Unsupervised discovery of ancestry-informative markers and genetic admixture proportions in biobank-scale datasets.

Admixture estimation plays a crucial role in ancestry inference and genome-wide association studies (GWASs). Computer programs such as ADMIXTURE and STRUCTURE are commonly employed to estimate the admixture proportions of sample individuals. However, these programs can be overwhelmed by the computational burdens imposed by the 105 to 106 samples and millions of markers commonly found in modern biobanks. An attractive strategy is to run these programs on a set of ancestry-informative SNP markers (AIMs) that exhibit substantially different frequencies across populations. Unfortunately, existing methods for identifying AIMs require knowing ancestry labels for a subset of the sample. This supervised learning approach creates a chicken and the egg scenario. In this paper, we present an unsupervised, scalable framework that seamlessly carries out AIM selection and likelihood-based estimation of admixture proportions. Our simulated and real data examples show that this approach is scalable to modern biobank datasets. OpenADMIXTURE, our Julia implementation of the method, is open source and available for free.

Multivariate genome-wide association analysis by iterative hard thresholding.

MOTIVATION: In a genome-wide association study, analyzing multiple correlated traits simultaneously is potentially superior to analyzing the traits one by one. Standard methods for multivariate genome-wide association study operate marker-by-marker and are computationally intensive. RESULTS: We present a sparsity constrained regression algorithm for multivariate genome-wide association study based on iterative hard thresholding and implement it in a convenient Julia package MendelIHT.jl. In simulation studies with up to 100 quantitative traits, iterative hard thresholding exhibits similar true positive rates, smaller false positive rates, and faster execution times than GEMMA's linear mixed models and mv-PLINK's canonical correlation analysis. On UK Biobank data with 470 228 variants, MendelIHT completed a three-trait joint analysis (n=185 656) in 20 h and an 18-trait joint analysis (n=104 264) in 53 h with an 80 GB memory footprint. In short, MendelIHT enables geneticists to fit a single regression model that simultaneously considers the effect of all SNPs and dozens of traits. AVAILABILITY AND IMPLEMENTATION: Software, documentation, and scripts to reproduce our results are available from https://github.com/OpenMendel/MendelIHT.jl.

Who did the ACA Medicaid expansion impact? Estimating the probability of being a complier.

Who enrolled in Medicaid as a consequence of the Affordable Care Act (ACA)? Using the 2010-2017 American Community Survey, I estimate how characteristics relating to work status and race/ethnicity affect the probability that an individual will be a complier, defined as those induced by the ACA Medicaid expansion to obtain Medicaid coverage. Across all states, I find that part-time workers, not non-workers, are the most likely to be compliers. This finding is not consistent with certain notions that Medicaid participants are the "undeserving poor" - a sentiment that may have hindered efforts to expand Medicaid in certain states. Additionally, I find that in non-expansion states, many of which have high Black populations, the probability of being a complier is higher for Blacks than for other racial/ethnic groups, suggesting that Black people in non-expansion states would be the largest beneficiaries of any new expansions. This paper not only identifies the types of individuals who were already impacted by the expansion but also identifies which populations would benefit the most from subsequent expansions.

A fast data-driven method for genotype imputation, phasing and local ancestry inference: MendelImpute.jl.

MOTIVATION: Current methods for genotype imputation and phasing exploit the volume of data in haplotype reference panels and rely on hidden Markov models (HMMs). Existing programs all have essentially the same imputation accuracy, are computationally intensive and generally require prephasing the typed markers. RESULTS: We introduce a novel data-mining method for genotype imputation and phasing that substitutes highly efficient linear algebra routines for HMM calculations. This strategy, embodied in our Julia program MendelImpute.jl, avoids explicit assumptions about recombination and population structure while delivering similar prediction accuracy, better memory usage and an order of magnitude or better run-times compared to the fastest competing method. MendelImpute operates on both dosage data and unphased genotype data and simultaneously imputes missing genotypes and phase at both the typed and untyped SNPs (single nucleotide polymorphisms). Finally, MendelImpute naturally extends to global and local ancestry estimation and lends itself to new strategies for data compression and hence faster data transport and sharing. AVAILABILITY AND IMPLEMENTATION: Software, documentation and scripts to reproduce our results are available from https://github.com/OpenMendel/MendelImpute.jl. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

OPENMENDEL: a cooperative programming project for statistical genetics.

