Stimulating Implementation Science in Genomics and Precision Medicine for Heart, Lung, Blood and Sleep Diseases: The Case of Familial Hypercholesterolemia

Posted on by Muin J. Khoury, Office of Public Health Genomics, Centers for Disease Control and Prevention, and George Mensah, Center for Translation Research and Implementation Science, National Heart, Lung, and Blood Institute

a heart puzzle with a person holding data chartsImplementation science is an emerging field of scientific inquiry that has been increasingly applied to genomics and precision medicine. In our recent papers on the state of scientific publications and NIH funding, we have identified areas of growth and limitations of the field and called for more training and workforce development for implementation science in genomic medicine.

In the context of common diseases, such as heart disease and cancer, we need to develop and test implementation strategies to identify facilitators and overcome barriers in the adaptation, integration, scale-up, and sustainability of proven-effective interventions and guidelines for preventing and/or managing. In particular, we can define T4 implementation research as “research to identify strategies to enhance sustainable uptake of proven-effective interventions into routine clinical practice” and is a part of the long journey from basic science discoveries to population health impact. (Read about the four phases of translation here and here.)

Since 2014, the Center for Translation Research and Implementation Science (CTRIS) at the National Heart, Lung and Blood Institute, has fostered and supported research to identify the best strategies for ensuring successful integration of evidence-based interventions within clinical and public health settings. This research will help tackle challenges in late-stage translation, the phase that leads to generalizable knowledge about implementation and how to turn scientific discoveries into improved health in the real world.

In the past year, CTRIS, in collaboration with NHLBI Divisions, and the CDC Office of Public Health Genomics, started developing a science-based framework for accelerating the implementation of genomics and precision medicine to reduce the burden of heart, lung, blood, and sleep disorders. Specifically, this collaboration will be

  • Developing a robust implementation science research agenda for clinically effective genomic and precision medicine applications;
  • Fostering learning health systems approaches to accelerate the identification, evaluation, and implementation of promising genomics and precision medicine applications;
  • Developing training, tools, resources, and partnerships in implementation science for researchers and practitioners to accelerate the population impact of genomics and precision medicine; and
  • Creating approaches to explore the ethical, legal, and social implications of implementation research, risk communication, and the return of results in genomics and -omics research.

So where to start? Familial hypercholesterolemia (FH) is an ideal candidate disease application for T4 translation research in genomic medicine. FH is an autosomal dominant genetic disorder affecting about 1 in 250 people in the United States. FH is characterized by markedly elevated low-density lipoprotein cholesterol (LDL-C) levels and markedly increased risk for early atherosclerotic heart disease. When FH is diagnosed and treated early in life, the risk is reduced by ~80%. However, the majority of persons with FH have never been diagnosed or treated effectively. Active case finding of FH followed by family-based “cascade” screening has the potential to identify many additional individuals with FH and help to ensure they are treated before the onset of heart disease. Cascade screening relies on the identification of an FH patient and active cholesterol testing, genetic testing or both of all potentially affected relatives, a cycle that is repeated for each relative found with FH.

Cascade screening for FH is highly effective and has been recommended by multiple evidence groups. The CDC Office of Public Health Genomics classifies cascade screening for FH as a Tier 1 genomic application, with evidence-based recommendations supporting implementation into clinical and public health programs.

In a recent study based on the National Health and Nutrition Examination Survey (NHANES), a nationally-representative sample of the US adult population, we observed a large disconnect between screening and treatment rates in adults with definite/probable FH. In spite of high rates of cholesterol screening and awareness, only about half of adults with definite/probable FH are on statin therapy, and even fewer eligible patients are prescribed a high-intensity statin. Young and uninsured patients are at the highest risk for under treatment. The study highlights a public health opportunity and an imperative to improve statin treatment rates in individuals with FH. Younger and uninsured adults with severe dyslipidemia in addition to those without a usual source of care are significantly less likely to be prescribed statins, highlighting the need for community-based interventions to target these adults with limited access to care. In addition, cascade screening and the use of genetic testing in relatives of affected individuals is an unmet need, can save lives and is cost-effective and is not practiced optimally in the United States.

