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A multidisciplinary approach to advancing the science of neurodevelopmental testing in cohorts of infants and young children

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A multidisciplinary approach to advancing the science of neurodevelopmental testing in cohorts of infants and young children
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  After birth, dosing continued via gavage at the same doses to pupsthroughPND22,afterwhichdosingcontinuedthroughdrinkingwaterat the same daily target dose as that provided by gavage. During theirfirst year of life, these rats were subjected to certain pre-weaningdevelopmental tests, but were not tested post-weaning. At ∼ 1 year of age, rats were anesthetized and CV was calculated based on actionpotentials recorded from tail muscle through surface ring electrodesinstalled around the distal tail. The mean control CV of 38.4 m/s is inagreementwiththebaselinemeasureof37.4 m/spreviouslyobtained.No main effect of treatment or sex, or interactive effect of treatmentand sex was observed. Supported by FDA/NCTR, NTP 224-93-001, andan ORISE Postdoctoral Fellowship (to JG).doi:10.1016/j.ntt.2010.04.032 NBTS32Binge cocaine during pregnancy in the rat Diana Dow-Edwards State University of New York, Brooklyn, NY, United States In spite of 20 years of investigations of the effects of prenatalcocaine exposure in rodents, no one has modeled the binge patternassociated with smoking crack/cocaine in a pregnant rat. Cocaine usehas gone down nationwide, but there remain a substantial number of individuals who have been exposed to crack/cocaine during prenatallife and the question remains, are the neurobehavioral alterationsgreater or perhaps less than those who have been exposed by otherroutes of administration? Crack smokers smoke repeatedly in a singlebinge. The rapidly increasing and decreasing blood/brain levels of cocaine as produced by smoking crack result in the greatest “ reinforcement ”  to the smoker and presumably result in parallel fetalexposure. The effects of these rapidly increasing and decreasingcocaine levels during gestation are for the most part unknown.Therefore, we wanted to establish a binge model of crack/cocaineabuseduringpregnancyintheratusinganindwellingjugularportandrepeated rapid intravenous dosing. To date, we have established that3 mg/kg cocaine five times a day throughout pregnancy has minoreffects on maternal weight gain, litter size and litter weight. Details of the dosing protocol as well as the results will be presented. Therefore,we conclude that 3 mg/kg cocaine administered IV five times a day isassociated with minimal toxicity to the dam and the litter.Supported by R21 DA026588.doi:10.1016/j.ntt.2010.04.033 NBTS33Use of neurodevelopmental data in children for risk assessmentof environmental chemicals Susan Makris, Ambuja Bale, Kathleen Raffaele US EPA, ORD, NCEA, Washington, DC, United States Some environmental chemicals target the nervous system and canelicit perturbations during critical windows of nervous systemdevelopment. A review of the US EPA Integrated Risk InformationSystem (IRIS) database was conducted to evaluate the impact of studies assessing neurodevelopmental endpoints in children on ha-zardcharacterization forenvironmental toxicants. IRIS documents arepublicly available hazard and dose response assessments of environ-mental chemicals for human health risk assessment. They includereviews of epidemiology and animal toxicology data and derivechronic oral and inhalation reference values (RfVs) for non-canceroutcomes. Whether epidemiological data, including neurodevelop-mental assessments in children, are used in RfV determinationdepends upon factors such as the relative placement of the studyresults in the toxicological and dose-response profile of the chemicaland an analysis of confidence in the data. To assess the impact of neurodevelopmental studies, the database of approximately 550 IRISassessments was surveyed. For assessments of chemicals withneurotoxic potential that included neurodevelopmental evaluationsin children, the use of these data in risk characterization was ana-lyzed. Criteria qualitatively affecting disposition of studies in the finalhazard assessment included (e.g.) sample size, selection of appro-priate testing procedures, and adequate consideration of confoundingfactors in data assessment. This effort demonstrated that criticalconsideration of study designs commonly used in neurodevelop-mental testing of children for epidemiological research can poten-tially improve/refine the assessment of risk for environmentaltoxicants. The