The Nutrition Guideline for UCD is an evidence- and consensus-based management guideline created through a rigorous, transparent, and systematic development process. The process was adapted from the Academy of Nutrition and Dietetics with the addition of specific techniques to draw on the expertise from clinical practice to fill in gaps where research is lacking. This modified Delphi-Nominal Group-Delphi process has been published in the Journal of Evaluation in Clinical Practice and is available at http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2753.2011.01807.x/pdf . The process is illustrated in Figure 1, below:

The core team and UCD work group chairs identified eight major areas of nutrition management in UCD and pressing issues within each area. Research questions for each area were formulated in the PICO (population, intervention, comparison, and outcomes) format.

The eight research questions were:

1. ACUTE NUTRITION MANAGEMENT: For individuals with UCD, what acute nutrition management interventions during hyperammonemia or intercurrent illness improve outcomes?
2. CHRONIC NUTRITION MANAGEMENT: For individuals with UCD, what medical nutrition therapies are necessary for chronic management of urea cycle disorders to optimize outcomes?
3. MONITORING (By stage of life and severe mild): For individuals with UCD, what monitoring supports nutrition management and promotes positive outcomes?
4. MEDICATIONS AND SUPPLEMENTS: For individuals with UCD, what supplements and pharmacological therapies or medications are associated with positive outcomes?
5. NUTRITION EDUCATION: For individuals with UCD, what nutrition education and patient support interventions are associated with positive outcomes?
6. LIVER TRANSPLANTATION: For individuals with UCD undergoing liver transplantation, what nutrition management interventions support positive outcomes?
7. WOMEN: For women with UCD, what nutrition management interventions support are necessary during menses, pregnancy, delivery, the postpartum period, and lactation to promote positive outcomes for mother and infant?
8. OTHER RELATED CONDITIONS: For individuals with Amino Acid Transport Deficiencies or Other Conditions that Present as UCDs, what nutrition interventions are associated with positive outcomes?

Workgroup members identified topics within each question where uncertainty and/or variation in practice existed. These questions and topics were used to direct the literature search, evidence summaries, and an initial Delphi survey.

Because of the known scarcity of published scientific literature in nutrition management of inborn metabolic disorders (IMDs), the search process included both published scientific studies and gray (practice) literature.

Scientific Literature: Search terms related to nutrition were developed from the guideline's eight research questions and the list of included disorders to identify relevant literature. Searches were conducted by a medical librarian at Emory University working in close collaboration with the project staff.

Predefined eligibility criteria were used for study selection. Included publications were human studies published in English between 1978 and August 2024 that reported data relevant to nutrition management of UCDs. No restrictions were placed on study design, participant age, or care setting. Articles were identified through searches of PubMed and PubMed Central. 

The titles and abstracts of 3258 identified articles were scanned for relevance to the research questions and matched with inclusion/exclusion criteria by the work group chairs and co-investigators. A total of 2115 articles were excluded for one or more of the following reasons: unrelated to UCD or research question(s) (n=1734), genetic studies not related to phenotype (n=319), animal or in vitro study (n=146), general overview article intended to educate providers on UCDs (n=30), and article not written in English (n=6). Excluded articles were noted, and 1143 qualifying articles were gathered for review and abstracting.

Gray Literature: Gray literature refers to reports of clinical practice and research that cannot be accessed through standard search systems and includes abstracts and presentations from scientific and practice-based meetings, clinical protocols and guidelines, unpublished research, communication among experts (including listserves), professional newsletters, and book chapters. The search for gray literature involved request to individuals (e.g., practitioners and researchers) and organizations for materials related to nutrition and UCDs. Twenty-seven (27) identified resources were screened and 24 were included based on relevance, substantive information not available in scientific literature, and currency.

Each article was adjudicated and assigned to one or more of the research questions. The number of sources relevant to each area was as follows:

• Acute Management-256
• Chronic Management-263
• Monitoring-401
• Medication and Supplements-263
• Nutrition Education-29
• Liver Transplant-115
• Menses, Pregnancy, Postpartum, Lactation-60
• Related Disorders-368

Separate systematic review and evidence analysis were conducted for each research question.

Each scientific article was critically reviewed by a trained analyst using a Quality Criteria Checklist. Training and the role of analysts were published in 2015 (L.470)

Quality criteria addressed: study design, selection and retention of subjects, groups comparable, intervention clearly described and followed, other intervening variables tracked, outcomes defined, measures valid, and appropriate statistical analysis. Based on number of criteria met, each article was assigned a quality rating of positive, neutral, or negative. Workgroup members then abstracted key information to Overview Tables for each question including: study design, sample size and characteristics, intervention, outcome findings, limitations, and author's conclusions.

