Little evidence for association between the TGFBR1*6A variant and colorectal cancer: a family-based association study on non-syndromic family members from Australia and Spain.

Genome-wide linkage studies have identified the 9q22 chromosomal region as linked with colorectal cancer (CRC) predisposition. A candidate gene in this region is transforming growth factor beta receptor 1 (TGFBR1). Investigation of TGFBR1 has focused on the common genetic variant rs11466445, a short exonic deletion of nine base pairs which results in truncation of a stretch of nine alanine residues to six alanine residues in the gene product. While the six alanine (*6A) allele has been reported to be associated with increased risk of CRC in some population based study groups this association remains the subject of robust debate. To date, reports have been limited to population-based case-control association studies, or case-control studies of CRC families selecting one affected individual per family. No study has yet taken advantage of all the genetic information provided by multiplex CRC families. Methods: We have tested for an association between rs11466445 and risk of CRC using several family-based statistical tests in a new study group comprising members of non-syndromic high risk CRC families sourced from three familial cancer centres, two in Australia and one in Spain. Results: We report a finding of a nominally significant result using the pedigree-based association test approach (PBAT; p = 0.028), while other family-based tests were non-significant, but with a p-value < 0.10 in each instance. These other tests included the Generalised Disequilibrium Test (GDT; p = 0.085), parent of origin GDT Generalised Disequilibrium Test (GDT-PO; p = 0.081) and empirical Family-Based Association Test (FBAT; p = 0.096, additive model). Related-person case-control testing using the 'More Powerful' Quasi-Likelihood Score Test did not provide any evidence for association (M-QL5; p = 0.41). Conclusions: After conservatively taking into account considerations for multiple hypothesis testing, we find little evidence for an association between the TGFBR1*6A allele and CRC risk in these families. The weak support for an increase in risk in CRC predisposed families is in agreement with recent meta-analyses of case-control studies, which estimate only a modest increase in sporadic CRC risk among 6*A allele carriers.

Suomen taloussuhdanteiden kansainvälinen yhteisvaihtelu

Taloussuhdanteiden yhteisvaihtelun tutkimus on eräs taloustieteiden vanhimmista tutkimusaloista. Finanssikriisi ja euroalueen kohtaamat talousvaikeudet ovat kuitenkin nostaneet aiheen jälleen hyvin ajankohtaiseksi. Kuluneiden kahdenkymmenen vuoden aikana tutkimusalueesta on muodostunut erittäin laaja lukuisine näkökulmineen ja debatteineen. Tutkielman aiheena on Suomen taloussuhdanteiden kansainvälinen yhteisvaihtelu valittujen vertailumaiden kanssa. Vertailumaat ovat Ruotsi, Norja, Tanska, Saksa, Ranska, Iso-Britannia ja Yhdysvallat. Tutkielmaan valitut taloussuhdannetta kuvaavat muuttujat ovat reaalinen bruttokansantuote, yksityinen kokonaiskulutus ja teollisuustuotantoindeksi. Aineisto on kerätty Lappeenrannan tiedekirjaston Nelli-portaalin OECD iLibrary-tietokannasta ja se kattaa aikajakson 1960 Q1- 2014 Q4. Maakohtainen taloussuhdanne operationalisoidaan laskemalla ensimmäinen logaritminen differenssi, joka edustaa perinteistä reaalisuhdanneteoreettisen koulukunnan näkemystä taloussuhdanteesta. Tutkielman näkökulmaksi valitaan yhden maan näkökulma, joka on hieman harvinaisempi näkökulma verrattuna laajempiin alueellisiin näkökulmiin. Tutkimusmenetelminä käytetään Pearsonin korrelaatiokerrointa, Engle-Granger- sekä Johansenin yhteisintegroituvuustestejä ja VAR-GARCH-BEKK –mallilla laskettua dynaamista korrelaatiota, jotka lasketaan Suomen ja vertailumaiden välille maapareittain. Tuloksia tulkitaan suomalaisen vientiä vertailumaihin suunnittelevan yrityksen näkökulmasta. Tutkielman tulosten perusteella Engle-Grangerin menetelmällä laskettu samanaikainen yhteisintegroituvuus Suomen ja vertailumaiden välillä on epätodennäköistä. Kun yhteisintegroituvuuden annetaan riippua myös viiveistä, saadaan Johansenin menetelmällä yhteisintegroituvuus Suomen ja Yhdysvaltojen välille reaalisessa bruttokansantuotteessa, Suomen ja Saksan, Suomen ja Ranskan sekä Suomen ja Yhdysvaltojen välille yksityisessä kokonaiskulutuksessa sekä Suomen ja Norjan välille teollisuustuotantoindeksissä. Tulosten tulkintaa vaikeuttavat niiden malliriippuvuus ja informaatiokriteerien toisistaan poikkeavat mallisuositukset, joten yhteisintegroituvuus on mahdollinen myös muiden maaparien kohdalla. Dynaamisten korrelaatiokuvaajien perusteella maaparien välisen yhteisvaihtelun voimakkuus muuttuu ajan mukana. Finanssikriisin aikana kokonaistuotannossa on havaittavissa korkeampi korrelaatio, mutta korrelaatio palaa sen jälkeen perustasolleen. Kokonaiskulutuksen korrelaatio on kokonaistuotantoa alhaisempi ja pitemmissä aikajaksoissa vaihtelevaa.

