DataSheet_2_Curation and expansion of the Human Phenotype Ontology for systemic autoinflammatory diseases improves phenotype-driven disease-matching.docx

IntroductionAccurate and standardized phenotypic descriptions are essential in diagnosing rare diseases and discovering new diseases, and the Human Phenotype Ontology (HPO) system was developed to provide a rich collection of hierarchical phenotypic descriptions. However, although the HPO terms for inborn errors of immunity have been improved and curated, it has not been investigated whether this curation improves the diagnosis of systemic autoinflammatory disease (SAID) patients. Here, we aimed to study if improved HPO annotation for SAIDs enhanced SAID identification and to demonstrate the potential of phenotype-driven genome diagnostics using curated HPO terms for SAIDs.MethodsWe collected HPO terms from 98 genetically confirmed SAID patients across eight different European SAID expertise centers and used the LIRICAL (Likelihood Ratio Interpretation of Clinical Abnormalities) computational algorithm to estimate the effect of HPO curation on the prioritization of the correct SAID for each patient.ResultsOur results show that the percentage of correct diagnoses increased from 66% to 86% and that the number of diagnoses with the highest ranking increased from 38 to 45. In a further pilot study, curation also improved HPO-based whole-exome sequencing (WES) analysis, diagnosing 10/12 patients before and 12/12 after curation. In addition, the average number of candidate diseases that needed to be interpreted decreased from 35 to 2.DiscussionThis study demonstrates that curation of HPO terms can increase identification of the correct diagnosis, emphasizing the high potential of HPO-based genome diagnostics for SAIDs.

精确且标准化的表型描述对于罕见病的诊断以及新疾病的发现至关重要，为此，人类表型本体（Human Phenotype Ontology，HPO）系统得以构建，旨在提供丰富的层级化表型描述集合。尽管针对原发性免疫缺陷症（Inborn Errors of Immunity，IEI）的HPO术语已得到改进和精心整理，然而，尚未探讨此整理过程是否能够提升系统性自身炎症性疾病（Systemic Autoinflammatory Disease，SAID）患者的诊断准确性。本研究旨在探究改进后的HPO术语标注是否能增强SAID的识别，并展示利用精心整理的HPO术语进行表型驱动基因组诊断的潜力。方法上，我们从八个不同欧洲SAID专业中心收集了98名基因确诊SAID患者的HPO术语，并利用LIRICAL（临床异常似然比解释）计算算法评估HPO整理对每位患者正确SAID识别优先级的影响。结果显示，正确诊断的比例从66%提升至86%，且最高排名的诊断数量从38增加到45。在进一步的试点研究中，整理过程也优化了基于HPO的whole-exome sequencing（WES）分析，整理前10/12患者在诊断，整理后12/12患者得到诊断。此外，平均需要解释的候选疾病数量从35减少至2。讨论部分表明，HPO术语的整理能够提高正确诊断的识别率，凸显了基于HPO的基因组诊断在SAID中的巨大潜力。