Please wait a minute...
Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

Postal Subscription Code 80-967

2018 Impact Factor: 1.847

Front. Med.    2014, Vol. 8 Issue (3) : 337-346    https://doi.org/10.1007/s11684-014-0349-8
RESEARCH ARTICLE
Clinical phenotype network: the underlying mechanism for personalized diagnosis and treatment of traditional Chinese medicine
Xuezhong Zhou1,2,*(),Yubing Li1,Yonghong Peng3,Jingqing Hu4,Runshun Zhang5,Liyun He6,Yinghui Wang5,Lijie Jiang6,Shiyan Yan6,Peng Li6,Qi Xie2,Baoyan Liu2,*()
1. School of Computer and Information Technology and Beijing Key Lab of Traffic Data Analysis and Mining, Beijing Jiaotong University, Beijing 100044, China
2. China Academy of Chinese Medical Sciences, Beijing 100700, China
3. School of Engineering and Informatics, University of Bradford, BD7 1DP, UK
4. Institute of Basic Theory of Traditional Chinese Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, China
5. Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
6. Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, China
 Download: PDF(1937 KB)   HTML
 Export: BibTeX | EndNote | Reference Manager | ProCite | RefWorks
Abstract

Traditional Chinese medicine (TCM) investigates the clinical diagnosis and treatment regularities in a typical schema of personalized medicine, which means that individualized patients with same diseases would obtain distinct diagnosis and optimal treatment from different TCM physicians. This principle has been recognized and adhered by TCM clinical practitioners for thousands of years. However, the underlying mechanisms of TCM personalized medicine are not fully investigated so far and remained unknown. This paper discusses framework of TCM personalized medicine in classic literatures and in real-world clinical settings, and investigates the underlying mechanisms of TCM personalized medicine from the perspectives of network medicine. Based on 246 well-designed outpatient records on insomnia, by evaluating the personal biases of manifestation observation and preferences of herb prescriptions, we noted significant similarities between each herb prescriptions and symptom similarities between each encounters. To investigate the underlying mechanisms of TCM personalized medicine, we constructed a clinical phenotype network (CPN), in which the clinical phenotype entities like symptoms and diagnoses are presented as nodes and the correlation between these entities as links. This CPN is used to investigate the promiscuous boundary of syndromes and the co-occurrence of symptoms. The small-world topological characteristics are noted in the CPN with high clustering structures, which provide insight on the rationality of TCM personalized diagnosis and treatment. The investigation on this network would help us to gain understanding on the underlying mechanism of TCM personalized medicine and would propose a new perspective for the refinement of the TCM individualized clinical skills.

Keywords personalized medicine      complex network      clinical phenotype network      traditional Chinese medicine     
Corresponding Author(s): Xuezhong Zhou   
Online First Date: 13 August 2014    Issue Date: 09 October 2014
 Cite this article:   
Xuezhong Zhou,Yubing Li,Yonghong Peng, et al. Clinical phenotype network: the underlying mechanism for personalized diagnosis and treatment of traditional Chinese medicine[J]. Front. Med., 2014, 8(3): 337-346.
 URL:  
https://academic.hep.com.cn/fmd/EN/10.1007/s11684-014-0349-8
https://academic.hep.com.cn/fmd/EN/Y2014/V8/I3/337
Fig.1  Symptom similarity distribution of 82 patients detected by three physicians. The distribution in purple color shows the symptom similarities among three physicians on same patients. We get 246 pairs of symptom similarities from 82 patients, in which 191 (77.6%) pairs have nonzero symptom similarities. Furthermore the similarities between the symptoms of different patients, which are captured by one physician, are also calculated. There are totally 9963 symptom pairs, in which 7625 (76.5%) pairs have nonzero symptom similarities.
Patient IDPhysician APhysician BInner symptom similarity between physiciansNumber of encounters of Physician A with symptom similarity higher than the inner cases
P01Physician 1Physician 20.16729
P01Physician 3Physician 20.098119
P02Physician 2Physician 10.213212
P03Physician 1Physician 30.158121
P03Physician 2Physician 10.22616
P04Physician 3Physician 10.098114
P04Physician 2Physician 30.12510
P05Physician 1Physician 30.158119
P05Physician 3Physician 20.144318
P07Physician 1Physician 30.083329
Tab.1  The comparison of inner symptom similarities between different physicians on same patients and the inter symptom similarities between different encounters held by same physicians
Fig.2  The frequency (represented by percentage) of the top 20 herbs of the three physicians prescribed for 33 patients. It shows that the first 20 herbs most frequently used by the three physicians have a highly different distribution.
