{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,6]],"date-time":"2026-05-06T07:01:18Z","timestamp":1778050878844,"version":"3.51.4"},"reference-count":30,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,10,24]],"date-time":"2021-10-24T00:00:00Z","timestamp":1635033600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,10,24]],"date-time":"2021-10-24T00:00:00Z","timestamp":1635033600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100006282","name":"Koning Boudewijnstichting","doi-asserted-by":"publisher","award":["2019-J1120010-213544"],"award-info":[{"award-number":["2019-J1120010-213544"]}],"id":[{"id":"10.13039\/501100006282","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000311","name":"Tuberous Sclerosis Association","doi-asserted-by":"publisher","award":["2014-S01"],"award-info":[{"award-number":["2014-S01"]}],"id":[{"id":"10.13039\/501100000311","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Orphanet J Rare Dis"],"published-print":{"date-parts":[[2021,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>Tuberous Sclerosis Complex (TSC), a multi-system genetic disorder, is associated with a wide range of TSC-Associated Neuropsychiatric Disorders <jats:italic>(<\/jats:italic>TAND). Individuals have apparently unique TAND profiles, challenging diagnosis, psycho-education, and intervention planning. We proposed that identification of natural TAND clusters could lead to personalized identification and treatment of TAND. Two small-scale studies showed cluster and factor analysis could identify clinically meaningful natural TAND clusters. Here we set out to identify definitive natural TAND clusters in a large, international dataset.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Method<\/jats:title>\n                <jats:p>Cross-sectional, anonymized TAND Checklist data of 453 individuals with TSC were collected from six international sites. Data-driven methods were used to identify natural TAND clusters. Mean squared contingency coefficients were calculated to produce a correlation matrix, and various cluster analyses and exploratory factor analysis were examined. Statistical robustness of clusters was evaluated with 1000-fold bootstrapping, and internal consistency calculated with Cronbach\u2019s alpha.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Ward\u2019s method rendered seven natural TAND clusters with good robustness on bootstrapping. Cluster analysis showed significant convergence with an exploratory factor analysis solution, and, with the exception of one cluster, internal consistency of the emerging clusters was good to excellent. Clusters showed good clinical face validity.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>Our findings identified a data-driven set of natural TAND clusters from within highly variable TAND Checklist data. The seven natural TAND clusters could be used to train families and professionals and to develop tailored approaches to identification and treatment of TAND. Natural TAND clusters may also have differential aetiological underpinnings and responses to molecular and other treatments.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s13023-021-02076-w","type":"journal-article","created":{"date-parts":[[2021,10,24]],"date-time":"2021-10-24T15:02:37Z","timestamp":1635087757000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Multivariate data analysis identifies natural clusters of Tuberous Sclerosis Complex Associated Neuropsychiatric Disorders (TAND)"],"prefix":"10.1186","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8915-1571","authenticated-orcid":false,"given":"Petrus J.","family":"de Vries","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Loren","family":"Leclezio","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sugnet","family":"Gardner-Lubbe","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Darcy","family":"Krueger","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mustafa","family":"Sahin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Steven","family":"Sparagana","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liesbeth","family":"De Waele","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna","family":"Jansen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2021,10,24]]},"reference":[{"key":"2076_CR1","doi-asserted-by":"crossref","unstructured":"Northrup H, Krueger DA, International Tuberous Sclerosis Complex Consensus Group. Tuberous sclerosis complex diagnostic criteria update: recommendations of the 2012 international Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol. 2013;49:243\u201354.","DOI":"10.1016\/j.pediatrneurol.2013.08.001"},{"key":"2076_CR2","doi-asserted-by":"publisher","first-page":"733","DOI":"10.1016\/S1474-4422(15)00069-1","volume":"14","author":"P Curatolo","year":"2015","unstructured":"Curatolo P, Moavero R, de Vries PJ. Neurological and neuropsychiatric aspects of tuberous sclerosis complex. Lancet Neurol. 