Use of Multivariable Mendelian Randomization to Address Biases Due to Competing Risk Before Recruitment.

Background: Mendelian randomization (MR) provides unconfounded estimates. MR is open to selection bias when the underlying sample is selected on surviving to recruitment on the genetically instrumented exposure and competing risk of the outcome. Few methods to address this bias exist. Methods: We show that this selection bias can sometimes be addressed by adjusting for common causes of survival and outcome. We use multivariable MR to obtain a corrected MR estimate for statins on stroke. Statins affect survival, and stroke typically occurs later in life than ischemic heart disease (IHD), making estimates for stroke open to bias from competing risk. Results: In univariable MR in the UK Biobank, genetically instrumented statins did not protect against stroke [odds ratio (OR) 1.33, 95% confidence interval (CI) 0.80-2.20] but did in multivariable MR (OR 0.81, 95% CI 0.68-0.98) adjusted for major causes of survival and stroke [blood pressure, body mass index (BMI), and smoking initiation] with a multivariable Q-statistic indicating absence of selection bias. However, the MR estimate for statins on stroke using MEGASTROKE remained positive and the Q statistic indicated pleiotropy. Conclusion: MR studies of harmful exposures on late-onset diseases with shared etiology need to be conceptualized within a mechanistic understanding so as to identify any potential bias due to survival to recruitment on both genetically instrumented exposure and competing risk of the outcome, which may then be investigated using multivariable MR or estimated analytically and results interpreted accordingly.

The association of early-life exposure to air pollution with lung function at ~17.5 years in the "Children of 1997" Hong Kong Chinese Birth Cohort.

BACKGROUND: Early-life air pollution exposure is associated with lung function in children and adolescents. However, whether the association of prenatal and early postnatal exposure to air pollution with lung function continues into adulthood remains unclear. OBJECTIVE: To investigate the associations of early exposure to air pollution with lung function at ~17.5 years in a non-western developed setting with more concentrated air pollutants. METHODS: We examined the associations of exposure to particular matter with an aerodynamic diameter of <10 µm (PM10), nitrogen dioxides (NO2), nitric oxide (NO), sulfur dioxide (SO2) in standard deviations (SD)) at different early life stages with lung function (indicated by forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1) and forced expiratory flow at 25%-75% of the pulmonary volume (FEF25%-75%)) in SD at ~17.5 years, personal history of wheezing and asthma in the population-representative Hong Kong Chinese birth cohort "Children of 1997"(n = 2942). RESULTS: Higher in utero and infancy and toddlerhood NO2 were associated with lower FEV1 (-0.022, 95% confidence interval (CI) -0.029 to -0.015 and - 0.026, 95% CI -0.033 to -0.019), FEV1/FVC (-0.035, 95% CI -0.050 to -0.021 and -0.052, 95% CI -0.066 to -0.038) and FEF25%-75% (-0.031, 95% CI -0.040 to -0.022 and -0.043, 95% CI -0.051 to -0.035). A similar association was observed for NO. Weak associations of NO2 and NO with FVC were observed (-0.011, 95% CI -0.018 to -0.003 and -0.010, 95% CI -0.020 to -0.001). NOx was associated with higher risk of wheezing (1.08, 95% CI 1.03 to 1.14) but not asthma (1.02, 95% CI 0.94 to 1.11). SO2 and PM10 were not clearly associated with lung function, wheezing or asthma. CONCLUSION: Our findings suggest that early exposure to air pollution from NO2 may have long-term effects on lung function, which could affect respiratory health throughout life.

The association of air pollution with body mass index: evidence from Hong Kong's "Children of 1997" birth cohort.

BACKGROUND: Child overweight and obesity have increased substantially in many countries. Physical and psychological effects of childhood obesity endure throughout adulthood. Much attention has been paid to energy intake and expenditure in childhood adiposity, but less to environmental factors, such as outdoor air quality. Here we assessed prospectively the association of exposure to air pollution with body mass index (BMI) in late childhood and early adolescence. METHODS: We assessed the association of air pollutants (particulate matter with a diameter of 10 µm or less (PM10), sulfur dioxide (SO2), nitric oxide (NO), and nitrogen dioxide (NO2)) at different growth phases (in utero, in infancy, and in childhood) with BMI at ~9, ~11, ~13, and ~15 years in a population-representative birth cohort from Hong Kong, "Children of 1997." We used partial least square regression to account for colinearity between pollutants and exposure periods. We also assessed whether associations varied by sex from model fit. RESULTS: Associations were sex-specific based on better model fit when including sex interaction terms. Among boys, higher SO2 in utero was associated with lower BMI at ~13 and ~15 years, higher SO2 in childhood with lower BMI at ~15 years, and higher NO2 in childhood with higher BMI at ~9, ~13, and ~15 years using a multi-pollutant model. CONCLUSIONS: These findings of air pollutant- and sex-specific associations with adiposity should give impetus to the investigation of their physiological effects, possibly operating as endocrine disruptors or via mitochondria, so as to protect the next generation of boys.

DNA methylation in blood as a mediator of the association of mid-childhood body mass index with cardio-metabolic risk score in early adolescence.

