The Expert Panel's goal was development of comprehensive evidence-based guidelines
addressing all of the major CV risk factors to assist pediatric care providerspediatricians,
family practitioners, nurses and nurse practitioners, physician assistants, and
registered dietitiansin both the promotion of CV health and the identification
and management of specific risk factors from infancy to young adulthood. An initial
assessment indicated that an innovative approach would be needed to develop a comprehensive
integrated product for the following reasons:
- A focus on CV risk reduction in children and adolescents addresses a disease processatherosclerosisin
which the clinical end point of manifest cardiovascular disease (CVD) occurs much
later in life. Therefore, the recommendations would need to address two different
goals: the prevention of risk factor developmentprimordial preventionand
the prevention of future CVD by effective management of identified risk factorsprimary
- Most systematic evidence reviews address one or, at most, a small number of finite
questions addressing the impact of specific interventions on specific health outcomes.
A rigorous literature search and review process involving explicit inclusion and
exclusion criteria often results in only a handful of in-scope articles for inclusion
in the review. These reviews seek direct, rigorous evidence of the causal effect
of an intervention on the designated outcomes or indirect evidence in the form of
a chain of causal evidence through surrogate or other intermediate outcomes linking
the interventions to the outcomes of interest. Often, in-scope evidence is limited
to randomized controlled trials (RCTs), systematic reviews, and meta-analyses published
over a defined time period. There is a defined format for abstracting studies, grading
the evidence, and presenting the results. The level of evidence leads to the conclusions
- Because of the scope of the effort by the Expert Panel, this evidence review needed
to address a broader array of questions concerning the development, progression,
and management of multiple CV risk factors extending from before birth to 21 years
of age, including studies with followup into later adulthooda scope and breadth
that had known gaps in the evidence base. In part, this task required assembling
and appraising the body of evidence pertaining to the role of single risk factors
and risk factor combinations in childhood in the development and progression of
atherosclerosis from childhood and adolescence to adulthood. Rather than relying
solely on RCTs, much of the evidence for guidelines in youth is available from epidemiologic
observational studies, which must be included in the review. In addition, this review
required critical appraisal of the body of evidence that addresses the impact of
managing risk factors in childhood on the development and progression of atherosclerosis.
Finally, because of known gaps in the evidence base relating risk factors and risk
reduction in childhood to clinical events in adulthood, the review had to include
the available evidence justifying the evaluation and treatment of risk factors in
childhood. The process of identifying, assembling, and organizing the evidence was
extensive; the review process was complex; and conclusions could be developed only
by interpretation of the body of evidence. Thus, there was explicit Expert Panel
involvement throughout the evidence review process.
The Expert Panel defined 14 critical questions for the literature search (Table
1-1) and the risk factors to be addressed (Table 12). The first phase of the
evidence review focused on critical questions 19, which address the association
between the development of atherosclerosis and the presence and intensity of CVD
risk factors in childhood and adolescence. The second phase of the evidence review
addressed critical questions 1014, which aim to assess the evidence for the
safety and efficacy of reduction of each risk factor and the impact of risk factor
change on the atherosclerotic process.
In addition to the typical RCTs, systematic reviews, and meta-analyses, two additional
types of studies were considered to provide evidence pertaining to the development
of atherosclerosis. Longitudinal observational studies were included to assess the
tracking of risk factors from youth to adulthood and the relationship of risk factors
in youth to the development of atherosclerosis. From the many available observational
studies in the literature, the Panel identified the 12 listed in Table 13
for inclusion in the evidence review. The panel used several criteria to evaluate
which studies should be in the evidence review, including sample size, and for longitudinal
studies the length of followup. In general, the studies were large, averaging more
than 1,000 subjects. Smaller studies that had long-term followup allowing evaluation
of the relationship between risk factors identified in infancy and early childhood
and adolescent and adult endpoints were also included. In addition, natural history
studies of genetic disorders known to alter CV risk status were included to provide
models of the consequences of prolonged risk exposure or risk protection.
The Expert Panel selected a literature search start date of January 1,1985, roughly
5 years before the previous expert panel process that had generated guidelines for
the management of cholesterol in childhood, the National Cholesterol Education Program's
Report of the Expert Panel on Blood Cholesterol Levels in Children and Adolescents,
which was published in 1992.
From an initial group of more than 1 million titles published between January 1,
1985, and June 30, 2007, the search was refined to ultimately include 648 studies:
50 systematic reviews, 33 meta-analyses, 293 RCTs, 194 observational studies, and,
in addition, 78 sets of guidelines relevant to pediatric CVD prevention, which were
provided as reference material. Each of the first four listed types of studies underwent
full text review and abstraction of critical information into evidence tables; each
study was graded individually using a unique algorithm developed for these Guidelines.