Simulation-Based Finite-Sample Normality Tests in Linear Regressions

In the literature on tests of normality, much concern has been expressed over the problems associated with residual-based procedures. Indeed, the specialized tables of critical points which are needed to perform the tests have been derived for the location-scale model; hence reliance on available significance points in the context of regression models may cause size distortions. We propose a general solution to the problem of controlling the size normality tests for the disturbances of standard linear regression, which is based on using the technique of Monte Carlo tests.

Essays on bootstrap in econometrics

Ma thèse est composée de trois essais sur l'inférence par le bootstrap à la fois dans les modèles de données de panel et les modèles à grands nombres de variables instrumentales #VI# dont un grand nombre peut être faible. La théorie asymptotique n'étant pas toujours une bonne approximation de la distribution d'échantillonnage des estimateurs et statistiques de tests, je considère le bootstrap comme une alternative. Ces essais tentent d'étudier la validité asymptotique des procédures bootstrap existantes et quand invalides, proposent de nouvelles méthodes bootstrap valides. Le premier chapitre #co-écrit avec Sílvia Gonçalves# étudie la validité du bootstrap pour l'inférence dans un modèle de panel de données linéaire, dynamique et stationnaire à effets fixes. Nous considérons trois méthodes bootstrap: le recursive-design bootstrap, le fixed-design bootstrap et le pairs bootstrap. Ces méthodes sont des généralisations naturelles au contexte des panels des méthodes bootstrap considérées par Gonçalves et Kilian #2004# dans les modèles autorégressifs en séries temporelles. Nous montrons que l'estimateur MCO obtenu par le recursive-design bootstrap contient un terme intégré qui imite le biais de l'estimateur original. Ceci est en contraste avec le fixed-design bootstrap et le pairs bootstrap dont les distributions sont incorrectement centrées à zéro. Cependant, le recursive-design bootstrap et le pairs bootstrap sont asymptotiquement valides quand ils sont appliqués à l'estimateur corrigé du biais, contrairement au fixed-design bootstrap. Dans les simulations, le recursive-design bootstrap est la méthode qui produit les meilleurs résultats. Le deuxième chapitre étend les résultats du pairs bootstrap aux modèles de panel non linéaires dynamiques avec des effets fixes. Ces modèles sont souvent estimés par l'estimateur du maximum de vraisemblance #EMV# qui souffre également d'un biais. Récemment, Dhaene et Johmans #2014# ont proposé la méthode d'estimation split-jackknife. Bien que ces estimateurs ont des approximations asymptotiques normales centrées sur le vrai paramètre, de sérieuses distorsions demeurent à échantillons finis. Dhaene et Johmans #2014# ont proposé le pairs bootstrap comme alternative dans ce contexte sans aucune justification théorique. Pour combler cette lacune, je montre que cette méthode est asymptotiquement valide lorsqu'elle est utilisée pour estimer la distribution de l'estimateur split-jackknife bien qu'incapable d'estimer la distribution de l'EMV. Des simulations Monte Carlo montrent que les intervalles de confiance bootstrap basés sur l'estimateur