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DLM: Homocysteine, Folate, B6 or B12 (2007-2011)

Citation:

Al-Delaimy WK, Rexrode KM, Hu FB, Albert CM, Stampfer MJ, Willett WC, Manson JE. Folate intake and risk of stroke among women. Stroke. 2004; 35(6):1259-63. 

PubMed ID: 15105514
 
Study Design:
Retrospective cohort study
Class:
B - Click here for explanation of classification scheme.
Quality Rating:
Positive POSITIVE: See Quality Criteria Checklist below.
Research Purpose:

The study aimed to assess the relation between folate intake and stroke incidence among women participating in the Nurses' Health Study.

Inclusion Criteria:
  • Female registered nurses who completed a mailed questionnaire on their medical history and lifestyle
  • Aged 30-55 years
  • Resided in 11 large US states
Exclusion Criteria:
  • Women who had implausibly high (>14 700 kJ/d [3500 kcal/d]) or low (<2100 kJ/d [500 kcal/d]) total energy intake,
  • Women who left 10 or more items blank
  • Women with cancers (excluding nonmelanoma skin cancer) or cardiovascular diseases diagnosed at baseline or before the development of stroke (during follow-up)
Description of Study Protocol:

Recruitment

In 1976,  121 700 female registered nurses aged 30 to 55 years and residing in 11 US states who completed a questionnaire on their medical history and lifestyle were enrolled .  

Design

Retrospective cohort study

Dietary Intake/Dietary Assessment Methodology :

In 1980, dietary intake was collected using a validated semiquantitative food frequency questionnaire (FFQ, 61 items); in 1984, the FFQ was expanded to include 116 items; similar FFQs were used to update diet in 1986, 1990, and 1994. 

Blinding used:

Incident stroke was ascertained after all the dietary data were collected prospectively.

Intervention

Not applicable  

Statistical Analysis

  • Person-time of follow up: was computed for each participant from the enrollment to endpoint;
  • Incident rate for each category of folate: was calculated;
  • Total and dietary folate intake variables: were energy-adjusted but folate supplement intake was not;
  • Total and dietary folate intakes: were grouped into quintiles;
  • Pooled logistic regression: was used to pool over each 2-year period;
  • The cumulative average of nutrient intake: was calculated from FFQs between 1980 and 1994;
  • Incident stroke between two FFQ cycle was examined in relation to the average diet from all the preceding diet measures;
  • Mantel extension tests for trend: obtained by selecting the median value for each category and modeling this as a continuous variable;
  • SAS version 6.12 was used;
  • All P values were 2 sided. 
Data Collection Summary:

Timing of Measurements

  • The cohort was established in 1976 and completed a mailed questionnaire on their medical history and lifestyle.
  • Every 2 years, follow-up questionnaires were sent to update information on potential risk factors and to identify newly diagnosed cases of CVD and other diseases.

Dependent Variables    

 

Incident stroke occurring after the date of return of the 1980 questionnaire and before June 1, 1998: 

  • 1) Nonfatal stroke: were asked for permission to review medical records of women who reported nonfatal stroke.
  • 2) Fatal strokes were ascertained by reports from relatives or postal authorities and a search of the National Death Index, and were then documented by medical records and death certificates.
  • 3) Nonfatal or fatal strokes that were confirmed by telephone, letter, or death certificate, but for which no medical records were available, were regarded as probable.
  • 4) Confirmed and probable strokes were considered in the analyses for total stroke.
  • 5) Strokes were confirmed by medical records according to the criteria of the National Survey of Stroke.
  • 6) Strokes were subcategorized as subarachnoid hemorrhages, intraparenchymal hemorrhages, thrombotic, embolic, or ischemic (including thrombotic, embolic, and nonhemorrhagic strokes).  

 

Independent Variables

Folic acid intake:

  • 1) in 1980, was collected using a validated semiquantitative food frequency questionnaire (FFQ, 61 items);
  • 2) in 1984, the FFQ was expanded to include 116 items;
  • 3) similar FFQs were used to update diet in 1986, 1990, and 1994; 
  • 4) average daily folate intake: a) was calculated by multiplying the frequency of consumption of each item by the nutrient content and totaling the nutrient intake for all food items; b) was adjusted for total energy intake using the residual approach; c) food composition values were obtained from the Harvard University Food Composition Database (November 22, 1993) derived from US Department of Agriculture sources and supplemented with manufacturer information.

