帕金森病在症状表现和进展方面具有异质性。增加对这两个方面的了解可以更好地管理患者并改善临床试验设计。以前的帕金森病进展建模方法假设亚组内的静态进展轨迹,并没有充分说明复杂的药物效应。我们的目标是建立帕金森病的统计进展模型,该模型可解释个体内和个体间的变异性和药物作用。
在这项纵向数据研究中,我们从帕金森病进展标志物倡议(PPMI)纵向观察研究中收集了423例早期帕金森病患者和196例健康对照者长达7年的数据.应用对比潜在变量模型,然后应用新颖的个性化输入输出隐马尔可夫模型来定义疾病状态。使用统计测试对七个关键的运动或认知结果(轻度认知障碍,痴呆症,运动障碍,电机波动的存在,运动波动导致的功能障碍,Hoehn和Yahr得分,和死亡)在学习阶段不使用。结果在来自美国国家神经系统疾病和中风研究所帕金森病生物标志物计划(PDBP)的610名帕金森病患者的独立样本中得到验证。
PPMI数据于2018年7月25日下载,药物信息于2018年9月24日下载,PDBP数据于2020年6月15日至6月24日下载。该模型发现了八种疾病状态,主要通过功能损害来区分,震颤,运动迟缓,和神经精神病学措施。状态8,终端状态,关键临床结局的患病率最高,包括19例记录的痴呆病例中的18例(95%).在研究开始时,333名患者中有4名(1%)处于状态8,333名患者中有138名(41%)在第5年达到第8阶段。然而,起始状态的排名与5年内达到状态8的排名不匹配。总的来说,从状态5开始的患者至终末期的时间最短(中位数2·75[95%CI1·75-4·25]年).
我们开发了早期帕金森病的统计进展模型,该模型考虑了个体内和个体间的变异性和药物作用。我们的预测模型发现了非连续的,重叠的疾病进展轨迹,支持使用非确定性疾病进展模型,并提示静态亚型分配在捕获帕金森病进展的全谱时可能无效。
迈克尔·J·福克斯基金会。
Parkinson\'s disease is heterogeneous in symptom presentation and progression. Increased understanding of both aspects can enable better patient management and improve clinical
trial design. Previous approaches to modelling Parkinson\'s disease progression assumed static progression trajectories within subgroups and have not adequately accounted for complex medication effects. Our objective was to develop a statistical progression model of Parkinson\'s disease that accounts for intra-individual and inter-individual variability and medication effects.
In this longitudinal data
study, data were collected for up to 7-years on 423 patients with early Parkinson\'s disease and 196 healthy controls from the Parkinson\'s Progression Markers Initiative (PPMI) longitudinal observational
study. A contrastive latent variable model was applied followed by a novel personalised input-output hidden Markov model to define disease states. Clinical significance of the states was assessed using statistical tests on seven key motor or cognitive outcomes (mild cognitive impairment, dementia, dyskinesia, presence of motor fluctuations, functional impairment from motor fluctuations, Hoehn and Yahr score, and death) not used in the learning phase. The results were validated in an independent sample of 610 patients with Parkinson\'s disease from the National Institute of Neurological Disorders and Stroke Parkinson\'s Disease Biomarker Program (PDBP).
PPMI data were download July 25, 2018, medication information was downloaded on Sept 24, 2018, and PDBP data were downloaded between June 15 and June 24, 2020. The model discovered eight disease states, which are primarily differentiated by functional impairment, tremor, bradykinesia, and neuropsychiatric measures. State 8, the terminal state, had the highest prevalence of key clinical outcomes including 18 (95%) of 19 recorded instances of dementia. At
study outset 4 (1%) of 333 patients were in state 8 and 138 (41%) of 333 patients reached stage 8 by year 5. However, the ranking of the starting state did not match the ranking of reaching state 8 within 5 years. Overall, patients starting in state 5 had the shortest time to terminal state (median 2·75 [95% CI 1·75-4·25] years).
We developed a statistical progression model of early Parkinson\'s disease that accounts for intra-individual and inter-individual variability and medication effects. Our predictive model discovered non-sequential, overlapping disease progression trajectories, supporting the use of non-deterministic disease progression models, and suggesting static subtype assignment might be ineffective at capturing the full spectrum of Parkinson\'s disease progression.
Michael J Fox Foundation.