State-of-the-art methods for exposure-health studies: Results from the exposome data challenge event.

The exposome recognizes that individuals are exposed simultaneously to a multitude of different environmental factors and takes a holistic approach to the discovery of etiological factors for disease. However, challenges arise when trying to quantify the health effects of complex exposure mixtures. Analytical challenges include dealing with high dimensionality, studying the combined effects of these exposures and their interactions, integrating causal pathways, and integrating high-throughput omics layers. To tackle these challenges, the Barcelona Institute for Global Health (ISGlobal) held a data challenge event open to researchers from all over the world and from all expertises. Analysts had a chance to compete and apply state-of-the-art methods on a common partially simulated exposome dataset (based on real case data from the HELIX project) with multiple correlated exposure variables (P > 100 exposure variables) arising from general and personal environments at different time points, biological molecular data (multi-omics: DNA methylation, gene expression, proteins, metabolomics) and multiple clinical phenotypes in 1301 mother-child pairs. Most of the methods presented included feature selection or feature reduction to deal with the high dimensionality of the exposome dataset. Several approaches explicitly searched for combined effects of exposures and/or their interactions using linear index models or response surface methods, including Bayesian methods. Other methods dealt with the multi-omics dataset in mediation analyses using multiple-step approaches. Here we discuss features of the statistical models used and provide the data and codes used, so that analysts have examples of implementation and can learn how to use these methods. Overall, the exposome data challenge presented a unique opportunity for researchers from different disciplines to create and share state-of-the-art analytical methods, setting a new standard for open science in the exposome and environmental health field.

Applying the exposome concept in birth cohort research: a review of statistical approaches.

The exposome represents the totality of life course environmental exposures (including lifestyle and other non-genetic factors), from the prenatal period onwards. This holistic concept of exposure provides a new framework to advance the understanding of complex and multifactorial diseases. Prospective pregnancy and birth cohort studies provide a unique opportunity for exposome research as they are able to capture, from prenatal life onwards, both the external (including lifestyle, chemical, social and wider community-level exposures) and the internal (including inflammation, metabolism, epigenetics, and gut microbiota) domains of the exposome. In this paper, we describe the steps required for applying an exposome approach, describe the main strengths and limitations of different statistical approaches and discuss their challenges, with the aim to provide guidance for methodological choices in the analysis of exposome data in birth cohort studies. An exposome approach implies selecting, pre-processing, describing and analyzing a large set of exposures. Several statistical methods are currently available to assess exposome-health associations, which differ in terms of research question that can be answered, of balance between sensitivity and false discovery proportion, and between computational complexity and simplicity (parsimony). Assessing the association between many exposures and health still raises many exposure assessment issues and statistical challenges. The exposome favors a holistic approach of environmental influences on health, which is likely to allow a more complete understanding of disease etiology.

Interactions Between Air Pollution and Pollen Season for Rhinitis Using Mobile Technology: A MASK-POLLAR Study.

BACKGROUND: Several studies have suggested an interaction between air pollution and pollen exposure with an impact on allergy symptoms. However, large studies with real-life data are not available. OBJECTIVE: To investigate associations between major air pollutants (ozone and particulate matter with a diameter of <2.5 µm) and allergic rhinitis (AR) control during grass and birch pollen seasons as well as outside the pollen season. METHODS: The daily impact of allergic symptoms was recorded by the Allergy Diary (Mobile Airways Sentinel NetworK [MASK-air]) app (a validated mHealth tool for rhinitis management) using visual analog scales (VASs) in Northern and Central Europe users in 2017 and 2018. Uncontrolled AR was defined using symptoms and medications. Pollutant levels were assessed using the System for Integrated modeLing of Atmospheric coMposition database. Pollen seasons were assessed by regions using Google Trends. Generalized estimating equation models were used to account for repeated measures per user, adjusting for sex, age, treatment, and country. Analyses were stratified by pollen seasons to investigate interactions between air pollutants and pollen exposure. RESULTS: A total of 3323 geolocated individuals (36,440 VAS-days) were studied. Associations between uncontrolled rhinitis and pollutants were stronger during the grass pollen season. Days with uncontrolled AR increased by 25% for an interquartile range increase in ozone levels during the grass pollen season (odds ratio of 1.25 [95% CI, 1.11-1.41] in 2017 and of 1.14 [95% CI, 1.04-1.25] in 2018). A similar trend was found for particulate matter with a diameter of less than 2.5 µm, especially in 2017. CONCLUSIONS: These results suggest that the relationship between uncontrolled AR and air pollution is modified by the presence of grass pollens. This study confirms the impact of pollutants in the grass pollen season but not in the birch pollen season.

