Human-Disease Phenotype Map Derived from PheWAS across 38,682 Individuals.

Phenome-wide association studies (PheWASs) have been a useful tool for testing associations between genetic variations and multiple complex traits or diagnoses. Linking PheWAS-based associations between phenotypes and a variant or a genomic region into a network provides a new way to investigate cross-phenotype associations, and it might broaden the understanding of genetic architecture that exists between diagnoses, genes, and pleiotropy. We created a network of associations from one of the largest PheWASs on electronic health record (EHR)-derived phenotypes across 38,682 unrelated samples from the Geisinger's biobank; the samples were genotyped through the DiscovEHR project.

Risk Factors for Postoperative Fever and Systemic Inflammatory Response Syndrome After Ureteroscopy for Stone Disease.

Infectious complications after ureteroscopy (URS) for stone disease lead to emergency department visits, hospitalizations, and other costly health care utilization. The objective of our study was to identify risk factors for postoperative fever (POF) and systemic inflammatory response syndrome (SIRS) after URS for stone disease. We performed a retrospective cohort study on 2746 patients who underwent 3298 URS for stone disease at Geisinger from 2008 to 2016.

Using Electronic Health Records To Generate Phenotypes For Research.

Electronic health records contain patient-level data collected during and for clinical care. Data within the electronic health record include diagnostic billing codes, procedure codes, vital signs, laboratory test results, clinical imaging, and physician notes. With repeated clinic visits, these data are longitudinal, providing important information on disease development, progression, and response to treatment or intervention strategies.

Using Adipose Measures from Health Care Provider-Based Imaging Data for Discovery.

The location and type of adipose tissue is an important factor in metabolic syndrome. A database of picture archiving and communication system (PACS) derived abdominal computerized tomography (CT) images from a large health care provider, Geisinger, was used for large-scale research of the relationship of volume of subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) with obesity-related diseases and clinical laboratory measures. Using a "greedy snake" algorithm and 2,545 CT images from the Geisinger PACS, we measured levels of VAT, SAT, total adipose tissue (TAT), and adipose ratio volumes.

Healthcare Utilization and Patients' Perspectives After Receiving a Positive Genetic Test for Familial Hypercholesterolemia.

Background: The MyCode Community Health Initiative (MyCode) is returning actionable results from whole exome sequencing. Familial hypercholesterolemia (FH) is an inherited condition characterized by premature cardiovascular disease.

Methods: We used multiple methods to assess care in 28 MyCode participants who received FH results.

Association between treatment of superficial bladder cancer and 10-year mortality in older adults with multiple chronic conditions.

Background: Multiple chronic conditions (MCC) are common among older patients with cancer; however, the exclusion of these patients from clinical trials has resulted in scarce knowledge concerning outcomes, resulting in variations in treatment. Superficial bladder cancer (SBC) disproportionately affects older adults, yet to the authors' knowledge few studies to date have examined whether treatment improves long-term survival. In the current study, the authors evaluated the association between treatment of SBC and 10-year mortality in medically complex older adults.

Rare variants in the splicing regulatory elements of EXOC3L4 are associated with brain glucose metabolism in Alzheimer's disease.

Background: Alzheimer's disease (AD) is one of the most common neurodegenerative diseases that causes problems related to brain function. To some extent it is understood on a molecular level how AD arises, however there are a lack of biomarkers that can be used for early diagnosis. Two popular methods to identify AD-related biomarkers use genetics and neuroimaging.

Min-redundancy and max-relevance multi-view feature selection for predicting ovarian cancer survival using multi-omics data.

Background: Large-scale collaborative precision medicine initiatives (e.g., The Cancer Genome Atlas (TCGA)) are yielding rich multi-omics data.

Genetic susceptibility to cerebrovascular disease: A systematic review.

Investigation of genetic susceptibility to cerebrovascular disease has been of growing interest. A systematic review of human studies assessing neurogenomic aspects of cerebrovascular disease was performed according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement. Any association study exploring genetic variants located in the exome associated with one of the major cerebrovascular diseases with at least 500 subjects was eligible for inclusion.

Genome-wide meta-analysis of macronutrient intake of 91,114 European ancestry participants from the cohorts for heart and aging research in genomic epidemiology consortium.

Macronutrient intake, the proportion of calories consumed from carbohydrate, fat, and protein, is an important risk factor for metabolic diseases with significant familial aggregation. Previous studies have identified two genetic loci for macronutrient intake, but incomplete coverage of genetic variation and modest sample sizes have hindered the discovery of additional loci. Here, we expanded the genetic landscape of macronutrient intake, identifying 12 suggestively significant loci (P < 1 × 10) associated with intake of any macronutrient in 91,114 European ancestry participants.

