Continuity of trajectories of autism symptom severity from infancy to childhood.

BACKGROUND: Behavioral symptom trajectories are informative of the development of young children at increased likelihood for autism spectrum disorder (ASD). METHODS: Developmental trajectories of early signs were examined in a cohort of siblings of children diagnosed with ASD (n = 502) from 6 to 18 months using the Autism Observation Scale for Infants (AOSI), and from 18 months to 5-7 years using the Autism Diagnostic Observation Schedule (ADOS). Diagnostic outcomes for ASD at age 3 confirmed diagnosis for 137 children. We further analyzed the conditional probability of a switch from a trajectory measured with the AOSI to a trajectory measured with the ADOS as well as predictors from age 6 months. RESULTS: We derived three early trajectories of behavioral signs ("Low," "Intermediate," and "Increasing") from 6 to 18 months using the AOSI. We then derived three similar, distinct trajectories for the evolution of symptom severity between 18 and 60-84 months of age (Low, Intermediate, Increasing) using the ADOS. Globally, the Low trajectory included children showing fewer ASD signs or symptoms and the Increasing trajectory included children showing more severe symptoms. We also found that most children in the Low AOSI trajectory stayed in the corresponding ADOS trajectory, whereas children in an Increasing AOSI trajectory tended to transition to an Intermediate or Increasing ADOS trajectory. Developmental measures taken at 6 months (early signs of ASD, Fine Motor, and Visual Reception skills) were predictive of trajectory membership. CONCLUSIONS: Results confirm substantial heterogeneity in the early emergence of ASD signs in children at increased likelihood for ASD. Moreover, we showed that the way those early behavioral signs emerge in infants is predictive of later symptomatology. Results yield clear clinical implications, supporting the need to repeatedly assess infants at increased likelihood for ASD as this can be highly indicative of their later development and behavior.

Precursors of self-regulation in infants at elevated likelihood for autism spectrum disorder.

Research concerning temperament in children and adults with autism spectrum disorder (ASD) has suggested a consistent profile of low positive affect, high negative affect, and low regulation (Visser et al., 2016). One area receiving less attention is individual differences among children diagnosed with ASD. The primary objective of this study was to use a person-centered approach to explore heterogeneity of early temperament precursors of regulation in a large sample of infants with elevated familial likelihood of ASD. Early precursors of regulation included temperament assessed at 6, 12, and 24 months whereas outcome measures were diagnosis of ASD, cognitive ability and adaptive behavior at 36 months. Participants included 176 low-likelihood and 473 elevated-likelihood infants, 129 of whom were diagnosed with ASD at 3 years. Results supported a three-profile solution: a well-regulated profile (high positive affect and high attentional focus and shifting), a low attention focus profile (higher attentional shifting compared to attentional focus), and a low attention shifting profile (higher attentional focus compared to attentional shifting). A higher proportion of children diagnosed with ASD were classified into the low attention shifting profile. Furthermore, children with the well-regulated profile were differentiated from the other profiles by a pattern of higher social competence and lower dysregulation whereas children with the low attention focus profile were distinguished from the other profiles by higher cognitive ability at 3 years. The findings indicate that the combination of early positive affect with attention measures may provide an enhanced tool for prediction of self-regulation and later outcomes.

Symptom trajectories in the first 18 months and autism risk in a prospective high-risk cohort.

BACKGROUND: Although early autism spectrum disorder (ASD) detection strategies tend to focus on differences at a point in time, behavioral symptom trajectories may also be informative. METHODS: Developmental trajectories of early signs of ASD were examined in younger siblings of children diagnosed with ASD (n = 499) and infants with no family history of ASD (n = 177). Participants were assessed using the Autism Observation Scale for Infants (AOSI) from 6 to 18 months. Diagnostic outcomes were determined at age 3 years blind to previous assessments. RESULTS: Semiparametric group-based modeling using AOSI scores identified three distinct trajectories: Group 1 ('Low', n = 435, 64.3%) was characterized by a low level and stable evolution of ASD signs, group 2 ('Intermediate', n = 180, 26.6%) had intermediate and stable levels, and group 3 ('Inclining', n = 61, 9.3%) had higher and progressively elevated levels of ASD signs. Among younger siblings, ASD rates at age 3 varied by trajectory of early signs and were highest in the Inclining group, membership in which was highly specific (94.5%) but poorly sensitive (28.5%) to ASD. Children with ASD assigned to the inclining trajectory had more severe symptoms at age 3, but developmental and adaptive functioning did not differ by trajectory membership. CONCLUSIONS: These prospective data emphasize variable early-onset patterns and the importance of a multipronged approach to early surveillance and screening for ASD.