views expressed are those of the authors and do notnecessarily reflect the views or policies of the U.S. EPA.doi:10.1016/j.ntt.2010.04.034 NBTS34 A multidisciplinary approach to advancing the science of neurodevelopmental testing in cohorts of infants and young children  J.S. LaKind, E. Youngstrom, M. Goodman, K. Squibb, P.H. Lipkin,L.G. Anthony, L. Kenworthy, D.R. Mattison LaKind Associates, LLC, United StatesDepartment of Epidemiology and Preventive Medicine, University of Maryland School of Medicine, United StatesDepartment of Medicine, Penn State College of Medicine, United StatesDepartment of Pediatrics, Penn State College of Medicine, United StatesDepartment of Psychology, University of North Carolina at Chapel Hill,United StatesDepartment of Psychiatry, University of North Carolina at Chapel Hill,United StatesDepartment of Epidemiology, Emory University School of Public Health,United StatesCenter for Development and Learning, The Kennedy Krieger Institute,Department of Pediatrics, The Johns Hopkins University School of Medicine, United StatesChildren's National Medical Center, Center for Autism SpectrumDisorders, Departments of Pediatrics, Psychiatry and Neurology, GeorgeWashington University School of Medicine, United StatesEunice Kennedy Shriver National Institute of Child Health and HumanDevelopment National Institutes of Health, United States With published research suggesting that growing numbers of children are affected by an array of neurodevelopmental disorders,questions regarding etiology will continue to be raised. Thesequestions can be addressed in part by well-designed epidemiologicalstudies. The uses of neurodevelopmental function tests in studies of environmental chemicals and pediatric neurodevelopmental disor-ders have been reviewed, but a comprehensive critical examination of methodologies commonly used in past studies has not been con-ducted. There are limitations associated with currently used tests; inaddition, many available neurodevelopmental tests have not beenused in the environmental chemical study arena. In addition,differences in methods for conducting neurodevelopmental epide-miologic studies of environmental chemicals can lead to difficultiesin performing weight-of-evidence assessments. Our research teamcritically reviewed commonly used neurodevelopmental tests in NBTS 2010 Abstract   505  epidemiological studies of associations between environmentalchemical exposure and adverse health effects, identified tests thatshould be considered for use in future studies, and developed guide-lines and/or criteria for selection, administration, and interpretationof neurodevelopmental tests in studies of environmental chemicalexposures. We developed a series of recommendations to move thefield of neurodevelopmental environmental epidemiology forward,including a proposed set of guidelines that can be used to help thedesign of future studies (similar to what has been done with clinicaltrials, studies of diagnostic assessment tools, and medical epidemio-logical studies). Improvements and consistency in study design, testselection, and reporting of results are needed in order for these typesof studies to be useful as part of regulatory weight-of-evidenceassessments.doi:10.1016/j.ntt.2010.04.035 NBTS35Getting the biggest bang for your buck: Choosing neurodevelopmental tests that maximize power  Lauren Kenworthy, L.G. Anthony, M. Goodman, J.S. LaKind, P.H. Lipkin,D.R. Mattison, K. Squibb, E. Youngstrom Children's National Medical Center, Center for Autism SpectrumDisorders, United StatesDept of Pediatrics, George Washington University School of Medicine,United StatesDept of Psychiatry, George Washington University School of Medicine,United StatesDept of Epidemiology, Emory University School of Public Health,United StatesDept of Medicine, University of Maryland School of Medicine,United StatesDept of Psychology, University of North Carolina at Chapel Hill,United StatesDept of Psychiatry, University of North Carolina at Chapel Hill,United StatesCenter for Development and Learning, Kennedy Krieger Institute, Dept of Pediatrics, Johns Hopkins University School of Medicine, United StatesEunice Kennedy Shriver National Institute of Child Health and HumanDevelopment, United StatesLaKind Associates, United StatesDept of Epidemiology and Preventive Medicine, University of MarylandSchool of Medicine, United States Introduction: Review of neurodevelopmental measures used toinvestigate the effects of polychlorinated biphenyls (PCBs) in childrenrevealed limitations of currently used tests that compromised thepower of specific studies to detect potential neurodevelopmentaleffects