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BACKGROUND: Patients with obstructive sleep apnea (OSA) are at increased risk of postoperative cardiorespiratory complications and death. Attempts to stratify this risk have been inadequate, and predictors from large well-characterized cohort studies are needed. RESEARCH QUESTION: What is the relationship between OSA severity, defined by various polysomnography-derived metrics, and risk of postoperative cardiorespiratory complications or death, and which metrics best identify such risk? STUDY DESIGN AND METHODS: Cohort study of 6770 consecutive patients who underwent diagnostic polysomnography for possible OSA and a procedure involving general anesthesia within a period spanning 2 years before and at least 5 years after polysomnography. Participants were identified by linking polysomnography and health databases. Relationships between OSA severity measures and the composite primary outcome of cardiorespiratory complications or death within 30 days of hospital discharge were investigated using univariable and multivariable analyses. RESULTS: The primary outcome was observed in 5.3% (n=361) of the cohort. While univariable analysis showed strong dose-response relationships between this outcome and multiple OSA severity measures, multivariable analysis showed its independent predictors were: age >65 years (OR 2.67 [95%CI 2.03-3.52], p<0.0001); age 55.1-65 years (OR 1.47 [1.09-1.98], p=0.0111); time between polysomnography and procedure ≥5 years (OR 1.32 [1.02-1.70], p=0.0331), body mass index ≥35kg/m2 (OR 1.43 [1.13-1.82], p=0.0032); presence of known cardiorespiratory risk factor (OR 1.63 [1.29-2.06], p<0.0001); >4.7% of sleep time at SpO2 less than 90% (T90) (OR 1.91 [1.51-2.42], p<0.0001); and cardiothoracic procedures (OR 7.95 [5.71-11.08], p<0.001). For non-cardiothoracic procedures, age, BMI, presence of known cardiorespiratory risk factor and T90 remained the significant predictors, and a risk score based on their odds ratios was predictive of outcome (area under receiver operating characteristic curve 0.7 [95%CI 0.64-0.75]). INTERPRETATION: These findings provide a basis for better identifying high-risk OSA patients and determining appropriate postoperative care.

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BACKGROUND: Accurate risk stratification is vital for primary prevention of cardiovascular disease (CVD). However, traditional tools such as the Framingham Risk Score (FRS) may underperform within the diverse intermediate-risk group, which includes individuals requiring distinct management strategies. OBJECTIVES: This study aimed to develop a lipidomic-enhanced risk score (LRS), specifically targeting risk prediction and reclassification within the intermediate group, benchmarked against the FRS. METHODS: The LRS was developed via a machine learning workflow using ridge regression on the Australian Diabetes, Obesity, and Lifestyle Study (AusDiab; n = 10,339). It was externally validated with the Busselton Health Study (n = 4,492), and its predictive utility for coronary artery calcium scoring (CACS)-based outcomes was independently validated in the BioHEART cohort (n = 994). RESULTS: LRS significantly improved discrimination metrics for the intermediate-risk group in both AusDiab and Busselton Health Study cohorts (all P < 0.001), increasing the area under the curve for CVD events by 0.114 (95% CI: 0.1123-0.1157) and 0.077 (95% CI: 0.0755-0.0785), with a net reclassification improvement of 0.36 (95% CI: 0.21-0.51) and 0.33 (95% CI: 0.15-0.49), respectively. For CACS-based outcomes in BioHEART, LRS achieved a significant area under the curve improvement of 0.02 over the FRS (0.76 vs 0.74; P < 1.0 × 10-5). A simplified, clinically applicable version of LRS was also created that had comparable performance to the original LRS. CONCLUSIONS: LRS, augmenting the FRS, presents potential to improve intermediate-risk stratification and to predict atherosclerotic markers using a simple blood test, suitable for clinical application. This could facilitate the triage of individuals for noninvasive imaging such as CACS, fostering precision medicine in CVD prevention and management.

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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.

