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1.  Visual disengagement in the infant siblings of children with an Autism Spectrum Disorder (ASD) 
Children with Autism Spectrum Disorders (ASDs) are impaired in visually disengaging attention in both social and non-social contexts, impairments that may, in subtler form, also affect the infant siblings of children with an ASD (ASD-sibs). We investigated patterns of visual attention (gazing) in six-month-old ASD-sibs (n = 17) and the siblings of typically developing children (COMP-sibs; n =17) during the Face-to-Face/Still-Face Protocol (FFSF), in which parents are sequentially responsive, nonresponsive, and responsive to their infants. Throughout the protocol, ASD-sibs shifted their gaze to and from their parents' faces less frequently than did COMP-sibs. The mean durations of ASD-sibs’ gazes away from their parents' faces were longer than those of COMP-sibs. ASD-sibs and COMP-sibs did not differ in the mean durations of gazes at their parents' faces. In sum, ASD-sibs showed no deficits in visual interest to their parents’ faces, but greater interest than COMP-sibs in non-face stimuli.
PMCID: PMC2860749  PMID: 18805943
autism spectrum disorders; siblings; at-risk; disengagement; early deficits
2.  The Development of Referential Communication and Autism Symptomatology in High-Risk Infants 
Non-verbal referential communication is impaired in children with Autism Spectrum Disorders (ASD). However, the development of difficulties with referential communication in the younger siblings of children with ASD (High-Risk Siblings)—and the degree to which early referential communication predicts later autism symptomatology—is not clear. We modeled the early developmental trajectories of three types of referential communication: responding to joint attention (RJA), initiating joint attention (IJA), and initiating behavioral requests (IBR) across 8, 10, 12, 15, and18 months of age in High-Risk Siblings (n = 40) and the infant siblings of children without ASD (Low-Risk Siblings; n = 21). Hierarchical Linear Modeling indicated that High-Risk Siblings exhibited lower levels of baseline RJA and IJA and a lower rate of linear change in IBR than Low-Risk Siblings. When the 10 High-Risk Siblings who received an ASD diagnosis were excluded from analyses, group differences in the development of referential communication remained significant only for RJA. Baseline levels of IJA were associated with later ASD symptomatology among High-Risk Siblings, suggesting that individual differences in referential communication development at 8 months may index early manifestations of ASD.
PMCID: PMC3880657  PMID: 24403864
Autism Spectrum Disorders; at-risk infants; referential communication; developmental trajectories; symptom severity
3.  Atypical Social Referencing in Infant Siblings of Children with Autism Spectrum Disorders 
Social referencing was investigated in 18-month-old siblings of children with autism spectrum disorders (ASD; “high-risk infants”). Infants were exposed to novel toys, which were emotionally tagged via adults’ facial and vocal signals. Infants’ information seeking (initiation of joint attention with an adult) and their approach/withdrawal behavior toward the toys before versus after the adults’ emotional signals was measured. Compared to both typically developing infants and high-risk infants without ASD, infants later diagnosed with ASD engaged in slower information seeking, suggesting that this aspect of referencing may be an early indicator of ASD. High-risk infants, both those who were and those who were not later diagnosed with ASD, exhibited impairments in regulating their behavior based on the adults’ emotional signals, suggesting that this aspect of social referencing may reflect an endophenotype for ASD.
PMCID: PMC3593052  PMID: 22456817
Autism; Social referencing; Joint attention; Behavior regulation
4.  Communicative Acts of Children with Autism Spectrum Disorders in the Second Year of Life 
This study examined the communicative profiles of children with autism spectrum disorders (ASD) in the second year of life.
Communicative acts were examined in 125 children 18 to 24 months of age: 50 later diagnosed with ASD; 25 with developmental delays (DD); and 50 with typical development (TD). Precise measures of rate, functions, and means of communication were obtained through systematic observation of videotaped Behavior Samples from the Communication and Symbolic Behavior Scales Developmental Profile (Wetherby & Prizant, 2002).
Children with ASD communicated at a significantly lower rate than children with DD and TD. The ASD group used a significantly lower proportion of acts for joint attention and a significantly lower proportion of deictic gestures with a reliance on more primitive gestures compared to DD and TD. Children with ASD who did communicate for joint attention were as likely as other children to coordinate vocalizations, eye gaze, and gestures. Rate of communicative acts and joint attention were the strongest predictors of verbal outcome at age 3.
By 18 to 24 months of age, children later diagnosed with ASD showed a unique profile of communication, with core deficits in communication rate, joint attention, and communicative gestures.
PMCID: PMC2756334  PMID: 19635941
5.  Behavior and Sleep Problems in Children with a Family History of Autism 
The present study explores behavioral and sleep outcomes in preschool age siblings of children with autism spectrum disorders (ASD). This study focuses on behavior problems that are common in children with ASD, such as emotional reactivity, anxiety, inattention, aggression, and sleep problems. Infant siblings were recruited from families with at least one older child with ASD (high-risk group, n = 104) or families with no history of ASD (low-risk group, n = 76). As part of a longitudinal prospective study, children completed the Mullen Scales of Early Learning and the Autism Diagnostic Observation Schedule, and parents completed the Child Behavior Checklist (CBCL) and the Social Communication Questionnaire at 36 months of age. This study focuses on developmental concerns outside of ASD; therefore, only siblings who did not develop an ASD were included in analyses. Negative binomial regression analyses revealed that children in the high-risk group were more likely to have elevated behavior problems on the CBCL Anxious/Depressed and Aggression subscales. To explore sleep problems as a correlate of these behavior problems, a second series of models was specified. For both groups of children, sleep problems were associated with elevated behavior problems in each of the areas assessed (reactivity, anxiety, somatic complaints, withdrawal, attention, and aggression). These findings support close monitoring of children with a family history of ASD for both behavioral and sleep issues.
PMCID: PMC3947924  PMID: 23436793
autism; siblings; behavior problems; sleep
6.  A Prospective Study of the Emergence of Early Behavioral Signs of Autism 
To examine prospectively the emergence of behavioral signs of autism in the first years of life in infants at low and high risk for autism.
A prospective longitudinal design was used to compare 25 infants later diagnosed with an autism spectrum disorder (ASD) with 25 gender-matched low-risk children later determined to have typical development. Participants were evaluated at 6, 12, 18, 24, and 36 months of age. Frequencies of gaze to faces, social smiles, and directed vocalizations were coded from video and rated by examiners.
