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Clin Transl Sci. 2019 Aug 6. doi: 10.1111/cts.12685. [Epub ahead of print]

Development of an integrated platform using multidisciplinary real-world data to facilitate biomarker discovery for medical products.

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Center for Devices and Radiological Health, Food and Drug Administration, CDRH/FDA, Silver Spring, MD.
High-Performance Integrated Virtual Environment - HIVE FDA, Silver Spring, MD.
Center for Human Genetics, Marshfield Clinic Research Institute MCRI, Marshfield, WI.


Translational multidisciplinary research is important for the CDRH's efforts for utilizing real-world data (RWD) to enhance predictive evaluation of medical device performance in patient subpopulations. As part of our efforts for developing new RWD-based evidentiary approaches, including in silico discovery of device-related risk predictors and biomarkers, this study aims to characterize the sex/race-related trends in hip replacement outcomes and identify corresponding candidate SNPs. Adverse outcomes were assessed by deriving RWD from a retrospective analysis of hip replacement hospital discharge data from the National Inpatient Sample (NIS). Candidate Single Nucleotide Polymorphisms (SNP) were explored using pre-existing data from the Personalized Medicine Research Project (PMRP). High-performance Integrated Virtual Environment (HIVE) was used for analyzing and visualizing putative associations between SNPs and adverse outcomes. Ingenuity Pathway Analysis (IPA) was used for exploring plausibility of the sex-related candidate SNPs and characterizing gene networks associated with the variants of interest. The NIS-based epidemiologic evidence showed that Periprosthetic Osteolysis (PO) was most prevalent among white males. The PMRP-based genetic evidence associated the PO-related male predominance with rs7121 (OR=4.89 [95% CI:1.41, 17.05]) and other candidate SNPs. SNP-based IPA analysis of the expected gene expression alterations and corresponding signaling pathways suggested possible role of sex-related metabolic factors in development of PO, which was substantiated by our ad hoc epidemiologic analysis identifying the sex-related differences in metabolic comorbidities in males vs. females with hip replacement related PO. Thus, our in silico study illustrates RWD-based evidentiary approaches that may facilitate cost/time-efficient discovery of biomarkers for informing use of medical products. This article is protected by copyright. All rights reserved.


Adverse outcomes in hip replacement; in silico discovery and plausibility analysis of biomarkers; novel epidemiologic and genetic evidentiary approaches; periprosthetic osteolysis


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