Combinatorial, additive and dose-dependent drug-microbiome associations.

During the transition from a healthy state to cardiometabolic disease, patients become heavily medicated, which leads to an increasingly aberrant gut microbiome and serum metabolome, and complicates biomarker discovery1-5. Here, through integrated multi-omics analyses of 2,173 European residents from the MetaCardis cohort, we show that the explanatory power of drugs for the variability in both host and gut microbiome features exceeds that of disease. We quantify inferred effects of single medications, their combinations as well as additive effects, and show that the latter shift the metabolome and microbiome towards a healthier state, exemplified in synergistic reduction in serum atherogenic lipoproteins by statins combined with aspirin, or enrichment of intestinal Roseburia by diuretic agents combined with beta-blockers. Several antibiotics exhibit a quantitative relationship between the number of courses prescribed and progression towards a microbiome state that is associated with the severity of cardiometabolic disease. We also report a relationship between cardiometabolic drug dosage, improvement in clinical markers and microbiome composition, supporting direct drug effects. Taken together, our computational framework and resulting resources enable the disentanglement of the effects of drugs and disease on host and microbiome features in multimedicated individuals. Furthermore, the robust signatures identified using our framework provide new hypotheses for drug-host-microbiome interactions in cardiometabolic disease.

Latent dirichlet allocation for double clustering (LDA-DC): discovering patients phenotypes and cell populations within a single Bayesian framework.

BACKGROUND: Current clinical routines rely more and more on "omics" data such as flow cytometry data from host and microbiota. Cohorts variability in addition to patients' heterogeneity and huge dimensions make it difficult to understand underlying structure of the data and decipher pathologies. Patients stratification and diagnostics from such complex data are extremely challenging. There is an acute need to develop novel statistical machine learning methods that are robust with respect to the data heterogeneity, efficient from the computational viewpoint, and can be understood by human experts. RESULTS: We propose a novel approach to stratify cell-based observations within a single probabilistic framework, i.e., to extract meaningful phenotypes from both patients and cells data simultaneously. We define this problem as a double clustering problem that we tackle with the proposed approach. Our method is a practical extension of the Latent Dirichlet Allocation and is used for the Double Clustering task (LDA-DC). We first validate the method on artificial datasets, then we apply our method to two real problems of patients stratification based on cytometry and microbiota data. We observe that the LDA-DC returns clusters of patients and also clusters of cells related to patients' conditions. We also construct a graphical representation of the results that can be easily understood by humans and are, therefore, of a big help for experts involved in pre-clinical research.

Data-Driven Score-Based Models for Generating Stable Structures with Adaptive Crystal Cells.

The discovery of new functional and stable materials is a big challenge due to its complexity. This work aims at the generation of new crystal structures with desired properties, such as chemical stability and specified chemical composition, by using machine learning generative models. Compared with the generation of molecules, crystal structures pose new difficulties arising from the periodic nature of the crystal and from the specific symmetry constraints related to the space group. In this work, score-based probabilistic models based on annealed Langevin dynamics, which have shown excellent performance in various applications, are adapted to the task of crystal generation. The novelty of the presented approach resides in the fact that the lattice of the crystal cell is not fixed. During the training of the model, the lattice is learned from the available data, whereas during the sampling of a new chemical structure, two denoising processes are used in parallel to generate the lattice along with the generation of the atomic positions. A multigraph crystal representation is introduced that respects symmetry constraints, yielding computational advantages and a better quality of the sampled structures. We show that our model is capable of generating new candidate structures in any chosen chemical system and crystal group without any additional training. To illustrate the functionality of the proposed method, a comparison of our model to other recent generative models based on descriptor-based metrics is provided.

Impairment of gut microbial biotin metabolism and host biotin status in severe obesity: effect of biotin and prebiotic supplementation on improved metabolism.

