Identifying adolescents at high risk of neurocognitive disorder: Development and validation of a composite risk index

项目概要 超过三分之一的中低收入国家 (LMIC) 儿童存在认知障碍并面临认知障碍风险 由于营养不良、免疫功能障碍、艾滋病毒和贫困相关寄生虫而导致的神经认知障碍 (ND) 感染。所有中低收入国家儿童——包括未暴露于艾滋病毒但未感染艾滋病毒的儿童 (HUU)，均面临 ND 风险，但已感染艾滋病毒 暴露于 HIV 的未感染者 (HEU) 的风险较高。目前还没有可靠的方法来分离 这些弱势儿童处于新发/进行性 ND 风险的连续体中。这个问题可以防止 风险分层，及时识别和针对高危儿童进行ND补救或预防 干预措施。该项目通过定义和验证综合风险指数 (CRI) 来解决这些问题，该指数 整合基于先前研究的严格确定的 ND 风险因素，以预测未来新的或进行性 ND。 危险因素包括营养不良、免疫功能障碍和艾滋病毒感染状况。这些因素将被综合起来 CRI 使用现代机器学习方法和从已建立的队列中获得的纵向数据 750 名 6 至 18 岁乌干达儿童（250 名 PHIV、250 名 HEU 和 250 名 HUU）。对于 HEU 和 HIV 感染者 儿童 该指数将分别细化为 CRI-HEU 和 CRI-HIV，以包括适用的孕产妇 ART、 儿童的病毒基因组和 cART 因素。 该队列的初步数据表明，认知指数在 12 个类别中存在显着差异。 个月的重新评估期。额外的初步数据表明，尽管进行了高效抗逆转录病毒疗法（HAART），慢性艾滋病毒感染仍 以及营养、免疫和病毒基因组因素与执行功能缺陷相关， 心理社会调整和生活质量。我们现在建议每年跟踪这个已经建立的队列 12 个月的时间收集 0、12、24 和 36 个月的额外数据，用于定义和验证 CRI。显色指数 将用于预测随访期间新发/进行性 ND。具体目标包括： 1. 通过结合营养、免疫参数和艾滋病毒状况及其相关摄入数据来制定 CRI 相互作用，并对 CRI 作为 12 个月 ND 的预测因子进行内部和外部验证。 2. 进一步对 CRI 的 24 至 36 个月“跨时间窗口”预测进行内部和外部验证。 3. 对于HEU和HIV感染儿童，将CRI分别细化为CRI-HEU和CRI-HIV，包括 母体 ART 类型、病毒基因组参数、当前 cART 治疗方案/依从性（如适用），以及 他们的互动。 总体影响：该项目推进了确保所有儿童生存和成长所需的科学 通过建立 ND 预测指数，对神经发育是否感染 HIV、HEU 或 HUU 进行评估。 被发现驱动该指数的可修改因素可以成为新型治疗的潜在目标 减轻 ND 和/或 HAND（如果感染了 HIV）的高负担的策略和行为干预措施。

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.