基于Lasso Cox回归模型的早期阿尔茨海默病转归预测研究

韩红娟; 秦瑶; 乔果果; 陈杜荣; 崔靖; 马艺菲; 张荣; 余红梅

doi:10.16462/j.cnki.zhjbkz.2023.08.007

基于Lasso Cox回归模型的早期阿尔茨海默病转归预测研究

doi: 10.16462/j.cnki.zhjbkz.2023.08.007

韩红娟^{1, 2},
秦瑶¹,
乔果果³,
陈杜荣¹,
崔靖¹,
马艺菲¹,
张荣¹,
余红梅^{1, 4, ,}

1.
山西医科大学公共卫生学院卫生统计学教研室，太原 030001
2.
山西医科大学基础医学院数学教研室，030001 太原
3.
山西医科大学公共卫生学院教学实验中心，太原 030001
4.
重大疾病风险评估山西省重点实验室，太原 030001

基金项目:

国家自然科学基金 81973154

山西省青年自然科学基金 201901D211330

山西省青年自然科学基金 20210302123242

山西省研究生创新项目 2022Y367

详细信息

通讯作者:
余红梅，E-mail: yu@sxmu.edu.cn

中图分类号: R741;R181
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- 被引次数: 0
出版历程
- 收稿日期: 2022-04-14
- 修回日期: 2022-12-15
- 网络出版日期: 2023-09-02
- 刊出日期: 2023-08-10

Prediction of early Alzheimer′s disease progression based on Lasso Cox regression model

1.
Department of Health Statistics, School of Public Health, Shanxi Medical University, Taiyuan 030001, China
2.
Department of Mathematics, School of Basic Medical Sciences, Shanxi Medical University, Taiyuan 030001, China
3.
Teaching Experiment Center, School of Public Health, Shanxi Medical University, Taiyuan 030001, China
4.
Shanxi Provincial Key Laboratory of Major Diseases Risk Assessment, Taiyuan 030001, China

Funds:

National Natural Science Foundation of China 81973154

Natural Science Foundation for Young Scientists of Shanxi Province 201901D211330

Natural Science Foundation for Young Scientists of Shanxi Province 20210302123242

