应用多层模型分析外周动脉病危险因素及Ⅳ期临床试验药物安全性和有效性
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摘要
目的从应用性研究的角度,探讨应用多层模型分析外周动脉病危险因素及IV期临床试验药物安全性和有效性的方法,为临床流行病学层次结构横向数据以及IV期临床试验重复测量纵向数据的分析提供参考。
方法在简述多层线性模型、多层Logistic回归模型和多层线性发展模型的原理和建模方法的基础上,采用SAS统计分析软件的PROC MIXED和PROC NLMIXED程序,应用性分析实际研究中横向数据组群水平变量对个体水平变量与应变量关系的调节作用,评价Ⅳ期临床试验重复测量的药物安全性和有效性指标纵向数据的变化情况,以及个体内部相关和个体间变异对研究指标的效应。
结果高危高血压患者踝臂指数(ABI)异常现患率横断面研究的应变量ABI值和ABI异常的数据均存在着组内相关性和组间异质性(P<0.05),不宜采用多重线性回归和固定效应Logistic回归分析,宜选用多层线性模型和多层Logistic回归模型分析。将组群变量京沪地区纳入空模型后,数据的组内相关性有所降低,该组群变量可解释15%的ABI值组间变异,46%的ABI异常组间变异,表明ABI值和ABI异常的人群分布存在区域聚集现象。以研究中心为组群水平解释变量、老年为个体水平随机斜率变量、其他个体背景变量为固定斜率变量所拟合的多层模型结果表明,京沪地区与老年之间有交互作用,性别、血清肌酐轻度升高、吸烟≥10包/年、体重指数和脉压差是导致高危高血压患者ABI值降低的主要危险因素；动脉壁增厚、血清肌酐轻度升高、很高危高血压是高危高血压患者发生ABI异常的主要危险因素(P<0.05)。
匹伐他汀Ⅳ期临床试验的数据是不完整、不平衡且不等距重复测量的纵向数据,不满足单元重复测量方差分析的应用条件,而多元重复测量方差分析又会造成信息量的损失,而多层线性发展模型充分利用了数据信息,检验效能较高。多层线性发展模型分析结果表明：(1)用药期间,安全性评价指标谷草转氨酶(AST)、谷丙转氨酶(ALT)和肌酸激酶(CK)的平均估计值均呈上升趋势,基线ALT(或CK)值越大的患者,其ALT(或CK值)上升速率越小(P<0.05)；AST值的主要影响因素是年龄、饮酒和基线ALT值；ALT值的主要影响因素是年龄、性别、基线BMI值和基线AST值；CK值的主要影响因素是性别、基线Cr值和基线AST值(P<0.05)。(2)用药期间,有效性评价指标TC、LDL-C和TG的平均估计值持续下降,HDL-C的平均估计值有所上升,基线TC(或LDL-C)值越大的患者,其TC(或LDL-C)值的降低速率越大,基线HDL-C值越大的患者,其HDL-C值的上升速率越小(P<0.05)。TC值的主要影响因素是性别、基线Cr值和基线AST值；LDL-C值的主要影响因素是年龄、基线HDL-C值、基线TG值和基线TC值；HDL-C值的主要影响因素是性别、基线TC值、基线LDL-C值和基线TG值；TG值的主要影响因素是血脂异常危险度、基线BMI值、基线Cr值、基线TC值、基线LDL-C值和基线HDL-C值(P<0.05)。
结论对于存在组内相关性或组间异质性的临床流行病学研究横向数据,宜选用多层线性模型、多层Logistic回归模型等多层模型分析；对于不完整、不平衡、不等距重复测量的Ⅳ期临床试验纵向数据,宜选用多层线性发展模型等多层模型分析。
Objective This application study sought to explore the methods of aplicating multilevel models in analysis of risk factors for peripheral arterial disease and efficacy and safety of drug in phase IV clinical trails, so as to provide the reference for analyzing the hierarchical structure cross-sectional data of clinical epidemiologic studies and repeated measure longitudinal data of phase IV clinical trials.
