Research on the development methodology for clinical practice guidelines for organic integration of traditional Chinese and Western medicine

Integrated traditional Chinese medicine (TCM) and Western medicine (WM) is a new medical science grounded in the knowledge bases of both TCM and WM, which then forms a unique modern medical system in China. Integrated TCM and WM has a long history in China, and has made important achievements in the process of clinical diagnosis and treatment. However, the methodological defects in currently published clinical practice guidelines limit its development. The organic integration of TCM and WM is a deeper integration of TCM and WM. To realize the progression of "integration" to "organic integration", a targeted and standardized guideline development methodology is needed. Therefore, the purpose of this study is to establish a standardized development procedure for clinical practice guidelines for the organic integration of TCM and WM to promote the systematic integration of TCM and WM research results into clinical practice guidelines in order to achieve optimal results as the whole is greater than the sum of the parts. Supplementary Information The online version contains supplementary material available at 10.1186/s40779-023-00481-9.


Introduction
Integrated traditional Chinese and Western medicine involves synthesizing the knowledge of traditional Chinese medicine (TCM) with the knowledge of Western medicine (WM).This process amalgamates the essence of the ancient and the modern, TCM and WM, and creates a brand-new medical science in our country, which is an important symbol of achieving the modernization of medical science [1].The root of integrated TCM and WM can be traced back to Chairman Ze-Dong Mao's series of directives in the last century.Chairman Mao said that we should combine the knowledge of TCM and WM to create a unified new medicine and new pharmacology in China.In 1955, in response to Chairman Mao's call, the Ministry of Health hosted the first national course for WM practitioners to learn TCM.Following this, various provinces and cities in China held a series of national courses for teaching TCM to WM practitioners: the door to integrated TCM and WM was officially opened.In 1981, the first National Congress of integrated TCM and WM was held.In the same year, the Chinese Association for Science and Technology approved the establishment of the Chinese Association of Integrated TCM and WM and the founding of the Chinese Journal of Integrated Traditional Chinese and Western Medicine [2].
The integration of TCM and WM has been developing for nearly 70 years, during which time it has not only experienced various challenges but has also achieved extraordinary successes.However, it is evident that although there are achievements in integrated TCM and WM the existing methods mostly stay at the experiential level, or simply involve the addition of certain treatment methods, and this cannot really guide its clinical diagnosis and treatment practices.The development of the diagnosis and treatment methods of integrated TCM and WM needs to focus on clinical practice, seek the convergence of TCM and WM relating to the clinical problems, and apply evidence-based methods as a breakthrough, to deeply explore the mechanism, form and level of the combination of TCM and WM in the practice of diagnosis and treatment.
"Organic integration of TCM and WM" is the development and deepening of the connotation of "integrated TCM and WM".Many scholars have proposed that TCM and WM should not only be integrated, but should also achieve organic integration.They believe that the future of integration of TCM and WM is the pathway "from integration to organic integration" [3].
To realize the progression of "integration" of TCM and WM to "organic integration", the first thing is to formulate complete and standardized clinical practice guidelines (guidelines for short) for the organic integration of TCM and WM.This should not be a simple superposition or piling up of evidence and recommendations of WM and TCM, but a deep organic integration of the advantages of applying both TCM and WM on the basis of clinical diagnosis and treatment pathways.However, at present, a problem of "incompatibility" in the guidelines for integrated TCM and WM remains.The recommendations of TCM and WM are mostly independent, inconsistent with the actual clinical diagnosis and treatment process and lacking important information, leading to low operability of the guidelines which means that they cannot be implemented in clinical practice, limiting the development of organic integration of TCM and WM.The standardized formulation, dissemination and implementation of guidelines for organic integration of TCM and WM is the only way for the real organic integration to be achieved [4].

Normative references
The following documents are indispensable for the application of this document.For dated references, the dated version only applies to this document.For undated references, the latest version (including all amendments) applies to this document.
There are no normative references in this document.

Terms and definitions
The following terms and definitions apply to this document.

Clinical practice guidelines (CPGs)
CPGs propose the optimal guidelines related to patients' specific clinical problems, based on the results of a systematic evaluation of available evidence, after a comprehensive analysis of the pros and cons of various alternative interventions.
At present, it is normal practice that evidence-based medicine methodology is based on comprehensive retrieval and strict evaluation of evidence, taking into account the patient's willingness and value preference, resource consumption and other factors.
Guidelines are then formulated using the same standardized and scientific method, which is the main method for formulating international and domestic guidelines.Domestic guideline developers often divide the guidelines into clinical practice guidelines and expert consensus.Some researchers tend to think that expert consensus is an occupational guidance document of lower quality and influence than guidelines, that is, the guidelines are more scientific, transparent and reliable.This standard does not define the above classifications here, and it is suggested that the guidelines and expert consensus should both be developed in accordance with the guidelines for the standard.

Integration
Origin of Chinese Characters records: "Integration" refers to a superficial connection, which often still has areas of incompatibility.
In Oxford Dictionary of English, "integrate" refers to the combination (one thing) with another to form a whole.

Organic integration
Origin of Chinese Characters records: Organic integration means the cooking gas comes out", "Organic Integration" means that materials enter into each other and become one.Organic integration is really the addition and integration of TCM and WM to form a new system.
In Oxford Dictionary of English, "organic" means "denoting or characterized by a harmonious relationship between the elements of a whole".

Clinical practice guidelines for organic integration of TCM and WM
Integrated TCM and WM is a comprehensive medical discipline based on the ontology and epistemology of TCM, as well as the reductionism, systematology, information theory and cybernetics of modern medicine.It studies the phenomenon, nature and timely evolution of human life and disease, promotes human health, and prevents and treats diseases.The organic integration of TCM and WM is based on the integration of TCM and WM, but goes further and lays more emphasis on the complementary advantages of TCM and WM in the interpretation of mechanisms, clinical research and clinical practice.
Guidelines for the organic integration of TCM and WM are guidelines that provide TCM doctors, WM and integrated TCM and WM doctors with recommendations on TCM and WM modalities.Generally, the topics of these guidelines are oriented towards the diagnosis and treatment of dominant diseases found in both TCM and WM.They aim to solve the problem of how to choose the intervention measures of TCM and WM in clinical practice.The guidelines for organic integration of TCM and WM should not be a simple superposition or stack of evidence and recommendations of WM and TCM.
It is the deep organic integration of the advantages of TCM and WM based on the clinical diagnosis and treatment pathways.
Except for the word "organic integration of TCM and WM" which has been used in the newly proposed "Clinical practice guidelines for organic integration of TCM and WM" in this standard, other previous guidelines in the field of integrated TCM and WM or words related to the discipline of integrated TCM and WM have all used the word "Integrated TCM and WM".

