EAL

FNOA: Antioxidants (2011-2012)

Citation:

Study Design:

Class:

- Click here for explanation of classification scheme.

Quality Rating:

Research Purpose:

To evaluate the relationship of dietary carotenoids, vitamin A, alpha-tocopherol and vitamin C with prevalent age-related macular degeneration (AMD) in the Age-Related Eye Disease Study (AREDS).

Inclusion Criteria:

Participants were 55 to 58 years of age at enrollment and had best-corrected visual acuity of 20/32 or better in at least one eye
Ocular media were sufficiently clear to obtain adequate-quality stereoscopic fundus photographs of the macula in all study eyes
At least one eye of each participant was free from advanced AMD (defined as neovascular (NV) AMD or foveal geographic atrophy (GA) and any eye disease that complicate assessment of AMD or lens opacity progression
Also, that eye could not have had previous ocular surgery (except cataract surgery)
Persons aged 55 through 59 years were recruited only if they had intermediate AMD or unilateral advanced AMD.

Exclusion Criteria:

Potential participants were excluded for illness or disorders that would make long-term follow-up or compliance with the study protocol unlikely or difficult
For this analysis, 110 persons aged 55 to 59 years were excluded because there were not age-matched controls for this group
Also, 128 persons with bilateral aphakia for whom refractive error data were not available were excluded.

Description of Study Protocol:

Recruitment

Cases recruited from 11 retinal specialty clinics; 4,757 participants enrolled from 1992 to 1998. Controls were recruited from from volunteers in response to public advertising.

Design

Case-Control Study

Blinding used

Not used

Intervention

Not applicable

Statistical Analysis

Demographic factors, medical history, treatment history and ocular factors associated with AREDS AMD categories were analyzed using logistic regression analysis and multivariate analysis
Nutrient intake values were adjusted for total energy intake (TEI) by computing nutrient densities and modeling categories of this variable using quintiles
To adjust for supplement use among subjects with advanced AMD, variables were used to evaluate these factors separately from food-based nutrients
Odds ratios and 95% confidence intervals were calculated using multiple logistic regression to examine the relationship of the AREDS AMD case group with levels of dietary intake
Multiple linear regression with log-transformed nutrient density scores were used to to evaluate AMD associated dietary nutrients.

Data Collection Summary:

Timing of Measurements

Demographic, lifestyle, medical characteristics and nutrient intake information was obtained from participants at enrollment.

Dependent Variables

Age-related macular degeneration

Independent Variables

Dietary intakes of vitamin A, retinol, beta-carotene, beta-cryptoxanthin, lutein/zeaxanthin, lycopene, vitamin C, alpha-tocopherol
Nutrient intake estimated from a self-administered semiquantitative food frequency questionnaire at enrollment.

Control Variables

Age
Sex
Energy intake.

Description of Actual Data Sample:

Initial N: 4,757 participants
Attrition (final N): 4,519 participants included in the analysis
Age: 38% older than 70 years
Ethnicity: 95% identified themselves as white
Other relevant demographics:
- 56% female
- 35% had a college degree
Anthropometrics:
- 55% smoked for at least six months
- 40% had hypertension
Location: United States.

Summary of Results:

AMD Group 2: Extensive Small or Nonextensive Intermediate Drusen

Those subjects aged 71-80 years old, female, with arthritis and using HClz have an increased likelihood of having extensive small or nonextensive intermediate drusen (OR greater than one).

The following are likely to be in a higher intake quintile of the examined nutrients (P≤0.15):

Those age 71-80 years old for beta-carotene
Females for beta-carotene, beta-cryptoxanthin, lutein/zeaxanthin and vitamin C
Those using HClz for vitamin C and alpha-tocopherol.

The following are likely to be in a lower intake quintile of the examined nutrients (P≤0.15):

Those age 71-80 years old for beta-cryptoxanthin
Those with arthritis for lycopene and alpha-tocopherol.

AMD Group 3: Extensive Intermediate Drusen or Large Drusen and Nutrient Intake

Those subjects aged 71-80 years old, hyperopic, white, ever smoked at least six months, with hypertension and arthritis, using HClz and diuretics and having lens opacity have an increased likelihood of having extensive intermediate drusen or large drusen (OR greater than one).

The following are likely to be in a higher intake quintile of the examined nutrients (P≤0.15):

Those age 71-80 years old for beta-carotene
Those college educated for beta-carotene, beta-cryptoxanthin, lutein/zeaxanthin, vitamin C and alpha-tocopherol
Those hyperopic for lutein/zeaxanthin
Females for beta-carotene, beta-cryptoxanthin, lutein/zeaxanthin, lycopene and vitamin C
White race for lycopene and alpha-tocopherol
Those with hypertension for beta-cryptoxanthin and vitamin C
Diuretic use for beta carotene.