Methods On the basis of the summary of the principles and building steps for multilevel linear model, multilevel logistic regression model and multilevel linear growth model, the PROC MIXED and PROC NLMIXED in SAS software were employed to analyze analyze the mediate effect of group-level variables on the relation of individual-level variables and depend variables in the cross-sectional data, evaluate the variation of safety and efficacy indicators in phase IV clinical trials repeated measure longitudinal data, and the effect of intra-individual correlation and between-individual variation on the interested indicators.
Results In the cross-sectional study on the prevalence of abnormal ankle brachial index (ABI) among high risk hypertensive patients, there were statistical significant intra-class correlation and between-group heterogeneity in the data of dependent variables ABI value and abnormal ABI (P<0.05). These data were not adapted to multiple linear regression and fixed effect logistic regression, they would adopt multilevel linear model and multilevel logistic regression model. After adding group-variable research center location to the empty models, the intra-class correlation decreased. The group-variable could explain15%between-group heterogeneity of ABI value and46%between-group heterogeneity of abnormal ABI; it indicated that there were region cluster in the distribution of ABI value and abnormal ABI. The results of multilevel models fitted by group-variable research center location, individual-level variabla aged and other individual background variables indicated that there were across-level interactions between research center location and aged, and the main risk factors for ABI value decrease were sex, slightly elevated serum creatinine, smoked, body mass index (BMI) and pulse pressure; the main risk factors for abnormal ABI were arterial wall thickening, slightly elevated serum creatinine and very high risk hypertension(P <0.05)
The data of pitavastatin phase IV clinical trail were incomplete, unbalanced and unequal period repeated measure longitudinal data. These data were not adapt to univariate repeated measure analysis of variance. The information of data were lost if they were analyzed by multivariate repeated measure analysis of variance. Multilevel linear model, however, could take full advantage of data information. The power of multilevel linear model was high. The results of multilevel linear model were as follow:Firstly, during the period of exposure on pitavastatin, the average estimate values of aspartate transaminase (AST), alanine transaminase (ALT) and creatine kinase (CK) increased. The higher baseline values of ALT or CK had smaller increase rate (P<0.05). The main influential factors for AST outcome value were age, drink and baseline ALT value. Those for ALT outcome value were age, sex, baseline BMI value and baseline AST value. Those for CK outcome value were sex, baseline creatinine (Cr) value and baseline AST value. Secondly, during the period of pitavastatin treatment, the average estimate values of total cholesterol (TC), low density lipoprotein cholesterol (LDL-C) and triglyceride (TG) reduced, that of high density lipoprotein cholesterol (HDL-C) increased. The higher baseline values of TC or LDL-C had bigger decrease rate, the higher baseline values of HDL-C had smaller increase rate (P<0.05). The main influential factors for TC outcome value were sex, baseline Cr value and baseline AST value. Those of LDL-C outcome value were age, baseline HDL-C value, baseline TG value and baseline TC value. Those of HDL-C outcome value were sex, baseline TC value, baseline LDL-C valure and baseline TG value. Those of TG outcome value were risk level of abnormal cholesterol, baseline BMI value, baseline Cr value, baseline TC value, baseline LDL-C value and baseline HDL-C value (P<0.05).
Conclusion While there are statistical significant intra-class correlation or between-group heterogeneity in the data of clinical epidemio logic studies, multilevel models such as multilevel linear model and multilevel logistic regression model must be adopted. For the incomplete, unbalanced and unequal period repeated measure data collected in phase Ⅳ clinical trails, multilevel models such as multilevel linear growth model must be adopted.