2015;14:733\u201345.","journal-title":"Lancet Neurol"},{"key":"2076_CR3","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1016\/j.pediatrneurol.2014.10.004","volume":"52","author":"PJ de Vries","year":"2015","unstructured":"de Vries PJ, Whittemore VH, Leclezio L, et al. Tuberous sclerosis associated neuropsychiatric disorders (TAND) and the TAND Checklist. Pediatr Neurol. 2015;52:25\u201335.","journal-title":"Pediatr Neurol"},{"key":"2076_CR4","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1097\/YCO.0000000000000136","volume":"28","author":"L Leclezio","year":"2015","unstructured":"Leclezio L, de Vries PJ. Advances in the treatment of tuberous sclerosis complex. Curr Opin Psychiatry. 2015;28:113\u201320.","journal-title":"Curr Opin Psychiatry"},{"key":"2076_CR5","doi-asserted-by":"publisher","first-page":"604","DOI":"10.1111\/j.1365-2788.2009.01185.x","volume":"53","author":"J Wulffaert","year":"2009","unstructured":"Wulffaert J, van Berckelaer-Onnes I, Kroonenberg P, Scholte E, Bhuiyan Z, Hennekam R. Simultaneous analysis of the behavioural phenotype, physical factors, and parenting stress in people with Cornelia de Lange syndrome. J Intellect Disabil Res. 2009;53:604\u201319.","journal-title":"J Intellect Disabil Res"},{"key":"2076_CR6","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1016\/j.pediatrneurol.2017.12.006","volume":"81","author":"L Leclezio","year":"2018","unstructured":"Leclezio L, Gardner-Lubbe S, de Vries PJ. Is it feasible to identify natural clusters of TSC-associated neuropsychiatric disorders (TAND)? Pediatr Neurol. 2018;81:38\u201344.","journal-title":"Pediatr Neurol"},{"key":"2076_CR7","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1186\/s11689-020-09327-0","volume":"12","author":"PJ de Vries","year":"2020","unstructured":"de Vries PJ, Belousiva E, Benedik M, et al. Natural clusters of tuberous sclerosis complex (TSC)-associated neuropsychiatric disorders (TAND): new findings from the TOSCA TAND research project. J Neurodev Disord. 2020;12:24.","journal-title":"J Neurodev Disord"},{"key":"2076_CR8","volume-title":"Mathematical methods of statistics","author":"H Cram\u00e9r","year":"1946","unstructured":"Cram\u00e9r H. Mathematical methods of statistics. Princeton: Princeton University Press; 1946."},{"key":"2076_CR9","unstructured":"R Core Team. R: a language and environment for statistical computing. Vienna, Austria: R Foundation for Statistical Computing; 2017. https:\/\/www.R-project.org\/."},{"key":"2076_CR10","unstructured":"Maechler, M., Rousseeuw, P., Struyf, A., Hubert, M., Hornik, K. cluster: cluster analysis basics and extensions. R package version 2.0.5.; 2016. https:\/\/CRAN.R-project.org\/package=cluster."},{"key":"2076_CR11","doi-asserted-by":"crossref","unstructured":"Efron B, Tibshirani RJ. An introduction to the bootstrap. Boca Raton: Chapman & Hall\/CRC; 1993. https:\/\/cds.cern.ch\/record\/526679\/files\/0412042312_TOC.pdf.","DOI":"10.1007\/978-1-4899-4541-9"},{"key":"2076_CR12","unstructured":"Revelle W. psych: procedures for personality and psychological research, Evanston, Illinois: Northwestern University; 2017. https:\/\/CRAN.R-project.org\/package=psych. Version = 1.7.5."},{"key":"2076_CR13","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1027\/1614-2241.2.2.57","volume":"2","author":"U Lorenzo-Seva","year":"2006","unstructured":"Lorenzo-Seva U, ten Berge JMF. Tucker\u2019s congruence coefficient as a meaningful index of factor similarity. Methodology. 