Control Variables

  • Age (5-year categories);
  • time period (2-year interval);
  • smoking history (never smoker, past smoker, current smoker [1 to 14, 15 to 24, and >=25 cigarettes/day]);
  • body mass index (BMI): <23, 23 to 24.9, 25 to 26.9, 27 to 29.9, 30 to 32.9, >=33 kg/m2;
  • hormone use and menopausal status (premenopausal, postmenopausal never user, postmenopausal current user, postmenopausal past user);
  • currently taking aspirin (yes, no);
  • vitamin E supplements (quintiles);
  • physical activity (<1 h/wk, >=1 to <2 h/wk, >=2 to <4 h/wk, >=4 to <7 h/wk, >=7 h/wk of moderate to vigorous activity);
  • alcohol use (0 g/day, 0.1 to 4.9 g/day, 5.0 to 14.9 g/day, >=15.0 g/day);
  • history of high blood pressure;
  • history of diabetes;
  • history of hypercholesterolemia;
  • parental history of myocardial infarction at or before the age of 65 years;
  • total caloric intake (quintiles);
  • nutrient variables (transfatty acid, P ratio, monosaturated fatty acids, total protein intake, cereal fiber, omega-3 fatty acid, {alpha} linolenic acid). 
Description of Actual Data Sample:

Initial N: The cohort was established in 1976 when 121 700 female registered nurses completed a mailed questionnaire on their medical history and lifestyle. A total of 98 462 women returned the 1980 diet questionnaire.

Attrition (final N):  After application of all the exclusion criteria, the final population consisted of 83 896 women.

Age: Aged 34 to 59 years in 1980 

Ethnicity: Not described

Other relevant demographics: Not described

Anthropometrics: Not described

Location: 11 US states

 

Summary of Results:

Table 1. Age- and Multivariable*-Adjusted Relative Risks of Total, Fatal, and Nonfatal Stroke According to the Quintiles of Total Folate Intake

 

 

 Quintiles of Total Folate Intake and Their Range (ug/d)

 P for trend
  1 2 3 4 5  
  30-210 211-271 272-354 355-526 >526  
Total Stroke (fatal and nonfatal)          
N of cases 235 219 238 217 231  
Age-adjusted RR 1.00 0.87 (0.73–1.05) 0.89 (0.74–1.06) 0.79 (0.66–0.96) 0.83 (0.69–0.99) P =0.06
Multivariable RR 1.00 0.99 (0.82–1.20) 1.09 (0.89–1.33) 1.01 (0.81–1.25) 0.99 (0.78–1.25) P =0.8
Multinutrient RR{dagger} 1.00 1.03 (0.85–1.25) 1.14 (0.92–1.40) 1.04 (0.83–1.31) 1.01 (0.79–1.29) P =0.8
Fatal Stroke            
N of cases 37 39 39 30 41  
Age-adjusted RR 1.00 1.20 (0.77–1.89) 1.27 (0.81–1.99) 1.03 (0.64–1.68) 1.17 (0.75–1.83) P =0.8
Multivariable RR 1.00 1.30 (0.82–2.07) 1.48 (0.91–2.40) 1.14 (0.66–1.99) 1.10 (0.61–1.97) P =0.9
Multinutrient RR{dagger} 1.00 1.32 (0.82–2.11) 1.52 (0.92–2.51) 1.17 (0.66–2.08) 1.14 (0.62–2.07) P =0.9
Nonfatal Stroke            
N of cases 198 180 199 187 190  
Age-adjusted RR

1.00

 0.81 (0.66–1.00) 0.82 (0.67–1.00) 0.74 (0.61–0.91) 0.77 (0.63–0.94) P =0.03

Multivariable RR

1.00

0.94 (0.76–1.16)

1.03 (0.83–1.28) 

 0.98 (0.77–1.24) 0.96 (0.74–1.25) P =0.8

Multinutrient RR{dagger}

1.00 

0.97 (0.79–1.21) 

1.07 (0.86–1.34)

