Repeat testing enhances long-term verbal memory in children with epilepsy.

To (i) determine whether accelerated long-term forgetting (ALF) can be found using standardized verbal memory test materials in children with genetic generalized epilepsy (GGE) and temporal lobe epilepsy (TLE), and (ii) to establish whether ALF is impacted by executive skills and repeat testing over long delays. One hundred and twenty-three children aged 8 to 16, (28 with GGE, 23 with TLE, and 72 typically developing; TD) completed a battery of standardized tests assessing executive functioning and memory for two stories. Stories were recalled immediately and after a 30-min delay. To examine whether repeat testing impacts long-term forgetting, one story was tested via free recall at 1-day and 2-weeks, and the other at 2-weeks only. Recognition was then tested for both stories at 2-weeks. Children with epilepsy recalled fewer story details, both immediately and after 30-min relative to TD children. Compared to TD children, the GGE group, but not the TLE group, showed ALF, having significantly poorer recall of the story tested only at the longest delay. Poor executive skills were significantly correlated with ALF for children with epilepsy. Standard story memory materials can detect ALF in children with epilepsy when administered over long delays. Our findings suggest that (i) ALF is related to poor executive skills in children with epilepsy, and (ii) repeated testing may ameliorate ALF in some children.

Recommendations for assessing appearance concerns related to plexiform and cutaneous neurofibromas in neurofibromatosis 1 clinical trials.

BACKGROUND/AIMS: Individuals with neurofibromatosis 1 may experience changes in their appearance due to physical manifestations of the disorders and/or treatment sequelae. Appearance concerns related to these physical changes can lead to psychological distress and poorer quality of life. While many neurofibromatosis 1 clinical trials focus on assessing changes in tumor volume, evaluating patients' perspectives on corresponding changes in symptoms such as physical appearance can be key secondary outcomes. We aimed to determine whether any existing patient-reported outcome measures are appropriate for evaluating changes in appearance concerns within neurofibromatosis 1 clinical trials. METHODS: After updating our previously published systematic review process, we used it to identify and rate existing patient-reported outcome measures related to disfigurement and appearance. Using a systematic literature search and initial triage process, we focused on identifying patient-reported outcome measures that could be used to evaluate changes in appearance concerns in plexiform or cutaneous neurofibroma clinical trials in neurofibromatosis 1. Our revised Patient-Reported Outcome Rating and Acceptance Tool for Endpoints then was used to evaluate each published patient-reported outcome measures in five domains, including (1) respondent characteristics, (2) content validity, (3) scoring format and interpretability, (4) psychometric data, and (5) feasibility. The highest-rated patient-reported outcome measures were then re-reviewed in a side-by-side comparison to generate a final consensus recommendation. RESULTS: Eleven measures assessing appearance concerns were reviewed and rated; no measures were explicitly designed to assess appearance concerns related to neurofibromatosis 1. The FACE-Q Craniofacial Module-Appearance Distress scale was the top-rated measure for potential use in neurofibromatosis 1 clinical trials. Strengths of the measure included that it was rigorously developed, included individuals with neurofibromatosis 1 in the validation sample, was applicable to children and adults, covered item topics deemed important by neurofibromatosis 1 patient representatives, exhibited good psychometric properties, and was feasible for use in neurofibromatosis 1 trials. Limitations included a lack of validation in older adults, no published information regarding sensitivity to change in clinical trials, and limited availability in languages other than English. CONCLUSION: The Response Evaluation in Neurofibromatosis and Schwannomatosis patient-reported outcome working group currently recommends the FACE-Q Craniofacial Module Appearance Distress scale to evaluate patient-reported changes in appearance concerns in clinical trials for neurofibromatosis 1-related plexiform or cutaneous neurofibromas. Additional research is needed to validate this measure in people with neurofibromatosis 1, including older adults and those with tumors in various body locations, and explore the effects of nontumor manifestations on appearance concerns in people with neurofibromatosis 1 and schwannomatosis.