Fig.3  Herb similarity of encounters on each physicians and the inner herb similarity between three physicians (physicians 1–3) on same patients. The herb similarities between encounters of each three physicians have a mean of 0.41, which is much larger than the mean (i.e., 0.27) of inner herb similarities of the three physicians prescribed for same patients. Furthermore, physician 1 has its most herb similarities in [0.5, 0.7] and its mean similarity is 0.62.
Fig.4  The symptom co-occurrence network generated from 242 insomnia outpatient encounters. The labels in the network represent degree (the number of links) of nodes. The node with highest degree (i.e., 222) is Dysphoria. There are no isolated nodes in the network and all the nodes have degree larger than 1, which means that all the nodes (i.e., symptoms) have neighboring nodes to form a single giant component.
Fig.5  Syndrome network on insomnia with shared symptoms as links. For 82 insomnia patients, we obtained 36 different syndrome types, which constitute a very dense network.
1 Piquette-Miller M, Grant DM. The art and science of personalized medicine. Clin Pharmacol Ther2007; 81(3): 311–315
https://doi.org/10.1038/sj.clpt.6100130 pmid: 17339856
2 Lesko LJ. Personalized medicine: elusive dream or imminent reality? Clin Pharmacol Ther2007; 81(6): 807–816
https://doi.org/10.1038/sj.clpt.6100204 pmid: 17505496
3 Hamburg MA, Collins FS. The path to personalized medicine. N Engl J Med2010; 363(4): 301–304
https://doi.org/10.1056/NEJMp1006304 pmid: 20551152
4 Meyers DA, Bleecker ER, Holloway JW, Holgate ST. Asthma genetics and personalised medicine. Lancet Respir Med2014; 2(5): 405–415
https://doi.org/10.1016/S2213-2600(14)70012-8 pmid: 24794577
5 Mosli MH, Sandborn WJ, Kim RB, Khanna R, Al-Judaibi B, Feagan BG. Toward a personalized medicine approach to the management of inflammatory bowel disease. Am J Gastroenterol2014; 109(7): 994–1004
https://doi.org/10.1038/ajg.2014.110 pmid: 24842338
6 Hutchinson L. Personalized cancer medicine: era of promise and progress. Nat Rev Clin Oncol2011; 8(3): 121
https://doi.org/10.1038/nrclinonc.2011.14 pmid: 21364683
7 Ginsburg GS, McCarthy JJ. Personalized medicine: revolutionizing drug discovery and patient care. Trends Biotechnol2001; 19(12): 491–496
https://doi.org/10.1016/S0167-7799(01)01814-5 pmid: 11711191
8 Pirmohamed M. Personalized pharmacogenomics: predicting efficacy and adverse drug reactions. Annu Rev Genomics Hum Genet2014 May 29. [Epub ahead of print]
pmid: 24898040
9 Weston AD, Hood L. Systems biology, proteomics, and the future of health care: toward predictive, preventative, and personalized medicine. J Proteome Res2004; 3(2): 179–196
https://doi.org/10.1021/pr0499693 pmid: 15113093
10 Chung KF. Defining phenotypes in asthma: a step towards personalized medicine. Drugs2014; 74(7): 719–728
https://doi.org/10.1007/s40265-014-0213-9 pmid: 24797157
11 Raciti GA, Nigro C, Longo M, Parrillo L, Miele C, Formisano P, Béguinot F. Personalized medicine and type 2 diabetes: lesson from epigenetics. Epigenomics2014; 6(2): 229–238
https://doi.org/10.2217/epi.14.10 pmid: 24811791
12 Fraser M, Berlin A, Bristow RG, van der Kwast T. Genomic, pathological, and clinical heterogeneity as drivers of personalized medicine in prostate cancer. Urol Oncol2014 Apr 22. [Epub ahead of print] doi:
https://doi.org/10.1016/j.urolonc.2013.10.020 pmid: 24768356
13 Barabási AL, Gulbahce N, Loscalzo J. Network medicine: a network-based approach to human disease. Nat Rev Genet2011; 12(1): 56–68
https://doi.org/10.1038/nrg2918 pmid: 21164525
14 Committee on A Framework for Developing A New Taxonomy of Disease. Towards precision medicine: building a knowledge network for biomedical research and a new taxonomy of disease. Washington, DC: National Academies Press, 2011
