Powerful gene-based testing by integrating long-range chromatin interactions and knockoff genotypes.

Gene-based tests are valuable techniques for identifying genetic factors in complex traits. Here, we propose a gene-based testing framework that incorporates data on long-range chromatin interactions, several recent technical advances for region-based tests, and leverages the knockoff framework for synthetic genotype generation for improved gene discovery. Through simulations and applications to genome-wide association studies (GWAS) and whole-genome sequencing data for multiple diseases and traits, we show that the proposed test increases the power over state-of-the-art gene-based tests in the literature, identifies genes that replicate in larger studies, and can provide a more narrow focus on the possible causal genes at a locus by reducing the confounding effect of linkage disequilibrium. Furthermore, our results show that incorporating genetic variation in distal regulatory elements tends to improve power over conventional tests. Results for UK Biobank and BioBank Japan traits are also available in a publicly accessible database that allows researchers to query gene-based results in an easy fashion.

Automated structural classification of lipids by machine learning.

MOTIVATION: Modern lipidomics is largely dependent upon structural ontologies because of the great diversity exhibited in the lipidome, but no automated lipid classification exists to facilitate this partitioning. The size of the putative lipidome far exceeds the number currently classified, despite a decade of work. Automated classification would benefit ongoing classification efforts by decreasing the time needed and increasing the accuracy of classification while providing classifications for mass spectral identification algorithms. RESULTS: We introduce a tool that automates classification into the LIPID MAPS ontology of known lipids with >95% accuracy and novel lipids with 63% accuracy. The classification is based upon simple chemical characteristics and modern machine learning algorithms. The decision trees produced are intelligible and can be used to clarify implicit assumptions about the current LIPID MAPS classification scheme. These characteristics and decision trees are made available to facilitate alternative implementations. We also discovered many hundreds of lipids that are currently misclassified in the LIPID MAPS database, strongly underscoring the need for automated classification. AVAILABILITY AND IMPLEMENTATION: Source code and chemical characteristic lists as SMARTS search strings are available under an open-source license at https://www.github.com/princelab/lipid_classifier.

Mspire-Simulator: LC-MS shotgun proteomic simulator for creating realistic gold standard data.

The most important step in any quantitative proteomic pipeline is feature detection (aka peak picking). However, generating quality hand-annotated data sets to validate the algorithms, especially for lower abundance peaks, is nearly impossible. An alternative for creating gold standard data is to simulate it with features closely mimicking real data. We present Mspire-Simulator, a free, open-source shotgun proteomic simulator that goes beyond previous simulation attempts by generating LC-MS features with realistic m/z and intensity variance along with other noise components. It also includes machine-learned models for retention time and peak intensity prediction and a genetic algorithm to custom fit model parameters for experimental data sets. We show that these methods are applicable to data from three different mass spectrometers, including two fundamentally different types, and show visually and analytically that simulated peaks are nearly indistinguishable from actual data. Researchers can use simulated data to rigorously test quantitation software, and proteomic researchers may benefit from overlaying simulated data on actual data sets.

Total Talus Replacements.

Background: Total talus replacements are a surgical treatment for talar avascular necrosis (AVN) replacing the entire talus. The potential for total talus replacements has increased with the advent of patient-specific implants using 3D printing based on computed tomographic scanning of the ipsilateral or contralateral talus. The primary aim of this review is to summarize the literature on total talus replacements, providing a historical survey, indications, controversies, complications, survival, and functional outcomes. Methods: A systematic review was performed. Articles with survival of total talus replacements were included. Basic percentages and a critical review of the literature was performed. Results: Nine articles with 115 patients were included. The mean age ranged from 27.6 to 72 years, but with 5 studies having a mean age of <50 years. Mean follow-up ranged from 12.8 to 152 months. The most common indication was avascular necrosis in 67 patients (58%). Five studies used customized implants and 4 studies used 3D printing. Four studies used ceramic prostheses, 3 cobalt chromium, 1 stainless steel, and 1 titanium with ceramic surface. Three studies involved a talus replacement in conjunction with an ankle replacement. Postoperative complications ranged from 0% to 33%. Of 24 functional outcomes scores, 66.7% demonstrated significant improvement. Conclusion: Total talus replacements are a promising alternative to tibiotalocalcaneal fusion for patients with avascular necrosis of the talus; however, further studies are required to ensure reliable outcomes prior to widespread adoption of this technology. Level of Evidence: Level IV, review of case series.

BIGKnock: fine-mapping gene-based associations via knockoff analysis of biobank-scale data.

We propose BIGKnock (BIobank-scale Gene-based association test via Knockoffs), a computationally efficient gene-based testing approach for biobank-scale data, that leverages long-range chromatin interaction data, and performs conditional genome-wide testing via knockoffs. BIGKnock can prioritize causal genes over proxy associations at a locus. We apply BIGKnock to the UK Biobank data with 405,296 participants for multiple binary and quantitative traits, and show that relative to conventional gene-based tests, BIGKnock produces smaller sets of significant genes that contain the causal gene(s) with high probability. We further illustrate its ability to pinpoint potential causal genes at [Formula: see text] of the associated loci.

Subtalar Arthrodesis Union Rates With and Without Adjacent Ankle Arthrodesis.

