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1. A multi-environmental source approach to explore associations between metals exposure and olfactory identification among school-age children residing in northern Italy

Author

Renzetti, Stefano, van Thriel, Christoph, Lucchini, Roberto G., Smith, Donald R., Peli, Marco, Borgese, Laura, Cirelli, Paola, Bilo, Fabjola, Patrono, Alessandra, Cagna, Giuseppa, Rechtman, Elza, Idili, Stefania, Ongaro, Elisa, Calza, Stefano, Rota, Matteo, Wright, Robert O., Claus Henn, Birgit, Horton, Megan K., and Placidi, Donatella

Published
2024
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3. Association of maternal education, neighborhood deprivation, and racial segregation with gestational age at birth by maternal race/ethnicity and United States Census region in the ECHO cohorts

Author

Dunlop, Anne L, Burjak, Mohamad, Dean, Lorraine T, Alshawabkeh, Akram N, Avalos, Lyndsay A, Aschner, Judy L, Breton, Carrie V, Charifson, Mia A, Cordero, Jose, Dabelea, Dana, D’Sa, Viren, Duarte, Cristiane S, Elliott, Amy J, Eick, Stephanie M, Ferrara, Assiamira, Fichorova, Raina N, Ganiban, Jody M, Gern, James E, Hedderson, Monique M, Herbstman, Julie B, Hipwell, Alison E, Huddleston, Kathi C, Karagas, Margaret, Karr, Catherine, Kerver, Jean M, Koinis-Mitchell, Daphne, Lyall, Kristen, Madan, Juliette, Marsit, Carmen, McEvoy, Cindy T, Meeker, John D, Oken, Emily, O’Shea, T Michael, Padula, Amy M, Sathyanarayana, Sheela, Schantz, Susan, Schmidt, Rebecca J, Snowden, Jessica, Stanford, Joseph B, Weiss, Scott, Wright, Robert O, Wright, Rosalind J, Zhang, Xueying, and McGrath, Monica

Subjects
Epidemiology, Public Health, Health Sciences, Basic Behavioral and Social Science, Prevention, Perinatal Period - Conditions Originating in Perinatal Period, Preterm, Low Birth Weight and Health of the Newborn, Behavioral and Social Science, Clinical Research, Minority Health, Maternal Health, Health Disparities, Pediatric, Women's Health, Reproductive health and childbirth, Pregnancy, Female, Child, Humans, Infant, Newborn, United States, Ethnicity, Gestational Age, Premature Birth, Censuses, Educational Status, Social Segregation, gestational age, premature birth, residential segregation, socioeconomic status, racial and ethnic health disparities, ECHO program, Public Health and Health Services, Health services and systems, Public health
Abstract

BackgroundIn the United States, disparities in gestational age at birth by maternal race, ethnicity, and geography are theorized to be related, in part, to differences in individual- and neighborhood-level socioeconomic status (SES). Yet, few studies have examined their combined effects or whether associations vary by maternal race and ethnicity and United States Census region.MethodsWe assembled data from 34 cohorts in the Environmental influences on Child Health Outcomes (ECHO) program representing 10,304 participants who delivered a liveborn, singleton infant from 2000 through 2019. We investigated the combined associations of maternal education level, neighborhood deprivation index (NDI), and Index of Concentration at the Extremes for racial residential segregation (ICERace) on gestational weeks at birth using linear regression and on gestational age at birth categories (preterm, early term, post-late term relative to full term) using multinomial logistic regression.ResultsAfter adjustment for NDI and ICERace, gestational weeks at birth was significantly lower among those with a high school diploma or less (-0.31 weeks, 95% CI: -0.44, -0.18), and some college (-0.30 weeks, 95% CI: -0.42, -0.18) relative to a master's degree or higher. Those with a high school diploma or less also had an increased odds of preterm (aOR 1.59, 95% CI: 1.20, 2.10) and early term birth (aOR 1.26, 95% CI: 1.05, 1.51). In adjusted models, NDI quartile and ICERace quartile were not associated with gestational weeks at birth. However, higher NDI quartile (most deprived) associated with an increased odds of early term and late term birth, and lower ICERace quartile (least racially privileged) associated with a decreased odds of late or post-term birth. When stratifying by region, gestational weeks at birth was lower among those with a high school education or less and some college only among those living in the Northeast or Midwest. When stratifying by race and ethnicity, gestational weeks at birth was lower among those with a high school education or less only for the non-Hispanic White category.ConclusionIn this study, maternal education was consistently associated with shorter duration of pregnancy and increased odds of preterm birth, including in models adjusted for NDI and ICERace.

