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ObjectivesThe challenges of understanding how interventions influence follow-up medical care are magnified during genomic testing because few patients have received it to date and because the scope of information it provides is complex and often unexpected. We tested a novel strategy for quantifying downstream healthcare utilization after genomic testing to more comprehensively and efficiently identify related services. We also evaluated the effectiveness of different methods for collecting these data.MethodsWe developed a risk-based approach for a trial of newborn genomic sequencing in which we defined primary conditions based on existing diagnoses and family histories of disease and defined secondary conditions based on unexpected findings. We then created patient-specific lists of services associated with managing primary and secondary conditions. Services were quantified based on medical record reviews, surveys, and telephone check-ins with parents.ResultsBy focusing on services that genomic testing would most likely influence in the short-term, we reduced the number of services in our analyses by more than 90% compared with analyses of all observed services. We also identified the same services that were ordered in response to unexpected findings as were identified during expert review and by confirming whether recommendations were completed. Data also showed that quantifying healthcare utilization with surveys and telephone check-ins alone would have missed the majority of attributable services.ConclusionsOur risk-based strategy provides an improved approach for assessing the short-term impact of genomic testing and other interventions on healthcare utilization while conforming as much as possible to existing best-practice recommendations.

The rapid development of genomic sequencing technologies has decreased the cost of genetic analysis to the extent that it seems plausible that genome-scale sequencing could have widespread availability in pediatric care. Genomic sequencing provides a powerful diagnostic modality for patients who manifest symptoms of monogenic disease and an opportunity to detect health conditions before their development. However, many technical, clinical, ethical, and societal challenges should be addressed before such technology is widely deployed in pediatric practice. This article provides an overview of the Newborn Sequencing in Genomic Medicine and Public Health Consortium, which is investigating the application of genome-scale sequencing in newborns for both diagnosis and screening.

Objectives. Newborn screening for cystic fibrosis (CF) provides a model to investigate the implications of applying multiple-mutation DNA testing in screening for any disorder in a pediatric population-based setting, where detection of affected infants is desired and identification of unaffected carriers is not. Widely applied 2-tiered CF newborn screening strategies first test for elevated immunoreactive trypsinogen (IRT) with subsequent analysis for a single CFTR mutation ([DELTA]F508), systematically missing CF-affected infants with any of the >1000 less common or population-specific mutations. Comparison of CF newborn screening algorithms that incorporate single- and multiple-mutation testing may offer insights into strategies that maximize the public health value of screening for CF and other genetic disorders. The objective of this study was to evaluate technical feasibility and practical implications of 2-tiered CF newborn screening that uses testing for multiple mutations (multiple-CFTR-mutation testing). Methods. We implemented statewide CF newborn screening using a 2-tiered algorithm: all specimens were assayed for IRT; those with elevated IRT then had multiple-CFTR-mutation testing. Infants who screened positive by detection of 1 or 2 mutations or extremely elevated IRT (>99.8%; failsafe protocol) were then referred for definitive diagnosis by sweat testing. We compared the number of sweat-test referrals using single- with multiple-CFTR-mutation testing. Initial physician assessments and diagnostic outcomes of these screened-positive infants and any affected infants missed by the screen were analyzed. We evaluated compliance with our screening and follow-up protocols. All Massachusetts delivery units, the Newborn Screening Program, pediatric health care providers who evaluate and refer screened-positive infants, and the 5 Massachusetts CF Centers and their affiliated genetic services participated. A 4-year cohort of 323 506 infants who were born in Massachusetts between February 1, 1999, and February 1, 2003, and screened for CF at ~2 days of age was studied. Results. A total of 110 of 112 CF-affected infants screened (negative predictive value: 99.99%) were detected with IRT/multiple-CFTR-mutation screening; 2 false-negative screens did not show elevated IRT. A total of 107 (97%) of the 110 had 1 or 2 mutations detected by the multiple- CFTR-mutation screen, and 3 had positive screens on the basis of the failsafe protocol. In contrast, had we used single-mutation testing, only 96 (87%) of the 110 would have had 1 or 2 mutations detectable by single-mutation screen, 8 would have had positive screens on the basis of the failsafe protocol, and an additional 6 infants would have had false-negative screens. Among 110 CF-affected screened-positive infants, a likely "genetic diagnosis" was made by the multiple-CFTR-mutation screen in 82 (75%) versus 55 (50%) with [DELTA]F508 alone. Increased sensitivity from multiple-CFTR-mutation testing yielded 274 (26%) more referrals for sweat testing and carrier identifications than testing with [DELTA]F508 alone. Conclusions. Use of multiple-CFTR-mutation testing improved sensitivity and postscreening prediction of CF at the cost of increased referrals and carrier identification. Pediatrics 2004;113:1573-1581; newborn screening, genetic screening, population screening, cystic fibrosis screening, cystic fibrosis, multiple-mutation testing, DNA screening., ABBREVIATIONS. CF, cystic fibrosis; MA-CF, Massachusetts CF newborn screening program; IRT, immunoreactive trypsinogen; CFTR, cystic fibrosis transmembrane conductance regulator; CFF, Cystic Fibrosis Foundation; NENSP, New England Newborn Screening Program; [IRT], [...]

