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. 2025 Jun 13;20(1):304.
doi: 10.1186/s13023-025-03642-2.

Validation of the self-report quantified Tuberous Sclerosis Complex-Associated Neuropsyciatric Disorders Checklist (TAND-SQ)

Nola Chambers  1 , Tosca-Marie Heunis  2 , Sugnet Gardner-Lubbe  3 , Jamie K Capal  4 , Stacey Bissell  5 , Anna W Byars  6 , Sebastián Cukier  7 , Peter E Davis  8 , Jennifer Flinn  9 , Tanjala T Gipson  10   11 , J Chris Kingswood  12   13 , Aubrey J Kumm  14 , Eva Schoeters  15   16 , Catherine Smith  17 , Shoba Srivastava  14   18 , Megumi Takei  19 , Stephanie Vanclooster  2   20 , Agnies M van Eeghen  21   22 , Robert Waltereit  23   24 , Darcy A Krueger  25   26 , Mustafa Sahin  8   27 , Liesbeth De Waele  28   29 , Anna C Jansen  2   30   31 , Petrus J de Vries  14
Affiliations

Validation of the self-report quantified Tuberous Sclerosis Complex-Associated Neuropsyciatric Disorders Checklist (TAND-SQ)

Nola Chambers et al. Orphanet J Rare Dis. .

Abstract

Background: Tuberous Sclerosis Complex (TSC) is a rare multi-system genetic disorder characterised by benign growths in multiple body systems. TSC-Associated Neuropsychiatric Disorders (TAND) are very common in individuals with TSC, but families often struggle to access appropriate clinical care. To address this gap, the new TAND-SQ Checklist allows individuals with TSC or their caregivers to self-report and quantify characteristics of TAND. The 33 items make up seven natural TAND clusters and an eighth cluster reflecting psychosocial difficulties in individuals with TSC and their caregivers. Respondents rate items as having ever been present to generate cluster scores (CS), and rate item severity (over the last month) on a 10-point scale to generate cluster severity scores (CSSmean) and a total TAND severity score (TTSSmean). The purpose of this study was to determine the reliability and validity of the CS, CSSmean and TTSSmean of the TAND-SQ.

Methods: A descriptive group design was used. Two convenience samples with existing clinical data were recruited from the TSC Alliance Natural History Database (NHD) in the USA (n = 69), and from the Developmental Synaptopathies Consortium Rare Diseases Clinical Research Network (RDCRN) study based at Boston and Cincinnati Children's Hospitals (n = 23), totalling 92 participants.

Results: Analyses showed good internal consistency for CS (Cronbach's alphas: 0.67-0.89) and CSSmean (0.76-0.95) with the exception of the eat/sleep cluster. Within the TAND-SQ, most CS and all CSSmean were significantly correlated to corresponding self-reported clinical diagnoses, and the TTSSmean was significantly correlated to a global self-rating of TAND burden (ρ = 0.75; p < .001). Significant correlations were observed between the CS and CSSmean and a range of relevant standardised behavioural measures in the RDCRN cohort. The TTSSmean was significantly correlated with global measures of adaptive behaviour (ρ = - 0.75; p < .001) and emotional/behavioural difficulties (ρ = 0.71; p = .001). All CS were significantly correlated with corresponding diagnoses of autism, ADHD, anxiety disorder, depressive disorder, scholastic difficulties, and neuropsychological difficulties where reported in the RDCRN and NHD cohorts.

Conclusions: Findings provide support for the reliability and validity of the CS, CSSmean and TTSSmean of the TAND-SQ and support their use in clinical decision-making for TAND management and in further research.

Keywords: Reliability; TAND; TAND-SQ Checklist; TSC-Associated Neuropsychiatric Disorders; Tuberous Sclerosis Complex; Validity.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: This study was approved by the Human Research Ethics Committee (HREC) at the University of Cape Town, South Africa (HREC reference number: 849/2020), the site of the principal investigator, and at the Vrije Universiteit Brussel, Belgium (BUN: 1432022000037), the site of the co-principal investigator. It was also approved by the Ethical and Independent Review Services for the Natural History Database Study (protocol number 15039-08) in the United States which permitted use of deidentified clinical data for TSC research at the TSC Alliance, and by the BCH Institutional Review Board (IRB, IRB-P00041212). For BCH and CCH sites, BCH agreed to serve as the reviewing IRB for this study and CCH (IRB number 2022-0421) agreed to cede IRB review to the BCH IRB. All TSC Alliance participants, and BCH and CCH participants were asked to provide informed consent before participating in this study. As part of the TANDem project, all participating data collection sites signed a data transfer agreement which ensured secure sharing of pseudonymised data. Competing interests: JC receives grant funding from the NIH and the Department of Defense for projects related to TSC and sits on the Scientific Advisory Committee for Marinus Pharmaceuticals in relation to TSC studies. SB receives grant funding from the TSA UK and Baily Thomas Charitable Fund for projects related to TSC. PD receives partial salary support from the NIH for participation in studies related to TSC, as well as from Aucta Pharmaceuticals for a study of topical sirolimus for facial angiofibromas in TSC and Marinus Pharmaceuticals for a study of ganaxolone for TSC‑related epilepsy. CS receives salary support from the TSC Alliance, a non‑profit organization that reports revenue from individual donors and corporations including Aeovian, BridgeBio, Jazz, LivaNova, Longboard, Mallinckrodt, Marinus, Neurelis, Nobelpharma, Noema, UCB, and Upsher-Smith. AvE is on the scientific advisory board and received grant support from Jazz Pharmaceuticals. She is also a member of ERN ITHACA. DAK reports grants from the National Institutes of Health (NINDS) and Food and Drug Administration (FDA) during the conduct of the study as well as research grants from Jazz Pharmaceuticals and personal fees from Longboard Pharmaceuticals, and grants and non‑financial support from TSC Alliance outside the submitted work. MS reports grant support from Novartis, Biogen, Astellas, Aeovian, Bridgebio, and Aucta and has served on Scientific Advisory Boards for Novartis, Roche, Regenxbio, SpringWorks Therapeutics, Jaguar Therapeutics, and Alkermes. ACJ was on the scientific advisory group of the TOSCA international disease registry sponsored by Novartis and Marinus Trust, and has provided consultancy to Jazz Pharmaceuticals and Aeovian. PJdV was a study steering committee member of three phase III trials in TSC sponsored by Novartis, was on the scientific advisory group of the TOSCA international disease registry sponsored by Novartis, and has provided consultancy to Jazz Pharmaceuticals. The remaining authors declared no competing interests.

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