EAL

FNOA: Antioxidants (2011-2012)

Citation:

Study Design:

Class:

- Click here for explanation of classification scheme.

Quality Rating:

Research Purpose:

To investigate dietary lutein/zeaxanthin and fatty acids in relation to risk of age-related macular degeneration (AMD) progression among participants in the Cardiovascular Health and Age-Related Maculopathy (CHARM) Study.

Inclusion Criteria:

Participants in the Cardiovascular Health and Age-Related Maculopathy (CHARM) study.

Participants with features of early AMD (intermediate drusen, soft drusen, and/or retinal pigment epithelium abnormalities) in the absence of geographic atrophy or neovascular AMD in at least one eye.

Exclusion Criteria:

No exclusion criteria were specified.

Description of Study Protocol:

Recruitment

Participants were recruited to participate in the CHARM Study. Details of recruitment strategies were not outlined.

Design

Prospective cohort study

Stereo photography of the macula was performed following pupil dilation. Each slide was graded based on the International Classification for AMD grading with minor modifications for the presence of hard, intermediate, distinct, and indistinct drusen, retinal pigment epithelium changes, geographic atrophy, and neovascular AMD.

AMD status at baseline was stratified six levels and those with AMD at specific levels were included in the analysis of AMD progression. Average length of follow-up to assess progression of AMD was seven years. Progression of AMD was defined by three different definitions, two quantitative and one qualitatiave.

Nutrient intakes at baseline were computed form the data collected with a food frequency questionnaire (FFQ). Nutrient composition data was derived from the Royal Melbourne Institute of Technologies fatty acid database for Australian foods and the USDA carotenoid database and the NUTTAB95 Australian Government nutrient database.

Blinding used

Not applicable

Intervention

Not applicable

Statistical Analysis

Three binary outcomes corresponding to the three definitions of progression were used in the logistic regression analysis.

The authors carried out linear, quintile, and quintile median analyses for energy-adjusted daily lutein/zeaxanthin intake and fat intake and adjusted the odds ratios for several factors.

For logistic regression analysis, all participants were divided into five groups based on quintiles of intake for relevant nutrients.

Data Collection Summary:

Timing of Measurements

Baseline data was collected in 1992-1994 (Participants from the Melbourne Visual Impairment Project) or 1995 (Age-related Macular Degeneration Trial). Average duration of follow-up was seven years.

Dependent Variables

Progression of AMD as measured by stereo photography of the macula and use of three different methods to define progression of AMD.

Independent Variables

Intake of lutein/zeaxanthin as measured by a food frequency questionnaire and analyzed by the United States Department of Agriculture carotenoid database and the NUTTAB95 (published by the Australian Government nutrient data table for use in Australia for nutrients other than fatty acids and carotenoids)
Intake of dietary fat (total fat, saturated fat, polyunsaturated fat, monounsaturated fat, trans fatty acids, ω-3 fatty acids, and ω-6 fatty acids) as measured by a food frequency questionnaire and analyzed by the Royal Melbourne Institute of Technologies fatty acid database for Australian Foods.

Control Variables

Age in years
Smoking
AMD family history
Source study
Duration of follow-up in years.

Description of Actual Data Sample:

Initial N: 254 subjects
- 134 females (53%)
- 117 males (46%)
Attrition (final N): No attrition; final n was 254
Age: 51-89 years, with a mean age 74, SD seven years
Ethnicity: Not specified
Other relevant demographics: No information was provided on education level or SES. It was reported that 12% of the participants had a family history of AMD.
Anthropometrics: At baseline the group had a mean BMI of 26.8 (SD 4.3) kg/m^²
Location: Australia.

Summary of Results:

In multivariate analysis adjusted for age, smoking (ever vs. never), AMD family history, source study, and duration of follow-up in years, energy-adjusted lutein/zeaxanthin intake was directly associated with AMD progression according to the most stringent of AMD used (P<0.025)
Of the fat variables examined, only ω-3 fatty acid intake was positively associated with AMD progression as defined by worsening in side-by-side comparison of baseline and follow-up macular photos (P=0.03)
No association of AMD progression was observed with the intake of total fat, saturated fat, polyunsaturated fat, monounsaturated fat, trans fatty acids, or ω-6 fatty acids.

