Bridging Differences in Cohort Analyses of the Relationship between Secondhand Smoke Exposure during Pregnancy and Birth Weight: The Transportability Framework in the ECHO Program.

BACKGROUND: Estimates for the effects of environmental exposures on health outcomes, including secondhand smoke (SHS) exposure, often present considerable variability across studies. Knowledge of the reasons behind these differences can aid our understanding of effects in specific populations as well as inform practices of combining data from multiple studies. OBJECTIVES: This study aimed to assess the presence of effect modification by measured sociodemographic characteristics on the effect of SHS exposure during pregnancy on birth weights that may drive differences observed across cohorts. We also aimed to quantify the extent to which differences in the cohort mean effects observed across cohorts in the Environmental influences on Child Health Outcomes (ECHO) consortium are due to differing distributions of these characteristics. METHODS: We assessed the presence of effect modification and transportability of effect estimates across five ECHO cohorts in a total of 6,771 mother-offspring dyads. We assessed the presence of effect modification via gradient boosting of regression trees based on the H-statistic. We estimated individual cohort effects using linear models and targeted maximum likelihood estimation (TMLE). We then estimated transported effects from one cohort to each of the remaining cohorts using a robust nonparametric estimation approach relying on TMLE estimators and compared them to the original effect estimates for these cohorts. RESULTS: Observed effect estimates varied across the five cohorts, ranging from significantly lower birth weight associated with exposure [-167.3g; 95% confidence interval (CI): -270.4, -64.1] to higher birth weight with wide CIs, including the null (42.4g; 95% CI: -15.0, 99.8). Transported effect estimates only minimally explained differences in the point estimates for two out of the four cohort pairs. DISCUSSION: Our findings of weak to moderate evidence of effect modification and transportability indicate that unmeasured individual-level and contextual factors and sources of bias may be responsible for differences in the effect estimates observed across ECHO cohorts. https://doi.org/10.1289/EHP13961.

Racial and Ethnic Disparities in Phthalate Exposure and Preterm Birth: A Pooled Study of Sixteen U.S. Cohorts.

BACKGROUND: Phthalate exposures are ubiquitous during pregnancy and may contribute to racial and ethnic disparities in preterm birth. OBJECTIVES: We investigated race and ethnicity in the relationship between biomarkers of phthalate exposure and preterm birth by examining: a) how hypothetical reductions in racial and ethnic disparities in phthalate metabolites might reduce the probability of preterm birth; and b) exposure-response models stratified by race and ethnicity. METHODS: We pooled individual-level data on 6,045 pregnancies from 16 U.S. cohorts. We investigated covariate-adjusted differences in nine urinary phthalate metabolite concentrations by race and ethnicity [non-Hispanic White (White, 43%), non-Hispanic Black (Black, 13%), Hispanic/Latina (38%), and Asian/Pacific Islander (3%)]. Using g-computation, we estimated changes in the probability of preterm birth under hypothetical interventions to eliminate disparities in levels of urinary phthalate metabolites by proportionally lowering average concentrations in Black and Hispanic/Latina participants to be approximately equal to the averages in White participants. We also used race and ethnicity-stratified logistic regression to characterize associations between phthalate metabolites and preterm birth. RESULTS: In comparison with concentrations among White participants, adjusted mean phthalate metabolite concentrations were consistently higher among Black and Hispanic/Latina participants by 23%-148% and 4%-94%, respectively. Asian/Pacific Islander participants had metabolite levels that were similar to those of White participants. Hypothetical interventions to reduce disparities in metabolite mixtures were associated with lower probabilities of preterm birth for Black [13% relative reduction; 95% confidence interval (CI): -34%, 8.6%] and Hispanic/Latina (9% relative reduction; 95% CI: -19%, 0.8%) participants. Odds ratios for preterm birth in association with phthalate metabolites demonstrated heterogeneity by race and ethnicity for two individual metabolites (mono-n-butyl and monoisobutyl phthalate), with positive associations that were larger in magnitude observed among Black or Hispanic/Latina participants. CONCLUSIONS: Phthalate metabolite concentrations differed substantially by race and ethnicity. Our results show hypothetical interventions to reduce population-level racial and ethnic disparities in biomarkers of phthalate exposure could potentially reduce the probability of preterm birth. https://doi.org/10.1289/EHP12831.

