Experiences of Spanish-Speaking Families with a Remote Neurodevelopmental Assessment.

U.S. Hispanic families with limited English proficiency experience barriers to autism diagnosis, such as lack of Spanish-speaking providers and assessments. Remote assessments in Spanish have the potential to address some of these barriers. This study explored the acceptability and feasibility of a remote developmental assessment (Parent Administered Neurodevelopmental Assessment, i.e., PANDABox) for Hispanic infants at high likelihood for autism. The PANDABox was translated into Spanish by two independent groups, synthesized, and reviewed by 10 native Spanish-speakers. Thirteen Spanish-speaking families completed the PANDABox-Spanish with their infant at high likelihood for autism. Remote developmental measures that exist in Spanish were administered for comparison. Families then participated in semi-structured interviews to explore their experiences, which were analyzed in Spanish using an inductive, grounded theory approach. Translation reviewers revealed the need to adapt peekaboo and storybook activities, build in dialogue addressing caregivers' concerns, and add visual supports. PANDABox families valued communicating directly to a Spanish-speaking specialist, felt that the translation was clear, and that, overall, the administration was easy. Families had mixed preferences for in-person or remote assessments, with some families valuing the accessibility and comfort of the PANDABox and others expressing concerns about the validity of remote versus in-person options. Families also discussed barriers related to literacy and confidentiality. The PANDABox-Spanish is a promising option for increasing accessibility to laboratory-grade neurodevelopmental assessment. More broadly, providers need to consider families' familiarity with common assessment activities, access to information about early identification, and concerns related to confidentiality.

Comparing the stability and reproducibility of brain-behavior relationships found using canonical correlation analysis and partial least squares within the ABCD sample.

Canonical correlation analysis (CCA) and partial least squares correlation (PLS) detect linear associations between two data matrices by computing latent variables (LVs) having maximal correlation (CCA) or covariance (PLS). This study compared the similarity and generalizability of CCA- and PLS-derived brain-behavior relationships. Data were accessed from the baseline Adolescent Brain Cognitive Development (ABCD) dataset (N > 9,000, 9-11 years). The brain matrix consisted of cortical thickness estimates from the Desikan-Killiany atlas. Two phenotypic scales were examined separately as the behavioral matrix; the Child Behavioral Checklist (CBCL) subscale scores and NIH Toolbox performance scores. Resampling methods were used to assess significance and generalizability of LVs. LV1 for the CBCL brain relationships was found to be significant, yet not consistently stable or reproducible, across CCA and PLS models (singular value: CCA = .13, PLS = .39, p < .001). LV1 for the NIH brain relationships showed similar relationships between CCA and PLS and was found to be stable and reproducible (singular value: CCA = .21, PLS = .43, p < .001). The current study suggests that stability and reproducibility of brain-behavior relationships identified by CCA and PLS are influenced by the statistical characteristics of the phenotypic measure used when applied to a large population-based pediatric sample.

Clinical neuroscience research is going through a translational crisis largely due to the challenges of producing meaningful and generalizable results. Two critical limitations within clinical neuroscience research are the use of univariate statistics and between-study methodological variation. Univariate statistics may not be sensitive enough to detect complex relationships between several variables, and methodological variation poses challenges to the generalizability of the results. We compared two widely used multivariate statistical approaches, canonical correlations analysis (CCA) and partial least squares correlation (PLS), to determine the generalizability and stability of their solutions. We show that the properties of the measures inputted into the analysis likely play a more substantial role in the generalizability and stability of results compared to the specific approach applied (i.e., CCA or PLS).

Feeding practices and weight status of children with congenital Zika syndrome: A longitudinal study in Brazil.

