Table 3 Unique PKU outcomes reported in studies included for data synthesis
Outcome | # (%) of articles TOTAL (n = 343) | # (%) of articles 2000–2004 (n = 84) | # (%) articles 2005–2009 (n = 67) | # (%) articles 2010–2014 (n = 120) | # (%) articles after 2014 (n = 72) |
|---|---|---|---|---|---|
1. CORE AREA: GROWTH AND DEVELOPMENT | 153 (45%) | 40 (48%) | 28 (42%) | 53 (44%) | 32 (44%) |
 Domain: Physical Growth and Anthropometry | 63 (18%) | 6 (7%) | 14 (21%) | 25 (21%) | 18 (25%) |
 Body mass index, overweight, or obesity status8* | 35 (10%) | 4 (5%) | 3 (4%) | 14 (12%) | 14 (19%) |
 Growth | 16 (5%) | 1 (1%) | 5 (7%) | 8 (7%) | 2 (3%) |
 Head circumference | 8 (2%) | 1 (1%) | 1 (1%) | 3 (3%) | 3 (4%) |
 Height/length5* | 42 (12%) | 4 (5%) | 7 (10%) | 18 (15%) | 13 (18%) |
 Weight | 38 (11%) | 2 (2%) | 9 (13%) | 16 (13%) | 11 (15%) |
 Body composition | 9 (3%) | 1 (1%) | 2 (3%) | 4 (3%) | 2 (3%) |
 Domain: Cognition and Development | 110 (32%) | 34 (40%) | 19 (28%) | 38 (32%) | 19 (26%) |
 Cognition and intelligence/IQ2 | 82 (24%) | 25 (30%) | 14 (21%) | 29 (24%) | 14 (19%) |
 Overall child development | 11 (3%) | 3 (4%) | 1 (1%) | 5 (4%) | 2 (3%) |
 Sensorimotor and motor functioning10* | 32 (9%) | 9 (11%) | 4 (6%) | 17 (14%) | 2 (3%) |
 Learning difficulties/disabilities | 1 (0%) | 0 (0%) | 1 (1%) | 0 (0%) | 0 (0%) |
 Academic achievement/school performance | 20 (6%) | 5 (6%) | 1 (1%) | 9 (8%) | 5 (7%) |
 Executive functioning10* | 32 (9%) | 9 (11%) | 5 (7%) | 11 (9%) | 7 (10%) |
2. CORE AREA: LIFE IMPACT | 156 (45%) | 28 (33%) | 24 (36%) | 61 (51%) | 43 (60%) |
 Domain: Child Life Impact | 35 (10%) | 4 (5%) | 1 (1%) | 20 (17%) | 10 (14%) |
 Child quality of life | 21 (6%) | 2 (2%) | 1 (1%) | 12 (10%) | 6 (8%) |
 Child psychosocial well-being and self-concept | 15 (4%) | 0 (0%) | 0 (0%) | 10 (8%) | 5 (7%) |
 Child social impact and function | 12 (3%) | 2 (2%) | 0 (0%) | 6 (5%) | 4 (6%) |
 Bodily pain or discomfort | 7 (2%) | 0 (0%) | 0 (0%) | 4 (3%) | 3 (4%) |
 Sleep problems | 1 (0%) | 0 (0%) | 0 (0%) | 1 (1%) | 0 (0%) |
 Overall clinician-assessed health status of child | 4 (1%) | 0 (0%) | 0 (0%) | 3 (3%) | 1 (1%) |
 Child understanding of and self-efficacy with management of PKU | 3 (1%) | 1 (1%) | 0 (0%) | 1 (1%) | 1 (1%) |
 Achievement of treatment goals | 1 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 1 (1%) |
 Domain: Caregiver/family Life Impact | 19 (6%) | 4 (5%) | 1 (1%) | 7 (6%) | 7 (10%) |