Published
2023

7. Association of maternal fish consumption and ω-3 supplement use during pregnancy with child autism-related outcomes: results from a cohort consortium analysis

Author

Smith, PB, Newby, KL, Jacobson, LP, Catellier, DJ, Gershon, R, Cella, D, Alshawabkeh, AN, Cordero, J, Meeker, J, Aschner, J, Teitelbaum, SL, Stroustrup, A, Mansbach, JM, Spergel, JM, Samuels-Kalow, ME, Stevenson, MD, Bauer, CS, Koinis Mitchell, D, Deoni, S, D’Sa, V, Duarte, CS, Monk, C, Posner, J, Canino, G, Seroogy, C, Bendixsen, C, Hertz-Picciotto, I, Keenan, K, Karr, C, Tylavsky, F, Mason, A, Zhao, Q, Sathyanarayana, S, LeWinn, KZ, Lester, B, Carter, B, Pastyrnak, S, Neal, C, Smith, L, Helderman, J, Weiss, ST, Litonjua, A, O’Connor, G, Zeiger, R, Bacharier, L, Volk, H, Ozonoff, S, Schmidt, R, Simhan, H, Kerver, JM, Barone, C, Fussman, C, Paneth, N, Elliott, M, Ruden, D, Porucznik, C, Giardino, A, Innocenti, M, Silver, R, Conradt, E, Bosquet-Enlow, M, Huddleston, K, Nguyen, R, Trasande, L, Swan, S, Lyall, Kristen, Westlake, Matt, Musci, Rashelle J, Gachigi, Kennedy, Barrett, Emily S, Bastain, Theresa M, Bush, Nicole R, Buss, Claudia, Camargo, Carlos A, Jr., Croen, Lisa A, Dabelea, Dana, Dunlop, Anne L, Elliott, Amy J, Ferrara, Assiamira, Ghassabian, Akhgar, Gern, James E, Hare, Marion E, Hertz-Picciotto, Irva, Hipwell, Alison E, Hockett, Christine W, Karagas, Margaret R, Lugo-Candelas, Claudia, O’Connor, Thomas G, Schmidt, Rebecca J, Stanford, Joseph B, Straughen, Jennifer K, Shuster, Coral L, Wright, Robert O, Wright, Rosalind J, Zhao, Qi, and Oken, Emily

Published
2024
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11. Associations between neighborhood characteristics and child well-being before and during the COVID-19 pandemic: A repeated cross-sectional study in the Environmental influences on Child Health Outcomes (ECHO) program

Author

Zhang, Xueying, Blackwell, Courtney K., Moore, Janet, Liu, Shelley H., Liu, Chang, Forrest, Christopher B., Ganiban, Jody, Stroustrup, Annemarie, Aschner, Judy L., Trasande, Leonardo, Deoni, Sean C.L., Elliott, Amy J., Angal, Jyoti, Karr, Catherine J., Lester, Barry M., McEvoy, Cindy T., O'Shea, T. Michael, Fry, Rebecca C., Shipp, Gayle M., Gern, James E., Herbstman, Julie, Carroll, Kecia N., Teitelbaum, Susan L., Wright, Robert O., and Wright, Rosalind J.

