Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

2015 Impact Factor: 1.863

Cover Story   2014, Volume 8 Issue 3
A real-world clinical research paradigm for traditional Chinese medicine, which is human-centered, data-oriented and problem-driven. With the idea of “from the clinic, to the clinic,” this paradigm integrates scientific computing with clinic, combining medical research with practice. (Courtesy of Dr. Guozheng Li, See Pages ://journal.hep.com.cn/fmd/EN/10.1007/s11684-014-0364-9">272-278 by Baoyan Liu for more information.)
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EDITORIAL
REVIEW
Applications of dynamical complexity theory in traditional Chinese medicine
Yan Ma,Shuchen Sun,Chung-Kang Peng
Front. Med.. 2014, 8 (3): 279-284.  
https://doi.org/10.1007/s11684-014-0367-6

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Traditional Chinese medicine (TCM) has been gradually accepted by the world. Despite its widespread use in clinical settings, a major challenge in TCM is to study it scientifically. This difficulty arises from the fact that TCM views human body as a complex dynamical system, and focuses on the balance of the human body, both internally and with its external environment. As a result, conventional tools that are based on reductionist approach are not adequate. Methods that can quantify the dynamics of complex integrative systems may bring new insights and utilities about the clinical practice and evaluation of efficacy of TCM. The dynamical complexity theory recently proposed and its computational algorithm, Multiscale Entropy (MSE) analysis, are consistent with TCM concepts. This new system level analysis has been successfully applied to many health and disease related topics in medicine. We believe that there could be many promising applications of this dynamical complexity concept in TCM. In this article, we propose some promising applications and research areas that TCM practitioners and researchers can pursue.

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Biosynthetic pathway of terpenoid indole alkaloids in Catharanthus roseus
Xiaoxuan Zhu,Xinyi Zeng,Chao Sun,Shilin Chen
Front. Med.. 2014, 8 (3): 285-293.  
https://doi.org/10.1007/s11684-014-0350-2

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Catharanthus roseus is one of the most extensively investigated medicinal plants, which can produce more than 130 alkaloids, including the powerful antitumor drugs vinblastine and vincristine. Here we review the recent advances in the biosynthetic pathway of terpenoid indole alkaloids (TIAs) in C. roseus, and the identification and characterization of the corresponding enzymes involved in this pathway. Strictosidine is the central intermediate in the biosynthesis of different TIAs, which is formed by the condensation of secologanin and tryptamine. Secologanin is derived from terpenoid (isoprenoid) biosynthetic pathway, while tryptamine is derived from indole biosynthetic pathway. Then various specific end products are produced by different routes during downstream process. Although many genes and corresponding enzymes have been characterized in this pathway, our knowledge on the whole TIA biosynthetic pathway still remains largely unknown up to date. Full elucidation of TIA biosynthetic pathway is an important prerequisite to understand the regulation of the TIA biosynthesis in the medicinal plant and to produce valuable TIAs by synthetic biological technology.

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Current situation and challenge of registry in China
Yang Zhang,Yuji Feng,Zhi Qu,Yali Qi,Siyan Zhan
Front. Med.. 2014, 8 (3): 294-299.  
https://doi.org/10.1007/s11684-014-0355-x

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Increasing emphasis has been placed on registries for an organized system used in developing clinical research to improve health care. China has sufficient data that can be applied broadly, but the heterogeneity and irregularity of registries limit their applicability. This article aims to describe the status of registries in China and the related challenges. Patient registries for observational studies were retrieved from the International Clinical Trials Registry to quantitatively evaluate the number of comparatively high-quality registries in China. A literature search was also performed to provide support and updates. A total of 64 patient registries were retrieved from ClinicalTrials.gov using disease, product, and health service as criteria. The sample sizes ranged from 15 to 30 400, with only 12 registries marked as completed. This article describes and compares the detailed information in many aspects. The efficient use of registries has already made considerable progress in China; however, registries still require standardization, high-quality transition, and coordinated development.

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Experience inheritance from famous specialists based on real-world clinical research paradigm of traditional Chinese medicine
Guanli Song,Yinghui Wang,Runshun Zhang,Baoyan Liu,Xuezhong Zhou,Xiaji Zhou,Hong Zhang,Yufeng Guo,Yanxing Xue,Lili Xu
Front. Med.. 2014, 8 (3): 300-309.  
https://doi.org/10.1007/s11684-014-0357-8

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The current modes of experience inheritance from famous specialists in traditional Chinese medicine (TCM) include master and disciple, literature review, clinical-epidemiology-based clinical research observation, and analysis and data mining via computer and database technologies. Each mode has its advantages and disadvantages. However, a scientific and instructive experience inheritance mode has not been developed. The advent of the big data era as well as the formation and practice accumulation of the TCM clinical research paradigm in the real world have provided new perspectives, techniques, and methods for inheriting experience from famous TCM specialists. Through continuous exploration and practice, the research group proposes the innovation research mode based on the real-world TCM clinical research paradigm, which involves the inheritance and innovation of the existing modes. This mode is formulated in line with its own development regularity of TCM and is expected to become the main mode of experience inheritance in the clinical field.

