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. 2016 Oct 8;388(10053):1659–1724. doi: 10.1016/S0140-6736(16)31679-8

Table 2.

Epidemiological evidence supporting causality for risk-outcome pairs included in the Global Burden of Disease study 2015

Outcome RCTs (n) RCTs with significant effect in the opposite direction (%) RCTs with null findings (%) Prospective observational studies (n)* Prospective observational studies with significant association in the opposite direction (%) Lower limit of RR >1·5 Dose-response relationship Biological plausibility† Analogy‡
Unsafe water, sanitation, and handwashing
Unsafe water source: chlorination or solar (point-of-use treatment) Diarrhoeal diseases 24 0 42% 6 0 Yes .. Yes No
Unsafe water source: filter Diarrhoeal diseases 11 0 45% 2 0 Yes .. Yes No
Unsafe water source: improved water Diarrhoeal diseases 0 .. .. 5 0 Yes .. Yes No
Unsafe water source: improved water Typhoid fever 0 .. .. 0 .. Yes .. Yes Yes
Unsafe water source: improved water Paratyphoid fever 0 .. .. 0 .. Yes .. Yes Yes
Unsafe water source: piped Diarrhoeal diseases 1 0 0 9 11% Yes .. Yes No
Unsafe water source: piped Typhoid fever 0 .. .. 0 .. Yes .. Yes Yes
Unsafe water source: piped Paratyphoid fever 0 .. .. 0 .. Yes .. Yes Yes
Unsafe sanitation: improved sanitation Diarrhoeal diseases 0 .. .. 9 0 Yes .. Yes No
Unsafe sanitation: improved sanitation Typhoid fever 0 .. .. 0 .. Yes .. Yes Yes
Unsafe sanitation: improved sanitation Paratyphoid fever 0 .. .. 0 .. Yes .. Yes Yes
Unsafe sanitation: piped Diarrhoeal diseases 0 .. .. 1 0 Yes .. Yes No
Unsafe sanitation: piped Typhoid fever 0 .. .. 0 .. Yes .. Yes Yes
Unsafe sanitation: piped Paratyphoid fever 0 .. .. 0 .. Yes .. Yes Yes
No handwashing with soap Diarrhoeal diseases 19 0 42% 0 .. No .. Yes No
No handwashing with soap Typhoid fever 0 .. .. 0 .. No .. Yes Yes
No handwashing with soap Paratyphoid fever 0 .. .. 0 .. No .. Yes Yes
No handwashing with soap Lower respiratory infections 1 0 0 6 0 No .. Yes No
Air pollution
Ambient particulate matter pollution Lower respiratory infections 0 .. .. 13 0 No Yes Yes No
Ambient particulate matter pollution Ischaemic stroke 0 .. .. 25 0 No Yes Yes Yes
Ambient particulate matter pollution Haemorrhagic stroke 0 .. .. 25 0 No Yes Yes Yes
Ambient particulate matter pollution Ischaemic heart disease 0 .. .. 16 0 No Yes Yes Yes
Ambient particulate matter pollution Chronic obstructive pulmonary disease 0 .. .. 11 0 No Yes Yes Yes
Ambient particulate matter pollution Tracheal, bronchial, and lung cancer 0 .. .. 27 0 No Yes Yes Yes
Household air pollution from solid fuels Lower respiratory infections 0 .. .. 0 .. No Yes Yes No
Household air pollution from solid fuels Cataract 0 .. .. 0 .. No Yes Yes No
Household air pollution from solid fuels Ischaemic stroke 0 .. .. 25 0 No Yes Yes Yes
Household air pollution from solid fuels Haemorrhagic stroke 0 .. .. 25 0 No Yes Yes Yes
Household air pollution from solid fuels Ischaemic heart disease 0 .. .. 16 0 No Yes Yes Yes
Household air pollution from solid fuels Chronic obstructive pulmonary disease 0 .. .. 0 .. No Yes Yes Yes
Household air pollution from solid fuels Tracheal, bronchial, and lung cancer 0 .. .. 0 .. No Yes Yes Yes
Ambient ozone pollution Chronic obstructive pulmonary disease 0 .. .. 4 0 No Yes Yes No
Other environmental risks
Residential radon Tracheal, bronchial, and lung cancer 0 .. .. 3 0 No Yes Yes No
Lead exposure Systolic blood pressure 0 .. .. 3 0 .. Yes Yes ..
