in progress

Draft Research Plan

Screening for Lipid Disorders in Children and Adolescents

May 13, 2021

Recommendations made by the USPSTF are independent of the U.S. government. They should not be construed as an official position of the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services.

The previous USPSTF recommendation was supported by two separate evidence reports, one focusing on familial hypercholesterolemia (FH) and one on multifactorial dyslipidemia. The proposed approach for the update is to combine FH and multifactorial dyslipidemia populations in one report with unified methods while acknowledging differences in the natural history of each condition. Background information and results will be presented separately for each population. 

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Figure 1 is the analytic framework that depicts the five Key Questions to be addressed in the systematic review. The figure illustrates how screening for familial hypercholesterolemia (FH) or multifactorial dyslipidemia in asymptomatic children and adolescents may result in delayed or reduced incidence of health outcomes (CVD events or mortality) or improve intermediate outcomes (serum lipid levels and atherosclerotic markers) in children, adults, or both (KQ1). There is also a question related to the diagnostic yield of serum lipid screening for FH or multifactorial dyslipidemia (KQ2) and the harms of screening for these conditions in children and adolescents (KQ3). Additionally, the figure illustrates how treatment of FH or multifactorial dyslipidemia with lifestyle modifications, lipid-lowering medications, or both in children and adolescents may delay or reduce the incidence of health outcomes (CVD events or mortality) or improve intermediate outcomes (serum lipid levels and atherosclerotic markers) in children, adults, or both (KQ4) and what harms are associated with these treatments (KQ5).

* Multifactorial dyslipidemia is defined as dyslipidemia not caused by FH.
† CVD events are defined as myocardial infarction or ischemic stroke.

Abbreviations: CVD = cardiovascular disease.

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  1. Does screening for FH or multifactorial dyslipidemia in asymptomatic children and adolescents delay or reduce the incidence of health outcomes (cardiovascular disease events* or mortality) or improve intermediate outcomes (serum lipid levels and atherosclerotic markers) in children, adults, or both?
  2. What is the diagnostic yield of serum lipid screening for FH or multifactorial dyslipidemia in children and adolescents?
  3. What are the harms of screening for FH or multifactorial dyslipidemia in children and adolescents?
  4. Does treatment of FH or multifactorial dyslipidemia with lifestyle modifications, lipid-lowering medications, or both in children and adolescents delay or reduce the incidence of health outcomes (cardiovascular disease events* or mortality) or improve intermediate outcomes (serum lipid levels and atherosclerotic markers) in children, adults, or both?
  5. What are the harms of treatment of FH or multifactorial dyslipidemia in children and adolescents?

* Cardiovascular disease events are defined as myocardial infarction or ischemic stroke.

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Contextual questions will not be systematically reviewed and are not shown in the Analytic Framework.

  1. What is the association between childhood and adolescent intermediate outcomes (serum lipid levels and atherosclerosis markers) and adult health outcomes (adult cardiovascular disease events or mortality)?
  2. What is the optimal timing of starting statin treatment in children and adolescents with FH?
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The Proposed Research Approach identifies the study characteristics and criteria that the Evidence-based Practice Center will use to search for publications and to determine whether identified studies should be included or excluded from the Evidence Review. Criteria are overarching as well as specific to each of the key questions.

  Inclusion criteria Exclusion criteria
Condition FH or multifactorial dyslipidemia,* as defined by the study  
Population All KQs: Asymptomatic children and adolescents age 20 years or younger at time of screening or treatment initiation
KQs 4, 5 (Treatment benefits and harms): Treatment studies can have populations identified in any manner (including cascade screening)
KQs 1–3: Children and adolescents with any of the following:
  • Known dyslipidemia
  • Diagnosis associated with secondary dyslipidemia
  • Established family history of FH   

KQs 4, 5: Diagnosis associated with secondary dyslipidemia

Interventions KQs 1–3 (Screening benefits, yield, and harms): Universal or selective screening using serum lipid panel (fasting or nonfasting lipid measurement, including one or more of the following: TC, LDL-C, HDL-C, non-HDL-C, TG)
KQs 4, 5 (Treatment benefits and harms):
  • Lipid-lowering medications
  • Lifestyle modifications, including diet or exercise or dietary supplements
KQs 1–3:
  • Genetic screening alone
  • Cascade screening   

KQs 4, 5 (In FH population):

    • Apheresis
    • Revascularization
Comparators KQs 1, 3 (Screening benefits and harms): No screening or usual care

KQ 2: No comparator or any confirmatory test

KQs 4, 5 (Treatment benefits and harms): No treatment or usual care

 
Outcomes KQs 1, 4 (Screening and treatment benefits):
  • Health outcomes:
    • Myocardial infarction
    • Ischemic stroke
    • CVD mortality
    • All-cause mortality
  • Intermediate outcomes:
    • Serum lipid levels (TC, LDL-C, HDL-C, and non–HDL-C, TG)
    • Atherosclerosis markers (carotid intima-media thickness, calcium score, pathological findings) 

KQ 2 (Yield):

  • Screen positivity
  • Positive predictive value  

KQ 3 (Screening harms):

  • Psychosocial effects
  • Overdiagnosis
  • False positives/negatives   

KQ 5 (Treatment Harms): All harms from:

  • Lipid-lowering medications (e.g., adverse events, long-term safety, overtreatment)
  • Lifestyle modifications (e.g., nutritional, psychosocial)
KQs 1, 4: Other serum markers (e.g., apolipoprotein A1, C-reactive protein)
Setting KQs 1, 3-5: Primary care or referable from primary care

KQ 2 (Yield): Primary care or referable from primary care, population-based or community settings

Settings not generalizable to primary care
Study design KQ 1 (Screening benefits): RCTs, CCTs

KQs 2, 3, 5 (Yield, screening and treatment harms): RCTs, CCTs, cohort studies, and observational studies

KQ 4 (Treatment benefits): RCTs

KQ 4: Comparative effectiveness studies
Country Studies that take place in countries categorized as “Very High” on the 2019 Human Development Index (as defined by the United Nations Development Programme) Primary studies that are conducted in countries that are not categorized as “Very High” on the Human Development Index
Publication language English Any language other than English
Quality rating Fair- or good-quality studies Poor-quality studies, according to design-specific USPSTF criteria

* Multifactorial dyslipidemia is defined as dyslipidemia not caused by FH.
Secondary causes of dyslipidemia include: renal (chronic renal disease, hemolytic uremic syndrome, nephrotic syndrome); infectious (acute viral or bacterial infections, HIV, hepatitis); hepatic (obstructive liver disease, cholestasis, biliary cirrhosis, Alagille syndrome); inflammatory (systemic lupus erythematosus, juvenile rheumatoid arthritis); storage (glycogen storage disease, Gaucher disease, cystine storage disease, Tay-Sachs disease, Niemann-Pick disease); and other (Kawasaki disease, anorexia nervosa, cancer, previous solid organ transplant, progeria, idiopathic hypercalcemia, Klinefelter syndrome, Werner syndrome, polycystic ovary syndrome, type 1 or 2 diabetes).

Abbreviations: CCT = controlled clinical trial; CVD = cardiovascular disease; FH = familial hypercholesterolemia; HDL-C = high-density lipoprotein cholesterol; KQ = key question; LDL-C = low-density lipoprotein cholesterol; RCT = randomized, controlled trial; TC = total cholesterol; TG = triglycerides; USPSTF = U.S. Preventive Services Task Force.

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