Calypso: a web software system supporting team-based, longitudinal genomic diagnostic care

项目概要/摘要 一些最具挑战性的诊断病例涉及具有复杂表型的患者， 随着时间的推移而发展，并与多个医学学科交叉。用于诊断此类疾病的两种主要临床环境 患者未确诊的疾病诊所和新生儿重症监护病房快速基因组测序计划。 这些诊所采用了一种方法，其中诊断分析是基于全面的基因组 测序数据;和分析是由一个大的，协作的临床团队进行。这个团队基础 这种方法利用了治疗医生对患者表型的详细了解， 遗传学家对遗传疾病的深入了解，生物信息学分析师在裁定变异方面的专业知识， 质量和预测的致病性，以及诊断病理学家的能力，综合所有相关的 信息并得出关于给定变体的临床意义的结论。诊断分析 患者在这两种环境中的治疗是一个长期的过程，通常持续数月甚至数年， 直到在患者中观察到新的表型或文献中报告了新的基因-疾病关联 为案件解决提供必要的洞察力。然而，现有的软件工具通常仅满足 生物信息学专家或诊断分子病理学家，但不是治疗医生或遗传学专家。 咨询师;专注于在单个时间点进行基因诊断，而不是随着时间的推移跟踪患者 在漫长的诊断过程中，因此无法充分支持基于团队的纵向 基因诊断护理。为了满足这一迫切需求，我们建议开发一个全面的软件 系统，Calypso，以满足这一迫切需要。Calypso将通过直观和 可视化iobio网络工具，为每个团队成员的诊断分析专门贡献量身定制; 通过系统性的变异重建，使患者基因组数据保持最新，从而促进长期的基因组护理， 注释基础设施。我们将把卡里普索交给临床团队， 诊所和我们的新生儿重症监护病房，是评估我们的工具对长期影响的理想测试场所。 在团队医学的背景下进行基因组诊断护理。我们还将集中部署和评估我们的 NHGRI未诊断疾病网络中的工具，以帮助实现协作诊断机会 由一个大型的临床研究联盟提出。

PROJECT SUMMARY/ABSTRACT Some of the most challenging diagnostic cases involve patients who present with complex phenotypes that evolve over time and intersect multiple medical disciplines. The two primary clinical settings for diagnosing such patients are undiagnosed disease clinics and neonatal intensive care unit rapid genome sequencing programs. These clinics have adopted an approach where diagnostic analysis is based on comprehensive genomic sequencing data; and analysis is carried out by a large, collaborative clinical team. This team-based approach leverages the treating physician’s detailed understanding of the patient’s phenotype, the medical geneticist’s deep knowledge of genetic diseases, the bioinformatic analyst’s expertise in adjudicating a variant’s quality and predicted pathogenicity, as well as the diagnostic pathologist’s ability to synthesize all relevant information and reach a conclusion regarding a given variant’s clinical significance. Diagnostic analysis of patients in both of these environments is a long-term process that often continues for months or even years, until new phenotypes in the patient are observed or novel gene-disease associations are reported in the literature that provide the necessary insight for case solution. However, existing software tools typically only cater to the bioinformatician expert or the diagnostic molecular pathologist, but not the treating physician or the genetic counselor; focus on making a genetic diagnosis at a single timepoint, rather than following the patient over time during a lengthy diagnostic process, and are therefore unable to adequately support team-based, longitudinal genomic diagnostic care. Addressing this pressing need, here we propose to develop a comprehensive software system, Calypso, to address this pressing need. Calypso will support team-based diagnostics via intuitive and visual iobio web tools tailored for each team member’s specialized contribution to diagnostic analysis; and facilitate long-term genomic care by keeping patient genomic data up-to-date via a systematic variant re- annotation infrastructure. We will put Calypso into the hands of the clinical teams in our undiagnosed disease clinic and our neonatal intensive care unit, ideal testing grounds for evaluating our tool’s impact on long-term genome diagnostic care in the context of team-based medicine. We will also centrally deploy and evaluate our tool in NHGRI’s Undiagnosed Disease Network to help realize the collaborative diagnostic opportunities presented by a large, clinically focused research consortium.