Longitudinal assessment of the health-related quality of life of children and adolescents with chronic kidney disease.

In this multi-center longitudinal cohort study conducted in Australia and New Zealand, we assessed the trajectories of health-related quality of life (HRQoL) in children with chronic kidney disease (CKD) over time. A total of 377 children (aged 6-18 years) with CKD stages 1-5 (pre-dialysis), dialysis, or transplant, were followed biennially for four years. Multi Attribute Utility (MAU) scores of HRQoL were measured at baseline and at two and four years using the McMaster Health Utilities Index Mark 3 tool, a generic multi-attribute, preference-based system. A multivariable linear mixed model was used to assess the trajectories of HRQoL over time in 199 children with CKD stage 1-5, 43 children receiving dialysis and 135 kidney transplant recipients. An interaction between CKD stage at baseline and follow-up time indicated that the slopes of the HRQoL scores differed between children by CKD stage at inception. Over half of the cohort on dialysis at baseline had received a kidney transplant by the end of year four and the MAU scores of these children increased by a meaningful amount averaging 0.05 (95% confidence interval 0.01 to 0.09) per year in comparison to those who were transplant recipients at baseline. The mean difference between baseline and year two MAU scores was 0.09 (95% confidence interval -0.05, 0.23), (Cohen's d effect size 0.31). Thus, improvement in HRQoL over time of children on dialysis at baseline was likely to have been driven by their transition from dialysis to transplantation. Additionally, children with CKD stage 1-5 and transplant recipients at baseline had no changes in their disease stage or treatment modality and experienced stable HRQoL over time.

Sex- and age-related differences in autistic behaviours in children with neurofibromatosis type 1.

This study investigated sex and age differences in autistic behaviours in children with neurofibromatosis type 1 (NF1) who scored within the clinical range on the Social Responsiveness Scale - Second Edition (T score ≥ 60). Thirty-four males and 28 females (3-16 years) were assessed with the Autism Diagnostic Observation Schedule - Second Edition and Autism Diagnostic Interview - Revised. Across both measures, males exhibited greater social communication deficits relative to females. Age-related abatement of social communication difficulties was observed for males but not females. Conversely, no sex differences were found for restricted/repetitive behaviours, which were stable over time for both males and females. The findings are discussed within the context of broader neurodevelopmental considerations that are common in NF1.

Association between socioeconomic status and academic performance in children and adolescents with chronic kidney disease.

BACKGROUND: Lower socioeconomic status (SES) is associated with lower academic achievement; however, this relationship is understudied in children with chronic kidney disease (CKD). This study examined the relationship between SES and academic performance in children and adolescents with CKD. METHODS: A total of 377 participants aged 6-18 years with CKD stages 1-5 (n = 199), on dialysis (n = 43) or with a kidney transplant (n = 135) were recruited. Five SES measures and a composite SES index were examined for associations with parent-rated average or above average academic performance in numeracy and literacy using multivariable logistic regression. RESULTS: Participants' median age was 12.6 years (IQR 8.9-15.5). Adjusted odds ratios (aOR) (95%CI) for better performance in numeracy and literacy, respectively, were 0.71 (0.44-1.15) and 0.75 (0.45-1.23) for children whose caregivers had lower educational attainment; 0.46 (0.26-0.80) and 0.53 (0.30-0.93) for lower household income; 0.52 (0.32-0.85) and 0.44 (0.26-0.73) for caregivers who were unemployed; 0.68 (0.41-1.12) and 0.59 (0.35-1.00) for caregivers with poor self-rated financial status; and 0.93 (0.53-1.64) and 1.00 (0.56-1.79) for caregivers who did not own their own home. Compared with the highest SES index quartile, the aORs for better performance by SES quartile in descending order were 1.24 (0.60-2.54), 0.76 (0.37-1.58), and 0.39 (0.18-0.86) for numeracy and 0.88 (0.41-1.85), 0.77 (0.35-1.66), and 0.32 (0.14-0.72) for literacy. No interactions were identified between SES and CKD stage, child age, or gender. CONCLUSIONS: Across all CKD stages, children from lower SES families are less likely to perform well in literacy and numeracy than those from higher SES households. A higher resolution version of the Graphical abstract is available as Supplementary information.

