 people aged 60 years and older identified from randomly sampled villages in North and South India, 5853 (78%) attended an eye examination including fundus photography. Fundus images were graded according to the Wisconsin Age-Related Maculopathy Grading System.
Results.
Fundus images were ungradable in 1587 people, mainly because of cataract. People 80 years of age and older were less likely to attend the eye examination and more likely to have ungradable images. For ages 60 to 79 years, the percent prevalence (95% confidence interval [CI]) were late AMD 1.2 (0.8–1.5); and early AMD: grade 1 (soft distinct drusen or pigmentary irregularities), 39.3 (37.2–41.5); grade 2 (soft distinct drusen with pigmentary irregularities or soft indistinct or reticular drusen), 6.7 (5.8–7.6); and grade 3 (soft indistinct or reticular drusen with pigmentary irregularities), 0.2 (0.1–0.4). For ages 80 and older, the respective percent prevalence was: late AMD, 2.5 (0.4–4.7); and early AMD: grade 1, 43.1(35.7–50.6); grade 2, 8.1 (4.3–12.0); and grade 3, 0.5 (0–1.5).
Conclusions.
The prevalence of early AMD (grades 1 and 2) is similar to that observed in Western populations, but grade 3 appears to be lower. The prevalence of late AMD is comparable to that in Western populations in the age group 60 to 79 years. It is likely that the prevalence in the 80 and older age group is underestimated.
doi:10.1167/iovs.09-4114
PMCID: PMC2868454  PMID: 19696177

Results 1-9 (9)