| BackgroundGlucolipid metabolic disorders(GLMD)are prevalent metabolic conditions characterized by abnormalities in both glucose and lipid metabolism,which can cause damage to multiple systems and organs and pose a significant threat to human health and well-being.Our team has pioneered the concept of GLMD and conducted a large amount of clinical and basic research,demonstrating that the Integrated Chinese and Western Medicine is clinically effective in preventing and treating GLMD.However,evaluating the clinical effectiveness of Integrated Chinese and Western Medicine for GLMD from a contemporary medical viewpoint and highlighting its clinical advantages is still an urgent issue.Here,we adopt the Core Outcome Sets(COS)research method to establish a comprehensive core outcome system for GLMD that reflects the characteristics of Integrated Chinese and Western Medicine and explores new methods for analyzing pattern effectiveness.This study aims to provide a reference for comprehensively evaluating the clinical effectiveness of GLMD and highlighting the advantages of Integrated Chinese and Western Medicine in treating this disorder.ObjectiveThe purpose of this study is to solve the problem of "what to evaluate" and "how to evaluate" the clinical effectiveness of integrated Chinese and Western medicine in the prevention and treatment of GLMD by constructing an outcome system for evaluating the effectiveness of GLMD,which includes the following three aspects1.By using the COS development method,we aim to sort and classify the commonly recognized outcomes of GLMD and explore the differences between the outcomes of traditional Chinese medicine and internationally recognized outcomes,as well as their possible complements.We will construct a COS for glucolipid metabolic disorders that reflects the characteristics of Integrated Chinese and Western Medicine and provides a reference for evaluating the clinical effectiveness of GLMD.2.Referring to the COS development path and combining the construction of the core pattern sets of traditional Chinese medicine,we integrate and analyze the distribution status of core patterns in clinical studies of glucolipid metabolic disorders,sort out the core pattern of GLMD,and enrich and supplement the unclear parts of the COS,providing a reference for the evaluation of the clinical effectiveness of Integrated Chinese and Western Medicine.3.Based on the prospectively collected case data of individuals with GLMD,we aim to explore the application method of traditional Chinese medicine pattern differentiation in evaluating clinical effectiveness,establish a path and framework for analyzing and displaying effectiveness comparisons based on pattern information,and provide a method and demonstration research for evaluating the effectiveness of traditional Chinese medicine pattern differentiation in treating glucolipid metabolic disorders.Methods1.The first part of the study aimed to construct a core outcome set for GLMD.The study protocol was developed in accordance with COMET Manual 1.0,T/CACM 1339-2020 Technical Specification for the Development of Core Indicator Sets for Clinical Trials in Chinese Medicine,and Methods and Practices for the Study of Core Indicator Sets for Clinical Evaluation.Firstly,the scope of application of the core outcome set for GLMD was determined and registered on the COMET website.Second,the outcomes were compiled and summarized from the clinical research literature on glycolipid metabolic diseases,drug development guidance on behalf of policy-making and regulatory parties,and interview data from physicians,nurses,and patients,respectively.Third,we established a pool of outcomes entries and classified the outcome domains attributed to each original outcome based on the outcome classification system.Fourth,a Delphi survey was conducted among the stakeholder groups of the core outcome set to obtain consensus opinions on the importance of the outcomes.Finally,a core outcome set for GLMD(COS-TCM-GLMD)was established.2.The second part of the study aimed to construct a core CM pattern set of GLMD.Following the methodology of COS study,the research plan was developed by drawing on the idea of constructing the core CM pattern set of TCM proposed by related scholars.Firstly,the scope of the core CM pattern of GLMD was determined.Second,we will conduct a systematic search of cross-sectional studies related to the patterns of glucolipid metabolic disorders,and organize the terminology and distribution of patterns.Thirdly,a hierarchical classification tree was drawn based on GB/T 16751.2-2021 Chinese Medicine Clinical Treatment Terminology