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Home » Strategic Planning » Report of the Ocular Epidemiology Strategic Planning Panel

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.

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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:

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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.

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

Screening.

Interventions.

Translational Research to Eye Health Services.

Overarching Methodologies.

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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:

    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:

    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:

  3. Determine the genetic, biological, behavioral, and environmental factors that cause ocular disease, and the processes leading to visual impairment resulting from these diseases.
  4. 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:

    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:

    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.

  5. Improve early diagnosis of ocular diseases and their underlying processes through new screening and detection strategies.
  6. 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:

    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:

  7. Develop and test interventions that prevent or treat ocular diseases and resulting disability, and identify predictors of response to treatment.
  8. 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:

    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:

  9. Identify and assess the strategies that will overcome barriers to eye care and convert evidence-based findings into improved patient and population outcomes.
  10. 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:

  11. Develop new methodologies to support ophthalmic epidemiological research.
  12. 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:

    B. Develop a battery of consistent measures, agreed upon by relevant research communities, to facilitate comparisons across studies of ocular diseases.

    Research Needs and Opportunities:
    There is a need for the development of a battery of consistent measures, agreed upon by relevant research communities, to facilitate comparisons across studies of ocular diseases.

    Research Strategies and Questions:

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Ocular Epidemiology Strategic Planning Panel



Jerome I. Rotter, M.D.
Medical Genetics Institute
Cedars-Sinai Medical Center
Los Angeles, CA

Rohit Varma, M.D., M.P.H.
Doheny Eye Institute
University of Southern California
Los Angeles, CA

Daniel E. Weeks, Ph.D.
Department of Human Genetics
University of Pittsburgh
Pittsburgh, PA

Karla Zadnik, O.D., Ph.D.
College of Optometry
The Ohio State University
Columbus, OH

NEI Program Staff:
Donald F. Everett, M.A.
Hemin R. Chin, Ph.D.
Natalie Kurinij, Ph.D.
P�ivi H. Miskala, M.P.H., Ph.D.
Maryann Redford, D.D.S., M.P.H.

Consultants to the Panel
Frederick Ferris, III, M.D.
National Eye Institute
Bethesda, MD

Michael Gorin, M.D., Ph.D.
Jules Stein Eye Institute
Los Angeles, CA

Margaret Pericak-Vance, Ph.D.
Duke University
Durham, NC

Chair:
Sheila K. West, Ph.D.
Wilmer Eye Institute
Johns Hopkins University
Baltimore, MD

Members:
Stanley P. Azen , Ph.D.
Keck School of Medicine
University of Southern California
Los Angeles, CA

Julie E. Buring, Sc.D.
Brigham and Women's Hospital
Harvard University
Boston, MA

Jonathan L. Haines, Ph.D.
Center for Human Genetics
Vanderbilt University
Nashville, TN

Jonathan M. Holmes, M.D.
Department of Ophthalmology
Mayo Clinic
Rochester, MN

Douglas A. Jabs, M.D., M.B.A.
Department of Ophthalmology
Mount Sinai School of Medicine
New York, NY

Paul P. Lee, M.D., J.D.
School of Medicine
Duke University
Durham, NC

Lance Liotta, M.D., Ph.D.
Center for Applied Proteomics
George Mason University
Manassas, VA

Ronald Klein, M.D., M.P.H.
University of Wisconsin
Madison, WI

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Appendix A: The Full Progress Report

Progress Report
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 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.

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Cataract

As the leading cause of blindness world wide, cataract should remain a primary focus for public health ophthalmology, in terms of prevention, better treatment strategies, and determination of disparities in access to surgical services. Highlights of progress include the following:

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Age Related Macular Degeneration (AMD)

AMD is a leading cause of blindness in Caucasian population in the United States. A number of large population-based epidemiological studies have provided information regarding the prevalence and/or incidence of AMD and its relation to visual loss in whites of European ancestry, African Americans, and Hispanics. These data have provided estimates of prevalence in the United States population and documented the relatively high prevalence of AMD, especially in persons 75 years of age or older. While the prevalence of early AMD as manifest by retinal drusen is similar in the three racial ethnic groups, there is a higher incidence of late AMD, especially neovascular AMD in whites compared to Hispanics and African Americans. The reason for this is not known and future investigations into the cause are likely to be a rich source of new information.

Some of the progress made in epidemiology of AMD includes the following:

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Diabetic Retinopathy

Diabetic retinopathy remains a leading cause of blindness in the western world and the prevalence of diabetes is dramatically increasing. There has been important progress in understanding this disease, and developing methods to prevent blindness from diabetic retinopathy in the last 15 years, both because of the development of new approaches toward prevention and because of new treatment strategies. Highlights of progress include the following:

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Retinitis Pigmentosa

Retinitis pigmentosa (RP) belongs to a group of inherited retinal degenerations that results in the destruction of the photoreceptor cells and ultimately in loss of vision. An estimated 100,000 people in the United States have RP.

