1 Department of Epidemiology, University of North Carolina School of Public Health, Chapel Hill, NC.
2 Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD.
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ABSTRACT |
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cardiovascular diseases; cerebrovascular accident; coronary disease; meta-analysis; myocardial infarction; tea
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INTRODUCTION |
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MATERIALS AND METHODS |
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Four reports on three early case-control studies (911
) were excluded because they did not include sufficient information to compute an estimate of relative risk or its standard error. (Throughout this paper, the term "relative risk" is used for incidence rate ratios estimated directly in cohort studies and by the exposure odds ratio in case-control studies.) In addition, two cross-sectional studies that measured serum levels and included undiagnosed cases (12
, 13
) were excluded. However, data from the latter cohort (13
) were included as drawn from a separate publication (14
). A report by Klatsky et al. (15
) was replaced by a more recent analysis of the same cohort (16
). In the report by Sato et al. (17
), results from the prospective part of the study were used. We contacted the authors of 11 studies (14
, 16
25
) for information not included in their papers, such as variance estimates, numbers of subjects in categories of tea consumption, and typical tea cup sizes in specific locales. Nine authors responded to our request (see Acknowledgments).
The studies addressed a diversity of cardiovascular diseases (International Classification of Diseases, Ninth Revision, codes 390459), which were combined in different ways (appendix table 1). We included the three outcome categories (myocardial infarction, stroke, and the broader category of coronary heart disease), which were examined in at least three studies. If a study provided more than one effect estimate for a single outcome category (14, 16
), only one estimate was used.
The following paragraphs in this section pertain to statistical methods. The statistical analyses included 1) extracting or computing a common, comparable relative risk estimate from each study; 2) searching for evidence of publication bias; 3) analyzing interstudy variation; and 4) computing summary effect estimates as indicated. Evidence of publication bias and heterogeneity was taken to contraindicate reliance on overall summaries (23). In the presence of heterogeneity of effect, the main purpose of the meta-analysis became the identification of sources of interstudy variation.
We attempted to place the studies on a common footing by estimating the relative risk of a 3 cups per day increase in tea consumption (e.g., from no tea consumption to 3 cups per day) (1 cup = 237 ml). For studies reporting relative risk estimates in categories of tea consumption, we used inverse variance-weighted categorical regression to estimate linear exposure-response curves. These analyses were conducted on the incidence rate scale for cohort studies and on the logit scale for case-control studies. We used the covariance-corrected method of Greenland and Longnecker (26) for studies that provided the relative risk of tea consumption for more than two categories of tea consumption and provided the person-time per number of all subjects and cases per category of tea consumption (18
, 20
, 21
, 25
, 27
30
). For other studies (14
, 17
, 19
, 22
, 23
, 33
, 34
), we used the method described by Berlin et al. (31
) and Greeland (32
) or the relative risk for tea consumption as continuous (16
, 24
).
We assigned exposure values, in cups per day, to the tea consumption categories in the original studies as follows. For case-control studies, we used the tea consumption of the control groups. The various measures of tea consumption (cups, grams, milliliters) were transformed to a common measure of cups per day (1 cup = 8 ounces = 237 ml). When category medians (14, 20
) or means (29
, 33
) were available, they were used. Category midranges were applied for the remaining closed-ended categories if they were no broader than 2 cups per day. If the highest, open-ended category included no more than 20 percent of the study subjects, we assigned that category a value equal to 1.2 times its lower boundary (18
, 21
23
, 25
, 27
). For the study by Stensvold et al. (19
), more detailed data from an earlier report (35
) on the same cohort were used to assign values to the tea consumption categories. Some of the closed-ended categories were wider than 2 cups per day in the studies by Rosenberg et al. (30
), Jick et al. (34
), and the Boston Collaborative Drug Surveillance Program (28
). For these studies, we assigned category medians from the National Health and Nutrition Examination Survey I Epidemiologic Followup Study (36
). In the Japanese study by Sato et al. (17
), 41 percent of the subjects were in the highest, open-ended category. For this study, we used category midranges for the closed-ended categories. We used the factor 1.4 times the lower boundary of 7 cups per day for the highest, open-ended category instead of 1.2, because we expected the distribution to be skewed to the right, given the large proportion of people in the highest category.
