Summary of Work packages
WORKPACKAGE 1: “Long term effects of maternal dietary intake in pregnancy on cognitive and behavioural development within 7,000 multi-ethnic preschool children”. The Generation R Study”
The main objective of WP1 is to examine and quantify nutrient effects of early programming (maternal dietary intake and nutritional status in early childhood). Within a large multi-ethnic population-based birth cohort, the Generation R Study (~10,000 participants), the WP will aim to assess whether maternal dietary intake in pregnancy is associated with behavioural and cognitive problems in the offspring. The specific objectives of WP1 are:
(i) To assess whether maternal dietary intake in pregnancy, such as intake of proteins, fatty acids, vitamins, minerals, and antioxidants, are associated with foetal neurodevelopment (using imaging techniques.
(ii) To assess whether maternal nutritional status in pregnancy, e.g. blood levels of n-3 and n-6 fatty acids, and folate, are associated with foetal neurodevelopment.
(iii) To investigate the associations of maternal dietary intake and maternal nutritional status in pregnancy with behavioural and cognitive development at age 3 and 5 years, and
(iv) To assess whether neurodevelopment causally underlies the relation between maternal dietary intake in pregnancy and mental performance in preschool children.
The observational study in WP1 is embedded in Generation R, an ongoing longitudinal study from foetal life onwards. WP1 will make use of existing data on 7,000 pregnant mothers and their children and data collected during the duration of this project when all children undergo extensive cognitive testing and psychiatric assessment. WP1 will examine the direct effects of both maternal dietary intake and nutritional status (blood levels of folate and fatty acids) behavioural and cognitive problems and on human brain morphology.
WORKPACKAGE 2: Interaction of fish intake and genetic variation in determining child behaviour – the Avon Longitudinal Study of Parents and Children (ALSPAC)
The main objective of WP2 is to build on work undertaken in the Avon Longitudinal Study of Parents and Children (ALSPAC) to contribute to a better understanding of the interactions of fish intake and genetic variation on the behaviour of children. Data from ALSPAC has shown that higher dietary fish intake of women during pregnancy is associated with improved pro-social and reduced hyperactive behaviour in children at the age of 6-7 years (Hibbeln et al 2007). The NUTRIMENTHE project proposes that this relationship is explained by the effects of enhanced concentrations of long-chain omega-3 fatty acids (n-3 LC-PUFA) in tissues of the foetus and/or the child. The specific objectives of WP2 are therefore to:
(i) Test this hypothesis by measuring polymorphisms of the genes FADS1 and FADS2 in both mothers and children (≈10,000 mothers and children taking part in the ALSPAC study). The initial analyses will compare the maternal genotypes with the levels of fatty acids in cord blood, to ensure that the previously reported relationships are repeated.
(ii) Link this data to the information on child diet, genotype and behaviour up to the age of 7 years.
(iii) Use statistical analyses to assess the relative importance of dietary fish intake and variants of FADS1 and FADS2 genes on behavioural outcomes in children.
WORKPACKAGE 3 “Follow-up of school age children whose mothers have received n-3 LCPUFA and or 5-methyl-tetrahydrofolate during pregnancy”
The main objective of WP3 is to determine whether during childhood there are long-term effects on cognitive development and mental performance as a consequence of DHA and folic acid supplementation during pregnancy. This workpackage proposes a long-term follow-up (7-9.5 years) of the 270 children whose mothers were participants in the “Nutraceuticals for a Healthier Life” Project (NUHEAL, QLK1-CT-1999-00888), funded by the EU in the 5th Framework Programme, and being followed up within “Early Nutrition Programming Project (EARNEST FP6 Integrated Project, www.metabolic-programming.org, FOOD-CT-2005-007036). The specific objectives of WP3 are to:
(i) Evaluate the effects of food intake during infancy and childhood on mental performance and mental illness in childhood such as depression, anxiety, stress, etc, related to the long-term effects of prenatal mother’s supplementation with DHA and 5-methyltetrahydrofolate.
(ii) Evaluate and compare the mental performance in those MTHFR homocygotic (677TT) children in front of those with MTHFR 677C→T (most common in the population) or MTHFR 677CC polymorphisms, considering folate and vitamin B12 nutritional status at the supervision time (7.5 y – 9.5 y).
(iii) Study the combined effects of MTHFR polymorphisms and polymorphisms of the genes FADS1 and FADS2 in both mothers and babies, related to the specific nutritional intervention during pregnancy, on later mental performance during childhood.
(iv) Understand the effects of pre-, post-natal, infancy and childhood diet and physical activity on mood, activation, attention, sleep, motivation, effort, perception, memory and intelligence.
