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 1.20-fold (95% confidence interval [CI], [1.10; 1.3]; p = 9.17 × 10-5) and 1.19-fold (95% CI, [1.11; 1.27]; p = 1.92 × 10-6), and PRSmix+ improved the prediction accuracy by 1.72-fold (95% CI, [1.40; 2.04]; p = 7.58 × 10-6) and 1.42-fold (95% CI, [1.25; 1.59]; p = 8.01 × 10-7) in European and South Asian ancestries, respectively. Compared to the previously cross-trait-combination methods with scores from pre-defined correlated traits, we demonstrated that our method improved prediction accuracy for coronary artery disease up to 3.27-fold (95% CI, [2.1; 4.44]; p value after false discovery rate (FDR) correction = 2.6 × 10-4). Our method provides a comprehensive framework to benchmark and leverage the combined power of PRS for maximal performance in a desired target population.

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. We limited our scope to tests available between October 1, 2019, and September 30, 2021. We characterized variability in the content and processes used by 21 companies offering 74 distinct test products that met our inclusion and exclusion criteria. A minority (8 of 21 companies) offered tests that assessed the presence of at least 1 US Centers for Disease Control and Prevention Tier 1 condition for which detection can impact an individual's clinical care and for which evidence-based guidelines for detection and management exist.

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. Data collection and qualitative analyses were guided by the Consolidated Framework for Implementation Research and socioecological model. Analysis focused on identifying barriers to delivering preconception RGCS at and across different levels of health care and exploring potential facilitators of preconception RGCS delivery. RESULTS: Barriers to preconception RGCS were identified at the levels of test characteristics, patients and couples, clinicians and care teams, and the external health care and policy environments. Across the different levels of care delivery, 3 themes of barriers emerged: (1) fragmentation and inconsistencies hinder care delivery, (2) gaps in knowledge, misconceptions, and uncertainties about RGCS are pervasive, and (3) expanding preconception RGCS in the diverse US population presents unique implementation challenges. Potential solutions were detailed by informants. CONCLUSION: Identifying individual and thematic barriers to preconception RGCS delivery may help to define strategies to alleviate obstacles.

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. We applied PRSmix to 47 and 32 diseases/traits in European and South Asian ancestries, respectively. PRSmix demonstrated a mean prediction accuracy improvement of 1.20-fold (95% CI: [1.10; 1.3]; P-value = 9.17 × 10-5) and 1.19-fold (95% CI: [1.11; 1.27]; P-value = 1.92 × 10-6), and PRSmix+ improved the prediction accuracy by 1.72-fold (95% CI: [1.40; 2.04]; P-value = 7.58 × 10-6) and 1.42-fold (95% CI: [1.25; 1.59]; P-value = 8.01 × 10-7) in European and South Asian ancestries, respectively. Compared to the previously established cross-trait-combination method with scores from pre-defined correlated traits, we demonstrated that our method can improve prediction accuracy for coronary artery disease up to 3.27-fold (95% CI: [2.1; 4.44]; P-value after FDR correction = 2.6 × 10-4). Our method provides a comprehensive framework to benchmark and leverage the combined power of PRS for maximal performance in a desired target population.

A Pooled Electronic Consultation Program to Improve Access to Genetics Specialists.

Innovative service delivery models are needed to increase access to genetics specialists. Electronic consultation (e-Consult) programs can connect clinicians with specialists. At Massachusetts General Hospital, an e-Consult service was created to address genomics-related questions. In its first year, the e-Consult service triaged 153 requests and completed 122 in an average of 3.2 days. Of the 95 e-Consults with actionable recommendations, there was documentation that most ordering clinicians followed through (82%). A variety of providers used the service, although the majority (77%) were generalists. E-Consult models should be considered as one way to increase access to genetics care.

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. Design, Setting, and Participants: This cross-sectional study used a mixed-methods approach including (1) quantitative analysis of multilevel factors associated with the timing of reproductive carrier screening and (2) qualitative analyses of data from interviews conducted with clinicians ordering carrier screenings. The setting was the Mass General Brigham, a large integrated health care system in the greater Boston, Massachusetts area. Participants included adult female patients who completed reproductive carrier screening performed by Myriad Women's Health between October 1, 2018, to September 30, 2019. Exposures: Site of care (ordering clinical location and hospital affiliate), ordering clinician specialty, and patient characteristics, including age at date of test collection, self-reported race and ethnicity, primary insurance payor, and number of comorbidities. Main Outcomes and Measures: The primary outcome was the timing of carrier screening (preconception vs prenatal). A series of 4 multilevel logistic regression models were fitted to measure the relative contribution of site, clinician, and patient-level factors on the timing of screening. Interviews with ordering clinicians (N = 9) were analyzed using a framework approach to explore barriers to preconception screening. Results: Among 6509 adult female patients who completed carrier screenings, 770 (12%) were Asian, 352 (5%) were Hispanic, 640 (10%) were non-Hispanic Black, 3844 (59%) were non-Hispanic White, 858 (13%) were other or multiple races and ethnicities, and 2611 (40%) were aged 31 to 35 years; 4701 (63%) had prenatal screening and 2438 (37%) had preconception screening; screenings were ordered by 161 distinct clinicians across 32 clinical locations affiliated with 4 hospitals. In model 1, adjusted for hospital (fixed effect), clinic and clinician (random effects), 49% of the variability in timing was associated with clinician-level effects (intraclass correlation coefficient [ICC], 0.49) and 28% was associated with clinic-level effects (ICC, 0.28). Clinician specialty explained the greatest amount of variation in screening timing. Interviewed clinicians (N = 9) supported preconception screening but cited several barriers to offering population-based preconception screening. Conclusions and Relevance: In this cross-sectional study, multilevel factors were associated with carrier screening timing. These findings suggest that increasing access to preconception screening may involve engaging specific medical specialties.