The log-rank test of Begg and Mazumdar (37) was used for evidence of publication bias, with low p values suggesting the presence of bias. In addition, funnel graphs in which the study-specific effect estimates are displayed in relation to the reciprocals of their estimated variances were created (38
). In the absence of publication bias, these graphs resemble a funnel with the estimates from the larger studies in the center, flanked symmetrically on either side by the less precise estimates.
To explore sources of heterogeneity among the studies, we performed stratified and meta-regression analyses (32, 39
). The meta-regressions were fit using inverse variance-weighted, linear regression. The dependent variable was the log relative risk, and the independent variables were the study characteristics suspected of being sources of heterogeneity. After transformation back to the original ratio scale, the meta-regressions estimate the ratio of the average relative risk estimates reported by studies with one characteristic to the average estimates reported by studies with another characteristic. In this way, these models quantify the degree to which characteristics of the studies are associated with their results. The fit of the meta-regression models was checked by calculating the residual sum of squares (32
).
We examined the following study characteristics in the stratified and meta-regression analyses: study design (cohort, case-control); mortality or morbidity data; geographic region (United States, United Kingdom, continental Europe, Asia, Australia); gender; adjustment for potential confounders by modeling, restriction, or stratification (sex and/or age, socio-economic status, smoking, other nondietary risk factors for cardiovascular disease including alcohol, dietary factors); publication year (before or during 1980, 19811990, during or after 1991); age of subjects (<50 years, >=50 years, all ages); participation rate (among the controls in case-control studies if separately reported); frequency of tea drinking in the study population (<50 percent, 50 percent drinking
1cup per day); and years of follow-up (cohort studies only). We were not able to investigate whether differences in dietary assessment methods accounted for heterogeneity because of the lack of description of the dietary assessment methods applied. Study characteristics were initially examined one by one, because of the lack of power to run them jointly due to the small number of studies. An attempt was made to examine jointly those characteristics that appeared in these analyses to be appreciably associated with the study-specific effect estimates.
To examine the effect of differences in the strength of tea in different regions quantitatively, we multiplied the assigned categorical dose by 0.5 and recalculated the summarized risk estimate for studies conducted in the United States on coronary heat disease or myocardial infarction. According to this calculation, we assume that the tea in the United States is half as strong as that in Europe. All analyses were conducted with Statistical Analysis System (SAS) software (40).
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RESULTS |
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The test for heterogeneity of the effect of tea on myocardial infarction showed no strong evidence of heterogeneity (p = 0.20) (table 3). The fixed-effects summary suggests a decrease in incidence of myocardial infarction of 11 percent associated with an increment of 3 cups of tea per day (summary relative risk = 0.89, 95 percent confidence interval: 0.79, 1.01) (table 3). The evidence of publication bias, however, urges caution in interpreting this result.
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Additionally, we calculated the summarized risk estimate for studies conducted in the United States on coronary heart disease or myocardial infarction, assuming that tea in the United States is half as strong as that in Europe. In this case, the summarized risk estimate for studies conducted in the United States for coronary heart disease or myocardial infarction is 0.90 (95 percent confidence interval: 0.81, 1.01) with each increment of 3 cups/day rather than 0.95 (table 3).
The geographic stratified risk estimates of coronary heart disease alone were fairly similar to the risk estimates of coronary heart disease or myocardial infarction combined, although the results of the three studies from the United States were too heterogeneous (p = 0.16) to be summarized.
For myocardial infarction, the effect estimates from studies in the United States were reasonably homogeneous and suggested little or no effect. The fixed-effects summary from these six studies from the United States was almost identical to the estimate from the one study from Italy that was included (relative risk = 0.89 vs. relative risk = 0.91).
