Study protocol for an evaluation of ASDetect - a Mobile application for the early detection of autism.

BACKGROUND: Autism Spectrum Conditions (ASC) can be reliably diagnosed by 24 months of age. However, despite the well-known benefits of early intervention, there is still a research-practice gap in the timely identification of ASC, particularly in low-resourced settings. The Social Attention and Communication Surveillance (SACS) tool, which assesses behavioural markers of autism between 12 to 24 months of age, has been implemented in Maternal and Child Health (MCH) settings, with excellent psychometric properties. ASDetect is a free mobile application based on the SACS, which is designed to meet the need for an effective, evidence-based tool for parents, to learn about children's early social-communication development and assess their child's 'likelihood' for ASC. STUDY AIMS: The primary aim of this study is to evaluate the psychometric properties of ASDetect in the early detection of children with ASC. A secondary aim is to assess ASDetect's acceptability and parental user experience with the application. METHODS: Families are recruited to download the application and participate in the study via social media, health professionals (e.g., MCH nurses, paediatricians) and word of mouth. All participating caregivers complete a demographic questionnaire, survey regarding their user experience, and the Social Responsiveness Scale-2 (SRS-2), an autism screening questionnaire; they are also invited to participate in focus groups. Children identified at 'high likelihood' for ASC based on the ASDetect results, the SRS-2 or parental and/or professional concerns undergo a formal, gold-standard, diagnostic assessment. Receiver Operating Characteristic analyses will be used to assess psychometric properties of ASDetect. Thematic analyses will be used to explore themes arising in the focus groups to provide insights regarding user experiences with the app. Multiple regression analyses will be carried out to determine the extent to which demographic factors, parental stress and beliefs on health surveillance and child results on ASDetect are associated with the parental user-experience of the application. DISCUSSION: With a strong evidence-base and global access, ASDetect has the potential to empower parents by providing them with knowledge of their child's social-communication development, validating and reassuring any parental concerns, and supporting them in communicating with other health professionals, ultimately enhancing child and family outcomes and well-being.

Preterm Birth and Maternal Mental Health: Longitudinal Trajectories and Predictors.

OBJECTIVE: To examine trajectories of psychological distress in mothers of children born very preterm (VPT, <30 weeks gestation) and full term from 2 to 13 years after the birth, and examine predictors of maternal psychological distress over time within the VPT group. METHODS: Mothers of children born VPT (n = 159) and full term (n = 71) completed questionnaires assessing their psychological distress when their child was 2, 7, and 13 years of age. Mixed models were used to examine differences between groups in maternal psychological distress over time. Family social risk, child neonatal medial risk, child sex, multiple pregnancy, and child's neurodevelopmental impairment in early childhood were examined as potential predictors of maternal psychological distress within the VPT group. RESULTS: Mothers of children born VPT displayed elevated psychological distress compared with mothers of full-term children, and this difference was consistent over time. Higher family social risk was associated with elevated maternal psychological distress throughout childhood across all time-points. There was evidence that mothers of children at higher neonatal medical risk displayed increasing psychological distress over time. CONCLUSIONS: Mothers of children born VPT show prolonged psychological distress. Mothers from socially disadvantaged background and those whose child has neonatal medical complications may require extensive support to prevent prolonged psychological distress and promote optimal outcomes for children and families.

Maternal resolution of preterm birth from 1 to 18 months.

Preterm birth can be traumatic for some mothers, involving feelings of grief over the hoped-for full-term pregnancy. In this longitudinal study, we interviewed 50 mothers of preterm infants, using the reaction to diagnosis interview when their child was 1 month and 18 months old. We examined change and stability in resolution status over time. Additionally, we explored possible predictors of resolution trajectories between 1 and 18 months. Findings indicated that resolution at 1 month was not yet common. The rate of resolution at 18 months was 62.6%, compared with 38.2% at 1 month. Prenatal precursors of preterm birth, lower medical neonatal risk, and lower maternal stress at 1 month significantly differentiated mothers who attained resolution as early as at 1 month from those who were unresolved at 1 and 18 months. Lower maternal stress at 1 month was the only predictor that significantly differentiated initially unresolved mothers who later attained resolution from those who remained unresolved at 18 months. Discussion focuses on maternal stress, which may mark a subgroup of mothers of preterm infants who are at risk of being unresolved through the first 18 months, and who may benefit from resolution-focused intervention.

Identification of a functional rare variant in autism using genome-wide screen for monoallelic expression.

