The United States COVID-19 Forecast Hub dataset

Academic researchers, government agencies, industry groups, and individuals have produced forecasts at an unprecedented scale during the COVID-19 pandemic. To leverage these forecasts, the United States Centers for Disease Control and Prevention (CDC) partnered with an academic research lab at the University of Massachusetts Amherst to create the US COVID-19 Forecast Hub. Launched in April 2020, the Forecast Hub is a dataset with point and probabilistic forecasts of incident cases, incident hospitalizations, incident deaths, and cumulative deaths due to COVID-19 at county, state, and national, levels in the United States. Included forecasts represent a variety of modeling approaches, data sources, and assumptions regarding the spread of COVID-19. The goal of this dataset is to establish a standardized and comparable set of short-term forecasts from modeling teams. These data can be used to develop ensemble models, communicate forecasts to the public, create visualizations, compare models, and inform policies regarding COVID-19 mitigation. These open-source data are available via download from GitHub, through an online API, and through R packages

Copy Number Variation in Neuropsychiatric Disorders

In this thesis, I characterize the contribution of rare copy number variation (CNV) to the genetic etiology of Tourette syndrome (TS) and bipolar disorder (BP). I accomplish this using several different study designs and various methods for CNV detection. As array data was widely available for the majority of samples evaluated, I make extensive use of this technology throughout this project and first provide an overview of the technical challenges involved and describe the analytical pipeline I developed to produce reliable CNV calls from such data.Then, in the largest TS CNV study conducted to date, I report the discovery of the first two genome-wide significant CNVs associated with the disorder, and demonstrate an increased global burden of large, singleton events and CNVs at known, pathogenic loci. Conditioned on this latter observation, I perform an exploratory analysis aimed at gene discovery through the identification of de novo copy number variants from whole-exome sequencing in a sample of affected proband, unaffected parent trios in TS.I then describe a CNV study of 26 large, multigenerational families with a high incidence of BP from two population isolates, using both microarray and whole-genome sequencing data. While thorough examination of these extended BP pedigrees revealed no segregating variants of large effect, I observe a significant increase in CNV burden across a subset of BP-related genes. Finally, I explore this notion further in a larger North American sample of unrelated individuals ascertained for BP. I demonstrate that although BP cases show no observable differences in the rate or size of rare CNVs, case CNVs affect more highly constrained, brain-expressed genes, and I provide evidence for an increased female CNV burden for BP

Mosaic de novo SNRPN gene variant associated with Prader-Willi syndrome.

BackgroundPrader-Willi syndrome (PWS) is an imprinting disorder caused by the absence of paternal expressed genes in the Prader-Willi critical region (PWCR) on chromosome 15q11.2-q13. Three molecular mechanisms have been known to cause PWS, including a deletion in the PWCR, uniparental disomy 15 and imprinting defects.ResultsWe report the first case of PWS associated with a single-nucleotide SNRPN variant in a 10-year-old girl presenting with clinical features consistent with PWS, including infantile hypotonia and feeding difficulty, developmental delay with cognitive impairment, excessive eating with central obesity, sleep disturbances, skin picking and related behaviour issues. Whole-exome sequencing revealed a de novo mosaic nonsense variant of the SNRPN gene (c.73C>T, p.R25X) in 10% of DNA isolated from buccal cells and 19% of DNA from patient-derived lymphoblast cells. DNA methylation study did not detect an abnormal methylation pattern in the SNRPN locus. Parental origin studies showed a paternal source of an intronic single-nucleotide polymorphism within the locus in proximity to the SNRPN variant.ConclusionsThis is the first report that provides evidence of a de novo point mutation of paternal origin in SNRPN as a new disease-causing mechanism for PWS. This finding suggests that gene sequencing should be considered as part of the diagnostic workup in patients with clinical suspicion of PWS

Loss-of-function in RBBP5 results in a syndromic neurodevelopmental disorder associated with microcephaly

