Neurodevelopmental and Behavioral Phenotyping

National Institute Of Mental Health

Investigators

Linked publications & trials

Abstract

The Neurodevelopmental and Behavioral Phenotyping Service conducts neurodevelopmental assessments on participants enrolled in NIH research protocols, and provides resources for protocol development, data analysis, and dissemination of neurodevelopmental assessment research data. NBPS 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 participants into a protocol that includes behavioral assessments (NCT00271622) and a collaborative protocol that provides assessment of specific rare genetic conditions (NCT02461420). 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 contribute to the development and implementation of treatment studies, including those testing novel therapeutic agents and gene therapy in ultra-rare genetic conditions. Finally, we provide consultation evaluations to studies which enroll patients with neurodevelopmental disorders, but which are not primarily targeting neurodevelopmental constructs. These evaluations may be necessary to diagnosis and provide services to patients whose neurodevelopmental disorders may otherwise interfere with their participation in research on potentially lifesaving experimental therapies. 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. Clarification of symptom profiles is paramount in considering the need for potential treatment targets and appropriate outcome measures. Differentiation of intellectual disability and ASD can be difficult because both conditions are associated with support needs in similar areas (e.g., social and communication skills). 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 engage in 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. Our collection of data builds on existing research by informing our understanding of how diagnostic measures function over time, and of how measurements differ within specific genetic disorders across differing impairment levels. We are also testing newly updated versions of tests to understand various psychometric properties, focusing particularly on the analysis of 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. While the potential for a better understanding of specific behavioral phenotypes has never been greater, the rare genetic conditions studied through this service are overly represented among individuals with developmental disabilities, and intellectual/developmental disability is the predominant phenotype for the majority of the individuals. While there are many available tools for measuring components of the phenotypes 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, especially in light of the growing number of clinical trials examining neurodevelopmental outcomes. 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 critical component of intellectual disability, 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. We are also exploring ways this metric can be clinically useful when children receive repeated evaluations. In addition to improving uses of existing measures, we also engage in measurement development, including the development and use of innovative modalities to reduce barriers to the inclusion of people with ID into research. 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. Finally, since the onset of the COVID-19 pandemic, we have contributed to studies examining the effects of COVID-19 and the pandemic on children's neurodevelopment, including an NIH intramural study, by providing guidance on inclusion and analysis.