15 Rzhetsky A, Wajngurt D, Park N, Zheng T. Probing genetic overlap among complex human phenotypes. Proc Natl Acad Sci USA2007; 104(28): 11694–11699
https://doi.org/10.1073/pnas.0704820104 pmid: 17609372
16 Blair DR, Lyttle CS, Mortensen JM, Bearden CF, Jensen AB, Khiabanian H, Melamed R, Rabadan R, Bernstam EV, Brunak S, Jensen LJ, Nicolae D, Shah NH, Grossman RL, Cox NJ, White KP, Rzhetsky A. A nondegenerate code of deleterious variants in Mendelian loci contributes to complex disease risk. Cell2013; 155(1): 70–80
https://doi.org/10.1016/j.cell.2013.08.030 pmid: 24074861
17 Lee DS, Park J, Kay KA, Christakis NA, Oltvai ZN, Barabási AL. The implications of human metabolic network topology for disease comorbidity. Proc Natl Acad Sci USA2008; 105(29): 9880–9885
https://doi.org/10.1073/pnas.0802208105 pmid: 18599447
18 van Driel MA, Bruggeman J, Vriend G, Brunner HG, Leunissen JA. A text-mining analysis of the human phenome. Eur J Hum Genet2006; 14(5): 535–542
https://doi.org/10.1038/sj.ejhg.5201585 pmid: 16493445
19 Zhou X, Menche J, Barabási AL, Sharma A. Human symptoms-disease network. Nat Commun2014; 5: 4212
https://doi.org/10.1038/ncomms5212 pmid: 24967666
20 Vidal M, Cusick ME, Barabási AL. Interactome networks and human disease. Cell2011; 144(6): 986–998
https://doi.org/10.1016/j.cell.2011.02.016 pmid: 21414488
21 Anonymous. The Inner Canon of Emperor Huang, Beijing: Chinese Medical Ancient Books Publishing House, 2003
22 Jiang L, Liu B, Xie Q, Yang S, He L, Zhang R, Yan S, Zhou X, Liu J. Investigation into the influence of physician for treatment based on syndrome differentiation. Evid Based Complement Alternat Med2013; 2013: 587234
https://doi.org/10.1155/2013/587234 pmid: 24288563
23 Hu J, Liu B. The basic theory, diagnostic, and therapeutic system of traditional Chinese medicine and the challenges they bring to statistics. Stat Med2012; 31(7): 602–605
https://doi.org/10.1002/sim.4409 pmid: 22238066
24 Lu AP, Jia HW, Xiao C, Lu QP. Theory of traditional Chinese medicine and therapeutic method of diseases. World J Gastroenterol2004; 10(13): 1854–1856
pmid: 15222022
25 Xu H, Chen K. Integrative medicine: the experience from China. J Altern Complement Med2008; 14(1): 3–7
https://doi.org/10.1089/acm.2006.6329 pmid: 18199020
26 Loscalzo J, Kohane I, Barabasi AL. Human disease classification in the postgenomic era: a complex systems approach to human pathobiology. Mol Syst Biol2007; 3: 124
https://doi.org/10.1038/msb4100163 pmid: 17625512
27 Liu B, Wang Y. Investigation on the concepts and their relationships among disease, symptoms and syndromes. J Tradit Chin Med2007; 48: 293–298
28 Li Y, Zhou X, Zhang R, Wang Y, Peng Y, Hu J, Xie Q, Xue Y, Xu L, Liu X, Liu B. Complex network approach for investigating the herb-symptom correspondence phenomenon and analyzing the TCM clinical herb-symptom association knowledge. BMC Complement Altern Med2014 (Accepted)
29 Zhou XZ, Zhang RS, Shah J, Rajgor D, Wang YH, Pietrobon R, Liu BY, Chen J, Zhu JG, Gao RL. Patterns of herbal combination for the treatment of insomnia commonly employed by highly experienced Chinese medicine physicians. Chin J Integr Med2011; 17(9): 655–662
https://doi.org/10.1007/s11655-011-0841-9 pmid: 21910065
30 Mirnezami R, Nicholson J, Darzi A. Preparing for precision medicine. N Engl J Med2012; 366(6): 489–491
https://doi.org/10.1056/NEJMp1114866 pmid: 22256780
31 O’Connor TG, McGuire S, Reiss D, Hetherington EM, Plomin R. Co-occurrence of depressive symptoms and antisocial behavior in adolescence: a common genetic liability. J Abnorm Psychol1998; 107(1): 27–37
pmid: 9505036
32 Zhou X, Peng Y, Liu B. Text mining for traditional Chinese medical knowledge discovery: a survey. J Biomed Inform2010; 43(4): 650–660
