Analysis of the costs of diagnosing cystic fibrosis with a newborn screening program

ANALYSIS OF THE COSTS OF DIAGNOSING CYSTIC FIBROSIS WITH A NEWBORN SCREENING PROGRAM DON S. LEE, MARJORIE A. ROSENBERG, PHD, FSA, ANDREW PETERSON, LINDA MAKHOLM, GARY HOFFMAN, RONALD H. LAESSIG, PHD, AND PHILIP M. FARRELL, MD, PHD

Objectives To compare the cost of diagnosing cystic fibrosis (CF) through a newborn screening program with the traditional method and to estimate the cost of CF diagnosis if a national newborn screening program is implemented. Study design Surveys were conducted to determine the annual number of sweat tests in 1991 and in 2000 after implementation of statewide screening. A national survey of sweat test costs was used to estimate the annual expense for diagnosing CF in the United States through newborn screening. Results Since the introduction of newborn screening for CF, the numbers of sweat tests ordered annually have decreased from 1670 to 804 (including 134 follow-up tests from screening). The current estimated annual cost of Wisconsin CF newborn screening and diagnosis is $4.58 per newborn infant. The estimated annual cost per newly diagnosed CF infant using the traditional method is $4.97 per newborn infant. If no additional sweat tests were ordered outside of the newborn screening program, the estimated annual cost of a Wisconsin CF newborn screening and diagnosis is $2.66 per newborn and $2.47 per newborn for a national CF newborn screening program. Conclusions A CF newborn screening program provides a potentially cost-saving alternative to the traditional method of diagnosis of CF. (J Pediatr 2003;142:617-23)

n the United States, as many as 1000 infants with cystic fibrosis (CF) are born each year, who are later diagnosed at a mean age ranging from 3 to 4 years.1,2 CF affects approximately 25,000 children and adults in the United States.2 Several studies have analyzed the costs of CF medical care3-6; however, no study has assessed diagnostic expenses comprehensively nor estimated the national costs of diagnosing CF with a newborn screening program. The traditional gold standard for the diagnosis of CF is through the sweat test.7,8 This strategy, summarized in Figure 1, relies on using sweat chloride analysis, in which a patient shows characteristic clinical features (eg, meconium ileus, diarrhea, growth failure, or chronic cough) or when there is a positive family history (which occurs in about 15% of cases).2 However, a large number of negative sweat tests are performed for every patient with CF diagnosed by the traditional method. In fact, without CF neonatal screening, up to 100 sweat tests may be performed to diagnose one CF patient.8-11 Earlier diagnosis of CF became feasible in 1979, when Crossley et al12 demonstrated in a retrospective study that newborn infants with CF have elevated blood immunoreactive trypsinogen (IRT) levels caused by obstructed pancreatic ductules. Others13,14 developed IRT testing procedures to screen for CF among newborn infants by using levels of trypsinogen generally above the 99th percentile. Diagnostic confirmation of CF has been accomplished in all these programs through the use of the sweat chloride test. Although the IRT test, as in the case of all neonatal screening tests,15 results in a large number of false-positive results, screening procedures improved after the principal CF gene mutation (∆F508) was discovered, and a 2-tier strategy was developed.16,17 Since 1994, the state of Wisconsin,18 as

I

CF IRT SLH Wisconsin

Cystic fibrosis Immunoreactive trypsinogen State Laboratory of Hygiene

See related articles, p 624 and p 631.

