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1.  Data Acquisition and Preprocessing in Studies on Humans: What Is Not Taught in Statistics Classes? 
The American statistician  2013;67(4):235-241.
The aim of this paper is to address issues in research that may be missing from statistics classes and important for (bio-)statistics students. In the context of a case study, we discuss data acquisition and preprocessing steps that fill the gap between research questions posed by subject matter scientists and statistical methodology for formal inference. Issues include participant recruitment, data collection training and standardization, variable coding, data review and verification, data cleaning and editing, and documentation. Despite the critical importance of these details in research, most of these issues are rarely discussed in an applied statistics program. One reason for the lack of more formal training is the difficulty in addressing the many challenges that can possibly arise in the course of a study in a systematic way. This article can help to bridge this gap between research questions and formal statistical inference by using an illustrative case study for a discussion. We hope that reading and discussing this paper and practicing data preprocessing exercises will sensitize statistics students to these important issues and achieve optimal conduct, quality control, analysis, and interpretation of a study.
doi:10.1080/00031305.2013.842498
PMCID: PMC3912269  PMID: 24511148
Statistical education; Applied statistics courses; Quality control; Data collection; Data cleaning; Data code book; Data dictionary
2.  Gender-specific differences in birthweight and the odds of puberty: NHANES III, 1988–94 
Summary
The association between birthweight and the odds ratio (OR) of pubertal status in girls aged between 8 and 11 and in boys aged between 8 and 12 was examined using the 1988–94 Third National Health and Nutrition Examination Survey (NHANES III). Girls (n = 956), and boys (n = 1199), who had data on birthweight and Tanner staging were included. Maternal-reported birthweight, smoking in pregnancy and other information were provided in a home interview, while Tanner staging to assess pubertal status was part of a medical examination. Multiple logistic regression models were computed for the endpoints of the OR [95% confidence interval (CI)] of being Tanner Stage 2+ vs. 1 or being 2+ vs. 1 in an asynchronous pubertal pathway after adjustment for the complex sampling design of NHANES, age, race, height and body mass index (BMI).
Birthweight was not associated with the OR of Tanner stage 2+ among girls; however, boys who were low birthweight (<2500 g) and boys born higher than average birthweight (3500–3999 g) were more likely to be Tanner stage 2+ than 1. Childhood BMI was associated with the OR of having entered puberty among girls, but not boys. In an analysis of asynchronous maturation, girls born at high birthweight (>4000 g) were more likely to have breast development 3+ than girls of normal birthweight, OR = 3.18 [95% CI 1.39, 8.25]. Thus, the birthweight–puberty association varies by gender and by pubertal pathway. Our findings need replication in prospective longitudinal studies, and research to understand the mechanisms underlying the relation of early life exposures to cancer risk.
doi:10.1111/j.1365-3016.2010.01097.x
PMCID: PMC4119173  PMID: 20415751
puberty; birthweight; childhood BMI; NHANES
3.  Menopausal Hormone Therapy and Lung Cancer-Specific Mortality Following Diagnosis: The California Teachers Study 
PLoS ONE  2014;9(7):e103735.
Previous results from research on menopausal hormone therapy (MHT) and lung cancer survival have been mixed and most have not studied women who used estrogen therapy (ET) exclusively. We examined the associations between MHT use reported at baseline and lung cancer-specific mortality in the prospective California Teachers Study cohort. Among 727 postmenopausal women diagnosed with lung cancer from 1995 through 2007, 441 women died before January 1, 2008. Hazard Ratios (HR) and 95% Confidence Intervals (CI) for lung-cancer-specific mortality were obtained by fitting multivariable Cox proportional hazards regression models using age in days as the timescale. Among women who used ET exclusively, decreases in lung cancer mortality were observed (HR, 0.69; 95% CI, 0.52–0.93). No association was observed for estrogen plus progestin therapy use. Among former users, shorter duration (<5 years) of exclusive ET use was associated with a decreased risk of lung cancer mortality (HR, 0.56; 95% CI, 0.35–0.89), whereas among recent users, longer duration (>15 years) was associated with a decreased risk (HR, 0.60; 95% CI, 0.38–0.95). Smoking status modified the associations with deceases in lung cancer mortality observed only among current smokers. Exclusive ET use was associated with decreased lung cancer mortality.
doi:10.1371/journal.pone.0103735
PMCID: PMC4117568  PMID: 25079077
4.  Childhood Abuse and Age at Menarche 
Purpose
Physical and sexual abuse are prevalent social hazards. We sought to examine the association between childhood physical and sexual abuse and age at menarche.
Methods
Among 68,505 participants enrolled in the Nurses’ Health Study II we investigated the association between childhood physical abuse and sexual abuse on menarche prior to age 11 (early) or after age 15 (late) using multivariate logistic regression analysis, mutually adjusting for both types of abuse.
