Do age at diagnosis, tumour thickness and tumour site explain sex differences in melanoma survival? A causal mediation analysis using cancer registry data.

Women diagnosed with melanoma have better survival than men, but little is known about potential intervention targets to reduce this survival gap by sex. We conducted a population-based study using Victorian Cancer Registry data including 5833 women and 6780 men aged 15 to 70 years when diagnosed with first primary melanoma between 2007 and 2015. Deaths to the end of 2020 were identified through linkage to the Victorian and national death registries. We estimated the effect of age at diagnosis, tumour thickness and tumour site on reducing the melanoma-specific survival gap by sex (ie, interventional indirect effects [IIEs]) on risk difference (RD) scale. Compared to women, there were 211 (95% CI: 145-278) additional deaths per 10 000 in men within 5 years following diagnosis. We estimated that 44% of this gap would be reduced by a hypothetical intervention shifting the distribution of melanoma thickness in men to be the same as that observed for women (IIEthickness RD 93 [95% CI: 75-118] per 10 000) and 20% by an intervention on tumour site (head and neck/trunk vs upper limb/lower limb; IIEsite RD 42 [95% CI: 15-72] per 10 000), while an intervention on age at diagnosis would have a negligible effect. Tumour thickness, tumour site and age at diagnosis mediated 65% of the effect of sex on 5-year melanoma survival in Victoria. Of these factors, tumour thickness had the most considerable mediating effect, suggesting that effective promotion of earlier detection of melanoma in men could potentially nearly halve the gap in melanoma-specific survival by sex.

Handling missing data when estimating causal effects with targeted maximum likelihood estimation.

Targeted maximum likelihood estimation (TMLE) is increasingly used for doubly robust causal inference, but how missing data should be handled when using TMLE with data-adaptive approaches is unclear. Based on data (1992-1998) from the Victorian Adolescent Health Cohort Study, we conducted a simulation study to evaluate 8 missing-data methods in this context: complete-case analysis, extended TMLE incorporating an outcome-missingness model, the missing covariate missing indicator method, and 5 multiple imputation (MI) approaches using parametric or machine-learning models. We considered 6 scenarios that varied in terms of exposure/outcome generation models (presence of confounder-confounder interactions) and missingness mechanisms (whether outcome influenced missingness in other variables and presence of interaction/nonlinear terms in missingness models). Complete-case analysis and extended TMLE had small biases when outcome did not influence missingness in other variables. Parametric MI without interactions had large bias when exposure/outcome generation models included interactions. Parametric MI including interactions performed best in bias and variance reduction across all settings, except when missingness models included a nonlinear term. When choosing a method for handling missing data in the context of TMLE, researchers must consider the missingness mechanism and, for MI, compatibility with the analysis method. In many settings, a parametric MI approach that incorporates interactions and nonlinearities is expected to perform well.

Sex-steroid hormones and risk of postmenopausal estrogen receptor-positive breast cancer: a case-cohort analysis.

PURPOSE: Sex-steroid hormones are associated with postmenopausal breast cancer but potential confounding from other biological pathways is rarely considered. We estimated risk ratios for sex-steroid hormone biomarkers in relation to postmenopausal estrogen receptor (ER)-positive breast cancer, while accounting for biomarkers from insulin/insulin-like growth factor-signaling and inflammatory pathways. METHODS: This analysis included 1208 women from a case-cohort study of postmenopausal breast cancer within the Melbourne Collaborative Cohort Study. Weighted Poisson regression with a robust variance estimator was used to estimate risk ratios (RRs) and 95% confidence intervals (CIs) of postmenopausal ER-positive breast cancer, per doubling plasma concentration of progesterone, estrogens, androgens, and sex-hormone binding globulin (SHBG). Analyses included sociodemographic and lifestyle confounders, and other biomarkers identified as potential confounders. RESULTS: Increased risks of postmenopausal ER-positive breast cancer were observed per doubling plasma concentration of progesterone (RR: 1.22, 95% CI 1.03 to 1.44), androstenedione (RR 1.20, 95% CI 0.99 to 1.45), dehydroepiandrosterone (RR: 1.15, 95% CI 1.00 to 1.34), total testosterone (RR: 1.11, 95% CI 0.96 to 1.29), free testosterone (RR: 1.12, 95% CI 0.98 to 1.28), estrone (RR 1.21, 95% CI 0.99 to 1.48), total estradiol (RR 1.19, 95% CI 1.02 to 1.39) and free estradiol (RR 1.22, 95% CI 1.05 to 1.41). A possible decreased risk was observed for SHBG (RR 0.83, 95% CI 0.66 to 1.05). CONCLUSION: Progesterone, estrogens and androgens likely increase postmenopausal ER-positive breast cancer risk, whereas SHBG may decrease risk. These findings strengthen the causal evidence surrounding the sex-hormone-driven nature of postmenopausal breast cancer.

