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The exposome concept takes a holistic approach facilitated by new and emerging technologies to describe ‘the totality of human environmental (i.e. non-genetic) exposures from conception onwards, complementing the genome’. It provides a framework to advance the environmental epidemiology field that has until now focused almost exclusively on single-exposure health effects. The exposome includes an external domain, measured by methods including geo-spatial modelling, questionnaire and biomonitoring of external exposures while the internal domain is commonly assessed through molecular omics platforms. The internal domain, in part, reflects the biological response to the external domain. New statistical frameworks are required to integrate and assess exposome-health effects. The pregnancy period is a key starting point to describe the dynamic exposome, due to its heightened sensitivity and potential lifetime impact. A handful of studies have started to move towards an exposome approach in assessing the effects of the multiple exposures during pregnancy on child development. New research projects are underway to test the exposome approach on a large scale.
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... NPPO neurobiological stimulation treatments comprise an 18-sessions cycle. These treatments aim to improve the psychophysical response to current environmental factors and the reorganization of the previous altered responses to exposome (Robinson & Vrijheid, 2015;Wild, 2005) at cognitive and behavioral levels (Fontani et al., 2012a(Fontani et al., , 2012bRinaldi et al., 2019). The NPPOs treatments are preprogrammed and can be administered via two modalities (Pinheiro Barcessat et al., 2020a), with a punctiform ACP on the auricle or with a planar ACP in the cervico-brachial region. ...
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Objectives Autism spectrum disorder (ASD) symptoms can become more evident because of different factors. Among these, depression, anxiety, and stress play an important role. Additionally, several studies have revealed the impact of the COVID-19 pandemic on participants with ASD. In previous studies, two noninvasive neurobiological stimulation treatments with radio electric asymmetric conveyer (REAC) technology, called neuropostural optimization (NPO) and neuropsychophysical optimization (NPPO), were shown to be effective in improving the subjective response to environmental stressors in the general population and in ASD population. Based on the proven efficacy of REAC NPO and NPPOs treatments in alleviating anxiety, stress, and depression, the purpose of this study is to verify how these treatments can reduce the severity of ASD symptoms expression, which is aggravated by depression, anxiety, and stress. The treatments’ effects were perceived by caregivers and assessed by the Autism Treatment Evaluation Checklist (ATEC). Methods This study involved 46 children with a previous diagnosis of ASD made using the Autism Diagnostic Observation Schedule and Autism Diagnostic Interview-Revised. The participants received one session of NPO treatment and one NPPOs treatment cycle of 18 sessions, administered within approximately 3 weeks. The Autism Treatment Evaluation Checklist (ATEC) was used to evaluate the efficacy of the REAC treatments. ATEC allows to evaluate four clusters (speech or language communication; sociability; sensory or cognitive awareness; and health/physical/behavior) through a numerical scale that measures increasing levels of ASD severity. Results The comparison between the scores of the ATEC administered pre- and post-REAC treatments highlighted an improvement of ASD symptoms in each of the four clusters of ATEC. Conclusions The results confirm the usefulness of REAC treatments to optimize the individual response to environmental stressors and reduce the symptomatic expression and deficits present in ASD.
... Increasing studies are revealing the impacts of the exposome on transcriptomics, metabolomics, proteomics, immunomics, epigenetics, glycomics, genomics, etc. [4,[20][21][22][23] (Figure 1), which provides in-depth and unique insights into the relationships between the exposome and diseases [24]. Several experts in the exposome field have systematically reviewed the relationships between environmental exposome and human diseases, such as asthma [25], cardiovascular diseases [26], pregnancy [27], cancer [28][29][30], gastrointestinal disease [31], skin disease [7], kidney disease [32], metabolic disease [33,34], and other health conditions [35,36]. Besides environmental exposures, humanistic exposome comprising lifestyle and socioeconomic factors also play important roles in defining and shaping one's health ( Figure 1) [37,38]. ...
