Latent Class Analysis of Prenatal Substance Exposure and Child Behavioral Outcomes.

OBJECTIVES: To predict behavioral disruptions in middle childhood, we identified latent classes of prenatal substance use. STUDY DESIGN: As part of the Environmental influences on Child Health Outcomes Program, we harmonized prenatal substance use data and child behavior outcomes from 2195 women and their 6- to 11-year-old children across 10 cohorts in the US and used latent class-adjusted regression models to predict parent-rated child behavior. RESULTS: Three latent classes fit the data: low use (90.5%; n = 1986), primarily using no substances; licit use (6.6%; n = 145), mainly using nicotine with a moderate likelihood of using alcohol and marijuana; and illicit use (2.9%; n = 64), predominantly using illicit substances along with a moderate likelihood of using licit substances. Children exposed to primarily licit substances in utero had greater levels of externalizing behavior than children exposed to low or no substances (P = .001, d = .64). Children exposed to illicit substances in utero showed small but significant elevations in internalizing behavior than children exposed to low or no substances (P < .001, d = .16). CONCLUSIONS: The differences in prenatal polysubstance use may increase risk for specific childhood problem behaviors; however, child outcomes appeared comparably adverse for both licit and illicit polysubstance exposure. We highlight the need for similar multicohort, large-scale studies to examine childhood outcomes based on prenatal substance use profiles.

Patterns of objectively measured motor activity among infants developing ASD and concerns for ADHD.

BACKGROUND: Heightened motor activity is a hallmark of attention-deficit/hyperactivity disorder (ADHD), yet high activity levels are also often reported in young children with autism spectrum disorder (ASD). It is currently unclear whether increased motor activity represents a distinct versus shared early predictor of ASD and ADHD; no prior studies have directly examined this prospectively. We investigated differences in longitudinal patterns of objectively measured motor activity during early development. METHODS: Participants included 113 infants at high and low risk for ASD or ADHD. Continuous motion-based activity was recorded using tri-axial accelerometers at 12, 18, 24, and 36 months of age. At 36 months, participants were categorized into one of three outcome groups: ASD (n = 19), ADHD Concerns (n = 17), and Typically Developing (TD; n = 77). Group differences in trajectories of motor activity were examined in structured and semistructured contexts. Associations with behaviors relevant to ASD, ADHD, and general development were also examined. RESULTS: In both structured and semistructured contexts, both the ASD and ADHD Concerns groups exhibited heightened activity relative to the TD group by 18 months; the ASD group exhibited higher activity than the ADHD Concerns group at 24-36 months in the structured context only. Attention/behavior regulation, nonverbal, and verbal development-but not social engagement-were differentially associated with objectively measured activity by outcome group across contexts. CONCLUSIONS: Overactivity may be a shared, rather than distinct, precursor of atypical development in infants/toddlers developing ASD and concerns for ADHD, emerging as early as 18 months. Group differences in overactivity may be context-specific and associated with different underlying mechanisms.

Placental DNA methylation levels at CYP2E1 and IRS2 are associated with child outcome in a prospective autism study.

DNA methylation acts at the interface of genetic and environmental factors relevant for autism spectrum disorder (ASD). Placenta, normally discarded at birth, is a potentially rich source of DNA methylation patterns predictive of ASD in the child. Here, we performed whole methylome analyses of placentas from a prospective study MARBLES (Markers of Autism Risk in Babies-Learning Early Signs) of high-risk pregnancies. A total of 400 differentially methylated regions (DMRs) discriminated placentas stored from children later diagnosed with ASD compared to typically developing controls. These ASD DMRs were significantly enriched at promoters, mapped to 596 genes functionally enriched in neuronal development, and overlapped genetic ASD risk. ASD DMRs at CYP2E1 and IRS2 reached genome-wide significance, replicated by pyrosequencing and correlated with expression differences in brain. Methylation at CYP2E1 associated with both ASD diagnosis and genotype within the DMR. In contrast, methylation at IRS2 was unaffected by within DMR genotype but modified by preconceptional maternal prenatal vitamin use. This study therefore identified two potentially useful early epigenetic markers for ASD in placenta.

