Joint Effects of Indoor Air Pollution and Maternal Psychosocial Factors During Pregnancy on Trajectories of Early Childhood Psychopathology.

BACKGROUND: Prenatal indoor air pollution and maternal psychosocial factors have been associated with adverse psychopathology. We used environmental exposure mixture methodology to investigate joint effects of both exposure classes on child behavior trajectories. METHODS: For 360 children from the South African Drakenstein Child Health Study, we created trajectories of Child Behavior Checklist scores (24, 42, 60 months) using latent class linear mixed effects models. Indoor air pollutants and psychosocial factors were measured during pregnancy (2nd trimester). After adjusting for confounding, single-exposure effects (per natural log-1 unit increase) were assessed using polytomous logistic regression models; joint effects using self-organizing maps (SOM), and principal component (PC) analysis. RESULTS: Three trajectories were chosen for both internalizing and externalizing problems, with "high" (externalizing) or "increasing" (internalizing) being the most adverse trajectories. High externalizing trajectory was associated with increased particulate matter (PM10) exposure (OR [95%-CI]: 1.25 [1.01,1.55]) and SOM exposure profile most associated with smoking (2.67 [1.14,6.27]). Medium internalizing trajectory was associated with increased emotional intimate partner violence (2.66 [1.17,5.57]), increasing trajectory with increased benzene (1.24 [1.02,1.51]) and toluene (1.21 [1.02,1.44]) and the PC most correlated with benzene and toluene (1.25 [1.02, 1.54]). CONCLUSIONS: Prenatal exposure to environmental pollutants and psychosocial factors was associated with internalizing and externalizing child behavior trajectories. Understanding joint effects of adverse exposure mixtures will facilitate targeted interventions to prevent childhood psychopathology.

Joint effects of prenatal exposure to indoor air pollution and psychosocial factors on early life inflammation.

It is hypothesized that air pollution and stress impact the central nervous system through neuroinflammatory pathways Despite this, the association between prenatal exposure to indoor air pollution and psychosocial factors on inflammatory markers in infancy has been underexplored in epidemiology studies. This study investigates the individual and joint effects of prenatal exposure to indoor air pollution and psychosocial factors on early life inflammation (interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α)). We analyzed data from the South African Drakenstein Child Health Study (N = 225). Indoor air pollution and psychosocial factor measurements were taken in the 2nd trimester of pregnancy. Circulating inflammatory markers (IL-1ß, Il-6, and TNF-α) were measured in serum in the infants at 6 weeks postnatal. Linear regression models were used to investigate associations between individual exposures and inflammatory markers. To investigate joint effects of environmental and psychosocial factors, Self-Organizing Maps (SOM) were used to create exposure profile clusters. These clusters were added to linear regression models to investigate the associations between exposure profiles and inflammatory markers. All models were adjusted for maternal age, maternal HIV status, and ancestry to control for confounding. Most indoor air pollutants were positively associated with inflammatory markers, particularly benzene and TNF-α in single pollutant models. No consistent patterns were found for psychosocial factors in single-exposure linear regression models. In joint effects analyses, the SOM profile with high indoor air pollution, low SES, and high maternal depressive symptoms were associated with higher inflammation. Indoor air pollutants were consistently associated with increased inflammation in both individual and joint effects models, particularly in combination with low SES and maternal depressive symptoms. The trend for individual psychosocial factors was not as clear, with mainly null associations. As we have observed pro- and anti-inflammatory effects, future research should investigate joint effects of these exposures on inflammation and their health effects.

Elimination of PBB-153; findings from a cohort of Michigan adults.

BACKGROUND: An industrial accident led to the widespread contamination of polybrominated biphenyl (PBB), a flame retardant, into the food system in Michigan in the 1970's. PBB continues to be detected in Michiganders' blood some forty years later. It is necessary to understand the elimination rate and half-life of PBB because it may provide clues on how to hasten the elimination of it from the human body. METHODS: Serum samples were taken from young adult and adult participants of the Michigan PBB registry from 1974 to 2019. A single compartment model was assumed for the elimination rate for PBB-153 in young adults and adults (≥16 years). Generalized linear mixed models were used to estimate the average elimination rate of PBB-153 and allowed for a random intercept and slope for the time between measurements. Models were adjusted for age at exposure, body mass index (BMI) at initial measurement, and smoking. Models were also stratified by demographic characteristics. RESULTS: In total, 1974 participants contributed 4768 samples over a forty-year span. The median initial PBB-153 level was 1.542 parts per billion (ppb) (Range: 0.001-1442.48 ppb). The adjusted median participant-specific half-life for PBB-153 was 12.23 years. The half-life of PBB-153 was lengthened by higher initial PBB level (∼1.5 years), younger age at exposure (∼5.4 years), higher BMI (∼1.0 years), and increased gravidity (∼7.3 years). Additionally, the half-life of PBB-153 was shortened by smoking status (∼-2.8 years) and breastfeeding (∼-3.5 years). CONCLUSIONS: Consistent with previous studies, PBB-153 has been demonstrated to have a long half-life in the human body and may be modified by some demographic characteristics. These updated estimates of half-life will further support evaluation of health effects associated with PBB exposure. Investigations into mechanisms to accelerate elimination and reduce body burdens of PBB-153, especially those related to body weight, are needed.

