Efficient and flexible Integration of variant characteristics in rare variant association studies using integrated nested Laplace approximation.

Rare variants are thought to play an important role in the etiology of complex diseases and may explain a significant fraction of the missing heritability in genetic disease studies. Next-generation sequencing facilitates the association of rare variants in coding or regulatory regions with complex diseases in large cohorts at genome-wide scale. However, rare variant association studies (RVAS) still lack power when cohorts are small to medium-sized and if genetic variation explains a small fraction of phenotypic variance. Here we present a novel Bayesian rare variant Association Test using Integrated Nested Laplace Approximation (BATI). Unlike existing RVAS tests, BATI allows integration of individual or variant-specific features as covariates, while efficiently performing inference based on full model estimation. We demonstrate that BATI outperforms established RVAS methods on realistic, semi-synthetic whole-exome sequencing cohorts, especially when using meaningful biological context, such as functional annotation. We show that BATI achieves power above 70% in scenarios in which competing tests fail to identify risk genes, e.g. when risk variants in sum explain less than 0.5% of phenotypic variance. We have integrated BATI, together with five existing RVAS tests in the 'Rare Variant Genome Wide Association Study' (rvGWAS) framework for data analyzed by whole-exome or whole genome sequencing. rvGWAS supports rare variant association for genes or any other biological unit such as promoters, while allowing the analysis of essential functionalities like quality control or filtering. Applying rvGWAS to a Chronic Lymphocytic Leukemia study we identified eight candidate predisposition genes, including EHMT2 and COPS7A.

[Permanent disability and premature mortality in a cohort of affiliates with the Spanish Social Security, 2004-2015]. / Incapacidad permanente y mortalidad prematura en una cohorte de afiliados a la Seguridad Social en España, 2004-2015.

OBJECTIVE: To describe a surveillance and monitoring system based on the analysis of the incidence rate of permanent disability (PD) and premature mortality (PM) in a sample of members of the Spanish Social Security. METHOD: Study of three birth cohorts (1950-1959, 1960-1969 and 1970-1979) of people affiliated to the general Social Security system, included in the Continuous Sample of Labour Lives, who has been active for at least one day between 2004 and 2015 (N = 753,341). For each cohort, the annual incidence rates of PD and MP were estimated according to occupation and economic activity in women and men. RESULTS: Between 2004 and 2015 the rates of PI and MP showed higher values in men with respect to women in practically all cohorts of births, occupations and economic activities groups. The trend throughout the observation period was increasing, both in the incidence of PD and PM in men and women, for the three birth cohorts and for all occupational categories. CONCLUSIONS: The results derived from this work allows the continuous monitoring of the temporal evolution of the incidence of permanent disability and premature mortality in a representative sample of social security affiliates.

Labor market situation after an episode of sickness absence due to malignant neoplasia. Evidence from a Spanish cohort.

BACKGROUND: Due to the progress in screening and cancer treatments, survivor's prognosis has improved enabling a more likely return to work. However, return to work after a cancer diagnosis may be complex because of an unbalanced health status and work demands relationship that may push them out of the labor market. The aim of this study is to assess the risk of dropping out of the labor market due to unemployment, partial retirement, and permanent disability during the year following an episode due to a malignant neoplasm compared to other non-malignant pathologies. METHODS: Cohort study of 9699 workers affiliated with the Social Security System in Catalonia, who had a sickness absence episode between 2012 and 2013 due to malignant neoplasm, mental, musculoskeletal disorders, cardiovascular diseases and injuries. Competing risk regression models were applied to assess the risk of dropping out of the labor market, by calculating subhazard ratios (SHR) in both sexes. Models were adjusted for age, occupational category, type of contract, economic activity, annual median salary and duration of the SA episode as potential confounders. RESULTS: Sickness absence due to malignant neoplasia represented 1.7% out of the 9699 episodes included between 2012 and 2013. Although, 80% of individuals continued working in the year following an episode due to malignant neoplasm, women showed a trend towards exiting the labor market because of partial retirement [SHR = 8.4(1.5-45.5)] and permanent disability [SHR = 5.8(1.5-22.9)] compared to non-malignant pathologies. There were no significant differences for unemployment either in women [SHR = 0.4(0.2-0.9)] and in men [SHR = 0.2(0.1-0.6)]. CONCLUSIONS: Although return to work is a common pathway among cancer survivors, partial retirement and permanent disability seem to be potential pathways to exit the labor market among women.

Did psychotropic drug consumption increase during the 2008 financial crisis? A cross-sectional population-based study in Spain.

