Homocyst(e)ine and cardiovascular disease: a systematic review of the evidence with special emphasis on case-control studies and nested case-control studies

Earl S Forda, S Jay Smithb, Donna F Stroupc, Karen K Steinbergd, Patricia W Muellere and Stephen B Thackerc

a Division of Nutrition and Physical Activity, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, Atlanta, GA, USA.
b Division of Environmental Health Laboratory Sciences, National Center for Environmental Health, Centers for Disease Control and Prevention, Atlanta, GA, USA.
c Epidemiology Program Office, Centers for Disease Control and Prevention, Atlanta, GA, USA.
d Office of Women's Health, Centers for Disease Control and Prevention, Atlanta, GA, USA.
e Division of Environmental Health Laboratory Sciences, National Center for Environmental Health, Centers for Disease Control and Prevention, Atlanta, GA, USA.

E Ford, Division of Nutrition and Physical Activity, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, 4770 Buford Highway, MS K24, Atlanta, GA 30341, USA.

Abstract

Background Elevated concentrations of homocyst(e)ine are thought to increase the risk of vascular diseases including coronary heart disease and cerebrovascular disease.

Methods We searched MEDLINE (1966–1999), EMBASE (1974–1999), SciSearch (1974– 1999), and Dissertation Abstracts (1999) for articles and theses about homocyst(e)ine concentration and coronary heart disease and cerebrovascular disease.

Results We included 57 publications (3 cohort studies, 12 nested case-control studies, 42 case-control studies) that reported results on 5518 people with coronary heart disease (11 068 control subjects) and 1817 people with cerebrovascular disease (4787 control subjects) in our analysis. For coronary heart disease, the summary odds ratios (OR) for a 5-µmol/l increase in homocyst(e)ine concentration were 1.06 (95% CI : 0.99–1.13) for 2 publications of cohort studies, 1.23 (95% CI : 1.07–1.41) for 10 publications of nested case-control studies, and 1.70 (95% CI : 1.50–1.93) for 26 publications of case-control studies. For cerebrovascular disease, the summary OR for a 5-µmol/l increase in homocyst(e)ine concentration were 1.10 (95% CI : 0.94–1.28) for 2 publications of cohort studies, 1.58 (95% CI : 1.35–1.85) for 5 publications of nested case-control studies, and 2.16 (95% CI : 1.65–2.82) for 17 publications of case-control studies.

Conclusions Prospective studies offer weaker support than case-control studies for an association between homocyst(e)ine concentration and cardiovascular disease. Although other lines of evidence support a role for homocyst(e)ine in the pathogenesis of cardiovascular disease, more information from prospective epidemiological studies or clinical trials is needed to clarify this role.

Keywords Homocyst(e)ine, meta-analysis, cardiovascular disease

Accepted 4 April 2001

Homocyst(e)ine is a thiol-containing amino acid generated when the essential amino acid methionine is metabolized to cysteine. Homocystinuria, an inherited autosomal recessive disease, was first reported in 1962, from Ireland, where cystathionine ß-synthase deficiency is particularly prevalent.1 In 1969, McCully proposed that elevated homocyst(e)ine concentration could be a risk factor for cardiovascular disease.2 In a meta-analysis of 27 studies published in 1995, Boushey and colleagues concluded that elevated homocyst(e)ine concentration was a risk factor for arteriosclerotic vascular disease.3 These authors found that a rise in homocyst(e)ine concentration of 5 µmol/l was associated with odds ratios (OR) of 1.6 (95% CI : 1.4–1.7) for coronary artery disease and 1.8 (95% CI : 1.3–1.9) for cerebrovascular disease. Only three nested case-control studies were included in that review, and, thus, the conclusions were based largely on cross-sectional and case-control studies. Case-control studies, which are subject to a variety of biases, particularly selection bias, and cross-sectional studies are generally considered inferior to nested case-control studies and cohort studies in determining causation. Subsequently, several additional narrative reviews of homocyst(e)ine and cardiovascular disease have been published.4–8 Because these reviews were not systematic and because new studies about homocyst(e)ine concentration as a risk factor for cardiovascular disease have been published, we updated the earlier meta-analysis. We produced separate risk estimates for cohort studies, nested case-control studies, and case-control studies and assessed the quality of the studies.

