Lavones excluded) were available; (3) the association of flavonoids or one of flavonoid subclasses with breast cancer risk was specifically evaluated; (4) relatively complete assessment of total flavonoids or flavonoid JI-101 chemical information subclass intake was performed; (5) relative risk (RR), hazard ratio (HR), or odds ratio (OR), and corresponding 95 confidence intervals (95 CI) were available. Because isoflavones have been studied extensively, including meta-analysises, studies focusing on isoflavones alone were not included in the present study. Originally, we included RCTs in our 11967625 search criteria, but because there were no RCTs on flavonoids, no RCTs are included in the present study.Data ExtractionWe recorded study characteristics as follows: (1) name of the first author and publication year; (2) country or origin; (3) study design (cohort or case-control study); (4) mean length of follow-up; (5) number of cases and controls; (6) assessment of exposure, especially the database for assessment of flavonoid intake; (7) exposures to flavonoids; (8) media of flavonoids intakes; (9) RR, HR or OR from the most fully adjusted model for the highest versus the lowest flavonoids exposure and their 95 CI; (10) confounders adjusted for in multivariate analysis.Table 1. Flavonoid subclasses, food sources and intakes [14].Flavonoid subclasses Flavonols Flavones Flavanones Flavan-3-ols Anthocyanidins IsoflavonesExample compounds Quercetin, kaempferol, myricetin, and isorhamnetin Luteolin, apigenin, and tangeretin Naringenin, hesperetin Catechin, epicatechin, epigallocatechin Cyanidin, delphinidin, pelargonidin, and malvidin Genistein, daidzein, and glyciteinMajor dietary sources Onions, broccoli, tea, and various fruits Herbs (especially parsley), celery, and chamomile tea Citrus fruit including oranges and grape fruit Cocoa or dark chocolate, apples, grape, red wine, and green tea Colored berries and other fruit, especially cranberries, black currants, and blueberries Soy products including fermented products, eg, tofu, tempeh, miso, and soy protein isolateEstimated daily intakes mg/d 12.9 1.6 14.4 156.9 3.1 1.2 (US and Netherlands) 25?0 (Asia)doi:10.1371/journal.pone.0054318.tTable 2. Characteristics of the included studies.Author, year and region Adjustments Premenopausal Postmenopausal (year) 1995?007 1351 (38408) SFFQ, Databases published in US and Europe 1069 (34651) SFFQ, Database from Netherlands 710 (90630) FFQ, Database published in Europe 125 (4647) 605 (2 203) 87 (4699) Total flavonoids(nd) 0.72(0.36 1.48) QFIQ, Database published in Netherland Urinary excretion analysis Urinary excretion analysis SFFQ, Databases published in Mexico FFQ, Database from USDA Flavonols(27.8) Flavones(2.5) Flavan-3-ols(7.9) Total flavonoids Flavonols(9.8) Flavones(0.13) Flavan-3-ols(162) Flavanones(31.2) Anthocyanidins(3.15) Flavonols(18.6) Flavones(0.5) Flavan-3-ols(36.4) Flavanones(33.7) Anthocyanidins(10.4) Flavanones(nd) Flavonols(nd) Flavan-3- 1.04(0.73 1.48) ols(nd) 1.12(0.77 1.63) 1.04(0.66 1.63) 1.53(0.77 3.04) 0.79(0.41 1.51) SFFQ, Database from Netherlands Total flavonoids(29.1) 1.02(0.72 1.44) QFIQ, Databases published in Finland Total flavonoids(24.2) 1.23(0.72 2.10) Flavonols(17.1) 1.05(0.83 1.34) Flavan-3-ols(14.8) 1.04(0.84 1.28) Total flavonoids(19.13) 1.03(0.85 1.25) (mg/d) TotalMean follow-up Cases/ Human parathyroid hormone-(1-34) site controls Assessment of exposure Flavonoids exposure and media of intake OR or RR (95 CI) 1986?998 1991?999 age, parity, age at