- Open Access
Consensus statement understanding health and malnutrition through a systems approach: the ENOUGH program for early life
- Jim Kaput1Email author,
- Ben van Ommen2,
- Bas Kremer2,
- Corrado Priami3,
- Jacqueline Pontes Monteiro4,
- Melissa Morine3,
- Fre Pepping5,
- Zoey Diaz6,
- Michael Fenech7,
- Yiwu He6,
- Ruud Albers8, 19,
- Christian A. Drevon9,
- Chris T. Evelo10,
- Robert E. W. Hancock11,
- Carel IJsselmuiden12,
- L. H. Lumey13,
- Anne-Marie Minihane14,
- Michael Muller15,
- Chiara Murgia16,
- Marijana Radonjic2,
- Bruno Sobral17 and
- Keith P. WestJr.18
© Springer-Verlag Berlin Heidelberg 2013
- Received: 19 September 2013
- Accepted: 2 December 2013
- Published: 22 December 2013
Nutrition research, like most biomedical disciplines, adopted and often uses experimental approaches based on Beadle and Tatum’s one gene—one polypeptide hypothesis, thereby reducing biological processes to single reactions or pathways. Systems thinking is needed to understand the complexity of health and disease processes requiring measurements of physiological processes, as well as environmental and social factors, which may alter the expression of genetic information. Analysis of physiological processes with omics technologies to assess systems’ responses has only become available over the past decade and remains costly. Studies of environmental and social conditions known to alter health are often not connected to biomedical research. While these facts are widely accepted, developing and conducting comprehensive research programs for health are often beyond financial and human resources of single research groups. We propose a new research program on essential nutrients for optimal underpinning of growth and health (ENOUGH) that will use systems approaches with more comprehensive measurements and biostatistical analysis of the many biological and environmental factors that influence undernutrition. Creating a knowledge base for nutrition and health is a necessary first step toward developing solutions targeted to different populations in diverse social and physical environments for the two billion undernourished people in developed and developing economies.
- Systems nutrition research
- Essential nutrients for optimal
- Underpinning of growth and health
Improving the nutritional health status of children and mothers in undernourished environments is essential for meeting the Millennium Development Goals (http://www.un.org/millenniumgoals/). Malnutrition is complex, multifaceted, and diverse in its health consequences, depending on extent, duration, and severity of coexisting deficiencies and comorbidities, and life stage of occurrence. An added complexity is the synergy between infection and malnutrition, articulated a half century ago (Scrimshaw et al. 1959): networks of interactions involving nutrients, pathogens, and host defense mechanisms can profoundly affect nutritional status, growth, and development. Genetic makeup and epigenetic mechanisms are increasingly recognized as determinants of metabolism and health both of which can be influenced by nutrition, pathogen exposure, and other environmental factors.
Significant progress (United Nations Standing Committee on Nutrition 2012) has been made in addressing the needs of populations with vitamin A, zinc, iron, iodine, and omega-3 fatty acids. Interventions focused on supplying single nutrients are unlikely to contribute significantly to optimizing the complex processes that maintain health and decrease or delay disease. Health may be defined as “the ability to adapt and self-manage” (Huber et al. 2011), a concept of metabolic health which has also been termed metabolic flexibility, or adaptability (Storlien et al. 2004). Environmental and nutritional factors contribute to metabolic flexibility and health: Inadequate nutritional status will probably reduce flexibility and increase susceptibility to chronic disease and infectious agents. The current biological knowledge for assessing the status and needs for essential nutrients is inadequate. Combining comprehensive measurements of individual and environmental variables with systems experimental strategies may confer deep insight into metabolic networks, modifiable by nutrients and physical activity, enabling new approaches of attaining personal and public health.
