Department of Biostatistics, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, United States of America.
Clinical Research Unit, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, United States of America.
PLoS One. 2024 May 16;19(5):e0302381. doi: 10.1371/journal.pone.0302381. eCollection 2024.
As people age, their ability to maintain homeostasis in response to stressors diminishes. Physical frailty, a syndrome characterized by loss of resilience to stressors, is thought to emerge due to dysregulation of and breakdowns in communication among key physiological systems. Dynamical systems modeling of these physiological systems aims to model the underlying processes that govern response to stressors. We hypothesize that dynamical systems model summaries are predictive of age-related declines in health and function. In this study, we analyze data obtained during 75-gram oral-glucose tolerance tests (OGTT) on 1,120 adults older than 50 years of age from the Baltimore Longitudinal Study on Aging. We adopt a two-stage modeling approach. First, we fit OGTT curves with the Ackerman model-a nonlinear, parametric model of the glucose-insulin system-and with functional principal components analysis. We then fit linear and Cox proportional hazards models to evaluate whether usual gait speed and survival are associated with the stage-one model summaries. We also develop recommendations for identifying inadequately-fitting nonlinear model fits in a cohort setting with numerous heterogeneous response curves. These recommendations include: (1) defining a constrained parameter space that ensures biologically plausible model fits, (2) evaluating the relative discrepancy between predicted and observed responses of biological interest, and (3) identifying model fits that have notably poor model fit summary measures, such as [Formula: see text], relative to other fits in the cohort. The Ackerman model was unable to adequately fit 36% of the OGTT curves. The stage-two regression analyses found no associations between Ackerman model summaries and usual gait speed, nor with survival. The second functional principal component score was associated with faster gait speed (p<0.01) and improved survival (p<0.01).
随着年龄的增长，人们应对压力源的体内平衡能力会下降。身体脆弱，是一种对压力源的弹性丧失的综合征，被认为是由于关键生理系统之间的调节和通信中断而出现的。这些生理系统的动态系统建模旨在对控制对压力源的反应的基本过程进行建模。我们假设动态系统模型摘要可预测与年龄相关的健康和功能下降。在这项研究中，我们分析了来自巴尔的摩老龄化纵向研究的 1120 名年龄在 50 岁以上的成年人进行的 75 克口服葡萄糖耐量测试（OGTT）的数据。我们采用两阶段建模方法。首先，我们使用 Ackerman 模型（葡萄糖-胰岛素系统的非线性参数模型）和功能主成分分析拟合 OGTT 曲线。然后，我们拟合线性和 Cox 比例风险模型，以评估通常的步行速度和存活率是否与第一阶段模型摘要相关。我们还为在具有许多异质响应曲线的队列环境中识别不合适的非线性模型拟合提出了建议。这些建议包括：（1）定义一个约束参数空间，以确保生物上合理的模型拟合；（2）评估预测和观察到的感兴趣的生物反应之间的相对差异；（3）识别具有明显较差的模型拟合摘要度量（例如，[公式：见文本]）的模型拟合，与队列中的其他拟合相比。Ackerman 模型无法充分拟合 36%的 OGTT 曲线。第二阶段回归分析发现 Ackerman 模型摘要与通常的步行速度或存活率之间没有关联。第二个功能主成分得分与较快的步行速度（p<0.01）和改善的存活率（p<0.01）相关。
