Bias from self selection and loss to follow-up in prospective cohort studies.

Self-selection into prospective cohort studies and loss to follow-up can cause biased exposure-outcome association estimates. Previous investigations illustrated that such biases can be small in large prospective cohort studies. The structural approach to selection bias shows that general statements about bias are not possible for studies that investigate multiple exposures and outcomes, and that inverse probability of participation weighting (IPPW) but not adjustment for participation predictors generally reduces bias from self-selection and loss to follow-up. We propose to substantiate assumptions in structural models of selection bias through calculation of genetic correlations coefficients between participation predictors, outcome, and exposure, and to estimate a lower bound for bias due to self-selection and loss to follow-up by comparing effect estimates from IPP weighted and unweighted analyses. This study used data from the Norwegian Mother and Child Cohort Study and the Medical Birth Registry of Norway. Using the example of risk factors for ADHD, we find that genetic correlations between participation predictors, exposures, and outcome suggest the presence of bias. The comparison of exposure-outcome associations from regressions with and without IPPW revealed meaningful deviations. Assessment of selection bias for entire multi-exposure multi-outcome cohort studies is not possible. Instead, it has to be assessed and controlled on a case-by-case basis.

Temperament traits in 4-year-old children born prematurely - may they suggest a threat for mental functioning? / Cechy temperamentalne u czteroletnich dzieci urodzonych przedwczesnie ­ czy moga sugerowac zagrozenie w funkcjonowaniu psychicznym?

OBJECTIVES: The aim of the study was to assess emotional functioning and identification of temperamental traits in 4-year-old children born prematurely with birth weight =< 1500 grams. The second aim was evaluation of autism spectrum disorders frequency in this group of children. METHODS: Eighty-six 4-year-old children born prematurely (gestational age =< 32 weeks, birth weight =< 1500 grams) were evaluated. All children underwent physical examination (with the assessment of motor function, vision and hearing), anthropometric measurements and psychomotor tests: Leiter International Performance Scale P-93, Children Vocabulary Test (TSD), temperament questionnaire (EAS-C), and CAST questionnaire. Parents were asked to fill in questionnaires assessing socio-economic conditions of the family and children attendance in kindergarten or early development support. RESULTS: In the EAS-C questionnaire hyperactivity and reduced emotionality were significantly more common comparing to population. Children with lower gestational age and lower birth weight were characterized with low emotionality score. Children with the CAST score ? 12 points were significantly smaller at birth, more often suffered from retinopathy of prematurity and had poorer results in neurodevelopmental tests - Leiter scale, Children Vocabulary Test. CONCLUSIONS: Children born prematurely are at greater risk of the occurrence of hyperactivity and autism spectrum symptoms. Detection of emotional disorders in children born prematurely is essential to implement the therapeutic support as early as possible.

Mercury-associated diagnoses among children diagnosed with pervasive development disorders.

Nelson and Bauman (Pediatrics 111:674-679, 2003) previously hypothesized that pervasive developmental disorder (PDD) was not associated with mercury (Hg) exposure because the medical conditions associated with Hg exposure were not associated with PDD. A hypothesis-testing longitudinal case-control study evaluated the frequency of medically diagnosed conditions previously associated with Hg poisoning, including: epilepsy, dysarthria, failure to thrive, cerebral palsy, or contact dermatitis and other eczema among children preceding their eventual PDD diagnosis (cases) compared to controls. A retrospective examination of medical records within the Vaccine Safety Datalink (VSD) was undertaken. Cases diagnosed with PDD (n = 534) were born from 1991 to 2000 and continuously enrolled until their PDD diagnosis. Controls (n = 26,367) were born from 1991 to 1993 and continuously enrolled from birth for 7.22 years. Within the first 5 years of life, cases compared to controls were significantly (p < 0.0001) more likely to be assigned a diagnosis of contact dermatitis and other eczema (odds ratio (OR) = 2.033), dysarthria (OR = 23.992), epilepsy (OR = 5.351), failure to thrive (OR = 25.3), and cerebral palsy (OR = 4.464). Similar results were observed when the data were separated by gender. Overall, the results of the present study and recently published studies provide direct evidence supporting a link in twelve of twelve categories (100%) of Hg poisoning associated symptoms as defined by Nelson and Bauman (Pediatrics 111:674-679, 2003) and symptoms observed in those with a PDD diagnosis. The results of this study support the biological plausibility of Hg poisoning to induce PDD diagnoses and rejection of the Nelson and Bauman (Pediatrics 111:674-679, 2003) hypothesis because those with a PDD diagnosis have an increased frequency of conditions previously associated with Hg poisoning.