Cognitive and academic outcomes in children with chronic kidney disease.

BACKGROUND: Few data exist on the cognitive and academic functioning of children with chronic kidney disease (CKD) over the trajectory of their illness. We aimed to determine the association between CKD stages and cognitive and academic performance in children over time. METHODS: We included 53 participants (aged 6-18 years) with CKD stages 1-5 (n = 37), on dialysis (n = 3), or with functioning kidney transplant (n = 22) from three units in Australia from 2015 to 2019. Participants undertook a series of psychometric tests and were invited for repeated assessments annually. We used linear regression and linear mixed models to investigate the effect of CKD stage, adjusted for socioeconomic status. RESULTS: At baseline, full-scale intelligence quotient (FSIQ) (95%CI) of children on kidney replacement therapy (KRT) was in the low average range (87: 78, 96) and average (101: 95, 108) for children with CKD 1-5. Mean (95%CI) FSIQ, word reading, numerical operations, and spelling scores for children on KRT were 14.3 (- 25.3, - 3.3), 11 (- 18.5, - 3.6), 8.5 (- 17.6, 0.76), and 10 (- 18.6, - 1.3) points lower than children with CKD Stages 1-5. Spelling and numerical operations scores declined by 0.7 (- 1.4, - 0.1) and 1.0 (- 2.0, 0.2) units per year increase in age, regardless of CKD stage. CONCLUSIONS: Children treated with KRT have low average cognitive abilities and lower academic performance for numeracy and literacy compared to both children with CKD 1-5 and to the general population. However, the rate of decline in academic performance over time is similar for children across the full spectrum of CKD. A higher resolution version of the Graphical abstract is available as Supplementary information.

Accelerated long-term forgetting in children with temporal lobe epilepsy: A timescale investigation of material specificity and executive skills.

Recently, children with temporal lobe epilepsy (TLE) were found to be at risk of accelerated long-term forgetting (ALF). In this study, we examined the temporal trajectory of ALF, while exploring the relationship between ALF, executive skills, and epilepsy variables. Fifty-one children, (23 with TLE and 28 typically developing) completed a battery of neuropsychological tests of verbal and visual memory, executive skills, and two experimental memory tasks (verbal and visual) involving recall after short (30-min) and extended (1-day and 2-week) delays. Side of seizure focus and hippocampal integrity were considered. On the visual task (Scene Memory), children with TLE performed comparably to typically developing children following a 30-min and 1-day delay, although worse than typically developing children at 2 weeks: ALF was observed in children with right TLE focus. The two groups did not differ on the experimental verbal memory task. Children with TLE also had worse performance than typically developing children on standardized verbal memory test and on tests of executive skills (i.e., verbal generativity, inhibition, working memory, complex attention). Only complex attention was associated with visual ALF. ALF was present for visuo-spatial materials in children with TLE at two weeks, and children with right TLE were most susceptible. A relationship was identified between complex attention and long-term forgetting. The findings extend our understanding of difficulties in long-term memory formation experienced by children with TLE.

Delineating the autistic phenotype in children with neurofibromatosis type 1.

