Subtyping cognitive profiles in Autism Spectrum Disorder using a Functional Random Forest algorithm.

DSM-5 Autism Spectrum Disorder (ASD) comprises a set of neurodevelopmental disorders characterized by deficits in social communication and interaction and repetitive behaviors or restricted interests, and may both affect and be affected by multiple cognitive mechanisms. This study attempts to identify and characterize cognitive subtypes within the ASD population using our Functional Random Forest (FRF) machine learning classification model. This model trained a traditional random forest model on measures from seven tasks that reflect multiple levels of information processing. 47 ASD diagnosed and 58 typically developing (TD) children between the ages of 9 and 13 participated in this study. Our RF model was 72.7% accurate, with 80.7% specificity and 63.1% sensitivity. Using the random forest model, the FRF then measures the proximity of each subject to every other subject, generating a distance matrix between participants. This matrix is then used in a community detection algorithm to identify subgroups within the ASD and TD groups, and revealed 3 ASD and 4 TD putative subgroups with unique behavioral profiles. We then examined differences in functional brain systems between diagnostic groups and putative subgroups using resting-state functional connectivity magnetic resonance imaging (rsfcMRI). Chi-square tests revealed a significantly greater number of between group differences (p < .05) within the cingulo-opercular, visual, and default systems as well as differences in inter-system connections in the somato-motor, dorsal attention, and subcortical systems. Many of these differences were primarily driven by specific subgroups suggesting that our method could potentially parse the variation in brain mechanisms affected by ASD.

Service utilization in a sample of preschool children with autism spectrum disorder: A Canadian snapshot.

OBJECTIVE: To describe services received by preschool children diagnosed with autism spectrum disorder (ASD) during the five-year period following their diagnosis. METHOD: An inception cohort of preschoolers diagnosed with ASD from Halifax (Nova Scotia), Montreal (Quebec), Hamilton (Ontario), Edmonton (Alberta) and Vancouver (British Columbia) were invited to participate. Parents/caregivers (n=414) described the services provided to their children at four time points: baseline (T1; within four months of diagnosis; mean age three years); six months later (T2); 12 months later (T3); and at school entry (T4). Data were first coded into 11 service types and subsequently combined into four broader categories (no services, behavioural, developmental and general) for analysis. RESULTS: More than 80% of children at T1, and almost 95% at T4 received some type of service, with a significant number receiving >1 type of service at each assessment point. At T1, the most common service was developmental (eg, speech-language therapy). Subsequently, the most common services were a combination of behavioural and developmental (eg, intensive therapy based on applied behaviour analysis and speech-language therapy). Service provision varied across provinces and over time. DISCUSSION: Although most preschool children with ASD residing in urban centres were able to access specialized services shortly after diagnosis, marked variation in services across provinces remains a concern.

OBJECTIF: Décrire les services qu'ont reçus des enfants d'âge préscolaire ayant un trouble du spectre autistique (TSA) pendant la période de cinq ans suivant leur diagnostic. MÉTHODOLOGIE: Une cohorte initiale d'enfants d'âge préscolaire ayant un TSA diagnostiqué et qui provenaient de Halifax (Nouvelle-Écosse), de Montréal (Québec), de Hamilton (Ontario), d'Edmonton (Alberta) ou de Vancouver (Colombie-Britannique) a été invitée à participer à l'étude. Les parents et les tuteurs (n=414) ont décrit les services fournis à leur enfant à quatre moments : au début (T1; dans les quatre mois suivant le diagnostic, âge moyen de trois ans); six mois plus tard (T2); 12 mois plus tard (T3) et à l'entrée à l'école (T4). Les chercheurs ont d'abord codé les données en 11 types de services, pour ensuite les regrouper en quatre catégories plus vastes (absence de services, comportementaux, développementaux et généraux) en vue de leur analyse. RÉSULTATS: Plus de 80 % des enfants ont reçu certains services à T1, et près de 95 % à T4, et un nombre significatif a reçu plus d'un type de services à chaque évaluation. À T1, le service le plus courant était de type développemental (p. ex., orthophonie). Par la suite, les services les plus courants étaient un mélange de services comportementaux et développementaux (p. ex., thérapie intensive selon l'analyse de comportement appliquée et orthophonie). La prestation des services variait selon les provinces et au fil du temps. EXPOSÉ: Même si la plupart des enfants d'âge préscolaire ayant un TSA qui habitaient dans un centre urbain avaient accès à des services spécialisés peu après le diagnostic, les variations marquées des services entre les provinces demeurent préoccupantes.

