Background
Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder characterized by the formation of hamartomas in multiple organ systems with a wide diversity of symptoms and severity across individuals [
1,
2]. The majority of individuals with TSC have central nervous system involvement with a wide range of structural manifestations, such as cortical tubers, subependymal nodules, and aberrations of gray and white matter as well as high rates of functional manifestations, such as epilepsy, intellectual disability (ID), and behavioural problems [
3‐
5]. The neurological, neuropsychiatric, and renal manifestations represent the greatest burden of disease of all TSC-related manifestations [
3].
TSC-associated neuropsychiatric disorders (TAND) is an umbrella term coined by the Neuropsychiatry Panel of the 2012 International Consensus Conference for TSC, and encompasses a range of neuropsychiatric manifestations across various levels of investigation [
2,
3,
5]. These include the behavioural level (observed behaviours such as sleep problems or aggressive behaviours), the psychiatric level (DSM/ICD defined psychiatric disorders such as autism spectrum disorders [ASD] or attention deficit hyperactivity disorder [ADHD]), the intellectual level (intellectual ability as defined by intelligence quotient [IQ]-type tests), the academic level (learning disorders, e.g., reading or mathematics difficulties), and the psychosocial level (e.g., self-esteem, family difficulties) [
3,
5,
6]. TAND represent a significant burden of disease and have a major impact on quality of life of individuals with TSC and their families, given their impact on education, employment, and social life of patients and their family [
3,
5].
The rate and pattern of TAND vary greatly among patients with TSC [
3,
5,
7‐
11]. Overall, about 90% of individuals with TSC exhibit TAND features to some extent during their lifetime, with ASD and ID reported in up to 50% of individuals [
3,
5,
6]. Results show differential rates in those with and without ID [
12]. However, even individuals with normal intellectual abilities are at risk of developing TAND manifestations, particularly in the academic, neuropsychological, and psychosocial domains [
8]. Despite the high rates of TAND, a 2010 survey of members of the Tuberous Sclerosis Association in the United Kingdom indicated that only 20% of individuals with TSC had ever received any assessment or treatment for TAND, suggesting a large assessment and treatment gap [
5,
6,
12,
13]. It is important to acknowledge that the majority of evidence for rates and patterns of TAND to date have come from relatively small studies and case reports. The largest published studies to date have included a few hundred participants [
10,
12,
14]. Furthermore, very little TAND data are available about adults with TSC [
15] or about the age-based pattern of TAND.
The underlying aetiology of TAND is likely to be combinatorial and multifactorial [
16]. There is evidence that the genetic aberrations of TSC may be sufficient to cause TAND manifestations, [
16,
17] with combinatorial and interactive contribution from functional and structural factors [
16‐
22]. Individuals with
TSC2 mutations have been reported to have a greater likelihood of ID than those with
TSC1, [
23‐
26] but both
TSC1 and
TSC2 mutations have been associated with the full range of intellectual ability from high IQ to profound ID [
25,
26]. Individuals with no mutation identified (NMI) after genetic testing have typically been described to have ID profiles between those with
TSC1 and
TSC2 [
23‐
26]. These studies have also been based on relatively small samples and no study to date has examined other aspects of TAND in relation to genotype.
The largest natural history study of TSC to date – the TOSCA (TuberOus SClerosis registry to increase disease Awareness) study is a multi-centre, international disease registry designed with the aim of providing deeper insights into the manifestations of TSC and its management [
27,
28]. In a previous publication outlining baseline findings from the TOSCA cohort of 2093 individuals, we presented topline findings of TAND features in the largest TSC cohort reported globally to date [
28]. Results showed that ID was observed in 54% of the evaluated participants and suggested that psychiatric disorders were typically diagnosed late. We also identified significant non-reported or missing data, which suggested that even in expert TSC centres around the globe, TAND may be underdiagnosed and therefore under-treated [
28].
