Clinician Diagnostic Certainty and the Role of the Autism Diagnostic Observation Schedule in Autism Spectrum Disorder Diagnosis in Young Children.

Importance: Autism spectrum disorder (ASD) affects 1 in 44 children. The Autism Diagnostic Observation Schedule (ADOS) is a semi-structured observation developed for use in research but is considered a component of gold standard clinical diagnosis. The ADOS adds time and cost to diagnostic assessments. Objective: To evaluate consistency between clinical diagnosis (index ASD diagnosis) and diagnosis incorporating the ADOS (reference standard ASD diagnosis) and to examine clinician and child factors that predict consistency between index diagnoses and reference standard diagnoses. Design, Setting, and Participants: This prospective diagnostic study was conducted between May 2019 and February 2020. Developmental-behavioral pediatricians (DBPs) made a diagnosis based on clinical assessment (index ASD diagnosis). The ADOS was then administered, after which the DBP made a second diagnosis (reference standard ASD diagnosis). DBPs self-reported diagnostic certainty at the time of the index diagnoses and reference standard diagnoses. The study took place at 8 sites (7 US and 1 European) that provided subspecialty assessments for children with concerns for ASD. Participants included children aged 18 months to 5 years, 11 months, without a prior ASD diagnosis, consecutively referred for possible ASD. Among 648 eligible children, 23 refused, 376 enrolled, and 349 completed the study. All 40 eligible DBPs participated. Exposures: ADOS administered to all child participants. Main Outcomes and Measures: Index diagnoses and reference standard diagnoses of ASD (yes/no). Results: Among the 349 children (279 [79.7%] male; mean [SD] age, 39.9 [13.4] months), index diagnoses and reference standard diagnoses were consistent for 314 (90%) (ASD = 250; not ASD = 64) and changed for 35. Clinician diagnostic certainty was the most sensitive and specific predictor of diagnostic consistency (area under curve = 0.860; P < .001). In a multilevel logistic regression, no child or clinician factors improved prediction of diagnostic consistency based solely on clinician diagnostic certainty at time of index diagnosis. Conclusions and Relevance: In this prospective diagnostic study, clinical diagnoses of ASD by DBPs with vs without the ADOS were consistent in 90.0% of cases. Clinician diagnostic certainty predicted consistency of index diagnoses and reference standard diagnoses. This study suggests that the ADOS is generally not required for diagnosis of ASD in young children by DBPs and that DBPs can identify children for whom the ADOS may be needed.

Pilot Study of Maternal Autoantibody-Related Autism.

OBJECTIVE: The objective of this study was to investigate the presence of maternal autoantibody-related autism spectrum disorder (MAR-ASD) in 2 geographically distinct DBPNet clinical sites (Pennsylvania and Arkansas). MAR-ASD is a biologically defined subtype of ASD that is defined by the presence of autoantibodies specific to proteins in the fetal brain and present in approximately 20% of a Northern California sample but has not been studied in other states. METHODS: Sixty-eight mothers of children with ASD were recruited from 2 DBPNet clinics and provided blood samples. Mothers also completed behavioral questionnaires about their children, and data from the child's clinical diagnostic assessment were abstracted. RESULTS: The mean age of mothers was 38.5 ± 6.1 years, and the mean age of children was 8.3 ± 2.7 years. MAR-ASD was present in 24% of the sample and similar across sites. Children of +MAR mothers had more severe autism symptoms as measured by Autism Diagnostic Observation Schedule comparison scores (W = 3604; p < 0.001) and the Social Communication Questionnaire (W = 4556; p < 0.001). There were no differences in IQ, adaptive function, or aberrant behavior. CONCLUSION: MAR-ASD is a subtype of autism that is present in similar frequencies across 3 states and related to autism severity.

Museum-archived and recent acquisition nitrates from the Atacama Desert, Chile, South America: refinement of the dual isotopic compositions (δ15N vs. δ18O).