Results
Fifty-seven percent of respondents reported some form of physical or sexual abuse in childhood. We found a positive dose-response association between severity of sexual abuse in childhood and risk for early menarche. Compared to women who reported no childhood sexual abuse, the adjusted odds ratio [AOR] for early menarche was 1.20 (95% confidence interval [CI], 1.10, 1.37) for sexual touching and 1.49 (95% CI, 1.34, 1.66) for forced sexual activity. Only severe physical abuse predicted early menarche (AOR=1.22, 95% CI, 1.10–1.37). Childhood physical abuse had a dose-response association with late age at menarche: AOR 1.17 (95% CI, 1.04, 1.32) for mild, 1.20 (95% CI, 1.08, 1.33) for moderate, and 1.50 (95% CI, 1.27, 1.77) for severe physical abuse. Sexual abuse was not associated with late menarche.
Conclusion
Childhood abuse was very prevalent in this large cohort of U.S. women. Severity of childhood sexual abuse was associated with risk for early onset of menarche, and physical abuse was associated with both early and late onset menarche.
Implications and Contribution
The severity of childhood sexual abuse and severe physical abuse were associated with risk for accelerated menarche, while severity of childhood physical was associated with risk for delayed onset of menarche. The nature of the association between different forms of childhood adversities and reproductive lifespan may vary.
doi:10.1016/j.jadohealth.2012.06.006
PMCID: PMC3950206  PMID: 23332491
menarche; adversities; child abuse; emotional support
5.  PARENTAL SMOKING IN PREGNANCY AND THE RISKS OF ADULT ONSET HYPERTENSION 
Hypertension  2012;61(2):494-500.
Fetal exposure to parental smoking may lead to developmental adaptations and promote various diseases in later life. This study evaluated the associations of parental smoking during pregnancy with the risk of hypertension in the daughter in adulthood, and assessed whether these associations are explained by birth weight or body weight throughout life. We used data on 33,086 participants of the Nurses’ Health Study II and the Nurses’ Mothers’ Cohort. Cox proportional hazards models were used to examine the associations of maternal and paternal smoking during pregnancy with the nurse daughter, with self-reported physician-diagnosed hypertension from 1989 until 2007. Overall, 8,575 (25.9%) mothers and 18,874 (57.0%) fathers smoked during pregnancy. During follow-up, 7,825 incident cases of adult-onset hypertension were reported. Both maternal and paternal smoking of ≥15 cigarettes/day during pregnancy were associated with increased risks of hypertension (RR 1.19, 95% CI 1.09 to 1.29, and RR 1.18, 95% CI 1.12 to 1.25, respectively) in the age-adjusted models. Further adjustment for birth weight did not affect the effect estimates appreciably, while additional adjustment for body shape and weight until age 18, or current body mass index, attenuated the associations with both maternal and paternal smoking (RR 1.07, 95% CI 0.98 to 1.16, and RR 1.06, 95% CI 1.01 to 1.12, respectively). The associations of parental smoking during pregnancy with the risk of hypertension in the offspring were largely explained by body weight throughout life, suggesting that these associations may not reflect direct intrauterine mechanisms.
doi:10.1161/HYPERTENSIONAHA.111.200907
PMCID: PMC3606889  PMID: 23266542
Pregnancy; parental smoking; hypertension; body mass index
6.  IGF2/H19 methylation at birth and risk of overweight and obesity in children 
The Journal of Pediatrics  2012;161(1):31-39.
Objective
To determine if aberrant DNA methylation at differentially methylated regions (DMRs) regulating Insulin-like Growth Factor 2 (IGF2) expression in umbilical cord blood (UCB) is associated with overweight or obesity in a multiethnic cohort.
Study design
UCB leukocytes of 204 infants born between 2005 and 2009 in Durham, NC were analyzed for DNA methylation at two IGF2 DMRs using Pyrosequencing. Anthropometric and feeding data were collected at age one year. Methylation differences were compared between children >85th percentile of CDC weight-for-age (WFA) and those ≤85th percentile of WFA at one year using generalized linear models, adjusting for post-natal caloric intake, maternal cigarette smoking and race/ethnicity.
Results
The methylation percentages at the H19 imprint center DMR was higher in infants with WFA>85th percentile (62.7%, 95%CI=59.9–65.5%) compared with infants with WFA≤85th percentile (59.3%, 95%CI=58.2–60.3), (p=0.02). At the intragenic IGF2 DMR, methylation levels were comparable between infants with WFA≤85th and those with WFA>85th percentile.
Conclusions
Our findings suggest that IGF2 plasticity may be mechanistically important in early childhood overweight or obese status. If confirmed in larger studies, findings suggest aberrant DNA methylation at sequences regulating imprinted genes may be useful identifiers of children at risk for early obesity.
