{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T21:24:59Z","timestamp":1775597099239,"version":"3.50.1"},"reference-count":22,"publisher":"Public Library of Science (PLoS)","issue":"5","license":[{"start":{"date-parts":[[2024,5,22]],"date-time":"2024-05-22T00:00:00Z","timestamp":1716336000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100008484","name":"biomarin pharmaceutical","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008484","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Background<\/jats:title>\n<jats:p>The CLN2 Clinical Rating Scale evaluates disease progression in CLN2 disease, an ultra-rare, neurodegenerative disorder with late infantile onset. To validate the Clinical Rating Scale, a comparison with the Pediatric Quality of Life Inventory (PedsQL) was conducted utilising clinical trial data investigating cerliponase alfa use in CLN2 disease.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Methods<\/jats:title>\n<jats:p>Linear regression and mixed effects models were used to investigate the relationship between the Clinical Rating Scale and PedsQL using open-label, single-arm, phase 1\/2 (NCT01907087) and ongoing extension study (NCT02485899) data of 23 children with CLN2 disease treated with cerliponase alfa for \u226596 weeks.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Results<\/jats:title>\n<jats:p>Correlations between the four Clinical Rating Scale domains were low. Linear mixed effects analyses showed significant correlation between PedsQL and Clinical Rating Scale (Total score or motor-language [ML] score adjusted p-values &lt;0.05), driven by the relationship with the PedsQL Physical domain. A statistically significant relationship was identified between the Clinical Rating Scale motor domain and PedsQL (Total score: adjusted p-value = 0.048, parameter estimate [PE] = 8.10; Physical domain score: adjusted p-value = 0.012; PE = 13.79).<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Conclusions<\/jats:title>\n<jats:p>Each domain of the Clinical Rating Scale provides unique information on disease state. Validity of the scale is supported by its relationship with the PedsQL. Among the four domains of the Clinical Rating Scale, motor has the highest correlation to PedsQL, suggesting motor function as a driver of patients\u2019 quality of life. The lack of association between the remaining domains of the Clinical Rating Scale and PedsQL suggests that additional disease-specific measures may be needed to fully capture the quality of life impact of CLN2 disease.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec005\">\n<jats:title>Trial registration<\/jats:title>\n<jats:p><jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/clinicaltrials.gov\/ct2\/show\/NCT01907087\" xlink:type=\"simple\">NCT01907087<\/jats:ext-link>, <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/clinicaltrials.gov\/ct2\/show\/NCT02485899\" xlink:type=\"simple\">NCT02485899<\/jats:ext-link>.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0302382","type":"journal-article","created":{"date-parts":[[2024,5,22]],"date-time":"2024-05-22T17:26:14Z","timestamp":1716398774000},"page":"e0302382","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":3,"title":["Exploring concurrent validity of the CLN2 Clinical Rating Scale: Comparison to PedsQL using cerliponase alfa clinical trial data"],"prefix":"10.1371","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8120-0287","authenticated-orcid":true,"given":"Nicola","family":"Specchio","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paul","family":"Gissen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emily","family":"de los Reyes","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew","family":"Olaye","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Charlotte","family":"Camp","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tristan","family":"Curteis","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Annabel","family":"Griffiths","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas","family":"Butt","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jessica","family":"Cohen-Pfeffer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter","family":"Slasor","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zlatko","family":"Sisic","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohit","family":"Jain","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Angela","family":"Schulz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2024,5,22]]},"reference":[{"issue":"6","key":"pone.0302382.ref001","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1212\/01.wnl.0000267885.47092.40","article-title":"Neurological deterioration in late infantile neuronal ceroid lipofuscinosis","volume":"69","author":"S Worgall","year":"2007","journal-title":"Neurology"},{"issue":"3","key":"pone.0302382.ref002","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1111\/j.1399-0004.2008.01054.x","article-title":"The