Sodium nitrate ores from the Atacama Desert in South America were economically important as they represented huge natural resources for the fertilizer and explosives industries during the early nineteenth to early twentieth centuries. Nitrogen and oxygen isotope ratios (δ15N and δ18O) of these desert nitrates generally show unique compositions (from close to 0 and up to ca. +50 ‰, respectively). The nitrates indicate the provenance as atmospheric in origin due to the mass-independent photochemical reaction of nitric oxide (NO) with ozone (O3) in the atmosphere to produce nitrate (NO3-). This paper examines the previously existing isotope data for specimens acquired from the Atacama Desert. It then reports new data from dual isotope analysis of historic nitrate specimens archived in museums in the UK. In the stable isotope signatures for nitrates from two areas of the Atacama Desert, Tarapacá in the north and Antofagasta in the south, were examined, and this analysis enabled a more detailed definition of their isotopic compositional ranges. This improved database is useful for tracing the provenance of the historic nitrates used in gunpowder and saltpetre, and also the cause of nitrate pollution in natural environments for which routine chemistry alone cannot provide the definite evidence for the origin.

Chip-Scale Droop-Free Fin Light-Emitting Diodes Using Facet-Selective Contacts.

Sub-micron-size light sources are currently extremely dim, achieving nanowatt output powers due to the current density and temperature droop. Recently, we reported a droop-free fin light-emitting diode (LED) pixel that at high current densities becomes a laser with record output power in the microwatt range. Here, we show a scalable method for selectively metallizing fins via their nonpolar side facet that allows electrical injection to sub-200 nm wide n-ZnO fins on p-GaN with at least 0.8 µm2 active area. Electrically addressable fin LEDs are fabricated in a linear array format using standard 2 µm resolution photolithography. Electroluminescence analysis across different pixels shows that the fin acts as the active region of the LED and generates a narrow-band ultraviolet emission between ≈368 and ≈390 nm. Investigating fins at high current densities, ranging from 100 to 2000 kA/cm2, shows that their emission increases without any decline even as the junction temperature reaches a range of 200-340 °C. The absence of electron leakage to p-GaN at high injection levels and an undetectable electron-hole escape from the fin at high temperatures indicate that the fin shape is highly efficient in controlling the nonradiative recombination pathways such as Auger recombination. The fin LED geometry is expected to enable the realization of high-brightness arrays of light sources at sub-micron-size regimes suitable for operation at high temperatures and high current densities.

Autism-Focused Online Training in Shared Decision-Making: A Randomized Controlled Trial.

OBJECTIVE: This medical education quasi-randomized controlled trial (quasi-RCT), involving 97 developmental-behavioral pediatrics fellows across the United States, examined differential effects of 2 autism-focused, online, interactive case-based trainings on shared decision-making (SDM). METHODS: An intervention case provided direct teaching about SDM, addressing autism treatment options. A comparison case focused on evidence-based practice (EBP) related to medication use in autism with no specific SDM teaching. Measured outcomes included self-reported SDM and attitudes toward concordance in medication-prescribing. RESULTS: After the intervention, both groups showed significantly increased SDM, but not medication-prescribing concordance (controlling for trainee level, autism patient numbers, and past SDM training). CONCLUSION: This quasi-RCT presents evidence that knowledge of SDM in care of children with autism can be enhanced by online case-based training focused either indirectly on evidence-based practice or directly on SDM. Consistent online SDM training can be provided to all trainees, irrespective of the location.

High-brightness lasing at submicrometer enabled by droop-free fin light-emitting diodes (LEDs).

"Efficiency droop," i.e., a decline in brightness of light-emitting diodes (LEDs) at high electrical currents, limits the performance of all commercial LEDs and has limited the output power of submicrometer LEDs and lasers to nanowatts. We present a fin p-n junction LED pixel that eliminates efficiency droop, allowing LED brightness to increase linearly with current. With record current densities of 1000 kA/cm2, the LEDs transition to lasing, with brightness over 20 µW. Despite a light extraction efficiency of only 15%, these devices exceed the output power of any previous electrically driven submicrometer LED or laser pixel by 100 to 1000 times while showing comparable external quantum efficiencies. Modeling suggests that spreading of the electron-hole recombination region in fin LEDs at high injection levels suppresses the nonradiative Auger recombination processes. Further refinement of this design is expected to enable a new generation of high-brightness LED and laser pixels for macro- and microscale applications.

