Pam Factor-Litvak - US grants

DESCRIPTION: There is considerable evidence that some mercury from "silver fillings" distributes to body tissues, particularly the brain. Occupational exposure to mercury vapor is associated with increases in the prevalence of tremor, peripheral neuropathy, cerebellar dysfunction, and abnormal measures of balance. Occupational exposure also is associated with deficits in neuropsychological tests of memory and visuospatial ability and increased reports of subjective symptoms and disturbed mood. The investigators propose to address the hypothesis that low dose mercury exposure, derived from amalgams in the mouth, may be associated with evidence of neurological dysfunction and neuropsychological deficits. By conducting a cross-sectional study, the investigators will test whether amalgam-derived mercury is adversely associated with tests of neurological function, visuospatial ability, memory and attention/executive function. The study sample will comprise approximately 750-840 Columbia University personnel, ages 30-49 years. Based on preliminary work, it is known that the cohort will have a wide range of visible amalgam surfaces. Measures of exposure will be urinary mercury concentration and the numbers of amalgam surfaces, total and occlusal. The proposed outcome measures tap a wide range of neurological and neuropsychological functions. A variety of tests will assess four domains of neuropsychological function: visuomotor/visuospatial function, memory, attention and executive function, and vocabulary. A self-reported questionnaire of mood and a symptom checklist will also be administered. In addition, the investigators will collect quantitative measures of postural sway. After control for confounding variables, including measures of social desirability and hypochondriasis, the dose-response relationships between exposure and each functional domain will be described. Results from this study will have potential public health applications. Adverse associations, if found, might lead to less use of mercury amalgams. Alternatively, evidence favoring the null hypothesis would allay widespread fears that a variety of health problems may be associated with amalgam exposure.

There is considerable evidence that some mercury from "silver" fillings distributes to body tissues, particularly the brain. By conducting a cross-sectional study of approximately 800 adults, aged 30-49, we will test whether amalgam-derived mercury is associated with decreased performance on tests of neurological function, balance, visuospatial ability, memory, attention/executive function, and renal function.

Severe deficiency of thyroid hormone during the prenatal and neonatal periods is associated with adverse neurodevelopmental outcomes in infancy and childhood. Maternal iodine deficiency during pregnancy leads to a lowered production of activated (i.e., iodinated) thyroid hormone (T3) and an increased risk of cretinism (with associated severe mental retardation) in the child. Congenital hypothyroidism and transient hypothyroidism of prematurity are associated with deficits in cognition during early life. In light of these observations, it is appropriate to ask whether sub-optimal maternal thyroid function, particularly during the first half of pregnancy when maternal contribution to fetal thyroid hormone is maximal, is associated with neurodevelopment of the child. Recent data suggest that children of mothers with 'low-normal' thyroid function are at risk for small deficits in cognition and increased reports of behavior problems. The overall goal of this project is to assess whether mild deficiencies in maternal thyroid function are associated with adverse neurodevelopment in the child, and, if so, to elucidate possible biologic mechanism. One possible mechanism is through damage to the choroid plexus, the site of production of the brain-specific transport protein for thyroid hormone. Animal studies suggest that the choroid plexus is damaged by exposure to environmental lead, raising the possibility that associations between lead exposure and cognition in the child arise through an effect of lead on transport of thyroid hormone to the brain. The proposed study draws on data from a prospective study designed to examine the associations between pre- and post-natal lead exposure and childhood development. The cohort comprises approximately 300 children, born in 1984-1985 in two towns in Kosovo, Yugoslavia who were followed through age 12. Sera are available to measure thyroid function in the mothers at mid-pregnancy and in the children at ages 4, 7 and 12. Outcomes, including cognition, motor function, behavior problems and anthropometric measurements, were measured repeatedly during infancy and childhood. This project will expand the findings of the Yugoslavia study to examine first, whether maternal thyroid function in the first half of pregnancy is associated with cognitive, behavioral and growth outcomes and second, whether the associations between Pb and these outcomes are mediated by exposure to thyroid hormone.

