OF PROPOSED PROJECT: The applicant proposes to establish a screening program for male infants by utilizing the first well-baby visit at six months of age to recruit the parents into the screening program. The reasoning behind this delayed newborn screening is that screening at the time of birth does not provide the optimum timing for discussion of all the parameters around Duchenne Muscular Dystrophy (DMD) testing, nor does it provide the best opportunity for obtaining informed consent. The applicant argues that presenting the screening at the first visit, but collecting the specimen at the second visit (9-12 months), allows time for the mother to investigate the decision fully and make a reasoned choice. Furthermore, the applicant notes that at the second planned visit a finger stick is performed to determine hematocrit, thus allowing an easy opportunity to collect another drop of blood for the DMD screening. Focus groups and surveys are planned among parents and healthcare providers to develop an informed consent instrument and educational materials to use in recruiting and screening infants. Participants will be recruited through the use of various methods (television, newspaper, magazines, Internet) and targeted education of managed care and private providers. A bioluminescence assay will be used to measure creatine kinase (CK) levels and multiplex ligation-dependent probe amplification (MLPA) techniques to detect deletions and duplications in all 79 exons of the dystrophin gene. Participants choosing to undergo screening and the participating healthcare providers will be asked to complete a """"""""screening experience"""""""" survey to assess their attitudes towards DMD screening and to evaluate the effectiveness of the program. While making a sound argument of the merits of newborn screening for DMD (including: 1) avoidance of the """"""""diagnostic odyssey"""""""" of prolonged and multiple medical evaluations; 2) allowing families earlier access to physical therapy and other supportive services, and; 3) providing an opportunity for choice of reproductive options in subsequent pregnancies) the applicant argues that the immediate post-natal period is not the best time for this decision to be made. Citing the DMD screening program in Wales as a model program, the authors point out that neonatal DMD screening may not give parents sufficient time for informed consent or education about DMD and may interfere with normal parental bonding to the new baby. A better option, they argue, would be to delay the testing, as was done in one study in which males were screened at 18 months of age; however, this timing allowed birth of subsequent affected males. Therefore, the applicant settles on the 6-12 month interval as the optimum, feeling that no new pregnancies would evolve before detection of an affected male, while allowing for true informed consent and parental bonding. It is noted that this timing affords another benefit unrelated to DMD screening in that it provides the opportunity for other screening programs under development, notably Fragile X syndrome. To oversee the project, an advisory board is planned consisting of representatives from the Muscular Dystrophy Association (MDA), the MDA clinics (six in Georgia), parents of sons with DMD, pediatric neurologists, and primary care providers. This board will meet twice yearly. The authors propose to use focus groups to assist in development of the informed consent instrument. With membership from parents of normal male infants as well as parents of children previously diagnosed with DMD, these groups will help determine the type and format of information that create the best opportunity for optimal informed consent. A clinical psychologist will provide guidance on establishing the focus groups, the development of surveys, and analyzing the results. The applicant proposes to use a marketing research company to recruit individuals for the parent focus groups. Consent forms are planned in English and Spanish. Educational materials for DMD will be developed from existing materials used by DMD screening programs. These culturally-sensitive materials will be distributed to parents in the primary care physician's (PCPs) office and maintained on a web-based DMD screening site. The educational materials are planned so as to present a balanced case for and against DMD screening and contain the consent form. Working with the Georgia Academy of Pediatricians and the Georgia Academy of Family Practitioners, the applicant proposes to develop information for PCPs that explains the rationale and operations of the DMD infant screening program. The applicant proposes to recruit participants for the DMD screening study in three ways: 1) An educational campaign using newspapers, parent magazines, parent websites, Georgia American Academy of Pediatrics (AAP) Blast fax, professional organization newsletters, prenatal classes, and development of parent-targeted posters and information brochures. An 800 line and a DMD screening website will provide parents other opportunities to acquire information; 2) Involvement of large managed care providers of pediatric primary care services; 3) Large multi-provider