Challenges in Implementing a Successful Newborn Cystic Fibrosis Screening Program

CHALLENGES IN IMPLEMENTING A SUCCESSFUL NEWBORN CYSTIC FIBROSIS SCREENING PROGRAM ANNE MARIE COMEAU, PHD, RICHARD PARAD, MD, MPH, ROBERT GERSTLE, MD, BRIAN P. O’SULLIVAN, MD, HENRY L. DORKIN, MD, MARK DOVEY, MD, KENAN HAVER, MD, TOM MARTIN, MD, AND ROGER B. EATON, PHD

Objective

To identify necessary components of a successful cystic fibrosis (CF) newborn screening (NBS) program.

Study design The approach to CF NBS used by the Massachusetts NBS program was examined. Results Several key components were identified that should be addressed when a state has made the decision to screen, and well in advance of actual implementation. These components include (1) inclusion of CF center directors in the development process; (2) logistics of choosing a screening algorithm relative to practices in place and community wishes; (3) projections of medical service needs from specific algorithms; (4) identification of critical reporting components; (5) identification of critical follow-up components; and (6) recognition of educational needs.

Conclusions Careful examination of a wide variety of issues is needed to ensure optimal implementation of NBS for CF. (J Pediatr 2005;147:S89-S93)

randomized clinical trial by investigators in Wisconsin has documented beneficial outcomes of newborn screening (NBS) for cystic fibrosis (CF).1 As a result of both this trial and a recommendation from a national workshop that some states implement pilot CF NBS programs even while evaluations of clinical utility continue,2 more newborns are being screened for CF.3 To ensure success of these efforts, several key components should be addressed well in advance of actual implementation. What is a successful CF NBS program, and who gets to define success? A successful screening program refers to the ability of the program to appropriately identify and refer for care those with CF, while meeting the needs of those who do not have CF, in particular those infants identified by the screening program because they are carriers. Some measures of success might include (1) how closely the screen approaches 100% sensitivity, (2) the ability of the screen to minimize intrusion on the lives of parents of unaffected infants, (3) the acceptability by the families of the integration of CF into existing screening programs, or (4) the acceptability and impact on primary care physicians (PCPs) who must deal with screening results and patient anxieties. Perhaps the first step in defining success is to know what NBS means to your community and to know what your community can bear. Typically a ‘‘community’’ would be a state. Ideally a CF NBS effort would be coordinated by the state NBS program, which can provide the centralized system necessary to integrate a new screen with existing screens. This article suggests some approaches that we have found to be useful in Massachusetts and offers some lessons learned that may assist in the successful implementation of a CF NBS program in other states. We began by reviewing what was known from existing programs and tailoring protocols to meet our needs; to that end, we are indebted to the Wisconsin workgroup for sharing protocols and data. The specifics of the Massachusetts model may not be applicable to all states because we (1) are a small state; (2) have 5 CF centers, with all residents being within a 2-hour drive of a CF center; (3) have a solid network of genetic counselors; and (4) could include CF

A

CF IRT

Cystic fibrosis Immunoreactive trypsinogen

NBS PCP

Newborn screening Primary care provider

From the New England Newborn Screening Program of the University of Massachusetts Medical School, The Children’s Hospital, Massachusetts General Hospital, and the New England Medical Center, Boston, Baystate Medical Center Children’s Hospital, Springfield, and the University of Massachusetts Memorial Health Care, Worcester, Mass. Supported in part by Program Funds of the New England Newborn Screening Program of University of Massachusetts Medical School and in part by the Health Resource and Services Administration grant no. 5 H46 MC 00198-02. Reprint requests: Anne Marie Comeau, PhD, New England Newborn Screening Program of University of Massachusetts Medical School, 305 South St, Jamaica Plain, MA 02130. E-mail: [email protected]. 0022-3476/$ - see front matter Copyright ª 2005 Elsevier Inc. All rights reserved. 10.1016/j.jpeds.2005.08.006

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NBS into an existing NBS program that used an integrated model of service delivery, providing a spectrum of services from pre-testing education through testing and post-testing tracking of outcomes. Nevertheless, we hope our experiences, recommendations, and data,4 along with other public data,5-9 will be used to refine testing algorithms and aid in developing other protocols in those states seeking to develop CF NBS.

