DNEA: an R package for fast and versatile data-driven network analysis of metabolomics data.

Background: Metabolomics is a high-throughput technology that measures small molecule metabolites in cells, tissues or biofluids. Analysis of metabolomics data is a multi-step process that involves data processing, quality control and normalization, followed by statistical and bioinformatics analysis. The latter step often involves pathway analysis to aid biological interpretation of the data.

CorrelationCalculator and Filigree: Tools for Data-Driven Network Analysis of Metabolomics Data.

A significant challenge in the analysis of omics data is extracting actionable biological knowledge. Metabolomics is no exception. The general problem of relating changes in levels of individual metabolites to specific biological processes is compounded by the large number of unknown metabolites present in untargeted liquid chromatography-mass spectrometry (LC-MS) studies.

Metabolomic signatures associated with weight gain and psychosis spectrum diagnoses: A pilot study.

Psychosis spectrum disorders (PSDs), as well as other severe mental illnesses where psychotic features may be present, like bipolar disorder, are associated with intrinsic metabolic abnormalities. Antipsychotics (APs), the cornerstone of treatment for PSDs, incur additional metabolic adversities including weight gain. Currently, major gaps exist in understanding psychosis illness biomarkers, as well as risk factors and mechanisms for AP-induced weight gain.

Trichloroethylene Metabolite -(1,2-Dichlorovinyl)-l-cysteine Stimulates Changes in Energy Metabolites and Amino Acids in the BeWo Human Placental Trophoblast Model during Syncytialization.

Syncytialization, the fusion of cytotrophoblasts into an epithelial barrier that constitutes the maternal-fetal interface, is a crucial event of placentation. This process is characterized by distinct changes to amino acid and energy metabolism. A metabolite of the industrial solvent trichloroethylene (TCE), -(1,2-dichlorovinyl)-l-cysteine (DCVC), modifies energy metabolism and amino acid abundance in HTR-8/SVneo extravillous trophoblasts.

Sustained Perturbation of Metabolism and Metabolic Subphenotypes Are Associated With Mortality and Protein Markers of the Host Response.

Unlabelled: Perturbed host metabolism is increasingly recognized as a pillar of sepsis pathogenesis, yet the dynamic alterations in metabolism and its relationship to other components of the host response remain incompletely understood. We sought to identify the early host-metabolic response in patients with septic shock and to explore biophysiological phenotyping and differences in clinical outcomes among metabolic subgroups.

Design: We measured serum metabolites and proteins reflective of the host-immune and endothelial response in patients with septic shock.

Alignment and Analysis of a Disparately Acquired Multibatch Metabolomics Study of Maternal Pregnancy Samples.

Untargeted liquid chromatography-mass spectrometry metabolomics studies are typically performed under roughly identical experimental settings. Measurements acquired with different LC-MS protocols or following extended time intervals harbor significant variation in retention times and spectral abundances due to altered chromatographic, spectrometric, and other factors, raising many data analysis challenges. We developed a computational workflow for merging and harmonizing metabolomics data acquired under disparate LC-MS conditions.

Body mass index associates with amyotrophic lateral sclerosis survival and metabolomic profiles.

Introduction/aims: Body mass index (BMI) is linked to amyotrophic lateral sclerosis (ALS) risk and prognosis, but additional research is needed. The aim of this study was to identify whether and when historical changes in BMI occurred in ALS participants, how these longer term trajectories associated with survival, and whether metabolomic profiles provided insight into potential mechanisms.

Methods: ALS and control participants self-reported body height and weight 10 (reference) and 5 years earlier, and at study entry (diagnosis for ALS participants).

Trichloroethylene modifies energy metabolites in the amniotic fluid of Wistar rats.

Exposure to trichloroethylene (TCE), an industrial solvent, is associated with several adverse pregnancy outcomes in humans and decreased fetal weight in rats. However, effects of TCE on energy metabolites in amniotic fluid, which have associations with pregnancy outcomes, has not been published previously. In the current exploratory study, timed-pregnant Wistar rats were exposed to 480 mg TCE/kg/day via vanilla wafer or to vehicle (wafer) alone from gestational day (GD) 6-16.

Metabolomics identifies shared lipid pathways in independent amyotrophic lateral sclerosis cohorts.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease lacking effective treatments. This is due, in part, to a complex and incompletely understood pathophysiology. To shed light, we conducted untargeted metabolomics on plasma from two independent cross-sectional ALS cohorts versus control participants to identify recurrent dysregulated metabolic pathways.

Comparing the Fasting and Random-Fed Metabolome Response to an Oral Glucose Tolerance Test in Children and Adolescents: Implications of Sex, Obesity, and Insulin Resistance.

As the incidence of obesity and type 2 diabetes (T2D) is occurring at a younger age, studying adolescent nutrient metabolism can provide insights on the development of T2D. Metabolic challenges, including an oral glucose tolerance test (OGTT) can assess the effects of perturbations in nutrient metabolism. Here, we present alterations in the global metabolome in response to an OGTT, classifying the influence of obesity and insulin resistance (IR) in adolescents that arrived at the clinic fasted and in a random-fed state.

Pharmacometabolomics identifies candidate predictor metabolites of an L-carnitine treatment mortality benefit in septic shock.

Sepsis-induced metabolic dysfunction contributes to organ failure and death. L-carnitine has shown promise for septic shock, but a recent phase II study of patients with vasopressor-dependent septic shock demonstrated a non-significant reduction in mortality. We undertook a pharmacometabolomics study of these patients (n = 250) to identify metabolic profiles predictive of a 90-day mortality benefit from L-carnitine.

