A Multivariate Statistical Analysis Of The Traditional Chinese Medicine Syndrome Type And Related Factors Of Multiple Myeloma

Research backgroundMultiple Myeloma(MM) is the most common type of hematologic tumor worldwide. it belongs to bone Bi-Syndrome,consumptive disease,lumbago and Erosion of bone in Traditional Chinese Medicine(TCM). But through consulting recent ten years'domestic literature, We have found that TCM syndrome differentiation of MM have many disadvantages, such as experiential inference, not unified standard, and lack of multicenter,large-scale evidence-based research. These are the obstacles in the development of TCM. So this study focuses on the objectification and standardization of TCM syndrome differentiation. From the perspective of Evidence-Based Medicine (EBM) and microcosmic syndrome differentiation, this study will make a discussion on the distribution of TCM syndrome type and related factors of MM by means of multivariate statistical method. It will supply an objective basis of TCM's standardization of syndrome differentiation.ObjectiveTo investigate newly diagnosed MM's distribution of TCM syndrome type, observe the relationship between distribution of TCM syndrome type and related factors (including age,gender,course of disease,clinical stage and types of Western Medicine); Emphasis on indexes of tumor burden and prognosis (such asβ2-MG,LDH,CRP,ALB in blood). From the perspective of microcosmic syndrome differentiation, the rule of TCM syndrome differentiation is summarized.MethodThis research includes two parts, one is the clinical retrospective study, the other is the prospective clinical study. 1.The clinical retrospective study of MM based on evidence-based medicineCombined with Dongzhimen Hospital Attached to Beijing TCM University, Affiliated Shuguang Hospital of Shanghai University of TCM, the First Affiliated Hospital of Guangzhou University of TCM, Guangzhou's TCM Hospital and Guangdong Provincial Hospital of TCM, From January 1997 to December 2007, the patients'cases were collected, who meet the inclusion and diagnostic criteria, and the statistical analysis has been made based on the data. By applying cluster analysis, and with clinical practice, distribution of TCM syndrome type was summarized. By means of Principal Component Analysis (PCA), the main and accessory symptoms were found. By means of correlation analysis, one-way anova, and chi-square test, we studied the relationship between distribution of TCM syndrome type and related factors (including age,gender,course of disease,clinical stage and types of Western Medicine), indexes of tumor burden and Prognosis.2. Prospective clinical study on MMInvestigating newly diagnosed MM cases during January 2008-January 2010, combined with Guangzhou's TCM Hospital, Guangdong Provincial Hospital of TCM and Jiangshu Provincial Hospital of TCM, we make differentiation according to clinical experience, Using frequency analysis, observing the distribution of asthenia and sthenia syndrome. By means of correlation analysis, one-way anova, and chi-square test, we observe relationship between distribution of TCM syndrome type and related factors (including course of disease,clinical stage and types of Western Medicine), Indexes of tumor burden and prognosis after the cases are diagnosed according to distribution of TCM syndrome type. We sum up the inherent laws through comparing the results of the retrospective and prospective clinical study.Result1.The clinical retrospective study of MM based on evidence-based medicine1.1 General data of patients:128 MM cases have been investigated, who meet the inclusion and diagnostic criteria. Including 26 cases in the First Affiliated Hospital of Guangzhou University of TCM,40 cases in Guangdong Provincial Hospital of TCM,11 cases in Guangzhou's TCM Hospital,24 cases in Dongzhimen Hospital attached to Beijing TCM University,27 cases in Affiliated Shuguang Hospital of Shanghai University of TCM. And male 72 examples(56.25%), female 56 cases (43.75%), Among the patients, the youngest was 16 years old, and the eldest was 88 years old, of the128 cases average age was 62.77±12.9 years old, The longest course was 120 months, and shortest course was three days, the average duration was 8.17±16.86 (month).Of the 128 cases,57 patients (44.53%) were at stageⅢA,41 patients (32.03%) were at stageⅢB,14 patients (10.94%) were at stageⅡA,6 patients (4.69%) were at stageⅡB,2 patients (1.56%) were at stageⅠA, 8 patients (6.25%) were at stageⅠB.93 examples were given types.29cases (31.2%) were IgG-κtype,11 cases (11.8%) were IgG-λtype,8 cases (8.6%) wereλtype,5 cases (5.4%) were IgA-κtype,12 cases (12.9 %) were IgA-λtype,7 cases (7.5%) were IgA type,8 cases (8.6%) wereκtype, 1 cases (1.1%) were IgA-IgG-κtype,9 cases (9.7%) were IgG type, 3 cases (3.2%) were unsecretarial type.1.2. MM's distribution of TCM syndrome type1.2.1 By applying cluster analysis, the five clinic syndrome types of MM can be summarized:deficiency of spleen and kidney,spleen-kidney yang deficiency,spleen-kidney yin deficiency,dampness-fluid accumulating in the interior,stagnation of phlegm,poison and blood stasis.1.2.2 Meanwhile, The experts summarized the five common clinic syndrome types of MM:①deficiency of spleen and kidney;②deficiency of spleen and kidney holding blood stasis,sputum and toxin;③spleen-kidney yang deficiency accompanying sputum-wetness;④spleen-kidney yin deficiency accompanying damp-heat-toxin。⑤spleen-kidney yin deficiency with sputum and blood stasis.1.2.3 By comparing their difference,advantages and disadvantages, We believe that the results of cluster analysis have many advantages, such as good dispersion,syndromes clear,bright lines,feature highlights,clarifying the differentiation factor, but can not fully cover the clinical practice; The views of the expert group were in accordance with clinical practice, meet the clinical need, but because of the clinical syndromes was very complex. we only could select the five clinic syndrome types as the common syndrome, the common syndrome occupied 94% of the total number of cases, the level and dispersion were not strong. it was considered that the relationship between them was mutual complemented。The former was the embody of the latter. So almost all specialists considered that the results of the cluster analysis could used as the basic clinic syndrome types of MM. And the first three were the positive asthenia syndrome, the rest two were the evil sthenia syndrome.1.2.4 By means of PCA, the main and accessory symptoms were summarized:deficiency of spleen and kidney:main symptoms:lassitude in loin and knee, lassitude, poor appetite, bone pain, weak pulse.accessory symptoms:little qi and lazy to talk, sallow complexion, (?)sterless complexion, spontaneous sweating, palpitation, pale tongue with whitish fur.yang deficiency of spleen and kidney:main symptoms:aversion to cold, and cold limbs, loose stool, pale complexion, abdominal distention, edema.accessory symptoms:weak taste and not thirsty, clear and long urine or urinating frequently at night, pale and enlarged tongue with whitish fur, deep Pulse.spleen-kidney yin deficiency:main symptoms:dry mouth and throat, feverish sensation over five centers, fever, polydipsia, night sweating.accessory symptoms:red tongue with less fur, stringy,thin and fast Pulse.dampness-fluid accumulating in the interior:main symptoms:abdominal distention, edema, poor appetite, weak taste and not thirsty, whitish fur.accessory symptoms:loose stool, palpitation, nausea, vomiting, limb numbness, pale and enlarged tongue with greasy fur, thin and deep Pulse.stagnation of phlegm,poison and blood stasis:main symptoms:dizziness, tinnitus, nausea, vomiting, little and yellow urine, fever, dim complexion.accessory symptoms:scaly skin, limb numbness, dry stool, polydipsia, insomnia, dark red tongue with yellow greasy fur, slippery pulse.1.2.5 The result of frequency analysis showed that deficiency of spleen and kidney accounted for 32.03%, yang deficiency of spleen and kidney accounted for 11.72%, Spleen-Kidney Yin Deficiency was 6.25%, dampness-fluid accumulating in the interior was 16%, stagnation of phlegm,poison and blood stasis occupied 34%. deficiency of spleen and kidney is most in deficiency Syndromes, stagnation of phlegm,poison and blood stasis is most in excess Syndromes.1.2.6 The symptoms with the highest frequency were lassitude in loin and knee,poor appetite,lassitude,little qi and lazy to talk,pale tongue with whitish fur, deep Pulse. Probability of dark red tongue was 41.4%. In 128 cases, probability of bone pain