Assessment of Autism Symptoms From 6 to 18 Months of Age Using the Autism Observation Scale for Infants in a Prospective High-Risk Cohort.

The objectives were to characterize behavioral signs of autism spectrum disorder (ASD) in younger siblings of diagnosed children (high-risk; HR) and examine classification features of the Autism Observation Scale for Infants (AOSI). Participants (501 HR and 180 low-risk [LR]) were assessed between 6 and 18 months using the AOSI and at age 3 for ASD diagnoses. Total AOSI scores differentiated HR infants later diagnosed with ASD starting at 12 months. ROC analyses identified 12- and 18-month cutoff scores associated with 0.52 sensitivity and 0.74 specificity and 0.73 sensitivity and 0.65 specificity, respectively. Although classification accuracy does not support use as a standalone screen, the AOSI identifies features associated with ASD starting at 6 months and differentiates HR infants with ASD by 12 months.

The association between social emotional development and symptom presentation in autism spectrum disorder.

Understanding differences in social-emotional behavior can help identify atypical development. This study examined the differences in social-emotional development in children at increased risk of an autism spectrum disorder (ASD) diagnosis (infant siblings of children diagnosed with the disorder). Parents completed the Brief Infant-Toddler Social-Emotional Assessment (BITSEA) to determine its ability to flag children with later-diagnosed ASD in a high-risk (HR) sibling population. Parents of HR (n = 311) and low-risk (LR; no family history of ASD; n = 127) children completed the BITSEA when their children were 18 months old and all children underwent a diagnostic assessment for ASD at age 3 years. All six subscales of the BITSEA (Problems, Competence, ASD Problems, ASD Competence, Total ASD Score, and Red Flags) distinguished between those in the HR group who were diagnosed with ASD (n = 84) compared to non-ASD-diagnosed children (both HR-N and LR). One subscale (BITSEA Competence) differentiated between the HR children not diagnosed with ASD and the LR group. The results suggest that tracking early social-emotional development may have implications for all HR children, as they are at increased risk of ASD but also other developmental or mental health conditions.

Developmental trajectories of adaptive behavior in autism spectrum disorder: a high-risk sibling cohort.

BACKGROUND: Children with autism spectrum disorder (ASD) often experience impairments in adaptive behavior. METHODS: Developmental trajectories of adaptive behavior in ASD were examined in children from high-risk (siblings of children diagnosed with ASD, n = 403) and low-risk (no family history of ASD, n = 163) families. Children were assessed prospectively at 12, 18, 24, and 36 months of age using the Vineland Adaptive Behavior Scales and underwent a blind independent diagnostic assessment for ASD at 36 months of age. RESULTS: The semi-parametric group-based modeling approach using standard scores on the Adaptive Behavior Composite revealed three distinct developmental trajectories: (a) Group 1 (21.2% of sample) showed average performance at 12 months and a declining trajectory; (b) Group 2 (52.8% of the sample) showed average performance at 12 months with a slightly declining trajectory; and (c) Group 3 (26.0% of the sample) showed a higher level of adaptive behavior at 12 months and a stable trajectory. The Mullen Scales of Early Learning Early Learning Composite and the Autism Observation Scale for Infants total score at 6 and 12 months predicted trajectory membership. CONCLUSIONS: The results emphasize heterogeneous development associated with ASD and the need for interventions tailored to individual presentations.

Developmental functioning and symptom severity influence age of diagnosis in Canadian preschool children with autism.