From the University of Wisconsin and the State Laboratory of Hygiene, Madison,Wisconsin. Supported by grants from the National Institutes of Health (DK 34108 and M01 RR03186-from the National Center for Research Resources to the University of Wisconsin Medical School) and the Cystic Fibrosis Foundation (A001-5-01). Submitted for publication April 30, 2002; revisions received September 5, 2002, and January 17, 2003; accepted February 27, 2003. Reprint requests: Philip M. Farrell, MD, PhD, Professor of Pediatrics and Dean, University of Wisconsin Medical School, Room 1217 MSC, 1300 University Ave, Madison,WI 53706-1532. E-mail: [email protected]. Copyright © 2003, Mosby, Inc. All rights reserved. 0022-3476/2003/$30.00 + 0

10.1067/mpd.2003.209

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well as many other regions19-21 perform CF neonatal screening with the use of both IRT and DNA analysis tests. Unless two CF mutations are demonstrated, however, the sweat chloride test is still used to confirm the diagnosis of CF. Because several regions of North American and Western Europe have been considering introduction of CF neonatal screening, we have been asked to provide data on the costs of various components. Such information would be useful for policy analysts and leaders of health care organizations. Therefore, this study was designed to determine the costs of diagnosing CF in Wisconsin through a newborn screening program compared with the traditional method that uses a sweat test to investigate either clinical symptoms and signs or a positive family history. We also estimated the cost of CF diagnosis if a universal newborn screening program were implemented in the United States.

METHODS To compare the direct annual costs of CF diagnosis by using a newborn screening program to the estimated annual costs of CF diagnosis using the traditional method, we obtained financial data from a variety of sources. We then used these data, together with national survey data, to estimate the annual costs of a nationwide CF newborn screening program applied to all babies born in the United States. We used data from the Wisconsin State Laboratory of Hygiene (SLH), which conducts a centralized neonatal screening program for the State of Wisconsin, and data from the Madison CF Center to estimate the annual costs of diagnosing CF using a newborn screening program during the year 2000. The annual cost of a CF newborn screening program is a function of the cost per test for the IRT/DNA screening, the cost per test for the sweat chloride testing, and the annual numbers of newborn infants who undergo the IRT/DNA and sweat chloride tests. To estimate the annual costs of diagnosing CF in Wisconsin’s screening program, we collected cost data for the 2-tier IRT/DNA test and the sweat chloride test over a 1-year period from the SLH centralized program and from the Madison CF Center, respectively. The State of Wisconsin requires a blood sample from every newborn at least 24 hours after birth for analyses that detect genetic diseases included in the testing panel. At the SLH, testing is conducted for 21 disorders in addition to CF. The pathways to CF diagnosis with a newborn screening program are shown in Figure 1. For CF screening, a fluoroimmunoassay (DELFIA, Perkin Elmer Wallac, Norton, Ohio) is performed on the blood to measure IRT levels.22 Newborn infants with IRT levels below the daily 96th percentile are reported as normal, whereas newborn infants with IRT levels above the daily 96th percentile are analyzed for the ∆F508 mutation with the use of PCR and electrophoretic techniques.18 From these samples, newborn infants with IRT levels <170 ng/mL and with no ∆F508 mutation are reported as not having CF. Newborn infants with IRT levels >170 ng/mL and no ∆F508 mutation are reported as possibly having CF, because values above this IRT threshold are associated with a higher probability of CF irrespective of the DNA 618 Lee et al