Here, we performed a detailed exploration of the largest TAND dataset to date using TOSCA baseline data of all the patients enrolled at the cut-off of September 30, 2015, with the specific aim of comparing childhood and adult TAND profiles, describing the age-related pattern of TAND, and examining TAND in relation to genotype.
Methods
A detailed description of the methods of the TOSCA registry has been provided previously [
27]. In short, individuals of any age with a documented visit for TSC before 12 months of enrollment or newly diagnosed with TSC were included in the study between August 2012 and August 2014.
Information on participant demography, family history, genotype, vital signs, prenatal history, clinical features of TSC across all organ systems, comorbidities, and rare manifestations were collected, both retrospectively and prospectively at baseline and annually thereafter for up to 5 years. Given that this was a natural history study, participants were followed up based on clinical need, and no clinical, laboratory or formal TAND evaluations were mandated by the protocol. The terms and operationalization of TAND manifestations and ‘levels’ were defined as in the primary TAND publication [
5].
The TOSCA registry was designed and conducted in accordance with the Guidelines for Good Clinical Practice and ethical principles outlined in the Declaration of Helsinki [
29,
30]. Written informed consent, with prior endorsement by all local institutional review boards (human research ethics committees) was obtained from all participants, parents, or guardians prior to registry enrollment.
For the purposes of this manuscript, descriptive statistics were used to summarize TAND data. Frequency of TAND features were extracted and presented as percentage of individuals with available data (excluding non-reported or missing data). Intellectual ability was categorized as normal (IQ > 70), mild ID (IQ 51–70), moderate ID (IQ 36–50), severe ID (IQ 20–35), and profound ID (IQ < 20), according to DSM-5/ICD-10 [
31,
32]. Psychiatric disorders were defined according to the DSM-5/ICD-10. Age-based patterns of TAND (children vs adults) and the association between TAND and genotype (
TSC1 vs
TSC2) were analyzed using Chi-square test. The TOSCA study included data collection on all levels of TAND as outlined above and summarised in the primary TAND manuscript [
5], apart from psychosocial characteristics, such as self-esteem, sibling, or family stressors, which were only included after the TOSCA database was set up.
Discussion
The TOSCA registry allowed exploration of the frequency of a wide range of TAND features in the largest cohort of TSC reported to date. We set out to examine the overall TAND profile, to compare childhood and adult patterns, age-based patterns, and genotype-TAND correlations. Results showed lower rates of behavioural and psychiatric disorders than previously reported, but similar rates of ID [
3,
6,
8,
12]. The very high rates of non-reported or missing data in this study (in excess of 60% for behavioural and intellectual levels) may, at least in part, have contributed to the lower rates observed. The rates of academic difficulties and neuropsychological deficits, reported in this study for the first time, were very high and suggested that between half and two-thirds of individuals with TSC will have difficulties in these two TAND levels. In spite of relatively similar rates of ID between children and adults, we observed a pattern of higher overactivity and impulsivity in children, and higher rates of anxiety and depressed mood in adults. Interestingly, some TAND characteristics such as sleep problems and severe aggression remained high across all age bands, suggesting persistence of these difficulties across the lifespan. With regards to genotype-TAND correlations, we observed a genotype-intellectual phenotype correlation and a higher frequency of ASD in association with
TSC2, similar to previous reports [
8,
26]. Interestingly, fewer other TAND-genotype correlations were observed. Self-injury, ASD, academic difficulties and neuropsychological deficits were the only other significant correlations with
TSC2. Given that all of these are known to be strongly correlated with intellectual level [
12], and given the differences observed here in IQ groups, these results have to be treated with caution and should be explored in relation to matched or stratified IQ groups in future studies. We also observed a potential pattern of more depressed and anxious mood, and higher rates of anxiety and depressive disorders in association with
TSC1 mutations. This was a novel observation not previously reported in the literature, but the same caveat in relation to IQ as potential confounder requires exploration in future studies. The TAND profile of individuals with NMI was also a novel finding. Intellectual, academic and neuropsychological profiles seemed to fall between the frequencies of those with
TSC1 and
TSC2 mutations, mapping onto intellectual findings previously reported [
8,
26]. However, the same pattern was not seen in behavioural and psychiatric manifestations.