Lead exposure Idiopathic intellectual disability 0 .. .. 8 0 No Yes Yes No
Occupational risks
Occupational exposure to asbestos Larynx cancer 0 .. .. 27 .. No .. Yes Yes
Occupational exposure to asbestos Tracheal, bronchial, and lung cancer 0 .. .. 18 0 Yes .. Yes Yes
Occupational exposure to asbestos Ovarian cancer 0 .. .. 15 0 No .. Yes Yes
Occupational exposure to asbestos Mesothelioma 0 .. .. 5 0 Yes .. Yes Yes
Occupational exposure to arsenic Tracheal, bronchial, and lung cancer 0 .. .. 3 0 No .. Yes No
Occupational exposure to benzene Leukaemia 0 .. .. 12 0 Yes .. Yes No
Occupational exposure to beryllium Tracheal, bronchial, and lung cancer 0 .. .. 4 0 No .. Yes No
Occupational exposure to cadmium Tracheal, bronchial, and lung cancer 0 .. .. 7 0 No .. Yes No
Occupational exposure to chromium Tracheal, bronchial, and lung cancer 0 .. .. 26 0 No .. Yes No
Occupational exposure to diesel engine exhaust Tracheal, bronchial, and lung cancer 0 .. .. 17 0 No .. Yes No
Occupational exposure to second-hand smoke Tracheal, bronchial, and lung cancer 0 .. .. 25 0 No .. Yes No
Occupational exposure to formaldehyde Nasopharyngeal cancer 0 .. .. 1 0 No .. Yes Yes
Occupational exposure to formaldehyde Leukaemia 0 .. .. 12 0 No .. Yes Yes
Occupational exposure to nickel Tracheal, bronchial, and lung cancer 0 .. .. 1 0 No .. Yes No
Occupational exposure to polycyclic aromatic hydrocarbons Tracheal, bronchial, and lung cancer 0 .. .. 39 0 No .. Yes No
Occupational exposure to silica Tracheal, bronchial, and lung cancer 0 .. .. 17 0 No .. Yes No
Occupational exposure to sulphuric acid Larynx cancer 0 .. .. 3 0 Yes .. Yes No
Occupational exposure to trichloroethylene Kidney cancer 0 .. .. 20 0 No .. Yes No
Occupational asthmagens Asthma 0 .. .. 3 0 No .. Yes No
Occupational particulate matter, gases, and fumes Chronic obstructive pulmonary disease 0 .. .. 1 0 No .. Yes No
Occupational noise Age-related and other hearing loss 0 .. .. 4 0 Yes .. Yes No
Occupational ergonomic factors Low back pain 0 .. .. 10 0 No .. Yes No
Child and maternal malnutrition
Non-exclusive breastfeeding Diarrhoeal diseases 0 .. .. 5 0 Yes .. Yes No
Non-exclusive breastfeeding Lower respiratory infections 0 .. .. 6 0 Yes .. Yes No
Discontinued breastfeeding Diarrhoeal diseases 0 .. .. 2 0 No .. Yes No
Childhood underweight Diarrhoeal diseases 0 .. .. 7 .. Yes .. Yes No
Childhood underweight Lower respiratory infections 0 .. .. 7 .. Yes .. Yes No
Childhood underweight Measles 0 .. .. 7 .. Yes .. Yes No
Childhood wasting Diarrhoeal diseases 0 .. .. 7 .. Yes .. Yes No
Childhood wasting Lower respiratory infections 0 .. .. 7 .. Yes .. Yes No
Childhood wasting Measles 0 .. .. 7 .. Yes .. Yes No
Childhood stunting Diarrhoeal diseases 0 .. .. 7 .. No .. Yes No
Childhood stunting Lower respiratory infections 0 .. .. 7 .. No .. Yes No
Childhood stunting Measles 0 .. .. 7 .. No .. Yes No
Iron deficiency Maternal haemorrhage 0 .. .. 0 .. No .. Yes Yes
Iron deficiency Maternal sepsis and other pregnancy-related infections 0 .. .. 0 .. No .. Yes Yes
