The GenoVA study: Equitable implementation of a pragmatic randomized trial of polygenic-risk scoring in primary care.

Polygenic risk scores (PRSs) hold promise for disease risk assessment and prevention. The Genomic Medicine at Veterans Affairs (GenoVA) Study is addressing three main challenges to the clinical implementation of PRSs in preventive care: defining and determining their clinical utility, implementing them in time-constrained primary care settings, and countering their potential to exacerbate healthcare disparities. The study processes used to test patients, report their PRS results to them and their primary care providers (PCPs), and promote the use of those results in clinical decision-making are modeled on common practices in primary care. The following diseases were chosen for their prevalence and familiarity to PCPs: coronary artery disease; type 2 diabetes; atrial fibrillation; and breast, colorectal, and prostate cancers. A randomized clinical trial (RCT) design and primary outcome of time-to-new-diagnosis of a target disease bring methodological rigor to the question of the clinical utility of PRS implementation. The study's pragmatic RCT design enhances its relevance to how PRS might reasonably be implemented in primary care. Steps the study has taken to promote health equity include the thoughtful handling of genetic ancestry in PRS construction and reporting and enhanced recruitment strategies to address underrepresentation in research participation. To date, enhanced recruitment efforts have been both necessary and successful: participants of underrepresented race and ethnicity groups have been less likely to enroll in the study than expected but ultimately achieved proportional representation through targeted efforts. The GenoVA Study experience to date offers insights for evaluating the clinical utility of equitable PRS implementation in adult primary care.

Quantifying the causal impact of biological risk factors on healthcare costs.

Understanding the causal impact that clinical risk factors have on healthcare-related costs is critical to evaluate healthcare interventions. Here, we used a genetically-informed design, Mendelian Randomization (MR), to infer the causal impact of 15 risk factors on annual total healthcare costs. We calculated healthcare costs for 373,160 participants from the FinnGen Study and replicated our results in 323,774 individuals from the United Kingdom and Netherlands. Robust causal effects were observed for waist circumference (WC), adult body mass index, and systolic blood pressure, in which a standard deviation increase corresponded to 22.78% [95% CI: 18.75-26.95], 13.64% [10.26-17.12], and 13.08% [8.84-17.48] increased healthcare costs, respectively. A lack of causal effects was observed for certain clinically relevant biomarkers, such as albumin, C-reactive protein, and vitamin D. Our results indicated that increased WC is a major contributor to annual total healthcare costs and more attention may be given to WC screening, surveillance, and mitigation.

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 (

Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitor Therapy: Payer Approvals and Rejections, and Patient Characteristics for Successful Prescribing.

BACKGROUND: Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) are a novel class of medications for patients with familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease requiring additional lipid lowering beyond dietary measures and statin use. Because of the drugs' high cost, rates of prescription approval by payers may be low. We aimed to identify payer approval and rejection rates for PCSK9i prescriptions and the potential factors influencing these rates. METHODS: This is a retrospective, descriptive cohort study using nationwide pharmacy claims linked to electronic medical records from a nationwide data warehouse. The data set includes >220 million patients from all 50 states and all payer types with 5140 distinct health plans. PCSK9i prescriptions were submitted for 51 466 patients in the pharmacy data set. The main outcome was approval or rejection of PCSK9i prescription claims. Factors associated with approval and rejection of these medications in the United States were assessed. RESULTS: Among patients who were prescribed a PCSK9i, 47.0% were approved for coverage by the payer. Variables that were associated with PCSK9i approval included age >65 years (P<0.01), history of atherosclerotic cardiovascular disease (P<0.01), prescription by a cardiologist or nonprimary care provider (P<0.01), statin intolerance (P=0.03), longer statin duration (P=0.01), and noncommercial payers (P<0.01). Higher low-density lipoprotein cholesterol levels were not associated with higher approval rates. Commercial third-party payers had the lowest approval rates (24.4%) and Medicare had the highest (60.9%). CONCLUSIONS: Rates of approval for PCSK9i therapy are low, even for patients who appear to meet labeled indications. Although a combination of clinical characteristics increases the likelihood of approval, payer type is the most significant factor.

Polygenic Risk Score Identifies Subgroup With Higher Burden of Atherosclerosis and Greater Relative Benefit From Statin Therapy in the Primary Prevention Setting.

