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

<p>Abstract</p> <p>Background</p> <p>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.</p> <p>Results</p> <p>In this report we identified a total of 73 imputed markers that yielded a nominally statistically significant association at <it>P </it>< 10 ^-5for 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.</p> <p>Conclusions</p> <p>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.</p

Asymptotic integral kernel for ensembles of random normal matrices with radial potentials

We use the steepest descents method to study the integral kernel of a family of normal random matrix ensembles with eigenvalue distribution P_{N}(z_{1},...,z_{N}) = Z_{N}^{-1} e^{-NSigma_{i=1}^{N}V_{alpha}(z_{i})} Pi_{1leqi<jleqN}|z_{i}-z_{j}|^{2} where V_{alpha}(z)=|z|^{alpha}, z in C and alpha in ]0,infty[. Asymptotic analysis with error estimates are obtained. A corollary of this expansion is a scaling limit for the n-point function in terms of the integral kernel for the classical Segal--Bargmann space

Coupling Functions:Dynamical Interaction Mechanisms in the Physical, Biological and Social Sciences

Dynamical systems are widespread, with examples in physics, chemistry, biology, population dynamics, communications, climatology and social science. They are rarely isolated but generally interact with each other. These interactions can be characterised by coupling functions -- which contain detailed information about the functional mechanisms underlying the interactions and prescribe the physical rule specifying how each interaction occurs. Coupling functions can be used, not only to understand, but also to control and predict the outcome of the interactions. This theme issue assembles ground-breaking work on coupling functions by leading scientists. After overviewing the field and describing recent advances in the theory, it discusses novel methods for the detection and reconstruction of coupling functions from measured data. It then presents applications in chemistry, neuroscience, cardio-respiratory physiology, climate, electrical engineering and social science. Taken together, the collection summarises earlier work on coupling functions, reviews recent developments, presents the state-of-the-art, and looks forward to guide the future evolution of the field

O perfil do cardiologista brasileiro : uma amostra de sócios da Sociedade Brasileira de Cardiologia

Background: Data from the international literature have shown changes in the profile of cardiologists and in their medical practices. However, there is no data on this in Brazilian cardiologists. Objective: To evaluate professional and personal characteristics of a sample of Brazilian cardiologists. Methods: This was a cross-sectional study; a questionnaire was sent by e-mail to cardiologists, active members of the Brazilian Society of Cardiology in 2017. The results were analyzed, and the level of significance set at p < 0.05. Results: The questionnaire was sent to 13,462 cardiologists, with 2,101 (15.6%) respondents, mostly men (71.8% versus 28.2%). Age distribution and marital status were significantly different between the sexes (p < 0.001). The number of cardiologists without children was higher among women (40.5% versus 16.1%; p < 0.001). The most common place of work was the public hospital (46.5%), followed by private hospital (28.5%) and private office (21.1%). The office was the main place of work for 23.9% of men and 14% of women (p < 0.001), with predominance of individuals older than 50 years (31.7% versus 10.1%, respectively; p < 0.001). Most cardiologists (64.2%) worked more than 40 hours a week (69% of them men and 51.9% of the women; p < 0.001). Eighty-eight percent of the sample earned more than BRL 11,000 (US$3,473.43), and 66.5$ 6,315.32) per month, versus 31.2% of the women (p < 0.001). A high level of work-related stress was reported by 11.3% of respondents. Conclusion: Most cardiologists were men, who showed higher workload and higher income; 11.3% of the cardiologists perceived stress as a great deal.Fundamento: Dados internacionais mostram mudanças no perfil e nas características da atuação dos cardiologistas. No entanto, não há na literatura dados acerca da realidade brasileira. Objetivo: Avaliar as características profissionais e pessoais de amostra de cardiologistas brasileiros. Método: Estudo transversal realizado por meio de questionário enviado via e-mail para os cardiologistas adimplentes da Sociedade Brasileira de Cardiologia em 2017. Os resultados foram analisados considerando nível de significância de p < 0,05. Resultados: Foram enviados 13.462 questionários, havendo 2.101 (15,6%) respostas, com predominância de homens (71,8% versus 28,2%). A distribuição etária e o estado civil foram significativamente diferentes entre os gêneros (p < 0,001). O número de cardiologistas sem filhos foi maior entre as mulheres (40,5% versus 16,1%; p < 0,001). O local de trabalho mais frequente foi hospital público (46,5%), seguido por hospital privado (28,5%) e consultório privado (21,1%). O consultório é a principal atividade de 23,9% dos homens e 14% das mulheres (p < 0,001), predominantemente entre aqueles com mais de 50 anos (31,7% versus 10,1%, respectivamente; p < 0,001). A maioria (64,2%) trabalha mais de 40 horas semanais (69% dos homens e 51,9% das mulheres; p < 0,001). A renda mensal de 88% é superior a R$11.000 (US$ 3,473.43), e 66,5% dos homens recebem mais que R$20.000,00 (US$ 6,315.32) mensais, contra 31,2% das mulheres (p < 0,001). Nível elevado de estresse foi relatado por 11,3%. Conclusões: Os homens são maioria entre os cardiologistas, têm maior carga de trabalho e renda superior à das mulheres. A taxa de estresse em grande proporção foi de 11,3%