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. Digital postdisclosure surveys and chart review evaluated the impact of disclosure. RESULTS: There were 60 participants (mean age 51 years, 37% women, 72% with no known CAD), including 30 (50%) referred by their cardiologists and 30 (50%) self-referred. Two (3%) participants had a monogenic variant pathogenic for familial hypercholesterolemia, and 19 (32%) had a high polygenic score in the top quintile of the population distribution. In a postdisclosure survey, both the genetic test report (in 80% of participants) and the discussion with the clinician (in 89% of participants) were ranked as very or extremely helpful in understanding the result. Of the 42 participants without CAD, 17 or 40% had a change in management, including statin initiation, statin intensification, or coronary imaging. CONCLUSIONS: Combined monogenic and polygenic assessments for CAD risk provided by preventive genomics clinics are beneficial for patients and result in changes in management in a significant portion of patients.

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

ABSTRACT: 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). A retrospective analysis was performed within the Veterans Health Administration evaluating prescription records for pain medications metabolized by CYP2D6 and interacting drugs from 2012 to 2017. Among 2,436,654 Veterans Health Administration pharmacy users with at least 1 opioid prescription, 34% met the definition of chronic use (longer than 90 days with more than 10 prescriptions or 120 days-supply). Opioids were commonly coprescribed with antidepressants interacting with CYP2D6 (28%). An estimated 21.6% (n = 526,905) of these patients are at an elevated risk of an undesirable response to their opioid medication based on predicted phenotypes and drug-drug interactions: 3.5% are predicted CYP2D6 ultrarapid metabolizers and at increased risk for toxicity, 5.4% are poor metabolizers at higher risk for nonresponse, and 12.8% are normal or intermediate metabolizers coprescribed a CYP2D6 inhibitor leading to phenoconversion into poor metabolizer. Despite the high rate of coprescription of opioids and interacting drugs, CYP2D6 testing was infrequent in the sample (0.02%), and chart review suggests that test results were used to optimize antidepressant treatments rather than pain medications. Using PGx testing combined with consideration of phenoconversion may allow for an enhanced precision medicine approach to pain management in Veterans.

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. METHODS: We performed a cross-sectional analysis of survey data from the All of Us Research Program. We compared the characteristics of participants who reported "None," "Some", and "A lot" of family health history knowledge using multinomial logistic regression. RESULTS: Self-rated family health history data were available for 116,799 participants. A minority of survey participants (37%) endorsed "A lot" of knowledge about their family health history (n = 43,661). Most participants (60%) endorsed "Some" family health history knowledge (n = 69,914) and 3% (n = 3224) endorsed "None." In adjusted analyses, those who indicated "Some" family health history knowledge or "None" were more likely to be assigned male sex at birth, identify as possible gender and sexual minorities, have a self-reported race other than White, have a lower household annual income (<$25,000), or report lower educational attainment (

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). Significant associations were tested for replication in the Penn Medicine Biobank (n = 5737) and the Million Veteran Program (n = 82,382). V122I was significantly associated with polyneuropathy in the UK Biobank (odds ratio [OR] = 6.4, 95% confidence interval [CI] 2.6-15.6, p = 4.2 × 10-5), which was replicated in the Penn Medicine Biobank (OR = 1.6, 95% CI 1.2-2.4, p = 6.0 × 10-3) and Million Veteran Program (OR = 1.5, 95% CI 1.2-1.8, p = 1.8 × 10-4). Polyneuropathy prevalence among V122I carriers was 2.1%, 9.0%, and 4.8% in the UK Biobank, Penn Medicine Biobank, and Million Veteran Program, respectively. The cumulative incidence of common hATTR amyloidosis manifestations (carpal tunnel syndrome, polyneuropathy, cardiomyopathy, heart failure) was significantly enriched in V122I carriers compared with non-carriers (HR = 2.8, 95% CI 1.7-4.5, p = 2.6 × 10-5) in the UK Biobank, with 37.4% of V122I carriers having at least one of these manifestations by age 75. Our findings show that V122I carriers are at increased risk of polyneuropathy. These results also emphasize the underdiagnosis of disease in V122I carriers with a significant proportion of subjects showing phenotypic changes consistent with hATTR amyloidosis. Greater understanding of the manifestations associated with V122I is critical for earlier diagnosis and treatment.