Common practices in malnutrition research
Frank deficiencies of the micronutrients (especially vitamin A, zinc, iron, iodine, folate, vitamin D) are prevalent globally. The success of preventing rickets (vitamin D), beriberi (thiamine), scurvy (vitamin C), and pellagra (niacin) justified interventions of single or a few nutrients in malnourished individuals. Major successes have been achieved in delivering specific micronutrients to needy populations. However, the impact of subclinical undernourishment and the needs of populations in different environments and with diverse cultural, genetic, and agricultural histories are unknown. Several limitations have become apparent in nutrition research as well as other health-related projects including
Experimental interventions in which one or at most a few nutrients are used for interventions, with notable exceptions such as http://ilins.org and (Darnton-hill et al. 2009). Only a small number of parameters were usually monitored, novel computational analyses were not used, resources for integrative approaches were lacking, and research funding culture continues to promote individual laboratories rather than collaborative consortia (other factors can also contribute)
Use of single biomarkers has often become the “gold standard” in essential nutrient research, underestimating the complexity of biological processes. Many biomarkers are poor predictors of health, growth and development, immune function, and cognitive ability
The failure of assessing “context or environment” in research and subsequent nutrient interventions. For example, the effects of malaria (Afacan et al. 2012), assessment of and need for interacting nutrients (Zimmermann and Kohrle 2002), presence of environmental contaminants (e.g., lead) (Zimmermann et al. 2006), differences in food matrix (Moretti et al. 2006), microbiotic diversity (Gordon et al. 2012), culture, and other factors may alter nutrient bioavailability and biological functions
Genetic, epigenetic, microbiome, diet, and environmental and cultural diversity have not been sufficiently integrated in nutrition research
We now understand that pathways interact with regulatory elements, with one another, and with systems critical to the endocrine, circulatory, digestive, nervous, and immune function (Afacan et al. 2012; MacLellan et al. 2012; Slikker et al. 2007; van Ommen et al. 2008a, b; Zhao et al. 2012). As an example, a map of the central immunity pathway linking the toll-like receptor 4 to the transcription factor NFκB (a master regulator responsive to nutrients) contains only 20 core components, but adding just the main interacting elements of these 20 core proteins expands the network to more than 800 proteins (Gardy et al. 2009).
Global quantitative measures on the genome, transcriptome, proteome; metabolome, and/or cytome levels are usually based on high-throughput technologies.
Measures over time in homeostatic and challenged states, allowing metabolic flux analyses.
Integration and (meta-) analyses of data with computational network biology methods.
Modeling to unravel mechanistic relationships of the biological processes.
The crucial missing factors from many system biology definitions and experimental approaches are the influence and measures of environment such as diet, physical activity and other lifestyle factors, and psychosocial factors, each of which may influence expression of genes, levels of proteins and metabolites and may promote mutagenic effects. For example, seasonal differences in nutrient availability were consistently associated with changes in blood concentrations of one-carbon metabolites and cofactors, resulting in altered epigenetic potential (Dominguez-Salas et al. 2013). Hence, experimental designs and approaches should incorporate more comprehensive assessment of biospecimens but also exposures to environmental factors. The results of combining such data and approaches will provide novel insight into mechanisms, complex biomarkers, but most importantly, an understanding of health beyond disease-specific symptoms (heart disease versus whole organism physiology associated with diet and lifestyle).
The influence of genetic diversity has also not been assessed when analyzing the response to nutritional intervention. Although analysis of common (>1 % frequency) variants is increasingly used in nutrition research (Merched and Chan 2013), genome sequencing projects demonstrate that all individuals encode unique variations (Consortium 2012) undetected by array technologies. These new variants may occur in any biological pathway including those expected to alter physiological processes or response to nutritional variables (Morine et al. 2010, 2011).
A major challenge for implementing and using systems approaches may be to assure sufficient and accurate quantitative data from the individual, family, and community levels with data standards adopted across studies. Assessing many factors and stressors that affect physiological processes will be a significant challenge since food and nutrition security is a complex system resulting from interrelationships between societal, legal, and economic factors spanning the farm to fork trajectory (Hammond and Dubé 2012). Nevertheless, data harmonization of each level of these multi-scale networks will enable integration from different studies for exploratory, diagnostic, and predictive computational modeling. Integration of genomic information with clinical, extensive physiological data, and metadata (individual patient exposures and status measures that affect health) is spawning new bioinformatics approaches that have yet to mature.
