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McPheeters ML, Lindegren ML, Sathe N, et al. Adjuvant Treatment for Phenylketonuria: Future Research Needs: Identification of Future Research Needs From Comparative Effectiveness Review No. 56 [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2012 Sep. (Future Research Needs Papers, No. 21.)

Cover of Adjuvant Treatment for Phenylketonuria: Future Research Needs

Adjuvant Treatment for Phenylketonuria: Future Research Needs: Identification of Future Research Needs From Comparative Effectiveness Review No. 56 [Internet].

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Appendix CPrioritization Surveys

Round One Survey Questions

Future Research Needs: Adjuvant Therapies for PKU

Please prioritize these areas for future research related to adjuvant therapies for PKU by adding stars to an item listed below. More stars indicate higher priority. You are given a total of 35 stars which you may allocate to any of the 52 items listed below. You may use up to five stars per item. To add stars to a selection, position your mouse over the dots in the right hand column.

Please complete this survey by 5 June 2012.

If you have any questions or difficulty with this system, please contact ude.tlibrednav@ehtas.alin

Remaining stars: (35 of 35)

  • Which domains of executive function (e.g., planning, inhibitory control) are most sensitive to changes in Phe in individuals with PKU?
  • Which measures, including executive function and affective disorder screens, are shown to be associated with changes in cognitive outcomes related to Phe level in individuals with PKU?
  • To what degree do measures of executive function vary with cognition, in the context of varying levels of Phe?
  • What is the validity, reliability, and responsiveness to change of existing tools for measuring executive function in individuals with PKU?
  • When measuring executive function in individuals with PKU, when and how frequently should these measures be assessed?
  • Which measures of ADHD are valid, sensitive, and reliable for use in individuals with PKU?
  • What are the clinical benefits and limitations of distinguishing attention-related symptoms due to elevated Phe levels vs. from non-PKU-related factors such as individual behavior?
  • To what degree does Phe level affect domains of social and emotional functioning in PKU?
  • What is the relationship between clinical measures of executive function and “real world”/adaptive functioning?
  • What are the effects of nutritional status on measures of executive function or emotion?
  • To what extent are poor cognitive outcomes related to dietary deficiencies compared with Phe levels?
  • In children ≤4 years old with PKU, what is the effect of BH4 plus diet compared with placebo plus diet or standard care on Phe control, cognitive outcomes (IQ and measures of executive function), QOL, liberalization of diet, and growth and development?
  • In individuals with PKU responsive to BH4, what is the effect of BH4 plus diet compared with diet/standard care on outcomes including Phe control, Phe tolerance, cognitive outcomes (IQ and executive function), quality of life, liberalization of diet, family functioning, and harms of treatment over the long term (>2 years)?
  • What characteristics of the individual or family moderate responsiveness to BH4 in individuals with PKU?
  • What is the comparative effectiveness of BH4 in addition to diet, relative to diet alone, to reduce behavioral and psychological comorbidities in individuals with PKU?
  • What characteristics of the individual, including disease severity, or characteristics of the family are associated with early vs. late initial response to BH4?
  • In individuals with PKU not currently adherent to diet or receiving treatment for PKU, what are the effects of BH4 in promoting return to care?
  • How does treatment with BH4 modify other care processes, including the transition to care as an adult?
  • In pregnant women with PKU, what is the effect of BH4 plus diet compared with placebo plus diet or standard care on Phe control, cognitive outcomes (IQ and measures of executive function), QOL, liberalization of diet, and pregnancy outcomes?
  • What harms to the mother and offspring are associated with BH4 use in pregnant women with PKU?
  • In individuals with PKU, what are the long-term effects (>6 months) of LNAAs on cognitive outcomes (IQ and executive function), quality of life, and liberalization of diet and harms of LNAAs?
  • What harms are associated with LNAA use in individuals with PKU?
  • What is the effectiveness of spectroscopy or other imaging techniques in assessing the effects of LNAAs or other therapies on neurotransmission of Phe?
  • What CNS biomarkers are effective for assessing the effects of LNAAs on the brain in individuals with PKU?
  • In individuals with PKU not currently adherent to diet or receiving treatment for PKU, what are the effects of LNAA in promoting return to care?
  • How does treatment with LNAAs modify other care processes?
  • How can the effects of LNAAs be measured and when should measurement occur?
  • What methods are effective for measuring brain amino acid absorption?
  • What are short-term effects of BH4 on outcomes including Phe control, Phe tolerance, cognitive outcomes (IQ and executive function), quality of life, and liberalization of diet, and harms of BH4 in specific subgroups (defined by age, dietary control, disease type)?
  • Among individuals with PKU using pharmacologic therapy, are supportive adherence models effective in increasing adherence to medication?
  • Are supportive adherence models (diet and/or drug) effective at improving long-term cognitive outcomes?
  • Among effective adherence support systems, have individual components been shown to drive effectiveness?
  • Is the effectiveness of adherence models moderated by characteristics of the individual, including age, gender, family structure and severity of disease?
  • What are the pharmacokinetic, pharmacodynamic, and pharmacogenomic factors associated with treatment response in individuals with PKU?
  • Are passive registries as effective as ongoing cohort studies for collecting adequate data to assess long-term effectiveness of adjuvant therapies?
  • In addition to blood Phe, what measures provide valid assessments of dietary control in individuals with PKU?
  • What are the components of an effective system of care for individuals with PKU?
  • What treatment-related factors at different ages are the greatest source of concern to families/caregivers?
  • In individuals with PKU, what timing of Phe monitoring is optimal for fine tuning diet and treatment?
  • What medical supports can bring individuals with PKU back to treatment and/or dietary adherence?
  • Which biomarkers are effective for demonstrating response to treatment or therapeutic efficacy in PKU?
  • What is the utility of the plasma Phe/Tyrosine ratio compared with plasma Phe level as a measure of Phe control in PKU?
  • Are medical foods adequate to overcome vitamin and mineral deficiencies over the lifetime in individuals with PKU?
  • What biomarkers are valid for understanding the effects of vitamin and mineral deficiencies in PKU?
  • What is an appropriate study duration for understanding cognitive and other effects in individuals with PKU?
  • How can nutritional status be effectively measured in PKU?
  • What is the role of functional neuroimaging in PKU?
  • What is the role of combination therapy in PKU?
  • How can the effectiveness of combination therapies be measured?
  • How should registry data collection be modified to allow for collection of efficacy data?
  • Are there critical periods of development during which promotion of adherence would facilitate long-term adherence to care?

