An evaluation of the National Institutes of Health grants portfolio: identifying opportunities and challenges for multi-omics research that leverage metabolomics data.

BACKGROUND: Through the systematic large-scale profiling of metabolites, metabolomics provides a tool for biomarker discovery and improving disease monitoring, diagnosis, prognosis, and treatment response, as well as for delineating disease mechanisms and etiology. As a downstream product of the genome and epigenome, transcriptome, and proteome activity, the metabolome can be considered as being the most proximal correlate to the phenotype. Integration of metabolomics data with other -omics data in multi-omics analyses has the potential to advance understanding of human disease development and treatment. AIM OF REVIEW: To understand the current funding and potential research opportunities for when metabolomics is used in human multi-omics studies, we cross-sectionally evaluated National Institutes of Health (NIH)-funded grants to examine the use of metabolomics data when collected with at least one other -omics data type. First, we aimed to determine what types of multi-omics studies included metabolomics data collection. Then, we looked at those multi-omics studies to examine how often grants employed an integrative analysis approach using metabolomics data. KEY SCIENTIFIC CONCEPTS OF REVIEW: We observed that the majority of NIH-funded multi-omics studies that include metabolomics data performed integration, but to a limited extent, with integration primarily incorporating only one other -omics data type. Some opportunities to improve data integration may include increasing confidence in metabolite identification, as well as addressing variability between -omics approach requirements and -omics data incompatibility.

Towards quality assurance and quality control in untargeted metabolomics studies.

We describe here the agreed upon first development steps and priority objectives of a community engagement effort to address current challenges in quality assurance (QA) and quality control (QC) in untargeted metabolomic studies. This has included (1) a QA and QC questionnaire responded to by the metabolomics community in 2015 which recommended education of the metabolomics community, development of appropriate standard reference materials and providing incentives for laboratories to apply QA and QC; (2) a 2-day 'Think Tank on Quality Assurance and Quality Control for Untargeted Metabolomic Studies' held at the National Cancer Institute's Shady Grove Campus and (3) establishment of the Metabolomics Quality Assurance and Quality Control Consortium (mQACC) to drive forward developments in a coordinated manner.

NIH-supported implementation science and nutrition research: a portfolio review of the past decade.

Objective: This portfolio analysis aims to describe the scope of NIH-funded extramural research grants at the intersection of nutrition research and implementation science (IS) from 2011 to 2022 and to offer insights into future research opportunities relevant to the Strategic Plan for NIH Nutrition Research 2020-2030. Methods: A portfolio analysis of funded grants using NIH reporting systems was conducted to identify nutrition research and IS awarded between fiscal years 2011 and 2022. The authors screened the titles and abstracts for inclusion criteria: research and career development awards involved a nutrition and/or dietary intervention and measured a stated implementation outcome or used an IS theory, model, or framework. Results: In total, 33 NIH-funded awards met the inclusion criteria. Almost half of the awards (48.5%) were investigator-initiated research projects compared to research career awards and cooperative agreements. While studies were predominantly conducted in the United States, 15.2% were conducted in low- and middle-income countries in Africa, Latin America, and Asia. Adults aged 19-64 years and children aged 2-11 years represented most of the study populations (45.5 and 15.2%, respectively). Studies provided nutrition/dietary guidelines and created culturally tailored interventions, which were then adapted in collaboration with community partners in schools, hospitals, and religious settings. The most cited IS outcomes were feasibility, costs, adoption, and acceptability. Sixteen awards (48.5%) used an IS theory, model, or framework to guide their work. Discussion: The findings show the breadth of NIH-funded nutrition and implementation research and highlight potential research opportunities.

Opportunities to advance implementation science and nutrition research: a commentary on the Strategic Plan for NIH Nutrition Research.

