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1.  Prevalence of Age-Related Macular Degeneration in Nakuru, Kenya: A Cross-Sectional Population-Based Study 
PLoS Medicine  2013;10(2):e1001393.
Using digital retinal photography and slit lamp examination in a population-based sample in the Nakuru District of Kenya, Andrew Bastawrous and colleagues determined the prevalence of age-related macular degeneration in adults 50 years and older.
Background
Diseases of the posterior segment of the eye, including age-related macular degeneration (AMD), have recently been recognised as the leading or second leading cause of blindness in several African countries. However, prevalence of AMD alone has not been assessed. We hypothesized that AMD is an important cause of visual impairment among elderly people in Nakuru, Kenya, and therefore sought to assess the prevalence and predictors of AMD in a diverse adult Kenyan population.
Methods and Findings
In a population-based cross-sectional survey in the Nakuru District of Kenya, 100 clusters of 50 people 50 y of age or older were selected by probability-proportional-to-size sampling between 26 January 2007 and 11 November 2008. Households within clusters were selected through compact segment sampling.
All participants underwent a standardised interview and comprehensive eye examination, including dilated slit lamp examination by an ophthalmologist and digital retinal photography. Images were graded for the presence and severity of AMD lesions following a modified version of the International Classification and Grading System for Age-Related Maculopathy. Comparison was made between slit lamp biomicroscopy (SLB) and photographic grading.
Of 4,381 participants, fundus photographs were gradable for 3,304 persons (75.4%), and SLB was completed for 4,312 (98%). Early and late AMD prevalence were 11.2% and 1.2%, respectively, among participants graded on images. Prevalence of AMD by SLB was 6.7% and 0.7% for early and late AMD, respectively. SLB underdiagnosed AMD relative to photographic grading by a factor of 1.7.
After controlling for age, women had a higher prevalence of early AMD than men (odds ratio 1.5; 95% CI, 1.2–1.9). Overall prevalence rose significantly with each decade of age. We estimate that, in Kenya, 283,900 to 362,800 people 50 y and older have early AMD and 25,200 to 50,500 have late AMD, based on population estimates in 2007.
Conclusions
AMD is an important cause of visual impairment and blindness in Kenya. Greater availability of low vision services and ophthalmologist training in diagnosis and treatment of AMD would be appropriate next steps.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Worldwide, 39 million people are blind, and 246 million people (mainly living in developing countries) have moderate or severe visual impairment. The third leading global cause of blindness (after cataracts and glaucoma) is age-related macular degeneration (AMD). This group of conditions is characterized by lesions in the macular (central) region of the retina, the tissue at the back of the eye that converts light into electrical messages and sends them to the brain. AMD, which affects older people, destroys the sharp central vision that is needed for reading or driving, leaving only dim, blurred images or a black hole at the center of vision. AMD can be diagnosed by examining digital photographs of the retina or by examining the retina directly using a special magnifying lens (slit lamp biomicroscopy). There is no cure for AMD, although injections into the eye of certain drugs, such as bevacizumab, that block the activity of vascular endothelial growth factor can slow the rate of vision loss caused by some forms of AMD.
Why Was This Study Done?
Most investigations of the prevalence (the proportion of a population with a disease) of AMD and of risk factors for AMD have studied people with European or Asian ancestry. Very little is known about AMD in African populations, and the data that are available mainly come from African populations living outside Africa. It is important to know whether AMD is an important cause of visual impairment and blindness in Africa, so that informed decisions can be made about the need for AMD programs in African countries. In this cross-sectional population-based study, the researchers investigate the prevalence of AMD among people aged 50 years or older living in Nakuru District (an ethnically diverse region of Kenya) and look for predictors of AMD in this population. In a cross-sectional population-based study, researchers observe a representative subset of a population at a single time point.
What Did the Researchers Do and Find?
The researchers randomly selected 100 clusters of 50 people aged 50 years or older for their study. Between January 2007 and November 2008, study participants had a comprehensive eye examination and completed a standardized interview that included questions about their age, gender, other demographic details, medical history, and exposure to possible risk factors for AMD. Based on digital retinal images, the prevalences of early and late AMD among the study population were 11.2% and 1.2%, respectively. The prevalences of early and late AMD judged by slit lamp biomicroscopy were 6.7% and 0.7%, respectively. After controlling for age, women had a higher prevalence of both early and late AMD than men. The overall prevalence of AMD rose with age: compared to the youngest age group, the oldest age group had a three-fold higher risk of developing late AMD. Of the people with any grade of AMD, 25.6% had some visual impairment and 2.5% were blind. Overall, 9.9% of the blindness seen in the study was attributable to AMD.
What Do These Findings Mean?
These findings identify AMD as an important cause of visual impairment and blindness in Nakuru District, Kenya. Extrapolation of these findings to the whole of Kenya suggests that 283,900 to 362,800 Kenyans had early AMD and 25,200 to 50,500 had late AMD in 2007. The accuracy of these findings is limited by the inability to obtain digital retinal images from all the participants (often because of electricity failures) and by other aspects of the study design. Moreover, because the methodology used in this study differed from some other studies of AMD, the prevalence of AMD reported here cannot be compared directly to those found in other studies. Nevertheless, these findings have several important implications. In particular, although recent evidence suggests that bevacizumab is likely to be both effective and affordable in Africa, the infrastructure required to deliver an adequate AMD service is currently prohibitively expensive in most African countries. Thus, these findings suggest that it is essential that research is undertaken to support the development of AMD treatment programs that are affordable and deliverable in Africa, and that low vision resources are provided for individuals with vision impairment.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001393.
The US National Eye Institute provides detailed information about age-related macular degeneration
The UK National Health Service Choices website also provides information about age-related macular degeneration, including personal stories about the condition
The UK Royal National Institute of Blind People has information on age-related macular degeneration, including a video of a person describing their experiences of the condition
AMD Alliance International provides written and audio information in several languages about age-related macular degeneration, including a large selection of personal stories; the Macular Degeneration Partnership also provides information about age-related macular degeneration, including a simulation of the condition
MedlinePlus has links to additional resources about age-related macular degeneration (in English and Spanish)
doi:10.1371/journal.pmed.1001393
PMCID: PMC3576379  PMID: 23431274
2.  Neovascular Age-Related Macular Degeneration Risk Based on CFH, LOC387715/HTRA1, and Smoking 
PLoS Medicine  2007;4(12):e355.
Background
Age-related macular degeneration (AMD) is the major cause of blindness in the elderly. Those with the neovascular end-stage of disease have irreversible loss of central vision. AMD is a complex disorder in which genetic and environmental factors play a role. Polymorphisms in the complement factor H (CFH) gene, LOC387715, and the HTRA1 promoter are strongly associated with AMD. Smoking also contributes to the etiology. We aimed to provide a model of disease risk based on these factors.
Methods and Findings
We genotyped polymorphisms in CFH and LOC387715/HTRA1 in a case–control study of 401 patients with neovascular AMD and 266 controls without signs of disease, and used the data to produce genetic risk scores for the European-descent population based on haplotypes at these loci and smoking history. CFH and LOC387715/HTRA1 haplotypes and smoking status exerted large effects on AMD susceptibility, enabling risk scores to be generated with appropriate weighting of these three factors. Five common haplotypes of CFH conferred a range of odds ratios (ORs) per copy from 1 to 4.17. Most of the effect of LOC387715/HTRA1 was mediated through one detrimental haplotype (carriage of one copy: OR 2.83; 95% confidence interval [CI] 1.91–4.20), with homozygotes being at particularly high risk (OR 32.83; 95% CI 12.53–86.07). Patients with neovascular macular degeneration had considerably higher scores than those without disease, and risk of blinding AMD rose to 15.5% in the tenth of the population with highest predicted risk.
Conclusions
An individual's risk of developing AMD in old age can be predicted by combining haplotype data with smoking status. Until there is effective treatment for AMD, encouragement to avoid smoking in those at high genetic risk may be the best option. We estimate that total absence of smoking would have reduced the prevalence of severe AMD by 33%. Unless smoking habits change or preventative treatment becomes available, the prevalence of AMD will rise as a consequence of the increasing longevity of the population.
Anne Hughes and colleagues show that an individual's risk of developing age-related macular degeneration in old age can be predicted by combining haplotype data with smoking status.
Editors' Summary
Background.