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After burn injury there is considerable variation in scar outcome, partially due to genetic factors. Scar vascularity is one characteristic that varies between individuals, and this study aimed to identify genetic variants contributing to different scar vascularity outcomes. An exome-wide array association study and gene pathway analysis was performed on a prospective cohort of 665 patients of European ancestry treated for burn injury, using their scar vascularity (SV) sub-score, part of the modified Vancouver Scar Scale (mVSS), as an outcome measure. DNA was genotyped using the Infinium HumanCoreExome-24 BeadChip, imputed to the Haplotype Reference Consortium panel. Associations between genetic variants (single nucleotide polymorphisms) and SV were estimated using an additive genetic model adjusting for sex, age, % total body surface area and number of surgical procedures, utilising linear and multinomial logistic regression. No individual genetic variants achieved the cut-off threshold for significance. Gene sets were also analysed using the Functional Mapping and Annotation (FUMA) platform, in which biological processes indirectly related to angiogenesis were significantly represented. This study suggests that SNPs in genes associated with angiogenesis may influence SV, but further studies with larger datasets are essential to validate these findings.

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PURPOSE: Age and body mass index (BMI) are critical considerations when assessing individual breast cancer risk, particularly for women with dense breasts. However, age- and BMI-standardized estimates of breast density are not available for screen-aged women, and little is known about the distribution of breast density in women aged < 40. This cross-sectional study uses three different modalities: optical breast spectroscopy (OBS), dual-energy X-ray absorptiometry (DXA), and mammography, to describe the distributions of breast density across categories of age and BMI. METHODS: Breast density measures were estimated for 1,961 Australian women aged 18-97 years using OBS (%water and %water + %collagen). Of these, 935 women had DXA measures (percent and absolute fibroglandular dense volume, %FGV and FGV, respectively) and 354 had conventional mammographic measures (percent and absolute dense area). The distributions for each breast density measure were described across categories of age and BMI. RESULTS: The mean age was 38 years (standard deviation = 15). Median breast density measures decreased with age and BMI for all three modalities, except for DXA-FGV, which increased with BMI and decreased after age 30. The variation in breast density measures was largest for younger women and decreased with increasing age and BMI. CONCLUSION: This unique study describes the distribution of breast density measures for women aged 18-97 using alternative and conventional modalities of measurement. While this study is the largest of its kind, larger sample sizes are needed to provide clinically useful age-standardized measures to identify women with high breast density for their age or BMI.

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OBJECTIVE: To estimate the prevalence of long COVID among Western Australian adults, a highly vaccinated population whose first major exposure to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was during the 2022 Omicron wave, and to assess its impact on health service use and return to work or study. STUDY DESIGN: Follow-up survey (completed online or by telephone). SETTING, PARTICIPANTS: Adult Western Australians surveyed 90 days after positive SARS-CoV-2 test results (polymerase chain reaction or rapid antigen testing) during 16 July - 3 August 2022 who had consented to follow-up contact for research purposes. MAIN OUTCOME MEASURES: Proportion of respondents with long COVID (ie, reporting new or ongoing symptoms or health problems, 90 days after positive SARS-CoV-2 test result); proportion with long COVID who sought health care for long COVID-related symptoms two to three months after infection; proportion who reported not fully returning to previous work or study because of long COVID-related symptoms. RESULTS: Of the 70 876 adults with reported SARS-CoV-2 infections, 24 024 consented to contact (33.9%); after exclusions, 22 744 people were invited to complete the survey, of whom 11 697 (51.4%) provided complete responses. Our case definition for long COVID was satisfied by 2130 respondents (18.2%). The risk of long COVID was greater for women (v men: adjusted risk ratio [aRR], 1.5; 95% confidence interval [CI], 1.4-1.6) and for people aged 50-69 years (v 18-29 years: aRR, 1.6; 95% CI, 1.4-1.9) or with pre-existing health conditions (aRR, 1.5; 95% CI, 1.4-1.7), as well as for people who had received two or fewer COVID-19 vaccine doses (v four or more: aRR, 1.4; 95% CI, 1.2-1.8) or three doses (aRR, 1.3; 95% CI, 1.1-1.5). The symptoms most frequently reported by people with long COVID were fatigue (1504, 70.6%) and concentration difficulties (1267, 59.5%). In the month preceding the survey, 814 people had consulted general practitioners (38.2%) and 34 reported being hospitalised (1.6%) with long COVID. Of 1779 respondents with long COVID who had worked or studied before the infection, 318 reported reducing or discontinuing this activity (17.8%). CONCLUSION: Ninety days after infection with the Omicron SARS-CoV-2 variant, 18.2% of survey respondents reported symptoms consistent with long COVID, of whom 38.7% (7.1% of all survey respondents) sought health care for related health concerns two to three months after the acute infection.

