Study on Yan-Xin Wang’s medication experience and regularity in treating Insomnia from the liver based on data mining

Backgroun d: Professor Yan-Xin Wang has been committed to the use of traditional Chinese medicine formulas to treat insomnia from the liver for many years, and has achieved excellent clinical results. In order to better inherit Yan-Xin Wang’s academic thoughts. The purpose of this study is to use clinical data to explore the clinical experience of Prof. Yan-Xin Wang in the application of Chinese medicine to treat insomnia patients from the liver, explore the compatibility and medication rules of traditional Chinese medicine, and give more clinical treatment ideas for insomnia. Methods: The general data and prescription information of insomnia patients treated with Chinese herbal medicine by Prof. Yan-Xin Wang from January 1, 2021, to December 31, 2021, were summarized according to the inclusion and exclusion criteria, and the data were subjected to frequency statistics and drug association rules, complex network diagram analysis and cluster analysis. Results: A total of 159 patients and prescriptions were included in the study, of which 81.1% were women and 18.9% were men, containing 128 herbs; the highest frequency of use was 91.8% for Bupleuri Radix . Six Chinese herbs were used more than 70% of the time, namely Bupleuri Radix , Scutellariae Radix , oyster shell, Glycyrrhizae Radix , Os Draconis, and Ziziphi Spinosae Semen . The top 20 herbs in terms of frequency of use were analyzed in terms of the four Qi, five flavours, and their attributions. The four Qi were mainly calm and warm, the five flavours were mainly bitter and acrid, followed by sweet, and the attributions were mainly to the liver, spleen, and heart meridians. The Chinese medicine association rules set the confidence level > 80% and the support level > 10%, resulting in 10 two-herb and three-herb associations with the highest confidence level, such as Os Draconis is associated with oyster shell, Platycodonis Radix is associated with Achyranthis Bidentatae Radix , Scutellariae Radix is associated with Bupleuri Radix , Os Draconis, Bupleuri Radix is associated with oyster shell, Os Draconis, Scutellariae Radix is associated with oyster shell, etc. Cluster analysis yielded 3 classes of drug formulas. The complex network diagram shows that the core prescription drugs are composed of Bupleuri Radix , Chuanxiong Rhizoma , Pseudostellariae Radix , Jujubae Fructus , Os Draconis, Coptidis Rhizoma , Scutellariae Radix , Ziziphi Spinosae Semen , Smilacis Glabrae Rhizoma , Cinnamomi Cortex , White Moutan Cortex , Atractylodis Rhizoma , Glycyrrhizae Radix , oyster shell, Rehmanniae Radix Praeparata , Tritici Levis Fructus , Pinelliae Rhizoma Praeparatum , and Cinnamomi Ramulus . Conclusion: Prof. Yan-Xin Wang believes that the main treatment for patients with insomnia is based on the liver, by tonifying the deficiency and supporting the righteousness, mutually regulating the liver and spleen, and calming the mind and nourishing the heart, while adding and subtracting appropriate herbs according to the patient’s co-morbidities, which can significantly improve the patient’s insomnia symptoms