results22,23; physicians are advised to refer the newborn for a sweat chloride test if any signs or symptoms of CF develop or if there is a positive family history.22 Newborn infants with a single ∆F508 mutation are reported as possibly having CF and are referred for a sweat chloride test. Newborn infants who have two ∆F508 mutations, about half of the patients with CF,18 are reported as having a genetic diagnosis of CF,11 and their parents, through communications with their primary care physician, are encouraged to bring their baby as soon as possible to a CF center. A sweat test is not performed routinely if two ∆F508 alleles are identified through screening. The follow-up sweat chloride test for infants with a high IRT level is generally performed at a CF center in Madison or Milwaukee or at one of three satellite centers. The Wisconsin Cystic Fibrosis Center in Madison performs an average of 150 sweat chloride tests per year. We compared the charges for a sweat chloride test at the Madison CF Center with the actual costs for performing a sweat chloride test. Our sweat test technician kept a detailed record of her time for performing the various procedures and also determined the expenses for supplies and equipment; from this information and with a adjustment for indirect costs, we calculated the cost per sweat test. For the analysis of statewide costs, we have used the Madison CF Center sweat test expenses as representative of the sweat test costs in Wisconsin. The numbers of annual sweat tests performed in Wisconsin were determined by surveying hospital and clinic laboratories with a questionnaire. Two surveys were performed with similar methods during 1991 (before routine CF neonatal screening) and for the year 2000. Specifically, we surveyed Wisconsin hospitals and large clinics with clinical laboratories by mailing a questionnaire to them seeking information on the number of sweat tests performed during the previous year and the methods used; to ensure a complete evaluation, hospitals/clinics that did not return the questionnaire were contacted by telephone. The hospitals responding positively reported data from a variety of readily available sources such as laboratory diaries, computer files, or billing records. The second objective in this study was to estimate the annual cost of nationwide CF diagnosis if a CF newborn screening program were to be implemented in the United States. To obtain the data needed, we conducted a national survey to estimate costs of sweat chloride tests. An e-mail survey was sent to 114 CF centers across the country to ask for data on their charge for the sweat test, including technical fees and professional fees for interpretation of sweat test results. Of the 68 CF centers who responded, 59 provided charge data. The average charge for the sweat chloride tests nationwide and our expenses for IRT/DNA analysis were used to determine the costs of diagnosing CF in a national CF newborn screening program.

RESULTS State of Wisconsin The costs to operate Wisconsin’s CF neonatal screening program in 2000 are summarized in Table I, A. The assumption in the analysis provided in Table I, A, is that all sweat tests The Journal of Pediatrics • June 2003

Fig 1. Pathways to CF diagnosis in Wisconsin by neonatal screening during 2000 or by traditional methods shown in the box.

are a result of the newborn screening program, and no additional tests are ordered. From January 2000 through December 2000, a total of 70,797 Wisconsin newborn IRT tests were performed at the SLH. DNA analyses were performed on blood from the 2926 newborn infants with the 4% highest daily IRT levels (top 4%). Of these, 2758 (or 94% of the 2926) had no ∆F508 mutation and had an IRT level <170 ng/mL. Twenty-four newborn infants (<1% of the 2926) had no ∆F508 mutation and an IRT >170 ng/mL. One hundred thirty-four newborn infants (4.6% of the 2926) had one ∆F508 mutation and 10 (0.3% of the 2926) had 2 ∆F508 mutations. In the year 2000, 20 newly diagnosed patients with CF were identified, 18 from newborn screening. The two patients missed by screening moved to Wisconsin from other states. The cost of IRT testing for the entire cohort of newborn infants at the SLH was calculated by multiplying the total number of tests completed by the cost of an IRT test (Table I, A). The cost of one IRT test (including overhead) is $1.50, and the total IRT cost for the year 2000 was $106,196. The cost of DNA analysis at the SLH is calculated by multiplying the number of IRT tests in the highest 4% (2926) by the cost of a DNA test estimated as $18 (again, including overhead, per G. Hoffman of the SLH). The total cost of DNA analysis for the year 2000 was $52,668. For those newborn infants referred for a sweat chloride test, the Madison CF Center charges $207 per test, consisting of $150 for laboratory fees and $57 for professional fees. The professional fees, however, are charged in only about 20% of the tests, that is, those in which direct physician involvement is needed to resolve issues related to the patient’s condition, amount of sweat obtained, or questions related to the chloride levels obtained (eg, borderline values).7 The average charge for a sweat chloride test is $161.40. Independently, by evaluating the labor, supply, equipment, space and indirect costs, we determined that the expenses encountered by the Madison CF Analysis of The Costs of Diagnosing Cystic Fibrosis With a Newborn Screening Program