Polybrominated biphenyls (PBBs) and prevalence of autoimmune disorders among members of the Michigan PBB registry.

BACKGROUND: Polybrominated biphenyls (PBBs), a class of endocrine disrupting chemicals, were the main chemicals present in one of the largest industrial accidents in the United States. We investigated the association between serum PBB-153 levels and autoimmune disorders among members of the Michigan PBB Registry. METHODS: Eight hundred and ninety-five members of the registry had both a serum PBB-153 measurement and had completed one or more questionnaires about autoimmune disorders. Autoimmune disorders were examined collectively and within specific organ systems. Sex-stratified unadjusted and adjusted log-binomial models were used to examine the association between tertiles of serum PBB-153 levels and autoimmune disorders. Models were adjusted by lifestage at exposure (in utero, childhood, adulthood), smoking history (never, past, current), and total serum lipid levels (continuous). We utilized cubic spline models to investigate non-linearity between serum PBB-153 levels and the prevalence of autoimmune disorders. RESULTS: Approximately 12.9% and 20.7% of male and female participants reported having one or more autoimmune disorders, respectively. After adjustment for potential confounders, we observed no association between PBB-153 tertiles and the composite classification of 'any autoimmune disorder' in either sex. We observed some evidence for an association between serum PBB-153 levels and rheumatoid arthritis in males and females; however, this was not statistically significant in females. We also observed some evidence for an association between serum PBB-153 levels and neurological- and thyroid-related autoimmune disorders in females, but again this was not statistically significant. Additionally, we identified dose-response curves for serum PBB-153 levels and the prevalence of autoimmune disorders that differed by lifestage of exposure and sex. CONCLUSIONS: We observed some evidence that increasing serum PBB-153 levels were associated with three specified autoimmune disorders. Studies focusing on these three autoimmune disorders and the potential non-linear trend differences by lifestage of exposure warrant further investigation.

Neighborhood characteristics as confounders and effect modifiers for the association between air pollution exposure and subjective cognitive functioning.

BACKGROUND: Air pollution has been associated with cognitive function in the elderly. Previous studies have not evaluated the simultaneous effect of neighborhood-level socioeconomic status (N-SES), which can be an essential source of bias. OBJECTIVES: We explored N-SES as a confounder and effect modifier in a cross-sectional study of air pollution and subjective cognitive function. METHODS: We included 12,058 participants age 50+ years from the Emory Healthy Aging Study in Metro Atlanta using the Cognitive Function Instrument (CFI) score as our outcome, with higher scores representing worse subjective cognitive function. We estimated 9-year average ambient carbon monoxide (CO), nitrogen oxides (NOx), and fine particulate matter (PM2.5) concentrations at residential addresses using a fusion of dispersion and chemical transport models. We collected census-tract level N-SES indicators and created two composite measures via principal component analysis and k-means clustering. Associations between pollutants and CFI and effect modification by N-SES were estimated via linear regression models adjusted for age, education, race and N-SES. RESULTS: N-SES confounded the association between air pollution and CFI, independent of individual characteristics. We found significant effect modifications by N-SES for the association between air pollution and CFI (p-values<0.001) suggesting that effects of air pollution differ depending on N-SES. Participants living in areas with low N-SES were most vulnerable to air pollution. In the lowest N-SES urban areas, interquartile range (IQR) increases in CO, NOx, and PM2.5 were associated with 5.4% (95%-confidence interval, -0.2,11.3), 4.9% (-0.4,10.4), and 9.8% (2.2,18.0) changes in CFI, respectively. In lowest N-SES suburban areas, IQR increases in CO, NOx, and PM2.5 were associated with higher changes in CFI, namely 13.0% (0.9,26.5), 13.0% (-0.1,27.8), and 17.3% (2.5,34.2), respectively. DISCUSSION: N-SES is an important confounder and effect modifier in our study. This finding could have implications for studying health effects of air pollution and identifying susceptible populations.