Published
2024
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17. An Industry-Relevant Metal Mixture, Iron Status, and Reported Attention- Related Behaviors in Italian Adolescents

Author

Schildroth, Samantha, Kordas, Katarzyna, White, Roberta F., Friedman, Alexa, Placidi, Donatella, Smith, Donald, Lucchini, Roberto G., Wright, Robert O., Horton, Megan, and Henn, Birgit Claus

Subjects
Hemoglobin, Teachers, Rating of, Mass spectrometry, Ethylenediaminetetraacetic acid, Teenagers -- Behavior, Youth -- Behavior, Teachers -- Behavior, Metal industry, Ferritin -- Behavior, Environmental issues, Health
Abstract

Background: Exposure to environmental metals has been consistently associated with attention and behavioral deficits in children, and these associations may be modified by coexposure to other metals or iron (Fe) status. However, few studies have investigated Fe status as a modifier of a metal mixture, particularly with respect to attention-related behaviors. Methods: We used cross-sectional data from the Public Health Impact of Metals Exposure study, which included 707 adolescents (10-14 years of age) from Brescia, Italy. Manganese, chromium, and copper were quantified in hair samples, and lead was quantified in whole blood, using inductively coupled plasma mass spectrometry. Concentrations of Fe status markers (ferritin, hemoglobin, transferrin) were measured using immunoassays or luminescence assays. Attention-related behaviors were assessed using the Conners Rating Scales Self-Report Scale- Long Form, Parent Rating Scales Revised-Short Form, and Teacher Rating Scales Revised-Short Form. We employed Bayesian kernel machine regression to examine associations of the metal mixture with these outcomes and evaluate Fe status as a modifier. Results: Higher concentrations of the metals and ferritin were jointly associated with worse self-reported attention-related behaviors: metals and ferritin set to their 90th percentiles were associated with 3.0% [[beta] = 0.03; 95% credible interval (CrI): -0.01, 0.06], 4.1% ([beta] = 0.04; 95% CrI: 0.00, 0.08), and 4.1% ([beta] = 0.04; 95% CrI: 0.00, 0.08) higher T-scores for self-reported attention deficit/hyperactivity disorder (ADHD) index, inattention, and hyperactivity, respectively, compared with when metals and ferritin were set to their 50th percentiles. These associations were driven by hair manganese, which exhibited nonlinear associations with all self-reported scales. There was no evidence that Fe status modified the neurotoxicity of the metal mixture. The metal mixture was not materially associated with any parent- reported or teacher-reported scale. Conclusions: The overall metal mixture, driven by manganese, was adversely associated with self-reported attention-related behavior. These findings suggest that exposure to multiple environmental metals impacts adolescent neurodevelopment, which has significant public health implications. https://doi.org/10.1289/EHP12988, Introduction Children living in proximity to steel-producing ferroalloy industry are commonly exposed to exogenous metals through inhalation or ingestion, including lead (Pb), manganese (Mn), chromium (Cr), and copper (Cu), through [...]

Published
2024
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25. Prenatal metal exposure, cord blood DNA methylation and persistence in childhood: an epigenome-wide association study of 12 metals

Author

Bozack, Anne K, Rifas-Shiman, Sheryl L, Coull, Brent A, Baccarelli, Andrea A, Wright, Robert O, Amarasiriwardena, Chitra, Gold, Diane R, Oken, Emily, Hivert, Marie-France, and Cardenas, Andres

Subjects
Biological Sciences, Genetics, Human Genome, Perinatal Period - Conditions Originating in Perinatal Period, Pediatric, Clinical Research, 2.2 Factors relating to the physical environment, Aetiology, 2.1 Biological and endogenous factors, Reproductive health and childbirth, Adult, DNA Methylation, Epigenome, Female, Fetal Blood, Humans, Infant, Infant, Newborn, Pregnancy, Prenatal Diagnosis, Prenatal Exposure Delayed Effects, DNA methylation, EWAS, Manganese, Metals, Prenatal exposure, Clinical Sciences, Paediatrics and Reproductive Medicine
Abstract

