Final Research Plan

Lipid Disorders in Children and Adolescents: Screening

August 19, 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.

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Panel 1

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 evidence 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.

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, CVD mortality, or all-cause mortality) or improve intermediate outcomes (serum lipid levels, atherosclerotic markers, body mass index, physical activity, sedentary behavior, dietary intake) 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, CVD mortality, or all-cause mortality) or improve intermediate outcomes (serum lipid levels, atherosclerotic markers, body mass index, physical activity, sedentary behavior, dietary intake) in children, adults, or both (KQ4) and what harms are associated with these treatments (KQ5).

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

Abbreviations: BMI = body mass index; CVD = cardiovascular disease.

  1. Does screening for FH or multifactorial dyslipidemia in asymptomatic children and adolescents delay or reduce the incidence of health outcomes (e.g., cardiovascular disease [CVD] events* or mortality) or improve intermediate outcomes (e.g., 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 behavioral interventions, lipid-lowering medications, or both in children and adolescents delay or reduce the incidence of health outcomes (e.g., CVD events* or mortality) or improve intermediate outcomes (e.g., 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?

* CVD events are defined as myocardial infarction or ischemic stroke.

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

  1. What is the association between lipid-related childhood and adolescent intermediate outcomes and adult health outcomes?
  2. What is the optimal timing of statin treatment initiation for FH?

The 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 (KQs).

  Included Excluded
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†
  • Homozygous FH
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
  • Behavioral interventions to promote healthy diet and physical activity
  • 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 concentrations (TC, LDL-C, HDL-C, and non–HDL-C, TG)
    • Atherosclerosis markers (carotid intima-media thickness, calcium score, pathological findings) 
    • Body mass index
  • Behavioral intermediate outcomes:
    • Physical activity, sedentary behavior, dietary intake (for behavioral counseling interventions)

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

KQ 2 (Yield): Recent large cohorts

KQs 3, 5 (Screening and treatment harms): RCTs, CCTs, cohort studies, 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)

KQ 2 (Yield): U.S. only

 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 familial hypercholesterolemia.
† 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; LDL-C = low-density lipoprotein cholesterol; RCT = randomized controlled trial; TC = total cholesterol; TG = triglycerides; U.S. = United States; USPSTF = U.S. Preventive Services Task Force.

The draft Research Plan was posted for public comment on the USPSTF website from May 13, 2021 to June 9, 2021. The USPSTF received comments regarding the selection of outcomes, expansion of the screening population to the family, and the inclusion of adult health outcomes in the Analytic Framework. In response, the USPSTF added body mass index, physical activity, sedentary behavior, and dietary intake as intermediate outcomes. The USPSTF retained the focus of the screening population on children for this evidence review because of other available lipid-related USPSTF recommendations in adults, and because of the current prevalence of lipid screening in the general adult population. Adult health outcomes were retained in the Analytic Framework in accordance with USPSTF methods.