An empirical evaluation of imputation accuracy for association statistics reveals increased type-I error rates in genome-wide associations

Background: Genome wide association studies (GWAS) are becoming the approach of choice to identify genetic determinants of complex phenotypes and common diseases. The astonishing amount of generated data and the use of distinct genotyping platforms with variable genomic coverage are still analytical challenges. Imputation algorithms combine directly genotyped markers information with haplotypic structure for the population of interest for the inference of a badly genotyped or missing marker and are considered a near zero cost approach to allow the comparison and combination of data generated in different studies. Several reports stated that imputed markers have an overall acceptable accuracy but no published report has performed a pair wise comparison of imputed and empiric association statistics of a complete set of GWAS markers. Results: In this report we identified a total of 73 imputed markers that yielded a nominally statistically significant association at P < 10(-5) for type 2 Diabetes Mellitus and compared them with results obtained based on empirical allelic frequencies. Interestingly, despite their overall high correlation, association statistics based on imputed frequencies were discordant in 35 of the 73 (47%) associated markers, considerably inflating the type I error rate of imputed markers. We comprehensively tested several quality thresholds, the haplotypic structure underlying imputed markers and the use of flanking markers as predictors of inaccurate association statistics derived from imputed markers. Conclusions: Our results suggest that association statistics from imputed markers showing specific MAF (Minor Allele Frequencies) range, located in weak linkage disequilibrium blocks or strongly deviating from local patterns of association are prone to have inflated false positive association signals. The present study highlights the potential of imputation procedures and proposes simple procedures for selecting the best imputed markers for follow-up genotyping studies.

Cross-National Analysis of the Associations between Traumatic Events and Suicidal Behavior: Findings from the WHO World Mental Health Surveys

Background: Community and clinical data have suggested there is an association between trauma exposure and suicidal behavior (i.e., suicide ideation, plans and attempts). However, few studies have assessed which traumas are uniquely predictive of: the first onset of suicidal behavior, the progression from suicide ideation to plans and attempts, or the persistence of each form of suicidal behavior over time. Moreover, few data are available on such associations in developing countries. The current study addresses each of these issues. Methodology/Principal Findings: Data on trauma exposure and subsequent first onset of suicidal behavior were collected via structured interviews conducted in the households of 102,245 (age 18+) respondents from 21 countries participating in the WHO World Mental Health Surveys. Bivariate and multivariate survival models tested the relationship between the type and number of traumatic events and subsequent suicidal behavior. A range of traumatic events are associated with suicidal behavior, with sexual and interpersonal violence consistently showing the strongest effects. There is a dose-response relationship between the number of traumatic events and suicide ideation/attempt; however, there is decay in the strength of the association with more events. Although a range of traumatic events are associated with the onset of suicide ideation, fewer events predict which people with suicide ideation progress to suicide plan and attempt, or the persistence of suicidal behavior over time. Associations generally are consistent across high-, middle-, and low-income countries. Conclusions/Significance: This study provides more detailed information than previously available on the relationship between traumatic events and suicidal behavior and indicates that this association is fairly consistent across developed and developing countries. These data reinforce the importance of psychological trauma as a major public health problem, and highlight the significance of screening for the presence and accumulation of traumatic exposures as a risk factor for suicide ideation and attempt.

Cross-National Analysis of the Associations among Mental Disorders and Suicidal Behavior: Findings from the WHO World Mental Health Surveys