Autosomal dominant mannose-binding lectin deficiency is associated with worse neurodevelopmental outcomes after cardiac surgery in infants.

OBJECTIVES: The MBL2 gene is the major genetic determinant of mannose-binding lectin (MBL)-an acute phase reactant. Low MBL levels have been associated with adverse outcomes in preterm infants. The MBL2Gly54Asp missense variant causes autosomal dominant MBL deficiency. We tested the hypothesis that MBL2Gly54Asp is associated with worse neurodevelopmental outcomes after cardiac surgery in neonates. METHODS: This is an analysis of a previously described cohort of patients with nonsyndromic congenital heart disease who underwent cardiac surgery with cardiopulmonary bypass before age 6 months (n = 295). Four-year neurodevelopment was assessed in 3 domains: Full-Scale Intellectual Quotient, the Visual Motor Integration development test, and the Child Behavior Checklist to assess behavior problems. The Child Behavior Checklist measured total behavior problems, pervasive developmental problems, and internalizing/externalizing problems. A multivariable linear regression model, adjusting for confounders, was fit. RESULTS: MBL2Gly54Asp was associated with a significantly increased covariate-adjusted pervasive developmental problem score (ß = 3.98; P = .0025). Sensitivity analyses of the interaction between age at first surgery and MBL genotype suggested effect modification for the patients with MBL2Gly54Asp (Pinteraction = .039), with the poorest neurodevelopment outcomes occurring in children who had surgery earlier in life. CONCLUSIONS: We report the novel finding that carriers of MBL2Gly54Asp causing autosomal dominant MBL deficiency have increased childhood pervasive developmental problems after cardiac surgery, independent of other covariates. Sensitivity analyses suggest that this effect may be larger in children who underwent surgery at earlier ages. These data support the role of nonsyndromic genetic variation in determining postsurgical neurodevelopment-related outcomes in children with congenital heart disease.

Social disadvantage and developmental diagnosis in pre-schoolers.

AIM: To explore the association between social disadvantage and developmental diagnoses in pre-school children. METHODS: Between 2012 and 2015, 845 pre-school children were assessed by the Child Assessment Team at Campbelltown Hospital. A social worker interviewed 469 families and these children were eligible for inclusion in the study. Autism spectrum disorder (ASD) was confirmed in 290 children. Of those without ASD, 72 did not have global developmental delay (GDD) and were excluded from the study. The remaining 107 children with GDD were used as the comparison group. Social risk factors in the two groups were compared using χ 2 tests. Variables with statistical significance were then entered into a logistic regression. RESULTS: After logistic regression, children with ASD were more likely to be male (odds ratio (OR) 3.1, 95% CI 0.195-0.529; P < 0.001) and their parents were more likely to have a clinically significant stress score (OR 1.3, 95% CI 0.334-0.992; P = 0.047). Children with GDD were more likely to live in a disadvantaged suburb (OR 1.7, 95% CI 1.042-2.940; P = 0.034), more likely to have a sole parent (OR 1.8, 95% CI 1.062-3.082; P = 0.029) and much more likely to have had involvement with child protection services (OR 3.9, 95% CI 2.044-7.416; P < 0.001). CONCLUSIONS: Children with GDD without autism were more likely to be disadvantaged and to have had contact with child protection services than children with ASD. This has implications for the assessment, early intervention and support services for children with disabilities and their families.

Autism with intellectual disability is associated with increased levels of maternal cytokines and chemokines during gestation.