Methods

With the assistance of a librarian, we performed a literature search of three electronic databases using OVID version 2: MEDLINE (1966–1999), EMBASE (1974–1999), and SciSearch (1974–1999). For MEDLINE, we used the exploded terms homocysteine and cardiovascular disease. In EMBASE and SciSearch, we searched terms for homocyst(e)ine and cardiovascular disease that corresponded to the exploded terms in MEDLINE. In addition, we searched for doctoral theses using the Dissertation Abstracts database for 1999. We augmented these searches by examining references in papers and by searching our own files. We did not ask experts for references, and there were no language restrictions. We did not use unpublished studies.

We limited our analysis to case-control studies, nested case-control studies, and cohort studies of fatal and non-fatal coronary heart disease and cerebrovascular disease. We excluded case series of patients,9,10 cross-sectional studies,11–14 angiographic studies,15–21 studies that did not provide results separately for patients with coronary heart disease and cerebrovascular disease,22–28 studies of carotid artery stenosis or wall thickness measured by ultrasound, a study of coronary artery calcification,29 a study of aortic atherosclerosis,30 and studies of special populations such as patients on dialysis31 and patients with systemic lupus erythematosus,32 diabetes,33,34 or cardiovascular disease.35 Furthermore, we excluded studies which failed to report at least one of three types of data: mean concentrations and standard deviations of circulating homocyst(e)ine (plasma or serum) for case and control subjects, odds ratios (OR) or measures of relative risk for >=4 levels of homocyst(e)ine concentration, or reported OR or measures of relative risk for a defined change in homocyst(e)ine concentration.17,36–42 All studies had to include a fasting or post-methionine loading homocyst(e)ine concentration.

Working in teams of two, six of us abstracted the studies and disagreements were resolved within the teams. When multiple papers from a single study had been published, we used the latest publication and supplemented it with data from the earlier publications. We did not contact authors to request additional data. We rated the quality of studies on five criteria; possible scores ranged from 0 to 10 (Table 1Go).43–46


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Table 1 Quality scoring criteria
 
Data Analysis

For studies that reported mean homocyst(e)ine concentration for a diseased group and a control group, we followed the methods used by Boushey and colleagues.3 The pooled variance [S2p] was calculated using the case and control group homocyst(e)ine variances weighted by their sample sizes. The slope was calculated by dividing the difference between the case and control means by S2p. The log OR for a 5-µmol/l change in homocyst(e)ine concentration was calculated by multiplying the slope by 5 and the variance of the log OR by dividing the sum of inverse sample sizes by S2p.

If a study reported standard errors, we estimated the standard deviations by multiplying the standard error by the square root of the sample size.47,48 For two studies, we used the range of homocyst(e)ine concentration to estimate the standard deviations by dividing the range by 6.49,50 For another study, we estimated the standard deviation by dividing by 2 the difference of the geometric mean and the geometric mean plus 2 standard deviations,51 and for three others, we estimated the standard deviation from the 5th and 95th percentiles by taking the difference between the percentiles and dividing by 3.3.52–54 For several studies, we assumed that medians or geometric means and standard deviations were equivalent to arithmetic means and standard deviations.49,51–53,55,56 For one study, we calculated mean homocyst(e)ine concentrations for case patients from the raw data reported in the publication.57 When studies had multiple control groups, we chose ones that were most likely to be population-based.

Some studies reported OR for disease at several (mean) concentrations of homocyst(e)ine, or ‘doses'. When four or more doses are available, a response slope, which we refer to as a dose-response estimate, can be estimated in a linear weighted regression model.58

We calculated both fixed-effects and random-effects estimates. The study weights for the fixed-effects model were the inverse of the variances; random-effects weights were calculated by the DerSimonian method.59 We stratified the analysis by: sex, study design, whether studies matched in the design phase, and quality of study.