Introduction
Sleep accounts for one-third of a person's life, and when it is unsatisfactory, numerous pathologies can develop within the human organism. According to epidemiological surveys, up to one-third of adults report suffering from insomnia [1]. A meta-analysis examining the combined prevalence of insomnia in the Chinese general population revealed a high prevalence rate of 15% among 115,988 subjects [2]. Undoubtedly, insomnia has a significant negative impact on our daily lives. In the realm of traditional Chinese medicine (TCM), insomnia is attributed to a loss of nourishment or disturbances in the mind and spirit. However, clinical observations indicate a significant increase in the number of patients experiencing insomnia due to an imbalance of liver Qi (Qi refers to the basic substance that constitutes the human body and maintains life activities, and is the unity of substance and function) and loss of drainage of the liver has increased significantly. Prof. Yan-Xin Wang has dedicated many years of research to the treatment of cerebrovascular diseases using a combined approach of Chinese and Western medicine, with a particular focus on sleep disorders. Despite this, there is a dearth of research concerning Prof. Yan-Xin Wang's academic perspectives on insomnia treatment. To effectively disseminate the experiences and academic insights of Chinese medicine practitioners, we have analyzed clinical cases from Prof. Yan-Xin Wang's treatment of insomnia based on liver theory. Modern data mining techniques have been employed to unveil medication rules and academic insights, providing a foundation and novel ideas for the clinical treatment of insomnia using Chinese medicine. In the current era, where traditional medicine collides with data-based analysis, data mining technology offers new perspectives, methods, and opportunities for the academic transmission of TCM. It enables a diversified exploration of the value of TCM cases, thereby facilitating the dissemination of TCM knowledge. This study employs data mining techniques to analyze individualized cases of insomnia patients treated by Prof. Yan-Xin Wang, aiming to unveil academic ideas and provide valuable reference experiences for the clinical treatment of insomnia using TCM.

Sources of information
A total of 159 patients with liver-related insomnia, such as liver depression and Qi stagnation, heart and liver fire, and liver and spleen disorder, were selected for this study from January 1, 2021, to December 31, 2021, and were treated at the outpatient clinic of the Department of Neurology at The First Affiliated Hospital of Anhui University of Traditional Chinese Medicine. The cases include basic patient information, treatment records, diagnosis, and prescriptions of Chinese medicine.

Disease diagnosis and inclusion and exclusion criteria
Disease diagnostic criteria. Meets the diagnostic criteria for insomnia in Western medicine as well as Chinese medicine [3,4]. Inclusion criteria. (1) Patients who met the diagnostic criteria of both Chinese and Western medicine; (2) patients aged ≥ 18 years; (3) patients with complete basic medical records in the selected medical records, including complete information on Chinese medicine prescriptions; (4) Chinese medicine prescriptions in the form of drinking tablets; (5) no concurrent treatment methods, such as acupuncture or Western medicine, were used, and the treatment was clinically assessed as effective; (6) the criteria for effective treatment included a 4-week follow-up assessment of the patient's sleep status, which involved subjective feelings and the Pittsburgh Sleep Quality Index scale. Prescriptions that showed subjective improvement in insomnia symptoms and scale scores indicating improved sleep quality were considered effective for clinical evaluation. Exclusion criteria. (1) Patients with organic insomnia; (2) patients who are concurrently taking oral Western medicine, proprietary Chinese medicine, creams, or granules for insomnia while also taking Chinese medicine; (3) patients who are poorly compliant and do not take Chinese medicine regularly and on time according to medical advice; (4) cases with incomplete treatment records that prevent the evaluation of treatment efficacy.

Research methodology
Database export and data specification. The screening criteria were entered into the hospital's integrated clinical research system, and they were checked by Prof. Yan-Xin Wang to ensure the completeness and accuracy of the data. Subsequently, the data was exported by an engineer from the hospital's information center. A total of 159 prescriptions were summarized in an Excel sheet, and Prof. Yan-Xin Wang rechecked the data. Data normalisation. The data was normalized according to the Chinese Pharmacopoeia and the Pharmacopoeia of the People's Republic of China (2005 Edition) [5,6] for the names of the entered Chinese medicines. For instance, fresh Rehmanniae Radix was standardized as Rehmanniae Radix, and Polygoni Multiflori Caulis was standardized as Polygoni Multiflori Caulis, among others. The classification of the drug based on the four Qi and five flavours system in Chinese medicine was also referenced [5]. Data analysis and mining. The included data were collated, data were cleaned using Microsoft Office Excel 2020 raw data, descriptive statistics on the frequency and use of drugs in the data were performed using Statistical Product and Service Solutions (SPSS) 26.0, four Qi and five flavours and attribution analysis as well as cluster analysis, and the data were standardized and imported into IBM SPSS Modeler 18.0 for drug association analysis, complex network diagram analysis, and visual presentation.

