Purpose
To identify risk factors for 4-year incidence and progression of age-related macular degeneration (AMD) in adult Latinos.
Design
Population-based prospective cohort study.
Methods
Participants, aged 40 or older, from The Los Angeles Latino Eye Study (LALES) underwent standardized comprehensive ophthalmologic examinations at baseline and at 4 years of follow-up. Age-related macular degeneration was detected by grading 30-degree stereoscopic fundus photographs using the modified Wisconsin Age-Related Maculopathy Grading System. Multivariate stepwise logistic regression was used to examine the independent association of incidence and progression of AMD and baseline sociodemographic, behavioral, clinical, and ocular characteristics.
Results
Multivariate analyses revealed that older age (OR per decade of age: 1.52; 95% CI: 1.29, 1.85) and higher pulse pressure (OR per 10 mm Hg: 2.54; 95% CI: 1.36, 4.76) were independently associated with the incidence of any AMD. The same factors were associated with early AMD, soft indistinct drusen, and retinal pigmentary abnormalities. Additionally, presence of clinically diagnosed diabetes mellitus was independently associated with increased retinal pigment (OR: 1.66; 95% CI: 1.01, 2.85), and male gender was associated with retinal pigment epithelial depigmentation (OR 2.50; 95% CI: 1.48, 4.23). Older age (OR per decade of age: 2.20; 95% CI: 1.82, 2.67) and current smoking (OR: 2.85; 95% CI: 1.66, 4.90) were independently associated with progression of AMD.
Conclusions
Several modifiable risk factors were associated with 4-year incidence and progression of AMD in Latinos. The results suggest that interventions aimed at reducing pulse pressure and promoting smoking cessation may reduce incidence and progression of AMD, respectively.
Age-related macular degeneration (AMD) is a progressive disorder of the macular area that becomes clinically apparent usually after 50 years of age. When it progresses to advanced stages it can result in severe loss of central vision with significant impact on quality of life. Age-related macular degeneration is the leading cause of irreversible blindness in the western world. With the shifting of population distribution to older age groups, the prevalence, effect, and healthcare cost of AMD is expected to increase substantially in these countries. In the United States alone, expenditure associated with AMD treatment in 2004 was $525 million. Prevalence of AMD in the United States is expected to increase from about 10 million in 2010 to about 20 million in 2050 6 and, hence, will continue to be an increasing public health problem, resulting in significant increase in healthcare expenses attributable to AMD.
Latinos constitute the largest and fastest-growing minority segment of the US population. If recent trends continue, the US Latino population is estimated to increase to 102.6 million in 2050, or 24.4% of the total population. But there is a relative lack of population-based data regarding ocular health in Latinos, and the factors associated with AMD incidence and progression among Latinos remain largely unexplored. Data from the Los Angeles Latino Eye Study (LALES) demonstrate a lower prevalence and incidence of early and late AMD compared to other populations. Therefore, it is important to understand whether different and modifiable factors are operative in Latinos that influence disease risk and progression and may explain the differences in rates.
In the LALES, examination of baseline data revealed several demographic (age, male gender, Native American ancestry, family history), behavioral (smoking, alcohol consumption), clinical (higher diastolic blood pressure [DBP], uncontrolled diastolic hypertension, pulse pressure), and ocular (presence of cataract, cataract surgery, and myopic refractive error) factors to be associated cross-sectionally with the prevalence of different AMD lesions in Latinos.
In the current analysis, we examine the relationships between these factors and the 4-year incidence and progression of AMD in the cohort to tease out factors that are associated with disease development vs those associated with disease duration. While cross-sectional studies can identify associations between risk factors and existing AMD, longitudinal incidence studies are required to determine the indicators that may be associated with the development of future AMD.
We believe that for the overall improvement of the public health status of the country it is imperative to reduce the incapacitating and costly burden of AMD in the fastest-growing segment of US population. Hence, it is crucial to identify the unique risk factors that are associated with and possibly contribute to the development of AMD in Latinos, which can aid in developing evidence-based public health programs to prevent vision loss in this population.