Despite population-wide recommendations by the U.S. Dietary Guidelines for Americans and others to encourage health-promoting dietary patterns, the proportion of Americans following dietary recommendations remains low. The gaps in the adoption and integration of evidence-based dietary interventions, practices, programs, and policies (EBIs) into community and clinical settings signal the need to strengthen efforts in implementation science (IS) in nutrition research to understand and alleviate barriers to adopting and sustaining healthy dietary behaviors and practices. Equally important is the translation of this research into practice in a variety of settings and across the diversity of populations. Recognizing this need, the U.S. National Institutes of Health (NIH) 2020-2030 Strategic Plan for NIH Nutrition Research calls for the expansion of IS as a key opportunity to advancing nutrition research. This commentary highlights three scientific opportunities to stimulate IS in nutrition research and provides examples for each opportunity. These include: (a) Advance consideration of implementation and dissemination early in the design of interventions to facilitate opportunities for equitable scale-up and sustainability of EBIs, (b) Develop and test strategies for equitable implementation of nutrition and diet EBIs in health care and community settings, and (c) Build and strengthen the infrastructure, capacity, and expertise needed to increase use of IS in clinical and community nutrition research to swiftly move the research into practice. By advancing the three opportunities identified in this commentary, the scientific community has the potential to advance the field of nutrition research and IS with the ultimate goal of improving public health.

While dietary guidelines have proven effective in clinical studies, most Americans do not follow these tested guidelines. More work is needed to bring research into practice so that all populations can benefit from the research. The U.S. National Institutes of Health recognizes this need and highlights it as a key opportunity in its 2020­2030 Strategic Plan for NIH Nutrition Research. This commentary describes three scientific opportunities that can help to stimulate the research needed to move research into practice, toward the ultimate goal of improving public health.

NIH Workshop Report: sensory nutrition and disease.

In November 2019, the NIH held the "Sensory Nutrition and Disease" workshop to challenge multidisciplinary researchers working at the interface of sensory science, food science, psychology, neuroscience, nutrition, and health sciences to explore how chemosensation influences dietary choice and health. This report summarizes deliberations of the workshop, as well as follow-up discussion in the wake of the current pandemic. Three topics were addressed: A) the need to optimize human chemosensory testing and assessment, B) the plasticity of chemosensory systems, and C) the interplay of chemosensory signals, cognitive signals, dietary intake, and metabolism. Several ways to advance sensory nutrition research emerged from the workshop: 1) refining methods to measure chemosensation in large cohort studies and validating measures that reflect perception of complex chemosensations relevant to dietary choice; 2) characterizing interindividual differences in chemosensory function and how they affect ingestive behaviors, health, and disease risk; 3) defining circuit-level organization and function that link and interact with gustatory, olfactory, homeostatic, visceral, and cognitive systems; and 4) discovering new ligands for chemosensory receptors (e.g., those produced by the microbiome) and cataloging cell types expressing these receptors. Several of these priorities were made more urgent by the current pandemic because infection with sudden acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the ensuing coronavirus disease of 2019 has direct short- and perhaps long-term effects on flavor perception. There is increasing evidence of functional interactions between the chemosensory and nutritional sciences. Better characterization of this interface is expected to yield insights to promote health, mitigate disease risk, and guide nutrition policy.

Knowledge gaps in understanding the metabolic and clinical effects of excess folates/folic acid: a summary, and perspectives, from an NIH workshop.

Folate, an essential nutrient found naturally in foods in a reduced form, is present in dietary supplements and fortified foods in an oxidized synthetic form (folic acid). There is widespread agreement that maintaining adequate folate status is critical to prevent diseases due to folate inadequacy (e.g., anemia, birth defects, and cancer). However, there are concerns of potential adverse effects of excess folic acid intake and/or elevated folate status, with the original concern focused on exacerbation of clinical effects of vitamin B-12 deficiency and its role in neurocognitive health. More recently, animal and observational studies have suggested potential adverse effects on cancer risk, birth outcomes, and other diseases. Observations indicating adverse effects from excess folic acid intake, elevated folate status, and unmetabolized folic acid (UMFA) remain inconclusive; the data do not provide the evidence needed to affect public health recommendations. Moreover, strong biological and mechanistic premises connecting elevated folic acid intake, UMFA, and/or high folate status to adverse health outcomes are lacking. However, the body of evidence on potential adverse health outcomes indicates the need for comprehensive research to clarify these issues and bridge knowledge gaps. Three key research questions encompass the additional research needed to establish whether high folic acid or total folate intake contributes to disease risk. 1) Does UMFA affect biological pathways leading to adverse health effects? 2) Does elevated folate status resulting from any form of folate intake affect vitamin B-12 function and its roles in sustaining health? 3) Does elevated folate intake, regardless of form, affect biological pathways leading to adverse health effects other than those linked to vitamin B-12 function? This article summarizes the proceedings of an August 2019 NIH expert workshop focused on addressing these research areas.