doi:10.1016/j.jpeds.2012.01.015
PMCID: PMC3360130  PMID: 22341586
Obesity; Breast Feeding; Child; DNA Methylation; Epigenetics; Genetic; Insulin-Like Growth Factor II
7.  Maternal BMI, IGF-I Levels, and Birth Weight in African American and White Infants 
At birth, elevated IGF-I levels have been linked to birth weight extremes; high birth weight and low birth weight are risk factors for adult-onset chronic diseases including obesity, cardiovascular disease, and type 2 diabetes. We examined associations between plasma IGF-I levels and birth weight among infants born to African American and White obese and nonobese women. Prepregnancy weight and height were assessed among 251 pregnant women and anthropometric measurements of full term infants (≥37 weeks of gestation) were taken at birth. Circulating IGF-I was measured by ELISA in umbilical cord blood plasma. Linear regression models were utilized to examine associations between birth weight and high IGF-I, using the bottom two tertiles as referents. Compared with infants with lower IGF-I levels (≤3rd tertile), those with higher IGF-I levels (>3rd tertile) were 130 g heavier at birth, (β-coefficient = 230, se = 58.0, P = 0.0001), after adjusting for gender, race/ethnicity, gestational age, delivery route, maternal BMI and smoking. Stratified analyses suggested that these associations are more pronounced in infants born to African American women and women with BMI ≥30 kg/m2; the cross product term for IGF-I and maternal BMI was statistically significant (P ≤ 0.0004). Our findings suggest that the association between IGF-I levels and birth weight depends more on maternal obesity than African American race/ethnicity.
doi:10.1155/2013/191472
PMCID: PMC3686113  PMID: 23861689
8.  Associations between Dietary Intake of Choline and Betaine and Lung Cancer Risk 
PLoS ONE  2013;8(2):e54561.
Evidence from human and animal research indicates that choline metabolic pathways may be activated during a variety of diseases, including cancer. We report results of a case-control study of 2821 lung cancer cases and 2923 controls that assessed associations of choline and betaine dietary intakes with lung cancer. Using multivariable logistic regression analyses, we report a significant association between higher betaine intake and lower lung cancer risk that varied by smoking status. Specifically, no significant association was observed between betaine intake and lung cancer among never-smokers. However, higher betaine intake was significantly associated with reduced lung cancer risk among smokers, and the protective effect was more evident among current than former smokers: for former and current smokers, the ORs (95% CI) of lung cancer for individuals with highest as compared to lowest quartiles of intake were 0.70(0.55–0.88) and 0.51(0.39–0.66) respectively. Significant linear trend of higher betaine intake and lower lung cancer risk was observed among both former (ptrend = 0.002) and current (ptrend<0.0001) smokers. A similar protective effect was also observed with choline intake both in overall analysis as well as among current smokers, with p-values for chi-square tests being 0.001 and 0.004 respectively, but the effect was less evident, as no linear trend was observed. Our results suggest that choline and betaine intake, especially higher betaine intake, may be protective against lung cancer through mitigating the adverse effect of smoking.
doi:10.1371/journal.pone.0054561
PMCID: PMC3562321  PMID: 23383301
9.  Investigating Multiple Candidate Genes and Nutrients in the Folate Metabolism Pathway to Detect Genetic and Nutritional Risk Factors for Lung Cancer 
PLoS ONE  2013;8(1):e53475.
Purpose
Folate metabolism, with its importance to DNA repair, provides a promising region for genetic investigation of lung cancer risk. This project investigates genes (MTHFR, MTR, MTRR, CBS, SHMT1, TYMS), folate metabolism related nutrients (B vitamins, methionine, choline, and betaine) and their gene-nutrient interactions.
Methods
We analyzed 115 tag single nucleotide polymorphisms (SNPs) and 15 nutrients from 1239 and 1692 non-Hispanic white, histologically-confirmed lung cancer cases and controls, respectively, using stochastic search variable selection (a Bayesian model averaging approach). Analyses were stratified by current, former, and never smoking status.
Results
Rs6893114 in MTRR (odds ratio [OR] = 2.10; 95% credible interval [CI]: 1.20–3.48) and alcohol (drinkers vs. non-drinkers, OR = 0.48; 95% CI: 0.26–0.84) were associated with lung cancer risk in current smokers. Rs13170530 in MTRR (OR = 1.70; 95% CI: 1.10–2.87) and two SNP*nutrient interactions [betaine*rs2658161 (OR = 0.42; 95% CI: 0.19–0.88) and betaine*rs16948305 (OR = 0.54; 95% CI: 0.30–0.91)] were associated with lung cancer risk in former smokers. SNPs in MTRR (rs13162612; OR = 0.25; 95% CI: 0.11–0.58; rs10512948; OR = 0.61; 95% CI: 0.41–0.90; rs2924471; OR = 3.31; 95% CI: 1.66–6.59), and MTHFR (rs9651118; OR = 0.63; 95% CI: 0.43–0.95) and three SNP*nutrient interactions (choline*rs10475407; OR = 1.62; 95% CI: 1.11–2.42; choline*rs11134290; OR = 0.51; 95% CI: 0.27–0.92; and riboflavin*rs8767412; OR = 0.40; 95% CI: 0.15–0.95) were associated with lung cancer risk in never smokers.