BACKGROUND: Early diagnosis of autism spectrum disorder (ASD) is essential in most Canadian jurisdictions to access interventions that improve long-term child outcomes. Our main objective was to identify factors associated with timing of ASD diagnosis in five provinces across Canada. METHODS: Factors influencing age of diagnosis were assessed in the analyses of an inception cohort of children diagnosed with ASD between ages 2 and 5 years. We examined bivariate associations and using a series of multiple variable regression models, evaluated the unique contributions of developmental functioning, ASD symptoms and demographic variables. Children with known genetic abnormalities, or severe sensory or motor impairments interfering with assessment were excluded. RESULTS: Participants were 421 children (84.6% boys). The mean age of diagnosis was 38.2 months (SD=8.7), an average of 19 months after parents identified initial concerns. Factors associated with later diagnosis included more advanced language and cognitive skills, and higher levels of restricted repetitive behaviour symptoms. Child sex and family demographics were not associated with age of diagnosis. In regression analyses, language and cognitive skills accounted for 6.8% of variance in age of diagnosis and ASD symptoms contributed an additional 5.5%. Provincial site accounted for 4.0% of variance in age of diagnosis, independent of developmental skills and ASD symptoms. INTERPRETATION: Diagnosis of ASD occurred, on average, 19 months after parents' initial concerns. Language and cognitive skills, symptom severity and provincial site accounted for variation in age of ASD diagnosis in this Canadian cohort. Variable presentation across the developmental continuum must be considered in planning assessment services to ensure timely ASD diagnosis so that outcomes can be improved. Policy and practice leadership is also needed to reduce interprovincial variability.

Joint trajectories of internalizing and externalizing problems in preschool children with autism spectrum disorder.

The co-occurring development of internalizing and externalizing problems were examined in an inception cohort of 392 children diagnosed with autism spectrum disorder at age 3 who were assessed on four occasions. Results indicated that internalizing and externalizing problems were stable over time and highly comorbid. Joint trajectory analysis suggested that 13% of the sample followed a dual high-risk trajectory. High risk was not found to be associated with intellectual ability or autism spectrum disorder symptom severity but was linked to lower income and gender: more girls than boys were found in the high/stable internalizing problems trajectory. The results suggest that 1 in 4 preschoolers followed a trajectory of internalizing or externalizing problems (or a combination of the two) that could be characterized as clinically elevated.

Functional impact of global rare copy number variation in autism spectrum disorders.

The autism spectrum disorders (ASDs) are a group of conditions characterized by impairments in reciprocal social interaction and communication, and the presence of restricted and repetitive behaviours. Individuals with an ASD vary greatly in cognitive development, which can range from above average to intellectual disability. Although ASDs are known to be highly heritable ( approximately 90%), the underlying genetic determinants are still largely unknown. Here we analysed the genome-wide characteristics of rare (<1% frequency) copy number variation in ASD using dense genotyping arrays. When comparing 996 ASD individuals of European ancestry to 1,287 matched controls, cases were found to carry a higher global burden of rare, genic copy number variants (CNVs) (1.19 fold, P = 0.012), especially so for loci previously implicated in either ASD and/or intellectual disability (1.69 fold, P = 3.4 x 10(-4)). Among the CNVs there were numerous de novo and inherited events, sometimes in combination in a given family, implicating many novel ASD genes such as SHANK2, SYNGAP1, DLGAP2 and the X-linked DDX53-PTCHD1 locus. We also discovered an enrichment of CNVs disrupting functional gene sets involved in cellular proliferation, projection and motility, and GTPase/Ras signalling. Our results reveal many new genetic and functional targets in ASD that may lead to final connected pathways.

Mapping autism risk loci using genetic linkage and chromosomal rearrangements.

Autism spectrum disorders (ASDs) are common, heritable neurodevelopmental conditions. The genetic architecture of ASDs is complex, requiring large samples to overcome heterogeneity. Here we broaden coverage and sample size relative to other studies of ASDs by using Affymetrix 10K SNP arrays and 1,181 [corrected] families with at least two affected individuals, performing the largest linkage scan to date while also analyzing copy number variation in these families. Linkage and copy number variation analyses implicate chromosome 11p12-p13 and neurexins, respectively, among other candidate loci. Neurexins team with previously implicated neuroligins for glutamatergic synaptogenesis, highlighting glutamate-related genes as promising candidates for contributing to ASDs.

Multiple Imputation When Rate of Change is the Outcome of Interest.

Little research has been devoted to multiple imputation (MI) of derived variables. This study investigates various MI approaches for the outcome, rate of change, when the analysis model is a two-stage linear regression. Simulations showed that competitive approaches depended on the missing data mechanism and presence of auxiliary terms.