Part 2:CM pattern,and the original CM pattern and terms of CM pattern were standardized and merged to establish an alternative CM pattern list.Fourthly,Meta-analysis was performed to calculate the prevalence rate of the alternative core CM pattern in the overall population.Fifth,a Delphi survey was conducted among the stakeholder groups of the core set of CM pattern to obtain consensus opinions on the importance of the CM pattern.Finally,a core CM pattern set of GLMD was established.3.The third part of this study aims to explore the application of traditional Chinese medicine pattern differentiation in evaluating clinical effectiveness.Firstly,a prospective clinical study will be conducted based on the diagnostic criteria for GLMD,and a data governance plan will be developed to collect clinical data of patients with this disorder,including basic information,anthropometric indicators,and repeated visits with patterns information after data cleaning.The number of diagnoses and the interval between visits will be calculated based on the collected data.Secondly,based on the diagnostic scale of glucolipid metabolic disorders developed by the team,we calculated 15 standardized CM patterns of patients and classified different groups according to the CM pattern characteristics of patients by consensus clustering method.Third,quantitative analysis was performed to analyze the variability of the patient’s inter-visit CM pattern,and a matrix of the number of patient inter-visit CM pattern transformations was constructed to show the transformation characteristics between each CM pattern cluster,while standard deviation,coefficient of variation and weighted standard deviation were calculated to assess the inter-visit variability of the CM pattern.Fourth,the dynamic change process of the CM pattern with consultation times was visualized in the form of a Sankey diagram.Fifth,a visual analog scoring(VAS)method was used to construct a symptom severity judgment scale to measure and transform the CM pattern information in the form of continuous variables.Sixth,the net change in comparative CM pattern effectiveness was assessed using methods such as differences-indifferences(DID)method after adjusting for confounding factors.Seventh,the effectiveness comparison results based on pattern information will be presented in a visualized manner using a forest plot,and a path and framework for analyzing and displaying effectiveness comparisons based on patterns information will be established.Results1.the first part of the study included a total of 27429 clinical research literature on GLMD in the literature system evaluation,and finally included 1198 eligible studies after inclusion and exclusion,with a maximum of 279 total publications in 2019,the maximum number of literature on disease type 2 diabetes mellitus totaling 798,the minimum number of literature on hyperlipidemia combined with NAFLD totaling 5,and the literature reported endpoints the minimum number of outcomes reported in the literature was 1,and most of the literature reported about 7-11 outcomes,only a small number of literature reported more than 20 outcomes,the most one reported 35 outcomes,only 14 disclosed the study registration number,and the interventions of the study were mainly the combination of Chinese and Western medicines,followed by simple Chinese medicine intervention.A total of 11,645 original outcome indicators were reported in the included literature,and after terminology normalization and merging,a list of original outcome indicators with a total of 875 outcomes was formed for 7 outcome domains(biomarkers,safety events,TCM-related outcomes,quality of survival,clinical signs/symptoms,composite outcomes/endpoint events,and economic assessment).For drug development guidelines,this study incorporated seven existing guidelines issued by drug development regulatory agencies in China and the United States,from which a total of 106 outcomes were analyzed.In terms of clinical surveys and interviews,3 physicians,3 nurses,and 17 patients were recruited to participate in semistructured interviews,and a total of 34 outcome indicators in 7 outcome domains were compiled based on the interview results,and the results were integrated to form 7 domains and 104 alternative outcomes for the Delphi survey.In terms of consensus formation,54 questionnaires were collected in the first round of Delphi survey,with a high degree of expert authority(Cr 0.86>0.7),and the results of the first round of Delphi survey showed that there were 31 outcomes that met the criteria for reaching consensus,and there were 27 outcomes that were considered important