Phenotypic homogeneity in childhood epilepsies evolves in gene-specific patterns across 3251 patient-years of clinical data.
Phenotypic homogeneity in childhood epilepsies evolves in gene-specific patterns across 3251 patient-years of clinical data.
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DOI：
10.1038/s41431-021-00908-8
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发表时间：
2021-11
期刊：
影响因子：
--
通讯作者：
Helbig I
中科院分区：
文献类型：
--
作者：
Lewis-Smith D;Ganesan S;Galer PD;Helbig KL;McKeown SE;O'Brien M;Khankhanian P;Kaufman MC;Gonzalez AK;Felmeister AS;Krause R;Ellis CA;Helbig I
虽然癫痫的遗传学研究可以在成千上万的个体中进行，但表型分析仍然是一项手动的、不可扩展的任务。一个特别的挑战是捕捉复杂表型随年龄的演变。在这里，我们提出了一种新的方法，应用表型相似性分析，共3251例患者-年的纵向电子病历数据，从先前报道的队列658个人与遗传性癫痫。在将临床数据映射到人类表型本体之后，我们确定了从出生到最大年龄25岁的每3个月年龄间隔内共享每种遗传病因的个体的表型相似性。所有27个基因中有140个（23%）和3个月龄间隔的足够数据用于计算表型相似性显著高于偶然预期。27种遗传病因中有11种具有显著的总体表型相似性轨迹。这些并不简单地反映了与单一表型特征的强统计学关联，而是似乎出现于复杂的临床特征星座，这些特征可能与个体没有强关联。纵向表型相似性分析是在临床实践中重建证候识别认知框架的一种尝试，它利用电子病历中的数据扩展了传统的表型分析方法，其规模远远超出了人工表型分析的能力。描述遗传性癫痫的表型同质性如何随年龄变化可以改善这些疾病的表型分类，预后咨询的准确性，并通过提供历史对照数据，设计和解释罕见疾病的精确临床试验。
While genetic studies of epilepsies can be performed in thousands of individuals, phenotyping remains a manual, non-scalable task. A particular challenge is capturing the evolution of complex phenotypes with age. Here, we present a novel approach, applying phenotypic similarity analysis to a total of 3251 patient-years of longitudinal electronic medical record data from a previously reported cohort of 658 individuals with genetic epilepsies. After mapping clinical data to the Human Phenotype Ontology, we determined the phenotypic similarity of individuals sharing each genetic etiology within each 3-month age interval from birth up to a maximum age of 25 years. 140 of 600 (23%) of all 27 genes and 3-month age intervals with sufficient data for calculation of phenotypic similarity were significantly higher than expect by chance. 11 of 27 genetic etiologies had significant overall phenotypic similarity trajectories. These do not simply reflect strong statistical associations with single phenotypic features but appear to emerge from complex clinical constellations of features that may not be strongly associated individually. As an attempt to reconstruct the cognitive framework of syndrome recognition in clinical practice, longitudinal phenotypic similarity analysis extends the traditional phenotyping approach by utilizing data from electronic medical records at a scale that is far beyond the capabilities of manual phenotyping. Delineation of how the phenotypic homogeneity of genetic epilepsies varies with age could improve the phenotypic classification of these disorders, the accuracy of prognostic counseling, and by providing historical control data, the design and interpretation of precision clinical trials in rare diseases.
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影响因子：
2.6
作者：
de Lange, Iris M.;Gunning, Boudewijn;Brilstra, Eva H.
通讯作者：
Brilstra, Eva H.
DOI：
10.1136/jamia.2009.001560
发表时间：
2010-09-01
影响因子：
6.4
作者：
Savova, Guergana K.;Masanz, James J.;Chute, Christopher G.
通讯作者：
Chute, Christopher G.
影响因子：
30.8
作者：
Chen, Wan-Jin;Lin, Yu;Wu, Zhi-Ying
通讯作者：
Wu, Zhi-Ying
影响因子：
11.2
作者：
Weckhuysen, Sarah;Mandelstam, Simone;de Jonghe, Peter
通讯作者：
de Jonghe, Peter
影响因子：
14.9
作者：
Köhler S;Gargano M;Matentzoglu N;Carmody LC;Lewis-Smith D;Vasilevsky NA;Danis D;Balagura G;Baynam G;Brower AM;Callahan TJ;Chute CG;Est JL;Galer PD;Ganesan S;Griese M;Haimel M;Pazmandi J;Hanauer M;Harris NL;Hartnett MJ;Hastreiter M;Hauck F;He Y;Jeske T;Kearney H;Kindle G;Klein C;Knoflach K;Krause R;Lagorce D;McMurry JA;Miller JA;Munoz-Torres MC;Peters RL;Rapp CK;Rath AM;Rind SA;Rosenberg AZ;Segal MM;Seidel MG;Smedley D;Talmy T;Thomas Y;Wiafe SA;Xian J;Yüksel Z;Helbig I;Mungall CJ;Haendel MA;Robinson PN
通讯作者：
Robinson PN