Birth outcomes associated with paternal polybrominated and polychlorinated biphenyl exposure.

In 1973-74, a polybrominated biphenyl (PBB) flame retardant mixture was shipped to Michigan livestock feed mills in place of a nutritional supplement and contaminated the food supply. Following the accident, the Michigan PBB Registry was established to study the long-term health effects of halogenated compounds and is now led by a community-academic partnership. PBB exposure is associated with altered DNA methylation in sperm, which may lead to adverse birth outcomes in children whose fathers have increased levels of serum PBB or polychlorinated biphenyl (PCB). Paternal PBB and PCB levels of men enrolled in the Michigan PBB Registry (n = 155) were analyzed against matched offspring birthweight and gestational age (n = 336). Birthweight and gestational age were dichotomized at the 25th percentile and 37 weeks, respectively, and paternal PBB and PCB levels were examined as continuous measures and divided into tertiles. Associations of offspring birthweight and gestational age with paternal PBB and PCB serum concentrations were modeled using multivariable linear spline and log-risk regression, adjusting for family clustering, paternal health and lifestyle factors, maternal PBB, and PCB serum concentrations, sex, and offspring gestational age (for birthweight). Fathers in the middle and upper PBB and PCB tertiles had increased risks for lowest quartile birthweight compared to the first tertile, with adjusted risk ratios (aRR) = 1.67 (95% CI: 0.93, 2.99) and aRR = 2.06 (95% CI: 1.12, 3.79) for PBB, and aRR = 1.47 (95% CI: 0.79, 2.75) and aRR = 1.34 (95% CI: 0.70, 2.54) for PCB, respectively. Elevated paternal PBB levels were not associated with an increased risk for preterm birth, while PCB levels were associated with a small, but not significant, decrease in gestational age, ß = -0.37 (95% CI: -0.76, 0.03) weeks per log unit increase PCB. The findings suggest that increased paternal PBB and PCB levels negatively impact offspring birthweight, and paternal PCB levels may negatively impact gestational age.

The association between alcohol intake and fecundability during menstrual cycle phases.

STUDY QUESTION: Is increased alcohol intake in different phases of the menstrual cycle associated with fecundability in women? SUMMARY ANSWER: Heavy intake (>6 drinks/week) of alcoholic beverages in the luteal phase and ovulatory subphase was associated with reduced odds of conception; moderate intake (3-6 drinks/week) during the luteal phase was also associated with reduced fecundability. WHAT IS KNOWN ALREADY: Despite strong indications for increased risk of infertility among drinking women with intention to conceive, inconsistencies in previous results point to possible residual confounding, and have not thoroughly investigated timing of drinking and other drinking patterns during the menstrual cycle. STUDY DESIGN, SIZE, DURATION: Participants in The Mount Sinai Study of Women Office Workers (MSSWOW), a prospective cohort study of fertility, were recruited and followed between 1990 and 1994, and completed daily diaries reporting their alcohol intake (type and number of drinks) for a maximum of 19 months of follow-up (N = 413). PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants were between 19 and 41 years of age. After completion of baseline surveys, they were asked to record their alcoholic beverage intake as number of drinks of beer, wine, and liquor per day, in addition to other exposures such as caffeine and smoking. Furthermore, they submitted urine samples each month to assess pregnancy. Menstrual cycle phases were calculated using the Knaus-Ognio approach. Discrete survival analysis methods were employed to estimate the association between categories of alcohol intake in each phase of menstrual cycle and fecundability. MAIN RESULTS AND THE ROLE OF CHANCE: In the luteal phase, both moderate drinking (3-6 drinks/week, Fecundability Odds Ratio (FOR)=0.56, CI: 0.31, 0.98) and heavy drinking (>6 drinks/week, FOR = 0.51, CI: 0.29, 0.89) were associated with a reduction in fecundability, compared to non-drinkers. For the follicular phase, heavy drinking in the ovulatory sub-phase (FOR = 0.39, CI: 0.19, 0.72) was similarly associated with reduced fecundability, compared to non-drinkers. For the pre-ovulatory sub-phase, heavy drinking (>6 drinks/week, FOR = 0.54, CI: 0.29, 0.97) was associated with reduction in fecundability, but this association was inconsistent when subjected to sensitivity tests. Each extra day of binge drinking was associated with 19% (FOR = 0.81, CI: 0.63, 0.98), and 41% (FOR = 0.59, CI: 0.33, 0.93) reduction in fecundability for the luteal phase and ovulatory sub-phase respectively, but no association was observed in the pre-ovulatory sub-phase. No meaningful differences in fecundability between beverages were observed in any menstrual phase. LIMITATIONS, REASONS FOR CAUTION: Patterns of alcohol intake in this cohort suggest a lower average alcohol intake compared to more recent national averages for the same demographic group. Sample sizes were small for some subgroups, resulting in limited power to examine specific beverage types in different phases of the menstrual cycle, or to assess interaction. In addition, the influence of male partner alcohol intake was not assessed, the data relied on self-report, and residual confounding (e.g. unmeasured behaviors correlated with alcohol intake) is a possibility. WIDER IMPLICATIONS OF THE FINDINGS: Results suggest an inverse association between alcohol and fecundability, and support the relevance of menstrual cycle phases in this link. More specifically, moderate to heavy drinking during the luteal phase, and heavy drinking in the ovulatory window, could disturb the delicate sequence of hormonal events, affecting chances of a successful conception. STUDY FUNDING/COMPETING INTEREST(S): Authors declare no conflict of interest. This work was supported by the National Institutes of Health grant, R01-HD24618. TRIAL REGISTRATION NUMBER: N/A.

