Breast density is a strong intermediate endpoint to investigate the association between early-life exposures and breast cancer risk. This study investigates the association between early-life growth and breast density in young adult women measured using Optical Breast Spectroscopy (OBS) and Dual X-ray Absorptiometry (DXA). OBS measurements were obtained for 536 female Raine Cohort Study participants at ages 27-28, with 268 completing DXA measurements. Participants with three or more height and weight measurements from ages 8 to 22 were used to generate linear growth curves for height, weight and body mass index (BMI) using SITAR modelling. Three growth parameters (size, velocity and timing) were examined for association with breast density measures, adjusting for potential confounders. Women who reached their peak height rapidly (velocity) and later in adolescence (timing) had lower OBS-breast density. Overall, women who were taller (size) had higher OBS-breast density. For weight, women who grew quickly (velocity) and later in adolescence (timing) had higher absolute DXA-breast density. Overall, weight (size) was also inversely associated with absolute DXA-breast density, as was BMI. These findings provide new evidence that adolescent growth is associated with breast density measures in young adult women, suggesting potential mediation pathways for breast cancer risk in later life.

OBJECTIVE: This study evaluates the performance of a multitrait polygenic risk score (PRS) in an independent cohort to predict incident or progression of keratoconus.
METHODS: Prospective cross-sectional and cohort study METHODS: Setting: Single-center; Study population: 1478 community-based young adults (18-30 years; 51% female), including 609 (52% female) who returned for an 8-year follow-up; Observation procedures: Scheimpflug imaging (Pentacam, Oculus), genotyping and development of a multitrait PRS previously validated to predict keratoconus in older adults.; Main outcome measure: Belin/Ambrόsio enhanced ectasia display (BAD-D) score and keratoconus, defined as BAD-D ≥2.6, were each analyzed against the PRS using linear and logistic regression, respectively.
RESULTS: Prevalence of keratoconus was 2.5% (95% confidence interval [CI] = 1.9-3.6) in the cross-sectional cohort. Each z-score increase in PRS was associated with worse BAD-D z-score by 0.13 (95%CI = 0.08-0.18) and 1.6 increased odds of keratoconus. The 8-year keratoconus incidence was 2.6% (95%CI = 1.3-4.0). Participants in the highest PRS decile were more likely to have incident keratoconus compared to the rest of the cohort (odds ratio = 3.85, 95%CI = 1.21-12.22). For each z-score increase in PRS, 8-year change in BAD-D z-score worsened by 0.11 (95%CI = 0.04-0.17).
CONCLUSIONS: A PRS for keratoconus could be useful in predicting incident keratoconus and progression, demonstrating its potential utility in clinical settings to identify patients at high risk of postsurgery ectasia or those who may benefit most from keratoconus intervention.