BACKGROUND: Existing research has demonstrated elevated autistic behaviours in children with neurofibromatosis type 1 (NF1), but the autistic phenotype and its relationship to other neurodevelopmental manifestations of NF1 remains unclear. To address this gap, we performed detailed characterisation of autistic behaviours in children with NF1 and investigated their association with other common NF1 child characteristics. METHODS: Participants were drawn from a larger cross-sectional study examining autism in children with NF1. The population analysed in this study scored above threshold on the Social Responsiveness Scale-Second Edition (T-score ≥ 60; 51% larger cohort) and completed the Autism Diagnostic Interview-Revised (ADI-R) and/or the Autism Diagnostic Observation Schedule-Second Edition (ADOS-2). All participants underwent evaluation of their intellectual function, and behavioural data were collected via parent questionnaires. RESULTS: The study cohort comprised 68 children (3-15 years). Sixty-three per cent met the ADOS-2 'autism spectrum' cut-off, and 34% exceeded the more stringent threshold for 'autistic disorder' on the ADI-R. Social communication symptoms were common and wide-ranging, while restricted and repetitive behaviours (RRBs) were most commonly characterised by 'insistence on sameness' (IS) behaviours such as circumscribed interests and difficulties with minor changes. Autistic behaviours were weakly correlated with hyperactive/impulsive attention deficit hyperactivity disorder (ADHD) symptoms but not with inattentive ADHD or other behavioural characteristics. Language and verbal IQ were weakly related to social communication behaviours but not to RRBs. LIMITATIONS: Lack of genetic validation of NF1, no clinical diagnosis of autism, and a retrospective assessment of autistic behaviours in early childhood. CONCLUSIONS: Findings provide strong support for elevated autistic behaviours in children with NF1. While these behaviours were relatively independent of other NF1 comorbidities, the importance of taking broader child characteristics into consideration when interpreting data from autism-specific measures in this population is highlighted. Social communication deficits appear similar to those observed in idiopathic autism and are coupled with a unique RRB profile comprising prominent IS behaviours. This autistic phenotype and its relationship to common NF1 comorbidities such as anxiety and executive dysfunction will be important to examine in future research. Current findings have important implications for the early identification of autism in NF1 and clinical management.

The mediating role of ADHD symptoms between executive function and social skills in children with neurofibromatosis type 1.

Children with neurofibromatosis type 1 (NF1) often experience executive dysfunction, attention deficit/hyperactivity disorder (ADHD) symptoms and poor social skills, however, the nature of the relationships between these domains in children with NF1 is unclear. This study investigated these relationships using primary caregiver ratings of executive functions, ADHD symptoms and social skills in children with NF1. Participants were 136 children with NF1 and 93 typically developing (TD) controls aged 3-15 years recruited from 3 multidisciplinary neurofibromatosis clinics in Melbourne and Sydney, Australia, and Washington DC, USA. Mediation analysis was performed on primary outcome variables: parent ratings of executive functions (Behavior Rating Inventory of Executive Function, Metacognition Index), ADHD symptoms (Conners-3/Conners ADHD Diagnostic and Statistical Manual for Mental Disorders Scales) and social skills (Social Skills Improvement System-Rating Scale), adjusting for potential confounders (full scale IQ, sex, and social risk). Results revealed significantly poorer executive functions, elevated ADHD symptoms and reduced social skills in children with NF1 compared to controls. Poorer executive functions significantly predicted elevated ADHD symptoms and poorer social skills. Elevated ADHD symptoms significantly mediated the relationship between executive functions and social skills problems although did not fully account for social dysfunction. This study provides evidence for the importance of targeting ADHD symptoms as part of future interventions aimed at promoting prosocial behaviors in children with NF1.

Longer term outcomes following serogroup B invasive meningococcal disease.

AIM: To characterise the physical, psychological, and quality of life burden associated with serogroup B invasive meningococcal disease (IMD) in children. METHODS: Children aged up to 14 years at the time of serogroup B IMD, who were admitted to intensive care units of two tertiary paediatric hospitals in New South Wales, Australia between January 2009 and December 2013 were recruited. Children underwent clinical and neuropsychological assessments up to 6 years post-disease. RESULTS: Eleven children were assessed, with a median age of 16 months (range 4-46 months) at time of disease. The median follow-up time was 50 months (range 10-67 months). Seven (63.6%) cases had one or more long-term sequelae involving permanent and evolving physical disability. Three cases had ongoing medical conditions including two with seizures and one with ataxia and hypermetropia. Five required ongoing medical and allied health care. Other complications identified included anxiety, speech delay, low average full-scale IQ score (median 85, interquartile range 89-103) and borderline memory impairment. CONCLUSIONS: Serogroup B IMD is associated with significant long-term morbidity and burden on the child and family with substantial economic implications. The impact of this on the total cost of IMD needs to be further quantified, and better considered in vaccine cost-effectiveness analyses.

