Neurodevelopmental and Behavioral Phenotyping

National Institute Of Mental Health

Investigators

Linked publications & trials

Abstract

The Neurodevelopmental and Behavioral Phenotyping Service provides a resource to the NIH Clinical Center, as well as to specific NIH research projects, by conducting neurodevelopmental assessments on participants enrolled in NIH research protocols. Assessments provide data on a variety of rare genetic conditions associated with neurodevelopmental disorders, such as Intellectual Disability and Autism Spectrum Disorder (ASD). The service enrolls patients into a protocol that includes behavioral assessments (NCT00271622) and a collaborative protocol that provides assessment of specific rare genetic conditions (NCT02461420), which includes an additional focus on studying adults with such conditions as well as children (NCT03426059). In addition, we participate in several other studies that are conducting behavioral phenotyping of conditions that have yet to have their natural histories fully explored. These characterization studies are necessary for understanding the breadth and depth of syndromes that cause lifelong impairments, based on developmental delays that often lead to Intellectual Disability and Autism Spectrum Disorder . We also continue to be involved in treatment studies, including those testing novel therapeutic agents and gene therapy in ultra-rare genetic conditions. Related to these efforts, we seek to take advantage of gains made in identification of genetic abnormalities in those already diagnosed with ASD or Intellectual Disability, by exploring whether genotypic differences may be reflected in behavioral phenotype differences among children diagnosed with these conditions. Our explorations of data previously collected through the NIMH intramural research program, as well as from several large-scale repositories and epidemiologic studies continue to produce novel findings about the onset and longitudinal course of neurodevelopmental disorders. We have focused on developmental milestone attainment differences in subpopulations, finding specific early delays are important markers for predicting genetic abnormalities in children who go on to have established neurodevelopmental diagnoses. We have continued our efforts to better describe the differentiation or additive effects of Intellectual Disability and ASD profiles within rare genetic conditions, given the implications of these diagnoses on lifelong disability and the need for potential treatment targets and appropriate outcome measures. Our collection of data is building on the work of research on existing standardized autism diagnostic instruments by analyzing data on how these measures function over time, and on how measurements differ within specific genetic disorders. We are also testing out newly updated versions of tests with different psychometric properties, to analyze their more fine-grained data for the detection of potential changes in skills over time. We also recognize that our psychometric work may be synergistic with the search for biomarkers, which hold great promise for intervention research. Thus, we have integrated into our research program several studies of putative biomarkers, with modalities including electrophysiology and neuroimaging. The potential for a better understanding of psychiatric disorders by fuller descriptions of specific behavioral phenotypes has never been greater. However, rare genetic conditions are overly represented among individuals with developmental disabilities, and intellectual/developmental disability is the predominant phenotype for the majority of the individuals evaluated through the service. While there are many available tools for many components of the phenotype in which we are interested, such as cognitive and social-communication skills, they are often not appropriate for use in the populations studied. Thus, our ability to describe the phenotype of these disorders is limited by the precision and validity with which we are able to measure the constituent behaviors. We recognize our responsibility to rectify this urgent unmet need. We have worked on these longstanding measurement concerns in both theoretical and applied ways. Leveraging our access to samples of interest, we have produced several rigorous psychometric evaluations of common measures. We select these measures based not only on their wide-spread use, but also on clinical experiences which suggest they may be flawed, and on their potential for use as outcome measures in clinical trials. Such work has included studies of measures in populations not represented in validation samples and of non-standardized usage of existing measures. For instance, impairment in adaptive behavior is a criterion for diagnosis of intellectual disability in both the DSM and ICD systems, reflecting its usefulness in quantifying individual functioning. As such, adaptive behavior is increasingly an outcome of interest in the study of neurodevelopmental disabilities. We have engaged in extensive theoretical and empirical investigation of the psychometric properties of person-ability scores, a metric used in specific measures, which may be especially useful as an outcome measure in clinical trials aiming to show maximal sensitivity to potential changes in skill development. Another area of methodologic and theoretical focus for our group is the differentiation of intellectual disability and ASD, an issue that has plagued the field since ASD was first described. This occurs because some symptoms of ASD social and communication skills which are less developed than peers are also observed in intellectual disability. In intellectual disability the impaired skills are commensurate with the overall developmental level, whereas in ASD they are a relative weakness, so differentiation depends wholly on thorough assessment and a nuanced understanding of the presentation of ASD in the context of intellectual disability. The range of samples to which we have access, from those ascertained due to risk or diagnosis of idiopathic ASD to those enrolled with extremely rare multi-systemic genetic conditions that greatly impact the CNS, affords us a special ability to produce both conceptual and practical contributions to this work. We have produced or been involved with a number of projects illustrating the impact of intellectual disability on the measurement of ASD symptoms as well as general evaluations of the psychometric properties of common ASD diagnostic instruments in intellectual disability. In addition to improving uses of existing measures, we also engage in measurement development, including the use of innovative modalities. This is especially important since many of the research participants we evaluate are not able to obtain a standard score on a cognitive measure normed for their age range, due to the severity of their cognitive impairments Many also have ancillary motor or receptive language impairments that make traditional cognitive tests challenging beyond their cognitive impairment. We have evaluated novel measures, such as the tablet-based NIH Toolbox Cognitive Battery, a set of tasks initially developed for use in normative populations. We have piloted this measure on specific groups -to provide data on performance in populations with intellectual disability. We also directly collaborate on a test for inclusion in a new version of this tool intended for infants and toddlers. This new subtest taps into concept formation, a critical prerequisite skill that has been studied extensively as a precursor to what is commonly described as nonverbal intelligence. Finally, since the onset of the COVID-19 pandemic, we have contributed to several ongoing studies examining the effects of COVID-19 and the pandemic itself on childrens neurodevelopment, including an NIH intramural study, by providing guidance on inclusion of measures for neurodevelopmental outcomes.