Supplementary Appendix. Number of participants. Top 5 over represented diseases Female infertility Adverse medical treatment
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1 Supplementary Appendix Supplementary Table A: Overrepresented and underrepresented diseases among published RCTs. Disease Burden of Disease in 2010 GBD (10 6 DALYs) Number of Trials Number of participants Trials per 10 6 DALY Top 5 over represented diseases Female infertility Adverse medical treatment Male infertility Peripheral vascular disease Participants per 10 3 DALYs ADHD Top 5 under represented diseases with at least one trial performed Neonatal sepsis RSV Rotavirus Self-harm Neonatal encephalopathy
2 Supplementary Table B. Proportional trial evidence for 239 diseases included in the analysis. Disease Burden of Disease in 2010 GBD (10 6 DALYs) Trials per 10 6 DALY Participants per 10 3 DALYs 2-Wheel road injury Wheel road injury Abortion Acne vulgaris Acute hepatitis A Acute hepatitis B Acute hepatitis C Acute hepatitis E ADHD Adverse medical treatment Alcohol use disorders Alopecia areata Alzheimer's disease Amoebiasis Amphetamine use Animal contact (non-venomous) Animal contact (venomous) Anxiety disorders Aortic aneurysm Appendicitis Ascariasis Asperger's Assault by firearm Assault by other means Assault by sharp object Asthma Atrial fibrillation Autism Bacterial skin diseases Benign prostatic hyperplasia Bicycle road injury Bipolar disorder Bladder cancer Brain cancer Breast cancer Campylobacter Cannabis use Cardiomyopathy Cataract Cellulitis Cervical cancer Chagas Chlamydia Cholera Cirrhosis alcohol Cirrhosis hepatitis B Cirrhosis hepatitis C Cirrhosis other Cleft lip & palate Cocaine use Colorectal cancer Conduct disorder Congenital heart anomalies COPD Cryptosporidiosis Cysticercosis Decubitus ulcer Dengue Dental caries Diabetes
3 Diabetic CKD Diptheria Down's syndrome Drowning Dysthymia Eating disorders Echinococcosis Eczema Edentulism Encephalitis Endocarditis Endometriosis Enteropathogenic E coli Enterotoxigenic E coli Epilepsy Esophageal cancer Falls Female infertility Fibroids Fire Food-borne trematodiases Forces of nature Fungal skin diseases G6PD deficiency Gall bladder diseases Gallbladder cancer Gastrititis & duodenitis Genital prolapse Glaucoma Glomerulonephritis Gonnorhea Gout HiB meningitis HiB pneumonia HIV (other) HIV-TB Hodgkin's lymphoma Hookworm Hypertensive CKD Hypertensive heart disease Inflammatory bowel disease Influenza Inguinal & femoral hernia Intellectual disability Interstitial lung diseases Intestinal obstructions Iodine deficiency Iron-deficiency anemia Ischemic heart disease Kidney cancers Larynx cancer Leishmaniasis Leprosy Leukemia Liver cancer alcohol Liver cancer hepatitis B Liver cancer hepatitis C Liver cancer other Low back pain Lung cancer Lymphatic filariasis Macular degeneration Major depressive disorder Malaria Male infertility
4 Maternal hemorrhage Maternal hypertension Maternal sepsis Measles Mechanical forces (firearm) Melanoma Meningococcal Migraine Mouth cancer Multiple sclerosis Myeloma Nasopharynx cancer Neck pain Neonatal encephalopathy Neonatal sepsis Neural tube defects Non-Hodgkin lymphoma Non-melanoma skin cancer Obstructed labor Onchocerciasis Opioid use Osteoarthritis Other cancers Other cardio & circulatory Other chromosomal anomalies Other CKD Other congenital anomalies Other diarrheal diseases Other digestive diseases Other drug use Other endocrine Other gynecological disorders Other hearing loss Other hemog Other infectious diseases Other lower respiratory Other maternal disorders Other mechanical forces Other meningitis Other mental & behavioral Other musculoskeletal Other neonatal disorders Other neurological disorders Other NTD Other nutritional deficiencies Other pharynx cancer Other respiratory diseases Other road injury Other sense organ disorders Other skin diseases Other STDs Other transport injuries Other unintentional injuries Other urinary diseases Other vision loss Otitis media Ovarian cancer Pancreatic cancer Pancreatitis Parkinson's disease Pedestrian road injury Peptic ulcer Periodontal disease Peripheral vascular disease Pneumococcal meningitis