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The exposome depicts the total exposures in the lifetime of an organism. Human exposome comprises exposures from environmental and humanistic sources. Biological, chemical, and physical environmental exposures pose potential health threats, especially to susceptible populations. Although still in its nascent stage, we are beginning to recognize the vast and dynamic nature of the exposome. In this review, we systematically summarize the biological and chemical environmental exposomes in three broad environmental matrices—air, soil, and water; each contains several distinct subcategories, along with a brief introduction to the physical exposome. Disease‐related environmental exposures are highlighted, and humans are also a major source of disease‐related biological exposures. We further discuss the interactions between biological, chemical, and physical exposomes. Finally, we propose a list of outstanding challenges under the exposome research framework that need to be addressed to move the field forward. Taken together, we present a detailed landscape of environmental exposome to prime researchers to join this exciting new field. We describe the biological and chemical components of the environmental exposomes in three major environmental matrices that are highly relevant to human and social‐economical health—air, soil, and water. We discuss how different exposome components can interact with each other. Finally, we propose a list of outstanding challenges to be tackled to push the field forward. The biological and chemical exposures in air, soil, and water were summarized and united under the exposome framework. Biological, chemical, and physical exposures are dynamically interweaved. A list of outstanding challenges was proposed to be tackled to push the field forward. The biological and chemical exposures in air, soil, and water were summarized and united under the exposome framework. Biological, chemical, and physical exposures are dynamically interweaved. A list of outstanding challenges was proposed to be tackled to push the field forward.
... See for instance the application of the exposome approach to the epidemiology of early life(Robinson & Vrijheid, 2015). ...
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I propose an approach that expands philosophical views of scientific change, on the basis of an analysis of contemporary biomedical research and recent developments in the philosophy of scientific change. Focusing on the establishment of the exposome in epidemiology as a case study and the role of data as a context for contrasting views on change, I discuss change at conceptual, methodological, material, and social levels of biomedical epistemology. Available models of change provide key resources to discuss this type of change, but I present the need for an approach that models transfer , alignment , and influence as key processes of change. I develop this as a pragmatic approach to scientific change, where processes might change substantially depending on specific circumstances, thus contributing to and complementing the debate on a crucial epistemological issue.
... 7 The approach to data integration of exposome research and EXPOsOMICS is thus an attempt to reframing the environment in terms that are not only genetic or molecular and thus reductive (Shostak & Moinester, 2015). As a result, in exposome research the notion of environment is used to discuss entities at very different levels of analysis and has been considered to include anything that is non-genetic (Wild, 2008), what is relevant to a specific analysis (Rappaport, 2011), as well as the maternal body (Robinson & Vrijheid, 2015). This juxtaposition between the external and internal dimensions of the analysis runs parallel with interpretations in continuous terms of the processes that population health studies intend to capture. ...
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In this paper, we analyse the relation between the use of environmental data in contemporary health sciences and related conceptualisations and operationalisations of the notion of environment. We consider three case studies that exemplify a different selection of environmental data and mode of data integration in data-intensive epidemiology. We argue that the diversification of data sources, their increase in scale and scope, and the application of novel analytic tools have brought about three significant conceptual shifts. First, we discuss the EXPOsOMICS project, an attempt to integrate genomic and environmental data which suggests a reframing of the boundaries between external and internal environments. Second, we explore the MEDMI platform, whose efforts to combine health, environmental and climate data instantiate a reframing and expansion of environmental exposure. Third, we illustrate how extracting epidemiological insights from extensive social data collected by the CIDACS institute yields innovative attributions of causal power to environmental factors. Identifying these shifts highlights the benefits and opportunities of new environmental data, as well as the challenges that such tools bring to understanding and fostering health. It also emphasises the constraints that data selection and accessibility pose to scientific imagination, including how researchers frame key concepts in health-related research.
... However, how to incorporate the hierarchical structure into a putative exposome analysis is one complexity of the exposome framework. This complexity remains to be addressed (Robinson & Vrijheid, 2015). ...
