Identifying Adolescents at High Risk of Neurocognitive Disorder: Development and Validation of a Composite Risk Index

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Project Summary More than 1 in 3 children from lower middle income countries (LMIC) are cognitively impaired and at risk of neurocognitive disorder (ND) due to malnutrition, immune dysfunction, HIV, and poverty-associated parasitic infections. All LMIC children – including HIV unexposed uninfected (HUU), are at risk of ND but HIV-infected and HIV-exposed uninfected (HEU) are at elevated risk. Presently, there is no reliable approach to separate these vulnerable children along the continuum of risk for new-onset/progressive ND. This problem prevents risk-stratification, timely identification and targeting of at-risk children for ND remediation or prevention interventions. This project solves these problems by defining and validating a composite risk index (CRI) that integrates rigorously identified ND risk factors based on prior research to predict future new or progressive ND. The risk factors include malnutrition, immune dysfunction and HIV status. These factors will be combined into the CRI using modern machine learning methods and longitudinal data available from established cohort of 750 Ugandan children age 6 – 18 years (250 PHIV, 250 HEU and 250 HUU). For HEU and HIV-infected children this index will be refined into CRI-HEU and CRI-HIV, respectively, to include applicable maternal ART, child's viral genome, and cART factors. Preliminary data from this cohort have demonstrated that cognitive indices vary significantly within the 12 months reassessment period. Additional preliminary data shows that despite HAART, chronic-HIV infection as well as nutritional, immunologic, and viral genome factors are associated with deficits in executive function, psychosocial adjustment, and quality of life. We now propose to follow this already established cohort every 12 months to collect additional data at 0, 12, 24 and 36 months to be used in defining and validating CRI. CRI will be used to predict new-onset/progressive ND during follow-up. Specific aims include: 1. To develop a CRI by combining intake data on nutrition, immune parameters and HIV status and their interactions and perform internal and external validation of CRI as predictor of ND at 12 months. 2. To further internally and externally validate CRI for “out-of-time-window” prediction from 24 to 36 months. 3. For HEU and HIV-infected children, to refine CRI into CRI-HEU and CRI-HIV, respectively, by including type of maternal ART, viral genome parameters, current cART regimen/adherence (as applicable), and their interactions. Overall Impact: This project advances the science needed to ensure that all children survive and thrive neurodevelopmentally whether HIV-infected, HEU, or HUU through establishment of predictive index for ND. Modifiable factors that are found to be driving this index can become potential targets for novel therapeutic strategies and behavioral interventions to mitigate the high burden of ND and/or HAND –if HIV infected.