and critical by more than 70%of the experts,with an average level of consistency in evaluation among experts,and a Kendall W coordination coefficient of 0.273(P<0.001),and 7 experts completed the open-ended questions at the end of the Delphi questionnaire recovered in the first round,and a total of 11 outcomes were collated and 1 outcome was included in the second round of Delphi survey.A total of 37 questionnaires were collected in the second round of the Delphi survey,and the degree of agreement between the 2 scores of experts before and after was strong(ICC correlation coefficient 0.884),with 31 indicators reaching consensus criteria.The final result was a list including 5 outcome domains:biomarkers(weight,medications,BMI,body fat percentage,waist-hip ratio,fasting glucose,glycated hemoglobin,2h postprandial glucose,fasting insulin,fasting C-peptide,glucose target range time,triglycerides,total cholesterol,LDL cholesterol,HDL cholesterol,HOMA-IR,HOMA-β,HOMA-IS,TyG),safety events(adverse events,hypoglycemic events),TCM-related outcomes(CM pattern score,CM symptom score),quality of survival(quality of life),and endpoint events(overall efficiency,complication rate,MACE,risk of coronary heart disease,diabetes remission,stroke events,all-cause death)for a total of 31 outcomes for core outcome set of Glucolipid Metabolic Diseases(COS-TCMGLMD).2.The second part of the study included a total of 16518 clinical studies containing information on the CM patterns of GLMD in the systematic evaluation of the literature,and finally 1142 eligible cross-sectional studies were included after inclusion and exclusion.The number of published literature showed an increasing trend after 2000,and the maximum number of literature for disease type 2 diabetes was 725(53%),and the average sample size of all included studies was 497.3(106.0,317.0),the average sample size reported for each disease type ranged from 298.2 to 811.9,the average number of CM patterns reported in the literature was 5.6(4.0,7.0),and the number of CM patterns reported increased as the sample size increased.In the included cross-sectional study,a total of 6363 original CM patterns names were reported,and the raw data were cleaned using GB/T 16751.2-2021 Chinese medicine clinical diagnosis and treatment terminology Part 2:CM patterns to form a list of original CM patterns with 4 primary categories and 28 secondary stratified categories,totaling 279 CM patterns,and 3 major categories were selected according to the number of CM patterns reported Seventeen CM patterns were selected based on the number of CM patterns reports,forming the Delphi survey alternative CM patterns.In the analysis of the distribution of the core CM patterns,the sample size of the alternative core CM patterns ranged from 5030 to 45370,and after Meta-analysis of the single group rate,it was found that the prevalence rate of all the alternative core CM patterns was>10%,and the highest symptom was Qi and Yin deficiency[27.4%(25.7%-29.3%)],and the lowest symptom was Yin and Yang deficiency[11.6%(10.3%-12.9%)],and there was no significant correlation between the prevalence of CM patterns and the number of published papers.In terms of consensus formation,a total of 48 valid questionnaires were returned in the first round of Delphi survey,with a high degree of expert authority(Cr 0.85>0.7),and the results of the first round of Delphi survey showed that there were 5 CM patterns that met the criteria for reaching consensus,and there were 4 CM patterns that were considered important and critical by more than 70%of experts,with an average level of inter-expert evaluation agreement,and a Kendall W coordination coefficient of 0.200(p<0.001).A total of 34 questionnaires were collected in the second round of Delphi survey,and the level of agreement between the 2 scores of experts before and after the survey was strong(ICC correlation coefficient 0.622),and there were 5 CM patterns with consensus criteria,forming a list of core symptom terms including damp-heat internal invasion pattern,phlegm-dampness pattern,phlegm-dirtiness pattern,phlegm-stasis pattern and qi deficiency and blood stasis pattern.3.In the third part of the study,regarding the characteristics of the study population,data from 539 consultations of 210 patients with GLMD were included.The main CM patterns at the first consultation were yin deficiency pattern(47.6%),dampness pattern(45.2%),yang deficiency pattern(44.8%)and blood deficiency pattern(43.8%),and the disease location CM patterns were mainly kidney pattern(33.8%)and liver pattern(31.9%).The clustering division combined with the characteristics