 1.02 (0.79–1.30) 0.97 (0.74–1.28) P =0.8

 *Age (5-year categories); time period (2-year interval); smoking history (never smoker, past smoker, current smoker [1 to 14, 15 to 24, and >=25 cigarettes/day]); body mass index (BMI): <23, 23 to 24.9, 25 to 26.9, 27 to 29.9, 30 to 32.9, >=33 kg/m2; hormone use and menopausal status (premenopausal, postmenopausal never user, postmenopausal current user, postmenopausal past user); currently taking aspirin (yes, no); vitamin E supplements (quintiles); physical activity (<1 h/wk, >=1 to <2 h/wk, >=2 to <4 h/wk, >=4 to <7 h/wk, >=7 h/wk of moderate to vigorous activity); alcohol use (0 g/day, 0.1 to 4.9 g/day, 5.0 to 14.9 g/day, >=15.0 g/day); history of high blood pressure, history of diabetes; history of hypercholesterolemia; parental history of myocardial infarction at or before the age of 65 years; total caloric intake (quintiles).

{dagger}The aforementioned covariates plus nutrient variables (transfatty acid, P ratio, monosaturated fatty acids, total protein intake, cereal fiber, omega-3 fatty acid, {alpha} linolenic acid).

Table 2. Multivariable*-Adjusted Relative Risks of Specific Subtypes of Stroke According to the Quintiles of Total Folate Intake

 

 

 

 Quintiles of Total Folate Intake and Their Range (ug/d)

 P for trend
  1 2 3 4 5  
  30-210 211-271 272-354 355-526 >526  
Ischemic Stroke            
N of cases 122 118 129 112 120  
Multivariable RR 1.00 1.01 (0.78–1.32) 1.11 (0.84–1.46) 1.00 (0.74–1.36) 1.03 (0.74–1.43) P =1.0
Thrombotic Stroke            
N of cases 59 68 74 64 58  
Multivariable RR 1.00 1.20 (0.84–1.73) 1.29 (0.89–1.89) 1.14 (0.66–1.99) 1.01 (0.64–1.61) P =0.7
Embolic Stroke            
N of cases 18 24 23 18 27  

Multivariable RR

 1.00 1.25 (0.66–2.36) 1.14 (0.58–2.22) 0.84 (0.39–1.81) 1.13 (0.52–2.46) P =0.9
Hemorrhagic Stroke            
N of cases 24 25 21 23 21  

Multivariable RR

1.00

1.20 (0.67–2.14)

1.05 (0.56–1.98)

 1.32 (0.67–2.58) 1.22 (0.56–2.66) P =0.7
Subarachnoid Stroke            
N of cases 32 39 25 35 35  

Multivariable RR

 1.00 1.36 (0.83–2.21) 0.92 (0.52–1.61) 1.15 (0.65–2.04) 0.95 (0.51–1.76) P =0.6

*Covariates are the same as in Table 1.

Other findings

  • Folate intake was 1) not related to age, BMI, calories, or alcohol intake, 2) inversely associated with intake of saturated and transfatty acids and prevalence of smoking, 3) positively associated with use of vitamin E supplements and the likelihood of exercising.
  • Dietary folate intake (excluding supplements) and folate supplement intake were not significantly related to risk of stroke (Appendix).
  • There was no significant interaction between folate and alcohol intake (P for interaction=0.1).
  • After excluding premenopausal women and stratifying the sample by hormonal replacement therapy (never-use or ever-use), the association between folate intake and total or ischemic incidence of stroke remained nonsignificant.
Author Conclusion:

Folate intake was not associated with incident stroke among women participating in the Nurses' Health Study.

Reviewer Comments:
  • Recall bias was minimized by the study since all the dietary data were collected prospectively.
  • The questionnaire used in the study was examined to have good validity and the lack of observed association was not due to inability to measure folate intake.
  • There was the possibility of residual or unmeasured confounding.
  • The study did not have the power to compare extreme values of folate intake in relation to risk of stroke.
  • Folate was inversely related to ischemic stroke in men but not in women.

 

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? 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.) 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? 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? 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? 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? Yes
  10.1. Were sources of funding and investigators' affiliations described? Yes
  10.2. Was the study free from apparent conflict of interest? Yes
 
 

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