OBJECTIVES: Gut microbiota is a key component in obesity and type 2 diabetes, yet mechanisms and metabolites central to this interaction remain unclear. We examined the human gut microbiome's functional composition in healthy metabolic state and the most severe states of obesity and type 2 diabetes within the MetaCardis cohort. We focused on the role of B vitamins and B7/B8 biotin for regulation of host metabolic state, as these vitamins influence both microbial function and host metabolism and inflammation. DESIGN: We performed metagenomic analyses in 1545 subjects from the MetaCardis cohorts and different murine experiments, including germ-free and antibiotic treated animals, faecal microbiota transfer, bariatric surgery and supplementation with biotin and prebiotics in mice. RESULTS: Severe obesity is associated with an absolute deficiency in bacterial biotin producers and transporters, whose abundances correlate with host metabolic and inflammatory phenotypes. We found suboptimal circulating biotin levels in severe obesity and altered expression of biotin-associated genes in human adipose tissue. In mice, the absence or depletion of gut microbiota by antibiotics confirmed the microbial contribution to host biotin levels. Bariatric surgery, which improves metabolism and inflammation, associates with increased bacterial biotin producers and improved host systemic biotin in humans and mice. Finally, supplementing high-fat diet-fed mice with fructo-oligosaccharides and biotin improves not only the microbiome diversity, but also the potential of bacterial production of biotin and B vitamins, while limiting weight gain and glycaemic deterioration. CONCLUSION: Strategies combining biotin and prebiotic supplementation could help prevent the deterioration of metabolic states in severe obesity. TRIAL REGISTRATION NUMBER: NCT02059538.

The Role of Instrumental Variables in Causal Inference Based on Independence of Cause and Mechanism.

Causal inference methods based on conditional independence construct Markov equivalent graphs and cannot be applied to bivariate cases. The approaches based on independence of cause and mechanism state, on the contrary, that causal discovery can be inferred for two observations. In our contribution, we pose a challenge to reconcile these two research directions. We study the role of latent variables such as latent instrumental variables and hidden common causes in the causal graphical structures. We show that methods based on the independence of cause and mechanism indirectly contain traces of the existence of the hidden instrumental variables. We derive a novel algorithm to infer causal relationships between two variables, and we validate the proposed method on simulated data and on a benchmark of cause-effect pairs. We illustrate by our experiments that the proposed approach is simple and extremely competitive in terms of empirical accuracy compared to the state-of-the-art methods.

Robust structure measures of metabolic networks that predict prokaryotic optimal growth temperature.

BACKGROUND: Metabolic networks reflect the relationships between metabolites (biomolecules) and the enzymes (proteins), and are of particular interest since they describe all chemical reactions of an organism. The metabolic networks are constructed from the genome sequence of an organism, and the graphs can be used to study fluxes through the reactions, or to relate the graph structure to environmental characteristics and phenotypes. About ten years ago, Takemoto et al. (2007) stated that the structure of prokaryotic metabolic networks represented as undirected graphs, is correlated to their living environment. Although metabolic networks are naturally directed graphs, they are still usually analysed as undirected graphs. RESULTS: We implemented a pipeline to reconstruct metabolic networks from genome data and confirmed some of the results of Takemoto et al. (2007) with today data using up-to-date databases. However, Takemoto et al. (2007) used only a fraction of all available enzymes from the genome and taking into account all the enzymes we fail to reproduce the main results. Therefore, we introduce three robust measures on directed representations of graphs, which lead to similar results regardless of the method of network reconstruction. We show that the size of the largest strongly connected component, the flow hierarchy and the Laplacian spectrum are strongly correlated to the environmental conditions. CONCLUSIONS: We found a significant negative correlation between the size of the largest strongly connected component (a cycle) and the optimal growth temperature of the considered prokaryotes. This relationship holds true for the spectrum, high temperature being associated with lower eigenvalues. The hierarchy flow shows a negative correlation with optimal growth temperature. This suggests that the dynamical properties of the network are dependant on environmental factors.

The advanced-DiaRem score improves prediction of diabetes remission 1 year post-Roux-en-Y gastric bypass.