[unreadable] DESCRIPTION (provided by applicant): Despite recent concern over the purported decline in sperm counts, there is little, if any, epidemiologic evidence regarding associations with environmental exposures or the timing of such exposures. Disruption of male reproductive function, and in particular decreased semen quality, is thought to be associated with exposure to endocrine active chemicals. To date, no direct evidence in humans either supports or refutes this conjecture. It is possible that exposure to such chemicals in utero and/or during early childhood may disrupt testicular development or development of related endocrine pathways, resulting in subtle disruption of male reproductive function. We propose to examine associations between prenatal exposures to one class of endocrine disruptors, the organochlorine compounds, and testicular and endocrine function in adult men including semen quality, fertility potential, current hormone concentrations and time to pregnancy. We also propose to examine whether such associations, if any, are mediated by disruptions of maternal thyroid function. From a follow up of the now adult members of the Columbia-Presbyterian cohort of the National Collaborative Perinatal Project and the Child Health and Development Study, we will obtain questionnaire data on fertility history, current lifestyle, socioeconomic status, and medical history, request a blood sample and request that the subject come to the clinic for two semen samples, approximately 3 weeks apart. Semen samples will be analyzed using a standard protocol at the University of California, Davis. Serum will be assayed for testosterone, estradiol, follicle stimulating hormone, luteinizing hormone and inhibin B. Stored, frozen prenatal sera will be assayed for organochlorine compounds, and for free thyroxine, thyroid stimulating hormone, and thyroid peroxidase antibodies. Statistical analysis will assess the associations between organochlorine compounds (total and in secondary analyses as specific congeners or groups of congeners) and each outcome variable. Other analyses will assess whether maternal thyroid function during pregnancy mitigates these associations. This study represents the first large systematic evaluation of prenatal exposures to organochlorine compounds and male reproduction and has important implications for basic science, public health and public policy. [unreadable] [unreadable]

DESCRIPTION (provided by applicant): The overall goal of this project is to assess whether exposure to endocrine disrupting compounds during pregnancy is associated with a) adverse development (cognitive function, height, weight, weight for height, and for females, age at menarche) in the offspring at birth, early childhood, middle childhood, and adolescence, b) mild deficiencies in maternal thyroid function, and c) whether adverse developmental findings, if any, are attributed in part to deficiencies in exposure to maternal thyroid hormone in utero. The proposed study draws on data from the Child Health and Development Study, a longitudinal follow up of children born between 1959 and 1966 to mothers enrolled in the Oakland, California membership of the Kaiser Foundation Health Plan. Prenatal sera has been appropriately frozen and stored, and are available to assess both exposure to organochlorine compounds and maternal thyroid function during pregnancy. Serial measures of growth are available in the same children from birth to age 17 years, as are standardized developmental examinations at ages 5, 9-11, and 15-17. The proposed measures of organochlorine exposure and exposure to measures of maternal thyroid function (thyroid stimulating hormone, free thyroxine, thyroid peroxidase antibodies and transthyretin - a protein responsible for the transport of thyroid hormone). Statistical analyses will estimate associations taking advantage of the repeated measures structure of the data. The analyses will employ generalized estimating equations (GEE) methods for repeated measures, taking account of potentially confounding variables. We will distinguish effects of prenatal organochlorine exposures from infancy through adolescence. We will also investigate a specific mechanism: via maternal thyroid function. Results will fully describe the effects of prenatal exposure and will also further knowledge about the relation between subclinical maternal thyroid hormone deficiency and childhood development. This line of research could lead to prenatal interventions.

