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1. Semi-parametric Benchmark Dose Analysis with Monotone Additive Models

Author

Stringer, Alex, Hocagil, Tugba Akkaya, Cook, Richard, Ryan, Louise, Jacobson, Sandra W., and Jacobson, Joseph L.

Subjects
Statistics - Methodology
Abstract

Benchmark dose analysis aims to estimate the level of exposure to a toxin that results in a clinically-significant adverse outcome and quantifies uncertainty using the lower limit of a confidence interval for this level. We develop a novel framework for benchmark dose analysis based on monotone additive dose-response models. We first introduce a flexible approach for fitting monotone additive models via penalized B-splines and Laplace-approximate marginal likelihood. A reflective Newton method is then developed that employs de Boor's algorithm for computing splines and their derivatives for efficient estimation of the benchmark dose. Finally, we develop and assess three approaches for calculating benchmark dose lower limits: a naive one based on asymptotic normality of the estimator, one based on an approximate pivot, and one using a Bayesian parametric bootstrap. The latter approaches improve upon the naive method in terms of accuracy and are guaranteed to return a positive lower limit; the approach based on an approximate pivot is typically an order of magnitude faster than the bootstrap, although they are both practically feasible to compute. We apply the new methods to make inferences about the level of prenatal alcohol exposure associated with clinically significant cognitive defects in children using data from an NIH-funded longitudinal study. Software to reproduce the results in this paper is available at https://github.com/awstringer1/bmd-paper-code.

Published
2023

3. Bayesian outcome selection modelling

Author

Dang, Khue-Dung, Ryan, Louise M., Cook, Richard J., Akkaya-Hocagil, Tugba, Jacobson, Sandra W., and Jacobson, Joseph L.

Subjects
Statistics - Methodology
Abstract

Psychiatric and social epidemiology often involves assessing the effects of environmental exposure on outcomes that are difficult to measure directly. To address this problem, it is common to measure outcomes using a comprehensive battery of different tests thought to be related to a common, underlying construct of interest. In the application that motivates our work, for example, researchers wanted to assess the impact of in utero alcohol exposure on child cognition and neuropsychological development, which were evaluated using a range of different tests. Statistical analysis of the resulting multiple outcomes data can be challenging, not only because of the need to account for the correlation between outcomes measured on the same individual, but because it is often unclear, a priori, which outcomes are impacted by the exposure under study. While researchers will generally have some hypotheses about which outcomes are important, a framework is needed to help identify outcomes that are sensitive to the exposure and to quantify the associated treatment or exposure effects of interest. We propose such a framework using a modification of stochastic search variable selection (SSVS), a popular Bayesian variable selection model and use it to quantify an overall effect of the exposure on the affected outcomes. We investigate the performance of the method via simulation and illustrate its application to data from a study involving the effects of prenatal alcohol exposure on child cognition.

Published
2022

6. Bayesian structural equation modeling for data from multiple cohorts

Author

Dang, Khue-Dung, Ryan, Louise M., Akkaya-Hocagil, Tugba, Cook, Richard J., Richardson, Gale A., Day, Nancy L., Coles, Claire D., Olson, Heather Carmichael, Jacobson, Sandra W., and Jacobson, Joseph L.

Subjects
Statistics - Applications
Abstract

While it is well known that high levels of prenatal alcohol exposure (PAE) result in significant cognitive deficits in children, the exact nature of the dose response is less well understood. In particular, there is a pressing need to identify the levels of PAE associated with an increased risk of clinically significant adverse effects. To address this issue, data have been combined from six longitudinal birth cohort studies in the United States that assessed the effects of PAE on cognitive outcomes measured from early school age through adolescence. Structural equation models (SEMs) are commonly used to capture the association among multiple observed outcomes in order to characterise the underlying variable of interest (in this case, cognition) and then relate it to PAE. However, it was not possible to apply classic SEM software in our context because different outcomes were measured in the six studies. In this paper we show how a Bayesian approach can be used to fit a multi-group multi-level structural model that maps cognition to a broad range of observed variables measured at multiple ages. These variables map to several different cognitive subdomains and are examined in relation to PAE after adjusting for confounding using propensity scores. The model also tests the possibility of a change point in the dose-response function.

Published
2020

7. A Hierarchical Meta-Analysis for Settings Involving Multiple Outcomes across Multiple Cohorts

Author

Hocagil, Tugba Akkaya, Ryan, Louise M., Cook, Richard J., Richardson, Gale A., Day, Nancy L., Coles, Claire D., Olson, Heather Carmichael, Jacobson, Sandra W., and Jacobson, Joseph L.

