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1.  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
Background
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.
Conclusions
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
Background
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 http://dx.doi.org/10.1371/journal.pmed.1001572.
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
doi:10.1371/journal.pmed.1001572
PMCID: PMC3866092  PMID: 24358029
2.  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.
Objective
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.
Method
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.
Results
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.
Conclusion
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
3.  Changes in Siblings after the Death of a Child from Cancer 
Cancer nursing  2012;35(5):347-354.
Background
Few studies have examined changes in siblings after the death of a brother or sister, particularly from mother, father, and sibling perspectives within the first year post-death.
Objective
This descriptive study identified and assessed the frequency of changes in siblings after a child's death from cancer.
Methods
Participants were recruited from cancer registries at three hospitals in the U.S. and Canada 3–12 months after the child's death. Thirty-six mothers, 24 fathers, and 39 siblings from 40 families were included. Semi-structured interviews using open-ended questions were conducted with each parent and sibling separately in the home. Content analysis identified emerging themes, and McNemar tests compared frequencies between each paired set of reports (sibling vs. mother, sibling vs. father, mother vs. father).
Results
Sixty-nine percent of participants reported personal changes in siblings (e.g., changes in personality, school work, goals/life perspective, activities/interests). Forty-seven percent noted changes in siblings' relationships with family members and peers. Only 21% of participants reported no changes attributed to the death. Comparisons of frequencies across informants were not significant.
Conclusions
Most siblings experienced changes in multiple areas of their lives after the death of a brother or sister to cancer. Some changes reflected siblings that were positively adapting to the death, while other changes reflected difficulties.
Implications for practice
Our findings offer guidance to improve aftercare for bereaved siblings and their families. Additional research is needed to further delineate the needs of bereaved siblings and to develop strategies to promote adaptation to loss.
doi:10.1097/NCC.0b013e3182365646
PMCID: PMC3338871  PMID: 22067687
4.  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.
doi:10.1371/journal.pone.0051049
PMCID: PMC3511407  PMID: 23226454
5.  Beyond Autism: A Baby Siblings Research Consortium Study of High-Risk Children at Three Years of Age 
Objective
First-degree relatives of persons with an autism spectrum disorder (ASD) are at increased risk for ASD-related characteristics. As little is known about the early expression of these characteristics, this study characterizes the non-ASD outcomes of 3-year-old high-risk (HR) siblings of children with ASD.
Method
Two groups of children without ASD participated: 507 HR siblings and 324 low-risk (LR) control subjects (no known relatives with ASD). Children were enrolled at a mean age of 8 months, and outcomes were assessed at 3 years. Outcome measures were Autism Diagnostic Observation Schedule (ADOS) calibrated severity scores, and Mullen Verbal and Non-Verbal Developmental Quotients (DQ).
Results
At 3 years, HR siblings without an ASD outcome exhibited higher mean ADOS severity scores and lower verbal and non-verbal DQs than LR controls. HR siblings were over-represented (21% HR versus 7% LR) in latent classes characterized by elevated ADOS severity and/or low to low-average DQs. The remaining HR siblings without ASD outcomes (79%) belonged to classes in which they were not differentially represented with respect to LR siblings.
Conclusions
Having removed a previously identified 18.7% of HR siblings with ASD outcomes from all analyses, HR siblings nevertheless exhibited higher mean levels of ASD severity and lower levels of developmental functioning than LR children. However, the latent class membership of four-fifths of the HR siblings was not significantly different from that of LR control subjects. One-fifth of HR siblings belonged to classes characterized by higher ASD severity and/or lower levels of developmental functioning. This empirically derived characterization of an early-emerging pattern of difficulties in a minority of 3-year-old HR siblings suggests the importance of developmental surveillance and early intervention for these children.
doi:10.1016/j.jaac.2012.12.011
PMCID: PMC3625370  PMID: 23452686
ASD; high-risk siblings; outcome; broad autism phenotype
6.  Plasma cytokine profiling in sibling pairs discordant for autism spectrum disorder 
Objective
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1186/1742-2094-10-38
PMCID: PMC3616926  PMID: 23497090
7.  Recurrence Risk for Autism Spectrum Disorders: A Baby Siblings Research Consortium Study 
Pediatrics  2011;128(3):e488-e495.
OBJECTIVE:
The recurrence risk of autism spectrum disorders (ASD) is estimated to be between 3% and 10%, but previous research was limited by small sample sizes and biases related to ascertainment, reporting, and stoppage factors. This study used prospective methods to obtain an updated estimate of sibling recurrence risk for ASD.
METHODS:
A prospective longitudinal study of infants at risk for ASD was conducted by a multisite international network, the Baby Siblings Research Consortium. Infants (n = 664) with an older biological sibling with ASD were followed from early in life to 36 months, when they were classified as having or not having ASD. An ASD classification required surpassing the cutoff of the Autism Diagnostic Observation Schedule and receiving a clinical diagnosis from an expert clinician.
RESULTS:
A total of 18.7% of the infants developed ASD. Infant gender and the presence of >1 older affected sibling were significant predictors of ASD outcome, and there was an almost threefold increase in risk for male subjects and an additional twofold increase in risk if there was >1 older affected sibling. The age of the infant at study enrollment, the gender and functioning level of the infant's older sibling, and other demographic factors did not predict ASD outcome.
