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模糊数学在膝关节骨性关节炎诊断和疗效评价中的应用
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摘要
目的运用模糊数学方法对KOA的中医证侯进行客观量化,初步建立该病的辨证分型模糊数学识别模型和临床疗效模糊数学评价模型,探索KOA证型概念的模糊数学理论基础,以期为KOA证型诊断和疗效评价专家诊疗系统的建立奠定一个平台。
     方法
     1.依据《中医临床路径实用指南》将膝痹病(KOA)的临床常见证候归纳为风寒湿痹证、风湿热痹证、瘀血闭阻证、肝肾亏虚证四个证型,参照《中医诊断学》和《中药新药临床研究指导原则》,结合膝关节骨关节炎的特点,制定KOA中医辨证要素和诊断标准,确定风寒湿痹证的辨证要素为10个、风湿热痹证11个、瘀血闭阻证10个、肝肾亏虚证15个。制定因素权重评判统计表,由8位中医临床医学专家依据各要素对各证型的重要程度和隶属度填写统计表,得到8个自信度矩阵,计算出各辨证要素的权重值。以阈值λ=0.500为标准,将各证型的辨证要素分为主要辨证要素和次要辨证要素。
     2.以《中药新药临床研究指导原则》中骨性关节炎的临床症状与体征为模板,改制成KOA辨证要素积分表。主要辨证要素与次要辨证要素按照4级量化法分别赋值0、2、4、6分及0、1、2、3分。对于几种难以区分轻重程度的要素,以有、无分别判定4分、0分或2分、0分。所有分值相加得到中医辨证总分。
     3.以论域U表示KOA的46个辨证要素,U={u1,u2,u3,…,u46},四个证型表示为:Aj=(A1,A2,A3,A4),(j=1,2,3,4),依据辨证要素的有无和对每一证型的典型程度不同分别设定分段函数,设立四种证型的标准特征子集,参照张定一的个体模式识别数学模型公式,以直接模糊模式识别法,运用最大隶属原则及阈值原则构建KOA各证型的数学量化模型,设定KOA的证型识别隶属函数。
     4.设辨证要素的量化级别为u (Zi),以四级量化法设定辨证要素的分段量化函数,确立KOA各证型病情严重程度指数函数,构建KOA疗效评价模糊数学模型。
     5.105例符合纳入标准的KOA住院患者分别以人工辨证法和模糊数学识别模型进行辨证,诊断一致者按就诊时间先后顺序分别进入风寒湿痹组、风湿热痹组、瘀血闭阻组、肝肾亏虚组,以《中医临床路径实用指南》中膝痹病(膝关节骨性关节炎)的治疗方案进行治疗,以6天为1个疗程,一共治疗2个疗程。于治疗开始前和治疗结束后分别以JOA膝关节骨性关节炎治疗效果判定标准、WOMAC指数、中医辨证总分、病情严重程度指数观察患者病情变化,以《中药新药临床研究指导原则》中的骨性关节炎疾病疗效判定标准评定治疗效果。
     结果
     1.纳入的105病例以模糊数学模型与人工辨证法进行辨证分型,结果一致者90例,辨证符合率为85.71%,其中风寒湿痹组24例,风湿热痹组13例,瘀血闭阻组13例,肝肾亏虚组40例,两种辨证方法的一致性经配对卡方检验,Kappa=0.795(P<0.01)。
     2.采用克朗巴赫α系数法检验KOA辨证要素积分表各维度的内部一致性信度,风寒湿痹维度中10个因子的克朗巴赫α系数在0.531~0.764之间,风湿热痹维度中11个因子的克朗巴赫α系数在0.613~0.740之间,瘀血闭阻维度中,因子苔白而干涩所得总分为0分,其余因子的克朗巴赫α系数在0.709~0.783之间,肝肾亏虚维度中15个因子的克朗巴赫α系数在0.813~0.846之间,4个证型维度的克朗巴赫α系数均大于0.700。
     3.四组的JOA总分、WOMAC指数得分、VAS得分治疗前后自身比较差异均有显著性意义(P<0.05)。风寒湿痹组、风湿热痹组、瘀血闭阻组的身体功能指数得分治疗前后自身比较差异有显著性意义(P<0.05),肝肾亏虚组的得分自身比较无统计学差异(P>0.05)。风寒湿痹组、风湿热痹组、肝肾亏虚组治疗前后中医辨证总分自身比较差异有显著性意义(P<0.05),瘀血闭阻组治疗前后中医辨证总分自身比较差异无统计学差异(P>0.05)。风寒湿痹组和风湿热痹组治疗前后的病情严重程度指数得分自身比较差异有显著性意义(P<0.05),瘀血闭阻组和肝肾亏虚组自身比较无统计学差异(P>0.05)。风寒湿痹组、风湿热痹组、瘀血闭阻组、肝肾亏虚组的治疗总有效率分别为:82.61%、58.33%8、84.62%、78.95%,所有患者的总有效率为77.91%。
     4.经pearson直线相关分析,风寒湿痹组的病情严重程度指数与JOA得分的相关系数为:r=-0.389(P>0.05),风湿热痹组、瘀血闭阻组、肝肾亏虚组的病情严重程度指数与JOA得分的相关系数分别为-0.733、-0.842、-0.700(P<0.01),所有86例的病情严重程度指数与JOA得分的相关系数为:r=-0.511(P<0.01)。风寒湿痹组的病情严重程度指数与WOMAC指数得分的相关系数为:r=0.413(P=0.05),风湿热痹组、瘀血闭阻组、肝肾亏虚组和所有86例患者的相关系数分别为:0.745、0.853、0.631、0.505(P<0.01)。风湿热痹组的中医辨证总分与JOA得分的相关系数为:r=-0.778(P<0.05),风寒湿痹组、瘀血闭阻组、肝肾亏虚组和所有86例的中医辨证总分与JOA得分的相关系数分别为-0.544、-0.877、-0.662、-0.650(P<0.01)。风寒湿痹组、风湿热痹组、瘀血闭阻组、肝肾亏虚组和所有86例的中医辨证总分与WOMAC指数得分的相关系数分别为:0.529、0.739、0.903、0.657、0.656(P<0.01)。