Age-related macular degeneration (AMD) is the leading cause of vision loss in the elderly. The macula is the central region of the retina, the tissue at the back of the eye that converts light into electrical messages and sends them to the brain. In the commonest form of AMD—“dry” AMD—the light-sensitive cells in the macula gradually die. In “wet” or “neovascular” AMD (one in 10 cases of AMD, but responsible for 90% of severe AMD-related blindness), abnormal blood vessels grow below the macula. Fluid leaking out of these vessels dislodges and damages the macula, after which loss of vision occurs rapidly. Both forms of AMD destroy the sharp central vision that is needed for reading and driving, leaving only dim, blurred images or a black hole at the center of vision. Neither form can be cured but with wet AMD the loss of vision can sometimes be slowed or halted if caught early by destroying the new blood vessels with laser surgery or a technique called photodynamic therapy or by blocking their formation by injecting special drugs into the eye.
Why Was This Study Done?
No-one knows what causes AMD but factors that increase a person's risk of developing the disease include increasing age, smoking, being white, and a family history of AMD. Recently, researchers have identified several “polymorphisms” (inherited DNA sequence variations that are common within populations) that are associated with AMD. These polymorphisms are in the complement factor H gene (the scientific symbol for this gene is CFH) and in a gene region called LOC387715/HTRA1. It would be useful to be able to use these risk factors to identify those people at the highest risk of developing neovascular AMD before the disease damages their vision. In this study, the researchers have investigated the association between AMD and polymorphisms in CFH and LOC387715/HTRA1 in more depth. They have then used this new information to build a model of AMD risk that should allow physicians to identify individuals at high risk of developing neovascular AMD.
What Did the Researchers Do and Find?
The researchers catalogued polymorphisms in CFH and LOC387715/HTRA1 in several hundred people with and without neovascular AMD. From these data, they identified three haplotypes (sets of polymorphisms that are inherited as a unit; everyone inherits two copies of each haplotype, one from each parent) in CFH that were more common in people with AMD than in those without and two that were associated with a decreased risk of developing AMD. In LOC387715/HTRA1 they identified one particularly detrimental haplotype. Compared to people without this haplotype, people with one copy of the deleterious haplotype were three times as likely to develop neovascular AMD; people with two copies were thirty times as likely to develop AMD. Smoking history also had a large effect on susceptibility to AMD. The researchers then developed a simple AMD risk scoring system based on CFH and LOC387715/HTRA1haplotypes and smoking status. From this, they calculated that people with the lowest risk scores have a minimal risk of developing AMD whereas about 15% of people with the highest risk scores are likely to develop AMD.
What Do These Findings Mean?
These findings indicate that it is possible to predict an individual's risk of developing AMD in old age by examining a small number of haplotypes and asking about their smoking status. The model developed by the researchers needs to be validated in other groups of people and may have to be modified if other gene variants that affect the risk of AMD are identified. For now, the results of this research provide physicians with a way to identify those individuals at the highest genetic risk of developing AMD so that they can step up their efforts to persuade these people to avoid smoking. In the future, when effective long-term treatments for AMD become available, the scoring system could also help doctors decide which of their elderly patients should be monitored most intensively for the early signs of AMD so that they can be treated before their vision is irreversibly damaged.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040355.
MedlinePlus provides links to information on macular degeneration and an encyclopedia page on macular degeneration (in English and Spanish)
Pages on the US National Institutes of Health NIH SeniorHealth site provides text and speech information about AMD
The US National Eye Institute and the UK Royal National Institute of Blind People also provide information about AMD
doi:10.1371/journal.pmed.0040355
PMCID: PMC2222948  PMID: 18162041
3.  Estimating Community Incidence of Salmonella, Campylobacter, and Shiga Toxin–producing Escherichia coli Infections, Australia 
Emerging Infectious Diseases  2008;14(10):1601-1609.
Estimated multipliers that linked surveillance of foodborne diseases with community incidence showed a high prevalence of these diseases.
To estimate multipliers linking surveillance of salmonellosis, campylobacteriosis, and Shiga toxin–producing Escherichia coli (STEC) infections to community incidence, we used data from a gastroenteritis survey and other sources. Multipliers for severe (bloody stool/long duration) and milder cases were estimated from the component probabilities of doctor visit, stool test, sensitivity of laboratory test, and reporting to surveillance system. Pathogens were classified by the same severity criteria and appropriate multipliers applied. Precision of estimates was quantified by using simulation techniques to construct 95% credible intervals (CrIs). The multiplier for salmonellosis was estimated at 7 (95% CrI 4–16), for campylobacteriosis at 10 (95% CrI 7–22), and for STEC at 8 (95% CrI 3–75). Australian annual community incidence rates per 100,000 population were estimated as 262 (95% CrI 150–624), 1,184 (95% CrI 756–2,670), and 23 (95% CrI 13–54), respectively. Estimation of multipliers allows assessment of the true effects of these diseases and better understanding of public health surveillance.
doi:10.3201/eid1410.071042
PMCID: PMC2609882  PMID: 18826825
Australia; surveillance; salmonellosis; campylobacteriosis; Shiga toxin-like Escherichia coli (STEC); notification-fraction; multipliers; credible interval; incidence; research
4.  Optical Coherence Tomography for Age-Related Macular Degeneration and Diabetic Macular Edema 
Executive Summary
Objective
The purpose of this evidence-based review was to examine the effectiveness and cost-effectiveness of spectral-domain (SD) optical coherence tomography (OCT) in the diagnosis and monitoring of patients with retinal disease, specifically age-related macular degeneration (AMD) and diabetic macular edema (DME). Specifically, the research question addressed was:
What is the sensitivity and specificity of spectral domain OCT relative to the gold standard?
Clinical Need: Target Population and Condition
The incidence of blindness has been increasing worldwide. In Canada, vision loss in those 65 years of age and older is primarily due to AMD, while loss of vision in those 18 years of age and older is mainly due to DME. Both of these conditions are diseases of the retina, which is located at the back of the eye. At the center of the retina is the macula, a 5 mm region that is responsible for what we see in front of us, our ability to detect colour, and fine detail. Damage to the macula gives rise to vision loss, but early detection of asymptomatic disease may lead to the prevention or slowing of the vision loss process.
There are two main types of AMD, ‘dry’ and ‘wet’. Dry AMD is the more prevalent of the two, accounting for approximately 85% of cases and characterized by small deposits of extracellular material called “drusen” that build up in Bruch’s membrane of the eye. Central vision loss is gradual with blurring and eventual colour fading. Wet AMD is a less prevalent condition (15% of all AMD cases) but it accounts for 90% of severe cases. It’s characterized by the appearance of retinal fluid with vision loss due to abnormal blood vessels/leakage within weeks to months of diagnosis. In 2003, the Canadian National Institute for the Blind (CNIB) prevalence estimate for AMD was 1 million Canadians, including approximately 400,000 affected Ontarians. The incidence in 2003 was estimated to be 78,000 new cases in Canada, with approximately one-third of these cases arising in Ontario (n=26,000). Over the next 25 years, the number of new cases is expected to triple.
DME is caused by complications of diabetes mellitus, both Type 1 and Type 2. It is estimated that 1-in-4 persons with diabetes has this condition, though it occurs more frequently among those with type 2 diabetes. The condition is characterized by a swelling of the retina caused by leakage of blood vessels at the back of the eye. In early stages of the disease, vision may still be normal but it can degrade rapidly in later stages. In 2003, the CNIB prevalence estimate for DME was 0.5 million Canadians, with approximately 200,000 Ontarians affected. The incidence of DME is more difficult to ascertain; however, based on an annual incidence rate of 0.8% (for those 20 years of age or older) and the assumption that 1-in-4 persons with diabetes is affected, the incidence of DME in Ontario is estimated to be 21,000 new cases per year.
Optical Coherence Tomography
Prior to the availability of OCT, the standard of care in the diagnosis and/or monitoring of retinal disease was serial testing with fluorescein angiography (FA), biomicroscopy (BM), and stereo-fundus photography (SFP). Each of these is a qualitative measure of disease based on subjective evaluations that are largely dependent on physician expertise. OCT is the first quantitative visual test available for the diagnosis of eye disease. As such, it is allows for a more objective evaluation of the presence/absence of retinal disease and it is the only test that provides a measure of retinal thickness. The technology was developed at the Michigan Institute of Technology (MIT) in 1991 as a real-time imaging modality and is considered comparable to histology. It’s a light-wave based technology producing cross-sectional images with scan rates and resolution parameters that have greatly improved over the last 10 years. It’s also a non-invasive, non-contact visual test that requires just 3 to 5 minutes to assess both eyes.