BackgroundPrenatal exposure to essential and non-essential metals impacts birth and child health, including fetal growth and neurodevelopment. DNA methylation (DNAm) may be involved in pathways linking prenatal metal exposure and health. In the Project Viva cohort, we analyzed the extent to which metals (As, Ba, Cd, Cr, Cs, Cu, Hg, Mg, Mn, Pb, Se, and Zn) measured in maternal erythrocytes were associated with differentially methylated positions (DMPs) and regions (DMRs) in cord blood and tested if associations persisted in blood collected in mid-childhood. We measured metal concentrations in first-trimester maternal erythrocytes, and DNAm in cord blood (N = 361) and mid-childhood blood (N = 333, 6-10 years) with the Illumina HumanMethylation450 BeadChip. For each metal individually, we tested for DMPs using linear models (considered significant at FDR

Published
2021

26. Prospective Associations of Early Pregnancy Metal Mixtures with Mitochondria DNA Copy Number and Telomere Length in Maternal and Cord Blood

Author

Smith, Anna R, Lin, Pi-I D, Rifas-Shiman, Sheryl L, Rahman, Mohammad L, Gold, Diane R, Baccarelli, Andrea A, Henn, Birgit Claus, Amarasiriwardena, Chitra, Wright, Robert O, Coull, Brent, Hivert, Marie-France, Oken, Emily, and Cardenas, Andres

Subjects
Prevention, Clinical Research, Reproductive health and childbirth, Bayes Theorem, Child, DNA Copy Number Variations, DNA, Mitochondrial, Female, Fetal Blood, Humans, Metals, Heavy, Mitochondria, Pregnancy, Telomere, Environmental Sciences, Medical and Health Sciences, Toxicology
Abstract

BackgroundMetal exposure during pregnancy influences maternal and child health. Oxidative stress and inflammation may mediate adverse effects of heavy metals, whereas essential metals may act as antioxidants. Mitochondrial DNA is a prime target for metal-induced oxidative damage. Telomere dysfunction is attributed to imbalances between reactive oxidant species and antioxidants.ObjectivesWe evaluated individual and joint associations of prenatal metals with mitochondrial DNA copy number (mtDNAcn) and telomere length (TL) in maternal and cord blood as biomarkers of inflammation and oxidative stress.MethodsWe measured six nonessential metals (arsenic, barium, cadmium, cesium, lead, mercury) and four essential metals (magnesium, manganese, selenium, zinc) in first-trimester maternal red blood cells in Project Viva, a U.S. prebirth cohort. We measured relative mtDNAcn (n=898) and TL (n=893) in second-trimester maternal blood and mtDNAcn (n=419) and TL (n=408) in cord blood. We used multivariable linear regression and quantile g-computation to estimate associations between prenatal metals and the biomarkers. We used generalized additive models and Bayesian kernel machine regression to examine nonlinearity and interactions.ResultsA 2-fold increase in maternal magnesium was associated with lower maternal [β=-0.07, 95% confidence interval (CI): -0.10, -0.01] and cord blood (β=-0.08, 95% CI: -0.20, -0.01) mtDNAcn. Lead was associated with higher maternal mtDNAcn (β=0.04, 95% CI: 0.01, 0.06). Selenium was associated with longer cord blood TL (β=0.30, 95% CI: 0.01 0.50). An association was observed between the nonessential metal mixture and higher maternal mtDNAcn (β=0.04, 95% CI: 0.01, 0.07). There was a nonlinear relationship between cord blood mtDNAcn and magnesium; maternal mtDNAcn and barium, lead, and mercury; and maternal TL and barium.DiscussionMaternal exposure to metals such as lead, magnesium, and selenium was associated with mtDNAcn and TL in maternal second trimester and cord blood. Future work will evaluate whether these biomarkers are associated with child health. https://doi.org/10.1289/EHP9294.

