Integrative polygenic risk score improves the prediction accuracy of complex traits and diseases.

Polygenic risk scores (PRSs) are an emerging tool to predict the clinical phenotypes and outcomes of individuals. We propose PRSmix, a framework that leverages the PRS corpus of a target trait to improve prediction accuracy, and PRSmix+, which incorporates genetically correlated traits to better capture the human genetic architecture for 47 and 32 diseases/traits in European and South Asian ancestries, respectively. PRSmix demonstrated a mean prediction accuracy improvement of 1.

Association Between a First-Degree Family History and Self-Reported Personal History of Obesity, Diabetes, and Heart and Blood Conditions: Results From the All of Us Research Program.

Background: Family history reflects the complex interplay of genetic susceptibility and shared environmental exposures and is an important risk factor for obesity, diabetes, and heart and blood conditions (ODHB). However, the overlap in family history associations between various ODHBs has not been quantified.

Methods And Results: We assessed the association between a self-reported family history of ODHBs and their risk in the adult population (age ≥20 years) of the AoU (All of Us) Research Program, a longitudinal cohort study of diverse participants across the United States.

An Environmental Scan of Consumer-Initiated Germline Genetic Testing for Health Risks.

As patient access to laboratory testing outside the clinic grows, health care providers can expect to confront increasing questions about the utility and interpretation of consumer-initiated genetic testing for health risks. We sought to characterize the marketplace diversity of consumer-initiated germline genetic testing options. An environmental scan was conducted to identify germline genetic testing companies that offer testing for at least one diagnosable health condition and are available for purchase by consumers in the US market without a visit to one's health care provider.

Multilevel barriers and facilitators to widespread use of preconception carrier screening in the United States.

Purpose: Although preconception reproductive genetic carrier screening (RGCS) is preferred to screening during pregnancy, population-wide preconception screening is not routinely performed in the United States. We explored the multilevel barriers to the widespread adoption of preconception RGCS in the United States via key informant interviews.

Methods: Semi-structured virtual video interviews were conducted with 29 informants with a breadth of professional expertise between May and October 2022.

Effectiveness of Medical Student Counseling for Hospitalized Patients Addicted to Tobacco (MS-CHAT): a Randomized Controlled Trial.

Background: Low-middle-income countries face an enormous burden of tobacco-related illnesses. Counseling for tobacco cessation increases the chance of achieving quit outcomes, yet it remains underutilized in healthcare settings.

Objective: We tested the hypothesis that utilizing trained medical students to counsel hospitalized patients who use tobacco will lead to an increase in patient quit rates, while also improving medical student knowledge regarding smoking cessation counseling.

A pooled electronic consultation program to improve access to genetics specialists.

Purpose: Given limited ambulatory access to genetics specialists, innovative service delivery solutions are needed. Electronic consultation (e-consult) programs are growing to connect clinicians to specialists. We explored the utilization and outcomes of a genetics and genomics e-consult program at Massachusetts General Hospital system in its first year.

Integrative polygenic risk score improves the prediction accuracy of complex traits and diseases.

Polygenic risk scores (PRS) are an emerging tool to predict the clinical phenotypes and outcomes of individuals. Validation and transferability of existing PRS across independent datasets and diverse ancestries are limited, which hinders the practical utility and exacerbates health disparities. We propose PRSmix, a framework that evaluates and leverages the PRS corpus of a target trait to improve prediction accuracy, and PRSmix+, which incorporates genetically correlated traits to better capture the human genetic architecture.

Association of Patient and Site-of-Care Characteristics With Reproductive Carrier Screening Timing in a Large Integrated Health System.

Importance: Reproductive genetic carrier screening can be performed prior to or during pregnancy to assess a reproductive couple's risk of having a child with a recessively inherited disorder. Although professional societies endorse preconception screening as preferable to prenatal screening to allow for greater reproductive choice, implementation of preconception screening is challenging.

Objective: To determine how carrier screening timing varies by multilevel factors associated with health care delivery including patient, clinician, and location across a large integrated health care system.

Clinical Implementation of Combined Monogenic and Polygenic Risk Disclosure for Coronary Artery Disease.

Background: State-of-the-art genetic risk interpretation for a common complex disease such as coronary artery disease (CAD) requires assessment for both monogenic variants-such as those related to familial hypercholesterolemia-as well as the cumulative impact of many common variants, as quantified by a polygenic score.

Objectives: The objective of the study was to describe a combined monogenic and polygenic CAD risk assessment program and examine its impact on patient understanding and changes to clinical management.