of environmental chemicals. We present here test selectioncriteria for maximizing power to detect effects. Methods: We con-ducted a critical review of the environmental epidemiology literatureon neurodevelopmental effects of PCBs and a needs assessmentworkshop attended by a multi-disciplinary team of internationalexperts from the public sector and academia. The panel was asked toidentify areas where improvements are needed to strengthen thecore methodological elements of neurodevelopmental epidemiologi-cal studies; and develop recommendations for meeting those needs.Results: Our review of the literature and workshop discussionproduced several recommendations, including emphasizing enhance-ment of power of individual studies to detect effects. For increasedpower, the following specific test properties are particularly im-portant: Test – retest reliability, or the extent to which tests scores arereproducible when the same person is administered the same test ontwo different occasions; Inter-rater reliability, or the extent to whichscores are reproducible when the same test is administered or scoredby different individuals; Concurrent predictive validity or diagnosticefficiency; Exposure sensitivity; Developmental sensitivity, or a welldistributed range of scores in typically developing children in the agerange to be assessed; For neurocognitive constructs which are poorlyoperationalized in the laboratory (e.g. executive function), ecologicalvalidity, or the ability for a measure to relate to real world func-tioning; Breadth or narrowness of the measure in relationship tothe neurocognitive function in question. Discussion: The power of investigations in environmental epidemiology to detect effects of exposures on children can be increased through the consideration of the specific tests administered in relation to key criteria.doi:10.1016/j.ntt.2010.04.036 NBTS36 Threats to study validity: The Flynn Effect, examiner drift, confounders, lost in translation, and other important considerations L.G. Anthony, E.A. Youngstrom, L.E. Kenworthy, J.S. LaKind, M.Goodman, K.S. Squibb, P.H. Lipkin, D.R. Mattison Children's National Medical Center George Washington University,United StatesUniversity of North Carolina, Chapel Hill, United StatesLaKind Associates, United StatesEmory University School of Public Health, United StatesUniversity of Maryland School of Medicine, United StatesKennedy Krieger Institute, Johns Hopkins University School of Medicine,United StatesEunice Kennedy Shriver National Institute of Child Health and HumanDevelopment, National Institutes of Health, United States Introduction: Concerns regarding the negative impact of environ-mental factors on neurodevelopment have lead to a large number of epidemiological studies examining associations between in utero andneonatal exposures and pediatric neurodevelopmental disorders. Areview of specific neurodevelopmental tests used in these studies hasidentified some limitations in the chosen tests and difficulties withtheir interpretation. An examination of threats to validity for studiesusing neurodevelopmental testing to evaluate effects of envi-ronmental exposures is essential. Methods: We first conducted acritical review of the environmental chemical exposure literature,which brought several important methodological considerations tothe forefront. A needs assessment workshop was held with ourinterdisciplinary team and invited international experts from thepublic sector and academia with recognized research experience inexperimental neurodevelopmental biology, neurology, neuropsychol-ogy, psychology, pediatrics, epidemiology, statistics/methodology,and chemical risk assessment. The panel was asked to identify areaswhere improvements are needed to strengthen the methodologicalelements of neurodevelopmental epidemiological studies; and todevelop recommendations for meeting those needs. Results: Basedon the review of the literature and workshop discussions, the panelrecommended developing study design methodological standards tominimize the following threats to validity: the use of tests withoutdated norms (accounting for the Flynn Effect); the powerfuleffects of different examiners, and differences in each examiner overtime (e.g., intermittent reliability reviews of administration/scoringstandards); the selection of risk and protective factors in environ-mental studies going beyond demographics and selected confoun-ders. Inclusion of other covariates (e.g., IQ) that are highly correlatedwith the dependent variable (e.g., language) would further improve NBTS 2010 Abstract  506
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