Genome-wide analysis identifies genetic effects on reproductive success and ongoing natural selection at the FADS locus

: Identifying genetic determinants of reproductive success may highlight mechanisms underlying fertility and identify alleles under present-day selection. Using data in 785,604 individuals of European ancestry, we identified 43 genomic loci associated with either number of children ever born (NEB) or childlessness. These loci span diverse aspects of reproductive biology, including puberty timing, age at first birth, sex hormone regulation, endometriosis and age at menopause. Missense variants in ARHGAP27 were associated with higher NEB but shorter reproductive lifespan, suggesting a trade-off at this locus between reproductive ageing and intensity. Other genes implicated by coding variants include PIK3IP1, ZFP82 and LRP4, and our results suggest a new role for the melanocortin 1 receptor (MC1R) in reproductive biology. As NEB is one component of evolutionary fitness, our identified associations indicate loci under present-day natural selection. Integration with data from historical selection scans highlighted an allele in the FADS1/2 gene locus that has been under selection for thousands of years and remains so today. Collectively, our findings demonstrate that a broad range of biological mechanisms contribute to reproductive success

A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants.

This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/ng.3448Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, with limited therapeutic options. Here we report on a study of >12 million variants, including 163,714 directly genotyped, mostly rare, protein-altering variants. Analyzing 16,144 patients and 17,832 controls, we identify 52 independently associated common and rare variants (P < 5 × 10(-8)) distributed across 34 loci. Although wet and dry AMD subtypes exhibit predominantly shared genetics, we identify the first genetic association signal specific to wet AMD, near MMP9 (difference P value = 4.1 × 10(-10)). Very rare coding variants (frequency <0.1%) in CFH, CFI and TIMP3 suggest causal roles for these genes, as does a splice variant in SLC16A8. Our results support the hypothesis that rare coding variants can pinpoint causal genes within known genetic loci and illustrate that applying the approach systematically to detect new loci requires extremely large sample sizes.We thank all participants of all the studies included for enabling this research by their participation in these studies. Computer resources for this project have been provided by the high-performance computing centers of the University of Michigan and the University of Regensburg. Group-specific acknowledgments can be found in the Supplementary Note. The Center for Inherited Diseases Research (CIDR) Program contract number is HHSN268201200008I. This and the main consortium work were predominantly funded by 1X01HG006934-01 to G.R.A. and R01 EY022310 to J.L.H

Food Insecurity and Hearing Loss Are Interrelated: A Cross-Sectional Population-Based Study

Objectives: We aimed to assess whether objectively measured hearing loss and self-perceived hearing handicap in adults are independently associated with food insecurity, and vice versa. Design: Cross-sectional population-based study. Population: 2,500 participants aged 50+ years from the Blue Mountains Hearing Study, with both complete pure-tone audiometry data and information on food security status. Measurements: The pure-tone average of frequencies 0.5, 1.0, 2.0 and 4.0 kHz (PTA0.5-4KHz) \u3e25 dB HL in the better ear, established the presence of hearing loss. Self-perceived hearing handicap was assessed by administering the Hearing Handicap Inventory for Elderly Screening (HHIE-S total scores of ≥8 indicates hearing handicap). A 12-item food security survey was administered, comprising statements related to individual and household food situations. Results: Food insecurity was reported by 12.8% of study participants. After adjusting for all potential confounders, any self-perceived hearing handicap significantly increased the likelihood of participants reporting food insecurity by 94% (p\u3c0.0001). Participants reporting any, mild or severe self-perceived hearing handicap had around 2-fold greater odds of experiencing food insecurity. Objectively measured hearing loss did not significantly influence the food security status of study participants. Conversely, food insecurity was significantly associated with both objectively measured hearing loss and self-perceived hearing handicap: multivariate-adjusted OR 1.37 (95% CI 1.01–1.88) and OR 1.83 (95% CI 1.40–2.39), respectively. Conclusions: Food insecurity was an important social determinant of hearing health among community-dwelling adults. Conversely, participants with a significant self-perceived hearing handicap were more likely to experience food insecurity. These findings add to our understanding of the substantial public health impact of both food insecurity and hearing loss and may highlight areas for future intervention

A comparison of health outcomes in older versus younger adults following a road traffic crash injury: a cohort study

Abstract Background Given the aging demographics of most developed countries, understanding the public health impact of mild/moderate road traffic crash injuries in older adults is important. We aimed to determine whether health outcomes (pain severity and quality of life measures) over 24 months differ significantly between older (65+) and younger adults (18–64). Methods Prospective cohort study of 364, 284 and 252 participants with mild/moderate injury following a vehicle collision at baseline, 12 and 24 months, respectively. A telephone-administered questionnaire obtained information on socio-economic, pre- and post-injury psychological and heath characteristics

Associations between hearing impairment and mortality risk in older persons : the Blue Mountains hearing study

