Joshua B. Hack, Joseph C. Watkins, John M. Schreiber, Michael F. Hammer
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Here, we test the hypothesis that the unsupervised subgroups (U1–U3) are distinguished by differential contributions of developmental and epileptic components.MethodsWe predicted that patients in the U1 and U2 subgroups would differ in timing of developmental delay and seizure onset, with earlier and concurrent onset of both features for the U3 subgroup. Standard statistical procedures were used to test these predictions, as well as to investigate clinically relevant associations among all five subgroups.ResultsTwo‐population proportion and Kruskal–Wallis tests supported the hypothesis of a reversed order of developmental delay and seizure onset for patients in U1 and U2, and nearly synchronous developmental delay/seizure onset for the U3 (termed DEE) subgroup. Association testing identified subgroup variation in treatment response, frequency of initial seizure type, and comorbidities, as well as different median ages of developmental delay onset for all five subgroups.SignificanceUnsupervised ML approaches discern differential developmental and epileptic components among patients with SCN8A‐related epilepsy. Patients in U1 (termed developmental encephalopathy) typically gain seizure control yet rarely experience improvements in development, whereas those in U2 (termed epileptic encephalopathy) have fewer if any developmental impairments despite difficulty in achieving seizure control. This understanding improves prognosis and clinical management and provides a framework to discover mechanisms underlying variability in clinical outcome of patients with SCN8A‐related disorders.","PeriodicalId":11768,"journal":{"name":"Epilepsia","volume":null,"pages":null},"PeriodicalIF":6.6000,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Patients carrying pathogenic SCN8A variants with loss‐ and gain‐of‐function effects can be classified into five subgroups exhibiting varying developmental and epileptic components of encephalopathy\",\"authors\":\"Joshua B. Hack, Joseph C. Watkins, John M. Schreiber, Michael F. Hammer\",\"doi\":\"10.1111/epi.18118\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"ObjectivePhenotypic heterogeneity presents challenges in providing clinical care to patients with pathogenic <jats:italic>SCN8A</jats:italic> variants, which underly a wide disease spectrum ranging from neurodevelopmental delays without seizures to a continuum of mild to severe developmental and epileptic encephalopathies (DEEs). An important unanswered question is whether there are clinically important subgroups within this wide spectrum. Using both supervised and unsupervised machine learning (ML) approaches, we previously found statistical support for two and three subgroups associated with loss‐ and gain‐ of‐ function vari‐ants, respectively. Here, we test the hypothesis that the unsupervised subgroups (U1–U3) are distinguished by differential contributions of developmental and epileptic components.MethodsWe predicted that patients in the U1 and U2 subgroups would differ in timing of developmental delay and seizure onset, with earlier and concurrent onset of both features for the U3 subgroup. Standard statistical procedures were used to test these predictions, as well as to investigate clinically relevant associations among all five subgroups.ResultsTwo‐population proportion and Kruskal–Wallis tests supported the hypothesis of a reversed order of developmental delay and seizure onset for patients in U1 and U2, and nearly synchronous developmental delay/seizure onset for the U3 (termed DEE) subgroup. Association testing identified subgroup variation in treatment response, frequency of initial seizure type, and comorbidities, as well as different median ages of developmental delay onset for all five subgroups.SignificanceUnsupervised ML approaches discern differential developmental and epileptic components among patients with SCN8A‐related epilepsy. Patients in U1 (termed developmental encephalopathy) typically gain seizure control yet rarely experience improvements in development, whereas those in U2 (termed epileptic encephalopathy) have fewer if any developmental impairments despite difficulty in achieving seizure control. 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引用次数: 0
摘要
目的表型异质性给致病性 SCN8A 变体患者的临床治疗带来了挑战,这些变体导致了广泛的疾病谱,从无癫痫发作的神经发育迟缓到从轻度到重度的发育性和癫痫性脑病(DEEs)。一个尚未解答的重要问题是,在这一广泛的疾病谱中是否存在临床上重要的亚群。利用监督和无监督机器学习(ML)方法,我们之前发现分别有两个和三个亚组与功能损失和功能增益变异相关。我们预测 U1 和 U2 亚组的患者在发育迟缓和癫痫发作的时间上会有所不同,而 U3 亚组的这两个特征会更早且同时出现。结果两组人口比例检验和 Kruskal-Wallis 检验支持以下假设:U1 和 U2 组患者的发育迟缓和癫痫发作顺序相反,而 U3(称为 DEE)亚组患者的发育迟缓/癫痫发作几乎同步。关联测试确定了治疗反应、初始发作类型频率和合并症方面的亚组差异,以及所有五个亚组发育迟缓发病年龄的中位数差异。U1(称为发育性脑病)患者通常能控制癫痫发作,但发育很少得到改善,而U2(称为癫痫性脑病)患者尽管难以控制癫痫发作,但发育障碍较少。这种认识有助于改善预后和临床管理,并为发现 SCN8A 相关疾病患者临床结局差异的内在机制提供了一个框架。
Patients carrying pathogenic SCN8A variants with loss‐ and gain‐of‐function effects can be classified into five subgroups exhibiting varying developmental and epileptic components of encephalopathy
ObjectivePhenotypic heterogeneity presents challenges in providing clinical care to patients with pathogenic SCN8A variants, which underly a wide disease spectrum ranging from neurodevelopmental delays without seizures to a continuum of mild to severe developmental and epileptic encephalopathies (DEEs). An important unanswered question is whether there are clinically important subgroups within this wide spectrum. Using both supervised and unsupervised machine learning (ML) approaches, we previously found statistical support for two and three subgroups associated with loss‐ and gain‐ of‐ function vari‐ants, respectively. Here, we test the hypothesis that the unsupervised subgroups (U1–U3) are distinguished by differential contributions of developmental and epileptic components.MethodsWe predicted that patients in the U1 and U2 subgroups would differ in timing of developmental delay and seizure onset, with earlier and concurrent onset of both features for the U3 subgroup. Standard statistical procedures were used to test these predictions, as well as to investigate clinically relevant associations among all five subgroups.ResultsTwo‐population proportion and Kruskal–Wallis tests supported the hypothesis of a reversed order of developmental delay and seizure onset for patients in U1 and U2, and nearly synchronous developmental delay/seizure onset for the U3 (termed DEE) subgroup. Association testing identified subgroup variation in treatment response, frequency of initial seizure type, and comorbidities, as well as different median ages of developmental delay onset for all five subgroups.SignificanceUnsupervised ML approaches discern differential developmental and epileptic components among patients with SCN8A‐related epilepsy. Patients in U1 (termed developmental encephalopathy) typically gain seizure control yet rarely experience improvements in development, whereas those in U2 (termed epileptic encephalopathy) have fewer if any developmental impairments despite difficulty in achieving seizure control. This understanding improves prognosis and clinical management and provides a framework to discover mechanisms underlying variability in clinical outcome of patients with SCN8A‐related disorders.
期刊介绍:
Epilepsia is the leading, authoritative source for innovative clinical and basic science research for all aspects of epilepsy and seizures. In addition, Epilepsia publishes critical reviews, opinion pieces, and guidelines that foster understanding and aim to improve the diagnosis and treatment of people with seizures and epilepsy.