Correction: Meta-analysis and multidisciplinary consensus statement: exome sequencing is a first-tier clinical diagnostic test for individuals with neurodevelopmental disorders.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Explanation of the Colour Change in Alexandrites.

Alexandrites are remarkable and rare gemstones. They display an extraordinary colour change according to the ambient lighting, from emerald green in daylight to ruby red in incandescent light from tungsten lamps or candles. While this colour change has been correctly attributed to chromium impurities and their absorption band in the yellow region of the visible light spectrum, no adequate explanation of the mechanism has been given. Here, the alexandrite effect is fully explained by considering the von Kries model of the human colour constancy mechanism. This implies that our colour constancy mechanism is real (objective) and primarily attuned to correct for the colour temperature of black-body illuminants.

Maternal polyunsaturated fatty acids and risk for autism spectrum disorder in the MARBLES high-risk study.

LAY ABSTRACT: Prior studies suggest that maternal polyunsaturated fatty acids intake during pregnancy may have protective effects on autism spectrum disorder in their children. However, they did not examine detailed timing of maternal polyunsaturated fatty acid intake during pregnancy, nor did they evaluate plasma concentrations. This study investigates whether maternal polyunsaturated fatty acids in defined time windows of pregnancy, assessed by both questionnaires and biomarkers, are associated with risk of autism spectrum disorder and other non-typical development in the children. Food frequency questionnaires were used to estimate maternal polyunsaturated fatty acid intake during the first and second half of pregnancy. Gas chromatography measured maternal plasma polyunsaturated fatty acid concentrations in the third trimester. In all, 258 mother-child pairs from a prospective cohort were included. All mothers already had a child with autism spectrum disorder and were planning a pregnancy or pregnant with another child. Children were clinically assessed longitudinally and diagnosed at 36 months. For polyunsaturated fatty acid intake from questionnaires, we only found mothers consuming more omega-3 in the second half of pregnancy were 40% less likely to have children with autism spectrum disorder. For polyunsaturated fatty acid concentrations in the third-trimester plasma, we did not observe any statistical significance in relation to the risk of autism spectrum disorder. However, our study confirmed associations from previous studies between higher maternal docosahexaenoic acid and eicosapentaenoic acid plasma concentrations in the late pregnancy and reduced risk for non-typical development. This study markedly advanced understandings of whether and when maternal polyunsaturated fatty acid intake influences risk for autism spectrum disorder and sets the stage for prevention at the behavioral and educational level.

An Exploratory Examination of Neonatal Cytokines and Chemokines as Predictors of Autism Risk: The Early Markers for Autism Study.

BACKGROUND: The identification of an early biomarker for autism spectrum disorder (ASD) would improve the determination of risk, leading to earlier diagnosis and, potentially, earlier intervention and improved outcomes. METHODS: Data were generated from the Early Markers for Autism study, a population-based case-control study of prenatal and neonatal biomarkers of ASD. Newborn bloodspots of children with ASD (n = 370), children with developmental delay (n = 140), and general population (GP) controls (n = 378) were analyzed for 42 different immune markers using a Luminex multiplex platform. Comparisons of immune marker concentrations between groups were examined using logistic regression and partial least squares discriminant analysis. RESULTS: Children with ASD had significantly increased neonatal levels of interleukin-6 (IL-6) and IL-8 compared with GP controls. An increase in IL-8 was especially significant in the ASD group with early onset compared with the GP group, with an adjusted odds ratio of 1.97 (95% confidence interval, 1.39-2.83; p = .00014). In addition, children with ASD had significantly elevated levels of eotaxin-1, interferon-γ, and IL-12p70 relative to children with developmental delay. We observed no significant differences in levels of immune markers between the developmental delay and GP groups. CONCLUSIONS: Elevated levels of some inflammatory markers in newborn bloodspots indicated a higher degree of immune activation at birth in children who were subsequently diagnosed with ASD. The data from this exploratory study suggest that with further expansion, the development of neonatal bloodspot testing for cytokine/chemokine levels might lead to the identification of biomarkers that provide an accurate assessment of ASD risk at birth.