Center to perform one sweat chloride test amounted to $167. The expected value of the total charges for the sweat chloride test for the Wisconsin newborn infants was $21,628. Using this expected value of the charges for the sweat chloride test, the total cost of CF newborn screening was estimated to be $180,491, or $9025 per newly diagnosed patient with CF. This amounts to $2.66 per screened baby (Table I, A). The annual number of sweat chloride tests in Wisconsin was evaluated in a survey that determined the number of sweat tests performed during 1991 and 2000 by 136 health care institutions. Table II summarizes the data. Before routine CF neonatal screening began, we determined that 1670 sweat tests were performed during 1991 to diagnose 16 new patients with CF, which is similar to the average number of patients diagnosed per year over a 9-year period with our newborn screening program in place.24 These sweat tests were performed by 44 institutions, but 20 performed 12 or less tests per year, that is, no more than 1 per month on the average. Assuming a sweat chloride test charge of $161.40 and 20 newly diagnosed patients with CF, we estimated the number of sweat tests to diagnose 20 children with CF in Wisconsin as 2087.50 and the total cost for the traditional method at $336,923, with an estimated annual cost per newly diagnosed CF child as $16,846, or $4.97 per newborn infant. The same survey for the year 2000, after 6 years of routine CF neonatal screening, revealed that 804 sweat tests were performed, including 134 done as follow-up evaluations in the screening program. These tests were done by 15 institutions, with 6 doing 12 or fewer such procedures per year. The decrease in the number of sweat chloride tests is a result of changes in physician practice patterns resulting from the introduction of the CF neonatal screening program. The reduction of 866 (1670-804) sweat chloride tests per year reduces costs by at least $139,772 ($161.40 · 866) per year. Section B of Table I is a revised view of section A, recognizing that cur619

Table I. Estimated Wisconsin costs of CF neonatal Screening program

Table II.Wisconsin sweat test surveys

A. Assuming all costs arise from screening program

IRT # Tests Top 4% Sweat test Total cost No./cost per diagnosed CF No./cost per birth*

Count

Cost ($) per test

Total cost ($)

70,797 2926 134

1.50 18.00 161.40

20

106,195.50 52,668.00 21,627.60 180,491.10 9024.56

67,769

2.66

B. Assuming costs arise from screening program and additional sweat tests for diagnosis

IRT # Tests Top 4% Sweat test Screening Additional tests Total cost No./cost per diagnosed CF No./Cost per birth*

Count

Cost ($) per test

Total cost ($)

70,797 2926

1.50 18.00

106,195.50 52,668.00

134 804

161.40 161.40

20

21,627.60 129,765.60 310,256.70 15,512.84

67,769

4.58

*Number of newborn IRT tests is 4% higher than the number of Wisconsin “births by occurrence” during 2000 (67,769 unique live births) because some dried blood specimen assays must be repeated due to factors such as collection too early (<24 hours after birth), inadequate specimen volume, or delayed mailing.

rently, these 804 sweat tests are completed, adding $129,766 to the total cost of screening and diagnosis. The current estimated annual costs in Wisconsin in 2000 are $310,257, resulting in $15,513 per CF diagnosis or $4.58 per newborn infant.

US National Estimates To compute an estimate of the annual costs for diagnosing CF through a national screening program, we used the annual numbers of newborn infants, with and without CF, together with national estimates of sweat test costs obtained through our survey (Table III). Data published by the US Vital Statistics show 4,064,948 births in the United States during the year 2000, of whom 3,202,932 were “white births.”25 The incidence of CF among white newborn infants has been calculated as 1 in 3419, whereas the incidence of CF among nonwhite births is estimated as 1 in 12,163.1 This yields an estimate of 1008 for the annual number of newborn infants with CF, which is close to the annual number of new 620 Lee et al

Year of survey No. of institutions surveyed No. performing sweat tests No. performing <12/y >50/y >100/y Total No. of annual sweat tests