Recent work has led to the identification of several susceptibility genes for autism spectrum disorder (ASD) and an increased appreciation of the importance of rare and de novo mutations. Some of the mutations may be very hard to detect using current strategies, especially if they are located in regulatory regions. We present a new approach to identify functional mutations that exploit the fact that many rare mutations disrupt the expression of genes from a single parental chromosome. The method incorporates measurement of the relative expression of the two copies of a gene across the genome using single nucleotide polymorphism arrays. Allelic expression has been successfully used to study common regulatory polymorphisms; however, it has not been implemented as a screening tool for rare mutation. We tested the potential of this approach by screening for monoallelic expression in lymphoblastoid cell lines derived from a small ASD cohort. After filtering regions shared across multiple samples, we identified genes showing monoallelic expression in specific ASD samples. Validation by quantitative sequencing demonstrated that the genes (or only part of them) are monoallelic expressed. The genes included both previously suspected risk factors for ASD and novel candidates. In one gene, named autism susceptibility candidate 2 (AUTS2), we identified a rare duplication that is likely to be the cause of monoallelic expression. Our results demonstrate the ability to identify rare regulatory mutations using genome-wide allelic expression screens, capabilities that could be expanded to other diseases, especially those with suspected involvement of rare dominantly acting mutations.

"I'm 'just' a community pediatrician" views and challenges of pediatricians working in the community in Israel.

BACKGROUND: There are ongoing changes around the world in the training and practice of pediatricians who work in the community. These changes are driven by the understanding that pediatricians are required to provide not only acute primary care but also to address more comprehensive concerns, particularly the 'new morbidities'. The present study examines the professional identity of Israeli pediatricians in the community in light of these changes, the barriers and challenges to their work and professional adaptations in the field. METHODS: We used a mixed-methods approach, collecting the perspectives of 137 pediatricians who work in the community through an anonymous online survey, followed by in-depth semi-structured interviews with 11 community pediatricians. RESULTS: The survey results show that community pediatricians in Israel have limited knowledge on a variety of developmental, behavioral and emotional issues; that they lack working relationships with medical or other professionals; and are rarely engaged with other community services. Three main themes arose from the interviews that support and deepen the survey results: perceptions of the profession (pediatrics in the community vs. community pediatrics), the stature of pediatricians in the community (during residency, the choice to work in the community, their daily work) and barriers and change in community pediatrics (isolation, limited resources and challenges arising from the nature of community work). CONCLUSIONS: The present study sheds light on the professional identity and the day-to-day challenges and successes of pediatricians working in the community. Continuing medical education, providing a supportive framework and professional community, better resources, more time with patients, and tools and opportunities for professional development would help pediatricians who work in the community to overcome some of these challenges. The research findings reinforce the need for policy change in the field of community pediatrics with a specific community training curriculum, provision of more resources and ongoing support for pediatricians. This requires partnership between the HMOs, the Ministry of Health, the Scientific Council (Israel Medical Association, professional organizations) and NGOs in order to turn individual-level solutions into system-level and policy-changing solutions.

Enhancing the primary care pediatrician's role in managing psychosocial issues: a cross sectional study of pediatricians and parents in Israel.

BACKGROUND: Psychosocial issues are an integral part of children's health and well-being, and it is widely acknowledged that pediatricians should be involved in their management. We examined the current perception of the pediatrician's role in the management of psychosocial problems in Israel from the perspective of parents and pediatricians, and identified possible barriers. METHODS: We assessed parents' and pediatricians' perspectives through a cross sectional survey. 1000 parents with children under 10 were randomly selected from a large database representing the Israeli population and phone-surveyed by a polling company. Due to a low response-rate (5.4%), there was an overrepresentation of married parents and underrepresentation of parents with primary or secondary education. 173 Pediatricians were recruited both at a medical conference and by a web-based questionnaire. RESULTS: 55% of the parents reported they were concerned with at least one psychosocial problem, yet less than 50% of them discussed these issues with the pediatrician. 59.9% of the parents did not perceive psychosocial problems as relevant to the pediatrician's role. Pediatricians with some previous training related to psychosocial issues were more likely to report on a lack of professional confidence (p = .037) and insufficient available resources (p = .022) as barriers to their involvement, while pediatricians who had no training were more likely to report on the parents' perception of their role as the barrier to involvement (p = .035). CONCLUSIONS: Parents tend to avoid the discussion of psychosocial concerns in pediatric settings due to their perception that it's irrelevant to the pediatrician's role. Trained pediatricians feel unconfident in their ability to manage psychosocial issues and report on a lack of suitable resources. These findings suggest current pediatric mental-health training is insufficient to equip pediatricians with the knowledge and skills required to their involvement in psychosocial problems, and imply necessary changes to environment of community-based pediatrics. In order to change the practice of pediatricians in the community to enable them to address a variety of psychological issues, appropriate training is needed, through all stages of the pediatrician's professional life, including medical school, pediatric residency and continuous medical education.

