Publications by authors named "Amy C Sturm"

71 Publications

Population genomic screening of young adults for familial hypercholesterolaemia: a cost-effectiveness analysis.

Eur Heart J 2021 Nov 11. Epub 2021 Nov 11.

School of Public Health and Preventive Medicine, Monash University, 553 St Kilda Rd, Melbourne, VIC 3004, Australia.

Aims: The aim of this study was to assess the impact and cost-effectiveness of offering population genomic screening to all young adults in Australia to detect heterozygous familial hypercholesterolaemia (FH).

Methods And Results: We designed a decision analytic Markov model to compare the current standard of care for heterozygous FH diagnosis in Australia (opportunistic cholesterol screening and genetic cascade testing) with the alternate strategy of population genomic screening of adults aged 18-40 years to detect pathogenic variants in the LDLR/APOB/PCSK9 genes. We used a validated cost-adaptation method to adapt findings to eight high-income countries. The model captured coronary heart disease (CHD) morbidity/mortality over a lifetime horizon, from healthcare and societal perspectives. Risk of CHD, treatment effects, prevalence, and healthcare costs were estimated from published studies. Outcomes included quality-adjusted life years (QALYs), costs and incremental cost-effectiveness ratio (ICER), discounted 5% annually. Sensitivity analyses were undertaken to explore the impact of key input parameters on the robustness of the model. Over the lifetime of the population (4 167 768 men; 4 129 961 women), the model estimated a gain of 33 488years of life lived and 51 790 QALYs due to CHD prevention. Population genomic screening for FH would be cost-effective from a healthcare perspective if the per-test cost was ≤AU$250, yielding an ICER of
Conclusion: Based on our model, offering population genomic screening to all young adults for FH could be cost-effective, at testing costs that are feasible.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/eurheartj/ehab770DOI Listing
November 2021

Genomic Screening for Pathogenic Transthyretin Variants Finds Evidence of Underdiagnosed Amyloid Cardiomyopathy From Health Records.

JACC CardioOncol 2021 Oct 19;3(4):550-561. Epub 2021 Oct 19.

Heart Institute, Geisinger Medical Center, Danville, Pennsylvania, USA.

Background: New treatments for transthyretin amyloidosis improve survival, but diagnosis remains challenging. Pathogenic or likely pathogenic (P/LP) variants in the transthyretin () gene are one cause of transthyretin amyloidosis, and genomic screening has been proposed to identify at-risk individuals. However, data on disease features and penetrance are lacking to inform the utility of such population-based genomic screening for

Objectives: This study characterized the prevalence of P/LP variants in identified through exome sequencing and the burden of associated disease from electronic health records for individuals with these variants from a large (N = 134,753), primarily European-ancestry cohort.

Methods: We compared frequencies of common disease features and cardiac imaging findings between individuals with and without P/LP variants.

Results: We identified 157 of 134,753 (0.12%) individuals with P/LP variants (43% male, median age 52 [Q1-Q3: 37-61] years). Seven P/LP variants accounted for all observations, the majority being V122I (p.V142I; 113, 0.08%). Approximately 60% (n = 91) of individuals with P/LP variants (all V122I) had African ancestry. Diagnoses of amyloidosis were limited (2 of 157 patients), although related heart disease diagnoses, including cardiomyopathy and heart failure, were significantly increased in individuals with P/LP variants who were aged >60 years. Fourteen percent (7 of 49) of individuals aged ≥60 or older with a P/LP variant had heart disease and ventricular septal thickness >1.2 cm, only one of whom was diagnosed with amyloidosis.

Conclusions: Individuals with P/LP variants identified by genomic screening have increased odds of heart disease after age 60 years, although amyloidosis is likely underdiagnosed without knowledge of the genetic variant.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jaccao.2021.07.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8543083PMC
October 2021

Evaluation of gene validity for CPVT and short QT syndrome in sudden arrhythmic death.

Eur Heart J 2021 Sep 24. Epub 2021 Sep 24.

Division of Cardiology, Toronto General Hospital, The Toronto General Hospital Research Institute, University Health Network, University of Toronto, 200 Elizabeth St, Toronto, ON M5G 2C4, Canada.

Aims: Catecholaminergic polymorphic ventricular tachycardia (CPVT) and short QT syndrome (SQTS) are inherited arrhythmogenic disorders that can cause sudden death. Numerous genes have been reported to cause these conditions, but evidence supporting these gene-disease relationships varies considerably. To ensure appropriate utilization of genetic information for CPVT and SQTS patients, we applied an evidence-based reappraisal of previously reported genes.

Methods And Results: Three teams independently curated all published evidence for 11 CPVT and 9 SQTS implicated genes using the ClinGen gene curation framework. The results were reviewed by a Channelopathy Expert Panel who provided the final classifications. Seven genes had definitive to moderate evidence for disease causation in CPVT, with either autosomal dominant (RYR2, CALM1, CALM2, CALM3) or autosomal recessive (CASQ2, TRDN, TECRL) inheritance. Three of the four disputed genes for CPVT (KCNJ2, PKP2, SCN5A) were deemed by the Expert Panel to be reported for phenotypes that were not representative of CPVT, while reported variants in a fourth gene (ANK2) were too common in the population to be disease-causing. For SQTS, only one gene (KCNH2) was classified as definitive, with three others (KCNQ1, KCNJ2, SLC4A3) having strong to moderate evidence. The majority of genetic evidence for SQTS genes was derived from very few variants (five in KCNJ2, two in KCNH2, one in KCNQ1/SLC4A3).

Conclusions: Seven CPVT and four SQTS genes have valid evidence for disease causation and should be included in genetic testing panels. Additional genes associated with conditions that may mimic clinical features of CPVT/SQTS have potential utility for differential diagnosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/eurheartj/ehab687DOI Listing
September 2021

Racial Disparities in Modifiable Risk Factors and Statin Usage in Black Patients With Familial Hypercholesterolemia.

J Am Heart Assoc 2021 09 25;10(17):e020890. Epub 2021 Aug 25.

Division of Endocrinology, Metabolism and Lipid Research Washington University School of Medicine St. Louis MO.