Conflict of interest
As for the difference between personal interests and professional obligations, an independent third party has reason to question whether an individual's professional behavior or decision is driven by personal interests (such as financial, academic, clinical income or social status), economic or professional relationships.

General
The guidelines for organic integration of TCM and WM should focus on clinical practice, seek the combination of TCM and WM from clinical problems, utilize evidence-based methods as the way forward, have as the goal the full integration of the recommendations of TCM and WM, and achieve the full integration of TCM and WM [5].The guidelines should meet the following requirements in the process of formulation.

General principles or methods
The first step in formulating a guideline is to establish a theme, that is, to clarify the purpose, significance and scope of application of the guideline.Generally speaking, the guideline consists of one "theme" and several "clinical problems".Clinical problems are the basis for formulating literature retrieval strategies and systematic evaluation and finally forming recommendations.The determination of the guideline theme mainly considers the following factors: 1) The theme has important clinical significance, such as diseases having a high incidence rate, morbidity or mortality or posing a heavy economic burden, and the implementation of the guideline is likely to improve important patient outcomes and reduce medical costs.2) The subject presents with large differences in clinical practice or clinical research results.3) At present, there are no existing effective guidelines on relevant topics for use.4) The research evidence is relatively sufficient; 5) The selected guideline theme is one of the "Dominant diseases" of integrated TCM and WM? "Dominant diseases" refer to diseases with "comparative advantages" in the efficacy, safety, compliance and other aspects of integrated TCM and WM.

For the determination of the theme of the clinical practice guidelines for organic integration of TCM and WM, the following questions should be considered:
Whether there is a relationship between WM diseases and TCM diseases or a relationship between WM diseases and TCM syndrome differentiation and whether, when selecting the guideline theme, the scope of integrated TCM and WM involved in the theme of the guidelines for organic integration TCM and WM has been determined through extensive professional consensus?
According to the guideline theme determined in question (1), it should be further determined whether the guideline is named by WM disease names, TCM disease names or TCM syndrome differentiation.Does the practice of diagnosis and treatment of the disease fully reflect the characteristics of organic integration of TCM and WM? Instead of simply focusing on TCM or WM, or simply adding the two.For example, for a viral cold or a certain stage, a certain subtype, a certain syndrome or a certain symptom of a viral cold, some Chinese medicine/traditional Chinese herbs may have the effect of replacing and/or supplementing WM, while some may exert attenuated and/or enhancing effects on WM or other WM therapies; and vice versa.

Considerations for the development of clinical practice guidelines for organic integration of TCM and WM
Dual diagnosis is often used in the existing guidelines for integrated TCM and WM.In dual diagnosis, the WM disease name is based on Western medical diagnostic criteria, and then the TCM disease name is based on the main symptoms of the disease.
Therefore, it can determine the scope of both the Western medical disease and the Chinese medical disease included in the guidelines.There are three patterns in general (Fig. S1).In the following diagram and examples, the pattern in Fig. S1a shows that Western diseases are included in the scope of TCM disease names.For example, knee osteoarthritis (KOA) falls under the category of "knee paralysis" in Chinese medicine.
The pattern in Fig. S1b shows that different diseases share common pathogenesis at different stages of development and can be diagnosed according to TCM pathogenesis in conjunction with WM disease names.For example, "blood stasis syndrome" is seen in the context of coronary heart disease, cerebral infarction, etc.The pattern in Fig. S1c shows that when the main symptoms of the disease are different at different stages of disease development, the range of WM diseases can involve multiple TCM disease categories.For example, diabetes mellitus falls under the Chinese medicine categories of "thirst disorders" and "spleen disease".For another example, IgA nephropathy does not have a specific Chinese medicine name and is mostly classified as "hematuria", "edema", "lumbago", "kidney wind", "consumptive disease", and other categories.

General principles or methods
The clinical question is the basis for the final recommendation.The method of constructing the questions can be guided by the current international model: the PICOS model.P is the specific population, which mainly defines the target population and specifies which characteristics are to be considered; I (or E) is the intervention or exposure, which may also be a prognostic factor or trial break; C is the control or another intervention that can be used for comparison; O is the outcome, which describes the outcome of interest; S is the study design, which defines which type of study design is used.A guideline often contains multiple PICOS questions.Identifying clinical questions for guidelines requires systematic literature reviews, qualitative interviews, and questionnaires with stakeholders.Questionnaires need to be broadly representative and therefore must take full account of the geographical distribution of respondents, and multidisciplinary balance (also, the gender or ethnic balance, where relevant).It is recommended that a stakeholder analysis be conducted before the interviews or research to identify the population that the guidelines are likely to involve or affect, to hear and obtain a wide range of stakeholder views before asking questions, selecting and ranking the outcomes.Guideline developers should fully consider the characteristics of combined treatment of diseases with TCM and WM treatment and include a specific outcome for TCM before ranking the outcomes importance.