In utero pyrethroid pesticide exposure in relation to autism spectrum disorder (ASD) and other neurodevelopmental outcomes at 3 years in the MARBLES longitudinal cohort.

BACKGROUND: We assessed the relationships between prenatal pyrethroid pesticide exposure and autism spectrum disorders (ASD) or non-typical development (non-TD) at 3 years. METHODS: Participants were mother-child pairs (n = 201) in the MARBLES (Markers of Autism Risk in Babies-Learning Early Signs) cohort. Because familial recurrence risk is high, MARBLES enrolls pregnant women with a family history of ASD. Children from these pregnancies were clinically assessed at 3 years of age and classified into 3 outcome categories: ASD, typically developing (TD), or non-TD (neither TD or ASD). Repeated maternal second and third trimester urine samples were analyzed for pyrethroid metabolite 3-phenoxybenzoic acid (3-PBA). Multinomial logistic regression was used to obtain relative risk ratios (RRR) linking 3-PBA concentrations averaged across each trimester and over pregnancy with child's outcome: ASD or non-TD vs. TD. Models were adjusted for specific gravity, maternal pre-pregnancy BMI, prenatal vitamin use, birth year, home-ownership, and pregnancy concentrations of TCPy (3,5,6-trichloro-2-pyridinol, a metabolite of chlorpyrifos). RESULTS: The median specific gravity corrected 3-PBA concentration of all samples was 1.46 ng/mL. Greater second trimester 3-PBA concentrations were associated with a relative risk ratio (RRR) for ASD of (RRR: 1.50 (95% CI 0.89 to 2.51), p = 0.12). There were no differences between non-TD and TD. CONCLUSIONS: This study found no evidence for differences in 3-PBA comparing non-TD with TD. A modestly elevated RRR was found comparing second trimester urinary 3-PBA concentrations for ASD versus TD; however, the confidence interval was wide and hence, these findings cannot be considered definitive.

Declining Gaze to Faces in Infants Developing Autism Spectrum Disorder: Evidence From Two Independent Cohorts.

Two independent cohorts (N = 155, N = 126) of infants at high and low risk for autism spectrum disorder (ASD) were followed prospectively between 6 and 36 months of age, when n = 46 were diagnosed with ASD. Gaze to adult faces was coded-during a developmental assessment (Cohort 1) or a play interaction (Cohort 2). Across both cohorts, most children developing ASD showed sharp declines in gaze to faces over time, relative to children without ASD. These findings suggest that declining developmental trajectories may be more common than previously recognized by retrospective methods. Trajectory-based screening methods could potentially identify children in the early stages of symptom onset and allow for early intervention before the full disorder has developed.

Can Familial Risk for ADHD Be Detected in the First Two Years of Life?

Objective: We evaluated trajectories of attention-deficit/hyperactivity (ADHD)-relevant behaviors in a sample of infants at high and low familial risk for ADHD who were prospectively evaluated at 12, 18, and 24 months of age.Method: Participants included 43 infants at risk for ADHD based on family history (i.e., diagnosed first-degree relative) and 40 low-risk infants (i.e., no family history of ADHD). Instances of inattention, out-of-seat, and grabbing behavior were coded from video; analogous constructs were rated by examiners unaware of familial risk status after completing structured standardized assessments with the infants/toddlers. At the end of each study visit, examiners solicited parents' concerns about their child's behavior. Differences in ADHD-related behaviors and parent concerns were examined between 12 and 24 months of age.Results: Infants with an older sibling or parent diagnosed with ADHD were distinguishable from infants with no family history of ADHD as early as 12 months of age based on directly observed and examiner reports of behavior, particularly with respect to hyperactive-impulsive behavior. Parents of infants at familial risk for ADHD also reported significantly more behavior/temperament concerns as early as 12 months of age compared to parents of infants at low risk for ADHD.Conclusions: These findings highlight the ability to detect genetic liability for ADHD by the end of the first year of life, suggesting that well-designed family risk studies of ADHD are feasible and may be clinically valuable. They also suggest the potential for earlier detection of risk for ADHD than has previously been possible.