https://doi.org/10.1016/j.jbi.2010.01.002 pmid: 20074663
33 Chen J, Lu P, Zuo X, Shi Q, Zhao H, Luo L, Yi J, Zheng C, Yang Y, Wang W. Clinical data mining of phenotypic network in angina pectoris of coronary heart disease. Evid Based Complement Alternat Med2012; 2012: 546230
https://doi.org/10.1155/2012/546230 pmid: 23002393
34 Zhao Y, Zhang NL, Wang T, Wang Q. Discovering symptom co-occurrence patterns from 604 cases of depressive patient data using latent tree models. J Altern Complement Med 2014; 20(4): 265–271
https://doi.org/10.1089/acm.2013.0178 pmid: 24444096
35 Liu B, Chen S, Zhou X, Ni Q, He L. The principle of patient classification for type 2 diabetes based on symptoms. Beijing J Tradit Chin Med (Beijing Zhong Yi)2009; 28: 267–269 (in Chinese)
36 Yan S, Zhang R, Zhou X, Li P, He L, Liu B. Exploring effective core drug patterns in primary insomnia treatment with Chinese herbal medicine: study protocol for a randomized controlled trial. Trials2013; 14(1): 61
https://doi.org/10.1186/1745-6215-14-61 pmid: 23448313
37 Zhang L, Wang, J, Wang Y. Research on FANG-ZHENG Correspondence. China J Tradit Chin Med Pharm (Zhonghua Zhong Yi Yao Za Zhi)2005; 20: 8–10 (in Chinese)
38 Zhang XP, Zhou XZ, Huang HK, Feng Q, Chen SB, Liu BY. Topic model for Chinese medicine diagnosis and prescription regularities analysis: case on diabetes. Chin J Integr Med2011; 17(4): 307–313
https://doi.org/10.1007/s11655-011-0699-x pmid: 21509676
39 Poon J, Luo Z, Zhang RS. Feature representation in the biclustering of symptom-herb relationship in Chinese medicine. Chin J Integr Med2011; 17(9): 663–668
https://doi.org/10.1007/s11655-011-0842-8 pmid: 21910066
40 Liu GP, Li GZ, Wang YL, Wang YQ. Modelling of inquiry diagnosis for coronary heart disease in Traditional Chinese Medicine by using multi-label learning. BMC Complement Altern Med2010; 10(1): 37
https://doi.org/10.1186/1472-6882-10-37 pmid: 20642856
41 Zhou X, Liu B, Wu Z, Feng Y. Integrative mining of traditional Chinese medicine literature and MEDLINE for functional gene networks. Artif Intell Med2007; 41(2): 87–104
https://doi.org/10.1016/j.artmed.2007.07.007 pmid: 17804209
42 Su SB, Jia W, Lu A, Li S. Evidence-Based ZHENG: A Traditional Chinese Medicine Syndrome 2013. Evid Based Complement Alternat Med2014; 2014: 484201
https://doi.org/10.1155/2014/484201 pmid: 24891871
43 Li S, Fan TP, Jia W, Lu A, Zhang W. Network pharmacology in traditional chinese medicine. Evid Based Complement Alternat Med2014; 2014: 138460
https://doi.org/10.1155/2014/138460 pmid: 24707305
44 Liu B, Zhou X, Wang Y, Hu J, He L, Zhang R, Chen S, Guo Y. Data processing and analysis in real-world traditional Chinese medicine clinical data: challenges and approaches. Stat Med2012; 31(7): 653–660
https://doi.org/10.1002/sim.4417 pmid: 22161304
45 Zhou X, Chen S, Liu B, Zhang R, Wang Y, Li P, Guo Y, Zhang H, Gao Z, Yan X. Development of traditional Chinese medicine clinical data warehouse for medical knowledge discovery and decision support. Artif Intell Med2010; 48(2–3): 139–152
https://doi.org/10.1016/j.artmed.2009.07.012 pmid: 20122820
46 Liu B, Zhang Y, Hu J, He L, Zhou X. Thinking and practice of accelerating transformation of traditional Chinese medicine from experience medicine to evidence-based medicine. Front Med2011; 5(2): 163–170
https://doi.org/10.1007/s11684-011-0143-9 pmid: 21695621
[1] Zixin Shu, Yana Zhou, Kai Chang, Jifen Liu, Xiaojun Min, Qing Zhang, Jing Sun, Yajuan Xiong, Qunsheng Zou, Qiguang Zheng, Jinghui Ji, Josiah Poon, Baoyan Liu, Xuezhong Zhou, Xiaodong Li. Clinical features and the traditional Chinese medicine therapeutic characteristics of 293 COVID-19 inpatient cases[J]. Front. Med., 2020, 14(6): 760-775.