Considerations for the development of clinical practice guidelines for organic integration of TCM and WM
The question formulation (Fig. S2) for the guidelines for organic integration of TCM and WM should be generated from the practice of integrating TCM and WM, especially for the most confusing problems faced by clinicians, and should reflect the characteristics and ideas related to the integration of Chinese and Western medicine.
The clinical questions identified should be specific and clear, and can function as a direct guide for the subsequent literature search.Clinical questions like "whether the combination of proprietary Chinese medicine with conventional Western medicine is better than conventional Western medicine alone in the treatment of a disease" are too broad.
Clinical questions for Chinese patent medicine should be identified in addition to the clinician research mentioned above, the clinical questionnaire should also be refined

General principles or methods
A Guideline Proposal/Protocol is a summary document that outlines a plan or series of steps showing how the guidelines will be developed, including all proposed methods.The proposal generally includes background, the institution, and organization developing or involved with it, the target population, the intended end users of the guideline, the composition and roles of the development team, the topic, purpose, scope and clinical issues.It should also show how evidence was obtained, how recommendations were generated, any external review and publication strategy, the timeline of key steps, funding and access to funding, conflict of interest investigation, and management methods.Chinese authors who need to register their guidelines can do this on the International Practice Guideline Registration Platform (http://www.guidelines-registry.cn/).

Regarding proposal writing on the clinical practice guidelines for organic integration of TCM and WM, the following points should be considered
Does the guideline explicitly use integrated TCM and WM models of diagnosis and treatment?(For example, "combination of WM diseases and TCM syndrome differentiation", "combination of WM and TCM at different stages of disease", "syndrome differentiation and targeted therapy", "multidisciplinary diagnosis and treatment").See Appendix C for details.

Formation of the guideline development team
The guidelines' development team should generally be composed of members with expertise in relevant clinical specialties (including TCM, WM, and integrated TCM and WM), evidence-based medicine, health economics, epidemiology, literature, statistics, and other professional skills.In additional relevant people from this and other fields should be included according to the appropriate content of the guideline, including inviting representatives from hospitals at different levels and patient representatives as members.Potential conflicts of interest must be considered before identifying members of the guideline development group.All panel members are required to conduct a conflict-of-interest survey and declare their interests (see Appendix D for details) and the results of all members' declaration-of-interest surveys will be published with the final guideline.In principle, relevant persons with significant conflicts of interest cannot participate in meetings related to the development of recommendations.

General principles or methods
Generally, the types of evidence collected include guidelines, systematic reviews, metaanalyses, randomized controlled trials, observational studies, qualitative studies, professional consensus, expert opinion, case studies and economics studies.
According to the research methods used, types of evidence can be classified as primary and secondary research.In general, if a high-quality systematic review/metaanalysis is retrieved that matches the clinical question of the guidelines and has been published in the last 2 years, it can be used directly to save time and cost.However, attention should be taken to ascertain whether any relevant literature has been published since the date of this systematic review search.If it is determined that there are no other relevant and high-quality systematic reviews/meta-analyses, then a systematic search of the original studies can be conducted.The literature for a particular study design should be selected based on the type of clinical question.In special cases, such as where the evidence has not been published, where there is no direct evidence, for rare diseases, for new diseases, etc., it may be difficult to retrieve appropriate research evidence.At this point, expert evidence may be the only or primary source of evidence.
The guidelines' formulation team needs to clearly define the inclusion and exclusion criteria for the literature, and rigorously apply the evaluation criteria of evidence-based medicine to scientifically evaluate the relevant literature.For example, quality evaluation of systematic reviews using the AMSTAR evaluation tool, quality evaluation of various types of original studies such as RCTs using the Cochrane Risk of Bias Assessment Tool, or the JBI principles of evaluation designed for specific studies.
The evidence evaluation should have resulted in an outcome summary table or evidence summary table (see Appendix E), which contains the PICO problems, the number of studies, the number of patients, outcome indicators and significance, a summary of the results for each outcome (including relative and absolute effect sizes), the quality of the evidence evaluation and the results of the evidence grading.This information provides a concise summary of the evidence for decision-makers to proceed to the generation of recommendations.

In response to the evidence search for clinical practice guidelines for organic integration of TCM and WM, the following questions should be considered
Has there been a complete retrieval of evidence sources for TCM, WM and integrated TCM and WM (such as consulting experts in the TCM field, searching the featured TCM database)?
Has there been a collection of characteristic evidence of TCM, such as TCM ancient books, expert experience?
Has there been a collection of evidence of patients' preference, willingness, and values for accepting TCM or WM treatments?
Besides the above considerations, has there been a complete retrieval of information on the "body of evidence" for a specific clinical question?First, the "body of evidence" can be derived from a synthesis of evidence from the best research design, or it can be composed of evidence from multiple research methods and multiple sources.
For example, when real world evidence exists, ancient documentary evidence and expert opinion evidence can be corroborated with real world evidence to form a "body of evidence".Again, for example, the "body of evidence" from randomized controlled trials provides evidence of intervention effectiveness, while studies such as observational studies or the registration and recording platforms of adverse reactions can provide research evidence of intervention implementation and safety, and the two types of evidence together support the designation of scientific and rational decisionmaking.

Considerations for evidence retrieval in the development of clinical practice guidelines for organic integration of TCM and WM
In the development of Guidelines for Organic Integration of TCM and WM, the evaluation of evidence sources needs to refer to the concept of "triple integration", which includes clinical research evidence, ancient literature and expert experience of TCM: none of the three can be ignored.However, a lot of work is still needed to deal with the definition of TCM expert opinions, because of the existence of overlap between the categorization of some expert opinions and the sources of ancient documents.In this standard, the expert opinions are those of contemporary medical practitioners, while the ancient literature refers to medical literature before 1911.
Ancient TCM literature and the experience of modern TCM experts should also be validated and evaluated by clinical studies (including traditional clinical studies or clinical studies based on real world data), so that they can enter the aggregation and evaluation of secondary studies and thus become a source of evidence for clinical practice guidelines.That is: the classical evidence of TCM is validated through the corroboration of ancient and modern evidence (Fig. S3).
If the expert opinion of traditional Chinese medicine must be used as the evidence source, the evidence can be collected in the same way as the case report or case series study.For example, because there is very little research evidence that can account for the effects of the intervention, the experts can develop the overall number of their patients and estimate the effectiveness of the intervention, and then use structured forms to collect and analyze the above information and submit it to the guidelines' development team as a summary of the survey results.
The formulation of guidelines for Organic Integration of TCM and WM is often faced with difficulties because of insufficient evidence, especially the lack of highquality studies on the comparison of integrated TCM and WM and non-integrated TCM and WM.At this point, the guidelines' development group needs to gather expert evidence that includes empirical feedback from long-term practice provided by people who are knowledgeable or technically skilled in a particular field, on the clinical issues that urgently need to be addressed.Unlike expert opinions, being collected systematically, expert evidence needs to provide facts to support the conclusion.And before the meeting forming the recommendations, expert evidence is provided to the consensus group members.If the evidence is properly summarized, expert evidence can be collected and evaluated in the same manner as a case report or a series of case studies.