Neurodevelopmental disorders in children born to mothers with systemic lupus erythematosus.

Children born to women with systemic lupus erythematosus seem to have a potentially increased risk of neurodevelopmental disorders compared to children born to healthy women. Recent experimental data suggest in utero exposure to maternal antibodies and cytokines as important risk factors for neurodevelopmental disorders. Interestingly, women with systemic lupus erythematosus display high levels of autoantibodies and cytokines, which have been shown, in animal models, to alter fetal brain development and induce behavioral anomalies in offspring. Furthermore, subjects with systemic lupus erythematosus and neurodevelopmental disorders share a common genetic predisposition, which could impair the fetal immune response to in utero immunologic insults. Moreover, systemic lupus erythematosus pregnancies are at increased risk of adverse obstetrical outcomes and medication exposures, which have been implicated as potential risk factors for neurodevelopmental disorders. In this article, we review the current state of knowledge on neurodevelopmental disorders and their potential determinants in systemic lupus erythematosus offspring.

Systematic resequencing of X-chromosome synaptic genes in autism spectrum disorder and schizophrenia.

Autism spectrum disorder (ASD) and schizophrenia (SCZ) are two common neurodevelopmental syndromes that result from the combined effects of environmental and genetic factors. We set out to test the hypothesis that rare variants in many different genes, including de novo variants, could predispose to these conditions in a fraction of cases. In addition, for both disorders, males are either more significantly or more severely affected than females, which may be explained in part by X-linked genetic factors. Therefore, we directly sequenced 111 X-linked synaptic genes in individuals with ASD (n = 142; 122 males and 20 females) or SCZ (n = 143; 95 males and 48 females). We identified >200 non-synonymous variants, with an excess of rare damaging variants, which suggest the presence of disease-causing mutations. Truncating mutations in genes encoding the calcium-related protein IL1RAPL1 (already described in Piton et al. Hum Mol Genet 2008) and the monoamine degradation enzyme monoamine oxidase B were found in ASD and SCZ, respectively. Moreover, several promising non-synonymous rare variants were identified in genes encoding proteins involved in regulation of neurite outgrowth and other various synaptic functions (MECP2, TM4SF2/TSPAN7, PPP1R3F, PSMD10, MCF2, SLITRK2, GPRASP2, and OPHN1).

Childhood and adolescent hyperactivity-inattention symptoms and academic achievement 8 years later: the GAZEL Youth study.

BACKGROUND: Children with attention deficit/hyperactivity disorder (ADHD) are at risk of negative academic outcomes. However, relatively few studies in this area have been based on long-term longitudinal designs and community-based settings. This study examined the link between childhood hyperactivity-inattention symptoms (HI-s) and subsequent academic achievement in a community setting, controlling for other behavioural symptoms, socio-economic status (SES) and environmental factors at baseline. METHOD: The sample consisted of 1264 subjects (aged 12 to 26 years at follow-up) recruited from the longitudinal GAZEL Youth study. Psychopathology, environmental variables and academic outcomes were measured through self-reports. Multivariate modelling was performed to evaluate the effects of childhood HI-s and other risk factors on academic achievement 8 years later. RESULTS: HI-s independently predicted grade retention [adjusted odds ratio (OR) 3.58, 95% confidence interval (CI) 2.38-5.39], failure to graduate from secondary school (adjusted OR 2.41, 95% CI 1.43-4.05), obtaining a lower-level diploma (adjusted OR 3.00, 95% CI 1.84-4.89), and lower academic performance. These results remained significant even after accounting for school difficulties at baseline. Negative academic outcomes were also significantly associated with childhood symptoms of conduct disorder (CD), even after accounting for adjustment variables. CONCLUSIONS: This longitudinal survey replicates, in a general population-based setting, the finding of a link between HI-s and negative academic outcomes.

