Publications by authors named "Colleen Caleshu"

37 Publications

Contributors to and consequences of burnout among clinical genetic counselors in the United States.

J Genet Couns 2021 Jul 28. Epub 2021 Jul 28.

Department of Genetics, Stanford University, Stanford, CA, USA.

Prior research has found that many genetic counselors (GCs) experience burnout. Studies of other clinicians have demonstrated that burnout can have significant detrimental consequences for clinicians, patients, and the healthcare system. We sought to explore the prevalence of, contributors to, and consequences of burnout among GCs. We performed a secondary data analysis of baseline data from Me-GC, a randomized controlled trial of meditation for GCs. We applied a systems model of burnout proposed by the National Academy of Medicine (NAM), which depicts burnout arising from a combination of contributors that include both work system and individual mediating factors, and then leading to consequences. Validated self-report scales were used to measure burnout and most contributors and consequences. Female and white GCs were over-represented in our sample. Over half (57.2%) of the 397 participants had Professional Fulfillment Index scores indicative of burnout. Multiple potential contributors were associated with burnout, consistent with its known multifactorial nature. Among work system factors, higher levels of burnout were associated with insufficient administrative support, lack of autonomy, and not feeling valued by non-GC colleagues. Individual mediating factors associated with greater burnout included higher levels of anxiety, depression, and stress. Participants with lower levels of burnout reported greater mindfulness, resilience, and use of professional self-care behaviors. Among variables categorized as consequences, higher levels of burnout were associated with lower levels of empathy, counseling alliance, and positive unconditional regard, as well as higher reactive distress, and a greater desire to reduce the amount of time spent on clinical care. Given the prevalence and potential consequences of burnout observed here, it is imperative that the field take steps to mitigate burnout risk.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jgc4.1485DOI Listing
July 2021

Genetic counselor experiences with telehealth before and after COVID-19.

J Genet Couns 2021 08 7;30(4):999-1009. Epub 2021 Jul 7.

Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, MN, USA.

While genetic counselor (GC) utilization of telehealth has increased in recent years, the onset of the COVID-19 pandemic significantly accelerated the adoption of telehealth for many. We investigated GC experiences with telehealth including perceived advantages, disadvantages, and barriers using a one-time online survey of GCs who provided direct patient care in recent years. The survey examined experiences with telehealth before and after the onset of COVID-19. We made broad comparisons to findings from a similar study our research team conducted five years ago. GCs reported an increase in the utilization of telehealth over time, with significant increases from pre-2017 (44%) to pre-COVID-19 (70%) and then to present (87%) (p<.001 and .02, respectively). There was no significant change in the total number of hours worked from pre-COVID-19 to the time of survey completion, nor were there significant changes in the amount of time spent on clinical responsibilities or interfacing with patients. However, the total number of hours worked in telehealth significantly increased (z = 5.05, p<.001) as did the percent of time spent interacting with patients via telehealth [t(72)=3.74, p<.001, d = 0.44]. Participants overwhelmingly preferred video (84%) over telephone; this differs from our previous survey where video was the preferred modality for 59% (p<.001). We utilized open-ended questions to elicit reasons for modality preference. The most-cited barrier to telehealth utilization was billing/reimbursement issues, with 39% noting this obstacle. This is consistent with our previous study where 30% cited billing/reimbursement as the primary barrier. These findings indicate a need for continued efforts to improve billing and reimbursement for genetic counseling offered via telehealth. They also present an opportunity for additional exploration regarding patient preferences for telehealth modality.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jgc4.1465DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8426975PMC
August 2021

U.S. Genetic counselors' perceptions of inpatient genetic counseling: A valuable model for medically complex patients.

J Genet Couns 2021 Jun 14. Epub 2021 Jun 14.

Stanford Center for Inherited Cardiovascular Disease, Stanford, CA, USA.

Some genetic counselors (GCs) provide care in the inpatient setting. However, there is little literature on inpatient genetic counseling. The purpose of our study was to describe GC's experiences with the provision of genetic counseling services within inpatient care settings. Participants were recruited from respondents to a quantitative survey study on inpatient genetic counseling, which recruited GCs via the National Society of Genetic Counselors forum. GCs seeing at least five inpatients per year were invited to participate in semi-structured interviews. The interview guide explored how and why their inpatient genetic counseling service started, workflow, and the perceived impact of the service. Interviews were transcribed, inductive analysis was used to develop a codebook, and thematic analysis was used to identify themes. Twenty-one inpatient genetic counselors participated in the study. Many participants worked primarily in outpatient roles with some inpatient duties (61.9%), while the rest worked primarily in inpatient roles (38.1%). Most participants have provided inpatient care for <2 years (66.7%). Many participants were involved in inpatient care across multiple specialties (66.7%), most frequently, pediatrics, neonatology, and neurology. Three themes were identified: (a) The convenience of inpatient genetic counseling leads to increased access to appropriate genetics care for medically complex patients and their inpatient healthcare providers, (b) the inpatient genetic counseling process and workflow is not standard and has multiple moving parts, and (c) genetic counselors are fulfilled by the diverse and unique opportunities of the inpatient care setting despite the emotional intensity of this environment. Participants described their inpatient care as valuable because it increases access to genetics services and adds genetics expertise to multidisciplinary inpatient teams. Overall, participants perceive inpatient genetic counseling as a way to bring genetics care directly to patients at a critical time point in their care, which benefits medically complex patients and their multidisciplinary inpatient team.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jgc4.1435DOI Listing
June 2021

Pathological Overlap of Arrhythmogenic Right Ventricular Cardiomyopathy and Cardiac Sarcoidosis.

Circ Genom Precis Med 2019 10 21;12(10):452-454. Epub 2019 Sep 21.