Conclusions
This study identified possible nutrient and genetic factors related to folate metabolism associated with lung cancer risk, which could potentially lead to nutritional interventions tailored by smoking status to reduce lung cancer risk.
doi:10.1371/journal.pone.0053475
PMCID: PMC3553105  PMID: 23372658
10.  Life-course origins of the ages at menarche and menopause 
A woman’s age at menarche (first menstrual period) and her age at menopause are the alpha and omega of her reproductive years. The timing of these milestones is critical for a woman’s health trajectory over her lifespan, as they are indicators of ovarian function and aging. Both early and late timing of either event are associated with risk for adverse health and psychosocial outcomes. Thus, the search for a relationship between age at menarche and menopause has consequences for chronic disease prevention and implications for public health. This article is a review of evidence from the fields of developmental biology, epidemiology, nutrition, demography, sociology, and psychology that examine the menarche–menopause connection. Trends in ages at menarche and menopause worldwide and in subpopulations are presented; however, challenges exist in constructing trends. Among 36 studies that examine the association between the two sentinel events, ten reported a significant direct association, two an inverse association, and the remainder had null findings. Multiple factors, including hormonal and environmental exposures, socioeconomic status, and stress throughout the life course are hypothesized to influence the tempo of growth, including body size and height, development, menarche, menopause, and the aging process in women. The complexity of these factors and the pathways related to their effects on each sentinel event complicate evaluation of the relationship between menarche and menopause. Limitations of past investigations are discussed, including lack of comparability of socioeconomic status indicators and biomarker use across studies, while minority group differences have received scant attention. Suggestions for future directions are proposed. As research across endocrinology, epidemiology, and the social sciences becomes more integrated, the confluence of perspectives will yield a richer understanding of the influences on the tempo of a woman’s reproductive life cycle as well as accelerate progress toward more sophisticated preventive strategies for chronic disease.
doi:10.2147/AHMT.S15946
PMCID: PMC3912848  PMID: 24600293
reproductive aging; growth; socioeconomic status; biomarker; ovarian function
11.  Intake of red meat and heterocyclic amines, metabolic pathway genes and bladder cancer risk 
We analyzed the association between meat intake, heterocyclic amines (HCAs) and bladder cancer (BC) risk in a large case-control study comprised of 884 BC cases and 878 healthy controls, recruited from 1999 to 2009. Epidemiologic and dietary data were collected via an in-person interview. Compared to the lowest quartile of red meat intake, the odds ratios (ORs) for the second, third and fourth quartiles were 1.17 (95% CI: 0.87–1.58), 1.47 (95% CI: 1.09–1.99) and 1.95 (95% CI: 1.41–2.68), respectively, (p-for trend <0.001). In a subset of participants with intakes of HCAs available, compared with those with the lowest quartile of intake, the ORs for the second, third and fourth quartiles were 1.47 (95% CI: 0.60–3.64), 2.58 (95% CI: 1.09–6.11) and 3.32 (95% CI: 1.37–8.01), respectively, (p for trend <0.001). In cumulative analysis of SNPs in the pathway, compared with subjects carrying 0–4 unfavorable genotypes, subjects carrying 5 and 6 or more unfavorable genotypes were at 1.60-fold (95% CI: 1.20–2.12) and 2.37-fold (95% CI: 1.82–3.10) increased risk, respectively. Moreover, subjects carrying six or more unfavorable genotypes and whose red meat intake was in the highest quartile were at 5.09-fold increased risk (95% CI: 2.89–8.96; p < 0.001). These results strongly support that high red meat intake, high intake of HCAs and carrying high number of unfavorable genotypes in the HCA metabolic pathways are associated with increased risk of BC in the study population.
doi:10.1002/ijc.27437
PMCID: PMC3415602  PMID: 22261697
bladder cancer risk; red meat intake; heterocyclic amines
12.  Gestational Weight Gain and Daughter's Age at Menarche 
Journal of Women's Health  2011;20(8):1193-1200.
Abstract
Background
Sexual development begins in utero and enters a dormant phase during infancy. The influence of maternal gestational weight gain (GWG) on daughter's age at menarche has not been explored.
Methods
We investigated the association between maternal GWG and age at menarche (<11 years, 11–15 years, >15 years of age) in a large cohort study of U.S. nurses, The Nurses' Health Study II (NHS II), and the Nurses' Mothers' Cohort Study.
Results
Among 32,218 respondents, 7% reported age at menarche age 15. Compared with women whose mothers gained 20–29 lbs during pregnancy, those whose mothers reported <10 lbs or >40 lbs of GWG were 30% more likely to report early onset menarche (<11 years of age) in logistic regression models adjusted for sociodemographic and maternal characteristics, and childhood body size and physical activity: adjusted odds ratio (OR) 1.31, 95% confidence interval (CI) 1.05-1.62, and 1.27, 95% CI 1.06-1.56. Maternal GWG was not associated with late menarche in the fully adjusted model (ptrend=0.07).
Conclusions
These results suggest that either extreme of maternal GWG may influence risk for early age at menarche in daughters. Maternal GWG may be a modifiable risk factor for early menarche.
doi:10.1089/jwh.2010.2517
PMCID: PMC3153868  PMID: 21711153
13.  Gestational Vitamin D and the Risk of Multiple Sclerosis in the Offspring 
Annals of neurology  2011;70(1):30-40.
Background
Vitamin D may have a protective role in the etiology of multiple sclerosis (MS), but the effect of gestational vitamin D on adult onset MS has not been studied.
Methods
In 2001, 35,794 mothers of participants of the Nurses’ Health Study II completed a questionnaire inquiring about their experiences and diet during pregnancy with their nurse-daughter. We studied the association of maternal milk intake, maternal dietary vitamin D intake, and predicted maternal serum 25-hydroxyvitamin D (25(OH)D) during pregnancy and their daughters’ risk of developing MS.