Perspective: Dietary Biomarkers of Intake and Exposure-Exploration with Omics Approaches.

While conventional nutrition research has yielded biomarkers such as doubly labeled water for energy metabolism and 24-h urinary nitrogen for protein intake, a critical need exists for additional, equally robust biomarkers that allow for objective assessment of specific food intake and dietary exposure. Recent advances in high-throughput MS combined with improved metabolomics techniques and bioinformatic tools provide new opportunities for dietary biomarker development. In September 2018, the NIH organized a 2-d workshop to engage nutrition and omics researchers and explore the potential of multiomics approaches in nutritional biomarker research. The current Perspective summarizes key gaps and challenges identified, as well as the recommendations from the workshop that could serve as a guide for scientists interested in dietary biomarkers research. Topics addressed included study designs for biomarker development, analytical and bioinformatic considerations, and integration of dietary biomarkers with other omics techniques. Several clear needs were identified, including larger controlled feeding studies, testing a variety of foods and dietary patterns across diverse populations, improved reporting standards to support study replication, more chemical standards covering a broader range of food constituents and human metabolites, standardized approaches for biomarker validation, comprehensive and accessible food composition databases, a common ontology for dietary biomarker literature, and methodologic work on statistical procedures for intake biomarker discovery. Multidisciplinary research teams with appropriate expertise are critical to moving forward the field of dietary biomarkers and producing robust, reproducible biomarkers that can be used in public health and clinical research.

Metabolomics in biomarker discovery: future uses for cancer prevention.

Metabolomics is the systematic study of small-molecular-weight substances in cells, tissues and/or whole organisms as influenced by multiple factors including genetics, diet, lifestyle and pharmaceutical interventions. These substances may directly or indirectly interact with molecular targets and thereby influence the risk and complications associated with various diseases, including cancer. Since the interaction between metabolites and specific targets is dynamic, knowledge regarding genetics, susceptibility factors, timing, and degree of exposure to an agent (drug or food component) is fundamental to understanding the metabolome and its potential use for predicting and preventing early phenotypic changes. The future of metabolomics rests with its ability to monitor subtle changes in the metabolome that occur prior to the detection of a gross phenotypic change reflecting disease. The integrated analysis of metabolomics and other 'omics' may provide more sensitive ways to detect changes related to disease and discover novel biomarkers. Knowledge regarding these multivariant characteristics is critical for establishing validated and predictive metabolomic models for cancer prevention. Understanding the metabolome will not only provide insights into the critical sites of regulation in health promotion, but will also assist in identifying intermediate or surrogate cancer biomarkers for establishing preemptive/preventative or therapeutic approaches for health. While unraveling the metabolome will not be simple, the societal implications are enormous.

The vitamin D paradox in Black Americans: a systems-based approach to investigating clinical practice, research, and public health - expert panel meeting report.

The Office of Dietary Supplements, the National Institute on Minority Health and Health Disparities, the National Institute on Aging, and the National Institute of Diabetes and Digestive and Kidney Diseases, all components of the U.S. National Institutes of Health, co-sponsored an expert panel meeting to discuss the vitamin D paradox in Black Americans. The paradox is that despite markedly low (or "deficient") measures of vitamin D status in Black Americans, the incidence of falls, fractures, or osteopenia are significantly lower compared to White American counterparts with similar vitamin D status. Six panelists were invited to engage in guided discussions on the state of the science with respect to key knowledge gaps impacting vitamin D status and bone health. They were also asked to reflect on best approaches for advancing the science. A central theme throughout the discussions was that there may be many factors that impact Vitamin D levels in Black Americans and understanding these factors may be key to understanding mechanisms for improving bone health in all populations. Data presented showed that although adiposity, skin pigmentation, vitamin D binding protein polymorphisms, and genetics all contributed to differences in 25(OH)D levels in Black vs. White Americans, no one factor alone could fully explain the vitamin D paradox in Black Americans. However, the panelists did agree that the paradox is significant and warrants further investigation. There was consensus that Black Americans gained no skeletal benefits from high doses of vitamin D supplementation, and that high levels of the biomarker of vitamin D status, serum 25-hydroxyvitamin D or 25(OH)D, in this population are almost certain to result in adverse effects. Some panelists proposed that additional studies are needed so that the Institute of Medicine (IOM) can better define the safe upper limits of vitamin D intake in this and other subpopulations. Others suggested a need for better, more generalizable biomarkers of bone health to advance the science.