5 Pneumococcal pneumonia Pneumoconiosis Poisonings Polycystic ovary Premenstrual syndrome Preterm birth complications Prostate cancer Protein-energy malnutrition Pruritus Psoriasis Pyelonephritis & UTI Rabies Refraction disorders Rheumatic heart disease Rheumatoid arthritis Rotavirus RSV pneumonia Salmonella Scabies Schistosomiasis Schizophrenia Self-harm Shigellosis Sickle cell SIDS Stomach cancer Stroke Syphilis Tension-type headache Testicular cancer Tetanus Thalassemia Thyroid cancer Trachoma Trichomoniasis Trichuriasis Trypanosomiasis Tuberculosis Typhoid fevers Upper respiratory infections Urolithiasis Urticaria Uterine cancer Varicella Vascular intestinal disorders Viral skin diseases Vitamin A deficiency War & legal intervention Whooping cough
6 Supplementary Table C. Linear regression analysis of the log-transformed number of trials and log-transformed number of participants randomized using log-transformed total DALYs and the log transformed ratio of DALYs in low-income regions to high-income regions as predictors. Univariable analysis with log(total DALYs) indicates a poor association between number of trials (Model 1. R 2 = 0.14) and number of participants (Model 3. R 2 = 0.11) (1) (2) (3) (4) Coefficients (SE, p-value) 1 ) Log(Trials+1) Log(Trials+1) Log(Participants+1 Log(Participants+1) Log(DALYs) (SE 0.044, (SE 0.041, (SE 0.136, (0.127, Log(Ratio of DALYs in Lowincome Regions to High-income Regions) (SE 0.020, (0.062, Observations R-squared Results are regression coefficients with standard errors and p-values in brackets.
7 Supplementary Table D. Sensitivity regression analysis of the log-transformed number of trials and log-transformed number of participants randomized using log-transformed total DALYs and ratio of DALYs in low income regions to high income regions as predictors. No offset of 1 was added and diseases with no trials were excluded. (1) (2) (3) (4) 1 Coefficients (SE, p-value) Log(Trials) Log(Trials) Log(Participants) Log(Participants) Log(DALYs) (SE 0.062, (SE 0.061, (SE 0.092, p=0.010) (0.094, p=0.007) Log(Ratio of DALYs in Lowincome Regions to High-income Regions) (SE 0.041, (0.063, p=0.448) Observations R-squared Results are regression coefficients with standard errors and p-values in brackets.
8 Supplementary Figure A. Participants per million DALYs for 239 diseases, classified into high-income, high-equal, low-equal and low-income diseases. (A) Participants per million DALYs for diseases predominant in high-income regions (top) to diseases predominant in low-income regions (bottom). (B) Variation of trials per million DALYs within disease-income categories. Note that scale on (B) is five times greater than that on (A). A. High income diseases 155 High-equal income diseases 99 Low-equal income diseases 71 Low income diseases Participants per million DALYs B. High income diseases Q1 Q2 Q3 Q High-equal income diseases Q1 Q2 Q3 Q Low-equal income diseases Q1 Q2 Q3 Q Low income diseases Q1 Q2 Q3 Q Participants per million DALYs
9 Supplementary Figure B. A. Number of randomized participants per one million population for ten regions. B. Number of randomized participants per one million DALYs for ten regions. C. Spearman s correlation coefficient between burden of disease (total DALYs in each region) and number of trials conducted for ten regions. A. High income Europe (330) 108 High income North America (254) 184 High income Asia/Australia (109) 54 North Africa/ Middle East (75) Central Asia/East Asia (122) Latin America (45) 8 Central/Eastern Europe (17) South Asia/Southeast Asia (52) 4 3 Caribbean and Oceania (1) Sub-Saharan Africa (15) Participants per Million People B. High income Europe (330) 395 High income North America (254) 688 High income Asia/Australia (109) 228 North Africa/ Middle East (75) Central Asia/East Asia (122) Latin America (45) Central/Eastern Europe (17) South Asia/Southeast Asia (52) Caribbean and Oceania (1) Sub-Saharan Africa (15) Participants per Million DALYs
10 C. High income Europe (330) High income North America (254) High income Asia/Australia (109) North Africa/ Middle East (75) Central Asia/East Asia (122) Latin America (45) Central/Eastern Europe (17) South Asia/Southeast Asia (52) Caribbean and Oceania (1) Sub-Saharan Africa (15) Spearman's coefficient for Participants vs DALYs
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