Subjects
Statistics - Methodology
Abstract

Evidence from animal models and epidemiological studies has linked prenatal alcohol exposure (PAE) to a broad range of long-term cognitive and behavioral deficits. However, there is virtually no information in the scientific literature regarding the levels of PAE associated with an increased risk of clinically significant adverse effects. During the period from 1975-1993, several prospective longitudinal cohort studies were conducted in the U.S., in which maternal reports regarding alcohol use were obtained during pregnancy and the cognitive development of the offspring was assessed from early childhood through early adulthood. The sample sizes in these cohorts did not provide sufficient power to examine effects associated with different levels and patterns of PAE. To address this critical public health issue, we have developed a hierarchical meta-analysis to synthesize information regarding the effects of PAE on cognition, integrating data on multiple endpoints from six U.S. longitudinal cohort studies. Our approach involves estimating the dose-response coefficients for each endpoint and then pooling these correlated dose-response coefficients to obtain an estimated `global' effect of exposure on cognition. In the first stage, we use individual participant data to derive estimates of the effects of PAE by fitting regression models that adjust for potential confounding variables using propensity scores. The correlation matrix characterizing the dependence between the endpoint-specific dose-response coefficients estimated within each cohort is then run, while accommodating incomplete information on some endpoints. We also compare and discuss inferences based on the proposed approach to inferences based on a full multivariate analysis

Published
2020

8. Fast Infant MRI Skullstripping with Multiview 2D Convolutional Neural Networks

Author

Jog, Amod, Grant, P. Ellen, Jacobson, Joseph L., van der Kouwe, Andre, Meintjes, Ernesta M., Fischl, Bruce, and Zöllei, Lilla

Subjects
Computer Science - Computer Vision and Pattern Recognition, Electrical Engineering and Systems Science - Image and Video Processing
Abstract

Skullstripping is defined as the task of segmenting brain tissue from a full head magnetic resonance image~(MRI). It is a critical component in neuroimage processing pipelines. Downstream deformable registration and whole brain segmentation performance is highly dependent on accurate skullstripping. Skullstripping is an especially challenging task for infant~(age range 0--18 months) head MRI images due to the significant size and shape variability of the head and the brain in that age range. Infant brain tissue development also changes the $T_1$-weighted image contrast over time, making consistent skullstripping a difficult task. Existing tools for adult brain MRI skullstripping are ill equipped to handle these variations and a specialized infant MRI skullstripping algorithm is necessary. In this paper, we describe a supervised skullstripping algorithm that utilizes three trained fully convolutional neural networks~(CNN), each of which segments 2D $T_1$-weighted slices in axial, coronal, and sagittal views respectively. The three probabilistic segmentations in the three views are linearly fused and thresholded to produce a final brain mask. We compared our method to existing adult and infant skullstripping algorithms and showed significant improvement based on Dice overlap metric~(average Dice of 0.97) with a manually labeled ground truth data set. Label fusion experiments on multiple, unlabeled data sets show that our method is consistent and has fewer failure modes. In addition, our method is computationally very fast with a run time of 30 seconds per image on NVidia P40/P100/Quadro 4000 GPUs.

Published
2019

9. Prenatal Alcohol Exposure is Associated with Regionally Thinner Cortex During the Preadolescent Period

Author

Robertson, Frances C, Narr, Katherine L, Molteno, Christopher D, Jacobson, Joseph L, Jacobson, Sandra W, and Meintjes, Ernesta M

Subjects
Substance Misuse, Perinatal Period - Conditions Originating in Perinatal Period, Congenital Structural Anomalies, Intellectual and Developmental Disabilities (IDD), Conditions Affecting the Embryonic and Fetal Periods, Brain Disorders, Alcoholism, Alcohol Use and Health, Fetal Alcohol Spectrum Disorders (FASD), Neurosciences, Pediatric, Reproductive health and childbirth, Neurological, Good Health and Well Being, Attention Deficit Disorder with Hyperactivity, Cerebral Cortex, Child, Female, Fetal Alcohol Spectrum Disorders, Follow-Up Studies, Humans, Image Processing, Computer-Assisted, Intelligence, Intelligence Tests, Longitudinal Studies, Male, Organ Size, Pregnancy, Prenatal Exposure Delayed Effects, Regression Analysis, Socioeconomic Factors, cortical thickness, development, fetal alcohol spectrum disorders, fetal alcohol syndrome, IQ, Psychology, Cognitive Sciences, Experimental Psychology
Abstract