方法在简述多层线性模型、多层Logistic回归模型和多层线性发展模型的原理和建模方法的基础上,采用SAS统计分析软件的PROC MIXED和PROC NLMIXED程序,应用性分析实际研究中横向数据组群水平变量对个体水平变量与应变量关系的调节作用,评价Ⅳ期临床试验重复测量的药物安全性和有效性指标纵向数据的变化情况,以及个体内部相关和个体间变异对研究指标的效应。
结果高危高血压患者踝臂指数(ABI)异常现患率横断面研究的应变量ABI值和ABI异常的数据均存在着组内相关性和组间异质性(P<0.05),不宜采用多重线性回归和固定效应Logistic回归分析,宜选用多层线性模型和多层Logistic回归模型分析。将组群变量京沪地区纳入空模型后,数据的组内相关性有所降低,该组群变量可解释15%的ABI值组间变异,46%的ABI异常组间变异,表明ABI值和ABI异常的人群分布存在区域聚集现象。以研究中心为组群水平解释变量、老年为个体水平随机斜率变量、其他个体背景变量为固定斜率变量所拟合的多层模型结果表明,京沪地区与老年之间有交互作用,性别、血清肌酐轻度升高、吸烟≥10包/年、体重指数和脉压差是导致高危高血压患者ABI值降低的主要危险因素；动脉壁增厚、血清肌酐轻度升高、很高危高血压是高危高血压患者发生ABI异常的主要危险因素(P<0.05)。
匹伐他汀Ⅳ期临床试验的数据是不完整、不平衡且不等距重复测量的纵向数据,不满足单元重复测量方差分析的应用条件,而多元重复测量方差分析又会造成信息量的损失,而多层线性发展模型充分利用了数据信息,检验效能较高。多层线性发展模型分析结果表明：(1)用药期间,安全性评价指标谷草转氨酶(AST)、谷丙转氨酶(ALT)和肌酸激酶(CK)的平均估计值均呈上升趋势,基线ALT(或CK)值越大的患者,其ALT(或CK值)上升速率越小(P<0.05)；AST值的主要影响因素是年龄、饮酒和基线ALT值；ALT值的主要影响因素是年龄、性别、基线BMI值和基线AST值；CK值的主要影响因素是性别、基线Cr值和基线AST值(P<0.05)。(2)用药期间,有效性评价指标TC、LDL-C和TG的平均估计值持续下降,HDL-C的平均估计值有所上升,基线TC(或LDL-C)值越大的患者,其TC(或LDL-C)值的降低速率越大,基线HDL-C值越大的患者,其HDL-C值的上升速率越小(P<0.05)。TC值的主要影响因素是性别、基线Cr值和基线AST值；LDL-C值的主要影响因素是年龄、基线HDL-C值、基线TG值和基线TC值；HDL-C值的主要影响因素是性别、基线TC值、基线LDL-C值和基线TG值；TG值的主要影响因素是血脂异常危险度、基线BMI值、基线Cr值、基线TC值、基线LDL-C值和基线HDL-C值(P<0.05)。
结论对于存在组内相关性或组间异质性的临床流行病学研究横向数据,宜选用多层线性模型、多层Logistic回归模型等多层模型分析；对于不完整、不平衡、不等距重复测量的Ⅳ期临床试验纵向数据,宜选用多层线性发展模型等多层模型分析。
Objective This application study sought to explore the methods of aplicating multilevel models in analysis of risk factors for peripheral arterial disease and efficacy and safety of drug in phase IV clinical trails, so as to provide the reference for analyzing the hierarchical structure cross-sectional data of clinical epidemiologic studies and repeated measure longitudinal data of phase IV clinical trials.
Methods On the basis of the summary of the principles and building steps for multilevel linear model, multilevel logistic regression model and multilevel linear growth model, the PROC MIXED and PROC NLMIXED in SAS software were employed to analyze analyze the mediate effect of group-level variables on the relation of individual-level variables and depend variables in the cross-sectional data, evaluate the variation of safety and efficacy indicators in phase IV clinical trials repeated measure longitudinal data, and the effect of intra-individual correlation and between-individual variation on the interested indicators.
