Deb K. Pal

Background: Sleep problems are common in young people with epilepsy and neurodevelopmental disorders, impacting learning, behaviour and family function. Sleep disturbances can trigger seizures, which in turn disrupt sleep, creating a vicious cycle. Available behavioural interventions have been designed and positively evaluated for typically developing children or selected neurodevelopmental disorder populations, but these do not address epilepsy-specific concerns. Most relevant interventions are delivered face to face by psychologists, limiting accessibility and scalability in the National Health Service. A digital intervention based on behavioural change techniques, adapted for parents of children with epilepsy, is a potential solution. Objectives: The overall aim was to broaden the perspective of the paediatric team managing young people with epilepsy beyond a narrow focus on seizures towards issues of importance to young people with epilepsy and their caregivers. To enable this, we (1) developed a core outcome set for childhood epilepsy research that was meaningful to children and their families and recommended candidate epilepsy-specific patient-reported outcome measures of children’s health-related quality of life and (2) produced an online behavioural intervention for sleep problems in young people with epilepsy, which we (3) evaluated using mixed-methods in a randomised controlled trial in the United Kingdom. Design: A systematic review and Delphi survey to identify items of the core outcome measure set, with steps toward identifying suitable core outcome measures (work package 1) and a randomised controlled trial with internal pilot (work package 4) of an online behavioural sleep intervention cocreated with parents and young people (work package 3). The trial was evaluated using both quantitative and qualitative methods (work package 2) and with a cost-effectiveness analysis (work package 4). Setting: Online and telephone survey of healthcare professionals. Online and in-person meetings of Delphi panel. Changing Agendas on Sleep, Treatment and Learning in Epilepsy Online Sleep Intervention was created in a university psychology lab. The clinical trial took place in 26 National Health Service paediatric outpatient clinics across the United Kingdom. Participants: Eighty-eight healthcare professionals completed a practice survey. One hundred and two stakeholders contributed to the core outcome set. Eighty-five children aged 4–12 years with clinician confirmed epilepsy and parent-reported sleep problems took part in the clinical trial. Interventions: Parental access to the Changing Agendas on Sleep, Treatment and Learning in Epilepsy Online Sleep Intervention online behavioural intervention plus standard care. The intervention arm was compared against standard care alone. Main outcome measures: The primary end point was total score on the Child Sleep Habits Questionnaire, 19-item version and incremental cost per quality-adjusted life-year gained. Results: Parent and clinician interviews before we designed the program highlighted a mismatch in patient expectations and healthcare providers’ capacity to meet specific health-related needs, including sleep problems. We developed a core outcome set for childhood epilepsy research, with multiple stakeholder input, comprising 10 domains and identified 2 leading candidate epilepsy-specific, patient-reported outcome measures of children’s health-related quality of life (work package 1). We also created an epilepsy-specific, online, parent-based behavioural intervention for sleep problems (Changing Agendas on Sleep, Treatment and Learning in Epilepsy Online Sleep Intervention) (work package 3). The internal pilot feasibility study demonstrated that parents’ treatment preferences would render a drug arm unfeasible and therefore a factorial drug/behaviour design was simplified to behaviour intervention versus standard care work package 4. Eighty-five children were randomised (42 standard care, 43 standard care + Changing Agendas on Sleep, Treatment and Learning in Epilepsy Online Sleep Intervention). The mean Child Sleep Habits Questionnaire score at 3 months did not differ significantly between standard care and standard care + Changing Agendas on Sleep, Treatment and Learning in Epilepsy Online Sleep Intervention groups [mean difference = 3.00 (1.46), 95% confidence interval 0.06 to 5.93, p = 0.05)]. There were no adverse effects in either group. We note that 20/43 families given access to Changing Agendas on Sleep, Treatment and Learning in Epilepsy Online Sleep Intervention did not engage with the core material. Reasons for this were explored in the qualitative assessments (work package 2) conducted at 3 and 6 months after randomisation. Twenty-two families participated in interviews. While Changing Agendas on Sleep, Treatment and Learning in Epilepsy Online Sleep Intervention content was described as ‘high quality’, one father reported being overwhelmed by the amount of information and noted that some of it conflicted with other sources. Engagement was further affected by time constraints and distractions. Four Changing Agendas on Sleep, Treatment and Learning in Epilepsy Online Sleep Intervention users also reported problems with parental sleep disruption and tiredness, including falling asleep, staying asleep, waking up or restless sleep. The economic analysis (work package 4) yielded an incremental cost-effectiveness ratio of £433,167 per quality-adjusted life-year gained and a probability of 0.01 for Changing Agendas on Sleep, Treatment and Learning in Epilepsy Online Sleep Intervention being cost-effective at a threshold of £20,000 per quality-adjusted life-year. The results of the full trial showed that the Changing Agendas on Sleep, Treatment and Learning in Epilepsy Online Sleep Intervention behavioural intervention plus standard care was not superior to standard care alone in improving parent report of child sleep problems in young people with epilepsy. However, there was a significant decrease of 16.5 minutes in child sleep onset latency between baseline and follow-up in the Changing Agendas on Sleep, Treatment and Learning in Epilepsy Online Sleep Intervention arm compared to standard care. Parental knowledge of child sleep also significantly increased in the intervention arm. Limitations: A significant proportion of participants randomised to the intervention did not engage with the online material. The health economics and secondary outcomes analyses were limited by large amounts of missing data in the final follow-up. Conclusions: These results suggest that an exclusive digital approach to solve sleep problems for children with epilepsy, despite objective efficacy, has limited effectiveness and cost-effectiveness as a public health strategy in the National Health Service. Future work: Future studies should evaluate a blended intervention of behaviour change techniques coached by paediatric epilepsy specialist nurses. Training in sleep management could be incorporated into secondary care mental health assessment and treatment. Trial registration: This trial is registered as ISRCTN13202325. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Programme Grants for Applied Research Programme (NIHR award ref: RP-PG-0615-20007) and is published in full in Programme Grants for Applied Research ; Vol. 14, No. 16. See the NIHR Funding and Awards website for further award information.

