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.

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.

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.

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.

Power analysis for idiographic (within-subject) clinical trials: Implications for treatments of rare conditions and precision medicine.

Power analysis informs a priori planning of behavioral and medical research, including for randomized clinical trials that are nomothetic (i.e., studies designed to infer results to the general population based on interindividual variabilities). Far fewer investigations and resources are available for power analysis of clinical trials that follow an idiographic approach, which emphasizes intraindividual variabilities between baseline (control) phase versus one or more treatment phases. We tested the impact on statistical power to detect treatment outcomes of four idiographic trial design factors that are under researchers' control, assuming a multiple baseline design: sample size, number of observations per participant, proportion of observations in the baseline phase, and competing statistical models (i.e., hierarchical modeling versus piecewise regression). We also tested the impact of four factors that are largely outside of researchers' control: population size, proportion of intraindividual variability due to residual error, treatment effect size, and form of outcomes during the treatment phase (phase jump versus gradual change). Monte Carlo simulations using all combinations of the factors were sampled with replacement from finite populations of 200, 1750, and 3500 participants. Analyses characterized the unique relative impact of each factor individually and all two-factor combinations, holding all others constant. Each factor impacted power, with the greatest impact being from larger treatment effect sizes, followed respectively by more observations per participant, larger samples, less residual variance, and the unexpected improvement in power associated with assigning closer to 50% of observations to the baseline phase. This study's techniques and R package better enable a priori rigorous design of idiographic clinical trials for rare diseases, precision medicine, and other small-sample studies.

A Voluntary Statewide Newborn Screening Pilot for Spinal Muscular Atrophy: Results from Early Check.

Prior to statewide newborn screening (NBS) for spinal muscular atrophy (SMA) in North Carolina, U.S.A., we offered voluntary screening through the Early Check (EC) research study. Here, we describe the EC experience from October 2018 through December 2020. We enrolled a total of 12,065 newborns and identified one newborn with 0 copies of SMN1 and two copies of SMN2, consistent with severe early onset of SMA. We also detected one false positive result, likely stemming from an unrelated blood disorder associated with a low white blood cell count. We evaluated the timing of NBS for babies enrolled prenatally (n = 932) and postnatally (n = 11,133) and reasons for delays in screening and reporting. Although prenatal enrollment led to faster return of results (median = 13 days after birth), results for babies enrolled postnatally were still available within a timeframe (median = 21 days after birth) that allowed the opportunity to receive essential treatment early in life. We evaluated an SMA q-PCR screening method at two separate time points, confirming the robustness of the assay. The pilot project provided important information about SMA screening in anticipation of forthcoming statewide expansion as part of regular NBS.

Emergence of Developmental Delay in Infants and Toddlers With an FMR1 Mutation.

BACKGROUND: Children with FMR1 gene expansions are known to experience a range of developmental challenges, including fragile X syndrome. However, little is known about early development and symptom onset, information that is critical to guide earlier identification, more accurate prognoses, and improved treatment options. METHODS: Data from 8 unique studies that used the Mullen Scales of Early Learning to assess children with an FMR1 gene expansion were combined to create a data set of 1178 observations of >500 young children. Linear mixed modeling was used to explore developmental trajectories, symptom onset, and unique developmental profiles of children <5 years of age. RESULTS: Boys with an FMR1 gene full mutation showed delays in early learning, motor skills, and language development as young as 6 months of age, and both sexes with a full mutation were delayed on all developmental domains by their second birthday. Boys with a full mutation continued to gain skills over early childhood at around half the rate of their typically developing peers; girls with a full mutation showed growth at around three-quarters of the rate of their typically developing peers. Although children with a premutation were mostly typical in their developmental profiles and trajectories, mild but significant delays in fine motor skills by 18 months were detected. CONCLUSIONS: Children with the FMR1 gene full mutation demonstrate significant developmental challenges within the first 2 years of life, suggesting that earlier identification is needed to facilitate earlier implementation of interventions and therapeutics to maximize effectiveness.

Outreach to new mothers through direct mail and email: recruitment in the Early Check research study.