General principles or methods
The most commonly used international standard for grading the quality of evidence is GRADE.Through taking a comprehensive consideration of risk of bias, publication bias, inconsistency, indirectness, imprecision (random error), effect sizes, doseresponse relationships, and confounding factors for included studies of systematic reviews, the GRADE evidence system classifies the effect indicators of systematic reviews as the "body of evidence" for quality assessment [6].In addition, Chen et al [7].
have developed a revised version of the "Delphi" literature basis and grading of recommendations (Chinese medicine), a grading system for recommendations, and the quality of evidence commonly used in guidelines/expert consensus for guidelines for TCM/WM, incorporating ancient and modern expert consensus and ancient literature into the quality of evidence grading and grading of recommendations.Chen et al [8].
have also developed the reference proposal for grading clinical research evidence and recommendations based on "body of evidence", incorporating expert opinions, experiences, and historical records, forming a grading standard for the quality of evidence based on body of evidence, so formulating a new grading standard for recommendations based on the GRADE standard.

In view of the evaluation of the quality of evidence and the classification of recommendations in the clinical practice guidelines for organic integration of TCM and WM, the following questions should be considered:
Is it necessary to classify the quality of evidence with TCM characteristics such as TCM ancient books and expert experience?Or is there a custom classification standard of the quality of evidence and recommendations for the Guidelines for Organic Integration of TCM and WM?
How should an appropriate grading system for the quality of evidence and recommendations be chosen in order to achieve a reasonable classification of included TCM and WM literature?In this process, is it necessary to make appropriate adjustments to the existing grading system of the quality of evidence and recommendations (especially the grading system based only on the modern medical system)?Has the adjustment method passed the consensus of the guide development group?

Points for attention in the formulation of clinical practice guidelines for organic integration of TCM and WM
It is reasonable and feasible to use the GRADE system to classify modern research evidence in the field of TCM, but there are still some challenges in the use of GRADE in guidelines for TCM / integrated TCM and WM.For example, evidence from ancient literature and expert experience is an important feature of TCM.When the evidence of modern medicine is insufficient and the evidence of ancient literature or expert experience is sufficient, it will be difficult for guidelines developers to choose a rating if they directly choose to use GRADE system, and more exploration and thinking are needed in the field of TCM.
Acknowledging that the classical medical records of ancient books and the experience of famous experts are important supplements to the clinical evidence system of TCM, the existing guidelines of TCM / integrated TCM and WM often adjust and modify the GRADE system according to the specific evidence problems of TCM under the concept of the GRADE method, but this must be carried out based on the full consensus of the guideline-making methodologists and the formulation team.
The mixed use of multiple quality-of-evidence or recommended grading standards is not advocated, mainly because of the systematic nature and integrity of the grading standards in the process of development and formulation.If a complete grading standard is separated and/or combined with another standard, it is bound to break the internal logic of the original standard.For example, GRADE classification is based on different initial evidence levels of different research types, and then considers its promotion or downgrading.For different clinical problems, it takes into account the intensity, feasibility, advantages and disadvantages of the study design, especially the internal bias, as well as the cost and feasibility of transforming evidence into decisionmaking, which are not fully reflected in other classification standards.

General principles and methods
Factors to be considered in the formation of recommendations: in addition to the quality of evidence, acceptability, feasibility, fairness, resource utilization, patients' values and preferences, and the balance of advantages and disadvantages are also factors that often need to be considered in the formulation of recommendations.In the actual operation, the above factors can be incorporated into the recommendation to form a framework for experts to judge item by item in the consensus meeting.In the process of formulating recommendations, the guidelines' working group should clarify and accurately define the factors to be considered in the formulation of recommendations, and quantify the criteria to be considered as far as possible.It is suggested that the scientific and transparent formulation of recommendations should be ensured with the help of predesigned content frameworks or auxiliary tools.As the formation of recommendations is affected by many factors, such as evidence, cost, and patient willingness, more and more evidence and recommendation classification standards no longer emphasize the one-to-one correspondence between recommendation intensity and evidence level, that is, high-level evidence may be weakly recommended and low-level evidence may also be strongly recommended.However, if the above situation occurs, it is recommended that the guidelines' development team should give a clear explanation.
The consensus method for the formation of recommendations: The consensus method is to collect a variety of suggestions or opinions from multiple individuals through a specific method to form a consistent conclusion or point of view.According to whether the formal consensus procedure or process is adopted, it can be divided into informal consensus method and formal consensus method.The informal consensus method is that participants fully express their own views, discuss them freely, and finally reach a consensus on recommendations.However, this lacks methods to reach a consensus, and individuals may not be able to fully express their true views because they are not familiar with the issue and feel pressure when they disagree with other people's views.In comparison, the formal consensus method adopts a structured process, clearly reaches a consensus, reduces the possible bias, and the results are more authoritative, reasonable and credible.