Background: Epilepsy in children presents challenges for families who must navigate the condition itself, along with complex medical information and the emotional realities of daily care. Underpinning a recent randomised control trial (CASTLE Sleep‐E) was the acknowledgement that sleep was a problem that had not been well addressed in other intervention studies in this population. The CASTLE Sleep‐E trial evaluated an online behavioural sleep intervention (CASTLE Online Sleep Intervention COSI]). An embedded qualitative study aimed to explore participating families' experiences of epilepsy, sleep and the trial itself. This paper focuses on the findings relating to participants' experiences of searching for information about sleep and epilepsy. Methods: Interpretive descriptive qualitative study embedded within a randomised controlled trial using remote interviews (October 2023 to February 2024) with parents ( n = 22) and children ( n = 22, aged 4–13 years) with epilepsy from both arms of the trial (COSI plus standard care or standard care alone). Data were reflexively thematically analysed. Patient and public involvement (parents and children) was central to both the main trial and this qualitative study. Findings: Five interrelated ‘information work’ themes were identified, four parent‐led themes: seeking information, surveillance as information work, sharing information and experiences, and struggling with information, and one child‐led theme: making sense of sleep and seizures. Conclusion: Many children with epilepsy and their parents become highly motivated information seekers; however, they face persistent gaps in credible, relevant and accessible guidance, particularly regarding the role of sleep in epilepsy. In response, they develop their own strategies for gathering, producing and interpreting information, often blending emotional labour, technology use and parental vigilance to improve sleep or address any sleep disturbance. These findings highlight a clear need for developing and implementing appropriate sleep support within paediatric epilepsy care. Patient or Public Contribution: Public and patient involvement (PPIE) was central to both the main trial and this qualitative study. A dedicated Advisory Panel (three children with epilepsy, ten parents of children with epilepsy and one adult who has lived with epilepsy since childhood) met regularly over a period of 6 years throughout the trial. Their insights and input shaped, informed and strengthened many aspects of our work from inception to dissemination, including refining the study aims and design, co‐developing materials and advising on data interpretation. Two of the Advisory Panel were co‐applicants on the programme grant. Advisory Panel members also contributed to the analysis and interpretation of qualitative data and reviewed the final manuscript for this paper, and their contributions are gratefully acknowledged. They were all compensated for their time and had any associated costs reimbursed. A more detailed account of PPIE is reported using the GRIPP2‐SF checklist.

The clinical utility of PRS may be hindered by reliance on large, heterogeneous data sets for generation that dilute phenotypic specificity. Meanwhile, small, well-defined clinical cohorts (target) are ubiquitous but insufficient for PRS development. We propose an external-PRS (ePRS) framework borrowing from the transfer learning literature that integrates genetic evidence from target cohorts, incorporating continuous evidence measures and genetic correlation for robust predictions. Simulation indicates superior performance of ePRS across varying genetic correlations between the source and target phenotypes. ePRS refines an idiopathic generalized epilepsy (IGE) PRS to improve differentiation between juvenile myoclonic epilepsy (JME) and other IGE subtypes and, leveraging a large attention deficit hyperactivity disorder GWAS, enhances predictions for impulsivity in JME. Finally, to address concerns about potential cross-platform artifacts, we train and evaluate ePRS in the Canadian Cystic Fibrosis (CF) Gene Modifier Study cohort to predict CF-related diabetes using UK Biobank type 2 diabetes (T2D) summary statistics as the external source phenotype. ePRS continues to improve prediction accuracy in this single-cohort, harmonized-QC setting and offers more precise risk stratification and personalized care across complex traits.