     5.经配对t检验,风寒湿痹组和风湿热痹组中医辨证总分的效应尺度分别达到-1.122、-1.523(P<0.05),肝肾亏虚组为-0.489(P<0.05),总表为-0.782(P<0.01)。风寒湿痹组和风湿热痹组病情严重程度指数的效应尺度分别为-0.986、-1.186(P<0.05),总表的效应尺度为-0.768(P=0.01)。
     结论
     1.本研究初步制定了KOA中医辨证要素积分表,临床试验经过克朗巴赫α系数法、平行效度分析法和效应尺度的验证,证明该表具有较好的信度、效度和反应度,在继续完善的基础上,可以作为评价KOA临床疗效的工具。
     2.本研究初步建立了KOA证型的模糊识别模型和疗效评价模型,并证实了KOA证型的模糊识别模型与专家辨证有较高的一致性,这两种模型与JOA膝关节骨性关节炎治疗效果判定标准和WOMAC指数有较强的相关性。两种模型可以编制为计算机程序,制作成自动化KOA证型专家诊疗系统。
     3.建议以中医理论为基础,进一步深化对KOA辨证分型和疗效评价的研究。采用多中心大样本的方法和多种数学手段,继续完善和修订KOA辨证要素条目,并更加科学、客观地对其量化,优化KOA证型的模糊识别模型和疗效评价模型。
Objectives To apply fuzzy mathematical method to objectively quantify thesyndromes of traditional Chinese medicine of KOA. To preliminarily establishthe fuzzy mathematical recognition model for syndrome type differentiationand fuzzy mathematical evaluation model for clinical efficacy of KOA. Toexplore the fuzzy mathematical theory of KOA syndrome type’s concept. Toestablish a platform for the diagnosis and evaluation expert system, which candistinguish different syndrome types and evaluate curative effect of KOA.Methods
     1. Referring to “A Practical Guide to The Clinical Pathway of ChineseMedicine”, the common clinical syndromes of knee arthralgia(KOA) weresummarized as wind-cold-dampness arthralgia, wind-fever-dampnessarthralgia, syndrome of blood stasis, deficiency of liver and kidney. Accordingto " Diagnostics of Chinese Medicine "," Clinical Research Guiding Principleof TCM New Drug" and the characteristics of KOA, we formulated the TCMdiagnostic criteria and differentiation factors of KOA. The differentiationfactors of wind-cold-dampness arthralgia were10,wind-fever-dampnessarthralgia11, syndrome of blood stasis10, deficiency of liver and kidney15.Based on the important degree and the membership grade of differentiationfactors for syndrome types, eight clinical TCM experts filled out the statisticaltables of factor weight evaluation, then the weight values of differentiationfactor were calculated. With the threshold λ=0.500as the standard, the differentiation factors of each syndrome type were divided into major andsecondary elements.
