Neurodevelopmental and Behavioral Phenotyping

National Institute Of Mental Health

Investigators

Linked publications, trials & patents

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 to the NIH intramural research community as well as to extramural researchers. 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), a collaborative protocol that provides assessment of specific rare genetic conditions (NCT02461420), and a protocol to evaluate the psychometric performance of an existing cognitive measure for use in individuals with intellectual disabilities. In addition, we contribute to several other studies that are conducting behavioral phenotyping of conditions that have yet to have their natural histories fully explored. These characterization studies are helping the field understand the breadth and depth of syndromes that cause lifelong impairments, based on developmental delays that often lead to Intellectual Disability and Autism Spectrum Disorder. This work has allowed us to contribute to the development and implementation of treatment studies, including those testing novel therapeutic agents and gene therapy in ultra-rare genetic conditions. Our work takes advantage of gains made “phenotype first” studies that have identified 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 in “genotype first” studies. 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. Work on developmental milestone attainment differences in subpopulations has found that specific early delays are important markers for predicting genetic abnormalities in children who go on to have established neurodevelopmental diagnoses. From a genotype-first perspective, our work has demonstrated that abnormalities in developmental milestones are implicated across many different genetic conditions. Further, these developmental milestones are consistently ranked among the most important functional impairments by parents of children with these genetic conditions. Taken together, this suggests that developmental milestones are key characteristics to inform neurodevelopmental phenotyping and for potential use as treatment outcomes. 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, and conducting qualitative research to ensure these symptoms are prioritized as treatment targets in patients and families are both paramount in considering appropriate outcome measures. 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. 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. 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. Measures for neurodevelopmental constructs that are widely available 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. Thus, we are testing how different tests work in these populations, including 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. For instance, since we know impairments in adaptive behavior are a critical component of intellectual disability and important to families, it 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 measures with innovative modalities to reduce barriers to the inclusion of people with Intellectual Disability 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 that focuses on the ability to match based on one or more concepts. 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 non-standardized usage of existing measures. In all of our work, we strive to embody the concepts of patient-focused drug development, to ensure that patients’ experiences, perspectives, needs, and priorities are meaningfully incorporated into the drug evaluation process and all research.