AIMS/HYPOTHESIS: Not all people with type 2 diabetes who undergo bariatric surgery achieve diabetes remission. Thus it is critical to develop methods for predicting outcomes that are applicable for clinical practice. The DiaRem score is relevant for predicting diabetes remission post-Roux-en-Y gastric bypass (RYGB), but it is not accurate for all individuals across the entire spectrum of scores. We aimed to develop an improved scoring system for predicting diabetes remission following RYGB (the Advanced-DiaRem [Ad-DiaRem]). METHODS: We used a retrospective French cohort (n = 1866) that included 352 individuals with type 2 diabetes followed for 1 year post-RYGB. We developed the Ad-DiaRem in a test cohort (n = 213) and examined its accuracy in independent cohorts from France (n = 134) and Israel (n = 99). RESULTS: Adding two clinical variables (diabetes duration and number of glucose-lowering agents) to the original DiaRem and modifying the penalties for each category led to improved predictive performance for Ad-DiaRem. Ad-DiaRem displayed improved area under the receiver operating characteristic curve and predictive accuracy compared with DiaRem (0.911 vs 0.856 and 0.841 vs 0.789, respectively; p = 0.03); thus correcting classification for 8% of those initially misclassified with DiaRem. With Ad-DiaRem, there were also fewer misclassifications of individuals with mid-range scores. This improved predictive performance was confirmed in independent cohorts. CONCLUSIONS/INTERPRETATION: We propose the Ad-DiaRem, which includes two additional clinical variables, as an optimised tool with improved accuracy to predict diabetes remission 1 year post-RYGB. This tool might be helpful for personalised management of individuals with diabetes when considering bariatric surgery in routine care, ultimately contributing to precision medicine.

Akkermansia muciniphila and improved metabolic health during a dietary intervention in obesity: relationship with gut microbiome richness and ecology.

OBJECTIVE: Individuals with obesity and type 2 diabetes differ from lean and healthy individuals in their abundance of certain gut microbial species and microbial gene richness. Abundance of Akkermansia muciniphila, a mucin-degrading bacterium, has been inversely associated with body fat mass and glucose intolerance in mice, but more evidence is needed in humans. The impact of diet and weight loss on this bacterial species is unknown. Our objective was to evaluate the association between faecal A. muciniphila abundance, faecal microbiome gene richness, diet, host characteristics, and their changes after calorie restriction (CR). DESIGN: The intervention consisted of a 6-week CR period followed by a 6-week weight stabilisation diet in overweight and obese adults (N=49, including 41 women). Faecal A. muciniphila abundance, faecal microbial gene richness, diet and bioclinical parameters were measured at baseline and after CR and weight stabilisation. RESULTS: At baseline A. muciniphila was inversely related to fasting glucose, waist-to-hip ratio and subcutaneous adipocyte diameter. Subjects with higher gene richness and A. muciniphila abundance exhibited the healthiest metabolic status, particularly in fasting plasma glucose, plasma triglycerides and body fat distribution. Individuals with higher baseline A. muciniphila displayed greater improvement in insulin sensitivity markers and other clinical parameters after CR. These participants also experienced a reduction in A. muciniphila abundance, but it remained significantly higher than in individuals with lower baseline abundance. A. muciniphila was associated with microbial species known to be related to health. CONCLUSIONS: A. muciniphila is associated with a healthier metabolic status and better clinical outcomes after CR in overweight/obese adults. The interaction between gut microbiota ecology and A. muciniphila warrants further investigation. TRIAL REGISTRATION NUMBER: NCT01314690.

Spectral consensus strategy for accurate reconstruction of large biological networks.

BACKGROUND: The last decades witnessed an explosion of large-scale biological datasets whose analyses require the continuous development of innovative algorithms. Many of these high-dimensional datasets are related to large biological networks with few or no experimentally proven interactions. A striking example lies in the recent gut bacterial studies that provided researchers with a plethora of information sources. Despite a deeper knowledge of microbiome composition, inferring bacterial interactions remains a critical step that encounters significant issues, due in particular to high-dimensional settings, unknown gut bacterial taxa and unavoidable noise in sparse datasets. Such data type make any a priori choice of a learning method particularly difficult and urge the need for the development of new scalable approaches. RESULTS: We propose a consensus method based on spectral decomposition, named Spectral Consensus Strategy, to reconstruct large networks from high-dimensional datasets. This novel unsupervised approach can be applied to a broad range of biological networks and the associated spectral framework provides scalability to diverse reconstruction methods. The results obtained on benchmark datasets demonstrate the interest of our approach for high-dimensional cases. As a suitable example, we considered the human gut microbiome co-presence network. For this application, our method successfully retrieves biologically relevant relationships and gives new insights into the topology of this complex ecosystem. CONCLUSIONS: The Spectral Consensus Strategy improves prediction precision and allows scalability of various reconstruction methods to large networks. The integration of multiple reconstruction algorithms turns our approach into a robust learning method. All together, this strategy increases the confidence of predicted interactions from high-dimensional datasets without demanding computations.