For stroke, the only case-control study conducted in Australia indicated a nonsignificant increased risk of 51 percent with each 3 cups/day (25). Cohort studies conducted in the United States, continental Europe, or Asia did not indicate strong evidence of heterogeneity (p = 0.21) with a significant reduction in stroke incidence of 12 percent per 3 cups of tea/day. The protective effect of tea on stroke increased in cohort studies by 5 percent with each year of follow-up (415 years).
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DISCUSSION |
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The small number of published studies for any specific cardiovascular disease outcome severely limited the ability to detect publication bias or heterogeneity. Tests of homogeneity are well known to have low power. Begg and Mazumdar (37) stated that their test for publication bias has moderate power with 25 studies and high power with 75 studies. It is impressive, therefore, that the p values from the tests for heterogeneity and publication bias were so low for stroke, despite the small number of studies in the published literature on the topic at hand. It would be of considerable interest to learn if epidemiologic researchers have examined results for tea and myocardial infarction and stroke and refrained from publishing them because they were not indicative of pronounced preventive effects. Only one of many possibilities is that publication bias on this question has been stronger in Europe, where more people drink tea, than in the United States.
If studies with positive associations have not been published, as suggested by the tests of publication bias and funnel graphs, the central tendency would be closer to the null value. One cannot predict what the stratified and meta-regression analysis of study characteristics would show if a sizable number of unpublished studies were brought to light. The evidence of publication bias did not disprove the hypothesis of a protective effect, but it tempered the strengths of the conclusion regarding preventive potential.
The outcomes investigated in the studies had different definitions and were combined in more or less broad categories. If tea has different effects on different aspects of cardiovascular diseases, a combined estimate from various outcomes may minimize a tea effect. The results of the pres-ent meta-analysis suggest this possibility because the study results were less heterogeneous for myocardial infarction alone than for any less specific outcome. These results suggest that a more precise definition of the outcome might improve the homogeneity among studies and the precision in the effect estimate.
Case-control studies tend to have a higher potential for recall and selection bias. Nevertheless, we saw little or no difference in results between cohort studies and case-control studies for coronary heart disease or myocardial infarction. For stroke, it remains unclear if the differences were due to regional differences or differences in study design. The low number of studies limited the power to detect differences among the studies. If we expected the differences to be small, as possibly for differences in adjustment for confounding, we have limited ability to detect small differences in the meta-analysis.
For cohort studies on stroke, we found an increased protective effect with increasing length of follow-up between 4 and 15 years, which might indicate the importance of early prevention.
The findings from the United Kingdom and Australia of a positive association were unique. One possible explanation involves the polyphenolic antioxidant flavonoids hypothesized to be one mechanism by which tea might reduce cardiovascular disease incidence (17
). In the United Kingdom, milk commonly is added to tea. Hertog et al. (27
) reported that more than 99 percent of tea drinkers added milk and argued that this difference might explain why they did not find evidence of a protective effect of tea. Hasalam (41
) showed that flavonoids are bound to protein. Further, indirect evidence suggested by Serafini et al. (42
) showed that adding milk to tea abolished its in vivo plasma antioxidant potential. In contrast to these findings, however, Hollman et al. (43
) and van het Hof et al. (44
) did not find different flavonoid plasma concentrations in subjects given tea with or without milk. The hypothesis has been stated for the findings from the United Kingdom studies on coronary heart disease. This is also a possible explanation for the findings for stroke in Australia, a population that is strongly influenced by immigrants from the United Kingdom. In any event, the hypothesis of Hertog et al. (27
) and Hasalam (41
) might explain why an inverse association would not be seen in the United Kingdom and Australia, but that hypothesis would not explain why a positive association was seen. The amount of fat in the milk that is added to the tea would seem woefully insufficient to increase cardiovascular disease risk.