OBJECTIVES AND SETTING: Although psychotropic drugs are used to treat mental health disorders, little evidence analyses the effects the 2008 economic downturn had on psychotropic drug consumption in the case of Spain. We analyse these effects, considering both gender and employment situation. PARTICIPANTS: We used the microdata from the face-to-face cross-sectional population-based Spanish National Health Survey for two periods: 2006-2007 (n=28 954) and 2011-2012 (n=20 509). Our samples included adults (>15 years old). METHODS: The response variables are consumption (or not) of antidepressants or sedatives and the explanatory variables are the year of the survey, gender and employment status. Covariates are mental health problems, mental health index General Health Questionnaire (GHQ-12) and self-reported health outcome variables such as self-rated health, chronic diseases, smoking behaviour, sleeping hours, body mass index, physical activity in the workplace, medical visits during the past year, age, region of residence (autonomous communities), educational level, marital status and social class of the reference person. Finally, we include interactions between time period, gender and employment status. We specify random effects logistic regressions and use Bayesian methods for the inference. RESULTS: The economic crisis did not significantly change the probability of taking antidepressant drugs (OR=0.56, 95% CI 0.18 to 2.56) nor sedatives (OR=1.21, 95% CI 0.26 to 5.49). In general, the probability of consuming antidepressants among men and women decreases, but there are differences depending on employment status. The probability of consuming sedatives also depends on the employment status. CONCLUSIONS: While the year of the financial crisis is not associated with the consumption of antidepressants nor sedatives, it has widened the gap in consumption differences between men and women. Although antidepressant use dropped, the difference in consumption levels between men and women grew significantly among the retired, and in the case of sedatives, risk of women taking sedatives increased in all groups except students.

[Work-Related Fatal Traffic Injuries in Spain According to Travelling Reasons and Sex(2010-2013)]. / Lesiones mortales de tráfico en España relacionadas con el trabajo según el motivo del desplazamiento y según sexo (2010-2013).

OBJECTIVE: Most studies about work-related traffic injuries in Spain are based in labor administration information. The aim of this study was to carry out a description of fatal work-related traffic injuries in Spain according to travelling reason between 2010 and 2013, based on the Transport Authority database. METHODS: Descriptive study of fatal work-related traffic injuries that drivers between 16 and 70 years old suffered, whose reason for travelling was recorded as labour, occurred during working or commuting hours, between 2010 and 2013. In order to assess statistically significant differences according to the reason for travelling (during working and commuting hours) in the distributions of the variables included, and separately for men and women, appropriate statistical tests were calculated for each variable. In particular, socio-demographic, driver-related, travelling conditions, and contributing factors at the time of the accident variables were taken into account. RESULTS: The total number of fatal work-related traffic injuries was 847, a 88.3% in men and 53,1% during working hours. Fatal work-related traffic injuries among men were significantly more frequent during working hours when the driver was a professional (74.7%), with an industrial vehicle or van (67.7%), and in routes longer than 50 kilometres (60.5%). Among women, fatal collisions occurred during commuting hours while driving their own car (98.7%), with a private car or motorcycle (98.7%) and in routes lower than 50 kilometres (79.6%). CONCLUSIONS: These results show a different pattern of fatal work-related traffic injuries according to reason for travelling, during working or commuting hours, between men and women. This should be deeply studied to direct road and occupational policies more precisely.

La mayoría de los estudios sobre las lesiones de tráfico relacionadas con el trabajo (LTT) en España se basan en información de la administración laboral. El objetivo de este estudio fue realizar una descripción de las LTT mortales en España según el motivo de desplazamiento entre 2010 y 2013.

[Contextual indicators to assess social determinants of health and the Spanish economic recession]. / Indicadores contextuales para evaluar los determinantes sociales de la salud y la crisis económica española.

OBJECTIVE: To provide indicators to assess the impact on health, its social determinants and health inequalities from a social context and the recent economic recession in Spain and its autonomous regions. METHODS: Based on the Spanish conceptual framework for determinants of social inequalities in health, we identified indicators sequentially from key documents, Web of Science, and organisations with official statistics. The information collected resulted in a large directory of indicators which was reviewed by an expert panel. We then selected a set of these indicators according to geographical (availability of data according to autonomous regions) and temporal (from at least 2006 to 2012) criteria. RESULTS: We identified 203 contextual indicators related to social determinants of health and selected 96 (47%) based on the above criteria; 16% of the identified indicators did not satisfy the geographical criteria and 35% did not satisfy the temporal criteria. At least 80% of the indicators related to dependence and healthcare services were excluded. The final selection of indicators covered all areas for social determinants of health, and 62% of these were not available on the Internet. Around 40% of the indicators were extracted from sources related to the Spanish Statistics Institute. CONCLUSIONS: We have provided an extensive directory of contextual indicators on social determinants of health and a database to facilitate assessment of the impact of the economic recession on health and health inequalities in Spain and its autonomous regions.