Survey I

Survey II

1991 136 44

2000 136 15

24 6 4 1670

9 3 2 804

Table III. Estimated costs of CF neonatal screening in the United States

IRT All births Top 4% Sweat test Total cost No./cost per diagnosed CF Cost per birth

Count

Cost ($) per test

Total cost ($)

4,064,948 168,002 7694

1.50 18.00 117.93

6,097,422.00 3,024,036.06 907,338.29 10,028,796.35 9952.40

1007.68

2.47

CF diagnoses registered with the Cystic Fibrosis Foundation.1,2 The Wisconsin costs of one IRT test and one DNA analysis, $1.50 and $18.00 respectively, were used to calculate costs at a national level (in Table III). In addition, as in Wisconsin, we assume that the same percentage of IRT tests are referred for DNA testing. Therefore, the estimated annual cost nationally of the IRT/DNA test is $9,121,458. Fifty-nine CF centers provided data as a result of our questionnaire on laboratory costs and professional fees for sweat chloride testing. Few centers separately identified the professional fees, that is, most provided one total charge. The maximum reported charge for a sweat test was $745 (much higher than the next highest at $294), and the minimum was $35. The distribution of sweat chloride test charges is shown in Figure 2. Trimming the data by removing the top two and bottom two values is one way of dealing with cost outliers. The trimmed range for the data is $43 to $282, with 85% of the charges ≤$160. The trimmed average sweat test charge was $117.93, with a standard error of $7.21. The median charge was $110. The projected total sweat test charge associated with screening follow-up nationwide is $907,338, assuming the same percentage of those having a sweat chloride test from the IRT screen. The estimated total cost of CF newborn screening and diagnosis was $10,028,796, which is equivalent The Journal of Pediatrics • June 2003

Fig 2. Distribution of survey of US sweat chloride test charges.

to $2.47 per screened baby or approximately $9952 per newly diagnosed patient with CF. A Monte Carlo26 simulation was completed to statistically model the total costs and allow for the high variability of the sweat test charges, as well as the variability in the numbers of newborn infants having IRT and sweat chloride tests. A 95% prediction interval for the US total costs are $9,329,072 to $11,591,366. The simulation predicted the average total cost as $10,046,833, which is very close to our estimate above.

DISCUSSION Previous studies on the economics of neonatal screening have tended to focus on potential savings in care after diagnosis.27 For instance, the limited studies of PKU outcomes after early diagnosis through screening suggest that the cost effectiveness is based on preventing expensive institutional care for children whose brain dysfunction could have been prevented.27,28 On the other hand, financial benefits of screening might also be realized through savings in the diagnostic aspect of care. Indeed, as screening tests such as the IRT/DNA method become less expensive through advances in technology and economies of scale, one might expect significant financial advantages. No one, to our knowledge, has previously determined the regional or national expenses associated with diagnosing CF by the traditional method involving sweat tests ordered because of signs or symptoms of the disease.9 Although CF center directors have been aware of the large number of negative sweat tests that are performed routinely every year,8-10 the quantitative experience of an entire region such as a state has never been documented. Therefore, we attempted to obtain annual sweat test data for the United States, Canada, or other states and learned that this goal is impossible to achieve retrospectively because such information has not been collected reliably on a regional basis. In our Analysis of The Costs of Diagnosing Cystic Fibrosis With a Newborn Screening Program

