Assessment of genes involved in lysosomal diseases using the ClinGen clinical validity framework.

Lysosomal diseases (LDs) are a heterogeneous group of rare genetic disorders that result in impaired lysosomal function, leading to progressive multiorgan system dysfunction. Accurate diagnosis is paramount to initiating targeted therapies early in the disease process in addition to providing prognostic information and appropriate support for families. In recent years, genomic sequencing technologies have become the first-line approach in the diagnosis of LDs.

Developing a scoring system for gene curation prioritization in lysosomal diseases.

Introduction: Diseases caused by lysosomal dysfunction often exhibit multisystemic involvement, resulting in substantial morbidity and mortality. Ensuring accurate diagnoses for individuals with lysosomal diseases (LD) is of great importance, especially with the increasing prominence of genetic testing as a primary diagnostic method. As the list of genes associated with LD continues to expand due to the use of more comprehensive tests such as exome and genome sequencing, it is imperative to understand the clinical validity of the genes, as well as identify appropriate genes for inclusion in multi-gene testing and sequencing panels.

Assessment of genes involved in lysosomal diseases using the ClinGen Clinical Validity framework.

Lysosomal diseases (LDs) are a heterogeneous group of rare genetic disorders that result in impaired lysosomal function, leading to progressive multiorgan system dysfunction. Accurate diagnosis is paramount to initiating targeted therapies early in the disease process in addition to providing prognostic information and appropriate support for families. In recent years, genomic sequencing technologies have become the first-line approach in the diagnosis of LDs.

ACR Appropriateness Criteria® Preprocedural Planning for Left Atrial Procedures in Atrial Fibrillation.

This document summarizes the relevant literature for the selection of preprocedural imaging in three clinical scenarios in patients needing endovascular treatment or cardioversion of atrial fibrillation. These clinical scenarios include preprocedural imaging prior to radiofrequency ablation; prior to left atrial appendage occlusion; and prior to cardioversion. The appropriateness of imaging modalities as they apply to each clinical scenario is rated as usually appropriate, may be appropriate, and usually not appropriate to assist the selection of the most appropriate imaging modality in the corresponding clinical scenarios.

Evaluation of enzyme activity predictions for variants of unknown significance in Arylsulfatase A.

Continued advances in variant effect prediction are necessary to demonstrate the ability of machine learning methods to accurately determine the clinical impact of variants of unknown significance (VUS). Towards this goal, the ARSA Critical Assessment of Genome Interpretation (CAGI) challenge was designed to characterize progress by utilizing 219 experimentally assayed missense VUS in the () gene to assess the performance of community-submitted predictions of variant functional effects. The challenge involved 15 teams, and evaluated additional predictions from established and recently released models.

Generating Clinical-Grade Gene-Disease Validity Classifications Through the ClinGen Data Platforms.

Clinical genetic laboratories must have access to clinically validated biomedical data for precision medicine. A lack of accessibility, normalized structure, and consistency in evaluation complicates interpretation of disease causality, resulting in confusion in assessing the clinical validity of genes and genetic variants for diagnosis. A key goal of the Clinical Genome Resource (ClinGen) is to fill the knowledge gap concerning the strength of evidence supporting the role of a gene in a monogenic disease, which is achieved through a process known as Gene-Disease Validity curation.

ClinGen variant curation expert panel recommendations for classification of variants in GAMT, GATM and SLC6A8 for cerebral creatine deficiency syndromes.

Cerebral creatine deficiency syndromes (CCDS) are inherited metabolic phenotypes of creatine synthesis and transport. There are two enzyme deficiencies, guanidinoacetate methyltransferase (GAMT), encoded by GAMT and arginine-glycine amidinotransferase (AGAT), encoded by GATM, which are involved in the synthesis of creatine. After synthesis, creatine is taken up by a sodium-dependent membrane bound creatine transporter (CRTR), encoded by SLC6A8, into all organs.

Variant Classification for Pompe disease; ACMG/AMP specifications from the ClinGen Lysosomal Diseases Variant Curation Expert Panel.

Accurate determination of the clinical significance of genetic variants is critical to the integration of genomics in medicine. To facilitate this process, the NIH-funded Clinical Genome Resource (ClinGen) has assembled Variant Curation Expert Panels (VCEPs), groups of experts and biocurators which provide gene- and disease- specifications to the American College of Medical Genetics & Genomics and Association for Molecular Pathology's (ACMG/AMP) variation classification guidelines. With the goal of classifying the clinical significance of GAA variants in Pompe disease (Glycogen storage disease, type II), the ClinGen Lysosomal Diseases (LD) VCEP has specified the ACMG/AMP criteria for GAA.

Evaluating the strength of evidence for genes implicated in peroxisomal disorders using the ClinGen clinical validity framework and providing updates to the peroxisomal disease nomenclature.

Peroxisomal disorders are heterogeneous in nature, with phenotypic overlap that is indistinguishable without molecular testing. Newborn screening and gene sequencing for a panel of genes implicated in peroxisomal diseases are critical tools for the early and accurate detection of these disorders. It is therefore essential to evaluate the clinical validity of the genes included in sequencing panels for peroxisomal disorders.

Lumping versus splitting: How to approach defining a disease to enable accurate genomic curation.

The dilemma of how to categorize and classify diseases has been debated for centuries. The field of medical genetics has historically approached nosology based on clinical phenotypes observed in patients and families. Advances in genomic sequencing and understanding of genetic contributions to disease often provoke a need to reassess these classifications.

The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources.

Purpose: Several groups and resources provide information that pertains to the validity of gene-disease relationships used in genomic medicine and research; however, universal standards and terminologies to define the evidence base for the role of a gene in disease and a single harmonized resource were lacking. To tackle this issue, the Gene Curation Coalition (GenCC) was formed.