There are two main types of OCT system, both licensed by Health Canada as class II devices. The original patent was based on a time domain (TD) system (available from 1995) that had an image rate of 100 to 400 scans per second and provided information for a limited view of the retina with a resolution in the range of 10 to 20 μm. The newer system, spectral domain (SD) OCT, has been available since 2006. Improvements with this system include (i) a faster scan speed of approximately 27,000 scans per second; (ii) the ability to scan larger areas of the retina by taking six scans radially-oriented 30 degrees from each other; (iii) increased resolution at 5μm; and (iv) ‘real-time registration,’ which was not previously available with TD.
The increased scan speed of SD systems enables the collection of additional real-time information on larger regions of the retina, thus, reducing the reliance on assumptions required for retinal thickness and volume estimates based on software algorithms. The faster scan speed also eliminates image distortion arising from patient movement (not previously possible with TD), while the improvement in resolution allows for clearer and more distinguishable retinal layers with the possibility of detecting earlier signs of disease. Real-time registration is a new feature of SD that enables the identification of specific anatomical locations on the retina, against which subsequent tests can be evaluated. This is of particular importance in the monitoring of patients. In the evaluation of treatment effects, for example, this enables the same anatomic retinal location to be identified at each visit.
Methods
Literature Search
A literature search was performed on February 13, 2009 using Ovid MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, the Cumulative Index to Nursing & Allied Health Literature (CINAHL), the Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) for studies published from January 2003 to February 2009. The subject headings and keywords searched included AMD, DME, and OCT (the detailed search strategy can be viewed in Appendix 1). Excluded were case reports, comments, editorials, non-systematic reviews, and letters. Abstacts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria, full-text articles were obtained. In total, 542 articles were included for review.
English-language articles and health technology assessments.
RCTs and observational studies of OCT and AMD or DME.
Studies focusing on either diagnosis or monitoring of disease.
Studies in which outcomes were not specific to those of interest in this report.
Studies of pediatric populations.
Studies on OCT as a screening tool.
Studies that did not assess comparative effectiveness of OCT with a referent, as specified below in “Comparisons of Interest”.
Outcomes of Interest
Studies of sensitivity, specificity.
Comparisons of Interest
Evidence exists for the following comparisons of interest:
OCT compared with the reference “fluorescein angiography” for AMD.
OCT compared with the reference “biomicroscopy” or “stereo or fundus photography” for DME.
Summary of Existing Evidence
No evidence for the accuracy of SD OCT compared to either FA, BM or SFP was published between January 2006 to February 2009; however, two technology assessments were found, one from Alberta and the other from Germany, both of which contain evidence for TD OCT. Although these HTAs included eight studies each, only one study from each report was specific to this review. Additionally, one systematic review was identified for OCT and DME. It is these three articles, all pertaining to time and not spectral domain OCT, as well as comments from experts in the field of OCT and retinal disease, that comprise the evidence contained in this review.
Upon further assessment and consultations with experts in the methodology of clinical test evaluation, it was concluded that these comparators could not be used as references in the evaluation of OCT. The main conclusion was that, without a third test as an arbiter, it is not possible to directly compare the sensitivity and specificity of OCT relative to either FA for AMD and stereo- or fundus – photography for DME. Therefore, in the absence of published evidence, it was deemed appropriate to consult a panel of experts for their views and opinions on the validity of OCT and its utility in clinical settings. This panel consisted of four clinicians with expertise in AMD and/or DME and OCT, as well as a medical biophysicist with scientific expertise in ocular technologies. This is considered level 5 evidence, but in the absence of an appropriate comparator for further evaluation of OCT, this may be the highest level of evidence possible.
Summary of Findings
The conclusions for SD OCT based on Level 5 evidence, or expert consultation, are as follows:
OCT is considered an essential part of the diagnosis and follow-up of patients with DME and AMD.
OCT is adjunctive to FA for both AMD and DME but should decrease utilization of FA as a monitoring modality.
OCT will result in a decline in the use of BM in the monitoring of patients with DME, given its increased accuracy and consistency.
OCT is diffusing rapidly and the technology is changing. Since FA is still considered pivotal in the diagnosis and treatment of AMD and DME, and there is no common outcome against which to compare these technologies, it is unlikely that RCT evidence of efficacy for OCT will ever be forthcoming.
In addition to the accuracy of OCT in the detection of disease, assessment of the clinical utility of this technology included a rapid review of treatment effects for AMD and DME. The treatment of choice for AMD is Lucentis®, with or without Avastin® and photodynamic therapy. For DME the treatment of choice is laser photocoagulation, which may be replaced with Lucentis® injections (Expert consultation). The evidence, as presented in systematic reviews and other health technology assessments, indicates that there are effective treatments available for both AMD and DME.
Considerations for the Ontario Health System
OCT testing is presently an uninsured service in Ontario with patients paying approximately $150 out-of-pocket per test. Several provinces do provide funding for this procedure, including British Columbia, Alberta, Saskatchewan, Newfoundland, Nova Scotia, Prince Edward Island, and the Yukon Territory. Provinces that do not provide such funding are Quebec, Manitoba and New Brunswick.
The demand for OCT is expected to increase with aging of the population.
PMCID: PMC3377511  PMID: 23074517
5.  Routine Eye Examinations for Persons 20-64 Years of Age 
Executive Summary
Objective
The objective of this analysis was to determine the strength of association between age, gender, ethnicity, family history of disease and refractive error and the risk of developing glaucoma or ARM?
Clinical Need
A routine eye exam serves a primary, secondary, and tertiary care role. In a primary care role, it allows contact with a doctor who can provide advice about eye care, which may reduce the incidence of eye disease and injury. In a secondary care role, it can via a case finding approach, diagnose persons with degenerative eye diseases such as glaucoma and or AMD, and lead to earlier treatment to slow the progression of the disease. Finally in a tertiary care role, it provides ongoing monitoring and treatment to those with diseases associated with vision loss.
Glaucoma is a progressive degenerative disease of the optic nerve, which causes gradual loss of peripheral (side) vision, and in advanced disease states loss of central vision. Blindness may results if glaucoma is not diagnosed and managed. The prevalence of primary open angle glaucoma (POAG) ranges from 1.1% to 3.0% in Western populations, and from 4.2% to 8.8% in populations of African descent. It is estimated up to 50% of people with glaucoma are aware that they have the disease. In Canada, glaucoma disease is the second leading cause of blindness in people aged 50 years and older. Tonometry, inspection of the optic disc and perimetry are used concurrently by physicians and optometrists to make the diagnosis of glaucoma. In general, the evidence shows that treating people with increased IOP only, increased IOP and clinical signs of early glaucoma or with normal-tension glaucoma can reduce the progression of disease.
Age-related maculopathy (ARM) is a degenerative disease of the macula, which is a part of the retina. Damage to the macula causes loss of central vision affecting the ability to read, recognize faces and to move about freely. ARM can be divided into an early- stage (early ARM) and a late-stage (AMD). AMD is the leading cause of blindness in developed countries. The prevalence of AMD increases with increasing age. It is estimated that 1% of people 55 years of age, 5% aged 75 to 84 years and 15% 80 years of age and older have AMD. ARM can be diagnosed during fundoscopy (ophthalmoscopy) which is a visual inspection of the retina by a physician or optometrist, or from a photograph of the retina. There is no cure or prevention for ARM. Likewise, there is currently no treatment to restore vision lost due to AMD. However, there are treatments to delay the progression of the disease and further loss of vision.
The Technology
A periodic oculo-visual assessment is defined “as an examination of the eye and vision system rendered primarily to determine if a patient has a simple refractive error (visual acuity assessment) including myopia, hypermetropia, presbyopia, anisometropia or astigmatism.” This service includes a history of the presenting complaint, past medical history, visual acuity examination, ocular mobility examination, slit lamp examination of the anterior segment, ophthalmoscopy, and tonometry (measurement of IOP) and is completed by either a physician or an optometrist.
Review Strategy
The Medical Advisory Secretariat conducted a computerized search of the literature in the following databases: OVID MEDLINE, MEDLINE, In-Process & Other Non-Indexed Citations, EMBASE, INAHTA and the Cochrane Library. The search was limited to English-language articles with human subjects, published from January 2000 to March 2006. In addition, a search was conducted for published guidelines, health technology assessments, and policy decisions. Bibliographies of references of relevant papers were searched for additional references that may have been missed in the computerized database search. Studies including participants 20 years and older, population-based prospective cohort studies, population-based cross-sectional studies when prospective cohort studies were unavailable or insufficient and studies determining and reporting the strength of association or risk- specific prevalence or incidence rates of either age, gender, ethnicity, refractive error or family history of disease and the risk of developing glaucoma or AMD were included in the review. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) system was used to summarize the overall quality of the body of evidence.