split-jackknife aident grandement à réduire les distorsions liées à l'approximation normale en échantillons finis. En outre, j'applique cette méthode bootstrap à un modèle de participation des femmes au marché du travail pour construire des intervalles de confiance valides. Dans le dernier chapitre #co-écrit avec Wenjie Wang#, nous étudions la validité asymptotique des procédures bootstrap pour les modèles à grands nombres de variables instrumentales #VI# dont un grand nombre peu être faible. Nous montrons analytiquement qu'un bootstrap standard basé sur les résidus et le bootstrap restreint et efficace #RE# de Davidson et MacKinnon #2008, 2010, 2014# ne peuvent pas estimer la distribution limite de l'estimateur du maximum de vraisemblance à information limitée #EMVIL#. La raison principale est qu'ils ne parviennent pas à bien imiter le paramètre qui caractérise l'intensité de l'identification dans l'échantillon. Par conséquent, nous proposons une méthode bootstrap modifiée qui estime de facon convergente cette distribution limite. Nos simulations montrent que la méthode bootstrap modifiée réduit considérablement les distorsions des tests asymptotiques de type Wald #$t$# dans les échantillons finis, en particulier lorsque le degré d'endogénéité est élevé.

Estudo sobre a valorização de produtos estruturados no mercado brasileiro entre 2006 e 2011

Produtos estruturados é uma combinação de ativos que inclui uma renda fixa e um ou mais derivativos embutidos. No Brasil, como ainda não existe uma regulamentação específica como nos Estados Unidos e Europa, a comercialização destes produtos é feita, principalmente, via Fundos de Investimentos Estruturados. O objetivo deste trabalho é avaliar se existe uma sobrevalorização na emissão de Fundos de Investimentos Estruturados. Para isso, calculou-se a diferença entre o preço de emissão e o preço teórico. Este preço teórico foi calculado sintetizando uma carteira composta de um componente renda fixa e os derivativos embutidos, valorizando-se os dois componentes com base na mesma metodologia abordada em publicações nacionais e internacionais. Foram analisados 40 fundos de Investimentos Fechados com emissão entre 2006 e 2011, observando-se que há indícios de uma diferença de preços, conclusão similar aos demais trabalhos que analisaram o tema. Esta diferença de preços encontrada pode ser explicada pelos custos de desenvolvimento dos produtos, pelos custos de hedge das operações e pelo fato dos pequenos investidores não terem acesso a este mercado diretamente. Adicionalmente, analisou-se a existência de uma relação de longo prazo entre as variáveis volatilidade e a diferença de preços encontrada. Através do Teste de Cointegração foi observado que existe uma tendência de longo prazo entre as variáveis. A Decomposição das Variâncias demonstra que as variações de margem são explicadas pelas variações na volatilidade e, por fim, o Teste da Causalidade de Granger indica que as variações da margem precedem as variações da volatilidade estimada. Com este resultado, espera-se contribuir para aumentar a transparência do mercado ao ilustrar a sofisticação das estruturas e, também, contribuir para o debate nas discussões sobre a nova regulamentação dos produtos estruturados que o Banco Central está em via de definir.