was 40.6%, probability of Pale,sallow and lusterless complexion was 57.81%.1.3. Correlation analysis of each factor1.3.1 Age:MM's distribution of TCM syndrome type has correlation with age. Through chi-square test, stagnation of phlegm, poison and blood stasis has significance differences in various age stage. Stagnation of phlegm,poison and blood stasis type was the most in 40-49th period, and the rarest above 80 years old.1.3.2 Gender:gender and distribution of TCM syndrome type was not related basically. Through chi-square test, there was no significant difference in sex.1.3.3 Course of disease:course of disease showed significant correlation with distribution of TCM syndrome type. Through one-way anova, the comparison of course of disease in all TCM syndromes showed that type of dampness-fluid accumulating in the interior and deficiency of spleen and kidney type were shorter, yang deficiency of spleen and kidney type was longer.1.3.4 Clinical stage:clinical stage was basically unrelated to Distribution of TCM syndrome type. There was significant statistical difference in clinical stage over the distribution of the five TCM syndromes. stagnation of phlegm, poison and blood stasis was found inⅢA, deficiency of spleen and kidney was found inⅢB.1.3.5 Type of western medicine:type of western medicine was basically unrelated to distribution of TCM syndrome type. deficiency of spleen.and kidney and stagnation of phlegm,poison and blood stasis were found on IgG-кtype.1.3.6 Bloodβ2-MG:Bloodβ2-MG was little inversely correlated with distribution of TCM syndrome type, But there was no significant statistical difference in them. Multiple comparisons showed no significant difference also.1.3.7 Blood LDH:Blood LDH was little inversely correlated with distribution of TCM syndrome type. There was no significant statistical difference in distribution of TCM syndrome type. Multiple comparisons showed significant difference. The blood LDH in yang deficiency of spleen and kidney was higher than those in the other two deficiency Syndromes. The blood LDH in stagnation of phlegm,poison and blood stasis was higher than dampness-fluid accumulating in the interior.1.3.8 Blood CRP:There was a positive correlation between blood CRP and distribution of TCM syndrome type. There was no significant statistical difference in distribution of TCM syndrome type. multiple comparisons showed the CRP in stagnation of phlegm,poison and blood stasis was the highest, but in yang deficiency of spleen and kidney was the lowest.1.3.9 Blood ALB:Blood ALB was positive correlated with distribution of TCM syndrome type. There was no significant statistical difference in distribution of TCM syndrome type.multiple comparisons showed the ALB in stagnation of phlegm,poison and blood stasis was the highest, but in yang deficiency of spleen and kidney was the lowest.2. Prospective clinical study on MM2.1. General data of patients:23 cases, Including 10 cases in Guangdong Provincial Hospital of TCM, 10 cases in Jiangsu Provincial Hospital of TCM,3 cases in Guangzhou's TCM Hospital. And male 15 examples (65.21%), female 8 cases (34.79%), Among the patients, the youngest is 51 years old. And the eldest 82, of the 23 cases Average age is 62.77±12.9 years old, the longest course is 36 months, and shortest course is 15 days. average duration is 9.85±9.67 (month).Of the 23 cases,6 patients (26.09%) are at stageⅢA,13 patients (56.52 %) are at stageⅢB,3 patients (13.04%) are at stageⅡA,1 patients (4.35 %) are at stageⅡB.5 cases (27.1%) are IgG-кtype,4cases (17.4%) are IgG-λtype,2 cases (8.7%) areλtype, 1 cases (4.35%) are IgA-кtype, 4 cases (17.4%) are IgA-λtype,2 cases (8.7%) are IgA type,2 cases (8.7 %) areкtype, lcases (4.35%) are IgD type,1 cases (4.35%) are IgG type,1 cases (4.35%) are unsecretarial type.2.2. Distribution of TCM syndrome type of MM2.2.1 Of the 23 cases,5 patients (21.7%) are deficiency of spleen and kidney,9 patients (39.1%) are deficiency of spleen and kidney holding sputum and blood stasis,4 patients (17.4%)are spleen-kidney yin deficiency accompanying sputum and blood stasis,3 patients (13.1%) are spleen-kidney yang deficiency accompanying damp-blood stasis-toxin。