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Table 3 Unique PKU outcomes reported in studies included for data synthesis

From: Outcomes in pediatric studies of medium-chain acyl-coA dehydrogenase (MCAD) deficiency and phenylketonuria (PKU): a review

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 DEVELOPMENT153 (45%)40 (48%)28 (42%)53 (44%)32 (44%)
 Domain: Physical Growth and Anthropometry63 (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%)
 Growth16 (5%)1 (1%)5 (7%)8 (7%)2 (3%)
 Head circumference8 (2%)1 (1%)1 (1%)3 (3%)3 (4%)
 Height/length5*42 (12%)4 (5%)7 (10%)18 (15%)13 (18%)
 Weight38 (11%)2 (2%)9 (13%)16 (13%)11 (15%)
 Body composition9 (3%)1 (1%)2 (3%)4 (3%)2 (3%)
 Domain: Cognition and Development110 (32%)34 (40%)19 (28%)38 (32%)19 (26%)
 Cognition and intelligence/IQ282 (24%)25 (30%)14 (21%)29 (24%)14 (19%)
 Overall child development11 (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/disabilities1 (0%)0 (0%)1 (1%)0 (0%)0 (0%)
 Academic achievement/school performance20 (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 IMPACT156 (45%)28 (33%)24 (36%)61 (51%)43 (60%)
 Domain: Child Life Impact35 (10%)4 (5%)1 (1%)20 (17%)10 (14%)
 Child quality of life21 (6%)2 (2%)1 (1%)12 (10%)6 (8%)
 Child psychosocial well-being and self-concept15 (4%)0 (0%)0 (0%)10 (8%)5 (7%)
 Child social impact and function12 (3%)2 (2%)0 (0%)6 (5%)4 (6%)
 Bodily pain or discomfort7 (2%)0 (0%)0 (0%)4 (3%)3 (4%)
 Sleep problems1 (0%)0 (0%)0 (0%)1 (1%)0 (0%)
 Overall clinician-assessed health status of child4 (1%)0 (0%)0 (0%)3 (3%)1 (1%)
 Child understanding of and self-efficacy with management of PKU3 (1%)1 (1%)0 (0%)1 (1%)1 (1%)
 Achievement of treatment goals1 (0%)0 (0%)0 (0%)0 (0%)1 (1%)
 Domain: Caregiver/family Life Impact19 (6%)4 (5%)1 (1%)7 (6%)7 (10%)
 Impact of PKU on caregiver/family quality of life10 (3%)0 (0%)0 (0%)5 (4%)5 (7%)
 Caregiver/family psychosocial well-being9 (3%)4 (5%)0 (0%)2 (2%)3 (4%)
 Caregiver/family economic impact5 (1%)1 (1%)1 (1%)2 (2%)1 (1%)
 Impact of PKU on caregiver/family diet1 (0%)0 (0%)0 (0%)1 (1%)0 (0%)
 Domain: Child and Caregiver/family Life Impact3 (1%)1 (1%)0 (0%)0 (0%)2 (3%)
 Strategies used by parents to help children cope with PKU1 (0%)0 (0%)0 (0%)0 (0%)1 (1%)
 Perceived control over behavior and skills2 (1%)1 (1%)0 (0%)0 (0%)1 (1%)
 Domain: Child Behaviour, Mental Health, and Temperament42 (12%)8 (10%)4 (6%)19 (16%)11 (15%)
 Behaviour problems and externalizing mental health or behaviour disorders19 (6%)5 (6%)2 (3%)8 (7%)4 (6%)
 Attention-deficit hyperactivity disorder (ADHD) or ADHD-like symptoms15 (4%)2 (2%)1 (1%)8 (7%)4 (6%)