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Previous studies have shown certain exposure factors (such as lifestyle and metabolism) are associated with colorectal cancer (CRC) events. However, the application of the exposome theoretical frame and the extent to which the exposome domain can modulate the risk of CRC remain unknown. Our study aimed to construct valid exposome measurements and examine the relationship between exposome counts and the risk of CRC. This study included 273,342 individuals in the UK Biobank. We used exploratory factor analysis to identify a valid construct of exposome factors. We then summed the exposome counts within each domain. Cox proportional hazard models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) of CRC risk related to the exposome factors and counts. During an 8.69 year median follow-up, 8642 CRC cases were identified. Seven domains were extracted from 18 variables, including air pollution, noise pollution, ecosystem, lifestyle, tobacco and alcohol use, social economics, and social support. The Cox model results showed that the ecosystem was positively related to the reduced CRC risk (HR=0.97; 95% CI: 0.949–0.991). Similar results were also found among the domains of healthy lifestyles (HR=0. 873; 95% CI: 0.854–0.893), and no tobacco and alcohol use (HR=0.880; 95% CI: 0.862–0.899). The disadvantageous social economic (HR=1.068; 95% CI: 1.046–1.090) and insufficient social support domains (HR=1.067; 95% CI: 1.042–1.094) were associated with an increased risk of CRC. Similar risk trends were also observed across the exposome count groups with CRC incidence. Our findings suggest that certain exposure domains are related to the incidence of CRC. Ecosystem, lifestyle, and social factors can be incorporated into prediction models to identify individuals at high risk of CRC.
... These factors can be subdivided into three domains: (1) an internal domain (endo-exposome), for example hormones, inflammation and oxidative stress; (2) a specific external domain (ecto-exposome), for example infectious agents, diet and lifestyle; and (3) a general external domain that includes education, socio-economic status and mental burden (Wild, 2012). During pregnancy the developing fetus is exposed to different endo-and ecto-exposome factors, most notably including oxidative stress, nutrition, and inflammation (Robinson and Vrijheid, 2015;Valero et al., 2021). A particular example of a complication of pregnancy in which the exposome is involved is gestational diabetes mellitus (GDM). ...
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Pregnancy complications including fetal growth restriction, preeclampsia, and preterm birth, as well as gestational diabetes, affect one in every four to five pregnancies. Accumulating evidence indicates that increased production of reactive oxygen species accompanies these complications. Given that reactive oxygen species are cell stress-inducing agents, they may have a causal role in disease pathophysiology, although the exact mechanisms by which they contribute to pregnancy complications are not completely understood. Since many environmental and lifestyle factors and exposures are known to modulate reactive oxygen species production, the exposome of pregnant women could contribute to increased generation of reactive oxygen species. The objective of this review is to provide a comprehensive overview of the endogenous and exogenous exposome factors that regulate reactive species in healthy and complicated pregnancies. We also provide a description of dietary interventions aimed at the reduction of reactive species in order to attenuate adverse pregnancy outcome. Dietary interventions in general hold minimal risk in pregnancy and could therefore be considered a promising therapeutic approach.
... Through this concept, he shared his vision for the need to develop a field that provided an environmental complement to the genome. He defined it as the totality of exposures from various internal and external sources from conception onward over a complete lifetime [4,5]. The concept of exposome is to complement the genome to better explain the causes of diseases [6]. ...
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Background—The exposome concept refers to the totality of exposures from internal and external sources, including chemical and biological agents from conception throughout the lifetime. Exposome is also made up of psychosocial components such as socio-economic status (SES), which will focus on in this review. Despite exposures to the same environmental nuisances, individuals and groups are impacted differently. According to the literature, health inequalities exist among different socioeconomic groups, and SES may influence the association between environmental nuisances and health outcomes. However, the variation of this interaction across ages has rarely been studied. There is a need to adopt a life course approach to understand the history of diseases better. Objective—The main objective of this review is to document how SES could modify the association between environmental nuisances and health outcomes, across different ages, as a first crucial step introducing the emerged concept of social exposome. Methods—The PubMed database was searched from January 2010 to August 2021 for systematic reviews published in English addressing the interaction between SES, environmental nuisances, and health outcomes. Socio-economic indicators considered include education, level of income, neighborhood environment. Environmental nuisances considered many environment nuisances, mainly air pollution and noise. Results—Among 242 literature reviews identified, 11 of them address the question of the effect modification. Overall, our work reveals that environmental nuisances were mostly associated with poorer health outcomes and that SES modified this association, increasing the health risk among the poorest. Very interestingly, our work reports the existence of this interaction across different ages, including pregnancy, childhood, and adulthood, and for various environmental nuisances. Conclusion—In conclusion, our work confirms that we are not all equal to face environmental nuisances. The poorest are more vulnerable to the health effect of environmental nuisances. Policy decisions and interventions should target this high-risk population as a priority. Further investigations are needed to formalize the concept of social exposome more precisely and then communicate about it.
