title: Evaluation of symptom, clinical chemistry and metabolomics profiles during Rehmannia six formula (R6) treatment: an integrated and personalized data analysis approach.
abstract: BACKGROUND
  Rehmannia Six Formula (R6, Chinese name is Liu Wei Di Huang Wan) is one of the most important classic Chinese medicine formula used to treat metabolic disorders related to aging. It was first reported in the Chinese medicine book titled 'Xiao Er Yao Zheng Zhi Jue by Qian Yi' (Chinese Song dynasty: 1035-1117). In modern times it is therefore often used to treat diabetes, pre-diabetes, fatigue and people with metabolic syndrome. The aim of this study is to measure changes in symptoms, clinical parameters and serum metabolite profiles during R6 treatment of human subjects with features of metabolic syndrome.
  
  
  METHODS
  Symptoms, clinical parameters and serum metabolites were measured before and after 4 and 8 weeks of R6 treatment. Nonlinear Principal Component Analysis was applied for the first time to conduct an integrated analysis of the three data sets. Correlation structures were compared before treatment and after 4 and 8 weeks of treatment. Additionally, a State Space Grid approach was used to study personalized changes in symptom profiles.
  
  
  RESULTS
  The symptoms 'hectic fever' and 'spontaneous sweating' were found to be most relieved during R6 treatment. Most of the symptoms were less correlated with other variables after 8 weeks of R6 treatment. LDL-C, total cholesterol, systolic blood pressure and waist size were found to decrease during R6 treatment. Additionally, 10 of the 15 measured phosphatidylcholines were found to decrease. Personalized symptom profiles as described by Chinese medical terms show that most Yin deficiencies are addressed first by R6 treatment. However, in subjects with reduced or less Yin deficiency but which do have a substantial Qi deficiency a reduction of Qi deficiency is subsequently observed.
  
  
  CONCLUSIONS
  R6 treatment was shown to improve the lipid profile indicating a reduction of cardiovascular risk. Additionally, the changes observed in correlation structure indicate a different angle of looking at treatment effects. Less strong correlations between symptoms and metabolites suggest a healthier situation after R6 treatment. A State Space Grid analysis showed that the effect of R6 was different for the Yin deficiency subjects and the Qi deficiency subjects. The observed decrease of Yin deficiency related symptoms is in agreement with the use of R6 in Chinese medicine to nourish Yin. Observing individual differences in treatment effects is therefore an essential step in the development of personalized medicine.
authors.affiliation: Division of Analytical Biosciences, LACDR, Leiden University, Leiden, The Netherlands; Sino-Dutch Centre for Preventive and Personalized Medicine, P.O. Box 360, 3700 AJ Zeist, The Netherlands; TNO Netherlands Organization for Applied Scientific Research, Microbiology & Systems Biology, P.O. Box 360, 3700 AJ Zeist, The Netherlands. Electronic address: herman.vanwietmarschen@tno.nl.
authors.forename: Herman A
authors.initials: HA
authors.lastname: van Wietmarschen
authors.forename: Jan
authors.initials: J
authors.lastname: van der Greef
authors.forename: Yan
authors.initials: Y
authors.lastname: Schroën
authors.forename: Mei
authors.initials: M
authors.lastname: Wang
mesh_terms: D000328:Adult; D001794:Blood Pressure / Q000187:drug effects; D002784:Cholesterol / Q000097:blood; D004365:Drugs, Chinese Herbal / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D005334:Fever / Q000188:drug therapy; D006801:Humans; D008297:Male; D024821:Metabolic Syndrome / Q000097:blood / Q000188:drug therapy*; D055432:Metabolomics; D008875:Middle Aged; D010713:Phosphatidylcholines / Q000097:blood; D025341:Principal Component Analysis; D019413:Qi; D032267:Rehmannia; D013546:Sweating / Q000187:drug effects; D016710:Yin Deficiency
chemical_list: D004365:Drugs, Chinese Herbal; D010713:Phosphatidylcholines; C476907:liu-wei-di-huang wan; D002784:Cholesterol
keywords: Diagnosis; Liu Wei Di Huang Wan; Nonlinear principal component analysis; Personalized medicine; Rehmannia 6 formula; Systems biology