Design and Effectiveness of the Youth Engaged Strategies for Changing Adolescent Norms! (YES-CAN!) Program for Reducing Skin Cancer Risk.

Adolescence is a critical period for reducing skin cancer risks, yet the development of effective interventions for middle and high school youth has lagged behind those for younger children. We developed and implemented the "Youth Engaged Strategies for Changing Adolescent Norms!" (YESCAN!) program, a school-based peer leader program that uses a youth-researcher partnership approach and a project-based curriculum to support high school students in developing and delivering short narrative videos and related material about skin cancer prevention to middle school students. Participating middle and high school students completed pre- and post-program surveys assessing skin cancer attitudes, perceived norms, and behavioral intentions. Middle school students (N = 97) reported positive pre- to post-program changes in future intentions to engage in sun protection and reduce UV exposure behaviors and on numerous measures of normative beliefs and attitudes. High school students (N = 13) reported positive changes on a smaller set of behavioral intentions, normative beliefs, and attitudes. These findings add to a growing body of support for youth-participatory, peer-led approaches to adolescent risk reduction in general and to skin cancer risks specifically. The YESCAN! program fills a need for effective skin cancer prevention among adolescents, while at the same time addressing educational objectives to develop 21st Century Skills.

Associations Between Prenatal Urinary Biomarkers of Phthalate Exposure and Preterm Birth: A Pooled Study of 16 US Cohorts.

Importance: Phthalate exposure is widespread among pregnant women and may be a risk factor for preterm birth. Objective: To investigate the prospective association between urinary biomarkers of phthalates in pregnancy and preterm birth among individuals living in the US. Design, Setting, and Participants: Individual-level data were pooled from 16 preconception and pregnancy studies conducted in the US. Pregnant individuals who delivered between 1983 and 2018 and provided 1 or more urine samples during pregnancy were included. Exposures: Urinary phthalate metabolites were quantified as biomarkers of phthalate exposure. Concentrations of 11 phthalate metabolites were standardized for urine dilution and mean repeated measurements across pregnancy were calculated. Main Outcomes and Measures: Logistic regression models were used to examine the association between each phthalate metabolite with the odds of preterm birth, defined as less than 37 weeks of gestation at delivery (n = 539). Models pooled data using fixed effects and adjusted for maternal age, race and ethnicity, education, and prepregnancy body mass index. The association between the overall mixture of phthalate metabolites and preterm birth was also examined with logistic regression. G-computation, which requires certain assumptions to be considered causal, was used to estimate the association with hypothetical interventions to reduce the mixture concentrations on preterm birth. Results: The final analytic sample included 6045 participants (mean [SD] age, 29.1 [6.1] years). Overall, 802 individuals (13.3%) were Black, 2323 (38.4%) were Hispanic/Latina, 2576 (42.6%) were White, and 328 (5.4%) had other race and ethnicity (including American Indian/Alaskan Native, Native Hawaiian, >1 racial identity, or reported as other). Most phthalate metabolites were detected in more than 96% of participants. Higher odds of preterm birth, ranging from 12% to 16%, were observed in association with an interquartile range increase in urinary concentrations of mono-n-butyl phthalate (odds ratio [OR], 1.12 [95% CI, 0.98-1.27]), mono-isobutyl phthalate (OR, 1.16 [95% CI, 1.00-1.34]), mono(2-ethyl-5-carboxypentyl) phthalate (OR, 1.16 [95% CI, 1.00-1.34]), and mono(3-carboxypropyl) phthalate (OR, 1.14 [95% CI, 1.01-1.29]). Among approximately 90 preterm births per 1000 live births in this study population, hypothetical interventions to reduce the mixture of phthalate metabolite levels by 10%, 30%, and 50% were estimated to prevent 1.8 (95% CI, 0.5-3.1), 5.9 (95% CI, 1.7-9.9), and 11.1 (95% CI, 3.6-18.3) preterm births, respectively. Conclusions and Relevance: Results from this large US study population suggest that phthalate exposure during pregnancy may be a preventable risk factor for preterm delivery.