Summary of Findings
A total of 498 citations for the period January 2000 through February 2006 were retrieved and an additional 313 were identified when the search was expanded to include articles published between 1990 and 1999. An additional 6 articles were obtained from bibliographies of relevant articles. Of these, 36 articles were retrieved for further evaluation. Upon review, 1 meta-analysis and 15 population-based epidemiological studies were accepted for this review
Primary Open Angle Glaucoma
Age
Six cross-sectional studies and 1 prospective cohort study contributed data on the association between age and PAOG. From the data it can be concluded that the prevalence and 4-year incidence of POAG increases with increasing age. The odds of having POAG are statistically significantly greater for people 50 years of age and older relative to those 40 to 49 years of age. There is an estimated 7% per year incremental odds of having POAG in persons 40 years of age and older, and 10% per year in persons 49 years of age and older. POAG is undiagnosed in up to 50% of the population. The quality of the evidence is moderate.
Gender
Five cross-sectional studies evaluated the association between gender and POAG. Consistency in estimates is lacking among studies and because of this the association between gender and prevalent POAG is inconclusive. The quality of the evidence is very low.
Ethnicity
Only 1 cross-sectional study compared the prevalence rates of POAG between black and white participants. These data suggest that prevalent glaucoma is statistically significantly greater in a black population 50 years of age and older compared with a white population of similar age. There is an overall 4-fold increase in prevalent POAG in a black population compared with a white population. This increase may be due to a confounding variable not accounted for in the analysis. The quality of the evidence is low.
Refractive Error
Four cross-sectional studies assessed the association of myopia and POAG. These data suggest an association between myopia defined as a spherical equivalent of -1.00D or worse and prevalent POAG. However, there is inconsistency in results regarding the statistical significance of the association between myopia when defined as a spherical equivalent of -0.5D. The quality of the evidence is very low.
Family History of POAG
Three cross-sectional studies investigated the association between family history of glaucoma and prevalent POAG. These data suggest a 2.5 to 3.0 fold increase in the odds having POAG in persons with a family history (any first-degree relative) of POAG. The quality of the evidence is moderate.
Age-Related Maculopathy
Age
Four cohort studies evaluated the association between age and early ARM and AMD. After 55 years of age, the incidence of both early ARM and AMD increases with increasing age. Progression to AMD occurs in up to 12% of persons with early ARM. The quality of the evidence is low
Gender
Four cohort studies evaluated the association between gender and early ARM and AMD. Gender differences in incident early ARM and incident AMD are not supported from these data. The quality of the evidence is lows.
Ethnicity
One meta-analysis and 2 cross-sectional studies reported the ethnic-specific prevalence rates of ARM. The data suggests that the prevalence of early ARM is higher in a white population compared with a black population. The data suggest that the ethnic-specific differences in the prevalence of AMD remain inconclusive.
Refractive Error
Two cohort studies investigated the association between refractive error and the development of incident early ARM and AMD. The quality of the evidence is very low.
Family History
Two cross-sectional studies evaluated the association of family history and early ARM and AMD. Data from one study supports an association between a positive family history of AMD and having AMD. The results of the study indicate an almost 4-fold increase in the odds of any AMD in a person with a family history of AMD. The quality of the evidence, as based on the GRADE criteria is moderate.
Economic Analysis
The prevalence of glaucoma is estimated at 1 to 3% for a Caucasian population and 4.2 to 8.8% for a black population. The incidence of glaucoma is estimated at 0.5 to 2.5% per year in the literature. The percentage of people who go blind per year as a result of glaucoma is approximately 0.55%.
The total population of Ontarians aged 50 to 64 years is estimated at 2.6 million based on the April 2006 Ontario Ministry of Finance population estimates. The range of utilization for a major eye examination in 2006/07 for this age group is estimated at 567,690 to 669,125, were coverage for major eye exams extended to this age group. This would represent a net increase in utilization of approximately 440,116 to 541,551.
The percentage of Ontario population categorized as black and/or those with a family history of glaucoma was approximately 20%. Therefore, the estimated range of utilization for a major eye examination in 2006/07 for this sub-population is estimated at 113,538 - 138,727 (20% of the estimated range of utilization in total population of 50-64 year olds in Ontario), were coverage for major eye exams extended to this sub-group. This would represent a net increase in utilization of approximately 88,023 to 108,310 within this sub-group.
Costs
The total cost of a major eye examination by a physician is $42.15, as per the 2006 Schedule of Benefits for Physician Services.(1) The total difference between the treatments of early-stage versus late-stage glaucoma was estimated at $167. The total cost per recipient was estimated at $891/person.
Current Ontario Policy
As of November 1, 2004 persons between 20 years and 64 years of age are eligible for an insured eye examination once every year if they have any of the following medical conditions: diabetes mellitus type 1 or 2, glaucoma, cataract(s), retinal disease, amblyopia, visual field defects, corneal disease, or strabismus. Persons between 20 to 64 years of age who do not have diabetes mellitus, glaucoma, cataract(s), retinal disease, amblyopia, visual field defects, corneal disease, or strabismus may be eligible for an annual eye examination if they have a valid “request for major eye examination” form completed by a physician (other than that who completed the eye exam) or a nurse practitioner working in a collaborative practice. Persons 20-64 years of age who are in receipt of social assistance and who do not have one of the 8 medical conditions listed above are eligible to receive an eye exam once every 2 years as a non-OHIP government funded service. Persons 19 years of age or younger and 65 years of age or older may receive an insured eye exam once every year.
Considerations for Policy Development
As of July 17, 2006 there were 1,402 practicing optometrists in Ontario. As of December 31, 2005 there were 404 practicing ophthalmologists in Ontario. It is unknown how many third party payers now cover routine eye exams for person between the ages of 20 and 64 years of age in Ontario.
PMCID: PMC3379534  PMID: 23074485
6.  Long Term Use of Aspirin and Age-Related Macular Degeneration 
Context
Aspirin is widely used for relief of pain and for cardio-protective effects. Its use is of concern to ophthalmologists when ocular surgery is being considered and also in the presence of age-related macular degeneration (AMD).
Objective
To examine the association of regular aspirin use with incidence of AMD.
Design, Setting, and Participants
A longitudinal population-based study of age-related eye diseases in Beaver Dam, Wisconsin. Examinations were performed every 5 years over a 20-year period (1988–1990 through 2008–2010). Participants were aged 43–86 years at the baseline examination. At subsequent examinations, study participants were asked if they had regularly used aspirin at least twice a week for more than 3 months.
Main Outcome Measure
The incidence of early AMD, late AMD, and 2 subtypes of late AMD (neovascular AMD and pure geographic atrophy) were assessed in retinal photographs according to the Wisconsin Age-Related Maculopathy Grading System.
Results
The mean duration of follow-up was 14.8 years. There were 512 incident cases of early (of 6243 person-visits at risk) and 117 incident cases of late AMD (of 8675 person-visits at risk) over the course of the study. Regular aspirin use 10 years prior to retinal examination was associated with late AMD (hazard ratio 1.63; 95% CI 1.01–2.63; P=0.05) with estimated incidence of 1.76% (1.17–2.64) in regular users and 1.03% (0.70–1.51) in non-users. For subtypes of late AMD, regular aspirin use 10 years prior to retinal examination was significantly associated with neovascular AMD (reported as hazard ratio 2.20; 95% CI 1.20–4.15; P=0.01) but not pure geographic atrophy (0.66; 0.25–1.95; P=0.45). Aspirin use 5 (0.86; 0.71–1.05; P=0.13) or 10 years prior (0.86; 0.65–1.13; P=0.28) to retinal examination was not associated with incident early AMD.
Conclusions
Among persons aged 43 years and older followed for 20 years, aspirin use 5 years prior to observed incidence was not associated with incident early or late AMD. However, regular aspirin use 10 years prior was associated with a small but statistically significant increase in the risk of incident late and neovascular AMD.
doi:10.1001/jama.2012.65406
PMCID: PMC3630794  PMID: 23288416
aspirin; age-related macular degeneration; epidemiology
7.  Estimating Foodborne Gastroenteritis, Australia 
Emerging Infectious Diseases  2005;11(8):1257-1264.
An estimated 4.0–6.9 million episodes of foodborne gastroenteritis occur in Australia each year.