Vitamin A deficiency Diarrhoeal diseases 19 0 63% 0 .. No .. Yes No
Vitamin A deficiency Measles 12 0 83% 0 .. Yes .. Yes No
Zinc deficiency Diarrhoeal diseases 14 0 29% 0 .. No .. Yes No
Zinc deficiency Lower respiratory infections 6 0 17% 0 .. No .. Yes No
Tobacco smoke
Smoking Tuberculosis 0 .. .. 4 0 No .. Yes Yes
Smoking Lower respiratory infections 0 .. .. 0 .. No .. Yes Yes
Smoking Lip and oral cavity cancer 0 .. .. 3 0 Yes .. Yes Yes
Smoking Nasopharyngeal cancer 0 .. .. 3 0 Yes .. Yes Yes
Smoking Oesophageal cancer 0 .. .. 5 0 Yes .. Yes Yes
Smoking Larynx cancer 0 .. .. 4 0 Yes .. Yes Yes
Smoking Stomach cancer 0 .. .. 9 0 No .. Yes Yes
Smoking Colon and rectum cancer 0 .. .. 19 0 No .. Yes Yes
Smoking Liver cancer 0 .. .. 54 0 Yes .. Yes Yes
Smoking Pancreatic cancer 0 .. .. 13 0 Yes .. Yes Yes
Smoking Tracheal, bronchial, and lung cancer 0 .. .. 38 0 Yes .. Yes Yes
Smoking Cervical cancer 0 .. .. 15 0 No .. Yes Yes
Smoking Kidney cancer 0 .. .. 8 0 Yes .. Yes Yes
Smoking Bladder cancer 0 .. .. 17 0 Yes .. Yes Yes
Smoking Leukaemia 0 .. .. 14 0 No .. Yes Yes
Smoking Ischaemic heart disease 0 .. .. 86 .. No .. Yes Yes
Smoking Ischemic stroke 0 .. .. 60 .. No .. Yes Yes
Smoking Haemorrhagic stroke 0 .. .. 60 .. No .. Yes Yes
Smoking Hypertensive heart disease 0 .. .. 5 .. No .. Yes Yes
Smoking Atrial fibrillation and flutter 0 .. .. 16 0 No .. Yes Yes
Smoking Aortic aneurysm 0 .. .. 10 0 No .. Yes Yes
Smoking Peripheral vascular disease 0 .. .. 10 0 No .. Yes Yes
Smoking Other cardiovascular and circulatory diseases 0 .. .. 1 0 No .. Yes Yes
Smoking Chronic obstructive pulmonary disease 0 .. .. 42 0 Yes .. Yes Yes
Smoking Silicosis 0 .. .. 0 .. No .. Yes Yes
Smoking Asbestosis 0 .. .. 0 .. No .. Yes Yes
Smoking Coal workers pneumoconiosis 0 .. .. 0 .. Yes .. Yes Yes
Smoking Other pneumoconiosis 0 .. .. 0 .. Yes .. Yes Yes
Smoking Asthma 0 .. .. 6 0 No .. Yes Yes
Smoking Interstitial lung disease and pulmonary sarcoidosis 0 .. .. 0 .. Yes .. Yes Yes
Smoking Other chronic respiratory diseases 0 .. .. 1 0 Yes .. Yes Yes
Smoking Peptic ulcer disease 0 .. .. 7 0 No .. Yes No
Smoking Diabetes mellitus 0 .. .. 51 0 No .. Yes No
Smoking Cataract 0 .. .. 10 0 No .. Yes No
Smoking Macular degeneration 0 .. .. 5 20% No .. Yes No
Smoking Rheumatoid arthritis 0 .. .. 5 0 No .. Yes No
Smoking Hip fracture 0 .. .. 15 20% No .. Yes Yes
Smoking Non-hip fracture 0 .. .. 14 14% No .. Yes Yes
Second-hand smoke Otitis media 0 .. .. 17 0 No Yes Yes No
Second-hand smoke Tracheal, bronchial, and lung cancer 0 .. .. 4 0 No Yes Yes Yes
Second-hand smoke Ischaemic heart disease 0 .. .. 4 25% No Yes Yes Yes
Second-hand smoke Ischaemic stroke 0 .. .. 10 0 Yes Yes Yes Yes
Second-hand smoke Haemorrhagic stroke 0 .. .. 10 0 Yes Yes Yes Yes
Alcohol and drug use
Alcohol use Tuberculosis 0 .. .. 3 0 No Yes Yes Yes
Alcohol use Lower respiratory infections 0 .. .. 2 0 No Yes Yes Yes
Alcohol use Lip and oral cavity cancer 0 .. .. 1 0 No Yes Yes Yes
Alcohol use Nasopharyngeal cancer 0 .. .. 1 0 No Yes Yes Yes
Alcohol use Other pharyngeal cancer 0 .. .. 1 0 No Yes Yes Yes
