'The cure for us is a lot of things': How young people with Prader-Willi syndrome view themselves and future clinical trials.

BACKGROUND: Despite work on the self-identities of people with intellectual disabilities, research has yet to describe the self-perceptions of people with Prader-Willi syndrome (PWS). The perspectives of those with PWS are also important for rapidly evolving clinical trials aimed at treating symptoms of PWS. METHOD: Twenty-one young people with PWS were administered a semi-structured interview that assessed how they perceive their syndrome and clinical trials. Transcribed interviews were reliably coded using content-driven, applied thematic analyses. RESULTS: Five themes emerged: struggles with chronic hunger and food-seeking that impede goals and relationships; struggles with anxiety and outbursts, schedule changes and school; distancing from PWS; needs for clinical trials that cure PWS, reduce hunger or anxiety, and lead to improved outcomes; and needs for advocacy and awareness of PWS. CONCLUSIONS: Findings shed new light on the self-perceptions of those with PWS and have important implications for current interventions and future clinical trials.

Attentional rather than sensory differences characterize auditory processing in Williams syndrome.

Individuals with Williams Syndrome (WS) exhibit an atypical auditory profile. Across two experiments, we used event-related potentials (ERPs) in a three-stimulus auditory oddball task to examine early sensory (P1, N1, P2) and later cognitive (P3a, P3b) stages of cortical auditory processing in adults with WS and age-matched typical peers. In Study 1, piano chords served as standard, target, and novel stimuli; whereas, in Study 2, a variety of non-piano sounds comprised the novel stimuli. Across both experiments, there were no group differences in the earliest stages of sensory encoding (P1, N1), along with evidence for atypically large P2 responses in participants with WS. Persons with WS exhibited larger than typical P3a responses when the novel stimuli were perceptually distinct from the standard and the target stimuli (Study 2), but not when task-relevant and -irrelevant stimuli were perceptually similar (Study 1). Further, the WS group demonstrated reduced goal-directed attention (attenuated P3b response). These group differences in ERPs were not directly related to IQ. Our results in the context of an active discrimination task point to a more complex profile of auditory processing in persons with WS than previously reported, with group differences emerging during the later stages of stimulus categorization and evaluation, but not within early stimulus detection and feature encoding.

Cognitive and adaptive advantages of growth hormone treatment in children with Prader-Willi syndrome.

BACKGROUND: People with Prader-Willi syndrome (PWS) typically have mild to moderate intellectual deficits, compulsivity, hyperphagia, obesity, and growth hormone deficiencies. Growth hormone treatment (GHT) in PWS has well-established salutatory effects on linear growth and body composition, yet cognitive benefits of GHT, seen in other patient groups, have not been well studied in PWS. METHODS: Study 1 included 96 children and youth with PWS aged 4-21 years who naturalistically varied in their exposures to GHT. Controlling for socioeconomic status, analyses compared cognitive and adaptive behavior test scores across age-matched treatment naïve versus growth hormone treated children. Study II assessed if age of treatment initiation or treatment duration was associated with subsequent cognition or adaptive behavior in 127, 4- to 21-year olds with PWS. Study III longitudinally examined cognitive and adaptive behavior in 168 participants who were either consistently on versus off GHT for up to 4-5 years. RESULTS: Compared to the treatment naïve group, children receiving GHT had significantly higher Verbal and Composite IQs, and adaptive communication and daily living skills. Children who began treatment before 12 months of age had higher Nonverbal and Composite IQs than children who began treatment between 1 and 5 years of age. Longitudinally, the groups differed in their intercepts, but not slopes, with each group showing stable IQ and adaptive behavior scores over time. CONCLUSIONS: Cognitive and adaptive advantages should be considered an ancillary benefit and additional justification for GHT in people with PWS. Future efforts need to target apparent socioeconomic inequities in accessing GHT in the PWS population.

Effects of MetAP2 inhibition on hyperphagia and body weight in Prader-Willi syndrome: A randomized, double-blind, placebo-controlled trial.