Predicting ASD Diagnosis in Children with Synthetic and Image-based Eye Gaze Data.

As early intervention is highly effective for young children with autism spectrum disorder (ASD), it is imperative to make accurate diagnosis as early as possible. ASD has often been associated with atypical visual attention and eye gaze data can be collected at a very early age. An automatic screening tool based on eye gaze data that could identify ASD risk offers the opportunity for intervention before the full set of symptoms is present. In this paper, we propose two machine learning methods, synthetic saccade approach and image based approach, to automatically classify ASD given children's eye gaze data collected from free-viewing tasks of natural images. The first approach uses a generative model of synthetic saccade patterns to represent the baseline scan-path from a typical non-ASD individual and combines it with the real scan-path as well as other auxiliary data as inputs to a deep learning classifier. The second approach adopts a more holistic image-based approach by feeding the input image and a sequence of fixation maps into a convolutional or recurrent neural network. Using a publicly-accessible collection of children's gaze data, our experiments indicate that the ASD prediction accuracy reaches 67.23% accuracy on the validation dataset and 62.13% accuracy on the test dataset.

A video-based measure to identify autism risk in infancy.

BACKGROUND: Signs of autism are present in the first 2 years of life, but the average age of diagnosis lags far behind. Instruments that improve detection of autism risk in infancy are needed. This study developed and tested the psychometric properties of a novel video-based approach to detecting ASD in infancy. METHODS: A prospective longitudinal study of children at elevated or lower risk for autism spectrum disorder was conducted. Participants were 76 infants with an older sibling with ASD and 37 infants with no known family history of autism. The Video-referenced Infant Rating System for Autism (VIRSA) is a web-based application that presents pairs of videos of parents and infants playing together and requires forced-choice judgments of which video is most similar to the child being rated. Parents rated participants on the VIRSA at 6, 9, 12, and 18 months of age. We examined split-half and test-retest reliability; convergent and discriminant validity; and sensitivity, specificity, and negative and positive predictive value for concurrent and 36-month ASD diagnoses. RESULTS: The VIRSA demonstrated satisfactory reliability and convergent and discriminant validity. VIRSA ratings were significantly lower for children ultimately diagnosed with ASD than children with typical development by 12 months of age. VIRSA scores at 18 months identified all children diagnosed with ASD at that age, as well as 78% of children diagnosed at 36 months. CONCLUSIONS: This study represents an initial step in the development of a novel video-based approach to detection of ASD in infancy. The VIRSA's psychometric properties were promising when used by parents with an older affected child, but still must be tested in community samples with no family history of ASD. If results are replicated, then the VIRSA's low-burden, web-based format has the potential to reduce disparities in communities with limited access to screening.

Shared and distinct developmental pathways to ASD and ADHD phenotypes among infants at familial risk.

Autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) are believed to share partially overlapping causal mechanisms suggesting that early risk markers may also overlap. Using latent profile analysis (LPA) in a sample of infants enriched for ASD and ADHD, we first examined the number of distinct groups of 3-year-old children, based on ADHD and ASD symptomatology. To investigate early predictors of ASD and ADHD symptom profiles, we next examined differences in trajectories of infant behaviors among the LPA classes spanning general development, negative affect, attention, activity level, impulsivity, and social behavior. Participants included 166 infants at familial risk for ASD (n = 89), ADHD (n = 38), or low-risk for both (n = 39) evaluated at 12, 18, 24, and 36 months of age. A three-class solution was selected reflecting a Typically Developing (TD) class (low symptoms; n = 108), an ADHD class (high ADHD/low ASD symptoms; n = 39), and an ASD class (high ASD/ADHD symptoms; n = 19). Trajectories of infant behaviors were generally suggestive of a gradient pattern of differences, with the greatest impairment within the ASD class followed by the ADHD class. These findings indicate a mixture of overlapping and distinct early markers of preschool ASD- and ADHD-like profiles that can be difficult to disentangle early in life.

First Parental Concerns and Age at Diagnosis of Autism Spectrum Disorder: A Retrospective Review from Malaysia.

BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental disorder. This is the first study to examine first parental concerns in ASD in Malaysia. We examined: i) age and type of first parental concerns (AOC); ii) association between AOC and severity; iii) time lag between AOC and diagnosis; and iv) factors associated with diagnostic delay. METHODS: Medical records of 366 patients (aged 1-18 years) with ASD, at the Developmental Paediatrics Clinic of University of Malaya Medical Centre (UMMC), Kuala Lumpur, were reviewed for this 16-month retrospective cohort study. A validated coding system was used for initial parent concerns. Severity was classified via the Diagnostic and Statistical Manual of Mental Disorders-5th edition (DSM-5) criteria. Time lag between AOC and age at diagnosis (AOD) was calculated. Potential predictors of delayed diagnosis were extracted. RESULTS: Three-quarters (75.1%) of parents had concerns by 36 months. Speech/language/communication concerns were most frequent (60.1%). Number of first concerns was significantly correlated with severity (social communication/interaction, SCI [P = 0.019] and restricted, repetitive patterns of behaviours and/or interests/activities, RRB [P < 0.001]). AOC and AOD were significantly negatively correlated with SCI and RRB (P < 0.001). Medians; AOC: 24 months, AOD: 46 months and time lag: 17 months. Higher initial screen time was associated with diagnostic delay (P = 0.031). CONCLUSION: First parental concerns and AOD were comparable to studies across countries. Speech/communication delays may represent universal first parental recognition of ASD.

The dysregulation profile in preschoolers with and without a family history of autism spectrum disorder.

BACKGROUND: The 'dysregulation profile' (DP) is a measure of emotional and behavioral dysregulation that may cut across diagnostic boundaries. Siblings of children with autism spectrum disorder (ASD) who do not develop ASD themselves are at risk for atypical outcomes including behavioral challenges and therefore may be a useful population in which to investigate the structure of the DP in preschoolers. METHODS: We sought to examine the factor structure and predictors of the DP in a sample enriched for a wide range of phenotypic variation-36-month-olds with and without family histories of ASD-and to determine whether children with genetic liability for ASD are at risk for a phenotype characterized by elevated dysregulation. Data were collected from 415 children with (n = 253) and without (n = 162) an older sibling with ASD, all without ASD themselves, at 18, 24, and 36 months of age. RESULTS: Our findings replicate prior reports, conducted in predominantly clinically referred and older samples, supporting the superiority of a bifactor model of the DP in the preschool period compared to the second-order and one-factor models. Examiner ratings were longitudinally and concurrently associated with the DP at 36 months of age. Family history of ASD was associated with higher dysregulation in the Anxious/Depressed dimension. CONCLUSIONS: These findings support the relevance of examining the structure of psychopathology in preschoolers and suggest that examiner observations as early as 18 months of age, particularly of overactivity, may help identify risk for later DP-related concerns. Non-ASD preschoolers with family histories of ASD may be at risk for a phenotype characterized by elevated dysregulation particularly in the Anxious/Depressed dimension by age 3.

Polychlorinated biphenyls influence on autism spectrum disorder risk in the MARBLES cohort.

BACKGROUND: Autism spectrum disorder (ASD) is suspected to have environmental and genetic contributions. Polychlorinated biphenyls (PCBs) are environmental risk factors of interest due to their potential as neurodevelopmental toxicants and environmental persistence despite a US production ban in the 1970s. METHODS: Participants were mother-child pairs from MARBLES, a high-risk pregnancy cohort that enrolls families who have one child diagnosed with ASD and are planning to have another child. PCB concentrations were measured in maternal blood at each trimester of pregnancy using gas chromatography coupled with triple quadruple mass spectrometry. Concentrations were summed into total PCB and two categories based on function/mechanisms of action: dioxin-like (DL), and ryanodine receptor (RyR)-activating PCBs. Multinomial logistic regression assessed risk of clinical outcome classification of ASD and non-typical development (Non-TD) compared to typically developing (TD) in the children at 3 years old. RESULTS: A total of 104 mother-child pairs were included. There were no significant associations for total PCB; however, there were borderline significant associations between DL-PCBs and decreased risk for Non-TD outcome classification (adjusted OR: 0.41 (95% CI 0.15-1.14)) and between RyR-activating PCBs and increased risk for ASD outcome classification (adjusted OR: 2.63 (95% CI 0.87-7.97)). CONCLUSION: This study does not provide strong supporting evidence that PCBs are risk factors for ASD or Non-TD. However, these analyses suggest the need to explore more deeply into subsets of PCBs as risk factors based on their function and structure in larger cohort studies where non-monotonic dose-response patterns can be better evaluated.