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Scientific computation of big data in real-world clinical research
Guozheng Li,Xuewen Zuo,Baoyan Liu
Front. Med.. 2014, 8 (3): 310-315.  
https://doi.org/10.1007/s11684-014-0358-7

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The advent of the big data era creates both opportunities and challenges for traditional Chinese medicine (TCM). This study describes the origin, concept, connotation, and value of studies regarding the scientific computation of TCM. It also discusses the integration of science, technology, and medicine under the guidance of the paradigm of real-world, clinical scientific research. TCM clinical diagnosis, treatment, and knowledge were traditionally limited to literature and sensation levels; however, primary methods are used to convert them into statistics, such as the methods of feature subset optimizing, multi-label learning, and complex networks based on complexity, intelligence, data, and computing sciences. Furthermore, these methods are applied in the modeling and analysis of the various complex relationships in individualized clinical diagnosis and treatment, as well as in decision-making related to such diagnosis and treatment. Thus, these methods strongly support the real-world clinical research paradigm of TCM.

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Discussion of solutions to ethical issues in real-world study
Sicheng Wang,Baoyan Liu,Ningning Xiong,Qi Xie,Runshun Zhang,Xuezhong Zhou,Jie Qiao
Front. Med.. 2014, 8 (3): 316-320.  
https://doi.org/10.1007/s11684-014-0354-y

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In recent years, the paradigm of real-world study (RWS) has been at the forefront of clinical research worldwide, particularly in the field of traditional Chinese medicine. In this paper, basic features and nature of real-world clinical studies are discussed, and ethical issues in different stages of RWS are raised and reviewed. Moreover, some preliminary solutions to these issues, such as protecting subjects during the process of RWS and performing ethical review, are presented based on recent practices and basic ethical rules to improve the scientific validity and ethical level of RWS.

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RESEARCH ARTICLE
Clinical research of traditional Chinese medicine in big data era
Junhua Zhang,Boli Zhang
Front. Med.. 2014, 8 (3): 321-327.  
https://doi.org/10.1007/s11684-014-0370-y

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With the advent of big data era, our thinking, technology and methodology are being transformed. Data-intensive scientific discovery based on big data, named “The Fourth Paradigm,” has become a new paradigm of scientific research. Along with the development and application of the Internet information technology in the field of healthcare, individual health records, clinical data of diagnosis and treatment, and genomic data have been accumulated dramatically, which generates big data in medical field for clinical research and assessment. With the support of big data, the defects and weakness may be overcome in the methodology of the conventional clinical evaluation based on sampling. Our research target shifts from the “causality inference” to “correlativity analysis.” This not only facilitates the evaluation of individualized treatment, disease prediction, prevention and prognosis, but also is suitable for the practice of preventive healthcare and symptom pattern differentiation for treatment in terms of traditional Chinese medicine (TCM), and for the post-marketing evaluation of Chinese patent medicines. To conduct clinical studies involved in big data in TCM domain, top level design is needed and should be performed orderly. The fundamental construction and innovation studies should be strengthened in the sections of data platform creation, data analysis technology and big-data professionals fostering and training.

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Methodological challenges to human medical study
Yixin Zhong,Baoyan Liu,Hua Qu,Qi Xie
Front. Med.. 2014, 8 (3): 328-336.  
https://doi.org/10.1007/s11684-014-0359-6

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With the transformation of modern medicinal pattern, medical studies are confronted with methodological challenges. By analyzing two methodologies existing in the study of physical matter system and information system, the article points out that traditional Chinese medicine (TCM), especially the treatment based on syndrome differentiation, embodies information conception of methodological positions, while western medicine represents matter conception of methodological positions. It proposes a new way of thinking about combination of TCM and western medicine by combinating two kinds of methodological methods.

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Clinical phenotype network: the underlying mechanism for personalized diagnosis and treatment of traditional Chinese medicine
Xuezhong Zhou,Yubing Li,Yonghong Peng,Jingqing Hu,Runshun Zhang,Liyun He,Yinghui Wang,Lijie Jiang,Shiyan Yan,Peng Li,Qi Xie,Baoyan Liu
Front. Med.. 2014, 8 (3): 337-346.  
https://doi.org/10.1007/s11684-014-0349-8

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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.