All-trans retinoic acid upregulates reduced CD38 transcription in lymphoblastoid cell lines from Autism spectrum disorder.

Deficits in social behavior in mice lacking the CD38 gene have been attributed to impaired secretion of oxytocin. In humans, similar deficits in social behavior are associated with autistic spectrum disorder (ASD), for which genetic variants of CD38 have been pinpointed as provisional risk factors. We sought to explore, in an in vitro model, the feasibility of the theory that restoring the level of CD38 in ASD patients could be of potential clinical benefit. CD38 transcription is highly sensitive to several cytokines and vitamins. One of these, all-trans retinoic acid (ATRA), a known inducer of CD38, was added during cell culture and tested on a large sample of N = 120 lymphoblastoid cell (LBC) lines from ASD patients and their parents. Analysis of CD38 mRNA levels shows that ATRA has an upmodulatory potential on LBC derived from ASD patients as well as from their parents. The next crucial issue addressed in our study was the relationship between levels of CD38 expression and psychological parameters. The results obtained indicate a positive correlation between CD38 expression levels and patient scores on the Vineland Adaptive Behavior Scale. In addition, analysis of the role of genetic polymorphisms in the dynamics of the molecule revealed that the genotype of a single-nucleotide polymorphism (rs6449182; C>G variation) in the CpG island of intron 1, harboring the retinoic-acid response element, exerts differential roles in CD38 expression in ASD and in parental LBC. In conclusion, our results provide an empirical basis for the development of a pharmacological ASD treatment strategy based on retinoids.

Autistic adults' subjective experiences of hoarding and self-injurious behaviors.

LAY ABSTRACT: Hoarding and self-injurious behaviors are relatively common in autism, but knowledge about their expressions in adulthood is scarce. Through interviews collecting subjective experiences of autistic adults, these behaviors were explored, and categorized to their underlying purposes. Findings portray the occurrence of these behaviors in the lives of autistic adults, their self-regulatory purposes, and their relationship to other behaviors in the domain of Restrictive and Repetitive Behaviors and Interests.

A Comparison of Children Born Preterm and Full-Term on the Autism Spectrum in a Prospective Community Sample.

Introduction: Previous research suggests children diagnosed with autism spectrum disorder (ASD or "autism") born extremely and very preterm face substantially delayed development than their peers born full-term. Further, children born preterm are proposed to show a unique behavioral phenotype, which may overlap with characteristics of autism, making it difficult to disentangle their clinical presentation. To clarify the presentation of autism in children born preterm, this study examined differences in key indicators of child development (expressive language, receptive language, fine motor, and visual reception) and characteristics of autism (social affect and repetitive, restricted behaviors). Materials and Methods: One fifty-eight children (136 full-term, twenty-two preterm) diagnosed with autism, aged 22-34 months, were identified prospectively using the Social Attention and Communication Surveillance tools during community-based, developmental surveillance checks in the second year of life. Those identified at "high likelihood" of an autism diagnosis were administered the Mullen Scales of Early Learning and the Autism Diagnostic Observation Schedule. Results: The children born preterm and full-term did not differ significantly in their fine motor, visual reception, expressive language, or receptive language skills. No significant differences in social affect and repetitive and restrictive behavior traits were found. Discussion: The findings of this study differs from previous research where children diagnosed with autism born very or extremely preterm were developmentally delayed and had greater autistic traits than their term-born peers. These null findings may relate to the large proportion of children born moderate to late preterm in this sample. This study was unique in its use of a community-based, prospectively identified sample of children diagnosed with autism at an early age. It may be that children in these groups differ from clinic- and hospital-based samples, that potential differences emerge later in development, or that within the autism spectrum, children born preterm and full-term develop similarly. It was concluded that within the current sample, at 2 years of age, children diagnosed with autism born preterm are similar to their peers born full-term. Thus, when clinicians identify characteristics of autism in children born preterm, it is important to refer the child for a diagnostic assessment for autism.

Do developmental and temperamental characteristics mediate the association between preterm birth and the quality of mother-child interaction?