DESCRIPTION (provided by applicant): The overall goal of this project is to assess whether exposure to metabolites of endocrine disrupting compounds during pregnancy is associated with a) adverse development (cognitive function, height, weight, weight for height, and for females, age at menarche) in the offspring at birth, early childhood, middle childhood, and adolescence, b) mild deficiencies in maternal thyroid function, and c) whether adverse developmental findings, if any, are attributed in part to deficiencies in exposure to maternal thyroid hormone in utero. We also aim to describe the relationships between the metabolites and parent compounds and to examine the associations between the metabolites and thyroid function in the pregnant women. The proposed study draws on data from the Child Health and Development Study, a longitudinal follow up of children born between 1959 and 1966 to mothers enrolled in the Oakland, California membership of the Kaiser Foundation Health Plan and expands upon previous NIH funded research. Prenatal sera has been appropriately frozen and stored, and are available to assess exposure to the metabolites of organochlorine compounds;exposure to organochlorine compounds and maternal thyroid function during pregnancy has already been measured. Serial measures of growth are available in the same children from birth to age 17 years, as are standardized developmental examinations at ages 5, 9-11, and 15-17. The proposed measures of organochlorine exposure and exposure to measures of maternal thyroid function (thyroid stimulating hormone, free thyroxine, and thyroid peroxidase antibodies). Statistical analyses will estimate associations taking advantage of the repeated measures structure of the data. The analyses will employ generalized estimating equations (GEE) methods for repeated measures, taking account of potentially confounding variables. We will distinguish effects of prenatal organochlorine metabolite exposures from infancy through adolescence. We will also investigate a specific mechanism: via maternal thyroid function. Results will fully describe the effects of prenatal exposure and will also further knowledge about the relation between subclinical maternal thyroid hormone deficiency and childhood development. This line of research could lead to prenatal interventions. PUBLIC HEALTH RELEVANCE: We will distinguish effects of prenatal organochlorine metabolite exposures from infancy through adolescence. We will also investigate a specific mechanism: via maternal thyroid function. Results will fully describe the effects of prenatal exposure and will also further knowledge about the relation between subclinical maternal thyroid hormone deficiency and childhood development. This line of research could lead to prenatal interventions.

DESCRIPTION (provided by applicant): Depletion of hematopoietic stem cell reserves, expressed as the shortening of leukocyte telomere length (LTL), sets a limit on longevity and increases the risk of cardiovascular disease. Until now, almost all research on LTL has focused on adults. Recent evidence suggests, however, that the factors which influence LTL from conception to birth could be as important as those which influence LTL over the remainder of the life course. The inter-individual variation in LTL at birth is so large that it rivals the averge shortening of LTL over the entire adult life course. In addition, higher paternal age at conception is associated with longer LTL in adult offspring, and since this effect must derive from the paternal germ line, it may be evident by the time of birth. However, no rigorous study has been done of the determinants of LTL at birth. This prospective investigation of the determinants of LTL at birth is an ancillary study which builds on a multisite NICHD-funded parent study of nulliparous women. The ancillary study will be done in 1,000 trios of mother, father, and baby. It will add to the rich array of data in the parent study in several ways, including the collection of paternal blood samples and the measurement of LTL in mothers, fathers, and babies for the 1,000 trios. The Aims of the study are to: 1) examine the relation of paternal age at conception (PAC) to LTL at birth, 2) examine whether maternal exposures and conditions are determinants of LTL at birth, 3) compare LTL at birth across sex, race/ethnicity and socioeconomic status, and 4) explore the relation of fetal growth rate to LTL at birth. This study will build a platform or further investigations including genetic and epigenetic influences on LTL at birth and changes in LTL during early childhood years. By identifying the determinants of LTL at birth, this research will provide a foundation for linking experience from conception to birth with health and longevity in later life. Moreover, this research has the potential to transform understanding of population health by opening novel investigations of the pathways through which intra-uterine experiences are biologically embedded in the individual's constitution, and might be reflected in risk factors for disease which emerge in childhood and evolve thereafter. PUBLIC HEALTH RELEVANCE: Much is known about telomere length (measured by leukocyte telomere length or LTL) in adults, and its important role in cardiovascular disease and longevity, but very little is known about LTL at birth. We do know, however, that individuals vary widely in LTL at birth, and this study examines whether exposures before birth (such as maternal exposures and paternal age at conception) explain the variation in LTL at birth. The results will help us understand whether interventions early in life (even as early as prenatal care) could improve the health of the population in later life.