CONCLUSIONS:
The sibling recurrence rate of ASD is higher than suggested by previous estimates. The size of the current sample and prospective nature of data collection minimized many limitations of previous studies of sibling recurrence. Clinical implications, including genetic counseling, are discussed.
doi:10.1542/peds.2010-2825
PMCID: PMC3164092  PMID: 21844053
autism; recurrence; sibling risk
8.  Individual Differences in the Real-Time Comprehension of Children with ASD 
Lay Abstract
Spoken language processing is related to language and cognitive skills in typically developing children, but very little is known about how children with autism spectrum disorders (ASD) comprehend words in real time. Studying this area is important because it may help us understand why many children with autism have delayed language comprehension. Thirty-four children with ASD (3–6 years old) participated in this study. They took part in a language comprehension task that involved looking at pictures on a screen and listening to questions about familiar nouns (e.g., Where’s the shoe?). Children as a group understood the familiar words, but accuracy and processing speed varied considerably across children. The children who were more accurate were also faster to process the familiar words. Children’s language processing accuracy was related to processing speed and language comprehension on a standardized test; nonverbal cognition did not explain additional information after accounting for these factors. Additionally, lexical processing accuracy at age 5½ was related to children’s vocabulary comprehension three years earlier, at age 2½. Autism severity and years of maternal education were unrelated to language processing. Words typically acquired earlier in life were processed more quickly than words acquired later. These findings point to similarities in patterns of language development in typically developing children and children with ASD. Studying real-time comprehension in children with ASD may help us better understand mechanisms of language comprehension in this population. Future work may help explain why some children with ASD develop age-appropriate language skills, whereas others experience lasting deficits.
Scientific Abstract
Many children with autism spectrum disorders (ASD) demonstrate deficits in language comprehension, but little is known about how they process spoken language as it unfolds. Real-time lexical comprehension is associated with language and cognition in children without ASD, suggesting that this may also be the case for children with ASD. This study adopted an individual differences approach to characterizing real-time comprehension of familiar words in a group of 34 three- to six-year-olds with ASD. The looking-while-listening paradigm was employed; it measures online accuracy and latency through language-mediated eye movements and has limited task demands. On average, children demonstrated comprehension of the familiar words, but considerable variability emerged. Children with better accuracy were faster to process the familiar words. In combination, processing speed and comprehension on a standardized language assessment explained 63% of the variance in online accuracy. Online accuracy was not correlated with autism severity or maternal education, and nonverbal cognition did not explain unique variance. Notably, online accuracy at age 5½ was related to vocabulary comprehension three years earlier. The words typically learned earliest in life were processed most quickly. Consistent with a dimensional view of language abilities, these findings point to similarities in patterns of language acquisition in typically developing children and those with ASD. Overall, our results emphasize the value of examining individual differences in real-time language comprehension in this population. We propose that the looking-while-listening paradigm is a sensitive and valuable methodological tool that can be applied across many areas of autism research.
doi:10.1002/aur.1304
PMCID: PMC3808474  PMID: 23696214
autism; comprehension; language processing; receptive vocabulary; eye-gaze methodology; individual differences
9.  Does epilepsy in multiplex autism pedigrees define a different subgroup in terms of clinical characteristics and genetic risk? 
Molecular Autism  2013;4:47.
Background
Autism spectrum disorders (ASD) and epilepsy frequently occur together. Prevalence rates are variable, and have been attributed to age, gender, comorbidity, subtype of pervasive developmental disorder (PDD) and risk factors. Recent studies have suggested disparate clinical and genetic settings depending on simplex or multiplex autism. The aim of this study was to assess: 1) the prevalence of epilepsy in multiplex autism and its association with genetic and non-genetic risk factors of major effect, intellectual disability and gender; and 2) whether autism and epilepsy cosegregate within multiplex autism families.
Methods
We extracted from the Autism Genetic Resource Exchange (AGRE) database (n = 3,818 children from 1,264 families) all families with relevant medical data (n = 664 children from 290 families). The sample included 478 children with ASD and 186 siblings without ASD. We analyzed the following variables: seizures, genetic and non-genetic risk factors, gender, and cognitive functioning as assessed by Raven’s Colored Progressive Matrices (RCPM) and Vineland Adaptive Behavior Scales (VABS).
Results
The prevalence of epilepsy was 12.8% in cases with ASD and 2.2% in siblings without ASD (P <10-5). With each RCPM or VABS measure, the risk of epilepsy in multiplex autism was significantly associated with intellectual disability, but not with gender. Identified risk factors (genetic or non-genetic) of autism tended to be significantly associated with epilepsy (P = 0.052). When children with prematurity, pre- or perinatal insult, or cerebral palsy were excluded, a genetic risk factor was reported for 6/59 (10.2%) of children with epilepsy and 12/395 (3.0%) of children without epilepsy (P = 0.002). Finally, using a permutation test, there was significant evidence that the epilepsy phenotype co-segregated within families (P <10-4).