Department of Medicine - Division of Cardiovascular Medicine (C.C., C.R., E.A., V.N.P., R.S.), Stanford University School of Medicine, CA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCGEN.119.002638DOI Listing
October 2019

Regional Variation in RBM20 Causes a Highly Penetrant Arrhythmogenic Cardiomyopathy.

Circ Heart Fail 2019 03;12(3):e005371

Division of Cardiovascular Medicine, Department of Medicine (V.N.P., C.C., C.R., M.T.W., E.A.A.), Stanford University School of Medicine, CA.

Background Variants in the cardiomyocyte-specific RNA splicing factor RBM20 have been linked to familial cardiomyopathy, but the causative genetic architecture and clinical consequences of this disease are incompletely defined. Methods and Results To define the genetic architecture of RBM20 cardiomyopathy, we first established a database of RBM20 variants associated with cardiomyopathy and compared these to variants observed in the general population with respect to their location in the RBM20 coding transcript. We identified 2 regions significantly enriched for cardiomyopathy-associated variants in exons 9 and 11. We then assembled a registry of 74 patients with RBM20 variants from 8 institutions across the world (44 index cases and 30 from cascade testing). This RBM20 patient registry revealed highly prevalent family history of sudden cardiac death (51%) and cardiomyopathy (72%) among index cases and a high prevalence of composite arrhythmias (including atrial fibrillation, nonsustained ventricular tachycardia, implantable cardiac defibrillator discharge, and sudden cardiac arrest, 43%). Patients harboring variants in cardiomyopathy-enriched regions identified by our variant database analysis were enriched for these findings. Further, these characteristics were more prevalent in the RBM20 registry than in large cohorts of patients with dilated cardiomyopathy and TTNtv cardiomyopathy and not significantly different from a cohort of patients with LMNA-associated cardiomyopathy. Conclusions Our data establish RBM20 cardiomyopathy as a highly penetrant and arrhythmogenic cardiomyopathy. These findings underline the importance of arrhythmia surveillance and family screening in this disease and represent the first step in defining the genetic architecture of RBM20 disease causality on a population level.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCHEARTFAILURE.118.005371DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6422044PMC
March 2019

Evaluating the Clinical Validity of Hypertrophic Cardiomyopathy Genes.

Circ Genom Precis Med 2019 02;12(2):e002460

Department of Pathology, Harvard Medical School/Massachusetts General Hospital, Boston (L.W., B.F.).

Background: Genetic testing for families with hypertrophic cardiomyopathy (HCM) provides a significant opportunity to improve care. Recent trends to increase gene panel sizes often mean variants in genes with questionable association are reported to patients. Classification of HCM genes and variants is critical, as misclassification can lead to genetic misdiagnosis. We show the validity of previously reported HCM genes using an established method for evaluating gene-disease associations.

Methods: A systematic approach was used to assess the validity of reported gene-disease associations, including associations with isolated HCM and syndromes including left ventricular hypertrophy. Genes were categorized as having definitive, strong, moderate, limited, or no evidence of disease causation. We also reviewed current variant classifications for HCM in ClinVar, a publicly available variant resource.

Results: Fifty-seven genes were selected for curation based on their frequent inclusion in HCM testing and prior association reports. Of 33 HCM genes, only 8 (24%) were categorized as definitive ( MYBPC3, MYH7, TNNT2, TNNI3, TPM1, ACTC1, MYL2, and MYL3); 3 had moderate evidence ( CSRP3, TNNC1, and JPH2; 33%); and 22 (66%) had limited (n=16) or no evidence (n=6). There were 12 of 24 syndromic genes definitively associated with isolated left ventricular hypertrophy. Of 4191 HCM variants in ClinVar, 31% were in genes with limited or no evidence of disease association.

Conclusions: The majority of genes previously reported as causative of HCM and commonly included in diagnostic tests have limited or no evidence of disease association. Systematically curated HCM genes are essential to guide appropriate reporting of variants and ensure the best possible outcomes for HCM families.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCGEN.119.002460DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6410971PMC
February 2019

Incident Atrial Fibrillation Is Associated With MYH7 Sarcomeric Gene Variation in Hypertrophic Cardiomyopathy.

Circ Heart Fail 2018 09;11(9):e005191

Division of Cardiovascular Medicine, Department of Medicine, Stanford University, CA (S.-P.L., E.A.A., M.V.P.).

Background Although atrial fibrillation (AF) is common in hypertrophic cardiomyopathy (HCM) patients, the relationship between genetic variation and AF has been poorly defined. Characterizing genetic subtypes of HCM and their associations with AF may help to improve personalized medical care. We aimed to investigate the link between sarcomeric gene variation and incident AF in HCM patients. Methods and Results Patients from the multinational Sarcomeric Human Cardiomyopathy Registry were followed for incident AF. Those with likely pathogenic or pathogenic variants in sarcomeric genes were included. The AF incidence was ascertained by review of medical records and electrocardiograms at each investigative site. One thousand forty adult HCM patients, without baseline AF and with likely pathogenic or pathogenic variation in either MYH7 (n=296), MYBPC3 (n=659), or thin filament genes (n=85), were included. Compared with patients with variation in other sarcomeric genes, those with MYH7 variants were younger on first clinical encounter at the Sarcomeric Human Cardiomyopathy Registry site and more likely to be probands than the MYBPC3 variants. During an average follow-up of 7.2 years, 198 incident AF events occurred. Patients with likely pathogenic or pathogenic mutations in MYH7 had the highest incidence of AF after adjusting for age, sex, proband status, left atrial size, maximal wall thickness, and peak pressure gradient (hazard ratio, 1.7; 95% CI, 1.1-2.6; P=0.009). Conclusions During a mean follow-up of 7.2 years, new-onset AF developed in 19% of HCM patients with sarcomeric mutations. Compared with other sarcomeric genes, patients with likely pathogenic or pathogenic variation in MYH7 had a higher rate of incident AF independent of clinical and echocardiographic factors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCHEARTFAILURE.118.005191DOI Listing
September 2018

Genotype and Lifetime Burden of Disease in Hypertrophic Cardiomyopathy: Insights from the Sarcomeric Human Cardiomyopathy Registry (SHaRe).

