to pool the results. Further, no previous review has investigated the preventability of ADRs among inpatients or the percentage of outpatients or inpatients with preventable ADRs (PADRs). Therefore, we applied meta-analysis techniques using a standard- ised definition for ADRs to estimate the percentage of adult outpatients and inpatients with PADRs, and the preventability of ADRs. Methods We carried out a meta-analysis on studies on PADRs in adults, adapting methods recommended by the Statement for Reporting Systematic Reviews and Meta-analyses [14], and following our study protocol. We searched seven databases; MEDLINE, Excerpta Medica Database (EMBASE), the Cochrane database of systematic reviews, Cumulative Index to Nursing & Allied Health Literature (CINAHL), International Pharmaceutical Ab- stract (IPA), PsycINFO and Web of Science (–September 2010) for relevant publications. References of included articles and previous reviews and meta-analysis on ADRs were reviewed to identify additional relevant articles and consider their inclusion. The databases’ search fields for titles, abstracts and index terms were searched using the databases’ index terms and other commonly utilised terminology on drug-related adverse events and preventability (Figure 1). No limits for the years of publication were set. The search was limited to English. Multiple publications of the same study were carefully reviewed [15]. The titles and abstracts were screened by one researcher (KMH). Studies were selected for inclusion from full-text articles in collaboration by two researchers (KH, KMH). An additional reviewer (SH) participated in the review process when uncertainty about eligibility criteria arose. We included original peer-reviewed research articles published in English regardless of the study design (prospective, retrospective, cross-sectional, or interventional). To avoid inconsistent estimates, Figure 1. Search strategy used in the search of eight bibliographic databases. doi:10.1371/journal.pone.0033236.g001 Preventable Adverse Drug Reactions – Meta-Analysis ADRs had to be defined according to the WHO: ‘‘a response which is noxious and unintended, and which occurs at doses normally used in humans for the prophylaxis, diagnosis, or therapy of disease, or for the modification of physiological function’’ [16], or according to Edwards and Aronson’s similar definition [17]. Small changes in wording were overlooked if the two researchers (KH, KMH) agreed that the functional meaning remained the same. Studies representing one or two specific disease areas (inclusion of patients, setting or sampling frame) or specific treatments were excluded. Included studies had to report the percentage of patients with PADRs or the preventability of ADRs. We excluded articles summarising previous results without original assessment of ADRs and the preventability of ADRs and studies conducted in paediatrics or intensive care, or focusing only on specific types of, life threatening or fatal ADRs. We also excluded studies if ADRs were identified exclusively through spontaneous reporting or International Classification Disease (ICD-9 or 10) codes, as these two strategies are known to underestimate the rate of ADRs [7,18]. Although we set no limitations on how preventability must be defined in original studies, we required a case by case preventability assessment. Thus, we excluded studies that consid- ered all type A ADRs, defined as dose dependent and predictable from the known pharmacological characteristics of the drug [19], as preventable without a separate preventability assessment. Studies were also excluded if the percentage of patients with PADRs and preventability of ADRs were inadequately reported. Data extraction To increase the reliability and efficiency of data extraction, we developed and piloted a paper data extraction form by adapting the checklist for Strengthening the Reporting of Observational Studies in Epidemiology [20]. Studies’ characteristics such as the study design, data source, sampling frame, population character- istics, and definition for ADRs, as well as the number of included patients, healthcare visits, ADRs, PADRs, patients with PADRs, and healthcare visits with PADRs were extracted by two researchers. The first (KH) extracted the data, and the second (KMH) confirmed the accuracy and completeness of the extraction. Any disagreements were noted and resolved by consensus. The extracted data were based on information reported in or calculated from the included articles. Authors were not contacted for complementary information. The number of PADRs in each study represented the sum of definitely, probably or possibly preventable cases, as reported in original studies. The percentage of patients with PADRs was calculated by dividing the reported number of healthcare visits (such as primary or emergency care visits or hospitalisations) with PADRs by the total number of healthcare visits. The percentages could be calculated only if the number of healthcare visits were interpretable in the original studies. The preventability of ADRs was calculated by dividing the number of PADRs by the total number of ADRs. If the number of PADRs, ADRs, healthcare visits or healthcare visits with PADRs was not directly reported, the two reviewers assessed whether they were interpretable based on other presented data. Risk of bias The two reviewers (KH, KMH) assessed independently the quality and the risk of bias in the original studies in conjunction with data extraction. To minimise inconsistent estimates, we required a standardised definition for ADRs [16,17], a case by case assessment of preventability, and more inclusive data sources than spontaneous reports or International Classification Disease (ICD-9 or 10) codes exclusively. No scoring system for quality assessment of PLoS ONE | www.plosone.org 2 March 2012 | Volume 7 | Issue 3 | e33236