Appendix A. Methodology

I. Background

For more than 35 years, the National Heart, Lung, and Blood Institute (NHLBI) has supported the development of clinical guidelines related to reducing cardiovascular (CV) risk. In October 2006, NHLBI Director Elizabeth Nabel, M.D., appointed an Expert Panel to develop an integrated clinical guideline addressing the known pediatric risk factors for the development of atherosclerosis to be used by pediatric care providers in caring for their patients. The goal of the guideline was to make it possible for the known CV risk factors to be identified and managed as part of routine pediatric care. The Expert Panel was chaired by Stephen R. Daniels, M.D., Ph.D., and included representatives from the medical specialties of pediatrics, family medicine, internal medicine, nutrition, epidemiology, and nursing—from both academic medicine and private practice. Previous NHLBI-facilitated CV risk-reduction guidelines for hypertension and cholesterol in children and adolescents were developed by expert panel consensus based on a traditional literature review and dealt with a single clinical topic. These guidelines differed in that a formal systematic review (SR) of the evidence initiated the process of recommendation development.

The goal of this panel was defined as development of a comprehensive evidence-based guideline addressing all of the major risk factors to assist pediatric care providers in both the promotion of CV health and the identification and management of specific risk factors from infancy into young adult life. From the outset, the panel realized that an innovative approach to the evidence review and to the guideline development process would be needed to develop the required comprehensive integrated product for the following reasons:

• A focus on CV risk reduction in children and adolescents addresses a disease process—atherosclerosis—in which the clinical end point of manifest cardiovascular disease (CVD) is remote. The recommendations would therefore need to address two different goals:  the prevention of risk factor development (i.e., primordial prevention) and the prevention of future CVD by effective management of identified risk factors (i.e., primary prevention).
• A traditional systematic evidence-based-medicine review deals with a single, finite question; the rigorous review process usually results in only a handful of articles for inclusion; only randomized controlled trials (RCTs), SRs, and meta-analyses (MAs) of RCTs published over a defined time period are usually included, and there is a defined format for abstraction of studies, grading of the evidence, and presentation of results. By contrast, this evidence review needed to deal with many questions, each addressing multiple risk factors over a time span extending from birth to age 21 years during which enormous physiologic changes occur; studies with followup into adult life would need to be included. Thus, the evidence review would be extensive, and the review process complex.
• Because of known gaps in the evidence base relating risk factors and risk reduction in childhood to clinical events in adult life, the review must include evidence informing the evaluation and treatment of risk factors in childhood, and there must be explicit Expert Panel involvement in the evidence review process.

The expert panel defined 14 critical questions for the search and the risk factors to be addressed, as detailed below. Questions 1–9 address the development of atherosclerosis relative to the presence and intensity of the risk factors in childhood and adolescence; the first phase of the evidence review was based on these. Questions 10–14 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; the second phase of the review was based on these.

Two additional types of studies were considered in addition to the classic schema of RCTs, SRs, and MAs to provide evidence related to the development of atherosclerosis. Longitudinal observational studies were included to examine the tracking of risk factors from youth into adulthood and the relationship of risk factors in youth to the development of atherosclerosis. The Expert Panel selected 12 major epidemiologic studies for this part of the review, which are detailed below. 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.

After the establishment of the Expert Panel, seven subcommittees were formed to focus on particular aspects of the Guidelines, with several Expert Panel members participating on more than one subcommittee. In addition, two oversight committees were formed:  a Science Team to ensure the scientific quality of the process and a Clinical Team to maintain the relevance of the recommendations to clinical practice throughout the Guidelines development process. The primary work occurred at the subcommittee level, with oversight by the full Expert Panel and coordination by NHLBI staff. The Expert Panel developed these Guidelines and report in the following steps:

• Framing the scope of and conducting the systematic literature review.
• Reviewing abstracts and full text of retrieved studies to identify relevant studies for inclusion.
• Selecting outcome variables to be recorded and compiling the data from included studies into evidence tables.
• Evaluating the quality of individual studies and assigning grades to each study; the process for this is described below.
• Critically reviewing and summarizing the content of the evidence tables.
• Identifying pertinent findings from the evidence review.
• Formulating draft recommendations for potential use in routine pediatric practice.
• Reaching consensus within the Expert Panel subcommittees and the full Expert Panel regarding final recommendations; the consensus process is described below.
• Developing grades for each recommendation based on the body of evidence reviewed.
• Developing supporting report text and graphics.
• Circulating a draft of the Guidelines and report for multiple levels of external review, including a public comment period.
• Preparing the final Guidelines and report for dissemination.

As can be easily appreciated, this is a modified evidence review process that combines the methodology of a traditional review with the explicit involvement of an Expert Panel. The following sections provide more detail regarding each of these steps, including the methodology used to conduct the systematic literature review and the process employed to translate the findings of this review into the Guidelines' recommendations.

II. Systematic Evidence Review

A. Scope of Review

The foundation of the systematic evidence review performed in support of the guideline development process was a series of critical questions related to CVD risk and prevention in youth. The questions encompassed defined risk factors, predefined outcome measures for each risk factor, and, most importantly, measures of CVD and target organ damage (TOD). Each of these elements was developed and refined through a review of the existing evidence by the Expert Panel.

• Critical questions. The critical questions (Table A–1) framed the search strategy for evidence to support the Expert Panel deliberations during the Guidelines development process. These questions pertained to the etiology and progression of the atherosclerotic process—spanning the prenatal period into young adult life—and the identification, treatment, and prevention of risk factors for CVD over that same time period. Within these areas, the critical questions considered multiple risk factors, the relationship of risk factors to measures of atherosclerosis, TOD and CVD, and risk factor reduction to delay the progression of atherosclerosis and the risk of future clinical CVD.

Table A–1. Critical Questions

• Risk factors. A set of 14 risk factors (Table A–2) for CVD further defined the search for and organization of the relevant body of evidence.

Table A–2. Risk Factors for Cardiovascular Disease

• In-scope outcome measures for each risk factor. A list of relevant end points or outcome measures was developed for each risk factor. The number of outcome measures varied according to risk factor and ranged from as few as 2 (for blood pressure (BP)) to as many as 17 (for diet/nutrition). Table A–8—shown in the Methodology:  Additional Tables subsection—provides a complete list of in-scope outcome measures by risk factor. Risk factor studies that did not report assessing at least one of these outcomes and/or did not meet other inclusion criteria as specified in Table A–8 were excluded from further analysis.
• Cardiovascular disease or target organ damage. In addition to these risk factors, outcomes related to CVD and measures of TOD were considered to be in scope. To facilitate review, each study was categorized according to whether it addressed atherosclerosis or clinical CVD. Those that addressed atherosclerosis were further categorized according to whether they assessed measures of TOD, including left ventricular mass or subclinical measures of atherosclerosis—including coronary calcium/calcification, carotid intima-media thickness, flow-mediated endothelium-dependent arterial dilation, or arterial distensibility.

To inform the identification of studies related to the critical questions, the Expert Panel held an inservice training with the contractor staff members who would be involved in overseeing the literature review to initiate the evidence review process. In addition, a series of group training sessions was held with the contractor staff at appropriate points throughout the process to clarify the scope of the review and expectations for supporting the production of high-quality, evidence-based guidelines.

B. Search Parameters

Based on the critical questions, risk factors, and types of CVD TOD of interest, search parameters were developed to identify published studies relevant to pediatric CV risk reduction. This process involved determining appropriate databases, dates, terms, and limits for the search, as described below.

