Watford Sean M, Grashow Rachel G, De La Rosa Vanessa Y, Rudel Ruthann A, Friedman Katie Paul, Martin Matthew T
ORAU, contractor to U.S. Environmental Protection Agency through the National Student Services Contract, Oak Ridge, TN.
Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, UNC-Chapel Hill, Chapel Hill, North Carolina, United States.
Comput Toxicol. 2018 Aug;7:46-57. doi: 10.1016/j.comtox.2018.06.003. Epub 2018 Jun 19.
Advances in technology within biomedical sciences have led to an inundation of data across many fields, raising new challenges in how best to integrate and analyze these resources. For example, rapid chemical screening programs like the US Environmental Protection Agency's ToxCast and the collaborative effort, Tox21, have produced massive amounts of information on putative chemical mechanisms where assay targets are identified as genes; however, systematically linking these hypothesized mechanisms with toxicity endpoints like disease outcomes remains problematic. Herein we present a novel use of normalized pointwise mutual information (NPMI) to mine biomedical literature for gene associations with biological concepts as represented by Medical Subject Headings (MeSH terms) in PubMed. Resources that tag genes to articles were integrated, then cross-species orthologs were identified using UniRef50 clusters. MeSH term frequency was normalized to reflect the MeSH tree structure, and then the resulting GeneID-MeSH associations were ranked using NPMI. The resulting network, called Entity MeSH Co-occurrence Network (EMCON), is a scalable resource for the identification and ranking of genes for a given topic of interest. The utility of EMCON was evaluated with the use case of breast carcinogenesis. Topics relevant to breast carcinogenesis were used to query EMCON and retrieve genes important to each topic. A breast cancer gene set was compiled through expert literature review (ELR) to assess performance of the search results. We found that the results from EMCON ranked the breast cancer genes from ELR higher than randomly selected genes with a recall of 0.98. Precision of the top five genes for selected topics was calculated as 0.87. This work demonstrates that EMCON can be used to link results to possible biological outcomes, thus aiding in generation of testable hypotheses for furthering understanding of biological function and the contribution of chemical exposures to disease.
生物医学科学领域的技术进步导致了众多领域数据的泛滥,这对如何最好地整合和分析这些资源提出了新的挑战。例如,像美国环境保护局的ToxCast这样的快速化学筛选项目以及合作项目Tox21,已经产生了大量关于假定化学机制的信息,其中检测靶点被确定为基因;然而,将这些假设机制与疾病结果等毒性终点进行系统关联仍然存在问题。在此,我们提出一种新的方法,即使用归一化逐点互信息(NPMI)从生物医学文献中挖掘与医学主题词表(MeSH词)所代表的生物学概念相关的基因关联。将标记基因与文章的资源进行整合,然后使用UniRef50聚类识别跨物种直系同源基因。对MeSH词频率进行归一化以反映MeSH树状结构,然后使用NPMI对所得的基因ID - MeSH关联进行排序。由此产生的网络,称为实体MeSH共现网络(EMCON),是一种可扩展的资源,用于识别和排序给定感兴趣主题的基因。通过乳腺癌发生的案例评估了EMCON的实用性。使用与乳腺癌发生相关的主题查询EMCON,并检索对每个主题重要的基因。通过专家文献综述(ELR)编制了一个乳腺癌基因集,以评估搜索结果的性能。我们发现,EMCON的结果将ELR中的乳腺癌基因排名高于随机选择的基因,召回率为0.98。选定主题的前五个基因的精确率计算为0.87。这项工作表明,EMCON可用于将结果与可能的生物学结果联系起来,从而有助于生成可测试的假设,以进一步理解生物学功能以及化学暴露对疾病的影响。