AIMS: There are no treatments for the extreme hyperphagia and obesity in Prader-Willi syndrome (PWS). The bestPWS clinical trial assessed the efficacy, safety and tolerability of the methionine aminopeptidase 2 (MetAP2) inhibitor, beloranib. MATERIALS AND METHODS: Participants with PWS (12-65 years old) were randomly assigned (1:1:1) to biweekly placebo, 1.8 mg beloranib or 2.4 mg beloranib injection for 26 weeks at 15 US sites. Co-primary endpoints were the changes in hyperphagia [measured by Hyperphagia Questionnaire for Clinical Trials (HQ-CT); possible score 0-36] and weight by intention-to-treat. ClinicalTrials.gov registration: NCT02179151. RESULTS: One-hundred and seven participants were included in the intention-to-treat analysis: placebo (n = 34); 1.8 mg beloranib (n = 36); or 2.4 mg beloranib (n = 37). Improvement (reduction) in HQ-CT total score was greater in the 1.8 mg (mean difference -6.3, 95% CI -9.6 to -3.0; P = .0003) and 2.4 mg beloranib groups (-7.0, 95% CI -10.5 to -3.6; P = .0001) vs placebo. Compared with placebo, weight change was greater with 1.8 mg (mean difference - 8.2%, 95% CI -10.8 to -5.6; P < .0001) and 2.4 mg beloranib (-9.5%, 95% CI -12.1 to -6.8; P < .0001). Injection site bruising was the most frequent adverse event with beloranib. Dosing was stopped early due to an imbalance in venous thrombotic events in beloranib-treated participants (2 fatal events of pulmonary embolism and 2 events of deep vein thrombosis) compared with placebo. CONCLUSIONS: MetAP2 inhibition with beloranib produced statistically significant and clinically meaningful improvements in hyperphagia-related behaviours and weight loss in participants with PWS. Although investigation of beloranib has ceased, inhibition of MetAP2 is a novel mechanism for treating hyperphagia and obesity.

The Prader-Willi syndrome Profile: validation of a new measure of behavioral and emotional problems in Prader-Willi syndrome.

BACKGROUND: Prader-Willi syndrome (PWS) is a rare, neurodevelopmental disorder caused by the lack of expression of paternally imprinted genes on chromosome 15q11-13. PWS features a complex behavioral phenotype, including hyperphagia, anxiety, compulsivity, rigidity, repetitive speech, temper outbursts, aggressivity, and skin-picking. Questionnaires exist for measuring hyperphagia, but not for the aggregation of other problems that are distinctive to PWS. A PWS-specific tool is needed for phenotypic research, and to help evaluate treatment efficacy in future clinical trials aimed at attenuating PWS's hyperphagia and related problems. In this 4-phase study, we leveraged our expertise in PWS with feedback from families and specialists to validate the PWS Profile, a novel, informant-based measure of behavioral and emotional problems in this syndrome. RESULTS: The authors developed a bank of 73 items that tapped both common and less frequent but clinically significant problems in PWS (Phase 1). An iterative feedback process with families and stakeholders was used to ensure content and construct validity (Phase 2). After adding, omitting, or revising items, in Phase 3, we pilot tested the measure in 112 participants. Results were reviewed by an international team of PWS specialists and revised again (Phase 3). The final, 57-item Profile was then administered to 761 participants (Phase 4). Principal component factor analyses (n = 873) revealed eight conceptually meaningful factors, accounting for 60.52% of test variance, and were readily interpretated as: Rigidity, Insistence; Aggressive Behaviors; Repetitive Questioning, Speech; Compulsive Behaviors; Depression, Anxiety; Hoarding; Negative Distorted Thinking; and Magical Distorted Thinking. Factors were internally consistent and showed good test-retest reliability and convergent validity with existent measures of behavioral problems. Profile factors were not related to IQ, BMI, or parental SES. Three Profile factors differed across PWS genetic subtypes. Age and gender differences were found in only one Profile factor, Hoarding. CONCLUSIONS: The PWS Profile is a valid, psychometrically-sound questionnaire that already has shown responsivity to treatment in a previous clinical trial. The Profile can extend the reach of future clinical trials by evaluating the impact of novel agents not only on hyperphagia, but also on the emotional and behavioral problems that characterize PWS.