We estimated for Australia the number of cases, hospitalizations, and deaths due to foodborne gastroenteritis in a typical year, circa 2000. The total amount of infectious gastroenteritis was measured by using a national telephone survey. The foodborne proportion was estimated from Australian data on each of 16 pathogens. To account for uncertainty, we used simulation techniques to calculate 95% credibility intervals (CrI). The estimate of incidence of gastroenteritis in Australia is 17.2 million (95% confidence interval 14.5–19.9 million) cases per year. We estimate that 32% (95% CrI 24%–40%) are foodborne, which equals 0.3 (95% CrI 0.2–0.4) episodes per person, or 5.4 million (95% CrI 4.0–6.9 million) cases annually in Australia. Norovirus, enteropathogenic Escherichia coli, Campylobacter spp., and Salmonella spp. cause the most illnesses. In addition, foodborne gastroenteritis causes ≈15,000 (95% CrI 11,000–18,000) hospitalizations and 80 (95% CrI 40–120) deaths annually. This study highlights global public health concerns about foodborne diseases and the need for standardized methods, including assessment of uncertainty, for international comparison.
doi:10.3201/eid1108.041367
PMCID: PMC3320479  PMID: 16102316
Keywords: gastroenteritis; foodborne; burden; uncertainty
8.  Estimating the number needed to vaccinate to prevent diseases and death related to human papillomavirus infection 
Background
A vaccine against human papillomavirus (HPV) types 6, 11, 16 and 18 is now licensed for use in Canada and many other countries. We sought to estimate the number needed to vaccinate to prevent HPV-related diseases and death.
Methods
A cohort model of the natural history of HPV infection was developed. Model simulations were based on 209 different parameter sets that reproduced Canadian HPV type-specific data for infection, cervical intraepithelial neoplasia, cervical cancer and genital warts. The number needed to vaccinate was calculated as the number of women who would need to be vaccinated to prevent an HPV-related event during their lifetime.
Results
Among 12-year-old girls, we estimated that the number needed to vaccinate to prevent an episode of genital warts would be 8 (80% credibility interval [CrI] 5–15) and a case of cervical cancer 324 (80% CrI 195–757). These estimates were based on the assumption that the vaccine procures lifelong protection and that its efficacy is 95%. If vaccine protection is assumed to wane at 3% per year, the predicted number needed to vaccinate would increase to 14 (80% CrI 6–18) and 9080 (80% CrI 1040–does not prevent), respectively. The latter number would be greatly reduced with the addition of a booster dose, to 480 (80% CrI 254–1572).
Interpretation
Our model predictions suggest that vaccination with the currently available HPV vaccine may significantly reduce the incidence of genital warts, cervical intraepithelial neoplasia and cervical cancer. However, the benefits (particularly in terms of cervical cancer reduction) are highly dependent on the duration of vaccine protection, on which evidence is currently limited.
doi:10.1503/cmaj.061709
PMCID: PMC1950193  PMID: 17709404
9.  Prevalence and Risks factors of Age-Related Macular Degeneration in Oklahoma Indians: The Vision Keepers Study 
Ophthalmology  2011;118(7):1380-1385.
Objective
To determine the prevalence of age-related macular degeneration (AMD) and indentify its risk factors in an Oklahoma Indian population.
Design
Cross sectional study design
Participants
A total of 1019 Oklahoma Indians who participated in baseline and second examinations of the Oklahoma Strong Heart Study were enrolled in Vision Keepers.
Methods
Retinal photographs of at least one eye were taken and graded for AMD by the University of Wisconsin Ocular Epidemiology Reading Center using the Wisconsin Age-Related Maculopathy Grading System. Retinal photographs of 986 participants were considered gradable and included in the study.
Main Outcome Measures
Age-related macular degeneration (early & late).
Results
The overall prevalence of any AMD in the Vision Keepers study was 35.2% including a prevalence of 0.81% for late AMD. The prevalence of early AMD increased from 30.6% in those aged 48–59 years to 46.1% in age group 70–82 years. When potential risk factor was considered individually in the univariate analyses, men with hypertension had significantly higher prevalence of AMD (p=0.02) than those without hypertension. In women high density lipoprotein-cholesterol and sun exposure were positively associated with the prevalence of AMD (p=0.01) while a history of using multivitamins was associated with lower AMD prevalence (p= 0.005). When multiple risk factors were considered simultaneously in the logistic regression analyses, only age showed significant association with AMD in both men (p=0.02) and women (p <0.0001) and was the only significant risk factor in men. In women, multivitamin use and total cholesterol had significant inverse association with AMD while sun exposure and high density lipoprotein cholesterol had positive association. When men and women are combined, age and high density lipoproteincholesterol had significant positive association while total cholesterol and multivitamin use and current alcohol use showed a significant inverse association with AMD.
Conclusion
This study was the first to report detailed prevalence of AMD in Oklahoma Indians and its risk factors. The prevalence appeared to be relatively high as compared to other ethnic groups. Some of the modifiable risk factors identified confirmed previous findings and can be used to design preventive programs to reduce the burden of AMD, though longitudinal data are still needed.
doi:10.1016/j.ophtha.2010.11.007
PMCID: PMC3129490  PMID: 21310490
10.  Is Age-Related Macular Degeneration Associated with Stroke Among Elderly Americans?§ 
Objective:
To investigate whether age-related macular degeneration (AMD) is associated with the development of ischemic and hemorrhagic stroke among elderly Americans.
Design:
Population-based cohort study.
Participants:
The five percent random sample of 2000-2003 Medicare enrollees was obtained. The cohort (n=1,519,086) consisted of enrollees who were aged 65 or older at the first two-year (January 1, 2000 to December 31, 2001).
Methods:
Baseline demographic variables and chronic conditions (AMD and type, history of myocardial infarction (MI), stroke, hypertension, and diabetes) were defined based on the occurrence of relevant ICD-9 codes in relevant diagnosis fields of the baseline Medicare Data. We excluded 215,900 persons who had a diagnosis of MI or stroke during baseline period to form a cohort of 1,303,186 individuals who were free of major cardio-cerebral vascular disease (CVD) at baseline.
Main Outcome Measures:
In two years of follow-up (January 1, 2002 to December 31, 2003), a total of 89,501 incident stroke cases were identified, including 80,018 ischemic, 7048 hemorrhagic, and 2,435 stroke cases of both types.
Results:
Baseline mean age was 75 years (Standard Divination=7.7), with 60% women and 88% whites. The prevalence of AMD was 10.6%, with 19.7% being neovascular AMD and 80.3% being non-neovascular AMD. Baseline age, gender, race, hypertension, and diabetes adjusted 2-year incident odds ratios and 95% confidence internal of stroke associated with AMD were 1.31 (1.26, 1.36) for neovascular AMD, 1.18 (1.15, 1.21) for non-neovascular AMD, and 1.21 (1.18, 1.23) for either neovascular or non-neovascular AMD.
Conclusion:
The findings are suggestive of an association between AMD, especially neovascular AMD, and incident stroke, independent of demographic factors and co-morbidity. These findings, if confirmed by other studies that control for smoking and other lifestyle covariables not measured in this study, suggest the possibility of shared common antecedents between stroke and AMD.
doi:10.2174/1874364100802010037
PMCID: PMC2687926  PMID: 19516892
Age-related macular degeneration; stroke; Medicare medical claims; follow-up study.
11.  How big is the burden of visual loss caused by age related macular degeneration in the United Kingdom? 
Aims: To predict the burden of blindness, partial sight, and visual impairment (binocular visual acuity 6/18 or less) due to late stage age related macular degeneration (AMD) in the ageing population of the United Kingdom.
Methods: A systematic review, followed by a request for data, was used to establish a pooled prevalence of AMD and corresponding visual loss. Prevalence figures were applied to the UK population. Using UK population trends, the future burden of AMD over the coming decade was established.
Results: Pooled data from six studies showed that the prevalence of visual loss caused by AMD increased exponentially from the age of 70–85 years of age, with 3.5% (95% CI 3.0 to 4.1) having visual impairment beyond the age of 75 years. The authors estimate that there are currently 214 000 (95% CI 151 000 to 310 000) with visual impairment caused by AMD (suitable for registration). This number is expected to increase to 239 000 (95% CI 168 000 to 346 000) by the year 2011. Currently there are 172 000 (95% CI 106 000 to 279 000) and 245 000 (95% CI 163 000 to 364 000) with geographical and neovascular AMD, respectively.
Conclusions: Estimates of visual impairment agree with official statistics for the number registered partially sighted or blind, caused by AMD, and are well below other figures often cited. Although these estimates are associated with wide confidence intervals (CI) and a number of caveats, they represent the best available data, which can be used to guide health and social care provision for older people in the UK setting. Implications for low vision services are outlined.