Conclusions
Epilepsy in multiplex autism may define a different subgroup in terms of clinical characteristics and genetic risk.
doi:10.1186/2040-2392-4-47
PMCID: PMC4176303  PMID: 24289166
Autism; Multiplex pedigree; Epilepsy; Intellectual disability
10.  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.
doi:10.1111/j.1532-7078.2012.00142.x
PMCID: PMC3880657  PMID: 24403864
Autism Spectrum Disorders; at-risk infants; referential communication; developmental trajectories; symptom severity
11.  Infant siblings and the investigation of autism risk factors 
Infant sibling studies have been at the vanguard of autism spectrum disorders (ASD) research over the past decade, providing important new knowledge about the earliest emerging signs of ASD and expanding our understanding of the developmental course of this complex disorder. Studies focused on siblings of children with ASD also have unrealized potential for contributing to ASD etiologic research. Moving targeted time of enrollment back from infancy toward conception creates tremendous opportunities for optimally studying risk factors and risk biomarkers during the pre-, peri- and neonatal periods. By doing so, a traditional sibling study, which already incorporates close developmental follow-up of at-risk infants through the third year of life, is essentially reconfigured as an enriched-risk pregnancy cohort study. This review considers the enriched-risk pregnancy cohort approach of studying infant siblings in the context of current thinking on ASD etiologic mechanisms. It then discusses the key features of this approach and provides a description of the design and implementation strategy of one major ASD enriched-risk pregnancy cohort study: the Early Autism Risk Longitudinal Investigation (EARLI).
doi:10.1186/1866-1955-4-7
PMCID: PMC3436647  PMID: 22958474
Autism; Cohort; Epidemiology; Pregnancy; Prospective; Sibling; Study Design
12.  Risk of Violent Crime in Individuals with Epilepsy and Traumatic Brain Injury: A 35-Year Swedish Population Study 
PLoS Medicine  2011;8(12):e1001150.
Seena Fazel and colleagues report findings from a longitudinal follow-up study in Sweden that evaluated the risks of violent crime subsequent to hospitalization for epilepsy, or traumatic brain injury. The researchers control for familial confounding with sibling controls. The analyses call into question an association between epilepsy and violent crime, although they do suggest that there may be a relationship between traumatic brain injury and violent crime.
Background
Epilepsy and traumatic brain injury are common neurological conditions, with general population prevalence estimates around 0.5% and 0.3%, respectively. Although both illnesses are associated with various adverse outcomes, and expert opinion has suggested increased criminality, links with violent behaviour remain uncertain.
Methods and Findings
We combined Swedish population registers from 1973 to 2009, and examined associations of epilepsy (n = 22,947) and traumatic brain injury (n = 22,914) with subsequent violent crime (defined as convictions for homicide, assault, robbery, arson, any sexual offense, or illegal threats or intimidation). Each case was age and gender matched with ten general population controls, and analysed using conditional logistic regression with adjustment for socio-demographic factors. In addition, we compared cases with unaffected siblings.
Among the traumatic brain injury cases, 2,011 individuals (8.8%) committed violent crime after diagnosis, which, compared with population controls (n = 229,118), corresponded to a substantially increased risk (adjusted odds ratio [aOR] = 3.3, 95% CI: 3.1–3.5); this risk was attenuated when cases were compared with unaffected siblings (aOR = 2.0, 1.8–2.3). Among individuals with epilepsy, 973 (4.2%) committed a violent offense after diagnosis, corresponding to a significantly increased odds of violent crime compared with 224,006 population controls (aOR = 1.5, 1.4–1.7). However, this association disappeared when individuals with epilepsy were compared with their unaffected siblings (aOR = 1.1, 0.9–1.2). We found heterogeneity in violence risk by age of disease onset, severity, comorbidity with substance abuse, and clinical subgroups. Case ascertainment was restricted to patient registers.
Conclusions
In this longitudinal population-based study, we found that, after adjustment for familial confounding, epilepsy was not associated with increased risk of violent crime, questioning expert opinion that has suggested a causal relationship. In contrast, although there was some attenuation in risk estimates after adjustment for familial factors and substance abuse in individuals with traumatic brain injury, we found a significantly increased risk of violent crime. The implications of these findings will vary for clinical services, the criminal justice system, and patient charities.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
News stories linking mental illness (diseases that appear primarily as abnormalities of thought, feeling or behavior) with violence frequently hit the headlines. But what about neurological conditions—disorders of the brain, spinal cord, and nerves? People with these disorders, which include dementia, Parkinson's disease, and brain tumors, often experience stigmatization and discrimination, a situation that is made worse by the media and by some experts suggesting that some neurological conditions increase the risk of violence. For example, many modern textbooks assert that epilepsy—a neurological condition that causes repeated seizures or fits—is associated with increased criminality and violence. Similarly, various case studies have linked traumatic brain injury—damage to the brain caused by a sudden blow to the head—with an increased risk of violence.
Why Was This Study Done?
Despite public and expert perceptions, very little is actually known about the relationship between epilepsy and traumatic brain injury and violence. In particular, few if any population-based, longitudinal studies have investigated whether there is an association between the onset of either of these two neurological conditions and violence at a later date. This information might make it easier to address the stigma that is associated with these conditions. Moreover, it might help scientists understand the neurobiological basis of violence, and it could help health professionals appropriately manage individuals with these two disorders. In this longitudinal study, the researchers begin to remedy the lack of hard information about links between neurological conditions and violence by investigating the risk of violent crime associated with epilepsy and with traumatic brain injury in the Swedish population.
What Did the Researchers Do and Find?
