FNOA: Antioxidants (2011-2012)

Citation:
 
Study Design:
Class:
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Quality Rating:
Research Purpose:

To examine the association of sunlight exposure and antioxidant level with age-related macular degeneration (AMD).

Inclusion Criteria:

Participants in the European Eye Study (EUREYE) who had gradable fundus images and data available on sunlight exposure.

Exclusion Criteria:

Participants in the European Eye Study (EUREYE) who did not have gradable fundus images or sunlight exposure data.

Description of Study Protocol:

Recruitment

Participants were recruited from random sampling of the population in several areas of Europe. 

Design

Case-control study: 

  • Participants were interviewed by field workers, underwent fundus photography and gave blood samples for antioxidant analysis. Information collected at interviews included participant's education, smoking and alcohol use, a brief medical history and sunlight exposure. A dietary questionnaire was administered. 
  • The questionnaire asked about time spent outdoors between the hours of 9 A.M. and 5 P.M. and between 11 A.M. and 3 P.M. daily throughout an individual's working life and in retirement up to one's current age. Information was collected about the use of hats and eyewear. Information from the questionnaire, residence calendar and geographical coordinates of residence were used to generate estimates of individual years of exposure to different wavelengths of light.
  • Fundus images were graded at a single reading center using the International Classification System for Age-Related Maculopathy, which identifies five mutually exclusive grades as follows: Grade zero (no early or late AMD), grade one (soft distinct drusen only or pigmentary irregularities only), grade two (soft indistinct or reticular drusen only or soft distinct drusen with pigmentary irregularities), grade three (soft indistinct or reticular drusen with pigmentary irregularities) and grade four (either neovascular AMD or geographic atrophy).
  • Diet information was obtained using the United Kingdom version of the European Prospective Investigation Into Cancer and Nutrition Study Food Frequency Questionnaire. Key antioxidants studied were vitamin C, zeaxanthin, lutein, α-tocopherol and dietary zinc. Potential confounders including age, sex, smoking status, education, history of diabetes, cardiovascular disease, demiquet (weight in kilograms divided by the demispan in centimeters squared), operated cataract, iris color, aspirin consumption and use of vitamin or mineral supplements or other antioxidants.

Statistical Analysis

  • Logistic regression was used to investigate the association between blue light exposure and neovascular AMD
  • The association by quartiles of key antioxidant levels was examined using interaction terms in the models with design-adjusted Wald tests
  • Multinomial survey logistic regression was used to investigate associations with blue light, key antioxidants and early AMD.
Data Collection Summary:

Timing of Measurements

  • All data and information was obtained at baseline
  • Participants were interviewed by field workers, underwent fundus photography, and gave blood samples for antioxidant analysis. Information collected at interviews included participant's education, smoking and alcohol use, a brief medical history and sunlight exposure. A dietary questionnaire was administered. 
  • Interviews took place before the eye examinations.

 Dependent Variables

  • Age-related macular degeneration (AMD) as measured by fundus photograph
  • Fundus images were graded at a single reading center using the International Classification System for Age-Related Maculopathy, which identifies five mutually exclusive grades as follows: Grade zero (no early or late AMD), grade one (soft distinct drusen only or pigmentary irregularities only), grade two (soft indistinct or reticular drusen only or soft distinct drusen with pigmentary irregularities), grade three (soft indistinct or reticular drusen with pigmentary irregularities) and grade four (either neovascular AMD or geographic atrophy).

Independent Variables

  • Sunlight exposure as measured by questionnaire and meteorological data
  • The questionnaire asked about time spent outdoors between the hours of 9 A.M. and 5 P.M. and between 11 A.M. and 3 P.M. daily throughout an individual's working life and in retirement up to one's current age. Information was collected about the use of hats and eyewear. Information from the questionnaire, residence calendar and geographical coordinates of residence were used to generate estimates of individual years of exposure to different wavelengths of light.
  • Antioxidant intake as measured by questionnaire with food intake converted to nutrients using food composition tables
  • Diet information was obtained using the United Kingdom version of the European Prospective Investigation Into Cancer and Nutrition Study Food Frequency Questionnaire. Key antioxidants studied were vitamin C, zeaxanthin, lutein, α-tocopherol, and dietary zinc. 
  • Blood levels of antioxidants as measured by reverse-phase high performance liquid chromatography.