Clinical information
A total of 159 cases were included in the study, comprising 129 women (81.1%) and 30 men (18.9%). Clinical feedback indicated that all patients experienced significant efficacy.

Patterns of Chinese medicine use
Single flavor distribution statistics. A total of 159 prescriptions containing 128 flavours of drugs were included in this study, which was counted in terms of frequency, and the following herbs were used ≥ 50 times in total, 23 flavours in detail ( Table 1). Analysis of the efficacy categories to which high-frequency drugs belong. An analysis of the efficacy categories to which the 23 heart failure-focused drugs belonged yielded that the drugs used to treat insomnia from the liver were predominantly deficiency tonics, tranquilizers, and heat-clearing agents, followed by diuretics and dampness-permeating agents, antiphlogistic agents, and drugs used to invigorate blood circulation and resolve blood stasis ( Table 2). Analysis of the four Qi, five flavours, and attribution of drugs. The frequency of use of the top 20 herbal medicines in 159 prescriptions was analyzed by the four Qi statistics, with calm and warm medicines dominating, with 608 and 573 times respectively; the five flavours was dominated by bitter, acrid and sweet medicines, with 379, 361 and 343 times respectively; the frequency of use was 1205 and 1058 times respectively, with medicines attributed to the liver and spleen meridians being the most frequent. The frequency of the four Qi, five flavours, and attribution statistics of the Chinese medicine radar chart (Figure 1-3). Chinese medicine association rule analysis. The composition law analysis was carried out on 159 prescriptions, and the minimum confidence was set to 80% and the minimum support was 10%, and through association analysis, it was clear that the binomial combination with the highest confidence was Os Draconis-oyster, and the three combinations with the highest confidence were bone fossil of big mammals and Bupleuri Radix-oyster (Table 3). Among them, confidence and support are two important parameters of association analysis, and the primary threshold is formulated according to the    (Figure 4). Core prescription analysis. The core prescriptions were obtained by complex network analysis through IBM SPSS Modeler 18.0 for drugs that were used more than 20 times, as demonstrated by complex network diagrams ( Figure 5).

Discussion
Insomnia is known as "sleepless disease", "no sleep", "blindness" and so on in the field of traditional Chinese medicine. The book The Huang Emperor's Canon of Eighty-One Difficult Issues (Eastern Han dynasty) for the first time introduced the word "sleepless" as the name of a disease and also explained for the first time that sleeplessness is related to the weakening of Qi, blood, and the lack of smooth circulation. The Inner Canon of the Yellow Emperor (221 B.C.E.-220 C.E.) explains that insomnia is caused by damage to the internal organs, and the main reason is closely related to the dysfunction of the internal organs and the imbalance of Yin (in Chinese philosophy, the female, latent, passive principle, characterized by dark, cold, wetness, passivity, disintegration, etc.) and Yang (in Chinese philosophy, the masculine, active and positive principle, characterized by light, warmth, dryness, activity, etc.) [7]. Although the book Inner Canon of the Yellow Emperor does not use the word "sleepless", the meaning of "blindness" is also insomnia. Sleeplessness is mainly manifested as not being able to fall asleep at night, waking up easily even if you fall asleep, or dreaming at night, and difficulty falling asleep again after waking up [8]. In addition to sleep-related problems, patients with sleeplessness will also appear fatigued, have dizziness, limb weakness, and other conditions. Different patients have different manifestations, so modern Chinese medicine divides insomnia diseases into liver fire disturbance,  disharmony between the heart and the kidney, deficiency of the heart and spleen pattern, and other symptom types based on literature and clinical experience, to distinguish treatment. Although the disease of insomnia is in the heart, liver, spleen, and kidney disorders can also cause the occurrence of sleeplessness. The experience of various generations of doctors can also know that liver disorders have a great impact on the occurrence of sleeplessness. The heart hides the spirit, the liver hides the blood, the kidney stores the essence, the essence and blood are mutually represented, and the liver Qi leaks out, then the sperm blood is lost, and the loss of spirit will lead to sleeplessness [9]. At the same time, healing follows the unity of form and spirit, because the disease itself is half physical and half psychological [10]. Therefore, Prof. Yan-Xin Wang believes that the treatment of patients with liver-related sleeplessness, or insomnia caused by disorders of the five internal organs, needs to be mainly treated with the liver.