1. Databases

Searches were performed in the following databases:

• PubMed/MEDLINE. Administered by the National Library of Medicine, National Institutes of Health (NIH), PubMed is an online interface that allows users to access more than 17 million citations from MEDLINE and other life science journals published since the 1950s.^[1]
• Cochrane Database of Systematic Reviews. Part of the Cochrane Library, the Cochrane Database of Systematic Reviews includes more than 3,000 high-quality, independent SRs on a range of clinical topics.^[2]
• National Guideline Clearinghouse (NGC). An initiative of the U.S. Department of Health and Human Services' (HHS') Agency for Healthcare Research and Quality, the NGC is a comprehensive repository of evidence-based clinical practice guidelines and related documents.^[3]

Searches were first conducted in PubMed/MEDLINE. Only unique studies from subsequent searches in the Cochrane database and the NGC were retained for consideration (i.e., those studies that were not already captured in the initial PubMed/MEDLINE search).

In addition to these databases, a preliminary search of EMBASE was conducted. The great majority of studies identified in this preliminary search were also found in the other databases; therefore, it was determined that proceeding with a complete EMBASE search would not contribute significant additional information to the review.

The literature search allowed for further input by the Expert Panel to ensure that in-scope studies were not overlooked. Members of the Expert Panel contributed additional relevant studies based on their routine scanning of the literature. A supplementary literature search was also conducted to identify potentially relevant studies authored by members of the Expert Panel. Additional studies identified by these supplementary methods were included only if they met the same criteria for inclusion established for the primary evidence review.

2. Search Dates

Original searches in PubMed/MEDLINE, Cochrane, and the NGC captured studies published between January 1, 1985, and December 31, 2006. Recognizing the timelag inherent in screening a large body of literature and developing evidence tables, the Expert Panel then called for an update of these searches to be conducted for the period between January 1, 2007, and June 30, 2007.

The Expert Panel established June 30, 2007, as the closing publication date for literature to be entered into the evidence review for these Guidelines. The Expert Panel recognized that, given the scope of these Guidelines and the nature of ongoing research in relevant areas, research findings might appear thereafter with the potential to have a material impact on one or more recommendations in the Guidelines. Therefore, to optimize the currency of the Guidelines, the Expert Panel sought, prospectively, to enable consideration of directly relevant, significant peer-reviewed evidence that might appear after the closing date. During a conference call convened on January 21, 2008, the Expert Panel Science Team established the following criteria to guide the full Expert Panel's consideration of studies published after the closing date:

• Any peer-reviewed published study identified by a member of the Expert Panel, as part of his or her routine surveillance of the literature, that is directly relevant to the recommendations of the Expert Panel will be considered for inclusion.
• To be included by the Expert Panel as evidence, the corresponding Risk Factor Team, or the full Expert Panel if applicable at a broader level, must judge that the findings of such recently published studies have the potential for a material impact on the content or strength of the recommendations of the Expert Panel.
• Such studies must meet the same basic criteria for inclusion established for the primary evidence review.
• If there is a difference of opinion about inclusion of a study, a final decision will be made by the Expert Panel Chair.
• Studies that are selected for inclusion will undergo abstraction and full text review by the process established for the primary evidence review. To distinguish it from the body of evidence assembled via the systematic literature search conducted through the closing date of June 30, 2007, the body of evidence from any such more recent studies will be documented separately from the evidence tables comprising data from the original search.

3. Search Terms

To explore the most appropriate search strategy and examine the sensitivity and specificity of particular search terms, an initial search was done in PubMed/MEDLINE. This search used broad medical subject heading (MeSH) terms and text words for the concepts of pediatric/young adult populations, CVD/TOD, and the risk factors. Terms were combined using the Boolean operators "AND," "OR," and "NOT," which are described briefly in Table A–3.

Table A–3. Boolean Operators Used To Combine Search Terms^[4]

The preliminary, broad search of PubMed/MEDLINE identified in excess of 1 million citations, signaling the need to refine the search terms to identify the most relevant ones. In consultation with the Expert Panel, key refinements in the search strategy were made, including (1) the use of major MeSH terms rather than MeSH terms, where appropriate; (2) the use of title and abstract terms rather than text words; (3) a reduction of the number of terms for each concept, leaving only the most central and essential terms; and (4) the application of excluded concepts to the search (in the form of "NOT" terms).