Objective. To examine whether treatment of premature infants with intratracheal recombinant human CuZn superoxide dismutase (r-h CuZnSOD) reduces bronchopulmonary dysplasia and improves pulmonary outcome at 1 year corrected age. Design. Three hundred two premature infants (600-1200 g birth weight) treated with exogenous surfactant at birth for respiratory distress syndrome were randomized to receive either intratracheal r-h CuZnSOD (5 mg/kg in 2 mL/kg saline) or placebo every 48 hours (as long as intubation was required) for up to 1 month of age. Short-term, as well as longer-term pulmonary outcome was assessed. Results. There were no differences between groups in the incidence of death or the development of bronchopulmonary dysplasia (oxygen requirement with an Edwards chest radiograph score of [greater than or equal to] 3) at 28 days of life or 36 weeks' postmenstrual age. r-h CuZnSOD was well-tolerated and not associated with significant increases in any adverse event. At a median of 1 year corrected age, health assessments and physical examinations were performed on 209 (80%) surviving infants, with complete data available on 189 infants. Thirty-seven percent of placebo-treated infants had repeated episodes of wheezing or other respiratory illness severe enough to require treatment with asthma medications such as bronchodilators and/or corticosteroids compared with 24% of r-h CuZnSOD-treated infants, a 36% reduction. In infants Conclusions. These data indicate that treatment at birth with r-h CuZnSOD may reduce early pulmonary injury, resulting in improved clinical status when measured at 1 year corrected age. r-h CuZnSOD appears to be a safe and effective therapy that improves pulmonary outcome in high-risk premature infants. Pediatrics 2003; 111:469-476; bronchopulmonary dysplasia, oxygen, antioxidant, superoxide dismutase, asthma, chronic lung disease., ABBREVIATIONS. BPD, bronchopulmonary dysplasia; CLD, chronic lung disease; PMA, postmenstrual age; SOD, superoxide dismutase; r-h CuZnSOD, recombinant human CuZnSOD; RDS, respiratory distress syndrome; IT, intratracheal(ly); DSMC, Data Safety Monitoring Committee; [...]

DNA analysis may be a useful diagnostic alternative to sweat chloride measurement in screening for cystic fibrosis (CF) in newborns and infants. Very small, premature, and sick newborns may not produce adequate sweat samples for chloride testing, and the test is unavailable at some facilities. A researcher brushed cheek cells from inside the mouth of 28 infants for use in DNA testing. CF mutations were detected in 21% of these infants. This rapid test provides a noninvasive alternative to sweat chloride testing for CF screening in infants suspected of having CF., Objectives. To assess the application of DNA-based cystic fibrosis transmembrane conductance regulator (CFTR) gene mutation analysis as a primary cystic fibrosis (CF) diagnostic test in preterm and term newborns and infants for whom the quantitative pilocarpine iontophoresis test (QPIT) cannot be used. Design. Retrospective survey. Setting. DNA Diagnostic Laboratory, Children's Hospital, Boston, Massachusetts. Buccal cell DNA samples were received from inpatients, outpatients, and three neonatal intensive care units. Outcome Measure. Detection of at least 1 of 12 CFTR mutations. Patients. Between November 1, 1992, and April 30, 1994, 28 newborns and infants under 12 months of age at risk for CF had CFTR DNA mutation analysis performed because a sweat chloride (SC) value could not be obtained. QPIT was either not performed (infant weight [is less than] 2 kg, QPIT not available at site of hospitalization, or infant not accessible to QPIT laboratory) or was inconclusive (sweat volume [is less than] 75 mg or indeterminate SC [[is greater than or equal to] 40, [is less than] 60 mEq/L]). The postnatal age at time of testing ranged from 1 day to 11 months, and gestational age at birth from 25 to 40 weeks. Results. Six (21%) of 28 infants with unobtainable or indeterminate QPIT had 1 or 2 CFTR mutations detected. Immediate CF diagnosis by direct detection of 2 CFTR mutations was made in 5 of these 6 patients. Definitive CF diagnosis in the infant with 1 CFTR mutation was delayed until an elevation in SC could be documented. The patients with no CFTR mutations detected had a low likelihood of CF. Conclusions. For infants in whom CF is suspected but QPIT cannot be obtained, buccal cell DNA-based CFTR mutation analysis can be used as a rapid, noninvasive primary diagnostic test. This simple mode of DNA collection may aid in the diagnosis of other inherited disorders in newborns. Pediatrics 1998;101:851-855; cystic fibrosis, CFTR, sweat chloride, pilocarpine iontophoresis, DNA mutation analysis, premature newborn., ABBREVIATIONS. SC, sweat chloride; QPIT, quantitative pilocarpine iontophoresis test; CF, cystic fibrosis; CFTR, cystic fibrosis transmembrane conductance regulator; CLD, chronic lung disease. For [is greater than] 35 years, a sweat [...]