Circulating phospholipid profiling identifies portal contribution to NASH signature in obesity.

BACKGROUND & AIMS: Non-alcoholic steatohepatitis (NASH) is characterized by steatosis, lobular inflammation, hepatocyte ballooning with fibrosis in severe cases, and high prevalence in obesity. We aimed at defining NASH signature in morbid obesity by mass spectrometry-based lipidomic analysis. METHODS: We analyzed systemic blood before and 12 months after bariatric surgery, along with portal blood and adipose tissue lipid efflux collected from obese women at the time of surgery (9 structural classes, 150 species). RESULTS: Increased concentrations of several glycerophosphocholines (PC), glycerophosphoethanolamines (PE), glycerophosphoinositols (PI), glycerophosphoglycerols (PG), lyso-glycerophosphocholines (LPC), and ceramides (Cer) were detected in systemic circulation of NASH subjects. Post-surgery weight loss (12 months) improved the levels of liver enzymes, as well as several lipids, but most PG and Cer species remained elevated. Analysis of lipids from hepatic portal system at the time of surgery revealed limited lipid alterations compared to systemic circulation, but PG and PE classes were found significantly increased in NASH subjects. We evaluated the contribution of visceral adipose tissue to lipid alterations in portal circulation by measuring adipose tissue lipid efflux ex vivo, and observed only minor alterations in NASH subjects. Interestingly, integration of clinical and lipidomic data (portal and systemic) led us to define a NASH signature in which lipids and clinical parameters are equal contributors. CONCLUSIONS: Circulatory (portal and systemic) phospholipid profiling and clinical data defines NASH signature in morbid obesity. We report weak contribution of visceral adipose tissue to NASH-related portal lipid alterations, suggesting possible contribution from other organs draining into hepatic portal system.

Beta-hydroxybutyrate dampens adipose progenitors' profibrotic activation through canonical Tgfß signaling and non-canonical ZFP36-dependent mechanisms.

BACKGROUND/PURPOSE: Adipose tissue contains progenitor cells that contribute to beneficial tissue expansion when needed by de novo adipocyte formation (classical white or beige fat cells with thermogenic potential). However, in chronic obesity, they can exhibit an activated pro-fibrotic, extracellular matrix (ECM)-depositing phenotype that highly aggravates obesity-related adipose tissue dysfunction. METHODS: Given that progenitors' fibrotic activation and fat cell browning appear to be antagonistic cell fates, we have examined the anti-fibrotic potential of pro-browning agents in an obesogenic condition. RESULTS: In obese mice fed a high fat diet, thermoneutral housing, which induces brown fat cell dormancy, increases the expression of ECM gene programs compared to conventionally raised animals, indicating aggravation of obesity-related tissue fibrosis at thermoneutrality. In a model of primary cultured murine adipose progenitors, we found that exposure to ß-hydroxybutyrate selectively reduced Tgfß-dependent profibrotic responses of ECM genes like Ctgf, Loxl2 and Fn1. This effect is observed in both subcutaneous and visceral-derived adipose progenitors, as well as in 3T3-L1 fibroblasts. In 30 patients with obesity eligible for bariatric surgery, those with higher circulating ß-hydroxybutyrate levels have lower subcutaneous adipose tissue fibrotic scores. Mechanistically, ß-hydroxybutyrate limits Tgfß-dependent collagen accumulation and reduces Smad2-3 protein expression and phosphorylation in visceral progenitors. Moreover, ß-hydroxybutyrate induces the expression of the ZFP36 gene, encoding a post-transcriptional regulator that promotes the degradation of mRNA by binding to AU-rich sites within 3'UTRs. Importantly, complete ZFP36 deficiency in a mouse embryonic fibroblast line from null mice, or siRNA knock-down in primary progenitors, indicate that ZFP36 is required for ß-hydroxybutyrate anti-fibrotic effects. CONCLUSION: These data unravel the potential of ß-hydroxybutyrate to limit adipose tissue matrix deposition, a finding that might exploited in an obesogenic context.

