Modeling the Effect of Drugs in Intergomics by Linking Drug Ontology and Pathways

描述（由申请人提供）：高通量实验现在经常成为临床试验的一部分，许多机构从常规患者群体中建立前瞻性生物样本收集，以进行蛋白质组学和代谢组学实验。由于这些样本是从患有合并症和接受药物治疗的常规临床人群中收集的，因此有必要以系统的方式在数据分析中考虑药物。越来越多的多种高通量技术（例如蛋白质组学和代谢组学）一起使用，这需要全面的途径网络，使代谢组的变化可追溯到蛋白质组，进而追溯到基因表达谱。在这项研究中，我们建议将临床数据中发现的药物疗法与用于高通量实验结果综合分析的生物途径数据联系起来。具体来说，我们将把生物途径的正式知识与新兴国家药品综合知识表示标准中的药物知识相结合，包括退伍军人管理局国家药物文件参考术语 (NDF-RT)、国家药物代码和 RxNorm 临床药物词汇表。这些术语的核心是用于药物知识表示的结构化产品标签 (SPL) 标准。 SPL 是 HL7 第 3 版标准的一部分，基于 HL7 参考信息模型 (RIM)。今天，所有美国制药商都向食品药品管理局 (FDA) 提交 SPL 数据。药效学知识在 SPL 中表示为使用 NDF-RT 作用机制 (MoA) 类别。在这个项目中，我们将扩展这些 MoA 类及其本体论定义，从而链接到各种途径网络资源中描述的生物途径，包括 KEGG、Reactome 和 NCI/Nature Protein Interaction Database (PID)，所有这些资源都使用不同的格式和模型。我们的集成方法包括 (1) 将原始路径资源转换为通用数据模式，以及 (2) 通过 (3) 连接 MoA 类来实现重叠内容的目的驱动协调。由于不存在单一路径数据模式，并且 SPL 已经是国家联合药物术语的中心，因此我们建议将路径数据集成到药物知识库本身中。由此产生的综合数据将根据临床护理和研究中遇到的药物频率进行评估。这项工作将对现有本体进行修订，并且仅在必要时产生新的本体来描述药物途径相互作用。该项目将展示 HL7/ISO 参考信息模型如何从现实主义角度表示生物实体和过程，从而为基础科学和临床医学之间的跨领域数据集成奠定重要的先例，这对于转化研究议程至关重要。公共卫生相关性：该项目将把国家药品目录与身体功能的生化调节和代谢模型结合起来。这将使研究人员能够更好地了解药物对同时测量体内大量蛋白质和化学物质的实验室测试结果的影响。

DESCRIPTION (provided by applicant): High throughput experiments are now frequently part of clinical trials and many institutions establish prospective biospecimen collections from routine patient populations in order to run proteomics and metabolomics experiments. Because these samples are collected from routine clinical populations with co-morbidities and on drug therapies, it is necessary to account for the drugs in the data analysis in a systematic manner. Increasingly multiple high-throughput technologies, such as proteomics and metabolomics, are being used together which requires comprehensive pathway networks that make changes in the metabolome traceable to the proteome and in turn to the gene expression profile. In this study we propose to link drug therapies found in the clinical data with biologic pathways data used for the integrated analysis of high-throughput experimental results. Specifically we will integrate formal knowledge of biological pathways with drug knowledge found in the emergent national standard for the comprehensive knowledge representation for medicinal products, including the Veteran Administrations National Drug File Reference Terminology (NDF-RT), the National Drug Codes and the RxNorm clinical drug vocabulary. The hub of these terminologies is the Structured Product Labeling (SPL) standard for drug knowledge representation. SPL is part of the HL7 version 3 standards and based on the HL7 Reference Information Model (RIM). All U.S. pharmaceutical manufacturers today submit SPL data to the Food and Drug Agency (FDA). Pharmacodynamic knowledge is represented in SPL as a using the NDF-RT mechanism of action (MoA) classes. In this project we will expand these MoA classes with their ontological definitions, and thus link to the biologic pathways described in various pathway network resources including KEGG, Reactome, and the NCI/Nature Protein Interaction Database (PID), all of which use different formats and models. Our methodology for integration consists of (1) transforming the original pathway resource into a common data schema, and (2) purpose-driven reconciliation of overlapping content, by (3) connecting the MoA classes. Because no single pathway data schema exists and because SPL is already the hub of the national federated drug terminology, we propose to integrate the pathway data into the drug knowledge base itself. The resulting integrated data will be evaluated against the frequency of drugs encountered in clinical care and research. This work will yield revisions of existing ontologies and, only where necessary, new ontologies to describe drug- pathway interactions. The project will demonstrate how the HL7/ISO Reference Information Model can represent biological entities and processes taking a realist perspective, and thus set an important precedence for cross-domain data integration between basic sciences and clinical medicine that is essential for the translational research agenda. PUBLIC HEALTH RELEVANCE: The project will combine the national drug catalog with models of the biochemical regulation and metabolism of body functions. This will allow researchers to understand better the effect which drugs have on the results of laboratory tests which measure a large number of proteins and chemicals in the body at the same time.