About 7% of individuals in the general population are expected to have clinically significant behavioural problems [
33]. However, much higher rates of behavioural difficulties are reported in patients with TSC [
7]. In a pilot validation study of the TAND checklist, all the participants (
n = 62) had reported at least one lifetime TAND behavioural difficulty, 97% had ≥2 behavioural difficulties and 89% reported ≥6 behavioural difficulties [
6]. The findings in this large-scale international study confirm the high rates of a wide range of behavioural problems in TSC. The comparison between children and adults showed a pattern of lower overactive/impulsive behaviours in adults but higher anxiety or depressed mood. These findings map well onto typical age-based expectations in psychopathology [
8,
9,
12]. However, our results also highlighted the fact that behavioural difficulties occurred across all ages in individuals with TSC. These findings underline the importance of expecting and evaluating for a changing profile of TAND difficulties from childhood into adulthood, as recommended in TAND assessment guidelines [
2,
34,
35].
Among the psychiatric problems associated with TSC, ASD, and ADHD are the most common neurodevelopmental disorders in children, and anxiety/mood disorders the most common in adults [
8]. The variable rates of ASD (17–68%) and ADHD (30–60%) reported in earlier studies can be understood based on different study methodologies, diagnostic criteria used, and level of intellectual ability of participants [
7,
8,
36]. In this study, ASD and ADHD were reported in 21.1% and 19.1% of participants, respectively. As highlighted in our baseline paper [
27] the diagnosis of ASD, in particular, was made very late (mean age, 7.8 years; median age, 5 years; range, 0–38 years) [
28]. In spite of very high rates of anxiety and depressed mood symptoms in the cohort, the rates of diagnoses of anxiety disorders or depressive disorders were surprisingly low in our study (anxiety disorder, 9.7%; depressive disorder, 6.1%). Taking together the high rates of non-reported or missing data, late ages of diagnoses and frequencies observed in our cohort, we suggest that psychiatric disorders are underdiagnosed and potentially diagnosed late in individuals with TSC. The low rates of ASD and ADHD observed in adults here, may suggest a cohort effect where adults were not assessed for developmental disorders in the past decades.
In line with previous reports, [
8,
26,
37] the TOSCA registry showed a genotype-intellectual phenotype pattern suggesting a greater likelihood of ID in participants with
TSC2 than those with
TSC1 mutations. However, it was also important to note that only 66.7% of those with
TSC1 had normal intellectual ability, suggesting that a third of individuals with
TSC1 may have ID. Similarly, even though
TSC2 mutations were more likely to be associated with ID, 42% of all individuals with
TSC2 mutations had normal intellectual ability. Our findings therefore reinforce the message that genotype (
TSC1 vs
TSC2) is not a clinically helpful predictor of intellectual ability at an individual level [
26].
The differences between those with
TSC1 and
TSC2 mutations observed in other aspects of TAND were of interest, particularly as all previous genotype-phenotype studies have suggested a more “severe” phenotype associated with
TSC2 [
38]. The possibility that specific aspects of TAND may be more likely in association with
TSC1 is therefore a potentially important observation. We acknowledge that a
TSC1 vs
TSC2 differentiation may be highly oversimplistic, given that specific TSC mutations may be associated with very different functional consequences at a biochemical level [
16,
26].
The challenge around unreported and missing TAND data in this study was significant. Fewer than 40% of behavioural data were available and only 39.9% of participants in the TOSCA registry received an evaluation of their intellectual ability. The overall rates of ID were consistent with previous studies, [
8,
12] but we did not observe a bimodal distribution of intellectual ability as previously reported [
23,
25,
39,
40]. Given that only about half of the TOSCA cohort received a formal evaluation for IQ, it is possible that more severely impaired individuals may not have been referred for an assessment of their intellectual or developmental quotient (as was done in the population-based study that observed the clear bimodal pattern) [
39]. Academic data were not reported or were missing in 43.4% of the cohort and 38.9% were not reported or were missing regarding neuropsychological skills. Only 48.8% of those with academic difficulties ever received evaluations, and only 41.6% were evaluated for neuropsychological deficits. Whilst the very high rates of academic and neuropsychological deficits in TSC were a novel finding in the TOSCA registry and underlines the recommendation that all children with TSC should receive evaluation of their academic and neuropsychological needs, [
2,
35] the very low proportion assessed raises significant clinical concern.