Regression of language and non-language skills in pervasive developmental disorders.

BACKGROUND: As part of the pervasive developmental disorders (PDD), there is a subgroup of individuals reported to have a different onset of symptom appearance consisting of an apparently normal early development, followed by a loss of verbal and/or non-verbal skills prior to 2 years of age. This study aims at comparing the symptomatology of children who displayed a regression and often an associated intellectual disability through investigation of two types of loss, namely language and other skill regression. METHODS: This study examined the occurrence of regression in 135 children with PDD, mean age 6.3 years. The sample was composed of 80 (59.4%) children diagnosed with autism, 44 (32.6%) with pervasive developmental disorder-not otherwise specified (PDD-NOS) and 11 (8%) with Asperger syndrome. The Autism Diagnostic Interview Revised (ADI-R) was used to evaluate the type of loss and to characterise associated factors including birth rank, gender and thimerosal exposure through vaccination. RESULTS: A total of 30 (22%) subjects regressed: nine (30%) underwent language regression alone, 17 (57%) lost a skill other than language and four (13%) lost both language and another skill. Significantly higher levels of regression were found in autism (30%) compared with PDD-NOS (14%) and Asperger syndrome (0%). Children who regressed in language skills spoke at a significantly earlier age ( = 12 months) than those who did not regress in this domain ( = 26 months). Parents and interviewers consistently reported developmental abnormalities prior to the loss. ADI-R domain mean scores indicated a more severe autistic symptomatology profile in children who regressed compared with those who did not, especially in the repetitive behaviour domain. Regression was not associated to thimerosal exposure, indirectly estimated by year of birth. CONCLUSIONS: A loss of skill, present in one out of five children with PDD, is associated with a slightly more severe symptomatology as measured by the ADI-R, particularly in the repetitive behaviours domain. Furthermore, although abnormalities are often noticed by the caregivers at the time of regression, the ADI-R reveals that other atypical behaviours were in fact present prior to the onset of regression in most cases. None of the secondary factors investigated were associated with regression. In children unexposed to thimerosal-containing vaccines, the rate of regression was similar to that reported in studies of samples exposed to thimerosal, suggesting that thimerosal has no specific association with regressive autism.

Hyperactivity-inattention symptoms in childhood and suicidal behaviors in adolescence: the Youth Gazel Cohort.

OBJECTIVE: Although a link has been suggested between attention deficit/hyperactivity disorder (ADHD) and completed suicide, little is known about the association with suicidal behaviors in community settings. This study addresses the relationship between childhood hyperactivity-inattention symptoms (HI-s) and subsequent suicidal behaviors. METHOD: Nine hundred sixteen subjects aged 7-18 were recruited from the general population and surveyed in 1991 and 1999. Parent and adolescent self-reports provided psychopathology and suicidal behavior pattern measures. Multivariate modeling was used to evaluate the effects of childhood HI-s and other risk factors on adolescent suicidal behaviors. RESULTS: In males, HI-s independently accounted for the risk of lifetime suicide plans/attempts (OR=3.25, P = 0.02) and adolescent 12-month prevalence rates of suicide plans/attempts (OR=5.46, P = 0.03). In females, HI-s did not independently heighten the likelihood of suicidal behaviors. CONCLUSION: This survey suggests a possible specific link between HI-s and suicide plans/attempts in males.

Autism and associated medical disorders in a French epidemiological survey.

OBJECTIVE: To estimate the prevalence of autism, to assess the strength of its association with specific medical disorders, and to test for a secular increase in its incidence. METHOD: An epidemiological survey was conducted among 325,347 French children born between 1976 and 1985 and living in three different French départements. Diagnosis, educational level, and associated medical conditions were abstracted from the records of children known to local educational authorities. Data were also pooled with those from another similar survey. RESULTS: One hundred seventy-four children (mean age: 11.6 years) with autism were identified. The prevalence rate was 5.35/10,000 (16.3/10,000 if other pervasive developmental disorders are included), with no difference according to geographical area or social class. Rates of medical conditions were as follows: 1.1% for tuberous sclerosis, 2.9% for chromosomal abnormalities including fragile X, 2.9% for cerebral palsy, 4.6% for sensory impairments, 0.6% for neurofibromatosis, 0.6% for congenital rubella, and 1.7% for Down syndrome. In the combined sample of 328 children with autism, the level and pattern of medical correlates were comparable, with tuberous sclerosis having a consistently strong association with autism. Prevalence rates were similar in successive birth cohorts. CONCLUSION: Medical disorders (excluding epilepsy and sensory impairments) accounted for fewer than 10% of the cases of autism. No secular increase in the prevalence of autism was found.