The following are likely to be in a lower intake quintile of the examined nutrients (P≤0.15):

Those age 71-80 years old for beta-cryptoxanthin, lutein/zeaxanthin and lycopene
White race for beta-carotene and lutein/zeaxanthin
Those who smoked for at least six months for beta-carotene, beta-cryptoxanthin, lutein/zeaxanthin, vitamin C and alpha-tocopherol
Those with arthritis, HClz use and diuretic use for lycopene
Those with lens opacity present fro beta-cryptoxanthin and lycopene.

AMD Group 4: Geographic Atrophy and Nutrient Intake:

Those subjects aged 71-80 years old, ever smoked at least six months, use antacids and use thyroid hormones have an increased likelihood of having geographic atrophy (OR greater than one).

The following are likely to be in a higher intake quintile of the examined nutrients (P≤0.15):

Those aged 71-80 years old for beta-carotene
Those college educated for beta-carotene, beta-cryptoxanthin, zeaxanthin, lycopene, vitamin C and alpha-tocopherol
Females for beta-carotene, beta-cryptoxanthin, lutein/zeaxanthin and vitamin C.

The following are likely to be in a lower intake quintile of the examined nutrients (P≤0.15):

Those who ever smoked for at least six months for beta-carotene, beta-cryptoxanthin, lutein/zeaxanthin and vitamin C
Those using thyroid hormones for alpha-tocopherol.

AMD Group 5: Neovascular AMD and Nutrient Intake

Those subjects aged 71-80 years old, BMI≥31, hyperopic, female, white, ever smoked at least six months, with hypertension and having lens opacity have an increased likelihood of having neovascular AMD (OR greater than one).

The following are likely to be in a higher intake quintile of the examined nutrients (P≤0.15):

Those aged 71-80 years old for beta-carotene
Those college educated for beta-carotene, beta-cryptoxanthin, lutein/zeaxanthin and vitamin C
Those hyperopic for lutein/zeaxanthin
Females for beta-carotene, beta-cryptoxanthin, lutein/zeaxanthin, lycopene and vitamin C
Those with hypertension for beta-cryptoxanthin and vitamin C.

The following are likely to be in a lower intake quintile of the examined nutrients (P≤0.15):

Those aged 71-80 for beta-cryptoxanthin and lutein/zeaxanthin
Those with a BMI≥31 for beta-cryptoxanthin, lutein/zeaxanthin and vitamin C.

Other Findings

Relationships in the direction of benefit included:

Lutein with extensive intermediate drusen or large drusen
Vitamin A and beta-carotene with neovascular AMD.

Lutein/zeaxanthin intake persisted as an independent factor for NV AMD and GA after adjustment with caloric intake, age, sex, and nutritional and non-nutritional covariates. Beta-carotene persisted for NV AMD; however, this relationship was not observed in comparison of highest to lowest quintiles. ARED subjects reporting higher intakes of lutein/zeaxanthin were also less likely to have large or extensive intermediate drusen than subjects in the lowest quintile of intake.

Author Conclusion:

Study participants reporting the highest dietary intake of lutein/zeaxanthin were statistically less likely to have advanced AMD (both NV and GA) or large or extensive intermediate drusen than those reporting lowest dietary intake. There are biological plausibility to these findings because lutein and xeaxanthin are the major diet based macular carotenoids. These compounds may affect the modulating of light or oxidant exposure.

No clear associations with other nutrients were seen. Findings of a possible benefit with higher vitamin E intake did not show a significant trend when combined with the findings from other studies.

This report provided further evidence that people reporting a higher intake of lutein/zeaxanthin from foods have a reduced likelihood of having NV AMD, GA and large or extensive intermediate drusen. If these cross-sectional results can be confirmed in prospective samples and experimental studies, lutein and zeaxanthin may be considered useful in food or supplement based intervention to reduce the risk of AMD.

Funding Source:

Government:

National Eye Institute, National Institutes for Health, Department of Health and Human Services

Industry:

Bausch and Lomb

Other:

In-Kind support reported by Industry:

Yes

Reviewer Comments:

The authors note the following limitations:

It is possible that uncontrolled confounding contributed to the association lutein/zeaxanthin intake with AMD
The sampling scheme for this clinic-based case-control design with more controls recruited from volunteers responding to public advertising and more cases from the clinic base may have increased the possibility of confounding
There may have been bias in the reporting of intake that could have affected the results of the study.

