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Table 2 Overview of the included umbrella reviews

From: Validity of observational evidence on putative risk and protective factors: appraisal of 3744 meta-analyses on 57 topics

Topic First author Year Type of studies N total studies a Median [IQR]
Min to max.b 		N total associationsc N associations included Convincing Highly suggestive Suggestive Weak Non-significant
One exposure with multiple outcomes
 Adiposity and cancer outcomes Kyrgiou 2017 OBS 507 6 [4; 11.50]
(2 to 44) 		194 67d 8 (11.9%) 14 (20.9%) 15 (22.4%) 11 (16.4%) 19 (28.4%)
 Antidepressant and adverse events Dragioti 2019 OBS 1012 6 [4; 11.25]
(2 to 44) 		120 120 3 (2.5%) 8 (6.7%) 24 (20%) 38 (31.7%) 47 (39.2%)
 Antipsychotics and life-threatening events Papola 2019 OBS 68 9 [6.75; 12.75]
(6 to 24) 		6 6 1 (16.7%) 2 (33.3%) 3 (50%) 0 (0%) 0 (0%)
 Low-dose aspirin and health outcomes Veronese 2020 OBS-RCT NR 3.50 [3; 7.75]
(2 to 32) 		156 42 0 (0%) 0 (0%) 0 (0%) 11 (26.2%) 31 (73.8%)
 Aspirin and cancer outcomes Song 2020 OBS NR 11 [7; 18.25]
(3 to 309) 		27 18e 0 (0%) 0 (0%) 0 (0%) 12 (66.7%) 6 (33.3%)
 Birth weight and later life events Belbasis 2016 OBS NR 10 [6.25; 16]
(3 to 45) 		78 78 3 (3.8%) 8 (10.3%) 10 (12.8%) 29 (37.2%) 28 (35.9%)
 Chocolate and health outcomes Veronesem 2018 OBS-RCT NR 5 [4; 6]
(4 to 6) 		19 7 0 (0%) 0 (0%) 0 (0%) 4 (57.1%) 3 (42.9%)
 Chronic kidney disease and mortality Kim 2020 OBS-RCT NR 9 [4; 14]
(2 to 26) 		105 49 0 (0%) 0 (0%) 22 (44.9%) 11 (22.4%) 16 (32.7%)
 Coffee and cancer risk Zhao 2020 OBS 448 15 [7; 21.25]
(4 to 54) 		36 36 0 (0%) 3 (8.3%) 7 (19.4%) 7 (19.4%) 19 (52.8%)
 C-reactive protein and health outcomes Markozannes 2020 OBS-MR 952 6 [4; 11]
(3 to 53) 		309 113 2 (1.8%) 12 (10.6%) 14 (12.4%) 67 (59.3%) 18 (15.9%)
 Depression and mortality Machado 2018 OBS 246 6 [4; 12]
(3 to 111) 		17 17 0 (0%) 4 (23.5%) 2 (11.8%) 11 (64.7%) 0 (0%)
 Antidepressants during pregnancy and neonatal outcomes Biffi 2020 OBS NR 7 [4; 10]
(3 to 28) 		69 69 0 (0%) 5 (7.2%) 11 (15.9%) 18 (26.1%) 35 (50.7%)
 Dietary Fiber and health outcomes Veronese 2018 OBS NR 12 [6; 19]
(3 to 26) 		21 21 2 (9.5%) 1 (4.8%) 9 (42.9%) 6 (28.6%) 3 (14.3%)
 Fish and ω-3 Fatty Acids consumptions and cancer outcomes Lee 2020 OBS NR 5 [3; 10]
(2 to 17) 		57 52f 0 (0%) 0 (0%) 2 (3.8%) 10 (19.2%) 40 (76.9%)
 Influenza vaccine in elderly and health outcomes Demurtas 2020 OBS-RCT NR 3.50 [2; 6.75]
(2 to 27) 		60 38 1 (2.6%) 3 (7.9%) 6 (15.8%) 15 (39.5%) 13 (34.2%)
 Handgrip strength and health outcomes Soysal 2020 OBS NR 9 [8; 10.50]
(7 to 34) 		11 8e 0 (0%) 1 (12.5%) 1 (12.5%) 4 (50%) 2 (25%)
 Human immunodeficiency virus infections and health outcomes Grabovac 2019 OBS NR 8 [4; 13.50]
(2 to 43) 		55 55 0 (0%) 0 (0%) 9 (16.4%) 30 (54.5%) 16 (29.1%)
 Metformin and cancer outcomes Yu 2019 OBS 327 7 [5; 15]
(2 to 29) 		33 33 1 (3%) 3 (9.1%) 5 (15.2%) 14 (42.4%) 10 (30.3%)
 Magnesium and health outcomes Veronese 2019 OBS-RCT NR 6 [3; 9.50]
(3 to 32) 		55 19 0 (0%) 0 (0%) 2 (10.5%) 7 (36.8%) 10 (52.6%)
 Obesity and gynecology/obstetric outcomes Kalliala 2017 OBS-RCT 427 6 [3; 9]
(2 to 40) 		248 144 11 (7.6%) 28 (19.4%) 23 (16%) 42 (29.2%) 40 (27.8%)
 Physical activity and cancer outcomes Rezende 2017 OBS 297 6 [3.25; 10]