While the public-health need to scale up implementation of FH diagnosis and cascade screening is clear, there are many challenges and limitations in implementation. Only a few studies have been published in this area as compared to two other priority Tier 1 cancer genomic applications (Lynch syndrome and hereditary breast and ovarian cancer, HBOC). Our recent analysis of the CDC Public Health Genomics Knowledge Base grant database shows that FH lags behind Lynch syndrome and HBOC in translation/implementation studies (55 studies for FH, 226 for HBOC, and 161 for Lynch syndrome); and NIH grants sponsoring such studies (102 grants for FH, 557 for HBOC, and 287 for Lynch syndrome).

So, what kind of T4 research questions can one envision in the context of preventing morbidity and mortality from FH at the population level?   In 2012, as part of a special Journal of National Cancer Institute monograph on multilevel analysis in the cancer care continuum, we discussed implementation challenges in genomic medicine, and provided examples of multilevel research in implementation and health care delivery for Lynch syndrome (see Table 1 here), which is associated with high risk of colorectal cancer, and other cancers. We have adapted this table to FH (see table below) to illustrate similar multilevel implementation questions in FH. T4 translation research in FH involve questions that range from patient-provider interactions to health systems issues to public health and policy interventions.

Clearly, FH illustrates the beginning of a long journey to apply principles of implementation science to reap the real world benefits of genomics and precision medicine to reduce the burden of heart, lung, blood, and sleep disorders in the United States and beyond.

Multilevel factors influencing the diagnosis, treatment and cascade screening for Familial Hypercholesterolemia (FH) in the United States (Adapted from Khoury et al, JNCI, 2012)

Level Examples of factors 
Persons with high cholesterol and family history of heart disease Understanding the importance of diagnosing Familial Hypercholesterolemia and cascade screening in their relatives; addressing the need for informed consent; understanding dynamics with other relatives; assessing whether screening of colorectal cancer patients for Lynch syndrome will improve their own outcomes; assessing how communication of information with relatives will be managed
Relatives of FH patients Health and functional status, health perception, cultural factors; knowledge about cascade screening, comorbidity; patterns of health-care use; access to health-care services and insurance which could be different from those of the affected patient with FH; geographic proximity to patients; family attitudes about screening; psychosocial impact of communication about FH through affected relatives
Provider team Knowledge and communication about FH screening recommendations; incentives for diagnosing and reporting FH, timing, knowledge of genetics and genetic counseling referral patterns; for FH patients; coordination between various specialties (primary care, cardiology, genetics); reimbursement of initiating contact with relatives of patients with FH
Laboratory process Comparing performance of different methods and approaches for screening for FH and the use of genetic testing; do we need local/centralized laboratories to undertake screening
Health-care organization Policies for screening cases, integration of information, guidelines into EHRs; presence of decision support tools; standard practices on contacts of patients and relatives; interface and communication between different parts of the organization (e.g., primary care, cardiology, genetics)
Community/state Insurance coverage and reimbursement; existence of state guidelines for recording FH in medical records; state efforts to promote adoption of guidelines; certification of qualified laboratory personnel
National health policy Medicare and Medicaid benefits for testing for FH; national policies and oversight and regulation of genomic tests and performance of laboratories; dealing with patent issues around genomic tests; professional societies standards and involvement of multiple groups (egg, primary care, cardiology, genetics); possible recommendations of advisory committees for universal screening similar to newborn screening; question of necessity of a centralized laboratory testing process for implementation; public health efforts to address disparities in implementation of FH case finding and cascade screening
Posted on by Muin J. Khoury, Office of Public Health Genomics, Centers for Disease Control and Prevention, and George Mensah, Center for Translation Research and Implementation Science, National Heart, Lung, and Blood InstituteTags ,
Page last reviewed: April 9, 2024
Page last updated: April 9, 2024