Psychometric validation of the NIH Toolbox for use with individuals with phenylketonuria: Evidence from the PHEFREE...

Recent advancements in the development of novel therapies to treat phenylketonuria (PKU) have fueled a call for new assessment tools that are sensitive to PKU-related neurocognitive disruptions. The present study evaluated the NIH Toolbox, a computer-administered battery of neurobehavioral measures, for assessing cognitive function in children and adults with early-treated PKU.

Data were examined from 91 individuals with PKU (aged 8-55 years) enrolled in an ongoing NIH-funded longitudinal study of hyperphenylalaninemia. Participants completed the NIH Toolbox as well as several validation instruments including the Wechsler Abbreviated Scale of Intelligence-Second Edition, Cambridge Neuropsychological Test Automated Battery (CANTAB), and Conners' Continuous Performance Test.

Consistent with prior research, crystallized cognition was intact in both children and adults. In contrast, fluid cognition deficits were observed primarily in younger children while older children and adults generally performed within expectations. NIH Toolbox composite scores demonstrated strong concurrent validity with Wechsler indices and moderate correlations with other established measures.

The NIH Toolbox shows promise as a valid and practical measure of neurocognitive function in PKU, supporting its potential integration into clinical trials and research protocols. Future research should prioritize longitudinal designs to assess test-retest reliability, sensitivity to change, and subgroup differences related to treatment modalities. Ongoing efforts, such as the PHEFREE consortium, will be critical for establishing the NIH Toolbox as a robust outcome measure for PKU intervention studies.