Immune abnormalities have been described in some individuals with autism spectrum disorders (ASDs) as well as their family members. However, few studies have directly investigated the role of prenatal cytokine and chemokine profiles on neurodevelopmental outcomes in humans. In the current study, we characterized mid-gestational serum profiles of 22 cytokines and chemokines in mothers of children with ASD (N=415), developmental delay (DD) without ASD (N=188), and general population (GP) controls (N=428) using a bead-based multiplex technology. The ASD group was further divided into those with intellectual disabilities (developmental/cognitive and adaptive composite score<70) (ASD+ID, N=184) and those without (composite score⩾70) (ASD-noID, N=201). Levels of cytokines and chemokines were compared between groups using multivariate logistic regression analyses, adjusting for maternal age, ethnicity, birth country and weight, as well as infant gender, birth year and birth month. Mothers of children with ASD+ID had significantly elevated mid-gestational levels of numerous cytokines and chemokines, such as granulocyte macrophage colony-stimulating factor, interferon-γ, interleukin-1α (IL-1α) and IL-6, compared with mothers of children with either ASD-noID, those with DD, or GP controls. Conversely, mothers of children with either ASD-noID or with DD had significantly lower levels of the chemokines IL-8 and monocyte chemotactic protein-1 compared with mothers of GP controls. This observed immunologic distinction between mothers of children with ASD+ID from mothers of children with ASD-noID or DD suggests that the intellectual disability associated with ASD might be etiologically distinct from DD without ASD. These findings contribute to the ongoing efforts toward identification of early biological markers specific to subphenotypes of ASD.

Behavioral, cognitive, and motor performance and physical development of five-year-old children who were born after intracytoplasmic sperm injection with the use of testicular sperm.

OBJECTIVE: To evaluate at the age of 5 years the behavioral, cognitive, and motor performance and physical development of children born after testicular sperm extraction (TESE) and intracytoplasmic sperm injection (ICSI). DESIGN: A prospective longitudinal cohort study. SETTING: Two university medical centers. PATIENT(S): A total of 103 5-year-olds who were born after TESE-ICSI. INTERVENTION(S): The follow-up of the children was performed by questionnaires at birth and again at 1 year and at 4 years of age. Five-year-old children were invited for individual assessment. Behavioral performance was assessed with the use of the Child Behavior Checklist for parents and teachers. Cognitive performance was assessed with the use of the Dutch Wechsler Preschool and Primary Scale of Intelligence test, 3rd version. Motor performance was assessed with the use of the Dutch Movement Assessment Battery for Children, 2nd version. Physical development was assessed by means of physical examination and medical history. MAIN OUTCOME MEASURE(S): Behavioral, cognitive, and motor performance and physical development. RESULT(S): Eighty-nine children were completely assessed, and 14 were partially assessed at the age of 5 years. The 5-year-old cohort assessed significantly better on behavioral and cognitive performance and significantly worse on motor performance-but still in the normal range-compared with the theoretic distribution in the general population. Four children (3.8%) of the 5-year-old cohort had developmental problems/delays. Two of them were previously diagnosed with a form of autism (pervasive developmental disorder-not otherwise specified). Two children had developmental problems based on our behavioral, cognitive, and/or motor assessments. CONCLUSION(S): The long-term effects on development and health in children born after TESE-ICSI procedures seem to be reassuring.

Autism Spectrum Disorders and Other Mental Health Problems: Exploring Etiological Overlaps and Phenotypic Causal Associations.

OBJECTIVE: Recent studies have highlighted the impact of coexisting mental health problems in autism spectrum disorders (ASD). No twin studies to date have reported on individuals meeting diagnostic criteria of ASD. This twin study reports on the etiological overlap between the diagnosis of ASD and emotional symptoms, hyperactivity, and conduct problems measured with the Strengths and Difficulties Questionnaire. METHOD: Genetic and environmental influences on the covariance between ASD and coexisting problems were estimated, in line with the correlated risks model prediction. Phenotypic causality models were also fitted to explore alternative explanations of comorbidity: namely, that coexisting problems are the result of or result in ASD symptoms; that they increase recognition of ASD; or that they arise due to an over-observation bias/confusion when differentiating between phenotypes. RESULTS: More than 50% of twins with broad spectrum/ASD met the borderline/abnormal levels cut-off criteria for emotional symptoms or hyperactivity, and approximately 25% met these criteria for the 3 reported problems. In comparison, between 13% and 16% of unaffected twins scored above the cut-offs. The phenotypic correlation between ASD and emotional symptoms was explained entirely by genetic influences and accompanied by a moderate genetic correlation (0.42). The opposite was true for the overlap with conduct problems, as nonshared-environmental factors had the strongest impact. For hyperactivity, the best-fitting model suggested a unidirectional phenotypic influence of hyperactivity on ASD. CONCLUSION: Our findings suggest a possible effect of hyperactivity on identification of ASD. The lack of genetic influences on conduct problems-ASD overlap further supports the genetic independence of these 2 phenotypes. Finally, the co-occurrence of emotional symptoms in ASD, compared to other co-occurring problems, is completely explained by common genetic effects.