The researchers used the National Patient Register to identify all the cases of epilepsy and traumatic brain injury that occurred in Sweden between 1973 and 2009. They matched each case (nearly 23,000 for each condition) with ten members of the general population and retrieved data on all convictions for violent crime over the same period from the Crime Register. They then linked these data together using the personal identification numbers that identify Swedish residents in national registries. 4.2% of individuals with epilepsy had at least one conviction for violence after their diagnosis, but only 2.5% of the general population controls did. That is, epilepsy increased the absolute risk of a conviction for violence by 1.7%. Using a regression analysis that adjusted for age, gender, and various socio-demographic factors, the researchers calculated that the odds of individuals with epilepsy committing a violent crime were 1.5 times higher than for general population controls (an adjusted odds ratio [aOR] of 1.5). The strength of this association was reduced when further adjustment was made for substance abuse, and disappeared when individuals with epilepsy were compared with their unaffected siblings (a sibling control study). Similarly, 8.8% of individuals with traumatic brain injury were convicted of a violent crime after their diagnosis compared to only 3% of controls, giving an aOR of 3.3. Again, the strength of this association was reduced when affected individuals were compared to their unaffected siblings (aOR = 2.0) and when adjustment was made for substance abuse (aOR = 2.3).
What Do These Findings Mean?
Although some aspects of this study may have affected the accuracy of its findings, these results nevertheless challenge the idea that there are strong direct links between epilepsy and violent crime. The low absolute rate of violent crime and the lack of any association between epilepsy and violent crime in the sibling control study argue against a strong link, a potentially important finding given the stigmatization of epilepsy. For traumatic brain injury, the reduced association with violent crime in the sibling control study compared with the general population control study suggests that shared familial features may be responsible for some of the association between brain injury and violence. As with epilepsy, this finding should help patient charities who are trying to reduce the stigma associated with traumatic brain injury. Importantly, however, these findings also suggest that some groups of patients with these conditions (for example, patients with head injuries who abuse illegal drugs and alcohol) would benefit from being assessed for their risk of behaving violently and from appropriate management.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001150.
This study is further discussed in a PLoS Medicine Perspective by Jan Volavka
The US National Institute of Neurological Disorders and Stroke provides detailed information about traumatic brain injury and about epilepsy (in English and Spanish)
The UK National Health Service Choices website provides information about severe head injury, including a personal story about a head injury sustained in a motor vehicle accident, and information about epilepsy, including personal stories about living with epilepsy
Healthtalkonline has information on epilepsy, including patient perspectives
MedlinePlus provide links to further resources on traumatic brain injury and on epilepsy (available in English and Spanish)
doi:10.1371/journal.pmed.1001150
PMCID: PMC3246446  PMID: 22215988
13.  Maternal Prenatal Weight Gain and Autism Spectrum Disorders 
Pediatrics  2013;132(5):e1276-e1283.
BACKGROUND:
The rising population of individuals identified with an autism spectrum disorder (ASD) calls for further investigation of its underlying etiology. A disturbance in the fetal steroid hormone environment may be a mechanism in which environmental and genetic risk factors interact. The mother, fetus, and placenta collectively create the fetal steroid environment. Prepregnancy BMI and pregnancy weight gain have served as markers for fetal steroid hormone exposure in other disease states. This study’s objective is to determine whether prepregnancy BMI and pregnancy weight gain are associated with increased ASD risk across study designs and cohorts while controlling for important confounding variables.
METHODS:
A population-based Utah ASD cohort (n = 128) was ascertained in a 3-county surveillance area and gender- and age-matched to 10 920 control subjects. A second, research-based ASD cohort of Utah children (n = 288) and their unaffected siblings (n = 493) were ascertained through participation in an ASD genetics study. Prenatal variables were obtained from birth certificate records.
RESULTS:
ASD risk was significantly associated with pregnancy weight gain (adjusted odds ratio = 1.10, 95% confidence interval: 1.03 to 1.17; adjusted odds ratio = 1.17, 95% confidence interval: 1.01 to 1.35 for each 5 pounds of weight gained), but not prepregnancy BMI, in population and research-based cohorts, respectively. When analyses were restricted to ASD cases with normal IQ, these associations remained significant.
CONCLUSIONS:
ASD risk associated with a modest yet consistent increase in pregnancy weight gain suggests that pregnancy weight gain may serve as an important marker for autism’s underlying gestational etiology. This justifies an investigation into phenomena that link pregnancy weight gain and ASD independent of prepregnancy BMI.
doi:10.1542/peds.2013-1188
PMCID: PMC3813395  PMID: 24167172
autism; prenatal; weight gain; risk factors; epidemiology
14.  Mood and Anxiety Symptoms in Psychiatric Inpatients with Autism Spectrum Disorder and Depression 
Recent reports suggest that individuals with autism spectrum disorders (ASD) may experience depression at a high frequency, yet few published studies address this issue, especially among adults. In the current investigation, we reviewed features of depression and comorbid traits among depressed inpatients with intellectual disabilities (ID) as a function of ASD. A retrospective chart review was performed for 53 inpatients meeting criteria for depression (13 individuals with ASD and ID and 40 matched individuals with ID but without ASD), all of whom had received a diagnosis of depression at the time of discharge from a specialty psychiatric unit for adults with ID. The depression diagnoses were based on a comprehensive clinical assessment; specific mood and anxiety symptoms were reported by informants at the time of intake using the Mood and Anxiety Semi-Structured (MASS) Interview for Patients with Intellectual Disabilities (Charlot, Deutsch, Hunt, Fletcher, & McIlvane, 2007). Overall, few qualitative differences were detected between the 2 groups. Both depressed inpatient groups had high rates of comorbid anxiety disorders as well as externalizing behaviors. Inpatients with ASD had a total of 2 more symptoms (out of 29 possible symptom items) than their depressed peers without an ASD diagnosis (mean scores of 12.23 and 9.85, respectively). Anxiety disorders were reported in 62% of individuals with ASD and 38% of those without ASD. Antipsychotic medication was prevalent among the patients with ASD and depression. Over 80% of the inpatients with ASD and depression, compared with 49% of the non-ASD group, were treated with these medications.