Genetic disorders of intellectual disability: expanding our concepts of phenotypes and of family outcomes.

Over the past two decades, great strides have been made in our understandings of how genetic conditions influence behavior and how such so-called "behavioral phenotypes" influence parent and family stress and coping. In this paper, we call for expansions in two directions. First, as a field we need to go beyond behavior in our concepts of phenotypes, to also include the many medical, physical, and other "non-behavioral" phenotypes that influence children's everyday lives. Second, in examining how etiology-related phenotypes affect others, we need to go beyond the outcome of parental stress. In this regard, we focus on parental health, well-being, and various life choices, as well as how parenting children with specific genetic disorders can often lead to positive perceptions and outcomes. We end by discussing remaining research issues and how these two expansions relate to clinical practice.

The Feasibility and Effectiveness of a Novel, On-Line Social Skills Intervention for Individuals With Prader-Willi Syndrome.

Introduction: People with neurodevelopmental disabilities, including Prader-Willi syndrome (PWS), are at heightened risk for the negative sequalae of loneliness, including depression and anxiety. While societal factors such as stigma or limited social opportunities contribute to loneliness, so too do deficits in social cognition and social skills. People with PWS have specific difficulties recognizing affect in others, accurately interpreting social interactions, and taking the perspectives of others. These features, combined with hyperphagia, rigidity, and insistence on sameness conspire to impede the abilities of people with PWS to make and sustain friendships and reduce feelings of loneliness. Methods: We developed and administered an intervention, Building Our Social Skills (BOSS), that aimed to improve social skill deficits in PWS. The 10-week intervention was administered on-line via Zoom to 51 young people with PWS in the U.S. (M age = 20.8, SD = 6.42). Two clinicians co-led groups of 6-8 participants in 30-min sessions, 3 times per week, and also trained 4 graduate students to co-lead groups with high fidelity. We used a pre-post intervention and 3-month follow-up design, with no control group, and mitigated this design limitation by triangulating across informants and methodologies. Specifically, parents completed the widely used Social Responsiveness Scale (SRS) and Child Behavior Checklist (CBCL), and participants were individually interviewed about their friendships and loneliness. Interview responses were reliably coded by independent raters. Results: Repeated measure multivariate analyses, with baseline values entered as covariates, revealed significant pre-to post-test improvements in the SRS's social cognition, motivation and communication subscales (p's < 0.001), with large effect sizes ( n p 2 = 0.920, 0.270, and 0.204, respectively). Participant and parental reports of loneliness were correlated with the CBCL's Internalizing domain, specifically the Anxiety/Depressed subdomain. Over time, parents reported getting along better with peers, increased contact with friends, more friends and less loneliness. Participants also reported significantly less loneliness and more friends. Conclusions: This mixed method, proof-of-concept study demonstrated the feasibility of delivering an on-line social skills intervention to young people with PWS. As no differences were found between clinician vs. graduate student outcomes, the BOSS curriculum holds considerable promise for wider dissemination and implementation in the PWS community.

A Longitudinal RCT of P-ESDM With and Without Parental Mindfulness Based Stress Reduction: Impact on Child Outcomes.

This randomized controlled trial (NCT03889821) examined Mindfulness Based Stress Reduction (MBSR) in conjunction with the Parent-implemented Early Start Denver Model (P-ESDM). A previous report described improved metrics of parental distress (Weitlauf et al. in Pediatrics 145(Supplement 1):S81-S92, 2020). This manuscript examines child outcomes. 63 children with ASD (< 36 months) and their parents received 12 P-ESDM sessions. Half of parents also received MBSR. Longitudinal examination of whole sample means revealed modest improvements in autism severity, cognitive, and adaptive skills. There was not a significant time × group interaction for children whose parents received MBSR. Future work should examine more proximal markers of child or dyadic change to enhance understanding of the impact of providing direct treatment for parents as part of early intervention initiatives.