Children with fetal alcohol spectrum disorders (FASD) may exhibit craniofacial dysmorphology, neurobehavioral deficits, and reduced brain volume. Studies of cortical thickness in FASD have yielded contradictory findings, with 3 reporting thicker cerebral cortex in frontal and temporal brain regions and 2 showing thinner cortex across multiple regions. All 5 studies included subjects spanning a broad age range, and none have examined continuous measures of prenatal alcohol exposure. We investigated the relation of extent of in utero alcohol exposure to cortical thickness in 78 preadolescent children with FASD and controls within a narrow age range. A whole-brain analysis using FreeSurfer revealed no significant clusters where cortical thickness differed by FASD diagnostic group. However, alcohol dose/occasion during pregnancy was inversely related to cortical thickness in 3 regions-right cuneus/pericalcarine/superior parietal lobe, fusiform/lingual gyrus, and supramarginal/postcentral gyrus. The effect of prenatal alcohol exposure on IQ was mediated by cortical thickness in the right occipitotemporal region. It is noteworthy that a continuous measure of maternal alcohol consumption during pregnancy was more sensitive than FASD diagnosis and that the effect on cortical thickness was most evident in relation to a measure of maternal binge drinking.

Published
2016

12. Effects of Prenatal Alcohol Exposure on Testosterone and Pubertal Development

Author

Carter, R Colin, Jacobson, Joseph L, Dodge, Neil C, Granger, Douglas A, and Jacobson, Sandra W

Subjects
Contraception/Reproduction, Substance Misuse, Pediatric, Clinical Research, Conditions Affecting the Embryonic and Fetal Periods, Alcoholism, Alcohol Use and Health, Neurosciences, Reproductive health and childbirth, Cancer, Good Health and Well Being, Adolescent, Adult, Alcohol Drinking, Ethanol, Female, Humans, Male, Pregnancy, Prenatal Exposure Delayed Effects, Puberty, Saliva, Testosterone, Fetal Alcohol Spectrum Disorder, Prenatal Alcohol Exposure, Tanner Stages, Clinical Sciences, Psychology, Substance Abuse
Abstract

BackgroundAnimal models have demonstrated fetal alcohol-related disruptions in neuroendocrine function in the hypothalamic-pituitary-gonadal axis and downstream effects on pubertal development and sexual behavior in males and females, but little is known about these effects in humans. This study examined whether prenatal alcohol exposure is associated with alterations in testosterone during adolescence and whether it affects timing of pubertal development.MethodsThe sample consisted of 265 African American adolescents from the Detroit Longitudinal Cohort Study for whom testosterone and/or pubertal development data were available. Subjects were offspring of women recruited at their first prenatal clinic visit to over represent moderate-to-heavy alcohol use, including a 5% random sample of low-level drinkers/abstainers. Mothers were interviewed at every prenatal visit about their alcohol consumption using a timeline follow-back approach and about their smoking and drug use and sociodemographic factors. At age 14 years, adolescents provided salivary samples, which were analyzed for testosterone (pg/ml), self-reported Tanner stages for pubertal development, and age at menarche (females).ResultsPrenatal alcohol exposure was related to elevated testosterone concentrations for males and females but not to changes in Tanner stages or age at menarche, after controlling for confounders. In regression models stratified by alcohol exposure, the expected relation between testosterone and pubic hair development was seen among males with light-to-no prenatal alcohol exposure, but not among those with moderate-to-heavy prenatal alcohol exposure. This interaction between testosterone and prenatal alcohol exposure was confirmed in multivariable models including an alcohol exposure group × testosterone interaction term and potential confounders.ConclusionsThis study is the first to show a relation between prenatal alcohol exposure and increased testosterone during adolescence and evidence of decreased testosterone responsiveness in tissues related to pubertal development in humans. Further studies examining androgen receptor expression and other hormonal and cellular factors affecting pubertal development may reveal important mechanisms underlying these teratogenic effects of alcohol exposure.

Published
2014

13. Alterations in Placental Inflammation-Related Gene Expression Partially Mediate the Effects of Prenatal Alcohol Consumption on Maternal Iron Homeostasis

Author

Masehi-Lano, Jacqueline J., primary, Deyssenroth, Maya, additional, Jacobson, Sandra W., additional, Jacobson, Joseph L., additional, Molteno, Christopher D., additional, Dodge, Neil C., additional, Wainwright, Helen C., additional, Meintjes, Ernesta M., additional, Lesseur, Corina, additional, Cheng, Haoxiang, additional, Li, Qian, additional, Hao, Ke, additional, Chen, Jia, additional, and Carter, R. Colin, additional

Published
2023
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17. Comparison of Polychlorinated Biphenyl Levels across Studies of Human Neurodevelopment

Author

Longnecker, Matthew P., Wolff, Mary S., Gladen, Beth C., Brock, John W., Grandjean, Philippe, Jacobson, Joseph L., Korrick, Susan A., Rogan, Walter J., Weisglas-Kuperus, Nynke, Hertz-Picciotto, Irva, Ayotte, Pierre, Stewart, Paul, Winneke, Gerhard, Charles, M. Judith, Jacobson, Sandra W., Dewailly, Éric, Boersma, E. Rudy, Altshul, Larisa M., Heinzow, Birger, Pagano, James J., and Jensen, Allan A.

