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.