Functional prediction of environmental variables using metabolic networks.

In this manuscript, we propose a novel approach to assess relationships between environment and metabolic networks. We used a comprehensive dataset of more than 5000 prokaryotic species from which we derived the metabolic networks. We compute the scope from the reconstructed graphs, which is the set of all metabolites and reactions that can potentially be synthesized when provided with external metabolites. We show using machine learning techniques that the scope is an excellent predictor of taxonomic and environmental variables, namely growth temperature, oxygen tolerance, and habitat. In the literature, metabolites and pathways are rarely used to discriminate species. We make use of the scope underlying structure-metabolites and pathways-to construct the predictive models, giving additional information on the important metabolic pathways needed to discriminate the species, which is often absent in other metabolic network properties. For example, in the particular case of growth temperature, glutathione biosynthesis pathways are specific to species growing in cold environments, whereas tungsten metabolism is specific to species in warm environments, as was hinted in current literature. From a machine learning perspective, the scope is able to reduce the dimension of our data, and can thus be considered as an interpretable graph embedding.

Using Unlabeled Data to Discover Bivariate Causality with Deep Restricted Boltzmann Machines.

An important question in microbiology is whether treatment causes changes in gut flora, and whether it also affects metabolism. The reconstruction of causal relations purely from non-temporal observational data is challenging. We address the problem of causal inference in a bivariate case, where the joint distribution of two variables is observed. We consider, in particular, data on discrete domains. The state-of-the-art causal inference methods for continuous data suffer from high computational complexity. Some modern approaches are not suitable for categorical data, and others need to estimate and fix multiple hyper-parameters. In this contribution, we introduce a novel method of causal inference which is based on the widely used assumption that if X causes Y, then P(X) and P(Y|X) are independent. We propose to explore a semi-supervised approach where P(Y|X) and P(X) are estimated from labeled and unlabeled data respectively, whereas the marginal probability is estimated potentially from much more (cheap unlabeled) data than the conditional distribution. We validate the proposed method on the standard cause-effect pairs. We illustrate by experiments on several benchmarks of biological network reconstruction that the proposed approach is very competitive in terms of computational time and accuracy compared to the state-of-the-art methods. Finally, we apply the proposed method to an original medical task where we study whether drugs confound human metagenome.

Autophagy inhibition blunts PDGFRA adipose progenitors' cell-autonomous fibrogenic response to high-fat diet.

Adipose tissue (AT) fibrosis in obesity compromises adipocyte functions and responses to intervention-induced weight loss. It is driven by AT progenitors with dual fibro/adipogenic potential, but pro-fibrogenic pathways activated in obesity remain to be deciphered. To investigate the role of macroautophagy/autophagy in AT fibrogenesis, we used Pdgfra-CreErt2 transgenic mice to create conditional deletion of Atg7 alleles in AT progenitor cells (atg7 cKO) and examined sex-dependent, depot-specific AT remodeling in high-fat diet (HFD)-fed mice. Mice with atg7 cKO had markedly decreased extracellular matrix (ECM) gene expression in visceral, subcutaneous, and epicardial adipose depots compared to Atg7lox/lox littermates. ECM gene program regulation by autophagy inhibition occurred independently of changes in the mass of fat tissues or adipocyte numbers of specific depots, and cultured preadipocytes treated with pharmacological or siRNA-mediated autophagy disruptors could mimic these effects. We found that autophagy inhibition promotes global cell-autonomous remodeling of the paracrine TGF-BMP family landscape, whereas ECM gene modulation was independent of the autophagic regulation of GTF2IRD1. The progenitor-specific mouse model of ATG7 inhibition confirms the requirement of autophagy for white/beige adipocyte turnover, and combined to in vitro experiments, reveal progenitor autophagy dependence for AT fibrogenic response to HFD, through the paracrine remodeling of TGF-BMP factors balance. Abbreviations: CQ: chloroquine; ECM: extracellular matrix; EpiAT: epididymal adipose tissue; GTF2IRD1: general transcription factor II I repeat domain-containing 1; HFD: high-fat diet; KO: knockout; OvAT: ovarian adipose tissue; PDGFR: platelet derived growth factor receptor; ScAT: subcutaneous adipose tissue; TGF-BMP: transforming growth factor-bone morphogenic protein.