Background Black men and women are at higher risk for, and suffer greater morbidity and mortality from, atherosclerotic cardiovascular disease (ASCVD) compared with adults of European Ancestry (EA). Black patients with familial hypercholesterolemia are at particularly high risk for ASCVD complications because of lifelong exposure to elevated levels of low-density-lipoprotein cholesterol. Methods and Results This retrospective study analyzed ASCVD prevalence and risk factors in 808 adults with heterozygous familial hypercholesterolemia from 5 US-based lipid clinics, and compared findings in Black versus EA patients. Multivariate logistic regression models were used to determine the strongest predictors of ASCVD as a function of race. No significant difference was noted in the prevalence of ASCVD in Black versus EA patients with familial hypercholesterolemia (39% versus 32%, respectively; =0.15). However, Black versus EA patients had significantly greater prevalence of modifiable risk factors, including body mass index (mean, 32±7 kg/m versus 29±6 kg/m; <0.001), hypertension (82% versus 50%; <0.001), diabetes (39% versus 15%; <0.001), and current smoking (16% versus 8%; =0.006). Black versus EA patients also had significantly lower usage of statins (61% versus 73%; =0.004) and other lipid-lowering agents. In a fully adjusted multivariate model, race was not independently associated with ASCVD (odds ratio, 0.92; 95% CI, 0.60-1.49; =0.72). Conclusions The strongest predictors of ASCVD in Black patients with familial hypercholesterolemia were hypertension and cigarette smoking. These data support wider usage of statins and other lipid-lowering therapies and greater attention to modifiable risk, specifically blood pressure management and smoking cessation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/JAHA.121.020890DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8649284PMC
September 2021

Genetic Testing for Heritable Cardiovascular Diseases in Pediatric Patients: A Scientific Statement From the American Heart Association.

Circ Genom Precis Med 2021 10 20;14(5):e000086. Epub 2021 Aug 20.

Genetic diseases that affect the cardiovascular system are relatively common and include cardiac channelopathies, cardiomyopathies, aortopathies, hypercholesterolemias, and structural diseases of the heart and great vessels. The rapidly expanding availability of clinical genetic testing leverages decades of research into the genetic origins of these diseases, helping inform diagnosis, clinical management, and prognosis. Although a number of guidelines and statements detail best practices for cardiovascular genetic testing, there is a paucity of pediatric-focused statements addressing the unique challenges in testing in this vulnerable population. In this scientific statement, we seek to coalesce the existing literature around the use of genetic testing for cardiovascular disease in infants, children, and adolescents.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/HCG.0000000000000086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8546375PMC
October 2021

Acceptability, Appropriateness, and Feasibility of Automated Screening Approaches and Family Communication Methods for Identification of Familial Hypercholesterolemia: Stakeholder Engagement Results from the IMPACT-FH Study.

J Pers Med 2021 Jun 21;11(6). Epub 2021 Jun 21.

Genomic Medicine Institute, Geisinger, Danville, PA 17822, USA.

Guided by the Conceptual Model of Implementation Research, we explored the acceptability, appropriateness, and feasibility of: (1) automated screening approaches utilizing existing health data to identify those who require subsequent diagnostic evaluation for familial hypercholesterolemia (FH) and (2) family communication methods including chatbots and direct contact to communicate information about inherited risk for FH. Focus groups were conducted with 22 individuals with FH (2 groups) and 20 clinicians (3 groups). These were recorded, transcribed, and analyzed using deductive (coded to implementation outcomes) and inductive (themes based on focus group discussions) methods. All stakeholders described these initiatives as: (1) acceptable and appropriate to identify individuals with FH and communicate risk with at-risk relatives; and (2) feasible to implement in current practice. Stakeholders cited current initiatives, outside of FH (e.g., pneumonia protocols, colon cancer and breast cancer screenings), that gave them confidence for successful implementation. Stakeholders described perceived obstacles, such as nonfamiliarity with FH, that could hinder implementation and potential solutions to improve systematic uptake of these initiatives. Automated health data screening, chatbots, and direct contact approaches may be useful for patients and clinicians to improve FH diagnosis and cascade screening.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/jpm11060587DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8234213PMC
June 2021

Limited-Variant Screening vs Comprehensive Genetic Testing for Familial Hypercholesterolemia Diagnosis.

JAMA Cardiol 2021 08;6(8):902-909

Department of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia.

Importance: Familial hypercholesterolemia (FH) is the most common inherited cardiovascular disease and carries significant morbidity and mortality risks. Genetic testing can identify affected individuals, but some array-based assays screen only a small subset of known pathogenic variants.

Objective: To identify the number of clinically significant variants associated with FH that would be missed by an array-based, limited-variant screen when compared with next-generation sequencing (NGS)-based comprehensive testing.

Design, Setting, And Participants: This cross-sectional study compared comprehensive genetic test results for clinically significant variants associated with FH with results for a subset of 24 variants screened by a limited-variant array. Data were deidentified next-generation sequencing results from indication-based or proactive gene panels. Individuals receiving next-generation sequencing-based genetic testing, either for an FH indication between November 2015 and June 2020 or as proactive health screening between February 2016 and June 2020 were included. Ancestry was reported by clinicians who could select from preset options or enter free text on the test requisition form.

Main Outcomes And Measures: Number of pathogenic or likely pathogenic (P/LP) variants identified.

Results: This study included 4563 individuals who were referred for FH diagnostic testing and 6482 individuals who received next-generation sequencing of FH-associated genes as part of a proactive genetic test. Among individuals in the indication cohort, the median (interquartile range) age at testing was 49 (32-61) years, 55.4% (2528 of 4563) were female, and 63.6% (2902 of 4563) were self-reported White/Caucasian. In the indication cohort, the positive detection rate would have been 8.4% (382 of 4563) for a limited-variant screen compared with the 27.0% (1230 of 4563) observed with the next-generation sequencing-based comprehensive test. As a result, 68.9% (848 of 1230) of individuals with a P/LP finding in an FH-associated gene would have been missed by the limited screen. The potential for missed findings in the indication cohort varied by ancestry; among individuals with a P/LP finding, 93.7% (59 of 63) of self-reported Black/African American individuals and 84.7% (122 of 144) of Hispanic individuals would have been missed by the limited-variant screen, compared with 33.3% (4 of 12) of Ashkenazi Jewish individuals. In the proactive cohort, the prevalence of clinically significant FH variants was approximately 1:191 per the comprehensive test, and 61.8% (21 of 34) of individuals with an FH-associated P/LP finding would have been missed by a limited-variant screen.

Conclusions And Relevance: Limited-variant screens may falsely reassure the majority of individuals at risk for FH that they do not carry a disease-causing variant, especially individuals of self-reported Black/African American and Hispanic ancestry.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamacardio.2021.1301DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8156154PMC
August 2021

Implementation strategies to improve statin utilization in individuals with hypercholesterolemia: a systematic review and meta-analysis.