In the final search strategy, a combination of MeSH terms, major MeSH terms, and title and abstract terms was employed to identify the full range of relevant literature. Search terms were identified to capture studies in the pediatric and young adult target populations (ages 0–21 years) that also addressed CVD/TOD and/or at least one of the risk factors. Specific search terms are provided in Table A–9 in the Methodology:  Additional Tables section.

4. Search Limits

A set of limits was applied to the search to help refine the results to the most useful types of studies. The first level of basic search limits included:

• Publication date:  published between January 1, 1985, and June 30, 2007
• Language:  English language abstract or full text
• Publication type:  no editorials, letters, comments, case reports, or non-SRs

Search terms and field tags used to apply these limits to the search are provided in Table A–9 in the Methodology:  Additional Tables section.

In addition to these basic limits, search terms were used to exclude studies examining certain out-of-scope conditions. For example, during a preliminary review of the literature, many studies were identified that focused on various pediatric conditions such as Kawasaki disease, otitis media, or congenital heart diagnoses. Through consultation with the Expert Panel, search terms were developed for the most commonly observed out-of-scope conditions. Studies containing these terms were prospectively excluded by using the Boolean operator "NOT."

5. Search Results

Systematic Reviews, Meta-Analyses, Randomized Controlled Trials, and the Guidelines

After applying the initial limits and using terms to eliminate out-of-scope concepts, the number of results returned from the original literature searches was still in excess of 60,000 citations. Given the size of these literature results, the Expert Panel determined that part of the review would focus on certain study types that would be most useful to the Expert Panel during Guidelines development:  SRs, MAs, RCTs, and guidelines. Search terms and field tags identifying study type were used to select these studies in the PubMed/MEDLINE database.

Secondary studies, such as SRs and MAs, compile results from primary analyses and, in some cases, review of these study types may lessen the need to examine primary evidence on a topic. However, given the breadth of this evidence review, there were no instances in which an SR or MA captured the entire scope of interest of a critical question; therefore, this review depended on RCTs as an important source of primary data on relevant interventions.

The schematic in Figure A–1 presents a simplified, high-level depiction of how the key search concepts were combined to achieve the overall search strategy.

Figure A–1. Overview of General Search Strategy for Identification of Relevant Systematic Reviews, Meta-Analyses, Randomized Controlled Trials, and Guidelines

Figure A-1 Text Description:

The figure is a flow chart with 7 labeled boxes linked by arrows. The top 3 boxes lead to a shared flowchart below. The chart flows in one direction with arrows pointing downward. Below, the flow chart is described as lists in which the possible next steps are listed beneath each box label.

1. Pediatric population AND CVD/TOD
   OR
2. Pediatric population AND Risk factors
   OR
3. Young adult population AND CVD/TOD AND Risk factors
   1. Forward to AND Basic search limits (e.g., publication date, language)
   2. Forward to NOT Excluded conditions (e.g., otitis media, congenital heart conditions)
   3. Forward to AND Systematic review, meta-analysis, randomized controlled trial, or guideline
   4. Forward to Yield: 10,300 studies for review

Major Observational Studies

In childhood, much of the evidence linking risk factors to atherosclerosis comes from epidemiologic studies. Therefore, in addition to including SRs, MAs, RCTs, and guidelines in the review, the Expert Panel determined that it was necessary for the evidence review to include major epidemiologic studies selected by the Expert Panel. These studies represent landmark longitudinal and natural history studies and other sentinel work that have provided important information and insight about atherosclerosis and CV risk in children. The major observational studies that were included are listed in Table A–4.