Epigenetic dysregulation has been associated with many inherited disorders. RBBP5 (HGNC:9888) encodes a core member of the protein complex that methylates histone 3 lysine-4 (H3K4) and has not been implicated in human disease. We identify five unrelated individuals with de novo heterozygous variants in RBBP5. Three nonsense/frameshift and two missense variants were identified in probands with neurodevelopmental symptoms including global developmental delay, intellectual disability, microcephaly, and short stature. Here, we investigate the pathogenicity of the variants through protein structural analysis and transgenic Drosophila models. Both missense p.(T232I) and p.(E296D) variants affect evolutionarily conserved amino acids located at the interface between RBBP5 and the nucleosome. In Drosophila, overexpression analysis identifies partial loss-of-function mechanisms when the variants are expressed using the fly Rbbp5 or human RBBP5 cDNA. Loss of Rbbp5 leads to a reduction in brain size. The human reference or variant transgenes fail to rescue this loss and expression of either missense variant in an Rbbp5 null background results in a less severe microcephaly phenotype than the human reference, indicating both missense variants are partial loss-of-function alleles. Haploinsufficiency of RBBP5 observed through de novo null and hypomorphic loss-of-function variants is associated with a syndromic neurodevelopmental disorder. Huang et al. report the first functional validation of candidate pathological variants in RBBP5. We present three truncating p.(K244Nfs*6), p.(W254*), p.(R307*) and two missense p.(T232I), p.(E296D) variants found de novo in affected individuals sharing phenotypes including microcephaly and short stature. RBBP5 is a core member of the COMPASS complex responsible for H3 lysine 4 methylation to activate developmental target genes (COMPASS complex adapted from Namitz et al., 2023). Differentiation of neural stem cells in humans and neuroblasts in Drosophila is conserved allowing for the study of neural development in the fly model organism (neural stem cell/neuroblast differentiation diagram adapted from Kim and Hirth, 2009). We used overexpression and rescue experiments to characterize the missense variants in the fly. Neural progenitor populations were evaluated in the larval brain and tissue specific phenotypes were quantified using adult eye and wing morphology studies. We identify that the truncating and missense variants are loss-of-function alleles. As additional patients are identified, the full phenotypic spectrum of RBBP5-related disorders will be elucidated. Created with Biorender.com. [Display omitted

Measurement of the W±ZW^{\pm}Z boson pair-production cross section in pppp collisions at s=13\sqrt{s}=13 TeV with the ATLAS Detector

The production of $W^{\pm}Z$ events in proton--proton collisions at a centre-of-mass energy of 13 TeV is measured with the ATLAS detector at the LHC. The collected data correspond to an integrated luminosity of 3.2 fb$^{-1}$. The $W^{\pm}Z$ candidates are reconstructed using leptonic decays of the gauge bosons into electrons or muons. The measured inclusive cross section in the detector fiducial region for leptonic decay modes is $\sigma_{W^\pm Z \rightarrow \ell^{'} \nu \ell \ell}^{\textrm{fid.}} = 63.2 \pm 3.2$ (stat.) $\pm 2.6$ (sys.) $\pm 1.5$ (lumi.) fb. In comparison, the next-to-leading-order Standard Model prediction is $53.4^{+3.6}_{-2.8}$ fb. The extrapolation of the measurement from the fiducial to the total phase space yields $\sigma_{W^{\pm}Z}^{\textrm{tot.}} = 50.6 \pm 2.6$ (stat.) $\pm 2.0$ (sys.) $\pm 0.9$ (th.) $\pm 1.2$ (lumi.) pb, in agreement with a recent next-to-next-to-leading-order calculation of $48.2^{+1.1}_{-1.0}$ pb. The cross section as a function of jet multiplicity is also measured, together with the charge-dependent $W^+Z$ and $W^-Z$ cross sections and their ratio

Reconstruction of primary vertices at the ATLAS experiment in Run 1 proton-proton collisions at the LHC

This paper presents the method and performance of primary vertex reconstruction in proton-proton collision data recorded by the ATLAS experiment during Run 1 of the LHC. The studies presented focus on data taken during 2012 at a centre-of-mass energy of [Formula: see text] TeV. The performance has been measured as a function of the number of interactions per bunch crossing over a wide range, from one to seventy. The measurement of the position and size of the luminous region and its use as a constraint to improve the primary vertex resolution are discussed. A longitudinal vertex position resolution of about [Formula: see text] is achieved for events with high multiplicity of reconstructed tracks. The transverse position resolution is better than [Formula: see text] and is dominated by the precision on the size of the luminous region. An analytical model is proposed to describe the primary vertex reconstruction efficiency as a function of the number of interactions per bunch crossing and of the longitudinal size of the luminous region. Agreement between the data and the predictions of this model is better than 3% up to seventy interactions per bunch crossing