Development Of Patient-Reported Outcome Scale Of Spleen Deficiency And Its Application In Efficacy Evaluation Of Integrated Western Medicine Disease And Traditional Chinese Medicine Syndrome

Background and aim: Objective quantification of Traditional Chinese Medicine(TCM)syndrome is a vital issue in clinical practice.The project aimed to develop a patientreported outcome(PRO)scale of a representative TCM syndrome,the spleen deficiency syndrome,based on subjective symptoms’ evaluation.Afterwards,on the foundation of spleen deficiency PRO scale,the project analyzed the epidemic features of spleen deficiency syndrome in natural population,then established the integrated efficacy evaluation system of non-alcoholic fatty liver disease(NAFLD)and spleen deficiency syndrome based on targeted metabolomics.Methods: The project contained four sub-studies.Study one was a literature study on the evaluation status of spleen deficiency syndrome.Five mainstream Chinese and English platforms were selected.Eligible literatures concerning syndrome differentiation of spleen deficiency published between 2014 and 2018 were included.Frequency statistics were carried out on the research diseases,the standard sources of syndrome differentiation and the number of references related to spleen deficiency syndrome.Meanwhile,the characterization information of spleen deficiency syndrome except tongue and pulse was extracted.Study two was the development of spleen deficiency PRO scale.Based on the characterization information of spleen deficiency syndrome from research one,current guidelines and previous experience,the spleen deficiency PRO scale was developed according to established procedures.To be specific,the procedures contained preliminary draft of the spleen deficiency PRO scale,multi-rounds Delphi consensus survey,expert demonstration and population reliability and validity test.Study three was an observational study on the epidemic features of spleen deficiency syndrome in natural population.This was a cross-sectional study involving natural population.The spleen deficiency PRO scale was used to evaluate and distinguish spleen deficiency syndrome.Demographic information,physical indicators and clinical chronic disease information were collected to evaluate the prevalence of spleen deficiency syndrome in natural population and its correlation with common chronic diseases.Study four was the establishment of the integrated efficacy evaluation system of NAFLD and spleen deficiency syndrome.This was post-analysis of a randomized controlled trial.On the basis of blinding,30 cases of treatment response of Homeostasis model assessment of insulin resistance(HOMA-IR)and 30 cases of treatment response of spleen deficiency PRO scale were included.The serum samples were collected before and after treatment for targeted quantitative metabolomics.The integrated efficacy evaluation method of NAFLD and spleen deficiency syndrome was then established based on commonresponded differential metabolites.Results: Study one: A total of 312 qualified literatures were included,covering 145 diseases.Chronic hepatitis B was the disease with the highest frequency involving spleen deficiency syndrome.Most of the criteria for syndrome differentiation of spleen deficiency referred to national/industrial standards,followed by self-designed criteria based on previous studies.More than 30% of the studies referred to two or more standards.Loose stool,lack of appetite and fatigue are frequent characterization information of spleen deficiency syndrome.Study two: The preliminary draft of spleen deficiency PRO scale was developed based on the selection of 10 symptoms and signs including laziness to speak,easy perspiration,tasteless,loose stool,increased saliva,gingival bleeding,cold limbs,insomnia,easy getting cold and change of diet habits.Three rounds of Delphi experts survey and demonstration revised the expression and weight of some items,and formed the test draft of spleen deficiency PRO scale.A total of 153 postgraduates majoring in TCM participated in the population reliability and validity test.The internal reliability,content validity,discriminative validity and structural validity of spleen deficiency PRO scale were all qualified.Study three: A total of 11999 subjects were included to receive spleen deficiency PRO scale,and data of 10,768 cases were included in following analysis.Based on spleen deficiency PRO scale,the incidence rate of spleen deficiency syndrome in natural population was approximate 11.6%.The spleen deficiency syndrome was independently related to waist-height ratio,body mass index,coronary heart disease,stroke,hyperuricemia,dyslipidemia,chronic obstructive pulmonary disease,and chronic nephritis.Study four: Based on the target quantitative metabolomics,38 serum metabolites were identified for both HOMA-IR treatment response and spleen deficiency PRO scale treatment response,respectively.Twenty-five common-responded serum metabolites were further confirmed after intersection.Logistics regression was used to establish the forecast model of integrated treatment response of NAFLD and spleen deficiency syndrome.Finally,nine core metabolites were confirmed,including adipic acid,pimelic acid,suberic acid,arachidonic acid,glyceric acid,lactic acid,oxoglutaric acid,gamma-linolenic acid and maleic acid.The prediction accuracy was83.3%.Conclusions: 1.Spleen deficiency syndrome is a basic syndrome of traditional Chinese medicine,involving a variety of modern medical diseases.At present,the syndrome differentiation standard of spleen deficiency syndrome is complex,so it is urgent to establish a unified syndrome differentiation standard;2.The spleen deficiency PRO scale based on subjective symptom assessment was developed and qualified through the reliability and validity test of the population.It could be used for uniform differentiation and quantitative evaluation of spleen deficiency syndrome;3.Based on the spleen deficiency PRO scale,the incidence rate of spleen deficiency syndrome in natural population was 11.6%.Spleen deficiency syndrome was significantly correlated with physical measurement indexes(waist-height ratio,body mass index)and common chronic diseases(coronary heart disease,stroke,hyperuricemia,dyslipidemia,chronic obstructive pulmonary disease,chronic nephritis);4.Based on targeted quantitative metabolomics,an integrated efficacy evaluation method of NAFLD and spleen deficiency syndrome was preliminarily established,which could evaluate whether HOMA-IR and PRO scales for spleen deficiency were simultaneously responsive to the treatment,with a prediction accuracy of 83.3%.