Meta-analysis and multidisciplinary consensus statement: exome sequencing is a first-tier clinical diagnostic test for individuals with neurodevelopmental disorders.

PURPOSE: For neurodevelopmental disorders (NDDs), etiological evaluation can be a diagnostic odyssey involving numerous genetic tests, underscoring the need to develop a streamlined algorithm maximizing molecular diagnostic yield for this clinical indication. Our objective was to compare the yield of exome sequencing (ES) with that of chromosomal microarray (CMA), the current first-tier test for NDDs. METHODS: We performed a PubMed scoping review and meta-analysis investigating the diagnostic yield of ES for NDDs as the basis of a consensus development conference. We defined NDD as global developmental delay, intellectual disability, and/or autism spectrum disorder. The consensus development conference included input from genetics professionals, pediatric neurologists, and developmental behavioral pediatricians. RESULTS: After applying strict inclusion/exclusion criteria, we identified 30 articles with data on molecular diagnostic yield in individuals with isolated NDD, or NDD plus associated conditions (such as Rett-like features). Yield of ES was 36% overall, 31% for isolated NDD, and 53% for the NDD plus associated conditions. ES yield for NDDs is markedly greater than previous studies of CMA (15-20%). CONCLUSION: Our review demonstrates that ES consistently outperforms CMA for evaluation of unexplained NDDs. We propose a diagnostic algorithm placing ES at the beginning of the evaluation of unexplained NDDs.

Neonatal vitamin D status in relation to autism spectrum disorder and developmental delay in the CHARGE case-control study.

Vitamin D appears essential for normal neurodevelopment and cognitive and behavioral function. We examined neonatal vitamin D in relation to the child's later diagnosis of autism spectrum disorder (ASD) or developmental delay (DD). Children aged 24-60 months enrolled in the population-based CHARGE case-control study were evaluated clinically for ASD (n = 357), DD (n = 134), or typical development (TD, n = 234) at the MIND Institute (Sacramento, CA) using standardized assessments. Total 25-hydroxyvitamin D (25[OH]D) was measured using sensitive isotope dilution liquid chromatography-tandem mass spectrometry in archived dried blood spots collected for the California Department of Public Health's Newborn Screening Program. Multinomial logistic regression was used to calculate ORs as measures of the associations between 25 nmol/L change in 25(OH)D and ASD and DD. Associations between 25(OH)D and scores on Mullen Scales of Early Learning and Vineland Adaptive Behavior Scales were assessed using robust linear regression. Effect modification was examined using stratified models and interaction product terms. Unadjusted mean (SD) 25(OH)D was lower for DD (73.2 [37.6]) than for TD (82.7 [39.3]) and ASD (80.1 [37.4]). After adjustment for maternal prepregnancy body mass index and education, a 25 nmol/L increase in total 25(OH)D was not associated with ASD (OR = 0.97; CI: 0.87-1.08) or DD (OR = 0.91; 95% CI: 0.78-1.06). Neonatal 25(OH)D was associated with significantly reduced ASD only in females (adjusted OR = 0.74; 95% CI: 0.55-0.99, Pinteraction = 0.03), and significantly reduced DD only in non-Hispanic white children (adjusted OR = 0.79; 95% CI: 0.63-0.98, Pinteraction = 0.11 for Hispanic, Pinteraction = 0.31 for other), driven by DD children with trisomy 21. This study provides evidence that neonatal vitamin D could be associated with ASD in females and with DD in non-Hispanic white children. Autism Res 2019, 12: 976-988. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Vitamin D appears essential for brain development and function. We examined neonatal total 25-hydroxyvitamin D (25[OH]D) measured in dried blood spots in relation to later diagnoses of autism spectrum disorder (ASD) or developmental delay (DD) and related assessment scores. Higher neonatal 25(OH)D was associated with a 26% reduction in the odds for ASD only in females. After taking into account factors that could contribute to vitamin D status, a significant association with 21% reduced odds for DD was found only in non-Hispanic white children. Though results were nonsignificant overall, certain subgroups might benefit from higher neonatal vitamin D.