Recoverability and estimation of causal effects under typical multivariable missingness mechanisms.

In the context of missing data, the identifiability or "recoverability" of the average causal effect (ACE) depends not only on the usual causal assumptions but also on missingness assumptions that can be depicted by adding variable-specific missingness indicators to causal diagrams, creating missingness directed acyclic graphs (m-DAGs). Previous research described canonical m-DAGs, representing typical multivariable missingness mechanisms in epidemiological studies, and examined mathematically the recoverability of the ACE in each case. However, this work assumed no effect modification and did not investigate methods for estimation across such scenarios. Here, we extend this research by determining the recoverability of the ACE in settings with effect modification and conducting a simulation study to evaluate the performance of widely used missing data methods when estimating the ACE using correctly specified g-computation. Methods assessed were complete case analysis (CCA) and various implementations of multiple imputation (MI) with varying degrees of compatibility with the outcome model used in g-computation. Simulations were based on an example from the Victorian Adolescent Health Cohort Study (VAHCS), where interest was in estimating the ACE of adolescent cannabis use on mental health in young adulthood. We found that the ACE is recoverable when no incomplete variable (exposure, outcome, or confounder) causes its own missingness, and nonrecoverable otherwise, in simplified versions of 10 canonical m-DAGs that excluded unmeasured common causes of missingness indicators. Despite this nonrecoverability, simulations showed that MI approaches that are compatible with the outcome model in g-computation may enable approximately unbiased estimation across all canonical m-DAGs considered, except when the outcome causes its own missingness or causes the missingness of a variable that causes its own missingness. In the latter settings, researchers may need to consider sensitivity analysis methods incorporating external information (e.g., delta-adjustment methods). The VAHCS case study illustrates the practical implications of these findings.

Should multiple imputation be stratified by exposure group when estimating causal effects via outcome regression in observational studies?

BACKGROUND: Despite recent advances in causal inference methods, outcome regression remains the most widely used approach for estimating causal effects in epidemiological studies with a single-point exposure and outcome. Missing data are common in these studies, and complete-case analysis (CCA) and multiple imputation (MI) are two frequently used methods for handling them. In randomised controlled trials (RCTs), it has been shown that MI should be conducted separately by treatment group. In observational studies, causal inference is now understood as the task of emulating an RCT, which raises the question of whether MI should be conducted by exposure group in such studies. METHODS: We addressed this question by evaluating the performance of seven methods for handling missing data when estimating causal effects with outcome regression. We conducted an extensive simulation study based on an illustrative case study from the Victorian Adolescent Health Cohort Study, assessing a range of scenarios, including seven outcome generation models with exposure-confounder interactions of differing strength. RESULTS: The simulation results showed that MI by exposure group led to the least bias when the size of the smallest exposure group was relatively large, followed by MI approaches that included the exposure-confounder interactions. CONCLUSIONS: The findings from our simulation study, which was designed based on a real case study, suggest that current practice for the conduct of MI in causal inference may need to shift to stratifying by exposure group where feasible, or otherwise including exposure-confounder interactions in the imputation model.

Metabolic Syndrome and Risk of Gastrointestinal Cancers: An Investigation Using Large-scale Molecular Data.