[Neurodevelopmental disorders in children with epilepsy]. / Narusheniia nervno-psikhicheskogo razvitiia u detei s épilepsiei.

Neurodevelopmental disorders, including intellectual disability, autistic-spectrum disorders, speech disorders, attention deficit hyperactivity disorder (ADHD), learning disabilities, are more prevalent in children with epilepsy compared with the general population. Marked developmental delay and regression of acquired skills are characteristic of epileptic encephalopathies. Conditions, in which neurodevelopmental disorders are associated with the marked epileptiform EEG activity, while clinical epileptic seizures are absent, represent a serious problem. The authors consider the features of epilepsy with electrical status epilepticus during slow-wave sleep, pseudo-Lennox syndrome, Landau-Kleffner syndrome, children autistic epileptiform regression, autosomal-dominant rolandic epilepsy with verbal dispraxy and a combination of epilepsy and subclinical epileptiform EEG activity with developmental dysphasia and ADHD. In addition to the optimization of basic treatment with antiepileptic drugs (AEDs), nootropic drugs which do not increase epileptiform activity (hopantenic acid), are recommended.

Causation model of autism: Audiovisual brain specialization in infancy competes with social brain networks.

Earliest identifiable findings in autism indicate that the autistic brain develops differently from the typical brain in the first year of life, after a period of typical development. Twin studies suggest that autism has an environmental component contributing to causation. Increased availability of audiovisual (AV) materials and viewing practices of infants parallel the time frame of the rise in prevalence of autism spectrum disorder (ASD). Studies have shown an association between ASD and increased TV/cable screen exposure in infancy, suggesting AV exposure in infancy as a possible contributing cause of ASD. Infants are attracted to the saliency of AV materials, yet do not have the experience to recognize these stimuli as socially relevant. The authors present a developmental model of autism in which exposure to screen-based AV input in genetically susceptible infants stimulates specialization of non-social sensory processing in the brain. Through a process of neuroplasticity, the autistic infant develops the skills that are driven by the AV viewing. The AV developed neuronal pathways compete with preference for social processing, negatively affecting development of social brain pathways and causing global developmental delay. This model explains atypical face and speech processing, as well as preference for AV synchrony over biological motion in ASD. Neural hyper-connectivity, enlarged brain size and special abilities in visual, auditory and motion processing in ASD are also explained by the model. Positive effects of early intervention are predicted by the model. Researchers studying causation of autism have largely overlooked AV exposure in infancy as a potential contributing factor. The authors call for increased public awareness of the association between early screen viewing and ASD, and a concerted research effort to determine the extent of causal relationship.

[The possibility of prenatal diagnosis of autism spectrum disorder]. / Az autizmusspektrum-zavarok prenatális diagnózisának lehetoségei.

Autism spectrum disorder (ASD) is an idiopathic multifactorial disease. Chromosomal abnormalities could be found only in a few percent (0.3-0.6) of cases. The estimated prevalence is 0.6 in Europe and the prevalence of the disease has been increased in last few decades. ASD have an impact on the quality of life of the patient and his family. The early diagnosis of ASD is most important. There are limited data regarding the measure of biparietal diameter (BPD) of the fetus in the first trimester of pregnancy. These data suggested the BPD is an important screening marker for ASD, but the complex prenatal screening is unresolved. There is a need for further investigations of the genetic background of ASD and to identify potentially first trimester ultrasound markers for ASD.

Epigenetic mechanisms: A possible link between autism spectrum disorders and fetal alcohol spectrum disorders.