Statistical methods for genome-wide association studies (GWAS) continue to improve. However, the increasing volume and variety of genetic and genomic data make computational speed and ease of data manipulation mandatory in future software. In our view, a collaborative effort of statistical geneticists is required to develop open source software targeted to genetic epidemiology. Our attempt to meet this need is called the OPENMENDEL project (https://openmendel.github.io). It aims to (1) enable interactive and reproducible analyses with informative intermediate results, (2) scale to big data analytics, (3) embrace parallel and distributed computing, (4) adapt to rapid hardware evolution, (5) allow cloud computing, (6) allow integration of varied genetic data types, and (7) foster easy communication between clinicians, geneticists, statisticians, and computer scientists. This article reviews and makes recommendations to the genetic epidemiology community in the context of the OPENMENDEL project.

Adsorption dynamics of tannin on deacetylated electrospun Konjac glucomannan fabric.

A nonwoven fabric of Konjac glucomannan (KGM) for the adsorption of tannin was fabricated by using electrospinning and then followed by deacetylation with alkaline solution. To analyze the adsorption dynamics of tannin, the time course of the adsorption of tannin on the nonwoven KGM fabric was measured by immersing the fabric in tannin solution at different concentrations of tannin and amounts of the fabric. The initial and late stages of the adsorption behavior could be expressed, respectively, by using a diffusion-limited equation and a stoichiometric equation. A discussion on the dependence of the control parameters on the adsorption behavior is presented. The results represent the first step to provide an effective adsorption procedure for tannin in the use of modified KGM fabric.

An efficient protocol for computing the pKa of Zn-bound water.

At a given pH, whether a metal-bound water molecule is deprotonated or not can be determined if the pKa of the metal-bound water molecule (denoted pKw) is known. Although protocols/tools to predict the protonation states of titratable amino acid residues and small molecules have been developed, an efficient and accurate method to predict the absolute pKw values of metal complexes is lacking. Here, we present calibrated methods for optimizing the geometries and computing the absolute pKw values of a wide range of Zn2+-complexes containing protein-like ligating groups. We tested 18 different geometry-optimization methods on 19 ultra high-resolution structures of Zn2+ complexes of varying coordination numbers and ligating atoms and 98 methods in reproducing 36 experimental pKw values of diverse Zn2+ complexes in the absence and presence of explicit water molecules. The results underscore the importance of estimating the Zn2+-bound water/hydroxide solvation properly, whereas correcting for the basis set superposition error was not found to be important. The protocol presented can be used to (i) evaluate the geometries of the different Zn2+-sites found in proteins and (ii) to dissect the individual contributions of the various factors modulating the pKw in Zn2+-sites found in proteins. Predicting absolute pKw values in various environments with efficiency and accuracy will indicate when a Zn2+-bound water molecule is deprotonated, thus providing physical insight into the mechanisms of enzyme-catalyzed reactions and the design of drug candidates that can displace a metal-bound water molecule.

Frequency, risk factors, and outcomes of central nervous system relapse in lymphoma patients treated with dose-adjusted EPOCH plus rituximab.

