Testing and Management of Iron Overload After Genetic Screening-Identified Hemochromatosis.

Importance: HFE gene-associated hereditary hemochromatosis type 1 (HH1) is underdiagnosed, resulting in missed opportunities for preventing morbidity and mortality. Objective: To assess whether screening for p.Cys282Tyr homozygosity is associated with recognition and management of asymptomatic iron overload. Design, Setting, and Participants: This cross-sectional study obtained data from the Geisinger MyCode Community Health Initiative, a biobank of biological samples and linked electronic health record data from a rural, integrated health care system. Participants included those who received a p.Cys282Tyr homozygous result via genomic screening (MyCode identified), had previously diagnosed HH1 (clinically identified), and those negative for p.Cys282Tyr homozygosity between 2017 and 2018. Data were analyzed from April 2020 to August 2023. Exposure: Disclosure of a p.Cys282Tyr homozygous result. Main Outcomes and Measures: Postdisclosure management and HFE-associated phenotypes in MyCode-identified participants were analyzed. Rates of HFE-associated phenotypes in MyCode-identified participants were compared with those of clinically identified participants. Relevant laboratory values and rates of laboratory iron overload among participants negative for p.Cys282Tyr homozygosity were compared with those of MyCode-identified participants. Results: A total of 86 601 participants had available exome sequences at the time of analysis, of whom 52 994 (61.4%) were assigned female at birth, and the median (IQR) age was 62.0 (47.0-73.0) years. HFE p.Cys282Tyr homozygosity was disclosed to 201 participants, of whom 57 (28.4%) had a prior clinical HH1 diagnosis, leaving 144 participants who learned of their status through screening. There were 86 300 individuals negative for p.Cys282Tyr homozygosity. After result disclosure, among MyCode-identified participants, 99 (68.8%) had a recommended laboratory test and 36 (69.2%) with laboratory or liver biopsy evidence of iron overload began phlebotomy or chelation. Fifty-three (36.8%) had iron overload; rates of laboratory iron overload were higher in MyCode-identified participants than participants negative for p.Cys282Tyr homozygosity (females: 34.1% vs 2.1%, P < .001; males: 39.0% vs 2.9%, P < .001). Iron overload (females: 34.1% vs 79.3%, P < .001; males: 40.7% vs 67.9%, P = .02) and some liver-associated phenotypes were observed at lower frequencies in MyCode-identified participants compared with clinically identified individuals. Conclusions and Relevance: Results of this cross-sectional study showed the ability of genomic screening to identify undiagnosed iron overload and encourage relevant management, suggesting the potential benefit of population screening for HFE p.Cys282Tyr homozygosity. Further studies are needed to examine the implications of genomic screening for health outcomes and cost-effectiveness.

A RE-AIM Framework Analysis of DNA-Based Population Screening: Using Implementation Science to Translate Research Into Practice in a Healthcare System.

Introduction: DNA-based population screening has been proposed as a public health solution to identify individuals at risk for serious health conditions who otherwise may not present for medical care. The clinical utility and public health impact of DNA-based population screening is a subject of active investigation. Geisinger, an integrated healthcare delivery system, was one of the first healthcare systems to implement DNA screening programs (MyCode Community Health Initiative (MyCode) and clinical DNA screening pilot) that leverage exome data to identify individuals at risk for developing conditions with potential clinical actionability. Here, we demonstrate the use of an implementation science framework, RE-AIM (Reach, Effectiveness, Adoption, Implementation and Maintenance), to conduct a post-hoc evaluation and report outcomes from these two programs to inform the potential impact of DNA-based population screening. Methods: Reach and Effectiveness outcomes were determined from the MyCode research program, while Adoption and Implementation outcomes were measured using the clinical DNA screening pilot. Reach was defined as the number of patients who were offered and consented to participate in MyCode. Effectiveness of DNA screening was measured by reviewing MyCode program publications and synthesizing findings from themes. Adoption was measured by the total number of DNA screening tests ordered by clinicians at the clinical pilot sites. Implementation was assessed by interviewing a subset of clinical pilot clinicians about the deployment of and recommended adaptations to the pilot that could inform future program dissemination. Results: Reach: As of August 2020, 68% (215,078/316,612) of individuals approached to participate in the MyCode program consented. Effectiveness: Published evidence reported from MyCode demonstrates that DNA screening identifies at-risk individuals more comprehensively than clinical ascertainment based on phenotypes or personal/family history. Adoption: From July 2018 to June 2021, a total of 1,026 clinical DNA screening tests were ordered by 60 clinicians across the three pilot clinic sites. Implementation: Interviews with 14 clinicians practicing at the pilot clinic sites revealed motivation to provide patients with DNA screening results and yielded future implementation strategies. Conclusion: The RE-AIM framework offers a pragmatic solution to organize, analyze, and report outcomes across differently resourced and designed precision health programs that include genomic sequencing and return of clinically actionable genomic information.

