| With the advent of the era of high concept and big data,high attention is paid to innovation and original thinking,and the generation of huge amounts of medical data greatly facilitates medical research.The mindset of human-universe correspondence and unity of form and spirit is consistent with the clinical practice-oriented philosophy in real world study.An important approach to the development of traditional Chinese medicine is effective integration of real world study methodology into diagnosis,treatment,and exploration of precise prescriptions in traditional Chinese medicine,and combination of original thinking of traditional Chinese medicine with imaginal thinking,figurative thinking and logical reasoning.As a common refractory disease of high incidence in clinical practice,resistant hypertension(RH)has complicated conditions and a long course,likely to lead to complication in multiple organs(such as the heart,brain and kidney),and in particular to major adverse cardiovascular events(MACE).Neither traditional Chinese medicine nor western medicine provides effective therapy for this disease,which presents a major threat to human health.In the previous study,the research group believed that RH was mostly a mixture of deficiency and reality,mainly reflected in the disease,the damage of zang-fu organs,the imbalance of Yin and Yang,qi and blood,and the combination of wind,fire,phlegm and blood stasis,which caused clinical syndrome differentiation difficulties.How to study the law of diagnosis and treatment of RH and its influencing factors with MACE in the real world,clarify the relationship between "disease,syndrome,disease and medicine(prescription)",and achieve precise medication to guide clinical practice and improve the therapeutic effect based on the dialectical prescription of special influencing factors is the focus of this research.1 PurposeThis research applies real world study method to explore precise syndrome differentiation and generation of prescriptions in diagnosis and treatment of RH in traditional Chinese medicine.To identify the key technology and range of application of the precise method,providing new ideas and methods for generation of shared techniques in precise prescription in treatment based on syndrome differentiation of traditional Chinese medicine.2 Contents2.1 Real world study on the rules of diagnosis and treatment of RH("disease-syndrome-medicine"),and comparison of difference in diagnosis and medication between western and traditional Chinese medicine for the group of RH without adverse events(RH group)with the group of RH combined with MACE(RH+MACE group).2.2 Screening the relevant factors for MACE in RH patients by GBM and XGBoosts algorithms,identification of rules of medication for main hazards,exploration of hazards of MACE for RH patients and scheme of precision medication considering the impact of clinical hazards on incidence of MACE,and identification of rules from "symptom" to "syndrome" "syndromes" to "prescription and medicine".3 Program3.1 Real world study of the rules of "disease-syndrome-medicine" for diagnosis of RH in traditional Chinese medicine and western medicine3.1.1 Source of casesOutpatient and admitted RH patients from January 1,2015 to November 30,2019 in the HIS of a third class hospital of traditional Chinese medicine in Beijing.3.1.2 Type of research designThis research is a cross-sectional research design under the real world study.3.1.3 Target groupsThe RH patients were divided into the group of RH without adverse events(RH group)and the group of RH combined with MACE(RH+MACE group)based on the 2018 Chinese Guidelines for the Management of Hypertension.3.1.4 Research methods(1)Identification of rules of diagnosis and treatment for the total RH population:basic description of the total RH population;frequency count and correlation analysis of diagnosis in western medicine,western medicines and their classification,syndrome elements in traditional Chinese medicine,and the traditional Chinese medicines;identification of core diagnosis and medication in traditional Chinese medicine and western medicine;and analysis of rules of diagnosis and treatment based on the aforesaid findings and on traditional Chinese medicine theories.(2)Comparison of the rules of diagnosis and treatment between the 2 groups:identification of diagnosis in western medicine,western medicines and their classification,syndrome elements in traditional Chinese medicine,and the connection between the syndrome elements and the traditional Chinese medicines prescribed;analysis of the difference in the core diagnosis and rues of medication between the 2 groups;and summary of the pathological characteristics of the 2 groups and approach to prescription for them,providing basis for further precision medication.3.1.5 Statistical methodsThis research uses R3.6.2 to conduct statistical analysis of the data.The main statistical methods used include general statistical methods,baseline analysis,correlation analysis,etc.3.2 Research of relevant factors of MACE of RH and the methods of Pivotal"Symptom-Medicine"3.2.1 Source of casesThis