Collect high-quality, high-dimensional genomic, proteomic, and/or metabolomics data with appropriate filtering from prospective and intervention studies.
Computational definition of systems networks and subnetworks associated with health and pathologies and the underlying pathways, functional attributes, and mechanisms.
Definition of biomarkers as hubs and bottlenecks connecting to different network elements of importance in signal transduction.
Network simulations and flux analyses to unravel physiological and pathological states and the impact of interventions.
Simulations integrating molecular interactions and correlations.
Computational predictions and actionable knowledge.
The first models of cellular responses, organs, systems, or conditions can be used as a “wind tunnel” for testing and designing intervention studies. Data from model organisms may provide an initial (tissue-specific) framework, describing in molecular detail, the processes of transport, metabolism and signaling in steady state, as well as during challenges with altered diet, physical activity, fasting, and sleeping (van Ommen et al. 2009).
Improve the design and implementation of multi-scale interventions studies for environmental enteropathies, related growth, immune- and learning disorders, and essential nutrient deficiencies.
ENOUGH (Fig. 2) will go beyond simply measuring metabolites in body fluids (so-called helicopter research; Glenn, 2006; Horowitz et al. 2009) to include engagement of community members (Tindana et al. 2007; Cohen et al. 2008; McCabe-Sellers et al. 2008; Horowitz et al. 2009). Active participatory research will promote comprehensive analyses and incorporate an understanding of local customs, conditions, and factors affecting nutrient accessibility. A challenge for international research projects is the patchwork rules and regulations for human study research (see (Seguin et al. 2008; Office for Human Research Protections 2012)). Nutrigenomics projects involving children, genetic analysis, physiological and environmental measurements, and international collaboration raise ethical questions. Although an effort to build research ethics review capacity in low- and middle-income countries has been initiated, intervention studies raise ethical problems for which few research ethics committees globally are prepared to act on. The Council on Health Research for Economic Development (COHRED) has developed and hosts a Health Research Web (http://www.healthresearchweb.org/) to foster interaction between research partners in different countries. A major aspect of their effort is the creation of tools for facilitating reviews by collaborating centers with distinct research ethics committees (aka institutional review boards (http://www.healthresearchweb.org/en/regulation_and_ethics_review_of_research)).
ENOUGH will contribute through scientific research to the building of local capacity and infrastructure by engaging governments, agencies, and communities (McCabe-Sellers et al. 2008), a process consistent with the goals of North–South knowledge and technology transfer (Singer and Daar 2001; Daar et al. 2007; Taylor et al. 2007; Séguin et al. 2008) and stimulation of economic development by research activities (www.cohred.org; Bhan et al. 2007). These collaborative research strategies may improve translation of basic research to local societies. One example of this capacity building is the Human Variome Project, aiming to understand the genetic basis of human diseases in developed and developing countries (Patrinos et al. 2010; Al Aama et al. 2011).
The availability of healthy and affordable food and clean water is essential for health. In addition, nutrient composition targeted to genetic and cultural conditions can now be analyzed and optimized. Malnutrition is a complex condition, which will be unresolved by systems nutrition research alone, but the multifaceted solutions to address this global problem require evidence from experimental studies, which acknowledge, measure, and analyze the gene-environment factors contributing to dysfunctional growth, metabolic, and cognitive processes. Research focused on the analysis and understanding of nutritional needs can contribute significantly to the continuation of international collaboration and implementation of systems concepts in academia, governments, industry, and NGOs. Only by combined efforts will the Millennium Development goals of improving nutrition, health, and the lives of women and children be reached.