In view of the method for forming the recommendations for the clinical practice guidelines for organic integration of TTCM and WM, the following question should be considered:
When forming the recommendations for the organic integration of TCM and WM, are clinical experts from TCM, WM and the integration of TCM and WM invited to agree on the recommendations?Does the generated recommendation explain the relationship between TCM treatment, WM treatment and integrated TCM and WM treatment?See Appendix F (recommendation Fusion example) for details.c) According to the national conditions in our country, the guidelines for the organic integration of TCM and WM should absorb the theories of TCM and WM, highlight the advantages of the organic integration of TCM and WM, and give patients an individualized, accurate and humanized multi-mode diagnosis and treatment plan for integrated TCM and WM.d) When formulating the guidelines, we should refine the best combination of "disease differentiation" in WM and "syndrome differentiation" in TCM, supplement the deficiency of "disease without syndrome" in WM, and make up for the embarrassment of "syndrome without disease and indefinite type" in TCM, so as to show the value of the combination of TCM and WM.It is necessary to refine the diagnosis and treatment modes of integrated TCM and WM, and form an accurate treatment method under the combination of syndrome differentiation, stage differentiation and disease differentiation.e) Under the guidance of the general principle of "cure the symptoms when it's urgent and cure the root causes when it's slow", we should promote the combination of dispelling pathogens and strengthening vital energy treatment, short-term cure and long-term regulation, and give full play to the complementary advantages of TCM and WM at different stages of treating the disease.
f) It is recommended that targeted recommendations are formulated according to different periods, different degrees of illness and different syndromes.g) When the recommendations of TCM and WM are given at the same time, the order of treatments and priority should be clearly specified, for example, at which stage of the disease is the organic integration of TCM and WM better than simple TCM or simple WM? How should they be combined?Which is the main one?What are the potential interactions?

General principles and methods
Recommendation intensity is the degree to which guidelines' developers comprehensively consider the quality, feasibility and acceptability of evidence, patients' values and wishes and other factors to understand the advantages and disadvantages of the implementation of recommendations.This must normally be described using technical terms and symbols and generally appears after the text of each recommendation.The text of the recommendation must be clear and feasible.The use of clear text language to express the recommended content is important and where necessary should include an explanation of the relevant technical terms or content.Each recommendation should specify its recommendation intensity, and the description of recommendation intensity generally refers to the use of clear language or symbols after the recommendation sentence to distinguish the different levels of recommendation intensity.In addition to marking the level of recommendations, reflecting the level of recommendations is proposed by describing them in standard terms, such as "suggestions" and "offer" to reflect strong recommendations and "considerations" to reflect weak recommendations.All these ensure that recommendations are clearly expressed and consistent in the full text of the guide.
Recommendations should not appear in large sections of the guidelines as far as possible, but should be summarized separately, or presented in bold, underlined form, or in the form of a table, which is clear, concise and easy to understand, and provides a direct reference for users.

Points for attention in clinical practice guidelines for organic integration of TCM and WM
When there is no evidence of the effect of the organic integration of a TCM and WM, it may not be possible to make recommendations based on the evidence, in which case, a statement can be made such as "because there is no evidence of the effectiveness (or harm) of intervention X, it is not possible to make a clear recommendation" or "unable to make recommendations due to lack of evidence".Sometimes, although there is no good evidence, the guideline from professional institutions is still needed (for example, clinical research shows that this problem is an urgent clinical problem), and at this time the guideline-making team should also make recommendations accordingly, which can be marked "based on the recommendations from a consensus of experts".For example, in the absence of strict research evidence, the evaluation of ancient books, medical records of TCM and WM experts can also become the basis for the formulation of recommendations, but their retrieval, selection, synthesis and evaluation methods should be determined in the guidelines plan and consistent with the quality of evidence of this guidelines and the classification method of recommendation opinions, and marked with a statement such as "consensual recommendation" or "expert consensus" after the corresponding recommendation opinion.

External examination and evaluation
After the formation of consensus recommendations, the guidelines development group should invite experts in relevant fields outside the formulation group, experts in the field of integrated TCM and WM, and other stakeholders as external assessors.In order to ensure the quality of the external audit, the external auditors must also submit the relevant declaration of conflict of interest.The external auditors can make comments through a variety of channels; the most common way of achieving this is to fill in the form.The content of the table generally revolves around the accuracy and clarity of the recommendations, the rationality of the guidelines' formulation method, especially the completeness and correctness of literature retrieval and evaluation, and the transparency of the guidelines' formulation process.
There are two main aspects to external audit: opinion solicitation and peer expert review.The purpose of soliciting opinions is to introduce the preliminary conclusions and relevant recommendations of the guidelines to different groups in society through various channels after writing the draft guidelines.Expert opinions are extensively solicited to ensure the applicability and extensibility of the guidelines.The peer review is an invitation to peer experts to review the guidelines from a professional perspective after the guidelines have been revised and refined by the guidelines development team based on the comments collected.

General principles and methods
The content of the report of guidelines generally includes abstract, introduction, main clinical problems, evidence, recommendations, reasons for recommendations, attached references, acknowledgments, list of personnel.The WHO handbook for guideline development proposes [9-10] that all guidelines should include executive summary, main body, and appendices, the executive summary should contain the main recommendations of the guidelines, and the main body should contain the table of contents, introduction, methods, recommendations, and conclusions.In addition, the systematic review and grading of results can be presented in the appendices.After the guidelines have been developed, they should be checked to ensure a full and complete report according to the Reporting Items for Practice Guidelines in Healthcare (RIGHT) inventory and checklist for the reporting of guidelines of TCM to fully consider reporting details from recommendation of TCM treatment.After the recommendations have been written, it is recommended that the guidelines' development team produce a flowchart of the implementation of the recommendations, pictures and videos or digital intelligent solutions which facilitate the implementation of the recommendations to be published together with the text of the guidelines or give download links in the guidelines text.

4.11.2
In response to the report of clinical practice guidelines for organic integration of TCM and WM, the following questions must be considered Does the title of the guidelines clearly state "guidelines for organic integration of TCM and WM?" Has a recommendation implementation pathway map or other visual form been developed to present the recommendation, which reflects the full organic integration of TCM and WM recommendations?
Is the report of clinical practice guidelines of organic integration for TCM and WM based on the pre-set model of integration of TCM and WM?

Promotion and implementation of guidelines
The guidelines' development organization has the responsibility and obligation to promote the dissemination and promotion of the guidelines.
In the process of guidelines implementation, obstacles may be encountered at multiple levels, and the process of guidelines promotion should take note of these obstacles and give reasonable suggestions to deal with them.Meanwhile, experts in the field can develop matched implementation strategies for the guidelines.

