Precision Medicine in Pediatric Attention-deficit/Hyperactivity Disorder: A Systematic Review of Behavioral, Neurobiological and Genetic Diagnostic Biomarkers

OBJECTIVE: Attention-deficit/hyperactivity disorder (ADHD) is one of the most common childhood psychiatric disorders and a common presenting concern in primary and developmental pediatric care. However, objective diagnostic tools are currently not available, leading to delayed and missed diagnoses. The current systematic review aimed to determine whether objective indices can serve as diagnostic markers for pediatric ADHD. METHOD: We conducted a systematic review of objective behavioral, neurobiological, and genetic biomarkers that could inform a precision medicine approach to diagnosis of pediatric ADHD. Following the PRISMA guidelines, we searched three major databases (MEDLINE, PsycInfo, and Scopus) for articles published between 2012 and 2024 that evaluated diagnostic biomarkers with a translational aim. RESULTS: A total of 111 studies met inclusion criteria, including 42 behavioral, 44 neuroimaging, and 25 genetic studies. Among behavioral studies, measures of physical activity achieved discriminant validity in the good to excellent range. Neuroimaging biomarkers were strongest when machine learning and multiple-features models were used. A particularly promising direction involved task-based NIRS paradigms targeting cognitive control. The results of the genetic studies underscored the complexity of the genetic architecture of ADHD, implicating rare and common variants, as well as epigenetic mechanisms. MicroRNA and methylation profiles demonstrated the strongest accuracy, overall. CONCLUSION: Our systematic review identified promising candidate diagnostic markers for ADHD across behavioral, neuroimaging, and genetic methods. Multimethod approaches are likely to yield the strongest diagnostic accuracy. The complexity and cost of these approaches limits potential for implementation of a precision medicine approach to pediatric ADHD diagnosis in primary care settings.