Comparison of maternal beliefs about causes of autism spectrum disorder and association with utilization of services and treatments.

BACKGROUND: This study aimed to describe parental perceptions of the causes of autism spectrum disorder (ASD) in an ethnically diverse sample and explore whether these perceptions relate to treatment choices. METHODS: The sample consisted of White (n = 224), Hispanic (n = 85), and Asian (n = 21) mothers of a child with ASD. A mixed methods approach was used in this secondary analysis focusing on parental perceptions about the causes of ASD and the relationship of these to utilization of services and treatment. RESULTS: Environmental and genetic factors were most often believed to be the cause or one of the causes of ASD by mothers across all ethnic groups studied. Asian mothers were more likely to cite multiple causes. Environmental causes were associated with receiving 20 or more hours of autism-related services per week, whereas belief in environmental exposures and vaccines and medications as causes were associated with complementary-alternative medicine (CAM) use. CONCLUSION: Our findings suggest that ethnic differences in autism causal beliefs and treatment choices may exist. Future research should be conducted to specifically confirm the findings, to understand parental motivation behind their service and treatment choices, and to gain more insight into the types, usage, and sources of CAM treatments. Clinicians can use parental autism causal beliefs in discussions about treatment recommendations.

Effects of Yoga on Attention, Impulsivity, and Hyperactivity in Preschool-Aged Children with Attention-Deficit Hyperactivity Disorder Symptoms.

OBJECTIVE: Behavioral therapies are first-line for preschoolers with attention-deficit hyperactivity disorder (ADHD). Studies support yoga for school-aged children with ADHD; this study evaluated yoga in preschoolers on parent- and teacher-rated attention/challenging behaviors, attentional control (Kinder Test of Attentional Performance [KiTAP]), and heart rate variability (HRV). METHODS: This randomized waitlist-controlled trial tested a 6-week yoga intervention in preschoolers with ≥4 ADHD symptoms on the ADHD Rating Scale-IV Preschool Version. Group 1 (n = 12) practiced yoga first; Group 2 (n = 11) practiced yoga second. We collected data at 4 time points: baseline, T1 (6 weeks), T2 (12 weeks), and follow-up (3 months after T2). RESULTS: At baseline, there were no significant differences between groups. At T1, Group 1 had faster reaction times on the KiTAP go/no-go task (p = 0.01, 95% confidence interval [CI], -371.1 to -59.1, d = -1.7), fewer distractibility errors of omission (p = 0.009, 95% CI, -14.2 to -2.3, d = -1.5), and more commission errors (p = 0.02, 95% CI, 1.4-14.8, d = 1.3) than Group 2. Children in Group 1 with more severe symptoms at baseline showed improvement at T1 versus control on parent-rated Strengths and Difficulties Questionnaire hyperactivity inattention (ß = -2.1, p = 0.04, 95% CI, -4.0 to -0.1) and inattention on the ADHD Rating Scale (ß = -4.4, p = 0.02, 95% CI, -7.9 to -0.9). HRV measures did not differ between groups. CONCLUSION: Yoga was associated with modest improvements on an objective measure of attention (KiTAP) and selective improvements on parent ratings.

Differential immune responses and microbiota profiles in children with autism spectrum disorders and co-morbid gastrointestinal symptoms.

