Report of the Ocular Epidemiology Strategic Planning Panel

Epidemiological Research: From Populations through Interventions to Translation

September 2007


Overview

The National Eye Institute (NEI) is committed to the goal of protecting and improving visual health. To be accomplished successfully, this goal will require a multi-disciplinary approach that encompasses basic, clinical, and public health sciences. The multi-disciplinary approach is embedded in the current National Plan for Eye and Vision Research (2004), wherein this Panel noted that the disease-specific program plans include epidemiological investigations as priorities. Such an approach is an important integration of epidemiology, which is a methodological science, into eye and vision research. For the purposes of this report, the term epidemiology will be used in the broad context, which includes classic observational studies, clinical trials (particularly randomized clinical trials), statistical genetics, and health services research.

Use of classic epidemiologic techniques in diverse groups of people has advanced our understanding of infectious, environmental, behavioral, and sociocultural factors that underlie disease incidence, progression, and outcome, and has produced the evidence for effective prevention and treatment strategies. Although the tools of epidemiology were developed to investigate the causes and cures for epidemics of infectious disease, modern epidemiology has applied these successfully to investigations of chronic diseases, which now represent the majority of burden of illness in the United States and in most developed countries. In the best sense of a multi-disciplinary approach, epidemiology is one component in the continuum of bench to person to population studies necessary to fully understand the pathogenesis of disease, the impact in populations, and the results of interventions. Ideally, rather than a linear continuum, this is a creative feedback loop in which the results from epidemiological investigations return to laboratory scientists who produce new insights at the genetic, molecular or cellular levels that can be tested in human population studies in conjunction with other exposures. At the other end, epidemiological findings are also at the interface with health services and social science researchers who provide insights into improved strategies for public health interventions. Indeed, a firm understanding of the behavior of disease in human populations is fundamental to the development and delivery of effective interventions. Ophthalmic epidemiology then is part of the core strategy of the NEI for improving visual health, with the broad aim of reducing the burden of visual impairment in populations through research into the causes, diagnosis, prevention, treatment, and rehabilitation of the major blinding diseases.

More recently, epidemiology has been undergoing an evolution, paralleling the remarkable technological advances in molecular medicine, the realization of the powerful ecological forces that affect populations, and the rapid development of interventional tools on the horizon. The ability to apply genetic and molecular biological tools in the context of populations, in connection with behavioral, environmental, and social factors, has broadened considerably the potential contribution of epidemiology to the goal of controlling the major blinding diseases. Such opportunities are an exciting component of the classic armamentarium of observational and clinical trial methodologies in epidemiology. The Panel has been charged with considering these unique opportunities while forging recommendations for future strategic research questions.

The purpose of the Panel’s report is to present the broad program goals for ophthalmic epidemiology, to highlight the progress in this field in the last fifteen years, and to recommend research strategies and questions for the next five years.

Program Goals

The broad program goals for ophthalmic epidemiology must support the overall mission of protecting and improving visual health. After careful review of the progress made by epidemiological research, and the opportunities for further contributions, the Panel has developed the following goals, which are not listed in priority order:

  • Determine the burden of eye diseases and their visual outcomes in a changing population, particularly disparities in the burden and the influences of sociocultural and demographic factors.
  • Determine the genetic, biological, behavioral, and environmental factors that cause ocular disease, and the processes leading to visual impairment resulting from these diseases.
  • Improve early diagnosis of ocular diseases and their underlying processes through new screening and detection strategies.
  • Develop and test new interventions that prevent or treat ocular diseases and resulting disability, and identify predictors of response to treatment.
  • Identify and assess the strategies that will overcome barriers to eye care and convert evidence-based findings into improved patient and population outcomes.
  • Develop new methodologies to support ophthalmic epidemiological research.

Highlights of Progress

The contributions from epidemiological research in the past fifteen years since its last evaluation in an NEI strategic plan have advanced our understanding of the magnitude and impact in populations of the burden of blindness and visual impairment and the individual ocular diseases. Epidemiology has contributed significantly to our knowledge of risk factors for the major blinding diseases, and has tested treatment and preventive interventions. Finally, epidemiological research has identified and evaluated health care delivery processes related to the ocular diseases and their consequences. The panel chose to highlight progress within the goals described above, reflecting the major blinding diseases and interventions. A more detailed report of research progress can be found in Appendix A.

