Matthew D. Davis - US grants

The contractor participates as the Reading Center in a controlled clinical trial to evaluate early vitrectomy in diabetic retinopathy. The Reading Center is responsible for the development of grading systems for fundus and iris photographs, and conducts independent gradings of all photographs taken on study patients. Photographs are utilized to establish patient eligibility and evaluate treatment effects.

EVALUATE EARLY TREATMENT OF DIABETIC RETINOPATHY

eye fundus photography; eye disorder diagnosis; disease /disorder classification; retina degeneration; biomedical registry /referral center; epidemiology; stereophotography; aging; disease /disorder proneness /risk;

In addition to an almost uniformly fatal prognosis for its victims, AIDS often results in ocular complications frequently leading to blindness. We have planned a natural history observational cohort study of retinal microvascular changes (including cotton wool spots) in patients who are asymptomatic but HIV antibody positive, patients with advanced ARC, and patients with AIDS. We will test the hypothesis that the occurrence of cotton wool spots and other retinal microvascular changes are indicators of progression of HIV infection and indicators for development of cytomegalovirus (CMV) retinitis. We also have developed a proposal for a randomized prospective therapeutic trial of two drugs (ganciclovir vs foscarnet) in the treatment of CMV retinitis, the most common retinal infection in AIDS and the leading cause of blindness in patients with HIV infection. The Fundus Photograph Reading Center is developing a photographic protocol including a combination of the seven standard stereoscopic 30 degrees fields to document the posterior pole and adjacent retina, as described by the Diabetic Retinopathy Study, and an adaptation of the matrix of wide-angle views (preferable 60 degrees fields) to document the majority of the post-equatorial fundus, as described by the Silicone Study. Photographs will be evaluated at the Reading Center for the Presence and severity of noninfectious AIDS retinopathy (including cotton wool spots, hemorrhages, and micoraneurysms) and infectious retinopathy, particularly CMV retinitis. We have planned development of a standardized grading protocol that entails comparison of the photographs being graded with selected standard photographs in order to quantitate lesions, and also utilizes direct measurement of some lesions and their change from baseline.

Visual impairment ranks among our leading health problems and will increase in importance as our population ages. Research at both basic and clinical levels is essential in attacking this growing problem. Because research is expensive and funds are limited, efficient use of these resources is essential. Biostatistical methods can assure that experiments are designed efficiently and analyzed properly. Without such direction, dollars, patient resources, and professional effort can easily be wasted. The University of Wisconsin (UW) Department of Ophthalmology has active clinical vision research programs of three types: (1) collaborative clinical trials (study leadership, reading center, and clinical center activities), (2) large epidemiologic surveys, (3) smaller individual investigator projects. In the first two areas, adequate biostatistical support has been available as an integral part of each study, but frequently this has not been the case for projects in the third category. Moreover, without a full- time Ph.D. statistician to coordinate the effort, it has not been possible to bring existing staff expertise to bear in the development of coordinating center capability for multicenter clinical trials or epidemiologic studies in ophthalmology. This proposal seeks funding to establish a Biostatistics Program under the general guidance of Dr. Matthew Davis and statistical leadership of Dr. David DeMets. The biostatistical staff of the Program will advise and consult with Department faculty engaged in individual clinical research projects regarding experimental design, data management, analysis of resultant data, and review of relevant literature. The Program would also provide a mechanism by which coordinating center capability will be developed, utilizing the skills of the full-time Ph.D. level biostatistician to be hired and those of staff members of the UW Biostatistics Center and the Department of Ophthalmology. The coordinating center will compete for participation in National Eye Institute multicenter studies. In order to develop this Program, funding for partial support for a Ph.D. biostatistician is needed, as well as some support for Dr. DeMets and his staff.

reading; vitrectomy; uveitis; reading disorder;

To estimate the rates of development and progression, and to identify the associated risk factors, for age-related macular degeneration (AMD) and cataract.

DESCRIPTION (Investigator's Abstract) "Considerable information is available concerning the natural course of diabetic retinopathy as it progresses from the early nonproliferative to the advanced proliferative stage, and a useful overall scale of retinopathy severity has been developed. Macular edema, a common feature of diabetic retinopathy and a common cause of visual loss, is not a part of the retinopathy severity scale, and its clinical features and natural course have not been well documented. Existing data from the NEI-sponsored Early Treatment Diabetic Retinopathy Study (ETDRS) and Diabetic Retinopathy Study (DRS), in which large numbers of patients with varying degrees of macular edema and varying retinopathy severity were followed for several years (initially with one eye randomly assigned to deferral of photo- coagulation), provide a unique opportunity to document the natural course of diabetic macular edema and to develop a classification. Specifically, goals of this project are: (1) to develop a classification of macular edema based upon fundus photographic and fluorescein angiographic characteristics; (2) to develop a scale that characterizes its overall severity; (3) to document its natural course; and (4) to determine risk factors (demographic, systemic, and ocular) for change in visual acuity and morphologic characteristics. In addition to careful examination of relationships using cross-tabulations and Spearman correlation coefficients, multivariate analyses (including logistic regression) will be used to establish the predictive value of selected baseline variables for the outcomes of interest. Since observations are correlated over time, the mixed effects model described by Laird and Ware, implemented with the efficient computational methods of Lindstrom and Bates, will be utilized. Results of these analyses will be translated into a clinically oriented classification and severity scale useful both to researchers evaluating treatments and to ophthalmologists managing patients."