Updating of guidelines
Guidelines should be updated 2 -3 years after publication.The guidelines panel should undertake long-term follow-up on the evidence related to guidelines recommendations after the guidelines are published.
The international trend in guidelines development emphasizes the dynamic development of systematic reviews, i.e., dynamic development through living systematic review.The guidelines update process is initiated when new relevant evidence emerges from new guidelines publication and the change in evidence has an impact on the strength or direction of this guideline's recommendations, at this point, the update may not be limited to 2 -3 years after guidelines publication.Guidelines updates should be published in a timely manner through the guidelines update organization's website and journals, and the updated content should be prominently and clearly marked.Disease differentiation is helpful to improve the accuracy of syndrome differentiation, and syndrome differentiation is helpful for the concretization of disease differentiation.
On the one hand, the content of the four diagnoses of TCM can be enriched and supplemented by the help of examination, pathology, imaging and other means.On the other hand, for some diseases with abnormal indicators without obvious clinical manifestations, the combination with WM can deal with the dilemma of unidentified syndromes in TCM.For some diseases that cannot be diagnosed positively by WM examination, the combination with TCM syndrome differentiation can make up for the lack of disease identification in WM.

C.2 Combination of WM and TCM at different stages of disease model
The mode of the combination of disease stage and syndrome is to differentiate the syndrome at different stages of the disease on the premise of making clear the diagnosis of the disease by WM, to combine the disease stage and syndrome vertically based on the combination of the disease and syndrome, and to differentiate and analyze the syndrome from dynamic multi-dimensional angles.Diseases can be staged according to the WM diagnosis, considering the disease process, the severity of the disease, and the test indicators [14].
To establish a modern diagnosis and treatment model of integrated TCM and WM based on "syndrome differentiation and treatment, combined with disease stage and syndrome", it is necessary to find the best combination point of "disease differentiation" and "syndrome differentiation" in WM and TCM, to supplement the deficiency of "disease without syndrome" in WM and make up for the embarrassment of "syndrome without disease or stages" in TCM, which shows the unique guiding value of Integrated TCM and WM.Refine the combination model of "macroscopic differentiation of syndromes + differentiation of stages + microscopic differentiation of diseases" to form an optimized treatment that combines syndrome differentiation, stage differentiation, and disease differentiation [15].

C.3 Mode of syndrome differentiation and targeted therapy
The mode of syndrome differentiation and targeted therapy involves combining the macro "state" and "syndrome" of TCM with the micro "symptom" and "target" to communicate the macro and micro diagnosis and treatment in integrated TCM and WM [16].
On the one hand, the idea of "syndrome differentiation and targeted therapy" requires "correction" of imbalances.From a macro perspective, when considering the state of cold and heat and the imbalance of Yin and Yang by diseases, the partial nature of drugs is used to restore the self-harmony of Yin and Yang in the human body and lead to recovery from disease.In view of diseases that have been unambiguously diagnosed in modern times, there needs to be a clear understanding of the physiological and pathological features of the disease identified with the help of modern medicine.
The whole process of the disease needs to be examined according to TCM thinking, the characteristics of various stages of the disease development must be clarified, and the core pathogenesis for syndrome differentiation and treatment must be summarized.On the other hand, it emphasizes the clinical "targeting", that is, to improve the targeting and precision of clinical treatment.The targeting of clinical treatment has three aspects: targeting the disease itself, targeting the typical symptoms, and targeting the clinical physical and chemical indicators.The research results of modern pharmacology are used to improve the precision of TCM prescription drugs and accurately target specific diseases.
In addition to the above, there may also be other modes of organic integration of TCM and WM for its specific clinical practice themes, such as the mode of syndrome combination (symptoms in WM and syndrome in TCM).The guideline development team also needs to discuss this in-depth to fit it into clinical practice.

D.2 Financial conflict of interest statement
The financial conflict of interest statement should contain the information shown in

D.3 Non-financial conflict of interest statement
The non-financial conflict of interest statement should contain the information shown in Table .D3.

Table.D3 Non-financial conflict of interest statement
Within the past 36 months: In addition to the above, within the past 36 months, is there anything else that you need to declare?If yes, please fill in the box below.

D.4 Declaration of interest publication of informed consent and authenticity
In order to ensure the authenticity and validity of the declaration, the conflict of interest declaration should be signed by the declarer.

Example:
Informed about the conflict of interest statement: I agree to make the above completed content public to other guideline development members, and agree that the statement of interest form will be published in the guideline.Clinically, the intervention effect of TCM therapies including cooling blood, detoxifying, purgating fu-organ, Fuzheng, warming.Yang and Tongqiao, is explored.

Statement
By actively sending medicine formula developed in TCM principle-methodologyformula-medication and using Western pathophysiology as the reference.

Fig. S1
Fig. S1 Diagram of the disease name relationship between organic integration of TCM and WM. a The scope of WM disease names is included in the category of TCM disease names category.b The scope of TCM disease names category includes a variety of WM diseases; c The scope of WM diseases involves a number of TCM disease names category.TCM traditional Chinese medicine, WM western medicine

4. 3 . 2
Regarding the question of establishing clinical practice guidelines for organic integration of TCM and WM, the following questions should be considered: Does the proposal of the problem come from the practice of integrated TCM and WM, and include the idea of integrated TCM and WM treatment?Refer to Appendix A (Example of clinical question formulation)?Are TCM clinicians and WM clinicians, as well as clinicians combining Chinese and Western medicine all selected for the questionnaire?Refer to Appendix B (Template for a basic framework for research on clinical questions and outcome indicators)?
by extensive searches of Chinese patent medicine codex books, national medical insurance catalogues and basic drug catalogues.Searches of the official State Drug Administration website to identify certain Chinese patent medicine that are legally marketed in mainland China are needed, and discontinued drugs should be eliminated.Questionnaire research on the use of Chinese patent medicine in clinical practice is needed to further explore the importance of clinical problems based on the use of certain proprietary Chinese medicine alone or in combination with Western medicine.

Fig. S2
Fig. S2 Example of the relationship between clinical question formulation and guideline topic (disease/syndrome differentiation).* The "TCM disease names" in the diagram on the left are shown as dashed boxes, as it is often not possible to match the WM names with the TCM disease names.TCM traditional Chinese medicine, WM western medicine, PICO population, intervention, control or comparison, outcome.