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Obesity is a risk factor for type 2 diabetes and cardiovascular disease. However, a substantial proportion of patients with these conditions have a seemingly normal body mass index (BMI). Conversely, not all obese individuals present with metabolic disorders giving rise to the concept of "metabolically healthy obese". We use lipidomic-based models for BMI to calculate a metabolic BMI score (mBMI) as a measure of metabolic dysregulation associated with obesity. Using the difference between mBMI and BMI (mBMIΔ), we identify individuals with a similar BMI but differing in their metabolic health and disease risk profiles. Exercise and diet associate with mBMIΔ suggesting the ability to modify mBMI with lifestyle intervention. Our findings show that, the mBMI score captures information on metabolic dysregulation that is independent of the measured BMI and so provides an opportunity to assess metabolic health to identify "at risk" individuals for targeted intervention and monitoring.

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SARS-CoV-2 transmission in Western Australia, Australia, was negligible until a wave of Omicron variant infections emerged in February 2022, when >90% of adults had been vaccinated. This unique pandemic enabled assessment of SARS-CoV-2 vaccine effectiveness (VE) without potential interference from background immunity from prior infection. We matched 188,950 persons who had a positive PCR test result during February-May 2022 to negative controls by age, week of test, and other possible confounders. Overall, 3-dose VE was 42.0% against infection and 81.7% against hospitalization or death. A primary series of 2 viral-vectored vaccines followed by an mRNA booster provided significantly longer protection against infection >60 days after vaccination than a 3-dose series of mRNA vaccine. In a population free from non-vaccine-derived background immunity, vaccines against the ancestral spike protein were ≈80% effective for preventing serious outcomes from infection with the SARS-CoV-2 Omicron variant.

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BACKGROUND: The relationship between OSA and cancer is unclear. RESEARCH QUESTION: What is the association between OSA and cancer prevalence and incidence in a large Western Australian sleep clinic cohort (N = 20,289)? STUDY DESIGN AND METHODS: OSA severity was defined by apnea-hypopnea index (AHI) and nocturnal hypoxemia (duration and percentage at oxygen saturation < 90%) measured by in-laboratory polysomnogram. Measures of potential confounding included age, sex, BMI, smoking status, socioeconomic status, and BP. Outcomes were determined from the Western Australian cancer and death registries. Analyses were confined within periods using consistent AHI scoring criteria: January 1, 1989, to July 31, 2002 (American Sleep Disorders Association criteria), and August 1, 2002, to June 30, 2013 (Chicago criteria). We examined associations of AHI and nocturnal hypoxemia with cancer prevalence using logistic regression and cancer incidence using Cox regression analyses. RESULTS: Cancer prevalence at baseline was 329 of 10,561 in the American Sleep Disorders Association period and 633 of 9,728 in the Chicago period. Nocturnal hypoxemia but not AHI was independently associated with prevalent cancer following adjustment for participant age, sex, BMI, smoking status, socioeconomic status, and BP. Of those without prevalent cancer, cancer was diagnosed in 1,950 of 10,232 (American Sleep Disorders Association) and 623 of 9,095 (Chicago) participants over a median follow-up of 11.2 years. Compared with the reference category (no OSA, AHI < 5 events per hour), univariable models estimated higher hazard ratios for cancer incidence for mild (AHI 5-15 events per hour), moderate (AHI 15.1-30 events per hour), and severe (AHI > 30 events per hour) OSA. Multivariable analyses consistently revealed associations between age and, in some cases, sex, BMI, and smoking status, with cancer incidence. After adjusting for confounders, multivariable models showed no independent association between OSA severity and increased cancer incidence. INTERPRETATION: Nocturnal hypoxemia is independently associated with prevalent cancer. OSA severity is associated with incident cancer, although this association seems secondary to other risk factors for cancer development. OSA is not an independent risk factor for cancer incidence.

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Autism omics research has historically been reductionist and diagnosis centric, with little attention paid to common co-occurring conditions (for example, sleep and feeding disorders) and the complex interplay between molecular profiles and neurodevelopment, genetics, environmental factors and health. Here we explored the plasma lipidome (783 lipid species) in 765 children (485 diagnosed with autism spectrum disorder (ASD)) within the Australian Autism Biobank. We identified lipids associated with ASD diagnosis (n = 8), sleep disturbances (n = 20) and cognitive function (n = 8) and found that long-chain polyunsaturated fatty acids may causally contribute to sleep disturbances mediated by the FADS gene cluster. We explored the interplay of environmental factors with neurodevelopment and the lipidome, finding that sleep disturbances and unhealthy diet have a convergent lipidome profile (with potential mediation by the microbiome) that is also independently associated with poorer adaptive function. In contrast, ASD lipidome differences were accounted for by dietary differences and sleep disturbances. We identified a large chr19p13.2 copy number variant genetic deletion spanning the LDLR gene and two high-confidence ASD genes (ELAVL3 and SMARCA4) in one child with an ASD diagnosis and widespread low-density lipoprotein-related lipidome derangements. Lipidomics captures the complexity of neurodevelopment, as well as the biological effects of conditions that commonly affect quality of life among autistic people.