The frequency of gaze to faces, shared smiles, and vocalizations to others were highly comparable between groups at 6 months of age, but significantly declining trajectories over time were apparent in the group later diagnosed with ASD. Group differences were significant by 12 months of age on most variables. Although repeated evaluation documented loss of skills in most infants with ASD, most parents did not report a regression in their child’s development.
These results suggest that behavioral signs of autism are not present at birth, as once suggested by Kanner, but emerge over time through a process of diminishment of key social communication behaviors. More children may present with a regressive course than previously thought, but parent report methods do not capture this phenomenon well. Implications for onset classification systems and clinical screening are also discussed.
PMCID: PMC2923050  PMID: 20410715
Autism; Onset; Infancy; Regression
7.  Response to Distress in Infants at Risk for Autism: A Prospective Longitudinal Study 
Infants and preschoolers with ASD show impairment in their responses to other people's distress relative to children with other developmental delays and typically developing children. This deficit is expected to disrupt social interactions, social learning, and the formation of close relationships. Response to distress has not been evaluated previously in infants with ASD earlier than 18 months of age.
Participants were 103 infant siblings of children with autism and 55 low-risk controls. All children were screened for ASD at 36 months and 14 were diagnosed with ASD. Infants' responsiveness to distress was evaluated at 12, 18, 24, and 36 months. An examiner pretended to hit her finger with a toy mallet and infants' responses were video-recorded. Attention to the examiner and congruent changes in affect were coded on four-point Likert scales.
Cross-sectional and longitudinal analyses confirm that the ASD group paid less attention and demonstrated less change in affect in response to the examiner's distress relative to the high-risk and low-risk participants who were not subsequently diagnosed with ASD. Group differences remained when verbal skills and general social responsiveness were included in the analytic models.
Diagnostic groups differ on distress response from 12 to 36 months of age. Distress-response measures are predictive of later ASD diagnosis above and beyond verbal impairments. Distress response is a worthwhile target for early intervention programs.
PMCID: PMC2920353  PMID: 20546081
autism; early identification; siblings; empathy; infancy
8.  Additive effects of social and non-social attention during infancy relate to later autism spectrum disorder 
Developmental Science  2014;17(4):612-620.
Emerging findings from studies with infants at familial high risk for autism spectrum disorder (ASD), owing to an older sibling with a diagnosis, suggest that those who go on to develop ASD show early impairments in the processing of stimuli with both social and non-social content. Although ASD is defined by social-communication impairments and restricted and repetitive behaviours, the majority of cognitive theories of ASD posit a single underlying factor, which over development has secondary effects across domains. This is the first high-risk study to statistically differentiate theoretical models of the development of ASD in high-risk siblings using multiple risk factors. We examined the prediction of ASD outcome by attention to social and non-social stimuli: gaze following and attentional disengagement assessed at 13 months in low-risk controls and high-risk ASD infants (who were subsequently diagnosed with ASD at 3 years). When included in the same regression model, these 13-month measures independently predicted ASD outcome at 3 years of age. The data were best described by an additive model, suggesting that non-social attention, disengagement, and social attention as evidenced by gaze following, have a cumulative impact on ASD risk. These data argue against cognitive theories of ASD which propose that a single underlying factor has cascading effects across early development leading to an ASD outcome, and support multiple impairment models of ASD that are more consistent with recent genetic and neurobiological evidence.
PMCID: PMC4253134  PMID: 25089324
9.  Abnormal social reward processing in autism as indexed by pupillary responses to happy faces 
Individuals with Autism Spectrum Disorders (ASD) typically show impaired eye contact during social interactions. From a young age, they look less at faces than typically developing (TD) children and tend to avoid direct gaze. However, the reason for this behavior remains controversial; ASD children might avoid eye contact because they perceive the eyes as aversive or because they do not find social engagement through mutual gaze rewarding.
We monitored pupillary diameter as a measure of autonomic response in children with ASD (n = 20, mean age = 12.4) and TD controls (n = 18, mean age = 13.7) while they looked at faces displaying different emotions. Each face displayed happy, fearful, angry or neutral emotions with the gaze either directed to or averted from the subjects.
Overall, children with ASD and TD controls showed similar pupillary responses; however, they differed significantly in their sensitivity to gaze direction for happy faces. Specifically, pupillary diameter increased among TD children when viewing happy faces with direct gaze as compared to those with averted gaze, whereas children with ASD did not show such sensitivity to gaze direction. We found no group differences in fixation that could explain the differential pupillary responses. There was no effect of gaze direction on pupil diameter for negative affect or neutral faces among either the TD or ASD group.
We interpret the increased pupillary diameter to happy faces with direct gaze in TD children to reflect the intrinsic reward value of a smiling face looking directly at an individual. The lack of this effect in children with ASD is consistent with the hypothesis that individuals with ASD may have reduced sensitivity to the reward value of social stimuli.
PMCID: PMC3461481  PMID: 22958650
Autism; Pupillary response; Reward processing
10.  Can Family Affectedness Inform Infant Sibling Outcomes of Autism Spectrum Disorders? 
Difficulties in communication and reciprocal social behavior are core features of autism spectrum disorders (ASD) and are often present, to varying degrees, in other family members. This prospective longitudinal infant sibling study examines whether social-communicative features of family members may inform which infants are at increased risk for ASD and other developmental concerns.
Two hundred and seventeen families participated in this study. Infant siblings were recruited from families with at least one older child diagnosed with an ASD (n = 135) or at least one typically developing older child (n = 82). Families completed the Social Responsiveness Scale to assess social and communication features of the broader autism phenotype (BAP), sometimes called quantitative autistic traits (QAT). Family affectedness was assessed in two ways: categorically, based on number of affected older siblings (i.e., typical, simplex, multiplex risk groups) and dimensionally, by assessing varying degrees of QAT in all family members. Infant siblings were assessed at 36 months of age and completed the Autism Diagnostic Observation Schedule and the Mullen Scales of Early Learning.
In structural equation models, comparisons between multiplex, simplex and typical groups revealed the highest rates of QAT in the multiplex group followed by the simplex and typical groups. Infant sibling outcomes were predicted by gender, family risk group, proband QAT, and additional sibling QAT.