 Impact of PKU on caregiver/family quality of life | 10 (3%) | 0 (0%) | 0 (0%) | 5 (4%) | 5 (7%) |
 Caregiver/family psychosocial well-being | 9 (3%) | 4 (5%) | 0 (0%) | 2 (2%) | 3 (4%) |
 Caregiver/family economic impact | 5 (1%) | 1 (1%) | 1 (1%) | 2 (2%) | 1 (1%) |
 Impact of PKU on caregiver/family diet | 1 (0%) | 0 (0%) | 0 (0%) | 1 (1%) | 0 (0%) |
 Domain: Child and Caregiver/family Life Impact | 3 (1%) | 1 (1%) | 0 (0%) | 0 (0%) | 2 (3%) |
 Strategies used by parents to help children cope with PKU | 1 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 1 (1%) |
 Perceived control over behavior and skills | 2 (1%) | 1 (1%) | 0 (0%) | 0 (0%) | 1 (1%) |
 Domain: Child Behaviour, Mental Health, and Temperament | 42 (12%) | 8 (10%) | 4 (6%) | 19 (16%) | 11 (15%) |
 Behaviour problems and externalizing mental health or behaviour disorders | 19 (6%) | 5 (6%) | 2 (3%) | 8 (7%) | 4 (6%) |
 Attention-deficit hyperactivity disorder (ADHD) or ADHD-like symptoms | 15 (4%) | 2 (2%) | 1 (1%) | 8 (7%) | 4 (6%) |
 Internalizing mental health or mood disorders and associated symptoms | 26 (8%) | 4 (5%) | 1 (1%) | 15 (13%) | 6 (8%) |
 Autism spectrum disorder (ASD) or ASD-like symptoms | 9 (3%) | 0 (0%) | 1 (1%) | 5 (4%) | 3 (4%) |
 Atypical behaviour and mental symptoms other than those specified | 1 (0%) | 0 (0%) | 0 (0%) | 1 (1%) | 0 (0%) |
 Temperament/personality | 4 (1%) | 1 (1%) | 0 (0%) | 3 (3%) | 0 (0%) |
 Domain: Disease Management and Feeding Behaviour | 113 (33%) | 19 (23%) | 21 (31%) | 41 (34%) | 32 (44%) |
 Age at treatment initiation | 4 (1%) | 1 (1%) | 0 (0%) | 3 (3%) | 0 (0%) |
 Infant breast and formula feeding | 2 (1%) | 0 (0%) | 0 (0%) | 1 (1%) | 1 (1%) |
 Dietary intake of phenylalanine | 28 (8%) | 5 (6%) | 5 (7%) | 10 (8%) | 8 (11%) |
 Dietary intake of amino acids other than phenylalanine | 6 (2%) | 2 (2%) | 0 (0%) | 3 (3%) | 1 (1%) |
 Dietary intake of medical foods or formula, modified low-protein foods, and protein substitutes | 9 (3%) | 2 (2%) | 0 (0%) | 6 (5%) | 1 (1%) |
 Dietary intake of protein5* | 42 (12%) | 9 (11%) | 5 (7%) | 20 (17%) | 8 (11%) |
 Dietary intake of energy | 30 (9%) | 8 (10%) | 6 (9%) | 11 (9%) | 5 (7%) |
 Overall dietary intake relative to standards | 5 (1%) | 0 (0%) | 0 (0%) | 3 (3%) | 2 (3%) |
 Dietary intake of fat | 17 (5%) | 5 (6%) | 2 (3%) | 6 (5%) | 4 (6%) |
 Dietary intake of specific fatty acids | 16 (5%) | 6 (7%) | 4 (6%) | 4 (3%) | 2 (3%) |
 Dietary intake of cholesterol | 7 (2%) | 3 (4%) | 1 (1%) | 3 (3%) | 0 (0%) |