     2. We took the clinical symptoms and signs of OA in " Clinical ResearchGuiding Principle of TCM New Drug" as template, restructured it into KOAdifferentiation factors integral table. According to4levels quantizationmethod, the major and secondary differentiation factors were respectivelyassigned0,2,4,6and0,1,2,3points. If the factor is difficult to quantize,assigned0,4or0,2points according to without it or with it. TCM total scoreis the sum of differentiation factor scores.
     3. Set U was used to express46differentiation factors of KOA, U={u1,u2,u3,…,u46}. The four syndrome types of KOA were expressed as: Aj=(A1, A2,A3, A4),(j=1,2,3,4). Based on the presence or absence of differentiationfactor and its typical degree of each syndrome type, we setted2piecewisefunctions and standard feature subset of four syndrome types respectively.Referring to Zhang Dingyi’s formula of individual pattern recognitionmathematical model, combined with direct fuzzy pattern recognition method,maximum membership principle and the threshold, we built mathematicalquantitative models and recognition of membership function for KOAsyndrome types.
     4. Quantitative levels of differentiation factor was defined as u (Zi), Piecewisequantization functions of differentiation factor were setted by4levelsquantization method, then we built fuzzy mathematical evaluation model byestablishment of KOA TCM syndrome severity index.
     5.105hospitalized KOA patients met the inclusion criteria KOA weredialectical with artificial recognition method and fuzzy mathematicsrecognition model. The patients whose diagnoses were consistent, werearranged to wind-cold-dampness arthralgia group, wind-fever-dampnessarthralgia group, syndrome of blood stasis group, deficiency of liver and kidney group according to visit order. All patients were treated by thetreatment program for knee arthralgia(KOA) in “A Practical Guide to TheClinical Pathway of Chinese Medicine”. One course of treatment is6days, allpatients received2courses of treatment. Before and after treatment, the JOAknee osteoarthritis curative effect criteria, WOMAC index, TCM total scoreand KOA TCM syndrome severity index were be used to observe thecondition changes. Therapeutic effects were assessed by the criterion forcurative effect of osteoarthritis from " Clinical Research Guiding Principle ofTCM New Drug".
     Results
     1.105hospitalized KOA patients met the inclusion criteria KOA weredialectical with artificial recognition method and fuzzy mathematicsrecognition model. Two methods were consistent in90cases, diagnosiscoincidence rate was85.71%, wind-cold-dampness arthralgia group24cases,wind-fever-dampness arthralgia group13cases, syndrome of blood stasisgroup13cases, deficiency of liver and kidney group group with40cases. Theconsistency of them was examined by paired chi-square test, Kappa=0.795(P<0.01).
     2. Using the Cronbach’s coefficient to test the internal consistency reliabilityof each dimension in KOA differentiation factors integral table. Cronbach’salpha coefficients of10factors in wind-cold-dampness arthralgia dimensionwere between0.531to0.764,11Cronbach’ s alpha coefficients ofwind-fever-dampness arthralgia dimension were in0.613~0.740, while insyndrome of blood stasis dimension, the score of “white and dry fur” was0,Cronbach’s alpha coefficients of other9factors were between0.709to0.783,Cronbach’s alpha coefficients of15factors in deficiency of liver and kidneydimension were in0.813~0.846. Cronbach’ s alpha coefficients of4syndrome dimensions were greater than0.700.