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Early-life exposure occurs during gestation through transfer to the fetus and later, during lactation. Recent monitoring data revealed that the Portuguese population is exposed to mycotoxins, including young children. This study aimed to develop a pilot study to assess the early-life exposure to mycotoxins through a mother-child cohort, and to identify the associated challenges. Participants were recruited during pregnancy (1st trimester) and followed-up in three moments of observation: 2nd trimester of pregnancy (mother), and 1st and 6th month of the child's life (mother and child), with the collection of biological samples and sociodemographic and food consumption data. The earlyMYCO pilot study enrolled 19 mother-child pairs. The analysis of biological samples from participants revealed the presence of 4 out of 15 and 5 out of 18 mycotoxins' biomarkers of exposure in urine and breast milk samples, respectively. The main aspects identified as contributors for the successful development of the cohort were the multidisciplinary and dedicated team members in healthcare units, reduced burden of participation, and the availability of healthcare units for the implementation of the fieldwork. Challenges faced, lessons learned, and suggestions were discussed as a contribution for the development of further studies in this area.
Chapter
With continuing advancements in the availability of geospatial data, analytical tools, and computational capacity of multidisciplinary and multiscale data, geospatial technology as a whole has become enormously powerful and functional. Complex concepts like human well-being and health require robust analytical capability, which modern-day geospatial tools can provide. While human well-being and health can be defined only conceptually, both medicine and technology are rather very practical hands-on matters. Unless both of these worlds are meaningfully bridged together, full mutual benefits are not reachable. Over the last 30 years or so, there have been tremendous advancements in the area of geospatial health; however, somehow, two aspects have not received as much attention as they should have received. These are (a) limitations of different spatial analytical tools and (b) progress in making Geospatial Individual Environmental Exposure (GIEE) available for advanced health research and also for clinical practice in a usable format. Most of the chapters in this book volume address the first issue. This chapter focuses on discussing how geospatial technology can contribute to (a) emerging health science research, and (b) the clinical practice of medicine. This chapter also provides background information on relevant concepts, terminologies, technologies, and organizations, which are often unfamiliar to the emerging geospatial health professionals. Hopefully, this chapter will provide a comprehensive idea irrespective of the geospatial specialty of the readers.
Article
Background Exposure to harmful environmental substances influences lifelong health, but the molecular interpretation of how it affects human health is poorly understood. Therefore, a framework that can efficiently apply the major technologies and fields related to exposomes is needed, as it would provide an important tool for the identification of the environmental factors affecting human health.ObjectWe aimed to develop a system that integrates multi-omics data and archives this information to ensure that omics analysis information can be utilised to understand the molecular phenotypical concerns associated with exposure to harmful environmental substances in humans.ResultWe established a data archive system called Online Resource of Environmental Omics (OREO) that standardises multi-omics cohort sample data of humans exposed to harmful environmental substances; integrates unstructured data; and can search, share, and store information. In addition, data profiling is provided to ensure that it can be applied to integrated omics analysis visualisation tools such as cBioportal. In the case of long-term exposure to low concentrations of harmful environmental substances, an integrated analysis of clinical observation and omics data could be performed.Conclusion We provide a brief account of multi-omics data repositories, the data processing method, and an analysis pipeline for the application of omics data. This data processing ability helps to comprehensively understand multi-omics data regarding harmful environmental substances.
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Objectives Numerous environmental contaminants have been linked to adverse reproductive health outcomes. However, the complex correlation structure of exposures and multiple testing issues limit the interpretation of existing evidence. Our objective was to identify, from a large set of contaminant exposures, exposure profiles associated with biomarkers of male reproductive function. Methods In this cross-sectional study (n=602), male partners of pregnant women were enrolled between 2002 and 2004 during antenatal care visits in Greenland, Poland and Ukraine. Fifteen contaminants were detected in more than 70% of blood samples, including metabolites of di(2-ethylhexyl) and diisononyl phthalates (DEHP, DiNP), perfluoroalkyl acids, metals and organochlorines. Twenty-two reproductive biomarkers were assessed, including serum levels of reproductive hormones, markers of semen quality, sperm chromatin integrity, epididymal and accessory sex gland function, and Y:X chromosome ratio. We evaluated multipollutant models with sparse partial least squares (sPLS) regression, a simultaneous dimension reduction and variable selection approach which accommodates joint modelling of correlated exposures. Results Of the over 300 exposure–outcome associations tested in sPLS models, we detected 10 associations encompassing 8 outcomes. Several associations were notably consistent in direction across the three study populations: positive associations between mercury and inhibin B, and between cadmium and testosterone; and inverse associations between DiNP metabolites and testosterone, between polychlorinated biphenyl-153 and progressive sperm motility, and between a DEHP metabolite and neutral α-glucosidase, a marker of epididymal function. Conclusions This global assessment of a mixture of environmental contaminants provides further indications that some organochlorines and phthalates adversely affect some parameters of male reproductive health.