BACKGROUND: The current study aims to evaluate the association between preterm birth and the quality of mother-child interaction of very preterm-, moderate preterm-, and full-term-born children at 18 and 36 months and to determine whether developmental and behavioral characteristics mediate the association between preterm birth and the quality of mother-child interaction. METHOD: Participants included 110 preterm-born children and 39 full-term-born children assessed at ages 18 and 36 months. Mother-child free play interactions, the Mullen Scales of Early Learning, the Infant Behavior Questionnaire, and the Early Childhood Behavior Questionnaire were administered. RESULTS: Significant associations between preterm birth and the quality of mother-child interaction were found at 18 and 36 months. The mother-child interaction quality was less optimal for the preterm-born children compared with the full-term-born children, mainly so for the very preterm-born children. Unlike behavioral characteristics, cognitive development was found to mediate the association between the gestational age-based group and the quality of mother-child interaction. CONCLUSIONS: Intervention programs for preterm-born children and their families, should consider maternal and children's behaviors during mother-child interactions, in addition to cognitive, language, motor and emotional regulation abilities, and particularly so with very preterm-born children, who exhibit slower cognitive development.

Early Minds: a pilot randomised controlled trial of a mindfulness program in early learning centres.

BACKGROUND: Optimal mental health is critical for a child's learning and academic functioning. As a universal service, early education centres play an important role in promoting children's mental health. Social-emotional learning programs are efficacious in reducing behavioural difficulties, enhancing competence, and improving learning abilities. Mindfulness practices, known to promote health and wellbeing in adults, have been adapted to education programs for younger populations, including pre-school children. Despite an increasing use of mindfulness-based programs in pre-school settings, there is a limited number of randomised trials and paucity of data on implementation fidelity of these programs. 'Early Minds' is a mindfulness-based program developed by Smiling Mind for 3-5-year-old children. This paper describes a protocol of a pilot randomised control trial, evaluating the implementation of the program in early learning centres (ELCs, i.e. pre-schools) in Melbourne, Australia. The primary aim of this pilot study is to examine the feasibility, acceptability, and fidelity of the program. The secondary aims are to assess the acceptability of the design and measures and to investigate preliminary impacts of the program on child social-emotional outcomes. METHODS: A convenience sample of six ELCs are recruited. Participants include educators, children, and their parents from 3- and/or 4-year-old ELC rooms. Upon completion of baseline surveys, rooms are randomly allocated to intervention and control arms by an independent statistician. 'Early Minds' is designed in a flexible delivery manner; meditations and activities are completed at least three times a week. Educators are trained in the program and have access to the activities and meditations on an app. Parents are encouraged to practice with their children at least three times a week. Educators document implementation fidelity throughout the 8 weeks of the program. Parents and educators complete follow-up surveys at 3 and 12 months post-randomisation, capturing feasibility and acceptability, child social-emotional behaviour and sleep, and educator, parent, and family wellbeing outcomes. DISCUSSION: This pilot study is the first to assess a mindfulness-based program in ELCs in Australia. Data on feasibility and acceptability, implementation fidelity, and potential impact on children's behaviour will inform the design of adequately powered evaluation trials. TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry, ACTRN12618000435280. Date registered 26 March 2018.

Cumulative Risk of the Oxytocin Receptor Gene Interacts with Prenatal Exposure to Oxytocin Receptor Antagonist to Predict Children's Social Communication Development.

Compelling evidence for the far-reaching role of oxytocin (OT) in social cognition and affiliative behaviors set the basis for examining the association between genetic variation in the OT receptor (OXTR) gene and risk for autism spectrum disorder (ASD). In the current study, gene-environment interaction between OXTR and prenatal exposure to either OT or OXTR antagonist (OXTRA) in predicting early social communication development was examined. One hundred and fifty-three children (age: M = 4.32, SD = 1.07) were assigned to four groups based on prenatal history: children whose mothers prenatally received OXTRA and Nifedipine to delay preterm labor (n = 27); children whose mothers received Nifedipine only to delay preterm labor (n = 35); children whose mothers received OT for labor augmentation (n = 56), and a no intervention group (n = 35). Participants completed a developmental assessment of intelligence quotient (IQ), adaptive behavior, and social communication abilities. DNA was extracted via buccal swab. A genetic risk score was calculated based on four OXTR single nucleotide polymorphisms (rs53576, rs237887, rs1042778, and rs2254298) previously reported to be associated with ASD symptomatology. OXTRrisk-allele dosage was associated with more severe autism diagnostics observation schedule (ADOS) scores only in the OXTRA group. In contrast, in the Nifedipine, OT, and no intervention groups, OXTRrisk-allele dosage was not associated with children's ADOS scores. These findings highlight the importance of both genetic and environmental pathways of OT in signaling early social development and raise the need for further research in this field. Autism Res 2019, 12: 1087-1100. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: In the current study, we examined if the association between prenatal exposure to an oxytocin receptor antagonist (OXTRA) and autism spectrum disorder (ASD) related impairments are dependent on an individual's genetic background for the oxytocin receptor gene (OXTR). Children who carried a greater number of risk alleles for the OXTR gene and whose mothers received OXTRA to delay preterm labor showed more ASD-related impairments. The results highlight the importance of both genetic and environmental pathways of oxytocin in shaping early social development.