Results
MS was diagnosed in 199 women. The relative risk (RR) of MS was lower among women born to mothers with high milk or vitamin D intake during pregnancy. The multivariate adjusted RR of MS was 0.62 (95% CI: 0.40– 0.95; p trend=0.001) for nurses whose mothers consumed 2–3 glasses of milk per day compared with those whose mothers consumed fewer than 3 glasses per month, and 0.57 (95% CI: 0.35–0.91; p trend=0.002) for nurses with mothers in the highest quintile of dietary vitamin D intake compared with those in the lowest. The predicted 25(OH) vitamin D level in the pregnant mothers was also inversely associated with the risk of MS in their daughters. Comparing extreme quintiles the adjusted RR was 0.59; (95% CI: 0.37–0.92; p trend =0.002).
Conclusion
Higher maternal milk and vitamin D intake during pregnancy may be associated with a lower risk of developing MS in the offspring.
doi:10.1002/ana.22456
PMCID: PMC3205990  PMID: 21786297
Multiple sclerosis; Epidemiology; prenatal; vitamin D
14.  Depression in pregnancy, infant birth weight and DNA methylation of imprint regulatory elements 
Epigenetics  2012;7(7):735-746.
Depressed mood in pregnancy has been linked to low birth weight (LBW, < 2,500 g), a risk factor for adult-onset chronic diseases in offspring. We examined maternal depressed mood in relation to birth weight and evaluated the role of DNA methylation at regulatory sequences of imprinted genes in this association. We measured depressed mood among 922 pregnant women using the CES-D scale and obtained birth weight data from hospital records. Using bisulfite pyrosequencing of cord blood DNA from 508 infants, we measured methylation at differentially methylated regions (DMRs) regulating imprinted genes IGF2/H19, DLK1/MEG3, MEST, PEG3, PEG10/SGCE, NNAT and PLAGL1. Multiple regression models were used to examine the relationship between depressed mood, birth weight and DMR methylation levels. Depressed mood was associated with a more that 3-fold higher risk of LBW, after adjusting for delivery mode, parity, education, cigarette smoking, folic acid use and preterm birth. The association may be more pronounced in offspring of black women and female infants. Compared with infants of women without depressed mood, infants born to women with severe depressed mood had a 2.4% higher methylation at the MEG3 DMR. Whereas LBW infants had 1.6% lower methylation at the IGF2 DMR, high birth weight (> 4,500 g) infants had 5.9% higher methylation at the PLAGL1 DMR compared with normal birth weight infants. Our findings confirm that severe maternal depressed mood in pregnancy is associated with LBW, and that MEG3 and IGF2 plasticity may play important roles.
doi:10.4161/epi.20734
PMCID: PMC3414394  PMID: 22677950
depression; DNA Methylation; epigenetics; fetal growth retardation; health status disparities; low birth weight
15.  Dietary α-, β-, γ- and δ-tocopherols in lung cancer risk 
Studies of vitamin E and cancer have focused on the α-tocopherol form of the vitamin. However, other forms of vitamin E, in particular γ-tocopherol may have unique mechanistic characteristics relevant to lung cancer prevention. In an ongoing study of 1,088 incident lung cancer cases and 1,414 healthy matched controls, we studied the associations between 4 tocopherols (α-, β-, γ-, and δ-tocopherol) in the diet and lung cancer risk. Using multiple logistic regression analysis, the adjusted odds ratios (OR) and 95% confidence intervals (CI) of lung cancer for increasing quartiles of dietary α-tocopherol intake were 1.0, 0.63 (0.50–0.79), 0.58 (0.44–0.76) and 0.39 (0.28–0.53), respectively (p-trend < 0.0001). For dietary intake of β-tocopherol, the OR and 95% CI for all subjects were: 1.0, 0.79 (0.63–0.98), 0.59 (0.45–0.78) and 0.56 (0.42–0.74), respectively (p-trend < 0.0001). Similar results for dietary γ-tocopherol intake were observed: 1.0, 0.84 (0.67–1.06), 0.76 (0.59–0.97) and 0.56 (0.42–0.75), respectively (p- trend = 0.0002). No significant association between δ-tocopherol intake and lung cancer risk was detected. When the 4 tocopherols were summed as total tocopherol intake, a monotonic risk reduction was also observed. When we entered the other tocopherols in our model, only the association with dietary α-tocopherol intake remained significant; i.e., increasing intake of dietary α-tocopherol accounted for 34–53% reductions in lung cancer risk. To the best of our knowledge, this is the first report of the independent associations of the 4 forms of dietary tocopherol (α-, β-, γ- and δ-tocohperol) on lung cancer risk. Given the limitations with case-control studies, these findings need to be confirmed in further investigations.
doi:10.1002/ijc.23649
PMCID: PMC3380426  PMID: 18546288
dietary tocopherols; lung cancer risk; diet and lung cancer; vitamin E and lung cancer
16.  Psychosocial Risk and Correlates of Early Menarche in Mexican-American Girls 
American Journal of Epidemiology  2011;173(10):1203-1210.