Exploring medication use patterns based on frequency analysis
From the liver treatment, support the right and replenish the deficiency. The ancient book Categorized Patterns with Clear-cut Treatments (1839 C.E.) is mainly based on drugs that nourish weakness in the treatment of sleeplessness. There are many causes of the disease, of which weakness is the main internal cause. The human body keeps Yin and Yang (Yin and Yang refer to the two basic properties of things and things that are opposed to each other), and the loss of positive Qi will lead to Yin and Yang imbalance, Qi and blood cannot run smoothly, and sleeplessness will occur [11]. The analysis of the efficacy frequency of TCM found that the most commonly used medicine is the deficiency tonic medicine, which shows that the core idea of Prof. Yan-Xin Wang in the treatment of sleeplessness is to replenish the deficiency to support righteousness, and to replenish the benefit to calm the mind. Studies have shown that tranquilizing drugs can effectively improve sleep quality and have a certain effect on reducing serum orexin-A receptor expression levels in insomnia patients [12]. Drug attribution shows that the liver meridian is the mainstay, followed by the spleen meridian and the heart meridian. It can be seen that Prof. Yan-Xin Wang's treatment of insomnia in TCM starts with the liver, spleen, and heart. Clinically sleepless patients are more likely to see liver Qi stagnation pattern, liver rebellion stomach, liver and spleen discord, which can lead to emotional failure, sighing, sluggishness, hiccups, etc. Clinical studies suggest that in order to treat insomnia, it is essential to address liver stagnation and relieve depression. This involves ensuring the patient's mood is comfortable, promoting the smooth flow of Qi, and extinguishing liver fire, which ultimately leads to stable sleep [13]. The book Essential Prescriptions from the Golden Cabinet (Eastern Han dynasty) talks about "liver disease, which will spread from the liver to the spleen, so the spleen must be treated first", and Imperially Commissioned Golden Mirror of the Orthodox Lineage of Medicine (1742 C.E.) said that "the liver is wood Qi, and it needs soil to nourish and water to irrigate". Patients with insomnia caused by liver disease usually have symptoms such as spleen deficiency and fatigue. The spleen is the source of the body's Qi and blood. Prof. Rong Hui believes that for the liver to play a normal role, it is necessary to have the spleen governs movement and transformation of grain and water and distribution of its essence, and the drainage of the liver is normal so that sleep can be stable [14]. Spleen blood is based on liver drainage, and liver blood is stored, which requires the metaplasia of the spleen, and the cooperation and symbiosis of the liver and spleen can allow the Qi and blood to run smoothly with the body, calmly nourishing the mind and calming the mind. Therefore, in the process of medication, a solid temper can better nourish the liver and make the treatment twice as effective. According to the frequency of medication of the four Qi and five flavors, it was found that the choice of medicinal properties was mainly neutral-property and warm medicine medicine, and cold and heat was used less. In the book Categorized Patterns with Clear-cut Treatments, there are sweet and warm products that can remove heat, invigorate Qi and spleen, and harmonize Yin and Yang to achieve a good sleep state [15]. Patients with insomnia are restless in their hearts and minds, so they should not overdose on drugs of cold and heat nature. The five flavors are mainly spicy, sweet, and bitter, followed by sour. The main disease of insomnia is located in the heart, with spicy medicine to calm the spirit, and sweet, bitter, and sour medicine each perform their duties and complement each other. It can be seen that Prof. Yan-Xin Wang uses gentle and cold and warm drugs together, and combines spicy, sweet, and bitter drugs to regulate the patient's Qi.
Thinning the liver and relieving depression at the same time, introducing drugs into the liver.  [19] found that Scutellariae Radix has a significant sedative effect in the study of the chemical composition and pharmacological effects of Gancao decoction. Among the associations of TCM, the confidence rate of Bupleuri Radix is 97.8%, and it has also occurred in clinical studies in the treatment of neurological diseases, and the combination of the two can make the liver Qi movementm organ smooth, thereby playing a role in sedation and restfulness [20]. In addition to Bupleuri Radix and Scutellariae Radix in high-frequency drugs, the frequency of use of oyster shell and Os Draconis is also very high, the frequency of Os Draconis is 71.7%, the taste is astringent, sweet, the sex is flat, and the heart, liver, and kidney meridian. The frequency of use of oyster shell is 76.1%, salty and wet, cool, and belongs to the liver and kidneys. Studies have found that the combination of the two can achieve the effects of calming the mind, calming the liver and latent Yang, solidifying astringency, and collecting Yin and latent Yang [21]. The above results reflect the general principles of Prof. Yan-Xin Wang's support to correct and replenish deficiency and treat insomnia from the liver, evacuate liver Qi without hurting the liver, replenish weakness without overfilling, and match different drugs according to different dialectics, with a degree of benefit and harmony.

