Norman Fost

Cystic Fibrosis Newborn Screening: Impact on Reproductive Behavior and Implications for Genetic Counseling

Objective. To evaluate the impact of newborn screening for cystic fibrosis (CF) on the reproductive knowledge and behavior of CF families and to determine if heterozygote detection with the immunoreactive trypsinogen (IRT) method in conjunction with DNA analysis (IRT/DNA) influences knowledge and attitudes about reproduction in false-positive families. Methods. The Wisconsin CF Neonatal Screening Project investigated 650 340 infants from 1985 to 1994 in a comprehensive randomized controlled trial to study both benefits and risks of newborn screening and to determine if early diagnosis would improve the prognosis of children with CF. Assessments of reproductive knowledge, attitudes, and behaviors of 135 families of children diagnosed as having CF in both the early treatment group and control groups were made 3 months after diagnosis using a questionnaire which was completed by 100 families. The same questionnaire was administered 1 year later to evaluate retention of information. It was completed by 71 families. A follow-up assessment tool was also administered in 1994 and responses obtained from 73 families. Knowledge, attitudes, and behavior among false-positive families were also assessed at the time of the sweat test in 206 families who experienced IRT screening and 109 families tested with the IRT/DNA method. Follow-up assessments were completed 1 year later in 106 IRT families and 63 IRT/DNA families. Results. In families with a CF child, 95% initially understood that there was a 1 in 4 risk in subsequent pregnancies, and there was good retention of this information 1 year later. At the 1994 assessment, 52% of families had not yet conceived more children, but 74% of these already had children. In the couples in whom CF was diagnosed in the first child, 70% (95% confidence interval = 54% to 85%) conceived more children. There were 43 subsequent pregnancies in 31 families. Prenatal diagnosis was used by 26% of the families (8/31) for 21% of the pregnancies (9/43). There were 3 pregnancies with CF detected, all of which were carried to term. In the false-positive groups, >95% of families initially understood that their child definitely did not have CF. There was no difference between false-positive IRT and IRT/DNA groups, and the information was retained at 1 year. Follow-up assessment 1 year after negative sweat tests revealed that 7% of the IRT and 10% of the IRT/DNA families still thought about the results often or constantly. When asked whether the experience of screening affected feelings about having more children, an affirmative response was obtained in 4% of IRT families but in 17% of IRT/DNA families. One year later, more than half of the false-positive IRT/DNA families did not understand that they were at increased risk of having a child with CF. Conclusions. We conclude that CF neonatal screening does not have a significant impact on the reproductive behavior of most families and that prenatal diagnosis is not used by the majority of CF families. IRT/DNA testing experiences seem to affect attitudes about having more children, and some parents are confused about the implications of the results, even with genetic counseling. However, persistent concerns about the sweat test result are limited. Questions raised by this study confirm the need for more research regarding the process of genetic counseling and its impact on reproductive attitudes and behavior in the newborn screening setting.

Newborn screening technology: proceed with caution.

The American College of Medical Genetics (ACMG) recommends a significant expansion in the number of conditions targeted by newborn screening (NBS) programs.1 In this commentary we advocate a more cautious approach. NBS dates to the early 1960s, when the technology developed to conduct large-scale testing on dried blood spots for phenylketonuria (PKU).2 PKU remains the paradigm condition for NBS because of features of the disease and its treatment, which are particularly advantageous to population screening. It is a condition that silently causes neurologic devastation but is amenable to early detection and effective prevention with a diet of moderate burden and complexity.3 Many children affected with PKU and their families have benefited from state screening programs over the past 4 decades because of collaboration between health departments, families, primary care providers, and metabolic specialists. However, PKU screening is not an unmitigated success.4,5 There was initial uncertainty about whether children with variant forms of hyperphenylalaninemia required treatment and about whether affected children require life-long dietary management.6 Indeed, some children with benign conditions were seriously harmed from unnecessary restrictions in their diets.5 In addition, long-term studies demonstrate decrements in cognitive function for affected children and adolescents who are not fully adherent to the diet,7,8 yet adherence to the diet is challenging because of its poor palatability, high cost, and limits on insurance coverage in many policies. Affected women who are off the diet are at high risk of bearing severely neurologically impaired children.9 Only recently have many programs begun tracking affected women to enable notification, education, and management. These difficulties by no means negate the value of NBS for PKU, but they highlight the problems with the successful implementation of a population-based screening program even when a model condition is targeted. … Address correspondence to Jeffrey R. Botkin, MD, MPH, Research Administration Building, 75 South 2000 East #108, Salt Lake City, UT 84112-8930. E-mail: jeffrey.botkin{at}hsc.utah.edu

