Core Outcome Set (COS)

What is a Core Outcome Set?

A Core Outcome Set (COS) is a small set of important outcomes that should be measured and reported in all research studies for a disease. A COS helps us compare different studies to one another to determine which treatments work best. A COS created with multi-stakeholder input also ensures evidence captures the priorities of patients, caregivers, and professionals. In November of 2023, ACD completed a study to establish a Core Outcome Set for CTD & GAMT. Learn more below about the recommended COS and the study that was conducted.

CTD & GAMT Core Outcome Set Report

  1. The Finalized Core Outcome Set

    Following one round of voting and several roundtable discussions, the following 8 outcomes were approved by more than 50% of consensus workshop attendees for inclusion in the Core Outcome Set (COS).

    1. Adaptive Functioning: An individual’s level of independence in functioning compared to similarly-aged peers, in areas including communication and practical tasks, such as daily living skills involving toileting, eating, dressing, and hygiene
    2. Cognitive Functioning: Specific mental abilities, including the ability to learn, think, remember, problem solve, as well as decision making, and attention
    3. Emotional Dysregulation: Having a difficult time appropriately managing and controlling one’s feelings and emotional responses
    4. Expressive Communication: Ability to express one’s needs and wants through communication
    5. Fine Motor Functions: Motor skills that involve the smaller muscles (e.g., wrists, hands, fingers) and allow for more precise movement
    6. MRS Brain Creatine*: Amount of creatine in the brain as determined by magnetic resonance spectroscopy (MRS), a technique that shows the levels of chemical components in the brain
    7. Seizure/Convulsions: Sudden and uncontrollable movements and/or loss of consciousness and/or loss of body control; episodes can be self-limiting and last for a few seconds, or they can persist, or come in clusters
    8. Serum Plasma Guanidinoacetate**: Amount of guanidinoacetate in the serum or plasma

    *In the case of GAMT deficiency, maintenance of this level is worth noting. However, it is anticipated that this biomarker may remain stable if the patient received oral creatine supplementation prior to the trial.

    **This outcome is not applicable in CTD trials.

    Note: Although Expressive Communication and Fine Motor Functions did not receive more than 50% of the votes in the Consensus Workshop voting, they were included based on unanimous agreement during group discussions among all attendees.

  2. Other Outcomes of Note

    Serum Plasma Creatine

    Definition: amount of creatine in the serum or plasma

    MRS Brain Guanidinoacetate

    Definition: amount of guanidinoacetate in the brain as determined by magnetic resonance spectroscopy (MRS), a technique that shows the levels of chemical components in the brain

    While Serum Plasma Creatine and MRS Brain Guanidinoacetate are not in the COS, discussions at the Consensus Workshop emphasized that measuring them in GAMT deficiency trials could provide valuable insights into the maintenance of oral supplementation results.

    MRI Brain General

    Definition: MRI (magnetic resonance imaging) is a technique that shows the various parts of the brain as an image; parts of the brain which may be affected in CCDS include the basal ganglia and cerebellum (which control the coordination of movement) or the white matter (which connects brain areas with nerves)

    While not deemed appropriate to include in the COS, there was consensus that when an MRI is performed, often at the same time as MRSpectroscopy, it is appropriate to note any abnormalities for comparison later in the trial. Changes have been observed in GAMT patients replenished with creatine supplementation and it is unknown if similar improvements may be observed in successful trials.

  3. The COS Development Process

    The CTD and GAMT deficiency Core Outcome Set (COS) study involved:

    1. Evidence Review Comprised of

    • Two independent rapid literature reviews of the currently reported outcomes for CTD and GAMT deficiency
    • In-person and online focus groups with caregivers of individuals with CTD and GAMT deficiency to identify important outcomes
    • A review of ACD’s CreatineInfo Patient Registry and Natural History Study to extract Patient Meaningful Outcomes

    2. Globally Distributed Delphi Survey

    • Three rounds of Delphi survey were conducted to systematically reduce the number of outcomes, based on patient, caregiver, and health professionals responses

    3. Consensus Workshop Meeting

    • A consensus workshop was held to determine which of the remaining 20 candidate outcomes, identified in our Delphi survey, should be incorporated into a Core Outcome Set (COS) for CTD and GAMT deficiency, for use in clinical trials.
    • Caregivers of individuals with CTD and GAMT deficiency as well as health professionals including clinicians, laboratory scientists, and researchers attended the Consensus Workshop.
    • A decision was made to include 8 outcomes in the final COS.