Childhood Metabolic Biomarkers Are Associated with Performance on Cognitive Tasks in Young Children.

OBJECTIVE: To evaluate the hypothesis that metabolic measures (fasting glucose, insulin, and Homeostatic Model of Assessment for Insulin Resistance [HOMA-IR] levels) are inversely associated with performance on cognitive tasks using data from young (4- to 6-year-old), typically developing, healthy children. STUDY DESIGN: Data were obtained from children participating in the Healthy Start study, a pre-birth cohort in Colorado. HOMA-IR, glucose, and insulin values were centered and scaled using the study sample means and SD. Thus, they are reported in number of SD units from the mean. Fully corrected T scores for inhibitory control (Flanker task), cognitive flexibility (Dimensional Change Card Sort test), and receptive language (Picture Vocabulary test) were obtained via the National Institutes of Health Toolbox cognition battery. RESULTS: Children included in this analysis (n = 137) were 4.6 years old, on average. Per 1-SD unit, fasting glucose (B = -2.0, 95% CI -3.5, -0.5), insulin (B = -1.7, 95% CI -3.0, -0.4), and HOMA-IR values (B = -1.8, 95% CI -3.1, -0.5) were each significantly and inversely associated with inhibitory control (P < .05 for all, respectively). Fasting glucose levels were also inversely associated with cognitive flexibility (B = -2.0, 95% CI -3.7, -0.2, P = .03). CONCLUSIONS: Our data suggest that metabolic health may impact fluid cognitive function in healthy, young children.

Trajectories of Nevus Development From Age 3 to 16 Years in the Colorado Kids Sun Care Program Cohort.

Importance: Nevi are a risk factor for melanoma and other forms of skin cancer, and many of the same factors confer risk for both. Understanding childhood nevus development may provide clues to possible causes and prevention of melanoma. Objectives: To describe nevus acquisition from the ages of 3 to 16 years among white youths and evaluate variation by sex, Hispanic ethnicity, and body sites that are chronically vs intermittently exposed to the sun. Design, Setting, and Participants: This annual longitudinal observational cohort study of nevus development was conducted between June 1, 2001, and October 31, 2014, among 1085 Colorado youths. Data analysis was conducted between February 1, 2015, and August 31, 2017. Main Outcomes and Measures: Total nevus counts on all body sites and on sites chronically and intermittently exposed to the sun separately. Results: A total of 557 girls and 528 boys (150 [13.8%] Hispanic participants) born in 1998 were included in this study. Median total body nevus counts increased linearly among non-Hispanic white boys and girls between the age of 3 years (boys, 6.31; 95% CI, 5.66-7.03; and girls, 6.61; 95% CI, 5.96-7.33) and the age of 16 years (boys, 81.30; 95% CI, 75.95-87.03; and girls, 77.58; 95% CI, 72.68-82.81). Median total body nevus counts were lower among Hispanic white children (boys aged 16 years, 51.45; 95% CI, 44.01-60.15; and girls aged 16 years, 53.75; 95% CI, 45.40-63.62) compared with non-Hispanic white children, but they followed a largely linear trend that varied by sex. Nevus counts on body sites chronically exposed to the sun increased over time but leveled off by the age of 16 years. Nevus counts on sites intermittently exposed to the sun followed a strong linear pattern through the age of 16 years. Hispanic white boys and girls had similar nevus counts on sites intermittently exposed to the sun through the age of 10 years, but increases thereafter were steeper for girls, with nevus counts surpassing those of boys aged 11 to 16 years. Conclusions and Relevance: Youths are at risk for nevus development beginning in early childhood and continuing through midadolescence. Patterns of nevus acquisition differ between boys and girls, Hispanic and non-Hispanic white youths, and body sites that are chronically exposed to the sun and body sites that are intermittently exposed to the sun. Exposure to UV light during this period should be reduced, particularly on body sites intermittently exposed to the sun, where nevi accumulate through midadolescence in all children. Increased attention to sun protection appears to be merited for boys, in general, because they accumulated more nevi overall, and for girls, specifically, during the adolescent years.

