MSGene: a multistate model using genetic risk and the electronic health record applied to lifetime risk of coronary artery disease.

Coronary artery disease (CAD) is the leading cause of death among adults worldwide. Accurate risk stratification can support optimal lifetime prevention. Current methods lack the ability to incorporate new information throughout the life course or to combine innate genetic risk factors with acquired lifetime risk.

Tissue informative cell-free DNA methylation sites in amyotrophic lateral sclerosis.

Cell-free DNA (cfDNA) is increasingly recognized as a promising biomarker candidate for disease monitoring. However, its utility in neurodegenerative diseases, like amyotrophic lateral sclerosis (ALS), remains underexplored. Existing biomarker discovery approaches are tailored to a specific disease context or are too expensive to be clinically practical.

A comprehensive analysis of clinical and polygenic germline influences on somatic mutational burden.

Tumor mutational burden (TMB), the total number of somatic mutations in the tumor, and copy number burden (CNB), the corresponding measure of aneuploidy, are established fundamental somatic features and emerging biomarkers for immunotherapy. However, the genetic and non-genetic influences on TMB/CNB and, critically, the manner by which they influence patient outcomes remain poorly understood. Here, we present a large germline-somatic study of TMB/CNB with >23,000 individuals across 17 cancer types, of which 12,000 also have extensive clinical, treatment, and overall survival (OS) measurements available.

MSGene: Derivation and validation of a multistate model for lifetime risk of coronary artery disease using genetic risk and the electronic health record.

Currently, coronary artery disease (CAD) is the leading cause of death among adults worldwide. Accurate risk stratification can support optimal lifetime prevention. We designed a novel and general multistate model (MSGene) to estimate age-specific transitions across 10 cardiometabolic states, dependent on clinical covariates and a CAD polygenic risk score.

Leveraging pleiotropy for joint analysis of genome-wide association studies with per trait interpretations.

We introduce pleiotropic association test (PAT) for joint analysis of multiple traits using genome-wide association study (GWAS) summary statistics. The method utilizes the decomposition of phenotypic covariation into genetic and environmental components to create a likelihood ratio test statistic for each genetic variant. Though PAT does not directly interpret which trait(s) drive the association, a per trait interpretation of the omnibus p-value is provided through an extension to the meta-analysis framework, m-values.

Ancestry-driven recalibration of tumor mutational burden and disparate clinical outcomes in response to immune checkpoint inhibitors.

The immune checkpoint inhibitor (ICI) pembrolizumab is US FDA approved for treatment of solid tumors with high tumor mutational burden (TMB-high; ≥10 variants/Mb). However, the extent to which TMB-high generalizes as an accurate biomarker in diverse patient populations is largely unknown. Using two clinical cohorts, we investigated the interplay between genetic ancestry, TMB, and tumor-only versus tumor-normal paired sequencing in solid tumors.

Ensemble neural network model for detecting thyroid eye disease using external photographs.

Purpose: To describe an artificial intelligence platform that detects thyroid eye disease (TED).

Design: Development of a deep learning model.

Methods: 1944 photographs from a clinical database were used to train a deep learning model.

Constructing germline research cohorts from the discarded reads of clinical tumor sequences.

Background: Hundreds of thousands of cancer patients have had targeted (panel) tumor sequencing to identify clinically meaningful mutations. In addition to improving patient outcomes, this activity has led to significant discoveries in basic and translational domains. However, the targeted nature of clinical tumor sequencing has a limited scope, especially for germline genetics.

Identifying causal variants by fine mapping across multiple studies.

Increasingly large Genome-Wide Association Studies (GWAS) have yielded numerous variants associated with many complex traits, motivating the development of "fine mapping" methods to identify which of the associated variants are causal. Additionally, GWAS of the same trait for different populations are increasingly available, raising the possibility of refining fine mapping results further by leveraging different linkage disequilibrium (LD) structures across studies. Here, we introduce multiple study causal variants identification in associated regions (MsCAVIAR), a method that extends the popular CAVIAR fine mapping framework to a multiple study setting using a random effects model.

Technology dictates algorithms: recent developments in read alignment.

Aligning sequencing reads onto a reference is an essential step of the majority of genomic analysis pipelines. Computational algorithms for read alignment have evolved in accordance with technological advances, leading to today's diverse array of alignment methods. We provide a systematic survey of algorithmic foundations and methodologies across 107 alignment methods, for both short and long reads.

Calciphylaxis associated with acute, reversible renal failure in the setting of alcoholic cirrhosis.

We describe a case of calciphylaxis in a 47-year-old man with alcohol-induced end-stage liver disease and acute renal failure secondary to hepatorenal syndrome. Possible contributing factors included transiently impaired renal function, protein C and S deficiencies, elevated calcium-phosphate product, hyperphosphatemia, low serum albumin, repeated albumin infusions, and elevated alkaline phosphatase level.

Molecular basis for leukocyte integrin alpha(E)beta(7) adhesion to epithelial (E)-cadherin.

Cadherins are expressed in tissue-restricted patterns and typically mediate homophilic adhesion. Cadherins also mediate lymphocyte adhesion, providing the opportunity for lymphocyte attachment to parenchymal cells. The best characterized example of lymphocyte adhesion to a tissue-specific cell adhesion molecule, as opposed to a vascular endothelial adhesion molecule, is the interaction between integrin alpha(E)beta(7) on intraepithelial lymphocytes and E-cadherin on epithelial cells.

Identification of structural markers for vitamin B12 and other corrinoid derivatives in solution using FTIR spectroscopy.

The identification of structural markers for B12/protein interactions is crucial to a complete understanding of vitamin B12 transport and metabolic reaction mechanisms of B12 coenzymes. Fourier transform infrared spectroscopy can provide direct measurements of changes in the side chains and corrin ring resulting from B12/protein interactions. Using FTIR spectroscopy in various solvent systems, we have identified structural markers for corrinoids in the physiological state.