Postgraduate Innovation Project in Shanxi Province 2022Y367

More Information

Corresponding author: YU Hongmei, E-mail: yu@sxmu.edu.cn

摘要

摘要: 目的探讨认知正常(normal cognition, NC)进展为轻度认知功能障碍(mild cognitive impairment, MCI)、MCI逆转为NC和MCI进展为阿尔茨海默病(Alzheimer′ disease, AD)的相关因素并建立预测模型。方法利用阿尔茨海默病神经影像学倡议(Alzheimer′s Disease Neuroimaging Initiative, ADNI)数据，分别构建NC进展为MCI、MCI逆转为NC和MCI进展为AD的Lasso Cox回归模型。结果共纳入502例NC和990例MCI患者，其中NC进展为MCI者104例，MCI逆转为NC者90例，MCI进展为AD者370例。结果显示较低的雷氏听觉和语言学习测试-学习成绩(HR=0.884 0, 95% CI: 0.778 0~0.990 0)、内嗅皮层萎缩(HR=0.999 6, 95% CI: 0.999 2~0.999 9)、较高的功能活动量表得分(HR=1.552 0, 95% CI: 1.292 0~1.813 0)和Tau蛋白(HR=1.003 0, 95% CI: 1.001 0~1.006 0)均是NC进展为MCI的相关因素；较低的AD评定量表-13条目得分(HR=0.925 0, 95% CI: 0.857 0~0.993 0)、功能活动量表得分(HR=0.826 0, 95% CI: 0.691 0~0.961 0)和较低浓度的Tau蛋白(HR=0.997 0, 95% CI: 0.994 0~0.999 0)均是MCI逆转为NC的相关因素；携带载脂蛋白E4(apolipoprotein E4, APOE4)基因(HR=1.304 0, 95% CI: 1.069 0~1.540 0)、较长的受教育年限(HR=1.055 0, 95% CI: 1.017 0~1.093 0)、较高的临床痴呆评定量表得分(HR=1.192 0, 95% CI: 1.060 0~1.324 0)、AD评定量表-13条目(HR=1.036 0, 95% CI: 1.011 0~1.061 0)、功能活动量表得分(HR=1.065 0, 95% CI: 1.039 0~1.091 0)和磷酸化Tau蛋白(HR=1.018 0, 95% CI: 1.009 0~1.027 0)、较低的雷氏听觉和语言学习测试-即时回忆(HR=0.973 0, 95% CI: 0.956 0~0.990 0)和较低浓度的Aβ淀粉样蛋白(HR=0.999 2, 95% CI: 0.998 8~0.999 6)均是MCI进展为AD的相关因素。结论 AD的疾病转归受多个因素影响，不同阶段的风险预测有利于对重点人群的健康管理干预和预防性护理，减少其未来疾病进展的风险。
- 阿尔茨海默病 /
- 轻度认知功能障碍 /
- 认知正常 /
- Lasso Cox回归模型
Abstract: Objective The study aims to explore predictors related to the progression from normal cognition (NC) to mild cognitive impairment (MCI), the reversion from MCI to NC, and the progression from MCI to Alzheimer′s disease (AD), and to establish corresponding prediction models. Methods Based on the Alzheimer′s Disease Neuroimaging Initiative (ADNI) database, three Lasso Cox regression models were developed to predict the transition from NC to MCI, the reversion from MCI to NC, and the progression from MCI to AD. Results The study included 502 NC and 990 MCI patients, of which 104 NC progressed to MCI, 90 MCI reverted to NC, and 370 MCI progressed to AD. The covariate effects of the predictors showed that lower Rey′s auditory verbal learning test-learning (HR=0.884 0, 95% CI: 0.778 0-0.990 0), atrophy of the entorhinal cortex (HR=0.999 6, 95% CI: 0.999 2-0.999 9), higher functional activities questionary score (HR=1.552 0, 95% CI: 1.292 0-1.813 0) and Tau protein (HR=1.003 0, 95% CI: 1.001 0-1.006 0) were associated with the progression from NC to MCI. Lower scores of Alzheimer′s disease assessment scale-13 (HR=0.925 0, 95% CI: 0.857 0-0.993 0), functional activity scale scores (HR=0.826 0, 95% CI: 0.691 0-0.961 0) and lower concentrations of Tau protein (HR=0.997 0, 95% CI: 0.994 0-0.999 0) were all relevant factors for MCI reversal to NC. The apolipoprotein E4 (APOE4) gene (HR=1.304 0, 95% CI: 1.069 0-1.540 0), longer years of education (HR=1.055 0, 95% CI: 1.017 0-1.093 0), higher clinical dementia rating sum of boxes score (HR=1.192 0, 95% CI: 1.060 0-1.324 0), Alzheimer′s disease assessment scale-13 entries (HR=1.036 0, 95% CI: 1.011 0-1.061 0), Rey′s auditory verbal learning test-immediate (HR=0.973 0, 95% CI: 0.956 0-0.990 0), functional activities questionary score (HR=1.065 0, 95% CI: 1.039 0-1.091 0), and phosphorylation Tau (HR=1.018 0, 95% CI: 1.009 0-1.027 0), lower Rey′s auditory verbal learning test-immediate (HR=0.973 0, 95% CI: 0.956 0-0.990 0) and lower concentrations of Aβ amyloid (HR=0.999 2, 95% CI: 0.998 8-0.999 6) were associated with the progression from MCI to AD. Conclusions The transformation among different stages of AD are affected by multiple factors. Risk prediction of AD is beneficial to perform health management intervention and preventive care in key populations, thereby reducing the risk of future disease progression.
- Alzheimer′s disease /
- Mild cognitive impairment /
- Normal cognition /
- Lasso Cox regression model

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图 1 基于Lasso Cox回归的变量选择

1. A、B、C子图是log(λ)与自变量数目对应曲线；纵坐标为偏似然偏差；下横坐标为log(λ)；上横坐标为不同log(λ)对应的模型中非零系数自变量的个数；D、E、F子图中每条曲线代表每个自变量系数的变化轨迹；a：偏似然偏差最小时最优调和系数；b：偏似然偏差一个标准误内最优调和系数；2. NC：认知正常；MCI：轻度认知功能障碍；AD：阿尔茨海默病。