School and educational support programmes for paediatric oncology patients and survivors: A systematic review of evidence and recommendations for future research and practice.

OBJECTIVES: The Psychosocial Standards of Care (PSSC) in paediatric oncology prescribe the minimum standards for education support. It is unknown, however, if published education support programmes for children with cancer meet the PSSC standards for education support. Successful implementation of standards for education support is challenging but may be achieved with guidance. We aimed to (1) review education support programmes for childhood cancer patients and survivors against the PSSC standards and (2) provide practical recommendations for future research and implementation of education support programmes. METHODS: We searched PsycINFO, PubMed, CINAHL, EMBASE, and Educational Resources Information and Center databases. We reviewed the education support programmes using five evaluation criteria derived from the PSSC and summarised the structure of identified programmes. We examined the features and limitations of programmes that met all evaluation criteria. RESULTS: We identified 20 education support programmes in paediatric oncology, including peer programmes (n = 3), teacher programmes (n = 5), and school re-entry programmes (SRPs n = 12). We found that three SRPs met all evaluation criteria and that SRP components were timed according to the child's position on the cancer trajectory (e.g., diagnosis and treatment, school re-entry, and follow up throughout schooling). The supporting evidence of the programmes, however, is unclear due to the lack of adequately designed studies. CONCLUSIONS: SRPs provide a promising structure for future education support programmes. We recommend strategies for developing and evaluating education support that adheres to the PSSC and adapts to international and local contexts.

Cognition, ADHD Symptoms, and Functional Impairment in Children and Adolescents With Neurofibromatosis Type 1.

Objective: We examined the contribution of attention and executive cognitive processes to ADHD symptomatology in NF1, as well as the relationships between cognition and ADHD symptoms with functional outcomes. Methods: The study sample consisted of 141 children and adolescents with NF1. Children were administered neuropsychological tests that assessed attention and executive function, from which latent cognitive variables were derived. ADHD symptomatology, adaptive skills, and quality of life (QoL) were assessed using parent-rated questionnaires. Path analyses were conducted to test relationships among cognitive functioning, ADHD symptomatology, and functional outcomes. Results: Significant deficits were observed on all outcome variables. Cognitive variables did not predict ADHD symptomatology. Neither did they predict functional outcomes. However, elevated ADHD symptomatology significantly predicted functional outcomes. Conclusion: Irrespective of cognitive deficits, elevated ADHD symptoms in children with NF1 negatively impact daily functioning and emphasize the importance of interventions aimed at minimizing ADHD symptoms in NF1.

Effects of anxiety on preferences for generic medicines in Australia.

Generic medicines have been available to consumers for ∼40 years, with varying degrees of uptake in different countries. Despite offering equivalent therapeutic qualities, generic medicines still struggle to be accepted by consumers. This study examines the role of a consumer's affective state and framing effects on the purchase of a branded versus a generic pharmaceutical product. These issues are examined in an experiment, with independent manipulations of consumer anxiety levels and the framing of generic alternatives by the pharmacist. The sample comprised 426 men and women within Australia who completed an online survey with a scenario of purchasing a pharmaceutical after visiting a General Practitioner. Results indicate that those consumers experiencing higher levels of anxiety and where the doctor prescribed the branded medicine are more likely to choose branded medicines over cheaper, generic alternatives. The effect of framing the generic alternative as either 'generic' or 'cheaper' was not significant.

Profiling the Word Reading Abilities of School-Age Children with Neurofibromatosis Type 1.

