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）的三分之一以上的儿童存在认知障碍， 神经认知障碍（ND）由于营养不良，免疫功能障碍，艾滋病毒，和贫困相关的寄生虫 感染.所有LMIC儿童-包括未暴露于HIV的未感染者（HUU），都有ND的风险，但HIV感染 而未感染艾滋病毒的人则面临更高的风险。目前，没有可靠的方法来分离 这些脆弱的儿童沿着新发/进行性ND的风险连续体。这个问题防止 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复合风险指数（CRI）来解决这些问题， 根据先前的研究整合了严格确定的ND风险因素，以预测未来新的或进行性ND。 风险因素包括营养不良、免疫功能障碍和艾滋病毒感染状况。这些因素将结合在一起， 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岁的乌干达儿童（250名艾滋病毒感染者、250名高浓缩铀和250名胡亚基）。高浓缩铀和艾滋病毒感染者 这一指数将分别细化为CRI-HEU和CRI-HIV，以包括适用的孕产妇抗逆转录病毒疗法， 儿童病毒基因组和cART因子。 该队列的初步数据表明，认知指数在12个年龄组中差异显著。 个月的重新评估期。额外的初步数据显示，尽管有HAART， 以及营养、免疫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。我们现在建议按照这个已经建立的队列， 12个月，用于在0、12、24和36个月时收集用于定义和验证CRI的额外数据。CRI 将用于预测随访期间新发/进展性ND。具体目标包括： 1.结合营养、免疫参数和艾滋病毒状况的摄入量数据， 相互作用，并在12个月时对CRI作为ND的预测因子进行内部和外部验证。 2.进一步在内部和外部验证CRI在24至36个月的“超时窗”预测。 3.对于高浓缩铀和感染艾滋病毒的儿童，将CRI分别细化为CRI-HEU和CRI-HIV，包括 母体ART类型、病毒基因组参数、当前cART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茁壮成长所需的科学 通过建立ND的预测指标，从神经发育方面评估是否为HIV感染、HEU或HUU。 发现驱动该指数的可修饰因子可以成为新的治疗药物的潜在靶点。 策略和行为干预，以减轻ND和/或HAND的高负担-如果HIV感染。

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.