Background: Suicide is a leading cause of death worldwide. Mental disorders are among the strongest predictors of suicide; however, little is known about which disorders are uniquely predictive of suicidal behavior, the extent to which disorders predict suicide attempts beyond their association with suicidal thoughts, and whether these associations are similar across developed and developing countries. This study was designed to test each of these questions with a focus on nonfatal suicide attempts. Methods and Findings: Data on the lifetime presence and age-of-onset of Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) mental disorders and nonfatal suicidal behaviors were collected via structured face-to-face interviews with 108,664 respondents from 21 countries participating in the WHO World Mental Health Surveys. The results show that each lifetime disorder examined significantly predicts the subsequent first onset of suicide attempt (odds ratios [ORs] = 2.9-8.9). After controlling for comorbidity, these associations decreased substantially (ORs = 1.5-5.6) but remained significant in most cases. Overall, mental disorders were equally predictive in developed and developing countries, with a key difference being that the strongest predictors of suicide attempts in developed countries were mood disorders, whereas in developing countries impulse-control, substance use, and post-traumatic stress disorders were most predictive. Disaggregation of the associations between mental disorders and nonfatal suicide attempts showed that these associations are largely due to disorders predicting the onset of suicidal thoughts rather than predicting progression from thoughts to attempts. In the few instances where mental disorders predicted the transition from suicidal thoughts to attempts, the significant disorders are characterized by anxiety and poor impulse-control. The limitations of this study include the use of retrospective self-reports of lifetime occurrence and age-of-onset of mental disorders and suicidal behaviors, as well as the narrow focus on mental disorders as predictors of nonfatal suicidal behaviors, each of which must be addressed in future studies. Conclusions: This study found that a wide range of mental disorders increased the odds of experiencing suicide ideation. However, after controlling for psychiatric comorbidity, only disorders characterized by anxiety and poor impulse-control predict which people with suicide ideation act on such thoughts. These findings provide a more fine-grained understanding of the associations between mental disorders and subsequent suicidal behavior than previously available and indicate that mental disorders predict suicidal behaviors similarly in both developed and developing countries. Future research is needed to delineate the mechanisms through which people come to think about suicide and subsequently progress from ideation to attempts.

Modeling associations between genetic markers using Bayesian networks

Motivation: Understanding the patterns of association between polymorphisms at different loci in a population ( linkage disequilibrium, LD) is of fundamental importance in various genetic studies. Many coefficients were proposed for measuring the degree of LD, but they provide only a static view of the current LD structure. Generative models (GMs) were proposed to go beyond these measures, giving not only a description of the actual LD structure but also a tool to help understanding the process that generated such structure. GMs based in coalescent theory have been the most appealing because they link LD to evolutionary factors. Nevertheless, the inference and parameter estimation of such models is still computationally challenging. Results: We present a more practical method to build GM that describe LD. The method is based on learning weighted Bayesian network structures from haplotype data, extracting equivalence structure classes and using them to model LD. The results obtained in public data from the HapMap database showed that the method is a promising tool for modeling LD. The associations represented by the learned models are correlated with the traditional measure of LD D`. The method was able to represent LD blocks found by standard tools. The granularity of the association blocks and the readability of the models can be controlled in the method. The results suggest that the causality information gained by our method can be useful to tell about the conservability of the genetic markers and to guide the selection of subset of representative markers.

Fruit flies (Diptera, Tephritidae) and their associations with native host plants in a remnant area of the highly endangered Atlantic Rain Forest in the State of Espirito Santo, Brazil

The results presented in this paper refer to a host survey, lasting approximately three and a half years (February 2003-july 2006), undertaken in the Vale do Rio Doce Natural Reserve, a remnant area of the highly endangered Atlantic Rain Forest located in Linhares County, State of Espirito Santo, Brazil. A total of 330 fruit samples were collected from native plants, representing 248 species and 51 plant families. Myrtaceae was the most diverse family with 54 sampled species. Twenty-eight plant species, from ten families, are hosts of ten Anastrepha species and of Ceratitis capitata (Wiedemann). Among 33 associations between host plants and fruit flies, 20 constitute new records, including the records of host plants for A. fumipennis Lima and A. nascimentoi Zucchi. The findings were discussed in the light of their implications for rain forest conservation efforts and the study of evolutionary relationships between fruit flies and their hosts.

Associations between glutathione peroxidase-1 Pro198Leu polymorphism, selenium status, and DNA damage levels in obese women after consumption of Brazil nuts