This manuscript emerged from a workshop entitled A Systems Nutrition Approach to Essential Nutrients (Wageningen, The Netherlands. 7–9 November 2012). The aim of the meeting was to discuss whether systems biology approaches could contribute to research on essential nutrient malnutrition. Participants (author status) from the fields of systems biology, omics technologies, ethics, capacity building, immunity, and international nutrition contributed to the workshop. Discussions focused on the related topics of immune function and infectious disease susceptibility in the malnourished, metabolic health including growth and cognitive function, bioinformatics needs and computational methods for system analysis, ethics, and sustainability. The workshop was cosponsored by the Bill and Melinda Gates Foundation, the Nestle Institute of Health Sciences, DSM, The Microsoft Research-University of Trento Institute of Computational and Systems Biology (COSBI), Wageningen University, and NuGO. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. JK and BS are employed by Nestle Institute of Health Sciences, a for-profit NESTEC company. However, no specific funding was provided for this work except for the sponsorship of the workshop. RAH is the Canada Research Chair and is funded by the Canadian Institutes for Health Research. BK, MR, and BvO are employed by TNO, a not-for-profit organization regulated by public law. TNO is an independent research organization dealing with health-related research, not part of any government, university or company. The organization may benefit from its knowledge, by supporting companies in their product development by consultancy and research. In these cases, the authors will not receive additional salary, additional personal income, or any form of financial support.
Conflict of interest
The following authors work for private or public companies: RA (NutriLeads), JK, and BS (Nestle Institute of Health Sciences). RAH is developing new treatments for infectious and inflammatory conditions and has patented and out-licensed such treatments.
This article does not contain any studies with human or animal subjects performed by the any of the authors.
- Al Aama J, Smith TD, Lo A et al (2011) Initiating a Human Variome Project Country Node. Hum Mutat 32:501–506. doi:10.1002/humu.21463 View ArticleGoogle Scholar
- Afacan NJ, Fjell CD, Hancock REW (2012) A systems biology approach to nutritional immunology: focus on innate immunity. Mol Aspects Med 33:14–25. doi:10.1016/j.mam.2011.10.013 PubMedView ArticleGoogle Scholar
- Berry EM (2011) The role of the sociotype in managing chronic disease: integrating bio-psycho-sociology with systems biology. Med Hypotheses 77:610–613. doi:10.1016/j.mehy.2011.06.046 PubMedView ArticleGoogle Scholar
- Bhan A, Singh J, Upshur R et al (2007) Grand challenges in global health: engaging civil society organizations in biomedical research in developing countries. PLoS Med 4:e272. doi:10.1371/journal.pmed.0040272 PubMed CentralPubMedView ArticleGoogle Scholar
- Brabin B, Combs G Jr, Abbe MRL, et al (2011) Executive summary: biomarkers of nutrition for development: building a consensus 1–3. doi:10.3945/ajcn.110.008227.Am
- Braddick O, Atkinson J, Wattam-Bell J (2011) VERP and brain imaging for identifying levels of visual dorsal and ventral stream function in typical and preterm infants. Prog Brain Res 189:95–111. doi:10.1016/B978-0-444-53884-0.00020-8 PubMedView ArticleGoogle Scholar
- Breuer K, Foroushani AK, Laird MR et al (2012) InnateDB: systems biology of innate immunity and beyond–recent updates and continuing curation. Nucleic Acids Res. doi:10.1093/nar/gks1147 PubMed CentralPubMedGoogle Scholar
