Eric A. Wright

Genetic identification of familial hypercholesterolemia within a single U.S. health care system

Unleashing the power of precision medicine Precision medicine promises the ability to identify risks and treat patients on the basis of pathogenic genetic variation. Two studies combined exome sequencing results for over 50,000 people with their electronic health records. Dewey et al. found that ∼3.5% of individuals in their cohort had clinically actionable genetic variants. Many of these variants affected blood lipid levels that could influence cardiovascular health. Abul-Husn et al. extended these findings to investigate the genetics and treatment of familial hypercholesterolemia, a risk factor for cardiovascular disease, within their patient pool. Genetic screening helped identify at-risk patients who could benefit from increased treatment. Science, this issue p. 10.1126/science.aaf6814, p. 10.1126/science.aaf7000 Genomic screening can prompt the diagnosis of familial hypercholesterolemia patients, the majority of whom are receiving inadequate lipid-lowering therapy. INTRODUCTION Familial hypercholesterolemia (FH) is a public health genomics priority but remains underdiagnosed and undertreated despite widespread cholesterol screening. This represents a missed opportunity to prevent FH-associated cardiovascular morbidity and mortality. Pathogenic variants in three genes (LDLR, APOB, and PCSK9) account for the majority of FH cases. We assessed the prevalence and clinical impact of FH-associated genomic variants in 50,726 individuals from the MyCode Community Health Initiative at Geisinger Health System who underwent exome sequencing as part of the DiscovEHR human genetics collaboration with the Regeneron Genetics Center. RATIONALE Genetic testing for FH is uncommon in clinical practice in the United States, and the prevalence of FH variants in U.S. populations has not been well established. We sought to evaluate FH prevalence in a large integrated U.S. health care system using genomic sequencing and electronic health record (EHR) data. We determined the impact of FH variants on low-density lipoprotein cholesterol (LDL-C) levels and coronary artery disease (CAD) risk. We assessed the likelihood of FH variant carriers achieving a presequencing EHR-based FH diagnosis according to established clinical diagnostic criteria. Finally, we examined the rates of statin medication use and outcomes in FH variant carriers. RESULTS Thirty-five known and predicted pathogenic variants in LDLR, APOB, and PCSK9 were identified in 229 individuals. The estimated FH prevalence was 1:256 in unselected participants and 1:118 in participants ascertained via the cardiac catheterization laboratory. FH variants were found in only 2.5% of individuals with severe hypercholesterolemia (maximum EHR-documented LDL-C ≥ 190 mg/dl) in the cohort, and a maximum LDL-C of ≥190 mg/dl was absent in 45% of FH variant carriers. Overall, FH variant carriers had 69 ± 3 mg/dl greater maximum LDL-C than sequenced noncarriers (P = 1.8 × 10−20) and had significantly increased odds of general and premature CAD [odds ratio (OR), 2.6 (P = 4.3 × 10−11) and 3.7 (P = 5.5 × 10−14), respectively]. The increased odds of general and premature CAD were most pronounced in carriers of LDLR predicted loss-of-function variants [OR, 5.5 (P = 7.7 × 10−13) and 10.3 (P = 9.8 × 10−19), respectively]. Fourteen FH variant carriers were deceased; chart review revealed that none of these individuals had a clinical diagnosis of FH. Before genetic testing, only 15% of FH variant carriers had an ICD-10 (International Classification of Diseases, 10th revision) diagnosis code for pure hypercholesterolemia or had been seen in a lipid clinic, suggesting that few had been previously diagnosed with FH. Retrospectively applying Dutch Lipid Clinic Network diagnostic criteria to EHR data, we found presequencing criteria supporting a probable or definite clinical diagnosis of FH in 24% of FH variant carriers, highlighting the limitations of using existing clinical criteria for EHR-based screening in the absence of genetic testing. Active statin use was identified in 58% and high-intensity statin use in 37% of FH variant carriers. Only 46% of carriers currently on statin therapy had a most recent LDL-C level below 100 mg/dl compared to 77% of noncarriers. CONCLUSION In summary, we show that large-scale genomic screening in patients with longitudinal EHR data has the ability to detect FH, uncover and characterize novel pathogenic variants, determine disease prevalence, and enhance overall knowledge of clinical impact and outcomes. The 1:256 prevalence of FH variants in this predominantly European-American cohort is in line with prevalence estimates from recent work in European cohorts. Our findings highlight the undertreatment of FH variant carriers and demonstrate a potential clinical benefit for large-scale sequencing initiatives in service of precision medicine. Prevalence and clinical impact of FH variants in a large U.S. clinical care cohort. (A) Distribution of 229 heterozygous carriers of an FH variant in the DiscovEHR cohort by FH gene. (B) Prevalence of an FH variant in the DiscovEHR cohort and according to recruitment site

Developing Pharmacogenomic Reports: Insights from Patients and Clinicians

Increasingly, for a variety of indications, patients have their genomes sequenced and actionable results returned. A subset of returned results is pharmacogenomic (PGx) variants involved in the metabolism or action of medications. Although the impact of these variants on health is well‐documented, little research exists on how to communicate these findings to patients and clinicians. We conducted semistructured interviews with end users to understand how best to communicate PGx results. Overall, patients and clinicians had similar opinions regarding report content, delivery, and application. Unique concerns specific to each stakeholder group were also expressed. Patients wanted an easy‐to‐understand individualized report that clinicians utilized to guide their care. Clinicians wanted reports that were easy‐to‐use, actionable, and integrated into their workflow. Implementation of these reports in a clinical setting will allow for broader user feedback and iterative improvement.

Identifying and Reducing Barriers to Improve Lipid Screening in Youth

Despite numerous published pediatric guidelines over the past two decades, little has changed in the way providers screen children for dyslipidemia. The acuity of this problem is most notable in youth likely to have heterozygous familial hypercholesterolemia (FH), one of the most common inherited diseases with a prevalence greater than all congenital defects that newborns are routinely screened for in the US. Because heterozygous FH is underdiagnosed in most countries there is a need to identify barriers and solutions to improve lipid screening in youth. This review summarizes different approaches to lipid screening and how point-of-care lipid testing may be used to improve screening.

Inability of Primary Care Providers to Predict Medication Fulfillment of New Prescriptions

Methods: We conducted a prospective cohort study as part of a randomized clinical trial (RCT). Providers at 24 primary care and family medicine Geisinger clinics were asked to complete a “best practice alert” (BPA) within the electronic health record (EHR) when placing an order for a new anti-hypertensive, antidiabetic, anti-hyperlipidemic or anti-asthmatic medication. The BPA asked: “In your opinion, how likely is it that this patient will pick up this medication?” The provider could select from a 5level Likert item with responses ranging from “very unlikely” to “very likely”. Provider response was correlated to the principle outcome variable (medication first fill after 14 days as identified from the records of the pharmacy to which the prescription was transmitted.

Discussion of learning assessments in postgraduate teaching and learning curricula

We thank Drs. Hoover and Peeters for their response to our paper on TLC programs. We applaud them for their continued advocacy of training future educators on the importance of developing appropriate learning assessments that directly relate to learning objectives, in-class activities, and course or