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Extracting terms from clinical records of traditional Chinese medicine
Cungen Cao,Meng Sun,Shi Wang
Front. Med.. 2014, 8 (3): 347-351.  
https://doi.org/10.1007/s11684-014-0361-z

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Health records of traditional Chinese medicine contain valuable clinical information which can be used for improvement of disease treatment and for medical research. In this paper, we present a practical iterative extraction method for extracting terms from the records. The method is based on a set of extraction rules, the Mesh, and the likelihood ratio technique, and achieved a precision rate of 88.18% and a recall rate of 94.21%.

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Clinical data quality problems and countermeasure for real world study
Runshun Zhang,Yinghui Wang,Baoyan Liu,Guangli Song,Xuezhong Zhou,Shizhen Fan,Xishui Pan
Front. Med.. 2014, 8 (3): 352-357.  
https://doi.org/10.1007/s11684-014-0351-1

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Real world study (RWS) has become a hotspot for clinical research. Data quality plays a vital role in research achievement and other clinical research fields. In this paper, the common quality problems in the RWS of traditional Chinese medicine are discussed, and a countermeasure is proposed.

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Ontological reconstruction of the clinical terminology of traditional Chinese medicine
Li Ma,Baoyan Liu,Qi Xie,Shusong Mao,Zhiwei Cui
Front. Med.. 2014, 8 (3): 358-361.  
https://doi.org/10.1007/s11684-014-0348-9

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This study proposes the ontological reconstruction of the current clinical terminology of traditional Chinese medicine (TCM). It also provides an overview of preliminary work related to the said reconstruction, including the ontology-based analysis of TCM clinical terminology. We conclude that the ontological reconstruction of TCM clinical terminology provides a proper translation from the idealized organizational model to real-world implementation and to a formalized, shared, and knowledge-based framework.

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An 84-month observational study of the changes in CD4 T-lymphocyte cell count of 110 HIV/AIDS patients treated with traditional Chinese medicine
Jian Wang,Biyan Liang,Xiaoping Zhang,Liran Xu,Xin Deng,Xiuhui Li,Lu Fang,Xinghua Tan,Yuxiang Mao,Guoliang Zhang,Yuguang Wang
Front. Med.. 2014, 8 (3): 362-367.  
https://doi.org/10.1007/s11684-014-0363-x

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This study aimed to evaluate the therapeutic effect of traditional Chinese medicine (TCM) by observing the changes in CD4 T-lymphocyte cell count of 110 cases with human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) treated continuously with TCM for 84 months. Information of 110 HIV/AIDS patients from 19 provinces and cities treated with TCM from 2004 to 2013 was collected. Changes in the indexes of CD4 counts (≤200, 201–350, 351–500 and>500 cells/mm3) at five time points (0, 12, 36, 60 and 84 months) and different treatments [TCM and TCM plus antiretroviral therapy (ART)] were compared. Repeated measures test indicated no interaction between group and time (P>0.05). Degrees of increasing and decreasing CD4 count of the two groups at four different frames were statistically significant compared with the baseline. The CD4 count between the two groups was not statistically significant. For CD4 count of≤200 cells/mm3, the mean CD4 count changes were 21 and 28 cells/mm3 per year for the TCM group and TCM plus ART group, respectively. For CD4 count of 201–350 cells/mm3, the mean CD4 count changes were 6 and 25 cells/mm3 per year for the TCM group and TCM plus ART group, respectively. For CD4 count of 351–500 cells/mm3, the mean CD4 count changes were -13 and -7 cells/mm3 per year for the TCM group and TCM plus ART group, respectively. For CD4 count of>500 cells/mm3, the mean CD4 count changes were -34 and -17 cells/mm3 per year for the TCM group and TCM plus ART group, respectively. Long-term use of TCM could maintain or slow the pace of declining CD4 counts in patients with HIV/AIDS, and may achieve lasting effectiveness.