The etiology of autism spectrum disorders (ASDs) still remains unclear and seems to involve a considerable overlap between polygenic, epigenetic and environmental factors. We have summarized the current understanding of the interplay between gene expression dysregulation via epigenetic modifications and the potential epigenetic impact of environmental factors in neurodevelopmental deficits. Furthermore, we discuss the scientific controversies of the relationship between prenatal exposure to alcohol and alcohol-induced epigenetic dysregulations, and gene expression alterations which are associated with disrupted neural plasticity and causal pathways for ASDs. The review of the literature suggests that a better understanding of developmental epigenetics should contribute to furthering our comprehension of the etiology and pathogenesis of ASDs and fetal alcohol spectrum disorders.

Maternal folate status as a risk factor for autism spectrum disorders: a review of existing evidence.

Emerging evidence from epidemiological studies supports the notion that maternal folate status regulated by dietary and genetic factors early in pregnancy may influence the risk of autism spectrum disorders (ASD). In this review, we provide an overview of what is known about the role of folate in the aetiology of neurodevelopmental disorders; summarise relevant biological, genetic and epigenetic mechanisms; and synthesise the evidence from human observational studies and randomised controlled trials that have examined the relationship between maternal folate and ASD or related traits. Much of the existing literature on this topic is subject to limitations such as potential confounding by healthy behaviours and other dietary factors, and exposure assessed within limited exposure windows. As the existing evidence is inconclusive, further research remains to be conducted in order to verify this hypothesis. Complete assessment of maternal functional folate status through the pre- and peri-conceptional periods requires biological measurement of folate, vitamin B12 and homocysteine and genetic variants involved in one-carbon metabolism and epigenetic mechanisms. In addition to more complete assessment of maternal functional folate status, careful consideration of potential confounding is warranted.

Is birth a critical period in the pathogenesis of autism spectrum disorders?

Birth is associated with a neuroprotective, oxytocin-mediated abrupt excitatory-to-inhibitory GABA shift that is abolished in autism, and its restoration attenuates the disorder in offspring. In this Opinion article, I discuss the links between birth-related stressful mechanisms, persistent excitatory GABA actions, perturbed network oscillations and autism. I propose that birth (parturition) is a critical period that confirms, attenuates or aggravates the deleterious effects of intrauterine genetic or environmental insults.

Of decrements and disorders: assessing impairments in neurodevelopment in prospective studies of environmental toxicant exposures.

Prenatal and early life neurodevelopment is exquisitely sensitive to insult from environmental exposures. Identifying the effects of environmental toxicants on neurodevelopmental disorders is particularly important from a public health perspective because many of these exposures are modifiable and may be targeted for intervention. Studying these associations in prospective cohort studies that measure quantitative, dimensional traits related to neurodevelopmental disorders, using standardized instruments such as psychometric tests or rating scales, mitigates many of the challenges that arise when studying clinically diagnosed disorders. We consider validity and feasibility impacts resulting from this design approach, including: 1) enhanced prospective exposure assessment with high quality environmental measures during developmentally relevant windows; 2) reduced bias because studies of continuous outcomes do not recruit cases and controls and are therefore not vulnerable to control selection bias; 3) enhanced statistical power because traits are measured on all individuals in the cohort and power is not limited by the number of cases; 4) reduced outcome misclassification because measuring quantitative traits avoids lumping together individuals with very heterogeneous phenotypes into one category. We use autism spectrum disorders (ASD) as an example to illustrate the advantages of this approach. Investigating the determinants of neurodevelopmental disorders - particularly modifiable determinants such as environmental toxicant exposures - is of great public health importance, given the apparent substantial rise of disorders like ASD over the past few decades. The use of prospective designs measuring quantitative, dimensional traits offers a powerful opportunity to provide important clues to the etiology of these disorders and is likely to accelerate our understanding of the role of environmental toxicant exposures as risk factors.

Ritual circumcision and risk of autism spectrum disorder in 0- to 9-year-old boys: national cohort study in Denmark.