- Bures J, Cyrany J, Kohoutova D et al (2010) Small intestinal bacterial overgrowth syndrome. World J Gastroenterol 16:2978–2990PubMed CentralPubMedView ArticleGoogle Scholar
- Cohen ER, Masum H, Berndtson K et al (2008) Public engagement on global health challenges. BMC Public Health 8:168. doi:10.1186/1471-2458-8-168 PubMed CentralPubMedView ArticleGoogle Scholar
- Consortium T 100 GP (2012) An integrated map of genetic variation from 1,092 human genomes. Nature 491:56–65. doi:10.1038/nature11632 View ArticleGoogle Scholar
- Daar AS, Berndtson K, Persad DL, Singer PA (2007) How can developing countries harness biotechnology to improve health? BMC Public Health 7:346. doi:10.1186/1471-2458-7-346 PubMed CentralPubMedView ArticleGoogle Scholar
- Darnton-hill I, Schultink W, Shrimpton R et al (2009) Multiple Micronutrient Supplementation During Pregnancy in Developing Country Settings. In: Dalmiya N, Darnton-Hill I, Schultink W, Shrimpton R (eds) Food Nutr. Bull. pp 1–100Google Scholar
- Dewey KG, Begum K (2011) Long-term consequences of stunting in early life. Matern Child Nutr 7(Suppl 3):5–18. doi:10.1111/j.1740-8709.2011.00349.x PubMedView ArticleGoogle Scholar
- Dominguez-Salas P, Moore SE, Cole D et al (2013) DNA methylation potential : dietary intake and blood concentrations of one-carbon metabolites and cofactors in rural African women. Am J Clin Nutr 97:1217–1227. doi:10.3945/ajcn.112.048462.The PubMed CentralPubMedView ArticleGoogle Scholar
- Fairweather-Tait SJ (2003) Human nutrition and food research: opportunities and challenges in the post-genomic era. Philos Trans R Soc L B Biol Sci 358:1709–1727View ArticleGoogle Scholar
- Fenech M (2004) Genome health nutrigenomics: nutrition and the science of optimal genome maintenance. Asia Pac J Clin Nutr 13:S15Google Scholar
- Fenech MF (2010) Dietary reference values of individual micronutrients and nutriomes for genome damage prevention : current status and a road map to the. Am J Clin Nutr 91:1438–1454. doi:10.3945/ajcn.2010.28674D.1 View ArticleGoogle Scholar
- Fu W, Stromberg A, Viele K et al (2011) NStatistics and bioinformatics in nutritional scienes: analysis of complex data in the era of systems biology. J Nutr Biochem 21:561–572. doi:10.1016/j.jnutbio.2009.11.007.Statistics View ArticleGoogle Scholar
- Gallagher M (2006) FOOD DESERTS. http://www.marigallagher.com/site_media/dynamic/project_files/Chicago_Food_Desert_Report.pdf
- Gardy JL, Lynn DJ, Brinkman FSL, Hancock REW (2009) Enabling a systems biology approach to immunology: focus on innate immunity. Trends Immunol 30:249–262. doi:10.1016/j.it.2009.03.009 PubMedView ArticleGoogle Scholar
- Glenn D (2006) Blood feud: a controversy over South American DNA samples held in North American laboratories ripples through anthropology. Chron High Educ 52(A14–6):A18Google Scholar
- Gordon JI, Dewey KG, Mills D a, Medzhitov RM (2012) The human gut microbiota and undernutrition. Sci Transl Med 4:137ps12. doi:10.1126/scitranslmed.3004347
- De Graaf AA, Freidig AP, De Roos B et al (2009) Nutritional systems biology modeling: from molecular mechanisms to physiology. PLoS Comput Biol 5:e1000554PubMed CentralPubMedView ArticleGoogle Scholar
- Van der Greef J, van Wietmarschen H, Schroën J et al (2010) Systems biology-based diagnostic principles as pillars of the bridge between Chinese and Western medicine. Planta Med 76:2036–2047. doi:10.1055/s-0030-1250450 PubMedView ArticleGoogle Scholar
- Guerrant RL, Deboer MD, Moore SR et al (2012) The impoverished gut-a triple burden of diarrhoea, stunting and chronic disease. Nat Rev Gastroenterol Hepatol. doi:10.1038/nrgastro.2012.239 PubMed CentralPubMedGoogle Scholar
