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

项目摘要 来自中低收入国家(LMIC)的儿童中，每3人中就有1人以上存在认知障碍和罹患 由营养不良、免疫功能障碍、艾滋病毒和贫困相关寄生虫引起的神经认知障碍(ND) 感染。所有LMIC儿童--包括未接触艾滋病毒的未感染儿童(HUU)--都有感染ND的风险，但感染了HIV 和暴露于艾滋病毒的未感染(HEU)的风险较高。目前，还没有可靠的方法来分离 这些易受伤害的儿童在新发/进行性新城疫的风险连续体上。此问题会阻止 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 整合基于先前研究的严格识别的新城疫风险因素，以预测未来新的或进展性新城疫。 风险因素包括营养不良、免疫功能障碍和艾滋病毒状况。这些因素将结合在一起形成 CRI使用现代机器学习方法和来自已建立的队列的纵向数据 750名6-18岁的乌干达儿童(250名艾滋病毒感染者、250名HEU儿童和250名HUU儿童)。针对HEU和艾滋病毒感染者 这一指数将分别细化为CRI-HEU和CRI-HIV，以包括适用的产妇抗逆转录病毒治疗， 儿童的病毒基因组和购物车因子。 来自这个队列的初步数据表明，认知指数在12个人中差异很大 3个月的重新评估期。额外的初步数据显示，尽管HAART，慢性艾滋病毒感染作为 以及营养、免疫学和病毒基因组因素与执行功能缺陷有关， 心理社会适应和生活质量。我们现在建议遵循这个已经建立的队列，每隔一年 12个月收集0个月、12个月、24个月和36个月的额外数据，用于定义和验证CRI。CRI 将用于在随访期间预测新发/进展性ND。具体目标包括： 1.将营养、免疫参数和艾滋病毒状况的摄入量数据结合起来，制定CRI及其 相互作用，并在12个月时进行CRI作为ND预测因子的内部和外部验证。 2.进一步在内部和外部验证CRI对24至36个月的“超出时间窗口”的预测。 3.对于HEU和感染艾滋病毒的儿童，将CRI分别细化为CRI-HEU和CRI-HIV，包括 母亲ART的类型、病毒基因组参数、当前CART方案/依从性(如果适用)，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的预测指标，对HIV感染者、HEU或HUU的神经发育进行预测。 已发现的驱动这一指数的可修改因素可能成为新疗法的潜在靶点 减轻新城疫和/或手部感染艾滋病毒的高负担的策略和行为干预。

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.