research needs complete information of electronic medical records,from the group of RH group and RH+MACE group among the admitted RH patients from January 1,2015 to November 30,2019 in a third class hospital of traditional Chinese medicine in Beijing.3.2.2 Type of research designThis research uses a retrospective study research design in the real world to study,the medical records of the patients that were first expressly diagnosed as having RH.3.2.3 Target groupsThe RH patients were divided into the RH group and the RH+MACE group based on the 2018 Chinese Guidelines for the Management of Hypertension.3.2.4 Research methodsThis research mainly uses the GBM and XGBoost algorithms in the Boosting Tree algorithms to screen the hazards,and analyzes the correlation between the main relevant factors and the western and traditional Chinese medicines with the association rules,so as to identify the precision medication.The specific methods are as follows(1)Structuring the method to screen variables for relevant factors of the RH group and the RH+MACE groupa.Structuring the objective function of the probability of the individual RH patient incurring MACE:the log-likelihood ratio is first introduced to structure the log function g(X)indicating the probability of the individual RH patient incurring MACE,where X is a factor having effect on the probability of the individual RH patient incurring MACE.b.Structuring several single regression tree models for the objective function of MACE:adaptive algorithms are used to automatically introduce multiple dimensions of factors(such as RH patients’ blood pressure,general condition,lifestyles,symptoms and signs,and combined diseases)into the objective function of MACE as concomitant variables,and structuring several single regression tree models till there are K(order of interaction)factors in the models.(2)Identifying relevant factors of individual RH patients incurring MACEEstimating the original value of the objective function g(X)for cardiovascular diseases,conducting linear addition of the single regression tree models with the Boosting algorithm,and identifying hazards of individual RH patients incurring MACE by continuous adjustment to residuals of the models.(3)Establishing methods for generation of precise prescription for main relevant factors of RH+MACEFor main relevant factors of RH+MACE,such as dizziness and chest distress.identifying associated core medicine suits with association rules,and analyzing the theoretical basis for treatment of the factors,so as to get the precise prescription for the relevant factors.(4)Establishing classification models for RH and RH+MACE patientsEstimating the original value of the objective function g(X),conducting linear addition of the single regression tree models with continuous iteration of the Boosting algorithm,and estimating the probability of individual RH patients being classified into the RH+MACE group.(5)Identifying the impact of hazards on the RH classification model based on the precise prescriptionBased on the precise prescription identified,with the assumption that the prescription is effective for the hazards,deleting the corresponding hazards,estimating again the probability of the RH patients incurring MACE,and identifying the significance of the relevant factors to RH leading to MACE,so as to provide guidance to improve precision of clinical medication.3.2.5 Statistical methodsThis research uses R3.6.2 for statistical analysis of the data,and screens the hazard variables with the GBM and XGBoost algorithms among the Boosting Tree algorithms.Other statistical methods used include baseline analysis,general statistical analysis,etc.4 Results4.1 Real world study on the rules of "disease-syndrome-medicine" for diagnosis of RH in traditional Chinese medicine and western medicine4.1.1 Target groupsBased on the screening procedure for RH,a total population of 4753 cases of RH outpatients and admitted RH patients from January 2,2015 to November 5,2019,among which 807 cases fall into the RH group and 3319 into the RH+MACE group.4.1.2 Age and gender distributionIn the total population of RH patients,there are significantly more male patients under age 60 than female patients.The incidence rate of female patients of above 60 increases gradually,higher than that of male patients(P<0.001).In the two groups,more than half(53.4%)of the patients in the RH group are under 60,and most(74.8%)of the patients in the RH+MACE group are above 60(P<0.001).There is no statistical difference between the two groups in terms of gender(P>0.05).4.1.3 Analysis of diagnosis names and associated diseases in western medicineThere are 3306 diagnosis names in western medicine among the total population of RH patients.With a lift>1,analysis of association rules indicates a high degree of association between lipid metabolism disorder and hypertension(385 cases,a confidence of 96.98%).Of the 2 groups,the RH group has numerous complex associated diseases(mainly hyperlipemia,diabetes and arthralgia,with multiple association nodes);the RH+MACE group is mainly associated with MACE diseases(such as grade 