Replicating previous cross-sectional and family history findings, the present study found elevated social and communication features of the BAP in siblings and fathers of ASD families, but not in mothers. While social and communication features of the BAP in mothers, fathers, and undiagnosed siblings did not predict infant sibling outcomes, having more than one affected older sibling did. Infant siblings from multiplex families were at significantly higher risk for ASD than infant siblings from simplex families in this sample.
PMCID: PMC2922056  PMID: 20546079
Autistic disorder; Pervasive developmental disorder; family factors; siblings; structural equation modeling
11.  What are infant siblings teaching us about autism in infancy? 
International research to understand infant patterns of development in autism spectrum disorders has recently focused on a research paradigm involving prospective longitudinal studies of infant siblings of children with autism. Such designs use a comparison group of infant siblings without any familial risks (the low- risk group) to gather longitudinal information about developmental skills across the first three years of life, followed by clinical diagnosis of ASD at 36 months. This review focuses on five topics: presence of ASD in the infant sibling groups, patterns and characteristics of motor development, patterns and characteristics of social and emotional development, patterns and characteristics of intentional communication, both verbal and nonverbal, and patterns that mark the onset of behaviors pathognomonic for ASD. Symptoms in all these areas typically begin to be detected during the age period of 12 –24 months in infants who will develop autism. Onset of the symptoms occurs at varying ages and in varying patterns, but the pattern of frank loss of skills and marked regression reported from previous retrospective studies in 20–30% of children is seldom reported in these infant sibling prospective studies. Two surprises involve the very early onset of repetitive and unusual sensory behaviors, and the lack of predictive symptoms at age 6 months. Contrary to current views that autism is a disorder that profoundly affects social development from the earliest months of life, the data from these studies presents a picture of autism as a disorder involving symptoms across multiple domains with a gradual onset that changes both ongoing developmental rate and established behavioral patterns across the first two to three years of life.
PMCID: PMC2791538  PMID: 19582867
12.  Same but different: Nine-month-old infants at average and high risk for autism look at the same facial features but process them using different brain mechanisms 
Lay Abstract
Reduced attention to the eyes and/or increased focus on the mouth have been described as features of atypical face processing in individuals with autism spectrum disorders (ASD). In this study, we examined whether 9-month-old infants at average vs. high risk for ASD differ in their detection of changes in individual facial features (eyes vs. mouth) and whether this ability is related to infants’ social and communicative skills. Eye tracking data and electrical brain activity were recorded while infants viewed repeated presentations of a smiling unfamiliar female face. Occasionally, the eyes or the mouth of that face were replaced with corresponding parts from a different face. There were no group differences in the number or duration of fixations on the eye or mouth regions for any of the face stimuli. Brain activity data revealed that all infants detected both eye and mouth changes, and that these changes were associated with changes in activity of the face-specific perception mechanisms for average-risk infants only. For all infants, the size and speed of brain responses correlated with parental reports of communication use and understanding, suggesting that differences in brain processing of faces and their features in infants are associated with individual differences in early communication skills.
Scientific Abstract
The study examined whether 9-month-old infants at average vs. high risk for autism spectrum disorder (ASD) process facial features (eyes, mouth) differently, and whether such differences are related to infants’ social and communicative skills. Eye tracking and visual event-related potentials (ERPs) were recorded in 35 infants (20 average-risk typical infants, 15 high-risk siblings of children with ASD) while they viewed photographs of a smiling unfamiliar female face. On 30% of the trials, the eyes or the mouth of that face were replaced with corresponding features from a different female. There were no group differences in the number, duration, or distribution of fixations, and all infants looked at the eyes and mouth regions equally. However, increased attention to the mouth was associated with weaker receptive communication skills and increased attention to the eyes correlated with better interpersonal skills. ERP results revealed that all infants detected eye and mouth changes but did so using different brain mechanisms. Changes in facial features were associated with changes in activity of the face perception mechanisms (N290) for the average-risk group, but not for the high-risk infants. For all infants, correlations between ERP and eye tracking measures indicated that larger and faster ERPs to feature changes were associated with fewer fixations on the irrelevant regions of stimuli. The size and latency of the ERP responses also correlated with parental reports of receptive and expressive communication skills, suggesting that differences in brain processing of human faces are associated with individual differences in social-communicative behaviors.
PMCID: PMC3422441  PMID: 22674669
Face processing; ERP; eye tracking; infants; ASD; Vineland
13.  Differentiating ASD from DLD in Toddlers 
Until recently children with autism spectrum disorders (ASD) were rarely diagnosed before the age of 3 to 4 years. But a major thrust of current research has been to lower the age of identification, due in part to evidence supporting the effectiveness of early intervention. Late talkers -- toddlers who appear to be developing normally but do not begin speaking, acquire words very slowly, and do not begin combining words at the typical ages --are also typically seen in their second year or early in the third year of life. This report presents the findings of a comparison of toddlers who received clinical diagnoses of ASD and those who were clinically diagnosed as DLD in order to examine the patterns of behavior in the second and third years of life in these two groups. Findings suggest that, when matched on expressive language level, toddlers with ASD and DLD are similar, and less skilled than toddlers with TD, in their use of gaze to regulate interactions, their ability to share emotions with others, to engage in back-and-forth interactions, their rate of communication, and the range of sounds and words produced. The children with DLD were similar to those with TD, and higher than those with ASD, in terms of their nonverbal cognitive skills, use of gestures to communicate, use of pretend play, and ability to respond to language. Children with DLD did show some weaknesses in interpersonal skills -- such as sharing affect, using gaze, and initiating communication. However, their ability to engage in pretend play, use gestures to communicate and respond to language are sufficient to differentiate them from age-mates with ASD. The clinical implications of these findings are discussed.
PMCID: PMC2940236  PMID: 20852731
14.  Non-Specialist Psychosocial Interventions for Children and Adolescents with Intellectual Disability or Lower-Functioning Autism Spectrum Disorders: A Systematic Review 
PLoS Medicine  2013;10(12):e1001572.
In a systematic review, Brian Reichow and colleagues assess the evidence that non-specialist care providers in community settings can provide effective interventions for children and adolescents with intellectual disabilities or lower-functioning autism spectrum disorders.