clinical and genetic epidemiology of neuronal ceroid lipofuscinosis in Newfoundland","volume":"74","author":"SJ Moore","year":"2008","journal-title":"Clin Genet"},{"key":"pone.0302382.ref003","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1053\/ejpn.2000.0437","article-title":"Specific substrate for CLN2 protease\/tripeptidyl-peptidase I assay","volume":"5","author":"M Junaid","year":"2001","journal-title":"Eur J Paediatr Neurol"},{"key":"pone.0302382.ref004","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1016\/j.pediatrneurol.2017.01.034","article-title":"Management Strategies for CLN2 Disease","volume":"69","author":"RE Williams","year":"2017","journal-title":"Pediatr 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observational cohort study","volume":"2","author":"M Nickel","year":"2018","journal-title":"The Lancet Child & adolescent health"},{"key":"pone.0302382.ref008","article-title":"An Adapted Clinical Measurement Tool for the Key Symptoms of CLN2 Disease","volume":"6","author":"KW Wyrwich","year":"2018","journal-title":"J Inborn Errors Metab"},{"issue":"20","key":"pone.0302382.ref009","doi-asserted-by":"crossref","first-page":"1898","DOI":"10.1056\/NEJMoa1712649","article-title":"Study of Intraventricular Cerliponase Alfa for CLN2 Disease","volume":"378","author":"A Schulz","year":"2018","journal-title":"The New England journal of medicine"},{"issue":"2","key":"pone.0302382.ref010","doi-asserted-by":"crossref","first-page":"S133","DOI":"10.1016\/j.ymgme.2018.12.342","article-title":"Persistent treatment effect of cerliponase alfa in children with CLN2 disease: A 3 year update from an ongoing multicenter extension study","volume":"126","author":"A Schulz","year":"2019","journal-title":"Mol Genet Metab"},{"key":"pone.0302382.ref011","unstructured":"ClinicalTrials.gov. A Phase 1\/2 Open-Label Dose-Escalation Study to Evaluate Safety, Tolerability, Pharmacokinetics, and Efficacy of Intracerebroventricular BMN 190 in Patients With Late-Infantile Neuronal Ceroid Lipofuscinosis (CLN2) Disease, 2016. https:\/\/clinicaltrials.gov\/ct2\/show\/NCT01907087?cond=cln2&rank=2. (Last accessed February 2018)."},{"key":"pone.0302382.ref012","unstructured":"European Medicines Agency. Brineura, cerliponase alfa\u2014Summary of product characteristics, 2017. https:\/\/www.ema.europa.eu\/en\/medicines\/human\/EPAR\/brineura (Last accessed February 2018)."},{"key":"pone.0302382.ref013","unstructured":"U.S. Food & Drug Administration (FDA). Drugs@FDA: FDA Approved Drug Products\u2014Biologic License Application (BLA): 761052, 2019. https:\/\/www.accessdata.fda.gov\/scripts\/cder\/daf\/index.cfm?event=BasicSearch.process. (Last accessed October 2019)."},{"key":"pone.0302382.ref014","unstructured":"Mapi Research Trust. Scaling and Scoring of the Pediatric Quality of Life Inventory PedsQL, 2017. http:\/\/www.pedsql.org\/PedsQL-Scoring.pdf. (Last accessed February 2017)."},{"issue":"6","key":"pone.0302382.ref015","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1586\/14737167.5.6.705","article-title":"The PedsQL\u2122 as a pediatric patient-reported outcome: reliability and validity of the PedsQL\u2122 Measurement Model in 25,000 children","volume":"5","author":"JW Varni","year":"2005","journal-title":"Expert Rev Pharmacoeconomics Outcomes Res"},{"key":"pone.0302382.ref016","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1367\/1539-4409(2003)003<0329:TPAAPP>2.0.CO;2","article-title":"The PedsQL 4.0 as a pediatric population health measure: Feasibility, reliability, and validity","volume":"3","author":"J Varni","year":"2003","journal-title":"Ambul Pediatr"},{"issue":"2","key":"pone.0302382.ref017","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1023\/A:1014836921812","article-title":"The PedsQL 4.0 Generic Core Scales: sensitivity, responsiveness, and impact on clinical decision-making","volume":"25","author":"JW Varni","year":"2002","journal-title":"Journal of behavioral medicine"},{"issue":"2","key":"pone.0302382.ref018","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1097\/00005650-199902000-00003","article-title":"The PedsQL: measurement model for the pediatric quality of life inventory","volume":"37","author":"JW Varni","year":"1999","journal-title":"Medical care"},{"key":"pone.0302382.ref019","unstructured":"Varni JW. PedsQL\u2122 Administration Guidelines, 1998. https:\/\/www.pedsql.org\/PedsQLguidelines.doc. (Last accessed February 2018)."},{"issue":"1","key":"pone.0302382.ref020","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1198\/tast.2009.0012","article-title":"Where\u2019s Waldo? Visualizing Collinearity Diagnostics","volume":"63","author":"M Friendly","year":"2009","journal-title":"The American Statistician"},{"key":"pone.0302382.ref021","unstructured":"R Core Team. R: A language and environment for statistical computing, 2017. 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