Figure 1. Variable selection based on Lasso Cox

1. Subplots A, B, and C are curves corresponding to log(λ) and the number of independent variables; the ordinate is the partial likelihood deviation; The lower axis is the log (λ); the upper axis shows the number of independent variables with nonzero coefficients corresponding to different log(λ) in the model; each curve in subplots D, E, and F represents the trajectory of the coefficient of each independent variable; a: the minimum optimal harmonic coefficient of partial likelihood deviation; b: the optimal harmonic coefficient within one standard error of partial likelihood deviation; 2. NC: normal cognition; MCI: mild cognitive impairment; AD: Alzheimer′s disease.

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图 2 NC进展为MCI的Lasso Cox回归预测列线图

1. NC：认知正常; 2. MCI：轻度认知功能障碍。

Figure 2. Nomogram of NC progression to MCI based on Lasso Cox regression

1. NC: normal cognition; 2. MCI: mild cognitive impairment.

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图 3 MCI逆转为NC的Lasso Cox回归预测列线图

1. MCI：轻度认知功能障碍; 2. NC：认知正常。

Figure 3. Nomogram of MCI reversion to NC based on Lasso Cox regression

1. MCI: mild cognitive impairment; 2. NC: normal cognition.

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图 4 MCI进展为AD的Lasso Cox回归预测列线图