 Internalizing mental health or mood disorders and associated symptoms26 (8%)4 (5%)1 (1%)15 (13%)6 (8%)
 Autism spectrum disorder (ASD) or ASD-like symptoms9 (3%)0 (0%)1 (1%)5 (4%)3 (4%)
 Atypical behaviour and mental symptoms other than those specified1 (0%)0 (0%)0 (0%)1 (1%)0 (0%)
 Temperament/personality4 (1%)1 (1%)0 (0%)3 (3%)0 (0%)
 Domain: Disease Management and Feeding Behaviour113 (33%)19 (23%)21 (31%)41 (34%)32 (44%)
 Age at treatment initiation4 (1%)1 (1%)0 (0%)3 (3%)0 (0%)
 Infant breast and formula feeding2 (1%)0 (0%)0 (0%)1 (1%)1 (1%)
 Dietary intake of phenylalanine28 (8%)5 (6%)5 (7%)10 (8%)8 (11%)
 Dietary intake of amino acids other than phenylalanine6 (2%)2 (2%)0 (0%)3 (3%)1 (1%)
 Dietary intake of medical foods or formula, modified low-protein foods, and protein substitutes9 (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 energy30 (9%)8 (10%)6 (9%)11 (9%)5 (7%)
 Overall dietary intake relative to standards5 (1%)0 (0%)0 (0%)3 (3%)2 (3%)
 Dietary intake of fat17 (5%)5 (6%)2 (3%)6 (5%)4 (6%)
 Dietary intake of specific fatty acids16 (5%)6 (7%)4 (6%)4 (3%)2 (3%)
 Dietary intake of cholesterol7 (2%)3 (4%)1 (1%)3 (3%)0 (0%)
 Dietary intake of carbohydrates15 (4%)3 (4%)3 (4%)6 (5%)3 (4%)
 Dietary intake of fibre7 (2%)3 (4%)1 (1%)2 (2%)1 (1%)
 Glycemic index of foods consumed1 (0%)0 (0%)0 (0%)0 (0%)1 (1%)
 Dietary intake of vitamins and minerals19 (6%)6 (7%)1 (1%)6 (5%)6 (8%)
 Dietary intake of major food groups4 (1%)0 (0%)0 (0%)2 (2%)2 (3%)
 Eating behaviour2 (1%)0 (0%)0 (0%)1 (1%)1 (1%)
 Frequency of dietary analysis1 (0%)0 (0%)0 (0%)1 (1%)0 (0%)
 Adherence to PKU diet27 (8%)1 (1%)7 (10%)7 (6%)12 (17%)
 Prescriptions of use of medications to manage PKU1 (0%)0 (0%)0 (0%)1 (1%)0 (0%)
 Phenylalanine tolerance26 (8%)1 (1%)7 (10%)7 (6%)11 (15%)
 Liberalization of PKU diet3 (1%)1 (1%)0 (0%)1 (1%)1 (1%)
 Child acceptability of PKU diet14 (4%)2 (2%)1 (1%)6 (5%)5 (7%)
 Caregiver/family acceptability of PKU diet11 (3%)0 (0%)2 (3%)7 (6%)2 (3%)
3. CORE AREA: RESOURCE USE11 (3%)2 (2%)1 (1%)7 (6%)1 (1%)
 Domain: Health Service Use and Costs11 (3%)2 (2%)1 (1%)7 (6%)1 (1%)
 Access to care1 (0%)0 (0%)0 (0%)0 (0%)1 (1%)
 Costs of care1 (0%)0 (0%)0 (0%)1 (1%)0 (0%)
 Emergency department use3 (1%)0 (0%)0 (0%)3 (3%)0 (0%)
 Hospitalization8 (2%)2 (2%)0 (0%)6 (5%)0 (0%)
 Outpatient care use5 (1%)2 (2%)0 (0%)3 (3%)0 (0%)
 Genetic counseling and family cascade carrier testing4 (1%)0 (0%)0 (0%)3 (3%)1 (1%)
 Health education service use1 (0%)0 (0%)0 (0%)1 (1%)0 (0%)
 Use of medical devices3 (1%)2 (2%)0 (0%)1 (1%)0 (0%)
