Effects of immediate telephone follow-up with providers on sweat chloride test timing after cystic fibrosis newborn screening identifies a single mutation.

OBJECTIVE: To assess whether reporting "possible cystic fibrosis (CF)" newborn screening (NBS) results via fax plus simultaneous telephone contact with primary care providers (PCPs) versus fax alone influenced 3 outcomes: undergoing a sweat chloride test, age at sweat chloride testing, and undergoing sweat testing before age 8 weeks. STUDY DESIGN: This was a retrospective cohort comparison of infants born in Wisconsin whose PCP received a telephone intervention (n = 301) versus recent historical controls whose PCP did not (n = 355). Intervention data were collected during a longitudinal research and quality improvement effort; deidentified comparison data were constructed from auxiliary NBS tracking information. Parametric and nonparametric statistical analyses were performed for group differences. RESULTS: Most infants (92%) with "possible CF" NBS results whose PCP lacked telephone intervention ultimately underwent sweat testing, underlining efficacy for fax-only reporting. Telephone intervention was significantly associated with improvements in the infants undergoing sweat testing at age ≤6 weeks and <8 weeks and a slight, statistically nonsignificant 3.5-day reduction in the infants' age at sweat testing. The effect of telephone intervention was greater for PCPs whose patients underwent sweat testing at community-affiliated medical centers versus those whose patients did so at academic medical centers (P = .008). CONCLUSION: Reporting "possible CF" NBS results via fax plus simultaneous telephone follow-up with PCPs increases the rate of sweat chloride testing before 8 weeks of age, when affected infants are more likely to receive full benefits of early diagnosis and treatment.

Factors that influence parents' experiences with results disclosure after newborn screening identifies genetic carrier status for cystic fibrosis or sickle cell hemoglobinopathy.

OBJECTIVE: Newborn screening (NBS) identifies genetic carriers for sickle cell hemoglobinopathy and cystic fibrosis. We aimed to identify factors during initial NBS carrier results disclosure by primary care providers (PCPs) that influenced parents' experiences and reactions. METHODS: Open-ended responses from telephone interviews with 270 parents of carriers were analyzed using mixed-methods. Conventional content analysis identified influential factors; chi-square tests analyzed relationships between factors and parent-reported reactions. RESULTS: Parents reported positive (35%) or negative (31%) reactions to results disclosure. Parents' experiences were influenced by specific factors: content messages (72%), PCP traits (47%), and aspects of the setting (30%). Including at least one of five specific content messages was associated (p<0.05) with positive parental reactions; omitting at least one of four specific content messages was associated (p<0.05) with negative parental reactions. Parents reported positive reactions when PCPs avoided jargon or were perceived as calm. Parents reported negative reactions to jargon usage and results disclosure by voicemail. CONCLUSION: Parents identified aspects of PCP communication which influenced their reactions and results disclosure experiences. PRACTICE IMPLICATIONS: Our findings suggest ways PCPs may improve communication of carrier results. PCPs should provide specific content messages and consider how their actions, characteristics, and setting can influence parental reactions.

A qualitative secondary evaluation of statewide follow-up interviews for abnormal newborn screening results for cystic fibrosis and sickle cell hemoglobinopathy.

PURPOSE: The purpose of this qualitative analysis was to assess parental acceptability of large-scale, telephone follow-up regarding their infants' newborn screening (NBS) results, indicating carrier status for sickle cell hemoglobinopathy (SCH) and cystic fibrosis (CF). METHODS: Analysis of 195 interview transcripts focused on parents' responses to two open-ended questions: "What was your reaction to being called by me?" and "What do you think of the state NBS program having follow-up people calling parents like you?" Responses were coded using conventional content analysis procedures, and nonparametric tests were performed to analyze quantitative data. RESULTS: Most parents reported favorable opinions about the follow-up. Favorable opinions were associated with several emotional reactions to receiving follow-up (P <0.001) and three reasons why parents found the interview beneficial (P < 0.05): it provided information, clarified NBS results, and answered questions. Seventeen parents of SCH carriers reportedly had not been told their infant's NBS results and received them for the first time during the follow-up interview. CONCLUSION: Parents of CF and SCH carrier infants had favorable opinions and identified specific benefits to receiving follow-up contact. This analysis demonstrates an information deficit among carrier parents and illustrates the importance of NBS follow-up and need for comprehensive communication and counseling.

Improving communication between doctors and parents after newborn screening.

BACKGROUND: Newborn screening (NBS) enables early treatment, and some consider it a natural vehicle for genetic screening. Bioethicists argue for caution since families of infants with carrier status can develop psychosocial complications. This paper describes the methods and feasibility of Wisconsin's statewide project for quality improvement of communication and psychosocial outcomes after NBS. METHODS: When NBS identifies carrier status for cystic fibrosis or sickle cell, we contact primary care providers (PCPs), answer questions, and invite them to rehearse informing the parents. Three months later, we telephone the parents, assess knowledge and psychosocial outcomes, provide counseling, and assist with self-referral to further resources. Afterward, evaluation surveys are provided to the parents, to be returned anonymously. RESULTS: Birthing facilities provided accurate PCP names for 73% of 817 infants meeting inclusion criteria; we identified PCPs for 21% more. We reached 47.3% of PCPs in time to invite a rehearsal; 60% of these accepted. We successfully called 50.2% of eligible parents; 61% recalled a PCP explanation, and 48.5% evaluated the explanation favorably. Evaluations by parents with limited health literacy were less favorable. CONCLUSION: It is feasible to follow parents for psychosocial outcomes after NBS. Preliminary data about communication is mixed, but further data will describe psychosocial outcomes and investigate outcomes' associations with communication.