Alcohol use Oesophageal cancer 0 .. .. 1 0 No Yes Yes Yes
Alcohol use Colon and rectum cancer 0 .. .. 6 0 No Yes Yes Yes
Alcohol use Liver cancer 0 .. 3 0 No Yes Yes Yes
Alcohol use Laryngeal cancer 0 .. .. 0 .. No Yes Yes Yes
Alcohol use Breast cancer 0 .. .. 12 0 No Yes Yes Yes
Alcohol use Ischaemic heart disease 0 .. .. 32 0 No Yes Yes Yes
Alcohol use Ischaemic stroke 0 .. .. 20 0 No Yes Yes Yes
Alcohol use Haemorrhagic stroke 0 .. .. 16 0 No Yes Yes Yes
Alcohol use Atrial fibrillation and flutter 0 .. .. 10 0 No Yes Yes Yes
Alcohol use Hypertensive heart disease 0 .. .. 2 0 No Yes Yes Yes
Alcohol use Pancreatitis 0 .. .. 4 0 No Yes Yes No
Alcohol use Epilepsy 0 .. .. 0 .. No Yes Yes No
Alcohol use Diabetes mellitus 0 .. .. 9 0 No Yes Yes No
Alcohol use Cirrhosis 0 .. .. 14 0 No Yes Yes Yes
Alcohol use Injuries 0 .. .. 29 0 No Yes Yes Yes
Alcohol use Self-harm 0 .. .. 0 .. No Yes Yes Yes
Alcohol use Interpersonal violence 0 .. .. 11 0 No Yes Yes Yes
Drug use Hepatitis B 0 .. .. 6 0 Yes .. Yes Yes
Drug use Hepatitis C 0 .. .. 16 0 Yes .. Yes Yes
Drug use Self-harm 0 .. .. 1 0 No .. Yes No
Dietary risks
Diet low in fruits Lip and oral cavity cancer 0 .. .. 2 0 No Yes Yes Yes
Diet low in fruits Nasopharyngeal cancer 0 .. .. 2 0 No Yes Yes Yes
Diet low in fruits Other pharyngeal cancer 0 .. .. 2 0 No Yes Yes Yes
Diet low in fruits Larynx cancer 0 .. .. 2 0 No Yes Yes Yes
Diet low in fruits Oesophageal cancer 0 .. .. 5 0 No Yes Yes Yes
Diet low in fruits Tracheal, bronchial, and lung cancer 0 .. .. 22 0 No Yes Yes Yes
Diet low in fruits Ischaemic heart disease 0 .. .. 9 0 No Yes Yes Yes
Diet low in fruits Ischaemic stroke 0 .. .. 9 0 No Yes Yes Yes
Diet low in fruits Haemorrhagic stroke 0 .. .. 5 0 No Yes Yes Yes
Diet low in fruits Diabetes mellitus 0 .. .. 9 0 No Yes Yes No
Diet low in vegetables Oesophageal cancer 0 .. .. 5 0 No Yes Yes No
Diet low in vegetables Ischaemic heart disease 0 .. .. 9 0 No Yes Yes Yes
Diet low in vegetables Ischaemic stroke 0 .. .. 8 0 No Yes Yes Yes
Diet low in vegetables Haemorrhagic stroke 0 .. .. 5 0 No Yes Yes Yes
Diet low in whole grains Ischaemic heart disease 0 .. .. 7 0 No Yes Yes Yes
Diet low in whole grains Ischaemic stroke 0 .. .. 6 0 No Yes Yes Yes
Diet low in whole grains Haemorrhagic stroke 0 .. .. 6 0 No Yes Yes Yes
Diet low in whole grains Diabetes mellitus 0 .. .. 10 0 No Yes Yes No
Diet low in nuts and seeds Ischaemic heart disease 1 0 100% 6 0 No Yes Yes No
Diet low in nuts and seeds Diabetes mellitus 1 0 100% 5 0 No Yes Yes No
Diet low in milk Colon and rectum cancer 0 .. .. 7 0 No Yes Yes No
Diet high in red meats Colon and rectum cancer 0 .. .. 8 0 No Yes Yes No
Diet high in red meats Diabetes mellitus 0 .. .. 9 11% No Yes Yes No
Diet high in processed meats Colon and rectum cancer 0 .. .. 9 11% No Yes Yes No
Diet high in processed meats Ischaemic heart disease 0 .. .. 5 0 No Yes Yes No
Diet high in processed meats Diabetes mellitus 0 .. .. 8 0 No Yes Yes No
Diet high in sugar-sweetened beverages Body-mass index 10 0 60% 22 0 .. Yes Yes ..
