A two-stage approach for the spatio-temporal analysis of high-throughput phenotyping data

High throughput phenotyping (HTP) platforms and devices are increasingly used for the characterization of growth and developmental processes for large sets of plant genotypes. Such HTP data require challenging statistical analyses in which longitudinal genetic signals need to be estimated against a background of spatio-temporal noise processes. We propose a two-stage approach for the analysis of such longitudinal HTP data. In a first stage, we correct for design features and spatial trends per time point. In a second stage, we focus on the longitudinal modelling of the spatially corrected data, thereby taking advantage of shared longitudinal features between genotypes and plants within genotypes. We propose a flexible hierarchical three-level P-spline growth curve model, with plants/plots nested in genotypes, and genotypes nested in populations. For selection of genotypes in a plant breeding context, we show how to extract new phenotypes, like growth rates, from the estimated genotypic growth curves and their first-order derivatives. We illustrate our approach on HTP data from the PhenoArch greenhouse platform at INRAE Montpellier and the outdoor Field Phenotyping platform at ETH Zürich.Ministerio de Ciencia, Innovación y Universidades | Ref. BCAM Severo Ochoa accreditation SEV-2017-0718Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung | Ref. project PhenoCOOL (project no. 169542)Horizon 2020 Framework Programme | Ref. grant agreement ID 731013 (EPPN2020)Ministerio de Ciencia, Innovación y Universidades | Ref. MTM2017-82379-

Usefulness of clinical scores to improve prediction of significant coronary heart disease after conventional treadmill exercise testing