Published
2021

27. Defining the Scope of Exposome Studies and Research Needs from a Multidisciplinary Perspective

Author

Zhang, Pei, Carlsten, Christopher, Chaleckis, Romanas, Hanhineva, Kati, Huang, Mengna, Isobe, Tomohiko, Koistinen, Ville M, Meister, Isabel, Papazian, Stefano, Sdougkou, Kalliroi, Xie, Hongyu, Martin, Jonathan W, Rappaport, Stephen M, Tsugawa, Hiroshi, Walker, Douglas I, Woodruff, Tracey J, Wright, Robert O, and Wheelock, Craig E

Subjects
Chemical Engineering, Engineering, Environmental Sciences, Pollution and Contamination, Generic health relevance, Good Health and Well Being, Environmental Science and Management, Environmental Engineering, Environmental Biotechnology, Chemical engineering, Pollution and contamination
Abstract

The concept of the exposome was introduced over 15 years ago to reflect the important role that the environment exerts on health and disease. While originally viewed as a call-to-arms to develop more comprehensive exposure assessment methods applicable at the individual level and throughout the life course, the scope of the exposome has now expanded to include the associated biological response. In order to explore these concepts, a workshop was hosted by the Gunma University Initiative for Advanced Research (GIAR, Japan) to discuss the scope of exposomics from an international and multidisciplinary perspective. This Global Perspective is a summary of the discussions with emphasis on (1) top-down, bottom-up, and functional approaches to exposomics, (2) the need for integration and standardization of LC- and GC-based high-resolution mass spectrometry methods for untargeted exposome analyses, (3) the design of an exposomics study, (4) the requirement for open science workflows including mass spectral libraries and public databases, (5) the necessity for large investments in mass spectrometry infrastructure in order to sequence the exposome, and (6) the role of the exposome in precision medicine and nutrition to create personalized environmental exposure profiles. Recommendations are made on key issues to encourage continued advancement and cooperation in exposomics.

Published
2021

35. Opportunities for Examining Child Health Impacts of Early-Life Nutrition in the ECHO Program: Maternal and Child Dietary Intake Data from Pregnancy to Adolescence

Author

Bragg, Megan G., Westlake, Matt, Alshawabkeh, Akram N., Bekelman, Traci A., Camargo, Carlos A., Jr., Catellier, Diane J., Comstock, Sarah S., Dabelea, Dana, Dunlop, Anne L., Hedderson, Monique M., Hockett, Christine W., Karagas, Margaret R., Keenan, Kate, Kelly, Nichole R., Kerver, Jean M., MacKenzie, Debra, Mahabir, Somdat, Maldonado, Luis E., McCormack, Lacey A., Melough, Melissa M., Mueller, Noel T., Nelson, Morgan E., O’Connor, Thomas G., Oken, Emily, O’Shea, T Michael, Switkowski, Karen M., Sauder, Katherine A., Wright, Rosalind J., Wright, Robert O., Zhang, Xueying, Zhu, Yeyi, and Lyall, Kristen

Published
2023
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36. Prenatal Trace Elements Mixture Is Associated with Learning Deficits on a Behavioral Acquisition Task among Young Children

Author

Merced-Nieves, Francheska M., Chelonis, John, Pantic, Ivan, Schnass, Lourdes, Téllez-Rojo, Martha M., Braun, Joseph M., Paule, Merle G., Wright, Rosalind J., Wright, Robert O., and Curtin, Paul

Abstract

Children are exposed to many trace elements throughout their development. Given their ubiquity and potential to have effects on children's neurodevelopment, these exposures are a public health concern. This study sought to identify trace element mixture-associated deficits in learning behavior using operant testing in a prospective cohort. We included 322 participants aged 6-7 years recruited in Mexico City with complete data on prenatal trace elements measurements (third trimester blood lead and manganese levels, and & urine cadmium and arsenic levels), demographic covariates, and the Incremental Repeated Acquisition (IRA), an associative learning task. Weighted quantile sum (WQS) regression models were used to estimate the joint association of the mixture of all four trace elements and IRA performance. Performance was adversely impacted by the mixture, with different elements relating to different aspects of task performance suggesting that prenatal exposure to trace element mixtures yields a broad dysregulation of learning behavior.