Please see later in the article for the Editors' Summary
The development of effective treatments for use by non-specialists is listed among the top research priorities for improving the lives of people with mental illness worldwide. The purpose of this review is to appraise which interventions for children with intellectual disabilities or lower-functioning autism spectrum disorders delivered by non-specialist care providers in community settings produce benefits when compared to either a no-treatment control group or treatment-as-usual comparator.
Methods and Findings
We systematically searched electronic databases through 24 June 2013 to locate prospective controlled studies of psychosocial interventions delivered by non-specialist providers to children with intellectual disabilities or lower-functioning autism spectrum disorders. We screened 234 full papers, of which 34 articles describing 29 studies involving 1,305 participants were included. A majority of the studies included children exclusively with a diagnosis of lower-functioning autism spectrum disorders (15 of 29, 52%). Fifteen of twenty-nine studies (52%) were randomized controlled trials and just under half of all effect sizes (29 of 59, 49%) were greater than 0.50, of which 18 (62%) were statistically significant. For behavior analytic interventions, the best outcomes were shown for development and daily skills; cognitive rehabilitation, training, and support interventions were found to be most effective for improving developmental outcomes, and parent training interventions to be most effective for improving developmental, behavioral, and family outcomes. We also conducted additional subgroup analyses using harvest plots. Limitations include the studies' potential for performance bias and that few were conducted in lower- and middle-income countries.
The findings of this review support the delivery of psychosocial interventions by non-specialist providers to children who have intellectual disabilities or lower-functioning autism spectrum disorders. Given the scarcity of specialists in many low-resource settings, including many lower- and middle-income countries, these findings may provide guidance for scale-up efforts for improving outcomes for children with developmental disorders or lower-functioning autism spectrum disorders.
Protocol Registration
PROSPERO CRD42012002641
Please see later in the article for the Editors' Summary
Editors' Summary
Newborn babies are helpless, but over the first few years of life, they acquire motor (movement) skills, language (communication) skills, cognitive (thinking) skills, and social (interpersonal interaction) skills. Individual aspects of these skills are usually acquired at specific ages, but children with a development disorder such as an autism spectrum disorder (ASD) or intellectual disability (mental retardation) fail to reach these “milestones” because of impaired or delayed brain maturation. Autism, Asperger syndrome, and other ASDs (also called pervasive developmental disorders) affect about 1% of the UK and US populations and are characterized by abnormalities in interactions and communication with other people (reciprocal socio-communicative interactions; for example, some children with autism reject physical affection and fail to develop useful speech) and a restricted, stereotyped, repetitive repertoire of interests (for example, obsessive accumulation of facts about unusual topics). About half of individuals with an ASD also have an intellectual disability—a reduced overall level of intelligence characterized by impairment of the skills that are normally acquired during early life. Such individuals have what is called lower-functioning ASD.
Why Was This Study Done?
Most of the children affected by developmental disorders live in low- and middle-income countries where there are few services available to help them achieve their full potential and where little research has been done to identify the most effective treatments. The development of effective treatments for use by non-specialists (for example, teachers and parents) is necessary to improve the lives of people with mental illnesses worldwide, but particularly in resource-limited settings where psychiatrists, psychologists, and other specialists are scarce. In this systematic review, the researchers investigated which psychosocial interventions for children and adolescents with intellectual disabilities or lower-functioning ASDs delivered by non-specialist providers in community settings produce improvements in development, daily skills, school performance, behavior, or family outcomes when compared to usual care (the control condition). A systematic review identifies all the research on a given topic using predefined criteria; psychosocial interventions are defined as therapy, education, training, or support aimed at improving behavior, overall development, or specific life skills without the use of drugs.
What Did the Researchers Do and Find?
The researchers identified 29 controlled studies (investigations with an intervention group and a control group) that examined the effects of various psychosocial interventions delivered by non-specialist providers to children (under 18 years old) who had a lower-functioning ASD or intellectual disability. The researchers retrieved information on the participants, design and methods, findings, and intervention characteristics for each study, and calculated effect sizes—a measure of the effectiveness of a test intervention relative to a control intervention—for several outcomes for each intervention. Across the studies, three-quarters of the effect size estimates were positive, and nearly half were greater than 0.50; effect sizes of less than 0.2, 0.2–0.5, and greater than 0.5 indicate that an intervention has no, a small, or a medium-to-large effect, respectively. For behavior analytic interventions (which aim to improve socially significant behavior by systematically analyzing behavior), the largest effect sizes were seen for development and daily skills. Cognitive rehabilitation, training, and support (interventions that facilitates the relearning of lost or altered cognitive skills) produced good improvements in developmental outcomes such as standardized IQ tests in children aged 6–11 years old. Finally, parental training interventions (which teach parents how to provide therapy services for their child) had strong effects on developmental, behavioral, and family outcomes.
What Do These Findings Mean?
Because few of the studies included in this systematic review were undertaken in low- and middle-income countries, the review's findings may not be generalizable to children living in resource-limited settings. Moreover, other characteristics of the included studies may limit the accuracy of these findings. Nevertheless, these findings support the delivery of psychosocial interventions by non-specialist providers to children who have intellectual disabilities or a lower-functioning ASD, and indicate which interventions are likely to produce the largest improvements in developmental, behavioral, and family outcomes. Further studies are needed, particularly in low- and middle-income countries, to confirm these findings, but given that specialists are scarce in many resource-limited settings, these findings may help to inform the implementation of programs to improve outcomes for children with intellectual disabilities or lower-functioning ASDs in low- and middle-income countries.