reading; vitrectomy; uveitis; reading disorder;

DESCRIPTION (provided by applicant): The University of Wisconsin Fundus Photograph Reading Center (UW FPRC) proposes to serve as photograph reading center for the DME Clinical Research Network. To accomplish this, we propose to: (I) Collaborate with other network investigators to develop ideas for clinical trials of promising new DME treatments, construct study protocols, carry out approved studies, analyze the resultant data, and prepare manuscripts. (2) Adapt or develop procedures for documenting and grading DME. We can provide protocols for DME imaging (color stereoscopic fundus photographs, fluorescein angiograms, and optical coherence tomograms), and are experienced at orienting, certifying, and giving feedback to clinic photographers. By extending the Early Treatment Diabetic Retinopathy Study classification, we have protocols for evaluation/grading of DME from color photographs and angiograms. We are developing a protocol for assessment of OCT scans. We are prepared to modify these protocols further, if necessary, to define the eligibility and outcome criteria appropriate to network goals. The UW FPRC principal investigator and staff are experienced at participation in collaborative multi-center clinical trials (e.g., Diabetic Retinopathy Study, Early Treatment of Diabetic Retinopathy Study, Diabetes Control and Complications Trial, and several drug trials) and in networks to conduct them (e.g., the Study of the Ocular Complications of AIDS), and are strongly committed to the study of DME and its potential treatments as a major public health priority.

[unreadable] DESCRIPTION (provided by applicant): Cytomegalovirus (CMV) retinitis and other ocular opportunistic infections (OIs) are a major cause of visual loss and morbidity among patients with AIDS. Although the epidemiology of CMV retinitis has been altered by highly active antiretroviral therapy (HAART), CMV retinitis remains among the most common OIs in patients with AIDS. Furthermore, there appear to be subtle abnormalities of vision (detected on contrast sensitivity and visual field testing) among patients with AIDS without ocular OIs, the long-term consequences of which are unknown. The Longitudinal Study of Ocular Complications of AIDS (LSOCA) is a multicenter, prospective, observational study of patients with AIDS. As of June 1,2002, 1,337 patients with a diagnosis of AIDS have been enrolled, of whom 348 (26%) had a major ocular complication (94% of which were CMV retinitis). Projected enrollment by August 2003 is 1,700 patients. The objectives of this study are: 1) to determine the characteristics (clinical, virologic, and immunologic) of and risk factors for CMV retinitis and other ocular complications of AIDS in the era of HAART; 2) to monitor trends in the incidence and prevalence of CMV retinitis and other ocular complications of AIDS; and 3) to evaluate the outcomes of CMV retinitis and other ocular complications of AIDS and determine risk factors for [unreadable] adverse outcomes. Over the next five years an additional 500 patients will be enrolled in the study, to replace those lost to mortality and withdrawal, thereby maintaining a stable population of patients under follow up. Participants will continue in follow-up for the duration of the study. All patients will be on a 3-month follow-up schedule. For patients with a major ocular complication, all follow-up visits will be clinic visits. For patients without a major complication, follow-up visits will alternate between clinic follow-up visits and telephone follow-up visits. Data will be collected from medical history, visual function testing, eye examinations, fundus photographs, quality of life assessment, laboratory studies, and collection of plasma and blood cells for banking. Banked specimens also will be analyzed for CMV DNA levels. Outcomes of interest include incidence of CMV retinitis, incidences of other ocular complications, visual outcomes, and mortality. Other outcomes of interest include sequelae of AIDS-related eye disease (e.g., retinal detachment), quality of life, and the effect of therapies on ocular disease. With an estimated 11,250 person-years of follow-up by 2008, LSOCA will be adequately powered to detect clinically meaningful relative risks even for uncommon events. [unreadable] [unreadable] This application is for the Fundus Photograph Reading Center. [unreadable] [unreadable]

DESCRIPTION (provided by applicant): The University of Wisconsin Fundus Photograph Reading Center (UW FPRC) proposes to serve as photograph reading center for the DME Clinical Research Network. To accomplish this, we propose to: (I) Collaborate with other network investigators to develop ideas for clinical trials of promising new DME treatments, construct study protocols, carry out approved studies, analyze the resultant data, and prepare manuscripts. (2) Adapt or develop procedures for documenting and grading DME. We can provide protocols for DME imaging (color stereoscopic fundus photographs, fluorescein angiograms, and optical coherence tomograms), and are experienced at orienting, certifying, and giving feedback to clinic photographers. By extending the Early Treatment Diabetic Retinopathy Study classification, we have protocols for evaluation/grading of DME from color photographs and angiograms. We are developing a protocol for assessment of OCT scans. We are prepared to modify these protocols further, if necessary, to define the eligibility and outcome criteria appropriate to network goals. The UW FPRC principal investigator and staff are experienced at participation in collaborative multi-center clinical trials (e.g., Diabetic Retinopathy Study, Early Treatment of Diabetic Retinopathy Study, Diabetes Control and Complications Trial, and several drug trials) and in networks to conduct them (e.g., the Study of the Ocular Complications of AIDS), and are strongly committed to the study of DME and its potential treatments as a major public health priority.