of the standardized CM patterns of each cluster population,the CM patterns of the sample population in this study can be divided into 5 clusters with different evidence characteristics:Qi stagnation and heat pattern(cluster 1),Yin and blood deficiency pattern(cluster 2),Yang deficiency and water-dampness pattern(cluster 3),Yin deficiency and heat pattern(cluster 4)and damp-heat pattern(cluster 5).In the analysis of inter-visit variability of patients’ CM patterns,among a total of 329 changes in CM patterns,more than half of the patients’ CM patterns would change in 2 visits before and after,with an overall change rate of 65.05%,and the inter-visit variability of all 5 clusters of CM patterns was large(CV>0.25),with the greatest degree of variability in the middle cluster 1(Qi stagnation and heat pattern)[CV 0.641(0.567,0.716),SD 0.103(0.090,0.116),w-SD 0.166].Using Sankey diagrams to demonstrate the CM patterns evolution in the first five visits,the results showed that CM pattern clusters 1,2,and 3 had a greater weight in visit 1,and CM pattern clusters 1,2,3,and 5 had a major transformational weight in visits 2-5,and it was common for each CM pattern cluster to transform into each other between visits.In terms of comparing the effectiveness of the CM patterns,the study population was divided into a group of unchanged CM patterns and a group of changed CM patterns according to the changes in the CM pattern clusters between the last visit and the current visit,and the differences in the CM pattern scores between the two groups were compared to assess the clinical effectiveness of the CM pattern.The results showed that the VAS scores of the CM pattern information of belching,dark color of the mouth and lips,depression,frequent farting,distension and fullness of the stomach and abdomen,chest tightness,chest pain,stringiness of the pulse,thirst and drinking,bitterness of the mouth,redness of the face,yellow and red urine,distress of the heart,dark red tongue,red tongue,yellow coating,and number of the pulse,as well as the score of the Qi stagnation pattern,the score of the heat pattern,and the total score were higher in the unchanged group than in the changed group,among them,the net difference between groups in facial redness[6.82(1.19,12.45)]and total score[5.05(0.79,9.32)]was statistically significant(P<0.05),the net differences in VAS scores for evidence information such as liking to sigh,eating a lot and being easily hungry,impatience and irritability,and bad breath were higher in the evidence change group than in the evidence unchanged group,with statistically significant net differences between groups for impatience and irritability[-6.78(-13.04,-0.53)](P<0.05),and sensitivity analysis showed that the above results were robust.Finally,this study developed the above process into a methodological framework for the evaluation of effectiveness using CM patterns as outcome(VACATION framework),which provides a preliminary scheme of what to measure,how to measure,how to evaluate and how to present the evaluation results.Conclusion1.This study established a COS for the clinical effectiveness evaluation of GLMD(COS-TCM-GLMD)which includes five domains and 31 core outcomes.The application of these COS will contribute to the comprehensive evaluation of the clinical effectiveness of Integrated Chinese and Western Medicine in preventing and treating GLMD,highlighting their clinical advantages,and promoting the understanding of comprehensive integrated control of GLMD.2.This study identified five core traditional Chinese medicine syndrome indicators for GLMD and supplemented them into the COS-TCM-GLMD.This will help to highlight the traditional Chinese medicine characteristics of the COS for evaluating the effectiveness of GLMD treatment and provide a basis for selecting pattern differentiation for evaluating the effectiveness of Integrated Chinese and Western Medicine.3.The VACATION framework for analyzing and displaying effectiveness comparisons based on pattern information established in this study provides a clear and convenient tool for evaluating the effectiveness of traditional Chinese medicine pattern differentiation in treating GLMD,in the absence of a unified methodology.These results,together with the first two parts of this study,have formed a system of COS for evaluating the effectiveness of GLMD treatment with Integrated Chinese and Western Medicine,preliminarily addressing the question of "what to evaluate" and "how to evaluate" the clinical effectiveness of Integrated Chinese and Western Medicine in treating GLDM. |
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