Novel screening method for familial hypercholesterolemia: Child-parent screening in primary care

Wald DS, et al. Child-parent familial hypercholesterolemia screening in primary care. N Engl J Med 2016;375:1628-37.

Bottom-line: In the UK, a child-parent FH screening strategy done at the time of routine immunizations by a GP identified FH in 1 child and 1 parent for every 360 children screened.

Lipid or FH mutation testing alone are each inadequate to diagnose FH in this population due to high false-positive rates.



  • Familial hypercholesterolemia (FH) is a genetic dyslipidemia that affects ~1 in 500 Canadians
  • Untreated FH leads to accelerated atherosclerosis;
    • By age 50, almost half of men and 20% of women with untreated FH have experienced a coronary event.
  • Only 5% of individuals with FH are properly diagnosed, often only after experiencing a cardiovascular event
  • Multiple countries have implemented various screening strategies, including screening of all adults +/- children ("universal screening"), to more selective screening of first-degree relatives of individuals identified to have FH ("cascade screening")
  • The goal of screening programs is to identify and treat FH before patients manifest clinical atherosclerosis

Who was involved in this study?

  • Timeframe: 2012-2015
  • Country: UK
  • Setting: 92 GP offices
  • Participants: 11,010 children (10,095 with valid screening test) presenting for their routine immunizations at ~1 year of age
  • Baseline characteristics
    • Median age 12.7 months
    • Family hx of premature MI 11%
    • Lipid panel, median
      • Total cholesterol 3.93 mmol/L
      • LDL 2.20 mmol/L
      • HDL 0.93 mmol/L
      • Triglycerides 0.67 mmol/L
    • Median age of parents: Mother 31 y, father 34 y

What was the screening intervention?

  1. Heel-stick capillary blood sample from the child to measure:
    • Lipid panel (total cholesterol, HDL, triglycerides)
    • Possible FH mutations (48 tested, including mutations of the LDL receptor, ApoB, & PCSK9)
  2. Both parents of a child with a positive screening test for either of the above: Venipuncture for same screening test

What counted as a "positive" screening test?

  • Children
    1. Total cholesterol >5.95 mmol/L (>99th percentile) + at least 1 FH mutation, or
    2.  Total cholesterol >5.95 mmol/L x2 (test repeated 3 months later)
  • Parents of children with a positive screening test
    1. If child had a FH mutation: Same FH mutation, or
    2. Higher cholesterol level of the 2 parents

How many children & parents had a positive screen for FH?

  • Children: Positive screening test = ~0.28% (prevalence & number needed to screen = ~360)
    • False positives:
      • 0.6% (64/10,095) had a single elevated cholesterol level (negative on repeat + no known FH mutation)
      • 0.17% (17/10,095) had a FH mutation without hyperlipidemia
  • Parents: Prevalence 0.28% (based on definition above)

What was the impact of screening?

  • Identified 1 in 360 children with FH. Notably, this likely captured every case of FH in this population based on a previous estimated prevalence of ~1 in 500;
  • Identified parents with FH at an age (31-34 y/o) where they may have already had years of atherosclerotic buildup, but were not likely to have developed a coronary event. These parents could therefore receive therapy early enough to modify their cardiovascular risk and at least delay their first coronary event.

What gaps in our knowledge remain?

  1. How do we treat these children with FH once we've identified them? At what age do we start lipid-lowering therapies?
  2. How do we treat and/or monitor individuals with a FH mutation but normal cholesterol levels?
  3. What is the financial impact of child-parent screening? Considerations include costs to society (cost of lipid + FH mutation screening, lipid-lowering therapies including PCSK9 inhibitors) and to individuals (lipid-lowering therapy and insurance premiums).
  4. Which is most effective and cost-effective between the 3 available screening methods: Cascade, child-parent, or universal screening? Would a hybrid cascade+child-parent screening strategy be best?

Testing: Coronary artery calcium to risk stratify in primary prevention

What the test entails

  • Single Computer tomography (CT) scan of the chest using either electron beam CT (EBCT) or multidetector CT (MDCT)
  • A radiologist or cardiologist evaluates the CT images and quantifies calcification of the coronary arteries (a marker of atherosclerotic plaque buildup) using the Agatston score


A 2004 meta-analysis identified the coronary artery calcium (CAC) score as an independent risk factor for coronary artery disease events (coronary death, non-fatal MI or revascularization)

  • CAC score: odds ratio (OR) for coronary heart disease event
    • No calcification (0): OR 1 (reference)
    • Low (1-100): OR 2.1
    • Medium (101-400): OR 5.4
    • High (>400): OR 10

The Multi-Ethnic Study of Atherosclerosis (MESA) population-based cohort provides the best evidence for use of the coronary artery calcium (CAC) score in risk stratification.

  • In a primary prevention cohort that included patients with a low (<5%), intermediate (5-20%) and high (>20%) 10-year risk of CVD based on the Framingham risk score, the CAC score was a statistically significant predictor of coronary or total CV events, but added little extra accuracy to the Framingham risk score used alone.
    • Indescriminate testing is the main limitation of these results. There is little value in obtaining a CAC score in a patient who is at low risk of a CV event based on their risk factors. Similarly, a CAC score is unlikely to reclassify a patient with a high Framingham score down into a low-risk category that doesn't warrant treatment.
  • To account with the limitations of the above study, the MESA investigators evaluated the performance of the CAC score (& other novel risk markers) in a sub-cohort of 1330 patients without diabetes with an "intermediate" Framingham score (10-year risk of coronary artery disease of 5-20%) over a median follow-up period of 7.6 years.
    • Addition of CAC score to the Framingham risk score correctly reclassified
      • ~25% of patients from an intermediate- to high-risk group (i.e. changed their estimated 10-year risk of a coronary event from 5-20% to >20%)
      • ~40% of patients from the intermediate- to low-risk group

Bottom line

  • Patients who should NOT get CAC scoring (low likelihood of altering management)
    • Low Framingham score
    • High Framingham score
    • Patients already receiving primary prevention therapies
    • Patients who have already made a decision for/against medical therapy for primary prevention
  • Patients for whom CAC scoring could be useful
    • Intermediate Framingham score + patient undecided about initiating therapy, or wishing for further stratification
    • High Framingham score + undecided about therapy
  • Clinicians can integrate the CAC score with traditional clinical risk factors to estimate a patient's 10-year CV risk using this calculator.


Prepared by: Ricky Turgeon BSc(Pharm), ACPR, PharmD

Last updated: 9 Sept 2016

Calcified LAD