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Effects of comprehensive therapy based on traditional Chinese medicine patterns on older patients with chronic obstructive pulmonary disease: a subgroup analysis from a four-center, randomized, controlled study
Minghang Wang,Jiansheng Li,Suyun Li,Yang Xie
Front. Med.. 2014, 8 (3): 368-375.  
https://doi.org/10.1007/s11684-014-0360-0

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This study aimed to evaluate the efficacy of comprehensive therapy based on traditional Chinese medicine (TCM) patterns on older patients with chronic obstructive pulmonary disease (COPD) through a four-center, open-label, randomized controlled trial. Patients were divided into the trial group treated using conventional western medicine and Bu-Fei Jian-Pi granules, Bu-Fei Yi-Shen granules, and Yi-Qi Zi-Shen granules based on TCM patterns respectively; and the control group treated using conventional western medicine. A total of 136 patients≥65 years completed the study, with 63 patients comprising the trial group and 73 comprising the control group. After the six-month treatment and the 12-month follow-up period, significant differences were observed between the trial and control groups in the following aspects: frequency of acute exacerbation (P≤0.040), duration of acute exacerbation (P = 0.034), symptoms (P≤0.034), 6-min walking distance (6MWD) (P≤0.039), dyspnea scale (P≤0.036); physical domain (P≤0.019), psychological domain (P≤0.033), social domain (P≤0.020), and environmental domain (P≤0.044) of the WHOQOL-BREF questionnaire; and daily living ability domain (P≤0.007), social activity domain (P≤0.018), depression symptoms domain (P≤0.025), and anxiety symptoms domain (P≤0.037) of the COPD-QOL. No differences were observed between the trial and control groups with regard to FVC, FEV1, and FEV1%.

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LETTER TO FRONTIERS OF MEDICINE
A study on specialist or special disease clinics based on big data
Zhuyuan Fang,Xiaowei Fan,Gong Chen
Front. Med.. 2014, 8 (3): 376-381.  
https://doi.org/10.1007/s11684-014-0356-9

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Correlation analysis and processing of massive medical information can be implemented through big data technology to find the relevance of different factors in the life cycle of a disease and to provide the basis for scientific research and clinical practice. This paper explores the concept of constructing a big medical data platform and introduces the clinical model construction. Medical data can be collected and consolidated by distributed computing technology. Through analysis technology, such as artificial neural network and grey model, a medical model can be built. Big data analysis, such as Hadoop, can be used to construct early prediction and intervention models as well as clinical decision-making model for specialist and special disease clinics. It establishes a new model for common clinical research for specialist and special disease clinics.

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Construction of a shared system-based real-world clinical research system
Huikun Wu,Xiaodong Li,Fan Yang,Dan Xie,Hui Li,Jingjing Huang,Mingxing Guo
Front. Med.. 2014, 8 (3): 382-388.  
https://doi.org/10.1007/s11684-014-0368-5

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Hubei Provincial Hospital of Traditional Chinese Medicine established research outpatient clinics to contribute to the major disease-entity research conducted by the National Traditional Chinese Medicine Clinical Research Base and to the construction of the National Traditional Chinese Medicine Treatment and Clinical Research Information Sharing System. With a view of developing a “real-world traditional Chinese medicine clinical research paradigm,” these clinics explored the mode of constructing research outpatient clinics from the aspects of clinical research, health management, and characteristics diagnosis and treatment.

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COMMENTARY
Mechanisms of “kidney governing bones” theory in traditional Chinese medicine
Dahong Ju,Meijie Liu,Hongyan Zhao,Jun Wang
Front. Med.. 2014, 8 (3): 389-393.  
https://doi.org/10.1007/s11684-014-0362-y

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Studies conducted by our group on the mechanism of “kidney governing bones” theory in traditional Chinese medicine (TCM) are reviewed in this paper. Conclusions can be summarized as follows. (1) Neuroendocrine-immune network (NIN)-osteoclast regulatory pathway OPG-RANKL-RANK is one of the mechanisms of “kidney governing bones.” Although kidney-reinforcing therapy is regarded as one of the holistic regulatory mechanisms of the body, characteristic holistic regulation in TCM can be reflected through nonselective regulation of the NIN during kidney reinforcement therapy, which can be used to treat osteoporosis through microadjustments in the microenvironment of the bone marrow. (2) Marrow exhaustion in TCM, which is the state wherein lipocytes in the bone marrow increase whereas other cells decrease, serves as the pathogenesis of osteoporosis brought about by failure of the “kidney governing bones.” (3) The kidney in TCM can be regarded as a complex system comprising multiple functional units in the body, including the unit “governing bones.” Kidney deficiency refers to a deficiency in only one or more units of the kidney system and not the whole system itself, which explains the kidney-reinforcing effect of many herbs; some herbs can treat osteoporosis, but some cannot. Although both classified as kidney-reinforcing agents, the former can resolve failure of the “kidney governing bones” unit while the latter regulates the failure of other units in the kidney system. Despite the current understanding on “kidney governing bones” theory, the mechanism of “kidney governing bones” remains complicated and unresolved. Thus, further studies in this area are warranted.

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