Interactions between ultraviolet light and MC1R and OCA2 variants are determinants of childhood nevus and freckle phenotypes.

BACKGROUND: Melanocytic nevi (moles) and freckles are well known biomarkers of melanoma risk, and they are influenced by similar UV light exposures and genetic susceptibilities to those that increase melanoma risk. Nevertheless, the selective interactions between UV exposures and nevus and freckling genes remain largely undescribed. METHODS: We conducted a longitudinal study from ages 6 through 10 years in 477 Colorado children who had annual information collected for sun exposure, sun protection behaviors, and full body skin exams. MC1R and HERC2/OCA2 rs12913832 were genotyped and linear mixed models were used to identify main and interaction effects. RESULTS: All measures of sun exposure (chronic, sunburns, and waterside vacations) contributed to total nevus counts, and cumulative chronic exposure acted as the major driver of nevus development. Waterside vacations strongly increased total nevus counts in children with rs12913832 blue eye color alleles and facial freckling scores in those with MC1R red hair color variants. Sunburns increased the numbers of larger nevi (≥2 mm) in subjects with certain MC1R and rs12913832 genotypes. CONCLUSIONS: Complex interactions between different UV exposure profiles and genotype combinations determine nevus numbers and size, and the degree of facial freckling. IMPACT: Our findings emphasize the importance of implementing sun-protective behavior in childhood regardless of genetic make-up, although children with particular genetic variants may benefit from specifically targeted preventive measures to counteract their inherent risk of melanoma. Moreover, we demonstrate, for the first time, that longitudinal studies are a highly powered tool to uncover new gene-environment interactions that increase cancer risk.

Parents' perceptions of skin cancer threat and children's physical activity.

INTRODUCTION: Sun exposure is a major risk factor for skin cancer, but without physical activity, children are at risk of childhood obesity. The objective of this study was to explore relationships between parental perceptions of skin cancer threat, sun protection behaviors, physical activity, and body mass index (BMI) in children. METHODS: This is a cross-sectional analysis nested within the Colorado Kids Sun Care Program sun safety intervention trial. In summer 2007, parent telephone interviews provided data on demographics, perceptions of skin cancer threat, sun protection behaviors, and physical activity. Physical examinations provided data on phenotype, freckling, and BMI. Data from 999 Colorado children born in 1998 were included in analysis. We used analysis of variance, Spearman's rho (ρ) correlation, and multivariable linear regression analysis to evaluate relationships with total amount of outdoor physical activity. RESULTS: After controlling for sex, race/ethnicity, skin color, and sun protection, regression analysis showed that each unit increase in perceived severity of nonmelanoma skin cancer was associated with a 30% increase in hours of outdoor physical activity (P = .005). Hours of outdoor physical activity were not related to perceived severity of melanoma or perceived susceptibility to skin cancer. BMI-for-age was not significantly correlated with perceptions of skin cancer threat, use of sun protection, or level of physical activity. CONCLUSION: The promotion of sun safety is not likely to inhibit physical activity. Skin cancer prevention programs should continue to promote midday sun avoidance and sun protection during outdoor activities.

Mailed intervention to promote sun protection of children: a randomized controlled trial.

BACKGROUND: Sun exposure, especially during childhood, is the most important preventable risk factor for skin cancer, yet few effective interventions to reduce exposure exist. PURPOSE: To test the effectiveness of a partially tailored mailed intervention based on the Precaution Adoption Process Model, delivered in the spring over 3 years to parents and children. DESIGN: RCT, with data collection through telephone interviews of parents and skin exams of children at baseline (Summer 2004) and annually (Summer 2005-2007). The control group received no intervention. SETTING/PARTICIPANTS: Families recruited in the Denver CO area, through private pediatric clinics, a large MCO, and community settings. Children born in 1998 were approximately 6 years of age at baseline; 867 children met inclusion criteria; analysis is reported for 677 white, non-Hispanic participants at highest risk for skin cancer. MAIN OUTCOME MEASURES: Primary outcomes were parent-reported child sun protection behaviors. Secondary outcomes included parents' risk perception, perceived effectiveness of and barriers to prevention behaviors, stage of change, reported sunburns, and observed tanning and nevus development. The longitudinal mixed-model analysis was conducted between 2008 and 2011. RESULTS: The intervention group reported more use of sunscreen, protective clothing, hats, shade-seeking, and midday sun avoidance; fewer sunburns; more awareness of the risk of skin cancer; higher perceived effectiveness of sun protection; higher stage of change; and lower perception of barriers to sun protection (all p<0.05). The intervention group had fewer nevi ≥2 mm in 1 year of the study, 2006 (p=0.03). No differences were found in tanning or nevi <2 mm. CONCLUSIONS: The level of behavior change associated with this single-modality intervention is not likely sufficient to reduce skin cancer risk. However, the intervention shows promise for inclusion in longer-term, multicomponent interventions that have sufficient intensity to affect skin cancer incidence.