statewide assessment, the total number of sweat tests identified in 1991, namely, 1670, to diagnose 16 patients with CF, seemed reasonable because the expectation of CF leaders is that 50 to 100 sweat tests will be performed for each patient diagnosed.8-10 Although the large number of negative sweat tests is a hidden cost in the health care system related to CF, it must be considered in comparison to costs of diagnosis through neonatal screening. Therefore, in calculating the statewide costs of diagnosing CF during 2000, we included information on the savings associated with a decreased number of sweat chloride tests. More specifically, with a decrease from 1670 (in 1991) to 804 (in 2002) per year, we determined that at least $139,772 has been saved in statewide health care costs (and possibly more because of the elimination of 29 sweat testing facilities that could have been more costly to operate, since they were doing only an occasional test). Interestingly, this level of savings already accounts for 77% of the cost to operate Wisconsin’s CF neonatal screening program (Table I, A). Moreover, it is likely that the annual number of sweat tests, as well as the number of sites performing such tests, will continue to decrease. In fact, during the year 2000, only 2 of 20 patients were diagnosed outside the newborn screening program, both of whom moved to Wisconsin from other states. Our survey also revealed that some physicians are obtaining sweat chloride tests merely as a habit. For instance, one allergist obtains two sweat chloride tests on every child referred to him for asthma. Although it is clear that the introduction of CF neonatal screening in a region will change medical practice over time, it is difficult to project what the appropriate number of additional sweat chloride tests (extraneous to infant follow-up) might be in a region with a newborn screening program. We predict that in a state such as Wisconsin, the number will continue to decrease, with fewer sites, perhaps 5 in total, performing quantitative pilocarpine iontophoresis.7 If the same happened 621

nationwide and physician behavior changed as in Wisconsin, one might expect that the savings in “unnecessary” sweat tests could potentially offset the start-up costs of a national CF neonatal screening program. In the transitional period immediately after introducing CF neonatal screening, however, a paradoxic increase in the number of sweat tests performed could occur, until a new equilibrium is reached as practice habits change, and eventually reduce the number of “unnecessary” sweat tests (not associated with newborn screening) to a new baseline. Thus, the cost of CF neonatal screening is not prohibitive. Even with sophisticated, highly specific DNA analysis added to IRT as a second tier, the cost per baby screened in the United States is projected to be $2.47 (Table III). From a public health and policy perspective, this level of expense should be appealing. It is similar to the costs for other screening tests such as PKU.22,27 In a previous study conducted in 1998 by Scotet et al,29 the estimated cost of the CF newborn screening program in Brittany, France, was $2.32 per child screened, or $6825 per child diagnosed with CF. These numbers do not include the cost of the sweat chloride test. In South Australia, Ranieri et al30 estimated the costs of screening for their neonatal screening program as $4590 per newly diagnosed newborn with CF. As in the French study, the South Australian program used a higher IRT threshold than Wisconsin (the top 1%), and their estimated costs did not include the cost of the sweat chloride test and some follow-up expenses. There are some limitations in our diagnostic cost study. First, our survey showed some financial costs were not included in this analysis, such as expenses for counseling. In Wisconsin, genetic counseling was shown to improve understanding of CF in families whose children are diagnosed with the disease or who are carriers of CF.31 Also, the total cost of the screening program in Wisconsin includes an additional fee by the State Department of Health for providing support to families whose children were diagnosed with a congenital disorder through the screening process. On the other hand, there are costs in the system used in the traditional method of diagnosis that have not been taken into account because of the limited information available. For instance, our experience with the control (standard diagnosis) group of the Wisconsin CF Neonatal Screening Project identified numerous patients who had had several “sick visits” and a variety of diagnostic tests, including some very expensive imaging studies, before being diagnosed by a positive sweat test.32 These costs should not be a surprise because it has been demonstrated conclusively that more than half of the patients diagnosed with CF by the traditional method are quite ill at the time of diagnosis.33,34 Finally, the variability of the incidence of CF diagnosis and cost numbers will affect the results and is a subject for future research. Several clinical studies have shown that early diagnosis and treatment improves a CF patient’s long-term growth and can actually prevent severe malnutrition.24,31 Other studies have also reported both nutritional benefits and pulmonary 622 Lee et al