Co-movement between two processes with local persistence

This paper introduces a residual based test where the null hypothesis of c:&InOvement between two processes with local persistenc~ can be tested, even under the presence of an endogenous regressor. It, therefore, fills in an existing lacuna in econometrics, in which longrun relationships can also be tested if the dependent and independent variables do not have a unit root, but do exhibit local persistence.

Estimação de parâmetros genéticos para produção de leite no dia do controle e produção acumulada até 305 dias, para as primeiras lactações de vacas da raça Caracu

Foram estimados parâmetros genéticos para produção de leite no dia do controle e produção acumulada até 305 dias (P305) de primeiras lactações de vacas da raça Caracu. O modelo animal considerado conteve efeito genético aditivo, como aleatório, além dos efeitos fixos de grupo contemporâneo e da idade ao parto, como covariável. Foram definidos dois grupos contemporâneos para explicar a variação ocorrida nas produções em cada controle leiteiro, compostos por ano, semana do controle e retiro (gc1) ou ano, mês do controle e retiro (gc2). Os componentes de variância foram estimados pelo método da máxima verossimilhança restrita. As variâncias fenotípicas, residuais e genéticas foram maiores no início da lactação, entretanto, a variância genética aditiva foi proporcionalmente menor em relação às demais variâncias. As estimativas de herdabilidade oscilaram entre 0,09 e 0,32 e foram maiores no final da lactação, indicando maior variabilidade genética nesse período. As correlações genéticas (r a) entre as produções em cada controle foram positivas e maiores, quanto menor a distância entre eles. A herdabilidade para P305 foi de 0,27 e as r a desta com os controles, positivas e elevadas, principalmente no meio da lactação. Os resultados indicam que a seleção direta para P305 proporciona maiores ganhos genéticos para essa característica que a obtida por meio de resposta correlacionada para as produções em cada controle.

Test post-weaning duration for performance, feed intake and feed efficiency in Nellore cattle

O objetivo neste estudo foi determinar o melhor período de avaliação para medidas de desempenho, consumo e eficiência alimentar. Durante 112 dias, 60 machos da raça Nelore, recém-desmamados, submetidos à prova de ganho de peso, foram alimentados em baias individuais para determinação do consumo alimentar e do desempenho. O peso corporal dos animais foi determinado a cada 28 dias, depois de jejum de 16 horas de líquidos e sólidos. As alterações na variância, variância relativa e correlações de Pearson e Spearman entre os dados dos períodos de avaliação reduzidos (28, 56 e 84 dias) e período total (112 dias) foram usados para determinar a melhor duração do período de avaliação. A duração do período de avaliação para ganho médio diário, consumo de matéria seca, conversão alimentar e consumo alimentar residual pode ser reduzida para 84, 28, 84 e 84 dias, respectivamente, pois tal redução não diminui significativamente a confiabilidade das avaliações em animais alimentados em baias individuais.

Secondary collisions revisited: real-world crash data and relationship to crash test criteria

Objectives: Previous research conducted in the late 1980s suggested that vehicle impacts following an initial barrier collision increase severe occupant injury risk. Now over 25years old, the data are no longer representative of the currently installed barriers or the present US vehicle fleet. The purpose of this study is to provide a present-day assessment of secondary collisions and to determine if current full-scale barrier crash testing criteria provide an indication of secondary collision risk for real-world barrier crashes. Methods: To characterize secondary collisions, 1,363 (596,331 weighted) real-world barrier midsection impacts selected from 13years (1997-2009) of in-depth crash data available through the National Automotive Sampling System (NASS) / Crashworthiness Data System (CDS) were analyzed. Scene diagram and available scene photographs were used to determine roadside and barrier specific variables unavailable in NASS/CDS. Binary logistic regression models were developed for second event occurrence and resulting driver injury. To investigate current secondary collision crash test criteria, 24 full-scale crash test reports were obtained for common non-proprietary US barriers, and the risk of secondary collisions was determined using recommended evaluation criteria from National Cooperative Highway Research Program (NCHRP) Report 350. Results: Secondary collisions were found to occur in approximately two thirds of crashes where a barrier is the first object struck. Barrier lateral stiffness, post-impact vehicle trajectory, vehicle type, and pre-impact tracking conditions were found to be statistically significant contributors to secondary event occurrence. The presence of a second event was found to increase the likelihood of a serious driver injury by a factor of 7 compared to cases with no second event present. The NCHRP Report 350 exit angle criterion was found to underestimate the risk of secondary collisions in real-world barrier crashes. Conclusions: Consistent with previous research, collisions following a barrier impact are not an infrequent event and substantially increase driver injury risk. The results suggest that using exit-angle based crash test criteria alone to assess secondary collision risk is not sufficient to predict second collision occurrence for real-world barrier crashes.