Circulation 2018 10 23;138(14):1387-1398. Epub 2018 Aug 23.

Cardiomyopathy Unit and Genetic Unit, Careggi University Hospital, Florence, Italy.

Background: A better understanding of the factors that contribute to heterogeneous outcomes and lifetime disease burden in hypertrophic cardiomyopathy (HCM) is critically needed to improve patient management and outcomes. The Sarcomeric Human Cardiomyopathy Registry (SHaRe) was established to provide the scale of data required to address these issues, aggregating longitudinal datasets curated by eight international HCM specialty centers.

Methods: Data on 4591 HCM patients (2763 genotyped), followed for a mean of 5.4±6.9 years (24,791 patient-years; median [interquartile range] 2.9 [0.3-7.9] years) were analyzed regarding cardiac arrest, cardiac transplantation, appropriate implantable cardioverter-defibrillator (ICD) therapy, all-cause death, atrial fibrillation, stroke, New York Heart Association Functional Class III/IV symptoms (all comprising the overall composite endpoint), and left ventricular ejection fraction (LVEF)<35%. Outcomes were analyzed individually and as composite endpoints.

Results: Median age of diagnosis was 45.8 [30.9-58.1] years and 37% of patients were female. Age of diagnosis and sarcomere mutation status were predictive of outcomes. Patients <40 years old at diagnosis had a 77% [95% confidence interval: 72%, 80%] cumulative incidence of the overall composite outcome by age 60, compared to 32% [29%, 36%] by age 70 for patients diagnosed >60 years. Young HCM patients (20-29 years) had 4-fold higher mortality than the general United States population at a similar age. Patients with pathogenic/likely pathogenic sarcomere mutations had two-fold greater risk for adverse outcomes compared to patients without mutations; sarcomere variants of uncertain significance were associated with intermediate risk. Heart failure and atrial fibrillation were the most prevalent adverse events, although typically not emerging for several years after diagnosis. Ventricular arrhythmias occurred in 32% [23%, 40%] of patients <40 years at diagnosis, but in 1% [1%, 2%] >60 years.

Conclusions: The cumulative burden of HCM is substantial and dominated by heart failure and atrial fibrillation occurring many years following diagnosis. Young age of diagnosis and the presence of a sarcomere mutation are powerful predictors of adverse outcomes. These findings highlight the need for close surveillance throughout life, and the need to develop disease-modifying therapies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCULATIONAHA.117.033200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6170149PMC
October 2018

Evolving Decisions: Perspectives of Active and Athletic Individuals with Inherited Heart Disease Who Exercise Against Recommendations.

J Genet Couns 2018 Sep 15. Epub 2018 Sep 15.

Stanford Center for Inherited Cardiovascular Disease, Stanford Healthcare, Stanford, CA, USA.

Individuals with hypertrophic cardiomyopathy (HCM) and long QT syndrome (LQTS) are advised to avoid certain forms of exercise to reduce their risk of sudden death. Cardiovascular genetic counselors facilitate both adaptation to, and decision-making about, these exercise recommendations. This study describes decision-making and experiences of active adults who exercise above physicians' recommendations. Purposive sampling was used to select adults with HCM and LQTS who self-identified as exercising above recommendations. Semi-structured interviews explored participants' decision-making and the psychological impact of exercise recommendations. Fifteen individuals were interviewed (HCM: 10; LQTS: 5; mean age: 40). Transcripts were coded and analyzed for underlying themes. Despite exercising above recommendations, nearly all participants made some modifications to their prior exercise regimen. Often these decisions changed over time, underscoring the importance of shared decision-making conversations beyond the initial evaluation. The importance of exercise was frequently cited as a reason for continued exercise, as were perceptions of sudden death risk as low, acceptable, or modifiable. Many participants reported that family and friends supported their exercise decisions, with a minority having family or friends that expressed significant reservations. Genetic counselors, cardiologists, and nurses can use these data to inform their counseling regarding exercise recommendations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10897-018-0297-6DOI Listing
September 2018

Mindfulness Among Genetic Counselors Is Associated with Increased Empathy and Work Engagement and Decreased Burnout and Compassion Fatigue.

J Genet Couns 2018 09 4;27(5):1175-1186. Epub 2018 Mar 4.

Department of Genetics, Stanford Center for Biomedical Ethics, Stanford, CA, USA.

Genetic counselors experience high rates of compassion fatigue and an elevated risk for burnout, both of which can negatively impact patient care and retention in the profession. In other healthcare professions, mindfulness training has been successfully used to address similar negative psychological sequelae and to bolster empathy, which is the foundation of our counseling work. We aimed to assess associations between mindfulness and key professional variables, including burnout, compassion fatigue, work engagement, and empathy. Data were collected via an anonymous, online survey that included validated measures of mindfulness and these key professional variables. The survey was completed by 441 genetic counselors involved in direct patient care. Half of the respondents (50.1%) reported engaging in yoga, meditation, and/or breathing exercises. Mindfulness was positively correlated with work engagement (r = 0.24, p < 0.001) and empathy (as measured through four subscales: perspective taking (r = 0.15, p = 0.002), empathic concern (r = 0.11, p = 0.03), fantasy (r = - 0.11, p = 0.03) and personal distress (r = - 0.15, p = 0.001)). Mindfulness was negatively correlated with compassion fatigue (r = - 0.48, p < 0.001) and burnout (r = - 0.50, p < 0.001). Given these findings, mindfulness training may be a valuable addition to graduate and continuing education for genetic counselors. The integration of mindfulness into the genetic counseling field will likely improve professional morale and well-being, while promoting workforce retention and bolstering the relational and counseling aspects of our clinical work.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10897-018-0236-6DOI Listing
September 2018

Adaptation and validation of the ACMG/AMP variant classification framework for MYH7-associated inherited cardiomyopathies: recommendations by ClinGen's Inherited Cardiomyopathy Expert Panel.