Exploring medication use patterns based on association rule analysis
The results of the correlation analysis showed that the binomial combination of Os Draconis and oyster shell had a confidence level of 99.1%, followed by Achyranthis Bidentatae Radix and Platycodonis Radix with a confidence level of 97.9%. This suggests that in the liver-based treatment of insomnia, oyster shell is most often used in combination with Os Draconis. Both are classified in the liver meridian. In Zou's [22] study on the compatibility law of sedative and tranquilizing formulas containing marine TCM, it was found that the main chemical components of oyster shell and Os Draconis were calcium salts, and the types of trace elements were similar, and both had pharmacological effects of calming and calming the nerves and anticonvulsants. In the Chinese herbal correlation analysis, the three combinations of Os Draconis-Bupleuri Radix, and oyster shell had a confidence level of 99%, and the combination of the three herbs exerted the effects of draining the liver, pacifying the liver, calming the mind, and subduing Yang. In modern pharmacological studies, it has been found that insomnia is related to the occurrence of oxidative stress [23] and that the MEK/ERK pathway can mediate oxidative stress and inflammatory responses and increase phosphorylation levels. Chaihu Longgu Muli decoction can inhibit oxidative stress and suppress the activation of phosphorylation activation of the MEK/ERK pathway, thus playing a role in the treatment of insomnia. The core drug group reflects the combination law of insomnia treatment with liver Qi and liver Yang as the core, with drugs such as tranquility and spleen strengthening, which is consistent with the treatment ideas obtained by frequency analysis. Among them are oyster shell and Scutellariae Radix, which are not classified as tranquilizing drugs but also have a tranquilizing effect. Followed by the blood activators Chuanxiong Rhizoma and Achyranthis Bidentatae Radix. The herbs used to clear heat are Coptidis Rhizoma and Prunellae Spica. Also, depending on the patient's syndromes, medicines such as warming interior, collecting astringency, and regulating Qi will be combined. As can be seen from the above, in treating insomnia from the liver, the treatment principle of tonifying the deficiencies and calming the mind is emphasized, and the treatment methods of invigorating blood and regulating Qi are supplemented.  [25] were given Chaihu Longgu Muli decoction and alprazolam for insomnia patients, and the results showed that the total effective rate of Chaihu Longgu Muli decoction was 82.86%, and the total effective rate of the alprazolam group was 85.71%, indicating that the effect of Chaihu Longgu Muli decoction in treating insomnia was comparable to that of alprazolam tablets. Yao et al. [26] found through network pharmacology that Chaihu Longgu Muli decoction can positively regulate sleep through serotonergic synapses, prolactin, and other signaling pathways. Class 2: Chuanxiong Rhizoma and Rehmanniae Radix Praeparata are taken from the Siwu decoction, the Siwu decoction first appeared in the Tang Dynasty in Dao-Ren Lin's Secrets of Treating Wounds and Rejoining Fractures Handed Down by an Immortal, which is a common recipe for nourishing blood and regulating menstruation, among which Chuanxiong Rhizoma rationalizes Qi and invigorates blood, Rehmanniae Radix Praeparata nourishes blood and Yin. In the treatment of 50 patients with insomnia, the application of Siwu decoction combined with Suanzaoren decoction achieved good efficacy [27]. Class 3: Fluoritum, Prunellae Spica, Pseudostellariae Radix, Cinnamomi Ramulus, and Smilacis Glabrae Rhizoma play the role of calming and calming the mind, soothing the liver and pouring fire, and strengthening the spleen and calming the heart. Clinical studies have found that the method of strengthening the spleen and nourishing the heart and then relaxing the liver and calming the nerves has a good effect in the treatment of insomnia, and the therapy of unclogging liver Qi by tonifying the heart and spleen can effectively improve sleep quality by regulating the levels of 5-HT and Dopamine [28]. Class 4: Atractylodis Rhizoma, Coptidis Rhizoma, Achyranthis Bidentatae Radix, and Aurantii Fructus are made from Baizhu pill and Baizhu decoction, which mainly play the role of invigorating Qi and eliminating ruffian, invigorating spleen and promoting diuresis and dampness. Modern studies have found that drugs including invigorating the spleen and removing dampness promote water absorption and the expression levels of gastrointestinal hormones motilin, somatostatin, and vasoactive intestinal peptide by increasing the expression levels of aquaporin 4 and aquaporin 8 in the intestinal mucosa, promoting digestion and absorption [29,30]. A meta-analysis of the treatment of insomnia with the method of invigorating the spleen and replenishing Qi found that the effect of invigorating the spleen combined with Western medicine in the treatment of insomnia was more significant than that of Western medicine alone [31]. Therefore, invigorating the spleen and promoting diuresis and dampness can help to improve the function of the spleen and stomach, promote the ability of the spleen to transport water and food, ensure the regulation of liver Qi and patency of Qi, achieve the purpose of treating insomnia.

