{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,11]],"date-time":"2026-10-11T04:11:09Z","timestamp":1791691869457,"version":"4.3.4"},"reference-count":34,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2024,9,18]],"date-time":"2024-09-18T00:00:00Z","timestamp":1726617600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100014593","name":"Neurocrine Biosciences","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100014593","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Epilepsia"],"published-print":{"date-parts":[[2024,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>\n                      Phenotypic heterogeneity presents challenges in providing clinical care to patients with pathogenic\n                      <jats:italic>SCN8A<\/jats:italic>\n                      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\u2010 and gain\u2010 of\u2010 function vari\u2010ants, respectively. Here, we test the hypothesis that the unsupervised subgroups (U1\u2013U3) are distinguished by differential contributions of developmental and epileptic components.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We predicted that patients in the U1 and U2 subgroups would differ in timing of developmental delay and seizure\u00a0onset, 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Two\u2010population proportion and Kruskal\u2013Wallis 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance<\/jats:title>\n                    <jats:p>Unsupervised ML approaches discern differential developmental and epileptic components among patients with SCN8A\u2010related 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\u2010related disorders.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/epi.18118","type":"journal-article","created":{"date-parts":[[2024,9,18]],"date-time":"2024-09-18T11:15:06Z","timestamp":1726658106000},"page":"3324-3334","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Patients carrying pathogenic\n                    <scp>\n                      <i>SCN8A<\/i>\n                    <\/scp>\n                    variants with loss\u2010 and gain\u2010of\u2010function effects can be classified into five subgroups exhibiting varying developmental and epileptic components of encephalopathy"],"prefix":"10.1111","volume":"65","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0469-4559","authenticated-orcid":false,"given":"Joshua B.","family":"Hack","sequence":"first","affiliation":[{"name":"BIO5 Institute University of Arizona  Tucson Arizona USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph C.","family":"Watkins","sequence":"additional","affiliation":[{"name":"Department of Mathematics University of Arizona  Tucson Arizona USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0615-2497","authenticated-orcid":false,"given":"John M.","family":"Schreiber","sequence":"additional","affiliation":[{"name":"Epilepsy Genetics Program Children\u2019s National Medical Center  Washington DC USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0172-429X","authenticated-orcid":false,"given":"Michael F.","family":"Hammer","sequence":"additional","affiliation":[{"name":"BIO5 Institute University of Arizona  Tucson Arizona USA"},{"name":"Neurology Department University of Arizona  Tucson Arizona USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,9,18]]},"reference":[{"key":"e_1_2_11_2_1","volume-title":"SCN8A\u2010related epilepsy and\/or neurodevelopmental disorders","author":"Hammer MF","year":"2023"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awab321"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awy326"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2023.104855"},{"key":"e_1_2_11_6_1","doi-asserted-by":"crossref","unstructured":"ChungKM HackJ AndrewsJ Galindo\u2010KellyM SchreiberJ WatkinsJ et\u00a0al.Clinical severity is correlated with age at seizure onset and biophysical properties of recurrent gain of function variants associated with SCN8A\u2010related epilepsy Epilepsia.2023.","DOI":"10.1111\/epi.17747"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1111\/epi.16288"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1111\/epi.14705"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000001211"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pediatrneurol.2021.06.011"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1212\/NXG.0000000000200060"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmg.2022.104577"},{"key":"e_1_2_11_13_1","first-page":"4","article-title":"The international SCN8A patient registry: a scientific resource to advance the understanding and treatment of a rare pediatric neurodevelopmental syndrome J registry","volume":"50","author":"Andrews J","year":"2023","journal-title":"Management"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1155\/2012\/403592"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejpn.2019.12.003"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-12-802002-9.00010-8"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41583-020-00418-4"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1242\/bio.060286"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yebeh.2020.107654"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1167.2010.02522.x"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1528-1157.2001.042suppl.3023.x"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejpn.2019.12.023"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1111\/epi.17239"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(23)00246-6"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13054-022-04079-w"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.3389\/fmed.2021.770343"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0718-21.2021"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.36255\/exon-publications-epilepsy-neurodevelopmental-disorders"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1005273"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12016-020-08787-5"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0180485"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI124611"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1111\/epi.17992"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.1111\/epi.17991"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.4046\/trd.2023.0104"}],"container-title":["Epilepsia"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/epi.18118","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,11,18]],"date-time":"2024-11-18T11:15:09Z","timestamp":1731928509000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/epi.18118"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,9,18]]},"references-count":34,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2024,11]]}},"alternative-id":["10.1111\/epi.18118"],"URL":"https:\/\/doi.org\/10.1111\/epi.18118","archive":["Portico"],"relation":{},"ISSN":["0013-9580","1528-1167"],"issn-type":[{"value":"0013-9580","type":"print"},{"value":"1528-1167","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,9,18]]},"assertion":[{"value":"2024-02-13","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-08-27","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-09-18","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}