BACKGROUND: Developmental language disorder (DLD) is one of the most common neurodevelopmental conditions. Due to variable rates of language growth in children under 5 years, the early identification of children with DLD is challenging. Early indicators are often outlined by speech pathology regulatory bodies and other developmental services as evidence to empower caregivers in the early identification of DLD.
OBJECTIVE: To test the predictive relationship between parent-reported early indicators and the likelihood of children meeting diagnostic criteria for DLD at 10 years of age as determined by standardized assessment measures in a population-based sample.
METHODS: Data were leveraged from the prospective Raine Study (n = 1626 second-generation children: n = 104 with DLD; n = 1522 without DLD). These data were transformed into 11 predictor variables that reflect well-established early indicators of DLD from birth to 3 years, including if the child does not smile or interact with others, does not babble, makes only a few sounds, does not understand what others say, says only a few words, says words that are not easily understood, and does not combine words or put words together to make sentences. Family history (mother and father) of speech and language difficulties were also included as variables. Regression analyses were planned to explore the predictive relationship between this set of early indicator variables and likelihood of meeting DLD diagnostic criteria at 10 years.
RESULTS: No single parent-reported indicator uniquely accounted for a significant proportion of children with DLD at 10 years of age. Further analyses, including bivariate analyses testing the predictive power of a cumulative risk index of combined predictors (odds ratio (OR) = 0.95, confidence interval (CI) = 0.85-1.09, p = 0.447) and the moderating effect of sex (OR = 0.89, CI = 0.59-1.32, p = 0.563) were also non-significant.
CONCLUSIONS: Parent reports of early indicators of DLD are well-intentioned and widely used. However, data from the Raine Study cohort suggest potential retrospective reporting bias in previous studies. We note that missing data for some indicators may have influenced the results. Implications for the impact of using early indicators as evidence to inform early identification of DLD are discussed.
CONCLUSIONS: What is already known on the subject DLD is a relatively common childhood condition; however, children with DLD are under-identified and under-served. Individual variability in early childhood makes identification of children at risk of DLD challenging. A range of \'red flags\' in communication development are promoted through speech pathology regulatory bodies and developmental services to assist parents to identify if their child should access services. What this paper adds to the existing knowledge No one parent-reported early indicator, family history or a cumulation of indicators predicted DLD at 10 years in the Raine study. Sex (specifically, being male) did not moderate an increased risk of DLD at 10 years in the Raine study. Previous studies reporting on clinical samples may be at risk of retrospective reporting bias. What are the potential or actual clinical implications of this work? The broad dissemination and use of \'red flags\' is well-intentioned; however, demonstrating \'red flags\' alone may not reliably identify those who are at later risk of DLD. Findings from the literature suggest that parent concern may be complemented with assessment of linguistic behaviours to increase the likelihood of identifying those who at risk of DLD. Approaches to identification and assessment should be considered alongside evaluation of functional impact to inform participation-based interventions.

BACKGROUND: Few studies have examined associations between gender non-conformity (GNC) in childhood or adolescence and mental health outcomes later in life. This study examined associations between (1) GNC and mental health over multiple time points in childhood and adolescence, and (2) GNC in childhood and/or adolescence and mental health in adulthood.
METHODS: Second generation participants from the Raine Study, a longitudinal cohort from Perth, Western Australia. Data were collected between 1995 and 2018, comprising seven waves: ages 5 (N = 2236), 8 (N = 2140), 10 (N = 2048), 14 (N = 1864), 17 (N = 1726), 22 (N = 1236) and 27 (N = 1190) years. History of GNC, v. absence of this history, was based on responses to item 110 from the Child Behaviour Checklist (CBCL)/Youth Self Report (YSR) (\'wishes to be of opposite sex\'). The CBCL/YSR were used to measure internalising and externalising symptoms. Items 18 (\'deliberate self-harm [DSH] or attempts suicide\') and 91 (\'talks/thinks about killing self\') were used as measures of suicidal ideation (SI) and DSH. For adults, Depression, Anxiety and Stress Subscales and Kessler Psychological Distress Scale assessed mental health.
RESULTS: Child and adolescent GNC was associated with elevated internalising and externalising behaviours and increased odds of DSH. A history of GNC was also associated with vulnerability for severe psychological distress in adulthood in some symptom scales.
CONCLUSIONS: GNC over the child and adolescent period is associated with significant emotional and behavioural difficulties, and psychological distress. A history of GNC in childhood and/or adolescence also predicts poorer mental health in adulthood on multiple symptom domains.