DESCRIPTION (provided by applicant): Major climatic events, such as hurricanes, appear to be increasing due to the consequences of global warming. Such events are likely associated with increased psychological stress. On October 29, 2012 Superstorm Sandy, a major hurricane, devastated the mid-Atlantic region of the United States, particularly the New York City/New Jersey area. Pregnant women are considered a vulnerable population and there is increasing evidence that acute psychosocial stressors may be associated with adverse pregnancy outcomes, such as decreases in birth weight and decreases in gestational length. Further, maternal exposure to stressful events may be associated with decreases in leukocyte telomere length (LTL) in the newborn. Capitalizing on a birth cohort currently being recruited, we propose a study to examine associations between exposure to Superstorm Sandy and pregnancy outcomes and newborn LTL. This study improves on previous studies of natural and manmade disasters because we will be able to parse exposure to specific trimesters and to the three months prior to conception; we have place controls, i.e. a cohort being recruited in an unaffected area using exactly the same measures; we have baseline information on maternal perceived stress, depression, anxiety, social support and resilience, and we have an adequate sample size to address the aims. Results from this study have the potential to inform emergency responders and clinicians how best to support and potentially mitigate the effects of psychological stress among pregnant women after a major natural disaster. Results will also set the stage for studies to inquire whether prenatal exposure to stressful events is associated with cognitive and behavioral problems in children.

DESCRIPTION (provided by applicant): Exposure to pyrethroid insecticides is a growing health concern due to the ban on residential use of organophosphate (OP) insecticides. Pyrethroids have replaced OP for residential pest control. Use is increasing across the U.S. and is particularly high in New York City (NYC). Experimental and preliminary epidemiologic data suggest that prenatal exposure may adversely affect child mental, motor and behavioral development. However, additionally research is urgently needed. The goals of this study are to examine whether biomarkers of prenatal exposure to pyrethroid insecticides are associated with adverse children's cognitive, motor and behavioral development. In doing so, we will also validate a urinary biomarker of prenatal exposure to these compounds for use in epidemiologic research. To accomplish this, we use data from two ongoing longitudinal birth cohorts which together comprise n=325 NYC mothers and children. Pyrethroid metabolites will be measured in urine samples collected and stored from all women during pregnancy. Between child ages 48-58 months, families will be invited to our clinic for development assessments. Cognitive development will be assessed using the Wechsler Preschool and Primary Scale of Intelligence-3rd edition; motor development using the Bruininks-OseretskyTest of Motor Proficiency, 2nd edition; and executive function using the Behavior Rating Inventory of Executive Function-Preschool Version. A home visit will be made to obtain data on the childrearing environment. Child blood samples will be collected to measure lead in whole blood. Questionnaires will be administered to the mother updating social and demographic information, smoking history, and maternal satisfaction and demoralization (the Psychiatric Epidemiology Research Instrument Demoralization Scale) and to gather data on pesticide use. Maternal intelligence will also be assessed (the Test of Non-Verbal Intelligence, 3rd edition). GIS mapping will be used to model neighborhood level SES and other characteristics which may act as a confounder in the current study. Multiple linear regression analysis will be used to examine associations between the pyrethroid metabolites and outcomes, adjusting for potential confounders and multiple comparisons. Results from this study will have immediate public health importance and will inform future studies examining pyrethroid toxicities. Indoor uses of pyrethroid insecticides have been increasing dramatically. Preliminary data suggest that prenatal pyrethroids exposure can adversely affects child learning and behavior. However, no prior study has evaluated associations between pyrethroid metabolites in maternal prenatal urine and cognitive, motor or behavioral outcomes in children.