Accumulating Data to Optimally Predict Obesity Treatment (ADOPT): Recommendations from the Biological Domain.

BACKGROUND: The responses to behavioral, pharmacological, or surgical obesity treatments are highly individualized. The Accumulating Data to Optimally Predict obesity Treatment (ADOPT) project provides a framework for how obesity researchers, working collectively, can generate the evidence base needed to guide the development of tailored, and potentially more effective, strategies for obesity treatment. OBJECTIVES: The objective of the ADOPT biological domain subgroup is to create a list of high-priority biological measures for weight-loss studies that will advance the understanding of individual variability in response to adult obesity treatments. This list includes measures of body composition, energy homeostasis (energy intake and output), brain structure and function, and biomarkers, as well as biobanking procedures, which could feasibly be included in most, if not all, studies of obesity treatment. The recommended high-priority measures are selected to balance needs for sensitivity, specificity, and/or comprehensiveness with feasibility to achieve a commonality of usage and increase the breadth and impact of obesity research. SIGNIFICANCE: The accumulation of data on key biological factors, along with behavioral, psychosocial, and environmental factors, can generate a more precise description of the interplay and synergy among them and their impact on treatment responses, which can ultimately inform the design and delivery of effective, tailored obesity treatments.

The rat thyroid hormone receptor (TR) Deltabeta3 displays cell-, TR isoform-, and thyroid hormone response element-specific actions.

The THRB gene encodes the well-described thyroid hormone (T3) receptor (TR) isoforms TRbeta1 and TRbeta2 and two additional variants, TRbeta3 and TRDeltabeta3, of unknown physiological significance. TRbeta1, TRbeta2, and TRbeta3 are bona fide T3 receptors that bind DNA and T3 and regulate expression of T3-responsive target genes. TRDeltabeta3 retains T3 binding activity but lacks a DNA binding domain and does not activate target gene transcription. TRDeltabeta3 can be translated from a specific TRDeltabeta3 mRNA or is coexpressed with TRbeta3 from a single transcript that contains an internal TRDeltabeta3 translation start site. In these studies, we provide evidence that the TRbeta3/Deltabeta3 locus is present in rat but not in other vertebrates, including humans. We compared the activity of TRbeta3 with other TR isoforms and investigated mechanisms of action of TRDeltabeta3 at specific thyroid hormone response elements (TREs) in two cell types. TRbeta3 was the most potent isoform, but TR potency was TRE dependent. TRDeltabeta3 acted as a cell-specific and TRE-dependent modulator of TRbeta3 when coexpressed at low concentrations. At higher concentrations, TRDeltabeta3 was a TRE-selective and cell-specific antagonist of TRalpha1, -beta1, and -beta3. Both TRbeta3 and TRDeltabeta3 were expressed in the nucleus in the absence and presence of hormone, and their actions were determined by cell type and TRE structure, whereas TRDeltabeta3 actions were also dependent on the TR isoform with which it interacted. Analysis of these complex responses implicates a range of nuclear corepressors and coactivators as cell-, TR isoform-, and TRE-specific modulators of T3 action.

Cell cycle-dependent expression of thyroid hormone receptor-beta is a mechanism for variable hormone sensitivity.

Thyroid hormone receptors (TRs) are ligand-regulatable transcription factors. Currently, little is known about the expression of TRs or other nuclear hormone receptors during the cell cycle. We thus developed a stable expression system to express green fluorescent protein-TRbeta in HeLa cells under tetracycline regulation, and studied TR expression during the cell cycle by laser scanning cytometry. Only approximately 9-15% of the nonsynchronized cell population expressed TR because the majority of cells were in G(1) phase and did not express detectable amounts of TR. However, when cells were synchronized in early S phase with hydroxyurea and then released, TR expression levels increased in a cell cycle-dependent manner and peaked to 30-40% cells expressing TR at late G(2)/M phase before declining to nonsynchronized levels. Moreover, we observed a direct correlation between transcriptional activity and TR expression during the cell cycle. Similar cell cycle-dependent findings also were observed for endogenous TR in rat pituitary GH(3) cells. Last, cycloheximide studies demonstrated that the increase in TR expression was primarily due to increased translation. These novel observations of cell cycle-dependent expression of TR suggest that differential hormone sensitivity can occur during the cell cycle and may contribute to cell cycle progression during normal development and oncogenesis.