  4. Delphi Round 3 Outcomes Considered at Consensus Workshop

    The following 20 outcomes were discussed and voted on at the consensus workshop based on results from the Delphi Survey:

    • Seizure/Convulsions
    • Caregiver Burden
    • Emotional Dysregulation
    • Aggressive Behaviors
    • Cognitive Functioning
    • Intellectual & Developmental Disability
    • Adaptive Functioning
    • Expressive Language
    • Receptive Language
    • Independence
    • Executive Functioning
    • Fine Motor Functions
    • MRS Brain Creatine
    • MRS Brain Phosphocreatine
    • MRI Brain General
    • MRS Brain Guanidinoacetate
    • EEG Epileptic Potentials
    • Serum Plasma Creatine
    • Serum Plasma Guanidinoacetate
    • Life Expectancy
  5. Caregiver Engagement

    PaReNts Project

    The goal of this project was to recruit and actively engage, train, and empower a group of CTD and GAMT “Family Collaborators” throughout the entire research process. Special focus was placed on patient-meaningful outcomes (PMOs) and the development of a core outcome set (COS).

    Delphi Survey Design

    Feedback was collected from the Family Collaborators to ensure the survey, used to identify important outcomes, was designed in a way that was easily understandable by caregivers.

    Caregiver Meeting

    A subset of the Family Collaborators was prepared for the Consensus Workshop in a preparation meeting. They were encouraged to ask questions, and seek clarification, on the remaining 20 outcomes.

    Consensus Workshop

    The subset of Parent Collaborators, with a similar number of health care professionals, participated in a Consensus Workshop, sharing their expertise and opinions on the remaining outcomes based on their lived, and clinical experiences.

  6. Next Steps

    We will be recommending an outcome measurement tool(s) (OMT) for each outcome in the COS.

    • We are currently applying for funding to pursue a follow-up project aimed at gathering and evaluating such measurement tools.
    • A manuscript describing the COS development project is being drafted.
    • The final COS will be published in a peer-reviewed journal.

  7. Thank You To Participants

    Thank you to everyone who participated in the PaReNts project, focus groups, Delphi surveys, and the consensus workshop. Your participation helped develop a core outcome set (COS) for CTD and GAMT deficiency!

Historical Study Materials and Background

CTD & GAMT caregivers, patients, and clinicians

Researchers across the globe are studying treatments to improve care for individuals with Creatine Transporter Deficiency (CTD) and GAMT Deficiency (GAMT). Those research projects need appropriate outcome measures to determine if they are successful.

The Delphi Survey aims to assist caregivers, patients, and clinicians in identifying a meaningful core outcome set.

Round 3 of the survey launched in August 2023 and is now closed. If you participated in Round 1 and/or Round 2, you were sent an invitation to participate in Round 3.

What are outcomes?

  • Outcomes are used to determine if a treatment is effective or not.
  • Outcomes may include how someone feels, what they can do, observable symptoms, or results of lab tests.

What is a Core Outcome Set (COS) and why is a COS used?

  • A ‘Core Outcome Set’ is a small set of outcomes that are established as important and should be collected in every research study of the same disease.
  • An established COS prevents studies from reporting only a selection of the outcomes that were measured. It is expected that they report on all outcomes in the COS.

Why is a COS important?

  • If researchers measure different outcomes, it is hard to compare and contrast the effectiveness of interventions or treatments.
  • A COS will help us compare CTD and GAMT deficiency studies to identify which treatments work best.

How can I contribute?

In multiple rounds of an online survey, we will show you a list of outcomes related to CTD and GAMT deficiency and ask you to rate how important each outcome is to you. The survey will be available in English, French, and Spanish. As a rare disease community, we need as many patients, caregivers, and clinicians as possible to participate!

Who is eligible?

  • Adult patients (18 years or older) diagnosed with CTD or GAMT deficiency
  • A parent or caregiver of a person diagnosed with CTD or GAMT deficiency
  • A health care professional experienced in caring for patients with CTD or GAMT deficiency (e.g., geneticist, dietician, physical therapist, speech therapist, psychologist, neurologist, etc.)

What is the time commitment?

  • You will be asked to complete 2-3 surveys within the next 3-5 months.
  • Each survey will take about 1 hour to complete.
  • After each survey you complete, you will be entered into a drawing to win:
    • One of five Amazon gift cards valued at $50 USD for the first survey round
    • One of five Amazon gift cards valued at $75 USD for the second survey round
    • If a third survey round is required, additional Amazon gift cards will be awarded

What is a Delphi Survey?