WORKPACKAGE 4 “Follow-up of school age children with different protein and food intakes in early childhood”
The main objective of WP4 is to analyze the effect of different protein intakes during the first 12 months of life on cognitive development and behaviour in boys and girls at 8.5 years old. The EU Childhood Obesity Programme (EU CHOP) is a large European collaborative prospective investigation into the long-term consequences of early protein intake by metabolic programming. This study is supported by the EC under the 5th Framework Programme for Research, Technology & Demonstration, Quality of Life and Management of Living Resources, Key Action 1 (Food, Nutrition & Health), contract number QLK1-CT2002-389, and the 6th Framework Programme for Research and Technical Development (Food Quality & Safety Priority), contract number FOOD-CT—2005-007036. EU CHOP started in 2002 in 5 European countries (Belgium, Germany, Italy, Poland and Spain). In a double-blind randomised intervention trial, 3 groups of healthy infants are compared in relation to long-term obesity risk. WP4 will undertake the follow up of these children. The specific objectives of WP4 are therefore to:
(i) Analyze the effect of different protein intakes during the first 12 months of life on cognitive development and behaviour in boys and girls at 8.5 years old.
(ii) Analyse the association between dietary intake and blood levels of essential LCPUFA and specific micronutrients (vitamins B1, B2, B6, B12 and folic acid, iron and zinc), measured from birth to 8.5 years-old at different time points, and cognitive and neurological development in boys and girls at 8.5 years old.
(iii) Analyse the association between different protein intakes (from birth to 8.5 years-old), IGF-1 and IGFBP-3 plasma levels (at 6 months, 5.5 years and 8.5 years-old), and cognitive and neurological development in boys and girls at 8.5 years.
(iv) Analyse the association between physical activity and socioeconomic level and familiar status, each one or in conjunction (measured at different time points with cognitive development and behaviour at 8.5 years-old.
WORKPACKAGE 5 “Evaluation of the effects of a micronutrient enriched food on mental function in school children”
The main objective of WP5 is to evaluate the effects of a micronutrient enriched food on the mental function of school children. This will be achieved through a long-term, double-blind, randomised controlled trial to investigate the effects of providing iron, zinc, the vitamins B2, B6, B12, folate and n-3 long chain polyunsaturated fatty acids (DHA/EPA on measures of cognition and behaviour in school aged children. The specific objectives of WP5 are therefore to:
(i) Investigate the effects of providing n-3 long chain polyunsaturated fatty acids (DHA/EPA), iron, zinc, the vitamins B2, B6, B12 and folate on measures of cognition in school aged children.
(ii) Develop a food product with DHA/EPA, iron, zinc, and the vitamins B2, B6, B12, Folate. Combining iron and fish oil in one food product is technically challenging (Hurrell, 2002), as the more bio-available iron compounds are more likely to catalyse oxidation reactions, in particular with regard to the highly labile polyunsaturated fatty acids. Inversely, iron compounds that generate little sensory problems in foods are likely.
(iii) Develop scientifically sound claims appealing to consumers based on the above and the other WPs.
WORKPACKAGE 6 “Quantitative requirements of n-3 LCP for neural function in children”
The main objective of WP6 is to define a breakpoint of intake levels beyond which a further increase of supply does not provide additional improvements of functional outcome. The establishment of the quantitative requirements of n-3 LC-PUFA is of major importance for ensuring adequate intakes by the population, thereby, allowing full utilization of the genetic potential of the childhood population. This knowledge is required for decisions on food and nutrition policy, for the development of food products, and other uses. However, intervention studies to address this question in healthy, omnivorous children appear unfeasible. School aged children with an inborn error of amino acid metabolism, phenylketonuria (PKU), must follow a strictly controlled protein-restricted diet that is devoid of dietary sources of n-3 LC-PUFA, such as eggs, meat, milk or fish. Accordingly, blood concentrations of n-3 LC-PUFA are reduced in PKU children. Previous studies have established that neural function of PKU children is improved by high dose supplementation of n-3 LC-PUFA which significantly improved visual evoked potential (VEP) latencies (Beblo et al 2001, Agostoni et al 2000) and fine motor skills and coordination (Beblo et al 2007). However, no dose response relationship has been established. The specific objectives of WP6 are therefore to:
(i) Define a breakpoint of intake levels beyond which a further increase of supply does not provide additional improvements of functional outcome (behaviour, neurophysiological measures and motor skills.
(ii) Establish, for the first time, quantitative requirements of n-3 LC-PUFA in children.