- Hammond RA, Dubé L (2012) A systems science perspective and transdisciplinary models for food and nutrition security. Proc Natl Acad Sci USA 109:12356–12363. doi:10.1073/pnas.0913003109 PubMed CentralPubMedView ArticleGoogle Scholar
- Hood L, Heath JR, Phelps ME, Lin B (2004) Systems biology and new technologies enable predictive and preventative medicine. Science (80) 306:640–643View ArticleGoogle Scholar
- Horowitz CR, Robinson M, Seifer S (2009) Community-based participatory research from the margin to the mainstream: are researchers prepared? Circulation 119:2633–2642. doi:10.1161/CIRCULATIONAHA.107.729863 PubMed CentralPubMedView ArticleGoogle Scholar
- Huber M, Knottnerus JA, Green L et al (2011) How should we define health? BMJ 343:d4163. doi:10.1136/bmj.d4163 PubMedView ArticleGoogle Scholar
- Kaput J, Astley S, Renkema M et al (2006) Harnessing Nutrigenomics: development of web-based communication, databases, resources, and tools. Genes Nutr 1:5–11. doi:10.1007/BF02829931 PubMed CentralPubMedView ArticleGoogle Scholar
- Kaput J, Ordovas JM, Ferguson L et al (2005) The case for strategic international alliances to harness nutritional genomics for public and personal health. Br J Nutr 94:623–632PubMedView ArticleGoogle Scholar
- Khulan B, Cooper WN, Skinner BM et al (2012) Periconceptional maternal micronutrient supplementation is associated with widespread gender related changes in the epigenome: a study of a unique resource in the Gambia. Hum Mol Genet 21:2086–2101. doi:10.1093/hmg/dds026 PubMedView ArticleGoogle Scholar
- Kibbe WA (2006) The Informatics and Bioinformatics Infrastructure of a Nutrigenomics Database. In: Kaput Rodriguez, R.L. J (ed) Nutr. Genomics. Discov. Path to Pers. Nutr. Wiley, Hoboken, NJ, pp 353–374Google Scholar
- Korpe PS, Petri WA (2012) Environmental enteropathy: critical implications of a poorly understood condition. Trends Mol Med 18:328–336. doi:10.1016/j.molmed.2012.04.007 PubMed CentralPubMedView ArticleGoogle Scholar
- Levine MM (2010) Immunogenicity and efficacy of oral vaccines in developing countries: lessons from a live cholera vaccine. BMC Biol 8:129. doi:10.1186/1741-7007-8-129 PubMed CentralPubMedView ArticleGoogle Scholar
- Lynn DJ, Chan C, Naseer M et al (2010) Curating the innate immunity interactome. BMC Syst Biol 4:117. doi:10.1186/1752-0509-4-117 PubMed CentralPubMedView ArticleGoogle Scholar
- MacLellan WR, Wang Y, Lusis AJ (2012) Systems-based approaches to cardiovascular disease. Nat Rev Cardiol 9:172–184. doi:10.1038/nrcardio.2011.208 PubMedView ArticleGoogle Scholar
- Maggini S, Wintergerst ES, Beveridge S, Hornig DH (2007) Selected vitamins and trace elements support immune function by strengthening epithelial barriers and cellular and humoral immune responses. Br J Nutr 98(Suppl 1):S29–S35. doi:10.1017/S0007114507832971 PubMedGoogle Scholar
- Mayer ML, Blohmke CJ, Falsafi R et al (2013) Rescue of dysfunctional autophagy attenuates hyperinflammatory responses from cystic fibrosis cells. J Immunol 190:1227–1238. doi:10.4049/jimmunol.1201404 PubMedView ArticleGoogle Scholar
- McCabe-Sellers B, Lovera D, Nuss H et al (2008) Personalizing nutrigenomics research through community based participatory research and omics technologies. OMICS 12:263–272. doi:10.1089/omi 2008.0041PubMedView ArticleGoogle Scholar
- McKay S, Gaudier E, Campbell D, Prentice A (2010) Environmental enteropathy: new targets for nutritional interventions. Int Health 2:172–180PubMedView ArticleGoogle Scholar
- Merched AJ, Chan L (2013) Nutrigenetics and nutrigenomics of atherosclerosis. Curr Atheroscler Rep 15:328. doi:10.1007/s11883-013-0328-6 PubMed CentralPubMedView ArticleGoogle Scholar
