Quantifying a systems map: network analysis of a childhood obesity causal loop diagram

Causal loop diagrams developed by groups capture a shared understanding of complex problems and provide a visual tool to guide interventions. This paper explores the application of network analytic methods as a new way to gain quantitative insight into the structure of an obesity causal loop diagram to inform intervention design. Identification of the structural features of causal loop diagrams is likely to provide new insights into the emergent properties of complex systems and analysing central drivers has the potential to identify leverage points. The results found the structure of the obesity causal loop diagram to resemble commonly observed empirical networks known for efficient spread of information. Known drivers of obesity were found to be the most central variables along with others unique to obesity prevention in the community. While causal loop diagrams are often specific to single communities, the analytic methods provide means to contrast and compare multiple causal loop diagrams for complex problems

System Model Network for Adipose Tissue Signatures Related to Weight Changes in Response to Calorie Restriction and Subsequent Weight Maintenance

International audienceNutrigenomics investigates relationships between nutrients and all genome-encoded molecular entities. This holistic approach requires systems biology to scrutinize the effects of diet on tissue biology. To decipher the adipose tissue (AT) response to diet induced weight changes we focused on key molecular (lipids and transcripts) AT species during a longitudinal dietary intervention. To obtain a systems model, a network approach was used to combine all sets of variables (bio-clinical, fatty acids and mRNA levels) and get an overview of their interactions. AT fatty acids and mRNA levels were quantified in 135 obese women at baseline, after an 8-week low calorie diet (LCD) and after 6 months of ad libitum weight maintenance diet (WMD). After LCD, individuals were stratified a posteriori according to weight change during WMD. A 3 steps approach was used to infer a global model involving the 3 sets of variables. It consisted in inferring intra-omic networks with sparse partial correlations and inter-omic networks with regularized canonical correlation analysis and finally combining the obtained omic-specific network in a single global model. The resulting networks were analyzed using node clustering, systematic important node extraction and cluster comparisons. Overall, AT showed both constant and phase-specific biological signatures in response to dietary intervention. AT from women regaining weight displayed growth factors, angiogenesis and proliferation signaling signatures, suggesting unfavorable tissue hyperplasia. By contrast, after LCD a strong positive relationship between AT myristoleic acid (a fatty acid with low AT level) content and de novo lipogenesis mRNAs was found. This relationship was also observed, after WMD, in the group of women that continued to lose weight. This original system biology approach provides novel insight in the AT response to weight control by highlighting the central role of myristoleic acid that may account for the beneficial effects of weight loss

Intégration de données hétérogènes complexes à partir de tableaux de tailles déséquilibrées

Les avancées des nouvelles technologies de séquençage ont permis aux études cliniques de produire des données volumineuses et complexes. Cette complexité se décline selon diverses modalités, notamment la grande dimension, l’hétérogénéité des données au niveau biologique (acquises à différents niveaux de l’échelle du vivant et à divers moments de l’expérience), l’hétérogénéité du type de données, le bruit (hétérogénéité biologique ou données entachées d’erreurs) dans les données et la présence de données manquantes (au niveau d’une valeur ou d’un individu entier). L’intégration de différentes données est donc un défi important pour la biologie computationnelle. Cette thèse s’inscrit dans un projet de recherche clinique sur l’obésité, DiOGenes, pour lequel nous avons fait des propositions méthodologiques pour l’analyse et l’intégration de données. Ce projet est basé sur une intervention nutritionnelle menée dans huit pays européens et vise à analyser les effets de différents régimes sur le maintien pondéral et sur certains marqueurs de risque cardio-vasculaire et de diabète, chez des individus obèses. Dans le cadre de ce projet, mes travaux ont porté sur l’analyse de données transcriptomiques (RNA-Seq) avec des individus manquants et sur l’intégration de données transcriptomiques (nouvelle technique QuantSeq) avec des données cliniques. La première partie de cette thèse est consacrée aux données manquantes et à l’inférence de réseaux à partir de données d’expression RNA-Seq. Lors d’études longitudinales transcriptomiques, il arrive que certains individus ne soient pas observés à certains pas de temps, pour des raisons expérimentales. Nous proposons une méthode d’imputation multiple hot-deck (hd-MI) qui permet d’intégrer de l’information externe mesurée sur les mêmes individus et d’autres individus. hd-MI permet d’améliorer la qualité de l’inférence de réseau. La seconde partie porte sur une étude intégrative de données cliniques et transcriptomiques (mesurées par QuantSeq) basée sur une approche réseau. Nous y montrons l’intérêt de cette nouvelle technique pour l’acquisition de données transcriptomiques et l’analysons par une approche d’inférence de réseau en lien avec des données cliniques d’intérêt.The development of high-throughput sequencing technologies has lead to a massive acquisition of high dimensional and complex datasets. Different features make these datasets hard to analyze : high dimensionality, heterogeneity at the biological level or at the data type level, the noise in data (due to biological heterogeneity or to errors in data) and the presence of missing data (for given values or for an entire individual). The integration of various data is thus an important challenge for computational biology. This thesis is part of a large clinical research project on obesity, DiOGenes, in which we have developed methods for data analysis and integration. The project is based on a dietary intervention that was led in eight Europeans centers. This study investigated the effect of macronutrient composition on weight-loss maintenance and metabolic and cardiovascular risk factors after a phase of calorie restriction in obese individuals. My work have mainly focused on transcriptomic data analysis (RNA-Seq) with missing individuals and data integration of transcriptomic (new QuantSeq protocol) and clinic datasets. The first part is focused on missing data and network inference from RNA-Seq datasets. During longitudinal study, some observations are missing for some time step. In order to take advantage of external information measured simultaneously to RNA-Seq data, we propose an imputation method, hot-deck multiple imputation (hd-MI), that improves the reliability of network inference. The second part deals with an integrative study of clinical data and transcriptomic data, measured by QuantSeq, based on a network approach. The new protocol is shown efficient for transcriptome measurement. We proposed an analysis based on network inference that is linked to clinical variables of interest