WORKPACKAGE 7: “Cross-cultural standardization of a neuropsychological battery for cognitive assessment in EU children”
The main objective of WP7 is to facilitate comparison between the childhood studies (WPs 1-5) by designing a standardized neuropsychological protocol (NP) in different languages, and taking into account cultural differences. Some concerns pertaining to studies about cognitive performance and nutrition have emerged and recent papers about methodological considerations in these studies have been promoted (Burgard, 2003; Hughes & Bryan, 2003; Schmitt et al, 2005; Westenhoefer, 2004). The first concern is related to the sensitivity of the neuropsychological tests to subtle effects of nutrition (Hughes& Bryan, 2003; Schmitt, 2005). Moreover, the NP has to be culture fair and comprehensive because very little research has been done to investigate the impact of nutrients on some domains, e.g. executive functions (Hugh & Bryan, 2003). The specific objectives of WP7 are therefore to:
(i) Design a culture fair standardized neuropsychological protocol (NP) adapted in different languages, specifically designed to measure long-term effects of nutrition on mental performance and cognitive development during childhood related (WPs 1-6),
(ii) Create consensus on analyses and interpretation of outcomes, facilitate comparison between the studies.
WORKPACKAGE 8: “Analysis of genetic polymorphisms as co-variables in determining interaction of nutrition and mental health”
The main objective of WP8 is to measure polymorphisms of the genes FADS1 and FADS2 (genes encoding for key enzymes in endogenous LC-PUFA synthesis) in subjects studied in other workpackages (WP2, WP3, WP6) where data on dietary intake and mental outcomes are available. Data from several studies have shown that the dietary intake of fish and/or of n-3 LCPUFA is associated with improved behavioural and cognitive outcomes in infants and children(Helland, 2003, Oken, 2005, Hibbeln, 2007). The specific objectives of WP8 are therefore to:
(i) Establish the relationship between polymorphisms of the genes FADS1 and FADS2 and plasma fatty acid concentrations, but also linked to the information on child behaviour, performance, and mental health (WPs 2, 3, 6).
(ii) In large data sets, such as the data from the ALSPAC study, to assess the relative importance of dietary fish intake and of genetic influences from FADS1 and FADS2 on n-3 LC-PUFA plasma contents and behavioural outcomes in children (WP2).
(iii) In the smaller intervention studies, the polymorphism data are confounding variables and statistical adjustment for them should enhance the precision of the study evaluation and the ability to quantify the relationship between dietary factors and mental outcomes (WPs 3,4,5,6).
(iv) Contribute towards developing advice on the dietary supply of n-3 LC-PUFA within the general EU population.
WORKPACKAGE 9: “Quantitative analysis of biochemical markers”
The main objective of WP9 is the cost effective provision of biochemical data for all of the partners in NUTRIMENTHE performing the clinical trials. Mental performance and the risk of mental disease has been related to a variety of nutrients (Black,, 2003) and the dietary intake does not necessarily describe availability. Thus it is important to include biochemical measures of nutritional status into the studies, which is not restricted to the analysis of nutritional markers itself, but extends to indicative metabolites, e.g. homocysteine or methylmalonic acid, which are related low pyridoxine, cobalamine and folic acid (Tucker, 2005). Furthermore, some trace elements such as iron or zinc have to be considered for their influence on mental performance (McCann, 2007). On the other hand, the intake has to be confirmed and documented by analysis of valid biochemical markers. Furthermore, any variation of the availability of micronutrient, when studying the influence of other markers has to be considered a confounding factor and quantification of blood or urine levels enables corresponding corrections. This enables the establishment of evaluation models not only on the level of dietary intake, but also on the level of plasma availability. Continuous data as obtained from biochemical analyses enhance the statistical power to detect an influence of diet on mental outcome as compared to pure allocation to dietary groups. The specific objectives of WP9 are therefore to:
(i) Develop and perform a variety of different methods that have to be applied for the
determination of biomarkers identified as relevant in the context of the NUTRIMENTHE
and centralised determination shall create synergy effects compared to the analysis of
low numbers of samples in individual laboratories.
(ii) Improve the quality of the data by standardised sample processing and analysis by
experienced personal.
(iii) Provide advice for other partners in NUTRIMENTHE in the corresponding details of study
planning so that they can rely on established laboratory routines.
WORKPACKAGE 10. “Consumer expectations - survey among parents and educators”
The main objective of WP10 is to provide the tools and information to understand how stakeholders, (parents/carers, educators/ teachers and children), perceive that food affects children's attention, sleep, motivation, effort and memory, and how that perception impacts on food choice. This includes an investigation on the dependencies of parental knowledge (e.g. socio-economic status), and its influence on infant feeding and weaning behaviour. This project will build on that knowledge to investigate more fully parental knowledge of the link between nutrition and brain function. The specific objectives of WP10 are to:
(i) Understand how parents/carers and teachers perceive that food affects children's attention, sleep, motivation, effort and memory.
(ii) Assess the attitudes of parents/carers and teachers towards nutrition and brain function in children.
(iii) Investigate the beliefs of parents/carers and teachers with regard to food and brain unction in children.
