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

项目摘要/摘要 一些最具挑战性的诊断病例涉及出现复杂表型的患者 随着时间的推移而演变，并与多个医学学科交叉。诊断这种疾病的两个主要临床环境 病人是未确诊的疾病诊所和新生儿重症监护病房的快速基因组测序计划。 这些诊所采用了一种基于全面基因组进行诊断分析的方法 测序数据；分析由一个大型的、协作的临床团队进行。这个以团队为基础的 方法充分利用了治疗医生对患者表型的详细了解，即 遗传学家对遗传病的深厚知识，生物信息学分析师在判断变种的专业知识 质量和预测的致病性，以及诊断病理学家综合所有相关 信息，并得出关于给定变异的临床意义的结论。诊断性分析 在这两种环境中的患者都是一个长期的过程，通常会持续几个月甚至几年， 直到观察到患者的新表型或文献中报道了新的基因与疾病的关联 为案件解决提供了必要的洞察力。然而，现有的软件工具通常只满足 生物信息学专家或诊断分子病理学家，而不是治疗医生或遗传学 辅导员；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、纵向的 基因组诊断护理。为了解决这一迫切需求，我们建议开发一个全面的软件 Calypso系统，以解决这一紧迫需求。Calypso将通过直观和 为每个团队成员对诊断分析的专门贡献量身定做的可视化iobio Web工具；以及 通过系统的变异恢复，使患者的基因组数据保持最新，从而促进长期基因组护理 注释基础结构。我们将把Calypso交给临床团队来治疗我们未确诊的疾病 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 团队医学背景下的基因组诊断护理。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，帮助实现协作诊断机会 由一个专注于临床的大型研究联盟提出。

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.