OBJECTIVE: The objective of this study was to describe feeding practices and weight status in a cohort of children with congenital Zika syndrome (CZS) in northeastern Brazil. METHODS: This longitudinal study of children with CZS (N = 156) included data collection on child feeding practices and weight status at five timepoints between 2018 and 2022. The average age of the children was 32.1 months at enrollment and 76.6 months at the fifth assessment. Multilevel models, with repeated observations nested within children, were used to estimate time-related differences in each outcome. RESULTS: Use of enteral feeding, such as gastrostomy, increased from 19.2% to 33.3% over 4 years (p < .001). Among children who did not exclusively use an enteral feeding method, the percentage experiencing at least one dysphagia-associated behavior, such as coughing or gagging, increased from 73.9% to 85.3% (p = .030) while consuming liquids and from 36.2% to 73.5% (p = .001) while consuming solids. Based on weight-for-age z-scores, the percentage of children who were moderately or severely underweight increased from 42.5% to 46.1% over the 4 years but was not statistically significant. Children exclusively using an enteral feeding method had significantly decreased odds of being underweight at assessments 3, 4, and 5. CONCLUSIONS: These data highlight the ongoing and increasing challenges of feeding young children with CZS. Our findings elucidate the physiological reasons children with CZS may be underweight and point to intervention targets, such as enteral feeding, to improve their feeding practices.

Developmental milestones and daily living skills in individuals with Angelman syndrome.

BACKGROUND: Angelman syndrome (AS) is a neurodevelopmental disorder associated with severe global developmental delay. However, the ages at which different developmental skills are achieved in these individuals remain unclear. We seek to determine the probability and the age of acquisition of specific developmental milestones and daily living skills in individuals with AS across the different molecular subtypes, viz. class I deletion, class II deletion, uniparental disomy, imprinting defect, and UBE3A variants. METHODS: Caregivers participating in a longitudinal multicenter Angelman Syndrome Natural History Study completed a questionnaire regarding the age at which their children achieved specific developmental milestones and daily living skills. The Cox Proportional Hazard model was applied to analyze differences in the probability of achievement of skills at various ages among five molecular subtypes of AS. RESULTS: Almost all individuals, regardless of molecular subtype, were able to walk with support by five years of age. By age 15, those with a deletion had at least a 50% probability of acquiring 17 out of 30 skills compared to 25 out of 30 skills among those without a deletion. Overall, fine and gross motor skills such as holding and reaching for small objects, sitting, and walking with support were achieved within a fairly narrow range of ages, while toileting, feeding, and hygiene skills tend to have greater variability in the ages at which these skills were achieved. Those without a deletion had a higher probability (25-92%) of achieving daily living skills such as independently toileting and dressing compared to those with a deletion (0-13%). Across all molecular subtypes, there was a low probability of achieving independence in bathing and brushing teeth. CONCLUSION: Individuals with AS without a deletion are more likely to achieve developmental milestones and daily living skills at an earlier age than those with a deletion. Many individuals with AS are unable to achieve daily living skills necessary for independent self-care.

Linking Angelman and dup15q data for expanded research (LADDER) database: a model for advancing research, clinical guidance, and therapeutic development for rare conditions.

Angelman syndrome (AS) and duplication 15q (dup15q) syndrome are rare neurogenetic conditions arising from a common locus on the long arm of chromosome 15. Individuals with both conditions share some clinical features (e.g. intellectual disability, epilepsy) and often require lifelong care. Disease-modifying therapies for both conditions are emerging, resulting in a significant need for a better understanding of the natural history of both AS and dup15q. Patient advocacy groups for both conditions recognized a need for a data repository that would link data on individuals from multiple sources to expand research, increase understanding of natural history, and accelerate the development of treatments, resulting in the Linking Angelman and Dup15q Data for Expanded Research (LADDER) Database. This paper describes the development and functionality of the LADDER Database - including challenges, lessons learned, and preliminary feasibility - and how it can be used as a model for other rare conditions.