Genetic testing and counseling for hereditary neurological diseases in Mali.

As genetic advances become incorporated into health care delivery, disparities between developing and developed countries may become greater. By addressing genetic health care needs and specific differences of developing countries, these disparities may be mitigated. We sought to describe the attitudes and knowledge of subjects with hereditary neurological diseases in Mali before and after receiving genetic testing and counseling for the first time. A questionnaire of attitudes and knowledge items was adapted and piloted for use in Mali. We found that the majority of subjects had positive attitudes toward genetic testing and counseling, both before and afterwards. Subjects responded to approximately half of the knowledge questions regarding hereditary transmission correctly before and after genetic testing and counseling. Neither overall attitudes nor knowledge scores changed significantly from baseline. Concerns about confidentiality were expressed by the majority of subjects. These findings indicate that, despite limited knowledge of patterns of inheritance, Malians understood the sensitive nature of this information and were favorable toward receiving genetic testing and counseling for diagnostic and prognostic purposes.

Efficacy and safety of dutasteride in patients with spinal and bulbar muscular atrophy: a randomised placebo-controlled trial.

BACKGROUND: Spinal and bulbar muscular atrophy (SBMA) is caused by polyglutamine expansion in the androgen receptor, which results in ligand-dependent toxicity. Animal models have a neuromuscular deficit that is mitigated by androgen-reducing treatment. We aimed to assess the efficacy and safety of the 5α-reductase inhibitor dutasteride in patients with SBMA, and to identify outcome measures for use in future studies of the disease. METHODS: We undertook a randomised, double-blind, placebo-controlled, single-site clinical trial in ambulatory, symptomatic men with genetically confirmed SBMA. Participants were assigned by random number table to receive dutasteride (0·5 mg per day) or placebo orally for 24 months. Patients and investigators were masked to treatment allocation. The primary outcome measure was quantitative muscle assessment (QMA). The final efficacy analysis included all patients who were compliant with study treatment at 24 months. This trial was registered with ClinicalTrials.gov, NCT00303446. FINDINGS: 50 men were randomly assigned to treatment groups (25 dutasteride, 25 placebo), and 44 were included in the efficacy analysis (21 dutasteride, 23 placebo). At 24 months, the placebo group showed a decrease of 4·5% (-0·30 kg/kg) from baseline in weight-scaled muscle strength as indicated by QMA, and the dutasteride group had an increase in strength of 1·3% (0·14 kg/kg); the difference between groups (5·8%, 95% CI -5·9 to 17·6; p=0·28) was not significant. Prespecified secondary outcome measures of creatine kinase, muscle strength and function, motor nerve conduction, activities of daily living, and erectile function did not show a significant difference between the study groups in change from baseline. Quality of life, as measured by the physical component summary of the Medical Outcomes Study 36-item Short Form version 2, favoured dutasteride (change in score from baseline: placebo, -3·6%, vs dutasteride, 2·1%; p=0·01), whereas the mental component summary favoured placebo (3·3%vs -3·2%; p=0·03). The dutasteride group had fewer patients reporting falls than did the placebo group (9 vs 16; p=0·048); there were no other significant differences in reported adverse events. INTERPRETATION: Our study did not show a significant effect of dutasteride on the progression of muscle weakness in SBMA, although there were secondary indications of both positive and negative effects compared with placebo. A longer trial duration or larger number of patients might be needed to show an effect on disease progression. Performance testing, QMA, and quality of life measures were identified as potentially useful endpoints for future therapeutic trials.

Clinical features of spinal and bulbar muscular atrophy.

Spinal and bulbar muscular atrophy is an X-linked motor neuron disease caused by a CAG repeat expansion in the androgen receptor gene. To characterize the natural history and define outcome measures for clinical trials, we assessed the clinical history, laboratory findings and muscle strength and function in 57 patients with genetically confirmed disease. We also administered self-assessment questionnaires for activities of daily living, quality of life and erectile function. We found an average delay of over 5 years from onset of weakness to diagnosis. Muscle strength and function correlated directly with serum testosterone levels and inversely with CAG repeat length, age and duration of weakness. Motor unit number estimation was decreased by about half compared to healthy controls. Sensory nerve action potentials were reduced in nearly all subjects. Quantitative muscle assessment and timed 2 min walk may be useful as meaningful indicators of disease status. The direct correlation of testosterone levels with muscle strength indicates that androgens may have a positive effect on muscle function in spinal and bulbar muscular atrophy patients, in addition to the toxic effects described in animal models.