Additional Information
Please access these websites via the online version of this summary at
This study is further discussed in a PLOS Medicine Perspective by Bello-Mojeed and Bakare
The US Centers for Disease Control and Prevention provides information (in English and Spanish) on developmental disabilities, including autism spectrum disorders and intellectual disability
The US National Institute of Mental Health also provides detailed information about autism spectrum disorders, including the publication “A Parent's Guide to Autism Spectrum Disorder”
Autism Speaks, a US non-profit organization, provides information about all aspects of autism spectrum disorders and includes information on the Autism Speaks Global Autism Public Health Initiative
The National Autistic Society, a UK charity, provides information about all aspects of autism spectrum disorders and includes personal stories about living with these conditions
The UK National Health Service Choices website has an interactive guide to child development and information about autism and Asperger syndrome, including personal stories, and about learning disabilities
The UK National Institute for Health and Care Excellence provides clinical guidelines for the management and support of children with autism spectrum disorders
The World Health Organization provides information on its Mental Health Gap Action Programme (mhGAP), which includes recommendations on the management of developmental disorders by non-specialist providers; the mhGAP Evidence Resource Center provides evidence reviews for parent skills training for management of children with intellectual disabilities and pervasive developmental disorders and interventions for management of children with intellectual disabilities
PROSPERO, an international prospective register of systematic reviews, provides more information about this systematic review
PMCID: PMC3866092  PMID: 24358029
15.  Redox metabolism abnormalities in autistic children associated with mitochondrial disease 
Translational Psychiatry  2013;3(6):e273-.
Research studies have uncovered several metabolic abnormalities associated with autism spectrum disorder (ASD), including mitochondrial disease (MD) and abnormal redox metabolism. Despite the close connection between mitochondrial dysfunction and oxidative stress, the relation between MD and oxidative stress in children with ASD has not been studied. Plasma markers of oxidative stress and measures of cognitive and language development and ASD behavior were obtained from 18 children diagnosed with ASD who met criteria for probable or definite MD per the Morava et al. criteria (ASD/MD) and 18 age and gender-matched ASD children without any biological markers or symptoms of MD (ASD/NoMD). Plasma measures of redox metabolism included reduced free glutathione (fGSH), oxidized glutathione (GSSG), the fGSH/GSSG ratio and 3-nitrotyrosine (3NT). In addition, a plasma measure of chronic immune activation, 3-chlorotyrosine (3CT), was also measured. Language was measured using the preschool language scale or the expressive one-word vocabulary test (depending on the age), adaptive behaviour was measured using the Vineland Adaptive Behavior Scale (VABS) and core autism symptoms were measured using the Autism Symptoms Questionnaire and the Social Responsiveness Scale. Children with ASD/MD were found to have lower scores on the communication and daily living skill subscales of the VABS despite having similar language and ASD symptoms. Children with ASD/MD demonstrated significantly higher levels of fGSH/GSSG and lower levels of GSSG as compared with children with ASD/NoMD, suggesting an overall more favourable glutathione redox status in the ASD/MD group. However, compare with controls, both ASD groups demonstrated lower fGSH and fGSH/GSSG, demonstrating that both groups suffer from redox abnormalities. Younger ASD/MD children had higher levels of 3CT than younger ASD/NoMD children because of an age-related effect in the ASD/MD group. Both ASD groups demonstrated significantly higher 3CT levels than control subjects, suggesting that chronic inflammation was present in both groups of children with ASD. Interestingly, 3NT was found to correlate positively with several measures of cognitive function, development and behavior for the ASD/MD group, but not the ASD/NoMD group, such that higher 3NT concentrations were associated with more favourable adaptive behaviour, language and ASD-related behavior. To determine whether difference in receiving medications and/or supplements could account for the differences in redox and inflammatory biomarkers across ASD groups, we examined differences in medication and supplements across groups and their effect of redox and inflammatory biomarkers. Overall, significantly more participants in the ASD/MD group were receiving folate, vitamin B12, carnitine, co-enzyme Q10, B vitamins and antioxidants. We then determined whether folate, carnitine, co-enzyme Q10, B vitamins and/or antioxidants influenced redox or inflammatory biomarkers. Antioxidant supplementation was associated with a significantly lower GSSG, whereas antioxidants, co-enzyme Q10 and B vitamins were associated with a higher fGSH/GSSG ratio. There was no relation between folate, carnitine, co-enzyme Q10, B vitamins and antioxidants with 3NT, 3CT or fGSH. Overall, our findings suggest that ASD/MD children with a more chronic oxidized microenvironment have better development. We interpret this finding in light of the fact that more active mitochondrial can create a greater oxidized microenvironment especially when dysfunctional. Thus, compensatory upregulation of mitochondria which are dysfunctional may both increase activity and function at the expense of a more oxidized microenvironment. Although more ASD/MD children were receiving certain supplements, the use of such supplements were not found to be related to the redox biomarkers that were related to cognitive development or behavior in the ASD/MD group but could possibly account for the difference in glutathione metabolism noted between groups. This study suggests that different subgroups of children with ASD have different redox abnormalities, which may arise from different sources. A better understanding of the relationship between mitochondrial dysfunction in ASD and oxidative stress, along with other factors that may contribute to oxidative stress, will be critical to understanding how to guide treatment and management of ASD children. This study also suggests that it is important to identify ASD/MD children as they may respond differently to specific treatments because of their specific metabolic profile.
PMCID: PMC3693408  PMID: 23778583
autism; inflammation; endophenotypes; mitochondrial disease; oxidative stress
16.  Restricted and Repetitive Behaviors in Toddlers and Preschoolers with Autism Spectrum Disorders Based on the Autism Diagnostic Observation Schedule (ADOS) 
Lay Abstract
Restricted and repetitive behaviors (RRBs) have long been considered one of the core characteristics of autism. RRBs include a very broad category of behaviors such as preoccupation with restricted patterns of interest (e.g. having very specific knowledge about vacuum cleaners), adherence to specific, nonfunctional routines (e.g. insisting on taking a certain route to school), repetitive motor manners (e.g., hand flapping), and preoccupation with parts of objects (e.g. peering at the wheels of toy cars while spinning them). Most research on RRBs has used caregiver reports either through interviews or questionnaires; thus, the purpose of this study was to use clinicians’ observations of RRBs, made during the Autism Diagnostic Observation Schedule (ADOS: Lord, Rutter, DiLavore & Risi, 2000) to discover how RRBs change over time in very young children who may have ASD and what other factors are related to having RRBs. The ADOS is a 45 minute long, semi-structured, standardized assessment of communication, social interaction and play, which was administered to 121 children with autism, 71 with pervasive developmental disorders-not otherwise specified (PDD-NOS), 90 with a nonspectrum disorder, and 173 children who were typically developing. Even during a relatively short-term observation in the context of an office visit, we found that RRBs occurred more frequently and were more severe in young children with autism and PDD-NOS diagnoses than children in other groups. Diagnostic group differences also emerged in the associations between RRB scores and participant characteristics (e.g. age, NVIQ scores, etc). We also examined different subtypes of RRBs and their associations with NVIQ, age, diagnosis, and gender.