The LADDER database: a model for advancing research, clinical guidance, and therapeutic development for rare conditions This paper describes the development and functionality of the Linking Angelman and Dup15q Data for Expanded Research (LADDER) Database, which is a data repository for two rare neurogenetic conditions: Angelman syndrome (AS) and duplication 15q (dup15q) syndrome. AS and dup15q syndrome arise from genetic abnormalities on chromosome 15 and share some clinical features (e.g. intellectual disability, epilepsy). LADDER was developed by patient advocacy organizations representing each condition in partnership with RTI International. LADDER links data on individuals from multiple sources to expand research, increase understanding of natural history, and accelerate the development of treatments for both AS and dup15q syndrome. The LADDER Database can be used as a model for expanding research and enhancing clinical trial readiness in other rare conditions.

Specificity of Early Childhood Hyperphagia Profiles in Neurogenetic Conditions.

Hyperphagia is highly penetrant in Prader-Willi syndrome (PWS) and has increasingly been reported in other neurogenetic conditions (NGC). The Hyperphagia Questionnaire (HQ) was completed by caregivers of 4-8-year-olds with PWS (n = 17), Angelman syndrome (AS; n = 22), Williams syndrome (WS; n = 25), or low-risk controls (LRC; n = 35). All NGC groups were significantly elevated in HQ Total and Behavior scores compared to LRC. Only AS and WS were significantly elevated in the Drive domain, and only PWS in the Severity domain. After controlling for externalizing behavior, HQ Total scores were higher for PWS relative to other groups. Hyperphagic symptoms may not differentiate PWS from other NGCs in early childhood. However, hyperphagic phenotypes may be most severe in PWS. Further investigation of these profiles may inform etiology and syndrome-specific treatments.

The Multiple Odysseys in Research and Clinical Care for Neurogenetic Conditions.

Neurogenetic conditions (NGC; e.g., fragile X, Angelman, Prader-Willi syndromes) represent the cause for intellectual or developmental disabilities in up to 60% of cases. With expanded diagnostic options and an increasing focus on the development of gene therapies comes the potential of improved quality of life for individuals with NGCs and their families. However, these emerging initiatives also bring new challenges and considerations for NGC researchers and clinicians, including considerations for supporting caregivers and assuring outcome measures for clinical trials adequately reflect the lived experiences of people with NGCs. This paper summarizes the advances and current and future challenges of research and clinical service provision for people with NGCs and their caregivers.

Disrupted Maturation of White Matter Microstructure After Concussion Is Associated With Internalizing Behavior Scores in Female Children.

BACKGROUND: Some children who experience concussions, particularly females, develop long-lasting emotional and behavioral problems. Establishing the potential contribution of preexisting behavioral problems and disrupted white matter maturation has been challenging due to a lack of preinjury data. METHODS: From the Adolescent Brain Cognitive Development cohort, 239 (90 female) children age 12.1 ± 0.6 years who experienced a concussion after study entry at 10.0 ± 0.6 years were compared to 6438 (3245 female) children without head injuries who were age 9.9 ± 0.6 years at baseline and 12.0 ± 0.6 years at follow-up. The Child Behavior Checklist was used to assess internalizing and externalizing behavior at study entry and follow-up. In the children with magnetic resonance imaging data available (concussion n = 134, comparison n = 3520), deep and superficial white matter was characterized by neurite density from restriction spectrum image modeling of diffusion magnetic resonance imaging. Longitudinal ComBat harmonization removed scanner effects. Linear regressions modeled 1) behavior problems at follow-up controlling for baseline behavior, 2) impact of concussion on white matter maturation, and 3) contribution of deviations in white matter maturation to postconcussion behavior problems. RESULTS: Only female children with concussion had higher internalizing behavior problem scores. The youngest children with concussion showed less change in superficial white matter neurite density over 2 years than children with no concussion. In females with concussion, less change in superficial white matter neurite density was correlated with increased internalizing behavior problem scores. CONCLUSIONS: Concussions in female children are associated with emotional problems beyond preinjury levels. Injury to superficial white matter may contribute to persistent internalizing behavior problems in females.