2 patients (8.7%) are stagnation of phlegm,poison and blood stasis.2.2.2 In clinical, the asthenia and sthenia syndrome account for the proportion are not high (7/23,30.4%), Syndrome of intermingled deficiency and excess is the most in clinical.2.3. Correlation Analysis of each factor2.3.1 Course of disease:course of disease shows little correlation with distribution of TCM syndrome type. There'is no statistical difference between them, but the course of spleen-kidney yang deficiency accompanying damp-stasis-toxin is longer.2.3.2 Clinical stage and type of western medicine:clinical stage and type of western medicine are basically unrelated to distribution of TCM syndrome type. There is no significant statistical difference in clinical stage and type of western medicine over the distribution of the five TCM syndromes.2.3.3 Bloodβ2-MG and LDH:Bloodβ2-MG and LDH are positive correlated with distribution of TCM syndrome type. There is no significant statistical difference in distribution of TCM syndrome type. Multiple comparisons show no significant differences also.2.3.4 Blood CRP:There is no correlation between blood CRP and distribution of TCM syndrome type. There is no significant statistical difference in distribution of TCM syndrome type. multiple comparisons show the CRP in stagnation of phlegm,poison and blood stasis is higher than in deficiency of spleen and kidney and deficiency of spleen and kidney holding sputum and blood stasis.2.3.5 Blood ALB:Blood ALB is positive correlated with distribution of TCM syndrome type. There is no significant statistical difference in distribution of TCM syndrome type. multiple comparisons show the ALB in spleen-kidney yang deficiency accompanying damp-blood stasis-toxin is lower than stagnation of phlegm,poison and blood stasis.Conclusion1. newly diagnosed MM's distribution of TCM syndrome type, the etiology and pathogenesis1.1 In the clinical retrospective study,by applying cluster analysis, the five clinic syndrome types of MM could be summarized:deficiency of spleen and kidney,spleen-kidney yang deficiency,spleen-kidney yin deficiency,dampness-fluid accumulating in the interior,stagnation of phlegm,poison and blood stasis. Meanwhile, the experts summarized the following five common clinic syndrome types of MM:①deficiency of spleen and kidney;②deficiency of spleen and kidney holding blood stasis and toxin;③spleen-kidney yang deficiency accompanying sputum-wetness;④spleen-kidney yin deficiency accompanying damp-heat-toxin。⑤spleen-kidney yin deficiency with sputum and blood stasis。By comparing their difference,advantages and disadvantages, it was considered that the relationship between them was mutual complemental。The former was the embody of the latter。So according to the write mode of syndrome differentiation and treatment in "Chinese Internal Medicine", almost all specialists considered that the results of the cluster analysis could be used as the basic clinic syndrome types of MM。In prospective clinical study on MM, there are the following five clinic syndrome types of MM, including deficiency of spleen and kidney,deficiency of spleen and kidney holding sputum and blood stasis,spleen-kidney yin deficiency accompanying sputum and blood stasis,spleen-kidney yang deficiency accompanying damp-blood stasis-toxin,stagnation of phlegm,poison and blood stasis. It shows the results of cluster analysis are the basic clinic syndrome types of MM, they reflect the basic elements of differentiation, we must use them flexibly according to the actual situation.1.2 The retrospective and prospective study show that etiology and pathogenesis of MM in TCM are asthenia of spleen and kidney, also closely correlated with phlegm coagulation, blood stasis,dampness and toxin. Because of six exogenous pathogens, emotional frustration, improper diet, misbalance of qi/blood and yin/yang,asthenia of spleen and kidney are easy to be made, wind cold dampness and Pathogenic toxin will take advantage of the body's weak points and attack organism, Noxious blood stasis and phlegm accumulate near channels,meridians,muscle and joint, which lead to insufficient nourishment for tendon. So bone Bi-Syndrome is induced. In the etiology and pathogenesis, The key point of its pathogenesis is asthenia of kidney, also closely correlated with phlegm coagulation, blood stasis,dampness and toxin. Pathogenic toxin appears together with stasis,phlegm and asthenia frequently. And the importance of the blood stasis should not be ignored in the whole course of the disease.1.3 The first symptom Is bone pain,anemia frequently. In clinic, when bone ache or anemia occurs, we should be alert of the existence of the disease. 