ANTECEDENTES: en el último consenso de la AHA/ACC se recomiendan puntajes clínicos para mejorar la sensibilidad (68%) y la especificidad (77%) de la prueba de esfuerzo, método diagnóstico de primera línea en el tratamiento de la enfermedad coronaria (una de las principales causas de morbimortalidad en Colombia y el mundo). Sin embargo, son pocas las instituciones del país que los utilizan y son difíciles de aplicar en poblaciones diferentes a aquellas para las cuales fueron desarrollados, haciéndose necesario realizar un estudio que valore su desempeño en nuestro medio. MATERIALES Y MÉTODOS: se escogieron las escalas de Morise y Duke para evaluar por qué han sido validadas en varias poblaciones y fueron citadas en el consenso de la AHA/ACC. Los puntajes de Morise y Duke clasificaron a los pacientes en probabilidad baja, intermedia o alta para enfermedad coronaria. OBJETIVOS PRIMARIOS: validar las escalas de predicción para enfermedad coronaria y determinar el mejor punto de corte para cada escala en un tiempo de seguimiento de un año. OBJETIVOS SECUNDARIOS: determinar un desenlace compuesto por infarto agudo del miocardio, muerte cardiaca, angina que requiere hospitalización, obstrucción coronaria mayor a 50% y/o angioplastia e implante de stent. Determinar el mejor punto de corte mediante curvas de ROC. CRITERIOS DE INCLUSIÓN: pacientes mayores de 18 años de edad, con sospecha de enfermedad coronaria. CRITERIOS DE EXCLUSIÓN: pacientes embarazadas, con enfermedad coronaria documentada, electrocardiograma no interpretable, incapacidad o contraindicación para realizar prueba de esfuerzo por cualquier motivo, depresión del segmento ST menor a 1 mm en el electrocardiograma de base, imposibilidad de realizar seguimiento, y datos incompletos que impidieran el cálculo de las escalas. ANÁLISIS ESTADÍSTICO: la muestra se calculó utilizando error alfa menor de 0,05, error beta menor de 0,20 (poder de 80%), probabilidad de clasificación correcta 0,4, nivel de kappa para la hipótesis nula 0,85 y nivel de kappa para la hipótesis alterna 0,7. Se utilizó el programa Tamaño de la Muestra (TaMaMu), versión 1,0, se requirieron 101 pacientes. RESULTADOS: se reclutaron 127 pacientes y se excluyeron 9; 2 por pruebas de esfuerzo submáximas y 7 por no ser posible el seguimiento, y se analizaron 118. El seguimiento promedio fue de 343 días (1- 564. Edad media: 59 años (29-83). Mujeres: 53% (63) y hombres: 47% (55). Edad media de 59 y de 57 años, respectivamente. Otras características: tabaquismo: 47% (55), dislipidemia: 68% (80), índice de masa corporal mayor a 27,5: 18% (45) y diabetes mellitus: 16% (19). La escala de Morise clasificó 36% (43) en bajo riesgo, 52% (61) en riesgo intermedio y 12% (14) en riesgo alto. Según Duke los resultados fueron 53% (63), 41% (48) y 6% (7) respectivamente. Al interpretar la prueba de esfuerzo aislada, los cardiólogos clasificaron a los pacientes así: 81% (95) negativas, 8% (10) sugestivas y 11% (14) positivas. El punto o desenlace final compuesto se presentó en 11% (14 pacientes). Al comparar a los pacientes con desenlace y sin éste, los primeros se clasificaban con más frecuencia como de alta probabilidad que aquellos que no, con diferencias estadísticamente significativas (Morise: p=0,0002 y Duke: 0,0005). En la escala de Morise con punto de corte de 48, se logró sensibilidad de 92% y especificidad de 68%. En Duke, con punto de corte de 38, fue de 100% y 31%. DISCUSIÓN: la concordancia para Morise es mejor que para los demás métodos evaluados. Adicionar los puntajes clínicos a la interpretación de la prueba de esfuerzo mejora las características operativas de la misma sin aumentar los costos, y se logra un ahorro de 10% a 18%. CONCLUSIONES: los puntajes clínicos aumentan la sensibilidad y la especificidad, por lo cual se deberían utilizar de manera rutinaria para el informe de una prueba de esfuerzo convencional. Sin embargo, se hace necesario buscar soluciones que mejoren aún más dicho desempeño.Q4Artículo original207-214BACKGROUND: in the last AHA/ACC expert consensus document, clinical scores to improve sensitivity (68%) and specificity (77% of the exercise testing, diagnostic method considered a first line diagnostic method for coronary heart disease treatment (one of the main causes of mortality in Colombia and worldwide), are recommended. Nevertheless, few institutions in our country use them and they are difficult to apply in populations different to the ones for which they were developed. For this reason, a study to assess its performance in our environment, is needed MATERIALS AND METHODS: Morise and Duke treadmill scores were chosen to assess the reason for its validation in several populations, and were mentioned in the AHA/ACC consensus. The Morise and Duke scores classified patients in at low, middle and high risk for coronary heart disease. PRIMARY OBJECTIVES: validate the prediction scales for coronary heart disease and determine the best cutoff value for each score in a one year follow-up. SECONDARY OBJECTIVES: determine the composite endpoint for acute myocardial infarction, cardiac death, angina requiring hospitalization, coronary obstruction >50% and/or angioplasty and stent implantation. Determine the best cutoff point through the ROC curves. INCLUSION CRITERIA: patients >18 years old with suspected coronary heart disease. EXCLUSION CRITERIA: pregnant women with documented coronary heart disease, uninterpretable EKG, incapacity or contraindication for performing exercise stress test for any reason, ST depression < 1 mm in basal EKG, follow-up impossibility and incomplete data that might hinder the score calculation. STATISTICAL ANALYSIS: the sample was calculated using alpha error < 0.05, beta error < 0.20 (power 80%), correct classification probability 0.4, kappa level for null hypothesis 0.85 and kappa level for alternate hypothesis 0,7. The Sample Size Program version 1.0 was used. 101 patients were required. RESULTS: 127 patients were enrolled and 9 were excluded: 2 because of submaximal exercise testings and 7 because the follow up was impossible. 118 patients were analyzed. Mean follow-up was 343 days (1 - 564). Mean age was 59 years (29 - 83). Women: 53% (63) and men: 47% (55). Mean age 59 and 57 years respectively. Other characteristics: cigarette smoking: 47% (55), dyslipidemia: 68% (80), body mass index > 27,5: 18% (45) and diabetes mellitus: 16% (19). Morise score classified 36% (43) patients at low risk, 52% (61) at intermediate risk and 12% (14) at high risk. According to Duke the results were 53% (63), 41% (48) and 6% (7) respectively. When interpreting an isolated exercise testing, cardiologists classified patients: 81% (95) negative, 8% (10) suggestive and 11% (14) positive. The composite endpoint appeared in 11% (14 patients). When comparing patients with and without outcomes, the first ones classified more frequently as having higher probability than those that had not, with statistically significant differences (Morise: p = 0,0002 and Duke: 0,0005). In the Morise score with cutoff value 48, 92% sensitivity and 68% specificity was achieved. In Duke, with cutoff value 38, it was 100% and 31% respectively. DISCUSSION: concordance for Morise is better than for the other evaluated methods. The addition of clinical scores to the exercise testing interpretation improves its operative characteristics without any cost increment, achieving savings of 10% to 18%. CONCLUSIONS: clinical scores increase sensitivity and specificity, and for this reason they should be used as routine in the conventional exercise testing report. Nevertheless, it is necessary to look for solutions to improve its performance even further

Antikaon angular distributions in the reaction γd→K−Θ+p→K−K+np{\gamma}d \to K^-{\Theta}^+p \to K^-K^+np near the threshold and the parity of the Θ+{\Theta}^+ pentaquark