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BACKGROUND: Breast density is a strong and potentially modifiable breast cancer risk factor. Almost everything we know about breast density has been derived from mammography, and therefore, very little is known about breast density in younger women aged <40. This study examines the acceptability and performance of two alternative breast density measures, Optical Breast Spectroscopy (OBS) and Dual X-ray Absorptiometry (DXA), in women aged 18-40. METHODS: Breast tissue composition (percent water, collagen, and lipid content) was measured in 539 women aged 18-40 using OBS. For a subset of 169 women, breast density was also measured via DXA (percent fibroglandular dense volume (%FGV), absolute dense volume (FGV), and non-dense volume (NFGV)). Acceptability of the measurement procedures was assessed using an adapted validated questionnaire. Performance was assessed by examining the correlation and agreement between the measures and their associations with known determinants of mammographic breast density. RESULTS: Over 93% of participants deemed OBS and DXA to be acceptable. The correlation between OBS-%water + collagen and %FGV was 0.48. Age and BMI were inversely associated with OBS-%water + collagen and %FGV and positively associated with OBS-%lipid and NFGV. CONCLUSIONS: OBS and DXA provide acceptable and viable alternative methods to measure breast density in younger women aged 18-40 years.

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We integrated lipidomics and genomics to unravel the genetic architecture of lipid metabolism and identify genetic variants associated with lipid species putatively in the mechanistic pathway for coronary artery disease (CAD). We quantified 596 lipid species in serum from 4,492 individuals from the Busselton Health Study. The discovery GWAS identified 3,361 independent lipid-loci associations, involving 667 genomic regions (479 previously unreported), with validation in two independent cohorts. A meta-analysis revealed an additional 70 independent genomic regions associated with lipid species. We identified 134 lipid endophenotypes for CAD associated with 186 genomic loci. Associations between independent lipid-loci with coronary atherosclerosis were assessed in ∼456,000 individuals from the UK Biobank. Of the 53 lipid-loci that showed evidence of association (P < 1 × 10-3), 43 loci were associated with at least one lipid endophenotype. These findings illustrate the value of integrative biology to investigate the aetiology of atherosclerosis and CAD, with implications for other complex diseases.

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Mammographic breast density is a strong breast cancer risk factor, and its routine clinical measurement could potentially be used to identify women at higher risk of breast cancer and/or monitor primary prevention strategies. Previous reports of optical breast spectroscopy (OBS), a novel approach to measuring breast density, demonstrated that it is safe (no ionizing radiation), portable, low-cost, and does not require image interpretation but have been limited to small, single-center studies. Reference measurements taken on a phantom breast prior to and after each woman's OBS assessment are required for the calibration of the system transfer function as a part of processing participant data. To inform the validity of participant data, a detailed description of the reference measurements and a repeatability analysis of these measurements taken before and after participant assessment is presented. Reference measurements for OBS from 539 women aged 18-40 years were obtained as a part of a high-throughput epidemiological pilot study. Of these, measurements from 20 women with no useable data due to device failure (3.7%) were excluded and from another 12 women due to user error. The intra-class correlation (ICC) within complete pairs of reference data (taken before and after assessment) was high (all ICC > 0.84). The analysis presented here confirms the OBS participant data as valid for use in ongoing epidemiological research, providing further supporting evidence of OBS as a measure of breast density. A novel method of measuring breast density is needed to bridge large gaps in the knowledge of breast density in younger women and its relation to later-life breast cancer risk.