Published
2003

21. Maternal ART throughout gestation prevents caudate volume reductions in neonates who are HIV exposed but uninfected

Author

Ibrahim, Abdulmumin, primary, Warton, Fleur L., additional, Fry, Samantha, additional, Cotton, Mark F., additional, Jacobson, Sandra W., additional, Jacobson, Joseph L., additional, Molteno, Christopher D., additional, Little, Francesca, additional, van der Kouwe, Andre J. W., additional, Laughton, Barbara, additional, Meintjes, Ernesta M., additional, and Holmes, Martha J., additional

Published
2023
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25. A hierarchical meta-analysis for settings involving multiple outcomes across multiple cohorts

Author

Hocagil, Tugba Akkaya, Ryan, Louise M., Cook, Richard J., Richardson, Gale A., Day, Nancy L., Coles, Claire D., Olson, Heather Carmichael, Jacobson, Sandra W., and Jacobson, Joseph L.

Subjects
Methodology (stat.ME), FOS: Computer and information sciences, 0104 Statistics, Statistics - Methodology
Abstract

Evidence from animal models and epidemiological studies has linked prenatal alcohol exposure (PAE) to a broad range of long-term cognitive and behavioral deficits. However, there is virtually no information in the scientific literature regarding the levels of PAE associated with an increased risk of clinically significant adverse effects. During the period from 1975-1993, several prospective longitudinal cohort studies were conducted in the U.S., in which maternal reports regarding alcohol use were obtained during pregnancy and the cognitive development of the offspring was assessed from early childhood through early adulthood. The sample sizes in these cohorts did not provide sufficient power to examine effects associated with different levels and patterns of PAE. To address this critical public health issue, we have developed a hierarchical meta-analysis to synthesize information regarding the effects of PAE on cognition, integrating data on multiple endpoints from six U.S. longitudinal cohort studies. Our approach involves estimating the dose-response coefficients for each endpoint and then pooling these correlated dose-response coefficients to obtain an estimated `global' effect of exposure on cognition. In the first stage, we use individual participant data to derive estimates of the effects of PAE by fitting regression models that adjust for potential confounding variables using propensity scores. The correlation matrix characterizing the dependence between the endpoint-specific dose-response coefficients estimated within each cohort is then run, while accommodating incomplete information on some endpoints. We also compare and discuss inferences based on the proposed approach to inferences based on a full multivariate analysis

Published
2022

29. Fetal Substance Exposure and Cumulative Environmental Risk in an African American Cohort

Author

Yumoto, Chie, Jacobson, Sandra W., and Jacobson, Joseph L.

Abstract

Two models of vulnerability to socioenvironmental risk were examined in 337 African American children (M = 7.8 years) recruited to overrepresent prenatal alcohol or cocaine exposure: The cumulative risk model predicted synergistic effects from exposure to multiple risk factors, and the fetal patterning of disease model predicted that prenatal insult will increase vulnerability to environmental risk. Four or more risks emerged as a threshold for poorer cognitive and behavioral outcome among the non-substance-exposed children, whereas substance-exposed children showed greater vulnerability to lower levels of environmental risk. Cumulative risk was associated with increased delinquent and internalizing behaviors only for the substance-exposed group. Results support the cumulative risk model for non-substance-exposed children and increased vulnerability to environmental risk among the substance-exposed group.

Published
2008
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32. Prenatal Exposure of the Northern Quebec Inuit Infants to Environmental Contaminants.

Author

Muckle, Gina, Ayotte, Pierre, Dewailly, Eric, Jacobson, Sandra W., and Jacobson, Joseph L.