TPH2 G/T polymorphism is associated with hyperphagia, IQ, and internalizing problems in Prader-Willi syndrome.

BACKGROUND: Prader-Willi syndrome (PWS) is a genetic, neurodevelopmental disorder characterized by intellectual disabilities, growth hormone dysregulation, hyperphagia, increased risks of morbid obesity, compulsive behaviors, and irritability. As aberrant serotonergic functioning is strongly implicated in PWS, we examined associations between the PWS phenotype and polymorphisms in tryptophan hydroxylase 2 (TPH2), the rate-limiting enzyme in the biosynthesis of serotonin in the brain. METHODS: Ninety-two individuals with PWS aged 4 to 50 years (M = 21.97) were genotyped for the TPH2 G703-T polymorphism. IQ testing was conducted in offspring, and parents completed questionnaires that tapped their child's compulsivity, hyperphagia, and other behavior problems. RESULTS: As expected, the frequency of G/T or T/T polymorphisms in participants with PWS (39%) was similar to rates found in the general population (38%). Compared to those with a homozygous (G/G) genotype, individuals with a T allele had significantly higher hyperphagic behavior, drive, and severity scores, and they also had a younger age of onset of hyperphagia. Those with a T allele also had higher IQ scores than their counterparts. Females with a T allele had significantly higher internalizing symptoms, primarily anxiety and depression, than all others. CONCLUSIONS: TPH2 G/T polymorphisms, and presumed loss of enzyme function, were associated with specific aspects of the PWS phenotype. Aberrant serotonergic functioning is strongly implicated in hyperphagia in PWS, and females with TPH2 T alleles may be at higher risk for affective or mood disorders. Findings hold promise for examining other serotonin-altering genes in PWS, and for future serotonin-altering treatment trials.

Attentional disengagement in adults with Williams syndrome.

Williams syndrome (WS) is a neurodevelopmental disorder characterized by a distinctive behavioral and cognitive profile, including widespread problems with attention. However, the specific nature of their attentional difficulties, such as inappropriate attentional allocation and/or poor attentional disengagement abilities, has yet to be elucidated. Furthermore, it is unknown if there is an underlying difficulty with the temporal dynamics of attention in WS or if their attentional difficulties are task-dependent, because previous studies have examined attention in established areas of deficit and atypicality (specifically, visuospatial and face processing). In this study, we examined attentional processing in 14 adults with WS (20-59 years) and 17 typically developing controls (19-39 years) using an attentional blink (AB) paradigm. The AB is the decreased ability to detect a second target when it is presented in close proximity to an initial target. Overall, adults with WS had an AB that was prolonged in duration, but no different in magnitude, compared with typically developing control participants. AB performance was not explained by IQ, working memory, or processing speed in either group. Thus, results suggest that the attention problems in WS are primarily due to general attentional disengagement difficulties rather than inappropriate attentional allocation.

Training Healthcare Professionals to Work With People With Intellectual and Developmental Disabilities.

This study assessed 155 healthcare providers, from nine disciplines, who work professionally with people with intellectual and developmental disabilities (IDD). Using a national, web-based survey, respondents rated their experience, comfort, and competence in treating individuals with different disability types and preferred methods of continuing education; respondents also provided suggestions for attracting others to work with the IDD population. Findings revealed that experiences, comfort, and competence were all higher concerning persons with autism spectrum disorder (ASD) and intellectual disability (ID), lower for those with deaf-blindness. Overall, levels of experience exceeded levels of comfort, which in turn exceeded levels of competence. The most helpful venues for continued training involved day-to-day contact with persons with IDD, which also characterized open-ended responses. Research and practical implications are discussed.