Diet low in fibre Colon and rectum cancer 0 .. .. 15 0 No Yes Yes No
Diet low in fibre Ischaemic heart disease 0 .. .. 12 0 No Yes Yes No
Diet low in calcium Colon and rectum cancer 0 .. .. 13 0 No Yes Yes No
Diet low in seafood omega-3 fatty acids Ischaemic heart disease 17 0 88% 16 0 No Yes Yes No
Diet low in polyunsaturated fatty acids Ischaemic heart disease 8 0 75% 11 0 No Yes Yes No
Diet high in trans fatty acids Ischaemic heart disease 0 .. .. 4 0 No Yes Yes No
Diet high in sodium Systolic blood pressure 45 0 73% .. .. .. Yes Yes ..
Diet high in sodium Stomach cancer 0 .. .. 3 0 No Yes Yes No
Sexual abuse and violence
Intimate partner violence HIV/AIDS 0 .. .. 2 0 No .. Yes No
Intimate partner violence Maternal abortion, miscarriage, and ectopic pregnancy 0 .. .. 1 0 Yes .. Yes No
Intimate partner violence Depressive disorders 0 .. .. 6 0 No .. Yes Yes
Intimate partner violence Self-harm 0 .. .. 2 0 Yes .. Yes Yes
Childhood sexual abuse Alcohol use disorders 0 .. .. 4 0 No .. Yes Yes
Childhood sexual abuse Depressive disorders 0 .. .. 5 0 No .. Yes Yes
Childhood sexual abuse Self-harm 0 .. .. 8 0 No .. Yes Yes
Low physical activity
Low physical activity Colon and rectum cancer 0 .. .. 20 15% No Yes Yes Yes
Low physical activity Breast cancer 0 .. .. 35 0 No Yes Yes Yes
Low physical activity Ischaemic heart disease 0 .. .. 45 9% No Yes Yes Yes
Low physical activity Ischaemic stroke 0 .. .. 27 11% No Yes Yes Yes
Low physical activity Diabetes mellitus 0 .. .. 57 7% No Yes Yes No
Metabolic risks
High fasting plasma glucose Ischaemic heart disease 8 0 100% 150 .. Yes Yes Yes Yes
High fasting plasma glucose Ischaemic stroke 9 0 100% 150 .. Yes Yes Yes Yes
High fasting plasma glucose Haemorrhagic stroke 9 0 100% 150 .. Yes Yes Yes Yes
High fasting plasma glucose Peripheral vascular disease 14 .. .. 4 0 Yes Yes Yes Yes
High fasting plasma glucose Tuberculosis 0 .. .. 17 0 Yes Yes Yes No
High fasting plasma glucose Chronic kidney disease 5 .. .. 32 .. Yes Yes Yes No
High total cholesterol Ischaemic heart disease 21 0 57% 88 .. Yes Yes Yes Yes
High total cholesterol Ischaemic stroke 21 0 57% 88 .. Yes Yes Yes Yes
High systolic blood pressure Rheumatic heart disease 0 .. .. 62 .. Yes Yes Yes Yes
High systolic blood pressure Ischaemic heart disease 56 0 .. 88 .. Yes Yes Yes Yes
High systolic blood pressure Ischaemic stroke 54 0 .. 150 .. Yes Yes Yes Yes
High systolic blood pressure Haemorrhagic stroke 54 0 .. 150 .. Yes Yes Yes Yes
High systolic blood pressure Cardiomyopathy and myocarditis 0 .. .. 62 .. Yes Yes Yes Yes
High systolic blood pressure Atrial fibrillation and flutter 20 5% 60% 88 .. Yes Yes Yes Yes
High systolic blood pressure Aortic aneurysm 0 .. .. 62 .. Yes Yes Yes Yes
High systolic blood pressure Peripheral vascular disease 0 .. .. 88 .. Yes Yes Yes Yes
High systolic blood pressure Endocarditis 0 .. .. 62 .. Yes Yes Yes Yes