Endometriosis, endocrine disrupters, and epigenetics: an investigation into the complex interplay in women with polybrominated biphenyl exposure and endometriosis.

PURPOSE: Endocrine disrupting compounds (EDCs) have been shown to affect multiple biologic processes especially steroid-hormone processes. We sought to determine differences in DNA methylation exists between women with and without endometriosis following exposure to polybrominated biphenyl (PBB). METHODS: Cross-sectional study of 305 females in the Michigan PBB Registry. DNA was extracted, and DNA methylation was interrogated using the MethylationEPIC BeadChip (Illumina, San Diego, California). Demographic data was analyzed using Chi-squared and T tests. Linear regressions were performed for each cytosine-guanine dinucleotide (CpG) site, modeling the logit transformation of the ß value as a linear function of the presence of endometriosis. Sensitivity analyses were conducted controlling for estradiol levels and menopausal status. Replication study performed evaluating for any association between CpGs reported in the literature and our findings. RESULTS: In total, 39,877 CpGs nominally associated with endometriosis (p < 0.05) after adjusting for age and cellular heterogeneity, although none remained significant after correction for multiple comparisons (FDR < 0.05). Pathway analysis of these CpGs showed enrichment in 68 biologic pathways involved in various endocrine, immunologic, oncologic, and cell regulation processes as well as embryologic reproductive tract development and function (FoxO, Wnt, and Hedgehog signaling). We identified 42,261 CpG sites in the literature reported to be associated with endometriosis; 2012 of these CpG sites were also significant in our cohort. CONCLUSION: We found 39,877 CpG sites that nominally associated with endometriosis (p < 0.05) after adjusting for age and cellular heterogeneity; however, none remained significant after correction for multiple comparisons (FDR < 0.05).

Polybrominated Biphenyl Exposure and Menstrual Cycle Function.

BACKGROUND: Brominated flame retardants, including polybrominated biphenyls (PBB), are persistent compounds reported to affect sex hormones in animals; less is known about potential effects in humans. An industrial accident in 1973-1974 exposed Michigan residents to PBB through contaminated food. We examined whether this exposure to PBB had long-term effects on menstrual cycle function. METHODS: In 2004-2006, we recruited reproductive-aged women in the Michigan PBB Registry who were not pregnant, lactating, or taking hormonal medications. Participants kept daily diaries and provided daily urine samples for up to 6 months. We assayed the urine samples for estrone 3-glucuronide (E13G), pregnanediol 3-glucuronide (Pd3G), and follicle stimulating hormone (FSH). We fit linear mixed models among women aged 35-42 years to describe the relation between serum PBB levels and log-transformed, creatinine-adjusted daily endocrine levels among women who were premenarchal during the exposure incident in 1973-1974 (n = 70). RESULTS: We observed that high (>3.0 parts per billion [ppb]) and medium (>1.0-3.0 ppb) PBB exposure were associated with lower E13G levels across the menstrual cycle and lower FSH levels during the follicular phase, compared with low PBB exposure (≤1.0 ppb). High PBB exposure was also associated with lower Pd3G levels across the cycle compared with low PBB exposure, whereas Pd3G levels were similar in women with medium and low PBB exposure. CONCLUSION: Our results are consistent with a hypothesized effect of exposure to an exogenous estrogen agonist but the modest sample size of the study requires cautious interpretation.