Sun damage in ultraviolet photographs correlates with phenotypic melanoma risk factors in 12-year-old children.

BACKGROUND: Ultraviolet (UV) photography has been used to motivate sun safety in behavioral interventions. The relationship between sun damage shown in UV photographs and melanoma risk has not been systematically investigated. OBJECTIVE: To examine the relationship between severity of sun damage in UV photographs and phenotypic melanoma risk factors in children. METHODS: UV, standard visible and cross-polarized photographs were recorded for 585 children. Computer software quantified sun damage. Full-body nevus counts, skin color by colorimetry, facial freckling, hair and eye color were collected in skin examinations. Demographic data were collected in telephone interviews of parents. RESULTS: Among 12-year-old children, sun damage shown in UV photographs correlated with phenotypic melanoma risk factors. Sun damage was greatest for children who were non-Hispanic white and those who had red hair, blue eyes, increased facial freckling, light skin and greater number of nevi (all P values < .001). Results were similar for standard visible and cross-polarized photographs. Freckling was the strongest predictor of sun damage in visible and UV photographs. All other phenotypic melanoma risk factors were also predictors for the UV photographs. LIMITATIONS: Differences in software algorithms used to score the photographs could produce different results. CONCLUSION: UV photographs portray more sun damage in children with higher risk for melanoma based on phenotype. Therefore sun protection interventions targeting those with greater sun damage on UV photographs will target those at higher melanoma risk. This study establishes reference ranges dermatologists can use to assess sun damage in their pediatric patients.

Effect of hair color and sun sensitivity on nevus counts in white children in Colorado.

BACKGROUND: It has been widely reported that individuals with a light phenotype (ie, light hair color, light base skin color, and propensity to burn) have more nevi and are at greater risk for developing skin cancer. No studies have systematically investigated how phenotypic traits may interact in relation to nevus development. OBJECTIVE: We sought to systematically examine whether any combinations of phenotype are associated with a greater or lesser risk for nevus development in white children. METHODS: In the summer of 2007, 654 children were examined to determine full body nevus counts, skin color by colorimetry, and hair and eye color by comparison with charts. Interviews of parents were conducted to capture sun sensitivity, sun exposure, and sun protection practices. RESULTS: Among 9-year-old children with sun sensitivity rating type II (painful burn/light tan), those with light hair had lower nevus counts than did those with dark hair (P value for interaction = .03). This relationship was independent of eye color, presence of freckling, sex, usual daily sun exposure, sunburn in 2004 to 2007, sun protection index, and waterside vacation sun exposure. The difference in nevus counts was further determined to be specific to small nevi (<2 mm) and nevi in intermittently exposed body sites. LIMITATIONS: Geographic and genetic differences in other study populations may produce different results. CONCLUSION: The standard acceptance that dark phenotype is a marker for low melanoma risk and light phenotype a marker for high risk may need to be reevaluated. In non-Hispanic white children, dark-haired individuals who burn readily and then tan slightly are more prone to nevus development, and may therefore be a previously underrecognized high-risk group for melanoma.

Tanning and increased nevus development in very-light-skinned children without red hair.