Autism spectrum disorder in infancy: developmental considerations in treatment targets.

PURPOSE OF REVIEW: This review explores recent literature to prioritize aspects of development to be targeted by intervention for infants and toddlers with autism spectrum disorder (ASD). RECENT FINDINGS: Recent investigation of early development in ASD, including prospective studies of infants at increased risk (i.e., those with an affected older sibling) identifies impairments in four key developmental domains that are predictive of ASD. These domains are early attentional control, emotion regulation, social orienting/approach, and communication development. Reciprocal relationships exist among these domains, both in ASD and in typical development. Thus, these domains represent key intervention targets, informing treatment models under investigation in recent clinical trials. SUMMARY: By targeting the earliest and foundational manifestations of atypical development, we can capitalize on neural plasticity and build skills that are most likely to have scaffolding effects on development. The optimal timing and procedures of intervention remain empirical questions, but as the field moves toward earlier identification of risk, we are now poised to evaluate the impact of tailored approaches before the developmental cascade that leads to ASD is fully manifested. Consideration regarding community translation of ASD-specific interventions for infants and toddlers is also needed, with a focus on feasibility, cost-effectiveness, and sustainability.

Diagnostic stability in young children at risk for autism spectrum disorder: a baby siblings research consortium study.

BACKGROUND: The diagnosis of autism spectrum disorder (ASD) made before age 3 has been found to be remarkably stable in clinic- and community-ascertained samples. The stability of an ASD diagnosis in prospectively ascertained samples of infants at risk for ASD due to familial factors has not yet been studied, however. The American Academy of Pediatrics recommends intensive surveillance and screening for this high-risk group, which may afford earlier identification. Therefore, it is critical to understand the stability of an ASD diagnosis made before age 3 in young children at familial risk. METHODS: Data were pooled across seven sites of the Baby Siblings Research Consortium. Evaluations of 418 later-born siblings of children with ASD were conducted at 18, 24, and 36 months of age and a clinical diagnosis of ASD or Not ASD was made at each age. RESULTS: The stability of an ASD diagnosis at 18 months was 93% and at 24 months was 82%. There were relatively few children diagnosed with ASD at 18 or 24 months whose diagnosis was not confirmed at 36 months. There were, however, many children with ASD outcomes at 36 months who had not yet been diagnosed at 18 months (63%) or 24 months (41%). CONCLUSIONS: The stability of an ASD diagnosis in this familial-risk sample was high at both 18 and 24 months of age and comparable with previous data from clinic- and community-ascertained samples. However, almost half of the children with ASD outcomes were not identified as being on the spectrum at 24 months and did not receive an ASD diagnosis until 36 months. Thus, longitudinal follow-up is critical for children with early signs of social-communication difficulties, even if they do not meet diagnostic criteria at initial assessment. A public health implication of these data is that screening for ASD may need to be repeated multiple times in the first years of life. These data also suggest that there is a period of early development in which ASD features unfold and emerge but have not yet reached levels supportive of a diagnosis.

Do reciprocal associations exist between social and language pathways in preschoolers with autism spectrum disorders?

BACKGROUND: Differences in how developmental pathways interact dynamically in children with autism spectrum disorder (ASD) likely contribute in important ways to phenotypic heterogeneity. This study aimed to model longitudinal reciprocal associations between social competence (SOC) and language (LANG) pathways in young children with ASD. METHODS: Data were obtained from 365 participants aged 2-4 years who had recently been diagnosed with an ASD and who were followed over three time points: baseline (time of diagnosis), 6- and 12 months later. Using structural equation modeling, a cross-lagged reciprocal effects model was developed that incorporated auto-regressive (stability) paths for SOC (using the Socialization subscale of the Vineland Adaptive Behavior Scales-2) and LANG (using the Preschool Language Scale-4 Auditory Comprehension subscale). Cross-domain associations included within-time correlations and lagged associations. RESULTS: SOC and LANG were highly stable over 12 months. Small reciprocal cross-lagged associations were found across most time points and within-time correlations decreased over time. There were no differences in strength of cross-lagged associations between SOC-LANG and LANG-SOC across time points. Few differences were found between subgroups of children with ASD with and without cognitive impairment. CONCLUSIONS: Longitudinal reciprocal cross-domain associations between social competence and language were small in this sample of young children with ASD. Instead, a pattern emerged to suggest that the two domains were strongly associated around time of diagnosis in preschoolers with ASD, and then appeared to become more independent over the ensuing 12 months.