Evaluating Sleep Disturbances in Children With Rare Genetic Neurodevelopmental Syndromes.

BACKGROUND: Adequate sleep is important for proper neurodevelopment and positive health outcomes. Sleep disturbances are more prevalent in children with genetically determined neurodevelopmental syndromes compared with typically developing counterparts. We characterize sleep behavior in Rett (RTT), Angelman (AS), and Prader-Willi (PWS) syndromes to identify effective approaches for treating sleep problems in these populations. We compared sleep-related symptoms across individuals with these different syndromes with each other, and with typically developing controls. METHODS: Children were recruited from the Rare Diseases Clinical Research Network consortium registries; unaffected siblings were enrolled as related controls. For each participant, a parent completed multiple sleep questionnaires including Pediatric Sleep Questionnaire (Sleep-Disordered Breathing), Children's Sleep Habits Questionnaire (CSHQ), and Pediatric Daytime Sleepiness Scale. RESULTS: Sleep data were analyzed from 714 participants, aged two to 18 years. Young children with AS had more reported sleep problems than children with RTT or PWS. Older children with RTT had more reported daytime sleepiness than those with AS or PWS. Finally, all individuals with RTT had more evidence of sleep-disordered breathing when compared with individuals with PWS. Notably, typically developing siblings were also reported to have sleep problems, except for sleep-related breathing disturbances, which were associated with each of the genetic syndromes. CONCLUSIONS: Individuals with RTT, AS, and PWS frequently experience sleep problems, including sleep-disordered breathing. Screening for sleep problems in individuals with these and other neurogenetic disorders should be included in clinical assessment and managements. These data may also be useful in developing treatment strategies and in clinical trials.

Mindfulness-Based Stress Reduction for Parents Implementing Early Intervention for Autism: An RCT.

BACKGROUND AND OBJECTIVES: Systems of care emphasize parent-delivered intervention for children with autism spectrum disorder (ASD). Meanwhile, multiple studies document psychological distress within these parents. This pilot longitudinal randomized controlled trial compared the parent-implemented Early Start Denver Model (P-ESDM) to P-ESDM plus mindfulness-based stress reduction (MBSR) for parents. We evaluated changes in parent functioning during active treatment and at follow-up. METHODS: Participants included children (<36 months old) with autism spectrum disorder and caregivers. Participants were randomly assigned to P-ESDM only (n = 31) or P-ESDM plus MBSR (n = 30). Data were collected at baseline, midtreatment, the end of treatment, and 1, 3, and 6 months posttreatment. Multilevel models with discontinuous slopes were used to test for group differences in outcome changes over time. RESULTS: Both groups improved during active treatment in all subdomains of parent stress (ß = -1.42, -1.25, -0.92; P < 0.001), depressive symptoms, and anxiety symptoms (ß = -0.62 and -0.78, respectively; P < 0.05). Parents who received MBSR had greater improvements than those receiving P-ESDM only in parental distress and parent-child dysfunctional interactions (ß = -1.91 and -1.38, respectively; P < 0.01). Groups differed in change in mindfulness during treatment (ß = 3.15; P < .05), with P-ESDM plus MBSR increasing and P-ESDM declining. Treatment group did not significantly predict change in depressive symptoms, anxiety symptoms, or life satisfaction. Differences emerged on the basis of parent sex, child age, and child behavior problems. CONCLUSIONS: Results suggest that manualized, low-intensity stress-reduction strategies may have long-term impacts on parent stress. Limitations and future directions are described.

Intellectual disabilities and child psychiatry: looking to the future.