Parents' Knowledge of Neonatal Screening and Response to False-positive Cystic Fibrosis Testing

Neonatal screening for cystic fibrosis (CF) has become feasible through analyzing dried blood specimens for immunoreactive trypsinogen (IRT), but the benefits and risks of such a screening program remain to be delineated. This study, a survey of the parents of 104 Wisconsin infants with false-positive IRT tests, showed parents had knowledge deficits about neonatal screening in general, misconceptions about test results, and high levels of anxiety. Parenting behaviors were reportedly unchanged during the usual 3-day waiting period between the news of the abnormal screeing test and the diagnostic sweat test. Most, but not all, parents were relieved by negative sweat test results subsequent to the abnormal IRT test. Factors associated with continued parental concern included having less than a high school education and/or having an infant with low Apgar scores. Additionally, those contacted by telephone were more likely to have misinformation and lingering concerns about the presence of CF in their child. J Dev Behav Pediatr 13:181–186, 1992. Index terms: cystic fibrosis, neonatal screening, trypsinogen, anxiety.

Research Ethics in the MySpace Era

Social networking web sites are popular among adolescents and may represent a new venue for conducting adolescent health research. Conducting research by using social networking web sites raises several concerns, including the social value of this research, fair subject selection, confidentiality, privacy, and informed consent. Addressing each of these concerns, we offer an ethical framework to promote informed and appropriate decisions.

Health Insurance Portability Accountability Act (HIPAA) Regulations: Effect on Medical Record Research

Objective:To evaluate the effect of impending HIPAA regulations on Applications for Exemptions from Institutional Review Board (IRB) approval. Summary Background Data:HIPAA was implemented to reduce potential for misuse of personal information and restricts access to medical records by insurers, employers, and clinical researchers. We hypothesized that HIPAA regulations adversely impact medical records research. Methods:The UW–Madison Human Subjects Committee database was accessed to evaluate success and delays in processing Applications for Exemption between September 1999 and March 2003. The number of protocols submitted, number of required revisions, and number considered nonexempt (requiring full IRB review) were determined. Results:Prior to 2000, applications for medical records research were rare (11 applications in 1999–2000). In anticipation of the implementation of HIPAA regulations, a new application process was instituted in 2001. During that year, 92 of 103 were approved by an expedited process with few requiring full IRB approval. In 2002 to 2003, submissions increased to 199 and approval without revision dropped to 59% (P < 0.0001) as the number requiring revision (25%) and full IRB approval (16%) increased significantly (P < 0.0001 and P < 0.05, respectively). Of the 31 requiring full IRB approval, 7 were pursued while 24 (77%) were abandoned. Conclusion:HIPAA appears to inhibit medical record and database research. Ethical considerations in healthcare research are paramount, but current HIPAA implementation strategies increase workload for HSC and researchers, and increase the dropout rate for proposed studies when investigators are unable or unwilling to meet the regulatory requirements. It is unclear whether or to what degree the new requirements add to protection of privacy. Studies designed to investigate the costs and effects on quantity and/or quality of research should be prospectively implemented.

The OHRP and SUPPORT

A group of medical ethicists and pediatricians asks for reconsideration of the recent Office for Human Research Protections decision about informed consent in SUPPORT.

Childhood Obesity and Medical Neglect

The incidence of childhood obesity has increased dramatically, including severe childhood obesity and obesity-related comorbid conditions. Cases of severe childhood obesity have prompted the following question: does childhood obesity ever constitute medical neglect? In our opinion, removal of a child from the home is justified when all 3 of the following conditions are present: (1) a high likelihood that serious imminent harm will occur; (2) a reasonable likelihood that coercive state intervention will result in effective treatment; and (3) the absence of alternative options for addressing the problem. It is not the mere presence or degree of obesity but rather the presence of comorbid conditions that is critical for the determination of serious imminent harm. All 3 criteria are met in very limited cases, that is, the subset of obese children who have serious comorbid conditions and for whom all alternative options have been exhausted. In these limited cases, a trial of enforced treatment outside the home may be indicated, to protect the child from irreversible harm.

