Search

SummaryProtein microarrays are a promising technology that measure protein levels in serum or plasma samples. Due to the high technical variability of these assays and high variation in protein levels across serum samples in any population, directly answering biological questions of interest using protein microarray measurements is challenging. Using within-array ranks of protein levels for analysis can mitigate the impact of between-sample variation on downstream analysis. Although ranks are sensitive to pre-processing steps, ranking methods that accommodate uncertainty provide robust and loss-function optimal ranks. Such ranking methods require Bayesian modeling that produces full posterior distributions for parameters of interest. Bayesian models that produce such outputs have been developed for other assays, for example DNA microarrays, but those modeling assumptions are not appropriate for protein microarrays. We develop and evaluate a Bayesian model to extract a full posterior distribution of normalized fluorescent signals and associated ranks for protein microarrays, and show that it fits well to data from two studies that use protein microrarrays from different manufacturing processes. We validate the model via simulation and demonstrate the downstream impact of using estimates from this model to obtain optimal ranks.

Shrinkage estimates of small domain parameters typically utilize a combination of a noisy "direct" estimate that only uses data from a specific small domain and a more stable regression estimate. When the regression model is misspecified, estimation performance for the noisier domains can suffer due to substantial shrinkage towards a poorly estimated regression surface. In this paper, we introduce a new class of robust, empirically-driven regression weights that target estimation of the small domain means under potential misspecification of the global regression model. Our regression weights are a convex combination of the model-based weights associated with the best linear unbiased predictor (BLUP) and those associated with the observed best predictor (OBP). The compromise parameter in this convex combination is found by minimizing a novel, unbiased estimate of the mean-squared prediction error for the small domain means, and we label the associated small domain estimates the "compromise best predictor", or CBP. Using a data-adaptive mixture for the regression weights enables the CBP to possess the robustness of the OBP while retaining the main advantages of the EBLUP whenever the regression model is correct. We demonstrate the use of the CBP in an application estimating gait speed in older adults.

1AbstractImportant goals of malaria surveillance efforts include accurately quantifying the burden of malaria over time, which can be useful to target and evaluate interventions. The majority of malaria surveillance methods capture active or recent infections which poses several challenges to achieving malaria surveillance goals. In high transmission settings, asymptomatic infections are common and therefore accurate measurement of malaria burden often demands active surveillance; in low transmission regions where infections are rare accurate surveillance requires sampling a large subset of the population; and in any context monitoring malaria burden over time necessitates serial sampling. Antibody responses to Plasmodium falciparum parasites persist after infection and therefore measuring antibodies has the potential to overcome several of the current difficulties associated with malaria surveillance. However, identifying which antibody responses are markers of the timing and intensity of past exposure to P. falciparum is challenging, particularly among adults who tend to be re-exposed multiple times over the course of their lifetime and therefore have similarly high antibody responses to many P. falciparum antigens. A previous analysis of 479 serum samples from individuals in three regions in southern Africa with different historical levels of P. falciparum malaria transmission (high, intermediate, and low) revealed regional differences in antibody responses to P. falciparum antigens among children under 5 years of age. Using a novel bioinformatic pipeline optimized for protein microarrays that minimizes between-sample technical variation, we used antibody responses to P. falciparum and P. vivax antigens as predictors in random forest models to classify adult samples into these three regions of differing historical malaria transmission with high accuracy. Many of the antigens that were most important for classification in these models do not overlap with previously published results and are therefore novel candidate markers for the timing and intensity of past exposure to P. falciparum. Measuring antibody responses to these antigens could potentially lead to improved malaria serosurveillance that captures the timing and intensity of past exposure.

Après l’implosion de la Yougoslavie, les chercheurs en balkanologie se sont naturellement intéressés aux processus de séparation linguistique initiés par les États nouvellement formés.Depuis la création de la Croatie en 1991, la construction d’une identité nationale « croate » s’est appuyée sur la transformation de la langue « serbo-croate », pour en faire une langue nationale propre. Ce processus, sans se limiter à la Croatie, a touché la plupart des états balkaniques.Ces mutations linguistiques ont-elles des conséquences sur la circulation des livres et des idées dans l’espace balkanique ? Les acteurs de la chaîne du livre sont-ils conduits à s’organiser différemment, voire à se positionner dans ce débat pour continuer à exercer leur métier ? Cette situation est-elle une source d’inspiration pour des auteurs serbes ou croates ?Cette manifestation donne la parole à différents observateurs de la chaîne du livre en Serbie et en Croatie et aux chercheurs intéressés par l’histoire des idées dans les Balkans.