OBJECTIVES: Many studies have reported the increased presence of gastrointestinal (GI) symptoms in children with autism spectrum disorders (ASD). Altered microbiome profiles, pro-inflammatory responses and impaired intestinal permeability have been observed in children with ASD and co-morbid GI symptoms, yet few studies have compared these findings to ASD children without GI issues or similarly aged typical developing children. The aim of this study was to determine whether there are biological signatures in terms of immune dysfunction and microbiota composition in children with ASD with GI symptoms. METHODS: Children were enrolled in one of four groups: ASD and GI symptoms of irregular bowel habits (ASDGI), children with ASD but without current or previous GI symptoms (ASDNoGI), typically developing children with GI symptoms (TDGI) and typically developing children without current or previous GI symptoms (TDNoGI). Peripheral blood mononuclear cells (PBMC) were isolated from the blood, stimulated and assessed for cytokine production, while stool samples were analyzed for microbial composition. RESULTS: Following Toll-Like receptor (TLR)-4 stimulation, the ASDGI group produced increased levels of mucosa-relevant cytokines including IL-5, IL-15 and IL-17 compared to ASDNoGI. The production of the regulatory cytokine TGFß1 was decreased in the ASDGI group compared with both the ASDNoGI and TDNoGI groups. Analysis of the microbiome at the family level revealed differences in microbiome composition between ASD and TD children with GI symptoms; furthermore, a predictive metagenome functional content analysis revealed that pathways were differentially represented between ASD and TD subjects, independently of the presence of GI symptoms. The ASDGI also showed an over-representation of the gene encoding zonulin, a molecule regulating gut permeability, compared to the other groups. CONCLUSIONS: Overall our findings suggest that children with ASD who experience GI symptoms have an imbalance in their immune response, possibly influenced by or influencing metagenomic changes, and may have a propensity to impaired gut barrier function which may contribute to their symptoms and clinical outcome.

Prenatal Maternal Serum Concentrations of Per- and Polyfluoroalkyl Substances in Association with Autism Spectrum Disorder and Intellectual Disability.

BACKGROUND: Emerging work has examined neurodevelopmental outcomes following prenatal exposure to per- and polyfluoroalkyl substances (PFAS), but few studies have assessed associations with autism spectrum disorder (ASD). OBJECTIVES: Our objective was to estimate associations of maternal prenatal PFAS concentrations with ASD and intellectual disability (ID) in children. METHODS: Participants were from a population-based nested case-control study of children born from 2000 to 2003 in southern California, including children diagnosed with ASD (n=553), ID without autism (n=189), and general population (GP) controls (n=433). Concentrations of eight PFAS from stored maternal sera collected at 15-19 wk gestational age were quantified and compared among study groups. We used logistic regression to obtain adjusted odds ratios for the association between prenatal PFAS concentrations (parameterized continuously and as quartiles) and ASD versus GP controls, and separately for ID versus GP controls. RESULTS: Geometric mean concentrations of most PFAS were lower in ASD and ID groups relative to GP controls. ASD was not significantly associated with prenatal concentrations of most PFAS, though significant inverse associations were found for perfluorooctanoate (PFOA) and perfluorooctane sulfonate (PFOS) [adjusted ORs for the highest vs. lowest quartiles 0.62 (95% CI: 0.41, 0.93) and 0.64 (95% CI: 0.43, 0.97), respectively]. Results for ID were similar. CONCLUSIONS: Results from this large case-control study with prospectively collected prenatal measurements do not support the hypothesis that prenatal exposure to PFAS is positively associated with ASD or ID. https://doi.org/10.1289/EHP1830.

Joint effects of prenatal air pollutant exposure and maternal folic acid supplementation on risk of autism spectrum disorder.