Model Checking for ROC Regression Analysis

The Receiver Operating Characteristic (ROC) curve is a prominent tool for characterizing the accuracy of continuous diagnostic test. To account for factors that might invluence the test accuracy, various ROC regression methods have been proposed. However, as in any regression analysis, when the assumed models do not fit the data well, these methods may render invalid and misleading results. To date practical model checking techniques suitable for validating existing ROC regression models are not yet available. In this paper, we develop cumulative residual based procedures to graphically and numerically assess the goodness-of-fit for some commonly used ROC regression models, and show how specific components of these models can be examined within this framework. We derive asymptotic null distributions for the residual process and discuss resampling procedures to approximate these distributions in practice. We illustrate our methods with a dataset from the Cystic Fibrosis registry.

Characterization of glucocorticoid receptor (NR3C1) gene polymorphisms and a family-based association study with hypertension

Hypertension is usually defined as having values of systolic blood pressure ≥140 mmHg, diastolic blood pressure ≥90 mmHg. Hypertension is one of the main adverse effects of glucocorticoid on the cardiovascular system. Glucocorticoids are essential hormones, secreted from adrenal glands in circadian fashion. Glucocorticoid's effect on blood pressure is conveyed by the glucocorticoid receptor (NR3C1), an omnipresent nuclear transcription factor. Although polymorphisms in this gene have long been implicated to be a causal factor for cardiovascular diseases such as hypertension, no study has yet thoroughly interrogated the gene's polymorphisms for their effect on blood pressure levels. Therefore, I have first resequenced ∼30 kb of the gene, encompassing all exons, promoter regions, 5'/3' UTRs as well as at least 1.5 kb of the gene's flanking regions from 114 chromosome 5 monosomic cell lines, comprised of three major American ethnic groups—European American, African American and Mexican American. I observed 115 polymorphisms and 14 common molecularly phased haplotypes. A subset of markers was chosen for genotyping study populations of GENOA (Genetic Epidemiology Network of Atherosclerosis; 1022 non-Hispanic whites, 1228 African Americans and 954 Mexican Americans). Since these study populations include sibships, the family-based association test was performed on 4 blood pressure-related quantitative variables—pulse, systolic blood pressure, diastolic blood pressure and mean arterial pressure. Using these analyses, multiple correlated SNPs are significantly protective against high systolic blood pressure in non-Hispanic whites, which includes rsb198, a SNP formerly associated with beneficial body compositions. Haplotype association analysis also supports this finding and all p-values remained significant after permutation tests. I therefore conclude that multiple correlated SNPs on the gene may confer protection against high blood pressure in non-Hispanic whites. ^

Assessment of oral bioaccessibility of arsenic in playground soil in Madrid (Spain): A three-method comparison and implications for risk assessment