Abstract

Through their marine-based diet, the Inuit of Nunavik (Quebec) are exposed to neurotoxic environmental contaminants that impact cognitive development. Mercury levels in Nunavik Inuit mothers and newborns were higher than in U.S. and Canadian populations but lower than in previous Arctic samples. Lead, polychlorinated biphenyls, chorinated pesticides, and possibly protective substances (selenium and N-3 polyunsaturated fatty acids) were also measured. (SV)

Published
2001

37. Food insecurity and nutritional biomarkers in relation to stature in Inuit children from Nunavik

Author

Pirkle, Catherine M., Lucas, Michel, Dallaire, Renee, Ayotte, Pierre, Jacobson, Joseph L., Jacobson, Sandra W., Dewailly, Eric, and Muckle, Gina

Subjects
Iron deficiency diseases -- Diagnosis -- Distribution, Food supply -- Health aspects, Inuit -- Food and nutrition -- Health aspects, Company distribution practices, Government, Health, Health care industry
Abstract

OBJECTIVES: Inuit in Canada experience alarming levels of food insecurity, but nutritional and physiological consequences are poorly documented, especially in school-age children. The objective of this study was to assess the relation of food insecurity to iron deficiency and stature in school-aged Inuit children from Nunavik (Northern Quebec). METHODS: Food insecurity, iron deficiency, and stature were assessed in a cohort of children. Food insecurity was determined by interviewing the children's mothers. Multiple logistic regression was used to evaluate the association of food insecurity to iron deficiency and short stature. We defined short stature as a height in the lowest tertile for age and sex, based on Canadian growth charts. The relation of food insecurity to height (cm) was analyzed with a general linear model. Statistical models controlled for age, sex, normal/overweight/obese status, prenatal lead exposure and postnatal polychlorinated biphenyls exposure. RESULTS: Half of the children (49.7%, n=145) were food insecure, while one third were iron depleted, 12.6% had anaemia, and 8.7% had irondeficiency anaemia. The multivariate odds ratio of anaemia was 1.82 (95% CI: 0.97, 3.42, p=0.06) for food-insecure children. Prevalence of short stature was 18.7%. Food-insecure children were an average of 2 cm shorter (95% CI: -0.48, -3.17) than food-secure children (p CONCLUSION: In this population, food-insecure children have greater burdens of nutritional deficiencies and slower linear growth. Considering the high prevalence of food insecurity among Inuit children in Nunavik, nutritional deficiencies and adverse effects on development should be carefully monitored. KEY TERMS: Food insecurity; nutritional deficiencies; iron; growth; children; indigenous health OBJECTIFS: Les Inuits du Canada presentent des niveaux d'insecurite alimentaire alarmants dont les consequences nutritionnelles et physiologiques sont meconnues, surtout chez les enfants d'age scolaire. L'objectif de notre etude etait d'evaluer la relation entre l'insecurite alimentaire, d'une part, et la carence en fer et la taille, d'autre part, chez les enfants inuits du Nunavik (Nord-du-Quebec) en age de frequenter l'ecole. METHODE: Nous avons evalue l'insecurite alimentaire, la carence en fer et la taille dans une cohorte d'enfants. L'insecurite alimentaire a ete determinee en interviewant les meres des enfants. Par regression logistique multiple, nous avons evalue l'association entre l'insecurite alimentaire et la carence en fer et la petite taille. Nous avons defini la petite taille comme etant la taille dans le tertile inferieur pour l'age et le sexe, selon les fiches de croissance canadiennes. Le rapport entre l'insecurite alimentaire et la taille (en centimetres) a ete analyse selon un modele lineaire general. Des modeles statistiques ont permis de rajuster les donnees selon l'age, le sexe, le poids normal/le surpoids/l'obesite, l'exposition prenatale au plomb et l'exposition postnatale aux biphenyles polychlores. RESULTATS: La moitie des enfants (49,7%, n=145) etaient confrontes a l'insecurite alimentaire, le tiers des enfants etaient carences en fer, 12,6% faisaient de l'anemie, et 8,7% presentaient une anemie ferriprive. Le rapport de cotes multivarie de l'anemie etait de 1,82 (IC de 95%: 0,97, 3,42, p=0,06) chez les enfants confrontes a l'insecurite alimentaire. La prevalence de la petite taille etait de 18,7%. Les enfants touches par l'insecurite alimentaire mesuraient en moyenne 2 cm de moins (IC de 95%: -0,48, -3,17) que les enfants epargnes par l'insecurite alimentaire (p CONCLUSION: Dans cette population, les enfants confrontes a l'insecurite alimentaire avaient un plus lourd fardeau de carences alimentaires et une croissance lineaire plus lente. Etant donne la forte prevalence de l'insecurite alimentaire chez les enfants inuits du Nunavik, les carences alimentaires et leurs effets indesirables sur le developpement devraient etre suivis attentivement. MOTS CLES: insecurite alimentaire; carences alimentaires; fer; croissance; enfant; sante autochtone, Food insecurity attains alarming levels in Inuit populations of northern Canada. (1) Measures of food insecurity traditionally encompass concepts of availability and access to sufficient food, as well as food [...]

Published
2014

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