3 hypertension and coronary atherosclerotic heart disease,with multiple association nodes).4.1.4 Diagnosis names and analysis of classes of syndromes in traditional Chinese medicineOf the total population of RH patients,diagnosis names in traditional Chinese medicine are mainly thoracic obstruction,insomnia,heart failure,thoracic obstruction and heartache.The classes of syndromes in traditional Chinese medicine include mainly qi xu xue yu,gan yang shang kang,tan yu hu jie and qi yin liang xu.4.1.5 Syndrome elements in traditional Chinese medicine and related analysisOf the total population of RH patients,disease locations in traditional Chinese medicine are mainly the liver,spleen and kidney,high confidence for "lung-heart-meridian"(13.6154).Core syndrome elements in traditional Chinese medicine are "qi deficiency,blood stasis,and phlegm",with high support and confidence for "qi deficiency-blood stasis"(support of 27.33%,confidence of 67.69%)and "phlegm-blood stasis"(support of 22.95%,confidence of 72.78%).Of the 2 group,the RH+MACE group has a high degree of association between the disease locations of the heart,lung,and meridian(lift:10.1916).In terms of disease elements,there is an obvious association rule of yin deficiency and yang hyperactivity among the RH group.The RH+MACE group has a high degree of association with qi deficiency,blood stasis,phlegm,kidney essence deficiency,and fever.4.1.6 Classification of western medicines and medicine-related analysisAmong the total population of RH patients,CCB,β receptor antagonist,and diuretic have the highest frequency of use(>60%among the total population).In terms of association rules,diuretic,CCB,and β receptor antagonist have the highest degree of association with other antihypertensive drugs(multiple association nodes).Among the 2 groups,the RH+MACE group uses more furosemide and spironolactone than the RH group(multiple association nodes).Diuretic,CCB,and βreceptor antagonist are common drugs for both groups.The RH+MACE group has a higher degree of association between blood-lipid regulating drugs and other drugs than the RH group(multiple association nodes).4.1.7 Names of traditional Chinese medicines and analysis of the composite prescriptionsFor the total population of RH patients,the expectorants(mainly fuling,zhuru,chenpi,banxia,and gancao),the qi-tonifying medicines(mainly huangqi,dangshen)and blood-activating medicines(mainly danshen,chishao,chuanxiong,danggui)have a high frequency of use and a high degree of association with other medicines(support>5%,and multiple association nodes).Spleen-strengthening medicines and expectorants(fuling,chenpi,banxia and gancao)are core prescriptions for both groups.For the RH group,there is an obvious tendency toward tianma gouteng decoction;and for the RH+MACE group,there is an obvious tendency toward danggui buxue decoction(huangqi and danggui)and danshen,chuanxiong(support>10%,and multiple association nodes).4.1.8 Analysis of association between syndrome elements and traditional Chinese medicinesAmong the 2 groups,the syndrome elements of the RH group are mainly qi deficiency,blood stasis,and yang hyperactivity;in the prescriptions,there is a high degree of association between yang hyperactivity and tianma gouteng decoction;(support>3%,and multiple association nodes).For the RH+MACE group,there is a high degree of association between phlegm syndromes and banxia,chenpi,fuling,gancao(support>5%,and multiple association nodes).4.2 Research of relevant factors of MACE of RH and the methods of Pivotal"Symptom-Medicine"4.2.1 Target groupsA total population of 2367 cases of admitted RH patients with complete EMR information from April 27,2015 to October 25,2019 are included in the research.Among them,152 patients are in the group of RH group,and 1286 are in the RH+MACE group,totaling 1438.4.2.2 General information(1)Age:the RH group has a lower average and median age than the RH+MACE group(P<0.001).(2)Gender,nationality,marriage and occupation:the incidence rate of female patients is higher than that of male patients in both groups(P=0.05).There is no statistical difference between the 2 groups in terms of nationality and marriage(P>0.05).(3)Solar terms of onset:the onset is mainly around the First Frost,Cold Dew,End of Heat and other solar terms for the RH group;for the RH+MACE group,the onset is mainly around Cold Dew,End of Heat,Beginning of Winter and other solar terms.(4)General physical examination:the RH+MACE group has faster breath than the RH group,and the RH group has higher systolic blood pressure and diastolic blood pressure than the RH group.There is no statistical difference in terms of height,weight,BMI,body temperature,and heart rate(P>0.05).4.2.3 Results of screening of the relevant factors with 2 Boosting Tree algorithms(1)GBM algorithm:the first 15 relevant factors are diastolic blood pressure,historical hypertension,historical cerebral infarction,systolic blood pressure,chest distress,age of 60 and above,age of 60 and below,time of smoking,heart rate,lack of vitality from the eye,constipation,body temperature,dyspnea,carotid atherosclerosis,and gender.The accuracy of the classification model is 89.25%,the precision 92.05%,the sensibility 96.43%,and the AUC of the ROC curve 0.851.