Background
Levels of evidence | Description |
---|---|
Convincing | • Associations with a statistical significance at P < 10−6 • More than 1000 cases included (or more than 20,000 participants for continuous outcomes) • The largest component study reporting a significant result at P < 0.05 • A 95% prediction interval that excluded the null • Absence of large heterogeneity (I2<50%) • No evidence of small study effects (P > 0.10) • No evidence of excess significance (P > 0.10) |
Highly suggestive | • Associations with a statistical significance at P < 10−6 • More than 1000 cases included (or more than 20,000 participants for continuous outcomes) • The largest component study reporting a significant result at P < 0.05. |
Suggestive | • Associations with a statistical significance at P < 0.001 • More than 1000 cases included (or more than 20,000 participants for continuous outcomes). |
Weak | • Associations with a statistical significance at P < 0.05 |
Methods
Data sources and searches
Study selection
Data extraction
Data synthesis and analysis
Results
Eligible umbrella reviews and meta-analyses of observational associations
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%) |
Assessment according to a set of 7 pre-specified quantitative criteria
n/N associations (crude proportion) | Proportions [95% CI] from meta-analysis of 57 topicsa | I2 | Range of proportions across topics | |
---|---|---|---|---|
Level of evidence: | ||||
Convincing | 99/3744 (2.6%) | 1.3% [1.0%; 2.2%] | 73.9% | 0–16.7% |
Highly suggestive | 253/3744 (6.7%) | 4.6% [2.9%; 6.6%] | 85.7% | 0–33.3% |
Suggestive | 440/3744 (11.8%) | 11.0% [8.5%; 13.8%] | 83.9% | 0–50% |
Weak | 1497/3744 (40.0%) | 39.1% [34.8%; 43.5%] | 86.2% | 0–71.4% |
Non-significant | 1455/3744 (38.9%) | 34.7% [29.2%; 40.3%] | 90.8% | 0–80.7% |
Criteria: | ||||
Statistical significance | ||||
P < 10-6 | 762/2289 (33.3%) | 29.0% [24.9%; 33.3%] | 74.8% | 0–66.7% |
P < 0.001 | 1377/2289 (60.2%) | 58.6% [54.1%; 63.0%] | 73.3% | 0–100% |
Cases > 1000 (or > 20,000 participants for continuous outcomes) | 1182/2107 (56.1%) | 65.3% [56.9%; 73.2%] | 94.9% | 1.7–100% |
Largest study with P < 0.05 | 1343/1781 (75.4%) | 74.9% [71.2%; 78.4%] | 63.6% | 28.6–100% |
95% prediction interval that excluded the null | 642/2136 (30.1%) | 30.3% [26.5%; 34.2%] | 71.0% | 9.0–100% |
Absence of large heterogeneity (I2<50%) | 1050/2277 (46.1%) | 46.6% [41.8%; 51.3%] | 79.5% | 0–88.2% |
No evidence of small study effects (P > 0.10) | 1628/2164 (75.2%) | 75.3% [72.2%; 78.3%] | 63.2% | 40–100% |
No evidence of excess significance (P > 0.10) | 1599/2052 (77.9%) | 77.7% [72.6%; 82.5%] | 83.0% | 33.3–100% |
Concordance between the 7 pre-specified quantitative criteria
Impact of each pre-specified criterion on number of associations deemed to have convincing evidence
Credibility assessment | N associations (total=1457)a | Proportion |
---|---|---|
Convincing | 99 | 6.8% |
Replace P < 10−6 by <0.001 | 134 | 9.2% |
Replace P < 10−6 by < 0.05 | 142 | 9.7% |
Without the minimum number of cases criterion | 149 | 10.2% |
Without the largest study at p < 0.05 criterion | 103 | 7.1% |
Without the 95% prediction interval criterion | 106 | 7.3% |
Without the heterogeneity I2<50% criterion | 159 | 10.9% |
Without the small study effects criterion | 122 | 8.4% |
Without the excess significance criterion | 111 | 7.6% |