Objective: Alterations in selenium (Se) status may result in suboptimal amounts of selenoproteins, which have been associated with increased oxidative stress levels. The Pro198Leu polymorphism at the glutathione peroxidase-1 (GPx1) gene is supposed to be functional. The response of Se status, GPx activity, and levels of DNA damage to a Se supplementation trial between the genotypes related to that polymorphism was investigated. Methods: A randomized trial was conducted with 37 morbidly obese women. Participants consumed one Brazil nut, which provided approximately 290 mu g of Se a day, for 8 wk. Blood Se concentrations, erythrocyte GPx activity, and DNA damage levels were measured at baseline and at 8 wk. The results were compared by genotypes. Results: The genotype frequencies were 0.487, 0.378, and 0.135 for Pro/Pro (the wild-type genotype), Pro/Leu, and Leu/Leu, respectively. At baseline, 100% of the subjects were Se deficient, and after the supplementation, there was an improvement in plasma Se (P < 0.001 for Pro/Pro and Pro/Leu, P < 0.05 for Leu/Leu), erythrocyte Se (P = 0.00 for Pro/Pro and Pro/Leu, P < 0.05 for Leu/Leu), and GPx activity (P = 0.00 for Pro/Pro, P < 0.00001 for Pro/Leu, P < 0.001 for Leu/Leu). In addition, the Pro/Pro group showed a decrease in DNA damage after Brazil nut consumption compared with baseline (P < 0.005), and those levels were higher in Leu/Leu subjects compared with those with the wild-type genotype (P < 0.05). Conclusion: Consumption of one unit of Brazil nuts daily effectively increases Se status and increases GPx activity in obese women, regardless of GPx1 Pro198Leu polymorphism. However, the evaluated biomarkers showed distinct results in response to the supplementation when the polymorphism was considered. (c) 2011 Elsevier Inc. All rights reserved.

Economic incentives for farmers in the Philippine uplands to adopt hedgerow intercropping

Land degradation in the Philippine uplands is severe and widespread. Most upland areas are steep, and intense rainfall on soils disturbed by intensive agriculture can produce high rates of soil loss. This has serious implications for the economic welfare of a growing upland population with few feasible livelihood alternatives. Hedgerow intercropping can greatly reduce soil loss from annual cropping systems and has been considered an appropriate technology for soil conservation research and extension in the Philippine uplands. However; adoption of hedgerow intercropping has been sporadic and transient, rarely continuing once external support has been withdrawn. The objective of this paper is to investigate the economic incentives for farmers in the Philippine uplands to adopt hedgerow intercropping relative to traditional open-field maize farming. Cost-benefit analysis is used to compare the economic viability of hedgerow intercropping, as it has been promoted to upland farmers, with the viability of traditional methods of open-field farming. The APSIM and SCUAF models were used to predict the effect of soil erosion on maize yields from open-field farming and hedgerow intercropping. The results indicate that there have been strong economic incentives for farmers with limited planning horizons to reject hedgerow intercropping because the benefits of sustained yields are not realized rapidly enough to compensate for high establishment costs. Alternative forms of hedgerow intercropping such as natural vegetation and grass strips reduce establishment and maintenance costs and are therefore more economically attractive to farmers than hedgerow intercropping with shrub legumes. The long-term economic viability of hedgerow intercropping depends on the economic setting and the potential for hedgerow intercropping to sustain maize production relative to traditional open-field farming. (C) 1998 Academic Press.

Between-year fluctuations in schizophrenia birth rate and associations with the Southern Oscillation Index, cloud cover and sunshine

Our group have recently proposed that low prenatal vitamin D may be a risk-modifying factor for schizophrenia. Climate variability impacts on vitamin D levels in a population via fluctuations in the amount of available UV radiation. In order to explore this hypothesis, we examined fluctuations in the birthrates for people with schizophrenia born between 1920 and 1967 and three sets of variables strongly associated with UV radiation. These included: (a) the Southern Oscillation Index (SOI), a marker of El Nino which is the most prominent meteorological factor that influences Queensland weather: (b) measures of cloud cover and (c) measures of sunshine. Schizophrenia births were extracted from the Queensland Mental Health register and corrected for background population birth rates. Schizophrenia birth rates had several apparently non-random features in common with the SO1. The prominent SO1 fluctuation event that occurred between 1937 and 1943 is congruent with the most prominent fluctuation in schizophrenia birth rates. The relatively flat profile of SOI activity between 1927 and 1936 also corresponds to the flattest period in the schizophrenia time series. Both time series have prominent oscillations in the 3 ~, year range between 1946 and 1960. Significant associations between schizophrenia birth rates and measures of both sunshine and cloud cover were identified,and all three time series shared periodicity in the 3-4 year range. The analyses suggest that the risk of schizophrenia is higher for those born during times of increased cloud cover,reduced sunshine and positive SO1. These ecological analyses provide initial support for the vitamin D hypothesis, however alternative non-genetic candidate exposures also need to be considered. Other sites with year-to-year fluctuations in cloud cover and sunshine should examine patterns of association between these climate variables and schizophrenia birth rates. The Stanley Foundation supported this project.

