Familial Hypercholesterolemia as a Prototype for Precision Public Health

November 19, 2019 by Muin J. Khoury, Office of Public Health Genomics and Betsy L. Thompson, Division for Heart Disease and Stroke Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia
Dr Khoury and Dr. Thompson

In October 2019, the 7th annual FH Foundation global summit on familial hypercholesterolemia (FH) took place in Atlanta, Georgia. The theme of the conference was, “Familial Hypercholesterolemia as a Prototype for Precision Public Health.” The meeting brought more than 300 participants from multiple countries to discuss the latest advances in the diagnosis, screening, treatment and community engagement related to FH.

Right from the first session, there was obvious energy, dedication, and collaboration among participants. It was also obvious how much progress has been made in FH in a few short years since the first meeting in 2013. In addition to the scientific presentations on the latest in FH, personal stories presented by patients brought to life the plight of affected patients, and their perseverance even in the midst of a health care community largely unaware of and unequipped to recognize the warning signs and symptoms of FH.

FH is a common genetic disease leading to high LDL cholesterol levels from birth. FH affects 1 in 250 people in the United States and leads to a significant increase in risk of premature – and largely preventable – cardiovascular disease. Although the risk of cardiovascular disease associated with FH is great, few people are aware of this risk. In the United States, fewer than 15% of the more than 1 million people with FH have been diagnosed. Of these, only half are taking cholesterol-lowering medications, and even fewer are taking high-intensity statins (a type of blood cholesterol-lowering medication) that greatly benefit many patients with FH.

Because relatives of patients with FH are often at increased risk of heart disease, evidence-based recommendations for screening relatives were issued more than a decade ago. The CDC office of Genomics and Precision Public Health has labelled cascade screening for FH as a priority genomic application for public health action.

FH is one aspect of the growing public health problem of hypercholesterolemia (also known as high blood cholesterol), frequent cause of death related to heart disease and stroke in the US and globally. In fact, more than 90 million adults have total cholesterol levels of 200 mg/dl or more. Statin therapy is recommended for nearly 37% of adults (age ≥21 years), or 86 million people. Among people for whom therapy is recommended, about 54.5%, or 47 million, adults are currently taking statins. Lowering cholesterol and improving management and control of hypercholesterolemia are critical components of CDC’s efforts to address heart disease prevention, detection, treatment and control.

Prior to the first FH summit in 2013, population data about FH were scarce. Since then, the CASCADE FH registry (which now has >6000 patients), electronic health records, claims data, and other surveys have catalyzed FH research. In addition, introduction of the ICD-10-CM codes for FH in 2016 contributed to approximately 197,000 individuals being coded as having FH. This specific coding presents an important opportunity for tracking the diagnosis and treatment of FH in the population and to identify gaps in healthcare delivery and disease prevention.

While opportunities to specifically diagnose and treat FH are critically important, for some patients this information comes too late. According to the CASCADE FH registry, the average age of FH diagnosis is 47 years, even though patients had high cholesterol documented in health records 10 years earlier. This represents a decade of lost opportunities for patients to be effectively treated and for their relatives to be screened. A recent 20-year follow up study clearly showed that, in patients with FH, initiation of statin therapy during childhood slowed the progression of carotid intima–media thickness and reduced the risk of cardiovascular disease in adulthood. Furthermore, longitudinal data on patients with FH from the registry clearly show room for substantial improvement even among those who are diagnosed with and treated for FH: 52% of diagnosed patients did not achieve the recommended LDL-C of less than 100 mg/dl.

In the absence of population screening guidelines specific to FH, and in the midst of all people with cholesterol-related health problems in the general population, how do we find and treat persons with FH? One answer to this question may be precision public health. Precision public health leverages emerging data by time, place, and persons, coupled with machine learning methods, to help find FH patients.

An important study related to this topic was presented at the summit. The FIND FH machine learning model was used on de-identified healthcare encounter data (including procedure and diagnostic codes, prescriptions, and laboratory findings) from 939 individuals diagnosed with FH and 80,000+ individuals without FH from four United States health care organizations. The model was then applied to a national health care encounter database of 170 million individuals and an integrated health care delivery system dataset with 174,000 individuals. The FIND FH model flagged 1.3 million of the 170 million patients in the national database and 866 of 174,000 individuals in the health care delivery system dataset as likely to have FH. FH experts reviewed a sample of flagged individuals and applied clinical FH diagnostic criteria. Of those reviewed, 87% in the national database and 77% in the health care delivery system dataset were categorized as having a high enough clinical suspicion of familial hypercholesterolemia to warrant guideline-based clinical evaluation and treatment. This analysis points to a “precision” screening tool that can be validated in other populations and be used to scan large, diverse, and disparate health care encounter databases to identify individuals with FH.

A precision genetic approach to public health shows real promise in refining the genetics of FH. Data presented at the meeting clearly suggest that there is much unwarranted variability in the severity of disease and outcomes of patients with FH who have the same mutations in the same genes. Multiple other genes, singly or in combinations (such as polygenic risk scores ), along with other environmental factors, can modify the level of risk in patients with FH. A major implication is that the case definition of FH may be changed to include possibly more affected people in the population.

Much more work is needed to refine the spectrum of disease risk and effective interventions associated with FH and other lipid disorders. This work can occur in the context of ongoing clinical and public health programs that reduce the burden of heart disease and stroke in the population.

We congratulate the FH Foundation and all attendees for a successful 2019 summit and look forward to future meetings and collaborations.