lme4qtl: linear mixed models with flexible covariance structure for genetic studies of related individuals.

BACKGROUND: Quantitative trait locus (QTL) mapping in genetic data often involves analysis of correlated observations, which need to be accounted for to avoid false association signals. This is commonly performed by modeling such correlations as random effects in linear mixed models (LMMs). The R package lme4 is a well-established tool that implements major LMM features using sparse matrix methods; however, it is not fully adapted for QTL mapping association and linkage studies. In particular, two LMM features are lacking in the base version of lme4: the definition of random effects by custom covariance matrices; and parameter constraints, which are essential in advanced QTL models. Apart from applications in linkage studies of related individuals, such functionalities are of high interest for association studies in situations where multiple covariance matrices need to be modeled, a scenario not covered by many genome-wide association study (GWAS) software. RESULTS: To address the aforementioned limitations, we developed a new R package lme4qtl as an extension of lme4. First, lme4qtl contributes new models for genetic studies within a single tool integrated with lme4 and its companion packages. Second, lme4qtl offers a flexible framework for scenarios with multiple levels of relatedness and becomes efficient when covariance matrices are sparse. We showed the value of our package using real family-based data in the Genetic Analysis of Idiopathic Thrombophilia 2 (GAIT2) project. CONCLUSIONS: Our software lme4qtl enables QTL mapping models with a versatile structure of random effects and efficient computation for sparse covariances. lme4qtl is available at https://github.com/variani/lme4qtl

The TAGA Study: A Study of Factors Determining Aortic Diameter in Families at High Risk of Abdominal Aortic Aneurysm Reveal Two New Candidate Genes

A variety of disorders are known to be related with aortic geometry, among them abdominal aortic aneurysm (AAA). This work aims to present the main determinants of abdominal aortic diameter in a new cohort of families at high risk of AAA. The Triple-A Genomic Analysis (TAGA) study comprises 407 individuals related in 12 families. Each family was collected through a proband with AAA. We calculated heritability and genetic correlations between abdominal aortic diameter and clinical parameters. A genome-wide linkage scan was performed based on 4.6 million variants. A predictive model was calculated with conditional forest. Heritability of the abdominal aortic diameter was 34%. Old age, male sex, higher height, weight, creatinine levels in serum, and better lung capacity were the best predictors of aortic diameter. Linkage analyses suggested the implication of Epidermal Growth Factor Receptor (EGFR) and Betacellulin (BTC) genes with aortic diameter. This is the first study to evaluate genetic components of variation of the aortic diameter in a population of AAA high-risk individuals. These results reveal EGFR, a gene that had been previously implicated in AAA, as a determinant of aortic diameter variation in healthy genetically enriched individuals, and might indicate that a common genetic background could determine the diameter of the aorta and future risk of AAA

HIV infection and placental malaria reduce maternal transfer of multiple antimalarial antibodies in Mozambican women

Objectives: Maternal Plasmodium falciparum-specific antibodies may contribute to protect infants against severe malaria. Our main objective was to evaluate the impact of maternal HIV infection and placental malaria on the cord blood levels and efficiency of placental transfer of IgG and IgG subclasses. Methods: In a cohort of 341 delivering HIV-negative and HIV-positive mothers from southern Mozambique, we measured total IgG and IgG subclasses in maternal and cord blood pairs by quantitative suspension array technology against eight P. falciparum antigens: Duffy-binding like domains 3-4 of VAR2CSA from the erythrocyte membrane protein 1, erythrocyte-binding antigen 140, exported protein 1 (EXP1), merozoite surface proteins 1, 2 and 5, and reticulocyte-binding-homologue-4.2 (Rh4.2). We performed univariable and multivariable regression models to assess the association of maternal HIV infection, placental malaria, maternal variables and pregnancy outcomes on cord antibody levels and antibody transplacental transfer. Results: Maternal antibody levels were the main determinants of cord antibody levels. HIV infection and placental malaria reduced the transfer and cord levels of IgG and IgG1, and this was antigen-dependent. Low birth weight was associated with an increase of IgG2 in cord against EXP1 and Rh4.2. Conclusions: We found lower maternally transferred antibodies in HIV-exposed infants and those born from mothers with placental malaria, which may underlie increased susceptibility to malaria in these children. © 2021 The British Infection Associatio

HIV infection and placental malaria reduce maternal transfer of multiple antimalarial antibodies in Mozambican women