- Moretti D, Zimmermann MB, Wegmuller R et al (2006) Iron status and food matrix strongly affect the relative bioavailability of ferric pyrophosphate in humans. Am J Clin Nutr 83:632–638PubMedGoogle Scholar
- Morine MJ, McMonagle J, Toomey S et al (2010) Bi-directional gene set enrichment and canonical correlation analysis identify key diet-sensitive pathways and biomarkers of metabolic syndrome. BMC Bioinformatics 11:499. doi:10.1186/1471-2105-11-499 PubMed CentralPubMedView ArticleGoogle Scholar
- Morine MJ, Priami C (2013) Analysis of biological systems. Imperial College Press, London (in press)Google Scholar
- Morine MJ, Tierney AC, van Ommen B et al (2011) Transcriptomic coordination in the human metabolic network reveals links between n-3 fat intake, adipose tissue gene expression and metabolic health. PLoS Comput Biol 7:e1002223. doi:10.1371/journal.pcbi.1002223 PubMed CentralPubMedView ArticleGoogle Scholar
- Morine MJ, Toomey S, McGillicuddy FC et al (2012) Network analysis of adipose tissue gene expression highlights altered metabolic and regulatory transcriptomic activity in high-fat-diet-fed IL-1RI knockout mice. J Nutr Biochem. doi:10.1016/j.jnutbio.2012.04.012 Google Scholar
- Norheim F, Gjelstad IMF, Hjorth M et al (2012) Molecular nutrition research: the modern way of performing nutritional science. Nutrients 4:1898–1944. doi:10.3390/nu4121898 PubMed CentralPubMedView ArticleGoogle Scholar
- Office for Human Research Protections (2012) International compilation of human research standards. 114Google Scholar
- Palsson BO (2006) Systems biology: properties of reconstructed networks. 322Google Scholar
- Patrinos G, Al Aama J, Al Aqeel A et al (2010) Recommendations for genetic variation data capture in developing countries to ensure a comprehensive worldwide data collection. Hum Mutat 31:1–8View ArticleGoogle Scholar
- Rozenblit L, Keil F (2002) The misunderstood limits of folk science: an illusion of explanatory depth. Cogn Sci 26:521–562. doi:10.1207/s15516709cog2605_1 PubMed CentralPubMedView ArticleGoogle Scholar
- Savy M, Edmond K, Fine PEM et al (2009) Landscape analysis of interactions between nutrition and vaccine responses in children. J Nutr 139:2154S–2218S. doi:10.3945/jn.109.105312.research PubMedView ArticleGoogle Scholar
- Scrimshaw N, Taylor C, Gordon J (1959) Interactions of nutrition and infection. Am J Med Sci 237:367–403PubMedView ArticleGoogle Scholar
- Séguin B, Hardy B-J, Singer PA, Daar AS (2008) Genomics, public health and developing countries: the case of the Mexican National Institute of Genomic Medicine (INMEGEN). Nat Rev Genet 9(Suppl 1):S5–S9. doi:10.1038/nrg2442 PubMedView ArticleGoogle Scholar
- Seguin B, Hardy BJ, Singer PA, Daar AS (2008) Genomic medicine and developing countries: creating a room of their own. Nat Rev Genet 9:487–493. doi:10.1038/nrg2379 PubMedView ArticleGoogle Scholar
- Singer PA, Daar AS (2001) Harnessing genomics and biotechnology to improve global health equity. Science (80) 294:87–89View ArticleGoogle Scholar
- Slikker W Jr, Paule MG, Wright LK et al (2007) Systems biology approaches for toxicology. J Appl Toxicol 27:201–217. doi:10.1002/jat.1207 PubMedView ArticleGoogle Scholar
- Storlien L, Oakes ND, Kelley DE (2004) Metabolic flexibility. Proc Nutr Soc 63:363–368. doi:10.1079/PNS2004349 PubMedView ArticleGoogle Scholar
- Stumbo PJ, Weiss R, Newman JW et al (2010) Web-enabled and improved software tools and data are needed to measure nutrient intakes and physical activity for personalized health research. J Nutr 140:2104–2115. doi:10.3945/jn.110.128371 PubMed CentralPubMedView ArticleGoogle Scholar
- Taylor AD, Brook D, Watters D et al (2007) North–south partnerships–a study of Canadian firms. Nat Biotechnol 25:978–979. doi:10.1038/nbt0907-978 PubMedView ArticleGoogle Scholar