Published
2022
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37. Blood DNA methylation biomarkers of cumulative lead exposure in adults.

Author

Colicino, Elena, Just, Allan, Kioumourtzoglou, Marianthi-Anna, Vokonas, Pantel, Cardenas, Andres, Sparrow, David, Weisskopf, Marc, Nie, Linda H, Hu, Howard, Schwartz, Joel D, Wright, Robert O, and Baccarelli, Andrea A

Subjects
DNA methylation, Epidemiology, Exposure Modeling, Metals, Methods, Personal exposure, Chemical Sciences, Environmental Sciences, Medical and Health Sciences
Abstract

BackgroundLead is a ubiquitous toxicant following three compartment kinetics with the longest half-life found in bones. Patella and tibia lead levels-validated measures of cumulative exposure-require specialized X-ray-fluorescence-spectroscopy available only in a few centers worldwide. We developed minimally invasive biomarkers reflecting individual cumulative lead exposure using blood DNA methylation profiles-obtainable via Illumina 450K or IlluminaEPIC bead-chip assays.MethodsWe developed and tested two methylation-based biomarkers from 348 Normative Aging Study (NAS) elderly men. We selected methylation sites with strong associations with bone lead levels via robust regressions analysis and constructed the biomarkers using elastic nets. Results were validated in a NAS subset, reporting specificity, and sensitivity.FindingsParticipants were 73 years old on average (standard deviation, SD = 6), with moderate lead levels of (mean ± SD patella: 27 ± 18 µg/g; tibia:21 ± 13 µg/g). Methylation-based biomarkers for lead in patella and tibia included 59 and 138 DNA methylation sites, respectively. Estimated lead levels were significantly correlated with actual measured values, (r = 0.62 patella, r = 0.59 tibia) and had low mean square error (MSE) (MSE = 0.68 patella, MSE = 0.53 tibia). Means and distributions of the estimated and actual lead levels were not significantly different across patella and tibia bones (p > 0.05). Methylation-based biomarkers discriminated participants highly exposed (>median) to lead with a specificity of 74 and 73% for patella and tibia lead levels, respectively, with 70% sensitivity.InterpretationDNA methylation-based lead biomarkers are novel tools that can be used to reconstruct decades' worth of individual cumulative lead exposure using only blood DNA methylation profiles and may help identify the consequences of cumulative exposure.

Published
2021

42. Incidence rates of childhood asthma with recurrent exacerbations in the US Environmental influences on Child Health Outcomes (ECHO) program