Rationale and Design of the Emory Healthy Aging and Emory Healthy Brain Studies.

Understanding the relationships between health and aging is essential for delaying morbidity and maximizing independence in aging populations as life expectancies increase. Loss of cognitive function is a feared age-associated condition and growing public health concern. Alzheimer's disease (AD), the most common cause of dementia, has no curative therapies. Characterizing the relationships between risk factors, biomarkers, and AD progression is critical for the development of effective disease prediction, clinical intervention, and ultimately, disease prevention. The Emory Healthy Aging Study (EHAS) and the Emory Healthy Brain Study (EHBS), which is nested within EHAS, aim to further the understanding of healthy aging and the pathogenesis of age-related illnesses in well-characterized, community-based prospective cohorts and to identify biomarkers for the earliest manifestations of AD for the facilitation of preventative interventions. The EHAS is an innovative, longitudinal, web-based study enrolling English-speaking adults in the U.S. who agree to be contacted for future studies. Using validated instruments, the annual questionnaire enquires about demographics, socioeconomics, self-reported cognitive function, personal and family medical history, lifestyle, and psychosocial factors. Cognitive assessments are also obtained using an ambulatory device. Nested within EHAS, the EHBS is enrolling up to 2,500 EHAS participants, 50-75 years old, who do not have a diagnosis of AD, mild cognitive impairment, or any other memory disorder. EHBS in-person, biennial study visits, include neuropsychological testing, cardiovascular measures, retinal and brain imaging, biospecimen collection (blood, cerebrospinal fluid, gut microbiome), and other assessments. Since spring 2016, EHAS and EHBS have enrolled 12,500 and 863 participants with completed baseline assessments, respectively. Data and biospecimens from EHBS participants will support a broad range of AD biomarker discovery efforts, and follow-up of EHAS participants will enable assessment of self-reported cognitive trajectories and accumulation of incident cases of a variety of health conditions. The EHAS design supports the interval deployment of new study instruments and targeted sampling for ancillary studies. This project will increase our knowledge about healthy aging, improve our understanding of risk factors for cognitive impairment and dementias, support development of biomarkers, and facilitate studies of age-associated disorders including AD.

Multigenerational metabolic profiling in the Michigan PBB registry.

Although polychlorinated biphenyls and polybrominated biphenyls are no longer manufactured the United States, biomonitoring in human populations show that exposure to these pollutants persist in human tissues. The objective of this study was to identify metabolic variations associated with exposure to 2,2'4,4',5,5'-hexabromobiphenyl (PBB-153) and 2,2'4,4',5,5'-hexachlorobiphenyl (PCB-153) in two generations of participants enrolled in the Michigan PBB Registry (http://pbbregistry.emory.edu/). Untargeted, high-resolution metabolomic profiling of plasma collected from 156 individuals was completed using liquid chromatography with high-resolution mass spectrometry. PBB-153 and PCB-153 levels were measured in the same individuals using targeted gas chromatography-tandem mass spectrometry and tested for dose-dependent correlation with the metabolome. Biological response to these exposures were evaluated using identified endogenous metabolites and pathway enrichment. When compared to lipid-adjusted concentrations for adults in the National Health and Nutrition Examination Survey (NHANES) for years 2003-2004, PCB-153 levels were consistent with similarly aged individuals, whereas PBB-153 concentrations were elevated (p<0.0001) in participants enrolled in the Michigan PBB Registry. Metabolic alterations were correlated with PBB-153 and PCB-153 in both generations of participants, and included changes in pathways related to catecholamine metabolism, cellular respiration, essential fatty acids, lipids and polyamine metabolism. These pathways were consistent with pathophysiological changes observed in neurodegenerative disease and included previously identified metabolomic markers of Parkinson's disease. To determine if the metabolic alterations detected in this study are replicated other cohorts, we evaluated correlation of PBB-153 and PCB-153 with plasma fatty acids measured in NHANES. Both pollutants showed similar associations with fatty acids previously linked to PCB exposure. Thus, the results from this study show metabolic alterations correlated with PBB-153 and PCB-153 exposure can be detected in human populations and are consistent with health outcomes previously reported in epidemiological and mechanistic studies.

