A modularity-based method reveals mixed modules from chemical-gene heterogeneous network.

For a multicomponent therapy, molecular network is essential to uncover its specific mode of action from a holistic perspective. The molecular system of a Traditional Chinese Medicine (TCM) formula can be represented by a 2-class heterogeneous network (2-HN), which typically includes chemical similarities, chemical-target interactions and gene interactions. An important premise of uncovering the molecular mechanism is to identify mixed modules from complex chemical-gene heterogeneous network of a TCM formula. We thus proposed a novel method (MixMod) based on mixed modularity to detect accurate mixed modules from 2-HNs. At first, we compared MixMod with Clauset-Newman-Moore algorithm (CNM), Markov Cluster algorithm (MCL), Infomap and Louvain on benchmark 2-HNs with known module structure. Results showed that MixMod was superior to other methods when 2-HNs had promiscuous module structure. Then these methods were tested on a real drug-target network, in which 88 disease clusters were regarded as real modules. MixMod could identify the most accurate mixed modules from the drug-target 2-HN (normalized mutual information 0.62 and classification accuracy 0.4524). In the end, MixMod was applied to the 2-HN of Buchang naoxintong capsule (BNC) and detected 49 mixed modules. By using enrichment analysis, we investigated five mixed modules that contained primary constituents of BNC intestinal absorption liquid. As a matter of fact, the findings of in vitro experiments using BNC intestinal absorption liquid were found to highly accord with previous analysis. Therefore, MixMod is an effective method to detect accurate mixed modules from chemical-gene heterogeneous networks and further uncover the molecular mechanism of multicomponent therapies, especially TCM formulae.

A network-based approach to investigate the pattern of syndrome in depression.

In Traditional Chinese Medicine theory, syndrome is essential to diagnose diseases and treat patients, and symptom is the foundation of syndrome differentiation. Thus the combination and interaction between symptoms represent the pattern of syndrome at phenotypic level, which can be modeled and analyzed using complex network. At first, we collected inquiry information of 364 depression patients from 2007 to 2009. Next, we learned classification models for 7 syndromes in depression using naïve Bayes, Bayes network, support vector machine (SVM), and C4.5. Among them, SVM achieves the highest accuracies larger than 0.9 except for Yin deficiency. Besides, Bayes network outperforms naïve Bayes for all 7 syndromes. Then key symptoms for each syndrome were selected using Fisher's score. Based on these key symptoms, symptom networks for 7 syndromes as well as a global network for depression were constructed through weighted mutual information. Finally, we employed permutation test to discover dynamic symptom interactions, in order to investigate the difference between syndromes from the perspective of symptom network. As a result, significant dynamic interactions were quite different for 7 syndromes. Therefore, symptom networks could facilitate our understanding of the pattern of syndrome and further the improvement of syndrome differentiation in depression.

A Module Analysis Approach to Investigate Molecular Mechanism of TCM Formula: A Trial on Shu-feng-jie-du Formula.

At the molecular level, it is acknowledged that a TCM formula is often a complex system, which challenges researchers to fully understand its underlying pharmacological action. However, module detection technique developed from complex network provides new insight into systematic investigation of the mode of action of a TCM formula from the molecule perspective. We here proposed a computational approach integrating the module detection technique into a 2-class heterogeneous network (2-HN) which models the complex pharmacological system of a TCM formula. This approach takes three steps: construction of a 2-HN, identification of primary pharmacological units, and pathway analysis. We employed this approach to study Shu-feng-jie-du (SHU) formula, which aimed at discovering its molecular mechanism in defending against influenza infection. Actually, four primary pharmacological units were identified from the 2-HN for SHU formula and further analysis revealed numbers of biological pathways modulated by the four pharmacological units. 24 out of 40 enriched pathways that were ranked in top 10 corresponding to each of the four pharmacological units were found to be involved in the process of influenza infection. Therefore, this approach is capable of uncovering the mode of action underlying a TCM formula via module analysis.

Pathway Pattern-based prediction of active drug components and gene targets from H1N1 influenza's treatment with maxingshigan-yinqiaosan formula.

Traditional Chinese Medicine (TCM) remedies are composed of different chemical compounds. To understand the underlying pharmacological basis, we need to explore the active components, which function systematically against multiple gene targets to exert efficacy. Predicting active component-gene target interactions could help us decipher the mechanism of action of TCM. Here, we introduce a Pathway Pattern-based method to prioritize the 153 candidate compounds and 7895 associated genes using the extracted Pathway Pattern, which is made up of groups of pathways. The gene prioritization result is compared to previous literature findings to demonstrate the top ranked genes' roles in the pathogenesis of H1N1 influenza. Further, molecular docking is utilized to validate compounds' effects through docking compounds into drug targets of oseltamivir. After setting thresholds, 16 active components, 29 gene targets and 162 active component-gene target interactions are finally identified to elucidate the pharmacology of maxingshigan-yinqiaosan formula. This novel strategy is expected to serve as a springboard for the efforts to standardize and modernize TCM.