PMCID: PMC1771556  PMID: 12598445
age related macular degeneration; blindness; partial sight; prevalence
12.  Dietary and lifestyle risk factors associated with age-related macular degeneration: A hospital based study 
Indian Journal of Ophthalmology  2013;61(12):722-727.
Aim:
To establish the frequency, associations and risk factors for age-related macular degeneration (AMD) in hospital population of South India.
Materials and Methods:
In this cross-sectional hospital based study, 3549 subjects (2090 men and 1459 women) above 45 years of age were screened randomly for AMD. Participants underwent ocular evaluation and were interviewed for lifestyle variables and dietary intake of carotenoids by structured food frequency questionnaire. AMD was defined according to the international classifications and grading system.
Results:
Either form of AMD was detected in 77 (2.2%) participants. Of which, early and late AMD was present in 63 (1.8%) and 14 (0.4%) subjects, respectively. Binary logistic analysis showed that the incidence of AMD was significantly higher with increasing age (Odds ratio [OR] 1.17; 95% CI 1.13-1.22) and diabetes (OR 3.97; 95% CI 2.11-7.46). However, AMD was significant among heavy cigarette smokers (OR 5.58; 95% CI 0.88-7.51) and alcoholics (OR 4.85; 95% CI 2.45-12.22). Dietary lutein/zeaxanthin (L/Z) and β-carotene intake were associated (P < 0.001) with the reduction in risk for AMD, with an OR of 0.38 and 0.65, respectively.
Conclusions:
Higher dietary intake of carotenoids, especially L/Z, was associated with lower risk for AMD. Risk of AMD is higher with increasing age and was prevalent among subjects with diabetes. Cessation of smoking and alcohol may reduce the risk of AMD in this population.
doi:10.4103/0301-4738.120218
PMCID: PMC3917390  PMID: 24178404
Age-related macular degeneration; carotenoids; cross-sectional studies; lutein
13.  Clonal Expansion of Staphylococcus epidermidis Strains Causing Hickman Catheter-Related Infections in a Hemato-Oncologic Department 
Journal of Clinical Microbiology  1998;36(9):2696-2702.
The detailed analysis of 411 strains of coagulase-negative staphylococci (CoNS) obtained from 40 neutropenic hemato-oncologic patients (61 Hickman catheter episodes) on intensive chemotherapy is described. By random amplification of polymorphic DNA (RAPD) analysis, a total of 88 different genotypes were detected: 51 in air samples and 30 in skin cultures prior to insertion, 12 in blood cultures after insertion, and only 5 involved in catheter-related infections (CRI). Two RAPD genotypes of Staphylococcus epidermidis predominated, and their prevalence increased during patient hospitalization. At insertion, these clones constituted 11 of 86 (13%) CoNS isolated from air samples and 33 of 75 (44%) CoNS isolated from skin cultures. After insertion, their combined prevalence increased to 33 of 62 (53%) in catheters not associated with CRI and 139 of 188 (74%) in catheters associated with CRI (P = 0.0041). These two predominant S. epidermidis clones gave rise to a very high incidence of CRI (6.0 per 1,000 catheter days) and a very high catheter removal rate for CRI, 70%, despite prompt treatment with vancomycin. A likely source of S. epidermidis strains involved in CRI appeared to be the skin flora in 75% of cases. The validity of these observations was confirmed by pulsed-field gel electrophoresis (PFGE) of SmaI DNA macrorestriction fragments of blood culture CoNS isolates. Again, two predominant CoNS genotypes were found (combined prevalence, 60%). RAPD and PFGE yielded concordant results in 75% of cases. Retrospectively, the same two predominant CoNS clones were also found among blood culture CoNS isolates from the same hematology department in the period 1991 to 1993 (combined prevalence, 42%) but not in the period 1978 to 1982. These observations underscore the pathogenic potential of clonal CoNS types that have successfully and persistently colonized patients in this hemato-oncology department.
PMCID: PMC105186  PMID: 9705416
14.  Kidney function, albuminuria and age-related macular degeneration in NHANES III 
Nephrology Dialysis Transplantation  2011;26(10):3159-3165.
Background. Age-related macular degeneration (AMD) and kidney disease may have shared risk factors, including cardiovascular disease risk factors; additionally AMD and dense deposit disease share a common causal link, with both associated with polymorphisms in the complement pathway. Accordingly, we explored a population-based cohort of US adults to examine if markers of kidney disease identify a higher risk population for prevalent AMD.
Methods. A cross-sectional nested case–control study matching on age, sex and race was performed using data on adult participants in the Third National Health and Nutrition Examination Survey. Predictor variables included urine albumin-to-creatinine ratio and estimated glomerular filtration rate (eGFR). Study outcomes included late AMD, defined as neovascular disease or geographic atrophy (5:1 matching), and a composite of both early AMD, defined as soft drusen or pigment irregularities with or without any drusen, and late AMD (1:1 matching).
Results. There were 51 participants with late AMD and 865 with any AMD. In conditional logistic regression adjusting for diabetes, hypertension and total cholesterol, lower eGFR was independently associated with late AMD [odds ratio (OR) = 3.05, 95% confidence interval (CI): 1.51–6.13], while albuminuria was not significant. For any AMD, neither albuminuria nor eGFR were significant in adjusted models. In sensitivity analyses excluding diabetics, albuminuria was associated with any AMD (OR = 1.56, 95% CI: 1.11–1.29 and 1.57, 95% CI: 0.61–3.69 for micro- and macroalbuminuria, respectively, P = 0.03).
Conclusions. Late AMD is more common among individuals with reduced kidney function. Whether this association reflects a common causal pathway or shared risk factors such as hypertension requires additional investigation.
doi:10.1093/ndt/gfr022
PMCID: PMC3247860  PMID: 21339308
age-related macular degeneration; albuminuria; chronic kidney disease; dense deposit disease; glomerular filtration rate
15.  The Relationship of Atherosclerosis to the 10-Year Cumulative Incidence of Age-Related Macular Degeneration: The Beaver Dam Studies 
Ophthalmology  2013;120(5):1012-1019.
Objective
To describe the relationships of intima-media layer thickness (IMT), plaque in the carotid artery, angina, myocardial infarction (MI), and stroke to the 10-year cumulative incidence of early and late age-related macular degeneration (AMD) and progression of AMD.
Design
Cohort study.
Participants
1700 persons aged 53–96 years who participated in both the Epidemiology of Hearing Loss Study and the Beaver Dam Eye Study in 1998–2000, with photographs gradable for AMD at a 5- (2003–2005) and/or 10-year (2008–2010) follow-up examination.
Methods
IMT and presence of plaque were assessed using B-mode ultrasonography of the carotid artery. Presence of angina, MI, and stroke were defined based on a self-reported history of physician diagnosis. Presence and severity of AMD were determined by systematic grading of stereoscopic color fundus photographs.
Main Outcome Measures
AMD.
Results
The 10-year cumulative incidence of early AMD was 15.7% and the 10-year cumulative incidence of late AMD was 4.0%. Adjusting for age, sex, body mass index, smoking status, Age-Related Maculopathy Susceptibility 2 and Complement Factor H genotypes and other factors, mean IMT was associated with the 10-year incidence of early AMD (odds ratio per 0.1 mm IMT 1.11, 95% confidence interval 1.00–1.21, P value=0.03) and late AMD (1.27, 1.10–1.47, P=0.001). Mean IMT was associated with the 10-year incidence of pure geographic atrophy (1.31, 1.05–1.64, P=0.02) but not exudative AMD (1.14, 0.97–1.34, P=0.11). Similar associations were found for maximum IMT. The number of sites with plaque was related to the incidence of late AMD (2.79 for 4–6 sites vs. none, 1.06–7.37, P=0.04) but not to early AMD. A history of angina, MI, or stroke was not related to any incident AMD outcome.
Conclusions
In these population-based data, carotid artery IMT and carotid plaques had a weak relationship to the incidence of late AMD, independent of systemic and genetic risk factors. Angina, MI, and stroke were not related to AMD. It is unclear whether the carotid IMT is a risk indicator of processes affecting Bruch’s membrane and the retinal pigment epithelium, or a measure of atherosclerosis affecting susceptibility to AMD.
doi:10.1016/j.ophtha.2012.11.003
PMCID: PMC3646961  PMID: 23399375
16.  The Cost-effectiveness of Welcome to Medicare Visual Acuity Screening and a Possible Alternative Welcome to Medicare Eye Evaluation Among Persons Without Diagnosed Diabetes Mellitus 
Archives of ophthalmology  2012;130(5):607-614.