advantages.35,36 Despite the evidence of significant benefits of newborn screening for CF, many regions have not implemented such a program, although a recent survey suggested that the majority of states are proceeding in that direction.37 With states facing limited financial resources, public health programs require financial analysis of any newborn screening program before its implementation. The results from this study will provide useful information to policy analysts and others regarding the annual costs of diagnosis of CF when newborn screening programs are being planned in other states and countries. We thank the Wisconsin CF Center Directors for their important role in this study, particularly Dr Michael Rock (University of Wisconsin Department of Pediatrics) and Dr Mark Splaingard (Medical College of Wisconsin Department of Pediatrics). We are grateful to all the investigators and staff involved in the Wisconsin CF Neonatal Screening Project, especially Anita Laxova, who has coordinated the study for 15 years. We also thank the 59 CF Center Directors in the United States, who responded to our survey for charge data on sweat tests and the Wisconsin hospital laboratory leaders who participated in the sweat test surveys reported herein.

REFERENCES 1. Kosorok MR, Wei W, Farrell PM. The incidence of cystic fibrosis. Stat Med 1996;15:449-62. 2. Cystic Fibrosis Foundation. 2000 Patient Registry Annual Data Report. Bethesda Md: September 2001. 3. Lieu TA, Ray GT, Farmer G, Shay GF. The cost of medical care for patients with cystic fibrosis in a health maintenance organization. Pediatrics 1999;103:e72. 4. Ireys HT, Anderson GF, Shaffer TJ, Neff JM. Expenditures for care of children with chronic illnesses enrolled in the Washington State Medicaid program, fiscal year 1993. Pediatrics 1997;100:197-204. 5. Wildhagen MF. Cost of care of patients with cystic fibrosis in The Netherlands in 1990-1. Thorax 1996;51:298-301. 6. Pauly MV. The economics of cystic fibrosis. In: Lloyd-Still JD, editor. Textbook of cystic fibrosis. Bristol: John Wright, PSG Inc; 1983; p. 465-76. 7. Farrell PM, Koscik RE. Sweat chloride concentrations in infants homozygous or heterozygous for F508 cystic fibrosis. Pediatrics 1996;97:524-8. 8. Howell DA, Lederberg S, Brusilow SW, Childs B, Cook CD, Heath EC. Evaluation of testing for cystic fibrosis. J Pediatr 1976;88:711-50. 9. Cystic Fibrosis Foundation. Problems in sweat testing. GAP Conference Reports. 1975. p. 2-15. 10. Shwachman H, Mahmoodian A. Pilocarpine iontophoresis sweat testing results of seven years’ experience. Mod Probl Pediatr 1966;10:158-82. 11. Rosenstein BJ, Cutting CR. The diagnosis of cystic fibrosis: a consensus statement. J Pediatr 1998;132:589-95. 12. Crossley JR, Elliott RB, Smith PA. Dried-blood spot screening for cystic fibrosis in the newborn. Lancet 1979;1:472-4. 13. Wilcken B, Brown ARD, Urwin R, Brown DA. Cystic fibrosis screening by dried blood spot trypsin assay: results in 75,000 newborn infants. J Pediatr 1983;102:383-7. 14. 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. 15. Kwon C, Farrell PM. The magnitude and challenge of false-positive newborn screening test results. Arch Pediatr Adolesc Med 2000;154:714-8. 16. Kerem B, Rommens JM, Buchanan JA, Markiewicz D, Cox TK, Chakravarti A, et al. Identification of the cystic fibrosis gene: genetic analysis. Science 1989;245:1073-80. 17. Farrell PM, Mischler EH, Fost NC, Wilfond BS, Tluczek A, Gregg RG, et al. Current issues in neonatal screening for cystic fibrosis and implications of the CF gene discovery. Pediatr Pulmonol Suppl 1991;7:11-8.