Within spectator model we study the reaction ${\gamma}d \to K^-{\Theta}^+p \to K^-K^+np$ in the threshold energy region. We present the predictions for the exclusive and inclusive antikaon angular distributions in the laboratory system for this reaction calculated for two possible parity states of the ${\Theta}^+$ resonance at 1.5 and 1.75 GeV beam energies with and without imposing the relevant kinematical cuts on those parts of the sampled phase space where contribution from the main background sources associated with the ${\phi}(1020)$, ${\Lambda}(1520)$ production as well as with the $K^-p$--rescattering in the final state, is expected to be dominant. We show that under chosen kinematics these distributions are sensitive to the ${\Theta}^+$ parity and, therefore, can be used as a filter for the determination of its parity.Comment: 18 pages, 8 figures; will be published in Phys.Atom.Nucl_4_200

Non-Invasive Mapping of the Gastrointestinal Microbiota Identifies Children with Inflammatory Bowel Disease

Background: Pediatric inflammatory bowel disease (IBD) is challenging to diagnose because of the non-specificity of symptoms; an unequivocal diagnosis can only be made using colonoscopy, which clinicians are reluctant to recommend for children. Diagnosis of pediatric IBD is therefore frequently delayed, leading to inappropriate treatment plans and poor outcomes. We investigated the use of 16S rRNA sequencing of fecal samples and new analytical methods to assess differences in the microbiota of children with IBD and other gastrointestinal disorders. Methodology/Principal Findings: We applied synthetic learning in microbial ecology (SLiME) analysis to 16S sequencing data obtained from i) published surveys of microbiota diversity in IBD and ii) fecal samples from 91 children and young adults who were treated in the gastroenterology program of Children’s Hospital (Boston, USA). The developed method accurately distinguished control samples from those of patients with IBD; the area under the receiver-operating-characteristic curve (AUC) value was 0.83 (corresponding to 80.3% sensitivity and 69.7% specificity at a set threshold). The accuracy was maintained among data sets collected by different sampling and sequencing methods. The method identified taxa associated with disease states and distinguished patients with Crohn’s disease from those with ulcerative colitis with reasonable accuracy. The findings were validated using samples from an additional group of 68 patients; the validation test identified patients with IBD with an AUC value of 0.84 (e.g. 92% sensitivity, 58.5% specificity). Conclusions/Significance: Microbiome-based diagnostics can distinguish pediatric patients with IBD from patients with similar symptoms. Although this test can not replace endoscopy and histological examination as diagnostic tools, classification based on microbial diversity is an effective complementary technique for IBD detection in pediatric patients.Natural Sciences and Engineering Research Council of Canada (Award NSERC PGS D)National Institutes of Health (U.S.) (1-R21-A1084032-01A1

In Vitro and In Vivo Efficacy of Ether Lipid Edelfosine against Leishmania spp. and SbV-Resistant Parasites

Leishmaniasis represents a major international health problem, has a high morbidity and mortality rate, and is classified as an emerging and uncontrolled disease by the World Health Organization. The migration of population from endemic to nonendemic areas, and tourist activities in endemic regions are spreading the disease to new areas. Unfortunately, treatment of leishmaniasis is far from satisfactory, with only a few drugs available that show significant side-effects. Here, we show in vitro and in vivo evidence for the antileishmanial activity of the ether phospholipid edelfosine, being effective against a wide number of Leishmania spp. causing cutaneous, mucocutaneous and visceral leishmaniasis. Our experimental mouse and hamster models demonstrated not only a significant antileishmanial activity of edelfosine oral administration against different wild-type Leishmania spp., but also against parasites resistant to pentavalent antimonials, which constitute the first line of treatment worldwide. In addition, edelfosine exerted a higher antileishmanial activity and a lower proneness to generate drug resistance than miltefosine, the first drug against leishmaniasis that can be administered orally. These data, together with our previous findings, showing an anti-inflammatory action and a very low toxicity profile, suggest that edelfosine is a promising orally administered drug for leishmaniasis, thus warranting clinical evaluation

The Multiplanet System TOI-421: A Warm Neptune and a Super Puffy Mini-Neptune Transiting a G9 V Star in a Visual Binary

