Preliminary statistical analyses were performed using R software [43] . In order to test if trait distributions deviated from Gaussian, a D'Agostino normality test was used (p = 0.05). Since most traits were not sampled from a Gaussian distribution, they were all normalized using a Box-Cox transformation except for phenotypes reaching the value zero, which were normalized using ln(1+x) transformation. Significant effects of age at the time of vaccination, of time of vaccination, of breeding unit and of time of experiment were detected for most traits by variance analysis taking into account these effects. Normed Principal Component Analysis (PCA, [44] , dudi.pca function, ade4 package [45] , R software [43] ) on a subset of ITs adjusted for age at the time of vaccination, time of vaccination, breeding unit and experiment (Table 1) were performed using a linear model. Clusters of ITs were detected using the R package mclust for normal mixture modelling and model-based clustering [46] . It combines model-based agglomerative hierarchical classification, based on the classification likelihood, and the expectation-maximization (E-M) algorithm for maximum likelihood estimation of multivariate mixture models. Variance components, genetic parameters and their standard errors were estimated by the Restricted Maximum Likelihood (REML) method [48] , using the WOMBAT software [49] . This is the reference method to estimate genetic parameters with a mixed model. Univariate and bivariate mixed linear animal models were employed to estimate heritability and genetic correlations, respectively. For the univariate analyses, the fixed part of the model included experiment time, age at the time of vaccination, vaccination time and herd of origin effects and the random part included a common litter environmental effect and direct genetic effects. In matrix notation y~X b zW a azW c cze where y = the vector of observations; X b , W a and W c are known incidence matrix relating observations to fixed and random effects; ß = a vector of fixed effects and covariates; a = the vector of direct genetic effects; c = the vector of common litter environmental effects; and e = the vector of random residual effects. All random effects were assumed to follow a normal distribution with zero mean. For bivariate analyses, the same effects as for univariate analyses were taken into account in the fixed part of the model and a direct genetic effect was included in the random part of the model. 95% confidence intervals (95CI) were calculated for heritability (h 2 ) estimates (h 2 ). Heritability estimates have been classified: high (h 2 .0.4), moderate (0.1,h 2 ,0.4) or weak (h 2 #0.1). A graphical representation of the genetic correlations combined with a hierarchical clustering (euclidian distance, average link) was obtained with the heatmap function from the Bioconductor software [50] . Comparisons of heritability average between subsets of traits were tested using the Wilcoxon Mann-Whitney Test (significance threshold p-value = 0.05). Figure S1 Heatmap of the phenotypic correlations between 32 ITs. The correspondence between colour scale and genetic correlation levels are presented on the right-hand side of the heatmap. (TIF)  Demographic, etiological, and histological pulmonary analysis of patients with acute respiratory failure: a study of 19 years of autopsies INTRODUCTION: Acute respiratory failure has been one of the most important causes of death in intensive care units, and certain aspects of its pulmonary pathology are currently unknown. OBJECTIVES: The objective was to describe the demographic data, etiology, and pulmonary histopathological findings of different diseases in the autopsies of patients with acute respiratory failure. METHOD: Autopsies of 4,710 patients with acute respiratory failure from 1990 to 2008 were reviewed, and the following data were obtained: age, sex, and major associated diseases. The pulmonary histopathology was categorized as diffuse alveolar damage, pulmonary edema, alveolar hemorrhage, and lymphoplasmacytic interstitial pneumonia. The odds ratio of the concordance between the major associated diseases and specific autopsy findings was calculated using logistic regression. RESULTS: Bacterial bronchopneumonia was present in 33.9% of the cases and cancer in 28.1%. The pulmonary histopathology showed diffuse alveolar damage in 40.7% (1,917) of the cases. A multivariate analysis showed a significant and powerful association between diffuse alveolar damage and bronchopneumonia, HIV/AIDS, sepsis, and septic shock, between liver cirrhosis and pulmonary embolism, between pulmonary edema and acute myocardial infarction, between dilated cardiomyopathy and cancer, between alveolar hemorrhage and bronchopneumonia and pulmonary embolism, and between lymphoplasmacytic interstitial pneumonia and HIV/AIDS and liver cirrhosis. CONCLUSIONS: Bronchopneumonia was the most common diagnosis in these cases. The most prevalent pulmonary histopathological pattern was diffuse alveolar damage, which was associated with different inflammatory conditions. Further studies are necessary to elucidate the complete pathophysiological mechanisms involved with each disease and the development of acute respiratory failure. Acute respiratory failure (ARF) is a major cause of death in patients with a variety of primary underlying diseases. In addition, the prevalences of comorbidities and mortality have been reported to be higher than 40-50% in ARF patients, especially in those with diffuse infiltrates as seen on chest X-rays. [1] [2] [3] The clinical and radiological findings in ARF are nonspecific, [4] [5] [6] and prompt investigation and diagnosis are essential to improving patient survival. [7] [8] [9] In this context, the complexity of clinical presentations makes diagnosis a constant challenge for the clinician. Despite recent advances, most types of diagnostic support are still expensive. Clinicians often initiate treatment to avoid the rapid progression of the disease and to spare the patient from more invasive procedures. Therefore, it is important to determine the leading causes of death in this population to establish correct prophylactic actions, which is the least expensive strategy for preventing further pulmonary dysfunction and avoiding the need for lung biopsies. 10 We performed a retrospective study of 4,710 autopsies on patients whose cause of death was ARF to better describe the demographic and etiological data and the associated histological pulmonary findings and diseases.