Psychometric evaluation of clinician- and caregiver-reported clinical severity assessments for individuals with CDKL5 deficiency disorder.

OBJECTIVE: The CDKL5 Clinical Severity Assessment (CCSA) is a comprehensive, content-validated measurement tool capturing the diverse challenges of cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD), a genetically caused developmental epileptic encephalopathy (DEE). The CCSA is divided into clinician-reported (CCSA-Clinician) and caregiver-reported (CCSA-Caregiver) assessments. The aim of this study was to evaluate the factor structure of these measures through confirmatory factor analysis (CFA) and evaluate their validity and reliability. METHODS: Participants were recruited from the International CDKL5 Clinical Research Network to take part in an in-clinic CCSA-Clinician evaluation (n = 148) and/or complete the CCSA-Caregiver questionnaire (n = 198). CFA was used to determine domains, and factor loadings and validity were assessed. For the CCSA-Clinician, inter-rater reliability was assessed by nine CDD experienced clinicians via 14 pre-recorded evaluations. Eight clinicians re-viewed and re-scored the videos after 4 weeks to evaluate intra-rater reliability. The CCSA-Caregiver was completed on a second occasion by 34 caregivers after 2-4 weeks to assess test-retest reliability. RESULTS: CFA resulted in three domains for the CCSA-Clinician (motor and movement, communication, vision) and four domains for the CCSA-Caregiver (seizures, behavior, alertness, feeding), with good item loadings across both measures. Structural statistics, internal consistency, discriminant validity, and reliability were satisfactory for both measures, and scores were consistent between known groups. SIGNIFICANCE: This study provides strong evidence that the CCSA measures are suitable to assess the clinical severity of individuals with CDD, supporting their use in clinical trials. Further evaluation of responsiveness to change in a longitudinal assessment is planned. Use may also be appropriate in similar DEEs but would require validation in those populations.

Parent-reported outcome measures evaluating communication in individuals with rare neurodevelopmental disorders: A systematic review.

BACKGROUND: Communication impairments are a leading concern for parent caregivers of individuals with rare neurodevelopmental disorders (RNDDs). Clinical trials of disease modifying therapies require valid and responsive outcome measures that are relevant to individuals with RNDDs. Identifying and evaluating current psychometric properties for communication measures is a critical step towards the selection and use of appropriate instruments. AIMS: This systematic review offers (1) a description of parent-reported communication measures and (2) evidence for their psychometric properties, in RNDDs. METHODS: The systematic review protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO; CRD42022334649). MEDLINE (Ovid), Embase, PsychINFO, Web of Science, CINAHL Plus, Cochrane Library, ClinicalTrials.gov, the Australian New Zealand Clinical Trials Registry were searched from inception to August 2023. Methodological assessment of quality was completed using the COnsensus-based Standards for the selection of health status Measurement INstruments (COSMIN) checklist. Parent-reported measures used in observational studies and clinical trials were identified. Data on utility, reliability and validity for RNDDs were extracted. MAIN CONTRIBUTION: Sixteen parent-reported communication measures were used in RNDD research, the Vineland Adaptive Behavior Scales being most commonly used. Validation data in RNDDs were identified for six of these measures. Limitations related to sample size or the scope of psychometric testing. CONCLUSIONS: Many communication measures have been used for RNDDs but there are few data validating their use. Valid and reliable methods of measuring communication in persons with RNDDs is a priority for future high-quality clinical trials. WHAT THIS PAPER ADDS: What is already known on the subject Communication is a critical domain for families with a child with a rare neurodevelopmental disorder (RNDD). Validated outcome measures are essential for accurate evaluation and interpretation of responses to treatments in clinical trials. What this paper adds to existing knowledge We identified 16 parent-reported communication measures that have been used with RNDDs, but only six measures had validation data for at least one RNDD. High quality evidence is accumulating, with all validation studies in this review published between 2020 to 2023. Modifications of existing measures may be required to assess communication for RNDDs. What are the clinical implications of this work? This systematic review catalogues the available psychometric data for communication measures and indicates an ongoing need for new validation studies to ensure they are fit-for-purpose for upcoming clinical trials in RNDDs. This review will inform the selection of communication measures for clinical trials and research studies.