Two years of newborn screening for Duchenne muscular dystrophy as a part of the statewide Early Check research program in North Carolina.

PURPOSE: Current and emerging treatments for Duchenne muscular dystrophy (DMD) position DMD as a candidate condition for newborn screening (NBS). In anticipation of the nomination of DMD for universal NBS, we conducted a prospective study under the Early Check voluntary NBS research program in North Carolina, United States. METHODS: We performed screening for creatine kinase-MM (CK-MM), a biomarker of muscle damage, on residual routine newborn dried blood spots (DBS) from participating newborns. Total creatine kinase testing and next generation sequencing of an 86-neuromuscular gene panel that included DMD were offered to parents of newborns who screened positive. Bivariate and multivariable analyses were performed to assess effects of biological and demographic predictors on CK-MM levels in DBS. RESULTS: We screened 13,354 newborns and identified 2 males with DMD. The provisional 1626 ng/mL cutoff was raised to 2032 ng/mL to improve specificity, and additional cutoffs (900 and 360 ng/mL) were implemented to improve sensitivity for older and low-birthweight newborns. CONCLUSION: Population-scale screening for elevated CK-MM in DBS is a feasible approach to identify newborns with DMD. Inclusion of birthweight- and age-specific cutoffs, repeat creatine kinase testing after 72 hours of age, and DMD sequencing improve sensitivity and specificity of screening.

The Toronto Adolescent and Youth Cohort Study: Study Design and Early Data Related to Psychosis Spectrum Symptoms, Functioning, and Suicidality.

BACKGROUND: Psychosis spectrum symptoms (PSSs) occur in a sizable percentage of youth and are associated with poorer cognitive performance, poorer functioning, and suicidality (i.e., suicidal thoughts and behaviors). PSSs may occur more frequently in youths already experiencing another mental illness, but the antecedents are not well known. The Toronto Adolescent and Youth (TAY) Cohort Study aims to characterize developmental trajectories in youths with mental illness and understand associations with PSSs, functioning, and suicidality. METHODS: The TAY Cohort Study is a longitudinal cohort study that aims to assess 1500 youths (age 11-24 years) presenting to tertiary care. In this article, we describe the extensive diagnostic and clinical characterization of psychopathology, substance use, functioning, suicidality, and health service utilization in these youths, with follow-up every 6 months over 5 years, including early baseline data. RESULTS: A total of 417 participants were enrolled between May 4, 2021, and February 2, 2023. Participants met diagnostic criteria for an average of 3.5 psychiatric diagnoses, most frequently anxiety and depressive disorders. Forty-nine percent of participants met a pre-established threshold for PSSs and exhibited higher rates of functional impairment, internalizing and externalizing symptoms, and suicidality than participants without PSSs. CONCLUSIONS: Initial findings from the TAY Cohort Study demonstrate the feasibility of extensive clinical phenotyping in youths who are seeking help for mental health problems. PSS prevalence is much higher than in community-based studies. Our early data support the critical need to better understand longitudinal trajectories of clinical youth cohorts in relation to psychosis risk, functioning, and suicidality.

Neuroimaging and Biosample Collection in the Toronto Adolescent and Youth Cohort Study: Rationale, Methods, and Early Data.