High systolic blood pressure Other cardiovascular and circulatory diseases 0 .. .. 88 .. No Yes Yes Yes
High systolic blood pressure Chronic kidney disease 8 .. .. 88 .. Yes Yes Yes No
High body-mass index Oesophageal cancer 0 .. .. 8 0 No Yes Yes Yes
High body-mass index Colon and rectum cancer 0 .. .. 38 0 No Yes Yes Yes
High body-mass index Liver cancer 0 .. .. 34 0 No Yes Yes Yes
High body-mass index Gallbladder and biliary tract cancer 0 .. .. 10 0 No Yes Yes Yes
High body-mass index Pancreatic cancer 0 .. .. 20 0 No Yes Yes Yes
High body-mass index Breast cancer (after menopause) 0 .. .. 44 2% No Yes Yes Yes
High body-mass index Breast cancer (before menopause) 0 .. .. 25 8% No Yes Yes No
High body-mass index Uterine cancer 0 .. .. 37 0 No Yes Yes Yes
High body-mass index Ovarian cancer 0 .. .. 31 3% No Yes Yes Yes
High body-mass index Kidney cancer 0 .. .. 28 0 No Yes Yes Yes
High body-mass index Thyroid cancer 0 .. .. 16 0 No Yes Yes Yes
High body-mass index Leukaemia 0 .. .. 17 0 No Yes Yes Yes
High body-mass index Ischaemic heart disease 0 .. .. 129 .. No Yes Yes Yes
High body-mass index Ischaemic stroke 0 .. .. 102 .. No Yes Yes Yes
High body-mass index Haemorrhagic stroke 0 .. .. 129 .. No Yes Yes Yes
High body-mass index Hypertensive heart disease 0 .. .. 85 .. No Yes Yes Yes
High body-mass index Diabetes mellitus 0 .. .. 85 .. Yes Yes Yes No
High body-mass index Chronic kidney disease 0 .. .. 57 .. No Yes Yes No
High body-mass index Osteoarthritis 0 .. .. 32 0 No Yes Yes Yes
High body-mass index Low back pain 0 .. .. 5 0 No Yes Yes Yes
Low bone mineral density Injuries 0 .. .. 12 .. No Yes Yes Yes
Low glomerular filtration rate Ischaemic heart disease 0 .. .. 10 0 Yes .. Yes Yes
Low glomerular filtration rate Ischaemic stroke 0 .. .. 12 0 Yes .. Yes Yes
Low glomerular filtration rate Haemorrhagic stroke 0 .. .. 12 0 Yes .. Yes Yes
Low glomerular filtration rate Peripheral vascular disease 0 .. .. 1 0 Yes .. Yes Yes
Low glomerular filtration rate Gout 0 .. .. 3 0 Yes .. Yes No

If multiple reports existed from one study, we counted them as one study. We only assessed the dose-response relationship for continuous risks. To evaluate the magnitude of the effect size for continuous risks, we evaluated the RR comparing the 75th percentile with the 25th percentile of the exposure distribution at the global level. Additional information for this table is found in the methods appendix (pp 245–63). RCT=randomised controlled trial. RR=relative risk.

*

Prospective cohort studies or non-randomised interventions.

†

Whether or not any biological or mechanistic pathway exists that could potentially explain the relationship of the risk-outcome pair.

‡

Whether or not the risk is associated with another outcome from the same category and whether or not any evidence exists that it can cause the current outcome through the same pathway.