Table A–4. Selected Major Observational Studies

A separate targeted search of PubMed/MEDLINE was conducted to identify literature relevant to these major studies related to the risk factors for the inclusive period of the evidence review from January 1, 1985, to June 30, 2007. The observational literature was also updated by the Expert Panel using the same criteria developed for the classic evidence review. Terms used to conduct this search are provided in Table A–10 in the Methodology:  Additional Tables section. NHLBI staff reviewed the titles and then the abstracts for studies to be included based on the 14 risk factors under review. When a longitudinal study reported results of the same variables at increasing intervals from the beginning of the observational period, the most recent report detailing the longest period of observation was selected for inclusion. Duplicate reports of the same results were excluded. The observational studies to be included in the evidence review were selected by the Expert Panel Risk Factor Teams.

Additional References

In an evidence-based review, studies included are generally limited to RCTs, SRs, and MAs. In addition to the epidemiologic studies described above, Expert Panel members also included studies that provided important information for each risk factor, defining the context in which the Guidelines' recommendations were developed. These references are not part of the evidence tables but are identified sequentially throughout the text and will be listed in Appendix B by section in numeric order, as identified in the text. Of particular importance were studies of genetic conditions impacting CV risk status and natural history studies of specific diseases known to be associated with accelerated atherogenesis.

Inclusion and Exclusion Criteria

In preparation for review of the literature, inclusion and exclusion criteria were developed by the Expert Panel. These criteria outlined additional boundaries for the review. Certain criteria were applied only by the Expert Panel, given that judgments regarding the application of these criteria required relevant clinical expertise; these criteria are marked with an asterisk below.

Inclusion criteria:

• Pertained to at least one of the specified risk factors and measured at least one of the predetermined outcomes
• Related to at least one of the critical questions
• Focused on the target population (ages 0–21 years)
  • For longitudinal studies and other studies with extended followup periods, the population was required to be in this age range at initiation, and this subcohort could be identified in subsequent analyses.
  • For the Guidelines, the target population was required to include at least part of this age range.
• Conducted in Europe, North America, Australia, New Zealand, Japan, or Israel
• In 2004, an NHLBI-appointed Task Force published The Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and Adolescents. This report included a complete review of the current evidence on this subject and detailed recommendations for managing BP throughout childhood.^[5]  These recommendations were used as the basic recommendations for BP management for these Guidelines and are considered complete until 2003 when the review for the report ended. The literature review for BP, therefore, was limited to January 1, 2003, through June 30, 2007; selected studies from 2008 identified by the Expert Panel that met all the criteria for inclusion in the evidence review were also included.

Exclusion criteria:

• Any study not meeting the above requirements was excluded from the review.
• Studies that otherwise met inclusion criteria but that were found, upon examination, to have measured risk factors in only an incidental way or as part of assessing the safety of an intervention were excluded. For example, a study of an asthma medication might measure BP to ensure that there were no adverse effects of the medication. Such studies that measured in-scope outcomes that were not linked to a risk factor condition were excluded from the review.
• Duplicate reports of findings based on the same original studies were generally excluded. For instances in which a series of studies (typically longitudinal studies or large RCTs) reported results for the same outcome measures over a period of time, the most recent studies and main results of trials were typically retained and older studies were excluded. These determinations were made individually during the review of each study.
• Studies that did not meet basic internal/external validity standards (e.g., as a result of narrowly defined patient population) were excluded.
• Studies that addressed the target population, often as part of a broader age range, but did not provide findings specific to patients in the target age range were excluded.
• Studies were excluded that on closer inspection were found not to be SRs, MAs, RCTs, guidelines, or reports from the selected epidemiologic studies.
• Studies were excluded that had an insufficient number of patients at followup to draw meaningful conclusions.
• Studies conducted in patients with diabetes focused on interventions that were related exclusively to glycemic control were excluded.
• For studies that focused on smoking as a risk factor, those that reported on interventions related to policymaking or merchant behavior were excluded.

During the review process, inclusion and exclusion criteria were modified to account for topics identified as irrelevant and certain included topics were clarified. Throughout this process, abstractors, and the Expert Panel were in close contact to resolve questions regarding the application of inclusion/exclusion criteria to individual studies.

