Newborn screening research sponsored by the NIH: From diagnostic paradigms to precision therapeutics.

Newborn screening (NBS) is a successful public health initiative that effectively identifies pre-symptomatic neonates so that treatment can be initiated before the onset of irreversible morbidity and mortality. Legislation passed in 2008 has supported a system of state screening programs, educational resources, and an evidence-based review process to add conditions to a recommended universal newborn screening panel (RUSP). The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH, has promoted NBS research to advance legislative goals by supporting research that will uncover fundamental mechanisms of disease, develop treatments for NBS disorders, and promote pilot studies to test implementation of new conditions. NICHD's partnerships with other federal agencies have contributed to activities that support nominations of new conditions to the RUSP. The NIH's Newborn Sequencing In Genomic Medicine and Public Health (NSIGHT) initiative funded research projects that considered how genomic sequencing could be integrated into NBS and its ethical ramifications. Recently, the workshop, "Gene Targeted Therapies: Early Diagnosis and Equitable Delivery," has explored the possibility of expanding NBS to include genetic diagnosis and precision, gene-based therapies. Although hurdles remain to realize such a vision, broad engagement of multiple stakeholders is essential to advance genomic medicine within NBS.

Studying the emergence of autism spectrum disorders in high-risk infants: methodological and practical issues.

Detecting early signs of autism is essential for timely diagnosis and initiation of effective interventions. Several research groups have initiated prospective studies of high-risk populations including infant siblings, to systematically collect data on early signs within a longitudinal design. Despite the potential advantages of prospective studies of young children at high-risk for autism, there are also significant methodological, ethical and practical challenges. This paper outlines several of these challenges, including those related to sampling (e.g., defining appropriate comparison groups), measurement and clinical implications (e.g., addressing the needs of infants suspected of having early signs). We suggest possible design and implementation strategies to address these various challenges, based on current research efforts in the field and previous studies involving high-risk populations.

Validity of the autism diagnostic interview-revised.

The factor structure, internal consistency, and convergent validity of the Autism Diagnostic Interview-Revised (ADI-R) algorithm items were examined in a sample of 226 youngsters with pervasive developmental disabilities. Exploratory factor analyses indicated a three-factor solution closely resembling the original algorithm and explaining 38% of the variance, with one significant discrepancy: Unlike the algorithm, all nonverbal communication items were associated with the Social factor. Internal consistencies of domain scores ranged from .54 to .84. Correlations between ADI-R domain and total scores and instruments assessing adaptive behavior, psychopathology, and autism were examined. They indicated some similarities between constructs, but also that the ADI-R measures autism in a unique fashion.

Early development in males with Fragile X syndrome: a review of the literature.

This article reviews the current bibliographic knowledge on early neurobehavioral development and milestones in Fragile X syndrome (FraX), with emphasis on males affected by the condition. Three broad areas of early development were examined: (1) gross and fine motor, (2) speech and language, and (3) social. The result of the current review indicates very limited information on the developmental milestones in all three areas. The scarce literature on motor development shows that in FraX there is an early developmental delay. Research on speech and language demonstrates pervasive deficits in conversational skills and severe developmental delay, with increasing discrepancy between language level and chronological age in young males with FraX. Finally, deficits in social development in FraX include abnormal gaze, approach and avoidance conflict, and high incidence of autistic spectrum disorders.

Social behavior profile in young males with fragile X syndrome: characteristics and specificity.

The present study characterizes distinctive and specific features of social behavior impairment, termed social behavior profile (SBP), in young males with fragile X syndrome (FraX). Fourteen males with FraX and autism (FraX+Aut), ages 3-8 years, were compared with either 41 FraX boys without autism (Aut), 7 age-matched males with developmental language delay and autism (DLD+Aut), or with 11 boys with non-selected (for language delay) idiopathic autism (IA), on several standardized instruments assessing social behavior and autistic features (i.e., autism diagnostic interview-revised, ADI-R). We found that FraX+Aut subjects displayed more impairment in overall cognition, problem/aberrant behavior, and adaptive behavior than the rest of the FraX cohort, even when individuals with pervasive developmental disorder (PDD) were included in the latter. Compared to both DLD+Aut and IA, FraX+Aut males were less impaired in ADI-R reciprocal social interaction (RECS) domain. However, boys with FraX+Aut were in general comparable to DLD+Aut subjects in problem/aberrant and adaptive behaviors. Based on the contrast between FraX+Aut and non-autistic FraX and DLD+Aut, we were able to identify measures (e.g., child behavior checklist (CBCL) withdrawn subscale) that better define social interaction impairment in FraX. Comparisons with DLD+Aut and IA led to the conclusion that communication impairment (COMM) and stereotypic behavior contribute relatively more to the diagnosis of autism in FraX+Aut. In agreement with recent studies, our data suggest that FraX+Aut, and more generally SBP, is a distinctive subphenotype among boys with FraX, which may share some pathophysiological mechanisms with IA.

Autism spectrum disorder in fragile X syndrome: communication, social interaction, and specific behaviors.

The present study extends our previous work on social behavior impairment in young males with fragile X syndrome (FraX). Specifically, we evaluated whether the autistic phenomenon in FraX is expressed as a range of behavioral impairments as in idiopathic autism (Aut). We also examined whether there are behaviors, identified as items of the Autism Diagnostic Interview-Revised (ADI-R), that in FraX predispose to or differentiate subjects with autism spectrum disorder (ASD) diagnosis. Finally, regression models were utilized to test the relative contribution of reduced communication and socialization skills to ADI-R scores and diagnoses. A cohort of 56 boys (3-8 years) with FraX was examined in terms of scores on measures of cognition (IQ was a co-variate in most analyses.), autistic behavior, problem/aberrant behavior, adaptive behavior, and language development. We found that, indeed, in terms of problem behavior and adaptive skills, there is a range of severity from FraX + Aut to FraX + PDD (Pervasive Developmental Disorder) to FraX + none. ADI-R items representing "Play" types of interaction appear to be "susceptibility" factors since they were abnormal across the FraX cohort. Integrated regression models demonstrated that items reflecting complex social interaction differentiated the FraX + ASD (Aut + PDD) subgroup from the rest of the FraX cohort, while abnormalities in basic verbal and non-verbal communication distinguished the most severely affected boys with FraX + Aut from the milder FraX + PDD cohort. Models incorporating language, adaptive communication, and adaptive socialization skills revealed that socialization was not only the main influence on scores but also a predictor of ASD diagnosis. Altogether, our findings demonstrate that the diagnosis of ASD in FraX reflects, to a large extent, an impairment in social interaction that is expressed with variable severity in young males with FraX.