Early-Life Environmental Exposures and Blood Pressure in Children.

BACKGROUND: Growing evidence exists about the fetal and environmental origins of hypertension, but mainly limited to single-exposure studies. The exposome has been proposed as a more holistic approach by studying many exposures simultaneously. OBJECTIVES: This study aims to evaluate the association between a wide range of prenatal and postnatal exposures and blood pressure (BP) in children. METHODS: Systolic and diastolic BP were measured among 1,277 children from the European HELIX (Human Early-Life Exposome) cohort aged 6 to 11 years. Prenatal (n = 89) and postnatal (n = 128) exposures include air pollution, built environment, meteorology, natural spaces, traffic, noise, chemicals, and lifestyles. Two methods adjusted for confounders were applied: an exposome-wide association study considering the exposures independently, and the deletion-substitution-addition algorithm considering all the exposures simultaneously. RESULTS: Decreases in systolic BP were observed with facility density (ß change for an interquartile-range increase in exposure: -1.7 mm Hg [95% confidence interval (CI): -2.5 to -0.8 mm Hg]), maternal concentrations of polychlorinated biphenyl 118 (-1.4 mm Hg [95% CI: -2.6 to -0.2 mm Hg]) and child concentrations of dichlorodiphenyldichloroethylene (DDE: -1.6 mm Hg [95% CI: -2.4 to -0.7 mm Hg]), hexachlorobenzene (-1.5 mm Hg [95% CI: -2.4 to -0.6 mm Hg]), and mono-benzyl phthalate (-0.7 mm Hg [95% CI: -1.3 to -0.1 mm Hg]), whereas increases in systolic BP were observed with outdoor temperature during pregnancy (1.6 mm Hg [95% CI: 0.2 to 2.9 mm Hg]), high fish intake during pregnancy (2.0 mm Hg [95% CI: 0.4 to 3.5 mm Hg]), maternal cotinine concentrations (1.2 mm Hg [95% CI: -0.3 to 2.8 mm Hg]), and child perfluorooctanoate concentrations (0.9 mm Hg [95% CI: 0.1 to 1.6 mm Hg]). Decreases in diastolic BP were observed with outdoor temperature at examination (-1.4 mm Hg [95% CI: -2.3 to -0.5 mm Hg]) and child DDE concentrations (-1.1 mm Hg [95% CI: -1.9 to -0.3 mm Hg]), whereas increases in diastolic BP were observed with maternal bisphenol-A concentrations (0.7 mm Hg [95% CI: 0.1 to 1.4 mm Hg]), high fish intake during pregnancy (1.2 mm Hg [95% CI: -0.2 to 2.7 mm Hg]), and child copper concentrations (0.9 mm Hg [95% CI: 0.3 to 1.6 mm Hg]). CONCLUSIONS: This study suggests that early-life exposure to several chemicals, as well as built environment and meteorological factors, may affect BP in children.

Google Trends and pollen concentrations in allergy and airway diseases in France.