[2] Qingwei Li, Han Wang, Xiuyang Li, Yujiao Zheng, Yu Wei, Pei Zhang, Qiyou Ding, Jiaran Lin, Shuang Tang, Yikun Zhao, Linhua Zhao, Xiaolin Tong. The role played by traditional Chinese medicine in preventing and treating COVID-19 in China[J]. Front. Med., 2020, 14(5): 681-688.
[3] Mengxue Huang, Jingjing Wang, Runshun Zhang, Zhuying Ni, Xiaoying Liu, Wenwen Liu, Weilian Kong, Yao Chen, Tiantian Huang, Guihua Li, Dan Wei, Jianzhong Liu, Xuezhong Zhou. Symptom network topological features predict the effectiveness of herbal treatment for pediatric cough[J]. Front. Med., 2020, 14(3): 357-367.
[4] Qiqi Zhao, Xin Gao, Guangli Yan, Aihua Zhang, Hui Sun, Ying Han, Wenxiu Li, Liang Liu, Xijun Wang. Chinmedomics facilitated quality-marker discovery of Sijunzi decoction to treat spleen qi deficiency syndrome[J]. Front. Med., 2020, 14(3): 335-356.
[5] Yuan Gao, Zhilei Wang, Jinfa Tang, Xiaoyi Liu, Wei Shi, Nan Qin, Xiaoyan Wang, Yu Pang, Ruisheng Li, Yaming Zhang, Jiabo Wang, Ming Niu, Zhaofang Bai, Xiaohe Xiao. New incompatible pair of TCM: Epimedii Folium combined with Psoraleae Fructus induces idiosyncratic hepatotoxicity under immunological stress conditions[J]. Front. Med., 2020, 14(1): 68-80.
[6] Hudan Pan, Yanfang Zheng, Zhongqiu Liu, Zhongwen Yuan, Rutong Ren, Hua Zhou, Ying Xie, Liang Liu. Deciphering the pharmacological mechanism of Guan-Jie-Kang in treating rat adjuvant-induced arthritis using omics analysis[J]. Front. Med., 2019, 13(5): 564-574.
[7] Li Ma, Bin Wang, Yuanxiong Long, Hanmin Li. Effect of traditional Chinese medicine combined with Western therapy on primary hepatic carcinoma: a systematic review with meta-analysis[J]. Front. Med., 2017, 11(2): 191-202.
[8] Yunfang Liu,Zhiping Yang,Jing Cheng,Daiming Fan. Barriers and countermeasures in developing traditional Chinese medicine in Europe[J]. Front. Med., 2016, 10(3): 360-376.
[9] Shuyang Sun,Zhiyuan Zhang. Patient-derived xenograft platform of OSCC: a renewable human bio-bank for preclinical cancer research and a new co-clinical model for treatment optimization[J]. Front. Med., 2016, 10(1): 104-110.
[10] Yan Ma,Kehua Zhou,Jing Fan,Shuchen Sun. Traditional Chinese medicine: potential approaches from modern dynamical complexity theories[J]. Front. Med., 2016, 10(1): 28-32.
[11] Zhiping Yang. Do not let precision medicine be kidnapped[J]. Front. Med., 2015, 9(4): 512-513.
[12] Li Ma,Baoyan Liu,Qi Xie,Shusong Mao,Zhiwei Cui. Ontological reconstruction of the clinical terminology of traditional Chinese medicine[J]. Front. Med., 2014, 8(3): 358-361.
[13] Runshun Zhang,Yinghui Wang,Baoyan Liu,Guangli Song,Xuezhong Zhou,Shizhen Fan,Xishui Pan. Clinical data quality problems and countermeasure for real world study[J]. Front. Med., 2014, 8(3): 352-357.
[14] Guanli Song,Yinghui Wang,Runshun Zhang,Baoyan Liu,Xuezhong Zhou,Xiaji Zhou,Hong Zhang,Yufeng Guo,Yanxing Xue,Lili Xu. Experience inheritance from famous specialists based on real-world clinical research paradigm of traditional Chinese medicine[J]. Front. Med., 2014, 8(3): 300-309.
[15] Jian Wang,Biyan Liang,Xiaoping Zhang,Liran Xu,Xin Deng,Xiuhui Li,Lu Fang,Xinghua Tan,Yuxiang Mao,Guoliang Zhang,Yuguang Wang. An 84-month observational study of the changes in CD4 T-lymphocyte cell count of 110 HIV/AIDS patients treated with traditional Chinese medicine[J]. Front. Med., 2014, 8(3): 362-367.
Viewed
Full text


Abstract

Cited

  Shared   
  Discussed