BACKGROUND & AIMS: Gastrointestinal cancer risk is influenced by the presence of metabolic syndrome (MetS). However, previous epidemiologic studies lacked full serological biomarker data for the classification of MetS, and the interaction of MetS with germline cancer risk variants is unknown. METHODS: We investigated the associations between MetS and gastrointestinal cancer risk (overall, colorectal, pancreatic, esophageal adenocarcinoma, esophageal squamous cell carcinoma, stomach cardia, stomach non-cardia, hepatocellular carcinoma, and intrahepatic bile duct cancer) in 366,016 United Kingdom Biobank participants with comprehensive serum biomarker and genotype data. MetS status was determined by 3 different definitions at baseline, and, in 15,152 participants, at a repeat assessment after a median of 4.3 years of follow-up. Multivariable hazard ratios and 95% confidence intervals for cancer outcomes were estimated using Cox proportional hazards models. Analyses stratified by polygenic risk score were conducted for colorectal and pancreatic cancers. RESULTS: During a median follow-up of 7.1 years, 4238 incident cases of a gastrointestinal cancer occurred. MetS at baseline was associated with higher risk of overall gastrointestinal cancer by any definition (hazard ratio, 1.21; 95% confidence interval, 1.13-1.29, harmonized definition). MetS was associated with increased risks of colorectal cancer, colon cancer, rectal cancer, hepatocellular carcinoma, pancreatic cancer in women, and esophageal adenocarcinoma in men. Associations for colorectal cancer and pancreatic cancer did not differ by polygenic risk score strata (P-heterogeneity 0.70 and 0.69, respectively), and 80% of participants with MetS at baseline retained this status at the repeat assessment. CONCLUSIONS: These findings underscore the importance of maintaining good metabolic health in reducing the burden of gastrointestinal cancers, irrespective of genetic predisposition.

Diet and risk of Barrett's oesophagus: Melbourne collaborative cohort study.

Barrett's oesophagus (BE) is the precursor of oesophageal adenocarcinoma, which has become the most common type of oesophageal cancer in many Western populations. Existing evidence on diet and risk of BE predominantly comes from case-control studies, which are subject to recall bias in measurement of diet. We aimed to investigate the potential effect of diet, including macronutrients, carotenoids, food groups, specific food items, beverages and dietary scores, on risk of BE in over 20 000 participants of the Melbourne Collaborative Cohort Study. Diet at baseline (1990-1994) was measured using a food frequency questionnaire. The outcome was BE diagnosed between baseline and follow-up (2007-2010). Logistic regression models were used to estimate OR and 95 % CI for diet in relation to risk of BE. Intakes of leafy vegetables and fruit were inversely associated with risk of BE (highest v. lowest quartile: OR = 0·59; CI: 0·38, 0·94; P-trend = 0·02 and OR = 0·58; CI: 0·37, 0·93; P-trend = 0·02 respectively), as were dietary fibre and carotenoids. Stronger associations were observed for food than the nutrients found in them. Positive associations were observed for discretionary food (OR = 1·54; CI: 0·97, 2·44; P-trend = 0·04) and total fat intake (OR per 10 g/d = 1·11; CI: 1·00, 1·23), the association for fat was less robust in sensitivity analyses. No association was observed for meat, protein, dairy products or diet scores. Diet is a potential modifiable risk factor for BE. Public health and clinical guidelines that incorporate dietary recommendations could contribute to reduction in risk of BE and, thereby, oesophageal adenocarcinoma.

Demographic and lifestyle risk factors for gastroesophageal reflux disease and Barrett's esophagus in Australia.

