Core Outcome Sets for Medium-Chain Acyl-CoA Dehydrogenase Deficiency and Phenylketonuria

BACKGROUND: Evidence to guide treatment of pediatric medium-chain acyl-coenzyme A abstract dehydrogenase (MCAD) deficiency and phenylketonuria (PKU) is fragmented because of large variability in outcome selection and measurement. Our goal was to develop core outcome sets (COSs) for these diseases to facilitate meaningful future evidence generation and enhance the capacity to compare and synthesize findings across studies.

METHODS: Parents and/or caregivers, health professionals, and health policy advisors completed a Delphi survey and participated in a consensus workshop to select core outcomes from candidate lists of outcomes for MCAD deficiency and PKU. Delphi participants rated the importance of outcomes on a nine-point scale (1–3: not important, 4–6: important but not critical, 7–9: critical). Candidate outcomes were progressively narrowed down over 3 survey rounds. At the workshop,
participants evaluated the remaining candidate outcomes using an adapted nominal technique, open discussion, and voting. After the workshop, we finalized the COSs and recommended measurement instruments for each outcome.

RESULTS: There were 85, 61, and 53 participants across 3 Delphi rounds, respectively. The candidate core outcome lists were narrowed down to 20 outcomes per disease to be discussed at the consensus workshop. Voting by 18 workshop participants led to COSs composed of 8 and 9 outcomes for MCAD deficiency and PKU, respectively, with measurement recommendations.

CONCLUSIONS: These are the first known pediatric COSs for MCAD deficiency and PKU. Adoption in future studies will help to ensure best use of limited research resources to ultimately improve care for children with these rare diseases.


Michael Pugliese, MSc, Kylie Tingley, PhD, Andrea Chow, MSc, Nicole Pallone, ArtDp, Maureen Smith, MEd, Pranesh Chakraborty, MD, Michael T. Geraghty, MD, Julie K. Irwin, PhD, John J. Mitchell, MD, Sylvia Stockler, MD, PhD,
Stuart G. Nicholls, PhD, Martin Offringa, MD, PhD, Alvi Rahman, MSc, Laure A. Tessier, MSc, Nancy J. Butcher, PhD,k,l
Ryan Iverson, BHS, Monica Lamoureux, MSc, Tammy J. Clifford, PhD, Brian Hutton, PhD, Karen Paik, BSc, Jessica Tao, MD, Becky Skidmore, MLS, Doug Coyle, PhD, Kathleen Duddy, MSN, Sarah Dyack, MD, Cheryl R. Greenberg, MD, CM, Shailly Jain Ghai, MD, Natalya Karp, MD, Lawrence Korngut, MD, Jonathan Kronick, MD, PhD, Alex MacKenzie, MD, Jennifer MacKenzie, MD, Bruno Maranda, MD, Murray Potter, MD, Chitra Prasad, MD, Andreas Schulze, MD, PhD, Rebecca Sparkes, MD, Monica Taljaard, PhD, Yannis Trakadis, MD, Jagdeep Walia, MBBS, Beth K. Potter, PhD, in collaboration with the Canadian Inherited Metabolic Diseases Research Network


Journal: Pediatrics
Volume: 148
Issue: 2
Pages: -
Year: 2021

Further Study Information

Current Stage: Completed
Date: April 2017 - August 2018
Funding source(s): CIHR Catalyst Grant: SPOR Innovative Clinical Trials

Health Area

Disease Category: Endocrine & metabolic

Disease Name: Inherited metabolic diseases, phenylketonuria (PKU), medium-chain acyl-CoA dehydrogenase deficiency (MCAD deficiency)

Target Population

Age Range: 0 - 18

Sex: Either

Nature of Intervention: Any

Stakeholders Involved

- Clinical experts
- Consumers (caregivers)
- Consumers (patients)
- Economists
- Epidemiologists
- Families
- Methodologists
- Patient/ support group representatives
- Policy makers
- Researchers
- Service providers
- Service users
- Statisticians

Study Type

- COS for clinical trials or clinical research
- COS for practice


- Delphi process
- Literature review

The purpose of the proposed catalyst research is to further develop a pan-Canadian resource, the Canadian Inherited Metabolic Diseases Research Network (CIMDRN) cohort and network, to support registry-based randomized comparative effectiveness trials. Our specific objectives are to:
1. Establish standardized sets of core patient-oriented outcomes to be used in future registry-based comparative effectiveness trials for children with IMD, beginning with two example IMD, phenylketonuria (PKU) and medium-chain acyl-CoA dehydrogenase deficiency (MCADD);
2. Define, develop, and incorporate measures of these outcomes into the CIMDRN platform; and
3. Conduct pilot feasibility studies with these outcomes and measures in preparation for future multi-year innovative clinical trial (iCT) applications to the SPOR iCT initiative.

To address the first objective, we will use established methods for developing core outcome sets for clinical trials, including a review to identify potential clinical and patient or family-reported outcomes, and a Delphi consensus approach to arrive at an agreed core outcome set for each disease. To pursue the second objective, we will identify candidate measures and data collection tools reflecting the outcomes and evaluate their face validity, measurement properties, relevance, and feasibility. Finally, we will integrate the outcome measures into the CIMDRN platform and database and conduct a pilot evaluation of their feasibility in five Canadian centres. Deliverables from this catalyst research will include: (i) core outcome sets and measures for PKU and MCADD, suitable for dissemination to stakeholders; (ii) at least two study protocols for registry-based randomized trials, with
primary and secondary outcomes specified from the core sets, for submission to future funding opportunities including the SPOR iCT initiative; (iii) a methodological tool kit that can be used to extend our methods to both other IMD and other rare pediatric diseases; and (iv) sustainable partnerships among stakeholders to support future trials and methods development.