Temporal Associations Among Energy Intake, Plasma Linoleic Acid, and Growth Improvement in Response to Treatment Initiation After Diagnosis of Cystic Fibrosis

OBJECTIVE. It is unclear why some patients with cystic fibrosis (CF) succeed (“responders”) in recovering from malnutrition and growth faltering after treatment initiation whereas others fail to do so (“nonresponders”). We conducted a study to test the hypothesis that sustained high energy intake (↑EN) and normal plasma essential fatty acid status are critical determinants of treatment responsiveness within 2 years after diagnosis of CF. METHODS. A total of 71 CF children who had pancreatic insufficiency but not meconium ileus and were enrolled in the Wisconsin CF Neonatal Screening Project were studied. Responders were defined by having achieved adequate weight gain, as indicated by a recovery of weight z score (Wtz) comparable to Wtz at birth (WtzBR) within 2 years of diagnosis. ↑EN and sustained normal plasma linoleic acid level (↑pLA) were defined by achieving energy intake ≥120% of estimated requirement for ≥75% of the time and maintaining plasma LA ≥26% of total fatty acids for ≥75% of the time, respectively. RESULTS. Thirty-two (68%) screened patients and 13 (54%) patients whose CF was diagnosed conventionally recovered WtzBR within 2 years of diagnosis. Screened patients responded at significantly younger ages (mean/median: 6.3/4.3 months) than patients whose CF was diagnosed conventionally (mean/median: 15.8/11.8 months). Proportionately fewer screened patients (33%) achieved ↑EN compared with patients whose CF was diagnosed conventionally (73%). However, more screened patients responded to ↑EN and recovered WtzBR (91%) than patients whose CF was diagnosed conventionally (56%), although this difference was of borderline significance. Compared with having neither ↑EN nor ↑pLA, the likelihood of being a responder was greatest with combined ↑EN and ↑pLA, followed by ↑EN only. The positive associations between ↑EN and ↑pLA to treatment responsiveness remained significant after adjustment for neonatal screening status, baseline height and weight status, and indices of pulmonary disease severity. CONCLUSION. ↑EN and ↑pLA are critical in promoting adequate weight gain in children with newly diagnosed CF.

Ashley Revisited: A Response to the Critics

The case of Ashley X involved a young girl with profound and permanent developmental disability who underwent growth attenuation using high-dose estrogen, a hysterectomy, and surgical removal of her breast buds. Many individuals and groups have been critical of the decisions made by Ashleys parents, physicians, and the hospital ethics committee that supported the decision. While some of the opposition has been grounded in distorted facts and misunderstandings, others have raised important concerns. The purpose of this paper is to provide a brief review of the case and the issues it raised, then address 25 distinct substantive arguments that have been proposed as reasons that Ashleys treatment might be unethical. We conclude that while some important concerns have been raised, the weight of these concerns is not sufficient to consider the interventions used in Ashleys case to be contrary to her best interests, nor are they sufficient to preclude similar use of these interventions in the future for carefully selected patients who might also benefit from them.

Genetic data and electronic health records: a discussion of ethical, logistical and technological considerations

Objective The completion of sequencing the human genome in 2003 has spurred the production and collection of genetic data at ever increasing rates. Genetic data obtained for clinical purposes, as is true for all results of clinical tests, are expected to be included in patients’ medical records. With this explosion of information, questions of what, when, where and how to incorporate genetic data into electronic health records (EHRs) have reached a critical point. In order to answer these questions fully, this paper addresses the ethical, logistical and technological issues involved in incorporating these data into EHRs. Materials and methods This paper reviews journal articles, government documents and websites relevant to the ethics, genetics and informatics domains as they pertain to EHRs. Results and discussion The authors explore concerns and tasks facing health information technology (HIT) developers at the intersection of ethics, genetics, and technology as applied to EHR development. Conclusions By ensuring the efficient and effective incorporation of genetic data into EHRs, HIT developers will play a key role in facilitating the delivery of personalized medicine.