Quality Criteria Checklist: Primary Research
Relevance Questions
	1.	Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (Not Applicable for some epidemiological studies)	Yes
	2.	Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about?	Yes
	3.	Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice?	Yes
	4.	Is the intervention or procedure feasible? (NA for some epidemiological studies)	Yes

Validity Questions
1.	Was the research question clearly stated?		Yes
	1.1.	Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified?	Yes
	1.2.	Was (were) the outcome(s) [dependent variable(s)] clearly indicated?	Yes
	1.3.	Were the target population and setting specified?	Yes
2.	Was the selection of study subjects/patients free from bias?		Yes
	2.1.	Were inclusion/exclusion criteria specified (e.g., risk, point in disease progression, diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study?	Yes
	2.2.	Were criteria applied equally to all study groups?	Yes
	2.3.	Were health, demographics, and other characteristics of subjects described?	Yes
	2.4.	Were the subjects/patients a representative sample of the relevant population?	Yes
3.	Were study groups comparable?		???
	3.1.	Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT)	Yes
	3.2.	Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline?	???
	3.3.	Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.)	Yes
	3.4.	If cohort study or cross-sectional study, were groups comparable on important confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis?	N/A
	3.5.	If case control study, were potential confounding factors comparable for cases and controls? (If case series or trial with subjects serving as own control, this criterion is not applicable.)	???
	3.6.	If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")?	N/A
4.	Was method of handling withdrawals described?		Yes
	4.1.	Were follow-up methods described and the same for all groups?	N/A
	4.2.	Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up, attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.)	Yes
	4.3.	Were all enrolled subjects/patients (in the original sample) accounted for?	Yes
	4.4.	Were reasons for withdrawals similar across groups?	Yes
	4.5.	If diagnostic test, was decision to perform reference test not dependent on results of test under study?	N/A
5.	Was blinding used to prevent introduction of bias?		No
	5.1.	In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate?	No
	5.2.	Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met.)	No
	5.3.	In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded?	N/A
	5.4.	In case control study, was case definition explicit and case ascertainment not influenced by exposure status?	Yes
	5.5.	In diagnostic study, were test results blinded to patient history and other test results?	N/A
6.	Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described?		Yes
	6.1.	In RCT or other intervention trial, were protocols described for all regimens studied?	N/A
	6.2.	In observational study, were interventions, study settings, and clinicians/provider described?	Yes
	6.3.	Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect?	N/A
	6.4.	Was the amount of exposure and, if relevant, subject/patient compliance measured?	N/A
	6.5.	Were co-interventions (e.g., ancillary treatments, other therapies) described?	N/A
	6.6.	Were extra or unplanned treatments described?	N/A
	6.7.	Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups?	N/A
	6.8.	In diagnostic study, were details of test administration and replication sufficient?	N/A
7.	Were outcomes clearly defined and the measurements valid and reliable?		Yes
	7.1.	Were primary and secondary endpoints described and relevant to the question?	Yes
	7.2.	Were nutrition measures appropriate to question and outcomes of concern?	Yes
	7.3.	Was the period of follow-up long enough for important outcome(s) to occur?	Yes
	7.4.	Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures?	Yes
	7.5.	Was the measurement of effect at an appropriate level of precision?	Yes
	7.6.	Were other factors accounted for (measured) that could affect outcomes?	Yes
	7.7.	Were the measurements conducted consistently across groups?	Yes
8.	Was the statistical analysis appropriate for the study design and type of outcome indicators?		Yes
	8.1.	Were statistical analyses adequately described and the results reported appropriately?	Yes
	8.2.	Were correct statistical tests used and assumptions of test not violated?	Yes
	8.3.	Were statistics reported with levels of significance and/or confidence intervals?	Yes
	8.4.	Was "intent to treat" analysis of outcomes done (and as appropriate, was there an analysis of outcomes for those maximally exposed or a dose-response analysis)?	N/A
	8.5.	Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)?	Yes
	8.6.	Was clinical significance as well as statistical significance reported?	Yes
	8.7.	If negative findings, was a power calculation reported to address type 2 error?	N/A
9.	Are conclusions supported by results with biases and limitations taken into consideration?		Yes
	9.1.	Is there a discussion of findings?	Yes
	9.2.	Are biases and study limitations identified and discussed?	Yes
10.	Is bias due to study's funding or sponsorship unlikely?		No
	10.1.	Were sources of funding and investigators' affiliations described?	Yes
	10.2.	Was the study free from apparent conflict of interest?	No