Genet Med 2018 03 4;20(3):351-359. Epub 2018 Jan 4.

Laboratory for Molecular Medicine, Partners Healthcare Personalized Medicine, Boston, Massachusetts, USA.

PurposeIntegrating genomic sequencing in clinical care requires standardization of variant interpretation practices. The Clinical Genome Resource has established expert panels to adapt the American College of Medical Genetics and Genomics/Association for Molecular Pathology classification framework for specific genes and diseases. The Cardiomyopathy Expert Panel selected MYH7, a key contributor to inherited cardiomyopathies, as a pilot gene to develop a broadly applicable approach.MethodsExpert revisions were tested with 60 variants using a structured double review by pairs of clinical and diagnostic laboratory experts. Final consensus rules were established via iterative discussions.ResultsAdjustments represented disease-/gene-informed specifications (12) or strength adjustments of existing rules (5). Nine rules were deemed not applicable. Key specifications included quantitative frameworks for minor allele frequency thresholds, the use of segregation data, and a semiquantitative approach to counting multiple independent variant occurrences where fully controlled case-control studies are lacking. Initial inter-expert classification concordance was 93%. Internal data from participating diagnostic laboratories changed the classification of 20% of the variants (n = 12), highlighting the critical importance of data sharing.ConclusionThese adapted rules provide increased specificity for use in MYH7-associated disorders in combination with expert review and clinical judgment and serve as a stepping stone for genes and disorders with similar genetic and clinical characteristics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/gim.2017.218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5876064PMC
March 2018

Clinically impactful differences in variant interpretation between clinicians and testing laboratories: a single-center experience.

Genet Med 2018 Mar 14;20(3):369-373. Epub 2017 Dec 14.

Stanford Center for Inherited Cardiovascular Disease, Stanford University, Stanford, California, USA.

PurposeTo describe the frequency and nature of differences in variant classifications between clinicians and genetic testing laboratories.MethodsRetrospective review of variants identified through genetic testing ordered in routine clinical care by clinicians in the Stanford Center for Inherited Cardiovascular Disease. We compared classifications made by clinicians, the testing laboratory, and other laboratories in ClinVar.ResultsOf 688 laboratory classifications, 124 (18%) differed from the clinicians' classifications. Most differences in classification would probably affect clinical care of the patient and/or family (83%, 103/124). The frequency of discordant classifications differed depending on the testing laboratory (P < 0.0001) and the testing laboratory's classification (P < 0.00001). For the majority (82/124, 66%) of discordant classifications, clinicians were more conservative (less likely to classify a variant pathogenic or likely pathogenic). The clinicians' classification was discordant with one or more submitter in ClinVar in 49.1% (28/57) of cases, while the testing laboratory's classification was discordant with a ClinVar submitter in 82.5% of cases (47/57, P = 0.0002).ConclusionThe clinical team disagreed with the laboratory's classification at a rate similar to that of reported disagreements between laboratories. Most of this discordance was clinically significant, with clinicians tending to be more conservative than laboratories in their classifications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/gim.2017.212DOI Listing
March 2018

Clinical Cardiovascular Genetic Counselors Take a Leading Role in Team-based Variant Classification.

J Genet Couns 2018 08 12;27(4):751-760. Epub 2017 Dec 12.

Stanford Center for Inherited Cardiovascular Disease, Stanford University, Stanford, CA, USA.

We sought to delineate the genetic test review and interpretation practices of clinical cardiovascular genetic counselors. A one-time anonymous online survey was taken by 46 clinical cardiovascular genetic counselors recruited through the National Society of Genetic Counselors Cardiovascular Special Interest Group. Nearly all (95.7%) gather additional information on variants reported on clinical genetic test reports and most (81.4%) assess the classification of such variants. Clinical cardiovascular genetic counselors typically (81.0%) classify variants in collaboration with cardiologist and/or geneticist colleagues, with the genetic counselor as the team member who is primarily responsible. Variant classification is a relatively recent (mean 3.2 years) addition to practice. Most genetic counselors learned classification skills on the job from clinical and laboratory colleagues. Recent graduates were more likely to have learned this in graduate school (p < 0.001). Genetic counselors are motivated to take responsibility for the classification of variants because of prior experiences with variant reclassification, inconsistencies between laboratories, and incomplete laboratory reports. They are also driven by a sense of professional duty and their proximity to the clinical context. This practice represents a broadening of the skill set of clinical cardiovascular genetic counselors and a unique expertise that they contribute to the interdisciplinary teams in which they work.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10897-017-0175-7DOI Listing
August 2018

Care in Specialized Centers and Data Sharing Increase Agreement in Hypertrophic Cardiomyopathy Genetic Test Interpretation.