1. MCI：轻度认知功能障碍; 2. AD：阿尔茨海默病; 3. ICV：颅内总容积。

Figure 4. Nomogram of MCI progression to AD based on Lasso Cox regression

1. MCI: mild cognitive impairment; 2. AD: Alzheimer′s disease; 3. ICV: total intracranial volume.

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表 1 研究变量基本信息

Table 1. Basic information of variables

变量 Variable	NC进展为MCI ^① Progression from NC to MCI ^①		MCI逆转为NC ^① Progression from MCI to NC ^①		MCI进展为AD ^① Progression from MCI to AD ^①
变量 Variable	是(n=104) Yes (n=104)	否(n=398) No (n=398)	是(n=90) Yes (n=90)	否(n=900) No (n=900)	是(n=370) Yes (n=370)	否(n=620) No (n=320)
性别(男/女) Gender (male/female)	56/48	186/212	48/42	543/357	222/148	366/254
婚姻状态(已婚/单身) Marital status (married/single)	76/28	272/126	71/19	703/197	298/72	483/137
携带APOE4(是/否) Carry APOE4(yes/no)	38/66	102/296	33/57	452/448	237/133	244/376
年龄/岁, [M(P₂₅, P₇₅)] Age /years, [M(P₂₅, P₇₅)]	74.45 (71.53, 79.45)	72.90 (69.30, 77.33)	67.90 (62.98, 75.80)	73.70 (68.50, 78.78)	74.40 (69.50, 79.20)	72.20 (66.30, 77.90)
受教育年限/年, [M(P₂₅, P₇₅)] Education/years, [M(P₂₅, P₇₅)]	16 (15, 18)	16 (14, 18)	16 (15, 18)	16 (14, 18)	16 (14, 18)	16 (14, 18)
临床痴呆评定量表得分 Clinical dementia rating sum of boxes score	0(0, 0)	0(0, 0)	1.00 (0.50, 1.50)	1.50 (1.00, 2.00)	2.00 (1.00, 2.50)	1.00 (0.50, 2.00)
AD评定量表-11条目得分 Alzheimer′s disease assessment scale-11 entries score	6.33 (5.00, 8.33)	5.00 (3.33, 7.33)	6.00 (4.25, 8.75)	10.00 (7.00, 13.33)	12.00 (9.33, 15.33)	8.00 (6.00, 11.00)
AD评定量表-13条目得分 Alzheimer′s disease assessment scale-13 entries score	10.33 (7.25, 13.92)	8.00 (5.33, 11.33)	9.84 (7.00, 12.92)	17.00 (12.00, 21.67)	20.00 (16.00, 24.33)	13.67 (10.00, 18.00)
AD评定量表单词再认条目得分 Task 4 word recognition of Alzheimer′s disease assessment scale score	3.00 (2.00, 5.00)	2.00 (1.00, 4.00)	3.00 (2.00, 4.25)	6.00 (4.00, 8.00)	7.00 (5.00, 9.00)	5.00 (3.00, 6.00)
简易精神状态量表得分 Mini-mental state examination score	29 (28, 30)	29 (29, 30)	29 (28, 30)	28 (26, 29)	27 (26, 29)	28 (27, 29)
雷氏听觉和语言学习测试-即时回忆 Rey′s auditory verbal learning test-immediate	41.00 (34.25, 49.50)	46.00 (39.00, 53.00)	43.00 (35.00, 50.00)	32.00 (26.00, 40.00)	29.00 (24.00, 33.00)	37.00 (29.00, 45.00)
雷氏听觉和语言学习测试-学习成绩 Rey′s auditory verbal learning test-learning	5.00 (3.25, 7.00)	6.00 (5.00, 8.00)	6.00 (4.00, 7.25)	4.00 (2.00, 6.00)	3.00 (2.00, 4.00)	5.00 (3.00, 7.00)
雷氏听觉和语言学习测试-遗忘 Rey′s auditory verbal learning test-forgetting	4 (2, 6)	3 (2, 5)	4 (2, 6)	5 (3, 6)	5 (4, 7)	4 (3, 6)
雷氏听觉和语言学习测试-遗忘百分比 Rey′s auditory verbal learning test-percent forgetting	38.46 (22.22, 61.15)	29.29 (14.29, 50)	35.71 (19.55, 57.14)	66.67 (37.50, 100.00)	85.71 (55.56, 100.00)	50.00 (27.27, 75.00)