Mexican-American girls have one of the fastest rates of decline in age at menarche. To date, no study has addressed the role of psychosocial factors on age at menarche in this population. Using data from a longitudinal cohort of Mexican-American girls from the Houston, Texas, metropolitan area recruited in 2005, the authors investigated associations between family life and socioeconomic environment and age at menarche in 523 girls. After adjusting for maternal age at menarche, daughter's age, and body mass index at baseline, perception of family life environment as conflict-prone was significantly associated with an earlier age at menarche (< 11 years). Additionally, there was a 2-fold higher risk (odds ratio = 2.22, 95% confidence interval: 1.12, 4.40) of early menarche among daughters of mothers who were single parents compared with those who were not. Furthermore, girls who matured early had a 2.5-fold increased risk (odds ratio = 2.69, 95% confidence interval: 1.04, 6.96) of experimenting with cigarettes compared with those who had an average-to-late age at menarche (≥ 11 years). This study provides important information regarding the role of family life environment and single parenting on age at menarche in Mexican Americans. Awareness of the impact of the family life environment and fathers’ absence during the early years should be emphasized when addressing early age at menarche across cultures.
doi:10.1093/aje/kwq498
PMCID: PMC3121322  PMID: 21454827
family cohesion; family conflict; menarche; Mexican Americans; single parenting; smoking; social support
17.  Association of cord blood methylation fractions at imprinted insulin-like growth factor 2 (IGF2), plasma IGF2, and birth weight 
Cancer Causes & Control  2012;23(4):635-645.
Purpose
Altered methylation at Insulin-like Growth Factor 2 (IGF2) regulatory regions has previously been associated with obesity, and several malignancies including colon, esophageal, and prostate adenocarcinomas, presumably via changes in expression and/or loss of imprinting, but the functional significance of these DNA methylation marks have not been demonstrated in humans. We examined associations among DNA methylation at IGF2 differentially methylated regions (DMRs), circulating IGF2 protein concentrations in umbilical cord blood (UCB) and birth weight in newborns.
Methods
Questionnaire data were obtained from 300 pregnant women recruited between 2005 and 2009. UCB DNA methylation was measured by bisulfite pyrosequencing. UCB plasma concentrations of soluble IGF2 were measured by ELISA assays. Generalized linear regression models were used to examine the relationship between DMR methylation and IGF2 levels.
Results
Lower IGF2 DMR methylation was associated with elevated plasma IGF2 protein concentrations (β = −9.87, p < 0.01); an association that was stronger in infants born to obese women (pre-pregnancy BMI > 30 kg/m2, β = −20.21, p < 0.0001). Elevated IGF2 concentrations were associated with higher birth weight (p < 0.0001) after adjusting for maternal race/ethnicity, pre-pregnancy BMI, cigarette smoking, gestational diabetes, and infant sex. These patterns of association were not apparent at the H19 DMR.
Conclusion
Our data suggest that variation in IGF2 DMR methylation is an important mechanism by which circulating IGF2 concentrations, a putative risk factor for obesity and cancers of the colon, esophagus, and prostate, are modulated; associations that may depend on pre-pregnancy obesity.
doi:10.1007/s10552-012-9932-y
PMCID: PMC3313040  PMID: 22392079
IGF2; H19; ELISA; DNA methylation; Epigenetics; Epidemiology
18.  MENOPAUSAL HORMONE THERAPY DOES NOT INFLUENCE LUNG CANCER RISK: RESULTS FROM THE CALIFORNIA TEACHERS STUDY 
Background
Results from studies examining the association between hormone therapy (HT) and lung cancer risk disagree.
Methods
We examined the associations between HT use and lung cancer risk among 60,592 postmenopausal women enrolled in the prospective California Teachers Study cohort. Between 1995 and 2007, 727 women were diagnosed with lung cancer. Multivariable Cox proportional hazards regression models were fit using age as the time metric.
Results
No measure of HT use was associated with lung cancer risk (all p-values for trend≥0.4). In addition, no variations in risk by smoking status (never, ever, former, current), type of HT (E-alone, E+P use), type of menopause, or lung cancer histology were observed.
Conclusions
Our findings do not support an association between HT and lung cancer.
Impact
This large-scale, prospective study, which capitalizes on the detailed hormone use, smoking history, and type of menopause information available within this unique cohort, was unable to find any association between intake of HT and lung cancer risk.
doi:10.1158/1055-9965.EPI-10-1182
PMCID: PMC3065239  PMID: 21266521
19.  Serum estrogen and tumor-positive estrogen receptor-alpha are strong prognostic classifiers of non-small-cell lung cancer survival in both men and women 
Carcinogenesis  2010;31(10):1778-1786.