Genetic variation affecting exon skipping contributes to brain structural atrophy in Alzheimer's disease.

Genetic variation in cis-regulatory elements related to splicing machinery and splicing regulatory elements (SREs) results in exon skipping and undesired protein products. We developed a splicing decision model to identify actionable loci among common SNPs for gene regulation. The splicing decision model identified SNPs affecting exon skipping by analyzing sequence-driven alternative splicing (AS) models and by scanning the genome for the regions with putative SRE motifs.

Current Scope and Challenges in Phenome-Wide Association Studies.

Purpose Of Review: Over many decades, researchers have been designing studies to investigate the relationship between genotypes and phenotypes to gain an understanding about the effect of genetics on disease. Recently, a high-throughput approach called phenome-wide associations studies (PheWAS) have been extensively used to identify associations between genetic variants and many diseases and traits simultaneously. In this review, we describe the value of PheWAS along with methodological issues and challenges in interpretation for current applications of PheWAS.

Metabolically Healthy Obesity and Risk of Kidney Function Decline.

Objective: The aim of this study was to examine the association between BMI categories, stratified by metabolic health status, and the risk of kidney function decline (KFD).

Methods: In this study, 42,128 adult patients with a stable BMI were classified over a 3-year baseline window by BMI and metabolic health status (assessed by Adult Treatment Panel-III criteria). KFD was defined as an estimated glomerular filtration rate (eGFR) decline ≥ 30%, eGFR < 15 mL/min/1.

Characterizing and Managing Missing Structured Data in Electronic Health Records: Data Analysis.

Background: Missing data is a challenge for all studies; however, this is especially true for electronic health record (EHR)-based analyses. Failure to appropriately consider missing data can lead to biased results. While there has been extensive theoretical work on imputation, and many sophisticated methods are now available, it remains quite challenging for researchers to implement these methods appropriately.

Genetic and environmental (physical fitness and sedentary activity) interaction effects on cardiometabolic risk factors in Mexican American children and adolescents.

Knowledge on genetic and environmental (G × E) interaction effects on cardiometabolic risk factors (CMRFs) in children is limited.  The purpose of this study was to examine the impact of G × E interaction effects on CMRFs in Mexican American (MA) children (n = 617, ages 6-17 years). The environments examined were sedentary activity (SA), assessed by recalls from "yesterday" (SAy) and "usually" (SAu) and physical fitness (PF) assessed by Harvard PF scores (HPFS).

Codon bias among synonymous rare variants is associated with Alzheimer's disease imaging biomarker.

Alzheimer's disease (AD) is a neurodegenerative disorder with few biomarkers even though it impacts a relatively large portion of the population and is predicted to affect significantly more individuals in the future. Neuroimaging has been used in concert with genetic information to improve our understanding in relation to how AD arises and how it can be potentially diagnosed. Additionally, evidence suggests synonymous variants can have a functional impact on gene regulatory mechanisms, including those related to AD.

How powerful are summary-based methods for identifying expression-trait associations under different genetic architectures?

Transcriptome-wide association studies (TWAS) have recently been employed as an approach that can draw upon the advantages of genome-wide association studies (GWAS) and gene expression studies to identify genes associated with complex traits. Unlike standard GWAS, summary level data suffices for TWAS and offers improved statistical power. Two popular TWAS methods include either (a) imputing the cis genetic component of gene expression from smaller sized studies (using multi-SNP prediction or MP) into much larger effective sample sizes afforded by GWAS - TWAS-MP or (b) using summary-based Mendelian randomization - TWAS-SMR.

PharmCAT: A Pharmacogenomics Clinical Annotation Tool.

Implementation of genomic medicine into clinical care continues to increase in prevalence in medical centers worldwide. As defined by the National Human Genome Research Institute, "Genomic medicine is an emerging medical discipline that involves using genomic information about an individual as part of their clinical care.…" The genomic information utilized falls broadly into two categories: 1) highly penetrant genetic disorders and 2) pharmacogenomics.

PLATO software provides analytic framework for investigating complexity beyond genome-wide association studies.

Genome-wide, imputed, sequence, and structural data are now available for exceedingly large sample sizes. The needs for data management, handling population structure and related samples, and performing associations have largely been met. However, the infrastructure to support analyses involving complexity beyond genome-wide association studies is not standardized or centralized.

Novel features and enhancements in BioBin, a tool for the biologically inspired binning and association analysis of rare variants.

Motivation: BioBin is an automated bioinformatics tool for the multi-level biological binning of sequence variants. Herein, we present a significant update to BioBin which expands the software to facilitate a comprehensive rare variant analysis and incorporates novel features and analysis enhancements.

Results: In BioBin 2.