For assessing heterogeneity among studies, we calculated both a weighted and unweighted {chi}2 statistic.60 Because these variances were not statistically equivalent, we calculated an unweighted {chi}2.61 Where results were statistically heterogeneous (P < 0.10), we checked for outliers.62 In order to assess the influence of individual studies, we performed sensitivity analyses and show results with and without outliers. To examine the possibility that publication bias may have affected our results, we examined plots of the OR versus the standard errors of the studies.63

Results

Coronary heart disease
The 38 publications on coronary heart disease47,51,53,55,64–97 included 5518 case subjects and 11 068 control subjects (Table 2Go). A single non-significant OR was <1.0.70 The summary OR were 1.55 (95% CI : 1.40–1.71) for 36 publications of nested or case-control studies, 1.46 (95% CI : 1.32–1.62) for 23 publications of men and 1.92 (95% CI : 1.25–2.93) for 9 publications of women (Table 4Go).


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Table 2 Studies of homocyst(e)ine concentration and coronary heart disease
 

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Table 4 Summary estimates of risk for coronary heart disease or cerebrovascular disease associated with changes in homocyst(e)ine concentration
 
Cohort studies
Two cohort studies of men (269 events among 3051 participants) have reported positive associations between homocyst(e)ine concentration and coronary heart disease.64,65 The authors of the Zutphen Elderly Study reported an OR of 1.01 (95% CI : 0.993–1.069) per 1-µmol/l increase for incident events which is equivalent to an OR of 1.05 (95% CI : 0.96–1.15) per 5-µmol/l increase.64 For the Caerphilly study, we calculated an OR of 1.07 (95% CI : 0.95–1.20).65 The fixed effects summary OR was 1.06 (95% CI : 0.99–1.13). A third cohort study used cardiovascular disease, consisting of coronary heart disease and stroke, as its endpoint.26

Nested case-control studies
The 10 nested case-control studies of five different study populations had 1934 case subjects and 4285 control subjects (66–75). Six studies included only men66,69–71,73,75 and four included men and women.67,68,72,74 For eight studies that reported mean concentrations of homocyst(e)ine for case and control participants, the authors of four studies concluded that elevated homocyst(e)ine concentration increased the risk of coronary heart disease, while the authors of the other four failed to reject the null hypothesis of no association. We used the most recent data from three publications of the Physicians' Health Study (PHS)69,98,99 to estimate an OR of 1.23 (95% CI : 1.06–1.41) for these eight studies. When we re-analysed the data using the earlier PHS data,98 the OR was the same (OR = 1.23, 95% CI : 1.06–1.43). Among men, we estimated an OR of 1.19 (95% CI : 1.02–1.40).

For two additional nested case-control study, we were able to estimate an OR from dose-response data.72,75 Adding these studies to the other eight nested case-control studies yielded a summary OR of 1.23 (95% CI : 1.07–1.41).

The only report that presented data separately for men and women found no significant association between homocyst(e)ine concentration and myocardial infarction for either sex.67 In two other studies, sex did not modify the association between homocyst(e)ine concentration and coronary heart disease.72,74 In addition, Arnesen et al. reported that the per 4-µmol/l change of homocyst(e)ine was 1.66 (95% CI : 0.67–4.12) for women compared with an adjusted relative risk 1.41 (95% CI : 1.16– 1.71) for all subjects.68

We excluded one other nested case-control study of homocyst(e)ine concentration and cardiovascular disease among women in which coronary heart disease or stroke were combined.28 A significant association between homocyst(e)ine concentration and cardiovascular disease was reported (OR = 1.24 per 5-µmol/l increase in homocyst(e)ine concentration).

Case-control studies
The 26 publications included 3315 case subjects and 4001 control subjects.47,51,53,55,76–97 The summary OR were 1.70 (95% CI : 1.50–1.93) for all men and women, 1.63 (95% CI : 1.44–1.85) for men and 2.11 (95% CI : 1.30–3.42) for women (Table 4Go). For case-control studies of men and women in which the authors reported an OR for four or more categories of the homocyst(e)ine distribution, the summary OR was 1.45 (95% CI : 0.71–2.97).51,82,83,85,87,93,100 The summary OR for studies that measured homocyst(e)ine after a post-methionine loading test was similar to that for studies that measured baseline homocyst(e)ine concentrations.

For studies that matched on age or other factors in selecting case and control subjects,55,77,82,87,88,91–93,96 the summary OR was 1.49 (95% CI : 1.28–1.74); for studies that did not match the OR was 1.85 (95% CI : 1.54–2.23).

Generally, study results were not heterogeneous except for case-control studies among women. No single study accounted for the heterogeneity. Rather, there appeared to be two clusters of studies.