Implement Sci 2021 04 13;16(1):40. Epub 2021 Apr 13.

Center for Pharmacy Innovation and Outcomes, Geisinger, Danville, PA, USA.

Background: Numerous implementation strategies to improve utilization of statins in patients with hypercholesterolemia have been utilized, with varying degrees of success. The aim of this systematic review is to determine the state of evidence of implementation strategies on the uptake of statins.

Methods And Results: This systematic review identified and categorized implementation strategies, according to the Expert Recommendations for Implementing Change (ERIC) compilation, used in studies to improve statin use. We searched Ovid MEDLINE, Embase, Scopus, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, and Clinicaltrials.gov from inception to October 2018. All included studies were reported in English and had at least one strategy to promote statin uptake that could be categorized using the ERIC compilation. Data extraction was completed independently, in duplicate, and disagreements were resolved by consensus. We extracted LDL-C (concentration and target achievement), statin prescribing, and statin adherence (percentage and target achievement). A total of 258 strategies were used across 86 trials. The median number of strategies used was 3 (SD 2.2, range 1-13). Implementation strategy descriptions often did not include key defining characteristics: temporality was reported in 59%, dose in 52%, affected outcome in 9%, and justification in 6%. Thirty-one trials reported at least 1 of the 3 outcomes of interest: significantly reduced LDL-C (standardized mean difference [SMD] - 0.17, 95% CI - 0.27 to - 0.07, p = 0.0006; odds ratio [OR] 1.33, 95% CI 1.13 to 1.58, p = 0.0008), increased rates of statin prescribing (OR 2.21, 95% CI 1.60 to 3.06, p < 0.0001), and improved statin adherence (SMD 0.13, 95% CI 0.06 to 0.19; p = 0.0002; OR 1.30, 95% CI 1.04 to 1.63, p = 0.023). The number of implementation strategies used per study positively influenced the efficacy outcomes.

Conclusion: Although studies demonstrated improved statin prescribing, statin adherence, and reduced LDL-C, no single strategy or group of strategies consistently improved outcomes.

Trial Registration: PROSPERO CRD42018114952 .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13012-021-01108-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8045284PMC
April 2021

Genetic counseling for patients with positive genomic screening results: Considerations for when the genetic test comes first.

J Genet Couns 2021 06 31;30(3):634-644. Epub 2021 Mar 31.

Genomic Medicine Institute, Geisinger, Danville, PA, USA.

Emerging genetic testing delivery models have enabled individuals to receive testing without a medical indication. This article will highlight key considerations for patient care in the setting of adult patients with positive results for monogenic disease identified through genomic screening. Suggestions for how to adapt genetic counseling to a genomic screening population will encompass topics such as phenotyping, risk assessments, and the use of existing guidelines and resources. Case examples will demonstrate principles of genotype-first patient care.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jgc4.1386DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8192338PMC
June 2021

Evaluation of a multidisciplinary lipid clinic to improve the care of individuals with severe lipid conditions: a RE-AIM framework analysis.

Implement Sci Commun 2021 Mar 19;2(1):32. Epub 2021 Mar 19.

Genomic Medicine Institute, Geisinger, Danville, PA, USA.

Background: Individuals with complex dyslipidemia, or those with medication intolerance, are often difficult to manage in primary care. They require the additional attention, expertise, and adherence counseling that occurs in multidisciplinary lipid clinics (MDLCs). We conducted a program evaluation of the first year of a newly implemented MDLC utilizing the RE-AIM (reach, effectiveness, adoption, implementation, and maintenance) framework to provide empirical data not only on program effectiveness, but also on components important to local sustainability and future generalizability.

Methods: The purpose of the MDLC is to increase the uptake of guideline-based care for lipid conditions. Established in 2019, the MDLC provides care via a centralized clinic location within the healthcare system. Primary care providers and cardiologists were invited to refer individuals with lipid conditions. Using a pre/post-study design, we evaluated the implementation outcomes from the MDLC using the RE-AIM framework.

Results: In 2019, 420 referrals were made to the MDLC (reach). Referrals were made by 19% (148) of the 796 active cardiology and primary care providers, with an average of 35 patient referrals per month in 2019 (SD 12) (adoption). The MDLC saw 83 patients in 2019 (reach). Additionally, 50% (41/82) had at least one follow-up MDLC visit, and 12% (10/82) had two or more follow-up visits in 2019 (implementation). In patients seen by the MDLC, we found an improved diagnosis of specific lipid conditions (FH (familial hypercholesterolemia), hypertriglyceridemia, and dyslipidemia), increased prescribing of evidence-based therapies, high rates of medication prior authorization approvals, and significant reductions in lipid levels by lipid condition subgroup (effectiveness). Over time, the operations team decided to transition from in-person follow-up to telehealth appointments to increase capacity and sustain the clinic (maintenance).

Conclusions: Despite limited reach and adoption of the MDLC, we found a large intervention effect that included improved diagnosis, increased prescribing of guideline-recommended treatments, and clinically significant reduction of lipid levels. Attention to factors including solutions to decrease the large burden of unseen referrals, discussion of the appropriate number and duration of visits, and sustainability of the clinic model could aid in enhancing the success of the MDLC and improving outcomes for more patients throughout the system.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s43058-021-00135-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7977494PMC
March 2021

Clinical Findings and Diagnostic Yield of Arrhythmogenic Cardiomyopathy Through Genomic Screening of Pathogenic or Likely Pathogenic Desmosome Gene Variants.

Circ Genom Precis Med 2021 04 8;14(2):e003302. Epub 2021 Mar 8.

Department of Translational Data Science and Informatics (E.D.C., C.D.N., B.K.F., C.M.H.), Geisinger, Danville, PA.

Background: Genomic screening holds great promise for presymptomatic identification of hidden disease, and prevention of dramatic events, including sudden cardiac death associated with arrhythmogenic cardiomyopathy (ACM). Herein, we present findings from clinical follow-up of carriers of ACM-associated pathogenic/likely pathogenic desmosome variants ascertained through genomic screening.

Methods: Of 64 548 eligible participants in Geisinger MyCode Genomic Screening and Counseling program (2015-present), 92 individuals (0.14%) identified with pathogenic/likely pathogenic desmosome variants by clinical laboratory testing were referred for evaluation. We reviewed preresult medical history, patient-reported family history, and diagnostic testing results to assess both arrhythmogenic right ventricular cardiomyopathy and left-dominant ACM.