Thyroid hormone levels associate with exposure to polychlorinated biphenyls and polybrominated biphenyls in adults exposed as children.

BACKGROUND: Michigan residents were directly exposed to endocrine-disrupting compounds, polybrominated biphenyl (PBB) and polychlorinated biphenyl (PCB). A growing body of evidence suggests that exposure to certain endocrine-disrupting compounds may affect thyroid function, especially in people exposed as children, but there are conflicting observations. In this study, we extend previous work by examining age of exposure's effect on the relationship between PBB exposure and thyroid function in a large group of individuals exposed to PBB. METHODS: Linear regression models were used to test the association between serum measures of thyroid function (total thyroxine (T4), total triiodothyronine (T3), free T4, free T3, thyroid stimulating hormone (TSH), and free T3: free T4 ratio) and serum PBB and PCB levels in a cross-sectional analysis of 715 participants in the Michigan PBB Registry. RESULTS: Higher PBB levels were associated with many thyroid hormones measures, including higher free T3 (p = 0.002), lower free T4 (p = 0.01), and higher free T3: free T4 ratio (p = 0.0001). Higher PCB levels were associated with higher free T4 (p = 0.0002), and higher free T3: free T4 ratio (p = 0.002). Importantly, the association between PBB and thyroid hormones was dependent on age at exposure. Among people exposed before age 16 (N = 446), higher PBB exposure was associated with higher total T3 (p = 0.01) and free T3 (p = 0.0003), lower free T4 (p = 0.04), and higher free T3: free T4 ratio (p = 0.0001). No significant associations were found among participants who were exposed after age 16. No significant associations were found between TSH and PBB or PCB in any of the analyses conducted. CONCLUSIONS: This suggests that both PBB and PCB are associated with thyroid function, particularly among those who were exposed as children or prenatally.

Thyroid hormones and menstrual cycle function in a longitudinal cohort of premenopausal women.

BACKGROUND: Previous studies have reported that hyperthyroid and hypothyroid women experience menstrual irregularities more often compared with euthyroid women, but reasons for this are not well-understood and studies on thyroid hormones among euthyroid women are lacking. In a prospective cohort study of euthyroid women, this study characterised the relationship between thyroid hormone concentrations and prospectively collected menstrual function outcomes. METHODS: Between 2004-2014, 86 euthyroid premenopausal women not lactating or taking hormonal medications participated in a study measuring menstrual function. Serum thyroid hormones were measured before the menstrual function study began. Women then collected first morning urine voids and completed daily bleeding diaries every day for three cycles. Urinary oestrogen and progesterone metabolites (estrone 3-glucuronide (E1 3G) and pregnanediol 3-glucuronide (Pd3G)) and follicle-stimulating hormone were measured and adjusted for creatinine (Cr). RESULTS: Total thyroxine (T4 ) concentrations were positively associated with Pd3G and E1 3G. Women with higher (vs lower) T4 had greater luteal phase maximum Pd3G (Pd3G = 11.7 µg/mg Cr for women with high T4 vs Pd3G = 9.5 and 8.1 µg/mg Cr for women with medium and low T4 , respectively) and greater follicular phase maximum E1 3G (E1 3G = 41.7 ng/mg Cr for women with high T4 vs E1 3G = 34.3 and 33.7 ng/mg Cr for women with medium and low T4 , respectively). CONCLUSIONS: Circulating thyroid hormone concentrations were associated with subtle differences in menstrual cycle function outcomes, particularly sex steroid hormone levels in healthy women. Results contribute to the understanding of the relationship between thyroid function and the menstrual cycle, and may have implications for fertility and chronic disease.

A joint modeling approach for multivariate survival data with random length.

In many biomedical studies that involve correlated data, an outcome is often repeatedly measured for each individual subject along with the number of these measurements, which is also treated as an observed outcome. This type of data has been referred as multivariate random length data by Barnhart and Sampson (1995). A common approach to handling such type of data is to jointly model the multiple measurements and the random length. In previous literature, a key assumption is the multivariate normality for the multiple measurements. Motivated by a reproductive study, we propose a new copula-based joint model which relaxes the normality assumption. Specifically, we adopt the Clayton-Oakes model for multiple measurements with flexible marginal distributions specified as semi-parametric transformation models. The random length is modeled via a generalized linear model. We develop an approximate EM algorithm to derive parameter estimators and standard errors of the estimators are obtained through bootstrapping procedures and the finite-sample performance of the proposed method is investigated using simulation studies. We apply our method to the Mount Sinai Study of Women Office Workers (MSSWOW), where women were prospectively followed for 1 year for studying fertility.