Behavioral Pediatrics Feeding Assessment Scale in Young Children With Autism Spectrum Disorder: Psychometrics and Associations With Child and Parent Variables.

OBJECTIVE: The factor structure and validity of the Behavioral Pediatrics Feeding Assessment Scale (BPFAS; Crist & Napier-Phillips, 2001) were examined in preschoolers with autism spectrum disorder (ASD). METHODS: Confirmatory factor analysis was used to examine the original BPFAS five-factor model, the fit of each latent variable, and a rival one-factor model. None of the models was adequate, thus a categorical exploratory factor analysis (CEFA) was conducted. Correlations were used to examine relations between the BPFAS and concurrent variables of interest. RESULTS: The CEFA identified an acceptable three-factor model. Correlational analyses indicated that feeding problems were positively related to parent-reported autism symptoms, behavior problems, sleep problems, and parenting stress, but largely unrelated to performance-based indices of autism symptom severity, language, and cognitive abilities, as well as child age. CONCLUSION: These results provide evidence supporting the use of the identified BPFAS three-factor model for samples of young children with ASD.

Development and evaluation of a treatment fidelity instrument for family-based treatment of adolescent anorexia nervosa.

OBJECTIVE: This study provides data on the psychometric properties of a newly developed measure of treatment fidelity in Family-Based Treatment (FBT) for adolescent anorexia nervosa (AN). The Family Therapy Fidelity and Adherence Check (FBT-FACT) was created to evaluate therapist adherence and competency on the core interventions in FBT. METHOD: Participants were 45 adolescents and their families sampled from three randomized clinical trials evaluating treatment for AN. Trained fidelity raters evaluated 19 therapists across 90 early session recordings using the FBT-FACT. They also rated an additional 15 session 1 recordings of an alternate form of family therapy-Systemic Family Therapy for the purpose of evaluating discriminant validity of the FBT-FACT. The process of development and the psychometric properties of the FBT-FACT are presented. RESULTS: Overall fidelity ratings for each session demonstrated moderate to strong inter-rater agreement. Internal consistency of the measure was strong for sessions 1 and 2 and poor for session 3. Principal components analysis suggests sessions 1 and 2 are distinct interventions. DISCUSSION: The FBT-FACT demonstrates good reliability and validity as a measure of treatment fidelity in the early phase of FBT.

Early weight gain predicts outcome in two treatments for adolescent anorexia nervosa.

OBJECTIVE: Determine whether early weight gain predicts full remission at end-of-treatment (EOT) and follow-up in two different treatments for adolescent anorexia nervosa (AN), and to track the rate of weight gain throughout treatment and follow-up. METHOD: Participants were 121 adolescents with AN (mean age = 14.4 years, SD = 1.6), from a two-site (Chicago and Stanford) randomized controlled trial. Adolescents were randomly assigned to family-based treatment (FBT) (n = 61) or individual adolescent focused therapy (AFT) (n = 60). Treatment response was assessed using percent of expected body weight (EBW) and the global score on the Eating Disorder Examination (EDE). Full remission was defined as having achieved ≥95% EBW and within one standard deviation of the community norms of the EDE. Full remission was assessed at EOT as well as 12-month follow-up. RESULTS: Receiver operating characteristic analyses showed that the earliest predictor of remission at EOT was a gain of 5.8 pounds (2.65 kg) by session 3 in FBT (area under the curve (AUC) = 0.670; p = .043), and a gain of 7.1 pounds (3.20 kg) by session 4 in AFT (AUC = 0.754, p = .014). Early weight gain did not predict remission at follow-up for either treatment. A survival analysis showed that weight was marginally superior in FBT as opposed to AFT (Wald chi-square = 3.692, df = 1, p = .055). DISCUSSION: Adolescents with AN who receive either FBT or AFT, and show early weight gain, are likely to remit at EOT. However, FBT is superior to AFT in terms of weight gain throughout treatment and follow-up.

Parent-therapist alliance in Family-Based Treatment for adolescents with anorexia nervosa.