Prevalence of pervasive developmental disorders in the British nationwide survey of child mental health.

OBJECTIVE: The prevalence of pervasive developmental disorders (PDD) is not well established and needs monitoring. The prevalence of PDD in the 1999 nationwide British survey of child and adolescent mental health was investigated. METHOD: A randomized, stratified sample of children (N= 12,529) aged 5 to 15 years was generated from the Child Benefit Register. Trained interviewers interviewed parents and youths aged 11 or older with a standardized diagnostic interview (Development and Well-Being Assessment), and questionnaire data (Strengths and Difficulties Questionnaire) were obtained from teachers and parents, who also completed self-report measures of psychological distress. Final diagnostic determination was achieved by a team of experienced clinicians using all data sources. RESULTS: A total of 10,438 (83%) interviews were conducted. There were 2 girls with Rett syndrome (weighted prevalence: 3.8/10,000 girls) and 27 children with other PDD (weighted prevalence: 26.1/10,000). Compared with children with a psychiatric disorder other than PDD, social but not behavioral problems were more frequent in the PDD group. Parents of children with PDD had higher rates of psychological distress than those from the two comparison groups. CONCLUSIONS: Consistent with other recent surveys, PDD rates are higher than those reported 30 years ago. The burden associated with PDD is very high.

Psychological adjustment in a french cohort of type 1 diabetic children. PEDIAB Collaborative Group.

The aim of the study was to determine whether IDDM affects the course of psychological adjustment in youths. The study sample included 164 children with IDDM (mean age=10.2) and their parents compared to 164 healthy controls matched for age, sex and socioeconomic status. Adjustment was measured with the Child Behavior Checklist, a parental rating scale, validated and adapted for the French population. Two-way ANOVAs on CBCL scale scores showed that scores for both internalizing and externalizing problem behaviors and the total CBCL score were significantly raised in diabetic children (p<0.001). Further comparisons on the 8 narrow-band scale scores of the CBCL indicated increased scores for diabetic children on 6 dimensions. A significant Gender x Status (IDDM versus Controls) interaction was found, supportive of higher rates of aggressive behaviors amongst male diabetic children (p<0.01). Controlling for age, no correlation was found between CBCL total, internalizing and externalizing scores and duration of IDDM or HbA1c levels within the diabetic group. Psychological adjustment to chronic illness needs to be considered with respect to both normal developmental demands as well as in the context of the specific challenges posed by the disease.

Depressive conduct disorder: symptom patterns and correlates in referred children and adolescents.

BACKGROUND: In order to examine the validity of the ICD-10 diagnostic category of depressive conduct disorder (DCD), a sample of 58 patients (mean age 11.6) with this diagnosis consecutively referred to a teaching hospital was compared with 151 patients with conduct disorder (CD) (mean age 12.3) and with 128 patients with depressive disorder (DD) (mean age 14.2). METHOD: Data on symptom profile, sociodemographic characteristics, duration of disorder, family history and psychosocial background were collected using the Maudsley item sheet. Comparison of the three groups was performed using SPSS. RESULTS: Controlling for age and gender differences, the DCD group had fewer biological depressive symptoms, fewer anxiety symptoms, less guilt and lower severity of overall depression compared to the DD group. They also displayed more self-injurious behaviour and had more adverse psychosocial circumstances than the DD subjects. Compared to the CD group, the DCD patients were less overtly aggressive and violent than the CD subjects, in addition to having significant depressive symptoms and a more frequent history of abuse. LIMITATIONS: The study was based on case-control and diagnosis had been reached after the discussion of clinicians involved in assessment. CONCLUSIONS: Overall, the results tentatively support the validity of this diagnostic subgrouping.

Diagnostic assessment in a sample of autistic and developmentally impaired adolescents.