Round Two Prioritization Survey Questions

Future Research Needs—Adjuvant Therapies for PKU

Thank you again for your participation in this project. The highest ranking research questions (separated into treatment-related and methodologic/other) resulting from the previous ranking survey are below. In this final survey, we ask that you rank each question from 1 (lowest) to 5 (highest) across seven AHRQ prioritization criteria:

  • Potential for significant health impact on the current and future health status of people with respect to burden of the disease and health outcomes (mortality, morbidity, and quality of life).
  • Potential to reduce important inappropriate (or unexplained) variation in clinical practices known to relate to quality of care, including potential to resolve controversy or dilemmas in what constitutes appropriate health care, and potential to improve decision-making for patient or provider, by decreasing uncertainty.
  • Potential for significant (nontrivial) economic impact related to the costs of health service to reduce unnecessary or excessive costs, to reduce high costs due to high volume use, to reduce high costs due to high unit cost or aggregate cost. Costs may impact consumers, patients, health care systems, or payers.
  • Potential risk from inaction Unintended harms from lack of prioritization of proposed research; opportunity cost of inaction.
  • Potential to address inequities, vulnerable, diverse populations (including issues for patient subgroups); potential to reduce health inequities.
  • Potential to allow assessment of ethical, legal, social issues pertaining to the condition.
  • Potential for new knowledge Research would not be redundant or the question is not sufficiently researched, including completed and in-process research; utility of available evidence is limited by changes in practice (e.g., disease detection or evolution in technology).

When all surveys are returned we will tally "scores" per question and present the highest ranking questions for each criterion.

Thank you!

QuestionHealth impactVariation in careEconomic impactRisk from inactionInequitiesELSINew knowledge
Treatment Questions
In individuals with PKU responsive to BH4 plus diet compared with diet/standard care on outcomes including Phe control, Phe tolerance, cognitive outcomes (IQ and executive function), quality of life, liberalization of diet, family functioning, and harms of treatment over the long term (>2years)?
In children ≤4 years old with PKU, what is the effect of BH4 plus diet compared with placebo plus diet or standard care on Phe control, cognitive outcomes (IQ and measures of executive function), QOL, liberalization of diet, and growth and development?
In pregnant women with PKU, what is the effect of BH4 plus diet compared with placebo plus diet or standard care on Phe control, cognitive outcomes (IQ and measures of executive function), QOL, liberalization of diet, and pregnancy outcomes?
What is the comparative effectiveness of BH4 in addition to diet, relative to diet alone, to reduce behavioral and psychological co-morbidities in individuals with PKU?
What are short-term effects of PH4 on outcomes including Phe control, Phe tolerance cognitive outcomes (IQ and executive function), quality of life, liberalization of diet, and harms of BH4 in specific subgroups (Defined by age, dietary control, disease type
In individuals with PKU not currently adherent to diet or receiving treatment for PKU, what are the effects of BH4 in promoting return to care?
What are the components of an effective system of care for individuals with PKU?
Are there critical periods of development during which promotion of adherence would facilitate long-term adherence to care?
Are supportive adherence models (diet and/or drug) effective at improving long-term cognitive outcomes?
What medical supports can bring individuals with PKU back to treatment and/or dietary adherence?
What characteristics of the individual, including disease severity, or characteristics of the family are associated with early vs. late initial response to BH4?
In individuals with PKU, what are the long-term effects (>6months) of LNAAs on cognitive outcomes (IQ and executive function), quality of life, and liberalization of diet and harms of LNAAs?
What harms are associated with LNAA use in individuals with PKU?
Methodologic/Other
What is the validity, reliability, and responsiveness to change of existing tools for measuring executive function in individuals with PKU?
Which measures, including executive function and disorder screens, are shown to be associated with changes in cognitive outcomes related to Phe level in individuals with PKU?
What methods are effective for measuring brain amino acid absorption?
What is the relationship between clinical measures of executive function and "real world"/ adaptive functioning?
In addition to blood Phe, what measures provide valid assessments of dietary control in individuals with PKU?
To what degree do measures of executive function vary with cognition, in the context of varying levels of Phe?
What biomarkers are valid for understanding the effects of vitamin and mineral deficiencies in PKU?
How should registry data collection be modified to allow for collection of efficacy data?
Which domains of executive function (e.g., planning inhibitory control) are most sensitive to changes in Phe in individuals with PKU?
When measuring executive function in individuals with PKU, when and how frequently should these measures be assessed?
To what degree does Phe level affect domains of social and emotional functioning in PKU?
To what extent are poor cognitive outcomes related to dietary deficiencies compared with Phe levels?
What is the effectiveness of spectroscopy or other imaging techniques in assessing the effects of LNAAs on neurotransmission of Phe?
How can the effectiveness of combination therapies be measured?

Thank you for participating in this project. We will notify you when the draft report is available for comment.

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