Collaborative Approach to Reach Everyone with Familial Hypercholesterolemia: CARE-FH Protocol.

The Collaborative Approach to Reach Everyone with Familial Hypercholesterolemia (CARE-FH) study aims to improve diagnostic evaluation rates for FH at Geisinger, an integrated health delivery system. This clinical trial relies upon implementation science to transition the initial evaluation for FH into primary care, attempting to identify individuals prior to the onset of atherosclerotic cardiovascular disease events. The protocol for the CARE-FH study of this paper is available online. The first phase of the project focuses on trial design, including the development of implementation strategies to deploy evidence-based guidelines. The second phase will study the intervention, rolled out regionally to internal medicine, community medicine, and pediatric care clinicians using a stepped-wedge design, and analyzing data on diagnostic evaluation rates, and implementation, service, and health outcomes.

Healthcare Utilization and Costs after Receiving a Positive BRCA1/2 Result from a Genomic Screening Program.

Population genomic screening has been demonstrated to detect at-risk individuals who would not be clinically identified otherwise. However, there are concerns about the increased utilization of unnecessary services and the associated increase in costs. The objectives of this study are twofold: (1) determine whether there is a difference in healthcare utilization and costs following disclosure of a pathogenic/likely pathogenic (P/LP) BRCA1/2 variant via a genomic screening program, and (2) measure the post-disclosure uptake of National Comprehensive Cancer Network (NCCN) guideline-recommended risk management. We retrospectively reviewed electronic health record (EHR) and billing data from a female population of BRCA1/2 P/LP variant carriers without a personal history of breast or ovarian cancer enrolled in Geisinger's MyCode genomic screening program with at least a one-year post-disclosure observation period. We identified 59 women for the study cohort out of 50,726 MyCode participants. We found no statistically significant differences in inpatient and outpatient utilization and average total costs between one-year pre- and one-year post-disclosure periods ($18,821 vs. $19,359, p = 0.76). During the first year post-disclosure, 49.2% of women had a genetic counseling visit, 45.8% had a mammography and 32.2% had an MRI. The uptake of mastectomy and oophorectomy was 3.5% and 11.8%, respectively, and 5% of patients received chemoprevention.

Treatment and Outcomes of Acute Pulmonary Embolism and Deep Venous Thrombosis: The CVRN VTE Study.

BACKGROUND: Few studies describe both inpatient and outpatient treatment and outcomes of patients with acute venous thromboembolism in the United States. METHODS: A multi-institutional cohort of patients diagnosed with confirmed pulmonary embolism or deep venous thrombosis during the years 2004 through 2010 was established from 4 large, US-based integrated health care delivery systems. Computerized databases were accessed and medical records reviewed to collect information on patient demographics, clinical risk factors, initial antithrombotic treatment, and vital status. Multivariable Cox regression models were used to estimate the risk of death at 90 days. RESULTS: The cohort comprised 5497 adults with acute venous thromboembolism. Pulmonary embolism was predominantly managed in the hospital setting (95.0%), while 54.5% of patients with lower extremity thrombosis were treated as outpatients. Anticoagulant treatment differed according to thromboembolism type: 2688 patients (92.8%) with pulmonary embolism and 1625 patients (86.9%) with lower extremity thrombosis were discharged on anticoagulants, compared with 286 patients (80.1%) with upper extremity thrombosis and 69 (54.8%) patients with other thrombosis. While 4.5% of patients died during the index episode, 15.4% died within 90 days. Pulmonary embolism was associated with a higher 90-day death risk than lower extremity thrombosis (adjusted hazard ratio 1.23; 95% confidence interval, 1.04-1.47), as was not being discharged on anticoagulants (adjusted hazard ratio 5.56; 95% confidence interval, 4.76-6.67). CONCLUSIONS: In this multicenter, community-based study of patients with acute venous thromboembolism, anticoagulant treatment and outcomes varied by thromboembolism type. Although case fatality during the acute episode was relatively low, 15.4% of people with thromboembolism died within 90 days of the index diagnosis.