Circ Cardiovasc Genet 2017 Oct;10(5)

From the California Department of Biological Sciences, State University, Stanislaus, Turlock, CA (A.F.); Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI (P.A., S.M.D.); Genetics Unit, Careggi University Hospital, Florence, Italy (F.G.); Cardiovascular Division, Brigham and Women's Hospital, Boston, MA (A.L.C., C.Y.H.); Department of Cardiology, Thoraxcenter, Erasmus Medical Center, Rotterdam, The Netherlands (M.M.); Referral Center for Myocardial Diseases, Azienda Ospedaliera Universitaria Careggi, Florence, Italy (I.O.); Stanford Center for Inherited Cardiovascular Disease, Stanford Medical Center, CA (E.A., C.C.); Division of Cardiovascular Medicine (E.A.) and Division of Medical Genetics (C.C.), Stanford University Medical Center, Stanford, CA; and Translational Research, MyoKardia Inc., South San Francisco, CA (E.M.G.).

Background: Clinically impactful differences in the interpretation of genetic test results occur between laboratories and clinicians. To improve the classification of variants, a better understanding of why discrepancies occur and how they can be reduced is needed.

Methods And Results: We examined the frequency, causes, and resolution of discordant variant classifications in the Sarcomeric Human Cardiomyopathy Registry (SHaRe), a consortium of international centers with expertise in the clinical management and genetic architecture of hypertrophic cardiomyopathy. Of the 112 variants present in patients at >1 center, 23 had discordant classifications among centers (20.5%; Fleiss κ, 0.54). Discordance was more than twice as frequent among clinical laboratories in ClinVar, a public archive of variant classifications (315/695 variants; 45.2%; Fleiss κ, 0.30; <0.001). Discordance in SHaRe most frequently occurred because hypertrophic cardiomyopathy centers had access to different privately held data when making their classifications (75.0%). Centers reassessed their classifications based on a comprehensive and current data summary, leading to reclassifications that reduced the discordance rate from 20.5% to 10.7%. Different interpretations of rarity and co-occurrence with pathogenic variants contributed to residual discordance.

Conclusions: Discordance in variant classification among hypertrophic cardiomyopathy centers is largely attributable to privately held data. Some discrepancies are caused by differences in expert assessment of conflicting data. Discordance was markedly lower among centers specialized in hypertrophic cardiomyopathy than among clinical laboratories, suggesting that optimal genetic test interpretation occurs in the context of clinical care delivered by specialized centers with both clinical and genetics expertise.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCGENETICS.116.001700DOI Listing
October 2017

Role of Genetic Testing in Inherited Cardiovascular Disease: A Review.

JAMA Cardiol 2017 10;2(10):1153-1160

Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts.

Importance: Genetic testing is a valuable tool for managing inherited cardiovascular disease in patients and families, including hypertrophic, dilated, and arrhythmogenic cardiomyopathies and inherited arrhythmias. By identifying the molecular etiology of disease, genetic testing can improve diagnostic accuracy and refine family management. However, unique features associated with genetic testing affect the interpretation and application of results and differentiate it from traditional laboratory-based diagnostics. Clinicians and patients must have accurate and realistic expectations about the yield of genetic testing and its role in management. Familiarity with the rationale, implications, benefits, and limitations of genetic testing is essential to achieve the best possible outcomes.

Observations: Successfully incorporating genetic testing into clinical practice requires (1) recognizing when inherited cardiovascular disease may be present, (2) identifying appropriate individuals in the family for testing, (3) selecting the appropriate genetic test, (4) understanding the complexities of result interpretation, and (5) effectively communicating the results and implications to the patient and family. Obtaining a detailed family history is critical to identify families who will benefit from genetic testing, determine the best strategy, and interpret results. Instead of focusing on an individual patient, genetic testing requires consideration of the family as a unit. Consolidation of care in centers with a high level of expertise is recommended. Clinicians without expertise in genetic testing will benefit from establishing referral or consultative networks with experienced clinicans in specialized multidisciplinary clinics.

Conclusions And Relevance: Genetic testing provides a foundation for transitioning to more precise and individualized management. By distinguishing phenotypic subgroups, identifying disease mechanisms, and focusing family care, gene-based diagnosis can improve management. Successful integration of genetic testing into clinical practice requires understanding of the complexities of testing and effective communication of the implications to patients and families.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamacardio.2017.2352DOI Listing
October 2017

Delivering Clinical Grade Sequencing and Genetic Test Interpretation for Cardiovascular Medicine.

Circ Cardiovasc Genet 2017 04;10(2)

From the Royal Brompton and Harefield NHS Foundation Trust, London (A.R.H.); Wellcome Trust Centre for Human Genetics, University of Oxford, United Kingdom (A.R.H.); Department of Genetics, Stanford University, Stanford, CA (E.A.A., R.L.G.); and Center for Inherited Cardiovascular Disease, Stanford University, Stanford, CA (V.N.P., R.L.G., C.C., E.A.A.).

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCGENETICS.116.001221DOI Listing
April 2017

Exercise restrictions trigger psychological difficulty in active and athletic adults with hypertrophic cardiomyopathy.

Open Heart 2016;3(2):e000488. Epub 2016 Oct 17.

Stanford Center for Inherited Cardiovascular Disease, Stanford University School of Medicine , Stanford, California , USA.

Objective: We examined the extent and nature of the psychological difficulty experienced by athletic adults with hypertrophic cardiomyopathy (HCM), correlates of that difficulty and coping mechanisms.

Methods: A survey assessed athletic history and psychological impact of exercise restrictions. LASSO penalised linear regression identified factors associated with psychological difficulty. Semistructured interviews provided deeper insight into the nature and origins of psychological difficulty.

