A GIANT LEAP FORWARD IN PREVENTIVE MEDICINE OR PANDORA’S BOX?

Grant # 1 R01 HG02085

National Institutes of Health

National Human Genome Research Institute

Principal Investigator: Susan E. Waisbren, Ph.D.

Project Period: 5/1/2000 — 4/30/2003

Grant # 5H46 MC 00158-02

Maternal and Child Health

Principal Investigator: Harvey Levy, MD

Project Period: 9/1/99 — 5/31/2002

Despite the potential of expanded newborn screening for biochemical genetic disorders as a significant advance in preventive medicine, there are serious concerns about its social, ethical and legal implications. These concerns apply to identification of the disorders as well as to the false positive results that occur. The arguments for and against expanded screening generally are related to the medical issues, the ways in which parents will respond to the information and how the child will be perceived by society. With technology, particularly tandem mass spectrometry, (MS-MS) as a driving force, there is the possibility of expanding screening for an even larger number of genetic disorders. It is important to study the ethical, social and legal implications of these programs now when they are new and still amendable to change.

The aims of this study are:

1. To compare newborn identification by expanded screening to clinical identification in children with biochemical genetic disorders in terms of the interaction between the parents and the health care system and elements of health outcome for the child and family. These include the ways in which information is provided to parents, parental response, types of medical care provided, psychosocial factors, and legal ramifications.

2. To assess the impact of a false positive screen compared to a normal screen in the expanded newborn program in terms of parental response and interactions with the health care system.

This is a 3-year prospective study limited to the disorders that have been recently added to the newborn screening list in Massachusetts. For aim 1, parents of newborn infants diagnosed through MS-MS in Massachusetts and Pennsylvania (where such screening has also been instituted) will be compared to parents of children diagnosed with the same metabolic disorders in the New England states where expanded newborn screening has not been adopted. Six months after the diagnosis is made and 1 year later, the mothers and fathers will be interviewed and the offspring will receive a neurodevelopmental evaluation.

For aim 2, parents of infants initially screened false positive for one of the biochemical genetic disorders will participate in a phone survey. A sample of parents of infants screened normal will also be included. When the infants are 6 months old, their parents will be interviewed about their knowledge of newborn screening, their response to the information they received, their overall adjustment to having a new baby and their level of stress.

List of Disorders included in the Study:

Tyrosinemia I (Fumarylacetoacetate hydrolase deficiency)

Tyrosinemia II (Tyrosine aminotransferase deficiency)

Citrullinemia

Argininosuccinic acidemia (ASA)

Hyperornithinemia-Hyperammonemia-Homocitrullinuria (HHH) syndrome

Methylmalonic acidemia (Methylmalonyl-CoA mutase deficiency) (MMA)

Propionic acidemia (Propionyl-CoA carboxylase deficiency) (PA)

Argininemia (Arginase deficiency)

Isovaleric Acidemia (Isovaleryl-CoA dehydrogenase deficiency)

Glutaric acidemia I (Glutaryl-CoA dehydrogenase deficiency) (GA I)

Glutaric acidemia II (Multiple acyl-CoA dehydrogenase deficiency) (GA II)

ß-Ketothiolase deficiency (2-Methylacetoacetyl-CoA thiolase deficiency)

ß-Methylcrotonyl CoA carboxylase deficiency

3-Hydroxy-3-methylglutaryl (HMG)-CoA lyase deficiency

CPT deficiency (Carnitine palmitoyltransferase deficiency)

Medium chain acyl-CoA dehydrogenase deficiency (MCAD)

Short chain acyl-CoA dehydrogenase (SCAD) deficiency

Long chain acyl-CoA dehydrogenase (LCAD) deficiency

Long chain hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency

Very long chain acyl-CoA dehydrogenase (VLCAD) deficiency

In Massachusetts, recruitment will be conducted through the New England Consortium of Metabolic Centers. Parents of children newly diagnosed because of clinical symptoms or a positive newborn screen will be sent a letter from the Director of their Metabolic Center. In Pennsylvania, the physicians of prospective subjects will be contacted by NeoGen Screening and asked to send a recruitment letter. The initial letter will outline the goals and procedures of the study. Enclosed will be a form for the family to return if they would rather not participate in the study. The families that do not return the form will be called after a period of 3 weeks to set up an appointment for the interview. A log containing only the child’s diagnosis and method of ascertainment will be maintained of all families who prefer not to participate.

Data will be collected 6 months after confirmation of a diagnosis of the biochemical genetic disorder and follow-up information will be collected 1 year later. The mother and father will be interviewed separately on each occasion.