Methods: The GenCC drafted harmonized definitions for differing levels of gene-disease validity on the basis of existing resources, and performed a modified Delphi survey with 3 rounds to narrow the list of terms.

ClinGen Variant Curation Interface: a variant classification platform for the application of evidence criteria from ACMG/AMP guidelines.

Background: Identification of clinically significant genetic alterations involved in human disease has been dramatically accelerated by developments in next-generation sequencing technologies. However, the infrastructure and accessible comprehensive curation tools necessary for analyzing an individual patient genome and interpreting genetic variants to inform healthcare management have been lacking.

Results: Here we present the ClinGen Variant Curation Interface (VCI), a global open-source variant classification platform for supporting the application of evidence criteria and classification of variants based on the ACMG/AMP variant classification guidelines.

Low-cost insulin for socially at-risk patients: evidence for effectiveness.

Objectives: The price of analogue insulin has increased dramatically, making it unaffordable for many patients and insurance carriers. By contrast, human synthetic insulins are available at a fraction of the cost. The objective of this study was to examine whether patients with financial constraints were more likely to use low-cost human insulins compared with higher-cost analogue insulins and to determine whether outcomes differ between users of each type of insulin.

Lack of recognition and documentation of stress hyperglycemia is a disruptor of optimal continuity of care.

Stress hyperglycemia (SH) is a manifestation of altered glucose metabolism in acutely ill patients which worsens outcomes and may represent a risk factor for diabetes. Continuity of care can assess this risk, which depends on quality of hospital clinical documentation. We aimed to determine the incidence of SH and documentation tendencies in hospital discharge summaries and continuity notes.

Discharge Practices for COVID-19 Patients: Rapid Review of Published Guidance and Synthesis of Documents and Practices at 22 US Academic Medical Centers.

Background: There are currently no evidence-based guidelines that provide standardized criteria for the discharge of COVID-19 patients from the hospital.

Objective: To address this gap in practice guidance, we reviewed published guidance and collected discharge protocols and procedures to identify and synthesize common practices.

Design: Rapid review of existing guidance from US and non-US public health organizations and professional societies and qualitative review using content analysis of discharge documents collected from a national sample of US academic medical centers with follow-up survey of hospital leaders SETTING AND PARTICIPANTS: We reviewed 65 websites for major professional societies and public health organizations and collected documents from 22 Academic Medical Centers (AMCs) in the US participating in the HOspital MEdicine Reengineering Network (HOMERuN).

Validation of a 2-Item Food Insecurity Screen Among Adult General Medicine Outpatients.

Food insecurity is defined as limited access to food and is associated with adverse physical, social, and emotional health outcomes. As social needs are addressed in heath care, efficient methods to identify patients living in food insecure households are necessary. A 2-item screen (HFSS-2) derived from the US Department of Agriculture Household Food Security Scale (HFSS-18) has been validated among parents of pediatric patients with a sensitivity of 97% and specificity of 83%.

Social Determinants of Health, From Assessment to Action:: A Review of 3 Studies from the Value Institute at ChristianaCare.

Introduction: The COVID-19 crisis highlights the importance of screening for and managing adverse social determinants of health (SDoH). Many of the same SDoH items that put individuals at increased risk of COVID-19 infection have increased dramatically due to the economic repercussions of slowing the viral spread.

Methods: This is a review of 3 studies conducted by the Health Services Research Core in the Value Institute at ChristianaCare.

Extended Venous Thromboembolism Prophylaxis in Medically Ill Patients: An NATF Anticoagulation Action Initiative.

Hospitalized patients with acute medical illnesses are at risk for venous thromboembolism (VTE) during and after a hospital stay. Risk factors include physical immobilization and underlying pathophysiologic processes that activate the coagulation pathway and are still present after discharge. Strategies for optimal pharmacologic VTE thromboprophylaxis are evolving, and recommendations for VTE prophylaxis can be further refined to protect high-risk patients after hospital discharge.

Preoperative evaluation of microvascular invasion with circulating tumour DNA in operable hepatocellular carcinoma.

Background & Aims: Microvascular invasion (MVI) is a critical prognostic factor for operable hepatocellular carcinoma (HCC). This study aimed to explore the performance of circulating tumour DNA (ctDNA) in evaluating MVI status preoperatively.

Methods: Seventy-three HCC patients were enrolled and randomly divided into a training cohort and a validation cohort in a 2:1 ratio, and preoperative blood and surgical tissue samples were obtained.

Analysis of Unregulated Sale of Lifesaving Prescription Drugs Online in the United States.

This cross-sectional analysis examines the prevalence of unregulated resale of insulin, albuterol, and epipenephrin online in the United States.

Germline DNA Sequencing Reveals Novel Mutations Predictive of Overall Survival in a Cohort of Patients with Pancreatic Cancer.

Purpose: Family history of -related tumors may correlate with response to chemotherapy and overall survival (OS) in pancreatic cancer. The frequency of germline mutations has been reported in patients predominantly under the age of 60 or with strong family history. We examine the incidence of deleterious germline mutations and compare the chemotherapy responses and OS in an unselected group of patients with metastatic pancreatic cancer.

The Unintended Consequences of Medicare Observation Status.

Background: Observation status is a classification for Medicare beneficiaries that are billed as outpatients for a hospitalization. This has implications for out-of-pocket expenses for patients as well as their access to post-acute care.

Methods: This is a review of 3 published studies performed by our research team to examine the potential unintended consequences of the current Medicare policies related to cost-sharing and post-acute care coverage for patients hospitalized under observation status.