? DESCRIPTION (provided by applicant): This grant application requests support for a new training program in Environmental Life Course Epidemiology. The training program will be directed by Drs. Pam Factor-Litvak and Robin Whyatt. It requests funds for two pre-doctoral trainees and one post-doctoral trainee in year 1, and gradually increases to a total of four pre doctoral and two post-doctoral trainees by year 5. The proposed mentors are well funded and well published investigators with considerable experience in training Master's, pre-doctoral and post-doctoral students. The theme of the program is to train a new generation of scientists in the life course approach to environmental epidemiology and population health that is to investigate early environmental exposures and outcomes which may not manifest themselves until later in the life course and to study the possible biologic, social, behavioral and psychological mechanisms behind such exposure - outcome relationships. The proposed program builds upon the long, distinguished and ongoing history of life course and molecular epidemiology approaches at Columbia. Pre doctoral trainees will complete the requirements for a PhD in epidemiology or environmental health sciences, including specific course requirements in the life course track and dissertation research related to the life course, and will be offered funding for a period of 5 years. Post-doctoral trainees will pursue research in environmental life course epidemiology under the guidance of experienced mentors. Thus, trainees will be uniquely prepared to perform environmental life course research in a variety of academic and public health settings.

Project Summary of the Study Design and Data Analytics Facility Core (Data FC) In the present application, the Center for Environmental Health in Northern Manhattan (CEHNM) will support three facility cores (FCs)?the Integrative Health Sciences Facility Core (IHSFC), the Exposure Assessment FC (Exposure FC), and the new Study Design and Data Analytics Facility Core (Data FC). The FCs will facilitate different aspects of the members? basic, patient-oriented, population-based, and translational research. Under IHSFC?s central coordination, the three FCs will form a highly effective pipeline of science to support members with a wide array of study design, exposure assessment, wet-lab, and data services throughout all the stages of their investigations. To empower this structure, we propose the new Data FC, which addresses the growing need for using complex design and advanced computational methods and tools in environmental health sciences. CEHNM has a long, highly successful record of study design, data management, and biostatistical support, which are currently offered by the IHSFC. We will transfer these services in the new and augmented Data FC. The Data FC will offer unique expertise, services, and resources to assist investigators from study conception through results dissemination. The Data FC will provide intellectual and computational infrastructure to plan, conduct and analyze studies by continuing to support existing services, which have a long-standing record of success within the CEHNM, including: (i) design of observational, clinical and experimental studies; (ii) biostatistical consultations; and (iii) data management. In this Center renewal, members will find in the Data FC highly expanded capacity, including: (iv) processing and analysis of a variety of ?omics data; (v) training and guidance on handling and analyzing Geographical Information Systems (GIS) data; and (vi) identifying, accessing, and analyzing the growing number of large data repositories in the public domain. Throughout these activities, the Data FC will (vii) offer educational programs on the use of these methods, while (viii) fostering attention to the development of new methods and tools. The unique combination of new and existing services in the new Data FC will multiply opportunities and effectiveness in using the rich data that CEHNM members generate?as well as those already available in-house or in the public domain?to answer groundbreaking questions in environmental health research. We have a unique opportunity to create this Data FC, because we can build on our extremely successful record of study design and data support, currently provided by the IHSFC. Over the first 4 years of the current grant cycle (2013-2016), CEHNM provided study design, data management, and biostatistical support to 45 pilot grant submissions/projects, 50 grant submissions (12 funded), and 16 pre- and 6 post-doctoral projects. These services directly supported 118 publications.