The role of tumor estrogen receptors (ERs) and serum estrogen in lung cancer is inconclusive. We investigated the hypothesis that ERs and functional single-nucleotide polymorphisms in the estrogen biosynthesis pathway are associated with poorer lung cancer survival. Lung cancer patients (n = 305) from a National Cancer Institute-Maryland (NCI-MD) case–case cohort in the Baltimore metropolitan area were used as a test cohort. To validate, 227 cases from the NCI-MD case–control cohort and 293 cases from a Norwegian lung cancer cohort were studied. Information on demographics, tobacco and reproductive histories was collected in an interviewer-administered questionnaire. Serum estrogen, progesterone, tumor messenger RNA expression of hormone receptors and germ line DNA polymorphisms were analyzed for associations with lung cancer survival. Patients in the highest tertile of serum estrogen had worse survival in all three cohorts (P combined < 0.001). Furthermore, the variant allele of estrogen receptor alpha (ER-α) polymorphism (rs2228480) was significantly associated with increased tumor ER-α levels and worse survival in all three cohorts [hazard ratio (HR) = 2.59, 95% confidence interval (CI): 1.20– 4.01; HR = 1.76, 95% CI: 1.08–2.87 and HR = 2.85, 95% CI: 1.31–4.36). Other polymorphisms associated with lower serum estrogen correlated with improved survival. Results were independent of gender and hormone replacement therapy. We report a significant association of increased serum estrogen with poorer survival among lung cancer male and female patients. Understanding the genetic control of estrogen biosynthesis and response in lung cancer could lead to improved prognosis and therapy.
doi:10.1093/carcin/bgq156
PMCID: PMC2981456  PMID: 20729390
20.  Pubertal Development in Mexican American Girls: The Family’s Perspective 
Qualitative health research  2009;19(9):1210-1222.
Mexican American (MA) girls are entering puberty earlier than in the past, yet few studies have explored the perceptions surrounding puberty among this group. We conducted separate focus groups for fathers, mothers, and daughters aged 6 to 12 years to explore perceptions of body image, pubertal development, communications, and sources of puberty-related information in MA participants. Our results revealed parental concerns about daughters’ weight and pubertal development, as well as differences in their communication with their daughters. Although both parents willingly discussed pubertal issues concerning their daughters, mothers had a more active role in conveying pubertal information to daughters. Among the girls, there was a gap in knowledge about the pubertal process between the younger and older girls. Our findings present opportunities and challenges for addressing obesity as a pubertal risk factor in MA girls; however, more studies are needed to understand family beliefs and sociocultural dynamics surrounding puberty in MAs.
doi:10.1177/1049732309344326
PMCID: PMC3183834  PMID: 19690203
adolescents; female; body image; families; fathers; focus groups; Mexican Americans; relationships; mother–child; women’s health; young women
21.  Mineral intake and lung cancer risk in the NIH-AARP Diet and Health Study 
Background
Using data from a case-control study, we previously reported that low dietary intakes of magnesium (Mg), iron (Fe), zinc (Zn), copper (Cu), but not selenium (Se) and calcium (Ca) were associated with increased lung cancer risk. Due to dietary recall bias in case-control studies our objective was to assess whether these findings hold in a prospective cohort study.
Methods
We analyzed data from the NIH-AARP Diet and Health study of 482,875 subjects (288,257 men and 194,618 women) who were cancer-free and completed a food frequency questionnaire (FFQ) at enrollment between 1995 and 2003. Cox proportional hazards models were computed to estimate the relative risk (RR) adjusted for potential confounders.
Results
During a mean follow-up of 7 years, 7,052 lung cancer cases were identified. For all subjects, we observed no significant associations between total (diet + supplement) Ca, Mg, Fe, Cu, Se, and Zn intakes and lung cancer risk. Total Ca intake was protective (P-trend<0.05) for current smokers and subjects with adenocarcinomas. Total Mg intake increased risk (P-trend<0.05) in men and current smokers. Total Fe intake was inversely associated with risk in women (P-trend<0.01). For dietary minerals, Mg increased risk (P-trend<0.05) in all subjects, among men and current smokers. Increased dietary Ca intake reduced risk in women (P-trend=0.05). Dietary Fe decreased risk in all subjects and among women (P-trend<0.05). Mineral intake from supplements did not affect lung cancer risk.
Conclusions
Dietary mineral consumption may influence lung cancer risk, but the associations differ by type of mineral and population subgroups.
doi:10.1158/1055-9965.EPI-10-0067
PMCID: PMC2921219  PMID: 20696660
Diet; minerals; lung cancer; smoking
22.  Preeclampsia and Adiponectin in Cord Blood 
Aims
To compare cord blood concentrations of total adiponectin in the offspring of pregnancies with and without preeclampsia.
Methods
Using a Luminex analyzer, cord blood adiponectin was measured in 182 singleton pregnancies with preeclampsia and compared to adiponectin measured in 511 singleton pregnancies without preeclampsia.
Results
Adiponectin levels in cord blood increased with increasing gestational age, but overall, crude levels were similar in pregnancies with and without preeclampsia. However, in pregnancies with early delivery (weeks 32–36), and in pregnancies with delivery after spontaneous contractions, adiponectin levels were higher in the preeclampsia group.
Conclusion
In preterm pregnancies and in pregnancies with spontaneous contractions, adiponectin levels in cord blood were higher in the preeclampsia group than in pregnancies without preeclampsia, maybe reflecting the need to optimize energy in preeclampsia.
doi:10.1159/000313376
PMCID: PMC2919428  PMID: 20395665
Preeclampsia; Cord blood; Adiponectin; Infant development
23.  Methylation variation at IGF2 differentially methylated regions and maternal folic acid use before and during pregnancy 
Epigenetics  2011;6(7):928-936.