 Dietary intake of carbohydrates | 15 (4%) | 3 (4%) | 3 (4%) | 6 (5%) | 3 (4%) |
 Dietary intake of fibre | 7 (2%) | 3 (4%) | 1 (1%) | 2 (2%) | 1 (1%) |
 Glycemic index of foods consumed | 1 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 1 (1%) |
 Dietary intake of vitamins and minerals | 19 (6%) | 6 (7%) | 1 (1%) | 6 (5%) | 6 (8%) |
 Dietary intake of major food groups | 4 (1%) | 0 (0%) | 0 (0%) | 2 (2%) | 2 (3%) |
 Eating behaviour | 2 (1%) | 0 (0%) | 0 (0%) | 1 (1%) | 1 (1%) |
 Frequency of dietary analysis | 1 (0%) | 0 (0%) | 0 (0%) | 1 (1%) | 0 (0%) |
 Adherence to PKU diet | 27 (8%) | 1 (1%) | 7 (10%) | 7 (6%) | 12 (17%) |
 Prescriptions of use of medications to manage PKU | 1 (0%) | 0 (0%) | 0 (0%) | 1 (1%) | 0 (0%) |
 Phenylalanine tolerance | 26 (8%) | 1 (1%) | 7 (10%) | 7 (6%) | 11 (15%) |
 Liberalization of PKU diet | 3 (1%) | 1 (1%) | 0 (0%) | 1 (1%) | 1 (1%) |
 Child acceptability of PKU diet | 14 (4%) | 2 (2%) | 1 (1%) | 6 (5%) | 5 (7%) |
 Caregiver/family acceptability of PKU diet | 11 (3%) | 0 (0%) | 2 (3%) | 7 (6%) | 2 (3%) |
3. CORE AREA: RESOURCE USE | 11 (3%) | 2 (2%) | 1 (1%) | 7 (6%) | 1 (1%) |
 Domain: Health Service Use and Costs | 11 (3%) | 2 (2%) | 1 (1%) | 7 (6%) | 1 (1%) |
 Access to care | 1 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 1 (1%) |
 Costs of care | 1 (0%) | 0 (0%) | 0 (0%) | 1 (1%) | 0 (0%) |
 Emergency department use | 3 (1%) | 0 (0%) | 0 (0%) | 3 (3%) | 0 (0%) |
 Hospitalization | 8 (2%) | 2 (2%) | 0 (0%) | 6 (5%) | 0 (0%) |
 Outpatient care use | 5 (1%) | 2 (2%) | 0 (0%) | 3 (3%) | 0 (0%) |
 Genetic counseling and family cascade carrier testing | 4 (1%) | 0 (0%) | 0 (0%) | 3 (3%) | 1 (1%) |
 Health education service use | 1 (0%) | 0 (0%) | 0 (0%) | 1 (1%) | 0 (0%) |
 Use of medical devices | 3 (1%) | 2 (2%) | 0 (0%) | 1 (1%) | 0 (0%) |
 Provision and coordination of services | 2 (1%) | 1 (1%) | 1 (1%) | 0 (0%) | 0 (0%) |
4. CORE AREA: DEATH | 9 (3%) | 0 (0%) | 1 (1%) | 6 (5%) | 2 (3%) |
 Domain: Death | 9 (3%) | 0 (0%) | 1 (1%) | 6 (5%) | 2 (3%) |
 Death | 9 (3%) | 0 (0%) | 1 (1%) | 6 (5%) | 2 (3%) |
5. CORE AREA: PATHOPHYSIOLOGICAL MANIFESTATIONS | 281 (82%) | 71 (85%) | 53 (79%) | 102 (85%) | 55 (76%) |
 Domain: Monitoring of Disease-specific Biomarkers and Surrogate Outcomes | 234 (68%) | 57 (68%) | 42 (63%) | 86 (72%) | 49 (68%) |
 Frequency of phenylalanine or tyrosine monitoring | 9 (3%) | 2 (2%) | 0 (0%) | 6 (5%) | 1 (1%) |
 Phenylalanine concentration in the blood and other tissues1 | 228 (66%) | 56 (67%) | 41 (61%) | 83 (69%) | 48 (67%) |
