Reference
Complete the bibliographic reference for the article according to AJE format.

Waisbren, S E, et al. Effect of expanded newborn screening for biochemical genetic disorders on child outcomes and parental stress. JAMA. 2003 Nov; 290(19): 2564 -2572

Category of HuGE information
Specify the types of information (from the list below) available in the article:

1. Prevalence of gene variant
2. Gene-disease association
3. Gene-environment interaction
4. Gene-gene interaction
5. Genetic test evaluation/monitoring

5. Genetic test evaluation/monitoring

Study hypotheses or purpose
The authors study hypotheses or main purpose for conducting the study.

Gene(s)
Identification of the following:

1. Gene name
2. Chromosome location
3. Gene product/function
4. Alleles
5. OMIM #

N/A

Environmental factor(s)
Identification of the major environmental factors studied (infectious, chemical, physical, nutritional, and behavioral)

N/A

Health outcome(s)
Identification of the major health outcome(s) studied

Between clinically identified children with biochemical genetic disorders and those children that were identified through expanded newborn screening: effect on medical outcomes, effect on developmental status of the child, impact on resource use and satisfaction with healthcare, and the impact on family and parental stress.

Between children with false-positive results for metabolic disorders and children screened with normal results: interaction with health care professionals, impact on child health, and impact on family and parental stress.

1. Case-control
2. Cohort 
3. Cross-sectional
4. Descriptive or case series
5. Clinical trial
6. Population screening

1. Case-control
6. Population Screening (Newborn Screening)

1. Disease case definition
2. Exclusion criteria
3. Gender
4. Race/ethnicity
5. Age
6. Time period
7. Geographic location
8. Number of participants

Case Group 1: Families of affected children with biochemical genetic disorders identified in a clinical setting.
(Clinically Identified Group)

1. Exclusion Criteria: Parents of children that died prior to enrollment, children who were identified from 2 metabolic centers that failed to obtain approval from their internal review board for the study (43), and eligible subjects who did not have their first evaluation as of December 1, 2002
2. Gender: Female 15 (46%)
3. Race: White 29 (88%)
4. Age at Diagnosis: Median 4 Months
5. Age at Evaluation: Median 34 Months
6. Time Period: February 1, 1999 - June 1, 2002
7. Geographic Location: Massachusetts , Maine , and Pennsylvania
8. Number of Participants: 33 (97% of eligible)

Case Group 2 (Sometimes used as controls for case group 1): Families of affected children with biochemical genetic disorders identified through expanded newborn screening.
(Newborn Screened Group)

1. Exclusion Criteria: Parents of children that died prior to enrollment, children who were identified from 2 metabolic centers that failed to obtain approval from their internal review board for the study (10), ,and eligible subjects that did not have their first evaluation as of December 1, 2002
2. Gender: Female 23 (46%)
3. Race: White 39 (78%)
4. Age at Diagnosis: Median 5 Days
5. Age at Evaluation: Median 9 Months
6. Time Period: February 1, 1999 - June 1, 2002
7. Geographic Location: Massachusetts , Maine , and Pennsylvania
8. Number of Participants: 50 (82% of eligible)
   

Case Group 3: Screened Children with false-positive results from MA and ME that were referred from a metabolic center and from PA who were sent recruitment information.
(False-Positive Group)

1. Exclusion Criteria: Parents of children that died prior to enrollment, children who were identified from 2 metabolic centers that failed to obtain approval from their internal review board for the study (202), and eligible subjects that did not have their first evaluation as of December 1, 2002
2. Gender: Female 46 (49%)
3. Race: White 76 (81%)
4. Age at Diagnosis: N/A
5. Age at Evaluation: Median 11 Months
6. Time Period: February 1, 1999 - June 1, 2002
7. Geographic Location: Massachusetts , Maine , and Pennsylvania
8. Number of Participants: 94 (75% of eligible)
   

1. Control selection criteria
2. Matching variables
3. Exclusion criteria
4. Gender
5. Race/ethnicity
6. Age
7. Time period
8. Geographic location
9. Number of participants

Control Group 1 (Used as controls for case group 3): Children with normal newborn screening results from MA, selected sequentially from the Commonwealth of Massachusetts Department of Public Health Birth Registry of Vital Records and Statistics.
(Normal Newborn Screening Group)

1. Exclusion Criteria: Parents of children that died prior to enrollment, and eligible subjects that did not have their first evaluation as of December 1, 2002 , and parents of newborns whose birth weight was less than 2500 g.
2. Matching Variables: None
3. Gender: Female 39 (48%)
4. Race: White 72 (89%)
5. Age at Diagnosis: N/A
6. Age at Evaluation: Median 6 Months
7. Time Period: February 1, 1999 - June 1, 2002
8. Geographic Location: Massachusetts
9. Number of Participants: 81 (63% of eligible)

Cohort definition
For study designs 2, 3, and 6, define the following if available:

1. Cohort selection criteria
2. Exclusion criteria
3. Gender
4. Race/ethnicity
5. Age
6. Time period
7. Geographic location
8. Number of participants

Newborn Screening Cohort: Approximately 214,000 newborns/year:
Maine : 13,000
Massachusetts : 81,000
Pennsylvania : 150,000

1. Environmental factor
2. Exposure assessment
3. Exposure definition
4. Number of participants with exposure data (%
   of total eligible)

1. Gene
2. DNA source
3. Methodology
4. Number of participants genotyped (% of total eligible) 

N/A

1. Prevalence of gene variant
2. Gene-disease association
3. Gene-environment interaction
4. Gene-gene interaction
5. Genetic test evaluation/monitoring

5. Genetic Test Evaluation/Monitoring

Children in the clinically identified group were more likely to be transferred to a neonatal intensive care unit, be hospitalized in the first 6 months of life, have symptoms at diagnosis, have medical complications, have neurological complications, require a gastrostomy tube, require special services, and have lower mental and motor development scores compared to the newborn screened group (all p-values < .05).

Mothers of children in the clinically identified group were more likely to have parental distress, to perceive their children as difficult, and to have a dysfunctional parent-child relationship, as measured by the Parental Stress Index (PSI) compared to children in the newborn screened group (all p-values < .001, except parental distress, whose p=.06).

Parents of children identified by newborn screening expressed greater satisfaction with their social support network and were less likely to engage in medico-legal proceedings than parents of clinically identified children (both p-values < .05).

False-positive children were more likely to be hospitalized than the true-negative control group (p=.06). The parents of false-positive children scored significantly higher on the PSI, including the parent-child dysfunction subscale (p<.001).

Children identified to have biochemical genetic disorders through expanded newborn screening experience fewer developmental and health problems compared to children whose disorders are identified clinically. Nevertheless, false-positive results place families at higher risk for stress.

The comparison of clinically diagnosed children and children diagnosed through expanded newborn screening assumes that the severity of the diseases in both groups would be equal if no screening had been done. Information on penetrance and severity of the disorders included in expanded newborn screening is missing, and the percentage of asymptomatic children who were never diagnosed through expanded screening is unknown.

The lack of matching on specific disease between the two groups, although needed due to small sample sizes, also leads one to question the results. It is very unlikely that all 20 diseases have the same severity, and the two groups differed in types of diseases diagnosed.