This Mentored Patient-Oriented Career Development Award (K23) will facilitate Dr. Leikauf?s development into an independent researcher and child psychiatrist. It will provide the foundation for him to meaningfully improve strategies for cost-effective personalization of care for ADHD and related emotional disorders in diverse practice settings through a deeper understanding of the underlying phenotypic heterogeneity of these disorders. Attention-Deficit/Hyperactivity Disorder (ADHD) is highly prevalent and functionally impairing, yet phenotypically heterogeneous. Despite the complexity of the phenotype, the diagnosis is most often made using DSM-based behavioral symptom rating scales during short visits in busy pediatric settings. Additionally, current treatments are widely used but have not been demonstrated to improve functional outcomes. Currently, treatment selection involves significant trial-and-error based on caregiver?s subjective report of symptomatic improvement. Cost-effective, objective measures that would aid in personalized treatment selection and address the full range of dysfunction for children with ADHD are critically needed. The heterogeneity of the disorder has limited the development of such tools. Until now, the field has relied on subtypes that have limited validity and are based exclusively on symptom rating scales. Recent developments in our ability to collect and analyze multidimensional data for individual subjects provide a new opening for progress in this crucial area. The project will use two multi-dimensional datasets from completed clinical trials as well as generate data from a smaller, prospective study. The anticipated outcomes are as follows: 1) identification of more phenotypically homogeneous groups of children with ADHD at baseline 2) identification of more homogeneous groups based on creating a multivariate classifier informed by mechanistic response to treatment, and 3) validation of classification schema. Dr. Leikauf?s specific training goals, in collaboration with his mentorship team, include acquisition of knowledge, experience, and skills in the following areas relevant to the proposed work: 1) modern machine-learning statistical techniques that allow reliable inferences to be drawn from high dimensional data with non-linear relationships between variables; 2) mentored experience conducting a multi- method/multi-dimensional prospective study with the goal of identifying personalized therapeutic targets 3) additional translational research/clinical experience to understand what is currently known about ADHD and its relationship to cognitive dysfunction including working memory, sustained attention, and response inhibition, and 4) training in acquisition and analysis of EEG. The results should have immediate clinical impact and provide the foundation for a future prospective personalized therapeutics trial. The experiences in this proposal, if awarded, will also develop Dr. Leikauf?s abilities and thereby enable him to have a fundamental impact on mental health treatment for children and adolescents.
The proposed research is relevant to public health because Attention-Deficit/Hyperactivity Disorder affects at least 5% of children, resulting in significant psychosocial impairment and predisposing children to very high rates of later psychiatric disorders. However, current treatments do not work for all children, do little to improve long-term functional outcomes, and, in practice, are discontinued by approximately half of families within 1-3 years due to poor tolerability or perceived lack of long-term efficacy. Personalized targeting of treatments to maximize benefit and minimize harms for each individual is urgently needed but has been stymied by our limited understanding of the heterogeneous relationships between self-report, cognitive, and physiologic measures of the symptoms of the disorder; this proposal aims to use modern computational approaches to integrate information across these different measures in order to identify more homogeneous ADHD subtypes based in neurologic and cognitive deficits rather than self-report.