 Tyrosine concentration in the blood7 | 39 (11%) | 9 (11%) | 5 (7%) | 18 (15%) | 7 (10%) |
 Phenylalanine to tyrosine ratio | 13 (4%) | 1 (1%) | 2 (3%) | 7 (6%) | 3 (4%) |
 Phenylalanine metabolism and kinetics | 4 (1%) | 2 (2%) | 0 (0%) | 1 (1%) | 1 (1%) |
 Large neutral amino acid (LNAA) concentration in the blood | 1 (0%) | 0 (0%) | 0 (0%) | 1 (1%) | 0 (0%) |
 Micronutrient deficiency | 2 (1%) | 0 (0%) | 0 (0%) | 0 (0%) | 2 (3%) |
 BH4 malabsorption | 1 (0%) | 0 (0%) | 1 (1%) | 0 (0%) | 0 (0%) |
 Pharmacokinetics of sapropterin | 2 (1%) | 0 (0%) | 1 (1%) | 0 (0%) | 1 (1%) |
 Domain: Monitoring of Non Disease-Specific Biomarkers and Surrogate Outcomes | 151 (44%) | 37 (44%) | 28 (42%) | 55 (46%) | 31 (43%) |
 Bone health | 29 (8%) | 4 (5%) | 3 (4%) | 14 (12%) | 8 (11%) |
 Blood health | 27 (8%) | 4 (5%) | 3 (4%) | 13 (11%) | 7 (10%) |
 Neurological health – Clinical symptoms and diagnoses | 20 (6%) | 3 (4%) | 4 (6%) | 9 (8%) | 4 (6%) |
 Neurological health – Biomarkers and surrogate outcomes8* | 35 (10%) | 12 (14%) | 5 (7%) | 12 (10%) | 6 (8%) |
 Neurotransmitters | 7 (2%) | 3 (4%) | 2 (3%) | 1 (1%) | 1 (1%) |
 Liver health | 6 (2%) | 0 (0%) | 0 (0%) | 4 (3%) | 2 (3%) |
 Kidney health | 9 (3%) | 2 (2%) | 0 (0%) | 4 (3%) | 3 (4%) |
 Metabolic syndrome/energy metabolism3 | 52 (15%) | 12 (14%) | 10 (15%) | 20 (17%) | 10 (14%) |
 Biomarkers of protein synthesis | 22 (6%) | 3 (4%) | 4 (6%) | 11 (9%) | 4 (6%) |
 Biomarkers of vitamins and trace minerals4 | 45 (13%) | 9 (11%) | 5 (7%) | 19 (16%) | 12 (17%) |
 Concentration of amino acids other than Phe/Tyr in the blood | 28 (8%) | 4 (5%) | 3 (4%) | 12 (10%) | 9 (13%) |
 Biomarkers of antioxidant status, oxidative stress and inflammation | 20 (6%) | 4 (5%) | 7 (10%) | 6 (5%) | 3 (4%) |
 Neonatal complications | 2 (1%) | 0 (0%) | 0 (0%) | 1 (1%) | 1 (1%) |
 Dermatological health | 6 (2%) | 0 (0%) | 1 (1%) | 1 (1%) | 4 (6%) |
 Gastrointestinal health | 8 (2%) | 0 (0%) | 0 (0%) | 4 (3%) | 4 (6%) |
 Immune system disorders | 1 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 1 (1%) |
 Infections | 4 (1%) | 0 (0%) | 0 (0%) | 1 (1%) | 3 (4%) |
 Musculoskeletal health | 9 (3%) | 0 (0%) | 0 (0%) | 7 (6%) | 2 (3%) |
 Respiratory health | 5 (1%) | 0 (0%) | 0 (0%) | 2 (2%) | 3 (4%) |
 Dental and oral health | 3 (1%) | 1 (1%) | 0 (0%) | 1 (1%) | 1 (1%) |
 Ear health | 1 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 1 (1%) |
 Eye health | 2 (1%) | 0 (0%) | 0 (0%) | 1 (1%) | 1 (1%) |