Objective
To estimate the cost-effectiveness of visual acuity screening performed in primary care settings and of dilated eye evaluations performed by an eye care professional among new Medicare enrollees with no diagnosed eye disorders. Medicare currently reimburses visual acuity screening for new enrollees during their initial preventive primary care health check, but dilated eye evaluations may be a more cost-effective policy.
Design
Monte Carlo cost-effectiveness simulation model with a total of 50 000 simulated patients with demographic characteristics matched to persons 65 years of age in the US population.
Results
Compared with no screening policy, dilated eye evaluations increased quality-adjusted life-years (QALYs) by 0.008 (95% credible interval [CrI], 0.005–0.011) and increased costs by $94 (95% CrI, −$35 to $222). A visual acuity screening increased QALYs in less than 95% of the simulations (0.001 [95% CrI, −0.002 to 0.004) and increased total costs by $32 (95% CrI, −$97 to $159) per person. The incremental cost-effectiveness ratio of a visual acuity screening and an eye examination compared with no screening were $29 000 and $12 000 per QALY gained, respectively. At a willingness-to-pay value of $15 000 or more per QALY gained, a dilated eye evaluation was the policy option most likely to be cost-effective.
Conclusions
The currently recommended visual acuity screening showed limited efficacy and cost-effectiveness compared with no screening. In contrast, a new policy of reimbursement for Welcome to Medicare dilated eye evaluations was highly cost-effective.
doi:10.1001/archopthalmol.2011.1921
PMCID: PMC3759517  PMID: 22232367
17.  Cardiovascular Disease, its Risk Factors and Treatment, and Age-related Macular Degeneration: Women’s Health Initiative Sight Exam Ancillary Study 
American journal of ophthalmology  2007;143(3):473-483.
Purpose
To examine the association of cardiovascular disease (CVD), CVD risk factors, and CVD treatment with age-related macular degeneration (AMD).
Design
Observational analysis of a randomized clinical trial.
Methods
Setting
The Women’s Health Initiative Sight Examination (WHISE), an ancillary study to the Women’s Health Initiative’s (WHI) clinical trial of hormone replacement therapy.
Study Population
4,288 women aged 63 years and older.
Observation Procedures
Information on CVD and its risk factors were obtained from a standardized questionnaire and examination.
Main Outcome Measure
AMD as determined by standardized grading of fundus photographs.
Results
Prevalence of any AMD was 21.4% (n=919). Of those with AMD, 5.8% (n=53) had signs of exudative AMD (n=39) or pure geographic atrophy (n=14), limiting the power to examine associations. Significant associations between late AMD and CVD risk factors were (odds ratio [OR], 95% confidence interval [CI]) older age (1.19, 1.13, 1.27, p < 0.0001), more pack years smoked (1.02 per pack-year smoked, 1.003, 1.03, p = 0.01), systolic blood pressure (0.84 per 10 mmHg, 0.71, 0.995, p = 0.04), report of taking calcium channel blockers (CCB) (2.49, 1.21, 5.12, p = 0.04), self-reported history of diabetes (2.00, 1.01, 3.96, p = 0.05), and greater body mass index (1.05 per 1 kg/m2, 1.001, 1.10, p = 0.05). History of myocardial infarction, stroke, use of statins, or white blood cell were not associated with AMD.
Conclusions
Results suggest that smoking, use of CCBs, diabetes, and obesity are risk factors for late AMD in women. However, the association of late AMD with systolic blood pressure and the effects of other CVD risk factors on early AMD need to be further explored.
doi:10.1016/j.ajo.2006.11.058
PMCID: PMC2812860  PMID: 17317391
18.  Polymorphisms in ARMS2/HTRA1 and Complement Genes and Age-Related Macular Degeneration in India: Findings from the INDEYE Study 
Purpose.
Association between genetic variants in complement factor H (CFH), factor B (CFB), component 2 (C2), and in the ARMS2/HTRA1 region with age-related macular degeneration (AMD) comes mainly from studies of European ancestry and case-control studies of late-stage disease. We investigated associations of both early and late AMD with these variants in a population-based study of people aged 60 years and older in India.
Methods.
Fundus images were graded using the Wisconsin Age-Related Maculopathy Grading System and participants assigned to one of four mutually exclusive stages based on the worse affected eye (0 = no AMD, 1–3 = early AMD, 4 = late AMD). Multinomial logistic regression was used to derive risk ratios (RR) accounting for sampling method and adjusting for age, sex, and study center.
Results.
Of 3569 participants, 53.2% had no signs of AMD, 45.6% had features of early AMD, and 1.2% had late AMD. CFH (rs1061170), C2 (rs547154), or CFB (rs438999) was not associated with early or late AMD. In the ARMS2 locus, rs10490924 was associated with both early (adjusted RR 1.22, 95% confidence interval [CI]: 1.13–1.33, P < 0.0001) and late AMD (adjusted RR 1.81, 95% CI: 1.15–2.86; P = 0.01); rs2672598 was associated only with early AMD (adjusted RR 1.12, 95% CI: 1.02–1.23; P = 0.02); rs10490923 was not associated with early or late AMD.
Conclusions.
Two variants in ARMS2/HTRA1 were associated with increased risk of early AMD, and for one of these, the increased risk was also evident for late AMD. The study provides new insights into the role of these variants in early stages of AMD in India.
We report results from a genetic association study of early AMD in an Indian population. Two variants in the ARMS/HTRA1 region were associated with early AMD but variants in C2, CFH, and CFB were not.
doi:10.1167/iovs.12-10073
PMCID: PMC3490538  PMID: 23060141
19.  Risk Alleles in CFH and ARMS2 and the Long Term Natural History of Age-Related Macular Degeneration. The Beaver Dam Eye Study 
JAMA ophthalmology  2013;131(3):383-392.
Objective
To describe relationships of risk alleles in complement factor H (CFH, rs1061170) and Age-Related Maculopathy susceptibility 2 (ARMS2, rs10490924) to the incidence and progression of age-related macular degeneration (AMD) over a 20-year period.
Methods
There were 4282 persons aged 43–86 years at the baseline examination in 1988–1990 enrolled in a population-based cohort study who participated in at least 1 pair of examinations spaced 5 years apart over a 20-year period and had gradable fundus photographs for AMD and genotype information on CFH and ARMS2. Low, intermediate, and high genetic risk for AMD was defined by the presence of 0–1, 2, or 3–4 risk alleles for CFH and ARMS2, respectively. Multi-state models (MSMs) were used to estimate progression of AMD over the entire age range.
Results
There were 2820 (66%), 1129 (26%), and 333 persons (8%) with low, intermediate, and high genetic risk for AMD, respectively. The 5-year incidences of early and late AMD were 9.1% and 1.6%, respectively, and increased with age but did not differ by sex. Using the MSM, of persons aged 45 years with no AMD in the low, intermediate, and high AMD genetic risk groups, 33.0%, 39.9%, and 46.5%, respectively were estimated to develop early AMD, and 1.4%, 5.2%, and 15.3%, respectively were estimated to develop late AMD by age 80 years.
Conclusions
These population-based data provide estimates of the long-term risk of the incidence and progression of AMD and its lesions by age and genetic risk alleles for CFH and ARMS2.
doi:10.1001/jamaophthalmol.2013.713
PMCID: PMC3602927  PMID: 23494043
age-related macular degeneration; ARMS2; CFH; epidemiology
20.  Incidence of Chlamydia trachomatis infection in women in England: two methods of estimation 
Epidemiology and Infection  2013;142(3):562-576.
SUMMARY
Information on the incidence of Chlamydia trachomatis (CT) is essential for models of the effectiveness and cost-effectiveness of screening programmes. We developed two independent estimates of CT incidence in women in England: one based on an incidence study, with estimates ‘recalibrated’ to the general population using data on setting-specific relative risks, and allowing for clearance and re-infection during follow-up; the second based on UK prevalence data, and information on the duration of CT infection. The consistency of independent sources of data on incidence, prevalence and duration, validates estimates of these parameters. Pooled estimates of the annual incidence rate in women aged 16–24 and 16–44 years for 2001–2005 using all these data were 0·05 [95% credible interval (CrI) 0·035–0·071] and 0·021 (95% CrI 0·015–0·028), respectively. Although, the estimates apply to England, similar methods could be used in other countries. The methods could be extended to dynamic models to synthesize, and assess the consistency of data on contact and transmission rates.
doi:10.1017/S0950268813001027
PMCID: PMC3915754  PMID: 23759367
Bayesian analysis; Chlamydia; evidence synthesis; incidence; multi-parameter evidence synthesis
21.  A statistical model to assess the risk of communicable diseases associated with multiple exposures in healthcare settings 
Background
The occurrence of communicable diseases (CD) depends on exposure to contagious persons. The effects of exposure to CD are delayed in time and contagious persons remain contagious for several days during which their contagiousness varies. Moreover when multiple exposures occur, it is difficult to know which exposure is associated with the CD.