Meeting recruitment targets for clinical trials and health research studies is a notable challenge. Unsuccessful efforts to recruit participants from traditionally underserved populations can limit who benefits from scientific discovery, thus perpetuating inequities in health outcomes and access to care. In this study, we evaluated direct mail and email outreach campaigns designed to recruit women who gave birth in North Carolina for a statewide research study offering expanded newborn screening for a panel of rare health conditions. Of the 54,887 women who gave birth in North Carolina from September 28, 2018, through March 19, 2019, and were eligible to be included on the study's contact lists, we had access to a mailing address for 97.9% and an email address for 6.3%. Rural women were less likely to have sufficient contact information available, but this amounted to less than a one percentage point difference by urbanicity. Native American women were less likely to have an email address on record; however, we did not find a similar disparity when recruitment using direct-mail letters and postcards was concerned. Although we sent letters and emails in roughly equal proportion by urbanicity and race/ethnicity, we found significant differences in enrollment across demographic subgroups. Controlling for race/ethnicity and urbanicity, we found that direct-mail letters and emails were effective recruitment methods. The enrollment rate among women who were sent a recruitment letter was 4.1%, and this rate increased to 5.0% among women who were also sent an email invitation. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? Under-representation by traditionally underserved populations in clinical trials and health research is a challenge that may in part reflect inequitable opportunities to participate. WHAT QUESTION DID THIS STUDY ADDRESS? Are direct-mail and email outreach strategies effective for reaching and recruiting women from traditionally underserved and rural populations to participate in large-scale, population-based research? WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? Despite sending recruitment letters and email invitations in roughly equal proportion by urbanicity and race/ethnicity, women living in rural areas were less likely to enroll (2.8%) than women from urban areas (4.2%). Additionally, enrollment rates decreased as the probability that women were members of a racial or ethnic minority group increased. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? Results from this study might encourage researchers to take a holistic and participant-centered view of barriers to study enrollment that may disproportionately affect underserved communities, including differences in willingness to participate, trust, and access to resources needed for uptake.

Comprehensive Assessment of Individuals With Significant Levels of Intellectual Disability: Challenges, Strategies, and Future Directions.

The variety and extent of impairments in individuals with severe-profound levels of intellectual disability (ID) impact their ability to complete valid behavioral assessments. Although standardized assessment is crucial for objectively evaluating patients, many individuals with severe-profound levels of ID perform at the floor of most assessments designed for their chronological age. Additionally, the presence of language and motor impairments may influence the individual's ability to perform a task, even when that task is meant to measure an unrelated construct leading to an underestimation of their true ability. This article provides an overview of the assessment protocols used by multiple groups working with individuals with severe-profound levels of ID, discusses considerations for obtaining high-quality assessment results, and suggests guidelines for standardizing these protocols across the field.

Preferences for Accessing Electronic Health Records for Research Purposes: Views of Parents Who Have a Child With a Known or Suspected Genetic Condition.

OBJECTIVES: The purpose of this study was to examine parental preferences for researchers accessing their child's electronic health record across 3 groups: those with a child with (1) a known genetic condition (fragile X syndrome FXS), (2) a suspected genetic condition (autism spectrum disorder [ASD]), and (3) no known genetic condition (typically developing). METHODS: After extensive formative work, a discrete choice experiment was designed consisting of 5 attributes, each with 2 or 3 levels, including (1) type of researcher, (2) the use of personally identifiable information, (3) the use of sensitive information, (4) personal importance of research, and (5) return of results. Stratified mixed logit and latent class conditional logit models were examined. RESULTS: Parents of children with FXS or ASD had relatively higher preferences for research conducted by nonprofits than parents of typically developing children. Parents of children with ASD also preferred research using non-identifiable and nonsensitive information. Parents of children with FXS or ASD also had preferences for research that was personally important and returned either summary or individual results. Although a few child and family characteristics were related to preferences, they did not overall define the subgroups of parents. CONCLUSIONS: Although electronic health record preference research has been conducted with the general public, this is the first study to examine the opinions of parents who have a child with a known or suspected genetic condition. These parents were open to studies using their child's electronic health record because they may have more to gain from this type of research.

Developmental Outcomes Among Young Children With Congenital Zika Syndrome in Brazil.