Project Summary Advanced training in environmental health and data science: molecules to populations. This application represents the consolidation of three NIEHS T32 training grants at Columbia University into a unified training program designed to address critical needs in the field of environmental health sciences. We propose a program with 18 predoctoral students and 8 postdoctoral scholars. Our mentoring team has substantial funding from NIEHS (>$13,000,000 per year) and other agencies (>$40,000,0000 per year) that provides a wealth of opportunities for original research by both pre- and postdoctoral trainees. Our predoctoral trainees will participate in: 1) a core curriculum in environmental health sciences (using a life course approach to study molecular mechanisms of disease, epidemiologic methods, health effects of climate change, and the exposome) 2) a core curriculum in data sciences, 3) specialized coursework to support dissertation research, 4) research rotations, 5) small interdisciplinary training groups, and 6) dissertation research. Although our trainees will continue to take traditional didactic coursework, the addition of small interdisciplinary training groups, workshops, and boot camps creates a facile platform that can rapidly evolve to enable student exposure to cutting-edge methods that address future needs in the field. Through a collaboration with the Columbia University Data Science Institute (DSI) we propose a highly innovative training program for our postdoctoral trainees. One of the leading data science programs in the world, the Columbia DSI will provide complementary training and support for our fellows, including participation in their existing data science postdoctoral fellows program based in computer science and engineering. Fellows will acquire advanced data science skills to complement their environmental health science research (the primary focus on their training). In their second year, these fellows will enhance their leadership skills by facilitating our workshops, bootcamps, and mini-courses (machine learning, data visualization, network science) for the predoctoral trainees. Thus, the postdoctoral trainees will acquire a skillset that prepares them to apply advanced data science approaches to environmental health in the laboratory and in the classroom. Moreover, each postdoctoral fellow will lead (with an assigned faculty mentor) a small interdisciplinary training group of predoctoral trainees, providing an ongoing forum for interaction and collaboration between the pre- and postdoctoral trainees and enhancing their skills in guiding team science.

PROJECT SUMMARY In 2018, the NIH Strategic Plan for Data Science identified a number of goals and cross-cutting themes to address in order to maximize the value of data generated through NIH-funded efforts. This included the enhancement of data sharing, access, and interoperability of NIH-supported data resources. One key barrier to achieving this goal is the lack of biomedical scientists with the ability to apply data science techniques to maximize the usability of the data and metadata produced by their research. Our NIEHS-supported training grant (T32 ES007322) provides a single, unified training program for 18 predoctoral students and 8 postdoctoral fellows within the environmental health sciences. Our program is designed to ensure trainees acquire skills in advanced data analytics to complement their primary training in environmental epidemiology, climate science, molecular mechanisms of disease, and the exposome. The integration of additional training in making diverse epidemiologic, toxicological and clinical data findable, accessible, interoperable and reusable (FAIR) and ready for use with artificial intelligence and machine learning (AI/ML) is a natural progression for our multi-disciplinary training program. We also benefit from the co-location of two other NIH-funded training grants, in nursing informatics and neuroscience, with activities training biomedical researchers in data science. We aim to leverage our collective expertise to develop a multidisciplinary curriculum that enables our trainees to develop the competencies and skills needed to make diverse biomedical data FAIR and AI/ML-ready. This curriculum will be designed to be flexible and module-based so it can be implemented in-full, as part of existing training seminars, or as stand-alone bootcamps, depending upon the needs of individual training programs. Our novel curriculum will combine didactic seminars, guided discussions and hands-on training activities to develop competencies and skills in use of data standards, the FAIR principles and AI/ML-readiness. This module-based curriculum will be centered on core foundational concepts, such as ontologies, common data elements and metadata annotation. To construct these modules, we will draw upon expertise from faculty both internal and external to Columbia University from within the fields of semantic science, information science, environmental health data science, and computer science. We will consult with educational professionals who will advise on evidence-based curricular design and provide independent evaluation of our curriculum and training activities using both quantitative and qualitative measures. Following successful evaluation, we propose to incorporate the developed curriculum and training activities into multiple existing training programs. Recorded lectures, discussion guides and training materials will be made available within a shared resource library. Formalizing supplementary training in the FAIR principles and ML/AI-readiness across our multiple training programs will accelerate the achievement of research training aims and develop a cadre of scientists poised to advance biomedical research through the application of data science.