A study paradigm integrating prospective epidemiologic cohorts and electronic health records to identify disease biomarkers.

Defining the full spectrum of human disease associated with a biomarker is necessary to advance the biomarker into clinical practice. We hypothesize that associating biomarker measurements with electronic health record (EHR) populations based on shared genetic architectures would establish the clinical epidemiology of the biomarker. We use Bayesian sparse linear mixed modeling to calculate SNP weightings for 53 biomarkers from the Atherosclerosis Risk in Communities study. We use the SNP weightings to computed predicted biomarker values in an EHR population and test associations with 1139 diagnoses. Here we report 116 associations meeting a Bonferroni level of significance. A false discovery rate (FDR)-based significance threshold reveals more known and undescribed associations across a broad range of biomarkers, including biometric measures, plasma proteins and metabolites, functional assays, and behaviors. We confirm an inverse association between LDL-cholesterol level and septicemia risk in an independent epidemiological cohort. This approach efficiently discovers biomarker-disease associations.

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.

Impact of a Patient-Facing Enhanced Genomic Results Report to Improve Understanding, Engagement, and Communication.

"The objective of this study was to" test the effectiveness of an enhanced genomic report on patient-centered outcome domains including communication, engagement and satisfaction. "Study design utilized" a prospective, randomized, mixed-methods desctiptive study of a whole genome sequencing results report, GenomeCOMPASS™, that was accessed by providers through the electronic health record and by patients through the associated patient portal. "The study was set in" an integrated healthcare delivery system in central Pennsylvania. "Eighty-four" parents of 46 children with undiagnosed Intellectual Disability, Autism Spectrum Disorder and/or multiple congenital anomalies who had participated in a previous study offering whole genome sequencing for their affected child were invited to enroll. Fifty-two parents enrolled. Following a traditional genetics results informing visit, the study coordinator stratified families by diagnostic result and uninformative result and then randomized families within each group to an intervention arm to receive the GenomeCOMPASS™ report or to the usual care arm to receive a summary letter from the medical geneticist. A letter inviting enrollment included a baseline survey, which once returned, constituted enrollment. Surveys were administered at 3 months post-genetics visit. At 6 months, the usual care arm crossed over to receive the intervention and were administered an additional survey at 3 months. Qualitative interviews were conducted following survey completion to augment the survey data regarding the patient centered outcomes of interest. Patient reported outcomes including communication, engagement, empowerment and satisfaction. In the intervention arm, GenomeCOMPASS™ reports were released to 14 families (N = 28 parents) and of those 21 (75%) returned 3 month surveys. In the usual care arm, 12 families (N = 24 parents) received usual care summary letters and of those 20 (83%) returned 3 month surveys. At crossover, GenomeCOMPASS™ reports were released to 20 individuals and 15 (75%) returned 3 month surveys. Qualitative interviews were conducted with 5 individuals. Use of the GenomeCOMPASS™ report was reported by this small group of parents to improve communication with providers and non-health professionals such as educators and therapists and led to increased engagement and high satisfaction. Providers and others involved in the children's care also endorsed the report's effectiveness. Reports that addressed negative findings, i.e. uninformative results, were not found to be useful. Although the number of users was small, this study supports that customizable template reports may provide a useful and durable source of information that can support and enhance the information provided by genetics professionals in traditional face-to-face encounters. TRIAL REGISTRATION: Clinicaltrials.gov (Record 2013-0594).