Results In the cross-sectional study on the prevalence of abnormal ankle brachial index (ABI) among high risk hypertensive patients, there were statistical significant intra-class correlation and between-group heterogeneity in the data of dependent variables ABI value and abnormal ABI (P<0.05). These data were not adapted to multiple linear regression and fixed effect logistic regression, they would adopt multilevel linear model and multilevel logistic regression model. After adding group-variable research center location to the empty models, the intra-class correlation decreased. The group-variable could explain15%between-group heterogeneity of ABI value and46%between-group heterogeneity of abnormal ABI; it indicated that there were region cluster in the distribution of ABI value and abnormal ABI. The results of multilevel models fitted by group-variable research center location, individual-level variabla aged and other individual background variables indicated that there were across-level interactions between research center location and aged, and the main risk factors for ABI value decrease were sex, slightly elevated serum creatinine, smoked, body mass index (BMI) and pulse pressure; the main risk factors for abnormal ABI were arterial wall thickening, slightly elevated serum creatinine and very high risk hypertension(P <0.05)
The data of pitavastatin phase IV clinical trail were incomplete, unbalanced and unequal period repeated measure longitudinal data. These data were not adapt to univariate repeated measure analysis of variance. The information of data were lost if they were analyzed by multivariate repeated measure analysis of variance. Multilevel linear model, however, could take full advantage of data information. The power of multilevel linear model was high. The results of multilevel linear model were as follow:Firstly, during the period of exposure on pitavastatin, the average estimate values of aspartate transaminase (AST), alanine transaminase (ALT) and creatine kinase (CK) increased. The higher baseline values of ALT or CK had smaller increase rate (P<0.05). The main influential factors for AST outcome value were age, drink and baseline ALT value. Those for ALT outcome value were age, sex, baseline BMI value and baseline AST value. Those for CK outcome value were sex, baseline creatinine (Cr) value and baseline AST value. Secondly, during the period of pitavastatin treatment, the average estimate values of total cholesterol (TC), low density lipoprotein cholesterol (LDL-C) and triglyceride (TG) reduced, that of high density lipoprotein cholesterol (HDL-C) increased. The higher baseline values of TC or LDL-C had bigger decrease rate, the higher baseline values of HDL-C had smaller increase rate (P<0.05). The main influential factors for TC outcome value were sex, baseline Cr value and baseline AST value. Those of LDL-C outcome value were age, baseline HDL-C value, baseline TG value and baseline TC value. Those of HDL-C outcome value were sex, baseline TC value, baseline LDL-C valure and baseline TG value. Those of TG outcome value were risk level of abnormal cholesterol, baseline BMI value, baseline Cr value, baseline TC value, baseline LDL-C value and baseline HDL-C value (P<0.05).
Conclusion While there are statistical significant intra-class correlation or between-group heterogeneity in the data of clinical epidemio logic studies, multilevel models such as multilevel linear model and multilevel logistic regression model must be adopted. For the incomplete, unbalanced and unequal period repeated measure data collected in phase Ⅳ clinical trails, multilevel models such as multilevel linear growth model must be adopted.
引文
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[4]Larsen K, Merlo J. Appropriate assessment of neighborhood effect on individual health:integration random and fixed effects in multilevel logistic regression[J]. AM J Epidemiol,2005,161(1):81-88.
[5]Kandel DB, Kiros GE, Schaffran C, et al. Racial/Ethnic differences in cigarette smoking initiation and progression to daily smoking: a multilevel analysis[J]. Am J Pub Heal,2004,94:128-135.
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[7]Haynes R, Reading R, Gale S. Household and neighbourhood risks for injury to 5-14 year old children[J]. Soc Sci Med,2003,57(4):625-636.
[8]高俊岭,傅华.上海市社区老年高血压患者血压水平影响因素的多水平分析[J].中华流行病学杂志,2009,30(4)：318-321.
[9]李佳萌,王伟.天津市大学生吸烟影响因素多水平模型分析[J].中华流行病学杂志,2006,27(6)：494-498.
[10]杨永利,付鹏钰,胡东生,等.中国成年人高血压患病区域聚集性及危险因素的多水平模型分析[J].中华流行病学杂志,2009,30(7)：716-719.
[11]陈峰,姚晨,孙高,等新药临床试验中重复测量资料的混合效应模型[J].中国卫生统计,2000,17(6)：373-376.
[12]Lannfelt L, Blennow K, Zetterberg H, et al. Safety, efficacy, and biomarker findings of PBT2 in targeting Aβ as a modifying therapy for alzheimer's disease:a phase Ha, double-blind, randomised, placebo-controlled trial[J]. Lancet Neurol,2008,7:779-786.
[13]Hansel TT, Benezet O, Kaffi H, et al. A multinational,12-week, randomized study comparing the efficacy and tolerability of ciclesonide and budesonide in patients with asthma[J]. Clin Ther,2006,28: 906-920.
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[15]姚光弼,徐道振,兰培,等.双环醇片治疗2200例慢性病毒性肝炎的安全性和疗效分析[J].中国新药与临床杂志,2005,24(6)：421-425.