Acknowledgements
We thank patients and their families, investigators, and staff from all the participating sites. We thank Manojkumar Patel, Novartis Healthcare Pvt. Ltd. for providing medical editorial assistance with this manuscript.
TOSCA Investigators
Japan: Nobuo Shinohara, Shigeo Horie, Masaya Kubota, Jun Tohyama, Katsumi Imai, Mari Kaneda, Hideo Kaneko, Yasushi Uchida, Tomoko Kirino, Shoichi Endo, Yoshikazu Inoue, Katsuhisa Uruno; Turkey: Ayse Serdaroglu, Zuhal Yapici, Banu Anlar, Sakir Altunbasak; Russia: Olga Lvova, Oleg Valeryevich Belyaev, Oleg Agranovich, Elena Vladislavovna Levitina, Yulia Vladimirovna Maksimova, Antonina Karas; China: Yuwu Jiang, Liping Zou, Kaifeng Xu, Yushi Zhang, Guoming Luan, Yuqin Zhang, Yi Wang, Meiling Jin, Dingwei Ye, Weiping Liao, Liemin Zhou, Jie Liu, Jianxiang Liao, Bo YAN, Yanchun Deng, Li Jiang, Zhisheng Liu, Shaoping Huang, Hua Li; Korea: Kijoong Kim; Taiwan: Pei-Lung Chen, Hsiu-Fen Lee, Jeng-Dau Tsai, Ching-Shiang Chi, Chao-Ching Huang; Australia: Kate Riney, Deborah Yates, Patrick Kwan; Thailand: Surachai Likasitwattanakul, Charcrin Nabangchang, Lunliya Thampratankul Krisnachai Chomtho, Kamornwan Katanyuwong, Somjit Sriudomkajorn; South Africa: Jo Wilmshurst; Israel: Reeval Segel, Tal Gilboa, Michal Tzadok, Aviva Fattal- Valevski; Greece: Panagiotis Papathanasopoulos, Antigone Syrigou Papavasiliou, Stylianos Giannakodimos, Stylianos Gatzonis, Evangelos Pavlou, Meropi Tzoufi; Netherlands: A.M.H. Vergeer; Belgium: Marc Dhooghe, Hélène Verhelst, Filip Roelens, Marie Cecile Nassogne, Pierre Defresne, Liesbeth De Waele, Patricia Leroy, Nathalie Demonceau, Benjamin Legros, Patrick Van Bogaert, Berten Ceulemans, Lina Dom; France: Pierre Castelnau, Anne De Saint Martin, Audrey Riquet, Mathieu Milh, Claude Cances, Jean-Michel Pedespan, Dorothee Ville, Agathe Roubertie, Stéphane Auvin, Patrick Berquin, Christian Richelme, Catherine Allaire, Sophie Gueden, Sylvie Nguyen The Tich, Bertrand Godet; Spain: Maria Luz Ruiz Falco Rojas, Jaume Campistol Planas, Antonio Martinez Bermejo, Patricia Smeyers Dura, Susana Roldan Aparicio, Maria Jesus Martinez Gonzalez, Javier Lopez Pison, Manuel Oscar Blanco Barca, Eduardo Lopez Laso, Olga Alonso Luengo, Francisco Javier Aguirre Rodriguez, Ignacio Malaga Dieguez, Ana Camacho Salas, Itxaso Marti Carrera, Eduardo Martinez Salcedo, Maria Eugenia Yoldi Petri, Ramon Cancho Candela; Portugal: Ines da Conceicao Carrilho, Jose Pedro Vieira, José Paulo da Silva Oliveira Monteiro, Miguel Jorge Santos de Oliveira Ferreira Leao, Catarina Sofia Marceano Ribeiro Luis, Carla Pires Mendonca; Lithuania: Milda Endziniene; Latvia: Jurgis Strautmanis; Estonia: Inga Talvik; Italy: Maria Paola Canevini, Antonio Gambardella, Dario Pruna, Salvatore Buono, Elena Fontana, Bernardo Dalla Bernardina; Romania: Carmen Burloiu, Iuliu Stefan Bacos Cosma, Mihaela Adela Vintan, Laura Popescu; Czech Republic: Karel Zitterbart; Slovakia: Jaroslava Payerova, Ladislav Bratsky, Zuzana Zilinska; Austria: Ursula Gruber-Sedlmayr, Matthias Baumann, Edda Haberlandt, Kevin Rostasy, Ekaterina Pataraia; United Kingdom: Frances Elmslie, Clare Ann Johnston, Pamela Crawford; Denmark: Peter Uldall; Sweden: Paul Uvebrant, Olof Rask; Norway: Marit Bjoernvold, Eylert Brodtkorb, Andreas Sloerdahl, Ragnar Solhoff, Martine Sofie Gilje Jaatun; Poland: Marek Mandera, Elzbieta Janina Radzikowska, Mariusz Wysocki; Germany: Michael Fischereder, Gerhard Kurlemann, Bernd Wilken, Adelheid Wiemer-Kruel, Klemens Budde, Klaus Marquard, Markus Knuf, Andreas Hahn, Hans Hartmann, Andreas Merkenschlager, Regina Trollmann.
