Significance This paper compares the probabilistic accuracy of short-term forecasts of reported deaths due to COVID-19 during the first year and a half of the pandemic in the United States. Results show high variation in accuracy between and within stand-alone models and more consistent accuracy from an ensemble model that combined forecasts from all eligible models. This demonstrates that an ensemble model provided a reliable and comparatively accurate means of forecasting deaths during the COVID-19 pandemic that exceeded the performance of all of the models that contributed to it. This work strengthens the evidence base for synthesizing multiple models to support public-health action.

Rationale: Coronary artery disease (CAD) is a major cause of morbidity and mortality worldwide. Recent genome-wide association studies (GWAS) revealed 163 loci associated with CAD. However, the precise molecular mechanisms by which the majority of these loci increase CAD risk are not known. Vascular smooth muscle cells (VSMCs) are critical in the development of CAD. They can play either beneficial or detrimental roles in lesion pathogenesis, depending on the nature of their phenotypic changes. Objective: To identify genetic variants associated with atherosclerosis-relevant phenotypes in VSMCs Methods and Results: We quantified twelve atherosclerosis-relevant phenotypes related to calcification, proliferation, and migration in VSMCs isolated from 151 multi-ethnic heart transplant donors. After genotyping and imputation, we performed association mapping using 6.3 million genetic variants. We demonstrated significant variations in calcification, proliferation, and migration. These phenotypes were not correlated with each other. We performed GWAS for twelve atherosclerosis-relevant phenotypes and identified four genome-wide significant loci associated with at least one VSMC phenotype. We overlapped the previously identified CAD GWAS loci with our dataset and found nominally significant associations at 79 loci. One of them was the chromosome 1q41 locus, which harbors MIA3. The G allele of the lead risk SNP rs67180937 was associated with lower VSMC MIA3 expression and lower proliferation. Lentivirus-mediated silencing of MIA3 in VSMCs resulted in lower proliferation, consistent with human genetics findings. Further, we observed a significant reduction of MIA3 protein in VSMCs in thin fibrous caps of late-stage atherosclerotic plaques compared to early fibroatheroma with thick and protective fibrous caps in mice and humans. Conclusions: Our data demonstrate that genetic variants have significant influences on VSMC function relevant to the development of atherosclerosis. Further, high MIA3 expression may promote atheroprotective VSMC phenotypic transitions, including increased proliferation, which is essential in the formation or maintenance of a protective fibrous cap.

Short-term probabilistic forecasts of the trajectory of the COVID-19 pandemic in the United States have served as a visible and important communication channel between the scientific modeling community and both the general public and decision-makers. Forecasting models provide specific, quantitative, and evaluable predictions that inform short-term decisions such as healthcare staffing needs, school closures, and allocation of medical supplies. Starting in April 2020, the US COVID-19 Forecast Hub (https://covid19forecasthub.org/) collected, disseminated, and synthesized tens of millions of specific predictions from more than 90 different academic, industry, and independent research groups. A multi-model ensemble forecast that combined predictions from dozens of different research groups every week provided the most consistently accurate probabilistic forecasts of incident deaths due to COVID-19 at the state and national level from April 2020 through October 2021. The performance of 27 individual models that submitted complete forecasts of COVID-19 deaths consistently throughout this year showed high variability in forecast skill across time, geospatial units, and forecast horizons. Two-thirds of the models evaluated showed better accuracy than a naïve baseline model. Forecast accuracy degraded as models made predictions further into the future, with probabilistic error at a 20-week horizon 3-5 times larger than when predicting at a 1-week horizon. This project underscores the role that collaboration and active coordination between governmental public health agencies, academic modeling teams, and industry partners can play in developing modern modeling capabilities to support local, state, and federal response to outbreaks. Significance Statement This paper compares the probabilistic accuracy of short-term forecasts of reported deaths due to COVID-19 during the first year and a half of the pandemic in the US. Results show high variation in accuracy between and within stand-alone models, and more consistent accuracy from an ensemble model that combined forecasts from all eligible models. This demonstrates that an ensemble model provided a reliable and comparatively accurate means of forecasting deaths during the COVID-19 pandemic that exceeded the performance of all of the models that contributed to it. This work strengthens the evidence base for synthesizing multiple models to support public health action.