OBJECTIVE: This study aimed to describe the role of parent alliance in Family-Based Treatment (FBT) for adolescents with anorexia nervosa (AN). Differences between parent and child alliance with the therapist, mothers' and fathers' alliance, and their relationship to outcome were examined. METHOD: Independent observers rated audiotapes of early therapy sessions to assess the therapeutic alliance of parents and adolescents with AN in FBT. Outcome was defined using a previously established cut-point for recovery from AN. RESULTS: Mothers' and fathers' alliance scores with the therapist were similar and significantly higher than adolescent alliance scores early in treatment. Combined parent alliance did not predict recovery at the end of treatment. Difference in alliance scores between mothers and fathers, and parents and their child also did not predict recovery at the end of treatment. CONCLUSIONS: In FBT, parents developed a strong alliance with the therapist early in treatment. These scores were consistent with the focus in FBT on parental management of eating disorder symptoms, as was the fact that alliance between adolescents and therapists was lower. Although parental therapeutic alliance was likely important in FBT, its role in treatment response remains uncertain.

Investigating phenotypic heterogeneity in children with autism spectrum disorder: a factor mixture modeling approach.

BACKGROUND: Autism spectrum disorder (ASD) is characterized by notable phenotypic heterogeneity, which is often viewed as an obstacle to the study of its etiology, diagnosis, treatment, and prognosis. On the basis of empirical evidence, instead of three binary categories, the upcoming edition of the DSM 5 will use two dimensions - social communication deficits (SCD) and fixated interests and repetitive behaviors (FIRB) - for the ASD diagnostic criteria. Building on this proposed DSM 5 model, it would be useful to consider whether empirical data on the SCD and FIRB dimensions can be used within the novel methodological framework of Factor Mixture Modeling (FMM) to stratify children with ASD into more homogeneous subgroups. METHODS: The study sample consisted of 391 newly diagnosed children (mean age 38.3 months; 330 males) with ASD. To derive subgroups, data from the Autism Diagnostic Interview-Revised indexing SCD and FIRB were used in FMM; FMM allows the examination of continuous dimensions and latent classes (i.e., categories) using both factor analysis (FA) and latent class analysis (LCA) as part of a single analytic framework. RESULTS: Competing LCA, FA, and FMM models were fit to the data. On the basis of a set of goodness-of-fit criteria, a 'two-factor/three-class' factor mixture model provided the overall best fit to the data. This model describes ASD using three subgroups/classes (Class 1: 34%, Class 2: 10%, Class 3: 56% of the sample) based on differential severity gradients on the SCD and FIRB symptom dimensions. In addition to having different symptom severity levels, children from these subgroups were diagnosed at different ages and were functioning at different adaptive, language, and cognitive levels. CONCLUSIONS: Study findings suggest that the two symptom dimensions of SCD and FIRB proposed for the DSM 5 can be used in FMM to stratify children with ASD empirically into three relatively homogeneous subgroups.

A randomized clinical trial of the efficacy of extended smoking cessation treatment for adolescent smokers.

INTRODUCTION: Relatively few well-designed smoking cessation studies have been conducted with teen smokers. This study examined the efficacy of extended cognitive-behavioral treatment in promoting longer term smoking cessation among adolescents. METHODS: Open-label smoking cessation treatment consisted of 10 weeks of school-based, cognitive-behavioral group counseling along with 9 weeks of nicotine replacement (nicotine patch). A total of 141 adolescent smokers in continuation high schools in the San Francisco Bay Area were randomized to either 9 additional group sessions over a 14-week period (extended group) or 4 monthly smoking status calls (nonextended group). Intention-to-treat logistic regression analysis was used to assess the primary outcome of biologically confirmed (carbon monoxide < 9 ppm) point prevalence abstinence at Week 26 (6-month follow-up from baseline). RESULTS: At Week 26 follow-up, the extended treatment group had a significantly higher abstinence rate (21%) than the nonextended treatment (7%; OR = 4.24, 95% CI: 1.20-15.02). Females also were more likely to be abstinent at the follow-up than males (OR = 4.15, 95% CI: 1.17-14.71). CONCLUSIONS: The significantly higher abstinence rate at follow-up for the extended treatment group provides strong support for continued development of longer term interventions for adolescent smoking cessation.