We examined demographic and lifestyle risk factors for incidence of gastroesophageal reflux disease (GERD) and Barrett's esophagus (BE) in an Australian cohort of 20,975 participants aged 40-63 at recruitment (1990-1994). Information on GERD and BE was collected between 2007 and 2010. GERD symptoms were defined as self-reported heartburn or acid regurgitation. BE was defined as endoscopically confirmed columnar-lined esophagus. Risk factors for developing GERD symptoms, BE diagnosis, age at symptom onset, and age at BE diagnosis were quantified using regression. During a mean follow-up of 15.8 years, risk of GERD symptoms was 7.5% (n = 1,318) for daily, 7.5% (n = 1,333) for 2-6 days/week, and 4.3% (n = 751) for 1 day/week. There were 210 (1.0%) endoscopically diagnosed BE cases, of whom 141 had histologically confirmed esophageal intestinal metaplasia. Female sex, younger age, lower socioeconomic position (SEP) and educational attainment, and former smoking were associated with higher GERD risk. Male sex and smoking were associated with earlier GERD symptom onset. Men, older participants, those with higher SEP, and former smokers were at higher BE risk. There was some evidence higher SEP was associated with earlier BE diagnosis. GERD and BE had different demographic risk factors but shared similar lifestyle factors. Earlier GERD symptom onset for men and smokers might have contributed to higher BE risk. The SEP patterns observed for GERD and BE suggest potential inequity in access to care. These findings would be important in the development of clinical risk prediction models for early detection of BE.

Diet and risk of gastro-oesophageal reflux disease in the Melbourne Collaborative Cohort Study.

OBJECTIVE: To examine associations between diet and risk of developing gastro-oesophageal reflux disease (GERD). DESIGN: Prospective cohort with a median follow-up of 15·8 years. Baseline diet was measured using a FFQ. GERD was defined as self-reported current or history of daily heartburn or acid regurgitation beginning at least 2 years after baseline. Sex-specific logistic regressions were performed to estimate OR for GERD associated with diet quality scores and intakes of nutrients, food groups and individual foods and beverages. The effect of substituting saturated fat for monounsaturated or polyunsaturated fat on GERD risk was examined. SETTING: Melbourne, Australia. PARTICIPANTS: A cohort of 20 926 participants (62 % women) aged 40-59 years at recruitment between 1990 and 1994. RESULTS: For men, total fat intake was associated with increased risk of GERD (OR 1·05 per 5 g/d; 95 % CI 1·01, 1·09; P = 0·016), whereas total carbohydrate (OR 0·89 per 30 g/d; 95 % CI 0·82, 0·98; P = 0·010) and starch intakes (OR 0·84 per 30 g/d; 95 % CI 0·75, 0·94; P = 0·005) were associated with reduced risk. Nutrients were not associated with risk for women. For both sexes, substituting saturated fat for polyunsaturated or monounsaturated fat did not change risk. For both sexes, fish, chicken, cruciferous vegetables and carbonated beverages were associated with increased risk, whereas total fruit and citrus were associated with reduced risk. No association was observed with diet quality scores. CONCLUSIONS: Diet is a possible risk factor for GERD, but food considered as triggers of GERD symptoms might not necessarily contribute to disease development. Potential differential associations for men and women warrant further investigation.

Explaining the link between adiposity and colorectal cancer risk in men and postmenopausal women in the UK Biobank: A sequential causal mediation analysis.

Mechanisms underlying adiposity-colorectal cancer (CRC) association are incompletely understood. Using UK Biobank data, we investigated the role of C-reactive protein (CRP), hemoglobin-A1c (HbA1c) and (jointly) sex hormone-binding globulin (SHBG) and testosterone, in explaining this association. Total effect of obesity versus normal-weight (based on waist circumference, body mass index, waist-hip ratio) on CRC risk was decomposed into natural direct (NDE) and indirect (NIE) effects using sequential mediation analysis. After a median follow-up of 7.1 years, 2070 incident CRC cases (men = 1,280; postmenopausal women = 790) were recorded. For men, the adjusted risk ratio (RR) for waist circumference (≥102 vs. ≤94 cm) was 1.37 (95% confidence interval [CI], 1.19-1.58). The RRsNIE were 1.08 (95% CI: 1.01-1.16) through all biomarkers, 1.06 (95% CI: 1.01-1.11) through pathways influenced by CRP, 0.99 (95% CI: 0.97-1.01) through HbA1c beyond (the potential influence of) CRP and 1.03 (95% CI: 0.99-1.08) through SHBG and testosterone combined beyond CRP and HbA1c. The RRNDE was 1.26 (95% CI: 1.09-1.47). For women, the RR for waist circumference (≥88 vs. ≤80 cm) was 1.27 (95% CI: 1.07-1.50). The RRsNIE were 1.08 (95% CI: 0.94-1.22) through all biomarkers, 1.08 (95% CI: 0.99-1.17) through CRP, 1.00 (95% CI: 0.98-1.02) through HbA1c beyond CRP and 1.00 (95% CI: 0.92-1.09) through SHBG and testosterone combined beyond CRP and HbA1c. The RRNDE was 1.18 (95% CI: 0.96-1.45). For men and women, pathways influenced by CRP explained a small proportion of the adiposity-CRC association. Testosterone and SHBG also explained a small proportion of this association in men. These results suggest that pathways marked by these obesity-related factors may not explain a large proportion of the adiposity-CRC association.