Predictors of progression in patients with Friedreich ataxia.

Friedreich ataxia is an inherited, progressive, neurodegenerative disorder that is clinically heterogeneous. It is caused by a trinucleotide (GAA) repeat expansion resulting in frataxin loss and oxidative stress. We assessed clinical features including the development of cardiomyopathy and scoliosis and disease progression including loss of ambulation and interference with activities of daily living relative to the length of the GAA repeat, age of onset, and age of diagnosis in a retrospective cohort study of 61 genetically confirmed patients. The use of antioxidants such as vitamins, dietary supplements, and idebenone was also examined. Linear regression and Cox proportional hazard models assessed predictors to disease milestones. The shorter GAA allele accounted for part of the variability in the age of diagnosis (46%) and less in the age of onset (27%). Multivariate analysis demonstrated that age at diagnosis, which may incorporate other genetic and environmental factors, is more important than GAA length in predicting cardiomyopathy, scoliosis, and disease progression.

Content of communication by pediatric residents after newborn genetic screening.

BACKGROUND: Newborn screening saves lives, but psychosocial complications after genetic screening have led to doubts about expanding programs. Because complications have been blamed on ineffective communication of results, a population-scale system to ensure communication quality may improve outcomes. The objective of this study was to develop and evaluate a method to assess the content of communication after newborn genetic screening. METHODS: We abstracted content data and calculated quantitative scores for 3 communication quality indicators (key content, early placement of good news, and excessive background content) for 59 transcribed conversations between pediatric residents and simulated parents of an "infant" who was found via newborn screening to carry either cystic fibrosis or sickle cell hemoglobinopathy. RESULTS: Only 8.5% of transcripts contained the key content items that were thought to be necessary for parental understanding; 27.1% included reassuring news about carrier status within the first 10% of content. Scores for 3 quality indicators fell in the low performance range in 35.6%, 30.5%, and 27.1% of transcripts, respectively. The most common topic was background about the disease (22% of content statements) even though the infant did not have the disease. Surprisingly, 50% of sickle trait transcripts included counseling about a possible risk for sudden death. CONCLUSIONS: Assessment of the content domain of communication quality identified some high-quality communication interspersed with many missed opportunities. If integrated into newborn screening, our method may help to alleviate some of society's ethical concerns about benefit and risk after newborn and other genetic screening.

Initially misleading communication of carrier results after newborn genetic screening.

BACKGROUND: Newborn screening saves lives, but the way in which parents learn of a positive screening test is also important for adherence with treatment plans and avoidance of psychosocial complications. The first messages provided to parents may be particularly important for understanding, especially when the infant is found to be a heterozygous carrier for sickle cell hemoglobinopathy (SCH) or cystic fibrosis (CF). This study investigated the prevalence of "initially misleading" communication, defined as the inclusion of 1 of 55 "bad-news" content items (eg, the screening test is positive) before any of 39 "good-news" content items (eg, the infant is healthy, normal, a carrier, or otherwise without problems). METHODS: As part of a larger study of the content of counseling after newborn genetic screening, we used a quantitative, explicit-criteria method to abstract 59 transcribed conversations between pediatric residents and standardized parents of an "infant" who was found through newborn screening to carry either CF or SCH. RESULTS: Of 59 transcripts, 41 were found to be misleading (at least 1 bad-news content statement before the first good-news content statement). There were significantly more misleading likely-CF-carrier than SCH-carrier transcripts (89.7% vs 50%). Among the misleading transcripts, the mean number of misleading statements was 5.5. The mean distance between the first bad-news and first good-news statements was 28.1 statements (20.5% of the total duration of counseling). DISCUSSION: The high prevalence of misleading content and the time lag before clarification does not bode well for parental understanding of infant carrier status. Future projects should improve curricula for training programs and develop quality-assurance efforts for community clinicians both to improve parental understanding and help assuage society's fears about the safety of genetic screening technologies.

Identification of genes responsible for osteoblast differentiation from human mesodermal progenitor cells.

Single human bone marrow-derived mesodermal progenitor cells (MPCs) differentiate into osteoblasts, chondrocytes, adipocytes, myocytes, and endothelial cells. To identify genes involved in the commitment of MPCs to osteoblasts we examined the expressed gene profile of undifferentiated MPCs and MPCs induced to the osteoblast lineage for 1-7 days by cDNA microarray analysis. As expected, growth factor, hormone, and signaling pathway genes known to be involved in osteogenesis were activated during differentiation. In addition, 41 transcription factors (TFs) were differentially expressed over time, including TFs with known roles in osteoblast differentiation and TFs not known to be involved in osteoblast differentiation. As the latter group of TFs coclustered with osteogenesis-specific TFs, they may play a role in osteoblast differentiation. When we compared the gene expression profile of MPCs induced to differentiate to chondroblasts and osteoblasts, significant differences in the nature and/or timing of gene activation were seen. These studies indicate that in vitro differentiation cultures in which MPCs are induced to one of multiple cell fates should be very useful for defining signals important for lineage-specific differentiation.