Independent studies report that periconceptional folic acid (FA) may decrease the risk of autism spectrum disorder (ASD) while exposure to air pollution may increase ASD risk. We examined the joint effects of gestational FA and air pollution exposures in association with ASD. We studied 346 ASD cases and 260 typically developing controls from the CHARGE case-control study. Self-reported FA intake for each month of pregnancy was quantified. Estimates of exposure to near roadway air pollution (NRP) and criteria air pollutant measures were assigned based on maternal residential history. Among mothers with high FA intake (>800 µg) in the first pregnancy month, exposure to increasing levels of all air pollutants, except ozone, during the first trimester was associated with decreased ASD risk, while increased ASD risk was observed for the same pollutant among mothers with low FA intake (≤800 µg). This difference was statistically significant for NO2 (e.g., NO2 and low FA intake: OR = 1.53 (0.91, 2.56) vs NO2 and high FA intake: OR = 0.74 (0.46, 1.19), P-interaction = 0.04). Mothers exposed to higher levels (≥ median) of any air pollutant during the first trimester of pregnancy and who reported low FA intake were at a higher ASD risk compared to mothers exposed to lower levels of that air pollutant and who reported high first month FA intake. Joint effects showed significant (alpha < 0.10) departures from expected interaction for NRP and NO2 . Our results suggest that periconceptional FA intake may reduce ASD risk in those with high prenatal air pollution exposure. Further study is needed to replicate these findings in larger sample sizes and to understand mechanisms of this potential relationship.. Autism Res 2018, 11: 69-80. © 2017 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: We examined interactions between periconceptional folic acid (FA) and air pollution exposure on risk of ASD. Mothers exposed to higher levels of air pollution during the first trimester of pregnancy and who reported low supplemental FA intake during the first pregnancy month were at a higher ASD risk compared to mothers exposed to lower levels of air pollution and who reported high first month FA intake. Our results suggest that periconceptional FA intake may reduce ASD risk in those with high prenatal air pollution exposure.

Combined Prenatal Pesticide Exposure and Folic Acid Intake in Relation to Autism Spectrum Disorder.

BACKGROUND: Maternal folic acid (FA) protects against developmental toxicity from certain environmental chemicals. OBJECTIVE: We examined combined exposures to maternal FA and pesticides in relation to autism spectrum disorder (ASD). METHODS: Participants were California children born from 2000-2007 who were enrolled in the Childhood Autism Risks from Genetics and the Environment (CHARGE) case-control study at age 2-5 y, were clinically confirmed to have ASD (n=296) or typical development (n=220), and had information on maternal supplemental FA and pesticide exposures. Maternal supplemental FA and household pesticide product use were retrospectively collected in telephone interviews from 2003-2011. High vs. low daily FA intake was dichotomized at 800µg (median). Mothers' addresses were linked to a statewide database of commercial applications to estimate agricultural pesticide exposure. RESULTS: High FA intake (≥800µg) during the first pregnancy month and no known pesticide exposure was the reference group for all analyses. Compared with this group, ASD was increased in association with <800µg FA and any indoor pesticide exposure {adjusted odds ratio [OR]=2.5 [95% confidence interval (CI): 1.3, 4.7]} compared with low FA [OR=1.2 (95% CI: 0.7, 2.2)] or indoor pesticides [OR=1.7 (95% CI: 1.1, 2.8)] alone. ORs for the combination of low FA and regular pregnancy exposure (≥6 mo) to pet pesticides or to outdoor sprays and foggers were 3.9 (95% CI: 1.4, 11.5) and 4.1 (95% CI: 1.7, 10.1), respectively. ORs for low maternal FA and agricultural pesticide exposure 3 mo before or after conception were 2.2 (95% CI: 0.7, 6.5) for chlorpyrifos, 2.3 (95% CI: 0.98, 5.3) for organophosphates, 2.1 (95% CI: 0.9, 4.8) for pyrethroids, and 1.5 (95% CI: 0.5, 4.8) for carbamates. Except for carbamates, these ORs were approximately two times greater than those for either exposure alone or for the expected ORs for combined exposures under multiplicative or additive models. CONCLUSIONS: In this study population, associations between pesticide exposures and ASD were attenuated among those with high versus low FA intake during the first month of pregnancy. Confirmatory and mechanistic studies are needed. https://doi.org/10.1289/EHP604.