BRING YOUR COMMUNITY’S CF CENTER DIRECTORS ON BOARD It is important to identify the CF center directors providing the tertiary care setting for diagnosis and treatment in the community, and to bring them together for discussion or as an advisory group before implementation. The first task is to determine whether your group of CF center directors is in support of CF NBS, and if not, to work to understand their concerns. The second task is to educate the CF center directors in the practical implications of CF NBS so that there will be few or no surprises. It is important, for example, to project the number of infants who will screen positive to help your CF center directors determine whether they are willing and able to bear the load of increased numbers of sweat tests generated by screening (both directly from the screen and indirectly from increased CF awareness as a result of the screen). In addition, because bringing healthy infants with CF to CF centers has potential risks for spread of infection, center directors should be provided with data, recommendations, and guidance for the separation of neonates from older clinic patients. This information will help them determine whether separate ‘‘clinics’’ or sweat sites should be established to separate newborns with CF from those who may be contagious. Projecting the number of infants expected to have a positive screening result by genetic probing will help center directors plan for the increased need for genetic counseling, particularly of the CF carrier families that are identified. Finally, where (1) sweat testing resources are limited or restricted; (2) patient inconvenience is too great, particularly because of long travel time to centers or testing laboratories; or 3) genetic counseling resources are insufficient, you will need a ‘‘Plan B,’’ which could include mobile sweat laboratories, use of more genetic testing, or teleconference counseling.

IDENTIFY CRITICAL TECHNICAL COMPONENTS OF ROUTINE NBS OFFERED BY YOUR STATE One of the first questions to ask is whether your community is defined as a state and served by a state NBS program. If not, a CF NBS would likely be offered as a supplemental program, and mechanisms for collecting specimens, reporting screening results, tracking follow-up of infants with positive CF screening results, and reimbursements must be considered. If you are working within an existing NBS program, these mechanisms should be in place. The Table summarizes Massachusetts’ consideration of the particular Key Technical Components that we believe have S90 Comeau et al

been essential to success. The specific Massachusetts CF Workgroup Action that was determined after considering the components might be less important than the act of addressing the issues by the whole Workgroup as outlined in this Table. The choice of screening algorithms may be driven by whether the NBS program in your community routinely and universally collects 2 specimens or only a single specimen. If 2 specimens are universally collected, the choice of screening algorithms is not bound by the specimen collection protocol. Some communities may choose a screening algorithm in which the only analyte is immunoreactive trypsinogen (IRT), assayed on 2 independent specimens separated in time (IRT/IRT algorithm). This avoids the identification of large numbers of CF carriers with associated needs for counseling. In these algorithms, age-specific cutoffs for IRT (initially at approximately 2 days of age and then at 14 days of age) have to be established. If your program collects only a single specimen universally, an algorithm with IRT as the primary screen followed by a DNA assay on the subpopulation of specimens with elevated IRT concentrations (IRT/DNA algorithm) is typically the algorithm of choice. For screening algorithms that include a DNA assay, the CF Foundation should be able to provide a list and frequency of CF genotypes observed in the centers serving your community, along with an indication of the percent of patients who have been genotyped in those centers so you can determine how well the sample represents the population. This information will help identify a reasonable panel of mutations to include in your screen. Other considerations when using DNA assays include whether and how to use assays for mutations associated with mild or variable phenotypes, neutral polymorphisms, or sequence variants, some of which have unknown or variable associations with disease. Algorithmic limitations to consider include those caused by available technology (eg, addressing specific mutation panels and changing panels); those caused by limitations in knowledge (eg, genotype/phenotype relationships of specific DNA sequences available for testing); and those caused by the intrinsic racial/ethnic makeup of your community. Once a particular screening algorithm has been chosen, abnormal ranges for the component arms of the CF screening algorithm must be determined. When using an IRT/DNA algorithm, another consideration might be whether a ‘‘failsafe’’ protocol should be included to identify CF-affected infants whose mutations are infrequent in your population.4

IDENTIFY CRITICAL REPORTING COMPONENTS FOR NBS IN YOUR STATE The mechanism by which NBS results are communicated varies widely between communities. In Massachusetts, the responsibility for finding and notifying the PCP of the infant with a positive CF screening result falls on the screening program. In other communities, that responsibility may belong to a maternal and child health bureau, the diagnostic center, or the birth hospital. Whichever system is in place, success in minimizing anxiety for parents and maximizing The Journal of Pediatrics  September 2005

Table. Key components to consider for a successful implementation of CF NBS and examples of Massachusetts CF Workgroup comments and actions