C. Literature Review Process

After completing electronic searches in each database, a total of 11,231 SRs, MAs, RCTs, guidelines, and major observational studies were identified for review. The distribution of search results by database and study type is presented in Table A–5. Abstracts and citations for these studies were compiled and organized using Reference Manager.

Table A–5. Distribution of Search Results by Database and Study Type for Studies Published Between January 1, 1985, and June 30, 2007

* Only unique results from Cochrane and NGC are displayed (i.e., duplicates of PubMed/MEDLINE results were excluded).

Figure A–2 outlines the phases of the literature review process and the number of studies excluded at each stage. Throughout each review phase, the Expert Panel provided guidance regarding the appropriate application of inclusion and exclusion criteria.

Abstracts and citations for these studies were compiled and organized using Reference Manager software. A review of titles and abstracts was first conducted for SRs, MAs, RCTs, and guidelines by trained abstractors. For the observational studies, titles and abstracts were reviewed by NHLBI staff. This phase of the review process resulted in a total of 561 SRs, MAs, and RCTs, as well as 78 guidelines and 196 observational studies, which were found to be potentially relevant, as indicated in Figure A–2.

Following the review of titles and abstracts, trained abstractors conducted a full-text review of the studies and excluded additional studies. NHLBI staff also reviewed the full text of these studies and identified additional studies to exclude. Following the full-text review phase, an additional 200 studies were excluded. Citations for studies excluded at the full-text level are provided online, along with the complete evidence tables.

Figure A–2. Overview of Review Phases and Excluded Studies at Each Phase

Figure A-2 Text Description:

The figure is a flow chart with 6 labeled boxes linked by arrows. The chart flows in one direction with arrows pointing downward with lateral boxes from the downward arrows. Below, the flow chart is described as lists in which the possible next steps are listed beneath each box label.

Search results: 11,231 studies

• 3,514 systematic reviews (SRs)
• 221 meta-analyses (MAs)
• 3,982 randomized controlled trials (RCTs)
• 2,583 guidelines
• 931 observational studies

Title and Abstract Review

Exclusions:

• 10,396 studies
• 3,434 SRs
• 177 MAs
• 3,545 RCTs
• 2,505 guidelines

Included: 835 studies

• 80 SRs
• 44 MAs
• 437 RCTs
• 78 guidelines
• 196 observational studies

Full-Text Review

Exclusions: 200 studies

• 30 SRs
• 13 MAs
• 138 RCTs
• 19 observational studies

Included: 29 studies published after June 2007

• 1 SR
• 3 MAs
• 5 RCTs
• 6 guidelines
• 14 observational studies

Final included: 664 studies

• 51 SRs
• 34 MAs
• 304 RCTs
• 84 guidelines*
• 191 observational studies

In addition to a review of the studies captured through the literature search process (i.e., studies published between January 1, 1985, and June 30, 2007), the NHLBI and the Expert Panel identified an additional 29 relevant studies that were published after June 30, 2007, for inclusion in the review.

At the end of the review process, a total of 664 studies were included for review—including 51 SRs, 34 MAs, 304 RCTs, 84 guidelines, and 191 observational studies. The distribution of the 664 studies included SRs, MAs, RCTs, major observational studies, and guidelines by risk factor is provided through the NHLBI Web site.

D. Data Collection and Quality Control

Systematic Reviews, Meta-Analyses, Randomized Controlled Trials, and Guidelines

To capture information from in-scope studies, Excel tables were developed and used for data abstraction of each study type (i.e., SR, MA, RCT). Through discussion with the Expert Panel, the types of information collected and the format of the tables were refined. Data collected in the abstraction tables included basic information about the study (e.g., year of publication), objective, patient population, intervention and comparator/control (if applicable), outcomes measured, and results. Data abstracted varied by study type. A complete list of data fields and definitions for these fields is provided through the NHLBI Web site.