Control Variables

  • Age
  • Sex
  • Smoking status
  • Education
  • History of diabetes, cardiovascular disease
  • Demiquet (weight in kilograms divided by the demispan in centimeters squared)
  • Operated cataract
  • Iris color
  • Aspirin consumption
  • Use of vitamin or mineral supplements or other antioxidants.
Description of Actual Data Sample:
  • Initial N: Of the 5,040 participants in the European Eye Study, 4,753 participants had gradable fundus image. The initial N was 4753.
  • Attrition (final N): No attrition; 55% of participants were women
    • 101 subjects with neovascular AMD
    • 2,182 with early AMD
    • 2,117 controls
  • Age: All participants were aged 65 or older, mean age of 73.2±5.6 years
  • Other relevant demographics: Data on education level and medical history was obtained at baseline but was not reported
  • Location: Participants were from Bergen, Norway; Tallinn, Estonia; Belfast, Ireland; Paris, France; Verona, Italy; Thessaloniki, Greece; and Alicante, Spain.
Summary of Results:
  • No association was found between blue light exposure and neovascular or early AMD
  • Significant  associations were found between blue light exposure and neovascular AMD in individuals in the quartile of lowest antioxidant level (vitamin C, zeaxanthin, vitamin E and dietary zinc)
  • Higher odds ratios for blue light were observed with combined low antioxidant levels, especially vitamin C, zeaxanthin and vitamin E
  • Combinations of blue light exposure and low plasma concentrations of antioxidants was associated with the early stages of AMD. The association appeared stronger at older ages, reaching a peak at ages 50 to 59 years.
  • Blue light exposure tended to be higher in participants form the study centers in southern Europe, while participants in an exclusively urban center (Paris) had the lowest exposure.

Association of Midday Blue Light Exposure with Neovascular AMD by Antioxidant Quartile

d

Quartile 1

OR

Quartile 2

OR

Quartile 3

OR

Quartile 4

OR

d Value 95% CI P Value 95% CI P Value 95% CI P Value 95% CI P
Vitamin C
N 549 1.40 <0.01 583 1.12 0.7 552 0.97 0.9 534 0/47 0.04
  (1.15 to 1.71) (0.57 to 2.20) (0.61 to 1.55) (0.24 to 0.93)

Range of quartile (μmol per L)

≤26.2      >26.2 to 44.4      >44.4 to 61.5      >61.5     
Mean (SD) 13.87      35.95      52.45      85.28     
μmol per L (7.62)      (5.00)      (4.89)      (27.26)     
Zeaxanthin             
N  572  1.47  0.04  546  0.54  0.2  558  0.98  0.9  543  1.26  0.06 
  (1.00 to 2.16) (0.21 to 1.36) (0.41 to 2.38) (0.99 to 1.60)

Range of quartile (μmol per L) 

≤0.015      >0.015 to 0.028      >0.028 to 0.054      >0.054     
Mean (SD)  0.010      0.0211      0.0391      0.0904     
μmol per L  (0.03)      (0.004)      (0.008)      (0.037)     
Lutein             
N  547  1.37  0.2  577  0.92  0.7  577  0.93  0.8  520  1.21  0.11 
  (0.76 to 2.46) 0.52 to 1.61) (0.40 to 2.19) (0.96 to 1.52)  

Range of quartile (μmol per L)  

≤(0.047)      >0.047 to 0.113      >0.113 to 0.275      >0.275      
Mean (SD)   0.0324     0.720      0.1824      ).502)     
μmol per L  (0.101)       (0.018)      (0.044)      (0.258)     
α-Tocopherol           
N  549  1.43  0.03  552  0.96  0.7  556  1.14  0.7  561  1.03  0.9 
  (1.06 to 1.94) (0.74 to 1.24) (0.57 to 2.25 (0.70 to 1.51)