Ethics approval and consent to participate
All patients (or their legal representatives) provided written informed consent before enrolling in the TOSCA disease registry. The study was designed, implemented, and reported in accordance with the principles of Good Clinical Practice, Good Pharmacoepidemiology Practices of the International Society for Pharmacoepidemiology (ISPE 2008), the STROBE (Strengthening and Reporting of Observational Studies in Epidemiology) guidelines, and the ethical principles laid down in the Declaration of Helsinki, and all local regulations. The study protocol and all amendments were reviewed and approved (if applicable) by independent ethics committee/institutional review board for each center: National Hospital Organization Central Ethics Committee; Gazi University Clinical Research Ethics Committee; Independent Multidisciplinary Committee on Ethical Review of Clinical Trials; Peking Union Medical College Hospital; Commissie Medische Ethiek UZ Brussel; CNIL (Commission National de l’Informatique et des Libertés), CCTIRS (Comité Consultatif sur le traitement de l’information en matière de recherche dans le domaine de la santé); Comité Etico Investigación Clínica de Euskadi (CEIC-E); Consejeria de Salud y Bienestar Social, Dirección General de Calidad, Investigación, Desarrollo e Innovación, Comité Coordinador de Ética de la Investigación Biomédica de Andalucía; Research Ethics Committee of the University of Tartu (UT REC); Ethikkommission der Medizinischen Universität Graz; North Wales REC – West; Regionala Etikprövningsnämnden i Göteborg; REK – Regionale komiteer for medisinsk og helsefaglig forskningsetikk; Komisja Bioetyczna przy Instytucie “Pomnik Centrum Zdrowia Dziecka”; Ethikkommission bei der Ludwig-Maximilians-Universitat München; Hokkaido University Hospital Independent clinical research Institutional Ethics Committee; Medical Juntendo University Institutional Ethics Committee; National Center for Chile Health and Deveropment of IRB; Osaka University Hospital of IRB; Ethics Committee at Moscow Institute of Pediatrics and Pediatric Surgery; Peking University First Hospital; Sanbo Brain Hospital Capital Medical University; Tianjin Children’s Hospital; Childrens Hospital Of Fudan University; Zhongshan Hospital Fudan University; Fudan University Shanghai Cancer Center; The Second Affiliated Hospital of Guangzhou Medical University; The First Affiliated Hospital, Sun Yan-Sen University; The First Affiliated Hospital Of Guangzhou Medical University; Shenzhen Children’s Hospital; West China Hospital, Sichuan University; Xijing Hospital; Children’s Hospital of Chongqing Medical University; Wuhan Children’s Hospital; The second affiliated hospital of Xi’an jiaotong university; Guangdong 999 brain hospital; Seoul National University Hospital Institutional Review Board; National Taiwan University Hospital (NTUH) Research Ethics Committee (REC); Institutional Review Board of the Taichung Veterans General Hospital; Institutional Review Board of Chung Shan Medical University Hospital; Institutional Review Board, Tungs’ Taichung MetroHarbor Hospital; Institutional Review Board of National Cheng Kung University Hospital; Metro South Human Research Ethics Committee; Sydney Children’s Hospital Network Human Research Ethics Committee; St Vincents Hospital Human Research Ethics Committee; Royal Melbourne Hospital Human Research Ethics Committee; Siriraj Institutional Review Board; The Institutional Review board, Faculty of Medicine, Chulalongkorn University, 3rd Floor, Ananthamahidol Building, King Chulalongkorn Memorial Hospital; The committee on Human Rights Related to Research Involving Human Subjects; Institutional Review board, Royal Thai Army Medical Department IRB RTA, 5th Floor, Phramongkutklaowejvitya Building, Phramongkutklao College of Medicine; Research Ethics Committee, Faculty of Medicine, Chiang Mai University; Research and Development, Queen Sirikit National Institute of Child Health; Human Research Ethics Committee, Faculty of Health Sciences, University of Cape Town; Shaare Zedek Meidcla center Helsinki comittee; Sheba Medical center Helsinki comittee; Tel Aviv Sourasly Medical center Helsinki comittee; General University Hospital of Patras Ethics Committee; Pendeli Children’s Hospital Ethics Committee; General University Hospital of Athens “G. Gennimatas” Ethics Committee; Evaggelismos General Hospital Ethics Committee; General University Hospital of Thessaloniki “AHEPA” Ethics Committee; General University Hospital of Ionnina Ethics Committee; METC UMC Utrecht; Direcció General de Regulació, Planificació i Recursos Sanitaris; Comité Ético de Investigación Clínica del Hospital Universitario Vall d’Hebron de Barcelona, Generalitat de Catalunya.Departament de Salut; Comité Ético de Investigación Clínica Hospital Universitario La Paz; Dirección General de Ordenación e Inspección, Consejería de Sanidad Comunidad de Madrid, Servicios de Control Farmacéutico y Productos Sanitarios; Comité Etico Investigación Clínica del Hospital Universitario y Politécnico de La Fe; Dirección General de Farmàcia i Productes Sanitaris, Generalitat de Valencia; Comité de Ética de la Investigación de Centro de Granada; Instituto Aragonés de Ciencias de la Salud (IACS);; Comité Etico Investigación Clínica Regional del Principado de Asturias;; Comité Etico Investigación Clínica Hospital 12 de Octubre;, Comité Etico Investigación Clínica Hospital Universitario Virgen de la Arrixaca;; Sección de Ordenación e Inspección Farmacéutica Departamento de Salud; Comité Ético de Investigación Clínica del Hospital Universitario del Río Hortega de Valladolid;, Comissão de Ética para a Saúde (CES), Centro Hospitalar de Lisboa Ocidental, EPE; Comissão de Ética para a Saúde (CES), Centro Hospitalar do Porto, E.P.E; Comissão de Ética para a Saúde (CES), Centro Hospitalar Lisboa Central, EPE; Comissão de Ética para a Saúde (CES), Hospital Garcia de Orta, EPE; Comissão de Ética para a Saúde (CES), Centro Hospitalar de São João, EPE; Comissão de Ética para a Saúde (CES), Hospital Professor Doutor Fernando Fonseca, EPE; Comissão de Ética para a Saúde (CES), Centro Hospitalar do Algarve, EPE (Unidade de Faro); LUHS Kaunas Regional Biomedical Research Ethics Committee; Paula Stradiņa klīniskās universitātes slimnīcas, Attīstības biedrības Klīniskās izpētes Ētikas komiteja, Ethics Committee for Clinical Research; Komisija Republike