Fig. S3
Fig. S3 Source levels of evidence developed and schematic diagram of the structure of clinical practice guidelines for organic integration of TCM and WM.

4. 8 . 3
Points for attention in clinical practice guidelines for organic integration of TCM and WM TCM and WM have their own relatively complete diagnosis and treatment systems.TCM has TCM decoction, proprietary Chinese medicine, TCM injection, external treatment methods including acupuncture, cupping, moxibustion, Tuina, traditional skills of TCM and many other treatment methods.WM also has many treatment methods, such as Western medications, surgery, interventional therapy, physiotherapy, chemotherapy, and psychotherapy.When forming a recommendation, attention should be paid to the following: a) In the analysis of the results of the evidence, for the sake of transparency in the formulation of the guidelines, attention needs to be paid to minimizing differences in importance of the outcome to assist in determining whether a recommendation is given, such as a reduction of at least 8 per 1000 people over five years and 10 per 1000 of nonfatal strokes.b) In the choice of a TCM intervention or a WM intervention, the values and preferences of patients should be obtained by combining the theme of the guidelines and the use and cost of the intervention, so as to fully assess the absolute benefits and hazards of different interventions as well as the potential treatment burden.

Outcome: 1 .Outcome: 1 .ForOutcome: 1 .Exposure: 1 .
The above guideline development methods are not sufficient to meet the whole process and methodological details of a guideline development.The guideline development team needs to integrate the above methodological points into the guideline development process in a sequential manner (see Appendix G).Guidelines' developers can still refer to the basic methodology of other published guidelines (especially in the field of WM) to understand many details of the guidelines' development process, such as the contributors and their role in guidelines development, literature retrieval and systematic review of the guidelines' development team.Treatment/Interv ention In men with premature ejaculation, did oral paroxetine combined with Shugan Yiyang capsules prolong intravaginal ejaculation latency time (IELT) after 8 weeks off the drug compared with oral paroxetine alone?Did the Chinese index of sexual function for premature ejaculation scale (CIPE) score improve?Population: Men with premature ejaculation (WM disease name) Intervention: Oral paroxetine combined with Shugan Yiyang capsules Comparison: Oral paroxetine alone Outcome: 1.The IELT after 8 weeks off the drug; 2. The CIPE score In elderly patients with gastrointestinal dysfunction due to sepsis, which method is more effective in improving patients' syndrome of spleen-stomach Qi deficiency compared with conventional WM treatment by combining this with Xiang-sha six jun-zi decoction?Population: Elderly patients with gastrointestinal dysfunction due to sepsis (WM disease name) Intervention: Xiang-sha six jun-zi decoction combined with conventional WM treatment Comparison: Conventional WM treatment Outcome: 1. Score of syndrome of spleen-stomach Qi deficiency scale; 2. Scale of gastrointestinal dysfunction score Table.A1 Treatment/intervention (Continued) chronic renal failure, which is more effective in improving edema combining oral keto acid tablets with reserved enemas in TCM (30 g calcined longgu, 30 g calcined oyster, 30 g dandelion) compared with oral keto acid tablets alone?Population: Patients with chronic renal failure (WM disease name) Intervention: Oral keto acid tablets combined with reserved enemas in TCM treatment Comparison: Oral keto acid tablets Outcome: Ankle circumference difference In patients with ulcerative colitis, oral mesalazine combined with Chinese herbs (basic formula of Chinese herbs: Astragalus 30 g, cinnamon 10 g, ginger 10 g, patrinia 20 g, coptis 10 g, atractylodis macrocephalae koidz 15 g, atractylodes 15 g, natural indigo15 g, bitter ginseng 15 g, salvia miltiorrhiza 15 g, roasted licorice 10 g; when there is obvious abscess and blood in stool add anemoside 15 g, cortex fraxini 12 g; when there is urgency and posterior heaviness, add bupleurum 12 g, cimicifugae rhizoma 69 g) Compared with oral mesalazine alone, which method is more effective in improving patient's diarrhea?Population: Patients with ulcerative colitis (WM disease name) Intervention: Oral mesalazine combined with TCM Comparison: Oral mesalazine Outcome: Frequency of diarrhea In patients with diabetic nephropathy, which regimen is more effective in improving renal function (SCr and BUN) and 24 h urine protein quantification in patients treated with hemiprostone combined with prostaglandin compared to hemiprostone alone or prostaglandin alone?Population: Patients with diabetic nephropathy (WM disease name) Intervention: Hemiprostone combined with prostaglandin Comparison: 1. Hemiprostone; 2. Prostaglandin Outcome: 1. Renal function (SCr and BUN); 2. 24 h urine protein quantification In patients with cerebral infarction, which is more effective in improving patients' neurological deficits and daily living ability, the combination of aspirin and Buyang huanwu decoction compared with aspirin alone?Population: Patients with cerebral infarction (WM disease name) Intervention: Aspirin in combination with Buyang huanwu decoction Comparison: Aspirin Outcome: 1.The national institute of health stroke scale; 2. The activity Table.A1 Treatment/intervention (continued) of patients with eczema of the yin deficiency and wet stagnation, which method is more effective in improving the area and severity index of eczema and the degree of itching?The use of oral Chinese herbs (rhizoma picrorhizae, forsythia, gypsum, poria, atractylodes, danpi, adenophorae radix, oyster, adenophorae radix, adenophorae radix, red bean, schizonepeta, radix paeoniae, bitter ginseng, astragalus) compared with oral levocetirizine hydrochloride combined with topical compound flumethasone?Population: patients with eczema of the yin deficiency and wet stagnation syndrome (TCM syndrome type and WM disease name) Intervention: Oral Chinese herbs Comparison: Oral levocetirizine hydrochloride combined with topical compound flumethasone The area of eczema; 2. The severity index of eczema; 3. The degree of itching In patients with shift work sleep disorders, which method is more effective in of daily living scale In patients with functional dyspepsia, which method is more effective in treating patients' gastric motility and restoring normal levels of gastrointestinal hormones, using Tuina massarge versus oral cisapride?Population: Patients with functional dyspepsia (WM disease name) Gastric motility (The number of migrating compound motor waves (MMC) and postprandial sinus contraction amplitude P, contraction frequency F); 2. Serum gastrointestinal hormone levels (Gastrin, growth inhibitor, motilin) improving sleep quality, head point Tuina therapy combined with oral eszopiclone versus oral eszopiclone tablets?Population: Patients with shift work sleep disorders (WM disease name) Intervention: Head point Tuina therapy combined with oral eszopiclone Comparison: Oral eszopiclone tablets Outcome: The Pittsburgh Sleep Quality Scale A.2 Prognostic clinical problems Examples of clinical problems posed in the prognostic category are shown in Table.HIV patients, what factors reduce patients' mortality?Population: HIV patients (WM disease name) Exposure: 1. Combined TCM treatment group on the basis of standardized WM treatment 2. Acute phase Comparison: 1. Standardized WM treatment 2. Non-acute phase (asymptomatic, pre-AIDS and AIDS phase) Outcome: Mortality rate of AIDS patients For elderly patients with gastric cancer, what factors can affect survival?Population: Elderly patients with gastric cancer (WM disease name) Exposure: 1. Tumor node metastasis classification; 2. Male; 3. Radical surgery Comparison: 1. Tumor node metastasis classification (compare with each other); 2. Female 3. Nonradical surgery Overall survival; 2. Disease free survival In patients with post-operative PTCA for coronary artery disease, whether different syndromes in TCM will affect the incidence of restenosis?Population: Patients with post-operative PTCA for coronary artery disease (WM disease name) Phlegm syndrome; 2. Qi stagnation syndrome; 3. Blood stasis syndrome; 4. Cold condensation syndrome Comparison: 1. Non-phlegm syndrome; 2. Non-qi stagnation syndrome; 3. Non-blood stasis syndrome; 4. Non-cold condensation syndrome corresponding clinical problems, please fill in the corresponding blank box and give the corresponding score value (classification A and classification B, such as efficacy outcome indicators and safety outcome indicators).important outcome indicators that we may have missed, and score them Please add any important outcome indicators that we may have missed and score them Please add any important outcome indicators that we may have missed and score them pathological diagnosis), and identify what the syndrome is according to the TCM syndrome types differentiation method.b) Disease differentiation is the main method, syndrome differentiation is the supplementary method.In clinical treatment, it is necessary to comprehensively consider both the characteristics of modern medical disease diagnosis and the characteristics of TCM syndrome diagnosis, prescribe drugs for the key pathological problems of the disease, and at the same time supplement this according to the results of TCM syndrome differentiation and treatment with drugs for the syndrome.c) Syndrome differentiation is the main method, disease differentiation is the supplementary method.According to the patient's information of four diagnoses, to identify the syndrome diagnosis of disease and the corresponding prescription.On this basis, appropriate consideration is given to the use of disease-specific drugs in the light of the understanding of disease pathology in modern medicine and the results of pharmacological research.d) Microcosmic syndrome differentiation.When a patient without any clinical symptoms, only has abnormal physical and chemical indicators, a comprehensive analysis can be made according to the patient's past medical history, physical tendency, physical and chemical indicators and the research results of modern TCM micro syndrome differentiation.e) Syndrome without disease, disease without syndrome."Syndrome without disease" is directly selecting the prescription herbs for the syndrome according to the results of TCM syndrome differentiation."Disease without syndrome" is directly selecting prescription drugs for pathology according to the pathophysiological mechanism of the disease.f) Combined TCM and WM, dual therapy.In view of the diseases diagnosed by WM, it is better to take Western drugs according to symptoms differentiation combined with syndrome differentiation in TCM than to use Chinese or Western medicine alone.
have published academic papers related to the contents of the guideline YES□ NO□ I have applied for a technical patent related to the content of the guideline YES□ NO□ I have religious, political, ideological and other personal beliefs related to the content of the guideline YES□ NO□ I have personal relationships with authors, editors, etc. of academic papers involved in the guideline YES□ NO□