(iv) Investigate food and nutrition related products and services promoted to influence children’s mental state and performance available in selected EU countries (c.f.WP11).
WORKPACKAGE 11: Economic Impact of improving mental function
The main objective of WP11 is to perform a comprehensive health economic analysis of pre - and postnatal nutritional interventions with proven or proposed long-term programming effects on mental performance. The economic analysis will take into account the social costs and benefits deriving within the whole human lifecycle and calculate the economic impact for different European Member States. In addition, WP11 will perform a systematic review of the literature of the effects of nutrition on mental performance. Currently there is a lack of understanding on the effects of early nutrition on mental performance. Therefore, no firm dietary recommendations can be made based on the evidence available. A systematic review and meta-analysis of randomized controlled trials resulting into a systematic evaluation of the effect of the nutrition in early life will contribute to new European guidelines for early nutrition concerning effects of nutrition on mental performance. The successful promotion of nutritional recommendations requires public resources (monetary and manpower), which as a consequence, will then not be available to promote other, and competing intervention programs. The allocation of these rare resources will depend on convincing society that e.g. improved infant nutrition is not only meaningful for better mental functioning, but economically beneficial as well. Societies will only invest their resources in such programmes if the achievements balance the investments and bring a higher benefit than competing programmes. Plenty of health economic studies have been performed with the respect to narrowly defined health outcomes, very few, however, have focused broader socio-economic consequences of interventions (e.g. the impact of a reduction of the environmental lead exposure for children with a concomitant increase in the IQ changes). However, the health economical consequences related to long term effects of pre- and postnatal nutritional interventions with proven or proposed long-term effects on the mental development have not been studied yet and this will be addressed through WP11.
WORKPACKAGE 12: Project Management and Reporting to the EC
The ambitious objectives and large scale of NUTRIMENTHE requires an appropriately robust management structure. The management activities of the project will be carried out in WP12, under which will be carried out the consortium management, project task management and reporting requirements. WP12 will therefore:
(i) Co-ordinate and manage the consortium and its members, over and above the technical management of the research work packages.
(ii) Create a management framework to gather together all project components, maintain overall consortium communication and act as the communication channel for all dialogue with the Commission.
(iii) Establish a dedicated, multi-skilled team reporting to the lead Project Manager of the project (Steering Group).
(iv) Establish an ultimate decision-making body comprising a representative from each participant (General Assembly).
(v) Ensure representation at all project Steering Group and General Assembly meetings.
(vi) Establish an effective project management structure incorporating the management teams detailed in Section 2.1.
(vii) Establish and implement project activity plans and reporting structures.
(viii) Set up and manage financial accounting records and reporting mechanisms.
(ix) Establish an Advisory Board comprising key stakeholders, including the Commission, health care professionals, industry, nutrition groups and consumer representatives.
(x) Assess and mitigate any potential or identified risks to the project.
(xi) Organise and implement project communication channels.
(xii) Conduct a mid-term assessment and a final review.
WORKPACKAGE 13: Training, dissemination and exploitation
A comprehensive dissemination and training programme is an integral part of the strategy for NUTRIMENTHE to meet its objectives. Dissemination and training is required both within the consortium itself and external to the project, ensuring that the outcomes of NUTRIMENTHE are communicated widely. The focus of WP13 is therefore on ensuring:
(i) Establishment of collaborative research practices within the consortium and appropriate networks and research infrastructures outside of the consortium.
(ii) A uniform approach to dissemination and training within the project.
(iii) Wide acceptance and take-up of the outcomes of the project with key stakeholders across the EU. This includes the publication of consistent recommendations on the effect of diet on mental performance. WP13 is essential in developing a cohesive approach to this research project through enabling the sharing of results and crosscutting training activities to take place across the various WPs. In the first instance, this will enable NUTRIMENTHE to achieve a cross-cultural neuropsychological battery for assessment, developed through training the neuropsychologists involved in the relevant WPs where assessment takes place. Further training activity involving stakeholders across Europe will include:
(i) Developing and updating public information on the nutritional requirements for children in the EU.
(ii) Training for students and scientists on the effect of diet on genetic regulation in childhood and metal performance, including behaviour disorders.
(iii) Training on the effect of different pathological conditions (obesity, PKU) related to early diet and nutrition on the mental performance of children.
WP13 will incorporate the results and outcomes from all of the WPs, but will in particular draw from WP10 (Consumer Expectations - Survey Among Parents and Educators) in order to direct dissemination to the public arena and ensure that the right media and key messages are communicated and feed in from the market survey in order to focus dissemination activities to industry, and WP11 (Economic Impact of Improving Mental Function) for the dissemination of the economic case of enhanced mental performance in children. WP13 will also be strongly linked to the Communications Working Group.
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