[16]田洪春,唐中玖,郑德福,等.三苯双脒肠溶片治疗肠道寄生虫感染Ⅳ期临床试验效果观察[J].寄生虫病与感染性疾病,2008,6(4)：176-179.
[17]黄翼然,马建辉,黄健,等.索拉非尼联合干扰素α一线治疗晚期肾癌Ⅳ期临床试验中期分析[J].中华泌尿外科杂志,2010,31(1)：5-7.
[18]杨道锋,郭威,田德英,等.低渗口服补液盐治疗儿童急性腹泻轻中度脱水的疗效和安全性评价[J].中华儿科杂志,2007,45(4)：252-255.
[19]金尔伦全国多中心双盲临床研究课题组.金尔伦盐酸纳洛酮治疗急性颅脑损伤病人随机双盲多中心前瞻性临床研究[J].中华神经外科杂志,2001,17(3)：135-139.
[20]赵维缁,袁涛,袁中元,等.口服胰岛素肠溶胶丸治疗2型糖尿病有效性和安全性的多中心临床观察[J].中华临床营养杂志,2010,18(2)：67-71.
[21]谭慧琼,俊朱,于丽天,等.缬沙坦长期治疗原发性高血压病人的安全性和疗效[J].中国新药与临床杂志,2002,2l(8)：493-495.
[22]陈弼沧,吴秋英,周艺,等.血脂康胶囊治疗高尿酸衄症疗效和安全性的随机双盲临床试验[J].中国中医药信息杂志,2006,13(8)：6-8.
[23]张伟滨,庄澄字,李建民,等.盐酸氨基葡萄糖治疗骨性关节炎有效性与安全性评价[J].中华外科杂志,2007,45(14)：998-1001.
[24]赵广,庞晓文,涂亚庭,等.盐酸氮事斯汀治疗荨麻疹疗效及安全性观察[J].临床皮肤科杂志,2003,32(7)：415-416.
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[19]高俊岭,傅华.上海市社区老年高血压患者血压水平影响因素的多水平分析[J].中华流行病学杂志,2009,30(4)：318-321.
[20]李佳萌,王伟.天津市大学生吸烟影响因素多水平模型分析[J].中华流行病学杂志,2006,27(6)：494-498.
[21]杨永利,付鹏钰,胡东生,等.中国成年人高血压患病区域聚集性及危险因素的多水平模型分析[J].中华流行病学杂志,2009,2009(30)：7.
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[27]姚光弼,徐道振,兰培,等.双环醇片治疗2200例慢性病毒性肝炎的安全性和疗效分析[J].中国新药与临床杂志,2005,24(6)：421-425.
[28]田洪春,唐中玖,郑德福,等.三苯双眯肠溶片治疗肠道寄生虫感染Ⅳ期临床试验效果观察[J].寄生虫病与感染性疾病,2008,6(4)：176-179.
[29]黄翼然,马建辉,黄健,等.索拉非尼联合干扰素a一线治疗晚期肾癌Ⅳ期临床试验中期分析[J].中华泌尿外科杂志,2010,31(1)：5-7.
[30]杨道锋,郭威,田德英,等.低渗口服补液盐治疗儿童急性腹泻轻中度脱水的疗效和安全性评 价[J].中华儿科杂志,2007,45(4)：252-255.
[3l]金尔伦全国多中心双盲临床研究课题组.金尔伦盐酸纳洛酮治疗急性颅脑损伤病人随机双盲多中心前瞻性临床研究[J].中华神经外科杂志,2001,17(3)：135-139.
[32]赵维纲,袁涛,袁中元,等.口服胰岛素肠溶胶丸治疗2型糖尿病有效性和安全性的多中心临床观察[J].中华临床营养杂志,2010,18(2)：67-71.
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[1]王济川,谢海义,姜宝法著.多层统计分析模型：方法与应用[M].第l版.北京：高等教育出版社,2008.
[2]Goldstein H. Multilevel statistical models[M].3rn ed. London: Halsted Press,2003.
[3]杨珉,李晓松.医学和公共卫生研究常用多水平统计模型[M].北京：北京大学医学出版社,2007.
[4]Larsen K, Merlo J. Appropriate assessment of neighborhood effect on individual health:integration random and fixed effects in multilevel logistic regression[J]. AM J Epidemiol,2005,161(1):81-88.