Study quality
Quality scores ranged from 6 to 9 for nested case-control studies and from 2 to 8 for case-control studies. After stratifying the case-control studies by a score of >=7 and <7, the summary OR was 1.46 (95% CI : 1.17–1.84) for the upper stratum51,88,91,93,94 and 1.75 (95% CI : 1.52–2.00) for the lower stratum.

Cerebrovascular disease
The 24 publications of cerebrovascular disease48–50,52,54,56,57,64,66,67,74,89,101–112 included 1817 case subjects and 4787 control subjects (Table 3Go). No study had a significant OR <1.0. The summary OR was 1.97 (95% CI : 1.61–2.40) for all nested case-control studies and case-control studies.


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Table 3 Studies of homocyst(e)ine concentration and cerebrovascular disease
 
Cohort studies
Two cohort studies (263 events among 2780 participants) have examined the association between homocyst(e)ine concentration and incident cerebrovascular disease.64,101 In the Zutphen Elderly Study, the authors reported that the risk for incident cerebrovascular disease increased by 1.01 (95% CI : 0.90–1.12) and for mortality from cerebrovascular disease by 1.04 (95% CI : 0.92–1.16) for a 5-µmol/l increase in homocyst(e)ine concentration.64 Using the dose-response data from the Framingham study, we estimated that the risk for cerebrovascular disease increased by 1.17 (95% CI : 1.14–1.20) for a 5-µmol/l increase in homocyst(e)ine concentration.101 The random-effects summary estimate of these two studies is 1.10 (95% CI : 0.94–1.28) per 5 µmol/l.

Nested case-control studies
Five publications included 316 case subjects and 1250 control subjects.52,66,67,74,102 The summary OR was 1.58 (95% CI : 1.35–1.85). Among men, the summary OR was 1.56 (95% CI : 1.30–1.88). The fixed-effects OR among women for a single study was 1.10 (95% CI : 0.98–1.24).67

Case-control studies
Seventeen publications included 1121 case subjects and 902 control subjects.48–50,54,56,57,89,103–112 The summary OR was 2.16 (95% CI : 1.65–2.82). Because these studies appeared to be heterogeneous, we removed a single study49 that had the largest homogeneity statistic. Consequently, the remaining studies were no longer heterogeneous and the summary OR changed to 2.25 (95% CI : 1.76–2.87). The OR were 1.95 (95% CI : 1.33– 2.85) for men,54,57,106,107 and 1.56 (95% CI : 1.09–2.24) for women.57,106,107

For studies that matched on age or other factors in selecting case and control subjects,49,50,103,108,109 the summary OR was 2.49 (95% CI : 1.05–5.91) and 2.06 (95% CI : 0.92–4.63) after an outlier was eliminated.103 For studies that did not match, the OR was 2.06 (95% CI : 1.60–2.66).

Study quality
Quality scores for case-control studies ranged from 2 to 7 with only a single study achieving the top score.

Publication bias
Funnel plots of the study effect size plotted against the study's weight for coronary heart disease and cerebrovascular disease suggested that we had not selectively omitted negative studies. However, funnel plot asymmetry was present for case-control studies of coronary heart disease (intercept = 3.1; P = 0.0001) as well as cerebrovascular disease (intercept = 3.3; P = 0.0001) but not for nested case-control studies of coronary heart disease.113

Discussion

In the most comprehensive meta-analysis to date, we have reviewed 57 publications that explored the relationship between homocyst(e)ine concentration and coronary heart disease or cerebrovascular disease. For coronary heart disease studies, we calculated summary OR for a 5-µmol/l increase in homocyst(e)ine of 1.06, 1.23, and 1.70 for cohort studies, nested case-control studies, and case-control studies, respectively. For cerebrovascular disease studies, these summary OR were 1.10, 1.58, and 2.16 for cohort studies, nested case-control studies, and case-control studies, respectively. Thus, the prospective studies, which are generally considered to have a stronger study design than case-control studies, found a weak but significant association between homocyst(e)ine concentration and coronary heart disease risk but a more robust association between homocyst(e)ine and cerebrovascular disease.