Author

Smith, P.B., Newby, K.L., Jacobson, L.P., Catellier, D.J., Gershon, R., Cella, D., Alshawabkeh, A., Aschner, J., Merhar, S., Ren, C., Reynolds, A., Keller, R., Pryhuber, G., Duncan, A., Lampland, A., Wadhawan, R., Wagner, C., Hudak, M., Mayock, D., Walshburn, L., Teitelbaum, S.L., Stroustrup, A., Trasande, L., Blair, C., Gatzke-Kopp, L., Swingler, M., Mansbach, J., Spergel, J., Puls, H., Stevenson, M., Bauer, C., Deoni, S., Duarte, C., Dunlop, A., Elliott, A., Croen, L., Bacharier, L., O’Connor, G., Kattan, M., Wood, R., Hershey, G., Ownby, D., Hertz-Picciotto, I., Hipwell, A., Karagas, M., Karr, C., Mason, A., Sathyanarayana, S., Lester, B., Carter, B., Neal, C., Smith, L., Helderman, J., Leve, L., Ganiban, J., Neiderhiser, J., Weiss, S., Zeiger, R., Tepper, R., Lyall, K., Landa, R., Ozonoff, S., Schmidt, R., Dager, S., Schultz, R., Piven, J., Volk, H., Vaidya, R., Obeid, R., Rollins, C., Bear, K., Pastyrnak, S., Lenski, M., Msall, M., Frazier, J., Washburn, L., Montgomery, A., Barone, C., McKane, P., Paneth, N., Elliott, M., Herbstman, J., Schantz, S., Porucznik, C., Silver, R., Conradt, E., Bosquet-Enlow, M., Huddleston, K., Bush, N., Nguyen, R., O'Connor, T., Samuels-Kalow, M., Miller, Rachel L., Schuh, Holly, Chandran, Aruna, Aris, Izzuddin M., Bendixsen, Casper, Blossom, Jeffrey, Breton, Carrie, Camargo, Carlos A., Jr., Canino, Glorisa, Carroll, Kecia N., Commodore, Sarah, Cordero, José F., Dabelea, Dana M., Ferrara, Assiamira, Fry, Rebecca C., Ganiban, Jody M., Gern, James E., Gilliland, Frank D., Gold, Diane R., Habre, Rima, Hare, Marion E., Harte, Robyn N., Hartert, Tina, Hasegawa, Kohei, Khurana Hershey, Gurjit K., Jackson, Daniel J., Joseph, Christine, Kerver, Jean M., Kim, Haejin, Litonjua, Augusto A., Marsit, Carmen J., McEvoy, Cindy, Mendonça, Eneida A., Moore, Paul E., Nkoy, Flory L., O’Connor, Thomas G., Oken, Emily, Ownby, Dennis, Perzanowski, Matthew, Rivera-Spoljaric, Katherine, Ryan, Patrick H., Singh, Anne Marie, Stanford, Joseph B., Wright, Rosalind J., Wright, Robert O., Zanobetti, Antonella, Zoratti, Edward, and Johnson, Christine C.

Published
2023
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43. Early-Life Critical Windows of Susceptibility to Manganese Exposure and Sex-Specific Changes in Brain Connectivity in Late Adolescence

Author

Rechtman, Elza, Navarro, Esmeralda, de Water, Erik, Tang, Cheuk Y., Curtin, Paul, Papazaharias, Demetrios M., Ambrosi, Claudia, Mascaro, Lorella, Cagna, Giuseppa, Gasparotti, Roberto, Invernizzi, Azzurra, Reichenberg, Abraham, Austin, Christine, Arora, Manish, Smith, Donald R., Lucchini, Roberto G., Wright, Robert O., Placidi, Donatella, and Horton, Megan K.

Published
2023
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44. Kernel Machine and Distributed Lag Models for Assessing Windows of Susceptibility to Environmental Mixtures in Children's Health Studies

Author

Wilson, Ander, Hsu, Hsiao-Hsien Leon, Chiu, Yueh-Hsiu Mathilda, Wright, Robert O., Wright, Rosalind J., and Coull, Brent A.

Subjects
Statistics - Applications, Statistics - Methodology
Abstract

Exposures to environmental chemicals during gestation can alter health status later in life. Most studies of maternal exposure to chemicals during pregnancy have focused on a single chemical exposure observed at high temporal resolution. Recent research has turned to focus on exposure to mixtures of multiple chemicals, generally observed at a single time point. We consider statistical methods for analyzing data on chemical mixtures that are observed at a high temporal resolution. As motivation, we analyze the association between exposure to four ambient air pollutants observed weekly throughout gestation and birth weight in a Boston-area prospective birth cohort. To explore patterns in the data, we first apply methods for analyzing data on (1) a single chemical observed at high temporal resolution, and (2) a mixture measured at a single point in time. We highlight the shortcomings of these approaches for temporally-resolved data on exposure to chemical mixtures. Second, we propose a novel method, a Bayesian kernel machine regression distributed lag model (BKMR-DLM), that simultaneously accounts for nonlinear associations and interactions among time-varying measures of exposure to mixtures. BKMR-DLM uses a functional weight for each exposure that parameterizes the window of susceptibility corresponding to that exposure within a kernel machine framework that captures non-linear and interaction effects of the multivariate exposure on the outcome. In a simulation study, we show that the proposed method can better estimate the exposure-response function and, in high signal settings, can identify critical windows in time during which exposure has an increased association with the outcome. Applying the proposed method to the Boston birth cohort data, we find evidence of a negative association between organic carbon and birth weight and that nitrate modifies the organic carbon, ...