We begin this article by examining the role of intellectual disabilities within child psychiatry, highlighting the relatively steady role of disabilities and the recent movement to examine behavior in specific genetic syndromes. We next propose five questions for future work. Questions relate to (1) specifying the nature of gene-brain-behavior connections; (2) delineating environmental effects and gene-environment interactions; (3) understanding behaviors, physical characteristics, health issues, and other personal characteristics by which children with intellectual disabilities influence others; (4) clarifying the roles of gender and aging in behavioral functioning; and (5) working to improve pharmacological, educational, and other interventions and supports for children and their families. Although great advances have occurred over the past 50 years, intellectual disability research lags behind other areas of child psychiatry; much remains to be discovered that might help these children.

Profiles and trajectories of impaired social cognition in people with Prader-Willi syndrome.

INTRODUCTION: People with Prader-Willi syndrome (PWS) have a distinctive behavioral phenotype that includes intellectual disability, compulsivity, inattention, inflexibility and insistence on sameness. Inflexibility and inattention are at odds with the cognitive flexibility and attention to social cues needed to accurately perceive the social world, and implicate problems in social cognition. This study assessed two social cognition domains in people with PWS; emotion recognition and social perception. We identified changes in social cognition over an approximate two-year time period (M = 2.23 years), relative strengths and weakness in social cognition, and correlates and predictors of social cognition. METHODS: Emotion recognition and social perception were examined at two time points in 94 individuals with PWS aged 5 to 62 years (M = 13.81, SD = 10.69). Tasks administered included: standardized IQ testing; parent-completed measures of inattention and inflexibility; standard emotion recognition photos (fear, sadness, anger, happy); and videotaped social perception vignettes depicting negative events with either sincere/benign or insincere/hostile interactions between peers. RESULTS: An atypical trajectory of negative emotion recognition emerged, marked by similar levels of poor performances across age, and confusion between sad and anger that is typically resolved in early childhood. Recognition of sad and fear were positively correlated with IQ. Participants made gains over time detecting social cues, but not in forming correct conclusions about the intentions of others. Accurately judging sincere intentions remained a significant weakness over time. Relative to sincere intentions, participant's performed significantly better in detecting negative social cues, and correctly judging trickery, deceit and lying. Age, IQ, inattention, and recognition of happy and sad accounted for 29% of variance in social perception. CONCLUSION: Many people with PWS have deficits in recognizing sad, anger and fear, and accurately perceiving the sincere intentions of other people. The impact of these deficits on social behavior and relationships need to be better understood.

Behavior in Prader-Willi syndrome: relationship to genetic subtypes and age.

BACKGROUND: Some behavioral features of Prader-Willi syndrome (PWS) are associated with the major genetic subtypes of this disorder. While most agree that those with maternal uniparental disomy (UPD) have a distinctive cognitive and psychiatric profile, findings are more controversial regarding possible differences among persons who vary in paternal deletion size. METHODS: Caregivers of 88 persons with PWS aged 5 to 51 years (M = 22 years) were administered measures of problem behavior, compulsivity, hyperphagia, and adaptive skills. The sample was well characterized as having relatively large, Type I (n = 26) or smaller, Type II (n = 29) deletions, or UPD (n = 33). RESULTS: No significant behavioral differences were found between the Type I versus Type II deletion groups. Within each genetic subtype, however, differences emerged in how advancing age related to behavior. Although age did not emerge as a significant correlate of behavior in the Type II or UPD groups, in the Type I group age was consistently associated with lower problem behaviors, adaptive skills, and externalizing symptoms. CONCLUSION: Although differences between deletion subtypes were not found, significant within-subtype differences emerged in relationships between age and behavior. Negative associations between age and behavior in the Type I group only may relate to non-imprinted genes that are deleted in Type I but not Type II cases, including CYFIP1. Altered expression of CYFIP1 is seen in other developmental disabilities, including 15q disorders, and haploinsufficiency of CYFIP1 in Type I PWS cases may be associated with age-related phenotypic effects. Findings underscore the importance of a life-span perspective in phenotypic research.

Strategies and correlates of jigsaw puzzle and visuospatial performance by persons with Prader-Willi syndrome.