BACKGROUND: The Toronto Adolescent and Youth (TAY) Cohort Study will characterize the neurobiological trajectories of psychosis spectrum symptoms, functioning, and suicidality (i.e., suicidal thoughts and behaviors) in youth seeking mental health care. Here, we present the neuroimaging and biosample component of the protocol. We also present feasibility and quality control metrics for the baseline sample collected thus far. METHODS: The current study includes youths (ages 11-24 years) who were referred to child and youth mental health services within a large tertiary care center in Toronto, Ontario, Canada, with target recruitment of 1500 participants. Participants were offered the opportunity to provide any or all of the following: 1) 1-hour magnetic resonance imaging (MRI) scan (electroencephalography if ineligible for or declined MRI), 2) blood sample for genomic and proteomic data (or saliva if blood collection was declined or not feasible) and urine sample, and 3) heart rate recording to assess respiratory sinus arrhythmia. RESULTS: Of the first 417 participants who consented to participate between May 4, 2021, and February 2, 2023, 412 agreed to participate in the imaging and biosample protocol. Of these, 334 completed imaging, 341 provided a biosample, 338 completed respiratory sinus arrhythmia, and 316 completed all 3. Following quality control, data usability was high (MRI: T1-weighted 99%, diffusion-weighted imaging 99%, arterial spin labeling 90%, resting-state functional MRI 95%, task functional MRI 90%; electroencephalography: 83%; respiratory sinus arrhythmia: 99%). CONCLUSIONS: The high consent rates, good completion rates, and high data usability reported here demonstrate the feasibility of collecting and using brain imaging and biosamples in a large clinical cohort of youths seeking mental health care.

Cognition and Educational Achievement in the Toronto Adolescent and Youth Cohort Study: Rationale, Methods, and Early Data.

BACKGROUND: Both cognition and educational achievement in youths are linked to psychosis risk. One major aim of the Toronto Adolescent and Youth (TAY) Cohort Study is to characterize how cognitive and educational achievement trajectories inform the course of psychosis spectrum symptoms (PSSs), functioning, and suicidality. Here, we describe the protocol for the cognitive and educational data and early baseline data. METHODS: The cognitive assessment design is consistent with youth population cohort studies, including the NIH Toolbox, Rey Auditory Verbal Learning Test, Wechsler Matrix Reasoning Task, and Little Man Task. Participants complete an educational achievement questionnaire, and report cards are requested. Completion rates, descriptive data, and differences across PSS status are reported for the first participants (N = 417) ages 11 to 24 years, who were recruited between May 4, 2021, and February 2, 2023. RESULTS: Nearly 84% of the sample completed cognitive testing, and 88.2% completed the educational questionnaire, whereas report cards were collected for only 40.3%. Modifications to workflows were implemented to improve data collection. Participants who met criteria for PSSs demonstrated lower performance than those who did not on numerous key cognitive indices (p < .05) and also had more academic/educational problems. CONCLUSIONS: Following youths longitudinally enabled trajectory mapping and prediction based on cognitive and educational performance in relation to PSSs in treatment-seeking youths. Youths with PSSs had lower cognitive performance and worse educational outcomes than youths without PSSs. Results show the feasibility of collecting data on cognitive and educational outcomes in a cohort of youths seeking treatment related to mental illness and substance use.

Age of diagnosis for children with chromosome 15q syndromes.

OBJECTIVE: The objective of this study was to identify the age of diagnosis for children with one of three neurogenetic conditions resulting from changes in chromosome 15 (Angelman syndrome [AS], Prader-Willi syndrome [PWS], and duplication 15q syndrome [Dup15q]). METHODS: Data about the diagnostic process for each condition were contributed by the advocacy organizations. Median and interquartile ranges were calculated for each condition by molecular subtype and year. Comparison tests were run to explore group differences. RESULTS: The median age of diagnosis was 1.8 years for both AS and Dup15q. PWS was diagnosed significantly younger at a median age of 1 month. Deletion subtypes for both PWS and AS were diagnosed earlier than nondeletion subtypes, and children with isodicentric duplications in Dup15q were diagnosed earlier than those with interstitial duplications. CONCLUSION: Understanding variability in the age of diagnosis for chromosome 15 disorders is an important step in reducing the diagnostic odyssey and improving access to interventions for these populations. Results from this study provide a baseline by which to evaluate efforts to reduce the age of diagnosis for individuals with these conditions.