Details of the search methodology and the abstraction and individual study grading
processes are provided in Appendix A. Methodology. The evidence tables are available
electronically on the NHLBI Web site at
Expert Panel members were grouped into subcommittees to focus on specific risk factors
according to their respective areas of expertise, with many Expert Panel members
participating on more than one subcommittee. In addition, two oversight committees
were formed: (1) a Science Team to ensure high scientific quality of the entire
evidence review and Guidelines development process and (2) a Clinical Team to maintain
the relevance of the recommendations to clinical practice throughout Guidelines
development. The Science Team, led by Samuel S. Gidding, M.D., addressed the first
nine critical questions and summarized the evidence for the origins of atherosclerosis
in childhood and the evidence for the role of risk factors in the atherosclerotic
process in Section II. State of the Science: Cardiovascular Risk Factors and the
Development of Atherosclerosis in Childhood. For each risk factor, the Expert Panel
provided an overview of the evidence, focusing on those studies it believed provided
the most important information. These summaries are provided in the risk factor-specific
sections of this document. Because of the volume and complexity of the literature
review, specific information on every study is provided only in the evidence tables.
The risk factor subcommittees critically evaluated the body of evidence relative
to each risk factor, using an evidence grading system from the American Academy
of Pediatrics (AAP) (Table 14). As shown in Table 14,
the AAP evidence grading system was modified to incorporate genetic natural history
studies in the Grade B evidence category. Each risk factor subcommittee then formulated
age-specific recommendations with grade and strength of recommendation assigned
using the AAP grading system, based on consideration of the entire body of evidence
used in developing each recommendation. The age categories corresponded with the
system used by the AAP publication Bright Futures: Guidelines for Health Supervision
of Infants, Children and Adolescents. Each risk factor subcommittee
reached internal consensus before presenting its recommendations to the full Expert
Panel. The final recommendations were then reviewed and approved by the entire Expert
Panel. Additional information on the Guidelines development process is provided
in Appendix A. Methodology. A draft Guidelines document was reviewed by multiple
professional societies and by many individuals within the National Institutes of
Health, the Centers for Disease Control and Prevention, and relevant U.S. Department
of Health and Human Services organizations. The Guidelines also underwent a 30-day
public comment period. In total, individual responses were developed for more than
Section II. State of the Science: Cardiovascular Risk Factors and the Development
of Atherosclerosis in Childhood summarizes all the evidence linking the presence
of risk factors in childhood and adolescence to the presence and severity of the
atherosclerotic process as assessed both pathologically and by imaging studies.
An overview of the role of screening for CV risk factors in children is addressed
in Section III. Screening for Cardiovascular Risk Factors. The next eight sections
(IVXI) address individual risk factors. Each risk factor section begins with
a brief description of the current status of the risk factor in childhood and adolescence.
Since this kind of information is often not available from studies that are included
in evidence reviews, selected references are used to provide the context within
which the recommendations were developed. This text is followed by the Expert Panel's
written summary of the evidence review relative to the specific risk factor. As
described above, Expert Panel members provided an overview of the evidence, focusing
on those studies that in their expert opinions provide the most important information
and identifying deficiencies in the evidence. Specific information on each study
is provided in the evidence tables available through the NHLBI Web site at
http://www.nhlbi.nih.gov/guidelines/cvd_ped/index.htm. The conclusions of
the Expert Panel's review of the evidence are then summarized, accompanied by the
evidence grades and the strength of the recommendation. Each risk factor section
ends with the Expert Panel's age-specific recommendations, accompanied by supportive
actions, which represent suggestions developed by Expert Panel consensus to support
implementation of the recommendations. The recommendations are integrated across
risk factors and developmentally across age groups into the Integrated Cardiovascular
Health Schedule (Section XV), which summarizes the age-specific recommendations
for all of the risk factors. To optimize accessibility, references are grouped by
risk factor and are listed sequentially at the end of each section. References from
the evidence review are identified by the unique PubMed identifier (PMID) number
that appears in bold text. Additional references do not include the PMID number.
By addressing the major population-based risk factors for CVD in a single evidence-based
set of Guidelines, the aim is to support pediatric care providers in optimizing
CV health in infancy, early childhood, and adolescenceBy extending risk factor modification
into childhood, our goal is to reduce the development of clinical CVD in the future
lives of children.
Table 11. Development of the Evidence Base: Critical Questions
- What is the evidence that atherosclerosis and atherosclerosis-related target organ
damage begin in childhood?
- What is the evidence that the presence of risk factors in childhood affects the
development and progression of atherosclerosis and atherosclerosis-related target
organ damage during childhood?
- What is the evidence that the presence of risk factors in childhood affects the
progression of atherosclerosis and atherosclerosis-related target organ damage in
- What is the evidence that indicates the relative importance of each risk factor
in the development and progression of atherosclerosis and atherosclerosis-related
target organ damage in childhood?