Predictors of Serum Polybrominated Diphenyl Ether (PBDE) Concentrations among Children Aged 1-5 Years.

Serum concentrations of PBDEs were measured using gas chromatography-tandem mass spectrometry in 80 children aged 15-71 months. Demographic and behavioral data were collected on parental questionnaires; a research nurse recorded anthropometric measures and insurance status. For a subset of children (n = 17), PBDEs were measured in house dust and child handwipes sampled during a home visit. In linear and Tobit regression, log-transformed PBDE congeners were modeled as a function of child characteristics, including neighborhood-level socioeconomic indicators. BDE congeners 47, 99, and 100 were highly correlated and summed for analysis; BDE-153 was examined individually. PBDE serum concentrations were associated with socioeconomic factors; for example, a $20,000 increase in median household income in a child's ZIP code was associated with a 34% decrease (95%CI = 14-49%) in BDE-153 and a 26% decrease (95%CI = 6-42%) in ∑BDE-47,-99,-100. Lower body-mass index (BMI) z-score and household smoking were strong predictors of higher BDE-153 levels. Among children who participated in a home visit, serum PBDE was positively correlated with handwipe PBDE (Spearman r ∑BDE-47, -99, -100 = 0.48, p = 0.09), but not dust PBDE. Results indicate socioeconomic factors and BMI are strong predictors of serum PBDE levels among young children. PBDEs measured on handwipes are more predictive of serum PBDE levels than vacuum-collected dust.

Exposure to phytoestrogens in utero and age at menarche in a contemporary British cohort.

Phytoestrogens are estrogenic compounds that occur naturally in plants. Phytoestrogens can cross the placenta, and animal studies have found associations between in utero exposure to phytoestrogens and markers of early puberty. We investigated the association between in utero exposure to phytoestrogens and early menarche (defined as <11.5 years of age at onset) using data from a nested case-control study within the Avon Longitudinal Study of Parents and Children, a longitudinal study involving families living in the South West of England. Concentrations of six phytoestrogens were measured in maternal urine samples collected during pregnancy. Logistic regression was used to explore associations between tertiles of phytoestrogen concentrations and menarche status, with adjustment for maternal age at menarche, maternal education, pre-pregnancy body mass index (BMI), child birth order, duration of breastfeeding, and gestational age at sample collection. Among 367 mother-daughter dyads, maternal median (interquartile range) creatinine-corrected concentrations (in µg/g creatinine) were: genistein 62.1 (27.1-160.9), daidzein 184.8 (88.8-383.7), equol 4.3 (2.8-9.0), O-desmethylangolensin (O-DMA) 13.0 (4.4-34.5), enterodiol 76.1 (39.1-135.8), and enterolactone 911.7 (448.1-1558.0). In analyses comparing those in the highest tertile relative to those in the lowest tertile of in utero phytoestrogen exposure, higher enterodiol levels were inversely associated with early menarche (odds ratio (OR)=0.47; 95% confidence interval (CI): 0.26-0.83), while higher O-DMA levels were associated with early menarche (OR=1.89; 95% CI: 1.04-3.42). These findings suggest that in utero exposure to phytoestrogens may be associated with earlier age at menarche, though the direction of association differs across phytoestrogens.

Quantile regression analysis of censored longitudinal data with irregular outcome-dependent follow-up.

In many observational longitudinal studies, the outcome of interest presents a skewed distribution, is subject to censoring due to detection limit or other reasons, and is observed at irregular times that may follow a outcome-dependent pattern. In this work, we consider quantile regression modeling of such longitudinal data, because quantile regression is generally robust in handling skewed and censored outcomes and is flexible to accommodate dynamic covariate-outcome relationships. Specifically, we study a longitudinal quantile regression model that specifies covariate effects on the marginal quantiles of the longitudinal outcome. Such a model is easy to interpret and can accommodate dynamic outcome profile changes over time. We propose estimation and inference procedures that can appropriately account for censoring and irregular outcome-dependent follow-up. Our proposals can be readily implemented based on existing software for quantile regression. We establish the asymptotic properties of the proposed estimator, including uniform consistency and weak convergence. Extensive simulations suggest good finite-sample performance of the new method. We also present an analysis of data from a long-term study of a population exposed to polybrominated biphenyls (PBB), which uncovers an inhomogeneous PBB elimination pattern that would not be detected by traditional longitudinal data analysis.