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Introduction: The exposome encompasses the totality of human environmental exposures. Recent developments in sensor technology have made it possible to better measure personal exposure to environmental pollutants and other factors. We aimed to discuss and demonstrate the recent developments in personal sensors to measure multiple exposures and possible acute health responses, and discuss the main challenges ahead. Methods: We searched for a range of sensors to measure air pollution, noise, temperature, UV, physical activity, location, blood pressure, heart rate and lung function and to obtain information on green space and emotional status/mood and put it on a person. Results and conclusions: We discussed the recent developments and main challenges for personal sensors to measure multiple exposures. We found and put together a personal sensor set that measures a comprehensive set of personal exposures continuously over 24 h to assess part of the current exposome and acute health responses. We obtained data for a whole range of exposures and some acute health responses, but many challenges remain to apply the methodology for extended time periods and larger populations including improving the ease of wear, e.g., through miniaturization and extending battery life, and the reduction of costs. However, the technology is moving fast and opportunities will come closer for further wide spread use to assess, at least part of the exposome.
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Background Preterm birth (PB) and fetal growth restriction (FGR) convey the highest risk of perinatal mortality and morbidity, as well as increasing the chance of developing chronic disease in later life. Identifying early in pregnancy the unfavourable maternal conditions that can predict poor birth outcomes could help their prevention and management. Here we used an exploratory metabolic profiling approach (metabolomics) to investigate the association between birth outcomes and metabolites in maternal urine collected early in pregnancy as part of the prospective mother–child cohort Rhea study. Metabolomic techniques can simultaneously capture information about genotype and its interaction with the accumulated exposures experienced by an individual from their diet, environment, physical activity or disease (the exposome). As metabolic syndrome has previously been shown to be associated with PB in this cohort, we sought to gain further insight into PB-linked metabolic phenotypes and to define new predictive biomarkers. Methods Our study was a case–control study nested within the Rhea cohort. Major metabolites (n = 34) in maternal urine samples collected at the end of the first trimester (n = 438) were measured using proton nuclear magnetic resonance spectroscopy. In addition to PB, we used FGR in weight and small for gestational age as study endpoints. Results We observed significant associations between FGR and decreased urinary acetate (interquartile odds ratio (IOR) = 0.18 CI 0.04 to 0.60), formate (IOR = 0.24 CI 0.07 to 0.71), tyrosine (IOR = 0.27 CI 0.08 to 0.81) and trimethylamine (IOR = 0.14 CI 0.04 to 0.40) adjusting for maternal education, maternal age, parity, and smoking during pregnancy. These metabolites were inversely correlated with blood insulin. Women with clinically induced PB (IPB) had a significant increase in a glycoprotein N-acetyl resonance (IOR = 5.84 CI 1.44 to 39.50). This resonance was positively correlated with body mass index, and stratified analysis confirmed that N-acetyl glycoprotein and IPB were significantly associated in overweight and obese women only. Spontaneous PB cases were associated with elevated urinary lysine (IOR = 2.79 CI 1.20 to 6.98) and lower formate levels (IOR = 0.42 CI 0.19 to 0.94). Conclusions Urinary metabolites measured at the end of the first trimester are associated with increased risk of negative birth outcomes, and provide novel information about the possible mechanisms leading to adverse pregnancies in the Rhea cohort. This study emphasizes the potential of metabolic profiling of urine as a means to identify novel non-invasive biomarkers of PB and FGR risk.