Multivariate analysis² of association between progression of age-related macular degeneration (AMD) and daily intake of lutein and zeaxanthin (L/Z) (n=252)

	Definition 1*		Definition 2**		Definition 3***
	OR (95% CI)	P value	OR (95% CI)	P value	OR (95% CI)	P value
LZ intake (mg per day)	2.65 (1.13-6.22)	0.02	1.72 (0.78-3.78)	0.18	1.84	0.09
Quintile median of L/Z intake (µg per day)	2.89 (1.01-8.25)	0.05	2.03 (0.78-5.32)	0.15	2.03
Quintiles of L/Z intake (µg per day)
Quintile 1 (≤520)		1.00		1.00		1.00
Quintile 2 (520-702)	1.59 (0.54-4.70)	0.40	0.83 (0.32-2.15)	0.69	0.91 (0.35-2.39)	0.85
Quintile 3 (702-880)	1.56 (0.52-4.67)	0.43	1.18 (0.46-3.00)	0.73	2.06 (0.82-5.17)	0.12
Quintile 4 (880-1,072)	3.30 (1.18-9.22)	0.02	2.06 (0.84-5.05)	0.12	2.09 (0.82-5.17)	0.11
Quintile 5 (1,072+)	2.51(0.85-7.42)	0.10	1.51 (0.59-3.68)	0.39	1.64 (0.64-4.23)	0.30

²covariates included age in years, smoking, AMD family history, source study, and duration of follow-up in years

*interlevel in the worse eye

**Interlevel and intralevel in either eye

***Side-by-side

Multivariate analysis² of association between progression of age-related macular degeneration (AMD) and energy-adjusted intake of of ω-3 fatty acids (n=252)

	Definition 1*		Definition 2**		Definition 3***
	OR (95% CI)	P value	OR (95% CI)	P value	OR (95% CI)	P value
ω-3 fatty acid intake(g)	1.82 (0.99-3.37)	0.06	1.58 (0.88-2.84)	0.12	1.65 (0.92-2.96)	0.09
Quintile median of ω-3 fatty acid intake (grams per day)	2.44 (0.98-6.04)	0.05	2.1 (0.91-4.96)	0.08	2.56 (1.11-5.91)	0.03
Quintiles of ω -3 fatty acid intake (grams per day)
Quintile 1 (≤0.90)		1.00		1.00		1.00
Quintile 2 (0.90-1.06)	1.00 (0.35-2.84)	1.00	1.08 (0.42-2.76)		1.09 (0.42-2.82)	0.86
Quintile 3 (1.06-1.20)	1.19 (0.42-3.40)	0.74	1.21 (0.47-3.13)		1.85 (0.73-4.73)	0.20
Quintile 4 (1.20-1.48)	1.73 (0.61-4.90)	0.30	2.22 (0.87-5.70)		2.57 (0.99-6.64)	0.05
Quintile 5 (1.48+)	2.20 (0.82-5.87)	0.12	1.93 (0.77-4,81)		2.42 (0.97-6.05)	0.06

²covariates included age in years, smoking, AMD family history, source study, and duration of follow-up in years

*interlevel in the worse eye

**Interlevel and intralevel in either eye

***Side-by-side

Author Conclusion:

The authors conclude that energy-adjusted lutein/zeaxanthin (L/Z) intake as a continuous variable was associated with AMD progression in the worse-affected eye when defined by the most stringent criteria
No association of AMD progression was observed with the intake of either total fat or other subgroups: Saturated fat, polyunsaturated fat, monounsaturated fat, trans fatty acids, or ω-6 fatty acids
The authors suggest that the findings of this study are counterintuitive, suggesting that increased intakes of dietary lutein/zeaxanthin and ω-3 fatty acids are associated with a progression of AMD.

Funding Source:

University/Hospital:	University of Melbourne, Monash University
Other:	Cancer Council of Victoria, Marshfield Clinic Research Foundation

Reviewer Comments:

A food frequency questionnaire was completed at one point in time. One FFQ may not accurately reflect intake of specific nutrients during the seven-year follow-up period
There was no discussion of dietary supplement intake (including antioxidant vitamins), which may have had a separate effect on progression of AMD.

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)	N/A
	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)	N/A

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?		???
	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?	No
	2.2.	Were criteria applied equally to all study groups?	???
	2.3.	Were health, demographics, and other characteristics of subjects described?	No
	2.4.	Were the subjects/patients a representative sample of the relevant population?	???
3.	Were study groups comparable?		Yes
	3.1.	Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT)	No
	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?	Yes
	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.)	N/A
	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?	Yes
	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?	N/A
	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?		Yes
	5.1.	In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate?	N/A
	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.)	Yes
	5.3.	In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded?	Yes
	5.4.	In case control study, was case definition explicit and case ascertainment not influenced by exposure status?	N/A
	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?	Yes
	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?		???
	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?	???
	7.5.	Was the measurement of effect at an appropriate level of precision?	???
	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?		No
	9.1.	Is there a discussion of findings?	Yes
	9.2.	Are biases and study limitations identified and discussed?	No
10.	Is bias due to study's funding or sponsorship unlikely?		Yes
	10.1.	Were sources of funding and investigators' affiliations described?	Yes
	10.2.	Was the study free from apparent conflict of interest?	Yes