Methods
Latinos (Hispanics, Hispanic Americans, and Latino Americans) are individuals who are born into or have descended from a Spanish-speaking community, regardless of race. In the United States, Latinos are a heterogeneous group, with the majority being of Mexican ancestry (66%). The Los Angeles Latino Eye Study is a population-based longitudinal study of eye disease in self-identified Latinos, aged 40 years and older, living in 6 census tracts in the city of La Puente, Los Angeles County, California. Baseline examination was performed from 2000 to 2003, with 4-year follow-up examination from 2004 to 2008. Details of the study design, methods, and baseline data have been reported elsewhere.
All eligible participants in the baseline LALES examination were invited to return for a home interview and a clinical examination. Similar questionnaire and examination procedures were used for both baseline and follow-up studies. In-home interviews were conducted after obtaining informed consent. Trained ophthalmologists and technicians performed a comprehensive ocular examination using standardized protocols, which included 30-degree stereoscopic color fundus photographs of Diabetic Retinopathy Study field 1 (centered on the optic disc), field 2 (centered on the macula), and a modified field 3 (nonstereoscopic, temporal to and including the fovea) on all participants.
Risk Factor Assessment
For this analysis, factors examined as possible risk factors included a number of sociodemographic, behavioral, clinical, and ocular characteristics selected in light of literature review and expert opinion. Among these, age, gender, country of birth, acculturation, working status, years of education, marital status, income, insurance coverage, smoking, alcohol intake, history of high blood pressure, history of heart attack, and history of stroke were self reported (obtained from home questionnaire). Diabetes, systolic blood pressure (SBP), DBP, pulse pressure, height, and weight were clinically assessed. Ocular factors such as cataract, lens opacities, refractive error, iris color, and axial length were assessed by comprehensive ophthalmologic examination. Age was defined as age at the baseline examination. Systolic and diastolic blood pressures were the average of 3 baseline measurements. Body mass index was calculated as body weight/height .
AMD Grading
In LALES, strict, uniform grading methods were adopted and used by experienced, masked graders at the Wisconsin Ocular Epidemiology Reading Center to grade individual AMD lesions following a modification of the Wisconsin Age-Related Maculopathy Grading System (WARMGS). Detailed descriptions of all grading procedures and definitions were previously reported. In brief, a lesion-by-lesion evaluation was performed at each examination to determine maximum drusen size, type, area, and retinal pigmentary abnormalities. Each eye was graded independent of the contralateral eye. Any clinically meaningful differences between 2 initial graders were adjudicated by a senior grader using standardized edit rules. Graders were masked to the year the photographs were taken. A side-by-side longitudinal grading of all eyes with meaningful (eg, defining incidence or progression of AMD and its lesions) clinical changes over the 4-year period was done before a final AMD grade was assigned. Strict quality control measures were also applied.
Definitions of Incident AMD
Definitions of AMD component lesions, including specific drusen size, drusen types, and retinal pigmentary abnormalities and incidence and progression of AMD, are the same as used in the Beaver Dam Eye Study (BDES) and have been described in detail elsewhere.
Incident early AMD was defined as the absence of signs of advanced AMD and the presence of 1) soft indistinct or reticular drusen or 2) hard distinct or soft distinct drusen with pigmentary abnormalities (retinal pigment epithelial [RPE] depigmentation or increased retinal pigment) at 4-year follow-up in participants who did not have any evidence of AMD at baseline. Incident advanced AMD was defined as the presence of either 1) geographic atrophy or 2) exudative AMD at follow-up in people who had no evidence of AMD at baseline.
The 6-step modified Beaver Dam Eye Study severity scale was used to estimate the 4-year progression of AMD . Person-specific progression was reported by concatenating the score given for each eye, thus defining overall severity using the score from the more affected eye. Progression of AMD was defined as 2 steps or more increase in severity at 4-year follow-up in subjects with a severity level of 1 through 3 at baseline. We also restricted the definition of progression to a 2-step progression in those with definitive evidence of AMD at baseline. Per-eye progression was also defined and examined for risk factors in this restricted group.