Modification of a parent-report sleep scale for individuals with CDKL5 deficiency disorder: a psychometric study.

STUDY OBJECTIVES: Sleep difficulties are common in CDKL5 deficiency disorder (CDD), a developmental and epileptic encephalopathy (DEE). This study evaluated the factor structure of the Disorders of Initiating and Maintaining Sleep (DIMS), Disorders of Excessive Daytime Somnolence (DOES) and Sleep Breathing Disorders (SBD) domains of the Sleep Disturbance Scale for Children (SDSC) for CDD. METHODS: A cross-sectional psychometric study design was used. Data were collected for 125 individuals aged 3 years or older who attended a US Centers of Excellence clinic or registered with the International CDKL5 Disorder Database. RESULTS: The median age was 10.3 years (range 3.2 - 40.7 years) and 105 (84%) were female. Two of the three SBD items related were not observed by most respondents and analysis was restricted to the DIMS and DOES domains. Using all items in the initial confirmatory factor analysis, two items in the DIMS domain and one item in the DOES domain loaded poorly. After deleting these items and repeating the analysis, item loading (0.524-0.814) and internal consistency (DIMS: 0.78, DOES: 0.76) statistics were good. The square of the inter-domain correlation coefficient was 0.17, less than Average Variance Extracted values for both domains and indicating good discriminant validity. The Tucker-Lewis and Comparative Fit indices were slightly lower than the threshold of >0.9 for establishing goodness of fit. CONCLUSIONS: The modified DIMS and DOES domains from the SDSC could be suitable clinical outcome assessments of insomnia and related impairments in CDD and potentially other DEE conditions.

Psychometric properties of QI-Disability in CDKL5 Deficiency Disorder: Establishing readiness for clinical trials.

CDKL5 Deficiency Disorder (CDD) is a rare genetic disorder with symptoms of epilepsy, developmental impairments, and other comorbidities. Currently, there are no outcome measures for CDD with comprehensive evidence of validation. This study aimed to evaluate the psychometric properties of the Quality of Life Inventory-Disability (QI-Disability) in CDD. Quality of Life Inventory-Disability was administered to 152 parent caregivers registered with the International CDKL5 Disorder Database (ICDD). Confirmatory factor analysis was conducted and the goodness of fit of the factor structure was assessed. Fixed-effects linear regression models examined the responsiveness of QI-Disability to reported changes in child health. A subset of parent caregivers (n = 56) completed QI-Disability, as well as additional health-related questions, on two occasions separated by four weeks to evaluate test-retest reliability. Test-retest reliability was assessed using intra-class correlations (ICCs) calculated from QI-Disability scores. Based upon adjustments for changes in child health, ICCs were recalculated to estimate responsiveness to change. Confirmatory factor analysis, internal consistency, and divergent validity were mostly satisfactory, except divergent validity was not satisfactory for the Social Interactions and Independence domains. The Physical Health, Social Interactions, Leisure, and Total scores responded to changes in the child's Physical health, and the Negative Emotions and Leisure domains responded to changes in the child's behavior. Unadjusted and adjusted ICC values were above 0.8 for the Positive Emotions, Negative Emotions, Social Interactions, Leisure, Independence domains and Total score, and above 0.6 for the Physical Health domain. Findings suggest that QI-Disability is suitable to assess the quality of life of children and adults with CDD and could be of value for upcoming clinical trials.

Enhanced Decision Making and Working Memory During Exercise in the Heat With Crushed Ice Ingestion.

