Cascade Screening for Familial Hypercholesterolemia in the United States: Public Health Impact and Challenges

This post is a summary of our recently published paper in JAMA and outlines the public health impact and challenges for cascade screening for Familial Hypercholesterolemia (FH) in the United States.

What is the public health impact of cascade screening for FH?

FH is a dominantly-inherited genetic disorder affecting about 1 in 250 people and is characterized by markedly elevated low-density lipoprotein cholesterol (LDL-C) levels and accelerated atherosclerotic cardiovascular disease (ASCVD)¹. Persons with FH have a risk of ASCVD of 2.5-10 fold that of the general population, but 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 ASCVD. Cascade screening relies on the identification of an FH patient (proband) and active cholesterol testing, genetic testing or both of all potentially affected relatives, a cycle that is repeated (‘cascaded’) 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 based on systematic reviews, supporting implementation into clinical and public health programs.

Cascade screening can reduce the average age at which individuals with FH are diagnosed, and increase the percentage of individuals taking lipid lowering therapies potentially resulting in reductions in LDL-C and coronary heart disease. Countries that have been using systematic approaches to cascade screening (including genetic testing) have been successful in identifying FH patients with improvements in care including treatment initiation that results in lower LDL-C levels . For example, cascade screening in the Netherlands identified, on average, 8 relatives with FH for each patient and significantly increased the proportion of FH patients on treatment. In addition, FH cascade testing strategies are cost-effective. The genetic screening program in the Netherlands found that, on average, 3.3 years of life were gained for each new case diagnosed at a cost of $8,700 per year of life gained. Recent data suggest an incremental cost effectiveness ratio of $2500-$4500 per quality-adjusted life year gained.

What are the challenges for cascade screening for FH?

One major barrier to cascade screening for FH in the US is the challenge of identifying the first case in a family (proband). Current estimates suggest that < 10% of FH cases have been identified. In adults, universal cholesterol screening recommendations have not fully been adopted. Lipid testing in children is more discriminative for FH than in adults, which is a rationale for recommending lipid screening in childhood, although the United States Preventive Services Task Force found insufficient evidence to support this practice,. However, a recent study from the UK demonstrated the efficacy of screening children for FH during routine immunization visits at 1-2 year of age using a combination of cholesterol levels and genetic testing: for every 1000 children screened, 8 people with FH were identified (4 children and 4 parents). Another potential strategy for index case identification utilizes machine-learning techniques to mine EHR data, laboratory data, and billing code data to “flag” individuals with characteristics consistent with FH for formal identification by a physician. Finally, a recent study also reported that large-scale DNA sequencing is effective in identifying FH cases that had not been diagnosed clinically and would not have been detected through a simple algorithm.

Another major barrier to cascade screening in the US healthcare system where privacy concerns mandate that the proband make the first contact with relatives. A randomized clinical trial is currently being conducted to determine if identification of probable FH probands through a search of EHR data leads to cascade screening if probands receive genetic testing results and counseling to contact relatives about their risk of FH. Potential advantages of genetic versus lipid testing for cascade screening include the ability to perform testing on saliva rather than blood, and the unequivocal identification of additional cases when cascading from the genetic test of the proband.

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