A psychologist will perform the neurodevelopmental testing. Subjects will be interviewed in their homes or at the metabolic center. A summary of the anticipated sample follows:

MS-MS Group

Clinical Group — New England

1. Interview contains questions that will provide information linked to the interaction model of client health behavior (Cox, 1982) with regards to background information and communication of the newborn screening results or the diagnosis of the child.
2. Well-Being Questionnaire (WBQ) (Bradley, 1994) is a 22-item quality of life measure providing a Total Well-Being score and 4 subscale scores (depression, anxiety, energy and positive well-being). The scale was developed through a broad World health Organization multi-center European study of diabetic patients.
3. The Parenting Stress Index (PSI) Third Edition, Short Form (Abidin, 1995) is a 36-item questionnaire providing a Total Stress Score and 3 scaled scores: parental distress, parent-child dysfunctional interaction, and difficult child.
4. Patient Enablement Instrument (PEI) (Howie et al, 1998). This is a 6-item measure shown to be significantly correlated with both patient satisfaction and to whether there is achievement of specific health care gains. It focuses on patient empowerment and on patients’ ability to understand and cope with their own or their child’s health and illness.
5. Vineland Adaptive Behavior Scale (Sparrow, Balla and Cicchetti, 1984). This measure is based on parental report of a child’s adaptation in the domains of communication, self-help, socialization and motor coordination. An overall Adaptive Behavior Composite score as well as subscales for each domain are provided. The composite score will be used to measure the child’s quality of life, since it reflects the child’s ability to communicate, take part in family and community activities, and develop independence.
6. Bayley Scales of Infant Development-2^nd Edition will be used to provide indices of cognitive and motor functioning for infants. The Stanford Binet Intelligence Scale will be used for children over 3 years of age. The Stanford Binet was selected because it has norms for children ages 2 _ years through adulthood. This broad normative range is useful for older children with developmental delays who might not be able to complete other standard intelligence tests. These tests will be administered to provide an objective measure of child health outcome.
7. Medical examination will be performed on each child at the time of the interview. Medical records will also be reviewed. Specific ratings of health, metabolic status and neurological functioning will be made.

Over the 3-year period, mothers and fathers of infants initially screened false positive for any of the 20 biochemical genetic disorders listed above will be invited to participate in a phone interview. For the purposes of this study, a false positive result is defined as a specimen in which an abnormality was found (a result above the cut-off level) and a repeat specimen was requested for this reason only. Parents will not be included who were requested to submit a repeat specimen for other reasons (e.g., an inadequate specimen, early discharge or prematurity.)

For the control group, parents of infants will be randomly selected from public birth records. These records (which include parents’ names and addresses, baby’s date of birth and birth weight) are open to the public and are generally available 3 months after the child’s birth. A check will be made with the death records to avoid mailing to parents whose child died. In addition, babies whose birth weight is less than 5 lbs. 11 oz. (2500 gms.) will be excluded, to limit recruiting parents of premature babies. Recruitment letters will be mailed in batches of 20 every three months to consecutive families beginning with the first child exactly 5 months old at the time of recruitment.

Procedures similar to those in aim 1 will be used to recruit parents. The recruitment letters will either be sent by the Metabolic Centers or the Screening Laboratories.

Prospective subjects will be called by the research assistant to confirm a time for the phone interview. The interviewer will be blind as to whether a repeat screen was requested from the family. Parents will be asked questions about their experiences with the newborn screening process and some may report that their child received a repeat screen. When the infants are 6 months old, parents in both groups will be interviewed over the phone.

It is anticipated that 90% of prospective subjects will agree to participate, but sometimes only 1 parent will be available. This will yield a sample size of about 85 in each group (since data from mothers and fathers will be analyzed separately).

Recruitment of parents of infants screened normal will continue until there are 85 mothers and 85 fathers enrolled.

1. Phone interview, similar to the interview used in Aim 1, contains questions that will provide information linked to the interaction model of client-health behavior with regards to background information and communication of the newborn screening results. Several open-ended questions will also be included to give parents the opportunity to discuss aspects of newborn screening that might not have been covered in the interview.
2. Parental Stress Inventory (PSI) (Abidin, 1995) (described above in Aim 1).
3. Well-Being Questionnaire (WBQ) (Bradley, 1994) (described above in Aim 1).

Abidin RR (1995) Parenting Stress Index (PSI) Third Edition. Odessa, Florida: Psychological Assessment Resources, Inc.

Bradley C (1994). Handbook of Psychology and Diabetes. London: Harwood Academic Publishers.

Cox CL (1982) An interaction model of client health behavior: theoretical prescription for nursing. Advances in Nursing Science, October: 41-56.

Howie JGR, Heaney DJ, Maxwell M, Walker JJ (1998) A comparison of a Patient Enablement Instrument (PEI) against two established satisfaction scales as an outcome measure of primary care consultations. Family Practice 15: 165-171.