F. Daniel Davis

Distribution and clinical impact of functional variants in 50,726 whole-exome sequences from the DiscovEHR study

Unleashing the power of precision medicine Precision medicine promises the ability to identify risks and treat patients on the basis of pathogenic genetic variation. Two studies combined exome sequencing results for over 50,000 people with their electronic health records. Dewey et al. found that ∼3.5% of individuals in their cohort had clinically actionable genetic variants. Many of these variants affected blood lipid levels that could influence cardiovascular health. Abul-Husn et al. extended these findings to investigate the genetics and treatment of familial hypercholesterolemia, a risk factor for cardiovascular disease, within their patient pool. Genetic screening helped identify at-risk patients who could benefit from increased treatment. Science, this issue p. 10.1126/science.aaf6814, p. 10.1126/science.aaf7000 More than 50,000 exomes, coupled with electronic health records, inform on medically relevant genetic variants. INTRODUCTION Large-scale genetic studies of integrated health care populations, with phenotypic data captured natively in the documentation of clinical care, have the potential to unveil genetic associations that point the way to new biology and therapeutic targets. This setting also represents an ideal test bed for the implementation of genomics in routine clinical care in service of precision medicine. RATIONALE The DiscovEHR collaboration between the Regeneron Genetics Center and Geisinger Health System aims to catalyze genomic discovery and precision medicine by coupling high-throughput exome sequencing to longitudinal electronic health records (EHRs) of participants in Geisinger’s MyCode Community Health Initiative. Here, we describe initial insights from whole-exome sequencing of 50,726 adult participants of predominantly European ancestry using clinical phenotypes derived from EHRs. RESULTS The median duration of EHR data associated with sequenced participants was 14 years, with a median of 87 clinical encounters, 687 laboratory tests, and seven procedures per participant. Forty-eight percent of sequenced individuals had one or more first- or second-degree relatives in the sample, and genome-wide autozygosity was similar to other outbred European populations. We found ~4.2 million single-nucleotide variants and insertion/deletion events, of which ~176,000 are predicted to result in loss of gene function (LoF). The overwhelming majority of these genetic variants occurred at a minor allele frequency of ≤1%, and more than half were singletons. Each participant harbored a median of 21 rare predicted LoFs. At this sample size, ~92% of sequenced genes, including genes that encode existing drug targets or confer risk for highly penetrant genetic diseases, harbor rare heterozygous predicted LoF variants. About 7% of sequenced genes contained rare homozygous predicted LoF variants in at least one individual. Linking these data to EHR-derived laboratory phenotypes revealed consequences of partial or complete LoF in humans. Among these were previously unidentified associations between predicted LoFs in CSF2RB and basophil and eosinophil counts, and EGLN1-associated erythrocytosis segregating in genetically identified family networks. Using predicted LoFs as a model for drug target antagonism, we found associations supporting the majority of therapeutic targets for lipid lowering. To highlight the opportunity for genotype-phenotype association discovery, we performed exome-wide association analyses of EHR-derived lipid values, newly implicating rare predicted LoFs, and deleterious missense variants in G6PC in association with triglyceride levels. In a survey of 76 clinically actionable disease-associated genes, we estimated that 3.5% of individuals harbor pathogenic or likely pathogenic variants that meet criteria for clinical action. Review of the EHR uncovered findings associated with the monogenic condition in ~65% of pathogenic variant carriers’ medical records. CONCLUSION The findings reported here demonstrate the value of large-scale sequencing in an integrated health system population, add to the knowledge base regarding the phenotypic consequences of human genetic variation, and illustrate the challenges and promise of genomic medicine implementation. DiscovEHR provides a blueprint for large-scale precision medicine initiatives and genomics-guided therapeutic target discovery. Therapeutic target validation and genomic medicine in DiscovEHR. (A) Associations between predicted LoF variants in lipid drug target genes and lipid levels. Boxes correspond to effect size, given as the absolute value of effect, in SD units; whiskers denote 95% confidence intervals for effect. The size of the box is proportional to the logarithm (base 10) of predicted LoF carriers. (B and C) Prevalence and expressivity of clinically actionable genetic variants in 76 disease genes, according to EHR data. G76, Geisinger-76. The DiscovEHR collaboration between the Regeneron Genetics Center and Geisinger Health System couples high-throughput sequencing to an integrated health care system using longitudinal electronic health records (EHRs). We sequenced the exomes of 50,726 adult participants in the DiscovEHR study to identify ~4.2 million rare single-nucleotide variants and insertion/deletion events, of which ~176,000 are predicted to result in a loss of gene function. Linking these data to EHR-derived clinical phenotypes, we find clinical associations supporting therapeutic targets, including genes encoding drug targets for lipid lowering, and identify previously unidentified rare alleles associated with lipid levels and other blood level traits. About 3.5% of individuals harbor deleterious variants in 76 clinically actionable genes. The DiscovEHR data set provides a blueprint for large-scale precision medicine initiatives and genomics-guided therapeutic discovery.

The Geisinger MyCode community health initiative: an electronic health record–linked biobank for precision medicine research

Purpose:Geisinger Health System (GHS) provides an ideal platform for Precision Medicine. Key elements are the integrated health system, stable patient population, and electronic health record (EHR) infrastructure. In 2007, Geisinger launched MyCode, a system-wide biobanking program to link samples and EHR data for broad research use.Methods:Patient-centered input into MyCode was obtained using participant focus groups. Participation in MyCode is based on opt-in informed consent and allows recontact, which facilitates collection of data not in the EHR and, since 2013, the return of clinically actionable results to participants. MyCode leverages Geisinger’s technology and clinical infrastructure for participant tracking and sample collection.Results:MyCode has a consent rate of >85%, with more than 90,000 participants currently and with ongoing enrollment of ~4,000 per month. MyCode samples have been used to generate molecular data, including high-density genotype and exome sequence data. Genotype and EHR-derived phenotype data replicate previously reported genetic associations.Conclusion:The MyCode project has created resources that enable a new model for translational research that is faster, more flexible, and more cost-effective than traditional clinical research approaches. The new model is scalable and will increase in value as these resources grow and are adopted across multiple research platforms.Genet Med 18 9, 906–913.