Objectives: Maternal Plasmodium falciparum-specific antibodies may contribute to protect infants against severe malaria. Our main objective was to evaluate the impact of maternal HIV infection and placental malaria on the cord blood levels and efficiency of placental transfer of IgG and IgG subclasses.Methods: In a cohort of 341 delivering HIV-negative and HIV-positive mothers from southern Mozambique, we measured total IgG and IgG subclasses in maternal and cord blood pairs by quantitative suspension array technology against eight P. falciparum antigens: Duffy-binding like domains 3-4 of VAR2CSA from the erythrocyte membrane protein 1, erythrocyte-binding antigen 140, exported protein 1 (EXP1), merozoite surface proteins 1, 2 and 5, and reticulocyte-binding-homologue-4.2 (Rh4.2). We performed univariable and multivariable regression models to assess the association of maternal HIV infection, placental malaria, maternal variables and pregnancy outcomes on cord antibody levels and antibody transplacental transfer.Results: Maternal antibody levels were the main determinants of cord antibody levels. HIV infection and placental malaria reduced the transfer and cord levels of IgG and IgG1, and this was antigen-dependent. Low birth weight was associated with an increase of IgG2 in cord against EXP1 and Rh4.2.Conclusions: We found lower maternally transferred antibodies in HIV-exposed infants and those born from mothers with placental malaria, which may underlie increased susceptibility to malaria in these children

Reduced Placental Transfer of Antibodies Against a Wide Range of Microbial and Vaccine Antigens in HIV-Infected Women in Mozambique.

Transplacental transfer of antibodies is essential for conferring protection in newborns against infectious diseases. We assessed the impact of different factors, including gestational age and maternal infections such as HIV and malaria, on the efficiency of cord blood levels and placental transfer of IgG subclasses. We measured total IgG and IgG subclasses by quantitative suspension array technology against 14 pathogens and vaccine antigens, including targets of maternal immunization, in 341 delivering HIV-uninfected and HIV-infected mother-infant pairs from southern Mozambique. We analyzed the association of maternal HIV infection, Plasmodium falciparum exposure, maternal variables and pregnancy outcomes on cord antibody levels and transplacental transfer. Our results show that maternal antibody levels were the main determinant of cord antibody levels. Univariable and multivariable analysis showed that HIV reduced the placental transfer and cord levels of IgG and IgG1 principally, but also IgG2 to half of the antigens tested. P. falciparum exposure and prematurity were negatively associated with cord antibody levels and placental transfer, but this was antigen-subclass dependent. Our findings suggest that lower maternally transferred antibodies may underlie increased susceptibility to infections of HIV-exposed infants. This could affect efficacy of maternal vaccination, especially in sub-Saharan Africa, where there is a high prevalence of HIV, malaria and unfavorable environmental factors

Chemical Analysis of the Brightest Star of the Cetus II Ultra-Faint Dwarf Galaxy Candidate

We present a detailed chemical abundance analysis of the brightest star in the ultra-faint dwarf (UFD) galaxy candidate Cetus II from high-resolution Magellan/MIKE spectra. For this star, DES J011740.53-173053, abundances or upper limits of 18 elements from Carbon to Europium are derived. Its chemical abundances generally follow those of other UFD galaxy stars, with a slight enhancement of the alpha-elements (Mg, Si, and Ca) and low neutron-capture element (Sr, Ba, Eu) abundances supporting the classification of Cetus II as a likely UFD. The star exhibits lower Sc, Ti, and V abundances than Milky Way (MW) halo stars with similar metallicity. This signature is consistent with yields from a supernova (SN) originating from a star with a mass of ~11.2 solar masses. In addition, the star has a Potassium abundance of [K/Fe] = 0.81 which is somewhat higher than the K abundances of MW halo stars with similar metallicity, a signature which is also present in a number of UFD galaxies. A comparison including globular clusters (GC) and stellar stream stars suggests that high K is a specific characteristic for some UFD galaxy stars and can thus be used to help classify objects as UFD galaxies.Comment: 15 pages, 7 figures, 5 tables, accepted to Ap