PURPOSE: To examine the effects of precooling via crushed ice ingestion on cognitive function during exercise in the heat. METHODS: Eleven active men ingested either 7 g·kg-1 of crushed ice (ICE) or thermoneutral water (CON) 30 minutes before running 90 minutes on a treadmill at a velocity equivalent to 65% VO2peak in hot and humid conditions (35.0°C [0.5°C], 53.1% [3.9%] relative humidity). Participants completed 3 cognitive tasks to investigate decision making (8-choice reaction time [CRT]), working memory (serial seven [S7]), and executive control (color multisource interference task [cMSIT]) on arrival, after precooling, and after running. RESULTS: Precooling significantly decreased preexercise core (Tcore) and forehead skin temperature in ICE compared with CON, respectively (Tcore 0.8°C [0.4°C], -0.2°C [0.1°C]; Thead -0.5°C [0.4°C], 0.2°C [0.8°C]; P ≤ .05). Postrun, ICE significantly reduced errors compared with CON for CRT (P ≤ .05; d = 0.90; 90% confidence interval, 0.13-1.60) and S7 (P ≤ .05; d = 1.05; 90% confidence interval, 0.26-1.75). Thermal sensation was lower after precooling with ICE (P ≤ .05), but no significant differences were recorded between conditions for cMSIT errors, skin temperature, heart rate, or ratings of perceived exertion or perceived thirst (P > .05). CONCLUSIONS: Precooling via ICE maintained cognitive accuracy in decision making and working memory during exercise in the heat. Thus, ICE may have the potential to improve sporting performance by resisting deleterious effects of exercise in a hot and humid environment on cognitive function.

Physical and perceptual cooling: Improving cognitive function, mood disturbance and time to fatigue in the heat.

This study investigated the effects of menthol swilling and crushed ice ingestion on cognitive function, total mood disturbance (TMD), and time to fatigue (TTF). Twelve male long-distance runners completed three counterbalanced running trials (3 × 30 minutes at 65% VO2peak and a TTF run at 100% VO2peak ) in hot, humid conditions (35.3 ± 0.3°C, 59.2 ± 2.5% relative humidity). Trials consisted of precooling with crushed ice ingestion and mid-cooling by menthol swilling (MIX), precooling with water ingestion and mid-cooling by menthol swilling (MENTH), and control (CON). Swilling with either 25 mL of menthol solution or placebo occurred upon entry to the heat, at 15-minute intervals during the run and prior to the TTF run. Core temperature, forehead skin temperature, tympanic temperature, perceived thermal sensation, and TMD were significantly lower with MIX compared with MENTH and CON (P < .05). Thirst was satiated in MIX compared with CON; however, MENTH did not have a significant effect. After 90 minutes of running and post-TTF run, fewer errors occurred in the executive control task (P < .05), as well as decision-making and working memory (P > .05; d = 0.5-0.79) between MIX and CON; however, MENTH had no effect compared with CON. The TTF run was significantly longer with MENTH (34.38%; P = .02) and MIX (39.06%; P = .001) compared with CON, with no difference between MENTH and MIX (P = .618). The physical reduction in core and internal head temperature seen with crushed ice ingestion may lead to improvements in cognitive function; however, both MENTH and MIX were sufficient for improving exercise performance.

Internal precooling decreases forehead and core temperature but does not alter choice reaction time during steady state exercise in hot, humid conditions.

This study aimed to determine if precooling via crushed ice ingestion reduces forehead skin temperature (Thead) and core temperature (Tcore) during exercise in the heat and whether it has an effect on choice reaction time (CRT). Ten males commenced a 30 min precooling period, ingesting either 7 g kg-1 of crushed ice (ICE) or room temperature water (CON) prior to cycling 60 min at 55% V̇O2peak in hot, humid conditions (35.0 ± 0.3 °C, 50.2 ± 2.1% Relative Humidity). The CRT task was completed upon arrival and after the precooling period in the lab, then at 15 min intervals during exercise in the heat. Precooling reduced Thead and Tcore to a greater degree in ICE (Thead: -0.8 ± 0.31 °C; Tcore: -0.9 ± 0.3 °C) compared with CON (Thead: -0.2 ± 0.3 °C; Tcore: -0.2 ± 0.2 °C) (p ≤ 0.001). Choice reaction time performance improved throughout the cycle for both conditions (p ≤ 0.05). Ice ingestion lowered thermal sensation (p = 0.003) and skin temperature (d = 0.88; Tskin), while heart rate, ratings of perceived exertion and thirst were similar between conditions (p > 0.05). Precooling effectively reduced Thead and Tcore but did not provide additional improvement in CRT during moderate exercise in the heat. Further investigation is required to determine whether the lower central and peripheral temperature after ice ingestion is beneficial for tasks of greater cognitive effort.