Results: 54 individuals (33% female, mean age 55.9) completed the survey. The majority were recreational athletes at the time of restriction (67%). There was a drop in athleticism after diagnosis, including time spent exercising (p=0.04) and identification as an athlete (p=0.0005). Most respondents (54%) found it stressful and/or difficult to adjust to exercise restrictions. Greater psychological morbidity was associated with history of elite or competitive athletics, athletic identity and decrease in time spent exercising. 16 individuals (44% female, mean age 52.4) were interviewed. Long-term effects included weight gain and uncertainty about exercising safely. The role of exercise in interviewees' lives contracted significantly after restriction, from multiple functions (eg, social, stress relief, fitness) to solely health maintenance. Interviewees reported a unique form of social support: having family and friends participate with them in lower intensity exercise. Lack of understanding from family or friends and avoiding exercise completely were detrimental to coping.

Conclusions: Athletic adults with HCM experience multifaceted, lasting difficulty adjusting to exercise recommendations. These data can guide clinicians in identifying patients at highest risk for distress and in helping to bolster coping and adaptation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/openhrt-2016-000488DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5073663PMC
October 2016

Theories for Psychotherapeutic Genetic Counseling: Fuzzy Trace Theory and Cognitive Behavior Theory.

J Genet Couns 2017 Apr 4;26(2):322-330. Epub 2016 Nov 4.

Stanford University, Palo Alto, CA, USA.

Psychotherapeutic genetic counseling is an increasingly relevant practice description. In this paper we aim to demonstrate how psychotherapeutic genetic counseling can be achieved by using psychological theories to guide one's approach to working with clients. We describe two illustrative examples, fuzzy trace theory and cognitive behavior theory, and apply them to two challenging cases. The theories were partially derived from evidence of beneficial client outcomes using a psychotherapeutic approach to patient care in other settings. We aim to demonstrate how these two specific theories can inform psychotherapeutic genetic counseling practice, and use them as examples of how to take a psychological theory and effectively apply it to genetic counseling.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10897-016-0023-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5383519PMC
April 2017

Response to A Different Vantage Point Commentary: Psychotherapeutic Genetic Counseling, Is it?

J Genet Couns 2017 04 2;26(2):334-336. Epub 2016 Nov 2.

Stanford University, Palo Alto, California, USA.

Whether genetic counseling is a form of psychotherapy is open for debate. Early practicioners in genetic counseling described it as such, and this claim has been replicated in recent publications. This commentary is a rebuttal to the claim that genetic counseling is distinct from psychotherapty. We argue that it is a a form of psychoterapy that aims to help clients manage a health threat that affects their psychological wellbeing, paralleling the goals of psychotherapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10897-016-0025-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5383505PMC
April 2017

Taming the genome: towards better genetic test interpretation.

Genome Med 2016 06 20;8(1):70. Epub 2016 Jun 20.

Stanford Center for Inherited Cardiovascular Disease, 300 Pasteur Drive, Stanford, CA, 94305, USA.

Advances in sequencing technology have taught us much about the human genome, including how difficult it is to interpret rare variation. Improvements in genetic test interpretation are likely to come through data sharing, international collaborative efforts to develop disease-gene specific guidelines, and computational analyses using big data.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13073-016-0325-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4915179PMC
June 2016

Interdisciplinary psychosocial care for families with inherited cardiovascular diseases.

Trends Cardiovasc Med 2016 10 28;26(7):647-53. Epub 2016 Apr 28.

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, Locked Bag 6, Newtown, Sydney, New South Wales, Australia; Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia; Department of Cardiology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia. Electronic address:

Inherited cardiovascular diseases pose unique and complex psychosocial challenges for families, including coming to terms with life-long cardiac disease, risk of sudden death, grief related to the sudden death of a loved one, activity restrictions, and inheritance risk to other family members. Psychosocial factors impact not only mental health but also physical health and cooperation with clinical recommendations. We describe an interdisciplinary approach to the care of families with inherited cardiovascular disease, in which psychological care provided by specialized cardiac genetic counselors, nurses, and psychologists is embedded within the cardiovascular care team. We report illustrative cases and the supporting literature to demonstrate common scenarios, as well as practical guidance for clinicians working in the inherited cardiovascular disease setting.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.tcm.2016.04.010DOI Listing
October 2016

Multidimensional structure-function relationships in human β-cardiac myosin from population-scale genetic variation.

Proc Natl Acad Sci U S A 2016 06 31;113(24):6701-6. Epub 2016 May 31.

Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305; Stanford Center for Inherited Cardiovascular Disease, Stanford University, Stanford, CA 94305;

Myosin motors are the fundamental force-generating elements of muscle contraction. Variation in the human β-cardiac myosin heavy chain gene (MYH7) can lead to hypertrophic cardiomyopathy (HCM), a heritable disease characterized by cardiac hypertrophy, heart failure, and sudden cardiac death. How specific myosin variants alter motor function or clinical expression of disease remains incompletely understood. Here, we combine structural models of myosin from multiple stages of its chemomechanical cycle, exome sequencing data from two population cohorts of 60,706 and 42,930 individuals, and genetic and phenotypic data from 2,913 patients with HCM to identify regions of disease enrichment within β-cardiac myosin. We first developed computational models of the human β-cardiac myosin protein before and after the myosin power stroke. Then, using a spatial scan statistic modified to analyze genetic variation in protein 3D space, we found significant enrichment of disease-associated variants in the converter, a kinetic domain that transduces force from the catalytic domain to the lever arm to accomplish the power stroke. Focusing our analysis on surface-exposed residues, we identified a larger region significantly enriched for disease-associated variants that contains both the converter domain and residues on a single flat surface on the myosin head described as the myosin mesa. Notably, patients with HCM with variants in the enriched regions have earlier disease onset than patients who have HCM with variants elsewhere. Our study provides a model for integrating protein structure, large-scale genetic sequencing, and detailed phenotypic data to reveal insight into time-shifted protein structures and genetic disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.1606950113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4914177PMC
June 2016

Sports genetics moving forward: lessons learned from medical research.