Statistical Analyses
The baseline characteristics of the cohort of this analysis and nonparticipants were analyzed using t tests for comparison of means and χ 2 tests for comparison of proportions. Sociodemographic, clinical, and ocular characteristics of participants with and without AMD were analyzed using t tests for comparison of means and χ 2 tests for comparison of proportions. Each AMD endpoint (any AMD, early AMD, soft indistinct drusen, increased retinal pigmentation, and decreased RPE) was modeled separately to investigate its association with different risk indicators.
The continuous variables of age, SBP, DBP and pulse pressure were initially modeled as both continuous and categorical variables. Due to departure from log-linearity assumption for the SBP, DBP, and pulse pressure, we modeled these in different ways and eventually dichotomized them into clinically meaningful categories. Age was modeled as a continuous variable (per decade of age). Other than employment status (employed, unemployed, retired) and smoking status (never, past, current), all other variables were dichotomous.
The unadjusted associations between the risk indicators and different endpoints were assessed by univariate logistic regression and odds ratios (OR) for each of the significant variables were calculated. The independent associations of significant predictors were evaluated by multiple logistic regression analyses with forward stepwise selection using a P ≤ .20 criterion for entry into the model. The final multivariate predictive model comprised those factors that were significant at an alpha level of 0.05 after mutual adjustment. Generalized estimating equation was used to examine the risk factors for progression per eye.
To further assess the nature of the relationship between these risk factors and the endpoints, we used local regression methods adjusting for other covariates from the final logistic regression model and generated LOWESS (locally weighted smoothing regression) plots. The LOWESS plot uses an iterative, locally weighted, least-squares method to plot the best-fit line that sheds light on the qualitative nature of the relationship.
Possible effect modification of the association between AMD and the predictors was tested by incorporating the proper interaction term in the logistic regressions models. The analyses were performed using SAS software 9.2 (Sas, Inc, Cary, North Carolina, USA) and Stata version 11 (StataCorp, College Station, Texas, USA). All tests for significance were at P value .05 level.
Results
Study Cohort
Of the 6100 living eligible participants identified, 4658 (76%) participated in the 4-year follow-up study. Mean follow-up period was 4.3 (± 0.03) years. Mean age of participants was 54.7 ± 10.5 years, 60% were female, and 76% were born outside of the United States. At baseline, the demographic and socioeconomic characteristics of the participants were determined to be representative of the overall Latino population in Los Angeles County.
Living eligible subjects not included in the analysis sample comprised nonparticipants of the follow-up study, as well as participants with either missing or nongradable fundus photographs at baseline or follow-up examinations ( Figure 1 ). Of those who completed the ophthalmologic examination (n = 4658), fundus photographs gradable for AMD lesions in at least 1 eye were available for 4029 participants. A total of 629 participants did not complete fundus photography for a variety of reasons. Of the 3931 follow-up participants with gradable fundus photographs, 3908 had gradable fundus photographs in at least 1 eye from their baseline examination, thus making this the analysis cohort.
The comparison of different demographic and clinical characteristics between participants included in the analysis cohort and the excluded subjects are summarized in Table 1 . The major differences were that those in the final analysis cohort were more educated, more likely to be married, more likely to have comorbidities, and less likely to report worse visual health status. In addition, a lower proportion of the final analysis cohort had cataract or diabetic retinopathy compared to those who were not included. While the differences were statistically significant, the differences in frequencies between the participants and the nonparticipants tended to be small.
