81 research outputs found
How good are your fits? Unbinned multivariate goodness-of-fit tests in high energy physics
Multivariate analyses play an important role in high energy physics. Such
analyses often involve performing an unbinned maximum likelihood fit of a
probability density function (p.d.f.) to the data. This paper explores a
variety of unbinned methods for determining the goodness of fit of the p.d.f.
to the data. The application and performance of each method is discussed in the
context of a real-life high energy physics analysis (a Dalitz-plot analysis).
Several of the methods presented in this paper can also be used for the
non-parametric determination of whether two samples originate from the same
parent p.d.f. This can be used, e.g., to determine the quality of a detector
Monte Carlo simulation without the need for a parametric expression of the
efficiency.Comment: 32 pages, 12 figure
Regulator constants and the parity conjecture
The p-parity conjecture for twists of elliptic curves relates multiplicities
of Artin representations in p-infinity Selmer groups to root numbers. In this
paper we prove this conjecture for a class of such twists. For example, if E/Q
is semistable at 2 and 3, K/Q is abelian and K^\infty is its maximal pro-p
extension, then the p-parity conjecture holds for twists of E by all orthogonal
Artin representations of Gal(K^\infty/Q). We also give analogous results when
K/Q is non-abelian, the base field is not Q and E is replaced by an abelian
variety. The heart of the paper is a study of relations between permutation
representations of finite groups, their "regulator constants", and
compatibility between local root numbers and local Tamagawa numbers of abelian
varieties in such relations.Comment: 50 pages; minor corrections; final version, to appear in Invent. Mat
A Disease Model for Wheezing Disorders in Preschool Children Based on Clinicians' Perceptions
Percolation in Models of Thin Film Depositions
We have studied the percolation behaviour of deposits for different
(2+1)-dimensional models of surface layer formation. The mixed model of
deposition was used, where particles were deposited selectively according to
the random (RD) and ballistic (BD) deposition rules. In the mixed one-component
models with deposition of only conducting particles, the mean height of the
percolation layer (measured in monolayers) grows continuously from 0.89832 for
the pure RD model to 2.605 for the pure RD model, but the percolation
transition belong to the same universality class, as in the 2- dimensional
random percolation problem. In two- component models with deposition of
conducting and isolating particles, the percolation layer height approaches
infinity as concentration of the isolating particles becomes higher than some
critical value. The crossover from 2d to 3d percolation was observed with
increase of the percolation layer height.Comment: 4 pages, 5 figure
Chronic obstructive pulmonary disease and related phenotypes: polygenic risk scores in population-based and case-control cohorts
Background Genetic factors influence chronic obstructive pulmonary disease (COPD) risk, but the individual variants
that have been identified have small effects. We hypothesised that a polygenic risk score using additional variants
would predict COPD and associated phenotypes.
Methods We constructed a polygenic risk score using a genome-wide association study of lung function (FEV1 and
FEV1/forced vital capacity [FVC]) from the UK Biobank and SpiroMeta. We tested this polygenic risk score in nine
cohorts of multiple ethnicities for an association with moderate-to-severe COPD (defined as FEV1/FVC <0·7 and FEV1
<80% of predicted). Associations were tested using logistic regression models, adjusting for age, sex, height, smoking
pack-years, and principal components of genetic ancestry. We assessed predictive performance of models by area
under the curve. In a subset of studies, we also studied quantitative and qualitative CT imaging phenotypes that
reflect parenchymal and airway pathology, and patterns of reduced lung growth.
Findings The polygenic risk score was associated with COPD in European (odds ratio [OR] per SD 1·81
[95% CI 1·74–1·88] and non-European (1·42 [1·34–1·51]) populations. Compared with the first decile, the tenth decile
of the polygenic risk score was associated with COPD, with an OR of 7·99 (6·56–9·72) in European ancestry and
4·83 (3·45–6·77) in non-European ancestry cohorts. The polygenic risk score was superior to previously described
genetic risk scores and, when combined with clinical risk factors (ie, age, sex, and smoking pack-years), showed
improved prediction for COPD compared with a model comprising clinical risk factors alone (AUC 0·80 [0·79–0·81]
vs 0·76 [0·75–0·76]). The polygenic risk score was associated with CT imaging phenotypes, including wall area
percent, quantitative and qualitative measures of emphysema, local histogram emphysema patterns, and destructive
emphysema subtypes. The polygenic risk score was associated with a reduced lung growth pattern.