Importance: Although birth defects in children with congenital Zika syndrome (CZS) are expected to result in significant intellectual disabilities, the extent of delay and profiles of development have yet to be fully described. Objectives: To describe the neurodevelopmental profiles of children with CZS and to test whether prenatal and postpartum characteristics were associated with the severity of developmental delays. Design, Setting, and Participants: This is a case series of the trajectories of developmental, behavioral, and medical needs of 121 young children with CZS who were assessed at a specialized rehabilitation center in Recife, Brazil, beginning in January 2018 as part of 5-year longitudinal study. Children were included if they had serologic confirmation of Zika virus and met clinical criteria accompanied by parental report of suspected exposure to Zika virus during pregnancy. Exposures: Prenatal Zika virus exposure. Main Outcomes and Measures: The Brazilian version of the Bayley Scales of Infant and Toddler Development, Third Edition, was administered by trained assessors as part of an initial comprehensive assessment battery. Caregiver interviews and medical record reviews were conducted to gather basic demographic information and medical comorbidities. Linear regression was used to identify potential factors for development. Results: The sample included 121 young children (mean [SD] age, 31.2 [1.9] months; 61 [50.4%] girls). At age approximately 2.5 years, nearly all children in this sample demonstrated profound developmental delays across all domains of functioning, with a mean (SD) developmental age equivalent to approximately 2 to 4 months (eg, cognitive domain, 2.24 [3.09] months; fine motor subscale, 2.15 [2.93] months; expressive language subscale, 2.30 [2.52] months). A relative strength was found in receptive language, with scores on this scale significantly higher than most other domains (eg, cognition: t = 3.73; P < .001; fine motor: t = 6.99; P < .001). Head circumference at birth was the single strongest factor associated with outcomes across all developmental domains (eg, cognitive: ß = 1.41; SE, 0.67; P = .04; fine motor: ß = 1.36; SE, 0.49; P = .007). Conclusions and Relevance: The findings of this study provide important information regarding the severity of disability that these children and their families will experience. The findings also establish an initial point from which to monitor developmental trajectories, medical comorbidities (eg, seizures), effectiveness of interventions, and cumulative consequences on families.

Food and Non-Food-Related Behavior across Settings in Children with Prader-Willi Syndrome.

This study sought to describe food- and non-food-related behaviors of children aged 3 to 18 years with Prader-Willi syndrome (PWS) in home and school settings, as assessed by 86 parents and 63 teachers using 7 subscales of the Global Assessment of Individual's Behavior (GAIB). General Behavior Problem, Non-Food-Related Behavior Problem, and Non-Food-Related Obsessive Speech and Compulsive Behavior (OS/CB) scores did not differ significantly between parent and teacher reports. Food-Related Behavior Problem scores were higher in parent versus teacher reports when the mother had less than a college education (difference of 13.6 points, 95% Confidence Interval (CI) 5.1 to 22). Parents assigned higher Food-Related OS/CB scores than teachers (difference of 5.7 points, 95% CI 2.4 to 9.0). Although teachers reported fewer Food-Related OS/CB, they scored overall OS/CB higher for interfering with daily activities compared with parents (difference of 0.9 points, 95% CI 0.4 to 1.4). Understanding how behaviors manifest in home and school settings, and how they vary with socio-demographic and patient characteristics can help inform strategies to reduce behavior problems and improve outcomes.

"Just tell me what's going on": The views of parents of children with genetic conditions regarding the research use of their child's electronic health record.

OBJECTIVE: The purpose of this study was to understand the ethical, legal, and social issues described by parents of children with known or suspected genetic conditions that cause intellectual and developmental disabilities regarding research use of their child's electronic health record (EHR). MATERIALS AND METHODS: We conducted 4 focus groups with parents of children with a known (n = 12) or suspected (n = 11) genetic condition, as well as 2 comparison groups with parents who had a child with no known genetic condition (n = 15). Focus group transcripts were coded and analyzed using directed content analysis. RESULTS: After weighing the risks and benefits, parents of children with known or suspected genetic conditions were willing to share their child's EHR for research studies under certain conditions. Preferences were for studies conducted by universities or nonprofits that might benefit their child or others with the same condition. Parents also valued return of research results. DISCUSSION: Trust, transparency, altruism, and concerns about privacy emerged as factors that affect parents' willingness to allow research use of their child's EHR. CONCLUSION: Researchers should consider how to build trust with parents by increasing transparency of the research process and explaining specifically how they will ensure the confidentiality of EHR data.

Decisional Capacity for Informed Consent in Males and Females with Fragile X Syndrome.