doi:10.1080/19315860802313947
PMCID: PMC3760522  PMID: 24009649
autism; autism spectrum disorders; depression; anxiety; antipsychotic medications; mood disorders
15.  Emotional Development in Adults with Autism and Intellectual Disabilities: A Retrospective, Clinical Analysis 
PLoS ONE  2013;8(9):e74036.
Individuals with intellectual disability (ID) are at risk for additional autism spectrum disorders (ASD). A large amount of research reveals deficits in emotion-related processes that are relevant to social cognition in ASD. However, studies on the structure and level of emotional development (ED) assessing emotional maturity according to the normative trajectory in typically developing children are scares. The level of ED can be evaluated by the ‘Scheme of Appraisal of Emotional Development’ (SAED), a semi-structured interview with a close caregiver. The SAED assesses the level of emotional developmental based on a five stage system in 10 domains, for example, ‘interaction with peers’ or ‘object permanence’, which are conducive to the overall emotional developmental level. This study examined the ED as measured by the SAED in 289 adults (mean age: 36 years) with ID with and without additional ASD. A lower level in ED was observed in ASD/ID combined that corresponded to the ED of typically developing children aged 1.5–3 years versus an ED with a corresponding age of 3–7 years in ID individuals without ASD. Moreover, distinct strengths in ‘object permanence’, and weaknesses in ‘interaction’, ‘verbal communication’, ‘experience of self’, ‘affect differentiation’, ‘anxiety’, and ‘handling of material objects’ led to a characteristic pattern of ED in ASD. SAED domains with highest discriminative power between ID individuals with and without ASD (5/10) were used to predict ASD group membership. The classification using a selection of SAED domains revealed a sensitivity of 77.5% and a specificity of 76.4%. ASD risk increased 2.7-fold with every SAED level. The recognition of delayed and uneven pattern of ED contributes to our understanding of the emotion-related impairments in adults with ID and ASD these individuals. Assessment of intra-individual ED could add value to the standard diagnostic procedures in ID, a population at risk for underdiagnosed ASD.
doi:10.1371/journal.pone.0074036
PMCID: PMC3774757  PMID: 24066092
16.  Alterations in Sensitivity to Estrogen, Dihydrotestosterone, and Xenogens in B-Lymphocytes from Children with Autism Spectrum Disorder and Their Unaffected Twins/Siblings 
Journal of Toxicology  2013;2013:159810.
It has been postulated that androgen overexposure in a susceptible person leads to excessive brain masculinization and the autism spectrum disorder (ASD) phenotype. In this study, the responses to estradiol (E2), dihydrotestosterone (DHT), and dichlorodiphenyldichloroethylene (DDE) on B-lymphocytes from ASD subjects and controls are compared. B cells were obtained from 11 ASD subjects, their unaffected fraternal twins, and nontwin siblings. Controls were obtained from a different cell bank. Lactate dehydrogenase (LDH) and sodium 2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide (XTT) reduction levels were measured after incubation with different concentrations of E2, DHT, and DDE. XTT/LDH ratio, representative of mitochondria number per cell, was calculated. E2, DHT, and DDE all cause “U”-shaped growth curves, as measured by LDH levels. ASD B cells show less growth depression compared to siblings and controls (P < 0.01). They also have reduced XTT/LDH ratios (P < 0.01) when compared to external controls, whereas siblings had values of XTT/LDH between ASD and external controls. B-lymphocytes from people with ASD exhibit a differential response to E2, DHT, and hormone disruptors in regard to cell growth and mitochondrial upregulation when compared to non-ASD siblings and external controls. Specifically, ASD B-lymphocytes show significantly less growth depression and less mitochondrial upregulation when exposed to these effectors. A mitochondrial deficit in ASD individuals is implied.
doi:10.1155/2013/159810
PMCID: PMC3836453  PMID: 24363669
17.  Impaired Prefrontal Hemodynamic Maturation in Autism and Unaffected Siblings 
PLoS ONE  2009;4(9):e6881.
Background
Dysfunctions of the prefrontal cortex have been previously reported in individuals with autism spectrum disorders (ASD). Previous studies reported that first-degree relatives of individuals with ASD show atypical brain activity during tasks associated with social function. However, developmental changes in prefrontal dysfunction in ASD and genetic influences on the phenomena remain unclear. In the present study, we investigated the change in hemoglobin concentration in the prefrontal cortex as measured with near-infrared spectroscopy, in children and adults with ASD during the letter fluency test. Moreover, to clarify the genetic influences on developmental changes in the prefrontal dysfunction in ASD, unaffected siblings of the ASD participants were also assessed.