Scientific Abstract
Restricted and repetitive behaviors (RRBs) observed during the Autism Diagnostic Observation Schedule (ADOS: Lord, Rutter, DiLavore & Risi, 2000) were examined in a longitudinal dataset of 455 toddlers and preschoolers (age 8–56 months) with clinical diagnosis of Autism Spectrum Disorders (ASD; autism, n = 121 and pervasive developmental disorders-not otherwise specified (PDD-NOS), n = 71), a nonspectrum disorder (NS; n = 90), or typical development (TD; n = 173). Even in the relatively brief semi-structured observations, Generalized Estimating Equations (GEE) analyses of the severity and prevalence of RRBs differentiated children with ASD from those with NS and TD across all ages. RRB total scores on the ADOS were stable over time for children with ASD and NS; however, typically developing preschoolers showed lower RRB scores than typically developing toddlers. Nonverbal IQ (NVIQ) was more strongly related to the prevalence of RRBs in older children with PDD-NOS, NS and TD than younger children under 2 years and those with autism. Item analyses revealed different relationships between individual items and NVIQ, age, diagnosis, and gender. These findings are discussed in terms of their implications for the etiology and treatment of RRBs as well as for the framework of ASD diagnostic criteria in future diagnostic systems.
PMCID: PMC3005305  PMID: 20589716
restricted and repetitive behaviors (RRBs); autism spectrum disorders (ASD); Autism Diagnostic Observation Schedule (ADOS); toddlers; preschoolers
17.  Plasma cytokine profiling in sibling pairs discordant for autism spectrum disorder 
Converging lines of evidence point to the existence of immune dysfunction in autism spectrum disorder (ASD), which could directly affect several key neurodevelopmental processes. Previous studies have shown higher cytokine levels in patients with autism compared with matched controls or subjects with other developmental disorders. In the current study, we used plasma-cytokine profiling for 25 discordant sibling pairs to evaluate whether these alterations occur within families with ASD.
Plasma-cytokine profiling was conducted using an array-based multiplex sandwich ELISA for simultaneous quantitative measurement of 40 unique targets. We also analyzed the correlations between cytokine levels and clinically relevant quantitative traits (Vineland Adaptive Behavior Scale in Autism (VABS) composite score, Social Responsiveness Scale (SRS) total T score, head circumference, and full intelligence quotient (IQ)). In addition, because of the high phenotypic heterogeneity of ASD, we defined four subgroups of subjects (those who were non-verbal, those with gastrointestinal issues, those with regressive autism, and those with a history of allergies), which encompass common and/or recurrent endophenotypes in ASD, and tested the cytokine levels in each group.
None of the measured parameters showed significant differences between children with ASD and their related typically developing siblings. However, specific target levels did correlate with quantitative clinical traits, and these were significantly different when the ASD subgroups were analyzed. It is notable that these differences seem to be attributable to a predisposing immunogenetic background, as no other significant differences were noticed between discordant sibling pairs. Interleukin-1β appears to be the cytokine most involved in quantitative traits and clinical subgroups of ASD.
In the present study, we found a lack of significant differences in plasma-cytokine levels between children with ASD and in their related non-autistic siblings. Thus, our results support the evidence that the immune profiles of children with autism do not differ from their typically developing siblings. However, the significant association of cytokine levels with the quantitative traits and the clinical subgroups analyzed suggests that altered immune responses may affect core feature of ASD.
PMCID: PMC3616926  PMID: 23497090
18.  The Effects of Birth Order and Birth Interval on the Phenotypic Expression of Autism Spectrum Disorder 
PLoS ONE  2012;7(11):e51049.
A rise in the prevalence of diagnosed cases of autism spectrum disorder (ASD) has been reported in several studies in recent years. While this rise in ASD prevalence is at least partially related to increased awareness and broadened diagnostic criteria, the role of environmental factors cannot be ruled out, especially considering that the cause of most cases of ASD remains unknown. The study of families with multiple affected children can provide clues about ASD etiology. While the majority of research on ASD multiplex families has focused on identifying genetic anomalies that may underlie the disorder, the study of symptom severity across ASD birth order may provide evidence for environmental factors in ASD. We compared social and cognitive measures of behavior between over 300 first and second affected siblings within multiplex autism families obtained from the Autism Genetic Resource Exchange dataset. Measures included nonverbal IQ assessed with the Ravens Colored Progressive Matrices, verbal IQ assessed with the Peabody Picture Vocabulary Test, and autism severity assessed with the Social Responsiveness Scale (SRS), an instrument established as a quantitative measure of autism. The results indicated that females were more severely impacted by ASD than males, especially first affected siblings. When first and second affected siblings were compared, significant declines in nonverbal and verbal IQ scores were observed. In addition, SRS results demonstrated a significant increase in autism severity between first and second affected siblings consistent with an overall decline in function as indicated by the IQ data. These results remained significant after controlling for the age and sex of the siblings. Surprisingly, the SRS scores were found to only be significant when the age difference between siblings was less than 2 years. These results suggest that some cases of ASD are influenced by a dosage effect involving unknown epigenetic, environmental, and/or immunological factors.
PMCID: PMC3511407  PMID: 23226454
19.  Functional Connectivity in the First Year of Life in Infants at Risk for Autism Spectrum Disorder: An EEG Study 
PLoS ONE  2014;9(8):e105176.
In the field of autism research, recent work has been devoted to studying both behavioral and neural markers that may aide in early identification of autism spectrum disorder (ASD). These studies have often tested infants who have a significant family history of autism spectrum disorder, given the increased prevalence observed among such infants. In the present study we tested infants at high- and low-risk for ASD (based on having an older sibling diagnosed with the disorder or not) at 6- and 12-months-of-age. We computed intrahemispheric linear coherence between anterior and posterior sites as a measure of neural functional connectivity derived from electroencephalography while the infants were listening to speech sounds. We found that by 12-months-of-age infants at risk for ASD showed reduced functional connectivity compared to low risk infants. Moreover, by 12-months-of-age infants later diagnosed with ASD showed reduced functional connectivity, compared to both infants at low risk for the disorder and infants at high risk who were not later diagnosed with ASD. Significant differences in functional connectivity were also found between low-risk infants and high-risk infants who did not go onto develop ASD. These results demonstrate that reduced functional connectivity appears to be related to genetic vulnerability for ASD. Moreover, they provide further evidence that ASD is broadly characterized by differences in neural integration that emerge during the first year of life.