To complete the data abstraction tables, trained abstractors reviewed full-text versions of each in-scope study. Two reviewers examined each full-text study; the first reviewer abstracted the appropriate data from each study, while the second reviewer concentrated on ensuring the accuracy and quality of data entered by the first reviewer as part of a thorough quality control process. For RCTs, contractor staff abstracted information for specific columns, including basic information about the study, objective, patient population, intervention and comparator/control (if applicable), and outcomes measured. For SRs and MAs, the contractor staff abstracted information for all columns. For observational studies, contractor staff abstracted the basic informational data, but full-text review and data entry were performed by NHLBI staff.

After data abstraction by the contractor, the data abstraction tables were submitted to NHLBI staff and the Expert Panel for review and/or completion of abstraction. For all study types, Expert Panel members were responsible for verifying data entered by the contractor. For RCTs, Expert Panel members selected the outcome variables to be abstracted and staff entered the results in the evidence tables, as well as recorded study results and conclusions. To facilitate this process, studies were forwarded to the relevant subcommittee within the Expert Panel, according to the primary risk factor of focus. For example, a study that examined the use of an intervention to improve cholesterol levels would have been forwarded to the subcommittee on lipids. Study reviews were rotated to ensure that each was reviewed by two subcommittee members. Subcommittee members completed abstraction of established columns and, in several cases, requested the addition of extra columns in the evidence tables to capture more specific information pertaining to the risk factor of interest. When Expert Panel members were not in agreement regarding such matters as study relevance or abstraction of specific data, these matters were brought to the Expert Panel Chair for resolution.

In addition to basic information about study design and results, aspects of study quality were considered by the Expert Panel during data abstraction. A customized quality grading system was developed to support the Expert Panel's interpretation of individual studies, particularly with regard to methodology and study design considerations. This novel grading system, the development of which drew largely from several existing grading schemes, was incorporated into the electronic data abstraction tables. The system used an algorithm that generated a quality grade for individual RCTs, according to the criteria outlined in Tables 11 and 12. SRs, MAs, and observational studies did not receive an individual quality grade.

After completion of data abstraction, evidence tables displaying key study information were developed from the data abstraction tables using Excel for use by the Expert Panel. These standard evidence tables were then sorted in a customized way for each subcommittee, so as to best support the Guidelines development process. Final evidence tables for all included SRs, MAs, RCTs, and observational studies will be provided online at http://www.nhlbi.nih.gov/guidelines/cvd_ped/index.htm.

Although reports of guidelines were captured as part of the literature search, they were not incorporated into evidence tables. Instead, the guidelines were reviewed for relevance, and those that were in scope were categorized according to the risk factor(s) addressed. A list of the in-scope guidelines was made available to Expert Panel members for their reference; full-text versions were made available as needed. Citations for in-scope guidelines, by risk factor, are also provided online.

Major Observational Studies

Excel tables were also developed for the epidemiologic observational studies, with basic information about each study entered into tables by skilled abstractors from contractor staff. Full-text review and abstraction of each study were performed by NHLBI staff, including identification of outcome variables and review of results and conclusions. These tables were then reviewed by Expert Panel members, who selected 191 studies as relevant to the evidence review. The tables were primarily categorized by risk factor and then sorted using the terms developed by the relevant Risk Factor Teams for inclusion in the review. Expert Panel members added additional relevant reports from any of these observational studies that appeared after conclusion of the formal review. The evidence tables for the observational studies also will be included on the NHLBI Web site.

III. Guidelines Development Process

A. Expert Panel and Subcommittee Discussion

Following establishment of the Expert Panel, in-person meetings were held in October 2006, February 2007, June 2008, and October 2008. These meetings enabled Expert Panel members to discuss key elements of the systematic evidence review, consider the approach and scope of the Guidelines, and review and refine the Guidelines' recommendations.

To facilitate discussion of the evidence related to particular risk factors, multiple subcommittee conference calls were held from February to December 2008, along with a continuous electronic correspondence. Across the seven subcommittees, more than 500 conference calls were completed. During these calls, subcommittee members established processes for developing and finalizing the Guidelines' recommendations for each risk factor and progressively shaped the final recommendations in the Guidelines. A SharePoint Web site was created to enable subcommittee members to share draft recommendations.

