The risk of dementia, disease progression and its impact on survival

研究数据：檀香山心脏计划（HHP）是一项关于心脏病和中风的前瞻性研究，涉及1900年至1919年出生的日裔美国男性队列。在1965年（EX 1）、1968年至1970年（EX 2）和1971年至1974年（EX 3）的三次中年检查（EX）期间收集临床和人口统计学信息。 作为HHP的扩展，檀香山亚洲老龄化研究（哈斯）于1991年开始，研究痴呆症的患病率，发病率和风险因素。在第一次哈斯考试（考试4），3,734名成员的HHP队列（80%的幸存者）参加。 随后在1994年（EX 5）、1996-1997年（EX 6）和1999-2000年（EX 7）使用多步骤程序进行了痴呆症的随访检查。 使用100分认知能力筛查仪（CASI）对整个样本进行筛查。CASI是一种跨文化验证的全球认知功能测试，旨在用于美国和日本的痴呆症比较研究。在实施例4中，使用CASI评分和年龄来鉴定参与者的亚组以进行痴呆评估。在随访检查中，CASI评分低于教育调整的临界点（低教育参与者为77分，高教育参与者为79分）或绝对下降至少9分的受试者被纳入特定痴呆检查的亚组。 符合痴呆标准的受试者接受神经成像和血液检查以诊断痴呆亚型。研究神经学家和至少两名其他具有老年病和痴呆症专业知识的医生达成了共识诊断。我们使用了截至2002年6月20日的死亡数据。 在EX 4的3，734名参与者中，有226人被诊断患有痴呆症，他们被称为流行病例。 分别有135、112和52例在EX 5、6和7诊断的痴呆病例。 研究1：估计特定年龄的痴呆率和痴呆对生存的影响。 总结：早期的工作讨论了痴呆的年龄特异性发病率。然而，以前的方法要么简单地将死亡视为删失，要么不包括任何协变量。提出了一个生存数据具有区间删失和左截断的疾病-死亡模型。这种方法可以包括与痴呆发作和死亡相关的风险因素，并允许半马尔可夫模型，其中痴呆后的生存可能取决于痴呆发作年龄。该模型可用于估计在存在竞争性死亡风险的情况下发生痴呆的累积风险。我们将这种方法应用于痴呆数据，以估计痴呆事件的年龄特异性和累积风险，并检查主要危险因素对痴呆发作和死亡的影响。 根据分析，我们发现患有痴呆症和早发痴呆症都显著增加死亡率。痴呆症的死亡风险增加了7.9倍。 研究2：死亡情况下认知轨迹和痴呆风险的联合建模 摘要：我们使用贝叶斯变点模型来拟合痴呆患者和正常老年人的认知功能轨迹。在真实的生活中，老年人易受两种竞争事件的影响，例如，痴呆和无痴呆的死亡。大多数人不会患痴呆症。在这篇文章中，我们使用了一个混合模型来拟合生存数据与竞争风险，包括痴呆症患者认知功能变化点后的痴呆发作时间和非痴呆症患者的死亡时间。 认知轨迹和生存过程的联合建模和参数估计使用马尔可夫链蒙特卡罗方法。使用来自哈斯的数据，我们显示了认知功能的轨迹和几个主要协变量的影响。 基于分析，我们发现，对于健康的老年受试者，CASI评分从70岁时的90分逐渐下降到95岁时的60分左右。对于痴呆受试者，加速下降的变化点分别为72岁和84岁，分别为较低和较高教育水平的受试者。 对于受教育程度较高的受试者，认知能力下降的加速发生较晚，但速度比受教育程度较低的受试者快。 这一发现与认知储备理论相一致。在95岁时，所有的痴呆症受试者都有相似的认知功能，无论教育水平如何。

Study Data: The Honolulu Heart Program (HHP) is a prospective study of heart disease and stroke involving a cohort of Japanese-American men born between 1900 and 1919. Clinical and demographic information were collected during three midlife examinations (EX) in 1965 (EX1), 1968 through 1970 (EX2), and 1971 through 1974 (EX3). As an extension of the HHP, the Honolulu Asia Aging Study (HAAS) was started in 1991 to study dementia prevalence, incidence and risk factors. At the first HAAS exam (examination 4), 3,734 members of the HHP cohort (80 percent of survivors) participated. Subsequent follow-up examinations for dementia were conducted in 1994 (EX5), 1996-1997 (EX6) and 1999-2000 (EX7) using a multistep procedure. The 100-point Cognitive Abilities Screening Instrument (CASI) was used to screen the entire sample. The CASI is a cross-culturally validated test of global cognitive function designed for use in comparative studies of dementia in the United States and Japan. In EX 4, CASI score and age were used to identify a subgroup of participants for dementia evaluation. In follow-up examinations, subjects with either CASI scores falling below education-adjusted cut-points (77 for participants with low education and 79 for high education) or with absolute drops of at least 9 points were included in a subgroup for specific dementia examination. Subjects who met the criteria for dementia underwent neuro-imaging and blood tests for diagnosis of dementia subtype. A consensus diagnosis was reached by the study neurologist and at least two other physicians with expertise in geriatrics and dementia. We used the death data recorded until June 20, 2002 . Among the 3,734 participants in EX 4, 226 people were diagnosed with dementia, and they were called prevalent cases. There were 135, 112 and 52 incident dementia cases diagnosed at EX 5, 6, and 7, respectively. Study 1: Estimate age-specific dementia rate and the impact of dementia on survival. Summary: Early work discussed the age-specific incidence of dementia. Previous approaches either treated deaths simply as censored or did not include any covariates, however. We proposed an illness-death model for survival data with interval-censoring and left-truncation. This approach can include risk factors related to dementia onset and death, and allow semi-Markov models where survival after dementia could depend on dementia onset age. This model can be used to estimate the cumulative risk of developing dementia in the presence of competing risks of death. We applied this method to dementia data to estimate the age-specific and cumulative risks of incident dementia and to examine the effect of major risk factors on dementia onset and death. Based on the analysis, we found that having dementia and early onset of dementia both significantly increase mortality rate. Having dementia increases the mortality hazard by 7.9-fold. Study 2: Joint modeling for cognitive trajectory and risk of dementia in the presence of death Summary: We used a Bayesian change point model to fit the trajectory of cognitive function for demented people as well as that for normal aged people. In real life, aging people are subject to two competing events, e.g., dementia and death without dementia. The majority of people do not develop dementia. In this article, we used a mixture model to fit the survival data with competing risks consisting of dementia onset time after the change point of cognitive function for demented subjects and death time for non-demented subjects. Cognitive trajectories and the survival process were modeled jointly and parameters were estimated using the Markov chain Monte Carlo method. Using data from the HAAS, we showed the trajectories of cognitive function and the effect of several major covariates. Based on the analysis, we found that for healthy aging subjects, CASI scores decrease gradually from 90 at age 70 to about 60 at age 95. For demented subjects, the change points for accelerated decline are age 72 and 84 for subjects with lower and higher education levels, respectively. For higher educated subjects, acceleration of cognitive decline occurs later but with a faster rate than for lower educated subjects. This finding is consistent with the theory of cognitive reserve. At age 95, all demented subjects have similar cognitive function regardless of education level.