Three methodologies to assess As bioaccessibility were evaluated using playgroundsoil collected from 16 playgrounds in Madrid, Spain: two (Simplified Bioaccessibility Extraction Test: SBET, and hydrochloric acid-extraction: HCl) assess gastric-only bioaccessibility and the third (Physiologically Based Extraction Test: PBET) evaluates mouth–gastric–intestinal bioaccessibility. Aqua regia-extractable (pseudo total) As contents, which are routinely employed in riskassessments, were used as the reference to establish the following percentages of bioaccessibility: SBET – 63.1; HCl – 51.8; PBET – 41.6, the highest values associated with the gastric-only extractions. For Madridplaygroundsoils – characterised by a very uniform, weakly alkaline pH, and low Fe oxide and organic matter contents – the statistical analysis of the results indicates that, in contrast with other studies, the highest percentage of As in the samples was bound to carbonates and/or present as calcium arsenate. As opposed to the As bound to Fe oxides, this As is readily released in the gastric environment as the carbonate matrix is decomposed and calcium arsenate is dissolved, but some of it is subsequently sequestered in unavailable forms as the pH is raised to 5.5 to mimic intestinal conditions. The HCl extraction can be used as a simple and reliable (i.e. low residual standard error) proxy for the more expensive, time consuming, and error-prone PBET methodology. The HCl method would essentially halve the estimate of carcinogenic risk for children playing in Madridplaygroundsoils, providing a more representative value of associated risk than the pseudo-total concentrations used at present

Fault isolation schemes for a class of continuous-time stochastic dynamical systems

In this paper a new method for fault isolation in a class of continuous-time stochastic dynamical systems is proposed. The method is framed in the context of model-based analytical redundancy, consisting in the generation of a residual signal by means of a diagnostic observer, for its posterior analysis. Once a fault has been detected, and assuming some basic a priori knowledge about the set of possible failures in the plant, the isolation task is then formulated as a type of on-line statistical classification problem. The proposed isolation scheme employs in parallel different hypotheses tests on a statistic of the residual signal, one test for each possible fault. This isolation method is characterized by deriving for the unidimensional case, a sufficient isolability condition as well as an upperbound of the probability of missed isolation. Simulation examples illustrate the applicability of the proposed scheme.

Bubble detection in Brazil’s stock market: application of the generalized superior augmented Dickey-Fuller test

Considering the importance of the proper detection of bubbles in financial markets for policymakers and market agents, we used two techniques described in Diba and Grossman (1988b) and in Phillips, Shi, and Yu (2015) to detect periods of exuberance in the recent history of the Brazillian stock market. First, a simple cointegration test is applied. Secondly, we conducted several augmented, right-tailed Dickey-Fuller tests on rolling windows of data to determine the point in which there’s a structural break and the series loses its stationarity.

The v-MFG test: Investigating maternal, offspring and maternal-fetal genetic incompatibility effects on disease and viability

The MFG test is a family-based association test that detects genetic effects contributing to disease in offspring, including offspring allelic effects, maternal allelic effects and MFG incompatibility effects. Like many other family-based association tests, it assumes that the offspring survival and the offspring-parent genotypes are conditionally independent provided the offspring is affected. However, when the putative disease-increasing locus can affect another competing phenotype, for example, offspring viability, the conditional independence assumption fails and these tests could lead to incorrect conclusions regarding the role of the gene in disease. We propose the v-MFG test to adjust for the genetic effects on one phenotype, e.g., viability, when testing the effects of that locus on another phenotype, e.g., disease. Using genotype data from nuclear families containing parents and at least one affected offspring, the v-MFG test models the distribution of family genotypes conditional on offspring phenotypes. It simultaneously estimates genetic effects on two phenotypes, viability and disease. Simulations show that the v-MFG test produces accurate genetic effect estimates on disease as well as on viability under several different scenarios. It generates accurate type-I error rates and provides adequate power with moderate sample sizes to detect genetic effects on disease risk when viability is reduced. We demonstrate the v-MFG test with HLA-DRB1 data from study participants with rheumatoid arthritis (RA) and their parents, we show that the v-MFG test successfully detects an MFG incompatibility effect on RA while simultaneously adjusting for a possible viability loss.