Physiol Genomics 2016 Mar 12;48(3):175-82. Epub 2016 Jan 12.

Division of Cardiovascular Medicine, Department of Medicine, Stanford University, Stanford, California; Center for Inherited Cardiovascular Disease, Division of Cardiovascular Medicine, Stanford University, Stanford, California; Department of Genetics, Stanford University, Stanford, California.

Sports genetics can take advantage of lessons learned from human disease genetics. By righting past mistakes and increasing scientific rigor, we can magnify the breadth and depth of knowledge in the field. We present an outline of challenges facing sports genetics in the light of experiences from medical research. Sports performance is complex, resulting from a combination of a wide variety of different traits and attributes. Improving sports genetics will foremost require analyses based on detailed phenotyping. To find widely valid, reproducible common variants associated with athletic phenotypes, study sample sizes must be dramatically increased. One paradox is that in order to confirm relevance, replications in specific populations must be undertaken. Family studies of athletes may facilitate the discovery of rare variants with large effects on athletic phenotypes. The complexity of the human genome, combined with the complexity of athletic phenotypes, will require additional metadata and biological validation to identify a comprehensive set of genes involved. Analysis of personal genetic and multiomic profiles contribute to our conceptualization of precision medicine; the same will be the case in precision sports science. In the refinement of sports genetics it is essential to evaluate similarities and differences between sexes and among ethnicities. Sports genetics to date have been hampered by small sample sizes and biased methodology, which can lead to erroneous associations and overestimation of effect sizes. Consequently, currently available genetic tests based on these inherently limited data cannot predict athletic performance with any accuracy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1152/physiolgenomics.00109.2015DOI Listing
March 2016

A Case for Inclusion of Genetic Counselors in Cardiac Care.

Cardiol Rev 2016 Mar-Apr;24(2):49-55

From the *Department of Internal Medicine, University of Michigan, Ann Arbor, MI; †Stanford Center for Inherited Cardiovascular Disease, Palo Alto, CA; ‡Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN; §Department of Medicine-Cardiology, University of Minnesota Physicians, Minneapolis, MN; ¶Center for Individualized Medicine, Mayo Clinic, Rochester, MN; ‖University of Wisconsin School of Medicine and Public Health, Madison, WI; **Genomic Medicine Institute, Cleveland Clinic, Cleveland, OH; ††Yale Cardiovascular Genetics Program, Yale Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT; ‡‡Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN; §§North Memorial, Humphrey Cancer Center, Robbinsdale, MN; ¶¶Mayo Clinic, Rochester, MN; ‖‖Department of Genetics, Yale University School of Medicine, New Haven, CT; ***Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN; and †††Section of Genetics, Rush University Medical Center, Chicago, IL.

Recent advances in genetic testing for heritable cardiac diseases have led to an increasing involvement of the genetic counselor in cardiology practice. We present a series of cases collected from a nationwide query of genetics professionals regarding issues related to cost and utilization of genetic testing. Three themes emerged across cases: (1) choosing the most appropriate genetic test, (2) choosing the best person to test, and (3) interpreting results accurately. These cases demonstrate that involvement of a genetic counselor throughout the evaluation, diagnosis, and continuing management of individuals and families with inherited cardiovascular conditions helps to promote the efficient use of healthcare dollars.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/CRD.0000000000000081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4715801PMC
November 2016

Cardiopulmonary responses and prognosis in hypertrophic cardiomyopathy: a potential role for comprehensive noninvasive hemodynamic assessment.

JACC Heart Fail 2015 May 8;3(5):408-418. Epub 2015 Apr 8.

Stanford University School of Medicine, Department of Medicine, Division of Cardiovascular Medicine, Stanford, California; Stanford Cardiovascular Institute, Stanford, California. Electronic address:

Objectives: This study sought to discover the key determinants of exercise capacity, maximal oxygen consumption (oxygen uptake [Vo2]), and ventilatory efficiency (ventilation/carbon dioxide output [VE/Vco2] slope) and assess the prognostic potential of metabolic exercise testing in hypertrophic cardiomyopathy (HCM).

Background: The intrinsic mechanisms leading to reduced functional tolerance in HCM are unclear.

Methods: The study sample included 156 HCM patients consecutively enrolled from January 1, 2007 to January 1, 2012 with a complete clinical assessment, including rest and stress echocardiography and cardiopulmonary exercise test (CPET) with impedance cardiography. Patients were also followed for the composite outcome of cardiac-related death, heart transplant, and functional deterioration leading to septal reduction therapy (myectomy or septal alcohol ablation).

Results: Abnormalities in CPET responses were frequent, with 39% (n = 61) of the sample showing a reduced exercise tolerance (Vo2 max <80% of predicted) and 19% (n = 30) characterized by impaired ventilatory efficiency (VE/Vco2 slope >34). The variables most strongly associated with exercise capacity (expressed in metabolic equivalents), were peak cardiac index (r = 0.51, p < 0.001), age (r = -0.25, p < 0.01), male sex (r = 0.24, p = 0.02), and indexed right ventricular end-diastolic area (r = 0.31, p = 0.002), resulting in an R(2) of 0.51, p < 0.001. Peak cardiac index was the main predictor of peak Vo2 (r = 0.61, p < 0.001). The variables most strongly related to VE/VCO2 slope were E/E' (r = 0.23, p = 0.021) and indexed left atrial volume index (LAVI) (r = 0.34, p = 0.005) (model R(2) = 0.15). The composite endpoint occurred in 21 (13%) patients. In an exploratory analysis, 3 variables were independently associated with the composite outcome (mean follow-up 27 ± 11 months): peak Vo2 <80% of predicted (hazard ratio: 4.11; 95% confidence interval [CI]: 1.46 to 11.59; p = 0.008), VE/Vco2 slope >34 (hazard ratio: 3.14; 95% CI: 1.26 to 7.87; p = 0.014), and LAVI >40 ml/m(2) (hazard ratio: 3.32; 95% CI: 1.08 to 10.16; p = 0.036).