Fig.F1 1 . 2 . 3 . 6 . 7 . 1 .
Fig. F1 shows recommendation flow chart and the relationships between Integrated TCM and WM by referring to part of the published guidelines.Table.F1 Examples of recommendations

2 . 1 . 1 . 1 .
Fig. F1 This figure takes the abnormal uterine bleeding of ovulation disorders as an example to show how to organically integrate Western medicine disease and stage classification with Chinese medicine disease and syndrome types, so highlighting different clinical problems at different stages and providing corresponding TCM and Western medicine treatment recommendation strategies.In the process of formulating the guideline, the guideline makers should fully consider the corresponding relationship between TCM syndrome types and Western disease types from clinical practice, and put forward clinical questions according to the different stages, types and syndrome types of the diseases, culminating in the making of recommendations.This is the treatment strategy of integrated Chinese and Western medicine, thereby achieving the purposes of enhancing efficiency and reducing toxicity and complications, thus improving clinical efficacy.

Table . D1
Experts' basic information

Table . D2
Financial conflict of interest statement YES□ NO□ I or my immediate family members have received fees, equipment, services, etc. from companies, institutions, or organizations that have an interest in the guideline to support research.Companies, institutions or organizations that have an interest in the guideline refer to companies, institutions or organizations that develop, manufacture, sell, promote, and provide products or services that are related to medical devices, equipment, drugs, preparations, etc. involved in the recommendations of the guideline.Immediate family members refer to those who have direct blood relationship or marriage to the expert, including a spouse, parent, and children.
companies, institutions, or organizations that have an interest in the guideline.

Evidence summary table and consensus voting tableTable . E1
: I promise that what I have stated is true and complete.If the information I have stated above changes at any time, I will promptly inform the guideline secretary group and complete a new statement of interest form.Summary of evidence

Consensus voting table is shown in Table. E2 Table. E2 Consensus Voting Table
Note 3:The direction and strength of recommendations can be expressed in different forms, such as A/B/C classification, etc., and the options in the table can be modified

Examples of relationship forms applied in recommendations for clinical practice guidelines for organic integration of traditional Chinese and Western medicine Table. F1 shows
examples of recommendations which can reflect the intervention relationship between traditional Chinese and Western medicine.