Enabling new translational discoveries using a genomic data-driven nosology

描述(由申请人提供)：与许多不同疾病有关的多种形式的生物分子数据(例如，基因表达、遗传学、蛋白质组学)和临床数据(例如，临床生物标记物、药物靶标和适应症)现在可以从公开可用的数据库和知识库中轻松获得。现在有机会将这些数据整合到统一的、全球一致的人类疾病或病因学表示中。这样的病因学将表达疾病如何在多个分子和临床轴上相互联系。在这次竞争性更新中，我们计划对该项目进行重大扩展。我们计划用更多类型的分子测量从更新的公共储存库中获取数据。基因和蛋白质测量的纳入将使疾病和疾病相似性的建模更加丰富，而不是mRNA测量。为了帮助将疾病中看到的分子变化与遗传差异联系起来，我们计划将表达数量性状基因座(EQTL)纳入我们的疾病模型，该模型是根据同时的遗传和表达测量建立的。为了扩大我们的病因学在个性化医疗中的效用，我们计划纳入更多关于疾病的定量流行病学测量，并使用概率关系建模来模拟疾病状态之间的转换。我们将把我们的病因学与著名的ICD-10以及正在开发中的ICD-11进行比较。我们将开发新的可视化方法来处理Nosolotics中看到的复杂的边和节点。我们还计划在两个驱动生物项目中测试我们的病毒学，这两个项目是小细胞肺癌和免疫学和疾病，特别是产生了可供临床试验的新诊断和治疗方法。 公共卫生相关性：在这次竞争性更新中，我们计划在第一个资助期的36份出版物的基础上，根据临床、分子和流行病学数据和知识创建一个新的疾病分类，并利用这个分类来确定小细胞肺癌和免疫性疾病的新诊断方法和药物。

DESCRIPTION (provided by applicant): Many forms of biomolecular (e.g., gene expression, genetics, proteomics) and clinical (e.g., clinical biomarkers, drug targets and indications) data pertaining to many different diseases are now readily available from publicly- available data repositories and knowledge-bases. There is now an opportunity to integrate these data into a unified, globally coherent representation of human disease, or nosology. Such a nosology would express how diseases are related to one another across multiple molecular and clinical axes. In this competitive renewal, we are planning a major expansion for this project. We plan to capture data from newer public repositories with more types of molecular measurements. Inclusion of genetic and protein measurements will enable a richer modeling of diseases and disease similarity, beyond mRNA measurements. To help link the molecular changes seen in disease to genetic differences, we plan to incorporate Expression Quantitative Trait Loci (eQTLs) into our disease models, built from simultaneous genetic and expression measurements. To expand the utility of our nosology in personalized medicine, we plan to incorporate more quantitative epidemiological measurements on disease, and to model transitions between disease states using probabilistic relational modeling. We will compare our nosology with the well-known ICD-10 as well as ICD-11, under development. We will develop novel visualization methods for the complex of edges and nodes seen in nosologies. We also plan to test our nosology in two Driving Biological Projects, in small cell lung cancer and immunology and disease, specifically yielding novel diagnostics and therapeutics ready for clinical trials. PUBLIC HEALTH RELEVANCE: In this competitive renewal, building from 36 publications in the first funding period, we plan to create a new disease classification based on clinical, molecular, and epidemiological data and knowledge, and to use this classification to identify novel diagnostics and drugs for small cell lung cancer and immunological disease.