Methods: Study participants attended an initial visit in a preventive genomics clinic and a disclosure visit to discuss results and recommendations, primarily via telemedicine.

Drug-drug-gene interaction risk among opioid users in the U.S. Department of Veterans Affairs.

Response to analgesic therapy is influenced by several factors including genetics and drug-drug interactions. Pharmacogenetic (PGx) variants in the CYP2D6 gene modify response to opioids by altering drug metabolism. We sought to determine the potential impact of PGx testing on the care of Veterans with noncancer pain prescribed opioids metabolized by CYP2D6 (codeine, hydrocodone, or tramadol).

Self-rated family health history knowledge among All of Us program participants.

Purpose: Disparities in access to genetics services are well-documented. Family health history is routinely used to determine whether patients should be screened for heritable conditions. We sought to explore variation in levels of self-rated family health history knowledge as a possible contributer to this disparity.

Rationale and Design of a Randomized Controlled Trial to Evaluate the Effectiveness of Medical Student Counseling for Hospitalized Patients Addicted to Tobacco (the MS-CHAT Trial).

Globally, India is the second largest consumer of tobacco. However, Indian medical students do not receive adequate training in smoking cessation counseling. Each patient hospitalization is an opportunity to counsel smokers.

Association of the transthyretin variant V122I with polyneuropathy among individuals of African ancestry.

Hereditary transthyretin-mediated (hATTR) amyloidosis is an underdiagnosed, progressively debilitating disease caused by mutations in the transthyretin (TTR) gene. V122I, a common pathogenic TTR mutation, is found in 3-4% of individuals of African ancestry in the United States and has been associated with cardiomyopathy and heart failure. To better understand the phenotypic consequences of carrying V122I, we conducted a phenome-wide association study scanning 427 ICD diagnosis codes in UK Biobank participants of African ancestry (n = 6062).

Identifying End Users' Preferences about Structuring Pharmacogenetic Test Orders in an Electronic Health Record System.

Pharmacogenetics (PGx) testing can be used for detecting genetic variations that may affect an individual's anticipated metabolism of, or response to, medications. Although several studies have focused on developing tools for delivering results from PGx testing, there is a relative dearth of information about how to design provider-friendly electronic order-entry systems for PGx. The U.

Early adoption of pharmacogenetic testing for veterans prescribed psychotropic medications.

Describe the characteristics of providers ordering, patients receiving, and clinical impact of a psychotropic pharmacogenetic test on veteran care. Observational cohort study linking veterans' laboratory results to electronic health record data. Changes in psychotropic medication prescribing were measured as a function of test results.

Association of Risk Alleles With Cardiovascular Disease in Blacks in the Million Veteran Program.

Background: Approximately 13% of black individuals carry 2 copies of the apolipoprotein L1 () risk alleles G1 or G2, which are associated with 1.5- to 2.5-fold increased risk of chronic kidney disease.

Projected Prevalence of Actionable Pharmacogenetic Variants and Level A Drugs Prescribed Among US Veterans Health Administration Pharmacy Users.

Importance: Implementation of pharmacogenetic testing to guide drug prescribing has potential to improve drug response and prevent adverse events. Robust data exist for more than 30 gene-drug pairs linking genotype to drug response phenotypes; however, it is unclear which pharmacogenetic tests, if implemented, would provide the greatest utility for a given patient population.

Objectives: To project the proportion of veterans in the US Veterans Health Administration (VHA) with actionable pharmacogenetic variants and evaluate how testing might be associated with prescribing decisions.

Toward greater understanding of patient decision-making around genome sequencing.

In the era of next-generation sequencing, it is essential to collect and understand the patient outcomes that result from this new technology. One critical determinant of these is the process by which individuals first decide whether and how to pursue genome sequencing. In this perspective article, we examine the literature on adult patient decision-making in genome sequencing and identify current research gaps to address.

Clinical Impact of 21-Gene Recurrence Score Test Within the Veterans Health Administration: Utilization and Receipt of Guideline-Concordant Care.

Introduction: Ensuring guideline-concordant cancer care is a Department of Veterans Affairs (VA) priority, especially as the number of breast cancer patients at VA medical centers (VAMCs) grows. We assessed the utilization and clinical impact of the 21-gene Recurrence Score test, which predicts 10-year risk of breast cancer recurrence and the likelihood of chemotherapy benefit, on veterans newly diagnosed with breast cancer.

Patients And Methods: We conducted a retrospective cohort study using 2011-2012 VA Central Cancer Registry, chart review, and laboratory test data.