Timing the r-process Enrichment of the Ultra-faint Dwarf Galaxy Reticulum II

The ultra-faint dwarf galaxy Reticulum II (Ret II) exhibits a unique chemical evolution history, with 72 − 12 + 10 % of its stars strongly enhanced in r-process elements. We present deep Hubble Space Telescope photometry of Ret II and analyze its star formation history. As in other ultra-faint dwarfs, the color-magnitude diagram is best fit by a model consisting of two bursts of star formation. If we assume that the bursts were instantaneous, then the older burst occurred around the epoch of reionization, forming ∼80% of the stars in the galaxy, while the remainder of the stars formed ∼3 Gyr later. When the bursts are allowed to have nonzero durations, we obtain slightly better fits. The best-fitting model in this case consists of two bursts beginning before reionization, with approximately half the stars formed in a short (100 Myr) burst and the other half in a more extended period lasting 2.6 Gyr. Considering the full set of viable star formation history models, we find that 28% of the stars formed within 500 ± 200 Myr of the onset of star formation. The combination of the star formation history and the prevalence of r-process-enhanced stars demonstrates that the r-process elements in Ret II must have been synthesized early in its initial star-forming phase. We therefore constrain the delay time between the formation of the first stars in Ret II and the r-process nucleosynthesis to be less than 500 Myr. This measurement rules out an r-process source with a delay time of several Gyr or more, such as GW170817

A Search for Faint Resolved Galaxies Beyond the Milky Way in DES Year 6: A New Faint, Diffuse Dwarf Satellite of NGC 55

We report results from a systematic wide-area search for faint dwarf galaxies at heliocentric distances from 0.3 to 2 Mpc using the full 6 yr of data from the Dark Energy Survey (DES). Unlike previous searches over the DES data, this search specifically targeted a field population of faint galaxies located beyond the Milky Way virial radius. We derive our detection efficiency for faint, resolved dwarf galaxies in the Local Volume with a set of synthetic galaxies and expect our search to be complete to M V ∼ (−7, −10) mag for galaxies at D = (0.3, 2.0) Mpc. We find no new field dwarfs in the DES footprint, but we report the discovery of one high-significance candidate dwarf galaxy at a distance of 2.2−0.12+0.05Mpc , a potential satellite of the Local Volume galaxy NGC 55, separated by 47′ (physical separation as small as 30 kpc). We estimate this dwarf galaxy to have an absolute V-band magnitude of −8.0−0.3+0.5mag and an azimuthally averaged physical half-light radius of 2.2−0.4+0.5kpc , making this one of the lowest surface brightness galaxies ever found with μ=32.3magarcsec−2 . This is the largest, most diffuse galaxy known at this luminosity, suggesting possible tidal interactions with its host

Viruses and Mycoplasma pneumoniae are the main etiological agents of community-acquired pneumonia in hospitalized pediatric patients in Spain

[Objectives]: To describe the etiology of community-acquired pneumonia (CAP) in hospitalized children in Spain and analyze the predictors of the etiology.[Hypothesis]: The different etiological groups of pediatric CAP are associated with different clinical, radiographic, and analytical data.[Design]: Observational, multicenter, and prospective study.[Patient selection]: This study included children aged 1 month to 17 years with CAP, who were hospitalized between April 2012 and May 2019.[Methods]: An extensive microbiological workup was performed. The clinical, radiographic, and analytical parameters were analyzed for three etiological groups.[Results]: Among the 495 children included, at least one causative pathogen was identified in 262 (52.9%): pathogenic viruses in 155/262 (59.2%); atypical bacteria (AB), mainly Mycoplasma pneumonia, in 84/262 (32.1%); and typical bacteria (TyB) in 40/262 (15.3%). Consolidation was observed in 89/138 (64.5%) patients with viral CAP, 74/84 (88.1%) with CAP caused by AB, and 40/40 (100%) with CAP caused by TyB. Para-pneumonic pleural effusion (PPE) was observed in 112/495 (22.6%) patients, of which 61/112 (54.5%) presented a likely causative pathogen: viruses in 12/61 (19.7%); AB in 23/61 (37.7%); and TyB in 26/61 (42.6%). Viral etiology was significantly frequent in young patients and in those with low oxygen saturation, wheezing, no consolidation, and high lymphocyte counts. CAP patients with AB as the etiological agent had a significantly longer and less serious course as compared to those with other causative pathogens.[Conclusions]: Viruses and M. pneumoniae are the main causes of pediatric CAP in Spain. Wheezing, young age, and no consolidation on radiographs are indicative of viral etiology. Viruses and AB can also cause PPE. Since only a few cases can be directly attributed to TyB, the indications for antibiotics must be carefully considered in each patient.Instituto de Investigación Hospital 12 de Octubre (i+12), Grant/Award Number: AY191212‐1; Instituto de Salud Carlos III (Ministry of Economy, Industry and Competitiveness) and co‐funded by the European Regional Development Funds, Grant/Award Number: Project PI17/01458; Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Grant/Award Number: PCAPE 2011_0025 Register 320/11; Research Project of Universidad Europea de Madrid, Grant/Award Number: 2017/UEM03Peer reviewe