Multimodal Analysis of Secondary Cerebellar Alterations After Pediatric Traumatic Brain Injury.

Importance: Traumatic brain injury (TBI) is known to cause widespread neural disruption in the cerebrum. However, less is known about the association of TBI with cerebellar structure and how such changes may alter executive functioning. Objective: To investigate alterations in subregional cerebellum volume and cerebral white matter microstructure after pediatric TBI and examine subsequent changes in executive function. Design, Setting, and Participants: This retrospective cohort study combined 12 data sets (collected between 2006 and 2020) from 9 sites in the Enhancing Neuroimaging Genetics Through Meta-Analysis Consortium Pediatric TBI working group in a mega-analysis of cerebellar structure. Participants with TBI or healthy controls (some with orthopedic injury) were recruited from trauma centers, clinics, and institutional trauma registries, some of which were followed longitudinally over a period of 0.7 to 1.9 years. Healthy controls were recruited from the surrounding community. Data analysis occurred from October to December 2022. Exposure: Accidental mild complicated-severe TBI (msTBI) for those in the TBI group. Some controls received a diagnosis of orthopedic injury. Main Outcomes and Measures: Volume of 18 cerebellar lobules and vermal regions were estimated from 3-dimensional T1-weighted magnetic resonance imaging (MRI) scans. White matter organization in 28 regions of interest was assessed with diffusion tensor MRI. Executive function was measured by parent-reported scores from the Behavior Rating Inventory of Executive Functioning. Results: A total of 598 children and adolescents (mean [SD] age, 14.05 [3.06] years; range, 5.45-19.70 years; 386 male participants [64.5%]; 212 female participants [35.5%]) were included in the study, with 314 participants in the msTBI group, and 284 participants in the non-TBI group (133 healthy individuals and 151 orthopedically injured individuals). Significantly smaller total cerebellum volume (d = -0.37; 95% CI, -0.52 to -0.22; P < .001) and subregional cerebellum volumes (eg, corpus medullare; d = -0.43; 95% CI, -0.58 to -0.28; P < .001) were observed in the msTBI group. These alterations were primarily seen in participants in the chronic phase (ie, >6 months postinjury) of injury (total cerebellar volume, d = -0.55; 95% CI, -0.75 to -0.35; P < .001). Smaller cerebellum volumes were associated with higher scores on the Behavior Rating Inventory of Executive Functioning Global Executive Composite score (ß = -208.9 mm3; 95% CI, -319.0 to -98.0 mm3; P = .008) and Metacognition Index score (ß = -202.5 mm3; 95% CI, -319.0 to -85.0 mm3; P = .02). In a subset of 185 participants with longitudinal data, younger msTBI participants exhibited cerebellum volume reductions (ß = 0.0052 mm3; 95% CI, 0.0013 to 0.0090 mm3; P = .01), and older participants slower growth rates. Poorer white matter organization in the first months postinjury was associated with decreases in cerebellum volume over time (ß=0.52 mm3; 95% CI, 0.19 to 0.84 mm3; P = .005). Conclusions and Relevance: In this cohort study of pediatric msTBI, our results demonstrated robust cerebellar volume alterations associated with pediatric TBI, localized to the posterior lobe. Furthermore, longitudinal cerebellum changes were associated with baseline diffusion tensor MRI metrics, suggesting secondary cerebellar atrophy. These results provide further understanding of secondary injury mechanisms and may point to new opportunities for intervention.

Insight and Recommendations for Fragile X-Premutation-Associated Conditions from the Fifth International Conference on FMR1 Premutation.