BACKGROUND: Google Trends (GTs) is a web-based surveillance tool that explores the searching trends of specific queries via Google. This tool proposes to reflect the real-life epidemiology of allergic rhinitis and asthma. However, the validation of GTs against pollen concentrations is missing at the country level. OBJECTIVES: In the present study, we used GTs (a) to compare the terms related to allergy in France, (b) to assess seasonal variations across the country for 5 years and (c) to compare GTs and pollen concentrations for 2016. METHODS: Google Trends queries were initially searched to investigate the terms reflecting pollen and allergic diseases. 13- and 5-year GTs were used in France. Then, 5-year GTs were assessed in all metropolitan French regions to assess the seasonality of GTs. Finally, GTs were compared with pollen concentrations (Réseau National de Surveillance en Aerobiology) for 2016 in seven regions (GTs) and corresponding cities (pollen concentrations). RESULTS: The combination of searches for "allergy" as a disease, "pollen" as a disease cause and "ragweed" as a plant was needed to fully assess the pollen season in France. "Asthma" did not show any seasonality. Using the 5-year GTs, an annual and clear seasonality of queries was found in all regions depending on the predicted pollen exposure for spring and a summer peak but not for winter peaks. The agreement between GT queries and pollen concentrations is usually poor except for spring trees and grasses. Moreover, cypress pollens are insufficiently reported by GTs. CONCLUSIONS: Google Trends cannot predict the pollen season in France.

Influence of the Urban Exposome on Birth Weight.

BACKGROUND: The exposome is defined as the totality of environmental exposures from conception onwards. It calls for providing a holistic view of environmental exposures and their effects on human health by evaluating multiple environmental exposures simultaneously during critical periods of life. OBJECTIVE: We evaluated the association of the urban exposome with birth weight. METHODS: We estimated exposure to the urban exposome, including the built environment, air pollution, road traffic noise, meteorology, natural space, and road traffic (corresponding to 24 environmental indicators and 60 exposures) for nearly 32,000 pregnant women from six European birth cohorts. To evaluate associations with either continuous birth weight or term low birth weight (TLBW) risk, we primarily relied on the Deletion-Substitution-Addition (DSA) algorithm, which is an extension of the stepwise variable selection method. Second, we used an exposure-by-exposure exposome-wide association studies (ExWAS) method accounting for multiple hypotheses testing to report associations not adjusted for coexposures. RESULTS: The most consistent statistically significant associations were observed between increasing green space exposure estimated as Normalized Difference Vegetation Index (NDVI) and increased birth weight and decreased TLBW risk. Furthermore, we observed statistically significant associations among presence of public bus line, land use Shannon's Evenness Index, and traffic density and birth weight in our DSA analysis. CONCLUSION: This investigation is the first large urban exposome study of birth weight that tests many environmental urban exposures. It confirmed previously reported associations for NDVI and generated new hypotheses for a number of built-environment exposures. https://doi.org/10.1289/EHP3971.

Urban upbringing and childhood respiratory and allergic conditions: A multi-country holistic study.

OBJECTIVE: We integratively assessed the effect of different indoor and outdoor environmental exposures early in life on respiratory and allergic health conditions among children from (sub-) urban areas. METHODS: This study included children participating in four ongoing European birth cohorts located in three different geographical regions: INMA (Spain), LISAplus (Germany), GINIplus (Germany) and BAMSE (Sweden). Wheezing, bronchitis, asthma and allergic rhinitis throughout childhood were assessed using parental-completed questionnaires. We designed "environmental scores" corresponding to different indoor, green- and grey-related exposures (main analysis, a-priori-approach). Cohort-specific associations between these environmental scores and the respiratory health outcomes were assessed using random-effects meta-analyses. In addition, a factor analysis was performed based on the same exposure information used to develop the environmental scores (confirmatory analysis, data-driven-approach). RESULTS: A higher early exposure to the indoor environmental score increased the risk for wheezing and bronchitis within the first year of life (combined adjusted odds ratio: 1.20 [95% confidence interval: 1.13-1.27] and 1.28 [1.18-1.39], respectively). In contrast, there was an inverse association with allergic rhinitis between 6 and 8 years (0.85 [0.79-0.92]). There were no statistically significant associations for the outdoor related environmental scores in relation to any of the health outcomes tested. The factor analysis conducted confirmed these trends. CONCLUSION: Although a higher exposure to indoor related exposure through occupants was associated with an increased risk for wheezing and bronchitis within the 1st year, it might serve as a preventive mechanism against later childhood allergic respiratory outcomes in urbanized environments through enhanced shared contact with microbial agents.