Background: Bradycardia and oxygen desaturation episodes are common among preterm very low birthweight (VLBW) infants in the Neonatal Intensive Care Unit (NICU), and their association with adverse outcomes such as bronchopulmonary dysplasia (BPD) is unclear. Methods: For 502 VLBW infants we quantified bradycardias (HR <100 for ≥ 4 seconds) and desaturations (SpO 2 <80% for ≥ 10 seconds), combined bradycardia and desaturation (BD) events, and percent time in events in the first 4 weeks after birth (32 infant-years of data). We tested logistic regression models of clinical risks (including a respiratory acuity score incorporating FiO 2 and level of respiratory support) to estimate the risks of BPD or death and secondary outcomes. We then tested the additive value of the bradycardia and desaturation metrics for outcomes prediction. Results: BPD occurred in 187 infants (37%). The clinical risk model had ROC area for BPD of 0.874. Measures of desaturation, but not bradycardia, significantly added to the predictive model. Desaturation metrics also added to clinical risks for prediction of severe intraventricular hemorrhage, retinopathy of prematurity and prolonged length of stay in the NICU. Conclusions: Oxygen desaturations in the first month of the NICU course are associated with risk of BPD and other morbidities in VLBW infants.

The past few years have seen an explosion of interest in understanding the role of regulatory DNA. This interest has driven large-scale production of functional genomics data and analytical methods. One popular analysis is to test for enrichment of overlaps between a query set of genomic regions and a database of region sets. In this way, new genomic data can be easily connected to annotations from external data sources. Here, we present an interactive interface for enrichment analysis of genomic locus overlaps using a web server called LOLAweb. LOLAweb accepts a set of genomic ranges from the user and tests it for enrichment against a database of region sets. LOLAweb renders results in an R Shiny application to provide interactive visualization features, enabling users to filter, sort, and explore enrichment results dynamically. LOLAweb is built and deployed in a Linux container, making it scalable to many concurrent users on our servers and also enabling users to download and run LOLAweb locally.

BACKGROUND: In premature infants, clinical changes frequently occur due to sepsis or non-infectious conditions, and distinguishing between these is challenging. Baseline risk factors, vital signs, and clinical signs guide decisions to culture and start antibiotics. We sought to compare heart rate (HR) and oxygenation (SpO2) patterns as well as baseline variables and clinical signs prompting sepsis work-ups ultimately determined to be late-onset sepsis (LOS) and sepsis ruled out (SRO). METHODS: At three NICUs, we reviewed records of very low birth weight (VLBW) infants around their first sepsis work-up diagnosed as LOS or SRO. Clinical signs prompting the evaluation were determined from clinician documentation. HR-SpO2 data, when available, were analyzed for mean, standard deviation, skewness, kurtosis, and cross-correlation. We used LASSO and logistic regression to assess variable importance and associations with LOS compared to SRO. RESULTS: We analyzed sepsis work-ups in 408 infants (173 LOS, 235 SRO). Compared to infants with SRO, those with LOS were of lower GA and BW, and more likely to have a central catheter and mechanical ventilation. Clinical signs cited more often in LOS included hypotension, acidosis, abdominal distension, lethargy, oliguria, and abnormal CBC or CRP (p <  0.05). HR-SpO2 data were available in 266 events. Cross-correlation HR-SpO2 before the event was associated with LOS after adjusting for GA, BW, and postnatal age. A model combining baseline, clinical and HR-SpO2 variables had AUC 0.821. CONCLUSION: In VLBW infants at 3-NICUs, we describe the baseline, clinical, and HR-SpO2 variables associated with LOS versus SRO.

Background Preterm very low birth weight (VLBW) infants experience physiologic maturation and transitions off therapies from 32–35 weeks postmenstrual age (PMA), which may impact episodic bradycardia and oxygen desaturation. We sought to characterize bradycardias and desaturations from 32–35 weeks PMA and test whether events at 32 weeks PMA are associated with NICU length of stay. Methods For 265 VLBW infants from 32–35 weeks PMA, we quantified the number and duration of bradycardias (HR <100 for ≥ 4s) and desaturations (SpO2 <80% for ≥ 10s) and compared events around discontinuation of CPAP, caffeine, and supplemental oxygen. We modeled associations between clinical variables, bradycardias and desaturations at 32 weeks PMA, and discharge PMA. Results Desaturations decreased from 60 to 41 per day at 32 and 35 weeks respectively (p<0.01). Duration of desaturations and number and duration of bradycardias decreased to a smaller extent (p<0.05), and there was a non-significant trend toward increased desaturations after stopping CPAP and caffeine. Controlling for clinical variables, longer duration of bradycardias and desaturations at 32 weeks PMA was associated with later discharge PMA. Conclusion Delayed recovery from bradycardias and desaturations at 32 weeks PMA, perhaps reflecting less physiologic resilience, is associated with prolonged NICU stay for VLBW infants.

Epidemiological outbreak data is often captured in line list and contact format to facilitate contact tracing for outbreak control.is an R epicontacts package that provides a unique data structure for combining these data into a single object in order to facilitate more efficient visualisation and analysis.