Heterogeneity and bias
We calculated both weighted and unweighted {chi}2 values for an assessment of heterogeneity. The weighted {chi}2 requires equality of intra-study variances. This requirement will often not be met in meta-analyses. Additionally, the weighted test may yield statistically significant results even with relative homogeneous means, if within-study variances are underestimated. This can happen when the true homocyst(e)ine variability among cases or controls is underestimated from an apparently very homogeneous small group of subjects. Because of these considerations, we considered that the unweighted {chi}2 statistic, which showed little heterogeneity among studies except for case-control studies among women and case-control studies of cerebrovascular disease among men and women, might be preferable for this analysis. We were unable to determine the reasons for the apparent heterogeneity for case-control studies of women. For case-control studies of cerebrovascular disease, eliminating a single study resolved the apparent heterogeneity. This study had the largest number of case subjects and was one of only two studies that found a lower mean or median homocyst(e)ine concentration among case subjects than control subjects.

Although the funnel plots did not suggest to us that publication bias was evident, funnel plot asymmetry was present among case-control studies of coronary heart disease and cerebrovascular disease.113 For both sets of studies, the intercepts for regression equations were positive and significant. In both instances, the slope was negative but not significant. Regardless of sample size threshold, funnel plot asymmetry, which can be caused by several sources of asymmetry, including selection bias, true heterogeneity, data irregularities, artefacts, or chance, persisted.113 Although the unweighted {chi}2 statistic we used to test for heterogeneity among OR did not indicate concerns about the presence of heterogeneity, the funnel plot asymmetry suggested otherwise. Our attempts to find possible sources of heterogeneity were not successful, however.

Excluded studies
Although we excluded various studies because of our study entry criteria, they do contain important information. Four cross-sectional studies11–14 and seven angiographic studies15–21 generally reported significant positive associations between homocyst(e)ine concentrations and cardiovascular disease. Five studies found a significant positive relationship between homocyst(e)ine concentration and carotid artery stenosis or intima or media thickness, an outcome that failed to meet our endpoint specification.114–118

In addition, the majority of case-control studies we excluded because the authors did not report their data in a format we could use reported a significant association between homocyst(e)ine concentration and coronary heart disease or cerebrovascular disease.36–40,42 These studies had 600 subjects with coronary heart disease, 325 subjects with cerebrovascular disease, and 778 control subjects. Although the reported or calculated OR for these studies tended to be higher than the summary OR for the case-control studies we included, adding the five studies would not have materially affected our conclusions.

Results of prospective versus retrospective studies
The results from cohort and nested case-control studies differed substantially from those for case-control studies. Generally, the study quality of the nested case-control studies was superior to that of case-control studies. Odds ratios of case-control studies of coronary heart disease were lower for higher quality studies than for lower quality ones. Data show that homocyst(e)ine concentrations decline during an acute cardiovascular event and rise after the event.49,81,85,119 How concentrations measured after an acute event compare with those before the acute event remains unknown, however. Additionally, some data suggest that endothelial cells injured by the atherosclerotic process may leak homocyst(e)ine into the circulation, resulting in an elevated homocyst(e)ine concentration.120 Thus, the timing of blood sample collection with respect to a cardiovascular disease event may affect the results.

A finding that homocyst(e)ine concentrations in stored blood specimens were unstable over time could explain why short-term studies would produce significant associations and longer-term studies would not. Verhoef and Stampfer thought this was an unlikely explanation but did not dismiss it entirely.121 Furthermore, freeze-thaw cycles are not thought to affect homocyst(e)ine concentrations.72 Nested case-control studies, which were not designed specifically to test the hypothesis that homocyst(e)ine concentration is a risk factor for cardiovascular disease, may not have followed proper blood collection and processing procedures, possibly narrowing any differences in homocyst(e)ine concentration between cases and controls and biasing the OR towards the null hypothesis. Fasting status does not appear to account for observed differences.122

Laboratory methods
Reporting of laboratory methods was inadequate in many studies. Often, authors did not describe the blood collection and processing methods adequately. For example, if samples are not held on ice, erythrocytes will continue to produce homocyst(e)ine increasing its concentration before centrifugation.123

Few studies address issues of quality control of the homocyst(e)ine assay. Preliminary data from the Centers for Disease Control and Prevention on 14 laboratories performing this assay on reference materials indicate a between-laboratory coefficient of variation of 12.1% to 13.3% in the normal range.124 For one reference material with a mean concentration of 11.1 µmol/l, the reported values ranged from 8.3 to 14 µmol/l. In the future, issues of quality control and laboratory standardization will need to be addressed.