Published
2019
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45. A Cross-validated Ensemble Approach to Robust Hypothesis Testing of Continuous Nonlinear Interactions: Application to Nutrition-Environment Studies

Author

Liu, Jeremiah Zhe, Lee, Jane, Lin, Pi-i Debby, Valeri, Linda, Christiani, David C., Bellinger, David C., Wright, Robert O., Mazumdar, Maitreyi M., and Coull, Brent A.

Subjects
Statistics - Applications
Abstract

Gene-environment and nutrition-environment studies often involve testing of high-dimensional interactions between two sets of variables, each having potentially complex nonlinear main effects on an outcome. Construction of a valid and powerful hypothesis test for such an interaction is challenging, due to the difficulty in constructing an efficient and unbiased estimator for the complex, nonlinear main effects. In this work we address this problem by proposing a Cross-validated Ensemble of Kernels (CVEK) that learns the space of appropriate functions for the main effects using a cross-validated ensemble approach. With a carefully chosen library of base kernels, CVEK flexibly estimates the form of the main-effect functions from the data, and encourages test power by guarding against over-fitting under the alternative. The method is motivated by a study on the interaction between metal exposures in utero and maternal nutrition on children's neurodevelopment in rural Bangladesh. The proposed tests identified evidence of an interaction between minerals and vitamins intake and arsenic and manganese exposures. Results suggest that the detrimental effects of these metals are most pronounced at low intake levels of the nutrients, suggesting nutritional interventions in pregnant women could mitigate the adverse impacts of in utero metal exposures on children's neurodevelopment.

Published
2019

47. Bayesian kernel machine regression-causal mediation analysis

Author

Devick, Katrina L., Bobb, Jennifer F., Mazumdar, Maitreyi, Henn, Birgit Claus, Bellinger, David C., Christiani, David C., Wright, Robert O., Williams, Paige L., Coull, Brent A., and Valeri, Linda

Subjects
Statistics - Methodology
Abstract

Greater understanding of the pathways through which an environmental mixture operates is important to design effective interventions. We present new methodology to estimate natural direct and indirect effects and controlled direct effects of a complex mixture exposure on an outcome through a mediator variable. We implement Bayesian Kernel Machine Regression (BKMR) to allow for all possible interactions and nonlinear effects of (1) the co-exposures on the mediator, (2) the co-exposures and mediator on the outcome, and (3) selected covariates on the mediator and/or outcome. From the posterior predictive distributions of the mediator and outcome, we simulate counterfactuals to obtain posterior samples, estimates, and credible intervals of the mediation effects. Our simulation study demonstrates that when the exposure-mediator and exposure-mediator-outcome relationships are complex, BKMR--Causal Mediation Analysis performs better than current mediation methods. We applied our methodology to quantify the contribution of birth length as a mediator between in utero co-exposure to arsenic, manganese and lead, and children's neurodevelopmental scores, in a prospective birth cohort in Bangladesh. Among younger children, we found a negative (adverse) association between the metal mixture and neurodevelopment. We also found evidence that birth length mediates the effect of exposure to the metal mixture on neurodevelopment for younger children. If birth length were fixed to its $75^{th}$ percentile value, the harmful effect of the metal mixture on neurodevelopment is attenuated, suggesting nutritional interventions to help increase fetal growth, and thus birth length, could potentially block the harmful effect of the metal mixture on neurodevelopment., Comment: 22 pages, 12 figures, and 1 tables

Published
2018

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