Results: One carrier had a prior diagnosis of dilated cardiomyopathy with arrhythmia; no other related diagnoses or diagnostic family history criteria were reported. Fifty-nine carriers (64%) had diagnostic testing in follow-up. Excluding the variant, 21/59 carriers satisfied at least one arrhythmogenic right ventricular cardiomyopathy task force criterion, 11 (52%) of whom harbored variants, but only 5 exhibited multiple criteria. Six (10%) carriers demonstrated evidence of left-dominant ACM, including high rates of atypical late gadolinium enhancement by magnetic resonance imaging and nonsustained ventricular tachycardia. Two individuals received new cardiomyopathy diagnoses and received defibrillators for primary prevention.

Conclusions: Genomic screening for pathogenic/likely pathogenic variants in desmosome genes can uncover both left- and right-dominant ACM. Findings of overt cardiomyopathy were limited but were most common in -variant carriers and notably absent in -variant carriers. Consideration of the pathogenic/likely pathogenic variant as a major criterion for diagnosis is inappropriate in the setting of genomic screening.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCGEN.120.003302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8284375PMC
April 2021

Developing and Optimizing Innovative Tools to Address Familial Hypercholesterolemia Underdiagnosis: Identification Methods, Patient Activation, and Cascade Testing for Familial Hypercholesterolemia.

Circ Genom Precis Med 2021 02 22;14(1):e003120. Epub 2021 Jan 22.

Geisinger, Danville, PA (G.C.-S., L.K.J., M.F.M., A.H.B., A.B., D.G.K., I.G.L., M.A.K., H.L.K., M.N.M., M.T.O., A.K.R., T.J.S., N.T.S., N.L.W., M.S.W., S.S.G., A.C.S.).

Background: Familial hypercholesterolemia (FH) is the most common cardiovascular genetic disorder and, if left untreated, is associated with increased risk of premature atherosclerotic cardiovascular disease, the leading cause of preventable death in the United States. Although FH is common, fatal, and treatable, it is underdiagnosed and undertreated due to a lack of systematic methods to identify individuals with FH and limited uptake of cascade testing.

Methods And Results: This mixed-method, multi-stage study will optimize, test, and implement innovative approaches for both FH identification and cascade testing in 3 aims. To improve identification of individuals with FH, in Aim 1, we will compare and refine automated phenotype-based and genomic approaches to identify individuals likely to have FH. To improve cascade testing uptake for at-risk individuals, in Aim 2, we will use a patient-centered design thinking process to optimize and develop novel, active family communication methods. Using a prospective, observational pragmatic trial, we will assess uptake and effectiveness of each family communication method on cascade testing. Guided by an implementation science framework, in Aim 3, we will develop a comprehensive guide to identify individuals with FH. Using the Conceptual Model for Implementation Research, we will evaluate implementation outcomes including feasibility, acceptability, and perceived sustainability as well as health outcomes related to the optimized methods and tools developed in Aims 1 and 2.

Conclusions: Data generated from this study will address barriers and gaps in care related to underdiagnosis of FH by developing and optimizing tools to improve FH identification and cascade testing.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCGEN.120.003120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892261PMC
February 2021

Association between triglycerides, known risk SNVs and conserved rare variation in SLC25A40 in a multi-ancestry cohort.

BMC Med Genomics 2021 01 6;14(1):11. Epub 2021 Jan 6.

Division of Medical Genetics, School of Medicine, University of Washington Medical Center, 1705 NE Pacific St, Box 357720, Seattle, WA, 98195, USA.

Background: Elevated triglycerides (TG) are associated with, and may be causal for, cardiovascular disease (CVD), and co-morbidities such as type II diabetes and metabolic syndrome. Pathogenic variants in APOA5 and APOC3 as well as risk SNVs in other genes [APOE (rs429358, rs7412), APOA1/C3/A4/A5 gene cluster (rs964184), INSR (rs7248104), CETP (rs7205804), GCKR (rs1260326)] have been shown to affect TG levels. Knowledge of genetic causes for elevated TG may lead to early intervention and targeted treatment for CVD. We previously identified linkage and association of a rare, highly conserved missense variant in SLC25A40, rs762174003, with hypertriglyceridemia (HTG) in a single large family, and replicated this association with rare, highly conserved missense variants in a European American and African American sample.

Methods: Here, we analyzed a longitudinal mixed-ancestry cohort (European, African and Asian ancestry, N = 8966) from the Electronic Medical Record and Genomics (eMERGE) Network. We tested associations between median TG and the genes of interest, using linear regression, adjusting for sex, median age, median BMI, and the first two principal components of ancestry.

Results: We replicated the association between TG and APOC3, APOA5, and risk variation at APOE, APOA1/C3/A4/A5 gene cluster, and GCKR. We failed to replicate the association between rare, highly conserved variation at SLC25A40 and TG, as well as for risk variation at INSR and CETP.

Conclusions: Analysis using data from electronic health records presents challenges that need to be overcome. Although large amounts of genotype data is becoming increasingly accessible, usable phenotype data can be challenging to obtain. We were able to replicate known, strong associations, but were unable to replicate moderate associations due to the limited sample size and missing drug information.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12920-020-00854-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7789246PMC
January 2021

Barriers, facilitators, and solutions to familial hypercholesterolemia treatment.

PLoS One 2020 23;15(12):e0244193. Epub 2020 Dec 23.

Genomic Medicine Institute, Geisinger, Danville, PA, United States of America.

Background: Familial hypercholesterolemia (FH) is an inherited lipid disorder that confers high risk for premature cardiovascular disease but remains undertreated. Causes are multifactorial and multilevel, ranging from underprescribing (at the clinician-level) to medication nonadherence (at the patient-level). We evaluated patient and clinician stakeholder barriers and facilitators for treatment of FH to explore possible solutions to the problem.

Methods And Results: Semi-structured interviews and focus groups guided by the Practical, Robust, Implementation and Sustainability Model (PRISM), were conducted with 33 patients and 17 clinician stakeholders across three healthcare systems. A total of14 patients and 9 clinician stakeholders participated in on-site focus groups and the remainder were individual interviews. Transcripts were coded using an iterative process to create a static codebook. We characterized patient and clinician stakeholder barriers into three categories: medical care-, medication-, and life-related. Feasibility of brainstormed solutions varied and was not always representative of the needs of all stakeholders. Patients suggested a need for childhood screening for FH and doctors being persistent about the importance of treating FH, creation of a patient peer group, data transparency, advocacy, and policy changes that would enable patients to receive better treatment. Clinician stakeholders suggested the need for clinical champions. Both groups of stakeholders discussed the need for education about FH.

