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Health and Environment-wide Associations based on Large population Surveys

Periodic Report Summary 4 - HEALS (Health and Environment-wide Associations based on Large population Surveys)

Project Context and Objectives:
Major achievements of the 4th period consist in: 1) the conduction of the EXHES survey in mothers and children (both twins and singletons) with longitudinal environmental and health assessments allowing to conduct EWAS analyses to understand the development of major non-communicable chronic diseases taken into account in HEALS and 2) the finalisation of the report on predictive biomarkers appropriate for environment-wide association health assessments to be applied to the unique databases of exposure and health at the European level gathered in HEALS using appropriate algorithms, models and statistical methods developed especially for HEALS. First results on EWAS have been obtained in both the pre-existing populations and the new EXHES mother-children birth cohort. Finally, the activities of reporting, networking, disseminating, training have continued in a successful way.
Specific results include:
Scientific findings
Modeling in view of EWAS
Methodological advancements consisted in the consolidation of:
− Establishment of the methodological framework for EWAS
− Methodologies for linking omics technologies to population studies
− Review and gathering of bioinformatics methods for descriptive and predictive data mining
− Development of imputation methods and machine learning have been applied to prevent the consequences of missing data

Exposome and EWAS application to population data
The finalization of the pilot European Exposure and Health Examination Survey (EXHES) that constitutes one of the milestones of the HEALS project, with around 5,000 families that have accepted to participate to the survey. The children sample include both singletons and twins.
Among the obtained results:
- Pathway analysis was completed for the 178 pairs of mother-child samples from PHIME cohort. DNA methylation pre-processing and processing analysis has been completed as well.
- EWAS analysis was performed to relate -omics, prenatal exposure and early life (since in utero) health outcomes such as weight, height, and head circumference, used for neurodevelopment monitoring, neurodevelopmental troubles, asthma and metabolic disorders in pre-existing population including singletons and twins to unravelling the causal links between environmental exposure and the potential risk of the emergence of the aforementioned diseases in the future.
- EWAS for neurodevelopmental disorders taking into account both internal and external exposome was conducted in EXHES Spain. Analogous analyses were conducted in other EXHES samples.
Most of the results have been published in peer-reviewed journal including some in a special issue of Environmental Research consecrated to the HEALS project.
Work is continuing on specific research questions that are of utility for the increase of the knowledgement of the considered health outcomes and as intermediate steps in the construction of the exposomic approach of the considered diseases.

Dissemination
A huge amount of papers has been finalized and accepted or are presently submitted (see list in the WP and at the end of this document). So far:
✓ 177 papers have already been published in the scientific literature, in journals such as Environmental Health Perspectives, Environment International, Nature Scientific Reports and the Lancet
✓ Papers available in open access in the Zenodo database
✓ 1280 quotes to date
✓ 374 presentations at scientific conferences and meetings
✓ One special issue in Environmental Research. 36 papers have been submitted.
✓ 8 HEALS newsletters
Other papers in preparation and to be submitted to peer-reviewed journals include:
1. The HEALS methodological framework and study design – soon to be submitted in Environmental Health Perspectives.
2. “A critical review of how much of the difference in disease between socio-economic and other social groups can be explained by differences in the “group” exposome”.
3. An overview of results from cohorts/population studies relating adverse health outcomes related to overweight, obesity, diabetes and metabolic disorders to environmental exposures of endocrine disruptors.
The HEALS paradigm and related issues have also been presented several times in scientific congresses and meetings and to stakeholders in public events.
Last but not least, the HEALS project is quoted in international publications.

Project Results:
The HEALS project managed to obtain:
- Creation of a large harmonized dataset of general population and twin data (n>50,000), as a result of the share of existing epidemiological data and biospecimens, in view of conducting pooled analyses in study-specific analyses and EWAS.
- EXHES database of environmental and health data as well as biomarkers of mother-children (both singletons and twins) followed-up in 10 European countries using e-EXHES.
- EXHES biobank of biospecimens
- Establishment of the HEALS Environmental Data Management System (EDMS) containing spatio-temporal referenced environmental data necessary for assessing the external exposome
- Development of the HEALS agent-based modelling (ABM) platform for transforming individual exposure to population exposure profiles considering quantitatively the impact of socio-economic dynamics on the human exposome
- Optimisation of the INTEGRA computational platform for integrated exposure modelling bridging the external and internal exposome
- Establishment of the HEALS exposure biology workflow for cross-omics analyses of the internal exposome, linking this to mechanistic identification of quantitative adverse outcome pathways
- Establishment of the HEALS database of metabolites and metabolic pathways associated with phenotypes of adverse health outcomes to reconstruct the internal exposome
- Creation of the HEALS GeoData platform containing exposome and health data at the European level since 1965 resulting from the HEALS project.
- EWAS analysis applied to health disorders
The list of the publications and presentations is available in the attached document.

Health data: A harmonized database containing datasets on symptoms, diseases, phenotypes from pre-existing studies of singletons and twins that are referenced spatially and temporally is presently available. It contains records for more than 50,000 individuals, most followed-up in time, some since birth and even in utero life.
Internal exposome: The work has progressed consistently towards the implementation of the HEALS conceptual framework in terms of the internal exposome through the enhancement and development of different interdisciplinary components. This allowed us to bring forward the implementation of the tools developed in the project to assess and estimate the internal and external exposome at the individual level.
Biomarkers of exposure and effects were compiled from various datasets. Omics have been employed on samples available from existing exposure/disease outcome studies. Progress was made towards the completion of the major objectives in terms of biokinetic modeling for internal dose and exposure reconstruction, the generic multi-route lifetime PBBK model, which includes among others gestation and breastfeeding and incorporates in utero exposure and mixtures interactions and novel bioinformatics for predictive biomarkers discovery. In addition, information from other existing initiatives on omics was collected and links to other omics databases were made accessible.
External exposome: Two harmonized databases were built: one containing risk factors from population-based studies of singletons and twins, and the other the exposure data available at the European level. A considerably large number of environmental data sets including food contamination have been identified, collected and analysed for their quality (assessing their QA/QC procedures). Environmental factors are assessed at various levels ranging from the ecological to the individual. A probabilistic exposure modelling framework to assess external exposure to chemicals for selected population groups was established. Data on non specific environmental determinants of exposure (social economic, community characteristics, health care system...) were also modelled and collected. Model derived information was recorded. The HEALS Environmental Data Management System (EDMS) was implemented to pull together the totality of the available environmental data.

Potential Impact:
The lessons learned from HEALS will be translated into scientific advice towards the development of protocols and guidelines for the setting up of a larger European environment and health examination survey and for enhancing environmental health risk assessment using the exposome. This will be employed to understand the development of the multifactorial diseases that demand both genetic and environmental exposures to occur. The implemented and developed technologies in HEALS will be available and active technology and knowledge transfer is scheduled to be pursued in the last period of the project. In the long term, this will include screening omics tools and advanced bioinformatics and big data analytics methods that will be available for usage by the global exposome community in support of the European and the Transatlantic Exposome Initiatives.
List of Websites:
www.heals-eu.eu