Studies of burden and causes of visual loss, disparities in the burden, sociodemographic factors.

  • Epidemiological research has provided estimates of the magnitude and causes of visual loss in the US and world-wide, and determined differences between population sub-groups, such as higher rates of different cataract sub-types in African Americans compared to Caucasians, and in women compared to men. African Americans and Latinos have higher prevalence of glaucoma compared to Caucasians, and Asians have more angle closure glaucoma. Although Caucasians and African Americans have similar rates of early age-related macular degeneration (AMD), Caucasians have higher rates of late AMD. Rates of diabetic retinopathy are high in Latinos. The remarkable rise in rates of myopia, especially among Asians, has been documented and many population studies have shown generational shifts. Research on these differences provides important clues to pathogenic mechanisms that explain such disparities.
  • Within the AIDS epidemic, clinical trials have determined the best treatment methods for cytomegalovirus (CMV) retinitis.
  • Considerable progress has been made into outcomes of visual loss, including decrements in quality of life, increases in measures of disability, and negative impact on function such as driving, falls, and performance on every day tasks. Such outcomes are key to determining the societal burden of visual loss, and appropriate rehabilitative strategies.

Studies of causes of major blinding diseases and processes leading to visual impairment.

  • Epidemiological research has identified modifiable environmental risk factors for major blinding eye diseases. These include smoking for cataract and AMD, ultraviolet B exposure for cataract, and nutritional factors for AMD. Near work has been associated with myopia.
  • In addition to aging, research has identified physiological risk factors for diseases, such as intraocular pressure and central corneal thickness for glaucoma, glycemic control and risk of diabetic retinopathy, and markers of inflammation for AMD.
  • Family history and high heritability have been shown as factors for AMD, glaucoma, myopia, and cataract. Progress has been made in elucidating the genes associated with eye diseases, for example, complement factor H (CFH) for AMD. Also, the interactions of genes and environment are being identified, such as smoking and variations in HTRA1/LOC387715.
  • Use of Polymerase Chain Reaction (PCR) has advanced understanding of infectious disease, and has been used to demonstrate re-emergence patterns of Chlamydia trachomatis following mass antibiotic treatment, and to explore the pathogenesis of resistant CMV.
  • Case control studies of contact lens associated corneal infections were key to identifying patient and product associated risk factors in these epidemics.

Screening.

  • For detecting amblyopia, autorefractor methods had a higher sensitivity than visual acuity screening methods using HOTV letter or Lea symbols, and photoscreener methods and stereoacuity screening tended to perform less well than visual acuity screening.
  • The development and reliability testing of digital imaging systems for diabetic retinopathy have shown them to be useful systems that are changing screening programs for this disease.
  • Intraocular pressure measurement is not sufficiently sensitive for detecting glaucoma so that its use in screening programs is not recommended.

Interventions.

  • Clinical trials on vascular endothelial growth factor (VEGF) inhibition and nutrients for AMD represent major advances in treatment for AMD. Recent trials have shown an improvement in visual acuity with use of novel drugs targeting VEGF inhibition.
  • Trials demonstrating the efficacy of laser treatment for diabetic retinopathy and macular edema were a major advance in preserving vision.
  • Either atropine or part-time patching are effective treatments for amblyopia. The finding that up to a quarter of older children responded to patching or spectacle treatment suggests that plasticity of the visual system extends through the teenage years.
  • A large, simple randomized trial has found that a single dose of azithromycin following surgery for trichiasis reduced recurrence by 30 percent compared to topical tetracycline.
  • Clinical trials have validated the value of lowering the intraocular pressure in the management of glaucoma, and treating persons with ocular hypertension.
  • Clinical trials of treatments for CMV retinitis in patients with AIDS have set the standards for treatments of this condition.
  • Trials of posterior chamber intraocular lenses (IOL) have demonstrated superior visual outcomes compared to anterior chamber IOL or aphakia.
  • Trials on treatment of ocular melanoma have shown no difference in survival (mortality) outcomes and little difference in quality-of-life outcomes between enucleation and eye-conserving radiotherapy using I-125 brachytherapy. In the trial of pre-enucleation radiation, there was no survival advantage to radiotherapy.
  • The Optic Neuritis Treatment Trial resulted in a standardized treatment approach to optic neuritis, an evaluation for those with optic neuritis, and description of the risk factors for the development of multiple sclerosis.