The Pregnancy Exposome: Multiple Environmental Exposures in the INMA-Sabadell Birth Cohort.

The "exposome" is defined as "the totality of human environmental exposures from conception onward, complementing the genome" and its holistic approach may advance understanding of disease etiology. We aimed to describe the correlation structure of the exposome during pregnancy to better understand the relationships between and within families of exposure and to develop analytical tools appropriate to exposome data. Estimates on 81 environmental exposures of current health concern were obtained for 728 women enrolled in The INMA (INfancia y Medio Ambiente) birth cohort, in Sabadell, Spain, using biomonitoring, geospatial modeling, remote sensors, and questionnaires. Pair-wise Pearson's and polychoric correlations were calculated and principal components were derived. The median absolute correlation across all exposures was 0.06 (5th-95th centiles, 0.01-0.54). There were strong levels of correlation within families of exposure (median = 0.45, 5th-95th centiles, 0.07-0.85). Nine exposures (11%) had a correlation higher than 0.5 with at least one exposure outside their exposure family. Effectively all the variance in the data set (99.5%) was explained by 40 principal components. Future exposome studies should interpret exposure effects in light of their correlations to other exposures. The weak to moderate correlation observed between exposure families will permit adjustment for confounding in future exposome studies.

Sun and ski holidays improve vitamin D status, but are associated with high levels of DNA damage.

Skin cancer is caused by solar UVR, which is also essential for vitamin D production. DNA damage (thymine dimers: T-T dimers) and vitamin D (25(OH)D) synthesis are both initiated by solar UVB. We aimed to investigate the simultaneous adverse and beneficial effects of solar UVB exposure in holidaymakers. Sun-seekers and skiers (n=71) were observed over 6 days through on-site monitoring, personal diary entries, and recording of personal UVB exposure doses with electronic dosimeters. Urine and blood samples were analyzed for T-T dimers and 25(OH)D, respectively. The volunteers had a statistically significant increase in vitamin D. There were strong associations between UVB exposure and post-holiday levels of T-T dimers and vitamin D, as well as between post-holiday T-T dimers and vitamin D. We conclude that UVB-induced vitamin D synthesis is associated with considerable DNA damage in the skin. These data, on two major health predictors, provide a basis for further field studies that may result in better understanding of the risks and benefits of "real life" solar exposure. However, vitamin D status can be improved more safely through the use of vitamin D dietary supplements.

Positive health effects of the natural outdoor environment in typical populations in different regions in Europe (PHENOTYPE): a study programme protocol.

INTRODUCTION: Growing evidence suggests that close contact with nature brings benefits to human health and well-being, but the proposed mechanisms are still not well understood and the associations with health remain uncertain. The Positive Health Effects of the Natural Outdoor environment in Typical Populations in different regions in Europe (PHENOTYPE) project investigates the interconnections between natural outdoor environments and better human health and well-being. AIMS AND METHODS: The PHENOTYPE project explores the proposed underlying mechanisms at work (stress reduction/restorative function, physical activity, social interaction, exposure to environmental hazards) and examines the associations with health outcomes for different population groups. It implements conventional and new innovative high-tech methods to characterise the natural environment in terms of quality and quantity. Preventive as well as therapeutic effects of contact with the natural environment are being covered. PHENOTYPE further addresses implications for land-use planning and green space management. The main innovative part of the study is the evaluation of possible short-term and long-term associations of green space and health and the possible underlying mechanisms in four different countries (each with quite a different type of green space and a different use), using the same methodology, in one research programme. This type of holistic approach has not been undertaken before. Furthermore there are technological innovations such as the use of remote sensing and smartphones in the assessment of green space. CONCLUSIONS: The project will produce a more robust evidence base on links between exposure to natural outdoor environment and human health and well-being, in addition to a better integration of human health needs into land-use planning and green space management in rural as well as urban areas.