X-linked Adrenal Hypoplasia Congenita: report of two families and a new NR0B1 mutation

Background: X-linked Adrenal Hypoplasia Congenita (X-linked AHC) tipically manifests as adrenal insufficiency in a bimodal clinical presentation (5–60 days and 2–13 years) and, at pubertal age, hypogonadotropic hypogonadism (HH) in males. It is caused by mutations in NR0B1 (present in Xp21.2), a gene with a critical role in the development of adrenals and hypothalamic-pituitary-gonadal (HPG) axis. It represents ~1% of all causes of primary adrenal insufficiency under age 18. We present two kindreds with NR0B1 mutations, one with a previously unreported mutation. Clinical case - family A: The proband presented with adrenal crisis at day 18 of life. Family history was relevant for an uncle death as a newborn. Hormonal assays revealed elevated ACTH (34,5 pmol/L, reference: T, leading to a premature stop codon, p.Lys362*, in exon 1. His mother and sister were both asymptomatic carriers for this mutation. This mutation, not described previously, leads probably to a non-functional truncated protein. Clinical case - family B: Kindred B had two males who presented with adrenal crisis at the newborn age (proband: 14 days; brother: 16 days). At 6 months of age, the proband had elevated ACTH (193.2 pmol/L, reference: G; p.Tyr81*, in exon 1, present in the two affected males. His mother and one sister were also asymptomatic carriers. Conclusion: Our kindreds highlights the clinical aspects of the rare X-linked AHC and its challenging differential diagnosis. The diagnosis was based on …. Completar … and an apparently X-linked mode of inheritance. Molecular analysis of the NR0B1 gene allowed the identification of the molecular defect in both families. Two different nonsense mutation in exon 1 were identified, giving rise most probably to truncated non-functional proteins, confirming the disease severity or the clinical phenotype of the affected boys. Mutation identification was relevant for genetic counseling of the parents, as well as for the patient’s sisters

Viscosupplementation for knee osteoarthritis: systematic review and meta-analysis

Objective: To evaluate the effectiveness and safety of viscosupplementation for pain and function in patients with knee osteoarthritis. Design: Systematic review and meta-analysis of randomised trials. Data sources Searches were conducted of Medline, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL) databases from inception to 11 September 2021. Unpublished trials were identified from the grey literature and trial registries. Eligibility criteria for study selection: Randomised trials comparing viscosupplementation with placebo or no intervention for knee osteoarthritis treatment. Main outcome measures: The prespecified primary outcome was pain intensity. Secondary outcomes were function and serious adverse events. Pain and function were analysed as standardised mean differences (SMDs). The prespecified minimal clinically important between group difference was −0.37 SMD. Serious adverse events were analysed as relative risks. Methods: Two reviewers independently extracted relevant data and assessed the risk of bias of trials using the Cochrane risk of bias tool. The predefined main analysis was based only on large, placebo controlled trials with ≥100 participants per group. Summary results were obtained through a random effects meta-analysis model. Cumulative meta-analysis and trial sequential analysis under a random effects model were also performed. Results: 169 trials provided data on 21 163 randomised participants. Evidence of small study effects and publication biases was observed for pain and function (Egger’s tests with P<0.001 and asymmetric funnel plots). Twenty four large, placebo controlled trials (8997 randomised participants) included in the main analysis of pain indicated that viscosupplementation was associated with a small reduction in pain intensity compared with placebo (SMD −0.08, 95% confidence interval −0.15 to −0.02), with the lower bound of the 95% confidence interval excluding the minimal clinically important between group difference. This effect corresponds to a difference in pain scores of −2.0 mm (95% confidence interval −3.8 to −0.5 mm) on a 100 mm visual analogue scale. Trial sequential analysis for pain indicated that since 2009 there has been conclusive evidence of clinical equivalence between viscosupplementation and placebo. Similar conclusions were obtained for function. Based on 15 large, placebo controlled trials on 6462 randomised participants, viscosupplementation was associated with a statistically significant higher risk of serious adverse events than placebo (relative risk 1.49, 95% confidence interval 1.12 to 1.98). Conclusion: Strong conclusive evidence indicates that viscosupplementation leads to a small reduction in knee osteoarthritis pain compared with placebo, but the difference is less than the minimal clinically important between group difference. Strong conclusive evidence indicates that viscosupplementation is also associated with an increased risk of serious adverse events compared with placebo. The findings do not support broad use of viscosupplementation for the treatment of knee osteoarthritis