Translational Research to Eye Health Services.

  • The creation of simple tools for estimating cataract surgical coverage and documenting cataract surgery outcomes are helping set targets and reduce the global burden of cataract.
  • Economic analyses of the cost benefit of screening and treating diabetic retinopathy has shown the overall cost savings to be accrued by society in saving sight from diabetic eye disease.
  • An innovative plan using cost benefit analyses for comprehensive eye care services in Australia, rooted in evidence based practices and public health approaches, has the potential for showing economic value to society.
  • A greater understanding of patient and health system barriers to use of care, using qualitative and quantitative techniques.

Overarching Methodologies.

  • The development of Generalized Estimating Equations, which allowed the use of both eyes (and other correlated data) in analyses while appropriately adjusting confidence limits, permitted more powerful analyses of epidemiological data.
  • Expanded use of Rasch analyses and other psychometric testing improved the development and proper use of questionnaires.
  • Development of statistical tools for investigating genotype and phenotype relationships and interactions has been essential for genetic inquiries.

Research Objectives

The Panel has reviewed the progress of research in Ophthalmic Epidemiology, and considered the needs and unique opportunities that are present now and in the future. Some of these have already been identified in the program plans created by the other NEI programs, and for completeness these are listed in Appendix B. Several key elements of the next phase were identified that cut across the specific research objectives: (1) Research in populations will broaden its scope from descriptive studies to those that are more hypothesis driven. This will require innovative uses of populations to address questions; (2) Epidemiologists will foster interdisciplinary collaboration with other specialties as appropriate (e.g. visual psychophysics, cognitive neuroscience, behavioral science, health outcomes, economics, genetics, statistics, etc ) to move to the next levels of investigation; (3) The development of biomarkers for early identification of disease, and careful characterization of phenotypes, will become a focus to promote treatment and prevention studies. Research groups will need to agree on descriptors (i.e., measurements) for comparisons of phenotypes across studies; (4) When appropriate, clinical trials must become a broader platform in which to conduct studies on pathogenesis of disease and progression.

The panel has identified several specific research strategies and questions that take advantage of the current needs and unique opportunities to advance the program goals. Each one is listed under the program goal and objective that will be advanced by its undertaking.

  1. Determine the burden of eye diseases and their visual outcomes in a changing population, particularly disparities in the burden and the influences of sociocultural and demographic factors.
  2. A. Exploit unique opportunities to address research questions of sociocultural reasons for disparities in eye disease or access to eye care.

    Research Needs and Opportunities:
    Researchers should exploit unique opportunities to address research questions of sociocultural reasons for disparities in eye disease or access to eye care. Sociocultural factors and behavioral factors are likely to influence progression of disease to its visually disabling consequences. These have been poorly characterized, and may explain some of the disparities in vision loss from diabetic retinopathy, cataract, refractive error, and glaucoma. This opportunity is a cross-cutting one, in which the research questions would overlap with program goal five.

    Research Strategies and Questions:

  • Determine sociocultural factors associated with disparities in diabetic retinopathy, AMD, cataract, glaucoma, and access to care for these conditions.
  • Determine the sociocultural and behavioral factors, in addition to other risk factors, that influence progression of disease to vision loss.

B. Conduct basic epidemiological characterization of disease-phenotypic descriptions, progression and outcomes, and risk factors.

Research Needs and Opportunities:
Basic epidemiological characterization of disease-phenotypic descriptions, progression and outcomes, and risk factors-are indicated where there is a public health problem and such data are absent and needed to move research in these diseases forward. The panel identified strabismus, ocular complications in AIDS cohorts in the era of HAART, and uveitis as diseases that merit such basic investigations.

Research Strategies and Questions:

  • Better define phenotype of different types of uveitis or strabismus.
  • Develop standardized reproducible and clinically relevant outcome measures for reporting outcomes and to be used in future clinical trials.
  • Determine the rate and risk factors for ocular complications in AIDS patient cohort.

C. Create a framework for evaluating the long-term outcomes of interventions, particularly surgical interventions.

Research Needs and Opportunities: There is an urgent need to create a framework for evaluating the long-term outcomes of interventions, particularly surgical interventions. The panel identified a critical need with regard to refractive surgery. The largest natural experiment in ophthalmology is underway, the creation of a large cohort of young persons undergoing refractive surgery for correction of refractive error, with no data on long-term consequences in later adult life.