逻辑记忆延迟回忆总分 Logical memory delayed recall total score	12.00 (10.00, 14.00)	13.00 (11.00, 16.00)	8.00 (7.75, 10.00)	6.00 (3.00, 8.00)	3.00 (1.00, 7.00)	8.00 (5.00, 9.00)
连线测验B的时间 Trail making test-part B time	80.50 (62.25, 99.75)	70.50 (54.00, 92.00)	71.00 (59.00, 86.25)	101.00 (73.00, 144.00)	112.00 (79.00, 169.00)	86.50 (66.25, 122.00)
功能活动量表得分 Functional activities questionary score	0 (0, 0)	0 (0, 0)	0 (0, 1)	2 (0, 5)	4 (1, 8)	1 (0, 3)
改进的临床前AD认知数字测试组合得分 Modified preclinical Alzheimer′s cognitive composite with digit symbol substitution score	-0.96 (-2.46, 1.20)	0.44 (-1.27, 2.01)	-1.93 (-3.83, -0.80)	-6.47 (-9.47, -3.49)	-8.64 (-10.67, -5.62)	-4.49 (-7.34, -1.97)
改进的临床前AD认知试验测试组合得分 Modified preclinical Alzheimer′s cognitive composite with trails test score	-0.90 (-2.66, 1.09)	0.62 (-1.41, 1.94)	-1.38 (-2.89, -0.47)	-5.91 (-8.87, -3.14)	-8.20 (-10.51, -5.29)	-3.81 (-6.84, -1.75)
脑室/×10⁴ mm³ Ventricles /×10⁴ mm³	3.62 (2.51, 5.08)	2.81 (2.02, 3.95)	2.61 (1.85, 3.37)	3.69 (2.56, 5.26)	3.89 (2.84, 5.66)	3.32 (2.23, 4.82)
海马体/×10³ mm³ Hippocampus/×10³ mm³	7.14 (6.56, 7.63)	7.59 (6.91, 8.03)	7.67 (7.00, 8.24)	6.69 (5.96, 7.46)	6.23 (5.61, 6.99)	7.13 (6.43, 7.78)
全脑/×10⁶ mm³ Whole Brain/×10⁶ mm³	1.02 (0.94, 1.08)	1.04 (0.96, 1.11)	1.05 (0.99, 1.16)	1.03 (0.96, 1.10)	1.00 (0.94, 1.09)	1.05 (0.98, 1.12)
内嗅皮层/×10³ mm³ Entorhinal/×10³ mm³	3.71 (3.27, 4.18)	3.90 (3.52, 4.35)	3.99 (3.55, 4.29)	3.50 (3.00, 3.98)	3.23 (2.77, 3.68)	3.72 (3.29, 4.14)
梭状回/×10⁴ mm³ Fusiform/×10⁴ mm³	1.74 (1.57, 1.92)	1.79 (1.64, 1.98)	1.85 (1.72, 2.01)	1.74 (1.57, 1.91)	1.67 (1.49, 1.83)	1.81 (1.64, 1.98)
中颞叶/×10⁵ mm³ Middle temporal lobe/×10⁵ mm³	1.95 (1.78, 2.18)	2.05 (1.88, 2.23)	2.06 (1.90, 2.29)	1.94 (1.78, 2.15)	1.86 (1.69, 2.03)	2.03 (1.85, 2.21)
ICV/×10⁶ mm³	1.50 (1.42, 1.64)	1.49 (1.38, 1.61)	1.49 (1.39, 1.65)	1.53 (1.43, 1.64)	1.54 (1.44, 1.66)	1.52 (1.42, 1.62)
Aβ淀粉样蛋白/×10³ pg/mL Amyloid beta protein/×10³ pg/mL	1.12 (0.80, 1.36)	1.29 (1.01, 1.51)	1.21 (0.96, 1.54)	0.86 (0.67, 1.11)	0.72 (0.58, 0.87)	1.04 (0.80, 1.27)
Tau蛋白/×10² pg/mL Tau protein/×10² pg/mL	2.40 (1.97, 2.98)	2.30 (1.90, 2.67)	2.30 (1.76, 2.59)	2.83 (2.22, 3.47)	3.17 (2.57, 3.79)	2.49 (1.95, 3.05)
磷酸化Tau蛋白/×10² pg/mL Phosphorylated Tau protein /×10² pg/mL	21.85 (17.63, 28.27)	20.47 (16.98, 24.52)	19.99 (15.27, 24.87)	27.53 (20.12, 34.84)	31.48 (24.45, 37.97)	23.35 (17.54, 29.51)
注：APOE4, 载脂蛋白E4；ICV, 颅内总容积；NC, 认知正常；MCI, 轻度认知功能障碍；AD, 阿尔茨海默病。 ①以[人数(占比/%)]或[M(P₂₅, P₇₅)]表示。 Note: APOE4, apolipoprotein E4; ICV, total intracranial volume; NC, normal cognition; MCI, mild cognitive impairment; AD, Alzheimer′s disease. ① [Number of people (proportion/%)] or [M(P₂₅, P₇₅)].