2006;2:57\u201364.","journal-title":"Methodology"},{"key":"2076_CR14","doi-asserted-by":"crossref","unstructured":"Gower JC, Dijksterhuis GB. Procrustes problems. Oxford Statistical Science Series, 30. Oxford, UK: Oxford University Press; 2004. http:\/\/www.oup.com\/uk\/catalogue\/?ci=9780198510581.","DOI":"10.1093\/acprof:oso\/9780198510581.001.0001"},{"issue":"3","key":"2076_CR15","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1007\/BF02310555","volume":"16","author":"LJ Cronbach","year":"1951","unstructured":"Cronbach LJ. Coefficient alpha and the internal structure of tests. Psychometrika. 1951;16(3):297\u2013334.","journal-title":"Psychometrika"},{"key":"2076_CR16","doi-asserted-by":"publisher","first-page":"666","DOI":"10.1177\/08830738040190090601","volume":"19","author":"P Prather","year":"2004","unstructured":"Prather P, de Vries PJ. Behavioral and cognitive aspects of tuberous sclerosis complex. J Child Neurol. 2004;19:666\u201374.","journal-title":"J Child Neurol"},{"key":"2076_CR17","doi-asserted-by":"publisher","first-page":"309","DOI":"10.1002\/ajmg.c.31637","volume":"178C","author":"PJ de Vries","year":"2018","unstructured":"de Vries PJ, Wilde L, de Vries MC, Moavero R, Pearson DA, Curatolo P. A clinical update on tuberous sclerosis complex-associated neuropsychiatric disorders (TAND). Am J Med Genet. 2018;178C:309\u201320.","journal-title":"Am J Med Genet"},{"key":"2076_CR18","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1007\/s00787-006-0570-3","volume":"16","author":"PJ de Vries","year":"2007","unstructured":"de Vries PJ, Hunt A, Bolton PF. The psychopathologies of children and adolescents with tuberous sclerosis complex (TSC): a postal survey of UK families. Eur Child Adolesc Psychiatry. 2007;16:16\u201324.","journal-title":"Eur Child Adolesc Psychiatry"},{"key":"2076_CR19","doi-asserted-by":"publisher","first-page":"387","DOI":"10.1002\/ajmg.a.32690","volume":"149A","author":"PJ de Vries","year":"2009","unstructured":"de Vries PJ, Gardiner J, Bolton PF. Neuropsychological attention deficits in tuberous sclerosis complex (TSC). Am J Med Genet. 2009;149A:387\u201395.","journal-title":"Am J Med Genet"},{"key":"2076_CR20","doi-asserted-by":"publisher","first-page":"261","DOI":"10.1093\/cercor\/bhj144","volume":"17","author":"K Ridler","year":"2007","unstructured":"Ridler K, Suckling J, Higgins NJ, et al. Neuroanatomical correlates of memory deficits in tuberous sclerosis complex. Cereb Cortex. 2007;17:261\u201371.","journal-title":"Cereb Cortex"},{"key":"2076_CR21","doi-asserted-by":"publisher","first-page":"437","DOI":"10.1007\/s10519-010-9423-4","volume":"41","author":"KM Tierney","year":"2011","unstructured":"Tierney KM, McCartney DL, Serfontein JR, de Vries PJ. Neuropsychological attention skills and related behaviours in adults with tuberous sclerosis complex. Behav Genet. 2011;41:437\u201344.","journal-title":"Behav Genet"},{"key":"2076_CR22","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1136\/jmg.2003.012757","volume":"41","author":"JC Lewis","year":"2004","unstructured":"Lewis JC, Thomas HV, Murphy KC, Sampson JR. Genotype and psychological phenotype in tuberous sclerosis. J Med Genet. 2004;41:203\u20137.","journal-title":"J Med Genet"},{"key":"2076_CR23","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1186\/1866-1955-6-10","volume":"6","author":"KE Eden","year":"2014","unstructured":"Eden KE, de Vries PJ, Moss J, Richards C, Oliver C. Self-injury and aggression in tuberous sclerosis complex: cross syndrome comparison and associated risk markers. J Neurodev Disord. 2014;6:10.","journal-title":"J Neurodev Disord"},{"key":"2076_CR24","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1016\/j.ridd.2017.03.007","volume":"64","author":"L Wilde","year":"2017","unstructured":"Wilde L, Eden K, de Vries P, Moss J, Welham A, Oliver C. Self-injury and aggression in adults with tuberous sclerosis complex: Frequency, associated person characteristics, and implications for assessment. Res Dev Disabil. 2017;64:119\u201330.","journal-title":"Res Dev Disabil"},{"key":"2076_CR25","doi-asserted-by":"publisher","first-page":"1247","DOI":"10.1093\/brain\/awf124","volume":"125","author":"PF Bolton","year":"2002","unstructured":"Bolton PF, Park RJ, Higgins JN, Griffiths PD, Pickles A. Neuro-epileptic determinants of autism spectrum disorders in tuberous sclerosis complex. Brain. 2002;125:1247\u201355.","journal-title":"Brain"},{"issue":"8","key":"2076_CR26","doi-asserted-by":"publisher","first-page":"766","DOI":"10.1212\/WNL.0000000000003002","volume":"87","author":"SS Jeste","year":"2016","unstructured":"Jeste SS, Varcin KJ, Hellemann GS, Gulsrud AC, Bhatt R, Kasari C, Wu J, Sahin M, Nelson CA III. Symptom profiles of autism spectrum disorder in tuberous sclerosis complex. Neurology. 