Research Strategies and Questions:

  • Partner with other organizations (public and private) and create a longitudinal cohort of refractive surgery patients with uniform baseline information and long-term follow-up to ascertain the sequelae of this procedure.
  • Determine the genetic, biological, behavioral, and environmental factors that cause ocular disease, and the processes leading to visual impairment resulting from these diseases.
  • A. Assess genetic and environmental risk factors and the interacting roles of both, in risk of disease onset and progression.

    Research Needs and Opportunities:
    Accurate assessment of genetic and environmental risk factors and the interacting roles of both, in risk of disease onset and progression will be crucial for a fuller determination of etiology. This research will need unique cohorts or populations that are cost efficient for the disease under study. Clinical trials or high-risk populations will provide useful platforms for these studies. This need is cross-cutting with goal one, to determine, using gene and environmental factors, the reasons for racial and ethnic diversity.

    Research Strategies and Questions: Possible research questions include:

    • Develop phenotype-genotype characterizations of AMD, diabetic retinopathy, glaucoma, refractive error, cataract, uveitis, and amblyopia.
    • Determine the genetic variations that interact with environmental risk factors that alter onset and progression of diabetic retinopathy, cataract, refractive error and amblyopia, AMD, uveitis, and glaucoma.

    B. Characterize physiological risk factors, as well as the genetic and environmental risk factors, to understand onset and progression of relevant diseases.

    Research Needs and Opportunities:
    Better characterization of physiological risk factors, as well as the genetic and environmental risk factors, is needed to understand onset and progression of relevant diseases.

    Research Strategies and Questions:

    • Identify structural and functional measures for determining early progression of glaucomatous damage.
    • Determine the role of vascular factors, e.g., blood pressure or perfusion pressure, in glaucoma.
    • Elucidate the ocular structures and visual correlates of abnormal eye growth and development in myopia.
    • Determine the physiological content of tears and other systemic ocular factors that influence dry eye.

    C. Exploit unique opportunities to obtain ocular samples in the context of therapeutic trials to address seminal questions of pathogenesis and determinants of treatment efficacy.

    Research Needs and Opportunities:
    There are unique opportunities in the context of therapeutic trials to obtain ocular samples including aqueous or vitreous to address seminal questions of pathogenesis and determinants of treatment efficacy (e.g., the opportunity to develop proteomic-genomic biomarkers for predicting early disease onset of AMD, provide risk assessment for progression of disease, and improved molecular imaging of the macula and the retina vasculature). Currently there is a significant opportunity to develop a bank of vitreous samples for patients taken at the time they are undergoing standard of care intraocular injection of anti VEGF therapy. Other examples can include opportunities during trials of any surgical intervention in which aqueous or vitreous can be easily obtained, such as during cataract surgery or surgical interventions for uveitis.

    Research Strategies and Questions:
    Collect vitreous samples during trials of intraocular injections for AMD before the first treatment instillation, and at each subsequent serial standard of care injection to characterize biomarkers for risk of progression.

  • Improve early diagnosis of ocular diseases and their underlying processes through new screening and detection strategies.
  • A. Develop and test novel imaging techniques or new biomarkers for disease onset or progression.

    Research Needs and Opportunities:
    In the context of clinical trials or disease cohorts, there is an opportunity to develop and test novel imaging techniques or new biomarkers for disease onset or progression. These are acutely needed for potential trials on prevention of disease onset. The panel recognized these opportunities especially for AMD, diabetic retinopathy, and cataract.

    Research Strategies and Questions:

    • Develop and test novel imaging techniques, biomarkers, and surrogate outcomes that correlate with disease development or progression.

    B. Develop better detection and screening strategies for glaucoma.

    Research Needs and Opportunities:
    The panel recognized a special need to develop better detection and screening strategies for glaucoma where the lifetime rate of blindness or vision loss for those with glaucoma is unknown and may be highly variable. The identification of biomarkers for early identification of those likely to be affected with subsequent vision loss is critical, as it would permit targeted, earlier, and/or more aggressive treatment.

    Research Strategies and Questions:

    • Determine markers for phenotypes at risk for severe disease and/or rapid disease progression in glaucoma.
  • Develop and test interventions that prevent or treat ocular diseases and resulting disability, and identify predictors of response to treatment.
  • A. Continue to conduct randomized clinical trials to test preventive or therapeutic interventions.