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BACKGROUND: Mammographic density (MD) phenotypes, including percent density (PMD), area of dense tissue (DA), and area of non-dense tissue (NDA), are associated with breast cancer risk. Twin studies suggest that MD phenotypes are highly heritable. However, only a small proportion of their variance is explained by identified genetic variants. METHODS: We conducted a genome-wide association study, as well as a transcriptome-wide association study (TWAS), of age- and BMI-adjusted DA, NDA, and PMD in up to 27,900 European-ancestry women from the MODE/BCAC consortia. RESULTS: We identified 28 genome-wide significant loci for MD phenotypes, including nine novel signals (5q11.2, 5q14.1, 5q31.1, 5q33.3, 5q35.1, 7p11.2, 8q24.13, 12p11.2, 16q12.2). Further, 45% of all known breast cancer SNPs were associated with at least one MD phenotype at p < 0.05. TWAS further identified two novel genes (SHOX2 and CRISPLD2) whose genetically predicted expression was significantly associated with MD phenotypes. CONCLUSIONS: Our findings provided novel insight into the genetic background of MD phenotypes, and further demonstrated their shared genetic basis with breast cancer.

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Introduction: We aimed to analyze long-term trends in characteristics of patients undergoing diagnostic polysomnography (PSG) and subsequently diagnosed with obstructive sleep apnea (OSA) to inform delivery of sleep services. Material and Methods: We studied 24,510 consecutive patients undergoing PSG at a tertiary-care sleep service between 1989 and 2013. OSA was defined by an apnea hypopnea index (AHI)≥ 5 events/hour. Changes to hypopnea definition and flow sensing techniques in 2002 created two distinct AHI scoring periods: American Sleep Disorders Association (ASDA) 1989 - July 2002 and American Academy of Sleep Medicine (Chicago) from August 2002. Results: Over 23.5 years there was a steady increase in proportion of females (15% to 45%), small increases in average age and BMI, and a small decline in socioeconomic status in the overall group. AHI varied between scoring periods both overall [ASDA 10.8/h (3.2-29.6), Chicago 24.3/h (11.8-48.1)] and in the large subgroup (80.7%) diagnosed with OSA [ASDA 20.7/h (10.6-44.1), Chicago 27.4/h (14.8-51.5)]. OSA diagnosis rates increased in the Chicago period (ASDA 66%, Chicago 91%). Increases in AHI and proportion diagnosed appeared better explained by changes in scoring methods than key OSA risk factors. Conclusion: Temporal increases in proportion of females and decreases in socioeconomic status of people undergoing PSG may reflect greater community awareness of sleep disorders. Temporal increases in age and obesity are consistent with secular trends. Changes in scoring methods have major impacts on OSA diagnosis and judgement of disease severity, with important implications for contemporary resourcing of sleep services and interpretation of historical OSA data.

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BACKGROUND: High participation in mammographic screening is essential for its effectiveness to detect breast cancers early and thereby, improve breast cancer outcomes. Breast density is a strong predictor of breast cancer risk and significantly reduces the sensitivity of mammography to detect the disease. There are increasing mandates for routine breast density notification within mammographic screening programs. It is unknown if breast density notification impacts the likelihood of women returning to screening when next due (i.e. rescreening rates). This study investigates the association between breast density notification and rescreening rates using individual-level data from BreastScreen Western Australia (WA), a population-based mammographic screening program. METHODS: We examined 981,705 screening events from 311,656 women aged 40+ who attended BreastScreen WA between 2008 and 2017. Mixed effect logistic regression was used to investigate the association between rescreening and breast density notification status. RESULTS: Results were stratified by age (younger, targeted, older) and screening round (first, second, third+). Targeted women screening for the first time were more likely to return to screening if notified as having dense breasts (Percentunadjusted notified vs. not-notified: 57.8% vs. 56.1%; Padjusted = 0.016). Younger women were less likely to rescreen if notified, regardless of screening round (all P < 0.001). There was no association between notification and rescreening in older women (all P > 0.72). CONCLUSIONS: Breast density notification does not deter women in the targeted age range from rescreening but could potentially deter younger women from rescreening. These results suggest that all breast density notification messaging should include information regarding the importance of regular mammographic screening to manage breast cancer risk, particularly for younger women. These results will directly inform BreastScreen programs in Australia as well as other population-based screening providers outside Australia who notify women about breast density or are considering implementing breast density notification.