| Characteristics | Analysis Cohort N =3908 | Nonparticipants or Excluded N = 2192 | P | ||
|---|---|---|---|---|---|
| N | % | N | % | ||
| Gender (female) | 2346 | 60.09 | 1257 | 57.53 | .05 |
| Age | |||||
| Mean (SD) | 54.29 (10.1) | 54.37 (11.35) | .77 | ||
| Acculturation (low <1.9) a | 1281 | 32.81 | 703 | 32.17 | .61 |
| Working status (employed) | 2001 | 51.26 | 1068 | 48.88 | .08 |
| Education level <12 years | 1348 | 34.53 | 695 | 31.81 | .031 |
| Marital status (married) | 2791 | 71.49 | 1447 | 66.22 | <.0001 |
| Income level >$40,000 | 499 | 12.90 | 266 | 12.26 | .48 |
| Health insurance | 1292 | 33.09 | 905 | 41.42 | <.0001 |
| ≥2 comorbidities | 1594 | 40.83 | 801 | 36.66 | .0014 |
| Self-reported health excellent/very good | 742 | 19.01 | 430 | 19.68 | .52 |
| History of hypertension | 1162 | 29.84 | 598 | 27.41 | .05 |
| History of diabetes | 689 | 17.65 | 414 | 18.95 | .21 |
| Self-reported vision excellent/good | 1643 | 42.09 | 846 | 38.72 | .01 |
| Status of ocular disease at baseline | |||||
| Any ocular disease | 1310 | 33.52 | 735 | 33.53 | .99 |
| Cataract | 597 | 15.55 | 371 | 19.49 | .002 |
| Glaucoma | 149 | 3.81 | 106 | 4.84 | .06 |
| AMD | 361 | 9.24 | 183 | 10.37 | .18 |
| Diabetic retinopathy | 521 | 13.34 | 289 | 15.55 | .02 |
a Acculturation was measured using the short-form Cuellar Acculturation Scale.
Table 2 compares the sociodemographic and clinical risk indicators of participants with any AMD to those without any AMD. The major differences between these 2 groups were age and age-related characteristics. Participants with AMD were statistically significantly older ( P < .001), had more comorbidities ( P = .004), and were more likely to be unemployed or retired ( P = .006) than those without AMD. The AMD incident cases were also more likely to have a history of hypertension, higher mean SBP, higher mean pulse pressure, and a history of any lens opacity or cataract surgery.
| Variables | No AMD a | Incident AMD a | P Value b |
|---|---|---|---|
| (N =3800) | (N = 100) | ||
| Sociodemographic characteristics | |||
| Age | 54.3 (10.1) | 60.8 (12.2) | <.001 |
| Gender: female | 2276 (59.9) | 56 (58.0) | .57 |
| Unemployed/retired | 1860 (49.1) | 65 (65) | .006 |
| Income <$20,000 | 1637 (43.1) | 47 (47.0) | .65 |
| Education <12 years | 2493 (65.6) | 64 (64.0) | .77 |
| Health insurance: Yes | 2542 (66.9) | 74 (74.0) | .11 |
| Vision insurance: Yes | 2007 (52.8) | 51 (51.0) | .74 |
| Acculturation score c | 1.8 (0.8) | 1.8 (0.9) | .93 |
| Country of birth (USA) | 903 (23.8) | 22 (22.0) | .77 |
| Marital status (married/partner) | 2706 (71.2) | 35 (35.0) | <.001 |
| Smoker | 496 (13.1) | 17 (17) | .24 |
| Clinical characteristics | |||
| Comorbidities | 1.5 (1.5) | 1.9 (1.6) | .004 |
| History of hypertension | 1137 (29.9) | 44 (44) | .001 |
| SBP | 122.9 (18.5) | 129.5 (17.4) | .006 |
| DBP | 75.8 (10.8) | 76.0 (10.7) | .92 |
| PP | 47.1 (14.4) | 53.4 (13.5) | <.001 |
| Ocular characteristics | |||
| Any lens opacity | 616 (16.5) | 21 (21.0) | .08 |
| Cataract surgery | 118 (3.1) | 8 (8.0) | .005 |
| Iris color (black/brown) | 3409 (89.6) | 89 (89.0) | .70 |
| OPP | 46.5 (8.1) | 47.2 (8.2) | .37 |
a Data are presented as mean (SD) for age, acculturation, SBP, DBP, PP, OPP, and comorbidities; frequency (%) for all other variables.
b P values were calculated using t test for continuous variables and χ 2 for categorical variables.
c Acculturation was measured using the short-form Cuellar Acculturation Scale.