Technical Technical component I component II No. of speciSensitivity mens collected required Massachusetts logistics and NBS program requirements

Single specimen

Projection

IRT/DNA screen

Goal: minimum 95% sensitivity

Massachusetts 5 CF Center Directors Comments

Concern about provider complacency with screen

Massachusetts IRT/DNA screen CF Workgroup* Action

Educate providers

Technical component III Genetic composition of population DF508 in only 65% CF chromosomes

Technical component IV Predicted no. of infants with positive screening results

Reporting

Follow-up

Track All reports through sweat through PCP. All 1 CF screens test result. Post-test to CF Center. genetic counseling to families of infants with 1 CF screen Track counseling. Most 1 screens Support needed 1 positive 85% or less result in offer for genetic CF screening sensitivity if only of genetic discussion result per work include DF508 counseling. Some day requiring 1 screens yield sweat test infants with inconclusive diagnostic results. Not enough Mixed, some Agree to Agree to staff and takes willing to average increase include more away from do, others 1/week mutations; do primary role want genetics NOT want to of CF center. include neutral Follow infants or mild DNA with inconclusive sequence diagnostic variants. results. Need for CFF guidance. Staged Set up agreements 1 CF screen Multiple follow-up: with genetics reported to mutations d relative risk departments at PCP. PCP in screen. CF center informs NBS Polymorphisms explained to hospitals which CF Center blocked in provider d diagnostic initial screen test post-test counseling 80,000 annual births; top 5% IRT referred to DNA screen

*The Massachusetts CF Workgroup, organized by the New England Newborn Screening Program, is led by Drs. Comeau and Parad of NENSP and includes CF Center Directors and their representatives from the 5 CF Centers in MA. Another group, the CF Genetics Workgroup, includes physician geneticists and genetic counselors who work with the CF Workgroup on genetics protocols.

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compliance with screening recommendations depends on a robust system of communication, education, and follow-up. In Massachusetts, all reports of CF-positive screening results are made by screening program personnel by telephone. We insist on speaking to the health care provider who will be speaking to the parents (and who will be delivering first notice of a positive screening result) to minimize miscommunication. At that time we provide ‘‘just-in-time education’’ about the screen to the PCP and data about the pre-diagnostic test probability of the infant having CF on the basis of screening category. The conversation includes ‘‘talking points’’ for the health care provider’s discussion with the parents, a report of our experience with the relative risk attributable to the particular screening result,4 and a plan of action. After all phone reports we fax information to the PCP reviewing the screening algorithm, screening results, screening recommendations, and contact information for the diagnostic centers. As soon as the particular CF center to which the infant will be referred is identified, we send an independent detailed report of the screening results to that center. One reporting issue that needs to be addressed is the timing of the report of a positive CF NBS result. Typically, definitive CF testing by sweat chloride analysis would be performed at 2 weeks of age or later, which means that there is a lag time between when screening results could be available and when they should be reported. This presents a need to choose between (1) generating and reporting screening results early, with other routinely reported NBS tests, (which could yield about two weeks of parental anxiety or likely higher rates of loss to follow-up), or (2) generating and reporting results later than other screening tests (requiring a screening program to provide 2 stages of written reports for all infants screened).

IDENTIFY CRITICAL FOLLOW-UP COMPONENTS FOR NBS IN YOUR STATE An integrated screening program offers the advantage of a centralized system from which all NBS positive results are reported and tracked to (at least) final diagnostic outcomes. The public health authority allows the CF centers to report sweat and genetic testing results to this centralized system for cohort analysis. The centralized system helps prevent babies from ‘‘falling through the cracks.’’ Centralization of outcome data from all CF centers allows the CF Workgroup to evaluate and modify screening algorithms, including cutoff values used for defining positive, negative, and borderline sweat test results, and to optimize protocols for follow-up on borderline values or sweat test results that may be inconsistent with observed genotype. CF centers should also report all affected infants with CF whose CF NBS result was (‘‘falsely’’) negative. Having a case definition in place before implementation will guide the reporting and data analysis for determining negative and positive predictive values for the screen. Another potential follow-up component to be evaluated might be the determination of the clinical utility of the screening information relative to the timing of the report of the positive CF screening S92 Comeau et al

result. For instance, 2 algorithms may identify a similar number of affected infants, but 1 algorithm may be better at predicting relative risk of a particular positive CF screening result or might be more useful for identifying affected infants earlier. Evaluation of clinical utility of the NBS has already proved invaluable, resulting in a critical clinical recommendation to isolate newborns with positive CF NBS results from other CF center clinic patients to prevent serious nosocomial infections.10,11