BACKGROUND: Relative risk reduction with statin therapy has been consistent across nearly all subgroups studied to date. However, in analyses of 2 randomized controlled primary prevention trials (ASCOT [Anglo-Scandinavian Cardiac Outcomes Trial-Lipid-Lowering Arm] and JUPITER [Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin]), statin therapy led to a greater relative risk reduction among a subgroup at high genetic risk. Here, we aimed to confirm this observation in a third primary prevention randomized controlled trial. In addition, we assessed whether those at high genetic risk had a greater burden of subclinical coronary atherosclerosis. METHODS: We studied participants from a randomized controlled trial of primary prevention with statin therapy (WOSCOPS [West of Scotland Coronary Prevention Study]; n=4910) and 2 observational cohort studies (CARDIA [Coronary Artery Risk Development in Young Adults] and BioImage; n=1154 and 4392, respectively). For each participant, we calculated a polygenic risk score derived from up to 57 common DNA sequence variants previously associated with coronary heart disease. We compared the relative efficacy of statin therapy in those at high genetic risk (top quintile of polygenic risk score) versus all others (WOSCOPS), as well as the association between the polygenic risk score and coronary artery calcification (CARDIA) and carotid artery plaque burden (BioImage). RESULTS: Among WOSCOPS trial participants at high genetic risk, statin therapy was associated with a relative risk reduction of 44% (95% confidence interval [CI], 22-60; P<0.001), whereas in all others, the relative risk reduction was 24% (95% CI, 8-37; P=0.004) despite similar low-density lipoprotein cholesterol lowering. In a study-level meta-analysis across the WOSCOPS, ASCOT, and JUPITER primary prevention, relative risk reduction in those at high genetic risk was 46% versus 26% in all others (P for heterogeneity=0.05). Across all 3 studies, the absolute risk reduction with statin therapy was 3.6% (95% CI, 2.0-5.1) among those in the high genetic risk group and 1.3% (95% CI, 0.6-1.9) in all others. Each 1-SD increase in the polygenic risk score was associated with 1.32-fold (95% CI, 1.04-1.68) greater likelihood of having coronary artery calcification and 9.7% higher (95% CI, 2.2-17.8) burden of carotid plaque. CONCLUSIONS: Those at high genetic risk have a greater burden of subclinical atherosclerosis and derive greater relative and absolute benefit from statin therapy to prevent a first coronary heart disease event. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00738725 (BioImage) and NCT00005130 (CARDIA). WOSCOPS was carried out and completed before the requirement for clinical trial registration.

Effect of hospitalist attending physicians on trainee educational experiences: a systematic review.

BACKGROUND: Trainees receive much of their inpatient education from hospitalists. PURPOSE: To characterize the effects of hospitalists on trainee education. DATA SOURCES: MEDLINE, Database of Reviews of Effectiveness (DARE), National Health Service (NHS) Economic Evaluation Database (EED), Health Technology Assessment (HTA), and the Cochrane Collaboration Database (last searched October 2008) databases using the term "hospitalist", and meeting abstracts from the Society of Hospital Medicine (SHM) (2002-2007), Society of General Internal Medicine (SGIM) (2001-2007), and Pediatric Academic Societies (PAS) (2000-2007). STUDY SELECTION: Original English language research studies meeting all of the following: involvement of hospitalists; comparison to nonhospitalist attendings; evaluation of trainee knowledge, skills, or attitudes. 711 articles were reviewed, 32 retrieved, and 6 included; 7,062 meeting abstracts were reviewed, 9 retrieved, and 2 included. DATA EXTRACTION: Two authors reviewed articles to determine study eligibility. Three authors independently reviewed included articles to abstract data elements and classify study quality. DATA SYNTHESIS: Seven studies were quasirandomized one was a noncontemporaneous comparison. All citations only measured trainee attitudes. In all studies comparing hospitalists to nonhospitalists, trainees were more satisfied with hospitalists overall, and with other aspects of their teaching, but ratings were high for both groups. One of 2 studies that distinguished nonhospitalist general internists from specialists showed that trainees preferred hospitalists, but the other did not demonstrate a hospitalist advantage over general internists. CONCLUSIONS: Trainees are more satisfied with inpatient education from hospitalists. Whether the increased satisfaction translates to improved learning is unclear.