Range of quartile (μmol per L)   

≤26.16      >2625 to 29.58      >29.58 to 34.33      >34.34     
Mean (SD)   221.66      27,34      31.81      40.50     
μmol per L  (2.90)      (1.28)      (1.38)      (6.84)     
Zinc
N 522  1.33  0.01  557  1.07  0.6  519  1.26  0.3  540  0.71  0.3 
  (1.10) to 1.62) (0.79 to 1.46) (0.76 to 2.09) (0.32 to 1.58)
Range of quartile (μmol per L)   ≤7.68      >7.68 to 9.76     >9.76 to 12.43      <12.43     
Mean (SD)   6.25      8.75      10.99      15.46     
μmol per L (1.01      (0.59)      (0.75)      (3.16)     
  • 95% CI for  blue light exposure, adjusted for age, sex, smoking status, diabetes mellitus, cardiovascular disease, education, aspirin use, retinol and cholesterol level
  • Reported as interaction of antioxidants with blue light exposure. Zinc is adjusted for energy intake.

Association of Midday Blue Light Exposure with Neovascular AMD by Joint Low Levels of Antioxidants

Joint Lowest Quartile of Antioxidants*                                        OR  ** (95% CI) P-value¹

P-value²

Vitamin C and zeaxanthin          1.66(1.15 to 2.38)                0.02                 0.05         
Vitamin C and lutein 1.37(0.60 to 3.09) 0.4 0.6
Vitamin C and α tocopherol 2.47(1.65 to 3.67) 0.001 <0.01 
Vitamin C and dietary zincº 1.53(1.20 to 1.95) 0.005 0.03
Zeaxanthin and lutein 1.43(0.75 to 2.73) 0.2 0.4
Zeaxanthin and α tocopherol 2.34(1.61 to 3.40) 0.001 <0.01
Zeaxanthin and dietary zinc 2.60(2.33 to 2.88) <0.001 <0.001
Lutein and α tocopherol 1.57(0.64 to 3.86)    
Vitamin C, zeaxanthin and α tocopherol 3.73(1.56 to 1.88) 0.01 0.02
Vitamin C, lutein and α tocopherol 2.61(0.49 to 13.90) 0.2 0.3
Vitamin C, zeaxanthin and dietary zinc 1.97(0.26 to 1.17) 0.1 0.1

 *Combined lowest quartiles.

**Odds ratio for the effect of 1-SD increase in blue light exposure, adjusted for age, sex, smoking status, diabetes, cardiovascular disease, education, aspirin use, retinol and cholesterol level.

ºAdjusted for energy intake.

¹Test of effect of blue light exposure.

²Test of interaction between joint lowest quartile of antioxidants with blue light exposure on association with neovascular AMD.

 

Author Conclusion:

Although it is not possible to establish causality between sunlight exposure and neovascular AMD, our results suggest that people in the general population should use ocular protection and follow dietary recommendations for the key antioxidant nutrients.

Funding Source:
Government: European Commission Vth Framework
Not-for-profit
Macular Disease Society
Reviewer Comments:
  • Data on sunlight exposure was self-reported and participants were asked to go back in time to recall exposure during different periods of their life. This data is subject to reporting error.
  • Participants were all greater than 65 years old. There was no mention of assessment of cognitive status to assure that recollections over time were not affected by confusion or memory loss.

 

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? ???
  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? Yes
  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) Yes
  3.2. Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline? Yes
  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.) Yes
  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%.) N/A
  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? 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? ???
  7.1. Were primary and secondary endpoints described and relevant to the question? N/A
  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? N/A
  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? ???
  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? Yes
  10.1. Were sources of funding and investigators' affiliations described? Yes
  10.2. Was the study free from apparent conflict of interest? Yes