2. The bulding of microcosmic syndrome differentiationThe clinical retrospective study shows that each influence factor is correlated with distribution of TCM syndrome type. And there are statistical differences in distribution of TCM syndrome type. Using these Indexes can achieve the syndrome differentiation objectively. In the prospective study, because of the few MM's samples, most of the above indexes have not been able to show the correlation and difference, the results are approximately same as the clinical retrospective study. These show that the results are practical. Using these indexes can help to achieve the syndrome differentiation of TCMobjectively.3.The relationship between mathematical statistics method, objectification and standardization of TCM syndrome differentiation3.1 Although using the cluster analysis in TCM can comprehensively reflect the clinical information characteristic and the basic elements of differentiation, it can not give dual attention to syndrome of intermingled deficiency and excess. Because of the TCM's complexity, the results of cluster analysis are the basic clinic syndrome types of MM only, we must use them flexibly according to the actual clinical situation. These show that the simply mathematical statistics method isn't fully suitable for the complex TCM. It should be considered comprehensively on clinical. The expert group opinion is still needed to reflect the clinic fact. The conclusion must connect with clinical practice.3.2 By means of PCA, We established the standard of TCM, without losing the original premise of the main information, used a few simple elements of response syndrome to reflect the general information, simplify and clarify the standard syndrome. Bur there are still many problems when applying PCA to TCM, such as Filtering elements of primary symptoms, reducing symptoms of elements, the best ways and means to extract the most convincing of the number of samples, etc. It is needed to continue research in the future to further explore clinical experience.3.3 Massive balanced sample numbers is needed to be able to guarantee the experimental result perfect. Because the incidence of MM is relatively low and the MM cases we collected are initially diagnosed, medical record which met the inclusion criteria is few, so the statistical significance is limited.The above shows TCM compound and complex characteristics, the simply mathematical statistics method isn't completely suitable for the complex TCM. The conclusions of mathematical statistics applying to the clinical practice don't cover all the aspects. Only supported by mathematics and experience simultaneously, can the TCM realize the objectification and standardization of TCM syndrome differentiation.4. compare with advantages and disadvantages of the retrospective and prospective clinical study.Although the retrospective study can gain the massive sample data within a short time, but some information and data maybe be ignored because of medical condition limit at that time, it will affect the accuracy of the partial results possibly. In the prospective clinical study, the information manifests completely, it has guaranteed the result's authenticity. Unfortunately, it's hard to get enough samples within a short time.In summary, The original intention of this study is to set up of TCM's standardization of syndrome differentiation by means of multivariate statistical method. Indeed, The application of mathematical statistics method for the TCM objective syndrome differentiation is feasible. But because of the TCM's complexity, the simply mathematical statistics method is not suitable for the complex TCM. It should be combined with the expert group opinion. And how to find the joint point for them which can be effectively applied to clinical practice, and easy to sum up, exchange, spread is the importat and difficult. point. This research belongs to the preliminary stage, it has certain limitation. Exploring the modern methodology on the study of TCM syndrome needs more endeavors.