Natural clusters of tuberous sclerosis complex (TSC)-associated neuropsychiatric disorders (TAND): new findings from the TOSCA TAND research project
Authors: de Vries Petrus J. , Belousova Elena , Benedik Mirjana P. , Carter Tom , Cottin Vincent , Curatolo Paolo , D’Amato Lisa , Beure d’Augères Guillaume , Ferreira José C. , Feucht Martha , Fladrowski Carla , Hertzberg Christoph , Jozwiak Sergiusz , Lawson John A. , Macaya Alfons , Marques Ruben , Nabbout Rima , O’Callaghan Finbar , Qin Jiong , Sander Valentin , Sauter Matthias , Shah Seema , Takahashi Yukitoshi , Touraine Renaud , Youroukos Sotiris , Zonnenberg Bernard , Kingswood J. Chris , Jansen Anna C. ,   on behalf of TOSCA Consortium and TOSCA Investigators, Shinohara Nobuo , Horie Shigeo , Kubota Masaya , Tohyama Jun , Imai Katsumi , Kaneda Mari , Kaneko Hideo , Uchida Yasushi , Kirino Tomoko , Endo Shoichi , Inoue Yoshikazu , Uruno Katsuhisa , Serdaroglu Ayse , Yapici Zuhal , Anlar Banu , Altunbasak Sakir , Lvova Olga , Belyaev Oleg Valeryevich , Agranovich Oleg , Levitina Elena Vladislavovna , Maksimova Yulia Vladimirovna , Karas Antonina , Jiang Yuwu , Zou Liping , Xu Kaifeng , Zhang Yushi , Luan Guoming , Zhang Yuqin , Wang Yi , Jin Meiling , Ye Dingwei , Liao Weiping , Zhou Liemin , Liu Jie , Liao Jianxiang , Yan Bo , Deng Yanchun , Jiang Li , Liu Zhisheng , Huang Shaoping , Li Hua , Kim Kijoong , Chen Pei-Lung , Lee Hsiu-Fen , Tsai Jeng-Dau , Chi Ching-Shiang , Huang Chao-Ching , Riney Kate , Yates Deborah , Kwan Patrick , Likasitwattanakul Surachai , Nabangchang Charcrin , Chomtho Lunliya Thampratankul Krisnachai , Katanyuwong Kamornwan , Sriudomkajorn Somjit , Wilmshurst Jo , Segel Reeval , Gilboa Tal , Tzadok Michal , Fattal-Valevski Aviva , Papathanasopoulos Panagiotis , Papavasiliou Antigone Syrigou , Giannakodimos Stylianos , Gatzonis Stylianos , Pavlou Evangelos , Tzoufi Meropi , Vergeer A. M. H. , Dhooghe Marc , Verhelst Hélène , Roelens Filip , Nassogne Marie Cecile , Defresne Pierre , De Waele Liesbeth , Leroy Patricia , Demonceau Nathalie , Legros Benjamin , Van Bogaert Patrick , Ceulemans Berten , Dom Lina , Castelnau Pierre , Martin Anne De Saint , Riquet Audrey , Milh Mathieu , Cances Claude , Pedespan Jean-Michel , Ville Dorothee , Roubertie Agathe , Auvin Stéphane , Berquin Patrick , Richelme Christian , Allaire Catherine , Gueden Sophie , Tich Sylvie Nguyen The , Godet Bertrand , Rojas Maria Luz Ruiz Falco , Planas Jaume Campistol , Bermejo Antonio Martinez , Dura Patricia Smeyers , Aparicio Susana Roldan , Gonzalez Maria Jesus Martinez , Pison Javier Lopez , Barca Manuel Oscar Blanco , Laso Eduardo Lopez , Luengo Olga Alonso , Rodriguez Francisco Javier Aguirre , Dieguez Ignacio Malaga , Salas Ana Camacho , Carrera Itxaso Marti , Salcedo Eduardo Martinez , Petri Maria Eugenia Yoldi , Candela Ramon Cancho , da Conceicao Carrilho Ines , Vieira Jose Pedro , da Silva Oliveira Monteiro José Paulo , de Oliveira Ferreira Leao Miguel Jorge Santos , Luis Catarina Sofia Marceano Ribeiro , Mendonca Carla Pires , Endziniene Milda , Strautmanis Jurgis , Talvik Inga , Canevini Maria Paola , Gambardella Antonio , Pruna Dario , Buono Salvatore , Fontana Elena , Bernardina Bernardo Dalla , Burloiu Carmen , Cosma Iuliu Stefan Bacos , Vintan Mihaela Adela , Popescu Laura , Zitterbart Karel , Payerova Jaroslava , Bratsky Ladislav , Zilinska Zuzana , Gruber-Sedlmayr Ursula , Baumann Matthias , Haberlandt Edda , Rostasy Kevin , Pataraia Ekaterina , Elmslie Frances , Johnston Clare Ann , Crawford Pamela , Uldall Peter , Dahlin Maria , Uvebrant Paul , Rask Olof , Bjoernvold Marit , Brodtkorb Eylert , Sloerdahl Andreas , Solhoff Ragnar , Jaatun Martine Sofie Gilje , Mandera Marek , Radzikowska Elzbieta Janina , Wysocki Mariusz , Fischereder Michael , Kurlemann Gerhard , Wilken Bernd , Wiemer-Kruel Adelheid , Budde Klemens , Marquard Klaus , Knuf Markus , Hahn Andreas , Hartmann Hans , Merkenschlager Andreas , Trollmann Regina 
Published: September 2020

Abstract
Background
Tuberous sclerosis complex (TSC)-associated neuropsychiatric disorders (TAND) have unique, individual patterns that pose significant challenges for diagnosis, psycho-education, and intervention planning. A recent study suggested that it may be feasible to use TAND Checklist data and data-driven methods to generate natural TAND clusters. However, the study had a small sample size and data from only two countries. Here, we investigated the replicability of identifying natural TAND clusters from a larger and more diverse sample from the TOSCA study.

Methods
As part of the TOSCA international TSC registry study, this embedded research project collected TAND Checklist data from individuals with TSC. Correlation coefficients were calculated for TAND variables to generate a correlation matrix. Hierarchical cluster and factor analysis methods were used for data reduction and identification of natural TAND clusters.

Results
A total of 85 individuals with TSC (female:male, 40:45) from 7 countries were enrolled. Cluster analysis grouped the TAND variables into 6 clusters: a scholastic cluster (reading, writing, spelling, mathematics, visuo-spatial difficulties, disorientation), a hyperactive/impulsive cluster (hyperactivity, impulsivity, self-injurious behavior), a mood/anxiety cluster (anxiety, depressed mood, sleep difficulties, shyness), a neuropsychological cluster (attention/concentration difficulties, memory, attention, dual/multi-tasking, executive skills deficits), a dysregulated behavior cluster (mood swings, aggressive outbursts, temper tantrums), and an autism spectrum disorder (ASD)-like cluster (delayed language, poor eye contact, repetitive behaviors, unusual use of language, inflexibility, difficulties associated with eating). The natural clusters mapped reasonably well onto the six-factor solution generated. Comparison between cluster and factor solutions from this study and the earlier feasibility study showed significant similarity, particularly in cluster solutions.

Conclusions
Results from this TOSCA research project in an independent international data set showed that the combination of cluster analysis and factor analysis may be able to identify clinically meaningful natural TAND clusters. Findings were remarkably similar to those identified in the earlier feasibility study, supporting the potential robustness of these natural TAND clusters. Further steps should include examination of larger samples, investigation of internal consistency, and evaluation of the robustness of the proposed natural clusters.