Adiposity and estrogen receptor-positive, postmenopausal breast cancer risk: Quantification of the mediating effects of fasting insulin and free estradiol.

Adiposity increases estrogen receptor (ER)-positive postmenopausal breast cancer risk. While mechanisms underlying this relationship are uncertain, dysregulated sex-steroid hormone production and insulin signaling are likely pathways. Our aim was to quantify mediating effects of fasting insulin and free estradiol in the adiposity and ER-positive postmenopausal breast cancer association. We used data from a case-cohort study of sex hormones and insulin signaling nested within the Melbourne Collaborative Cohort Study. Eligible women, at baseline, were not diagnosed with cancer, were postmenopausal, did not use hormone therapy and had no history of diabetes or diabetes medication use. Women with ER-negative disease or breast cancer diagnosis within the first follow-up year were excluded. We analyzed the study as a cumulative sampling case-control study with 149 cases and 1,029 controls. Missing values for insulin and free estradiol were multiply imputed with chained equations. Interventional direct (IDE) and indirect (IIE) effects were estimated using regression-based multiple-mediator approach. For women with body mass index (BMI) >30 kg/m2 compared to women with BMI 18.5-25 kg/m2 , the risk ratio (RR) of breast cancer was 1.75 (95% confidence interval [CI] 1.05-2.91). The estimated IDE (RR) not through the mediators was 1.03 (95% CI 0.43-2.48). Percentage mediated effect through free estradiol was 72% (IIE-RR 1.56; 95% CI 1.11-2.19). There was no evidence for an indirect effect through insulin (IIE-RR 1.12; 95% CI 0.68-1.84; 28% mediated). Our results suggest that circulating free estradiol plays an important mediating role in the adiposity-breast cancer relationship but does not explain all of the association.

Mediation analysis of the alcohol-postmenopausal breast cancer relationship by sex hormones in the EPIC cohort.

Alcohol consumption is associated with higher risk of breast cancer (BC); however, the biological mechanisms underlying this association are not fully elucidated, particularly the extent to which this relationship is mediated by sex hormone levels. Circulating concentrations of estradiol, testosterone, their free fractions and sex-hormone binding globulin (SHBG), were examined in 430 incident BC cases and 645 matched controls among alcohol-consuming postmenopausal women nested within the European Prospective Investigation into Cancer and Nutrition. Mediation analysis was applied to assess whether individual hormone levels mediated the relationship between alcohol intake and BC risk. An alcohol-related hormonal signature, obtained by partial least square (PLS) regression, was evaluated as a potential mediator. Total (TE), natural direct and natural indirect effects (NIE) were estimated. Alcohol intake was positively associated with overall BC risk and specifically with estrogen receptor-positive tumors with respectively TE = 1.17(95%CI: 1.01,1.35) and 1.36(1.08,1.70) for a 1-standard deviation (1-SD) increase of intake. There was no evidence of mediation by sex steroids or SHBG separately except for a weak indirect effect through free estradiol where NIE = 1.03(1.00,1.06). However, an alcohol-related hormonal signature negatively associated with SHBG and positively with estradiol and testosterone was associated with BC risk (odds ratio [OR] = 1.25 [1.07,1.47]) for a 1-SD higher PLS score, and had a statistically significant NIE accounting for a mediated proportion of 24%. There was limited evidence of mediation of the alcohol-BC association by individual sex hormones. However, a hormonal signature, reflecting lower levels of SHBG and higher levels of sex steroids, mediated a substantial proportion of the association.