Methods
A statistical model at the individual level is presented to estimate the risk of CD to patients, in healthcare settings, with multiple observed exposures to other patients and healthcare workers and unobserved exposures to unobserved or unobservable sources. The model explores the delayed effect of observed exposure, of source contagiousness and of unobserved exposure. It was applied to data on influenza-like illness (ILI) among patients in a university hospital during 3 influenza seasons: from 2004 to 2007. Over a total of 138,411 patients-days of follow-up, 64 incident ILI cases were observed among 21,519 patients at risk of ILI.
Results
The ILI risk per 10,000 patients-days associated with observed exposure was about 129.1 (95% Credible Interval (CrI): 84.5, 182.9) and was associated at 72% with exposures to patients or healthcare workers 1 day earlier and at 41% with the 1st day of source contagiousness. The ILI risk associated with unobserved exposure was 0.8 (95% CrI: 0.3, 1.6) per 10,000 patients-days in non-epidemic situation in the community and 4.3 (95% CrI: 0.4, 11.0) in epidemic situation.
Conclusions
The model could be an interesting epidemiological tool to further assess the relative contributions of observed and unobserved exposures to CD risk in healthcare settings.
doi:10.1186/1471-2288-13-26
PMCID: PMC3599894  PMID: 23425160
Disease transmission; Infectious; Health facilities; Influenza; Human; Models; Statistical; Risk
22.  Physical activity and the 15‐year cumulative incidence of age‐related macular degeneration: the Beaver Dam Eye Study 
The British Journal of Ophthalmology  2006;90(12):1461-1463.
Background
Cardiovascular disease and age‐related macular degeneration (AMD) may share common risk factors. Physical activity improves the cardiovascular risk profile; however, there have been few studies investigating a relationship between physical activity and the long‐term incidence of AMD.
Methods
The 15‐year cumulative incidence of AMD was determined through four examination phases at 5‐year intervals of a population‐based study conducted in Beaver Dam, Wisconsin, USA, initiated in 1988–90 (n = 3874 men and women between ages 43 and 86 years). Early AMD (pigment abnormalities or soft indistinct drusen), exudative AMD and geographic atrophy were determined by grading stereoscopic colour fundus photographs. Measures of physical activity were obtained through a questionnaire administered at the baseline examination.
Results
After controlling for age, sex, history of arthritis, systolic blood pressure, body mass index, smoking and education, people with an active lifestyle (defined as regular activity ⩾3 times/week) at baseline were less likely to develop exudative AMD (odds ratio (OR) 0.3, 95% confidence interval (CI) 0.1 to 0.7) compared with people without an active lifestyle. After multivariate adjustment, increased categories of number of blocks walked per day decreased the risk of exudative AMD (OR 0.7, 95% CI 0.6 to 0.97). Physical activity was not related to the incidence of early AMD or pure geographic atrophy.
Conclusions
These data show a protective effect of physical activity for incident exudative AMD, independent of body mass index and other confounders. They also suggest a possible modifiable behaviour that might be protective against developing AMD.
doi:10.1136/bjo.2006.103796
PMCID: PMC1857544  PMID: 17077116
23.  C-Reactive Protein and the Incidence of Macular Degeneration – Pooled Analysis of 5 Cohorts 
JAMA ophthalmology  2013;131(4):507-513.
Objectives
To investigate the relationship between high-sensitivity C-reactive protein (hsCRP) and future risk of age-related macular degeneration (AMD) in US men and women.
Methods
We measured hsCRP in baseline blood samples from participants in five ongoing cohort studies. Patients were initially free of AMD. We prospectively identified 647 incident cases of AMD and selected age- and sex-matched controls for each AMD case (2 controls for each case with dry AMD, or 3 controls for each case of neovascular AMD). We used conditional logistic regression models to examine the relationship between hsCRP and AMD, and pooled findings using meta-analytic techniques.
Results
After adjusting for cigarette smoking status, participants with high (> 3 mg/L) compared with low (< 1 mg/L) hsCRP levels, had cohort-specific odds ratios (OR) for incident AMD ranging from 0.94 (95% CI 0.58-1.51) in the Physicians’ Health Study to 2.59 (95% CI 0.58-11.67) in the Women’s Antioxidant and Folic Acid Cardiovascular Study. After testing for heterogeneity between studies (Q=5.61, p=0.23), we pooled findings across cohorts, and observed a significantly increased risk of incident AMD for high versus low hsCRP levels (OR=1.49, 95% CI 1.06-2.08). Risk of neovascular AMD was also increased among those with high hsCRP levels (OR=1.84, 95% CI 1.14-2.98).
Conclusion
Overall these pooled findings from 5 prospective cohorts add further evidence that elevated levels of hsCRP predict greater future risk of AMD. This information might shed light on underlying mechanisms, and could be of clinical utility in the identification of persons at high risk of AMD who may benefit from increased adherence to lifestyle recommendations, eye examination schedules, and therapeutic protocols.
doi:10.1001/jamaophthalmol.2013.2303
PMCID: PMC3625501  PMID: 23392454
24.  Prospective study of lutein/zeaxanthin intake and risk of age-related macular degeneration2 
Background
The association between lutein/zeaxanthin intake and age-related macular degeneration (AMD) risk may differ by smoking status, vitamin C and E intakes, and body fatness.
Objective
The objective was to evaluate the association between lutein/zeaxanthin intake and AMD risk by smoking status, intake of antioxidant vitamins, and body fatness.
Design
We conducted a prospective follow-up study of 71 494 women and 41 564 men aged ≥50 y and had no diagnosis of AMD or cancer. Diet was assessed with a validated semiquantitative food-frequency questionnaire.
Results
During up to 18 y of follow-up, we documented 673 incident cases of early AMD and 442 incident cases of neovascular AMD with a visual loss of 20/30 or worse due primarily to AMD. Lutein/zeaxanthin intake was not associated with the risk of self-reported early AMD. There was a statistically nonsignificant and nonlinear inverse association between lutein/zeaxanthin intake and neovascular AMD risk; the pooled multivariate relative risks for increasing quintiles of intake were 1.00 (referent), 0.80, 0.84, 0.97, and 0.72 (95% CI: 0.53, 0.99) (P for trend = 0.14). For early AMD, the association with lutein/zeaxanthin intake did not vary by smoking status, intakes of vitamins C and E, or body mass index. For neovascular AMD, a nonlinear inverse association was found among never smokers.
Conclusions
These data do not support a protective role of lutein/zeaxanthin intake on risk of self-reported early AMD. The suggestion of inverse associations related to the risk of neovascular AMD needs to be examined further.
PMCID: PMC2504741  PMID: 18541575
25.  Age-Related Macular Degeneration and Incident Cardiovascular Disease: The Multi-Ethnic Study of Atherosclerosis 
Ophthalmology  2011;119(4):765-770.
Objective
To determine whether age-related macular degeneration (AMD) is a risk indicator for coronary heart disease (CHD) and cardiovascular disease (CVD) events independent of other known risk factors in a multi-ethnic cohort.
Design
Population-based prospective cohort study.
Participants
A diverse population sample of 6233 men and women aged 45–84 without known CVD from the Multi-Ethnic Study of Atherosclerosis (MESA).
Methods
Participants in the MESA had retinal photographs taken between 2002 and 2003. Photographs were evaluated for AMD. Incident CHD/CVD events were ascertained during clinical follow-up visits for up to 8 years after the retinal images were taken.
Main Outcome Measures
Incident CHD/CVD events.
Results
Of the 6814 persons at risk of CHD, there were 893 participants with early AMD (13.1%) and 27 (0.5%) at baseline. Over a mean follow-up period of 5.4 years, there was no statistically significant difference in incident CHD or CVD between the AMD and non-AMD groups (5.0%vs. 3.9%, p=0.13 for CHD and 6.6 vs. 5.5%, p=0.19 for CVD, respectively). In Cox regression models adjusting for CVD risk factors, there was no significant relationship between presence of any AMD and any CHD/CVD events (HR=0.99, 95% CI 0.74–1.33, p=0.97). No significant association was found between subgroups of early AMD or late AMD and incident CHD/CVD events.
Conclusions
In persons without a history of cardiovascular disease, AMD was not associated with an increased risk of CHD or CVD.
doi:10.1016/j.ophtha.2011.09.044
PMCID: PMC3314126  PMID: 22197438

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