Marci Schwartz

Patient-Centered Precision Health In A Learning Health Care System: Geisinger’s Genomic Medicine Experience

Health care delivery is increasingly influenced by the emerging concepts of precision health and the learning health care system. Although not synonymous with precision health, genomics is a key enabler of individualized care. Delivering patient-centered, genomics-informed care based on individual-level data in the current national landscape of health care delivery is a daunting challenge. Problems to overcome include data generation, analysis, storage, and transfer; knowledge management and representation for patients and providers at the point of care; process management; and outcomes definition, collection, and analysis. Development, testing, and implementation of a genomics-informed program requires multidisciplinary collaboration and building the concepts of precision health into a multilevel implementation framework. Using the principles of a learning health care system provides a promising solution. This article describes the implementation of population-based genomic medicine in an integrated learning health care system-a working example of a precision health program.

Adding Protective Genetic Variants to Clinical Reporting of Genomic Screening Results: Restoring Balance

Most clinical genetic testing is limited to diagnostic testing for monogenic diseases, such as hereditary breast and ovarian cancer syndrome and hypertrophic cardiomyopathy, and focused on a limited number of genes among individuals with a high pretest probability for the genetic condition. The key clinical question has been whether a causal pathogenic variant is present, which has represented a pragmatic approach because DNA sequencing was expensive and interpretive knowledge limited. Medicine is now entering the era of sequencing-based screening of healthy populations like the MyCode Community Health Initiative cohort1 and the All of Us cohort.2 This means that assessment of a broader spectrum of genetic contribution to risk, including both pathogenic and protective variants,3 will be important to answer clinical questions about penetrance4 and prognosis.5 For example, loss-of-function alleles in the PCSK9 gene are known to be protective against coronary artery disease (CAD).4

Early cancer diagnoses through BRCA1/2 screening of unselected adult biobank participants

PurposeThe clinical utility of screening unselected individuals for pathogenic BRCA1/2 variants has not been established. Data on cancer risk management behaviors and diagnoses of BRCA1/2-associated cancers can help inform assessments of clinical utility.MethodsWhole-exome sequences of participants in the MyCode Community Health Initiative were reviewed for pathogenic/likely pathogenic BRCA1/2 variants. Clinically confirmed variants were disclosed to patient–participants and their clinicians. We queried patient–participants’ electronic health records for BRCA1/2-associated cancer diagnoses and risk management that occurred within 12 months after results disclosure, and calculated the percentage of patient–participants of eligible age who had begun risk management.ResultsThirty-seven MyCode patient–participants were unaware of their pathogenic/likely pathogenic BRCA1/2 variant, had not had a BRCA1/2-associated cancer, and had 12 months of follow-up. Of the 33 who were of an age to begin BRCA1/2-associated risk management, 26 (79%) had performed at least one such procedure. Three were diagnosed with an early-stage, BRCA1/2-associated cancer—including a stage 1C fallopian tube cancer—via these procedures.ConclusionScreening for pathogenic BRCA1/2 variants among unselected individuals can lead to occult cancer detection shortly after disclosure. Comprehensive outcomes data generated within our learning healthcare system will aid in determining whether population-wide BRCA1/2 genomic screening programs offer clinical utility.

Generation and Implementation of a Patient-Centered and Patient-Facing Genomic Test Report in the EHR

Context: Communication of genetic laboratory results to patients and providers is impeded by the complexity of results and reports. This can lead to misinterpretation of results, causing inappropriate care. Patients often do not receive a copy of the report leading to possible miscommunication. To address these problems, we conducted patient-centered research to inform design of interpretive reports. Here we describe the development and deployment of a specific patient-centered clinical decision support (CDS) tool, a multi-use patient-centered genomic test report (PGR) that interfaces with an electronic health record (EHR). Implementation Process: A PGR with a companion provider report was configured for implementation within the EHR using locally developed software (COMPASS™) to manage secure data exchange and access. Findings: We conducted semi-structured interviews with patients, family members, and clinicians that showed they sought clear information addressing findings, family implications, resources, prognosis and next steps relative to the genomic result. Providers requested access to applicable, available clinical guidelines. Initial results indicated patients and providers found the PGR contained helpful, valuable information and would provide a basis for result-related conversation between patients, providers and family. Major Themes: Direct patient involvement in the design and development of a PGR identified format and presentation preferences, and delivery of relevant information to patients and providers, prompting the creation of a CDS tool. Conclusions: Research and development of patient-centered CDS tools designed to support improved patient outcomes, are enhanced by early and substantial engagement of patients in contributing to all phases of tool design and development.

Exome Sequencing–Based Screening for BRCA1/2 Expected Pathogenic Variants Among Adult Biobank Participants

Key Points Question Can population-level genomic screening identify those at risk for disease? Findings In this cross-sectional study of an unselected population cohort of 50 726 adults who underwent exome sequencing, pathogenic and likely pathogenic BRCA1 and BRCA2 variants were found in a higher proportion of patients than was previously reported. Meaning Current methods to identify BRCA1/2 variant carriers may not be sufficient as a screening tool; population genomic screening for hereditary breast and ovarian cancer may better identify patients at high risk and provide an intervention opportunity to reduce mortality and morbidity.

Managing Secondary Genomic Findings Associated With Arrhythmogenic Right Ventricular Cardiomyopathy: Case Studies and Proposal for Clinical Surveillance

DNA variants that are expected to confer risk for arrhythmogenic right ventricular cardiomyopathy (ARVC) are recommended as returnable secondary findings from clinical genomic sequencing. However, ARVC presents several distinct challenges for the care and management of patients ascertained through this genome-first approach. We discuss these challenges and present recent cases that exemplify their impact in a clinical setting. We also propose a standard approach to management of genome-first ARVC evaluations and surveillance and finally discuss potential diagnostic innovations that may provide substantial benefits to patients in this setting, particularly given the acceleration of precision health. The increasing use of wide-scale sequencing in both clinical medicine and research is creating scenarios in which genetic risk for cardiovascular diseases are identified unexpectedly, often before symptoms manifest. The cardiovascular genetic community has developed recommendations for detection and management of genotype-positive, phenotype-negative patients in the context of directed familial cascade screening. However, approaches to managing secondary findings identified through diagnostic sequencing for other conditions or as part of large-scale exome or genome sequencing research efforts remain uncertain.1 These scenarios pose novel challenges to medical care by necessitating clinical decisions about what constitutes an actionable genetic finding and what particular action should be taken. As a starting point, the American College of Medical Genetics and Genomics has published recommendations for the reporting of secondary findings from clinical sequencing.2,3 These recommendations currently include a minimum list of 59 genes representing 27 conditions, which were selected based on the availability of confirmatory diagnostic testing and the existence of potential preventive or treatment measures. Research studies often use this list as a starting place to design their return of results protocols. One of these conditions is ARVC, also known as arrhythmogenic right ventricular dysplasia. Although the identification of a pathogenic DNA variant associated with …