Purpose: To assess whether hearing loss predicts an increased risk of mortality. Methods: The Blue Mountains Hearing Study examined 2956 persons (49+ years) during 1997 to 2000. The Australian National Death Index was used to identify deaths until 2005. Hearing loss was defined as the pure-tone average (0.5−4 kHz) of air-conduction hearing thresholds greater than 25 dB HL. Associations between hearing loss and mortality risk were estimated using Cox regression and structural equation modeling (SEM). Results: When we used Cox regression, we discovered that hearing loss was associated with increased risk of cardiovascular (hazard ratio [HR] 1.36, 95% confidence interval [CI] 1.08−1.84) and all-cause (AC) mortality (HR 1.39, 95% CI 1.11−1.79) after adjustment for age and sex but not after multivariable adjustment. SEM pathway analysis, however, revealed a greater AC mortality risk (HR 2.58, 95% CI 1.64−4.05) in persons with hearing loss, which was mediated: cognitive impairment (HR 1.45, 95% CI 1.08−1.94) and walking disability (HR 1.63, 95% CI 1.24−2.15). These variables increased mortality both directly and indirectly through effects on self-rated health. Conclusions: Hearing loss was associated with increased AC mortality via three mediating variables: disability in walking, cognitive impairment, and self-rated health. It is important to recognize that persons with combined disabilities are at increased risk of cardiovascular and AC mortality.8 page(s

Predictors of time to claim closure following a non-catastrophic injury sustained in a motor vehicle crash: a prospective cohort study

Abstract Background Research suggests that exposure to the compensation system (including time to case closure) could adversely influence a persons’ recovery following injury. However, the long-term predictors of time to claim closure following minor road traffic injuries remain unclear. We aimed to assess a wide spectrum of factors that could influence time to claim closure (socio-demographic, compensation-related, health, psychosocial and pre-injury factors) over 24 months following a non-catastrophic injury. Methods Prospective cohort study of 364 participants involved in a compensation scheme following a motor vehicle crash. We used a telephone-administered questionnaire to obtain information on potential explanatory variables. Information on time to claim closure was obtained from an insurance regulatory authority maintained database, and was classified as the duration between the crash date and claim settlement date, and categorized into  12–24 (medium) and > 24 months (late). Results Just over half of claimants (54 %) had settled their claim by 12 months, while 17 % and 30 % took > 12–24 months and > 24 months for claim closure, respectively. Whiplash at baseline was associated with claim closure time of > 12–24 months versus  12–24 months than  12–24 months and > 24 months, respectively. Each 1-unit increase in Orebro Musculoskeletal Pain Screening Questionnaire scores at baseline was associated with greater odds of both medium (> 12–24 months) and delayed claim settlement date (> 24 months): multivariable-adjusted OR 1.04 (95 % CU 1.01–1.07) and 1.02 (95 % CI 1.00–1.05), respectively. Conclusions Around a third of claimants with a minor injury had not settled by 24 months. Health-related factors and lawyer involvement independently influenced time to claim closure

Comparison of health outcomes between hospitalised and non-hospitalised persons with minor injuries sustained in a road traffic crash in Australia : a prospective cohort study

Objectives: This prospective cohort study aimed to investigate whether there are differences in health outcomes among persons with mild or moderate injuries who were hospitalised compared with those not hospitalised following a road traffic crash. Setting: Sydney Metropolitan, New South Wales, Australia. Participants: Persons aged ≥18 years involved in a motor vehicle crash were surveyed at baseline (n=364), and at 12 (n=284) and 24 months (n=252). A telephone-administered questionnaire obtained information on a range of socioeconomic, and preinjury and postinjury psychological and heath characteristics of all participants. Primary outcome measure: Participants who reported admission to hospital for 24 h or more (but less than 7 days) after the crash were classified as being hospitalised; those admitted for less than 24 h were classified as non-hospitalised. Results: Around 1 in 5 participants (19.0%) were hospitalised for ≥24 h after the crash. After adjusting for age and sex, hospitalised participants compared with those not hospitalised had approximately 2.6 units (p=0.01) lower Short Form-12 Physical Component Summary (SF-12 PCS) scores (poorer physical well-being) and approximately 4.9 units lower European Quality of Life visual analogue scale (EQ-VAS) scores ( p=0.05), 12 months later. After further adjusting for education level, whiplash, fracture and injury severity score, participants who were hospitalised had approximately 3.3 units lower SF-12 PCS ( p=0.04), 12 months later. The association with EQ-VAS did not persist after multivariable adjustment. No significant differences were observed between the 2 groups in health outcomes at 24-month follow-up. Conclusions: These findings indicate that long-term health status is unlikely to be influenced by hospitalisation status after sustaining a mild/moderate injury in a vehicle-related crash

Factor Models and General Definition

This chapter introduces the common version of linear factor models and also discusses its limits and developments. It introduces different notations and discusses the model and its structure. The chapter lists out the reasons why factor models are generally used in finance, and further explains the limits of this approach. It also deals with the different steps in the building of factor models, i.e. factor selection and parameter estimation. Finally, the chapter gives a historical perspective on the use of factor models such as capital asset pricing model (CAPM), Sharpe's market model and arbitrage pricing theory (APT) in finance

Socio-demographic, psychological, health and injury-related characteristics of participants in the sub-acute phase, stratified by age-group (n = 64).

<p>Socio-demographic, psychological, health and injury-related characteristics of participants in the sub-acute phase, stratified by age-group (n = 64).</p

Flowchart of study participation.

<p>Flowchart of study participation.</p