The Human Microbiome and Obesity: Moving beyond Associations.

Mounting evidence indicates that the gut microbiome responds to diet, antibiotics, and other external stimuli with speed and high precision and in ways that impact a variety of metabolic conditions including obesity and non-alcoholic fatty liver disease. Despite a decade of research establishing a strong association between the gut microbiota and obesity in humans, a causal relationship and the underlying mechanism remain outstanding. Several technological and methodological limitations in obesity and microbiome research have made it difficult to establish causality in this complex relationship. Additionally, limited collaborative interaction between microbiome and obesity researchers has delayed progress. Here, we discuss the current status of microbiome research as it relates to understanding obesity from the perspective of both communities, outline the underlying research challenges, and suggest directions to advance the obesity-microbiome field as a whole, with particular emphasis on the development of microbiome-targeted therapies for obesity prevention and treatment.

Joint National Cancer Institute-Food and Drug Administration workshop on research strategies, study designs, and statistical approaches to biomarker validation for cancer diagnosis and detection.

Cancer remains the second leading cause of death in the United States, in spite of tremendous advances made in therapeutic and diagnostic strategies. Successful cancer treatment depends on improved methods to detect cancers at early stages when they can be treated more effectively. Biomarkers for early detection of cancer enable screening of asymptomatic populations and thus play a critical role in cancer diagnosis. However, the approaches for validating biomarkers have yet to be addressed clearly. In an effort to delineate the ambiguities related to biomarker validation and related statistical considerations, the National Cancer Institute, in collaboration with the Food and Drug Administration, conducted a workshop in July 2004 entitled "Research Strategies, Study Designs, and Statistical Approaches to Biomarker Validation for Cancer Diagnosis and Detection." The main objective of this workshop was to review basic considerations underpinning the study designs, statistical methodologies, and novel approaches necessary to rapidly advance the clinical application of cancer biomarkers. The current commentary describes various aspects of statistical considerations and study designs for cancer biomarker validation discussed in this workshop.

Thyroid hormone action at the cellular, genomic and target gene levels.

Thyroid hormone (TH) plays important roles in metabolism, growth and differentiation. Thyroid hormone receptors (TRs) are ligand-regulatable transcription factors that bind both TH and DNA enhancer sequences in the promoter region of target genes where they can interact with co-repressor and co-activator complexes. These interactons, in turn, have consequent effects on transcription. This review describes studies on TH action from our laboratory examining the cellular localization and motility of TRs using green fluorescent fusion proteins, gene expression profiles of TH in WT and TRalpha and TRbeta KO mice, as well as general transcription factor and co-activator recruitment on the promoters of target genes by TH in chromatin immunoprecipitation assays.

Biomarkers in molecular medicine: cancer detection and diagnosis.

In spite of advances in diagnostics and therapeutics, cancer remains the second leading cause of death in the U.S. Successful cancer treatment depends not only on better therapies but also on improved methods to assess an individual's risk of developing cancer and to detect cancers at early stages when they can be more effectively treated. Current cancer diagnostic imaging methods are labor-intensive and expensive, especially for screening large asymptomatic populations. Effective screening strategies depend on methods that are noninvasive and detect cancers in their early stages of development. There is increasing interest and enthusiasm in molecular markers as tools for cancer detection and prognosis. It is hoped that newly discovered cancer biomarkers and advances in high-throughput technologies would revolutionize cancer therapies by improving cancer risk assessment, early detection, diagnosis, prognosis, and monitoring therapeutic response. These biomarkers will be used either as stand-alone tests or to complement existing imaging methods.

Understanding the Cellular and Molecular Mechanisms of Physical Activity-Induced Health Benefits.