Breast cancer among women in Michigan following exposure to brominated flame retardants.

In this updated follow-up, we investigated the breast cancer experience among women in Michigan exposed to brominated flame retardants, some 30 years following exposure. Michigan residents were enrolled in a study cohort after exposure to polybrominated biphenyls (PBBs) through the consumption of contaminated food products. PBB concentrations were measured in serum at the time of enrolment. Cancer experience was determined by linkage to the Michigan Cancer Registry. We conducted a nested case-control study that included 51 women diagnosed with breast cancer during 1974-2004 and 202 age-matched controls. While the data suggest an increase in breast cancer risk with higher PBB exposure, this did not reach statistical significance. The OR of having breast cancer among women with PBB concentrations ≥10 ng/mL compared to women with PBB concentrations at or below the limit of detection of 1 ng/mL was 2.60, 95% CI 0.93 to 7.27, (p=0.07), when adjusted for age and family history of cancer in a first-degree female relative. It remains important to examine exposure to brominated chemicals and possible health effects, and to continue following the cancer experience of participants in this study.

Serum polybrominated diphenyl ether concentrations and thyroid function in young children.

Thyroid hormones are essential for proper neurodevelopment in early life. There is evidence that exposure to polybrominated diphenyl ethers (PBDEs) affects thyroid function, but previous studies have been inconsistent, and no studies among children have been conducted in the United States where PBDE levels are particularly high. Serum levels of seven PBDE congeners and thyroid hormones and other thyroid parameters were measured in 80 children aged 1-5 years from the southeastern United States between 2011 and 2012. Parents of the children completed questionnaires with details on demographics and behaviors. Multivariate linear regression models were used to estimate the associations between serum PBDE levels, expressed as quartiles and as log-transformed continuous variables, and markers of thyroid function. BDE-47, 99, 100 and 153 were detected in >60% of samples, and were summed (∑PBDE). PBDE congeners and ∑PBDE were positively associated with thyroid-stimulating hormone (TSH). A log-unit increase in ∑PBDE was associated with a 22.1% increase in TSH (95% CI: 2.0%, 47.7%). Compared with children in the lowest quartile of ∑PBDE exposure, children in higher quartiles had greater TSH concentrations as modeled on the log-scale (second quartile: ß=0.32, 95% confidence interval (CI): -0.09, 0.74; third quartile: ß=0.44, 95% CI: 0.04, 0.85; and fourth quartile: ß=0.49, 95% CI: 0.09, 0.89). There was also a tendency toward lower total T4 and higher free T3 with increasing PBDE exposure. Results suggest that exposure to PBDEs during childhood subclinically disrupts thyroid hormone function, with impacts in the direction of hypothyroidism.

Exploring autism spectrum disorder (ASD) and attention deficit disorder (ADD/ADHD) in children exposed to polybrominated biphenyl.

Background: Although the causes of attention-deficit/hyperactivity disorder (ADHD) and autism have not been identified, exposure to endocrine-disrupting chemicals, such as polybrominated biphenyl (PBB), during fetal development and early life has been suspected to impact neurological development. This study aims to investigate the association between prenatal and early life exposure to PBB and the development of ADHD and autism later in life. Methods: Data from the Michigan PBB Registry, a cohort of Michigan residents who had been exposed to PBB in a mass contamination event in 1973, was leveraged for this nested case-control analysis among two distinct samples: (1) Those who self-reported ADHD or autism diagnosis, and (2) mothers who reported their child's ADHD or autism diagnosis. PBB exposure was measured in participants of the PBB Registry, and the mother's PBB level was used in mother-reported analyses. Cases were matched with controls by sex and year of birth. Conditional logistic regression models were used to estimate the association between PBB level and case status. Results: PBB levels were higher among those who were exposed in early life compared with those exposed in utero (geometric mean: 0.300 ng/ml vs. 0.016 ng/ml). Among women in this cohort, a higher than expected proportion of self-reported ADHD diagnosis (11.11%), compared with population estimates. PBB was not associated with ADHD or autism in either self-reported or mother-reported analyses. Conclusions: This study adds to the sparse literature about prenatal and early life exposure to PBB-153 and ADHD and autism. Future studies should examine potential effect modification by sex.