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Glaucoma

Glaucoma is now the leading cause of irreversible blindness world wide and the second leading cause of blindness, behind cataract, in the world. Thus, it is critical that significant emphasis and resources continue to be contributed towards determining the pathophysiology and management of this disease. The past 15 years have provided significant data in these areas both in the U.S. and worldwide. Progress includes the following:

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Cornea

The area of cornea and external ocular surface disease is, by definition, a broad one, and highlights of the past 15 years have been in the following major areas: corneal infections, corneal transplantation, herpetic keratitis, and keratoconus. Ongoing studies seek to evaluate donor tissue age and corneal transplant outcomes. Progress includes the following:

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Refractive Error

Epidemiologic research funded by the NEI in the area of refractive error has been robust in the recent past. The research program has been focused in four major areas, and much of the emphasis has been specifically on myopia, rather than on refractive error in general: (1) prevalence of refractive error; (2) risk factors for myopia; (3) treatment of myopia; (4) genetic epidemiology of myopia. Highlights of progress include the following:

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Pediatric Ophthalmology

Amblyopia
A research consortium has been established to efficiently undertake a number of treatment trials for amblyopia. The Pediatric Eye Disease Investigator Group (PEDIG) findings include the following:

Strabismus

Retinopathy of Prematurity

Screening for Pediatric Eye Disease

Congenital Cataract

Population-based Studies on Prevalence of Pediatric Eye Disease

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Infectious Diseases

Infectious eye disease is still a leading cause of avoidable blindness world wide, and the NEI has a long history of research support for control of these conditions. The epidemiology efforts have been focused on trachoma and the ocular complications of AIDS. Both areas have been highly successful. Each is described in turn:

Trachoma
Caused by repeated episodes of ocular Chlamydia trachomatis infection, trachoma is the leading infectious cause of blindness world wide. With a donation program of azithromycin, global efforts to eliminate blinding trachoma have been intensified. The World Health Organization has endorsed a multi-faceted control strategy, SAFE, consisting of Surgery (to correct trichiasis), Antibiotics (to decrease the community pool of infection, Face washing and Environmental change (to interrupt transmission). Considerable research progress in trachoma has been made, and only the highlights are summarized below:

Ocular complications of AIDS

With the onset of the AIDS epidemic in the 1980's, there was an associated epidemic of cytomegalovirus (CMV) retinitis, which by the early 1990's had become the most common intraocular infection at major urban centers in the United States and possibly in the United States as a whole. A consortium, the Studies of the Ocular Complications of AIDS (SOCA), has been productive in determining appropriate treatment; studies using data from more than one trial in this consortium were important in describing the course of CMV retinitis in the pre-HAART era for comparison with the effects of highly active antiretroviral therapy (HAART). The cohort study of patients with AIDS is a unique resource because it contains ophthalmic data over time and includes patients with AIDS from all risk groups for HIV infection. The results of these studies are summarized below:

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Health Services Research

Traditionally, the NEI has funded limited research into eye health services but recent demonstrations of disparities in rates of vision loss and better appreciation of research into potential economic trade-offs have made this area of inquiry more prominent. Ophthalmic epidemiology has contributed to this field, as part of collaborative efforts, in the following advances.

Development of Outcomes Relative to Patient-centered Perspectives

Improved Understanding Value of Health Care Services

Identifying How to Improve Outcomes of Care by Better Application of Evidence-Based Medicine and RCT Findings

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Overarching Methodology

Current Methods Used for Mapping Genes Associated with Ocular Diseases

Ophthalmology makes tremendous use of innovative genetic studies geared towards describing the interplay between environmental and genetic factors that contribute to the development of either single-gene or polygenic (multifactor) ocular diseases. A combination of powerful and flexible statistical methods together with a detailed understanding of the molecular forces directing the mechanisms of new mutations is essential in describing the genetic factors conferring susceptibility or resistance, affecting the severity or progression of ocular diseases, and in further characterizing the range of environmental influences that contribute to the elevation of such risks.

Depending on the type of available clinical data, numerous genetic study approaches are being implemented, each with its own advantages and disadvantages. However, great progress has been obtained through the interlink between the different findings of all such methods. One of the most frequent techniques conducted for mapping ocular susceptible genes is based on gathering family disease and environmental history across two or three generations, and on collecting DNA samples that are then analyzed as part of "linkage analysis" computational methods. This strategy is focused on detecting whether a certain set of genes occurs more frequently than would be expected by chance, namely with a preponderance in the diseased population versus the population at large. However, there are challenges involved in this sort of study, mostly due to the sometimes missing parental genotypes, due to partially informative families (deceased relatives), and to insufficient information describing possible environmental factors that modify susceptibility to illness.