Methodology/Principal Findings
Study participants included 27 individuals with high-functioning ASD, age- and IQ-matched 24 healthy non-affected siblings, and 27 unrelated healthy controls aged 5 to 39 years. The relative concentration of hemoglobin ([Hb]) in the prefrontal cortex was measured during the letter fluency task. For children, neither the [oxy-Hb] change during the task nor task performances differed significantly among three groups. For adults, the [oxy-Hb] increases during the task were significantly smaller in the bilateral prefrontal cortex in ASD than those in control subjects, although task performances were similar. In the adult siblings the [oxy-Hb] change was intermediate between those in controls and ASDs.
Conclusion/Significance
Although indirectly due to a cross-sectional design, the results of this study indicate altered age-related change of prefrontal activity during executive processing in ASD. This is a first near-infrared spectroscopy study that implies alteration in the age-related changes of prefrontal activity in ASD and genetic influences on the phenomena.
doi:10.1371/journal.pone.0006881
PMCID: PMC2731203  PMID: 19727389
18.  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.
doi:10.1038/tp.2013.51
PMCID: PMC3693408  PMID: 23778583
autism; inflammation; endophenotypes; mitochondrial disease; oxidative stress
19.  Autism traits in the RASopathies 
Journal of medical genetics  2013;51(1):10-20.
Background
Mutations in Ras/mitogen-activated protein kinase (Ras/MAPK) pathway genes lead to a class of disorders known as RASopathies, including neurofibromatosis type 1 (NF1), Noonan syndrome (NS), Costello syndrome (CS), and cardio-facio-cutaneous syndrome (CFC). Previous work has suggested potential genetic and phenotypic overlap between dysregulation of Ras/MAPK signalling and autism spectrum disorders (ASD). Although the literature offers conflicting evidence for association of NF1 and autism, there has been no systematic evaluation of autism traits in the RASopathies as a class to support a role for germline Ras/MAPK activation in ASDs.
Methods
We examined the association of autism traits with NF1, NS, CS and CFC, comparing affected probands with unaffected sibling controls and subjects with idiopathic ASDs using the qualitative Social Communication Questionnaire (SCQ) and the quantitative Social Responsiveness Scale (SRS).
Results
Each of the four major RASopathies showed evidence for increased qualitative and quantitative autism traits compared with sibling controls. Further, each RASopathy exhibited a distinct distribution of quantitative social impairment. Levels of social responsiveness show some evidence of correlation between sibling pairs, and autism-like impairment showed a male bias similar to idiopathic ASDs.
Conclusions
Higher prevalence and severity of autism traits in RASopathies compared to unaffected siblings suggests that dysregulation of Ras/MAPK signalling during development may be implicated in ASD risk. Evidence for sex bias and potential sibling correlation suggests that autism traits in the RASopathies share characteristics with autism traits in the general population and clinical ASD population and can shed light on idiopathic ASDs.
doi:10.1136/jmedgenet-2013-101951
PMCID: PMC4230531  PMID: 24101678
20.  Infant head growth in male siblings of children with and without autism spectrum disorders 
PURPOSE
Previous research has indicated that children with autism exhibit accelerated head growth (HG) in infancy, although the timing of acceleration varies between studies. We examined infant HG trajectory as a candidate autism endophenotype by studying sibling pairs.
METHODS
We retrospectively obtained serial head orbitofrontal circumference measurements of: a) 48 sibling pairs in which one (n=28) or both (n=20) sibs were affected by an autism spectrum disorder (ASD); and b) 85 control male sibling pairs.
RESULTS
Rate of HG of ASD subjects was slightly accelerated compared to controls, but the magnitude of difference was below the limit of reliability of standard measurement methods. Sibling intra class correlation for rate of HG was highly statistically significant; the magnitude was significantly stronger among autism-affected families (ICC=.63) than among controls (ICC=.26), p<.01.
CONCLUSION
Infant HG trajectory appears familial—possibly endophenotypic—but was not a reliable marker of autism risk among siblings of ASD probands in this sample.
doi:10.1007/s11689-009-9036-5
PMCID: PMC2908031  PMID: 20651949
infancy; head circumference; brain growth; autism; endophenotype; pervasive developmental disorder
21.  Infant head growth in male siblings of children with and without autism spectrum disorders 
Previous research has indicated that children with autism exhibit accelerated head growth (HG) in infancy, although the timing of acceleration varies between studies. We examined infant HG trajectory as a candidate autism endophenotype by studying sibling pairs. We retrospectively obtained serial head orbitofrontal circumference measurements of: a) 48 sibling pairs in which one (n = 28) or both (n = 20) sibs were affected by an autism spectrum disorder (ASD); and b) 85 control male sibling pairs. Rate of HG of ASD subjects was slightly accelerated compared to controls, but the magnitude of difference was below the limit of reliability of standard measurement methods. Sibling intra class correlation for rate of HG was highly statistically significant; the magnitude was significantly stronger among autism-affected families (ICC = .63) than among controls (ICC = .26), p < .01. Infant HG trajectory appears familial—possibly endophenotypic—but was not a reliable marker of autism risk among siblings of ASD probands in this sample.
doi:10.1007/s11689-009-9036-5
PMCID: PMC2908031  PMID: 20651949
Infancy; Head circumference; Brain growth; Autism; Endophenotype; Pervasive developmental disorder
22.  Autism from a Biometric Perspective 
Purpose:
The aim of this pilot study was to test autistic children, siblings and their parents using a biometric device based on the gas discharge visualization (GDV) technique in order to assess their psycho-emotional and physiological functional state based on the activity of the autonomic nervous system.