Prenatal exposure to phthalates and autism spectrum disorder in the MARBLES study.

BACKGROUND: Evidence from experimental and observational studies suggests that prenatal phthalate exposures may be associated with autism spectrum disorder (ASD). We examined whether prenatal phthalate exposures were associated with an increased risk of ASD. METHODS: We quantified 14 metabolites of eight phthalates in 636 multiple maternal urine samples collected during 2nd and 3rd trimesters of pregnancy from 201 mother-child pairs in MARBLES (Markers of Autism Risk in Babies - Learning Early Signs), a high-risk ASD longitudinal cohort. At 3 years old, children were clinically assessed for ASD and classified into three diagnostic categories: ASD (n = 46), non-typical development (Non-TD, n = 55), and typical development (TD, n = 100). We used multinomial logistic regression to evaluate the association of phthalate metabolite concentrations with ASD and Non-TD. RESULTS: Most associations of phthalate biomarkers with both ASD and Non-TD were null, with the exception that monoethyl phthalate (MEP) was significantly associated with an increased risk of Non-TD (per 2.72-fold relative increase in concentration: Relative risk ratio (RRR) = 1.38; 95% confidence interval (CI): 1.01, 1.90). When stratified by prenatal vitamin use during the first month of pregnancy, among mothers who took vitamins, ASD risk was inversely associated with mono-isobutyl phthalate (MiBP, RRR = 0.44; 95% CI: 0.21, 0.88), mono(3-carboxypropyl) phthalate (MCPP, RRR = 0.41; 95% CI: 0.20, 0.83) and mono-carboxyisooctyl phthalate (MCOP, RRR = 0.49; 95% CI: 0.27, 0.88), but among mothers who did not take prenatal vitamins, Non-TD risk was positively associated with MCPP (RRR = 5.09; 95% CI: 2.05, 12.6), MCOP (RRR = 1.86; 95% CI: 1.01, 3.39), and mono-carboxyisononyl phthalate (MCNP, RRR = 3.67; 95% CI: 1.80, 7.48). When stratified by sex, among boys, MEP, monobenzyl phthalate, MCPP, MCNP, and sum of di(2-ethylhexyl) phthalate metabolites (ΣDEHP) were positively associated with Non-TD risk, but associations with ASD were null. Among girls, associations with both ASD and Non-TD were null. CONCLUSIONS: Our study showed that phthalate exposures in mid- to late pregnancy were not associated with ASD in children from this high-risk ASD cohort. Further studies should be conducted in the general population without high-risk genes to confirm our findings.

Early Detection of ADHD: Insights From Infant Siblings of Children With Autism.

Converging evidence suggests shared genetic underpinnings of attention deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). Studies of infants at risk for ASD have proliferated over the past decade; the few studies that have followed these infants beyond age 3 report a range of difficulties facing a subset of these infants as they reach school age, including elevated levels of attention problems and externalizing behavior. Given this, we aimed to identify early predictors of school-age ADHD outcomes in a sample of infant siblings at risk for ASD. This study reports on a sample of 59 infants at high and low risk for ASD who had been followed for more than a decade, collecting data at regular intervals from 3 to 36 months and then determining diagnostic outcome at 8-10 years of age. Seventeen participants were diagnosed with Diagnostic and Statistical Manual of Mental Disorders (5th ed.) ADHD at school age (n = 14 high risk, 3 low risk). As infants, the ADHD outcome group demonstrated atypical longitudinal patterns of sustained visual attention. A significantly larger proportion of their parents reported behavior/temperament problems at 36 months of age, and examiners noted the presence of inattentive, hyperactive, and/or impulsive behaviors in this group by 18 months of age. These data suggest that behavioral indicators of risk for later ADHD may be present early in development, which may improve earlier detection and treatment of the disorder.