The effect of prenatal marijuana exposure (PME) on child neurodevelopment remains poorly understood. Prior studies have demonstrated inconsistent results.
This study evaluated the association between PME and neuropsychological test scores in late childhood and early adulthood, accounting for a wide range of parental characteristics.
This study evaluated participants from the Raine Study, a cohort of 2868 children born between 1989 and 1992. Children whose mothers provided information on marijuana use during pregnancy were included. The primary outcome was the Clinical Evaluation of Language Fundamentals (CELF) at age 10. Secondary outcomes included the Peabody Picture Vocabulary Test (PPVT), Child Behaviour Checklist (CBCL), McCarron Assessment of Neuromuscular Development (MAND), Coloured Progressive Matrices (CPM), Symbol Digit Modality Test (SDMT) and Autism Spectrum Quotient (AQ) scores. Exposed and unexposed children were matched by propensity score using optimal full matching. Missing covariate data were imputed using multiple imputation. Inverse probability of censoring weighting (IPCW) was used to adjust for missing outcome data. Linear regression within matched sets, adjusted by IPCW, evaluated score differences between exposed and unexposed children. As a secondary analysis, modified Poisson regression, adjusted by match weights and IPCW, evaluated the risk of clinical deficit in each outcome following PME.
Of the 2804 children in this cohort, 285 (10.2%) had PME. After optimal full matching and IPCW, exposed children scored similarly on CELF Total (-0.33 points, 95% confidence interval [CI] -4.71, 4.05), Receptive (+0.65 points, 95% CI -4.08, 5.38) or Expressive (-0.53 points, 95% CI -5.07, 4.02). PME was not associated with secondary outcomes or risks of clinical deficit in any neuropsychological assessments.
After adjusting for sociodemographic and clinical covariates, PME was not associated with worse neuropsychological test scores at age 10 or autistic traits at 19-20.

Investigate if childhood measures of sleep health are associated with epigenetic age acceleration in late adolescence.
Parent-reported sleep trajectories from age 5 to 17, self-reported sleep problems at age 17, and six measures of epigenetic age acceleration at age 17 were studied in 1192 young Australians from the Raine Study Gen2.
There was no evidence for a relationship between the parent-reported sleep trajectories and epigenetic age acceleration (p ≥ 0.17). There was a positive cross-sectional relationship between self-reported sleep problem score and intrinsic epigenetic age acceleration at age 17 (b = 0.14, p = 0.04), which was attenuated after controlling for depressive symptom score at the same age (b = 0.08, p = 0.34). Follow-up analyses suggested this finding may represent greater overtiredness and intrinsic epigenetic age acceleration in adolescents with higher depressive symptoms.
There was no evidence for a relationship between self- or parent-reported sleep health and epigenetic age acceleration in late adolescence after adjusting for depressive symptoms. Mental health should be considered as a potential confounding variable in future research on sleep and epigenetic age acceleration, particularly if subjective measures of sleep are used.

The aim of this research note is to encourage child language researchers and clinicians to give careful consideration to the use of domain-specific tests as a proxy for language; particularly in the context of large-scale studies and for the identification of language disorder in clinical practice.
We report on data leveraged through the prospective Raine Study cohort. Participants included 1626 children aged 10 years (n = 104 with developmental language disorder [DLD] and n = 1522 without DLD). We assessed the predictive utility of common language measures including subtests of a standardised omnibus language assessment, non-verbal intelligence, and a domain-specific receptive vocabulary test.
Children with DLD performed within the average range on a measure of non-verbal intelligence (z = -0.86) and receptive vocabulary (z = -0.38), as well as two out of the six subtests on the omnibus language assessment (zs > -1.50). The magnitude of the predictive relationship between language assessments and the likelihood of a child meeting criteria for DLD at 10 years was assessed using a logistic regression model, which was significant: χ2(8) = 16.91, p = 0.031. Semantic Relationships (OR = 1.13, CI = 1.04 - 1.23, p = .004), Formulated Sentences (OR = 1.07, CI = 1.01 - 1.13, p = .028), Recalling Sentences (OR = 1.20, CI = 1.15 - 1.26, p < .001), and Sentence Assembly (OR = 1.17, CI = 1.07 - 1.30, p = .001) were significant predictors of DLD.
Domain-specific language assessments, particularly those testing receptive vocabulary, may overestimate the language ability of children with DLD. Caution is urged when using such tests by clinicians and researchers, especially those measuring language skills of children at scale. Future directions for measuring the functional impact of DLD are presented.