- Tindana PO, Singh JA, Tracy CS et al (2007) Grand challenges in global health: community engagement in research in developing countries. PLoS Med 4:e273. doi:10.1371/journal.pmed.0040273 PubMed CentralPubMedView ArticleGoogle Scholar
- Tucker KL, Smith CE, Lai C-Q, Ordovas JM (2013) Quantifying diet for nutrigenomic studies. Annu Rev Nutr 33:349–371. doi:10.1146/annurev-nutr-072610-145203 PubMedView ArticleGoogle Scholar
- United Nations Standing Committee on Nutrition (2012) What progress in nutrition? Nutr Rev 5:134. doi:10.1111/j.1753-4887.1947.tb04238.x Google Scholar
- Van Ommen B, Cavallieri D, Roche HM et al (2008a) The challenges for molecular nutrition research 4: the “nutritional systems biology level”. Genes Nutr 3:107–113. doi:10.1007/s12263-008-0090-5 PubMed CentralPubMedView ArticleGoogle Scholar
- Van Ommen B, Fairweather-Tait S, Freidig A et al (2008b) A network biology model of micronutrient related health. Br J Nutr 99(Suppl 3):S72–S80. doi:10.1017/S0007114508006922 PubMedGoogle Scholar
- Van Ommen B, Keijer J, Heil SG, Kaput J (2009) Challenging homeostasis to define biomarkers for nutrition related health. Mol Nutr Food Res 53:795–804. doi:10.1002/mnfr.200800390 PubMedView ArticleGoogle Scholar
- Van Ommen B, Bouwman J, Dragsted LO et al (2010a) Challenges of molecular nutrition research 6: the nutritional phenotype database to store, share and evaluate nutritional systems biology studies. Genes Nutr 5:189–203. doi:10.1007/s12263-010-0167-9 PubMed CentralPubMedView ArticleGoogle Scholar
- Van Ommen B, El-Sohemy A, Hesketh J et al (2010b) The micronutrient genomics project: creating a community driven knowledge base for micronutrient research. Genes Nutr 5:285–296PubMed CentralPubMedView ArticleGoogle Scholar
- Van Wietmarschen HA, Reijmers TH, van der Kooij AJ et al (2011) Sub-typing of rheumatic diseases based on a systems diagnosis questionnaire. PLoS One 6:e24846. doi:10.1371/journal.pone.0024846 PubMed CentralPubMedView ArticleGoogle Scholar
- Verkerke HP, Petri WA, Marie CS (2012) The dynamic interdependence of amebiasis, innate immunity, and undernutrition. Semin Immunopathol 34:771–785. doi:10.1007/s00281-012-0349-1 PubMed CentralPubMedView ArticleGoogle Scholar
- Von Bertalanffy L (1951) General system theory: a new approach to unity of science. Hum Biol 23:203–361Google Scholar
- Westerberg AC, Henriksen C, Ellingvåg A et al (2010) First year growth among very low birth weight infants. Acta Paediatr 99:556–562. doi:10.1111/j.1651-2227.2009.01667.x PubMedView ArticleGoogle Scholar
- Westerberg AC, Schei R, Henriksen C et al (2011) Attention among very low birth weight infants following early supplementation with docosahexaenoic and arachidonic acid. Acta Paediatr 100:47–52. doi:10.1111/j.1651-2227.2010.01946.x PubMedView ArticleGoogle Scholar
- Wintergerst ES, Maggini S, Hornig DH (2007) Contribution of selected vitamins and trace elements to immune function. Ann Nutr Metab 51:301–323. doi:10.1159/000107673 PubMedView ArticleGoogle Scholar
- Zhao L, Nicholson JK, Lu A et al (2012) Targeting the human genome-microbiome axis for drug discovery: inspirations from global systems biology and traditional Chinese medicine. J Proteome Res 11:3509–3519. doi:10.1021/pr3001628 PubMedView ArticleGoogle Scholar
- Zimmermann MB, Kohrle J (2002) The impact of iron and selenium deficiencies on iodine and thyroid metabolism: biochemistry and relevance to public health. Thyroid 12:867–878PubMedView ArticleGoogle Scholar
- Zimmermann MB, Muthayya S, Moretti D et al (2006) Iron fortification reduces blood lead levels in children in Bangalore, India. Pediatrics 117:2014–2021. doi:10.1542/peds.2005-2440 PubMedView ArticleGoogle Scholar