A sample of 43 autistic and developmentally impaired adolescents were assessed with the Autism Diagnostic Interview (ADI), DSM-III-R criteria, and the clinician's diagnosis. DSM-III-R criteria for autism have low specificity and agree poorly with the other two definitions. Detailed results of the ADI are provided that confirm the usefulness and discriminant validity of this semi-structured diagnostic interview in a sample of very retarded autistic subjects.

Microcephaly and macrocephaly in autism.

Data from a series of 126 autistic children ages 2-16 years and referred to an Autism Diagnosis Unit in South-West France were examined. Macrocephaly (head circumference > 97th centile) was observed in 16.7% of the sample, a significantly higher proportion than that expected. Macrocephaly was more frequent among older subjects but was otherwise not associated with gender, developmental level, the presence of epilepsy or of medical disorders, or severity of autistic symptomatology. Microcephaly (head circumference < 3rd centile) was also significantly raised and found in 15.1% of the sample. Microcephaly was significantly associated with the presence of medical disorders. Results support those from recent studies suggesting a raised rate of macrocephaly in autism which, pooling published data, can be estimated to be 20%. It is argued that the raised incidence of microcephaly among low-functioning autistic subjects with medical disorders might have contributed to delay the recognition of an increased head circumference among a minority of subjects with idiopathic autism.

The Vineland Adaptive Behavior Scales: supplementary norms for individuals with autism.

Vineland Adaptive Behavior Scales Special Population norms are presented for four groups of individuals with autism: (a) mute children under 10 years of age; (b) children with at least some verbal skills under 10 years of age; (c) mute individuals who are 10 years of age or older; and (d) individuals with at least some verbal skills who are 10 years of age or older. The sample included 684 autistic individuals ascertained from cases referred for the DSM-IV autism/PDD field trial collaborative study and five university sites with expertise in autism. Young children had higher standard scores than older individuals across all Vineland domains. In the Communication domain, younger verbal children were least impaired, older mute individuals most impaired, and younger mute and older verbal individuals in the midrange. Verbal individuals achieved higher scores in Daily Living Skills than mute individuals. The expected profile of a relative weakness in Socialization and relative strength in Daily Living Skills was obtained with age-equivalent but not standard scores. Results high-light the importance of employing Vineland special population norms as well as national norms when evaluating individuals with autism.

Diagnosing autism: analyses of data from the Autism Diagnostic Interview.

Results from ROC curves of items from two scales, the Autism Diagnostic Interview (ADI) and Autism Diagnostic Interview-Revised (ADI-R), operationalizing DSM-IV criteria for autism are presented for 319 autistic and 113 other subjects from 8 international autism centers. Analyses indicate that multiple items were necessary to attain adequate sensitivity and specificity if samples with varying levels of language were considered separately. Although considering only current behavior was generally sufficient when a combination cutoff and additive model was employed, predictive power was highest when history was taken into account. A single set of criteria, as operationalized by individually structured questions in the ADI/ADI-R, was effective in differentiating autism from mental handicap and language impairment in subjects with a range of chronological ages and developmental levels.

A case-control study of autism and mumps-measles-rubella vaccination using the general practice research database: design and methodology.

BACKGROUND: An association between mumps-measles-rubella (MMR) vaccination and the onset of symptoms typical of autism has recently been suggested. This has led to considerable concern about the safety of the vaccine. METHODS: A matched case-control study using data derived form the United Kingdom General Practice Research Database. Children with a possible diagnosis of autism will be identified from their electronic health records. All diagnoses will be validated by a detailed review of hospital letters and by using information derived from a parental questionnaire. Ten controls per case will be selected from the database. Conditional logistic regression will be used to assess the association between MMR vaccination and autism. In addition case series analyses will be undertaken to estimate the relative incidence of onset of autism in defined time intervals after vaccination. The study is funded by the United Kingdom Medical Research Council. DISCUSSION: Electronic health databases offer tremendous opportunities for evaluating the adverse effects of vaccines. However there is much scope for bias and confounding. The rigorous validation of all diagnoses and the collection of additional information by parental questionnaire in this study are essential to minimise the possibility of misleading results.