New insights on the impacts of e-waste towards marine bivalves: the case of the rare earth element Dysprosium

With the technological advances and economic development, the multiplicity and wide variety of applications of electrical and electronic equipment have increased, as well as the amount of end-of-life products (waste of electrical and electronic equipment, WEEE). Accompanying their increasing application, there is an increasing risk to aquatic ecosystems and inhabiting organisms. Among the most common elements present in WEEE are rare earth elements (REE) such as Dysprosium (Dy). The present study evaluated the metabolic and oxidative stress responses of mussels Mytilus galloprovincialis exposed to an increasing range of Dy concentrations, after a 28 days experimental period. The results obtained highlighted that Dy was responsible for mussel’s metabolic increase associated with glycogen expenditure, activation of antioxidant and biotransformation defences and cellular damage, with a clear loss of redox balance. Such effects may greatly impact mussel’s physiological functions, including reproduction capacity and growth, with implications for population conservation. Overall the present study pointed out the need for more research on the toxic impacts resulting from these emerging pollutants, especially towards marine and estuarine invertebrate species.publishe

A seleção e controlo de qualidade dos materiais na construção em taipa

A construção em taipa tem atraído bastante atenção nos últimos anos devido à sua elevada sustentabilidade. Contudo, não é um material normalizado, pelo que a sua utilização em Portugal precisa ser suportada pela normalização internacional disponível. Este artigo apresenta a abordagem geral considerada nestes documentos para selecionar e avaliar a adequabilidade dos solos para construir em taipa, e discute a necessidade de controlo de qualidade deste material

Red and near-infrared absorbing dicyanomethylene squaraine cyanine dyes: photophysicochemical properties and anti-tumor photosensitizing effects

Photodynamic therapy is a medical modality developed for the treatment of several diseases of oncological and non-oncological etiology that requires the presence of a photosensitizer, light and molecular oxygen, which combined will trigger physicochemical reactions responsible for reactive oxygen species production. Given the scarcity of photosensitizers that exhibit desirable characteristics for its potential application in this therapeutic strategy, the main aims of this work were the study of the photophysical and photochemical properties and the photobiological activity of several dicyanomethylene squaraine cyanine dyes. Thus, herein, the study of their aggregation character, photobleaching and singlet oxygen production ability, and the further application of the previously synthesized dyes in Caco-2 and HepG2 cancer cell lines, to evaluate their phototherapeutic effects, are described. Dicyanomethylene squaraine dyes exhibited moderate light-stability and, despite the low singlet oxygen quantum yields, were a core of dyes that exhibited relevant in vitro photodynamic activity, as there was an evident increase in the toxicity of some of the tested dyes exclusive to radiation treatments.This research was funded by the European Investment Funds by FEDER/COMPETE/POCI under projects POCI-01-0145-FEDER-006958 (CITAB) and POCI-01-0145-FEDER-007491 (CICS-UBI) and Funds by FCT – Portuguese Foundation for Science and technology, under the projects UIDB/04033/2019 (CITAB) and UIDB/00616/2020 (CQ-VR). This work was also supported by funds from the Health Sciences Research Center (CICS-UBI) through National Funds by FCT—Foundation for Science and Technology (UID/Multi/00709/2019). The research at CQFM was supported by Project UID/NAN/50024/2019 and M-ERA-NET/0002/2015 from FCT. E. L. was supported by the FCT PhD grant SFRH/BD/147645/2019