Hypothesis:
We hypothesize that the biometric assessment based on GDV will enable us: (1) to evaluate some specific features associated with autism spectrum disorder (ASD) as well as to compare autistic children to their siblings and to controls; (2) to analyze the differences in individual values of parents of autistic children versus parents of normal children.
Results:
Out of total of 48 acupuncture points present on ten fingertips of both hands and associated to organs/organ systems, autistic children differed significantly from controls (p < 0.05) in 36 (images without filter) and 12 (images with filter), siblings differed significantly from controls (p < 0.05) in 12 (images without filter) and seven (images with filter), autistic children differed significantly (p < 0.05) from siblings in eight (images without filter) and one (images with filter), fathers of autistic children differed significantly (p < 0.05) from controls in 14 (images without filter) and three (images with filter) and mothers of autistic children differed significantly (p < 0.05) from controls in five (images without filter) and nine (images with filter) acupuncture points.
Conclusions:
All compared groups have shown significant difference on both psycho-emotional (images without filter) and physiological (images with filter) levels. However, the differences between autistic children and controls expressed on psycho-emotional level were the most significant as compared to the other groups. Therefore, the activity of the sympathetic autonomic nervous system is significantly altered in children with autism. The biometric method based on GDV is a promising step in autism research that may lead towards creating a disease profile and identify unique signature/biomarker for autism. Further work should involve more participants in order to augment our findings.
doi:10.3390/ijerph7051984
PMCID: PMC2898030  PMID: 20623006
autism; biometric evaluation; electro-photonic emission; gas discharge visualization (GDV)
23.  Autism, language and communication in children with sex chromosome trisomies 
Archives of disease in childhood  2010;96(10):954-959.
Purpose
Sex chromosome trisomies (SCTs) are found on amniocentesis in 2.3–3.7 per 1000 same-sex births, yet there is a limited database on which to base a prognosis. Autism has been described in postnatally diagnosed cases of Klinefelter syndrome (XXY karyotype), but the prevalence in non-referred samples, and in other trisomies, is unclear. The authors recruited the largest sample including all three SCTs to be reported to date, including children identified on prenatal screening, to clarify this issue.
Design
Parents of children with a SCT were recruited either via prenatal screening or via a parental support group, to give a sample of 58 XXX, 19 XXY and 58 XYY cases. Parents were interviewed using the Vineland Adaptive Behavior Scales and completed questionnaires about the communicative development of children with SCTs and their siblings (42 brothers and 26 sisters).
Results
Rates of language and communication problems were high in all three trisomies. Diagnoses of autism spectrum disorder (ASD) were found in 2/19 cases of XXY (11%) and 11/58 XYY (19%). After excluding those with an ASD diagnosis, communicative profiles indicative of mild autistic features were common, although there was wide individual variation.
Conclusions
Autistic features have not previously been remarked upon in studies of non-referred samples with SCTs, yet the rate is substantially above population levels in this sample, even when attention is restricted to early-identified cases. The authors hypothesise that X-linked and Y-linked neuroligins may play a significant role in the aetiology of communication impairments and ASD.
doi:10.1136/adc.2009.179747
PMCID: PMC3182523  PMID: 20656736
24.  Early-Life Family Structure and Microbially Induced Cancer Risk 
PLoS Medicine  2007;4(1):e7.
Background
Cancer may follow exposure to an environmental agent after many decades. The bacterium Helicobacter pylori, known to be acquired early in life, increases risk for gastric adenocarcinoma, but other factors are also important. In this study, we considered whether early-life family structure affects the risk of later developing gastric cancer among H. pylori+ men.
Methods and Findings
We examined a long-term cohort of Japanese-American men followed for 28 y, and performed a nested case-control study among those carrying H. pylori or the subset carrying the most virulent cagA+ H. pylori strains to address whether family structure predicted cancer development. We found that among the men who were H. pylori+ and/or cagA+ (it is possible to be cagA+ and H. pylori− if the H. pylori test is falsely negative), belonging to a large sibship or higher birth order was associated with a significantly increased risk of developing gastric adenocarcinoma late in life. For those with cagA+ strains, the risk of developing gastric cancer was more than twice as high (odds ratio 2.2; 95% confidence interval 1.2–4.0) among those in a sibship of seven or more individuals than in a sibship of between one and three persons.
Conclusions
These results provide evidence that early-life social environment plays a significant role in risk of microbially induced malignancies expressing five to eight decades later, and these findings lead to new models to explain these interactions.
This study suggests that early-life social environment has a significant role in risk of microbially induced malignancies such as gastric adenocarcinoma occuring five to eight decades later.
Editors' Summary
Background.