How Geisinger made the case for an institutional duty to return genomic results to biobank participants

To return or not to return the results of genomics research: that has been the question at the crux of an ongoing debate spawned by the increasingly rapid evolution of genomics.1 Like many debates, this one arises from conflicting perspectives on broader concerns: for example, the purported distinction between research and patient care, the relationship between health care institutions and the communities they serve, and the role of patient- and research-participant-engagement in such debates (and in their resolution). In 2012, Geisinger began to lay the groundwork for a significant expansion of the MyCode Community Health Initiative, a research platform comprised not only of a biobank established five years earlier but also of the clinical data collected in the electronic health records of the biobanks patient–participants and of the investigations made possible by these resources. Advances in genomic knowledge, coupled with steady decreases in sequencing costs, supplied the immediate context for this effort, which also entailed extensive internal discussion and patient–participant engagement focused on the ethical question, should Geisinger return clinically actionable results of genomics research to MyCodes patient–participants whose sequenced genomes yield such results? In convening the internal discussions, the aim was to enlist organizational leaders, clinicians, and investigators in a process of ethical analysis and reflection for the purpose of identifying what obligations, if any, Geisinger has toward its patient–participants with regard to the return of results. Through engagement with the patient–participants, nearly 100 of whom were convened through focus groups described below, the aim was to solicit their views on the very same question.2 After the focus groups, the views of the engaged participants were clear: they overwhelmingly favored the return of results. Additional discussions were then held with leadership, researchers and Geisingers Institutional Review Board (IRB) and ultimately, Geisinger did indeed decide to return genomic results to that subset of MyCode participants whose sequenced genomes are found to contain one or more of the genetic variants on a defined list (based in part on the March 2013 clinical testing recommendations of the American College of Medical Genetics and Genomics3) and to integrate those clinically actionable results in genetically informed plans of care for these patient–participants. Soon after this decision, in early 2014, Geisinger announced an ambitious collaboration in genomics discovery with the Tarrytown, NY-based Regeneron Pharmaceuticals and embarked upon the anticipated expansion of MyCode—the current goal of which is to increase the ranks of patient–participants to at least 250,000 over five years. Against the backdrop of President Obamas recently announced Precision Medicine Initiative (PMI), which calls for the development of a one-million-participant cohort, Geisinger hopes to become a funded member of the PMI consortium and is considering a many-fold increase in the size of MyCode, inspired, in large measure, by rapid growth in the number of consented participants.4 Here we describe the development of the ethical rationale for returning genomic results to patient–participants in the MyCode Community Health Initiative with special attention to the aforementioned internal discussions, reflections and focus groups through which the institution sought to engage patient–participants.

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.

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.

Leadership Perspectives on Operationalizing the Learning Health Care System in an Integrated Delivery System

Introduction: Healthcare leaders need operational strategies that support organizational learning for continued improvement and value generation. The learning health system (LHS) model may provide leaders with such strategies; however, little is known about leaders’ perspectives on the value and application of system-wide operationalization of the LHS model. The objective of this project was to solicit and analyze senior health system leaders’ perspectives on the LHS and learning activities in an integrated delivery system. Methods: A series of interviews were conducted with 41 system leaders from a broad range of clinical and administrative areas across an integrated delivery system. Leaders’ responses were categorized into themes. Findings: Ten major themes emerged from our conversations with leaders. While leaders generally expressed support for the concept of the LHS and enhanced system-wide learning, their concerns and suggestions for operationalization where strongly aligned with their functional area and strategic goals. Discussion: Our findings suggests that leaders tend to adopt a very pragmatic approach to learning. Leaders expressed a dichotomy between the operational imperative to execute operational objectives efficiently and the need for rigorous evaluation. Alignment of learning activities with system-wide strategic and operational priorities is important to gain leadership support and resources. Practical approaches to addressing opportunities and challenges identified in the themes are discussed. Conclusion: Continuous learning is an ongoing, multi-disciplinary function of a health care delivery system. Findings from this and other research may be used to inform and prioritize system-wide learning objectives and strategies which support reliable, high value care delivery.

Parental attitudes and expectations towards receiving genomic test results in healthy children

Little evidence is available to guide returning genomic results in children without medical indication for sequencing. Professional guidelines for returning information on adult-onset conditions are conflicting. The goal of this study was to provide preliminary information on parental attitudes and expectations about returning medically actionable genomic results in children who have been sequenced as part of a population biobank.Four focus groups of parents with a child enrolled in a population biobank were conducted. A deliberative engagement format included education about professional guidelines and ethical issues around returning results to children. Parents were presented two scenarios where their healthy child has a pathogenic variant for: (a) a medically actionable childhood condition; (b) a hereditary cancer syndrome with no medical management until adulthood. Thematic analysis was conducted on verbatim transcripts. Regardless of the scenario, parents stated that the genomic information was important, was like other unexpected medical information, and disclosure should be tailored to the childs age and result. Parents wanted the results in their childs medical record. Reasons for learning adult-onset results in their healthy children included to prepare their child for necessary medical action in adulthood. Parents also provided suggestions for program design. This preliminary evidence suggests that parents desire genomic results and expect to use this information to protect their childs health. More empirical research on psychosocial adjustment to such information with continued engagement of parents and children is needed to further inform how to best support families in the communication and use of genomic information.