Investigations of participant retention in longitudinal health and medical research, document  strategies that work best but overlook social marketing\'s capacity to influence participant retention. After applying the social marketing framework: the idea that determining what longitudinal participants \'buy\' (product), at what cost (price), in what location (place) and through which communication channels (promotion),  this paper  aims to inform and enhance retention efforts.
This qualitative study was conducted through in-depth interviews with participants from the Raine Study that began in Western Australia in 1989. The Generation 2 participants, initially enrolled into the Raine Study as babies by their parents (Generation 1), are now young adults invited to attend follow-up studies and tests every few years. Our study defined \'active\' participants (n = 17) as those who agreed to attend their 27 year follow-up, and \'inactive\' (n = 12) participants as those who had attended neither of the past two follow-ups (22 and 27 years).
Raine Study participants experienced core, actual and augmented product benefits. Inactive participants focused on the costs (price) associated with participation, and were more likely to suggest tele-health (place) strategies to overcome barriers to follow-up attendance. Both active and inactive participants found professional processes and friendly staff made the Raine Study environment appealing, suggested that social media (promotion) was underutilised, and offered novel ideas to enhance engagement.
Social marketing can support the development of differentiated strategies addressing the unique needs and wants of active and inactive participants. Sophisticated cohort segmentation can reach participants in a more meaningful way, reinforce the study \'brand\' and guard against attrition.

Environmental exposure to phthalates and bisphenol A (BPA), chemicals used in the production of plastics, may increase risk for asthma and allergies. However, little is known about the long-term effects of early life exposure to these compounds. We investigated if prenatal exposure to these compounds was associated with asthma, allergy and lung function outcomes from early childhood into adulthood in a cohort study.
Maternal serum samples collected from 846 pregnant women in the Raine Study were assayed for BPA and phthalate metabolites. The children of these women were followed up at 5, 13 and 22 years where spirometry and respiratory questionnaires were conducted to determine asthma and allergy status. Lung function trajectories were derived from longitudinal spirometry measurements. Multinomial logistic regression and weighted quantile sum regression was used to test associations of individual and chemical mixtures with asthma phenotypes and lung function trajectories.
Effects of prenatal BPA and phthalates on asthma phenotypes were seen in male offspring, where BPA was associated with increased risk for persistent asthma, while mono-iso-butyl phthalate and mono-iso-decyl phthalate was associated with increased risk for adult asthma. Prenatal BPA had no effect on lung function trajectories, but prenatal phthalate exposure was associated with improved lung function.
Prenatal BPA exposure was associated with increased likelihood of persistent asthma in males, while prenatal phthalate exposure was associated with increased likelihood of adult asthma in males. Results suggest that prenatal exposure to prenatal BPA and phthalates affect asthma risk, particularly in males, however lung function was not adversely affected.

This study sought to determine the prevalence of Developmental Language Disorder (DLD) in Australian school-aged children and associated potential risk factors for DLD at 10 years.
This study used a cross-sectional design to estimate the prevalence of DLD in Generation 2 of the prospective Raine Study. Participants included 1626 children aged 10 years with available language data. Primary outcomes included variables matching diagnostic criteria for DLD. Associations of other potential prenatal and environmental variables were analysed as secondary outcomes.
The prevalence of DLD in this sample was 6.4% (n = 104) at 10 years. This sub-cohort comprised 33.7% (n = 35) with expressive language deficits, 20.2% (n = 21) with receptive language deficits, and 46.2% (n = 48) with receptive-expressive deficits. No significant difference in sex distribution was observed (52.9% male, p = 0.799). Children who were exposed to smoke in utero at 18 weeks gestation were at increased risk of DLD at 10 years (OR = 2.56, CI = 1.23-5.35, p = 0.012).
DLD is a relatively prevalent condition in Australian children, even when assessed in middle childhood years. These findings can inform future research priorities, and public health and educational policy which account for the associations with potential risk factors.