Implementation of genomic medicine in a health care delivery system: a value proposition?

The United States health care system is undergoing significant change and is seeking innovations in care delivery and reimbursement models that will lead to improved value for patients, providers, payers, and employers. Genomic medicine has the potential to be a disruptive innovation that if implemented intelligently can improve value. The article presents the perspective of the leaders of a large integrated healthcare delivery system regarding the decision to invest in implementation of genomic medicine.

Impact of age cutoffs on a lynch syndrome screening program.

PURPOSE: To determine the impact of applying an age cutoff to tumor-based Lynch syndrome (LS) screening, specifically focusing on changes in relative effectiveness, efficiency, and cost. The project was undertaken to answer questions about implementation of the LS screening program in an integrated health care delivery system. PATIENTS AND METHODS: Clinical data extracted from an internal cancer registry, previous modeling efforts, published literature, and gray data were used to populate decision models designed to answer questions about the impact of age cutoffs in LS screening. Patients with colorectal cancer (CRC) were stratified at 10-year intervals from ages 50 to 80 years and compared with no age cutoff. Outcomes are reported for a cohort of 325 patients screened and includes total cost to screen, LS cases present in the cutoff category, number of LS cases expected to be identified by screening, cost per LS case detected, and total number and percentage of LS cases missed. CONCLUSION: Applying an age cutoff to an LS screening program has considerable potential for decreasing total screening costs and increasing efficiency, but at a loss of effectiveness. Imposing an age cutoff of 50 years reduces the cost of the screening program to 16% of a program with no age cutoff, but at the expense of missing more than half of the cases. Failure to identify LS cases is magnified by a cascade effect in family members. The results of this analysis influenced the final policy in our system.

Multilevel research and the challenges of implementing genomic medicine.

Advances in genomics and related fields promise a new era of personalized medicine in the cancer care continuum. Nevertheless, there are fundamental challenges in integrating genomic medicine into cancer practice. We explore how multilevel research can contribute to implementation of genomic medicine. We first review the rapidly developing scientific discoveries in this field and the paucity of current applications that are ready for implementation in clinical and public health programs. We then define a multidisciplinary translational research agenda for successful integration of genomic medicine into policy and practice and consider challenges for successful implementation. We illustrate the agenda using the example of Lynch syndrome testing in newly diagnosed cases of colorectal cancer and cascade testing in relatives. We synthesize existing information in a framework for future multilevel research for integrating genomic medicine into the cancer care continuum.

Lynch syndrome screening implementation: business analysis by a healthcare system.

OBJECTIVE: To characterize the current state of evidence and apply simulation modeling to support decision making about provision and coverage of a Lynch syndrome (LS) screening program among colorectal cancer (CRC) patients in our integrated healthcare delivery system. STUDY DESIGN: Application of multiple methods for synthesizing evidence guided by needs of our clinical and administrative decision makers. METHODS: Narrative and focused reviews, computerized simulation models of multiple screening options, queries of our electronic data warehouse, and extensive communication with decision makers. RESULTS: Review of published evidence at the time of the study period revealed that screening unselected CRC patients for LS would likely cost less than $25,000 per life-year saved (compared with no screening) and that screening with immunohistochemistry is substantially more efficient than other options. Our simulation models suggest that not only does including BRAF mutation testing substantially improve efficiency but that adding methylation testing improves it further. We characterized a variety of other metrics that contributed not only to local decisions but to the broader evidence base on this topic. CONCLUSION: The current state of evidence at the time of the study period suggests an LS screening program can be both effective in reducing mortality from CRC and cost-effective. However, direct evidence remains limited and multiple factors could threaten success of such a program. We have identified opportunities for optimizing the efficiency of available screening protocols. While there was enough evidence for our system to proceed with an LS screening program, we recognize the threats to program success and will prospectively collect outcome data supporting empirical examination of the program.