OBJECTIVE: Based on converging observations in animal, clinical and ecological studies, we hypothesised a possible impact of ritual circumcision on the subsequent risk of autism spectrum disorder (ASD) in young boys. DESIGN: National, register-based cohort study. SETTING: Denmark. PARTICIPANTS: A total of 342,877 boys born between 1994 and 2003 and followed in the age span 0-9 years between 1994 and 2013. MAIN OUTCOME MEASURES: Information about cohort members' ritual circumcisions, confounders and ASD outcomes, as well as two supplementary outcomes, hyperkinetic disorder and asthma, was obtained from national registers. Hazard ratios (HRs) with 95% confidence intervals (CIs) associated with foreskin status were obtained using Cox proportional hazards regression analyses. RESULTS: With a total of 4986 ASD cases, our study showed that regardless of cultural background circumcised boys were more likely than intact boys to develop ASD before age 10 years (HR = 1.46; 95% CI: 1.11-1.93). Risk was particularly high for infantile autism before age five years (HR = 2.06; 95% CI: 1.36-3.13). Circumcised boys in non-Muslim families were also more likely to develop hyperkinetic disorder (HR = 1.81; 95% CI: 1.11-2.96). Associations with asthma were consistently inconspicuous (HR = 0.96; 95% CI: 0.84-1.10). CONCLUSIONS: We confirmed our hypothesis that boys who undergo ritual circumcision may run a greater risk of developing ASD. This finding, and the unexpected observation of an increased risk of hyperactivity disorder among circumcised boys in non-Muslim families, need attention, particularly because data limitations most likely rendered our HR estimates conservative. Considering the widespread practice of non-therapeutic circumcision in infancy and childhood around the world, confirmatory studies should be given priority.

The role of trace elements, thiamin (e) and transketolase in autism and autistic spectrum disorder.

Although there has been much research into autism or autistic spectrum disorder (ASD), there is room for considerable conjecture regarding the etiology of these developmental brain disorders. ASD is marked by a complex interaction between environmental factors and genetic predisposition, including epistasis. This manuscript argues that changes in oxidative metabolism, thiamine homeostasis, heavy metal deposition and cellular immunity have a role in the etiopathogenesis of autism and ASD. Recent findings from our group and others provide evidence for abnormal thiol metabolism, marked by significant alteration in the deposition of several trace heavy metal species. Together with these, we find differences in thiamine homeostasis in ASD patients, which can be corrected by supplementation. We hypothesize that altered thiol metabolism from heavy metal toxicity, one of the key mechanisms for oxidative stress production, may be responsible for the biochemical alterations in transketolase, dysautonomia and abnormal thiamine homeostasis. Although it is unknown why these particular metals accumulate, we suspect that children with ASD and forms of autism may have particular trouble excreting thiol-toxic heavy metal species, many of which exist as divalent cations. We maintain mercury accumulation is evidence of altered clearance. Together with concomitant oxidative stress, these findings may offer an intriguing component or possible mechanism for oxidative stress-mediated neurodegeneration in ASD patients. Regardless of the exact cause, these factors may be more important to the etiology of this symptomatically diverse disease spectrum. Here, we offer insight into new avenues of exploration as well as the development of novel treatment approaches for these growing and devastating diseases.

Evidence for autism spectrum disorder in Jacobsen syndrome: identification of a candidate gene in distal 11q.

PURPOSE: Jacobsen syndrome, also called the 11q terminal deletion disorder, is a contiguous gene disorder caused by the deletion of the end of the long arm of chromosome 11. Intellectual skills range from low average to severe/profound intellectual disability and usually correlate with deletion size. Comprehensive genotype/phenotype evaluations are limited, and little is known about specific behavioral characteristics associated with 11q terminal deletion disorder. METHODS: In this prospective study, 17 patients with 11q terminal deletion disorder underwent cognitive and behavioral assessments. Deletion sizes were determined by array comparative genomic hybridization. RESULTS: Deletion sizes ranged from 8.7 to 14.5 Mb across the patients. We found that 8 of 17 patients (47%) exhibited behavioral characteristics consistent with an autism spectrum disorder diagnosis. There was no correlation between deletion size and the presence of autism spectrum disorder, implicating at least one predisposing gene in the distal 8.7 Mb of 11q. The findings from three additional patients with autistic features and "atypical" distal 11q deletions led to the identification of an autism "critical region" in distal 11q containing four annotated genes including ARHGAP32 (also known as RICS), a gene encoding rho GTPase activating protein. CONCLUSION: Results from this study support early autism spectrum disorder screening for patients with 11q terminal deletion disorder and provide further molecular insights into the pathogenesis of autism spectrum disorder.