Conclusions: In HCM, peak cardiac index is the main determinant of exercise capacity, but it is not significantly related to ventilatory efficiency. Peak Vo2, ventilatory inefficiency, and LAVI are associated with an increased risk of major events in the short-term follow-up.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jchf.2014.11.011DOI Listing
May 2015

Clinical interpretation and implications of whole-genome sequencing.

JAMA 2014 Mar;311(10):1035-45

Stanford Center for Inherited Cardiovascular Disease, Stanford, California2Stanford Cardiovascular Institute, Stanford, California3Division of Cardiovascular Medicine, Stanford University, Stanford, California4Stanford Center for Genomics and Personalized.

Importance: Whole-genome sequencing (WGS) is increasingly applied in clinical medicine and is expected to uncover clinically significant findings regardless of sequencing indication.

Objectives: To examine coverage and concordance of clinically relevant genetic variation provided by WGS technologies; to quantitate inherited disease risk and pharmacogenomic findings in WGS data and resources required for their discovery and interpretation; and to evaluate clinical action prompted by WGS findings.

Design, Setting, And Participants: An exploratory study of 12 adult participants recruited at Stanford University Medical Center who underwent WGS between November 2011 and March 2012. A multidisciplinary team reviewed all potentially reportable genetic findings. Five physicians proposed initial clinical follow-up based on the genetic findings.

Main Outcomes And Measures: Genome coverage and sequencing platform concordance in different categories of genetic disease risk, person-hours spent curating candidate disease-risk variants, interpretation agreement between trained curators and disease genetics databases, burden of inherited disease risk and pharmacogenomic findings, and burden and interrater agreement of proposed clinical follow-up.

Results: Depending on sequencing platform, 10% to 19% of inherited disease genes were not covered to accepted standards for single nucleotide variant discovery. Genotype concordance was high for previously described single nucleotide genetic variants (99%-100%) but low for small insertion/deletion variants (53%-59%). Curation of 90 to 127 genetic variants in each participant required a median of 54 minutes (range, 5-223 minutes) per genetic variant, resulted in moderate classification agreement between professionals (Gross κ, 0.52; 95% CI, 0.40-0.64), and reclassified 69% of genetic variants cataloged as disease causing in mutation databases to variants of uncertain or lesser significance. Two to 6 personal disease-risk findings were discovered in each participant, including 1 frameshift deletion in the BRCA1 gene implicated in hereditary breast and ovarian cancer. Physician review of sequencing findings prompted consideration of a median of 1 to 3 initial diagnostic tests and referrals per participant, with fair interrater agreement about the suitability of WGS findings for clinical follow-up (Fleiss κ, 0.24; P < 001).

Conclusions And Relevance: In this exploratory study of 12 volunteer adults, the use of WGS was associated with incomplete coverage of inherited disease genes, low reproducibility of detection of genetic variation with the highest potential clinical effects, and uncertainty about clinically reportable findings. In certain cases, WGS will identify clinically actionable genetic variants warranting early medical intervention. These issues should be considered when determining the role of WGS in clinical medicine.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jama.2014.1717DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4119063PMC
March 2014

A clinical approach to inherited hypertrophy: the use of family history in diagnosis, risk assessment, and management.

Circ Cardiovasc Genet 2013 Feb;6(1):118-31

Center for Inherited Cardiovascular Disease, Stanford University School of Medicine, Stanford, CA 94305-5406, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCGENETICS.110.959387DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3898734PMC
February 2013

Cardiac structural and sarcomere genes associated with cardiomyopathy exhibit marked intolerance of genetic variation.

Circ Cardiovasc Genet 2012 Dec 16;5(6):602-10. Epub 2012 Oct 16.

Stanford Center for Inherited Cardiovascular Disease, Stanford Hospital & Clinics, CA, USA.

Background: The clinical significance of variants in genes associated with inherited cardiomyopathies can be difficult to determine because of uncertainty regarding population genetic variation and a surprising amount of tolerance of the genome even to loss-of-function variants. We hypothesized that genes associated with cardiomyopathy might be particularly resistant to the accumulation of genetic variation.

Methods And Results: We analyzed the rates of single nucleotide genetic variation in all known genes from the exomes of >5000 individuals from the National Heart, Lung, and Blood Institute's Exome Sequencing Project, as well as the rates of structural variation from the Database of Genomic Variants. Most variants were rare, with over half unique to 1 individual. Cardiomyopathy-associated genes exhibited a rate of nonsense variants, about 96.1% lower than other Mendelian disease genes. We tested the ability of in silico algorithms to distinguish between a set of variants in MYBPC3, MYH7, and TNNT2 with strong evidence for pathogenicity and variants from the Exome Sequencing Project data. Algorithms based on conservation at the nucleotide level (genomic evolutionary rate profiling, PhastCons) did not perform as well as amino acid-level prediction algorithms (Polyphen-2, SIFT). Variants with strong evidence for disease causality were found in the Exome Sequencing Project data at prevalence higher than expected.

Conclusions: Genes associated with cardiomyopathy carry very low rates of population variation. The existence in population data of variants with strong evidence for pathogenicity suggests that even for Mendelian disease genetics, a probabilistic weighting of multiple variants may be preferred over the single gene causality model.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCGENETICS.112.963421DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3526690PMC
December 2012
-->