BACKGROUND: Subtalar arthrodesis is the surgical procedure commonly performed to treat subtalar arthritis. Subtalar arthrodesis may have a higher nonunion rate if there is a preexisting adjacent joint arthrodesis. The aim of this retrospective cohort study was to compare the subtalar arthrodesis union rate of patients with native tibiotalar joints to that of patients with prior tibiotalar arthrodesis. The secondary aim was to assess risk factors for nonunion. METHODS: A retrospective cohort study of consecutive patients that underwent a subtalar arthrodesis in a single center between 2010 and 2020. The primary outcome of union was determined based on bridging callus on radiographs and clinical symptoms. If there was uncertainty, then a nonweightbearing CT was acquired. Chi-squared test and Mann-Whitney tests compared differences in demographics and risk factors for nonunion between groups. A logistical regression model was performed to determine risk factors for nonunion. RESULTS: Eighteen patients had an adjacent ankle arthrodesis and 53 patients did not. The successful subtalar arthrodesis union rate in those with a preexisting ankle joint arthrodesis (44.4%) was approximately half that in those without an ankle joint arthrodesis (86.8%) (P < .001). On multivariate logistic regression, an adjacent ankle arthrodesis was the only significant risk factor for nonunion. The odds ratio of nonunion of the subtalar joint with an adjacent ankle arthrodesis present was 4.90 (95% CI 1.02-23.56) compared to a subtalar arthrodesis with a native ankle joint. In addition, 9.4% of patients without an ankle arthrodesis underwent a revision subtalar arthrodesis compared with 44.4% of those with an adjacent ankle arthrodesis (P = .001). CONCLUSION: In our study, we found that patients undergoing a subtalar arthrodesis with an adjacent ankle arthrodesis have a significantly increased risk of nonunion compared with those undergoing a subtalar arthrodesis with a native ankle. Patients with a previously fused ankle need counseling about the high risk of nonunion and potential additional surgery.

HIV-1 Vpr suppresses expression of the thiazide-sensitive sodium chloride co-transporter in the distal convoluted tubule.

HIV-associated nephropathy (HIVAN) impairs functions of both glomeruli and tubules. Attention has been previously focused on the HIVAN glomerulopathy. Tubular injury has drawn increased attention because sodium wasting is common in hospitalized HIV/AIDS patients. We used viral protein R (Vpr)-transgenic mice to investigate the mechanisms whereby Vpr contributes to urinary sodium wasting. In phosphoenolpyruvate carboxykinase promoter-driven Vpr-transgenic mice, in situ hybridization showed that Vpr mRNA was expressed in all nephron segments, including the distal convoluted tubule. Vpr-transgenic mice, compared with wild-type littermates, markedly increased urinary sodium excretion, despite similar plasma renin activity and aldosterone levels. Kidneys from Vpr-transgenic mice also markedly reduced protein abundance of the Na+-Cl- cotransporter (NCC), while mineralocorticoid receptor (MR) protein expression level was unchanged. In African green monkey kidney cells, Vpr abrogated the aldosterone-mediated stimulation of MR transcriptional activity. Gene expression of Slc12a3 (NCC) in Vpr-transgenic mice was significantly lower compared with wild-type mice, assessed by both qRT-PCR and RNAScope in situ hybridization analysis. Chromatin immunoprecipitation assays identified multiple MR response elements (MRE), located from 5 kb upstream of the transcription start site and extending to the third exon of the SLC12A3 gene. Mutation of MRE and SP1 sites in the SLC12A3 promoter region abrogated the transcriptional responses to aldosterone and Vpr, indicating that functional MRE and SP1 are required for the SLC12A3 gene suppression in response to Vpr. Thus, Vpr attenuates MR transcriptional activity and inhibits Slc12a3 transcription in the distal convoluted tubule and contributes to salt wasting in Vpr-transgenic mice.

CNVScope: Visually Exploring Copy Number Aberrations in Cancer Genomes.

MOTIVATION: DNA copy number (CN) data are a fast-growing source of information used in basic and translational cancer research. Most CN segmentation data are presented without regard to the relationship between chromosomal regions. We offer both a toolkit to help scientists without programming experience visually explore the CN interactome and a package that constructs CN interactomes from publicly available data sets. RESULTS: The CNVScope visualization, based on a publicly available neuroblastoma CN data set, clearly displays a distinct CN interaction in the region of the MYCN, a canonical frequent amplicon target in this cancer. Exploration of the data rapidly identified cis and trans events, including a strong anticorrelation between 11q loss and17q gain with the region of 11q loss bounded by the cell cycle regulator CCND1. AVAILABILITY: The shiny application is readily available for use at http://cnvscope.nci.nih.gov/, and the package can be downloaded from CRAN (https://cran.r-project.org/package=CNVScope), where help pages and vignettes are located. A newer version is available on the GitHub site (https://github.com/jamesdalg/CNVScope/), which features an animated tutorial. The CNVScope package can be locally installed using instructions on the GitHub site for Windows and Macintosh systems. This CN analysis package also runs on a linux high-performance computing cluster, with options for multinode and multiprocessor analysis of CN variant data. The shiny application can be started using a single command (which will automatically install the public data package).