Associations between rural background and where South Australian general practitioners work

Objective: To determine the association between rural background on practice location of general practitioners (GPs) (rural or urban). Design: Comparison of data from two postal surveys. Subjects: 268 rural and 236 urban GPs practising in South Australia. Main outcome measures: Association between practice location (rural or urban) and demographic characteristics, training, qualifications, and rural background. Results: Rural GPs were younger than urban GPs (mean age 47 versus 50 years, P<0,01) and more likely to be male (81% versus 67%, P=0.001), to be Australian-born (72% Versus 61%, P=0,01), to have a partner (95% versus 85%, P= 0.001), and to have children (94% Versus 85%, P=0.001). Similar proportions of rural and urban GPs were trained in Australia and were Fellows of the Royal Australian College of General Practitioners, but more rural GPs were vocationally registered (94% versus 84%, P=0,001). Rural GPs were more likely to have grown up in the country (37% versus 27%, P= 0,02), to have received primary (33% versus 19%, P=0,001) and secondary (25% versus 13%, P=0,001) education there, and to have a partner who grew up in the country (49% Versus 24%, P=0.001). In multivariate analysis, only primary education in the country (odds ratio [OR], 2.43; 95% CI, 1.09-5.56) and partner of rural background (OR, 3.14; 95% CI, 1.96-5.10) were independently associated with rural practice. Conclusion: Our findings support the policy of promoting entry to medical school of students with a rural background and provide an argument for policies that address the needs of partners and maintain quality primary and secondary education in the country.

Management of Patients With Rheumatoid Arthritis in Latin America A Consensus Position Paper From Pan-American League of Associations of Rheumatology and Grupo Latino Americano De Estudio de Artritis Reumatoide

Objective: A consensus meeting of representatives of 18 Latin-American and Caribbean countries gathered in Renaca, Chile, for 2 days to identify problems and provide recommendations for the care of patients with rheumatoid arthritis (RA) in Latin America, a region where poverty and other health priorities make the efforts to provide effective and high quality care difficult. This report includes recommendations for health professionals, patients, and health authorities in Latin America, with an emphasis oil education and therapeutic issues. Methods: Fifty-one rheumatologists (list available only online on the JCR website) from 18 Latin-American and Caribbean countries with a special interest in RA participated in the consensus meeting. Participants were experts identified and appointed by the National Societies of Rheumatology affiliated with the Pan-American League of Associations for Rheumatology (PANLAR) and by the Grupo Latino Americano De Estudio de Artritis Reumatoide (GLADAR)-an independent group of Latin American rheumatologist researchers were also invited to the meeting. Eight topics were identified as priorities: patient, community and allied health professional education, health policy and decision making, programs for early detection and appropriate treatment of RA, role of classic disease modifying antirheumatic drugs (DMARDs), role of biologic therapy, and drug safety surveillance. To reach consensus, a survey with questions relevant to the topic of interest was sent to all participants before the meeting. During a 2 day meeting, the answers of the survey were reviewed and discussed by each group, with final recommendations on action items. Results: The specific topic of the survey was answered by 86% of the participants and 68% of them answered the entire survey. It was agreed that RA and rheumatic diseases which are currently not but should be public health priorities in Latin America, because of their prevalence and impact on quality of life. Conclusions: Strategic areas identified as priorities for our region included: early diagnosis and access to care by multidisciplinary teams, creation of databases to identify infections with the use of biologic agents in RA which are relevant to Latin America, and overall efforts to improve the care of RA patients in accordance with international standards. Implementation of educational programs aimed to improve self-management for patients with RA was also considered crucial.

Compensation for obesity-induced insulin resistance in dogs: Causal web analysis of the associations of leptin and GLP-1.

Obesity affects aspects of glucose homeostasis such as insulin secretion and insulin sensitivity. Hormones secreted by adipocytes like leptin mediate the metabolic consequences of obesity. Incretin hormones like glucagon-like peptide-1 (GLP-1) increase insulin secretion in response to changes in blood glucose concentration and have been proposed to regulate insulin secretion in fasting, overweight dogs. The aim of this study was to examine hormonal mechanisms by which adiposity alters glucose homeostasis, plasma insulin concentration, and insulin sensitivity in spontaneously overweight dogs.