An alternative approach is based on "association studies", a complementary strategy for detecting complex disease susceptibility genes. The advantage of this technique is the use of population-based rather than family-based DNA. A nonrandom association of alleles represents disequilibrium between closely linked genetic loci, a genetic set that usually dissipates slowly over successive generations even in a large set population. This particular information genetically differentiates the affected and non-affected individuals. However, careful clinical design is usually taken to ensure a correct matching for ethnicity or other factors that may contribute to genetic differences. For example, population stratification due to recent admixture of different populations or inappropriate matching of patients and controls may falsely affect these results. Nevertheless, these problems are circumvented with the family-based study designs.

Another strategy complementing association studies is based on searching for an increased prevalence of a particular functional genetic variant among cases. This aim is accomplished by searching for differences in the frequency of a gene allele between a sample of patients and controls, a result that will directly implicate a gene as influencing ocular disease susceptibility. Needless to say, both family and population oriented studies are complementary and useful in summarizing the total number of genetic mutations that affect a given disease.

In concert with the different statistical algorithms and clinical designs we are also benefiting from the recent molecular laboratory technological advances that have enabled the genotyping of hundreds of thousands of genetic alleles on a single chip. While nowadays we are provided with an extraordinary collection of genetic information, scientists are nevertheless posed with the challenge of producing innovative and novel analytic methods that will efficiently incorporate the full range of information being generated. Moreover, the inherent biologic complexity of complex ocular diseases necessitates a critical need for cooperation between molecular and computational researchers, without which novel discoveries and insights into the biological underpinnings of complex diseases will nevertheless lag and further impede a whole understanding of the underlying mechanisms.

Meta Data Analyses: Combining Information from Multiple Data Sources

In a recent paper by Samsa, Hu and Root (Journal of Biomedicine and Biotechnology, 2005:2, 113-123) a method is proposed for combining the results of composite relative risks due to the issue of risk factor colinearity and heterogeneity of the different cohorts. As stated by the authors, "creating multivariable regression models containing partial regression coefficients is central to the practice of epidemiology. Combining partial regression coefficients across datasets is difficult when the correlations among the risk factors in question are moderate to strong." The univariable synthesis method proposed by the authors has the advantage that correlations among the predictors are explicitly considered in the quantitative estimation of the partial regression coefficients.

Strategies for Conducting Gene-Environment Studies in Ocular Disease

Investigations of interactions capitalize on traditional epidemiologic study designs, with the case-control and case-only the most widely used. In the traditional case-control design, the exposure of interest is compared among the cases (diseased individuals) and controls and the odds ratio tabulated reflecting the relative effect of the exposure (the gene) on disease. This can be easily expanded to incorporate risk due to a third, here environmental, risk factor. The case-only design uses only diseased individuals and examines the association between genetic and environmental measures and an odds ratio is again calculated. While more powerful in detecting an interaction, the case-only design is only valid in the absence of gene-environment association. Said differently, the genetic and environmental factors examine must be independent.

The study designs described above can and have been implemented in various ways. For diseases with established lifestyle or environmental risks, research addressing interaction has focused on identification of genes that differentially effect risk for disease. Genes of interest are generally chosen based on their relationship with the known environmental factor. Such an approach may be useful in diabetic retinopathy where glycemic control and blood pressure have been shown to be important. Examination of genes that relate to these risks may prove to be important in interactions and disease progression. In contrast, for diseases with known genetic risk factors, examination of environmental risk factors has been of great interest. Following identification of candidate genes, generally from linkage and cloning studies, specific variants may then be associated with environmental risk factors. For example, recent work has examined interactions between smoking behavior, body-mass index, and risk genes for AMD. However, studies designed to specifically detect gene-environment interactions can also be used to identify new genes for disease. Segregation analyses, examination of affected sibling pairs, and genome-wide association studies can all be adapted to take environmental exposure variables into account and focus results on the detection of genes which are involved in a gene-environment interaction. Segregation analysis and the use of affected sibling pairs will capitalize on differences in the environmental exposure of interested among individuals with disease. Similarly, genome-wide association tests can be calculated to test the joint effect of marker and environmental exposure on disease risk.

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Appendix B: Objectives Already in the NEI Strategic Plan, National Plan for Eye and Vision Research (2004)

Retinal Diseases Program

Corneal Diseases Program

Lens and Cataract Program

Glaucoma and Optic Neuropathies Program

Strabismus, Amblyopia, and Visual Processing Program

Low Vision and Blindness Rehabilitation

This page was last modified in November 2007