Interpretation A risk score comprised of genetic variants can identify a small subset of individuals at markedly
increased risk for moderate-to-severe COPD, emphysema subtyp
Overlap of Genetic Risk between Interstitial Lung Abnormalities and Idiopathic Pulmonary Fibrosis
Rationale: Interstitial lung abnormalities (ILAs) are associated with the highest genetic risk locus for idiopathic pulmonary fibrosis (IPF); however, the extent to which there are unique associations among individuals with ILAs or additional overlap with IPF is not known.Objectives: To perform a genome-wide association study (GWAS) of ILAs.Methods: ILAs and a subpleural-predominant subtype were assessed on chest computed tomography (CT) scans in the AGES (Age Gene/Environment Susceptibility), COPDGene (Genetic Epidemiology of Chronic Obstructive Pulmonary Disease [COPD]), Framingham Heart, ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points), MESA (Multi-Ethnic Study of Atherosclerosis), and SPIROMICS (Subpopulations and Intermediate Outcome Measures in COPD Study) studies. We performed a GWAS of ILAs in each cohort and combined the results using a meta-analysis. We assessed for overlapping associations in independent GWASs of IPF.Measurements and Main Results: Genome-wide genotyping data were available for 1,699 individuals with ILAs and 10,274 control subjects. The MUC5B (mucin 5B) promoter variant rs35705950 was significantly associated with both ILAs (P = 2.6 × 10-27) and subpleural ILAs (P = 1.6 × 10-29). We discovered novel genome-wide associations near IPO11 (rs6886640, P = 3.8 × 10-8) and FCF1P3 (rs73199442, P = 4.8 × 10-8) with ILAs, and near HTRE1 (rs7744971, P = 4.2 × 10-8) with subpleural-predominant ILAs. These novel associations were not associated with IPF. Among 12 previously reported IPF GWAS loci, five (DPP9, DSP, FAM13A, IVD, and MUC5B) were significantly associated (P < 0.05/12) with ILAs.Conclusions: In a GWAS of ILAs in six studies, we confirmed the association with a MUC5B promoter variant and found strong evidence for an effect of previously described IPF loci; however, novel ILA associations were not associated with IPF. These findings highlight common genetically driven biologic pathways between ILAs and IPF, and also suggest distinct ones
Whole-genome sequencing in diverse subjects identifies genetic correlates of leukocyte traits: The NHLBI TOPMed program
Many common and rare variants associated with hematologic traits have been discovered through imputation on large-scale reference panels. However, the majority of genome-wide association studies (GWASs) have been conducted in Europeans, and determining causal variants has proved challenging. We performed a GWAS of total leukocyte, neutrophil, lymphocyte, monocyte, eosinophil, and basophil counts generated from 109,563,748 variants in the autosomes and the X chromosome in the Trans-Omics for Precision Medicine (TOPMed) program, which included data from 61,802 individuals of diverse ancestry. We discovered and replicated 7 leukocyte trait associations, including (1) the association between a chromosome X, pseudo-autosomal region (PAR), noncoding variant located between cytokine receptor genes (CSF2RA and CLRF2) and lower eosinophil count; and (2) associations between single variants found predominantly among African Americans at the S1PR3 (9q22.1) and HBB (11p15.4) loci and monocyte and lymphocyte counts, respectively. We further provide evidence indicating that the newly discovered eosinophil-lowering chromosome X PAR variant might be associated with reduced susceptibility to common allergic diseases such as atopic dermatitis and asthma. Additionally, we found a burden of very rare FLT3 (13q12.2) variants associated with monocyte counts. Together, these results emphasize the utility of whole-genome sequencing in diverse samples in identifying associations missed by European-ancestry-driven GWASs
Editorial Statement About JCCAP’s 2023 Special Issue on Informant Discrepancies in Youth Mental Health Assessments: Observations, Guidelines, and Future Directions Grounded in 60 Years of Research
Issue 1 of the 2011 Volume of the Journal of Clinical Child and Adolescent Psychology (JCCAP) included a Special Section about the use of multi-informant approaches to measure child and adolescent (i.e., hereafter referred to collectively as “youth”) mental health (De Los Reyes, 2011). Researchers collect reports from multiple informants or sources (e.g., parent and peer, youth and teacher) to estimate a given youth’s mental health. The 2011 JCCAP Special Section focused on the most common outcome of these approaches, namely the significant discrepancies that arise when comparing estimates from any two informant’s reports (i.e., informant discrepancies). These discrepancies appear in assessments conducted across the lifespan (Achenbach, 2020). That said, JCCAP dedicated space to understanding informant discrepancies, because they have been a focus of scholarship in youth mental health for over 60 years (e.g., Achenbach et al., 1987; De Los Reyes & Kazdin, 2005; Glennon & Weisz, 1978; Kazdin et al., 1983; Kraemer et al., 2003; Lapouse & Monk, 1958; Quay et al., 1966; Richters, 1992; Rutter et al., 1970; van der Ende et al., 2012). Thus, we have a thorough understanding of the areas of research for which they reliably appear when clinically assessing youth. For instance, intervention researchers observe informant discrepancies in estimates of intervention effects within randomized controlled trials (e.g., Casey & Berman, 1985; Weisz et al., 2017). Service providers observe informant discrepancies when working with individual clients, most notably when making decisions about treatment planning (e.g., Hawley & Weisz, 2003; Hoffman & Chu, 2015). Scholars in developmental psychopathology observe these discrepancies when seeking to understand risk and protective factors linked to youth mental health concerns (e.g., Hawker & Boulton, 2000; Hou et al., 2020; Ivanova et al., 2022). Thus, the 2011 JCCAP Special Section posed a question: Might these informant discrepancies contain data relevant to understanding youth mental health? Suppose none of the work in youth mental health is immune from these discrepancies. In that case, the answer to this question strikes at the core of what we produce―from the interventions we develop and implement, to the developmental psychopathology research that informs intervention development
Genetic determinants of telomere length from 109,122 ancestrally diverse whole-genome sequences in TOPMed
Genetic studies on telomere length are important for understanding age-related diseases. Prior GWASs for leukocyte TL have been limited to European and Asian populations. Here, we report the first sequencing-based association study for TL across ancestrally diverse individuals (European, African, Asian, and Hispanic/Latino) from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program. We used whole-genome sequencing (WGS) of whole blood for variant genotype calling and the bioinformatic estimation of telomere length in n = 109,122 individuals. We identified 59 sentinel variants (p < 5 × 10−9) in 36 loci associated with telomere length, including 20 newly associated loci (13 were replicated in external datasets). There was little evidence of effect size heterogeneity across populations. Fine-mapping at OBFC1 indicated that the independent signals colocalized with cell-type-specific eQTLs for OBFC1 (STN1). Using a multi-variant gene-based approach, we identified two genes newly implicated in telomere length, DCLRE1B (SNM1B) and PARN. In PheWAS, we demonstrated that our TL polygenic trait scores (PTSs) were associated with an increased risk of cancer-related phenotypes
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