OBJECTIVE: To examine the relationship between tanning and nevus development in very-light-skinned children. DESIGN: Prospective cohort nested within a randomized controlled trial. Skin examinations in 3 consecutive years (2004, 2005, and 2006) included full-body counts of nevi, skin color and tanning measurement using colorimetry, and hair and eye color evaluation by comparison with charts. Telephone interviews of parents provided sun exposure, sun protection, and sunburn history. SETTING: Large managed-care organization and private pediatric offices in the Denver, Colorado, metropolitan area. PARTICIPANTS: A total of 131 very-light-skinned white children without red hair and 444 darker-skinned white children without red hair born in Colorado in 1998. MAIN OUTCOME MEASURES: Full-body nevus counts at ages 6 to 8 years. RESULTS: Among very-light-skinned white children, geometric mean numbers of nevi for minimally tanned children were 14.8 at age 6 years; 18.8 at age 7 years; and 22.3 at age 8 years. Mean numbers of nevi for tanned children were 21.2 at age 6 years; 27.9 at age 7 years; and 31.9 at age 8 years. Differences in nevus counts between untanned and tanned children were statistically significant at all ages (P < .05 for all comparisons). The relationship between tanning and number of nevi was independent of the child's hair and eye color, parent-reported sun exposure, and skin phototype. Among darker-skinned white children, there was no relationship between tanning and nevi. CONCLUSIONS: Very-light-skinned children who tan (based on objective measurement) develop more nevi than children who do not tan. These results suggest that light-skinned children who develop tans may be increasing their risk for developing melanoma later in life.

Melanocytic nevus development in Colorado children born in 1998: a longitudinal study.

OBJECTIVE: To describe the development of nevi from 3 to 8 years of age in a birth cohort of children in Colorado. DESIGN: Longitudinal observational study. SETTING: Large managed care organization and university and private primary care practices. PARTICIPANTS: Annual convenience samples of children born in 1998 (range, n = 137 to n = 870) (participation rates, 18.8%-76.0%). We recruited children through the managed care organization, private primary care practices, and community settings. MAIN OUTCOME MEASURES: Total whole body nevus counts, counts by nevus diameter (< 2, 2 to < 5, or > or = 5 mm), and counts for chronically and intermittently exposed body sites. RESULTS: Non-Hispanic white children had significantly more nevi than did other racial/ethnic groups and developed an average of 4 to 6 new nevi per year from 3 to 8 years of age. Non-Hispanic white boys had significantly more nevi than did girls beginning at 6 years of age (median, 21 [interquartile range, 28] vs 17 [17]; P = .002). This difference was due to nevi of less than 2 mm and nevi in chronically exposed body sites. Development of new nevi leveled off in chronically exposed body sites at 7 years of age and at a higher level for boys than girls. CONCLUSIONS: Children in Colorado developed more small nevi and fewer large nevi compared with children in other regions of the world, highlighting the importance of studying nevus development in various locations where sun exposure patterns and behavioral norms vary. The sex difference in nevus development could be owing to variation in sun exposure and/or a biological predisposition of boys to develop more nevi. Studies of nevus development can aid in the understanding of the complicated relationship between nevus development and malignant melanoma.

Vacations to waterside locations result in nevus development in Colorado children.

Nevi are a main risk factor for malignant melanoma, and most nevi develop in childhood. This study examined the relationship between vacations and nevi in 681 White children born in 1998 who were lifetime residents of Colorado. Vacation histories were assessed through telephone interviews of parents, whereas nevus and phenotypic characteristics were assessed through skin exams at age 7. Multiple linear and logistic regression were used to assess the influence of vacations on counts of nevi <2 mm in size and the presence of any nevi > or = 2 mm after controlling for other variables. Each waterside vacation > or = 1 year before the exam at age 7 was found to be associated with a 5% increase in nevi <2 mm. Waterside vacations <1 year before the skin exam were not related to nevus count (<2 mm); regardless of timeframe, waterside vacations were not related to the presence of nevi > or = 2 mm. UV dose received on waterside vacations, number of days spent on waterside vacations, and nonwaterside vacations were not significantly related to nevi <2 or > or = 2 mm. These results suggest that there is a lag of at least 1 year in the development of new nevi after vacation sun exposure. It appears that a threshold dose of UV exposure is received quickly on each waterside vacation. Parents of young children should exercise caution in selection of vacation locations to reduce melanoma risk.