Long-term Relapse of Type 2 Diabetes After Roux-en-Y Gastric Bypass: Prediction and Clinical Relevance.

OBJECTIVE: Roux-en-Y gastric bypass (RYGB) induces type 2 diabetes remission (DR) in 60% of patients at 1 year, yet long-term relapse occurs in half of these patients. Scoring methods to predict DR outcomes 1 year after surgery that include only baseline parameters cannot accurately predict 5-year DR (5y-DR). We aimed to develop a new score to better predict 5y-DR. RESEARCH DESIGN AND METHODS: We retrospectively included 175 RYGB patients with type 2 diabetes with 5-year follow-up. Using machine learning algorithms, we developed a scoring method, 5-year Advanced-Diabetes Remission (5y-Ad-DiaRem), predicting longer-term DR postsurgery by integrating medical history, bioclinical data, and antidiabetic treatments. The scoring method was based on odds ratios and variables significantly different between groups. This score was further validated in three independent RYGB cohorts from three European countries. RESULTS: Compared with 5y-DR patients, patients who had relapsed after 5 years exhibited more severe type 2 diabetes at baseline, lost significantly less weight during the 1st year after RYGB, and regained more weight afterward. The 5y-Ad-DiaRem includes baseline (diabetes duration, number of antidiabetic treatments, and HbA1c) and 1-year follow-up parameters (glycemia, number of antidiabetic treatments, remission status, 1st-year weight loss). The 5y-Ad-DiaRem was accurate (area under the receiver operating characteristic curve [AUROC], 90%; accuracy, 85%) at predicting 5y-DR, performed better than the Diabetes Remission score (DiaRem) and the Advanced-DiaRem (AUROC, 81% and 84%; accuracy, 79% and 78%, respectively), and correctly reclassified 13 of 39 patients misclassified with the DiaRem. The 5y-Ad-DiaRem robustness was confirmed in the independent cohorts. CONCLUSIONS: The 5y-Ad-DiaRem accurately predicts 5y-DR and appears relevant to identify patients at risk for relapse. Using this score could help personalize patient care after the 1st year post-RYGB to maximize weight loss, limit weight regains, and prevent relapse.

A Data Integration Multi-Omics Approach to Study Calorie Restriction-Induced Changes in Insulin Sensitivity.

Background: The mechanisms responsible for calorie restriction (CR)-induced improvement in insulin sensitivity (IS) have not been fully elucidated. Greater insight can be achieved through deep biological phenotyping of subjects undergoing CR, and integration of big data. Materials and Methods: An integrative approach was applied to investigate associations between change in IS and factors from host, microbiota, and lifestyle after a 6-week CR period in 27 overweight or obese adults (ClinicalTrials.gov: NCT01314690). Partial least squares regression was used to determine associations of change (week 6 - baseline) between IS markers and lifestyle factors (diet and physical activity), subcutaneous adipose tissue (sAT) gene expression, metabolomics of serum, urine and feces, and gut microbiota composition. ScaleNet, a network learning approach based on spectral consensus strategy (SCS, developed by us) was used for reconstruction of biological networks. Results: A spectrum of variables from lifestyle factors (10 nutrients), gut microbiota (10 metagenomics species), and host multi-omics (metabolic features: 84 from serum, 73 from urine, and 131 from feces; and 257 sAT gene probes) most associated with IS were identified. Biological network reconstruction using SCS, highlighted links between changes in IS, serum branched chain amino acids, sAT genes involved in endoplasmic reticulum stress and ubiquitination, and gut metagenomic species (MGS). Linear regression analysis to model how changes of select variables over the CR period contribute to changes in IS, showed greatest contributions from gut MGS and fiber intake. Conclusion: This work has enhanced previous knowledge on links between host glucose homeostasis, lifestyle factors and the gut microbiota, and has identified potential biomarkers that may be used in future studies to predict and improve individual response to weight-loss interventions. Furthermore, this is the first study showing integration of the wide range of data presented herein, identifying 115 variables of interest with respect to IS from the initial input, consisting of 9,986 variables. Clinical Trial Registration: clinicaltrials.gov (NCT01314690).