Type 2 diabetes mellitus, blood cholesterol, triglyceride and colorectal cancer risk in Lynch syndrome.

BACKGROUND: Type 2 diabetes mellitus and high total cholesterol and triglycerides are known to be associated with increased colorectal cancer risk for the general population. These associations are unknown for people with a germline DNA mismatch repair gene mutation (Lynch syndrome), who are at high risk of colorectal cancer. METHODS: This study included 2023 (56.4% female) carriers with a mismatch repair gene mutation (737 in MLH1, 928 in MSH2, 230 in MSH6, 106 in PMS2, 22 in EPCAM) recruited by the Colon Cancer Family Registry between 1998 and 2012. Weighted Cox regression was used to estimate the hazard ratios (HR) and 95% confidence intervals (CI) for the associations between self-reported type 2 diabetes, high cholesterol, triglyceride and colorectal cancer risk. RESULTS: Overall, 802 carriers were diagnosed with colorectal cancer at a median age of 42 years. A higher risk of colorectal cancer was observed in those with self-reported type-2 diabetes (HR 1.92; 95% CI, 1.03-3.58) and high cholesterol (HR 1.76; CI 1.23-2.52) compared with those without these conditions. There was no evidence of high triglyceride being associated with colorectal cancer risk. CONCLUSION: For people with Lynch syndrome, self-reported type-2 diabetes mellitus and high cholesterol were associated with increased colorectal cancer risk.

Physical activity and the risk of colorectal cancer in Lynch syndrome.

Greater physical activity is associated with a decrease in risk of colorectal cancer for the general population; however, little is known about its relationship with colorectal cancer risk in people with Lynch syndrome, carriers of inherited pathogenic mutations in genes affecting DNA mismatch repair (MMR). We studied a cohort of 2,042 MMR gene mutations carriers (n = 807, diagnosed with colorectal cancer), from the Colon Cancer Family Registry. Self-reported physical activity in three age-periods (20-29, 30-49 and ≥50 years) was summarized as average metabolic equivalent of task hours per week (MET-hr/week) during the age-period of cancer diagnosis or censoring (near-term exposure) and across all age-periods preceding cancer diagnosis or censoring (long-term exposure). Weighted Cox regression was used to estimate the hazard ratio (HR) and 95% confidence intervals (CI) for the association between physical activity and colorectal cancer risk. Near-term physical activity was associated with a small reduction in the risk of colorectal cancer (HR ≥35 vs. <3.5 MET-hr/week, 0.71; 95% CI, 0.53-0.96). The strength and direction of associations were similar for long-term physical activity, although the associations were not nominally significant. Our results suggest that physical activity is inversely associated with the risk of colorectal cancer for people with Lynch syndrome; however, further confirmation is warranted. The potential modifying effect of physical activity on colorectal cancer risk in people with Lynch syndrome could be useful for risk prediction and support counseling advice for lifestyle modification to reduce cancer risk.

Risk factors for metachronous colorectal cancer following a primary colorectal cancer: A prospective cohort study.

Individuals diagnosed with colorectal cancer (CRC) are at risk of developing a metachronous CRC. We examined the associations between personal, tumour-related and lifestyle risk factors, and risk of metachronous CRC. A total of 7,863 participants with incident colon or rectal cancer who were recruited in the USA, Canada and Australia to the Colon Cancer Family Registry during 1997-2012, except those identified as high-risk, for example, Lynch syndrome, were followed up approximately every 5 years. We estimated the risk of metachronous CRC, defined as the first new primary CRC following an interval of at least one year after the initial CRC diagnosis. Observation time started at the age at diagnosis of the initial CRC and ended at the age at diagnosis of the metachronous CRC, last contact or death whichever occurred earliest, or were censored at the age at diagnosis of any metachronous colorectal adenoma. Cox regression was used to derive hazard ratios (HRs) and 95% confidence intervals (CIs). During a mean follow-up of 6.6 years, 142 (1.81%) metachronous CRCs were diagnosed (mean age at diagnosis 59.8; incidence 2.7/1,000 person-years). An increased risk of metachronous CRC was associated with the presence of a synchronous CRC (HR = 2.73; 95% CI: 1.30-5.72) and the location of cancer in the proximal colon at initial diagnosis (compared with distal colon or rectum, HR = 4.16; 95% CI: 2.80-6.18). The presence of a synchronous CRC and the location of the initial CRC might be useful for deciding the intensity of surveillance colonoscopy for individuals diagnosed with CRC.