Folic acid (FA) supplementation before and during pregnancy has been associated with decreased risk of neural tube defects although recent reports suggest it may also increase the risk of other chronic diseases. We evaluated exposure to maternal FA supplementation before and during pregnancy in relation to aberrant DNA methylation at two differentially methylated regions (DMRs) regulating insulin-like growth factor 2 (IGF2) expression in infants. Aberrant methylation at these regions has been associated with IGF2 deregulation and increased susceptibility to several chronic diseases. Using a self-administered questionnaire, we assessed FA intake before and during pregnancy in 438 pregnant women. Pyrosequencing was used to measure methylation at two IGF2 DMRs in umbilical cord blood leukocytes. Mixed models were used to determine relationships between maternal FA supplementation before or during pregnancy and DNA methylation levels at birth. Average methylation at the H19 DMR was 61.2%. Compared to infants born to women reporting no FA intake before or during pregnancy, methylation levels at the H19 DMR decreased with increasing FA intake (2.8%, p = 0.03 and 4.9%, p = 0.04, for intake before and during pregnancy, respectively). This methylation decrease was most pronounced in male infants (p = 0.01). Methylation alterations at the H19 DMR are likely an important mechanism by which FA risks and/or benefits are conferred in utero. Because stable methylation marks at DMRs regulating imprinted genes are acquired before gastrulation, they may serve as archives of early exposures with the potential to improve our understanding of developmental origins of adult disease.
doi:10.4161/epi.6.7.16263
PMCID: PMC3154433  PMID: 21636975
folic acid; epigenetics; IGF2; periconception; prenatal; exposure
24.  Diethylstilbestrol Exposure in Utero and Depression in Women 
American Journal of Epidemiology  2010;171(8):876-882.
Diethylstilbestrol (DES) is an estrogenic endocrine disruptor with long-term health effects, possibly including depression, following exposure in utero. Understanding the relation between in utero DES exposure and depression will provide insight to the potential adverse effects of bisphenol A, a functionally similar and ubiquitous endocrine disruptor. The association between in utero DES exposure and depression was assessed among participants in the Nurses’ Health Study II who first reported their history of antidepressant use in 1993 and lifetime history of depressive symptoms in 2001. DES exposure was reported by 1,612 (2.2%) women. A history of depression at baseline was higher among women exposed to DES in utero compared with those not exposed (age-adjusted odds ratio (OR) = 1.47, 95% confidence interval (CI): 1.26, 1.72) (P < 0.001). Incident depression (first use of antidepressants among women who also reported depressive symptoms) during follow-up (1995–2005) was reported by 19.7% of women exposed to DES and 15.9% unexposed (age-adjusted OR = 1.41, 95% CI: 1.22, 1.63) (P < 0.001). Adjustment for risk factors of depression and correlates of DES exposure moderately attenuated the association (multivariable-adjusted OR = 1.30, 95% CI: 1.13, 1.51) (P = 0.0004). These results suggest that the neurophysiologic effects of in utero exposure to DES could lead to an increased risk of depression in adult life. Further research should assess whether in utero exposure to bisphenol A has similar adverse effects.
doi:10.1093/aje/kwq023
PMCID: PMC2877444  PMID: 20332145
antidepressive agents; bisphenol A-glycidyl methacrylate; cohort studies; depression; diethylstilbestrol; endocrine disruptors
25.  Energy Balance, the PI3K-AKT-mTOR Pathway Genes and the Risk of Bladder Cancer 
We evaluated the association between energy balance and risk of bladder cancer and assessed joint effects of genetic variants in the mTOR pathway genes with energy balance. The study included 803 Caucasian bladder cancer patients and 803 healthy Caucasian controls matched to cases by age (± 5 years) and gender. High energy intake (OR=1.60; 95% CI=1.23-2.09) and low physical activity (OR=2.82; 95% CI=2.10-3.79) were each associated with significantly increased risk of bladder cancer with dose-response trends (P for trend<0.001). However, obesity (BMI ≥30) was not associated with the risk. Among 222 SNPs, 28 SNPs located in 6 genes of mTOR pathway were significantly associated with the risk. Further, the risk associated with high energy intake and low physical activity was only observed among subjects carrying a high number of unfavorable genotypes in the pathway. Moreover, when physical activity, energy intake and genetic variants were analyzed jointly, the study population was clearly stratified into a range of low to high risk subgroups as defined energy balance status. Compared to subjects within the most favorable energy balance category (low energy intake, intensive physical activity, low number of unfavorable genotypes), subjects in the worst energy balance category (high energy intake, low physical activity, and carrying seven or more unfavorable genotypes) had 21.93-fold increased risk (95% CI=6.7 to 71.77). Our results provide the first strong support that physical activity, energy intake and genetic variants in the mTOR pathway jointly influence bladder cancer susceptibility and these results have implications in bladder cancer prevention.
doi:10.1158/1940-6207.CAPR-09-0263
PMCID: PMC2867666  PMID: 20354165
bladder cancer; energy intake; physical activity; obesity; PI3K-AKT-mTOR Pathway

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