Although the theory that certain cancers might be caused by infectious agents (such as bacteria and viruses) has been around for some time, concrete evidence linking specific cancers and infections is only recently beginning to emerge. There is now very good evidence that stomach cancer, once one of the frequent types worldwide but now less common, is strongly associated with a particular infection of the stomach lining. This specific bacterium colonizing the stomach, Helicobacter pylori (or H. pylori), often infects people early in childhood through close contact with other people, and tends to stay in the body throughout life. However, most people do not suffer any symptoms as a result of being colonized with H. pylori. Researchers are interested in the relationship between stomach cancer and aspects of someone's upbringing, for example whether an individual has a large number of sisters and brothers and whether they are the youngest or oldest in a large group of siblings. One reason for being interested in this topic is that if H. pylori is mainly spread from one child to another in the home, we might expect children from large sibling groups, and the youngest children in a group, to be at greater risk of being infected, and then more likely to get stomach cancer later in life. Furthermore—and this was the primary reason for the study—the researchers wished to determine whether, among H. pylori+ people, the structure of the family affects the risk of developing stomach cancer much later in life. With all study participants being H. pylori+, the essential comparison was between people of high and low birth order.
Why Was This Study Done?
This group of researchers had already done a previous study that had shown that people who carry H. pylori in their stomachs are more likely to get stomach cancer, and also that younger children in a sibling group are more likely to get stomach cancer. In the period following that study, the examined population has become older and more of the people concerned have developed stomach cancer. This meant that the researchers could go back and extend their previous work to see, more reliably, whether stomach cancer was linked to family structure. It also meant that the researchers could look at the effects of each factor not only in isolation, but also the combined effect of all the different factors. The researchers also stratified for the most virulent strains (those that were cagA+).
What Did the Researchers Do and Find?
In this study, the researchers started out with a pool of 7,429 Japanese-American men living in Hawaii, USA, who had donated blood samples between 1967 and 1975. Of these men, 261 eventually developed stomach cancer. Each of the 261 men was then matched with a similarly aged man from the original pool of 7,429 men who did not have stomach cancer. The researchers then went back to the original blood samples taken many years before and tested the samples to see if the men were infected with H. pylori at the time the sample was taken and, if so, whether a particular strain of the bacterium, cagA, was present. The researchers then looked at whether the risk of getting stomach cancer was associated with the number of siblings a man had and whether he was older or younger than the other siblings.
Similar to the prior study, they found that men who had stomach cancer were three times more likely to carry H. pylori compared to men who did not develop stomach cancer. In men who had H. pylori, those with large numbers of siblings were more likely to get stomach cancer, and this was especially true for men who had the cagA strain of H. pylori. In the whole group of men with cancer, the order of birth (whether a man was older or younger in his sibling group) did not seem to be particularly linked to development of stomach cancer. However, in men who had the cagA strain of H. pylori, those from the largest sibships were at highest risk of developing gastric cancer; in this group, one particular type of cancer (the most common type—intestinal-type gastric cancer) was also associated with later birth order.
What Do These Findings Mean?
The researchers initially thought that men with H. pylori would be at a higher risk of getting stomach cancer if they had a large number of sisters and brothers, and especially if they were a younger sibling in a large group. This idea was supported by their data. These findings support the idea that people often get H. pylori from their older sisters and brothers, but there is not conclusive proof of this. There might be some other factor that explains the association between large family size and stomach cancer, for example that people from large families might be poorer and more at risk from stomach cancer for some other reason. Currently, most doctors do not recommend routinely testing people without any symptoms to see if they have H. pylori, but people with pain or discomfort in the upper abdomen would generally be screened for H. pylori and then treated to eliminate the infection if it is found. The main novel idea is that those people who are born in a large sibship, and/or are of higher birth order, are more likely to acquire their H. pylori from a genetically related person (a sibling) than from an unrelated person (friend/classmate). This “family-structure effect” could be the explanation as to why there is a higher risk of stomach cancer developing later—the strain from a genetically related person already is “preadapted” to the new host, and has a “head-start” on immunity, compared to a strain from an unrelated person. The researchers hypothesize that it is the nature of that initial interaction with the host that sets the stage for the kind of events that lead to cancers decades later.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040007.
A Perspective article by Dimitrios Trichopoulos and Pagona Lagiou discusses these findings further
MedLine Plus encyclopedia entry on stomach cancer
Wikipedia entry on Helicobacter pylori (Wikipedia is an internet encyclopedia that anyone can edit)
The US National Cancer Institute publishes information about stomach cancer
doi:10.1371/journal.pmed.0040007
PMCID: PMC1769414  PMID: 17227131
25.  Bereavement among South African adolescents following a sibling’s death from AIDS 
While increasing attention has been paid in recent years to studying the impact of parental death from AIDS on children, we know little about how a sibling’s death from AIDS affects children. In this qualitative descriptive study, 11 in-depth interviews were conducted by trained social workers with adolescents who had lost a sibling to AIDS, in KwaZulu-Natal Province, South Africa. The average time since the sibling’s death was 18 months. These adolescents had been actively involved in caring for their sick sibling, yet they received inadequate emotional support from any source both before and after the sibling’s death. HIV/AIDS stigma as well as the family’s daily struggle to survive caused these adolescents to keep their feelings and their grief to themselves. Despite the trauma of losing a beloved sibling and the hardships of their environment, they demonstrated remarkable fortitude as well as concern for others. More research is needed on the issue of sibling bereavement associated with AIDS, and interventions that address the multiple needs of these vulnerable young people need to be developed.
doi:10.2989/16085906.2011.575544
PMCID: PMC3156418  PMID: 21852964
children and youths; grief; HIV/AIDS; psychological aspects; qualitative research; sibling loss

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