OBJECTIVE: Reading difficulties are one of the most significant challenges for children with neurofibromatosis type 1 (NF1). The aims of this study were to identify and categorize the types of reading impairments experienced by children with NF1 and to establish predictors of poor reading in this population. METHOD: Children aged 7-12 years with NF1 (n = 60) were compared with typically developing children (n = 36). Poor word readers with NF1 were classified according to impairment type (i.e., phonological, surface, mixed), and their reading subskills were compared. A hierarchical multiple regression was conducted to identify predictors of word reading. RESULTS: Compared to controls, children with NF1 demonstrated significantly poorer literacy abilities. Of the 49 children with NF1 classified as poor readers, 20 (41%) were classified with phonological dyslexia, 24 (49%) with mixed dyslexia, and 5 (10%) fell outside classification categories. Children with mixed dyslexia displayed the most severe reading impairments. Stronger working memory, better receptive language, and fewer inattentive behaviors predicted better word reading skills. CONCLUSIONS: The majority of children with NF1 experience deficits in key reading skills which are essential for them to become successful readers. Weaknesses in working memory, receptive language, and attention are associated with reading difficulties in children with NF1.

Neurocognitive Dysfunction and Smaller Brain Volumes in Adolescents and Adults With a Fontan Circulation.

BACKGROUND: Neurocognitive outcomes beyond childhood in people with a Fontan circulation are not well defined. This study aimed to investigate neurocognitive functioning in adolescents and adults with a Fontan circulation and associations with structural brain injury, brain volumetry, and postnatal clinical factors. METHODS: In a binational study, participants with a Fontan circulation without a preexisting major neurological disability were prospectively recruited from the Australia and New Zealand Fontan Registry. Neurocognitive function was assessed by using Cogstate software in 107 participants with a Fontan circulation and compared with control groups with transposition of the great arteries (n=50) and a normal circulation (n=41). Brain MRI with volumetric analysis was performed in the participants with a Fontan circulation and compared with healthy control data from the ABIDE I and II (Autism Brain Imaging Data Exchange) and PING (Pediatric Imaging, Neurocognition, and Genetics) data repositories. Clinical data were retrospectively collected. RESULTS: Of the participants with a Fontan circulation who had a neurocognitive assessment, 55% were male and the mean age was 22.6 years (SD 7.8). Participants with a Fontan circulation performed worse in several areas of neurocognitive function compared with those with transposition of the great arteries and healthy controls (P<0.05). Clinical factors associated with worse neurocognitive outcomes included more inpatient days during childhood, younger age at Fontan surgery, and longer time since Fontan procedure (P<0.05). Adults with a Fontan circulation had more marked neurocognitive dysfunction than adolescents with a Fontan circulation in 2 domains (psychomotor function, P=0.01 and working memory, P=0.02). Structural brain injury was present in the entire Fontan cohort; the presence of white matter injury was associated with worse paired associate learning (P<0.001), but neither the presence nor severity of infarct, subcortical gray matter injury, and microhemorrhage was associated with neurocognitive outcomes. Compared with healthy controls, people with a Fontan circulation had smaller global brain volumes (P<0.001 in all regions) and smaller regional brain volumes in most cerebral cortical regions (P<0.05). Smaller global brain volumes were associated with worse neurocognitive functioning in several domains (P<0.05). A significant positive association was also identified between global brain volumes and resting oxygen saturations (P≤0.04). CONCLUSIONS: Neurocognitive impairment is common in adolescents and adults with a Fontan circulation and is associated with smaller gray and white matter brain volume. Understanding modifiable factors that contribute to brain injury to optimize neurocognitive function is paramount.

Accelerated long-term forgetting in children with genetic generalized epilepsy: The temporal trajectory and contribution of executive skills.