The premutation of the fragile X messenger ribonucleoprotein 1 (FMR1) gene is characterized by an expansion of the CGG trinucleotide repeats (55 to 200 CGGs) in the 5' untranslated region and increased levels of FMR1 mRNA. Molecular mechanisms leading to fragile X-premutation-associated conditions (FXPAC) include cotranscriptional R-loop formations, FMR1 mRNA toxicity through both RNA gelation into nuclear foci and sequestration of various CGG-repeat-binding proteins, and the repeat-associated non-AUG (RAN)-initiated translation of potentially toxic proteins. Such molecular mechanisms contribute to subsequent consequences, including mitochondrial dysfunction and neuronal death. Clinically, premutation carriers may exhibit a wide range of symptoms and phenotypes. Any of the problems associated with the premutation can appropriately be called FXPAC. Fragile X-associated tremor/ataxia syndrome (FXTAS), fragile X-associated primary ovarian insufficiency (FXPOI), and fragile X-associated neuropsychiatric disorders (FXAND) can fall under FXPAC. Understanding the molecular and clinical aspects of the premutation of the FMR1 gene is crucial for the accurate diagnosis, genetic counseling, and appropriate management of affected individuals and families. This paper summarizes all the known problems associated with the premutation and documents the presentations and discussions that occurred at the International Premutation Conference, which took place in New Zealand in 2023.

Adaptive Skills of Individuals with Angelman Syndrome Assessed Using the Vineland Adaptive Behavior Scales, 2nd Edition.

In the current study, we examined adaptive skills and trajectories over time in 257 individuals with Angelman syndrome (AS) using the Vineland Adaptive Behavior Scales, 2nd Edition. Multilevel linear models were used to examine differences between molecular subtypes over time, from one year to 13 years of age, in the adaptive domains of communication, daily living skills, socialization and motor skills. Individuals with non-deletion subtypes typically demonstrated a higher level of adaptive skills compared to those with deletion subtypes. Statistically significant growth was observed in all adaptive domains through at least early adolescence. Individuals with AS should continue to receive developmental services and educational supports through adolescence and into adulthood given the slow rates of growth being observed across adaptive domains.

Enabling endpoint development for interventional clinical trials in individuals with Angelman syndrome: a prospective, longitudinal, observational clinical study (FREESIAS).

BACKGROUND: Angelman syndrome (AS) is a rare neurodevelopmental disorder characterized by the absence of a functional UBE3A gene, which causes developmental, behavioral, and medical challenges. While currently untreatable, comprehensive data could help identify appropriate endpoints assessing meaningful improvements in clinical trials. Herein are reported the results from the FREESIAS study assessing the feasibility and utility of in-clinic and at-home measures of key AS symptoms. METHODS: Fifty-five individuals with AS (aged < 5 years: n = 16, 5-12 years: n = 27, ≥ 18 years: n = 12; deletion genotype: n = 40, nondeletion genotype: n = 15) and 20 typically developing children (aged 1-12 years) were enrolled across six USA sites. Several clinical outcome assessments and digital health technologies were tested, together with overnight 19-lead electroencephalography (EEG) and additional polysomnography (PSG) sensors. Participants were assessed at baseline (Clinic Visit 1), 12 months later (Clinic Visit 2), and during intermittent home visits. RESULTS: The participants achieved high completion rates for the clinical outcome assessments (adherence: 89-100% [Clinic Visit 1]; 76-91% [Clinic Visit 2]) and varied feasibility of and adherence to digital health technologies. The coronavirus disease 2019 (COVID-19) pandemic impacted participants' uptake of and/or adherence to some measures. It also potentially impacted the at-home PSG/EEG recordings, which were otherwise feasible. Participants achieved Bayley-III results comparable to the available natural history data, showing similar scores between individuals aged ≥ 18 and 5-12 years. Also, participants without a deletion generally scored higher on most clinical outcome assessments than participants with a deletion. Furthermore, the observed AS EEG phenotype of excess delta-band power was consistent with prior reports. CONCLUSIONS: Although feasible clinical outcome assessments and digital health technologies are reported herein, further improved assessments of meaningful AS change are needed. Despite the COVID-19 pandemic, remote assessments facilitated high adherence levels and the results suggested that at-home PSG/EEG might be a feasible alternative to the in-clinic EEG assessments. Taken altogether, the combination of in-clinic/at-home clinical outcome assessments, digital health technologies, and PSG/EEG may improve protocol adherence, reduce patient burden, and optimize study outcomes in AS and other rare disease populations.