  • A survey designed to gather opinions from multiple people and eventually reach consensus
  • Delphi surveys are confidential to ensure that everyone has an equal say.
  • Delphi surveys have multiple rounds (usually between 2 and 3). This means that participants get more than one chance to give their opinion.
  • The figure below outlines the steps involved in a Delphi survey:

What happens in Round 1 of the Delphi Survey?

  • The research team has developed a list of possible outcomes that we want to ask you about. We created this list after looking at many research papers, analyzing data from our CreatineInfo Patient Registry, and conducting focus groups with parents/caregivers of CTD and GAMT deficiency patients.
  • In round 1, we will ask you to rate the importance of each outcome on a scale from 1 to 9.
  • When you complete the survey, your ratings will be sent back to the research team along with the ratings from all other participants. We will then summarize the responses for each participant group (patients, parents/caregivers, and health care professionals) in a graph. These graphs will be included in round 2 of the Delphi Survey.

What happens in round 2 (and possibly round 3) of the Delphi Survey?

  • We will ask you to complete the survey again. You will be given a reminder of how you rated each outcome last time. You will also see the summary graph showing how each group rated the outcomes. No one can see another individual participant’s ratings, you can only see the overall results for each group as a whole.
  • Looking at your previous ratings and the summary graphs, we will ask you if you would like to stick with your original rating or change it. You are not under any pressure to change your rating if you don’t want to. It is perfectly fine for you to stick to your own rating even if you rated the outcome differently than the majority of the group.
  • The research team will review the results from round 2 and decide if a 3rd round is needed. In that case, the steps above would be repeated in round 3.

What happens after the Delphi Survey?

  • After the last round, you will be invited to discuss the results in a virtual meeting. You can decide later if you would like to participate in the meeting.
  • At the end of this process, the research team will produce a report on the outcomes that patients, parents/caregivers, and health care professionals agreed were the most important outcomes. These are called the ‘core outcomes’ for CTD and GAMT Deficiency in children and youth.

This information is adapted from the Core Outcome Measures in Effectiveness Trials initiative,

Why are we doing round 2?

Round 2 is your chance to see how others rated each outcome and reconsider your rating. A Delphi survey is a consensus survey. This means the end goal is to come to a decision together.

Why am I seeing an overview of responses from other participants?

A Delphi survey is a consensus survey. This means that we work as a group to come to an agreement throughout the process.

Why are there so many outcomes?

The outcomes come from multiple sources, including scientific literature, caregiver focus groups, and ACD’s patient registry. Our team originally gathered over 1,000 outcomes and condensed those to the list of 85 you saw in round 1. Through the Delphi process, we will reduce this to the final 8-10 outcomes.

Why are some of the outcomes so similar?

The outcomes we gathered came from many sources. Sometimes different terms are used for similar outcomes. This is why we need your help to find the most accurate terms for the most important outcomes for GAMT and CTD.

All of these outcomes are important! What should I do?

  • This is the tricky part! Since our goal is to reduce this list to 8-10 outcomes for a final COS, we will need to be slightly more selective in which outcomes we rate as “most important”.  
  • Please be selective in which outcomes you rate as “most important”. Reminder, our goal is to reduce these outcomes down to 8-10.

What happens after round 2?

We will do a third and final round of the Delphi survey, approximately 1 month later. In round 3, you will be asked to rank your most important outcomes. After round 3, there will be a final consensus workshop with a small group of patients, caregivers, and CCDS experts to finalize the COS.

How do I participate?

If you completed the previous round(s), you will receive an email with a personalized email link. If you did not participate in round 1 or did not receive a personalized email link, you can participate by clicking this link.

I did not complete round 1. Can I still participate in round 2?

Yes, you can participate in round 2 even if you did not complete round 1.

Why did we remove outcomes in round 2?

Only outcomes that were rated “Important” or “Most Important” by at least 70% of participants in round 1 were included in round 2. This is intentional and part of the consensus process.

What happened to my comments from round 1?

Round 1 comments will be shared and discussed in the consensus meeting, helping us arrive at the best final Core Outcome Set.

Link to Round 2 FAQ Sheet PDF

If you have questions please contact Emily at

Establishing Core Outcome Sets (COS) for CTD and GAMT deficiency

Why are we doing this study?

Researchers across the globe are studying treatments to improve care for individuals with Creatine Transporter Deficiency (CTD) and GAMT Deficiency (GAMT). Those research projects need appropriate outcome measures to determine if they are successful.

Study Goal:

To develop Core Outcome Sets for CTD and GAMT deficiency.