Conclusions: Proposed solutions to improve treatment of FH proffered by participants in this study included resources for both patients and clinician stakeholders that clarify cardiovascular disease risks from FH, develop programs to screen for and identify FH at younger ages, and foster open conversations between patients and clinicians about treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0244193PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7757879PMC
March 2021

Impact of variant reclassification in the clinical setting of cardiovascular genetics.

J Genet Couns 2021 04 7;30(2):503-512. Epub 2020 Oct 7.

Division of Human Genetics, The Ohio State University, Columbus, OH, USA.

Genetic testing for cardiovascular disease (CVD) has advanced over the past ten years, but these advancements have posed new challenges in variant classification. To address these challenges, ACMG/AMP published guidelines for variant interpretation in 2015. This study aimed to determine what impact these guidelines have on variant classification in clinical cardiovascular genetics. A retrospective chart review identified patients who underwent clinical genetic testing and had a variant identified in a gene associated with CVD. For each variant, systematic evidence review was performed and ACMG guidelines were applied for classification. These classifications were compared to those provided on patients' genetic test reports. This study identified 223 unique variants in 237 patients. Seventy-nine (35%) of the variants had classifications that differed from their clinical reports. Twenty-eight (35%) of these reclassifications would have changed medical management recommendations for 38 patients. Application of these guidelines resulted in reclassification for approximately one-third of the variants in this study. Clinicians can have a more active role in the process of variant classification. Variant classifications should be updated over time in the clinical CVD setting due to the impact reclassifications can have on clinical screening recommendations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jgc4.1336DOI Listing
April 2021

Uncertainty management for individuals with Lynch Syndrome: Identifying and responding to healthcare barriers.

Patient Educ Couns 2021 02 3;104(2):403-412. Epub 2020 Aug 3.

Genomic Medicine Institute, Geisinger, Danville, PA, USA.

Objective: Examine the uncertainty management process of individuals with Lynch syndrome (LS).

Methods: 19 phone interviews were conducted with individuals with LS. The interview guide included questions on family communication, risk perceptions, and uncertainty management. Data were analyzed using the constant comparison method to code for emergent themes.

Results: Qualitative analysis found individuals with LS tried to manage their uncertainty through preventive care, but were often confounded by healthcare barriers. Healthcare barriers included cost and insurance issues, absence of coordinated care, insufficient provider knowledge, and lack of patient-centered communication. Participants reported increased uncertainty and anxiety due to these barriers and used alternative uncertainty management strategies such as advocating for themselves with providers, seeking information online, and communicating with family for emotional support.

Conclusion: Healthcare barriers identified in this study exacerbated uncertainty and anxiety for individuals with LS and challenged their ability to engage in preventive care. In response, participants used alternative uncertainty management strategies to reduce their uncertainty, which may have unintended negative consequences.

Practice Implications: Findings support the need for providers to partner with specialists in genetics and/or LS to better care for individuals with LS. Findings highlight opportunities for interventions in healthcare to better support individuals with LS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.pec.2020.07.017DOI Listing
February 2021

Genetic Testing for Inherited Cardiovascular Diseases: A Scientific Statement From the American Heart Association.

Circ Genom Precis Med 2020 08 23;13(4):e000067. Epub 2020 Jul 23.

Advances in human genetics are improving the understanding of a variety of inherited cardiovascular diseases, including cardiomyopathies, arrhythmic disorders, vascular disorders, and lipid disorders such as familial hypercholesterolemia. However, not all cardiovascular practitioners are fully aware of the utility and potential pitfalls of incorporating genetic test results into the care of patients and their families. This statement summarizes current best practices with respect to genetic testing and its implications for the management of inherited cardiovascular diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/HCG.0000000000000067DOI Listing
August 2020

Clinical outcomes of a genomic screening program for actionable genetic conditions.

Genet Med 2020 11 30;22(11):1874-1882. Epub 2020 Jun 30.

Genomic Medicine Institute, Geisinger, Danville, PA, USA.

Purpose: Three genetic conditions-hereditary breast and ovarian cancer syndrome, Lynch syndrome, and familial hypercholesterolemia-have tier 1 evidence for interventions that reduce morbidity and mortality, prompting proposals to screen unselected populations for these conditions. We examined the impact of genomic screening on risk management and early detection in an unselected population.

Methods: Observational study of electronic health records (EHR) among individuals in whom a pathogenic/likely pathogenic variant in a tier 1 gene was discovered through Geisinger's MyCode project. EHR of all eligible participants was evaluated for a prior genetic diagnosis and, among participants without such a diagnosis, relevant personal/family history, postdisclosure clinical diagnoses, and postdisclosure risk management.

Results: Eighty-seven percent of participants (305/351) did not have a prior genetic diagnosis of their tier 1 result. Of these, 65% had EHR evidence of relevant personal and/or family history of disease. Of 255 individuals eligible to have risk management, 70% (n = 179) had a recommended risk management procedure after results disclosure. Thirteen percent of participants (41/305) received a relevant clinical diagnosis after results disclosure.

Conclusion: Genomic screening programs can identify previously unrecognized individuals at increased risk of cancer and heart disease and facilitate risk management and early cancer detection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41436-020-0876-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605431PMC
November 2020

Genetic testing in dyslipidemia: A scientific statement from the National Lipid Association.

J Clin Lipidol 2020 Jul - Aug;14(4):398-413. Epub 2020 May 7.

Professor of Medicine and Biochemistry, Department of Medicine and Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada. Electronic address:

The genetic basis for more than 2 dozen monogenic dyslipidemias has largely been defined. Genetic technologies, such as DNA sequencing, can detect both rare and common DNA variants underlying dyslipidemias, and these methods are increasingly available. Although patients with extreme abnormalities in low-density lipoprotein cholesterol, triglycerides, or high-density lipoprotein cholesterol may be considered for genetic testing, it is only in a minority of patients that the results will alter treatment or outcomes. Currently, there is potential clinical utility of genetic testing for familial hypercholesterolemia, familial chylomicronemia syndrome, sitosterolemia, lysosomal acid lipase deficiency, and a few other rare disorders, and this will increase the demand for reliable genetic diagnostic methods at lower cost. Clinical indications for genetic testing for most dyslipidemias are not clearly established and currently no guidelines exist. A shared decision-making model between the patient and the provider is essential as patient values and preferences play a very strong role. Potential benefits of genetic testing include providing a firm diagnosis in many cases, guiding optimal management and prevention strategies, advancing care strategies beyond currently available treatments, and contributing to overall scientific progress. Understanding the limitations and risks of genetic testing techniques is also important, as is careful interpretation of genetic test results to achieve the greatest benefit. Here we review laboratory methods, as well as technical, biological, clinical, and ethical implications and applications of genetic testing in dyslipidemias.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jacl.2020.04.011DOI Listing
August 2021

Pediatric reporting of genomic results study (PROGRESS): a mixed-methods, longitudinal, observational cohort study protocol to explore disclosure of actionable adult- and pediatric-onset genomic variants to minors and their parents.