The beneficial effects of physical activity (PA) are well documented, yet the mechanisms by which PA prevents disease and improves health outcomes are poorly understood. To identify major gaps in knowledge and potential strategies for catalyzing progress in the field, the NIH convened a workshop in late October 2014 entitled "Understanding the Cellular and Molecular Mechanisms of Physical Activity-Induced Health Benefits." Presentations and discussions emphasized the challenges imposed by the integrative and intermittent nature of PA, the tremendous discovery potential of applying "-omics" technologies to understand interorgan crosstalk and biological networking systems during PA, and the need to establish an infrastructure of clinical trial sites with sufficient expertise to incorporate mechanistic outcome measures into adequately sized human PA trials. Identification of the mechanisms that underlie the link between PA and improved health holds extraordinary promise for discovery of novel therapeutic targets and development of personalized exercise medicine.

Molecular diagnostics: a new frontier in cancer prevention.

The promise of molecular diagnostics for cancer prevention in terms of early detection rests on two premises: assays can be developed to measure proteins, DNA, RNA or metabolites that accurately and reproducibly detect incipient neoplasias; and that this early detection will eventually result in a decrease in morbidity and mortality and therefore benefit patients. Novel molecular technologies, including laser capture microdissection, time-of-flight mass spectrometry, DNA microarrays, tissue arrays, protein microarrays and antibody microarrays, are being developed to investigate the molecular differences between disease and normal cells and detect cancer-specific alterations in proteins, DNA and RNA in body fluids. Although literally hundreds of articles are published each year describing alterations in genes or proteins that are associated with cancer, very few result in useful molecular diagnostics for early cancer detection. Thus, there remains a critical need for new biomarkers for use in early detection and for assay methods that allow the translation of these biomarkers from the laboratory to the clinic.

It's all about balance: cellular responses to nutrients and development of disease.

Responding to nutrient availability is an important homeostatic mechanism in the growth, development, and function of cells and tissues. However, these adaptations can also play a role in the development of disease. Our symposium, "Cellular Responses to Nutrients and Development of Disease," presented research about how cells sense nutrients and how the resulting signal transduction controls cellular processes from gene transcription to impacting various pathophysiologic processes. Dr. Michael Kilberg discussed the transcription program triggered by amino acid limitation that leads to growth arrest in normal cells and sustained growth in tumor cells. Dr. Noa Noy elaborated on the role of lipid-binding proteins in retinoic acid signaling, focusing on fatty acid-binding protein 5 (FABP5), which promotes cell growth by delivering this molecule to the nuclear receptor peroxisome proliferator-activated receptor δ (PPARδ). Dr. Li-Na Wei discussed the many functions of the protein receptor interacting protein 140 (RIP140) as a coregulator of nuclear receptors and as a cytoplasmic protein that regulates insulin-stimulated glucose uptake, lipolysis, and inflammation. Dr. Ruma Banerjee presented state-of-the-art approaches for studying the gaseous signaling molecule hydrogen sulfide (H2S), discussing its concentrations, metabolism, and functions in the regulation of redox signaling. Finally, Dr. Maria Hatzoglou described how the stress-induced increases in amino acid transport, mammalian target of rapamycin (mTOR) signaling, and protein synthesis in pancreatic ß-cells can contribute to the progression of diabetes.

Executive summary of NIH workshop on the Use and Biology of Energy Drinks: Current Knowledge and Critical Gaps.

Sales of energy drinks in the United States reached $12.5 billion in 2012. Emergency department visits related to consumption of these products have increased sharply, and while these numbers remain small relative to product sales, they raise important questions regarding biological and behavioral effects. Although some common ingredients of energy drinks have been extensively studied (e.g., caffeine, B vitamins, sugars, inositol), data on other ingredients (e.g., taurine) are limited. Summarized here are data presented elsewhere in this issue on the prevalence and patterns of caffeine-containing energy drink use, the effects of these products on alertness, fatigue, cognitive functions, sleep, mood, homeostasis, as well as on exercise physiology and metabolism, and the biological mechanisms mediating the observed effects. There are substantial data on the effects of some energy drink ingredients, such as caffeine and sugars, on many of these outcomes; however, even for these ingredients many controversies and gaps remain, and data on other ingredients in caffeine-containing energy drinks, and on ingredient interactions, are sparse. This summary concludes with a discussion of critical gaps in the data and potential next steps.