Rare Mendelian disorders affect 300-400 million people globally. Although genetic testing has become widely adopted, gene-specific evidence for tailored variant interpretation remains scattered across resources. We present Gene Portals, a framework for gene-centered multimodal knowledge bases that co-localize expert-harmonized clinical data, functional assays, population variation, structural annotations and gene-specific ACMG/AMP specifications within a single resource. A modular interface integrates this unified evidence with VCEP-refined ACMG specifications to enable automated gene-specific variant classification, infer molecular mechanisms, and support cross-gene analyses. We demonstrate the framework’s utility across five Gene portals spanning eleven neurodevelopmental disorder-associated genes, integrating data from 4,423 individuals with 2,838 unique variants, 36,149 ClinVar submissions, and 1,044 expert-curated molecular readouts. By organizing evidence that is otherwise dispersed across multiple sources into a unified, queryable framework, the SCN, GRIN, CACNA1A, SATB2 and SLC6A1 Gene Portals became widely used community resources and provide an extensible template for standardized rare-disease variant interpretation and mechanism-aware discovery.

We evaluated the clinical and cost effectiveness of an online sleep intervention (COSI) for parents of children with epilepsy. We conducted a multicentre, parallel-group, unblinded, randomised controlled trial. We recruited children aged 4–12 years with epilepsy and sleep problems through 26 UK outpatient clinics. Participants were randomly assigned (1:1) via a computer-generated minimisation algorithm. The primary outcome was the Children’s Sleep Habits Questionnaire (CSHQ) at three months. Cost-effectiveness was estimated at six months. We conducted intention to treat analyses. 85 children were enrolled (42 SC; 43 SC + COSI). At three months, the adjusted mean CSHQ difference between arms was 3.00 (95% CI 0.06–5.93; p = 0.05), indicating significant superiority of SC. Children in the SC + COSI group showed a mean 16.5-minute reduction in sleep onset latency by actigraphy and parents increased their knowledge. Only 23 (53%) families accessed the core intervention materials. Incremental mean cost of SC + COSI was £1,232 (95% credibility interval £535–£3,455) with a mean incremental Quality Adjusted Life Year (QALY) of 0.00 (95% CI -0.03 to 0.04), yielding an incremental cost-effectiveness ratio of £433,167 per QALY gained a (0.04 probability of being cost-effective at the £30,000/QALY threshold). Improved objective sleep onset latency and enhanced parental knowledge suggest that the underlying behaviour change techniques hold value.

Objectives: Sleep problems are common in children with epilepsy. We aimed to evaluate the clinical effectiveness and incremental cost-effectiveness of an online resource for parents of children with epilepsy (CASTLE Online Sleep Intervention, or COSI) combined with standard care (SC) versus SC alone over six months. Design: We conducted a multicentre, parallel-group, unblinded, randomised controlled trial with an internal pilot. Setting: 26 UK NHS paediatric epilepsy outpatient clinics. Participants: Children aged 4–12 years with clinician-confirmed epilepsy and caregiver-reported sleep problems. Interventions: Participants were randomly assigned (1:1) via a computer-generated minimisation algorithm to SC or SC plus COSI. Main outcome measures: The primary outcome, assessed at three months, was the Children’s Sleep Habits Questionnaire (CSHQ). Cost-effectiveness was estimated at six months, with utilities from the Child Health Utility 9-Dimensions Index and costs from an NHS and Personal Social Services perspective. Safety analyses included all randomised participants. Analyses were performed on an intention to treat basis. Results: 85 children were enrolled between 30.08.2022 and 18.10. 2023, (42 SC; 43 SC+COSI). At three months, the adjusted mean CSHQ difference between SC+COSI and SC was 3.00 (95% CI 0.06–5.93; p=0.05), indicating no significant superiority. No adverse events were reported. Children in the SC+COSI group showed a mean 16.5-minute reduction in sleep onset latency and parents increased their knowledge. Only 23 (53%) families accessed the core online materials. Incremental mean cost of SC+COSI was £1,232 (95% credibility interval £535–£3,455) with a mean incremental QALY of 0.00 (95% CI -0.03 to 0.04), yielding an incremental cost-effectiveness ratio of £433,167 per QALY gained a (0.04 probability of being cost-effective at the £30,000/QALY threshold). Conclusions: An online Parent-Directed Behavioural Sleep Intervention did not reduce parent-rated sleep problems in children with epilepsy in the NHS context. However, improved objective sleep onset latency and enhanced parental knowledge suggest that the underlying behaviour change techniques have merit. Blended delivery through specialist nurses or similar support may improve engagement and outcomes. Trial registration: ISRCTN13202325. Funding: NIHR Programme Grant for Applied Research RP-PG-0615-20007.