     3. After treatment, the scores of JOA, WOMAC index, VAS in four groupswere significant different as before(P <0.05). Except deficiency of liver andkidney group, the scores of physical function index in other groups weresignificant different as before(P <0.05).Only the TCM total score in bloodstasis group had no statistical difference than pre-treatment(P>0.05). Inwind-cold-dampness arthralgia group and wind-fever-dampness arthralgiagroup, the scores of KOA TCM syndrome severity index were significantdifferent as before(P <0.05), the scores of other2groups had strikingdifference as before(P>0.05). Total effective rate of each group were:wind-cold-dampness arthralgia group82.61%, wind-fever-dampnessarthralgia group58.33%, syndrome of blood stasis group84.62%, deficiencyof liver and kidney group group78.95%. Total effective rate of all patientswas77.91%.
     4. Through Pearson linear correlation analysis, the correlation coefficient ofKOA TCM syndrome severity index and JOA score were:wind-cold-dampness arthralgia group-0.389(P>0.05), wind-fever-dampnessarthralgia group-0.733(P <0.01), syndrome of blood stasis group-0.842(P<0.01), deficiency of liver and kidney group group-0.700(P <0.01), thecorrelation coefficient of86cases was-0.511(P <0.01). The correlationcoefficient of KOA TCM syndrome severity index and WOMAC index scorewere: wind-cold-dampness arthralgia group0.413(P=0.05),wind-fever-dampness arthralgia group0.745(P <0.01), syndrome of bloodstasis group0.853(P <0.01), deficiency of liver and kidney group group0.631(P <0.01), all of86cases0.505(P <0.01). The correlation coefficientof TCM total score and JOA score were: wind-cold-dampness arthralgia group-0.544(P <0.01), wind-fever-dampness arthralgia group-0.778(P<0.05),syndrome of blood stasis group-0.877(P <0.01), deficiency of liver andkidney group group-0.662(P <0.01), all of86cases-0.650(P <0.01). The correlation coefficient of TCM total score and WOMAC index score were:wind-cold-dampness arthralgia group0.529(P <0.01), wind-fever-dampnessarthralgia group0.739(P<0.01), syndrome of blood stasis group0.903(P<0.01), deficiency of liver and kidney group group0.657(P <0.01), all of86cases0.656(P <0.01).
     5. By means of paired t-test, the effect sizes of TCM total score were:wind-cold-dampness arthralgia group-1.122(P <0.05), wind-fever-dampnessarthralgia group-1.523(P<0.05), deficiency of liver and kidney group group-0.489(P <0.05), all of86cases-0.782(P <0.01). The effect sizes of KOATCM syndrome severity index were: wind-cold-dampness arthralgia group-0.986(P <0.05), wind-fever-dampness arthralgia group-1.186(P<0.05),all of86cases-0.768(P=0.01).
     Conclusions
     1. This study preliminarily developed a KOA differentiation factors integraltable. Through Cronbach alpha coefficient method, analysis of parallel validity,effect size, clinical trials had proved that the table has good reliability, validityand responsiveness. After further improvement, it can be used as a tool toevaluate the clinical efficacy of KOA.
     2. In this study, a fuzzy mathematical recognition model for syndrome typedifferentiation and a fuzzy mathematical evaluation model for clinical efficacyof KOA have been preliminary established. The higher consistency of theformer and expert diagnosis have been confirmed. Both models have strongcorrelation with JOA knee osteoarthritis curative effect criteria and WOMACindex. They can be prepared as a computer program and be made into expertdiagnosis system that can automatically recognize KOA syndrome types.
     3. Based on the theory of Chinese medicine, further research on the the KOAsyndrome types and efficacy evaluation should be deepened. By using themeans of multicenter large sample and various mathematics methods, continue to improve and amend the KOA syndrome element entries, quantifythem more scientifically and objectiveiy, optimize these two models.
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