 Provision and coordination of services2 (1%)1 (1%)1 (1%)0 (0%)0 (0%)
4. CORE AREA: DEATH9 (3%)0 (0%)1 (1%)6 (5%)2 (3%)
 Domain: Death9 (3%)0 (0%)1 (1%)6 (5%)2 (3%)
 Death9 (3%)0 (0%)1 (1%)6 (5%)2 (3%)
5. CORE AREA: PATHOPHYSIOLOGICAL MANIFESTATIONS281 (82%)71 (85%)53 (79%)102 (85%)55 (76%)
 Domain: Monitoring of Disease-specific Biomarkers and Surrogate Outcomes234 (68%)57 (68%)42 (63%)86 (72%)49 (68%)
 Frequency of phenylalanine or tyrosine monitoring9 (3%)2 (2%)0 (0%)6 (5%)1 (1%)
 Phenylalanine concentration in the blood and other tissues1228 (66%)56 (67%)41 (61%)83 (69%)48 (67%)
 Tyrosine concentration in the blood739 (11%)9 (11%)5 (7%)18 (15%)7 (10%)
 Phenylalanine to tyrosine ratio13 (4%)1 (1%)2 (3%)7 (6%)3 (4%)
 Phenylalanine metabolism and kinetics4 (1%)2 (2%)0 (0%)1 (1%)1 (1%)
 Large neutral amino acid (LNAA) concentration in the blood1 (0%)0 (0%)0 (0%)1 (1%)0 (0%)
 Micronutrient deficiency2 (1%)0 (0%)0 (0%)0 (0%)2 (3%)
 BH4 malabsorption1 (0%)0 (0%)1 (1%)0 (0%)0 (0%)
 Pharmacokinetics of sapropterin2 (1%)0 (0%)1 (1%)0 (0%)1 (1%)
 Domain: Monitoring of Non Disease-Specific Biomarkers and Surrogate Outcomes151 (44%)37 (44%)28 (42%)55 (46%)31 (43%)
 Bone health29 (8%)4 (5%)3 (4%)14 (12%)8 (11%)
 Blood health27 (8%)4 (5%)3 (4%)13 (11%)7 (10%)
 Neurological health – Clinical symptoms and diagnoses20 (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%)
 Neurotransmitters7 (2%)3 (4%)2 (3%)1 (1%)1 (1%)
 Liver health6 (2%)0 (0%)0 (0%)4 (3%)2 (3%)
 Kidney health9 (3%)2 (2%)0 (0%)4 (3%)3 (4%)
 Metabolic syndrome/energy metabolism352 (15%)12 (14%)10 (15%)20 (17%)10 (14%)
 Biomarkers of protein synthesis22 (6%)3 (4%)4 (6%)11 (9%)4 (6%)
 Biomarkers of vitamins and trace minerals445 (13%)9 (11%)5 (7%)19 (16%)12 (17%)
 Concentration of amino acids other than Phe/Tyr in the blood28 (8%)4 (5%)3 (4%)12 (10%)9 (13%)
 Biomarkers of antioxidant status, oxidative stress and inflammation20 (6%)4 (5%)7 (10%)6 (5%)3 (4%)
 Neonatal complications2 (1%)0 (0%)0 (0%)1 (1%)1 (1%)
 Dermatological health6 (2%)0 (0%)1 (1%)1 (1%)4 (6%)
 Gastrointestinal health8 (2%)0 (0%)0 (0%)4 (3%)4 (6%)
 Immune system disorders1 (0%)0 (0%)0 (0%)0 (0%)1 (1%)
 Infections4 (1%)0 (0%)0 (0%)1 (1%)3 (4%)
 Musculoskeletal health9 (3%)0 (0%)0 (0%)7 (6%)2 (3%)
 Respiratory health5 (1%)0 (0%)0 (0%)2 (2%)3 (4%)
 Dental and oral health3 (1%)1 (1%)0 (0%)1 (1%)1 (1%)
 Ear health1 (0%)0 (0%)0 (0%)0 (0%)1 (1%)
 Eye health2 (1%)0 (0%)0 (0%)1 (1%)1 (1%)
  1. 1–10indicates top ten most reported or discussed unique outcomes, ties indicated with an asterisks; p indicates neuro-psychological outcomes
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