PURPOSE: Long-term memory, which is critical for social and vocational functioning, is impaired in children with genetic generalized epilepsy (GGE). In this study, we examined the relationship between the temporal pattern of long-term forgetting for visual and verbal materials and executive skills in children with GGE. METHOD: Thirty-two children, 17 with GGE and 25 typically developing age-matched controls completed standardized tests of short-term memory (recall after a 30-minute delay), executive skills, and experimental long-term memory tasks (one verbal and one visual) involving recall after one short (30-minute), and two long (1-day, 2-week) delays. RESULTS: On the long-term visual memory task, children with GGE performed comparably with typically developing children at a 30-minute delay (p = .298), although obtained lower object placement accuracy score, at 1 day (p = .039) and at 2 weeks (p = .022) relative to typically developing children. On the verbal task, the between-group difference was not significant at any delay. In children with GGE, poorer object placement accuracy at two weeks correlated with lower visuospatial short-term memory (r = -0.624, p = .005) and verbal working memory (r = -0.448, p = .041). CONCLUSIONS: This study provided several novel findings. For the first time, accelerated long-term forgetting (ALF) was found in long-term visual memory in children with GGE, despite comparable learning and recall at 30 min. Study results indicated that deficits in long-term visual memory are present after one day, increase over time, and may relate to reduced executive skills. Our findings can be used to inform our understanding of the temporal trajectory of ALF and contribution of executive skills.

Developmental outcomes following vaccine-proximate febrile seizures in children.

OBJECTIVE: To compare the developmental and behavioral outcomes of children experiencing an initial vaccine-proximate (VP) febrile seizure (FS) to those having a non-VP-FS (NVP-FS) and controls who have not had a seizure. METHODS: In this prospective multicenter cohort study, children with their first FS before 30 months of age between May 2013 and April 2016 were recruited from 4 Australian pediatric hospitals and classified as having VP-FS or NVP-FS. Similar-aged children with no seizure history were recruited as controls. The Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III) was administered to participants with FS 12 to 24 months after their initial FS and to controls 12 to 42 months of age at the time of assessment. The primary outcome was the Bayley-III cognitive score. Children's preacademic skills were assessed with the Woodcock-Johnson Tests of Achievement, Third Edition, and their behavior and executive functioning were obtained from parent questionnaires. RESULTS: There was no significant difference in cognitive function between children with VP-FS (n = 62), those with NVP-FS (n = 70), and controls (n = 90) (F 2,219 = 2.645, p = 0.07). There were no differences between the groups for all other measures and no increased risk of borderline/significant impairment or behavior in the clinical range in children with VP-FS compared to those with NVP-FS or controls. CONCLUSION: VP-FS was not associated with an increased risk of developmental or behavioral problems in young children compared to children with NVP-FS or controls. Parents and providers should be reassured by the absence of adverse effects of VP-FS on the development of children.

Reproducibility of cognitive endpoints in clinical trials: lessons from neurofibromatosis type 1.

OBJECTIVE: Rapid developments in understanding the molecular mechanisms underlying cognitive deficits in neurodevelopmental disorders have increased expectations for targeted, mechanism-based treatments. However, translation from preclinical models to human clinical trials has proven challenging. Poor reproducibility of cognitive endpoints may provide one explanation for this finding. We examined the suitability of cognitive outcomes for clinical trials in children with neurofibromatosis type 1 (NF1) by examining test-retest reliability of the measures and the application of data reduction techniques to improve reproducibility. METHODS: Data were analyzed from the STARS clinical trial (n = 146), a multi-center double-blind placebo-controlled phase II trial of lovastatin, conducted by the NF Clinical Trials Consortium. Intra-class correlation coefficients were generated between pre- and post-performances (16-week interval) on neuropsychological endpoints in the placebo group to determine test-retest reliabilities. Confirmatory factor analysis was used to reduce data into cognitive domains and account for measurement error. RESULTS: Test-retest reliabilities were highly variable, with most endpoints demonstrating unacceptably low reproducibility. Data reduction confirmed four distinct neuropsychological domains: executive functioning/attention, visuospatial ability, memory, and behavior. Test-retest reliabilities of latent factors improved to acceptable levels for clinical trials. Applicability and utility of our model was demonstrated by homogeneous effect sizes in the reanalyzed efficacy data. INTERPRETATION: These data demonstrate that single observed endpoints are not appropriate to determine efficacy, partly accounting for the poor test-retest reliability of cognitive outcomes in clinical trials in neurodevelopmental disorders. Recommendations to improve reproducibility are outlined to guide future trial design.