Incidence of AMD and Risk Factors
The incidences of late AMD (n = 8), incident geographic atrophy (n = 3), and incident exudative AMD (n = 5) were too small to allow robust risk factor analysis.
At 4-year follow-up, 100 of the 3908 participants (2.5%) were found to have any AMD (92 early and 8 late AMD). Of these, 35 participants were at level 10, 25 at level 20, 31 at level 40, 5 at level 50, and 4 at level 60 of the BDES severity scale.
In univariate analysis, age was the strongest risk factor. After age adjustment, the sociodemographic and clinical factors associated with the incidence of any AMD included older age, retirement, higher SBP, higher pulse pressure, presence of any cataract, cortical opacity, history of cataract surgery, and refractive error (myopia). Using stepwise logistic regression we found only older age (OR per decade of age: 1.52; 95% CI: 1.29, 1.85) and higher pulse pressure (OR 2.54; 95% CI: 1.36, 4.76 for >40 compared to ≤40 mm Hg) to be independently associated with incidence of any AMD ( Table 3 ). To further evaluate whether the effect of pulse pressure was independent of hypertension, we restricted the analysis to normotensive participants with a baseline SBP of 140 mm Hg or less and baseline DBP of 90 mm Hg or less. The analysis revealed similar age-adjusted independent relationship between pulse pressure and any AMD (OR for AMD: 2.60; 95% CI: 1.38, 4.87).
| Risk Factor | Incidence of Any AMD | Incidence of Early AMD | Incidence of Soft Indistinct Drusen | Incidence of Increased Retinal Pigment | Incidence of Decreased Retinal Pigment | Progression of Any AMD |
|---|---|---|---|---|---|---|
| OR (95% CI) a | OR (95% CI) a | OR (95% CI) a | OR (95% CI) a | OR (95% CI) a | OR (95% CI) a | |
| Age (per decade) | 1.52 (1.29, 1.85) | 1.61 (1.32, 1.96) | 1.69 (1.37, 2.10) | 1.20 (1.01, 1.50) | 1.30 (1.02, 1.65) | 2.20 (1.82, 2.67) |
| Pulse pressure | ||||||
| ≤40 mm Hg | 1 | 1 | 1 | 1 | 1 | ∼ |
| >40 mm Hg | 2.54 (1.36, 4.76) | 2.79 (1.45, 5.35) | 2.69 (1.31, 5.52) | 3.18 (1.56, 6.52) | 1.91 (1.00, 3.77) | |
| Diabetes | ∼ | ∼ | ∼ | ∼ | ∼ | |
| No | 1 | |||||
| Yes | 1.66 (1.01, 2.85) | |||||
| Smoking status | ∼ | ∼ | ∼ | ∼ | ∼ | |
| Nonsmoker | 1 | |||||
| Ever/past smoker | 1.25 (0.75, 2.07) | |||||
| Current smoker | 2.85 (1.66, 4.90) | |||||
| Gender | ∼ | ∼ | ∼ | ∼ | ∼ | |
| Female | 1 | |||||
| Male | 2.50 (1.48, 4.23) |
a Odds ratios and confidence intervals adjusted for other variables in the model.
Increasing age (OR per decade of age: 1.61; 95% CI: 1.32, 1.96) and higher pulse pressure (OR 2.79; 95% CI: 1.45, 5.35 for >40 mm Hg compared to ≤40 mm Hg) were statistically significant independent predictors of the incidence of early AMD, similar to any AMD ( Table 3 ). The LOWESS plot revealed a relatively insidious increase in predicted probability of early AMD incidence up to 40 mm Hg of pulse pressure and a steep increase when pulse pressure reached more than 40 mm Hg ( Figure 2 ). LOWESS analysis was suggestive of a nominal increase of predicted incidence of early AMD with increasing age from 40 to 65 years. The increasing trend was pronounced after age 65 years, with a very steep rise in people aged 80 year or older ( Figure 3 ).
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