Pubertal hormones and mental health problems in children and adolescents: a systematic review of population-based studies.

Given the increased prevalence of mental health problems during adolescence, there is considerable interest in understanding potential biological mechanisms including the contribution of pubertal hormones. This systematic review of 55 papers aimed to synthesize the evidence for the effect of pubertal hormones on the risk for mental health problems in children and adolescents. The pattern of findings from included studies suggested associations of testosterone and estradiol with certain types of mental health problems, but with inconsistencies relating to DHEA and DHEA-S. However, the state of evidence for the causal effects of hormones was determined to be weak given assessment of bias from confounding, hormone measurement error, selection bias and missingness. Further investigations with careful consideration of study design and analysis, particularly accounting for short-term variation of hormone levels and appropriate selection of confounders, is necessary to advance our understanding of hormonal effects on mental health. Such efforts will improve knowledge of risk mechanisms, and may support the development of targeted intervention efforts for mental health problems.

Characterization of Puberty in an Australian Population-Based Cohort Study.

PURPOSE: Current knowledge of the characteristics of puberty beyond age at menarche and thelarche is limited, particularly within population-based cohorts. Secular trends and concerns of the health effects of early puberty reinforce the value of contemporary studies characterizing the timing, tempo, duration, and synchronicity of puberty. METHODS: The Childhood to Adolescence Transition Study is a unique Australian cohort of individuals followed annually from late childhood to late adolescence, with up to eight assessments of pubertal stage from 9 to 19 years of age (N = 1,183; 636 females). At each assessment, females reported their Tanner Stage of breast and pubic hair development, while males reported on genital/pubic hair development. Nonlinear mixed-effects models characterized pubertal trajectories and were used to derive each individual's estimates of timing, tempo, and synchronicity. Parametric survival models were used to estimate the overall duration of puberty. RESULTS: Timing of mid-puberty (Tanner Stage 3) ranged from 12.5 to 13.5 years, with females developing approximately 6 months before males. Pubertal tempo (at mid-puberty) was similar across sex (between half and one Tanner Stage per year), but the overall duration of puberty was slightly shorter in males. Most females exhibited asynchronous changes of breast and pubic hair development. DISCUSSION: Estimates of pubertal timing and tempo are consistent with reports of cohorts from two or more decades ago, suggesting stabilization of certain pubertal characteristics in predominantly White populations. However, our understanding of the duration of puberty and individual differences in pubertal characteristics (e.g., synchronicity of physical changes) remains limited.

Characteristics of Puberty in a Population-Based Sample of Danish Adolescents.

PURPOSE: To describe the duration, timing, tempo, and synchronicity of puberty, as well as the correlation between timing and tempo of puberty. METHODS: Overall, 15,819 of 22,439 invited children participated in the Puberty Cohort within the Danish National Birth Cohort. Participants completed a web-based questionnaire every 6 months through maturation with questions on current pubertal status. Girls reported current Tanner stage of breast and pubic hair development, and timing of menarche. Boys reported current Tanner stage of genital and pubic hair development, timing of first ejaculation, and vocal changes. While accounting for this interval-censored puberty information, we estimated the duration of puberty. Then, we used a nonlinear mixed effect growth model to estimate timing, tempo, synchronicity of puberty, and correlation between timing and tempo of puberty. RESULTS: In girls, the average duration of breast development was longer, whereas the average tempo was slower than pubic hair development. The average timing of breast development was earlier than the average timing of pubic hair development. The majority of girls had asynchronous puberty. In boys, the average duration was longer and average tempo slower for genital than pubic hair development. The average timing of genital and pubic hair development were comparable; hence, the majority had synchronous pubertal development. Adolescents who had earlier timing also tended to have a faster tempo. DISCUSSION: Being one of the largest puberty cohorts worldwide, these unique contemporary data can help physicians, parents, and children to understand and anticipate expected progression through pubertal development.