Risk for ASD in Preterm Infants: A Three-Year Follow-Up Study.

BACKGROUND: The aim of this study was to examine the long-term risk for autism spectrum disorders (ASD) in individuals who are born preterm and full-term using both observational instruments and parental reports. Neonatal risk factors and developmental characteristics associated with ASD risk were also examined. METHOD: Participants included 110 preterm children (born at a gestational age of ≤ 34 weeks) and 39 full-term children assessed at ages 18, 24, and 36 months. The Autism Diagnostic Observation Schedule, the Modified Checklist for Autism in Toddlers, the Autism Diagnostic Interview-Revised, the Social Communication Questionnaire, and the Mullen Scales of Early Learning were administered. RESULTS AND CONCLUSIONS: The long-term risk for ASD was higher when parental reports were employed compared to observational instruments. At 18 and 24 months, a higher long-term risk for ASD was found for preterm children compared to full-term children. At 36 months, only one preterm child and one full-term child met the cutoff for ASD based on the ADOS, yet clinical judgment and parental reports supported an ASD diagnosis for the preterm child only. Earlier gestational age and lower general developmental abilities were associated with elevated ASD risk among preterm children.

Developmental assessment of preterm infants: Chronological or corrected age?

The aim of this study is to examine the effect of age correction on the developmental assessment scores of preterm infants, using for the first time, the Mullen scales of early learning (MSEL) test. Participants included 110 preterm infants (born at a gestational age of ≤ 34 weeks) at ages 1, 4, 8, 12, 18, 24 and 36 months. The corrected age-based MSEL composite score and each of the five MSEL scale scores were significantly higher than chronological age-based scores at all ages. These corrected scores were significantly higher than the chronological scores regardless of gestational age whether weight was, or adequate or small for gestational age. Larger differences between corrected and chronological age-based scores significantly correlated with earlier gestational age and with lower birth weight between 1 and 24 months but not at 36 months. Using chronological age-based scores yielded significantly more infants identified with developmental delays than using corrected age-based scores. The findings indicate that clinicians and researchers, as well as family members, should be aware of and acknowledge the distinction between corrected and chronological ages when evaluating preterm infants in research and clinical practices.

Preterm-infant emotion regulation during the still-face interaction.

Very-preterm (VPT), moderately-preterm (MPT), and full-term (FT) infants' emotion-regulation behaviors were assessed via the Still-Face procedure at a corrected age of four months. As a developmental task during the first year of life, emotion regulation is important for social and cognitive development. Although substantial evidence indicates that VPT infants exhibit emotion-regulation difficulties, little is known about MPT infants' emotion regulation capabilities, this group also possibly being at risk. The participants included 135 parent-infant dyads: 46 VPT (gestational age 24-32 weeks), 51 MPT (gestational age 32-34 weeks), and 38 FT (gestational age 37-41 weeks). The infants' affect, gaze-aversion, and self-comforting behaviors were coded. Preterm infants responded to parental still face in similar fashion to FT infants, displaying robust still-face and recovery effects. The preterm infants exhibited less developed emotion-regulation behaviors, however, manifested in less positive affect and more gaze aversion in the face-to-face and reunion episodes compared to FT infants. With respect to self-comforting behaviors, each group displayed a significantly different pattern of behaviors throughout the procedure, suggesting better emotion regulation skills among MPT infants compared to the VPT infants. The findings on gaze aversion and self-comforting behaviors could have implications for strategies to incorporate into intervention programs supporting development of emotion regulation skills.

Early developmental trajectories of preterm infants.