Explore medication rules based on cluster analysis
The results of complex network analysis and cluster analysis are cross-verified and echoed, which shows that the results are reliable.

Conclusions
To sum up, Prof. Yan-Xin Wang's treatment of insomnia from the liver is mainly based on liver soothing, liver softening, and liver calming, supplemented by spleen invigoration, heart calming, fire purging, mind calming, and mind tonifying. In the course of treatment, the prescription is flexibly added and subtracted according to the patient's syndrome while soothing the liver and regulating Qi. Chaihu Longgu Muli decoction, Siwu decoction, and other prescriptions are often used for reasonable modifications. The prescription is rigorous, which has also been verified in clinical practice. Since each data mining method has its advantages and limitations, and the application scope is different, this comprehensive analysis can complement each other's advantages and reveal the intrinsic relationship between the compatibility of TCM from multiple aspects. The results were limited due to the limitations in the scope of the data, such as not fully considering the geographical variability of the patients corresponding to whom the prescription was prepared. At the same time, different parameter settings in the data mining algorithm result in variations in the display of pre-mining and formal data mining results based on the size and type of data. Therefore, the display of the results also differs.
Given the above limitations, it is first necessary to expand the scope of data in the later stage and include various factors such as geography and patient constitution in the classification scope to achieve more accurate data mining. Secondly, the special nature of TCM prescription differs from ordinary structured data. Therefore, in algorithm selection, multi-category and multi-cross methods should be used for data processing to improve the accuracy of results. Applying more data mining methods will help summarize more clinical experience and provide valuable insights for the treatment of clinical insomnia.