Les vortex acoustiques sont des faisceaux d'ondes tridimensionnels ayant une phase hélicoïdale. Leur étude a récemment permis l'essor d'une nouvelle modalité de manipulation sans contact : les pinces acoustiques mono faisceaux, basées sur les vortex focalisés d'amplitude élevée qui génèrent des forces de rappel tridimensionnelles et sélectives par pression de radiation acoustique. Les pinces acoustiques offrent des possibilités prometteuses pour des applications biologiques, comme la manipulation directe de cellules ou l'étude de leurs propriétés mécaniques. Cela implique d'augmenter fortement la fréquence des systèmes existants. Un autre phénomène non linéaire est alors amplifié : un écoulement induit par l'atténuation visqueuse des ondes dans le volume, le streaming d'Eckart. Cet écoulement, qui peut perturber la manipulation acoustique, est important à caractériser. Du fait de la géométrie complexe des vortex focalisés, la prédiction du streaming à partir des grandeurs acoustiques est mal connue et fait l'objet de cette étude. Des simulations numériques reposant sur une décomposition des échelles temporelles sont proposées. D'abord le champ acoustique 3D est calculé, puis utilisé comme terme source dans une simulation CFD. Les résultats obtenus permettent de prédire la structure de l'écoulement et de quantifier les vitesses à partir de l'amplitude des vortex acoustiques et de leur charge topologique. Enfin, ces résultats sont utilisées pour étudier le comportement à haute fréquence d'une pince acoustique opérant dans l'eau à 50~MHz sur des billes de verre d'une dizaine de micromètres, taille proche de celle d'une cellule.

BACKGROUND: Severe malaria resulting from Plasmodium falciparum infection is the leading parasitic cause of death in children worldwide, and severe malarial anemia (SMA) is the most common clinical presentation. The evidence in support of current blood transfusion guidelines for patients with SMA is limited. METHODS: We conducted a retrospective cohort study of 911 hospitalized children with SMA in a holoendemic region of Zambia to examine the association of whole blood transfusion with in-hospital survival. Data were analyzed in adjusted logistic regression models using multiple imputation for missing data. RESULTS: The median age of patients was 24 months (interquartile range, 16–30) and overall case fatality was 16%. Blood transfusion was associated with 35% reduced odds of death in children with SMA (odds ratio, 0.65; 95% confidence interval, .52–.81; P = .0002) corresponding to a number-needed-to-treat (NNT) of 14 patients. Children with SMA complicated by thrombocytopenia were more likely to benefit from transfusion than those without thrombocytopenia (NNT = 5). Longer storage time of whole blood was negatively associated with survival and with the posttransfusion rise in the platelet count but was not associated with the posttransfusion change in hemoglobin concentration. CONCLUSIONS: Whole blood given to pediatric patients with SMA was associated with improved survival, mainly among those with thrombocytopenia who received whole blood stored for

PURPOSE: The growing size of public variant repositories prompted us to test the accuracy of pathogenicity prediction of DNA variants using population data alone. METHODS: Under the a priori assumption that the ratio of the prevalence of variants in healthy population vs that in affected populations form 2 distinct distributions (pathogenic and benign), we used a Bayesian method to assign probability to a variant belonging to either distribution. RESULTS: The approach, termed Bayesian prevalence ratio (BayPR), accurately parsed 300 of 313 expertly curated CFTR variants: 284 of 296 pathogenic/likely pathogenic variants in 1 distribution and 16 of 17 benign/likely benign variants in another. BayPR produced an area under the receiver operating characteristic curve of 0.99 for 103 functionally confirmed missense CFTR variants, which is equal to or exceeds 10 commonly used algorithms (area under the receiver operating characteristic curve range 0.54–0.99). Application of BayPR to expertly curated variants in 8 genes associated with 7 Mendelian conditions led to the assignment of a disease-causing probability of ≥80% to 1350 of 1374 (98.3%) pathogenic/likely pathogenic variants and of ≤20% to 22 of 23 (95.7%) benign/likely benign variants. CONCLUSION: Irrespective of the variant type or functional effect, the BayPR approach provides probabilities of pathogenicity for DNA variants responsible for Mendelian disorders using only the variant counts in affected and unaffected population samples.

Côte d’Ivoire has one of the largest HIV epidemics in West Africa with around half million people living with HIV. Key populations like gay men and other men who have sex with men (MSM) are often disproportionately burdened with HIV due to specific acquisition and transmission risks. Quantifying the MSM population sizes at subnational level is critical to improving the HIV prevention interventions. While survey-based direct estimates of MSM numbers are available at a few urban centers in Cˆote d’Ivoire, no data on MSM population size exists at other areas without any community infrastructure to facilitate sufficient access to the MSM community. We use this limited data in a Bayesian regression setup to produce first empirically calculated estimates of the numbers of MSM in all areas of Cˆote d’Ivoire prioritized in the HIV response. Our hierarchical model imputes missing covariates using geospatial information and allows for proper uncertainty quantification leading to meaningful confidence bounds for the predicted MSM population size estimates. The intended impact of this process is to increase uptake and use of high quality, comprehensive epidemiologic and interventional data in program planning. These estimates will help design future surveys and support the planning of the scale and content of HIV prevention and treatment programs for MSM in Cˆote d’Ivoire.