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Polypharmacy increases the risk of drug-drug interactions (DDIs). Combining epidemiological studies with pharmacokinetic modeling, we detected and evaluated high-dimensional DDIs among 30 frequent drugs. Multidrug combinations that increased the risk of myopathy were identified in the US Food and Drug Administration Adverse Event Reporting System (FAERS) and electronic medical record (EMR) databases by a mixture drug-count response model. CYP450 inhibition was estimated among the 30 drugs in the presence of 1 to 4 inhibitors using in vitro / in vivo extrapolation. Twenty-eight three-way and 43 four-way DDIs had significant myopathy risk in both databases and predicted increases in the area under the concentration-time curve ratio (AUCR) >2-fold. The high-dimensional DDI of omeprazole, fluconazole, and clonidine was associated with a 6.41-fold (FAERS) and 18.46-fold (EMR) increased risk of myopathy local false discovery rate (<0.005); the AUCR of omeprazole in this combination was 9.35. The combination of health record informatics and pharmacokinetic modeling is a powerful translational approach to detect high-dimensional DDIs., (© 2017 American Society for Clinical Pharmacology and Therapeutics.)

Background: Adverse events induced by drug-drug interactions are a major concern in the United States. Current research is moving toward using electronic health record (EHR) data, including for adverse drug events discovery. One of the first steps in EHR-based studies is to define a phenotype for establishing a cohort of patients. However, phenotype definitions are not readily available for all phenotypes. One of the first steps of developing automated text mining tools is building a corpus. Therefore, this study aimed to develop annotation guidelines and a gold standard corpus to facilitate building future automated approaches for mining phenotype definitions contained in the literature. Furthermore, our aim is to improve the understanding of how these published phenotype definitions are presented in the literature and how we annotate them for future text mining tasks. Results: Two annotators manually annotated the corpus on a sentence-level for the presence of evidence for phenotype definitions. Three major categories (inclusion, intermediate, and exclusion) with a total of ten dimensions were proposed characterizing major contextual patterns and cues for presenting phenotype definitions in published literature. The developed annotation guidelines were used to annotate the corpus that contained 3971 sentences: 1923 out of 3971 (48.4%) for the inclusion category, 1851 out of 3971 (46.6%) for the intermediate category, and 2273 out of 3971 (57.2%) for exclusion category. The highest number of annotated sentences was 1449 out of 3971 (36.5%) for the "Biomedical & Procedure" dimension. The lowest number of annotated sentences was 49 out of 3971 (1.2%) for "The use of NLP". The overall percent inter-annotator agreement was 97.8%. Percent and Kappa statistics also showed high inter-annotator agreement across all dimensions. Conclusions: The corpus and annotation guidelines can serve as a foundational informatics approach for annotating and mining phenotype definitions in literature, and can be used later for text mining applications. [ABSTRACT FROM AUTHOR]