Gray literature and practice resources were systematically reviewed using an adapted abstraction and critical appraisal process. Trained reviewers used a specially developed quality criteria checklist for gray literature that included: clear purpose, relevance to intended users, systematic development process, clear clinical recommendations, applicability to practice, and free of conflict of interest. A co-investigator abstracted clinical practices and outcome information onto Gray Literature Overview Tables.

Key information from all eligible evidence sources (scientific and gray literature) for each question was summarized on an overview table. Evidence was then synthesized into evidence summaries by research question and topics, and a preliminary conclusion statement was drafted by the work group chairs. These were discussed with the Core Team, refined, and became the preliminary guideline.

Consensus-based input: Many issues of concern to nutrition management were not addressed or were inconclusive from scientific and gray literature. For these issues, expert input from metabolic dietitians, physicians, and nurse practitioners was sought using an initial Delphi survey. Results were added to the preliminary guideline which was sent to experts invited to a nominal group process meeting, where discussions focused on areas of uncertainty for each question. Following this, a second-round Delphi survey was developed regarding recommendations in areas where there was not research evidence or expert consensus. The same group of clinicians was invited to participate in both the first- and second-round Delphi surveys; however, because responses were ananymous, it could not be determined whether the same individuals responded to both surveys. The criterion for consensus was set at 80% agreement. By systematically employing these consensus techniques, the level of agreement with specific practice statement could be quantified.

Input of key stakeholders (individuals with UCDs and their families): A UCD parent and executive director of the National Urea Cycle Disorders Foundation participated in the nominal group process meeting.

The conclusion statement for each question, recommendations, and evidence summaries by topic represents a synthesis of evidence from scientific publications, gray literature, and Delphi and nominal group consensus techniques.

Specific recommendations for nutrition management within each of the eight research questions were drafted by the UCD work group chairs, in consultation with the Core Team, utilizing the evidence summaries, conclusion statements and the results of consensus-based input. Each recommendation was rated with respect to strength of the body of evidence (strong, fair, weak, consensus, insufficient evidence) and need for clinical action (imperative or conditional) co-principal investigators and a consultant; any discrepancies were discussed and resolved. See Appendix A: Recommendation Rating Definitions.

These practice recommendations along with background and other information to support their implementation are contained throughout the Guideline for Nutrition Management of Individuals with UCD document. The complete Guideline was reviewed, using AGREE II criteria, by an external panel of metabolic dietitians, physicians and an expert in guideline development methodology who were not involved in the evidence analysis or guidelines development phases. When finalized, the guideline will be available for dissemination and field-testing. All Guidelines for Nutrition Management of Individuals with Inherited Metabolic Disorders can be accessed through the Medical Nutrition Therapy for Prevention Program (MNT4P) and Genetic Metabolic Dietitians International (GMDI) websites.

Production of guidelines is achieved with a secure, web-based application written in PHP, MySQL and hosted by Apache HTTP running on a Linux server. Guidelines for an unlimited number of IMD can be supported with the application. For each IMD, forms exist for literature management, Delphi and Nominal survey management, and final guideline development. Published literature data is initially obtained via XML through the NCBI E-Utilities API. User-entered data is archived as changes are made, and content is locked through internal publishing prior to final guideline development. References for literature and tables are managed natively. Users are kept apprised of guideline development with automated email notifications. Built-in discussion forums are utilized for online group dialogue. Application security is maintained through use of SSL, user accounts and user-level access controls for each form. Backup is performed nightly. The complete UCD Nutrition Management Guideline can be accessed through both the MNT4P and GMDI websites.

As a result of the evidence analysis and consensus processes, important priorities for future research were identified. Furthermore, implementation of these practice recommendations has the potential to reduce unwarranted variation in care, promote more consistent and proactive nutrition management across metabolic centers, and provide a common framework for evaluating clinical outcomes and generating practice-based evidence to inform future updates to the guideline. 

An oversight committee reviews the status of Nutrition Management Guidelines for Individuals with IMD annually. New literature may be scanned, and, in conjunction with the workgroup chair, a determination is made regarding the need for a topic-specific or full guideline update. Guidelines are intended to undergo formal reassessment every five years after initial release using the methodology described above, although timing may vary based on available resources, emerging evidence, and prioritization needs. Earlier updates may occur when important advances in UCD research or clinical practice emerge.