private primary care practices in rural and urban settings. An innovative """"""""lunch and learn"""""""" program is proposed for these groups in which the genetic counselor will provide seminars to these groups throughout the state. Additionally, the authors propose to conduct surveys of PCPs (medical doctors, office nurses, and office personnel) from various practice settings (urban and rural managed care and traditional point of service practices) to determine how best to incorporate screening of target male infants into their practice setting and to evaluate the acceptability of screening among health care professionals. The applicant proposes to use a standard bioluminescence screening test to measure CK levels in dried blood spots. It plans to recruit 500 samples from unaffected, healthy males, six weeks to 12 months of age, including normal males from the major ethnic/racial groups for assay development and validation prior to initiation of the screening program. CK values from affected males, age 0-6 months, will be used to determine positive cutoff values. A newborn male population of 66,500 is potentially available annually, allowing, it suggests, the detection of 18 affected males. The actual screening will consist of an initial CK determination. Those specimens testing positive with the CK assay will be submitted for isoenzyme determination. Those with CK-BB isoenzyme will be considered negative for DMD. Those with CK-MM isozyme will be considered screen positive and will be tested by the Molecular Genetics Laboratory within the screening laboratory for gene deletion or duplication. Parents of screen positive males will be contacted and offered a serum CK test with a 24-hour turnaround, in order minimize the waiting period before a diagnosis is made. For the molecular testing the authors propose to use a new technique, MLPA that will identify all 79 exons in the dystrophin gene following a DNA extraction using the Quiagen protocol. Families of all confirmed males will be referred to an MDA clinic. The applicant intends to obtain information on the screening program from four sources: 1) the focus groups and surveys of parents and primary care providers with data analysis by the clinical psychologist; 2) the CK pilot screening data set with data analysis and interpretation of this and the molecular testing provided by the director of the biochemical laboratory and director of the deoxyribonucleic acid (DNA) laboratory; 3) the molecular diagnostic testing; and 4) the post-screening surveys with data analysis by the clinical psychologist. Several groups will be queried in the post-screening surveys: 1) parents who received information and declined testing for their infant son; 2) parents who had their son screened, and he was found to be normal; 3) parents who had their son screened and had to be retested and found on a second screen to be normal (false positives); 4) parents whose son was screened positive and diagnosed with DMD, and; 5) primary care providers of parents who chose to have their son screened. In these surveys, data will be sought toward these points: 1) factors that influence access to and uptake of infant screening; 2) parental understanding of informed consent; 3) factors that influence loss to follow-up; 4) acceptability of screening; 5) impact of transient positive screening results on families; 6) attitudes of diagnosed families toward the screening and diagnostic process; 7) attitudes of false positive and true negative families toward the screening process, and; 8) assessments of other potential risks and benefits of infant screening for DMD. Healthcare providers of screened families will be surveyed to evaluate: 1) their perception of the parents understanding of informed consent; 2) acceptability of screening in their primary care practice setting; 3) impact of transient positive screening results on families, and; 4) other potential risks and benefits of infant screening for DMD. Outcome measures for the project include: 1) number of males diagnosed; 2) percentage of parents who complete screening who would choose to have another son tested; 3) ratings for the screening experience as positive or negative on a scale of 1-5; 4) ratings for the program's level of support on a scale of 1-5; 5) age at diagnosis of DMD in the screened population versus the historical age of diagnosis of DMD patients in the Georgia population; 6) the sensitivity, specificity, and PPV of the CK screening and molecular diagnostic tests; 7) cost of infant CK screening compared to costs of newborn screening for metabolic disorders; 8) time from screening to diagnosis compared to existing metabolic screening programs; 9) the informed consent process to determine how well it informed; 10) ratings of risk and benefits associated with the screen; 11) provider attitudes toward screening of patients in a PCP practice setting; 12) amount of time and cost added to the provider visit to discuss and collect the test; 13) level of inconvenience experienced by the parents or providers, and; 14) provider and parent opinions and suggestions about program improvements. These data points will be tracked throughout the project.