The FAT Score, a Fibrosis Score of Adipose Tissue: Predicting Weight-Loss Outcome After Gastric Bypass.

Context: Bariatric surgery (BS) induces major and sustainable weight loss in many patients. Factors predicting poor weight-loss response (PR) need to be identified to improve patient care. Quantification of subcutaneous adipose tissue (scAT) fibrosis is negatively associated with post-BS weight loss, but whether it could constitute a predictor applicable in clinical routine remains to be demonstrated. Objective: To create a semiquantitative score evaluating scAT fibrosis and test its predictive value on weight-loss response after Roux-en-Y gastric bypass (RYGB). Methods: We created a fibrosis score of adipose tissue (FAT score) integrating perilobular and pericellular fibrosis. Using this score, we characterized 183 perioperative scAT biopsy specimens from severely obese patients who underwent RYGB (n = 85 from a training cohort; n = 98 from a confirmation cohort). PR to RYGB was defined as <28% of total weight loss at 1 year (lowest tertile). The link between FAT score and PR was tested in univariate and multivariate models. Results: FAT score was directly associated with increasing scAT fibrosis measured by a standard quantification method (P for trend <0.001). FAT score interobserver agreement was good (κ = 0.76). FAT score ≥2 was significantly associated with PR. The association remained significant after adjustment for age, diabetes status, hypertension, percent fat mass, and interleukin-6 level (adjusted odds ratio, 3.6; 95% confidence interval, 1.8 to 7.2; P = 0.003). Conclusion: The FAT score is a new, simple, semiquantitative evaluation of human scAT fibrosis that may help identify patients with a potential limited weight-loss response to RYGB.

Sparse Zero-Sum Games as Stable Functional Feature Selection.

In large-scale systems biology applications, features are structured in hidden functional categories whose predictive power is identical. Feature selection, therefore, can lead not only to a problem with a reduced dimensionality, but also reveal some knowledge on functional classes of variables. In this contribution, we propose a framework based on a sparse zero-sum game which performs a stable functional feature selection. In particular, the approach is based on feature subsets ranking by a thresholding stochastic bandit. We provide a theoretical analysis of the introduced algorithm. We illustrate by experiments on both synthetic and real complex data that the proposed method is competitive from the predictive and stability viewpoints.

Insulin resistance and inflammation predict kinetic body weight changes in response to dietary weight loss and maintenance in overweight and obese subjects by using a Bayesian network approach.

BACKGROUND: The ability to identify obese subjects who will lose weight in response to energy restriction is an important strategy in obesity treatment. OBJECTIVE: We aimed to identify obese subjects who would lose weight and maintain weight loss through 6 wk of energy restriction and 6 wk of weight maintenance. DESIGN: Fifty obese or overweight subjects underwent a 6-wk energy-restricted, high-protein diet followed by another 6 wk of weight maintenance. Network modeling by using combined biological, gut microbiota, and environmental factors was performed to identify predictors of weight trajectories. RESULTS: On the basis of body weight trajectories, 3 subject clusters were identified. Clusters A and B lost more weight during energy restriction. During the stabilization phase, cluster A continued to lose weight, whereas cluster B remained stable. Cluster C lost less and rapidly regained weight during the stabilization period. At baseline, cluster C had the highest plasma insulin, interleukin (IL)-6, adipose tissue inflammation (HAM56+ cells), and Lactobacillus/Leuconostoc/Pediococcus numbers in fecal samples. Weight regain after energy restriction correlated positively with insulin resistance (homeostasis model assessment of insulin resistance: r = 0.5, P = 0.0002) and inflammatory markers (IL-6; r = 0.43, P = 0.002) at baseline. The Bayesian network identified plasma insulin, IL-6, leukocyte number, and adipose tissue (HAM56) at baseline as predictors that were sufficient to characterize the 3 clusters. The prediction accuracy reached 75.5%. CONCLUSION: The resistance to weight loss and proneness to weight regain could be predicted by the combination of high plasma insulin and inflammatory markers before dietary intervention.