EDUCATE YOUR PCP COMMUNITY Our experience has been that the primary care community will be receptive to CF NBS if sufficient support is in place to relieve them of responsibility for all aspects of followup, particularly for those infants and their families who will screen positive and have a negative diagnosis (normal sweat test result). On first contact with PCPs with initial screening results, it is helpful to communicate a specific patient management plan, to assure them that CF centers are prepared to see their patients who need sweat testing and to provide guidelines for booking sweat tests. When possible, it is especially helpful to indicate that genetic counseling is not their responsibility, but that of a genetic counselor associated with the CF center. Some health care providers may call you back to report that 1 or more parents had prenatal/preconceptual screening and will question whether your follow-up recommendation stands. Our experience to date has been that most of the information from such calls is inadequate to change our follow-up recommendations, although some of the information can be used to lower parental anxiety levels. The use of DNA testing in NBS (which is coupled to a functional assay [IRT]) is not equivalent to prenatal carrier screening (which may fail to detect unusual CF mutations). You should be prepared to provide the primary health care provider with current recommendations by the American Academy of Pediatrics12 regarding the genetic testing of children for whom there is no clinical concern, because some will ask about sweat testing or DNA testing of older siblings. Responding to PCPs who call regarding a clinical concern for CF in an infant whose screening result was negative provides an important educational opportunity. We have found it useful to state that the sweat test is still the gold standard in the diagnosis of CF, even when sophisticated screening methods, including DNA assays, are in place. We have found that many of these phone-in queries present a ‘‘teachable moment’’ to introduce some basic issues of genetic testing, such as how much reliance can be placed on carrier testing results if assay parameters are unknown. Most importantly, these interactions appear to prevent provider complacency and may even contribute to earlier diagnosis for affected infants whose CF NBS result is negative.

CONCLUSIONS CF NBS should not be a stand-alone screen, either in its practical implementation or in how the outcomes of the infants identified by this and other NBS programs are The Journal of Pediatrics  September 2005

evaluated. Ideally, it should be integrated within an existing and experienced NBS program. Before implementation, there must be recognition and informed acceptance of responsibility for the follow-up of unaffected infants by care providers in addition to the follow-up and care of affected infants. A special thanks to Jaime Hale who helped with finalizing the manuscript.

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Challenges In Implementing A Successful Newborn Cystic Fibrosis Screening Program

5. Hammond KB, Abman SH, Sokol RJ, Accurso FJ. Efficacy of statewide neonatal screening for cystic fibrosis by assay of trypsinogen concentrations. N Engl J Med 1991;325:769-74. 6. Gregg RG, Wilfond BS, Farrell PM, Laxova A, Hassemer D, Mischler EH. Application of DNA analysis in a population-screening program for neonatal diagnosis of cystic fibrosis (CF): comparison of screening protocols. Am J Hum Genet 1993;52:616-26. 7. Gregg RG, Simantel A, Farrell PM, Koscik R, Kosorok MR, Laxova A, et al. Newborn screening for cystic fibrosis in Wisconsin: comparison of biochemical and molecular methods. Pediatrics 1997;99:819-24. 8. Scotet V, de Braekeleer M, Roussey M, Rault G, Parent P, Dagorne M, et al. Neonatal screening for cystic fibrosis in Brittany, France: assessment of 10 years’ experience and impact on prenatal diagnosis. Lancet 2000;356: 789-94. 9. Farrell P, Shen G, Splaingard M, Colby CE, Laxova A, Kosorok MR, et al. Acquisition of Pseudomonas aeruginosa in children with CF. Pediatrics 1997;100:E2. 10. Saiman L, Siegel J. The Cystic Fibrosis Foundation Consensus Conference on Infection Control Participants. Infection control recommendations for patients with cystic fibrosis: microbiology, important pathogens and infection control practices to prevent patient-to-patient transmission. Infect Control Hosp Epidemiol 2003;24(5 Suppl):S6-52. 11. Saiman L, Siegel J. Infection Control in Cystic Fibrosis. Clin Microbiol Rev 2004;17:57-71. 12. American Academy of Pediatrics, Committee on Bioethics. Ethical issues with genetic testing in pediatrics. Pediatrics 2001;107:1451-5.

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