PMCID: PMC4139321  PMID: 25140874
20.  Latent Class Analysis of Early Developmental Trajectory in Baby Siblings of Children with Autism 
Siblings of children with autism (sibs-A) are at increased genetic risk for autism spectrum disorders (ASD) and milder impairments. To elucidate diversity and contour of early developmental trajectories exhibited by sibs-A, regardless of diagnostic classification, latent class modeling was used.
Sibs-A (n=204) were assessed with the Mullen Scales of Early Learning from age 6–36 months. Mullen T scores served as dependent variables. Outcome classifications at age 36 months included: ASD (n=52); non-ASD social/communication delay (broader autism phenotype; BAP) (n=31); and unaffected (n=121). Child-specific patterns of performance were studied using latent class growth analysis. Latent class membership was then related to diagnostic outcome through estimation of within-class proportions of children assigned to each diagnostic classification.
A 4-class model was favored. Class 1 represented accelerated development and consisted of 25.7% of the sample, primarily unaffected children. Class 2 (40.0% of the sample), was characterized by normative development with above-average nonverbal cognitive outcome. Class 3 (22.3% of the sample) was characterized by receptive language, and gross and fine motor delay. Class 4 (12.0% of the sample), was characterized by widespread delayed skill acquisition, reflected by declining trajectories. Children with an outcome diagnosis of ASD were spread across Classes 2, 3, and 4.
Results support a category of ASD that involves slowing in early non-social development. Receptive language and motor development is vulnerable to early delay in sibs-A with and without ASD outcomes. Non-ASD sibs-A are largely distributed across classes depicting average or accelerated development. Developmental trajectories of motor, language, and cognition appear independent of communication and social delays in non-ASD sibs-A.
PMCID: PMC3432306  PMID: 22574686
autism; trajectories; broader autism phenotype
21.  Developmental pathways to autism: A review of prospective studies of infants at risk☆ 
•Prospective studies of infants at familial risk are characterizing developmental pathways to ASD.•Children with ASD show social and communication difficulties in the second year of life.•Early neurocognitive markers include atypical neural response to gaze and slowed disengagement.•Mapping how ASD unfolds from birth is central to early identification and intervention.
Autism Spectrum Disorders (ASDs) are neurodevelopmental disorders characterized by impairments in social interaction and communication, and the presence of restrictive and repetitive behaviors. Symptoms of ASD likely emerge from a complex interaction between pre-existing neurodevelopmental vulnerabilities and the child's environment, modified by compensatory skills and protective factors. Prospective studies of infants at high familial risk for ASD (who have an older sibling with a diagnosis) are beginning to characterize these developmental pathways to the emergence of clinical symptoms. Here, we review the range of behavioral and neurocognitive markers for later ASD that have been identified in high-risk infants in the first years of life. We discuss theoretical implications of emerging patterns, and identify key directions for future work, including potential resolutions to several methodological challenges for the field. Mapping how ASD unfolds from birth is critical to our understanding of the developmental mechanisms underlying this disorder. A more nuanced understanding of developmental pathways to ASD will help us not only to identify children who need early intervention, but also to improve the range of interventions available to them.
PMCID: PMC3969297  PMID: 24361967
ASD; Autism; Infant sibling; High-risk; Causal path; Developmental mechanisms
22.  Family function, Parenting Style and Broader Autism Phenotype as Predicting Factors of Psychological Adjustment in Typically Developing Siblings of Children with Autism Spectrum Disorders 
Iranian Journal of Psychiatry  2014;9(2):55-63.
Siblings of children with autism are at a greater risk of experiencing behavioral and social problems. Previous researches had focused on environmental variables such as family history of autism spectrum disorders (ASDs), behavior problems in the child with an ASD, parental mental health problems, stressful life events and “broader autism phenotype” (BAP), while variables like parenting style and family function that are shown to influence children’s behavioral and psychosocial adjustment are overlooked. The aim of the present study was to reveal how parenting style and family function as well as BAP effect psychological adjustment of siblings of children with autism.
The Participants included 65 parents who had one child with an Autism Spectrum Disorder and one typically developing child. Of the children with ASDs, 40 were boys and 25 were girls; and they were diagnosed with ASDs by a psychiatrist based on DSM-IV-TR criteria and Autism Diagnostic Interview-Revised (ADI-R). The Persian versions of the six scales were used to collect data from the families. Pearson’s correlation test and regression analysis were used to determine which variables were related to the psychological adjustment of sibling of children with ASDs and which variables predicted it better.
Significant relationships were found between Strengths and Difficulties Questionnaire (SDQ) total difficulties, prosocial behaviors and ASDs symptoms severity, parenting styles and some aspects of family function. In addition, siblings who had more BAP characteristics had more behavior problems and less prosocial behavior. Behavioral problems increased and prosocial behavior decreased with permissive parenting style. Besides, both of authoritarian and authoritative parenting styles led to a decrease in behavioral problems and an increase in prosocial behaviors. Our findings revealed that some aspects of family function (affective responsiveness, roles, problem solving and behavior control) were significantly correlated with behavioral problems and prosocial behaviors in typically developing (TD) siblings of children with ASDs.
Siblings of children with ASDs, due to genetic liability, are at a greater risk of psychological maladjustment. Furthermore, environmental factors like parenting styles and family function also have a significant effect on psychological maladjustment.
PMCID: PMC4300466  PMID: 25632281
Autism spectrum disorders (ASDs); broader autism phenotype; sibling; parenting style; psychological adjustment
23.  Gastrointestinal Dysfunction in Autism: Parental Report, Clinical Evaluation, & Associated Factors 
Autism Research  2012;5(2):101-108.