BMC Pediatr 2020 05 15;20(1):222. Epub 2020 May 15.

Genomic Medicine Institute, Geisinger, Danville, PA, USA.

Background: Exome and genome sequencing are routinely used in clinical care and research. These technologies allow for the detection of pathogenic/likely pathogenic variants in clinically actionable genes. However, fueled in part by a lack of empirical evidence, controversy surrounds the provision of genetic results for adult-onset conditions to minors and their parents. We have designed a mixed-methods, longitudinal cohort study to collect empirical evidence to advance this debate.

Methods: Pediatric participants in the Geisinger MyCode® Community Health Initiative with available exome sequence data will have their variant files assessed for pathogenic/likely pathogenic variants in 60 genes designated as actionable by MyCode. Eight of these genes are associated with adult-onset conditions (Hereditary Breast and Ovarian Cancer Syndrome (HBOC), Lynch syndrome, MUTYH-associated polyposis, HFE-Associated Hereditary Hemochromatosis), while the remaining genes have pediatric onset. Prior to clinical confirmation of results, pediatric MyCode participants and their parents/legal guardians will be categorized into three study groups: 1) those with an apparent pathogenic/likely pathogenic variant in a gene associated with adult-onset disease, 2) those with an apparent pathogenic/likely pathogenic variant in a gene associated with pediatric-onset disease or with risk reduction interventions that begin in childhood, and 3) those with no apparent genomic result who are sex- and age-matched to Groups 1 and 2. Validated and published quantitative measures, semi-structured interviews, and a review of electronic health record data conducted over a 12-month period following disclosure of results will allow for comparison of psychosocial and behavioral outcomes among parents of minors (ages 0-17) and adolescents (ages 11-17) in each group.

Discussion: These data will provide guidance about the risks and benefits of informing minors and their family members about clinically actionable, adult-onset genetic conditions and, in turn, help to ensure these patients receive care that promotes physical and psychosocial health.

Trial Registration: ClinicalTrials.gov Identifier: NCT03832985. Registered 6 February 2019.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12887-020-02070-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7227212PMC
May 2020

Predictive Utility of Polygenic Risk Scores for Coronary Heart Disease in Three Major Racial and Ethnic Groups.

Am J Hum Genet 2020 05;106(5):707-716

Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN 55905, USA. Electronic address:

Because polygenic risk scores (PRSs) for coronary heart disease (CHD) are derived from mainly European ancestry (EA) cohorts, their validity in African ancestry (AA) and Hispanic ethnicity (HE) individuals is unclear. We investigated associations of "restricted" and genome-wide PRSs with CHD in three major racial and ethnic groups in the U.S. The eMERGE cohort (mean age 48 ± 14 years, 58% female) included 45,645 EA, 7,597 AA, and 2,493 HE individuals. We assessed two restricted PRSs (PRS and PRS; 28 and 50 variants, respectively) and two genome-wide PRSs (PRS and PRS; 1.7 M and 6.6 M variants, respectively) derived from EA cohorts. Over a median follow-up of 11.1 years, 2,652 incident CHD events occurred. Hazard and odds ratios for the association of PRSs with CHD were similar in EA and HE cohorts but lower in AA cohorts. Genome-wide PRSs were more strongly associated with CHD than restricted PRSs were. PRS, the best performing PRS, was associated with CHD in all three cohorts; hazard ratios (95% CI) per 1 SD increase were 1.53 (1.46-1.60), 1.53 (1.23-1.90), and 1.27 (1.13-1.43) for incident CHD in EA, HE, and AA individuals, respectively. The hazard ratios were comparable in the EA and HE cohorts (p = 0.77) but were significantly attenuated in AA individuals (p= 2.9 × 10). These results highlight the potential clinical utility of PRSs for CHD as well as the need to assemble diverse cohorts to generate ancestry- and ethnicity PRSs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajhg.2020.04.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212267PMC
May 2020

Pharmacogenomic (PGx) Counseling: Exploring Participant Questions about PGx Test Results.

J Pers Med 2020 Apr 23;10(2). Epub 2020 Apr 23.

Coriell Institute for Medical Research, Camden, NJ 08003, USA.

As pharmacogenomic (PGx) use in healthcare increases, a better understanding of patient needs will be necessary to guide PGx result delivery. The Coriell Personalized Medicine Collaborative (CPMC) is a prospective study investigating the utility of personalized medicine. Participants received online genetic risk reports for 27 potentially actionable complex diseases and 7 drug-gene pairs and could request free, telephone-based genetic counseling (GC). To explore the needs of individuals receiving PGx results, we conducted a retrospective qualitative review of inquiries from CPMC participants who requested counseling from March 2009 to February 2017. Eighty out of 690 (12%) total GC inquiries were focused on the discussion of PGx results, and six salient themes emerged: "general help", "issues with drugs", "relevant disease experience", "what do I do now?", "sharing results", and "other drugs". The number of reported medications with a corresponding PGx result and participant engagement were significantly associated with PGx GC requests ( < 0.01 and < 0.02, respectively). Our work illustrates a range of questions raised by study participants receiving PGx test results, most of which were addressed by a genetic counselor with few requiring referrals to prescribing providers or pharmacists. These results further support a role for genetic counselors in the team-based approach to optimal PGx result delivery.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/jpm10020029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7354504PMC
April 2020

Perspectives from individuals with familial hypercholesterolemia on direct contact in cascade screening.

J Genet Couns 2020 12 29;29(6):1142-1150. Epub 2020 Mar 29.

Genomic Medicine Institute, Geisinger, Danville, PA, USA.