BACKGROUND: Central nervous system (CNS) relapse in non-Hodgkin lymphoma (NHL) is a rare but serious complication that carries a poor prognosis. The use of infusional etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (EPOCH-R) for frontline treatment of diffuse large B cell lymphoma (DLBCL) is increasing, though little is known about incidence of and risk factors for CNS relapse with this regimen PATIENTS AND METHODS: We completed a chart review of patients with NHL who received EPOCH-R as front line therapy. Data obtained included baseline and treatment characteristics including if patients received CNS directed therapy. We measured overall survival (OS), progression free survival (PFS), and progression to CNS involvement. RESULTS: We identified 223 patients who met the inclusion criteria, 72% had DLBCL. Of all the patients, 5.8% experienced CNS relapse, and 38.6% were treated with CNS prophylaxis. There was no difference in rate of CNS relapse, OS, or PFS between patients who had and had not received CNS prophylaxis. Patients whose serum lactate dehydrogenase was greater than twice the upper limit of normal at diagnosis and those with extranodal disease were significantly more likely to have CNS relapse (P = .0247 and 0.022, respectively) than their counterparts. CONCLUSIONS: The rate of CNS relapse in this patient population approaches 6%, not significantly different from reports on those receiving R-CHOP. The results of this study suggest that CNS prophylaxis might be more selectively used among patients treated with EPOCH-R with certain high-risk features.

Sole rearrangement but not amplification of MYC is associated with a poor prognosis in patients with diffuse large B cell lymphoma and B cell lymphoma unclassifiable.

Rearrangement of MYC is associated with a poor prognosis in patients with diffuse large B cell lymphoma (DLBCL) and B cell lymphoma unclassifiable (BCLU), particularly in the setting of double hit lymphoma (DHL). However, little is known about outcomes of patients who demonstrate MYC rearrangement without evidence of BCL2 or BCL6 rearrangement (single hit) or amplification (>4 copies) of MYC. We identified 87 patients with single hit lymphoma (SHL), 22 patients with MYC-amplified lymphoma (MYC amp) as well as 127 DLBCL patients without MYC rearrangement or amplification (MYC normal) and 45 patients with DHL, all treated with either R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) or intensive induction therapy. For SHL and MYC amp patients, the 2-year progression-free survival rate (PFS) was 49% and 48% and 2-year overall survival rate (OS) was 59% and 71%, respectively. SHL patients receiving intensive induction experienced higher 2-year PFS (59% vs. 23%, P = 0·006) but similar 2-year OS as compared with SHL patients receiving R-CHOP. SHL DLBCL patients treated with R-CHOP, but not intensive induction, experienced significantly lower 2-year PFS and OS (P < 0·001 for both) when compared with MYC normal patients. SHL patients appear to have a poor prognosis, which may be improved with receipt of intensive induction.

Exploring the nature of cellulose microfibrils.

Ultrathin cellulose microfibril fractions were extracted from spruce wood powder using combined delignification, TEMPO-catalyzed oxidation, and sonication processes. Small-angle X-ray scattering of these microfibril fractions in a "dilute" aqueous suspension (concentration 0.077 wt %) revealed that their shape was in the form of nanostrip with 4 nm width and only about 0.5 nm thicknesses. These dimensions were further confirmed by TEM and AFM measurements. The 0.5 nm thickness implied that the nanostrip could contain only a single layer of cellulose chains. At a higher concentration (0.15 wt %), SAXS analysis indicated that these nanostrips aggregated into a layered structure. The X-ray diffraction of samples collected at different preparation stages suggested that microfibrils were delaminated along the (11̅0) planes from the Iß cellulose crystals. The degree of oxidation and solid-state (13)C NMR characterizations indicated that, in addition to the surface molecules, some inner molecules of microfibrils were also oxidized, facilitating the delamination into cellulose nanostrips.

CT Gray-Level Texture Analysis as a Quantitative Imaging Biomarker of Epidermal Growth Factor Receptor Mutation Status in Adenocarcinoma of the Lung.