Response to Name in Infants Developing Autism Spectrum Disorder: A Prospective Study.

OBJECTIVE: To examine longitudinal patterns of response to name from 6-24 months of age in infants at high and low risk for autism spectrum disorder (ASD). STUDY DESIGN: A response to name task was tested at 6, 9, 12, 15, 18, and 24 months of age in 156 infant siblings of children with ASD (high-risk) or typical development (low-risk). At 36 months of age, participants were classified into 1 of 3 outcome groups: group with ASD (n = 20), high-risk group without ASD (n = 76), or low-risk group without ASD (n = 60). Differences in longitudinal performance were assessed using generalized estimating equations, and sensitivity and specificity for identifying ASD were calculated. Differences in age 36-month functioning were examined between infants who developed ASD and repeatedly vs infrequently failed to respond to name. RESULTS: At 9 months of age, infants developing ASD were more likely to fail to orient to their names, persisting through 24 months. Sensitivity/specificity for identifying ASD based on at least 1 failure between 12 and 24 months were estimated at .70 in this sample. One-half of the infants who developed ASD had repeated failures in this timeframe, and demonstrated lower age 36-month receptive language, and earlier diagnosis of ASD than infants with ASD who had infrequent failures. CONCLUSIONS: In addition to recommended routine broad-based and ASD-specific screening, response to name should be regularly monitored in infants at risk for ASD. Infants who consistently fail to respond to their names in the second year of life may be at risk not only for ASD but also for greater impairment by age 3 years.

A Novel Way to Measure and Predict Development: A Heuristic Approach to Facilitate the Early Detection of Neurodevelopmental Disorders.

PURPOSE OF REVIEW: Substantial research exists focusing on the various aspects and domains of early human development. However, there is a clear blind spot in early postnatal development when dealing with neurodevelopmental disorders, especially those that manifest themselves clinically only in late infancy or even in childhood. RECENT FINDINGS: This early developmental period may represent an important timeframe to study these disorders but has historically received far less research attention. We believe that only a comprehensive interdisciplinary approach will enable us to detect and delineate specific parameters for specific neurodevelopmental disorders at a very early age to improve early detection/diagnosis, enable prospective studies and eventually facilitate randomised trials of early intervention. In this article, we propose a dynamic framework for characterising neurofunctional biomarkers associated with specific disorders in the development of infants and children. We have named this automated detection 'Fingerprint Model', suggesting one possible approach to accurately and early identify neurodevelopmental disorders.

Editorial: Early detection of mental health and neurodevelopmental disorders: the ethical challenges of a field in its infancy.

The signs of many mental health and neurodevelopmental conditions first appear in childhood and diagnosis can reliably be made by school age for most. Such conditions can be chronically disabling and confer significant long-term impairment. Determining early risk signs and first emerging symptoms of disorder is imperative to enhance early detection and to identify targets and ideal time points for prevention and intervention efforts. This Special Issue of JCPP focuses on the prospect of earlier identification of conditions that are traditionally diagnosed later in childhood. Ten invited empirical articles cover topics related to the science of early detection. Several are focused on prediction of later diagnosis, of functional impairment, and of future service utilization, while others cover instrument development and topics related to screening. The papers span the conditions of ADHD, ASD, dyslexia, mood dysregulation, disruptive behavior disorders, and anxiety disorders. This Editorial provides an overview of the invited contributions and the perspectives they provide on the ethical challenges and choices of a field still in its infancy.

Early pragmatic language difficulties in siblings of children with autism: implications for DSM-5 social communication disorder?