We report the discovery of a warm Neptune and a hot sub-Neptune transiting TOI-421 (BD-14 1137, TIC 94986319), a bright (V = 9.9) G9 dwarf star in a visual binary system observed by the Transiting Exoplanet Survey Satellite (TESS) space mission in Sectors 5 and 6. We performed ground-based follow-up observations—comprised of Las Cumbres Observatory Global Telescope transit photometry, NIRC2 adaptive optics imaging, and FIbre-fed Echellé Spectrograph, CORALIE, High Accuracy Radial velocity Planet Searcher, High Resolution Échelle Spectrometer, and Planet Finder Spectrograph high-precision Doppler measurements—and confirmed the planetary nature of the 16 day transiting candidate announced by the TESS team. We discovered an additional radial velocity signal with a period of five days induced by the presence of a second planet in the system, which we also found to transit its host star. We found that the inner mini-Neptune, TOI-421 b, has an orbital period of P_b = 5.19672 ± 0.00049 days, a mass of M_b = 7.17 ± 0.66 M⊕, and a radius of R_b = 2.68^(+0.19)_(-0.18) R⊕, whereas the outer warm Neptune, TOI-421 c, has a period of Pc = 16.06819 ± 0.00035 days, a mass of M_c = 16.42^(+1.06)_(-1.04) M⊕, a radius of R_c = 5.09^(+0.16)_(-0.15) R⊕ and a density of ρ_c = 0.685^(+0.080)_(-0.072) g cm⁻³. With its characteristics, the outer planet (ρ_c = 0.685^(+0.080)_(-0.072) g cm⁻³) is placed in the intriguing class of the super-puffy mini-Neptunes. TOI-421 b and TOI-421 c are found to be well-suited for atmospheric characterization. Our atmospheric simulations predict significant Lyα transit absorption, due to strong hydrogen escape in both planets, as well as the presence of detectable CH4 in the atmosphere of TOI-421 c if equilibrium chemistry is assumed

A pair of Sub-Neptunes transiting the bright K-dwarf TOI-1064 characterised with CHEOPS

Funding: TGW, ACC, and KH acknowledge support from STFC consolidated grant numbers ST/R000824/1 and ST/V000861/1, and UKSA grant ST/R003203/1.We report the discovery and characterization of a pair of sub-Neptunes transiting the bright K-dwarf TOI-1064 (TIC 79748331), initially detected in the Transiting Exoplanet Survey Satellite (TESS) photometry. To characterize the system, we performed and retrieved the CHaracterising ExOPlanets Satellite (CHEOPS), TESS, and ground-based photometry, the High Accuracy Radial velocity Planet Searcher (HARPS) high-resolution spectroscopy, and Gemini speckle imaging. We characterize the host star and determine Teff,⋆=4734±67K⁠, R⋆=0.726±0.007R⊙⁠, and M⋆=0.748±0.032M⊙⁠. We present a novel detrending method based on point spread function shape-change modelling and demonstrate its suitability to correct flux variations in CHEOPS data. We confirm the planetary nature of both bodies and find that TOI-1064 b has an orbital period of Pb = 6.44387 ± 0.00003 d, a radius of Rb = 2.59 ± 0.04 R⊕, and a mass of Mb=13.5+1.7−1.8 M⊕, whilst TOI-1064 c has an orbital period of Pc=12.22657+0.00005−0.00004 d, a radius of Rc = 2.65 ± 0.04 R⊕, and a 3σ upper mass limit of 8.5 M⊕. From the high-precision photometry we obtain radius uncertainties of ∼1.6 per cent, allowing us to conduct internal structure and atmospheric escape modelling. TOI-1064 b is one of the densest, well-characterized sub-Neptunes, with a tenuous atmosphere that can be explained by the loss of a primordial envelope following migration through the protoplanetary disc. It is likely that TOI-1064 c has an extended atmosphere due to the tentative low density, however further radial velocities are needed to confirm this scenario and the similar radii, different masses nature of this system. The high-precision data and modelling of TOI-1064 b are important for planets in this region of mass–radius space, and it allow us to identify a trend in bulk density–stellar metallicity for massive sub-Neptunes that may hint at the formation of this population of planets.Publisher PDFPeer reviewe

The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals

To dissect the genetic architecture of blood pressure and assess effects on target-organ damage, we analyzed 128,272 SNPs from targeted and genome-wide arrays in 201,529 individuals of European ancestry and genotypes from an additional 140,886 individuals were used for validation. We identified 66 blood pressure loci, of which 17 were novel and 15 harbored multiple distinct association signals. The 66 index SNPs were enriched for cis-regulatory elements, particularly in vascular endothelial cells, consistent with a primary role in blood pressure control through modulation of vascular tone across multiple tissues. The 66 index SNPs combined in a risk score showed comparable effects in 64,421 individuals of non-European descent. The 66-SNP blood pressure risk score was significantly associated with target-organ damage in multiple tissues, with minor effects in the kidney. Our findings expand current knowledge of blood pressure pathways and highlight tissues beyond the classic renal system in blood pressure regulation

The trans-ancestral genomic architecture of glycemic traits

Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 x 10(-8)), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution. A trans-ancestry meta-analysis of GWAS of glycemic traits in up to 281,416 individuals identifies 99 novel loci, of which one quarter was found due to the multi-ancestry approach, which also improves fine-mapping of credible variant sets.Peer reviewe