(2)XGBoost algorithm:the first 15 relevant factors are diastolic blood pressure,age of 60 and below,heart rate,systolic blood pressure,chest distress,gender,age of 61 and above,edema of lower extremity,tough tongue,constipation,historical hypertension,grade 3 hypertension,historical cerebral infarction,lack of vitality from the eye,and dyspnea.The accuracy of the classification model is 93.4%,the precision 94.2%,the sensibility 98.9%,and the AUC of the ROC curve 0.897.(3)Combined results of the 2 algorithms:12 relevant factors appear in both algorithms(diastolic blood pressure,systolic blood pressure,age of 60 and above,age of 60 and below,gender,historical hypertension,historical cerebral infarction,heart rate,chest distress,lack of vitality from the eye,constipation,and dyspnea).Based on the clinical characteristics of the 2 groups.4.2.4 Identification and analysis of precision medication with the symptoms as main relevant factors(1)Results of western medicines:"chest distress" has a high degree of association with furosemide and spironolactone,β receptor antagonists(such as metoprolol and bisoprolol fumarate),with multiple association nodes."Lack of vitality from the eye",has a high degree of association with diuretics(such as furosemide and spironolactone),β receptor antagonists(such as metoprolol tartrate and metoprolol succinate sustdined-release tablets)."Dyspnea" does not have a signifigant association.(2)Results of traditional Chinese medicines:"chest distress" has a high degree of association with expectorants(such as banxia,chenpi,fuling)(support>13%,multiple association nodes)."Lack of vitality from the eye" has a high degree of association with qi and spleen-tonifying medicines(such as huangqi,dangshen,gancao),expectorants(such as fuling,chenpi)(support>13%,multiple association nodes)."Dyspnea" does not have a significant association.(3)Symptoms and syndrome:"chest distress,chord,greasy,lack of eyes,lower limb edema" and "blood stasis" have high correlation degree(support>13%,confidence>60%),"lack of vitality from the eye" has a high correlation with qi deficiency(support>13%,confidence>47%).(4)Precision medicine results:If "chest distress" amalgamative "moss is greasy,vein is slippery",can use "banxia,chenpi,fuling";if "chest distress" combined with "lack of vitality from the eye,lower limb edema",can use "huangqi,danshen,baishu,gancao";if "lack of vitality from the eye" combined with "moss is greasy,vein is slippery",can use "fuling,chenpi",if " lack of vitality from the eye" combined with"pulse string,chest tightness",can use "chishao,danggui,chuanxiong".4.2.5 Identification of significance of symptoms as main factors to the estimate of probability of RH+MACEThe waterfall plot based on the significance of the 20 hazards indicates that the initial probability of an individual RH patient being classified into the RH+MACE group is 98.57%.After improvement of the 2 main hazards,the probability drops to 94.78%.5 Conclusions5.1 The pathogenesis of RH is based on deficient root and excessive superficial.The pathological properties are feng huo tan yu xu.When RH has no adverse events,it is mostly yinxu yangkang,fengyangshangrao.After the combination of adverse cardiovascular events,tanyu hujie,accumulate poison fire,block qi,decoction fluid injury,and feng huo tan yu xu cause and effect each other,making the disease more complex and changeable.5.2 RH treatment should be both virtual and real.When RH has no adverse events,it should pinggan,buqi and qutan,mainly including tianmagouteng decoction,dangguibuxue decoction,wendan decoction.After the combination of adverse cardiovascular events,it should buqihuoxue,tanyutongzhi,mainly including dang gui bu xue decoction,huanglian wen dan decoction,guanxin Ⅱ and xiongshao capsule.5.3 In this study,descriptive and inferential statistics and association rules were used to explore the law of disease-evidence-medicine,and then relevant factors were screened by GBM,XGBoost and other lifting tree algorithms,so as to seek the intrinsic association between syndrome-syndrome and drug,and the mining method of precision medicine was feasible6 Innovations6.1 With RH as an example,this research takes an early step in combining real world study with big data technology to explore key techniques for generation of precise prescriptions,providing new ideas and methods for the shared techniques to improve the precision of prescriptions in treatment based on syndrome differentiation of traditional Chinese medicine.6.2 This research takes an early step in identifying the rules of precise prescriptions in traditional Chinese medicine and western medicine for the common refractory disease of RH in clinical practice.It takes an initial step in addressing the precision medication from the perspectives of "disease-syndrome","symptom-syndrome","syndrome-medicine" and "symptom-medicine",providing scientific basis for clinical medication. |
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