Comparison of six treatments of ascites in patients with liver cirrhosis. A clinical trial.

UNLABELLED: A national multicenter study (34 centers) compared six treatments in 328 patients with cirrhotic ascites. Excluded were patients with g.i. bleeding within the last six months, chronic encephalopathy, cancer, tuberculosis or the following complications persisting after three weeks: acute encephalopythy, fever greater than 38 degrees C, infected ascites or biochemical abnormalities: blood urea greater than 8 mmol/l, natremia less than 130 mmol/l, kaliemia less than 2.5 or greater than 5.5 mmol/l, WBC greater than 12000 mm3, total bilirubin greater than 85.5 mumol/l. In each center patients were randomized into two treatment groups, each center using 2 of 6 proposed treatments: (1) Spironolactone and 500 mg Na p.d (77 patients), (2) Spironolactone + furosemide or Moduretic (amiloride + hydrochlorothiazide) and 500 mg Na p.d (80 patients), (3) Spironolactone + Furosemide or Moduretic and unrestricted sodium diet (86 patients), (4) Concentrated ascites reinfusion and 500 mg Na p.d. (36 patients), (5) Unmodified ascites reinfusion and 500 mg Na p.d. (23 patients), (6) Slow ascites drainage and 500 mg Na p.d. (31 patients). Statistical analysis methods were X2, variance analysis and Spotvoll-Stoline and Dunn-Sidak tests. Before treatment, there was no significant difference between the 6 groups. RESULTS: After one month of treatment, no difference was found in the frequency of total or partial regression of ascites, complications of cirrhosis, mortality, acceptability of treatment. Mechanical treatments induced more rapid weight loss but more frequent recurrence; comparison of groups 2 and 3 did not confirm any benefit associated with unrestricted Na diet. Duration of treatment and hospitalization were shorter in group 4 than in groups 3 and 6.

The broad autism phenotype: findings from an epidemiological survey.

This study aimed to determine if relatives of children with autism and less severe pervasive developmental disorders (PDDs) have higher rates of various components of the broad autistic phenotype. Psychiatric and medical disorders were investigated. Parents of children with PDDs were selected from an epidemiological survey and compared with parents of control children with non-autistic developmental problems. Rates of abnormalities and disorders were compared in relatives of 79 cases and 61 controls. Medical and autoimmune disorders in both groups were endorsed by few relatives. Specific developmental disorders were commoner in parents of controls. Depression and anxiety were significantly more prevalent in mothers of children with PDDs. Significantly more PDD children had at least one first-degree relative with anxiety and one second-degree relative with OCD. PDDs were commoner in first-degree relatives. The implications of the findings for the definition of the broad phenotype of autism are discussed.

Ethnicity and adolescent deliberate self-harm

The characteristics of all adolescents referred to the psychiatric service of a tertiary hospital following an episode of deliberate self-harm (DSH) were studied. Of 100 adolescents selected over a 3-year period, 64 White and 28 Black adolescents were compared to identify factors associated with DSH in Black adolescents. The main findings were: (1) the referral rate for Black adolescents was in proportion to the community composition; (2) the characteristics of Black and White adolescents referred following DSH were similar for background socio-demographic variables, psychiatric symptoms, circumstances of the attempt and outcome. However, more social stress was reported in the Black group.

[Contribution of epidemiology to etiological research in psychiatry: from risk factors to risk mechanisms]. / La contribution de l'épidémiologie à la recherche étiologique en psychiatrie: des facteurs de risque aux mécanismes du risque.

Over the last 25 years, the burgeoning of psychiatric epidemiology has generated a considerable knowledge base on the prevalence and incidence of psychiatric disorders. For most disorders, risk factor research has also led to the identification of vulnerability factors in the genetic, biological, psychological and social arenas. However, the delineation of psychopathological mechanisms requires a better understanding of the developmental connexions and sequences of intervention of the postulated risk factors. Similarly, psychopathological models should benefit from the study of protective influences and processes. The importance of longitudinal approaches to the study of causation in psychopathology is emphasized. While future research endeavors need to be theory-driven and to rely on more sophisticated measurement strategies, etiological research in psychiatry will continue to benefit from the range of research methods provided by epidemiology.