Slovenije za medicinsko etiko; Comitato Etico Indipendente Presso La Fondazione Ptv Policlinico Tor Vergata Di Roma; Comitato Etico Regione Calabria Sezione Centro c/o A.O.U. Mater Domini Di Catanzaro; Comitato Etico Azienda Ospedaliera Universitaria Di Cagliari; Comitato Etico Cardarelli-Santobono c/o Ao Cardarelli; Comitato Etico Per La Sperimentazione Clinica Delle Province Di Verona E Rovigo, Presso Aoui Verona; Eticka Komise Fn Brno; Eticka Komisia Dfnsp Bratislava; Eticka Komisia Pri Dfn Kosice; Eticka Komisia Bratislavskeho Samospravneho Kraja; Comisia Națională de Bioetică a Medicamentului și a Dispozitivelor Medicale; Comitato Etico Milano area 1 c/o ASST FBF Sacco - P.O. L. Sacco; Comité de Ética de la Investigación de Centro Hospital Universitario Virgen del Rocío; Comité Ético de Investigación Clínica Fundació Sant Joan de Déu Generalitat de Catalunya. Departament de Salut; Comité Ético de Investigación Clínica Hospital Infantil Universitario Niño Jesús; Consejería de Sanidad Dirección General de Salus Pública Junta de Castilla León; Dirección General de Asistencia Sanitaria, Consejería de Sanidad Gobierno del Principado de Asturias; Dirección General de Planificación, Ordenación Sanitaria y Farmacéutica e Investigación, Consejeria de Sanidad y Política Social Región de Murcia; Ethics Committee at Moscow Institute of Pediatrics and Pediatric Surgery; Paula Stradiņa klīniskās universitātes slimnīcas, Attīstības biedrības Klīniskās izpētes Ētikas komiteja, Ethics Committee for Clinical Research; The First Affiliated Hospital of The Fourth Military Medical University; Zhongshan hospital fudan university.
Competing interests
P.J.dV., E.B., T.C., V.C., P.C., G.B.d’A., J.C.K., J.C.F., M.F., C.F., C.H., S.J., R.N., F.O’C, J.Q., M.S., R.T., M.D., J.A.L., A.M., S.Y., M.P.B., B.Z. and A.C.J. received honoraria and support for the travels from Novartis. V.C. received personal fees for consulting, lecture fees and travel from Actelion, Bayer, Biogen Idec, Boehringer Ingelheim, Gilead, GSK, MSD, Novartis, Pfizer, Roche, Sanofi; grants from Actelion, Boehringer Ingelheim, GSK, Pfizer, Roche; personal fees for developing educational material from Boehringer Ingelheim and Roche. P.J.dV. has been on the study steering group of the EXIST-1, 2 and 3 studies sponsored by Novartis, and co-PI on two investigator-initiated studies part-funded by Novartis. RN received grant support, paid to her institution, from Eisai and lectures fees from Nutricia, Eisai, Advicenne and GW Pharma. Y.T. received personal fee from Novartis for lecture and for copyright of referential figures from the journals, and received grant from Japanese government for intractable epilepsy research. S.J. was partly financed by the EC Seventh Framework Programme (FP7/2007–2013; EPISTOP, grant agreement no. 602391), the Polish Ministerial funds for science (years 2013–2018) for the implementation of international cofinanced project and the grant EPIMARKER of the Polish National Center for Research and Development No STRATEGMED3/306306/4/2016. J.C.K., P.C., C.H., J.A.L., and J.Q. received research grant from Novartis. R.M., L.D’A. and S.S. are employees of Novartis. V.S. reported no competing interest. This study was funded by Novartis Pharma AG. All authors approved the final version of the manuscript prior to submission.