B. Established Parameters for Guidelines Recommendation Development

The Expert Panel adopted an evidence grading system from the American Academy of Pediatrics (AAP) to assess the quality of the body of evidence as a whole and the evidence in support of particular statements.^[6]  The grading system is shown in Table A–6; it was modified by the addition of genetic natural history studies to the grade B evidence category; an example of a genetic natural history study is the development of atherosclerosis in a child with homozygous familial hypercholesterolemia who has severely elevated cholesterol levels from birth. Studies of such genetic conditions are believed to represent a natural intervention and to function as surrogates for a specific lifelong risk exposure. Genetic variation shares features with random assignment in clinical trials in that the variation occurs by chance within a society and the presence of the genetic variation does not alter exposure to environmental or other factors.^[7]  Table A–6 shows the modified system used to assess the quality of the body of evidence.

Table A–6. Evidence Quality for Grades of Evidence

Drawing from the same AAP system, Table A–7 depicts the Guidelines' definitions for evidence-based statements.

Table A–7. Guidelines' Definitions for Evidence-Based Statements

The Expert Panel also developed a definition of consensus to guide decisionmaking regarding Guidelines recommendations within the subcommittees and among the full Expert Panel. The final definition included the following elements:

• Committee deliberations regarding a given recommendation generally reflected deference to the expert risk factor subcommittee that was originally charged with critically appraising the evidence and drafting the recommendation.
• Voting was "in support of" or "opposed to" a recommendation.
• Agreement by at least 80 percent (or 11 of 14 members) of the Expert Panel constituted a strong consensus. A recommendation with this level of agreement is presented in the Guidelines as a consensus of the Expert Panel. However, discussion of the issues in the Guidelines document may address areas of difference.
• A proposed recommendation that was supported by less than 60 percent (or less than 8 of 14 members) of the Expert Panel was not included in the Guidelines. However, review of the subject could be included in the discussion for that risk factor area.
• Agreement by 60–80 percent (9 or 10 of 14 members) of the Expert Panel constituted a moderate consensus in support of the recommendation. A recommendation with this level of agreement was presented with that language in the Guidelines and accompanied by discussion of the conflicting issues. In developing the discussion in support of a recommendation, the actual vote of the Expert Panel was considered.

In considering the various pediatric age groups covered by the Guidelines' recommendations, the Expert Panel agreed to formulate the Guidelines' recommendations according to the chronological timetable used by the AAP Bright Futures program:^[8]

• Preconception/prenatal
• 0–12 months
• 1–4 years
• 5–10 years
• 11–17 years
• 18–21 years

Studies were not always specific to an age group, and the Expert Panel used judgment in determining how those studies informed age-specific recommendations.

C. Completion of the Guidelines

At the final full Expert Panel meeting in October 2008, the Expert Panel reviewed each recommendation proposed by each subcommittee in detail. According to the established definition of consensus, the Expert Panel agreed on a complete set of recommendations and supporting text in the draft Guidelines report.

In April 2009, a draft version of the Guidelines was circulated to other NIH Agencies and multiple professional organizations for review and comment. The draft version was also posted on the NHLBI Web site for public comment for a 30-day period from June 19 to July 20, 2009. In total, the Expert Panel considered more than 1,000 comments from more than 50 reviewers, and individual responses were developed for more than 1,000 comments. The draft version of the Guidelines also underwent a separate review by the NHLBI and components of the HHS. After considering all comments, the Expert Panel made appropriate revisions to the draft report. The summary report was published in final form November 11, 2011.

Methodology:  Additional Tables

Table A–8. Outcome Measures

Table A–9. Search Terms and Limits

Table A–10. Search Terms for Major Longitudinal and Other Sentinel Studies

Table A–11. Quality Criteria for Assessment of Individual Randomized Controlled Trials

Table A–12. Randomized Controlled Trial Grading Scheme

REFERENCES

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