Child marriage and the mental health of adolescent girls: a longitudinal cohort study from Uttar Pradesh and Bihar, India.

Background: There has been much speculation about the role of inequitable gender norms and early marriage in mental health and suicide risks in girls and young women, but no prospective study has yet investigated this relationship. Understanding these links has become particularly important in the context of the COVID-19 pandemic which has led to increased risk of child marriage in the most vulnerable girls. Methods: We examined the association between early marriage and mental health in girls using data from Understanding the Lives of Adolescents and Young Adults (UDAYA), a longitudinal study in adolescents in Uttar Pradesh and Bihar, India. The study included girls who were unmarried at wave 1 (2015-2016) and participated at wave 2 data collection (2018-2019). Information on mental health (Patient Health Questionnaire-9 (PHQ-9)), suicidal thoughts, plans and attempts were collected at both waves. Logistic regression with survey weights was used to estimate the association between marrying between the two waves and mental health. Findings: Between waves 1 and 2, 1825 (23%) participants (n = 7864) married. Unmarried girls with depressive symptoms (PHQ score≥9) at wave 1 had greater odds of transitioning into marriage by wave 2 than those without (adjusted-OR 1.5; 95% CI 1.1 to 2.0). The odds of wave 2 depressive symptoms were higher in newly married vs unmarried girls (adjusted-OR 2.0; 95% CI 1.6-2.5). Among newly married girls, the odds of depressive symptoms were higher for those who experienced any abuse than those who did not (adjusted-OR 1.6; 95% CI 1.2-2.2). This effect was larger for girls who had not given birth (adjusted-OR 2.2; 95% CI 1.4-3.3). Interpretation: Our findings show poor mental health preceded and was a consequence of child marriage. Mental health should be considered in policies and programming aimed at reducing early marriage; equally the mental health of young brides should be a focus for community and maternal health services. Funding: Bill and Melinda Gates Foundation and David and Lucile Packard Foundation.

Sex-steroid hormones and risk of postmenopausal estrogen receptor-positive breast cancer: a case-cohort analysis.

Purpose: Sex-steroid hormones are associated with postmenopausal breast cancer but potential confounding from other biological pathways is rarely considered. We estimated risk ratios for sex-steroid hormone biomarkers in relation to postmenopausal estrogen receptor (ER)-positive breast cancer, while accounting for biomarkers from insulin/insulin-like growth factor-signaling and inflammatory pathways. Methods: This analysis included 1,208 women from a case-cohort study of postmenopausal breast cancer within the Melbourne Collaborative Cohort Study. Weighted Poisson regression with a robust variance estimator was used to estimate risk ratios (RRs) and 95% confidence intervals (CIs) of postmenopausal ER-positive breast cancer, per doubling plasma concentration of progesterone, estrogens, androgens, and sex hormone binding globulin (SHBG). Analyses included sociodemographic and lifestyle confounders, and other biomarkers identified as potential confounders. Results: Increased risks of postmenopausal ER-positive breast cancer were observed per doubling plasma concentration of progesterone (RR: 1.22, 95% CI: 1.03 to 1.44), androstenedione (RR: 1.20, 95% CI: 0.99 to 1.45), dehydroepiandrosterone (RR: 1.15, 95% CI: 1.00 to 1.34), total testosterone (RR: 1.11, 95% CI: 0.96 to 1.29), free testosterone (RR: 1.12, 95% CI: 0.98 to 1.28), estrone (RR: 1.21, 95% CI: 0.99 to 1.48), total estradiol (RR: 1.19, 95% CI: 1.02 to 1.39) and free estradiol (RR: 1.22, 95% CI: 1.05 to 1.41). A possible decreased risk was observed for SHBG (RR: 0.83, 95% CI: 0.66 to 1.05). Conclusion: Progesterone, estrogens and androgens likely increase postmenopausal ER-positive breast cancer risk, whereas SHBG may decrease risk. These findings strengthen the causal evidence surrounding the sex hormone-driven nature of postmenopausal breast cancer.