Although informed consent is critical for all research, there is increased ethical responsibility as individuals with intellectual or developmental disabilities (IDD) become the focus of more clinical trials. This study examined decisional capacity for informed consent to clinical trials in individuals with fragile X syndrome (FXS). Participants were 152 adolescents and adults (80 males, 72 females) with FXS who completed a measure of decisional capacity and a comprehensive battery of neurocognitive and psychiatric measures. Females outperformed males on all aspects of decisional capacity. The ability to understand aspects of the clinical trial had the strongest association with the ability to appreciate and reason about the decision. Scaffolding improved understanding, suggesting researchers can take steps to improve decisional capacity and the informed consent process.

Supporting informed clinical trial decisions: Results from a randomized controlled trial evaluating a digital decision support tool for those with intellectual disability.

BACKGROUND: Informed consent requires that individuals understand the nature of the study, risks and benefits of participation. Individuals with intellectual disabilities (ID) have cognitive and adaptive impairments that may affect their ability to provide informed consent. New treatments and clinical trials for fragile X syndrome, the most commonly known inherited cause of ID, necessitate the development of methods to improve the informed consent process. The goal of this study was to compare the efficacy of a digital decision support tool with that of standard practice for informed consent and to examine whether the tool can improve decisional capacity for higher functioning individuals. METHODS: Participants (N = 89; mean age = 21.2 years) were allocated to the experimental group (consenting information provided via the digital decision support tool), or the comparison group (information provided via standard practice). Participants were assessed on four aspects of decisional capacity (Understanding, Appreciating, Reasoning, and Expressing a choice). We used regression analyses to test the impact of the tool on each outcome, repeating the analyses on the higher functioning subsample. RESULTS: No differences existed in any domain of decisional capacity for the sample in full. However, participants in the higher IQ subsample who used the tool scored better on Understanding after adjustment (ß = 0.25, p = 0.04), but not on Appreciating or Reasoning. No differences by experimental group existed in the decision to join the hypothetical trial for the full sample or higher functioning subsample. CONCLUSIONS: A decision support tool shows promise for individuals with fragile X syndrome with higher cognitive abilities. Future studies should examine the level of cognitive ability needed for sufficient understanding, whether these findings can be translated to other clinical populations, and the impact of the tool in larger trials and on trial retention.

Early Check: translational science at the intersection of public health and newborn screening.

BACKGROUND: Newborn screening (NBS) occupies a unique space at the intersection of translational science and public health. As the only truly population-based public health program in the United States, NBS offers the promise of making the successes of translational medicine available to every infant with a rare disorder that is difficult to diagnose clinically, but for which strong evidence indicates that presymptomatic treatment will substantially improve outcomes. Realistic NBS policy requires data, but rare disorders face a special challenge: Screening cannot be done without supportive data, but adequate data cannot be collected in the absence of large-scale screening. The magnitude and scale of research to provide this expanse of data require working with public health programs, but most do not have the resources or mandate to conduct research. METHODS: To address this gap, we have established Early Check, a research program in partnership with a state NBS program. Early Check provides the infrastructure needed to identify conditions for which there have been significant advances in treatment potential, but require a large-scale, population-based study to test benefits and risks, demonstrate feasibility, and inform NBS policy. DISCUSSION: Our goal is to prove the benefits of a program that can, when compared with current models, accelerate understanding of diseases and treatments, reduce the time needed to consider inclusion of appropriate conditions in the standard NBS panel, and accelerate future research on new NBS conditions, including clinical trials for investigational interventions. TRIAL REGISTRATION: Clinicaltrials.gov registration # NCT03655223 . Registered on August 31, 2018.

Early Identification of Fragile X Syndrome through Expanded Newborn Screening.

Over the past 20 years, research on fragile X syndrome (FXS) has provided foundational understanding of the complex experiences of affected individuals and their families. Despite this intensive focus, there has been little progress on earlier identification, with the average age of diagnosis being 3 years. For intervention and treatment approaches to have the greatest impact, they need to begin shortly after birth. To access this critical timespan, differential methods of earlier identification need to be considered, with an emerging focus on newborn screening practices. Currently, barriers exist that prevent the inclusion of FXS on standard newborn screening panels. To address these barriers, an innovative program is being implemented in North Carolina to offer voluntary screening for FXS under a research protocol, called Early Check. This program addresses the difficulties observed in prior pilot studies, such as recruitment, enrollment, lab testing, and follow-up. Early Check provides an opportunity for stakeholders and the research community to continue to gain valuable information about the feasibility and greater impact of newborn screening on the FXS population.