OBJECTIVE: The purpose of this study was to investigate the radiogenomic correlation between CT gray-level texture features and epidermal growth factor receptor (EGFR) mutation status in adenocarcinoma of the lung. MATERIALS AND METHODS: This retrospective study included 25 patients with exon 19 short inframe deletion (exon 19) and 21 patients with exon 21 L858R point (exon 21) EGFR mutations among 125 patients with EGFR mutant adenocarcinoma of the lung. The randomly formed control group consisted of 20 patients selected from 126 patients with EGFR mutation-negative (wild-type) adenocarcinomas. Five gray-level texture features (contrast, correlation, inverse difference moment, angular second moment, and entropy) were analyzed. RESULTS: Contrast differentiated both exon 19 (p = 0.00027) and exon 21 (p = 0.00001) mutants from the wild type. Wild-type adenocarcinomas had high scores for contrast (mean, 1598.547) compared with EGFR mutants (mean, 679.463). Correlation differentiated both exon 19 (p = 0.017) and exon 21 (p = 0.0015) mutants from wild-type adenocarcinomas. Inverse difference moment differentiated exon 19 mutants from exon 21 mutants (p = 0.019) and both exon 19 (p = 0.044) and exon 21 (p = 0.00001) mutants from wild-type adenocarcinomas. Angular second moment and entropy were not associated with statistically significant differences between mutation statuses. CONCLUSION: Contrast, correlation, and inverse difference moment texture features correlate with EGFR mutation status in adenocarcinoma of the lung. Further investigation with larger prospective studies is needed to validate the role of CT gray-level texture analysis as a quantitative imaging biomarker.

Instrumentation on multi-scaled scattering of bio-macromolecular solutions.

The design, construction and initial tests on a combined laser light scattering and synchrotron X-ray scattering instrument can cover studies of length scales from atomic sizes in Angstroms to microns and dynamics from microseconds to seconds are presented. In addition to static light scattering (SLS), dynamic light scattering (DLS), small angle X-ray scattering (SAXS) and wide angle X-ray diffraction (WAXD), the light scattering instrument is being developed to carry out studies in mildly turbid solutions, in the presence of multiple scattering. Three-dimensional photon cross correlation function (3D-PCCF) measurements have been introduced to couple with synchrotron X-ray scattering to study the structure, size and dynamics of macromolecules in solution.

Incidence and risk factors for retinopathy of prematurity in extreme low birth weight Chinese infants.

The objective of this study is to determine the incidence and risk factors of retinopathy of prematurity (ROP) in extremely low birth weight (ELBW) Chinese infants. A retrospective medical record review of all ELBW (≤1,000 g) neonates screened for ROP from 2007 to 2012 was performed in Hong Kong. ROP screening was conducted at 2 neonatal intensive care units by 3 pediatric ophthalmologists using the Royal College of Ophthalmologists ROP guideline and the International Classification of ROP. Maternal and neonatal covariates were analyzed using univariate and multivariate regression analyses for both ROP and Type 1 ROP. In 131 ELBW Chinese infants, the mean gestational age (GA) and birth weight (BW) were 27.3 ± 3.3 weeks and 806.9 ± 133.7 g, respectively. The incidence of ROP and Type 1 ROP was 53.4 and 14.5 %, respectively. For ROP, a lighter BW, smaller GA, vaginal delivery, postnatal hypotension, inotrope use, bronchopulmonary dysplasia, surfactant use, invasive mechanical ventilation, and supplementary oxygen were independent risk factors for ROP, while PET was protective (P ≤ 0.02). On multivariate analysis, a smaller GA was a risk factor, while PET and congenital heart disease were protective for ROP development (P ≤ 0.01). For Type 1 ROP, a lighter BW, smaller GA, surfactant use, and invasive mechanical ventilation were independent risk factors for ROP, while PET was protective (P ≤ 0.02). There were no significant covariates on multivariate analysis for Type 1 ROP. In ELBW, preterm Chinese infants, a smaller GA was a risk factor for ROP, while PET and congenital heart disease were protective for ROP development in multivariate analysis.

Differences in risk factors for retinopathy of prematurity development in paired twins: a Chinese population study.

