Er remains unclear. There have been few metaanalyses of NSAIDs use and Title Loaded From File cancer risk in general, which included some studies of bladder cancer and did not exclusively focus on this disease 10781694 [11]. The effect of NSAIDs on the risk of bladder cancer remains to be determined. Therefore, we conducted a comprehensive meta-analysis of studies exclusively dedicated to the relationship between the 3 most commonly used analgesics and bladder cancer risk.NSAIDs Use and Bladder Cancer RiskFigure 1. Flow diagram of study identification. doi:10.1371/journal.pone.0070008.gMaterials and Methods Search StrategyA systematic literature search up to November 1 of 2012 was performed in Title Loaded From File PubMed database to identify eligible studies. Search terms included “acetaminophen,” “aspirin,” “nonsteroidal antiinflammatory agents,” or “NSAID” combined with “bladder cancer,” “bladder neoplasms,” or “bladder carcinoma”. The titles and abstracts of the studies identified in the search were scanned to exclude any clearly irrelevant studies. The full texts of the remaining articles were read to determine whether they contained information on the topic of interest. Furthermore, we also manually searched the reference lists of every article retrieved and review papers to find any additional published studies. All searches were conducted independently 16985061 by 2 authors (HZ and DJ). The results were compared, and any questions or discrepancies were resolved through iteration and consensus.measures of RR like risk ratio, rate ratio, hazard ratio (HR), and odds ratio (OR) were included in the meta-analysis. In practice, these measures of effect yield a similar estimate of RR, since the absolute risk of bladder cancer is low.Data ExtractionData abstraction was conducted independently by 2 researchers (HZ and DJ), with disagreements resolved by consensus. The following information were collected: the first author’s last name, year of publication, country in which the study was performed, study design, years of follow-up or the study period, study participants age range, number of subjects and number of bladder cancer cases, used drugs, exposure definition, information source, control of confounding factors by matching or adjustment, and RR estimates with corresponding 95 CIs. If a study provided several risk estimates, the most completely adjusted estimate was extracted. Differences in data extraction were resolved by consensus, referring back to the original article.Study SelectionTo be eligible, studies had to fulfill the following 4 inclusion criteria: 1) had a case-control or prospective study design; 2) reported results on aspirin, non-aspirin NSAIDs or acetaminophen use; 3) the outcome was bladder cancer incidence or mortality; and 4) reported the estimate of relative risk (RR) with their corresponding 95 confidence interval (CI) (or sufficient data to calculate of these effect measure). Studies reporting differentStatistical analysisSeparate analyses were performed according to use of acetaminophen, aspirin, and non-aspirin NSAIDs. Study-specific risk estimates were extracted from each article, and log risk estimates were weighted by the inverse of their variances to obtain a pooled risk estimate. We pooled study-specific log RRs toNSAIDs Use and Bladder Cancer RiskTable 1. Characteristics of studies included in the meta-analysis.Study Piper (23) Derby (24) Pommer (25) Castelao (26) Kaye (27) Friis (28) Friis (29) S ensen (30)Year 1985 1996 1999 2000 2001 2002 2003Cou.Er remains unclear. There have been few metaanalyses of NSAIDs use and cancer risk in general, which included some studies of bladder cancer and did not exclusively focus on this disease 10781694 [11]. The effect of NSAIDs on the risk of bladder cancer remains to be determined. Therefore, we conducted a comprehensive meta-analysis of studies exclusively dedicated to the relationship between the 3 most commonly used analgesics and bladder cancer risk.NSAIDs Use and Bladder Cancer RiskFigure 1. Flow diagram of study identification. doi:10.1371/journal.pone.0070008.gMaterials and Methods Search StrategyA systematic literature search up to November 1 of 2012 was performed in PubMed database to identify eligible studies. Search terms included “acetaminophen,” “aspirin,” “nonsteroidal antiinflammatory agents,” or “NSAID” combined with “bladder cancer,” “bladder neoplasms,” or “bladder carcinoma”. The titles and abstracts of the studies identified in the search were scanned to exclude any clearly irrelevant studies. The full texts of the remaining articles were read to determine whether they contained information on the topic of interest. Furthermore, we also manually searched the reference lists of every article retrieved and review papers to find any additional published studies. All searches were conducted independently 16985061 by 2 authors (HZ and DJ). The results were compared, and any questions or discrepancies were resolved through iteration and consensus.measures of RR like risk ratio, rate ratio, hazard ratio (HR), and odds ratio (OR) were included in the meta-analysis. In practice, these measures of effect yield a similar estimate of RR, since the absolute risk of bladder cancer is low.Data ExtractionData abstraction was conducted independently by 2 researchers (HZ and DJ), with disagreements resolved by consensus. The following information were collected: the first author’s last name, year of publication, country in which the study was performed, study design, years of follow-up or the study period, study participants age range, number of subjects and number of bladder cancer cases, used drugs, exposure definition, information source, control of confounding factors by matching or adjustment, and RR estimates with corresponding 95 CIs. If a study provided several risk estimates, the most completely adjusted estimate was extracted. Differences in data extraction were resolved by consensus, referring back to the original article.Study SelectionTo be eligible, studies had to fulfill the following 4 inclusion criteria: 1) had a case-control or prospective study design; 2) reported results on aspirin, non-aspirin NSAIDs or acetaminophen use; 3) the outcome was bladder cancer incidence or mortality; and 4) reported the estimate of relative risk (RR) with their corresponding 95 confidence interval (CI) (or sufficient data to calculate of these effect measure). Studies reporting differentStatistical analysisSeparate analyses were performed according to use of acetaminophen, aspirin, and non-aspirin NSAIDs. Study-specific risk estimates were extracted from each article, and log risk estimates were weighted by the inverse of their variances to obtain a pooled risk estimate. We pooled study-specific log RRs toNSAIDs Use and Bladder Cancer RiskTable 1. Characteristics of studies included in the meta-analysis.Study Piper (23) Derby (24) Pommer (25) Castelao (26) Kaye (27) Friis (28) Friis (29) S ensen (30)Year 1985 1996 1999 2000 2001 2002 2003Cou.