Sesso et al. (20) suggested that higher tea consumption might be a surrogate for a healthier lifestyle. Weak inverse associations of tea consumption with smoking, body mass index, and dietary risk factors have been reported (16
, 19
, 29
). Residual confounding and lack of control for lifestyle factors might explain why some studies appear to suggest a protective effect of tea on cardiovascular disease. These problems may also explain regional differences. In the United Kingdom and in continental Europe, tea consumption is very common and therefore may not be restricted to people with healthier behaviors. Perhaps residual confounding and lack of control for lifestyle factors are especially pronounced in the United States, where fewer people drink tea and where weaker associations between tea and cardiovascular disease have been reported.
An important limitation of the studies was imprecision of the exposure measurement. Only the study from Japan investigated green tea. All other studies referred simply to tea. Some studies mention that the subjects were asked only about the frequency of tea consumption without any more detailed questions about the kind or preparation of tea. Tea comprises a heterogeneous group of beverages, including fermented black tea, half fermented oolongs, unfermented green tea, and sweetened or unsweetened ice tea, and it might even be understood to include fruit tea or herbal teas. It is to be expected that study subjects give a summary answer for any kind of tea if they are asked only about their tea consumption without more detailed questions. Different kinds of tea differ in the kind and quantity of substances and, even within the same kind of tea, differences exist. According to the analysis of Prior and Cao (45), the phenol content and antioxidant capacity of black, green, and herbal or berry teas can vary more than twofold. The mean total phenol content of black tea is 129.3 mg/g, of green tea, 71.7 mg/g, and of herbal/berry tea, 51.7 mg/g. In addition, the method of preparation affects the content of tea.
The information available was insufficient for us to address the kinds of tea, the methods of preparation, or the differences in tea strength. These factors might help to explain the regional differences we found, however. For instance, it might be expected that the kind of tea, method of preparation, and preference of tea strength differ among the regions and that there might be more similarity within a region than between regions. It is likely that the varying characteristics of tea have different effects on cardiovascular disease. If, for instance, Europeans tend to drink stronger tea than North Americans do, the effect per cup of tea could be higher in the European studies. We examined this hypothesis by recalculating the summarized risk estimate for coronary heart disease or myocardial infarction in the way that the tea in the United States is assumed to be only half as strong as that in Europe. In this case, the risk estimate for studies conducted in the United States decreased only from 0.95 to 0.90 with each 3 cups/day and is still very different from the summarized risk estimate in continental Europe of 0.27. It appears, therefore, that differences in tea strength may explain only a small fraction of the regional differences.
Because of the high consumption and distribution of tea worldwide, hypothetical health effects of tea are important public health issues. It appears worthwhile to address the regional differences in future research, while improving control for potential confounders and measurement of the many characteristics of tea and its preparation and consumption. Of greatest and most immediate importance would be for all investigators who have unpublished results on tea and cardiovascular disease to bring those results forward.
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APPENDIX |
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* ICD-9, International Classification of Diseases, Ninth Revision; CHD, coronary heart disease; IHD, ischemic heart disease; MI, myocardial infarction; BCDSP, Boston Collaborative Drug Surveillance Program.
1, age; 2, gender; 3, education/profession; 4, race; 5, poverty index/social class; 6, marital status; 7, religion; 8, Framingham type A personality score/Bortner personality score; 9, year of interview; 10, geographic area; 11, smoking; 12, body mass index; 13, physical activity; 14, aspirin use; 15, history of myocardial infarction, coronary heart disease, hypertension; 16, other baseline disease; 17, diabetes; 18, family history of myocardial infarction or coronary heart disease; 19, family history of diabetes; 20, number of visits of physician in the previous year; 21, systolic and/or diastolic blood pressure; 22, serum cholesterol; 23, serum high density lipoprotein; 24, alcohol; 25, calories/energy; 26, fat; 27, saturated fat; 28, cholesterol; 29, dietary fiber/whole grain; 30, vitamin C; 31, vitamin E; 32, beta-carotene; 33, antioxidant vitamins; 34, salt intake; 35, calcium; 36, fish; 37, coffee.
Numbers in parentheses, reference citation.
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ACKNOWLEDGMENTS |
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NOTES |
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REFERENCES |
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