Alcohol drinking, and HP infection status did not show Title Loaded From File significant association with NERD.Meta-AnalysisTo get an overview of the accumulated reports concerning association between coffee consumption and the four upper gastrointestinal disorders, we performed meta-analyses using the random effects model. For peptic ulcer diseases, we found six casecontrol and four cohort studies fulfilling the inclusion criteria for meta-analysis (Table S1). We have found other five studiesevaluating the association of coffee with peptic ulcer diseases (Table S2), which did not meet the criteria and could not be used in our meta-analysis. A total of 10 Title Loaded From File papers met the inclusion criteria and were included in the meta-analysis, together with our present study (Figure 3). For GERD (RE and NERD), we 24195657 could not perform meta-analysis, because a number of studies meeting the criteria was too small. Meta-analysis was executed using a random effects model, because a test of heterogeneity was statistically significant. As shown in Figure 3A, the meta-analysis of two case-control and three cohort studies showed no significant association between coffee consumption and GU (pooled odds ratio, 0.88; 95 CI, 0.49 to 1.60; p for heterogeneity, 0.0008; I2, 78.9 ). The metaanalysis of five case-control and three cohort studies also detected no significant association between coffee consumption and DU (Figure 3B; pooled odds ratio 1.17; 95 CI, 0.79 to 1.73; p for heterogeneity, 0.0174; I2, 58.8 ). For PU, we analyzed three casecontrol and five cohort studies (Figure 3C), which again denied significant association with coffee consumption (pooled odds ratio 0.99; 95 CI, 0.75 to 1.32; p for heterogeneity, ,0.0001; I2, 76.9 ). To sum up, the meta-analyses could not detect a significant association of coffee consumption with the upper gastrointestinal ulcer diseases. Publication bias of each meta-analysis was further assessed by a funnel plot and funnel plot regression, in which p-values less than 0.1 were considered statistically significant. In all meta-analyses we performed, significance tests of the asymmetry were not significant (GU: p = 0.582, DU: p = 0.146, PU: p = 0.396). We thence concluded that publication bias can be considered as nonsignificant.No Relation of Coffee with Peptic Ulcer and GERDFigure 3. Forest plots of the odds ratios and 95 confidential intervals for upper gastrointestinal peptic ulcer. Forest plots of the odds ratios and 95 confidential intervals for gastric ulcer (A), duodenal ulcer (B), and peptic ulcer (C) relating coffee intake. The gray box represents the odds ratio estimates in each study, and the horizontal line indicates the 95 confidential intervals for each study. Diamonds at the bottom represent the pooled odds ratio estimates. Weights are from random effect meta-analysis. doi:10.1371/journal.pone.0065996.gNo Relation of Coffee with Peptic Ulcer and GERDDiscussionAll the four upper gastrointestinal disorders examined in the present study have been considered as acid-related diseases [3]. Therefore, it is easy to conceive that coffee containing caffeine stimulates the gastric acid production [4,43?5], and consequentially increases the risk of these disorders. Especially for PU, it has been repeatedly reported that the coffee is a risk factor for both gastric and duodenal ulcer [9,16]. However, multivariate analysis of the healthy subjects (Table 3) could not detect significant association between coffee intake and upper gastroduodenal ul.Alcohol drinking, and HP infection status did not show significant association with NERD.Meta-AnalysisTo get an overview of the accumulated reports concerning association between coffee consumption and the four upper gastrointestinal disorders, we performed meta-analyses using the random effects model. For peptic ulcer diseases, we found six casecontrol and four cohort studies fulfilling the inclusion criteria for meta-analysis (Table S1). We have found other five studiesevaluating the association of coffee with peptic ulcer diseases (Table S2), which did not meet the criteria and could not be used in our meta-analysis. A total of 10 papers met the inclusion criteria and were included in the meta-analysis, together with our present study (Figure 3). For GERD (RE and NERD), we 24195657 could not perform meta-analysis, because a number of studies meeting the criteria was too small. Meta-analysis was executed using a random effects model, because a test of heterogeneity was statistically significant. As shown in Figure 3A, the meta-analysis of two case-control and three cohort studies showed no significant association between coffee consumption and GU (pooled odds ratio, 0.88; 95 CI, 0.49 to 1.60; p for heterogeneity, 0.0008; I2, 78.9 ). The metaanalysis of five case-control and three cohort studies also detected no significant association between coffee consumption and DU (Figure 3B; pooled odds ratio 1.17; 95 CI, 0.79 to 1.73; p for heterogeneity, 0.0174; I2, 58.8 ). For PU, we analyzed three casecontrol and five cohort studies (Figure 3C), which again denied significant association with coffee consumption (pooled odds ratio 0.99; 95 CI, 0.75 to 1.32; p for heterogeneity, ,0.0001; I2, 76.9 ). To sum up, the meta-analyses could not detect a significant association of coffee consumption with the upper gastrointestinal ulcer diseases. Publication bias of each meta-analysis was further assessed by a funnel plot and funnel plot regression, in which p-values less than 0.1 were considered statistically significant. In all meta-analyses we performed, significance tests of the asymmetry were not significant (GU: p = 0.582, DU: p = 0.146, PU: p = 0.396). We thence concluded that publication bias can be considered as nonsignificant.No Relation of Coffee with Peptic Ulcer and GERDFigure 3. Forest plots of the odds ratios and 95 confidential intervals for upper gastrointestinal peptic ulcer. Forest plots of the odds ratios and 95 confidential intervals for gastric ulcer (A), duodenal ulcer (B), and peptic ulcer (C) relating coffee intake. The gray box represents the odds ratio estimates in each study, and the horizontal line indicates the 95 confidential intervals for each study. Diamonds at the bottom represent the pooled odds ratio estimates. Weights are from random effect meta-analysis. doi:10.1371/journal.pone.0065996.gNo Relation of Coffee with Peptic Ulcer and GERDDiscussionAll the four upper gastrointestinal disorders examined in the present study have been considered as acid-related diseases [3]. Therefore, it is easy to conceive that coffee containing caffeine stimulates the gastric acid production [4,43?5], and consequentially increases the risk of these disorders. Especially for PU, it has been repeatedly reported that the coffee is a risk factor for both gastric and duodenal ulcer [9,16]. However, multivariate analysis of the healthy subjects (Table 3) could not detect significant association between coffee intake and upper gastroduodenal ul.
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