Familial hypercholesterolemia (FH) is the most common inherited form of high cholesterol that significantly increases the risk for coronary artery disease. Early detection and treatment can decrease morbidity and mortality and provide important risk information to family members. However, FH remains vastly underdiagnosed and undertreated. Cascade screening is the process of iteratively testing first-degree relatives for a genetic disease. It has been shown to effectively identify individuals with undiagnosed FH. The majority of research on methods for cascade screening has been conducted outside of the United States (U.S.). For indirect contact, index cases encourage relatives to undergo testing, and for direct contact, healthcare providers (HCP) obtain the index case's consent to contact relatives and offer information. Currently, there is not an accepted strategy for cascade screening programs in the U.S. This study investigated perspectives on direct and indirect contact for cascade screening from individuals with FH. An online survey was designed in collaboration with the Familial Hypercholesterolemia Foundation (FHF). Fifty-eight percent of U.S. index cases (11/19, 57.9%) and all international index cases (8/8, 100%) indicated willingness to provide contact information for certain at-risk relatives to a HCP for the purpose of directly informing relatives of their risk for FH in a hypothetical scenario. These findings provide an example of U.S. data and additional international data suggesting that some individuals with FH may consider direct contact a reasonable approach to improve screening uptake among family members. These initial findings need further confirmation in a larger group.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jgc4.1266DOI Listing
December 2020

An International, Multicentered, Evidence-Based Reappraisal of Genes Reported to Cause Congenital Long QT Syndrome.

Circulation 2020 02 27;141(6):418-428. Epub 2020 Jan 27.

Division of Cardiology, Toronto General Hospital and University of Toronto, Canada (A.A, M.C., M.H.G.).

Background: Long QT syndrome (LQTS) is the first described and most common inherited arrhythmia. Over the last 25 years, multiple genes have been reported to cause this condition and are routinely tested in patients. Because of dramatic changes in our understanding of human genetic variation, reappraisal of reported genetic causes for LQTS is required.

Methods: Utilizing an evidence-based framework, 3 gene curation teams blinded to each other's work scored the level of evidence for 17 genes reported to cause LQTS. A Clinical Domain Channelopathy Working Group provided a final classification of these genes for causation of LQTS after assessment of the evidence scored by the independent curation teams.

Results: Of 17 genes reported as being causative for LQTS, 9 () were classified as having limited or disputed evidence as LQTS-causative genes. Only 3 genes () were curated as definitive genes for typical LQTS. Another 4 genes () were found to have strong or definitive evidence for causality in LQTS with atypical features, including neonatal atrioventricular block. The remaining gene () had moderate level evidence for causing LQTS.

Conclusions: More than half of the genes reported as causing LQTS have limited or disputed evidence to support their disease causation. Genetic variants in these genes should not be used for clinical decision-making, unless accompanied by new and sufficient genetic evidence. The findings of insufficient evidence to support gene-disease associations may extend to other disciplines of medicine and warrants a contemporary evidence-based evaluation for previously reported disease-causing genes to ensure their appropriate use in precision medicine.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCULATIONAHA.119.043132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7017940PMC
February 2020

Genetic testing preferences and intentions in patients with clinically diagnosed familial hypercholesterolemia.

J Genet Couns 2020 12 25;29(6):919-927. Epub 2019 Nov 25.

National Human Genome Research Institute, Bethesda, MD, USA.

Purpose: Familial hypercholesterolemia (FH) is a common Mendelian disorder characterized by elevated LDL cholesterol levels, which if untreated can cause premature heart disease. Less than 10% of cases in the United States are diagnosed. This study investigates decision-making factors associated with intentions to have FH genetic testing among patients clinically diagnosed with FH.

Methods: Fifty-three clinically diagnosed adults with FH and no genetic testing were recruited through the FH Foundation and lipid clinics. Participants completed a survey containing items capturing various reasons to engage in genetic testing.

Results: Exploratory factor analysis of survey items identified three factors: (a) aversion to FH genetic information, (b) curiosity regarding medical/family history, (c) and psychological reassurance. Psychological reassurance was, in turn, the only significant predictor of genetic testing intentions. The positive effect of reassurance on genetic testing intention was moderated by aversion such that individuals who were low in reassurance were more inclined to decline testing if aversion was high.

Conclusion: Findings suggest that clinically diagnosed patients' decisions about FH genetic testing are driven principally by psychological reassurance, particularly when low in aversion to FH genetic information.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jgc4.1194DOI Listing
December 2020

Prevalence and Electronic Health Record-Based Phenotype of Loss-of-Function Genetic Variants in Arrhythmogenic Right Ventricular Cardiomyopathy-Associated Genes.

Circ Genom Precis Med 2019 11 22;12(11):e002579. Epub 2019 Oct 22.

Department of Imaging Science and Innovation (E.D.C., L.J., S.R., B.K.F., C.M.H.), Geisinger, Danville, PA.

Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is associated with variants in desmosome genes. Secondary findings of pathogenic/likely pathogenic variants, primarily loss-of-function (LOF) variants, are recommended for clinical reporting; however, their prevalence and associated phenotype in a general clinical population are not fully characterized.

Methods: From whole-exome sequencing of 61 019 individuals in the DiscovEHR cohort, we screened for putative loss-of-function variants in , , , and . We evaluated measures from prior clinical ECG and echocardiograms, manually over-read to evaluate ARVC diagnostic criteria, and performed a PheWAS (phenome-wide association study). Finally, we estimated expected penetrance using Bayesian inference.

Results: One hundred forty individuals (0.23%; 59±18 years old at last encounter; 33% male) had an ARVC variant (G). None had an existing diagnosis of ARVC in the electronic health record, nor significant differences in prior ECG or echocardiogram findings compared with matched controls without variants. Several G individuals satisfied major repolarization (n=4) and ventricular function (n=5) criteria, but this prevalence matched controls. PheWAS showed no significant associations of other heart disease diagnoses. Combining our best genetic and disease prevalence estimates yields an estimated penetrance of 6.0%.

Conclusions: The prevalence of ARVC loss-of-function variants is ≈1:435 in a general clinical population of predominantly European descent, but with limited electronic health record-based evidence of phenotypic association in our population, consistent with a low penetrance estimate. Prospective deep phenotyping and longitudinal follow-up of a large sequenced cohort is needed to determine the true clinical relevance of an incidentally identified ARVC loss-of-function variant.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCGEN.119.002579DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6876858PMC
November 2019

Patient assessment of chatbots for the scalable delivery of genetic counseling.

J Genet Couns 2019 12 24;28(6):1166-1177. Epub 2019 Sep 24.

Geisinger, Genomic Medicine Institute, Danville, PA, USA.

