Publications by authors named "Daniel Hui"

Apart from ancestry, personal or environmental covariates may contribute to differences in polygenic score (PGS) performance. We analyzed the effects of covariate stratification and interaction on body mass index (BMI) PGS (PGS) across four cohorts of European (N = 491,111) and African (N = 21,612) ancestry. Stratifying on binary covariates and quintiles for continuous covariates, 18/62 covariates had significant and replicable R differences among strata.

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An inverse correlation between stature and risk of coronary artery disease (CAD) has been observed in several epidemiologic studies, and recent Mendelian randomization (MR) experiments have suggested causal association. However, the extent to which the effect estimated by MR can be explained by cardiovascular, anthropometric, lung function, and lifestyle-related risk factors is unclear, with a recent report suggesting that lung function traits could fully explain the height-CAD effect. To clarify this relationship, we utilized a well-powered set of genetic instruments for human stature, comprising >1,800 genetic variants for height and CAD.

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Apart from ancestry, personal or environmental covariates may contribute to differences in polygenic score (PGS) performance. We analyzed effects of covariate stratification and interaction on body mass index (BMI) PGS (PGS) across four cohorts of European (N=491,111) and African (N=21,612) ancestry. Stratifying on binary covariates and quintiles for continuous covariates, 18/62 covariates had significant and replicable R differences among strata.

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An inverse correlation between stature and risk of coronary artery disease (CAD) has been observed in several epidemiologic studies, and recent Mendelian randomization (MR) experiments have suggested causal association. However, the extent to which the effect estimated by MR can be explained by established cardiovascular risk factors is unclear, with a recent report suggesting that lung function traits could fully explain the height-CAD effect. To clarify this relationship, we utilized a well-powered set of genetic instruments for human stature, comprising >1,800 genetic variants for height and CAD.

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Solid tumors account for approximately 90% of all adult human cancers. As such, the development of novel cellular therapies has become of increasing importance to target solid tumor malignancies, such as prostate, lung, breast, bladder, colon, and liver cancers. One such cellular therapy relies on the use of chimeric antigen receptor T cells (CAR-T cells).

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Loss or absence of hearing is common at both extremes of human lifespan, in the forms of congenital deafness and age-related hearing loss. While these are often studied separately, there is increasing evidence that their genetic basis is at least partially overlapping. In particular, both common and rare variants in genes associated with monogenic forms of hearing loss also contribute to the more polygenic basis of age-related hearing loss.

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Article Synopsis
  • Polygenic risk scores (PRS) show promise for precision medicine but face challenges in generalizing across different ancestry groups and ages.
  • The study generated body mass index (BMI) PRS using genome-wide association study (GWAS) data from various ancestry groups, finding that performance improved with cross-ancestry data, particularly for African ancestry participants.
  • Additionally, the research highlighted that PRS were less effective in children compared to teenagers and adults, and identified links between BMI PRS and comorbidities like type 2 diabetes and coronary atherosclerosis.
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Widespread availability of antiretroviral therapies (ART) for HIV-1 have generated considerable interest in understanding the pharmacogenomics of ART. In some individuals, ART has been associated with excessive weight gain, which disproportionately affects women of African ancestry. The underlying biology of ART-associated weight gain is poorly understood, but some genetic markers which modify weight gain risk have been suggested, with more genetic factors likely remaining undiscovered.

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Multiple sclerosis is a leading cause of neurological disability in adults. Heterogeneity in multiple sclerosis clinical presentation has posed a major challenge for identifying genetic variants associated with disease outcomes. To overcome this challenge, we used prospectively ascertained clinical outcomes data from the largest international multiple sclerosis registry, MSBase.

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Genome-wide association studies (GWAS) are being conducted at an unprecedented rate in population-based cohorts and have increased our understanding of the pathophysiology of many complex diseases. Regardless of the context, the practical utility of this information ultimately depends upon the quality of the data used for statistical analyses. Quality control (QC) procedures for GWAS are constantly evolving.

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One goal of genomic medicine is to uncover an individual's genetic risk for disease, which generally requires data connecting genotype to phenotype, as done in genome-wide association studies (GWAS). While there may be clinical promise to employing prediction tools such as polygenic risk scores (PRS), it currently stands that individuals of non-European ancestry may not reap the benefits of genomic medicine because of underrepresentation in large-scale genetics studies. Here, we discuss why this inequity poses a problem for genomic medicine and the reasons for the low transferability of PRS across populations.

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Rationale And Objectives: Residency training often overlaps with prime childbearing years, yet variability in availability and duration of parental leave in residency can complicate the decision to become parents. Gender disparities in attitudes towards parenthood in residency is well recognized, with females generally reporting more concerns surrounding prolonged training, hindrance of future career plans, and negative perception from peers. However, gender of the department chair has not yet been examined as a factor influencing parental leave policies for residents in Radiology.

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Objective: To investigate the importance of rare variants in adult-onset hearing loss.

Study Design: Genomic association study.

Setting: Large biobank from tertiary care center.