Lay Abstract
Gastrointestinal dysfunction (GID) in children with autism spectrum disorder (ASD) is not well understood. Differences in factors associated with GID, such as eating habits, have been reported between ASD and non-ASD populations, but relationships between these factors and GID have not been examined. There is also the possibility that what we do know about GID in ASD is influenced by parents’ perceptions of GID in their children. Although parents know their children best, they are not necessarily experts in determining GID. This study examined how well parents and pediatric gastrointestinal clinicians agree on GID in children, and how factors thought to relate to GID in ASD, actually do relate to GID. 121 children were studied, in three groups: co-occurring ASD and GID, ASD without GID, and GID without ASD. Clinical evaluations by pediatric gastroenterologists validated parental reports of GID in ASD, with constipation the leading type of GID in ASD. Presence of GID in ASD was not associated with differences in diet or medications, but was associated with language and social impairments. These findings suggest that healthcare providers of children with ASD should be vigilant for GID, particularly in children who lack the ability to communicate verbally.
Scientific Abstract
The objectives of this study were to characterize gastrointestinal dysfunction (GID) in autism spectrum disorder (ASD), to examine parental reports of GID relative to evaluations by pediatric gastroenterologists, and to explore factors associated with GID in ASD. 121 children were recruited into three groups: co-occurring ASD and GID, ASD without GID, and GID without ASD. A pediatric gastroenterologist evaluated both GID groups. Parents in all three groups completed questionnaires about their child’s behavior and GI symptoms, and a dietary journal. Functional constipation was the most common type of GID in children with ASD (85.0%). Parental report of any GID was highly concordant with a clinical diagnosis of any GID (92.1%). Presence of GID in children with ASD was not associated with distinct dietary habits or medication status. Odds of constipation were associated with younger age, increased social impairment, and lack of expressive language (adjusted odds ratio in nonverbal children: 11.98, 95% CI 2.54 – 56.57). This study validates parental concerns for GID in children with ASD, as parents were sensitive to the existence, although not necessarily the nature, of GID. The strong association between constipation and language impairment highlights the need for vigilance by healthcare providers to detect and treat GID in children with ASD. Medications and diet, commonly thought to contribute to GID in ASD, were not associated with GID status. These findings are consistent with a hypothesis that GID in ASD represents pleiotropic expression of genetic risk factors.
PMCID: PMC3335766  PMID: 22511450
Autism; Constipation; Diet; Functional Gastrointestinal Disorders; Nonverbal Communication; Social Behavior
24.  Better working memory for non-social targets in infant siblings of children with Autism Spectrum Disorder 
Developmental science  2010;13(1):244-251.
We compared working memory (WM) for location of social vs. non-social targets in infant siblings of children with Autism Spectrum Disorders (sibs-ASD, n=25) and typically developing children (sibs-TD, n=30) at 6.5 and 9 months of age. There was a significant interaction of risk group and target-type on WM, in which the sibs-ASD had better WM for non-social targets as compared to controls. There was no group by stimulus interaction on two non-memory measures. The results suggest that the increased competency of sibs-ASD in WM (creating, updating, and using transient representations) for non-social stimuli distinguishes them from sibs-TD by 9 months of age. This early emerging strength is discussed as a developmental pathway that may have implications for social attention and learning in children at risk for ASD.
PMCID: PMC2818009  PMID: 20121880
25.  Broader Autism Phenotype in Iranian Parents of Children with Autism Spectrum Disorders vs. Normal Children 
Iranian Journal of Psychiatry  2012;7(4):157-163.
The aim of the present study was to compare the broader autism phenotype in Iranian parents of children with autism spectrum disorders and parents of typically developing children.
Parents of children with ASD and parents of typically developing children were asked to complete the Persian version of the Autism Spectrum Quotient (AQ). In the ASD group, families included 204 parents (96 fathers and 108 mothers) of children diagnosed as having autism (Autistic Disorder, or AD) (n=124), Asperger Syndrome (AS) or High Functioning Autism (HFA) (n=48) and Pervasive Developmental Disorder Not Otherwise Specified (PDD-NOS) (n=32) by psychiatrists based on the Diagnostic and Statistical Manual of Mental Disorders-4thedition (DSM-IV-TR) criteria. In the control group, 210 (108 fathers and 102 mothers) parents of typically developing children. Parents of typically developing children were selected from four primary schools. Based on family reports, their children did not have any psychiatric problems. Total AQ score and each of the 5 subscales were analyzed using two-way ANOVAs with sex and group as factors.
The mean age of ASD fathers was 40.6 years (SD=5.96; range 31-54), and of ASD mothers was 34.7 years (SD=4.55; range 28-45). The mean age of control fathers was 37 years (SD=4.6; range 29-45) and of control mothers was 34.11 years (SD=4.86; range 28-45). Group differences were found in age (p ‹ 0/001). On total AQ, a main effect for group and sex was found. ASD parents scored higher than controls (F(1,410)=77.876, P ‹ 0/001) and males scored higher than females (F(1,410)=23.324, P ‹ 0/001). Also, Group by Sex interaction was significant (F(1,410)=4.986, P ‹ 0/05). Results of MANOVA analysis displayed significant differences between ASD's subgroups on total AQ and subscales scores (F (15, 1121)=13.924, p < 0.0005; Wilk's Lambda= 0.624, partial =0.145). Pairwise comparisons between ASD's subgroups and Normal group showed that mean scores for the Asperger group are significantly more than other groups in total AQ, attention switching and communication subscales (p < 0.05). The frequencies of BAP (X^2=52.721 (DF=1), P ‹ 0/001), MAP (X^2=17.133 (DF=1), P ‹ 0/001) and NAP (X^2=12.722 (DF=1), P ‹ 0/001) in ASD parents were significantly more than control parents. The frequencies of Broader Autism Phenotype (BAP) (X^2=3.842 (DF=1), P›0/05) and Medium Autism phenotype (MAP) (X^2=0.060 (DF=1), P›0/05) did not significantly differ in ASD fathers and mothers, but the proportion of fathers in Narrow Autism Phenotype(NAP) range was more than mothers (X2=14.344, P ‹ 0/001).
Results of the present study revealed that parents of children with ASD scored significantly higher than control parents on total AQ and its subscales and the rates of BAP, MAP and NAP were higher in ASD parents than in controls. In addition, in ASD's subgroups, the parents of Asperger children scored significantly more than other subgroups (Autism and PDD-nos) and the normal group on total AQ and some subscales.
PMCID: PMC3570573  PMID: 23408558
Autistic disorder; Child; Iran; Parents

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