(2 to 38) 		46 46 1 (2.2%) 2 (4.3%) 5 (10.9%) 5 (10.9%) 33 (71.7%)
 Physical activity and atrial fibrillation outcomes Valenzuela 2020 OBS NR 8 [7; 19]
(6 to 20) 		5 5 0 (0%) 0 (0%) 0 (0%) 3 (60%) 2 (40%)
 Statins and multiple non-cardiovascular outcomes Yazhou 2018 OBS-RCT NR 6 [4; 9]
(2 to 27) 		278 115 0 (0%) 2 (1.7%) 21 (18.3%) 42 (36.5%) 50 (59.8%)
 Serum uric acid and health outcomes Li 2017 OBS-RCT-MR NR 5 [3; 9]
(2 to 31) 		152 76 0 (0%) 7 (9.2%) 9 (11.8%) 41 (53.9%) 19 (25%)
 Type 2 diabetes mellitus and cancer Tsilidis 2015 OBS 474 14 [9; 21]
(5 to 45) 		27 27 2 (7.4%) 4 (14.8%) 4 (14.8%) 10 (37%) 7 (25.9%)
 Tea consumption and cancer Kim 2020 OBS NR 10 [6.75; 16]
(4 to 53) 		150 68g 0 (0%) 1 (1.5%) 2 (2.9%) 18 (26.5%) 47 (69.1%)
 Telomere length and health outcomes Smith 2019 OBS NR 5.50 [3; 8]
(2 to 20) 		50 50 0 (0%) 1 (2%) 0 (0%) 23 (46%) 26 (52%)
 Vitamin D and health outcomes Theodoratou 2014 OBS-RCT NR 7 [5; 10]
(2 to 37) 		48 48 0 (0%) 6 (12.5%) 7 (14.6%) 16 (33.3%) 19 (39.6%)
Multiple exposures with one outcome
 Risk factor for attention deficit hyperactivity disorder Kim 2020 OBS NR 6 [4; 9]
(2 to 30) 		63 63 5 (7.9%) 3 (4.8%) 11 (17.5%) 26 (41.3%) 18 (28.6%)
 Risk and protective factors for mental disorders with onset in childhood/adolescence Marco 2020 OBS 192 6 [4.50; 9]
(2 to 26) 		23 23 0 (0%) 0 (0%) 1 (4.3%) 8 (34.8%) 14 (60.9%)
 Environmental factors and serum biomarkers for atrial fibrillation Belbasis 2020 OBS NR 6 [4; 8]
(3 to 31) 		51 51 6 (11.8%) 11 (21.6%) 8 (15.7%) 10 (19.6%) 16 (31.4%)
 Factors associated to loneliness Solmi 2020 OBS NR 13 [8; 18]
(3 to 31) 		5 5 0 (0%) 0 (0%) 1 (20%) 4 (80%) 0 (0%)
 Risk factor for amyotrophic lateral sclerosis Belbasis 2016 OBS NR 8 [5.75; 9.25]
(3 to 20) 		16 16 0 (0%) 0 (0%) 3 (18.8%) 6 (37.5%) 7 (43.8%)
 Risk and protective factors for anxiety and obsessive compulsive disorders Fullana 2019 OBS 216 3 [2; 6]
(2 to 112) 		427 128fg 4 (3.1%) 2 (1.6%) 3 (2.3%) 60 (46.9%) 59 (46.1%)
 Environmental risk factors and biomarkers for autism spectrum disorder Kim 2019 OBS NR 8 [3.50; 13]
(2 to 24) 		67 67 8 (11.9%) 7 (10.4%) 11 (16.4%) 26 (38.8%) 15 (22.4%)
 Environmental risk factors for bipolar disorder Bortolato 2017 OBS 54 8 [5; 10]
(3 to 13) 		7 7 1 (14.3%) 1 (14.3%) 2 (28.6%) 2 (28.6%) 1 (14.3%)
 Risk factors for colorectal cancer metastasis and recurrence Xu 2020 OBS NR 6 [3.50; 9]
(2 to 41) 		47 47 0 (0%) 0 (0%) 4 (8.5%) 27 (57.4%) 16 (34%)
 Non-genetic biomarkers and colorectal cancer risk Zhang 2020 OBS-RCT-MR NR 7 [3; 10]
(2 to 28) 		112 65 0 (0%) 0 (0%) 4 (6.2%) 25 (38.5%) 36 (55.4%)
 Risk factors for chronic obstructive pulmonary disease Bellou 2019 OBS-MR NR 5 [4; 11]
(3 to 22) 		22 18 0 (0%) 0 (0%) 8 (44.4%) 5 (27.8%) 5 (27.8%)
 Environmental risk factors for dementia Bellou 2017 OBS NR 7 [4.75; 13]
(3 to 43) 		76 76 7 (9.2%) 5 (6.6%) 10 (13.2%) 33 (43.4%) 21 (27.6%)
 Risk factors for depression Kohler 2018 OBS-MR NR 7.50 [5; 11]
(3 to 77) 		140 134 0 (0%) 0 (0%) 41 (30.6%) 57 (42.5%) 36 (26.9%)
 Risk factors for eating disorders Solmi 2020 OBS NR 6 [4; 9]
(2 to 33) 		49 49 0 (0%) 0 (0%) 6 (12.2%) 35 (71.4%) 8 (16.3%)
 Risk factors for endometrial cancer Raglan 2019 OBS 604 4 [3; 6]
(2 to 28) 		127 127 3 (2.4%) 13 (10.2%) 14 (11%) 26 (20.5%) 71 (55.9%)
 Environmental risk factors for obesity Solmi 2018 OBS-RCT 166 8 [6; 10.75]