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Plasma lipids are known heritable risk factors for cardiovascular disease, but increasing evidence also supports shared genetics with diseases of other organ systems. We devised a comprehensive three-phase framework to identify new lipid-associated genes and study the relationships among lipids, genotypes, gene expression and hundreds of complex human diseases from the Electronic Medical Records and Genomics (347 traits) and the UK Biobank (549 traits). Aside from 67 new lipid-associated genes with strong replication, we found evidence for pleiotropic SNPs/genes between lipids and diseases across the phenome.

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Nonhealing diabetic foot ulcers (DFUs) are characterized by low-grade chronic inflammation, both locally and systemically. We prospectively followed a group of patients who either healed or developed nonhealing chronic DFUs. Serum and forearm skin analysis, both at the protein expression and the transcriptomic level, indicated that increased expression of factors such as interferon-γ (IFN-γ), vascular endothelial growth factor, and soluble vascular cell adhesion molecule-1 were associated with DFU healing.

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In complex trait genetics, the ability to predict phenotype from genotype is the ultimate measure of our understanding of genetic architecture underlying the heritability of a trait. A complete understanding of the genetic basis of a trait should allow for predictive methods with accuracies approaching the trait's heritability. The highly polygenic nature of quantitative traits and most common phenotypes has motivated the development of statistical strategies focused on combining myriad individually non-significant genetic effects.

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Vitamin D is a nutrient and a hormone with multiple effects on immune regulation and respiratory viral infections, which can worsen asthma and lead to severe asthma exacerbations. We set up a complete experimental and analytical pipeline for ATAC-Seq and RNA-Seq to study genome-wide epigenetic changes in human bronchial epithelial cells of asthmatic subjects, following treatment of these cells with calcitriol (vitamin D3) and Poly (I:C)(a viral analogue). This approach led to the identification of biologically plausible candidate genes for viral infections and asthma, such as DUSP10 and SLC44A1.

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The semaphorins represent a large family of signaling molecules with crucial roles in neuronal and cardiac development. While normal semaphorin function pertains largely to development, their involvement in malignancy is becoming increasingly evident. One member, Semaphorin 3C (SEMA3C), has been shown to drive a number of oncogenic programs, correlate inversely with cancer prognosis, and promote the progression of multiple different cancer types.

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Growth factor receptor tyrosine kinase (RTK) pathway activation is a key mechanism for mediating cancer growth, survival, and treatment resistance. Cognate ligands play crucial roles in autocrine or paracrine stimulation of these RTK pathways. Here, we show SEMA3C drives activation of multiple RTKs including EGFR, ErbB2, and MET in a cognate ligand-independent manner via Plexin B1.

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Background: The prevention of bleeding with adequately sustained levels of clotting factor, after a single therapeutic intervention and without the need for further medical intervention, represents an important goal in the treatment of hemophilia.

Methods: We infused a single-stranded adeno-associated viral (AAV) vector consisting of a bioengineered capsid, liver-specific promoter and factor IX Padua (factor IX-R338L) transgene at a dose of 5×10 vector genomes per kilogram of body weight in 10 men with hemophilia B who had factor IX coagulant activity of 2% or less of the normal value. Laboratory values, bleeding frequency, and consumption of factor IX concentrate were prospectively evaluated after vector infusion and were compared with baseline values.

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Prostate cancer (PCa) is among the most commonly-occurring cancers worldwide and a leader in cancer-related deaths. Local non-invasive PCa is highly treatable but limited treatment options exist for those with locally-advanced and metastatic forms of the disease underscoring the need to identify mechanisms mediating PCa progression. The semaphorins are a large grouping of membrane-associated or secreted signalling proteins whose normal roles reside in embryogenesis and neuronal development.

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Background: Inferring local ancestry in individuals of mixed ancestry has many applications, most notably in identifying disease-susceptible loci that vary among different ethnic groups. Many software packages are available for inferring local ancestry in admixed individuals. However, most of these existing software packages require specific formatted input files and generate output files in various types, yielding practical inconvenience.

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Adeno-associated virus (AAV) has become one of the most promising vectors in gene transfer in the last 10 years with successful translation to clinical trials in humans and even market approval for a first gene therapy product in Europe. Administration to humans, however, revealed that adaptive immune responses against the vector capsid can present an obstacle to sustained transgene expression due to the activation and expansion of capsid-specific T cells. The limited number of peripheral blood mononuclear cells (PBMCs) obtained from samples within clinical trials allows for little more than monitoring of T-cell responses.

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Adeno-associated virus (AAV) vectors delivered through the systemic circulation successfully transduce various target tissues in animal models. However, similar attempts in humans have been hampered by the high prevalence of neutralizing antibodies to AAV, which completely block vector transduction. We show in both mouse and nonhuman primate models that addition of empty capsid to the final vector formulation can, in a dose-dependent manner, adsorb these antibodies, even at high titers, thus overcoming their inhibitory effect.

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Immune responses directed against viral capsid proteins constitute a main safety concern in the use of adeno-associated virus (AAV) as gene transfer vectors in humans. Pharmacological immunosuppression has been proposed as a solution to the problem; however, the approach suffers from several potential limitations. Using MHC class II epitopes initially identified within human IgG, named Tregitopes, we showed that it is possible to modulate CD8+ T cell responses to several viral antigens in vitro.

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