PURPOSE: To determine the differences in risk factors for retinopathy of prematurity (ROP) in paired twins. METHODS: A retrospective medical record review was performed for all paired twins screened for ROP between 2007 and 2012. Screening was offered to very low birth weight (≤ 1500 grams) and preterm (≤ 32 weeks) neonates. Twins 1 and 2 were categorized based on the order of delivery. Maternal and neonatal covariates were analyzed using univariate and multivariate regression analyses for both ROP and Type 1 ROP. RESULTS: In 34 pairs of Chinese twins, the mean gestational age (GA) was 30.2 ± 2.0 weeks. In Twin 1, smaller GA (OR = 0.44, P = 0.02), higher mean oxygen concentration (OR = 1.34, P = 0.03), presence of thrombocytopenia (OR = 1429.60, P < 0.0001), and intraventricular hemorrhage (OR = 18.67, P = 0.03) were significant risk factors for ROP. For Twin 2, a smaller GA (OR = 0.45, P = 0.03) was the only risk factor. There were no significant risk factors for ROP in Twin 1 or Twin 2 on multivariate analysis. CONCLUSION: In Chinese twin pairs, smaller GA was the only common risk factor for ROP while Twin 1 was more susceptible to the postnatal risks for ROP.

Second-order group knockoffs with applications to GWAS.

Conditional testing via the knockoff framework allows one to identify -- among large number of possible explanatory variables -- those that carry unique information about an outcome of interest, and also provides a false discovery rate guarantee on the selection. This approach is particularly well suited to the analysis of genome wide association studies (GWAS), which have the goal of identifying genetic variants which influence traits of medical relevance. While conditional testing can be both more powerful and precise than traditional GWAS analysis methods, its vanilla implementation encounters a difficulty common to all multivariate analysis methods: it is challenging to distinguish among multiple, highly correlated regressors. This impasse can be overcome by shifting the object of inference from single variables to groups of correlated variables. To achieve this, it is necessary to construct "group knockoffs." While successful examples are already documented in the literature, this paper substantially expands the set of algorithms and software for group knockoffs. We focus in particular on second-order knockoffs, for which we describe correlation matrix approximations that are appropriate for GWAS data and that result in considerable computational savings. We illustrate the effectiveness of the proposed methods with simulations and with the analysis of albuminuria data from the UK Biobank. The described algorithms are implemented in an open-source Julia package Knockoffs.jl, for which both R and Python wrappers are available.

Controlled Variable Selection from Summary Statistics Only? A Solution via GhostKnockoffs and Penalized Regression.

Identifying which variables do influence a response while controlling false positives pervades statistics and data science. In this paper, we consider a scenario in which we only have access to summary statistics, such as the values of marginal empirical correlations between each dependent variable of potential interest and the response. This situation may arise due to privacy concerns, e.g., to avoid the release of sensitive genetic information. We extend GhostKnockoffs He et al. [2022] and introduce variable selection methods based on penalized regression achieving false discovery rate (FDR) control. We report empirical results in extensive simulation studies, demonstrating enhanced performance over previous work. We also apply our methods to genome-wide association studies of Alzheimer's disease, and evidence a significant improvement in power.

Beyond guilty by association at scale: searching for causal variants on the basis of genome-wide summary statistics.

Understanding the causal genetic architecture of complex phenotypes is essential for future research into disease mechanisms and potential therapies. Here, we present a novel framework for genome-wide detection of sets of variants that carry non-redundant information on the phenotypes and are therefore more likely to be causal in a biological sense. Crucially, our framework requires only summary statistics obtained from standard genome-wide marginal association testing. The described approach, implemented in open-source software, is also computationally efficient, requiring less than 15 minutes on a single CPU to perform genome-wide analysis. Through extensive genome-wide simulation studies, we show that the method can substantially outperform usual two-stage marginal association testing and fine-mapping procedures in precision and recall. In applications to a meta-analysis of ten large-scale genetic studies of Alzheimer's disease (AD), we identified 82 loci associated with AD, including 37 additional loci missed by conventional GWAS pipeline. The identified putative causal variants achieve state-of-the-art agreement with massively parallel reporter assays and CRISPR-Cas9 experiments. Additionally, we applied the method to a retrospective analysis of 67 large-scale GWAS summary statistics since 2013 for a variety of phenotypes. Results reveal the method's capacity to robustly discover additional loci for polygenic traits and pinpoint potential causal variants underpinning each locus beyond conventional GWAS pipeline, contributing to a deeper understanding of complex genetic architectures in post-GWAS analyses.