    Research Needs and Opportunities:
    The panel acknowledges the ongoing need for randomized clinical trials to test preventive or therapeutic interventions, and viewed these as unique opportunities in the following ways. First, the advent of novel treatments such as gene therapy, stem cell interventions, novel drugs and devices and drug delivery systems should be given high priority. Second, the panel recognized that for some diseases there are key issues in trials of timing and/or aggressiveness of treatment needed to delay or prevent progression. Third, trials are platforms upon which risk assessment components (biomarkers and genetics) can be added to identify factors related to treatment efficacy where blood and other ocular samples are obtainable. Fourth, the panel foresees opportunities to incorporate such risk profiles into the design of clinical trials, for example, where patients may be stratified on the basis of biomarkers into alternative treatment arms.

    An example of innovative sampling should be applied to trials of the efficacy of VEGF receptor kinase inhibitors in AMD, in which sustained responses are unpredictable and variable. There is a need to develop proteome-genome biomarkers that are useful to assess efficacy of treatment. Therefore, the collection of vitreous or other ocular samples at various time points will add to our knowledge of pathophysiology of disease and treatment response for a number of ocular diseases.

    Research Strategies and Questions:
    Characterize the genomic markers in vitreous using VEGF trial platforms and determine the complete sequence of the vitreous proteome at three phases of macular degeneration, before during and after successful or unsuccessful therapy with anti-VEGF inhibitors.

    B. Determine the genetic variation that can influence and sometimes predict response to treatment.

    Research Needs and Opportunities:
    Underlying genetic variation can influence and sometimes predict response to treatment. Knowledge of such variation can lead to safer and more effective targeted or individualized treatments. The field of pharmacogenetics should be further utilized.

    Research Strategies and Questions:

    • Characterize the pharmacogenetic interactions in ocular response to drugs.

    C. Develop methods to undertake clinical trials in vision rehabilitation.

    Research Needs and Opportunities:
    The panel recognized a special and urgent case for the development of methods to undertake clinical trials in Vision Rehabilitation. Better methods are needed to assess disability due to vision loss and methods that judge the outcome of vision rehabilitation strategies, including rehabilitation potential and coping mechanisms.

    Research Strategies and Questions:

    • Develop standardized sets of performance base measures, as well as the self reported measures, should be developed to asses the impact of visual impairment, as individuals respond to and cope very differently with visual impairment.
    • Develop and rigorously test interventions to decrease disability due to vision loss.
  • Identify and assess the strategies that will overcome barriers to eye care and convert evidence-based findings into improved patient and population outcomes.
  • A. Develop strategies to enhance patient use of eye care services and to assist providers in more fully implement the results of best-evidence based care practices.

    Research Needs and Opportunities:
    In this broad intersection of epidemiology and health services research, the panel determined two specific areas that complement the previous goals. These are, first, research on strategies to enhance patient use of eye care services, especially overcoming barriers to accessing eye care and improving patient compliance; second, strategies to assist providers in more fully implement the results of best-evidence based care practices.

    Research Strategies and Questions:

    • Develop and evaluate methods to overcome disparities in access to care and enhance compliance for patients needing care for cataract, diabetic retinopathy, and glaucoma.
    • Develop and validate techniques to assist providers to better implement the lessons of best-evidence medicine in their care of patients.
  • Develop new methodologies to support ophthalmic epidemiological research.
  • A. Develop new analytical, computational, and informatic methodologies to handle high dimensional and/or complex data.

    Research Needs and Opportunities:
    There is an urgent need to develop new analytical, computational, and informatic methodologies to handle high dimensional and/or complex data that is now technologically and financially feasible to collect. Millions of data points can be generated at each of the DNA, RNA, protein, and phenotypic (clinical, ocular imaging, visual fields, OCT, etc.) levels for each study subject. The panel recognizes that developing new methodology is an issue across all NIH Institutes, and every institute should devote resources to advance these developments. These are issues that are not unique to NEI, but the panel recommends that NEI consider taking the lead in promoting these activities in cross-institute Road Map initiatives.

    Research Strategies and Questions:

    • Develop efficient data management software for integrating diverse high dimensional data sources.
    • Develop new methodologies for querying and analyzing these multiple data sources, with a focus on integration of multiple data types to address