- What is the evidence that racial or ethnic background, geographic region, or socioeconomic
status affect cardiovascular (CV) risk factor status in childhood/adolescence?
- What is the evidence that risk factors cluster in childhood?
- What is the evidence that risk factor clustering is consistent in childhood?
- What is the evidence that risk factors present in childhood persist (i.e., track)
- What is the evidence that an increase in the number and/or intensity of risk factors
in childhood alters (a) the development and progression of atherosclerosis and atherosclerosis-related
target organ damage in childhood; (b) the development and progression of atherosclerosis
and atherosclerosis-related target organ damage in adulthood; and/or (c) the development
of clinical CV disease (CVD) in adulthood?
- What is the evidence that risk factors in childhood can be decreased?
- What is the evidence that a decrease in risk factors in childhood can be sustained?
- What is the evidence that a decrease in risk factors in childhood alters (a) the
development and progression of atherosclerosis and atherosclerosis-related target
organ damage in childhood; (b) the development and progression of atherosclerosis
and atherosclerosis-related target organ damage in adulthood; and (c) the development
of clinical CVD in adulthood?
- What is the evidence that acquisition of risk factors or risk behaviors can be prevented
in childhood and adolescence?
- What is the evidence that preservation of a low-risk state from childhood, adolescence,
or young adulthood to later adult life is associated with (a) decreased development/progression
of atherosclerosis and atherosclerosis-related target organ damage and/or (b) decreased
incidence of clinical CVD?
Table 12. Evaluated Risk Factors
Table 13. Selected Observational Studies
National Health and Nutrition Examination Survey
Bogalusa Heart Study
Pathobiological Determinants of Atherosclerosis in Youth
Princeton Lipid Research Clinics Follow-Up Study
Cardiovascular Risk in Young Finns Study
National Heart, Lung, and Blood Institute Growth and Health Study
Special Turku Coronary Risk Factor Intervention Project (observational followup
from this randomized controlled trial)
Coronary Artery Risk Development in Young Adults Study
Minnesota Children's Blood Pressure Study
Beaver County Lipid Study
Fels Longitudinal Study
Table 14. Evidence Grading System
EVIDENCE QUALITY GRADES FOR THE BODY OF EVIDENCE
Well-designed randomized controlled trials or diagnostic studies performed on a
population similar to the guideline's target population
Randomized controlled trials or diagnostic studies with minor limitations; genetic
natural history studies; overwhelmingly consistent evidence from observational studies
Observational studies (case-control and cohort design)
Expert opinion, case reports, or reasoning from first principles (bench research
or animal studies)
GUIDELINE DEFINITIONS FOR EVIDENCE-BASED STATEMENTS
The Expert Panel believes that the benefits of the recommended approach clearly
exceed the harms and that the quality of the supporting evidence is excellent (grade
A or B). In some clearly defined circumstances, strong recommendations may be made
on the basis of lesser evidence when high-quality evidence is impossible to obtain
and the anticipated benefits clearly outweigh the harms.
Clinicians should follow a strong recommendation unless a clear and compelling rationale
for an alternative approach is present.
The Expert Panel feels that the benefits exceed the harms but the quality of the
evidence is not as strong (grade B or C). In some clearly defined circumstances,
recommendations may be made on the basis of lesser evidence when high-quality evidence
is impossible to obtain and when the anticipated benefits clearly outweigh the harms.
Clinicians should generally follow a recommendation but remain alert to new information
and sensitive to patient preferences.
Either the quality of the evidence that exists is suspect (grade D) or well-performed
studies (grade A, B or C) show little clear advantage to one approach versus another.
Clinicians should be flexible in their decision-making regarding appropriate practice,
although they may set boundaries on alternatives; patient and family preference
should have a substantial influencing role.
There is both a lack of pertinent evidence (grade D) and an unclear balance between
benefits and harms.
Clinicians should not be constrained in their decision-making and be alert to new
published evidence that clarifies the balance of benefit versus harm; patient and
family preference should have a substantial influencing role.
NCEP Expert Panel of Blood Cholesterol Levels in Children and Adolescents. National
Cholesterol Education Program (NCEP): Highlights of the Report of the Expert Panel
on Blood Cholesterol Levels in Children and Adolescents. Pediatrics 1992;89:495-501.
American Academy of Pediatrics Steering Committee on Quality Improvement and Management.
Classifying recommendations for clinical practice guidelines. Pediatrics 2004;114:874-877.
Hagan JF, Duncan PM, eds. 2008. Bright Futures: Guidelines for Health Supervision
of Infants, Children and Adolescents, Third Edition. Elk Grove Village, IL: American
Academy of Pediatrics.
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