Genetic and Metabolite Variability in One-Carbon Metabolism Applied to an Insulin Resistance Model in Patients With Schizophrenia Receiving Atypical Antipsychotics.

Patients with schizophrenia are at high risk of pre-mature mortality due to cardiovascular disease (CVD). Our group has completed studies in pharmacogenomics and metabolomics that have independently identified perturbations in one-carbon metabolism as associated with risk factors for CVD in this patient population. Therefore, this study aimed to use genetic and metabolomic data to determine the relationship between folate pharmacogenomics, one-carbon metabolites, and insulin resistance as measured using the homeostatic model assessment for insulin resistance (HOMA-IR) as a marker of CVD.

: Paired Untargeted LC-HRMS Metabolomics Feature Matching and Concatenation of Disparately Acquired Data Sets.

LC-HRMS experiments detect thousands of compounds, with only a small fraction of them identified in most studies. Traditional data processing pipelines contain an alignment step to assemble the measurements of overlapping features across samples into a unified table. However, data sets acquired under nonidentical conditions are not amenable to this process, mostly due to significant alterations in chromatographic retention times.

Application of Differential Network Enrichment Analysis for Deciphering Metabolic Alterations.

Modern analytical methods allow for the simultaneous detection of hundreds of metabolites, generating increasingly large and complex data sets. The analysis of metabolomics data is a multi-step process that involves data processing and normalization, followed by statistical analysis. One of the biggest challenges in metabolomics is linking alterations in metabolite levels to specific biological processes that are disrupted, contributing to the development of disease or reflecting the disease state.

Pharmacologic modulation of brain metabolism by valproic acid can induce a neuroprotective environment.

Objective: Traumatic brain injury (TBI) is a leading cause of trauma-related morbidity and mortality. Valproic acid (VPA) has been shown to attenuate brain lesion size and swelling within the first few hours following TBI. Because injured neurons are sensitive to metabolic changes, we hypothesized that VPA treatment would alter the metabolic profile in the perilesional brain tissues to create a neuroprotective environment.

Serum Levels of Branched Chain Amino Acids Predict Duration of Cardiovascular Organ Failure in Septic Shock.

Background: Sepsis shifts cardiac metabolic fuel preference and this disruption may have implications for cardiovascular function. A greater understanding of the role of metabolism in the development and persistence of cardiovascular failure in sepsis could serve to identify novel pharmacotherapeutic approaches.

Methods: Secondary analysis of prospective quantitative proton nuclear magnetic resonance (1H-NMR) metabolomic data from patients enrolled in a phase II randomized control trial of L-carnitine in septic shock.

Using l-Carnitine as a Pharmacologic Probe of the Interpatient and Metabolic Variability of Sepsis.

Objective: The objective of this review is to discuss the therapeutic use and differential treatment response to Levo-carnitine (l-carnitine) treatment in septic shock, and to demonstrate common lessons learned that are important to the advancement of precision medicine approaches to sepsis. We propose that significant interpatient variability in the metabolic response to l-carnitine and clinical outcomes can be used to elucidate the mechanistic underpinnings that contribute to sepsis heterogeneity.

Methods: A narrative review was conducted that focused on explaining interpatient variability in l-carnitine treatment response.

Mitochondrial Nutrient Utilization Underlying the Association Between Metabolites and Insulin Resistance in Adolescents.

Context: A person's intrinsic metabolism, reflected in the metabolome, may describe the relationship between nutrient intake and metabolic health.

Objectives: Untargeted metabolomics was used to identify metabolites associated with metabolic health. Path analysis classified how habitual dietary intake influences body mass index z-score (BMIz) and insulin resistance (IR) through changes in the metabolome.

Pathway Analysis for Targeted and Untargeted Metabolomics.

Recent advances in analytical techniques, particularly LC-MS, generate increasingly large and complex metabolomics datasets. Pathway analysis tools help place the experimental observations into relevant biological or disease context. This chapter provides an overview of the general concepts and common tools for pathway analysis, including Mummichog for untargeted metabolomics.

Deep annotation of untargeted LC-MS metabolomics data with Binner.

Motivation: When metabolites are analyzed by electrospray ionization (ESI)-mass spectrometry, they are usually detected as multiple ion species due to the presence of isotopes, adducts and in-source fragments. The signals generated by these degenerate features (along with contaminants and other chemical noise) obscure meaningful patterns in MS data, complicating both compound identification and downstream statistical analysis. To address this problem, we developed Binner, a new tool for the discovery and elimination of many degenerate feature signals typically present in untargeted ESI-LC-MS metabolomics data.

Rapid metabolic shifts occur during the transition between hunger and satiety in Drosophila melanogaster.

Metabolites are active controllers of cellular physiology, but their role in complex behaviors is less clear. Here we report metabolic changes that occur during the transition between hunger and satiety in Drosophila melanogaster. To analyze these data in the context of fruit fly metabolic networks, we developed Flyscape, an open-access tool.

Untargeted Metabolomics Differentiates l-Carnitine Treated Septic Shock 1-Year Survivors and Nonsurvivors.

l-Carnitine is a candidate therapeutic for the treatment of septic shock, a condition that carries a ≥40% mortality. Responsiveness to l-carnitine may hinge on unique metabolic profiles that are not evident from the clinical phenotype. To define these profiles, we performed an untargeted metabolomic analysis of serum from 21 male sepsis patients enrolled in a placebo-controlled l-carnitine clinical trial.