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INTRODUCTION: The apolipoprotein E (APOE) genotype is the strongest genetic risk factor for late-onset Alzheimer's disease. However, its effect on lipid metabolic pathways, and their mediating effect on disease risk, is poorly understood. METHODS: We performed lipidomic analysis on three independent cohorts (the Australian Imaging, Biomarkers and Lifestyle [AIBL] flagship study, n = 1087; the Alzheimer's Disease Neuroimaging Initiative [ADNI] 1 study, n = 819; and the Busselton Health Study [BHS], n = 4384), and we defined associations between APOE ε2 and ε4 and 569 plasma/serum lipid species. Mediation analysis defined the proportion of the treatment effect of the APOE genotype mediated by plasma/serum lipid species. RESULTS: A total of 237 and 104 lipid species were associated with APOE ε2 and ε4, respectively. Of these 68 (ε2) and 24 (ε4) were associated with prevalent Alzheimer's disease. Individual lipid species or lipidomic models of APOE genotypes mediated up to 30% and 10% of APOE ε2 and ε4 treatment effect, respectively. DISCUSSION: Plasma lipid species mediate the treatment effect of APOE genotypes on Alzheimer's disease and as such represent a potential therapeutic target.

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Obstructive sleep apnea (OSA) is a highly prevalent condition in people living with schizophrenia or other psychotic disorder. Its treatment with continuous positive airway pressure therapy (CPAP) can dramatically improve daytime and physical health function. People with a psychotic disorder, however, are rarely diagnosed and treated and there are no large-scale studies showing evidence of successful treatment with CPAP. Using a retrospective case-control study approach (N = 554), we examined adherence to and effectiveness of a CPAP trial in individuals with comorbid psychotic disorder and OSA (psychosis group, n = 165) referred for a CPAP trial at the West Australian Sleep Disorders Research Institute. Given that antipsychotic medication is an important confounder, we included a psychiatric (non-psychosis) comparison group taking antipsychotic medication (antipsychotic group, n = 82), as well as a nonpsychiatric control group (OSA control group, n = 307) also diagnosed with OSA and referred for CPAP. Variables included OSA symptom response, CPAP engagement, and usage at 3 months. The Psychosis group had the most severe OSA at baseline and they attended fewer clinic appointments overall. However, there were no other group differences either in CPAP adherence or treatment response. CPAP was equally effective in normalizing OSA symptoms and daytime sleepiness in all groups. CPAP usage was longer per night in the Psychosis and Antipsychotic groups, perhaps suggesting a role of sedation from antipsychotic medications. In conclusion, OSA is treatable and CPAP feasible in people with severe mental illness and antipsychotic medications are not a barrier to treatment response.

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LAY ABSTRACT: Autism spectrum disorders are complex, with a strong genetic basis. Genetic research in autism spectrum disorders is limited by the fact that these disorders are largely heterogeneous so that patients are variable in their clinical presentations. To address this limitation, we investigated the genetics of individual dimensions of the autism spectrum disorder phenotypes, or autistic-like traits. These autistic-like traits are continuous variations in autistic behaviours that occur in the general population. Therefore, we meta-analysed data from four different population cohorts in which autistic-like traits were measured. We performed a set of genetic analyses to identify common variants for autistic-like traits, understand how these variants related to autism spectrum disorders, and how they contribute to neurobiological processes. Our results showed genetic associations with specific autistic-like traits and a link to the immune system. We offer an example of the potential to use a dimensional approach when dealing with heterogeneous, complex disorder like autism spectrum disorder. Decomposing the complex autism spectrum disorder phenotype in its core features can inform on the specific biology of these features which is likely to account to clinical variability in patients.

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Mammographic breast density (MBD) is a strong and highly heritable predictor of breast cancer risk and a biomarker for the disease. This study systematically assesses MBD as an endophenotype for breast cancer-a quantitative trait that is heritable and genetically correlated with disease risk. Using data from the family-based kConFab Study and the 1994/1995 cross-sectional Busselton Health Study, participants were divided into three status groups-cases, relatives of cases and controls. Participant's mammograms were used to measure absolute dense area (DA) and percentage dense area (PDA). To address each endophenotype criterion, linear mixed models and heritability analysis were conducted. Both measures of MBD were significantly associated with breast cancer risk in two independent samples. These measures were also highly heritable. Meta-analyses of both studies showed that MBD measures were higher in cases compared to relatives (ß = 0.48, 95% CI = 0.10, 0.86 and ß = 0.41, 95% CI = 0.06, 0.78 for DA and PDA, respectively) and in relatives compared to controls (ß = 0.16, 95% CI = -0.24, 0.56 and ß = 0.16, 95% CI = -0.21, 0.53 for DA and PDA, respectively). This study formally demonstrates, for the first time, that MBD is an endophenotype for breast cancer.