Introduction The prevalence of mental health symptoms in people with epilepsy (PWE) is elevated compared with that of the general population. These symptoms can negatively impact epilepsy management and patient outcomes but can be treated once recognised. It is, therefore, important to screen for these symptoms to identify needs and put in place appropriate support. Unfortunately, mental health symptoms are rarely addressed in epilepsy services due to time constraints, lack of resources and communication between psychological and medical professionals. These barriers can result in diagnostic overshadowing, where symptoms may be attributed to the disease and reduce the level of support PWE receive. Implementing an online screening tool embedded in the electronic health record (EHR) platform with supported referral pathways may remove some of these barriers. Methods and analysis We will follow the Integrating Mental and Physical Healthcare: Research Training and Services framework, which is a routine clinical data collection tool used by clinical teams to electronically screen psychological symptoms among patients with long-term physical health conditions. Patient outcomes including mental health, physical health and psychosocial outcomes will be collected and uploaded to the EHR platform in real-time. An appropriate referral pathway will be recommended depending on severity of the outcome scores. We will initially pilot the tool for individuals aged 13 years and above through epilepsy clinics at King’s College Hospital. Following this, the acceptability and feasibility of the tool will be assessed at baseline, 6 and 12 months. Ethics and dissemination Ethics approval was obtained from the National Health Service Research Ethics Committee of South Central—Oxford C, reference: 21/EM/0205. This study is expected to inform the use of integrated electronic mental health screening for youth in epilepsy clinics and improve access to psychological support. The findings will be disseminated through academic peer-reviewed journals, poster presentations and scientific meetings.

Elevated impulsivity is a key component of attention-deficit hyperactivity disorder (ADHD), bipolar disorder and juvenile myoclonic epilepsy (JME). We performed a genome-wide association, colocalization, polygenic risk score, and pathway analysis of impulsivity in JME (n = 381). Results were followed up with functional characterisation using a drosophila model. We identified genome-wide associated SNPs at 8q13.3 (P = 7.5 × 10⁻⁹) and 10p11.21 (P = 3.6 × 10⁻⁸). The 8q13.3 locus colocalizes with SLCO5A1 expression quantitative trait loci in cerebral cortex (P = 9.5 × 10⁻³). SLCO5A1 codes for an organic anion transporter and upregulates synapse assembly/organisation genes. Pathway analysis demonstrates 12.7-fold enrichment for presynaptic membrane assembly genes (P = 0.0005) and 14.3-fold enrichment for presynaptic organisation genes (P = 0.0005) including NLGN1 and PTPRD. RNAi knockdown of Oatp30B, the Drosophila polypeptide with the highest homology to SLCO5A1, causes over-reactive startling behaviour (P = 8.7 × 10⁻³) and increased seizure-like events (P = 6.8 × 10⁻⁷). Polygenic risk score for ADHD genetically correlates with impulsivity scores in JME (P = 1.60 × 10⁻³). SLCO5A1 loss-of-function represents an impulsivity and seizure mechanism. Synaptic assembly genes may inform the aetiology of impulsivity in health and disease.

Genetic variants in the SLC6A1 gene can cause a broad phenotypic disease spectrum by altering the protein function. Thus, systematically curated clinically relevant genotype-phenotype associations are needed to understand the disease mechanism and improve therapeutic decision-making. We aggregated genetic and clinical data from 172 individuals with likely pathogenic/pathogenic (lp/p) SLC6A1 variants and functional data for 184 variants (14.1% lp/p). Clinical and functional data were available for a subset of 126 individuals. We explored the potential associations of variant positions on the GAT1 3D structure with variant pathogenicity, altered molecular function and phenotype severity using bioinformatic approaches. The GAT1 transmembrane domains 1, 6 and extracellular loop 4 (EL4) were enriched for patient over population variants. Across functionally tested missense variants (n = 156), the spatial proximity from the ligand was associated with loss-of-function in the GAT1 transporter activity. For variants with complete loss of in vitro GABA uptake, we found a 4.6-fold enrichment in patients having severe disease versus non-severe disease (P = 2.9 × 10⁻³, 95% confidence interval: 1.5–15.3). In summary, we delineated associations between the 3D structure and variant pathogenicity, variant function and phenotype in SLC6A1-related disorders. This knowledge supports biology-informed variant interpretation and research on GAT1 function. All our data can be interactively explored in the SLC6A1 portal (https://slc6a1-portal.broadinstitute.org/).