(2 to 22) 		60 26 4 (15.4%) 2 (7.7%) 1 (3.8%) 15 (57.7%) 4 (15.4%)
 Prognostic biomarkers for gastric cancer Zhou 2019 OBS >1000 7 [4; 11]
(3 to 51) 		119 119 3 (2.5%) 7 (5.9%) 3 (2.5%) 82 (68.9%) 24 (20.2%)
 Risk factors for gestational diabetes Giannakou 2019 OBS NR 8 [5; 14]
(3 to 40) 		61 61 1 (1.6%) 13 (21.3%) 9 (14.8%) 28 (45.9%) 10 (16.4%)
 Peripheral biomarkers and major mental disorders Carvalho 2020 OBS NR 7 [5; 13]
(3 to 55) 		358 318g 0 (0%) 0 (0%) 3 (0.9%) 175 (55%) 140 (44%)
 Environmental risk factors for multiple sclerosis Belbasis 2015 OBS NR 8 [6; 12]
(3 to 30) 		44 44 2 (4.5%) 2 (4.5%) 2 (4.5%) 17 (38.6%) 21 (47.7%)
 Prognostic biomarkers for pancreatic ductal adenocarcinoma Wang 2020 OBS >300 4 [3; 6]
(2 to 43) 		63 63 0 (0%) 2 (3.2%) 1 (1.6%) 41 (65.1%) 19 (30.2%)
 Environmental risk factors and Parkinson’s Bellou 2016 OBS 755 7 [5; 10]
(2 to 67) 		75 75 2 (2.7%) 6 (8%) 9 (12%) 18 (24%) 40 (53.3%)
 Risk and protective factors for prostate cancer Markozannes 2016 OBS 1907 5 [3.75; 7]
(2 to 45) 		248 176d 0 (0%) 2 (1.1%) 7 (4%) 25 (14.2%) 142 (80.7%)
 Non-genetic risk factors for pre-eclampsia Giannakou 2017 OBS NR 7 [4; 12.25]
(3 to 34) 		130 64h 1 (1.6%) 11 (17.2%) 5 (7.8%) 22 (34.4%) 25 (39.1%)
 Risk and protective factors for psychosis Ruada 2018 OBS 683 6 [3; 9]
(2 to 55) 		170 128i 1 (0.8%) 2 (1.6%) 11 (8.6%) 64 (50%) 50 (39.1%)
 Environmental risk factors for rheumatic diseases Belbasis 2018 OBS NR 10.50 [7; 13]
(3 to 51) 		42 42 0 (0%) 0 (0%) 7 (16.7%) 26 (61.9%) 9 (21.4%)
 Risk factors and peripheral biomarkers for schizophrenia spectrum disorders Belbasis 2017 OBS-MR NR 8 [5.25; 13]
(3 to 42) 		98 98 1 (1%) 4 (4.1%) 5 (5.1%) 52 (53.1%) 36 (36.7%)
 Non-genetic risk factors for skin cancer Belbasis 2016 OBS NR 10 [7; 18]
(3 to 41) 		85 85 4 (4.7%) 9 (10.6%) 11 (12.9%) 34 (40%) 27 (31.8%)
 Risk factors for type 2 diabetes mellitus Bellou 2018 OBS-MR NR 9.50 [6; 14]
(3 to 88) 		155 142 11 (7.7%) 34 (23.9%) 28 (19.7%) 43 (30.3%) 26 (18.3%)
  1. IQR interquartile range, MA meta-analyses, MR Mendelian randomization, NR not reported, OBS observational studies, OCD obsessive and compulsive disorders, RCT randomized controlled trials
  2. aTotal number of primary studies included in the meta-analyses assessed by the umbrella reviews
  3. bMedian number IQR and minimum and maximum number of primary studies included in the associations assessed
  4. cTotal number of associations assessed in the included umbrella reviews
  5. dThe umbrella review presented data for continuous and binary outcomes but their principal analyses focused only on continuous outcomes which we included hence the lowest number of included associations in our work compared with the original umbrella review
  6. eSome associations were excluded as they were assessed by a mix of RCTs and observational studies
  7. fAssociations assessed by only one study were removed
  8. gDuplicated associations were excluded
  9. hExcluded associations assessing genetic factors
  10. iThe authors of the umbrella review mention 170 associations but only report 145. Out of the 145, 17 meta-analyses were excluded because included only one study
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BMC Medicine

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