BACKGROUND AND OBJECTIVES: Preterm infants are at risk for neuro-developmental impairments and atypical developmental trajectories. The aims of this study were to delineate early developmental trajectories of preterm and full-term infants. METHODS: The cognitive, language, and motor development of 149 infants - 19 extremely preterm (EPT), 34 very preterm (VPT), 57 moderately preterm (MPT), and 39 full-term (FT) - was evaluated using Mullen Scales at 1, 4, 8, 12, and 18 months. Mixed models were applied to examine group differences. Gender, maternal education, and neurobehavior were included as predictors of developmental trajectories. RESULTS: The EPT and VPT infants achieved significantly lower scores than the FT infants in all domains, with a significantly increasing gap over time. The MPT infants' trajectories were more favorable than those of the EPT and VPT infants yet lower than the FT infants on the Visual Reception, Gross, and Fine Motor subscales. Male gender and lower maternal education were associated with lower scores that declined over time. Abnormal neonatal neurobehavior was associated lower Mullen scores and with less stability in scores over time. CONCLUSIONS: The EPT and VPT infants were found to have disadvantages across all domains. The MPT infants revealed more favorable developmental trajectories yet displayed vulnerability compared to the FT infants. Gender, maternal education, and neonatal neurobehavior are important in predicting the developmental outcomes of preterm infants.

Stability of early risk assessment for autism spectrum disorder in preterm infants.

Stability and change in early autism spectrum disorder risk were examined in a cohort of 99 preterm infants (⩽34 weeks of gestation) using the Autism Observation Scale for Infants at 8 and 12 months and the Autism Diagnostic Observation Schedule-Toddler Module at 18 months. A total of 21 infants were identified at risk by the Autism Observation Scale for Infants at 8 months, and 9 were identified at risk at 12 months, including 4 children who were not previously identified. At 18 months, eight children were identified at risk for autism spectrum disorder using the Autism Diagnostic Observation Schedule-Toddler Module, only half of whom had been identified using the original Autism Observation Scale for Infants cutoffs. Results are discussed in relation to early trajectories of autism spectrum disorder risk among preterm infants as well as identifying social-communication deficiencies associated with the early preterm behavioral phenotype.

Autism Diagnostic Interview-Revised (ADI-R) Algorithms for Toddlers and Young Preschoolers: Application in a Non-US Sample of 1,104 Children.

The current study aimed to investigate the Autism Diagnostic Interview-Revised (ADI-R) algorithms for toddlers and young preschoolers (Kim and Lord, J Autism Dev Disord 42(1):82-93, 2012) in a non-US sample from ten sites in nine countries (n = 1,104). The construct validity indicated a good fit of the algorithms. The diagnostic validity was lower, with satisfactorily high specificities but moderate sensitivities. Young children with clinical ASD and lower language ability were largely in the mild-to-moderate or moderate-to-severe concern ranges of the ADI-R, nearly half of the older and phrase speech ASD-group fell into the little-to-no concern range. Although broadly the findings support the toddler algorithms, further work is required to understand why they might have different properties in different samples to further inform research and clinical use.

Low CD38 expression in lymphoblastoid cells and haplotypes are both associated with autism in a family-based study.

BACKGROUND: Impairments in social processes characterize one of the core deficits in autism spectrum disorders (ASD) and accumulating evidence suggests that oxytocin neurotransmission is implicated in mediating social adaptation in ASD. Using a mouse model, CD38, a transmembrane protein expressed in immune cells but also in brain, was found to be critical for social behavior via regulation of oxytocin secretion. This prompted us to both examine CD38 expression in human lymphoblastoid cell lines (LBC) as well as to test association between SNPs across the CD38 gene and ASD. METHODS: LBC's were derived from 44 ASD lines and 40 "unaffected" parents. Family-based association (UNPHASED) was examined by genotyping 11 tagging SNPs spanning the CD38 gene identified using HapMap data in 170 trios. An additional SNP (rs3796863) associated in a study by Munesue et al. with ASD was also genotyped. RESULTS: A highly significant reduction in CD38 expression was observed in immortalized lymphocytes derived from ASD subjects compared to their "unaffected" parents (F517.2, P50.00024, df51). Haplotype analysis showed significant association (permutation corrected) between three and seven locus haplotypes and DSM IV ASD in low functioning (IQ < 70) subjects. CONCLUSIONS: The current report supports a role for CD38 in conferring risk for ASD. Notably, our study shows that this gene is not only associated with low functioning ASD but that CD38 expression is markedly reduced in LBC derived from ASD subjects compared to "unaffected" parents, strengthening the connection between oxytocin and ASD.