A 3-bp deletion in the HBS1L-MYB intergenic region on chromosome 6q23 is associated with HbF expression.

Fetal hemoglobin (HbF) is regulated as a multigenic trait. By genome-wide association study, we confirmed that HBS1L-MYB intergenic polymorphisms (HMIP) and BCL11A polymorphisms are highly associated with HbF in Chinese ß-thalassemia heterozygotes. In this population, the variance in HbF resulting from the HMIP is 13.5%; that resulting from the BCL11A polymorphism is 6.4%. To identify the functional variant in HMIP, we used 1000 Genomes Project data, single nucleotide polymorphism imputation, comparisons of association results across populations, potential transcription factor binding sites, and analysis of phylogenetic conservation. Based on these studies, a hitherto unreported association between HbF expression and a 3-bp deletion, between 135 460 326 and 135 460 328 bp on chromosome 6q23 was found. This 3-bp deletion is in complete linkage disequilibrium with rs9399137, which is the single nucleotide polymorphism in HMIP most significantly associated with HbF among Chinese, Europeans, and Africans. Chromatin immunoprecipitation assays confirmed erythropoiesis-related transcription factors binding to this region in K562 cells. Based on transient expression of a luciferase reporter plasmid, the DNA fragment encompassing the 3-bp deletion polymorphism has enhancer-like activity that is further augmented by the introduction of the 3-bp deletion. This 3-bp deletion polymorphism is probably the most significant functional motif accounting for HMIP modulation of HbF in all 3 populations.

Embracing change.

Whether small or large, rural or urban, public or private, health care organizations have no choice but to face change and embrace it. Hospital leaders must be proactive and make the most of the opportunities ahead of them.

Ocular Surface Evaluation in Immunoglobulin G4-Related Ophthalmic Disease.

PURPOSE: To evaluate the functional and structural changes of the meibomian glands and ocular surface in immunoglobulin G4-related ophthalmic disease (IgG4-ROD) patients. DESIGN: Cross-sectional, matched case-control comparison study. METHODS: This study included 64 patients with biopsy-proven IgG4-ROD (aged 63.4 ± 12.2 years, 39 male) and 64 sex- and age-matched healthy controls. Patients were managed by hospitals covering the publicly funded ophthalmology service in Hong Kong. Outcome measures included anterior segment examination and keratographic and meibographic imagings. RESULTS: A total of 64 worst-affected eyes of the 64 IgG4-ROD patients were analyzed. Corneal fluorescein staining (P = .0187), lid margin telangiectasia (P = .0360), lid-parallel conjunctival folds (P = .0112), papillae (P = .0393), meibomian gland plugging (P = .0001), meibomian gland expressibility (P = .0001), and meibum quality (P = .0001) were more significant in IgG4-ROD patients compared with healthy controls. Both upper and lower meibomian gland dropouts (P = .001 and .0003), and tear meniscus height (P = .0001) were higher in IgG4-ROD patients. Non-invasive tear break-up time (NITBUT) (P = .0166) and Schirmer test results (P = .0243) were lower in IgG4-ROD patients. Upper (r = 0.336, P = .0140) meibomian gland dropouts and NITBUT (r = -0.293, P = .0497) were positively and negatively correlated with the IgG4-ROD onset age, respectively. The number of extraocular organ involvement was negatively correlated with the Schirmer test(r = -0.341, P = .0167). Lower NITBUT was found in IgG4-ROD eyes with lacrimal gland enlargement than in IgG4-ROD eyes without lacrimal gland enlargement radiologically (P < .0001). CONCLUSIONS: IgG4-ROD patients showed features of both aqueous tear deficiency and evaporative dry eye disease. We recommend ocular surface evaluation to all patients newly diagnosed with IgG4-ROD. Further studies are warranted to clarify the mechanism of IgG4-related dry eye disease.