The joint effect of air pollution exposure and copy number variation on risk for autism.

Autism spectrum disorder is a complex trait with a high degree of heritability as well as documented susceptibility from environmental factors. In this study the contributions of copy number variation, exposure to air pollutants, and the interaction between the two on autism risk, were evaluated in the population-based case-control Childhood Autism Risks from Genetics and Environment (CHARGE) Study. For the current investigation, we included only those CHARGE children (a) who met criteria for autism or typical development and (b) for whom our team had conducted both genetic evaluation of copy number burden and determination of environmental air pollution exposures based on mapping addresses from the pregnancy and early childhood. This sample consisted of 158 cases of children with autism and 147 controls with typical development. Multiple logistic regression models were fit with and without environmental variable-copy number burden interactions. We found no correlation between average air pollution exposure from conception to age 2 years and the child's CNV burden. We found a significant interaction in which a 1SD increase in duplication burden combined with a 1SD increase in ozone exposure was associated with an elevated autism risk (OR 3.4, P < 0.005) much greater than the increased risks associated with either genomic duplication (OR 1.85, 95% CI 1.25-2.73) or ozone (OR 1.20, 95% CI 0.93-1.54) alone. Similar results were obtained when CNV and ozone were dichotomized to compare those in the top quartile relative to those having a smaller CNV burden and lower exposure to ozone, and when exposures were assessed separately for pregnancy, the first year of life, and the second year of life. No interactions were observed for other air pollutants, even those that demonstrated main effects; ozone tends to be negatively correlated with the other pollutants examined. While earlier work has demonstrated interactions between the presence of a pathogenic CNV and an environmental exposure [Webb et al., 2016], these findings appear to be the first indication that global copy number variation may increase susceptibility to certain environmental factors, and underscore the need to consider both genomics and environmental exposures as well as the mechanisms by which each may amplify the risks for autism associated with the other. Autism Res 2017, 10: 1470-1480. © 2017 International Society for Autism Research, Wiley Periodicals, Inc.

Neonatal Cytokine Profiles Associated With Autism Spectrum Disorder.

BACKGROUND: Autism spectrum disorder (ASD) is a complex neurodevelopmental condition that can be reliably diagnosed at age 24 months. Immunological phenomena, including skewed cytokine production, have been observed among children with ASD. Little is known about whether immune dysregulation is present before diagnosis of ASD. METHODS: We examined neonatal blood spots from 214 children with ASD (141 severe, 73 mild/moderate), 62 children with typical development, and 27 children with developmental delay as control subjects who participated in the Childhood Autism Risks from Genetics and the Environment study, a population-based case-control study. Levels of 17 cytokines and chemokines were compared across groups and in relation to developmental and behavioral domains. RESULTS: Interleukin (IL)-1ß and IL-4 were independently associated with ASD compared with typical development, although these relationships varied by ASD symptom intensity. Elevated IL-4 was associated with increased odds of severe ASD (odds ratio [OR] = 1.40, 95% confidence interval [CI], 1.03, 1.91), whereas IL-1ß was associated with increased odds of mild/moderate ASD (OR = 3.02, 95% CI, 1.43, 6.38). Additionally, IL-4 was associated with a higher likelihood of severe ASD versus mild/moderate ASD (OR = 1.35, 95% CI, 1.04, 1.75). In male subjects with ASD, IL-4 was negatively associated with nonverbal cognitive ability (ß = -3.63, SE = 1.33, p = .04). CONCLUSIONS: This study is part of a growing effort to identify early biological markers for ASD. We demonstrate that peripheral cytokine profiles at birth are associated with ASD later in childhood and that cytokine profiles vary depending on ASD severity. Cytokines have complex roles in neurodevelopment, and dysregulated levels may be indicative of genetic differences and environmental exposures or their interactions that relate to ASD.