2016;87(8):766\u201372.","journal-title":"Neurology"},{"key":"2076_CR27","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1016\/j.yebeh.2010.10.023","volume":"20","author":"AM van Eeghen","year":"2011","unstructured":"van Eeghen AM, Numis AI, Staley BA, Therrien SE, Thibert RL, Thiele EA. Characterizing sleep disorders of adults with tuberous sclerosis complex: a questionnaire-based study and review. Epilepsy Behav. 2011;20:68\u201374.","journal-title":"Epilepsy Behav"},{"key":"2076_CR28","doi-asserted-by":"publisher","first-page":"868","DOI":"10.1016\/j.celrep.2017.07.008","volume":"20","author":"JO Lipton","year":"2017","unstructured":"Lipton JO, Boyle LM, Yuan ED, et al. Aberrant proteostasis of BMAL1 underlies circadian abnormalities in a paradigmatic mTOR-opathy. Cell Rep. 2017;20:868\u201380.","journal-title":"Cell Rep"},{"key":"2076_CR29","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1016\/j.pediatrneurol.2014.10.006","volume":"52","author":"L Leclezio","year":"2015","unstructured":"Leclezio L, Jansen A, Whittemore VH, de Vries PJ. Pilot validation of the tuberous sclerosis-associated neuropsychiatric disorders (TAND) checklist. Pediatr Neurol. 2015;52:16\u201324.","journal-title":"Pediatr Neurol"},{"key":"2076_CR30","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1016\/j.nurt.2010.05.001","volume":"7","author":"PJ de Vries","year":"2010","unstructured":"de Vries PJ. Targeted treatments for cognitive and neurodevelopmental disorders in tuberous sclerosis complex. Neurotherapeutics. 2010;7:275\u201382.","journal-title":"Neurotherapeutics"}],"container-title":["Orphanet Journal of Rare Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13023-021-02076-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13023-021-02076-w\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13023-021-02076-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,10,24]],"date-time":"2021-10-24T15:08:47Z","timestamp":1635088127000},"score":1,"resource":{"primary":{"URL":"https:\/\/ojrd.biomedcentral.com\/articles\/10.1186\/s13023-021-02076-w"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,24]]},"references-count":30,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2021,12]]}},"alternative-id":["2076"],"URL":"https:\/\/doi.org\/10.1186\/s13023-021-02076-w","relation":{},"ISSN":["1750-1172"],"issn-type":[{"value":"1750-1172","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,10,24]]},"assertion":[{"value":"21 August 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 October 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 October 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"All procedures contributing to this work complied with the ethical standards of the relevant national and international committees on human experimentation and with the Helsinki Declaration of 1975, as revised in 2008. The protocol was peer-reviewed in the Department of Psychiatry at the University of Cape Town and submitted for ethical approval by the Faculty of Health Sciences, Human Research Ethics Committee (Ethics Ref 340\/2015). Additional study sites obtained ethical approval or waivers from their respective HREC\/IRB bodies.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"This work was supported by a Ph.D. studentship from the Tuberous Sclerosis Association in the United Kingdom (Grant: 2014-S01) (LL), a project grant from the King Baudoin Foundation Fund Dr & Mrs Charles Tournay-Dubisson to PdV and AJ (2019-J1120010-213544), and by the National Research Foundation and Struengmann Fund, University of Cape Town (to PdV). The funding bodies played no role in the design of the study in collection, analysis, and interpretation of data, or in writing the manuscript. PdV was a study steering committee member of three phase III trials sponsored by Novartis. PdV and AJ are on the scientific advisory group of the TOSCA international disease registry sponsored by Novartis. MS reports grant support from Novartis, Roche, Biogen, Astellas, Aeovian, Bridgebio, Aucta and Quadrant Biosciences unrelated to this project. He has served on Scientific Advisory Boards for Roche, Celgene, Regenxbio, Alkermes and Takeda.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"447"}}