Needs Identified in CER and via Stakeholder Input

Table 4 lists the research needs identified in the CER and those generated via stakeholders organized by Key Question. Where identified, possibly relevant ongoing research is included.

Table 4

Research needs identified in CER and by stakeholders.

Stakeholders also identified several research questions that fell out of the scope of the current project’s Key Questions and analytic framework. Therefore, these questions could not be included in the prioritization process. They are, however, important questions to the field, and therefore we list them here:

• What is the effectiveness of medications to treat ADHD, anxiety, depression, and other mental health comorbidities in individuals with PKU?
• What methods are effective for identifying and reaching individuals with PKU not currently under care?
• What is the natural history of PKU?
• How does defining responsiveness in terms of Phe level or Phe tolerance or in terms of cognition or other long-term outcomes affect care for individuals with PKU?

We also identified a number of nonresearch issues/recommendations in the report and expanded with stakeholder feedback; we include these issues in the Discussion section of the report. We did not ask stakeholders to prioritize these nonresearch issues but note that further exploration would benefit our understanding of PKU.

Round One Prioritization

As noted, we presented the expanded list of research needs in Table 5 to stakeholders in an initial survey (round one survey). We requested that stakeholders review EHC prioritization criteria and then assign a number of points to each question to indicate priority. Eight of nine stakeholders completed the survey.

Table 5

Questions indentified as high priority in round one survey.

Table 5 lists the highest priority questions (questions scoring at least 5 points) identified via the round one survey. We organized questions broadly by area of focus (methodologic/other or treatment) and present them by category in no particular order.

Final Prioritization

In our round two/final survey we requested that stakeholders score each of the 27 high-priority needs (Table 5) on each of the following EHC selection criteria⁴ using a 1 (low) to 5 (high) point scale:

• Potential for significant health impact
• Potential to reduce variation in clinical practices
• Potential for significant economic impact
• Potential risk from inaction
• Potential to address inequities
• Potential to allow assessment of ethical, legal, social issues pertaining to the condition
• Potential for new knowledge

Eight of nine stakeholders completed the survey. We tallied the scores for each need/question on each criterion to determine an overall score and divided the questions by range of scores into top, middle, and lower tiers (presented in no particular order within each tier in Table 8); we combined and clarified two treatment questions related to adherence supports into one as one question was effectively a subquestion addressing modifiers of adherence program effects. Thus, six needs/questions comprise the top tier/highest priority treatment-related needs.

Table 8

Middle and lower priority research questions.

The results are presented below in two sections: first, the top-tier methodologic questions (Table 6), followed by those that received lower priority scores, and second, the top tier treatment-related questions (Table 7), followed by lower priority treatment questions.

Table 6

Highest priority methodologic and other questions.

Table 7

Highest priority treatment-related research questions, PICOTS elements, and potential study designs.

Of note, the scores were all very close, and no set of recommended studies should be considered low priority. The rating provides a relative measure; all of the research questions are important, but a subset comprises a priority set that should be addressed first. We broke down top tier treatment-related questions into PICOTS elements (Table 7). As methods-related questions typically do not involve effectiveness outcomes, we did not delineate PICOTS.

Highest Priority Research Agenda

The questions below are those that were prioritized into the top tier of the potential research questions. We have expanded on specific issues that might warrant consideration by investigators wishing to study any of the highest priority research questions. Clearly, across the board, studies should be rigorous and include appropriate comparison groups. They should be adequately powered to assess effects, and followup should continue for an adequate period of time so as not to limit measurement to immediate or short-term outcomes. We outline specific considerations for the top tier of methodologic questions and for the top tier intervention research questions below.

Many, if not most, individuals with PKU are likely to be treated with combination approaches, and methods for designing studies that assess the effectiveness of different combinations, rather than individual treatments, should be developed and validated. The question of whether or how registry data can support this and other types of effectiveness research warrants consideration by the PKU community.

Three primary measurement issues reached top priority level. First, there is an urgent need to identify approaches beyond blood Phe, which cannot be assessed immediately, for capturing the degree to which individuals are maintaining dietary control. This information is critical for guiding treatment, and to the degree that it is possible the effects of dietary deficiencies themselves on cognitive outcomes should be disaggregated from the effects of increasing Phe so that future studies can account for any potential effect of nutrition that may confound studies focused on Phe. Finally, related to this question, is a need for more research identifying biomarkers that can identify vitamin and mineral deficiencies.

The intervention research questions that were prioritized into the top tier are presented in Table 7. Where appropriate we specify design-related issues as identified by the EPC team for investigators to consider. We also identify and describe methodologic challenges inherent in studying these questions that will warrant attention by the investigators who choose to pursue them in the Discussion chapter.

Middle and Lower Priority Research Agenda

None of the research questions identified through this process was considered unimportant, and certainly, this is a field with substantial room for research growth. The questions listed in Table 8 might be considered second tier in terms of immediacy and need for answers, but they are, nonetheless important. Our focus for this project is on identifying a highest priority subset for immediate action, so we do not discuss the questions in this section but provide them for use by investigators and funders in the field. They also provide insight for policy makers into areas that are currently lacking in definitive, research-based evidence.