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表 2 不同转归的Lasso Cox模型分析结果(HR及其95% CI)及模型评价

Table 2. Results of transformation among different stages of AD based on the Lasso Cox model(HR and 95% CI) and model evaluation

变量 Variable	NC进展为MCI Progression from NC to MCI	MCI逆转为NC Progression from MCI to NC	MCI进展为AD Progression from MCI to AD
性别(男/女) Gender(male/female)	－	0.855 0(0.372 0~1.337 0)	－
婚姻状态(已婚/单身) Marital status(married/single)	－	1.490 0(0.957 0~2.022 0)	－
携带APOE4(是/否) Carry APOE4(yes/no)	1.217 0(0.764 0~1.669 0)	－	1.304 0(1.069 0~1.540 0) ^①
年龄/岁 Age/years	－	－	0.984 0(0.967 0~1.001 0)
受教育年限/年 Education/years	－	－	1.055 0(1.017 0~1.093 0) ^②
临床痴呆评定量表得分 Clinical dementia rating sum of boxes score	2.045 0(0.570 0~3.519 0)		1.192 0(1.060 0~1.324 0) ^②
AD评定量表-13条目得分 Alzheimer′s disease assessment scale-13 entries score	1.040 0(0.970 0~1.110 0)	0.925 0(0.857 0~0.993 0) ^①	1.036 0(1.011 0~1.061 0) ^②
AD评定量表单词再认条目得分 Task 4 word recognition of Alzheimer′s disease assessment scale score	1.069 0(0.876 0~1.262 0)	－	－
简易精神状态量表得分 Mini-mental state examination score	－	－	0.972 0(0.909 0~1.035 0)
雷氏听觉和语言学习测试-即时回忆 Rey′s auditory verbal learning test-immediate	－	－	0.973 0(0.956 0~0.990 0) ^②
雷氏听觉和语言学习测试-学习成绩 Rey′s auditory verbal learning test-learning	0.884 0(0.778 0~0.990 0) ^①	－	－
雷氏听觉和语言学习测试-遗忘百分比 Rey′s auditory verbal learning test-percent forgetting	1.007 0(0.999 0~1.015 0)	1.001 0(0.992 0~1.007 0)	1.001 0(0.997 0~1.005 0)
逻辑记忆延迟回忆总分 Logical memory delayed recall total score	0.924 0(0.828 0~1.020 0)	1.060 0(0.960 0~1.159 0)	0.959 0(0.917 0~1.002 0)
连线测验B的时间 Trail making test-part B time	－	0.994 0(0.9850~1.002 0)	1.001 0(0.999 0~1.003 0)
功能活动量表得分 Functional activities questionary score	1.552 0(1.292 0~1.813 0) ^③	0.826 0(0.691 0~0.961 0) ^②	1.065 0(1.039 0~1.091 0) ^③
改进的临床前AD认知数字测试组合得分 Modified preclinical Alzheimer′s cognitive composite with digit symbol substitution score	1.004 0(0.864 0~1.143 0)	－	－
改进的临床前AD认知试验测试组合得分 Modified preclinical Alzheimer cognitive composite with trails test score	－	1.063 0(0.903 0~1.223 0)	－
脑室/×10⁴ mm³ Ventricles/×10⁴ mm³	1.000 0(0.999 8~1.000 2)	1.000 0(0.999 8~1.0002)	－
海马体/×10³ mm³ Hippocampus/×10³ mm³	0.999 9(0.999 5~1.000 3)	1.000 2(0.999 8~1.000 1)	0.999 9(0.999 7~1.000 1)
内嗅皮层/×10³ mm³ Entorhinal/×10³ mm³	0.999 6(0.999 2~0.999 9) ^①	1.000 1(0.999 9~1.000 3)	0.999 8(0.999 6~1.000 0)
梭状回/×10⁴ mm³ Fusiform/×10⁴ mm³	－	－	0.999 9(0.999 8~1.000 1)
中颞叶/×10⁵ mm³ Middle temporal lobe/×10⁵ mm³	0.999 9(0.999 7~1.000 1)	－	0.999 9(0.999 7~1.000 1)
ICV/×10⁶ mm³	－	－	1.000 0(0.999 8~1.000 2)
Aβ淀粉样蛋白/×10³ pg/mL Amyloid beta protein/×10³ pg/mL	0.999 7(0.999 2~1.000 3)	1.000 2(0.999 8~1.000 6)	0.999 2(0.998 8~0.999 6) ^③
Tau蛋白/×10² pg/mL Tau protein/×10² pg/mL	1.003 0(1.001 0~1.006 0) ^①	0.997 0(0.994 0~0.999 0) ^①	－
磷酸化Tau蛋白/×10² pg/mL Phosphorylated Tau protein/×10² pg/mL	－	－	1.018 0(1.009 0~1.027 0) ^③
AIC	1 063.715 0	1 012.672 0	4 069.952 0
BIC	1 126.994 0	1 076.342 0	4 158.056 0
C指数 C index	0.767 0	0.825 0	0.841 0
注：APOE4, 载脂蛋白E4；ICV, 颅内总容积；AIC, 赤池信息准则；BIC, 贝叶斯信息准则；NC, 认知正常；MCI, 轻度认知功能障碍；AD, 阿尔茨海默病。 ① P＜0.05。② P＜0.01。③ P＜0.001。 Note: APOE4, apolipoprotein E4; ICV, total intracranial volume; AIC, Akaike information criterion; BIC, Bayesian information criterion; NC, normal cognition; MCI, mild cognitive impairment; AD, Alzheimer′s disease. ① P＜0.05. ② P＜0.01. ③ P＜0.001.

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