title: Methods for estimating causal relationships of adverse events with dietary supplements.
abstract: OBJECTIVE
  Dietary supplement use has increased over past decades, resulting in reports of potentially serious adverse events. The aim of this study was to develop optimised methods to evaluate the causal relationships between adverse events and dietary supplements, and to test these methods using case reports.
  
  
  METHODS
  Causal relationship assessment using prospectively collected data.
  
  
  METHODS
  4 dietary supplement experts, 4 pharmacists and 11 registered dietitians (5 men and 14 women) examined 200 case reports of suspected adverse events using the modified Naranjo scale and the modified Food and Drug Administration (FDA) algorithm.
  
  
  METHODS
  The distribution of evaluation results was analysed and inter-rater reliability was evaluated for the two modified methods employed using intraclass correlation coefficients (ICC) and Fleiss' κ.
  
  
  RESULTS
  Using these two methods, most of the 200 case reports were categorised as 'lack of information' or 'possible' adverse events. Inter-rater reliability among entire assessors ratings for the two modified methods, based on ICC and Fleiss' κ, were classified as more than substantial (modified Naranjo scale: ICC (95% CI) 0.873 (0.850 to 0.895); Fleiss' κ (95% CI) 0.615 (0.615 to 0.615). Modified FDA algorithm: Fleiss' κ (95% CI) 0.622 (0.622 to 0.622).
  
  
  CONCLUSIONS
  These methods may help to assess the causal relationships between adverse events and dietary supplements. By conducting additional studies of these methods in different populations, researchers can expand the possibilities for the application of our methods.
authors.affiliation: Department of Drug Evaluation & Informatics, Graduate School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Ide
authors.affiliation: Department of Drug Evaluation & Informatics, Graduate School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamada
authors.affiliation: Department of Drug Evaluation & Informatics, Graduate School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan.
authors.forename: Mamoru
authors.initials: M
authors.lastname: Kitagawa
authors.affiliation: Department of Drug Evaluation & Informatics, Graduate School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Kawasaki
authors.affiliation: Department of Drug Evaluation & Informatics, Graduate School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan.
authors.forename: Yuma
authors.initials: Y
authors.lastname: Buno
authors.affiliation: Kikugawa General Hospital, Shizuoka, Japan.
authors.forename: Kumi
authors.initials: K
authors.lastname: Matsushita
authors.affiliation: Shizuoka City Public Health Center, Shizuoka, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Kaji
authors.affiliation: Faculty of Pharmacy, Keio University, Tokyo, Japan.
authors.forename: Kazuko
authors.initials: K
authors.lastname: Fujimoto
authors.affiliation: Shizuoka City Shizuoka Hospital, Shizuoka, Japan.
authors.forename: Masako
authors.initials: M
authors.lastname: Waki
authors.affiliation: Hamamatsu Institute of Clinical Pharmacology & Therapeutics, Shizuoka, Japan.
authors.forename: Mitsuyoshi
authors.initials: M
authors.lastname: Nakashima
authors.affiliation: Information Center, National Institutes of Biomedical Innovation, Health and Nutrition, Tokyo, Japan.
authors.forename: Keizo
authors.initials: K
authors.lastname: Umegaki
mesh_terms: D000328:Adult; D000368:Aged; D000465:Algorithms; D019587:Dietary Supplements / Q000009:adverse effects*; D005260:Female; D006801:Humans; D008297:Male; D011446:Prospective Studies; D011795:Surveys and Questionnaires; D014481:United States; D014486:United States Food and Drug Administration
keywords: CLINICAL PHARMACOLOGY; NUTRITION & DIETETICS; STATISTICS & RESEARCH METHODS