A barrier to incorporating genomics more broadly is limited access to providers with genomics expertise. Chatbots are a technology-based simulated conversation used in scaling communications. Geisinger and Clear Genetics, Inc. have developed chatbots to facilitate communication with participants receiving clinically actionable genetic variants from the MyCode Community Health Initiative (MyCode ). The consent chatbot walks patients through the consent allowing them to opt to receive more or less detail on key topics (goals, benefits, risks, etc.). The follow-up chatbot reminds participants of suggested actions following result receipt and the cascade chatbot can be sent to at-risk relatives by participants to share their genetic test results and facilitate cascade testing. To explore the acceptability, usability, and understanding of the study consent, post-result follow-up and cascade testing chatbots, we conducted six focus groups with MyCode participants. Sixty-two individuals participated in a focus group (n = 33 consent chatbot, n = 29 follow-up and cascade chatbot). Participants were mostly female (n = 42, 68%), Caucasian (n = 58, 94%), college-educated (n = 33,53%), retirees (n = 38, 61%), and of age 56 years or older (n = 52, 84%). Few participants reported that they knew what a chatbot was (n = 10, 16%), and a small number reported that they had used a chatbot (n = 5, 8%). Qualitative analysis of transcripts and notes from focus groups revealed four main themes: (a) overall impressions, (b) suggested improvements, (c) concerns and limitations, and (d) implementation. Participants supported using chatbots to consent for genomics research and to interact with healthcare providers for care coordination following receipt of genomic results. Most expressed willingness to use a chatbot to share genetic information with relatives. The consent chatbot presents an engaging alternative to deliver content challenging to comprehend in traditional paper or in-person consent. The cascade and follow-up chatbots may be acceptable, user-friendly, scalable approaches to manage ancillary genetic counseling tasks.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jgc4.1169DOI Listing
December 2019

Hypertrophic cardiomyopathy genetic test reports: A qualitative study of patient understanding of uninformative genetic test results.

J Genet Couns 2019 12 13;28(6):1087-1097. Epub 2019 Aug 13.

Division of Human Genetics, The Ohio State University, Columbus, Ohio.

Studies have shown that patients with hypertrophic cardiomyopathy (HCM) may misinterpret the meaning of uninformative genetic testing results to mean that a genetic etiology and family members' risk is ruled out. We hypothesized that poor comprehension of the laboratory genetic test report may contribute to this misunderstanding. We conducted a qualitative study to examine patient understanding of uninformative laboratory results and reports and elicit suggestions for an improved report. Fifteen participants with HCM were interviewed after undergoing genetic testing and receiving their report. While all patients read the report, most participants reported only partially reading it. Most reported not understanding the report at all or only partially understanding it because a provider explained it to them. Some participants said that the report was helpful for understanding their result, but there was evidence of misunderstanding; most participants stated that specific aspects of the report were unhelpful. While most of our participants communicated risk with relatives, none said that the report helped with the communication. Most participants did not recall or find the accompanying physician-directed result letter useful for their understanding or familial communication. Many participants expressed need for a supplemental report that illustrates a personalized clinical 'action plan' that could summarize clinical and familial implications of the result for the patient and their family. We conclude that laboratory reports and physician-directed result letters did not help participants understand their results or their familial implications. Our results suggest opportunities for research to explore the utility of a patient-directed result supplement to improve patient comprehension of genetic test results and outline clinical recommendations via a patient action plan.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jgc4.1159DOI Listing
December 2019

Barriers and Facilitators to Genetic Testing for Familial Hypercholesterolemia in the United States: A Review.

J Pers Med 2019 Jul 1;9(3). Epub 2019 Jul 1.

Department of Population Medicine, Harvard Pilgrim Health Care Institute and Harvard Medical School, Boston, MA 02215 USA.

Familial Hypercholesterolemia (FH) is an underdiagnosed condition in the United States (US) and globally, affecting an estimated 1/250 individuals. It is a genetic risk factor for premature cardiovascular disease and is responsible for an estimated 600,000 to 1.2 million preventable vascular events. Studies show that FH genetic testing can identify a causal gene variant in 60 to 80% of clinically suspected FH cases. However, FH genetic testing is currently underutilized in clinical settings in the US despite clinical recommendations and evidence supporting its use. Reasons for underutilization are not well understood. We conducted a literature review in the PubMed/MEDLINE database and eight peer-reviewed journals. After filtering for and reviewing 2340 articles against our inclusion criteria, we included nine commentaries or expert opinions and eight empirical studies reported between January 2014 and March 2019 in our review. After applying the Consolidated Framework for Implementation Research (CFIR), we identified a total of 26 potential barriers and 15 potential facilitators (estimated barrier to facilitator ratio of 1.73). We further estimated ratios of potential barriers to facilitators for each CFIR domain (Characteristics of Intervention, Outer Setting, Inner Setting, Characteristics of Individuals, and Process). Findings derived from our systematic approach to the literature and calculations of estimated baseline ratios of barriers and facilitators can guide future research to understand FH genetic testing implementation in diverse clinical settings. Our systematic approach to the CFIR could also be used as a model to understand or compare barriers and facilitators to other evidence-based genetic testing processes in health care settings in the US and abroad.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/jpm9030032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6789613PMC
July 2019

Ankyrin-B dysfunction predisposes to arrhythmogenic cardiomyopathy and is amenable to therapy.

J Clin Invest 2019 07 2;129(8):3171-3184. Epub 2019 Jul 2.

Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.

Arrhythmogenic cardiomyopathy (ACM) is an inherited arrhythmia syndrome characterized by severe structural and electrical cardiac phenotypes, including myocardial fibrofatty replacement and sudden cardiac death. Clinical management of ACM is largely palliative, owing to an absence of therapies that target its underlying pathophysiology, which stems partially from our limited insight into the condition. Following identification of deceased ACM probands possessing ANK2 rare variants and evidence of ankyrin-B loss of function on cardiac tissue analysis, an ANK2 mouse model was found to develop dramatic structural abnormalities reflective of human ACM, including biventricular dilation, reduced ejection fraction, cardiac fibrosis, and premature death. Desmosomal structure and function appeared preserved in diseased human and murine specimens in the presence of markedly abnormal β-catenin expression and patterning, leading to identification of a previously unknown interaction between ankyrin-B and β-catenin. A pharmacological activator of the WNT/β-catenin pathway, SB-216763, successfully prevented and partially reversed the murine ACM phenotypes. Our findings introduce what we believe to be a new pathway for ACM, a role of ankyrin-B in cardiac structure and signaling, a molecular link between ankyrin-B and β-catenin, and evidence for targeted activation of the WNT/β-catenin pathway as a potential treatment for this disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/JCI125538DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6668697PMC
July 2019
-->