BACKGROUND: We evaluated early pragmatic language skills in preschool-age siblings of children with autism spectrum disorder (ASD), and examined correspondence between pragmatic language impairments and general language difficulties, autism symptomatology, and clinical outcomes. METHODS: Participants were younger siblings of children with ASD (high-risk, n = 188) or typical development (low-risk, n = 119) who were part of a prospective study of infants at risk for ASD; siblings without ASD outcomes were included in analyses. Pragmatic language skills were measured via the Language Use Inventory (LUI). RESULTS: At 36 months, the high-risk group had significantly lower parent-rated pragmatic language scores than the low-risk group. When defining pragmatic language impairment (PLI) as scores below the 10(th) percentile on the LUI, 35% of the high-risk group was identified with PLI versus 10% of the low-risk group. Children with PLI had higher rates of general language impairment (16%), defined as scores below the 10(th) percentile on the Receptive or Expressive Language subscales of the Mullen Scales of Early Learning, relative to those without PLI (3%), but most did not evidence general language impairments. Children with PLI had significantly higher ADOS scores than those without PLI and had higher rates of clinician-rated atypical clinical best estimate outcomes (49%) relative to those without PLI (15%). CONCLUSIONS: Pragmatic language problems are present in some siblings of children with ASD as early as 36 months of age. As the new DSM-5 diagnosis of Social (Pragmatic) Communication Disorder (SCD) is thought to occur more frequently in family members of individuals with ASD, it is possible that some of these siblings will meet criteria for SCD as they get older. Close monitoring of early pragmatic language development in young children at familial risk for ASD is warranted.

Diagnostic stability in young children at risk for autism spectrum disorder: a baby siblings research consortium study.

BACKGROUND: The diagnosis of autism spectrum disorder (ASD) made before age 3 has been found to be remarkably stable in clinic- and community-ascertained samples. The stability of an ASD diagnosis in prospectively ascertained samples of infants at risk for ASD due to familial factors has not yet been studied, however. The American Academy of Pediatrics recommends intensive surveillance and screening for this high-risk group, which may afford earlier identification. Therefore, it is critical to understand the stability of an ASD diagnosis made before age 3 in young children at familial risk. METHODS: Data were pooled across seven sites of the Baby Siblings Research Consortium. Evaluations of 418 later-born siblings of children with ASD were conducted at 18, 24, and 36 months of age and a clinical diagnosis of ASD or Not ASD was made at each age. RESULTS: The stability of an ASD diagnosis at 18 months was 93% and at 24 months was 82%. There were relatively few children diagnosed with ASD at 18 or 24 months whose diagnosis was not confirmed at 36 months. There were, however, many children with ASD outcomes at 36 months who had not yet been diagnosed at 18 months (63%) or 24 months (41%). CONCLUSIONS: The stability of an ASD diagnosis in this familial-risk sample was high at both 18 and 24 months of age and comparable with previous data from clinic- and community-ascertained samples. However, almost half of the children with ASD outcomes were not identified as being on the spectrum at 24 months and did not receive an ASD diagnosis until 36 months. Thus, longitudinal follow-up is critical for children with early signs of social-communication difficulties, even if they do not meet diagnostic criteria at initial assessment. A public health implication of these data is that screening for ASD may need to be repeated multiple times in the first years of life. These data also suggest that there is a period of early development in which ASD features unfold and emerge but have not yet reached levels supportive of a diagnosis.

Common genetic variants on 5p14.1 associate with autism spectrum disorders.

Autism spectrum disorders (ASDs) represent a group of childhood neurodevelopmental and neuropsychiatric disorders characterized by deficits in verbal communication, impairment of social interaction, and restricted and repetitive patterns of interests and behaviour. To identify common genetic risk factors underlying ASDs, here we present the results of genome-wide association studies on a cohort of 780 families (3,101 subjects) with affected children, and a second cohort of 1,204 affected subjects and 6,491 control subjects, all of whom were of European ancestry. Six single nucleotide polymorphisms between cadherin 10 (CDH10) and cadherin 9 (CDH9)-two genes encoding neuronal cell-adhesion molecules-revealed strong association signals, with the most significant SNP being rs4307059 (P = 3.4 x 10(-8), odds ratio = 1.19). These signals were replicated in two independent cohorts, with combined P values ranging from 7.4 x 10(-8) to 2.1 x 10(-10). Our results implicate neuronal cell-adhesion molecules in the pathogenesis of ASDs, and represent, to our knowledge, the first demonstration of genome-wide significant association of common variants with susceptibility to ASDs.