Obesity is associated with higher cardio-metabolic risk even in childhood and adolescence; whether this association is mediated by epigenetic mechanisms remains unclear. We examined the extent to which mid-childhood body mass index (BMI) z-score (median age 7.7 years) was associated with cardio-metabolic risk score in early adolescence (median age 12.9 years) via mid-childhood DNA methylation among 265 children in the Project Viva. We measured DNA methylation in leukocytes using the Infinium Human Methylation450K BeadChip. We assessed mediation CpG-by-CpG using epigenome-wide association analyses, high-dimensional mediation analysis, and natural effect models. We observed mediation by mid-childhood DNA methylation at 6 CpGs for the association between mid-childhood BMI z-score and cardio-metabolic risk score in early adolescence in the high-dimensional mediation analysis (accounting for 10% of the total effect) and in the natural effect model (ß = 0.04, P = 3.2e-2, accounting for 13% of the total effect). The natural direct effect of BMI z-score on cardio-metabolic risk score was still evident (ß = 0.27, P = 1.1e-25). We also observed mediation by mid-childhood DNA methylation at 5 CpGs that was in the opposite direction from the total effect (natural effect model: ß = -0.04, P = 2.0e-2). Mediation in different directions implies a complex role of DNA methylation in the association between BMI and cardio-metabolic risk and needs further investigation. Future studies with larger sample size and greater variability in cardio-metabolic risk will further help elucidate the role of DNA methylation for cardio-metabolic risk.

The association of air pollution with height: Evidence from Hong Kong's "Children of 1997" birth cohort.

OBJECTIVES: Within populations, height is positively associated with economic success and in economically developed populations inversely associated with health. Recent studies also suggest air pollution may result in higher bone turnover markers among children, which may affect growth. However, few studies have investigated the effect of air pollution on height or growth rate. We therefore assessed the associations of several air pollutants with height at different ages. METHODS: We simultaneously assessed associations of particulate matter with a diameter of 10 micrometers or less (PM10 ), sulfur dioxide (SO2 ), nitric oxide (NO), and nitrogen dioxide (NO2 ) in utero, in infancy, and in childhood with height at different ages (∼9, ∼11, ∼13, and ∼15 years), in a population-representative birth cohort "Children of 1997" (n = 8327) from the developed non-Western setting of Hong Kong with relatively high air pollution and short children, using partial least square regression. RESULTS: After considering multiple comparison, higher SO2 in childhood was associated with shorter height at ∼13 years (-0.20 cm, 99% CI -0.32 to -0.06). This difference was not evident at ∼15 years. CONCLUSIONS: These observations suggest that air pollution may affect the trajectory of growth and development rather than final height, with corresponding implications for health in later life.

Inflammation and bone mineral density: A Mendelian randomization study.

Osteoporosis is a common age-related disorder leading to an increase in osteoporotic fractures and resulting in significant suffering and disability. Inflammation may contribute to osteoporosis, as it does to many other chronic diseases. We examined whether inflammation is etiologically relevant to osteoporosis, assessed from bone mineral density (BMD), as a new potential target of intervention, or whether it is a symptom/biomarker of osteoporosis. We obtained genetic predictors of inflammatory markers from genome-wide association studies and applied them to a large genome wide association study of BMD. Using two-sample Mendelian randomization, we obtained unconfounded estimates of the effect of high-sensitivity C-reactive protein (hsCRP) on BMD at the forearm, femoral neck, and lumbar spine. After removing potentially pleiotropic single nucleotide polymorphisms (SNPs) possibly acting via obesity-related traits, hsCRP, based on 16 SNPs from genes including CRP, was not associated with BMD. A causal relation of hsCRP with lower BMD was not evident in this study.

The Association of Air Pollution With Pubertal Development: Evidence From Hong Kong's "Children of 1997" Birth Cohort.

Many pollutants are endocrine disruptors with impacts on reproduction and health in animals, but evidence in humans, of which sex-specific effects on pubertal development may be an indicator, is less clear. We examined the association of air pollution in utero and during early life with pubertal development in Hong Kong, China, an area with a high level of air pollution compared with other similarly developed cities. We assessed sex-specific associations of particulate matter less than or equal to 10 µm in diameter (PM10), nitric oxide, sulfur dioxide, and nitrogen dioxide in different growth phases with clinically assessed pubertal stage at approximately age 11 years (as indicated by Tanner stage) in a large population-representative birth cohort, the "Children of 1997." We used partial least squares regression to account for colinearity between air pollutants. Among 1,938 girls, PM10 exposure in utero and during infancy was negatively associated with pubertal stage and breast development, whereas among 2,136 boys, sulfur dioxide and nitrogen dioxide exposure in utero, during infancy, and in childhood were negatively associated with pubertal stage. These sex-specific associations with pubertal development are consistent with endocrine-disrupting effects. Given the health impact of altered pubertal timing, further investigation across the life course may help quantify the full effects and the corresponding need for preventive measures.

The association of air pollution with birthweight and gestational age: evidence from Hong Kong's 'Children of 1997' birth cohort.

Background: Previous studies from Western settings have found inconsistent associations of air pollutants with birth outcomes, which are open to residual confounding by socioeconomic position (SEP). We assessed this association in the economically developed non-Western setting of Hong Kong, with high levels of air pollution but little social patterning of these outcomes. Methods: We obtained PM10, SO2, NO and NO2 from monitoring stations, and assessed their associations with birthweight and gestational age in a large population-representative birth cohort 'Children of 1997', using partial least-square regression to account for the colinearity between pollutants. Results: PM10 (per 5.7 µg/m3 higher) and NO2 (per 10.9 µg/m3 higher) were associated with birthweight lower by 47.0 g (95% confidence interval (CI) 36.2-56.3) and 16.9 g (95% CI 10.8-22.6), respectively; and were associated with gestational age shorter by 2.1 days (95% CI 1.7-2.4) and 0.7 days (95% CI 0.5-0.8), respectively. Conclusions: Given minimal confounding by SEP in our setting, these findings provide unequivocal evidence of adverse effects of PM10 and NO2 exposure during pregnancy on birthweight and gestational age. Physiological mechanisms need to be better understood to support effective public health action globally.