Some individuals with Prader-Willi syndrome exhibit strengths in solving jigsaw puzzles. We compared visuospatial ability and jigsaw puzzle performance and strategies of 26 persons with Prader-Willi syndrome and 26 MA-matched typically developing controls. Individuals with Prader-Willi syndrome relied on piece shape. Those in the control group used a different, picture-focused strategy. Individuals with Prader-Willi syndrome performed better than did the control group on an achromatic interlocking puzzle, whereas scores on puzzles with pictures (interlocking or noninterlocking) did not differ. Visuospatial scores related to performance on all puzzles in the control group and on the noninterlocking puzzle in the Prader-Willi syndrome group. The most proficient jigsaw puzzlers with Prader-Willi syndrome tended to be older and have shape-based strategies.

Eye Tracking as a Marker of Hyperphagia in Prader-Willi Syndrome.

This study examined the feasibility of eye tracking measures as markers of hyperphagia in 42 children and adults with Prader-Willi syndrome (PWS). Gaze data collected during free visual exploration of complex displays revealed that food images may not have an overall superior salience in PWS. However, increased attention to food in the context of other high-interest items was associated with higher scores on caregiver reports of hyperphagia. The study also provided preliminary evidence of test-retest reliability of eye tracking measures, suggesting that gaze characteristics may be a promising objective marker of food-related interests in PWS.

Intranasal carbetocin reduces hyperphagia in individuals with Prader-Willi syndrome.

BACKGROUND: Prader-Willi syndrome (PWS) is a genetic neurodevelopmental disorder of life-threatening hyperphagia, obesity, intellectual deficits, compulsivity, and other behavioral problems. The efficacy and safety of i.n. carbetocin, an oxytocin analog, was evaluated in a prospective, randomized, double-blinded trial in adolescents with PWS. METHODS: Eligible patients aged 10-18 years with genetically confirmed PWS were randomized (1:1) to i.n. carbetocin or placebo 3 times daily for 14 days. The primary efficacy endpoint was change in parent/caregiver-rated Hyperphagia in PWS Questionnaire-Responsiveness (HPWSQ-R) total score. Secondary efficacy endpoints included HPWSQ-R behavior, drive, and severity domains; clinician-rated HPWSQ; Children's Yale-Brown Obsessive-Compulsive Severity Scale; food domain of the Reiss Profile; and Clinical Global Impression-Improvement scale. Endpoints were assessed using analysis of covariance. Relationship between primary and secondary endpoints was assessed using Pearson correlation coefficients. Safety was assessed throughout the study. RESULTS: Demographics and clinical characteristics were similar between treatment groups (carbetocin, n = 17; placebo, n = 20). Patients receiving carbetocin had statistically significant reductions in HPWSQ-R total score at study end (-15.6) versus patients receiving placebo (-8.9; P = 0.029); several secondary efficacy endpoints also demonstrated significant differences (P < 0.05). Treatment effects for the primary and secondary endpoints were highly correlated (P ≤ 0.0001). Incidence of adverse events (AEs) was similar between treatment groups. CONCLUSION: I.n. carbetocin was well tolerated and improved hyperphagia and behavioral symptoms of PWS. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01968187FUNDING. The study was funded by Ferring Pharmaceuticals. Recruitment was aided by ongoing work in PWS performed through Eunice Kennedy Shriver National Institute of Child Health and Human Development grant U54 HD083211.

Three steps toward improving the measurement of behavior in behavioral phenotype research.

As the numbers of syndrome-specific behavioral articles continue to grow, it seems a good time to pause and take stock of patterns that are emerging across these many studies. This article takes note of these patterns and summarizes the authors' reading of the behavioral phenotype waters. The authors propose that there are (at least) three overarching themes that relate to individual differences within syndromes. These include the roles of (1) development across the lifespan, (2) gender differences, and (3) other subject and environmental factors. The authors end with a cautionary note about measures and the need to supplement (alongside weaknesses and psychiatric vulnerabilities) the strengths and positive affect and attributes of individuals who have genetic syndromes.