Premature white matter microstructure in female children with a history of concussion.

Childhood concussion may interfere with neurodevelopment and influence cognition. Females are more likely to experience persistent symptoms after concussion, yet the sex-specific impact of concussion on brain microstructure in children is understudied. This study examined white matter and cortical microstructure, based on neurite density (ND) from diffusion-weighted MRI, in 9-to-10-year-old children in the Adolescent Brain Cognitive Development Study with (n = 336) and without (n = 7368) a history of concussion, and its relationship with cognitive performance. Multivariate regression was used to investigate relationships between ND and group, sex, and age in deep and superficial white matter, subcortical structures, and cortex. Partial least square correlation was performed to identify associations between ND and performance on NIH Toolbox tasks in children with concussion. All tissue types demonstrated higher ND with age, reflecting brain maturation. Group comparisons revealed higher ND in deep and superficial white matter in females with concussion. In female but not male children with concussion, there were significant associations between ND and performance on cognitive tests. These results demonstrate a greater long-term impact of childhood concussion on white matter microstructure in females compared to males that is associated with cognitive function. The increase in ND in females may reflect premature white matter maturation.

Misunderstood terms and concepts identified through user testing of educational materials for fragile X premutation: "Not weak or fragile?"

Complicated genetic mechanisms and unpredictable health risks associated with the FMR1 premutation can result in challenges for patient education when the diagnosis is made in a newborn. From October 15, 2018, to December 10, 2021, North Carolina parents could obtain FMR1 premutation results about their newborns through a voluntary expanded newborn screening research study. The study provided confirmatory testing, parental testing, and genetic counseling. We developed web-based educational materials to augment information about fragile X premutation conveyed by a genetic counselor. Many genetics education materials are developed for the lay population. However, relatively little research is published on how well individuals understand these materials. We conducted three rounds of iterative user testing interviews to help refine web-based educational materials that support understanding and self-paced learning. The participants included 25 parents with a 2-year college degree or less and without a child identified with fragile X syndrome, premutation, or gray-zone allele. Content analysis of interview transcripts resulted in iterative changes and ultimately saturation of findings. Across all rounds of interviews, there were two terms that were commonly misunderstood (fragile and carrier) and two terms that elicited initial misconceptions that were overcome by participants. Many also had difficulty understanding the relationship between fragile X premutation and fragile X syndrome as well as appreciating the implications of having a "fragile X gene." Website layout, formatting, and graphics also influenced comprehension. Despite iterative changes to the content, certain issues with understandability persisted. The findings support the need for user testing to identify misconceptions that may interfere with understanding and using genetic information. Here, we describe a process used to develop and refine evidence-based, understandable parental resources on fragile X premutation. Additionally, we provide recommendations to address ongoing educational challenges and discuss the potential impact of bias on the part of expert content developers.

Pilot protocol for the Parent and Infant Inter(X)action Intervention (PIXI) feasibility study.

This paper provides the detailed protocol for a pilot study testing the feasibility, acceptability, and initial efficacy of a targeted two-phase, remotely delivered early intervention program for infants with neurogenetic conditions (NGC) and their caregivers. The Parent and Infant Inter(X)action Intervention (PIXI) is designed to support parents and infants with a NGC diagnosed in the first year of life. PIXI is implemented in two phases, with the first phase focusing on psychoeducation, parent support, and how to establish routines for supporting infant development. Phase II helps parents learn targeted skills to support their infant's development as symptoms may begin to emerge. The proposed non-randomized feasibility pilot study will establish the feasibility of a year-long virtually implemented intervention program to support new parents of an infant diagnosed with an NGC.