[5]Kandel DB, Kiros GE, Schaffran C, et al. Racial/Ethnic differences in cigarette smoking initiation and progression to daily smoking: a multilevel analysis[J]. Am J Pub Heal,2004,94:128-135.
[6]Merlo J, Asplund K, Lynch J, et al. Population effects on individual systolic blood pressure: a multilevel analysis of the World Health Organization MONICA Project[J]. AM J Epidemiol,2004, 159(12):1168-1179.
[7]Haynes R, Reading R, Gale S. Household and neighbourhood risks for injury to 5-14 year old children[J]. Soc Sci Med,2003,57(4):625-636.
[8]高俊岭,傅华.上海市社区老年高血压患者血压水平影响因素的多水平分析[J].中华流行病学杂志,2009,30(4)：318-321.
[9]李佳萌,王伟.天津市大学生吸烟影响因素多水平模型分析[J].中华流行病学杂志,2006,27(6)：494-498.
[10]杨永利,付鹏钰,胡东生,等.中国成年人高血压患病区域聚集性及危险因素的多水平模型分析[J].中华流行病学杂志,2009,30(7)：716-719.
[11]陈峰,姚晨,孙高,等新药临床试验中重复测量资料的混合效应模型[J].中国卫生统计,2000,17(6)：373-376.
[12]Lannfelt L, Blennow K, Zetterberg H, et al. Safety, efficacy, and biomarker findings of PBT2 in targeting Aβ as a modifying therapy for alzheimer's disease:a phase Ha, double-blind, randomised, placebo-controlled trial[J]. Lancet Neurol,2008,7:779-786.
[13]Hansel TT, Benezet O, Kaffi H, et al. A multinational,12-week, randomized study comparing the efficacy and tolerability of ciclesonide and budesonide in patients with asthma[J]. Clin Ther,2006,28: 906-920.
[14]Vermeulen JH, Gyurkovits K, Rauer H, et al. Randomized comparison of the efficacy and safety of ciclesonide and budesonide in adolescents with severe asthma[J]. Respiratory Medicine,2007,101: 2182-2191.
[15]姚光弼,徐道振,兰培,等.双环醇片治疗2200例慢性病毒性肝炎的安全性和疗效分析[J].中国新药与临床杂志,2005,24(6)：421-425.
[16]田洪春,唐中玖,郑德福,等.三苯双脒肠溶片治疗肠道寄生虫感染Ⅳ期临床试验效果观察[J].寄生虫病与感染性疾病,2008,6(4)：176-179.
[17]黄翼然,马建辉,黄健,等.索拉非尼联合干扰素α一线治疗晚期肾癌Ⅳ期临床试验中期分析[J].中华泌尿外科杂志,2010,31(1)：5-7.
[18]杨道锋,郭威,田德英,等.低渗口服补液盐治疗儿童急性腹泻轻中度脱水的疗效和安全性评价[J].中华儿科杂志,2007,45(4)：252-255.
[19]金尔伦全国多中心双盲临床研究课题组.金尔伦盐酸纳洛酮治疗急性颅脑损伤病人随机双盲多中心前瞻性临床研究[J].中华神经外科杂志,2001,17(3)：135-139.
[20]赵维缁,袁涛,袁中元,等.口服胰岛素肠溶胶丸治疗2型糖尿病有效性和安全性的多中心临床观察[J].中华临床营养杂志,2010,18(2)：67-71.
[21]谭慧琼,俊朱,于丽天,等.缬沙坦长期治疗原发性高血压病人的安全性和疗效[J].中国新药与临床杂志,2002,2l(8)：493-495.
[22]陈弼沧,吴秋英,周艺,等.血脂康胶囊治疗高尿酸衄症疗效和安全性的随机双盲临床试验[J].中国中医药信息杂志,2006,13(8)：6-8.
[23]张伟滨,庄澄字,李建民,等.盐酸氨基葡萄糖治疗骨性关节炎有效性与安全性评价[J].中华外科杂志,2007,45(14)：998-1001.
[24]赵广,庞晓文,涂亚庭,等.盐酸氮事斯汀治疗荨麻疹疗效及安全性观察[J].临床皮肤科杂志,2003,32(7)：415-416.