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Background There is a need to evaluate complex interaction effects on human health, such as those induced by mixtures of environmental contaminants. The usual approach is to formulate an additive statistical model and check for departures using product terms between the variables of interest. In this paper, we present an approach to search for interaction effects among several variables using boosted regression trees. Methods We simulate a continuous outcome from real data on 27 environmental contaminants, some of which are correlated, and test the method’s ability to uncover the simulated interactions. The simulated outcome contains one four-way interaction, one non-linear effect and one interaction between a continuous variable and a binary variable. Four scenarios reflecting different strengths of association are simulated. We illustrate the method using real data. Results The method succeeded in identifying the true interactions in all scenarios except where the association was weakest. Some spurious interactions were also found, however. The method was also capable to identify interactions in the real data set. Conclusions We conclude that boosted regression trees can be used to uncover complex interaction effects in epidemiological studies.
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There is little consistency in the literature concerning factors that influence motor coordination in children. A hypothesis-free "exposome" approach was used with 7359 children using longitudinal information covering 3 generations in regard to throwing a ball accurately at age 7 years. The analyses showed an independent robust negative association with mother's unhappiness in her midchildhood (6-11 years). No such association was present for study fathers. The offspring of parents who described themselves as having poor eyesight had poorer ability. This hypothesis-free approach has identified a strong negative association with an unhappy childhood. Future studies of this cohort will be used to determine whether the mechanism is manifest through differing parenting skills, or a biological mechanism reflecting epigenetic effects.
Article
Recent evidence demonstrates important maternal effects on an offspring's risk of developing metabolic disease. These effects extend across the full range of maternal environments and partly involve epigenetic mechanisms. The maternal effects can be explained in evolutionary terms, and there is some evidence for their transmission into succeeding generations. Unbalanced maternal diet or body composition, ranging from poor to rich environments, adversely influences the offspring's response to later challenges such as an obesogenic diet or physical inactivity, increasing the risk of disease. Adopting a life course approach that takes into account intergenerational effects has important implications for prevention of non-communicable diseases, particularly in populations undergoing rapid economic transition
Article
Background: Because ambient air pollution exposure occurs as mixtures, consideration of joint effects of multiple pollutants may advance our understanding of the health effects of air pollution. Methods: We assessed the joint effect of air pollutants on pediatric asthma emergency department visits in Atlanta during 1998-2004. We selected combinations of pollutants that were representative of oxidant gases and secondary, traffic, power plant, and criteria pollutants, constructed using combinations of criteria pollutants and fine particulate matter (PM2.5) components. Joint effects were assessed using multipollutant Poisson generalized linear models controlling for time trends, meteorology, and daily nonasthma upper respiratory emergency department visit counts. Rate ratios (RRs) were calculated for the combined effect of an interquartile range increment in each pollutant's concentration. Results: Increases in all of the selected pollutant combinations were associated with increases in warm-season pediatric asthma emergency department visits (eg, joint-effect RR = 1.13 [95% confidence interval = 1.06-1.21] for criteria pollutants, including ozone, carbon monoxide, nitrogen dioxide, sulfur dioxide, and PM2.5). Cold-season joint effects from models without nonlinear effects were generally weaker than warm-season effects. Joint-effect estimates from multipollutant models were often smaller than estimates based on single-pollutant models, due to control for confounding. Compared with models without interactions, joint-effect estimates from models including first-order pollutant interactions were largely similar. There was evidence of nonlinear cold-season effects. Conclusions: Our analyses illustrate how consideration of joint effects can add to our understanding of health effects of multipollutant exposures and also illustrate some of the complexities involved in calculating and interpreting joint effects of multiple pollutants.
Article
Epidemiological studies evaluate multiple exposures, but the extent of multiplicity often remains non-transparent when results are reported. There is extensive debate in the literature on whether multiplicity should be adjusted for in the design, analysis, and reporting of most epidemiological studies, and, if so, how this should be done. The challenges become more acute in an era where the number of exposures that can be studied (the exposome) can be very large. Here, we argue that it can be very insightful to visualize and describe the extent of multiplicity by reporting the number of effective exposures for each category of exposures being assessed, and to describe the distribution of correlation between exposures and/or between exposures and outcomes in epidemiological datasets. The results of new proposed associations can be placed in the context of this background information. An association can be assigned to a percentile of magnitude of effect based on the distribution of effects seen in the field. We offer an example of how such information can be routinely presented in an epidemiological study/dataset using data on 530 exposure and demographic variables classified in 32 categories in the National Health and Nutrition Examination Survey (NHANES). Effects that survive multiplicity considerations and that are large may be prioritized for further scrutiny.