first pregnancy, age at menarch.Lavones excluded) were available; (3) the association of flavonoids or one of flavonoid subclasses with breast cancer risk was specifically evaluated; (4) relatively complete assessment of total flavonoids or flavonoid subclass intake was performed; (5) relative risk (RR), hazard ratio (HR), or odds ratio (OR), and corresponding 95 confidence intervals (95 CI) were available. Because isoflavones have been studied extensively, including meta-analysises, studies focusing on isoflavones alone were not included in the present study. Originally, we included RCTs in our 11967625 search criteria, but because there were no RCTs on flavonoids, no RCTs are included in the present study.Data ExtractionWe recorded study characteristics as follows: (1) name of the first author and publication year; (2) country or origin; (3) study design (cohort or case-control study); (4) mean length of follow-up; (5) number of cases and controls; (6) assessment of exposure, especially the database for assessment of flavonoid intake; (7) exposures to flavonoids; (8) media of flavonoids intakes; (9) RR, HR or OR from the most fully adjusted model for the highest versus the lowest flavonoids exposure and their 95 CI; (10) confounders adjusted for in multivariate analysis.Table 1. Flavonoid subclasses, food sources and intakes [14].Flavonoid subclasses Flavonols Flavones Flavanones Flavan-3-ols Anthocyanidins IsoflavonesExample compounds Quercetin, kaempferol, myricetin, and isorhamnetin Luteolin, apigenin, and tangeretin Naringenin, hesperetin Catechin, epicatechin, epigallocatechin Cyanidin, delphinidin, pelargonidin, and malvidin Genistein, daidzein, and glyciteinMajor dietary sources Onions, broccoli, tea, and various fruits Herbs (especially parsley), celery, and chamomile tea Citrus fruit including oranges and grape fruit Cocoa or dark chocolate, apples, grape, red wine, and green tea Colored berries and other fruit, especially cranberries, black currants, and blueberries Soy products including fermented products, eg, tofu, tempeh, miso, and soy protein isolateEstimated daily intakes mg/d 12.9 1.6 14.4 156.9 3.1 1.2 (US and Netherlands) 25?0 (Asia)doi:10.1371/journal.pone.0054318.tTable 2. Characteristics of the included studies.Author, year and region Adjustments Premenopausal Postmenopausal (year) 1995?007 1351 (38408) SFFQ, Databases published in US and Europe 1069 (34651) SFFQ, Database from Netherlands 710 (90630) FFQ, Database published in Europe 125 (4647) 605 (2 203) 87 (4699) Total flavonoids(nd) 0.72(0.36 1.48) QFIQ, Database published in Netherland Urinary excretion analysis Urinary excretion analysis SFFQ, Databases published in Mexico FFQ, Database from USDA Flavonols(27.8) Flavones(2.5) Flavan-3-ols(7.9) Total flavonoids Flavonols(9.8) Flavones(0.13) Flavan-3-ols(162) Flavanones(31.2) Anthocyanidins(3.15) Flavonols(18.6) Flavones(0.5) Flavan-3-ols(36.4) Flavanones(33.7) Anthocyanidins(10.4) Flavanones(nd) Flavonols(nd) Flavan-3- 1.04(0.73 1.48) ols(nd) 1.12(0.77 1.63) 1.04(0.66 1.63) 1.53(0.77 3.04) 0.79(0.41 1.51) SFFQ, Database from Netherlands Total flavonoids(29.1) 1.02(0.72 1.44) QFIQ, Databases published in Finland Total flavonoids(24.2) 1.23(0.72 2.10) Flavonols(17.1) 1.05(0.83 1.34) Flavan-3-ols(14.8) 1.04(0.84 1.28) Total flavonoids(19.13) 1.03(0.85 1.25) (mg/d) TotalMean follow-up Cases/ controls Assessment of exposure Flavonoids exposure and media of intake OR or RR (95 CI) 1986?998 1991?999 age, parity, age at first pregnancy, age at menarch.