Challenges
Combining the studies quantitatively proved difficult. Authors tended to report their results in various ways, used different cutoff values for establishing normal ranges, did not always report the boundaries of these homocyst(e)ine quantiles, and were unlikely to report an OR per µmol/l change of homocyst(e)ine concentration. Thus, the OR that we calculated from the reported homocyst(e)ine concentration means were largely based on unadjusted data, since most authors reported unadjusted means only. Because homocyst(e)ine concentrations increase with age, and because in a number of these studies the control subjects were younger than case subjects, some of the reported differences in mean homocyst(e)ine concentrations may have been attributable to age. Accordingly, the summary OR produced may have overestimated the association between homocyst(e)ine concentration and cardiovascular disease.

Attempting to incorporate study quality into a meta-analysis is a controversial subject.45 In general, studies with higher quality scores reported a smaller effect size than studies with lower quality scores. Furthermore, studies of coronary heart disease, but not cerebrovascular disease, that had matched on one or more variables in the design phase produced a lower summary OR than studies that had failed to match.

If homocyst(e)ine is indeed a risk factor for cardiovascular disease, the form of the relationship (linear, curvilinear, or threshold) needs to be established. To date, no accepted optimal homocyst(e)ine concentration in humans has been defined based on epidemiological or other data. Such data are needed to formulate treatment and screening guidelines for health professionals and for public policy, such as the setting of objectives for population means and distributions. One way to define the form of the relation between homocyst(e)ine concentration and cardiovascular disease and to define an optimal upper limit would be to pool the data from the various nested case-control studies.

Recommendations
To facilitate the performance and review of meta-analyses in the future, investigators should report detailed blood collection and processing methods, information about quality control practices, the time interval from illness event to the blood draw as well as the interval from the blood draw to analysis, and both crude and adjusted homocyst(e)ine means and standard deviations for cases and controls. Furthermore, investigators should report the regression coefficient and standard error or the OR and confidence limits per unit or multiple unit change of homocyst(e)ine concentration, examine the form of the exposure-disease relationship by checking for non-linearity, and present adjusted risk estimates in addition to crude or age-adjusted estimates. The optimal set of potential confounders is not yet clear but should include age at a minimum. Also, because risk estimates may differ for different outcomes, the results should be presented separately for coronary heart disease, stroke and other manifestations of cardiovascular disease.

Conclusions

Homocyst(e)ine concentration is only weakly related to coronary heart disease and somewhat more strongly related to cerebrovascular disease. Additional prospective studies or clinical trials may help to clarify the relation between homocyst(e)ine concentration and risk of cardiovascular disease with care taken to include women and minority populations. Prospective studies suggest that the population attributable fraction of hyperhomocyst(e)inaemia may be smaller than previously thought and may be smaller than that of other proven, highly prevalent, modifiable risk factors for cardiovascular disease such as smoking, hypertension, hypercholesterolaemia, sedentary lifestyle, and overweight. At present, it is premature to formulate public health recommendations on recommended homocyst(e)ine concentrations, screening policies, and prevention measures in the general population.



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Figure 1 Estimated odds ratios per 5-µmol/l change in homocyst(e)ine concentration and coronary heart disease by individual cohort studies, nested case-control studies, and case-control studies. Odds ratios are plotted in order of year of publication and, within year of publication, according to alphabetical order of first author's name. If authors of studies that included men and women reported results for the two sexes combined, a single odds ratio representing the combined sample was graphed. Otherwise, if no combined results were reported, sex-specific odds ratios were graphed

 


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Figure 2 Estimated odds ratios per 5-µmol/l change in homocyst(e)ine concentration and cerebrovascular disease by individual cohort studies, nested case-control studies, and case-control studies. Odds ratios are plotted in order of year of publication and, within year of publication, according to alphabetical order of first author's name. If authors of studies that included men and women reported results for the two sexes combined, a single odds ratio representing the combined sample was graphed. Otherwise, if no combined results were reported, sex-specific odds ratios were graphed

 
Acknowledgments

The authors thank Elyse Weitman for her research assistance and Barbara A Bowman, PhD and Wayne H Giles, MD, MPH for their helpful comments.

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