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18. Gregg RG, Wilfond BS, Farrell PM, Laxova A, Hasemer 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 1995;52:616-26. 19. Ranieri E, Ryall RG, Morris CP, Nelson PV, Carey WF, Pollard AC. Neonatal screening for cystic fibrosis using immunoreactive trypsinogen and direct gene analysis. Br Med J 1991;302:1237-40. 20. Wilcken B, Wiley V, Sherry G, Bayliss U. Neonatal screening for cystic fibrosis: a comparison of two strategies for case detection in 1.2 million babies. J Pediatr 1995;127:965-70. 21. Férec C, Verlingue C, Parent P, Morin JF, Codet JP, Raulf G. Neonatal screening for cystic fibrosis: result of a pilot study using both immunoreactive trypsinogen and cystic fibrosis gene mutation analyses. Hum Genet 1995;96:542-8. 22. Farrell PM, Aronson RA, Hoffman G, Laessig RH. Newborn screening for cystic fibrosis in Wisconsin: first application of population-based molecular genetics testing. Wisc Med J 1994;93:415-21. 23. Gregg RG, Simantel A, Farrell PM, Koscik RE, Kosorok MR, Laxova A, et al. Newborn screening for cystic fibrosis in Wisconsin: comparison of biochemical and molecular methods. Pediatrics 1997;99:819-24. 24. Farrell PM, Kosorok MR, Rock MJ, Laxova A, Zeng L, Lai HC, et al. Early Diagnosis of cystic fibrosis through neonatal screening prevents severe malnutrition and improves long-term growth. Pediatrics 2001;107:1-13. 25. National Vital Statistics Report, Vol 49, No. 5. July 24, 2001. p. 11. 26. Ross S. Simulation. San Diego: Academic Press; 1997. 27. Dhondt JL, Farriaux JP, Sailly JC, Lebrun T. Economic evaluation of cost-benefit ratio of neonatal screening procedure of phenylketonuria and hypothyroidism. J Inherit Metab Dis 1991;14:633-9.

28. Dagenais DL, Courville L, Dagenais MG. A cost-benefit analysis of the Quebec network of genetic medicine. Soc Sci Med 1985;20:601-7. 29. Scotet V, 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. 30. Ranieri E, Lewis BD, Gerace RL, Ryall RG, Morris B, Nelson PV, et al. Neonatal screening for cystic fibrosis using immunoreactive trypsinogen and direct gene analysis: four years’ experience. Br Med J 1994;308:1469-72. 31. Ciske DJ, Haavisto A, Laxova A, Zeng L, Rock MJ, Farrell PM. Genetic counseling and neonatal screening for cystic fibrosis: an assessment of the communication process. Pediatrics 2001;107:699-705. 32. Farrell PM, Mischler EH. Newborn screening for cystic fibrosis. Adv Pediatr 1992;39:31-64. 33. Lai HC, Kosorok MR, Sondel SA, Chen ST, FitzSimmons SC, Green CG, et al. Growth status in children with cystic fibrosis based on the national cystic fibrosis patient registry data: evaluation of various criteria use to identify malnutrition. J Pediatr 1998;132:478-85. 34. Rosenstein BJ, Langbaum TS, Metz SJ. Cystic fibrosis: diagnostic considerations. Johns Hopkins Med J 1982;150:113-20. 35. Waters DL, Wilcken B, Irwig L, Van Asperen P, Mellis C, Simpson JM, et al. Clinical outcomes of newborn screening for cystic fibrosis. Arch Dis Child Fetal Neonatal Ed 1999;80:F1-7. 36. Mérelle ME, Schouten JP, Gerritsen J, Dankert-Roelse JE. Influence of neonatal screening and centralized treatment on long-term clinical outcome and survival of CF patients. Eur Respir 2001;18:306-15. 37. Bobadilla JL, Farrell MH, Farrell PM. Applying CFTR molecular genetics to facilitate the diagnosis of cystic fibrosis through screening. Adv Pediatr 2002;49:131-90.

50 Years Ago in The Journal of Pediatrics FOUR RECURRENT ATTACKS OF PNEUMOCOCCUS MENINGITIS WITH RECOVERY Tribiano CW. J Pediatr 1953;42:609-11 Complete reference for article discussed (Jan-June 1953 is Vol 42; July-Dec 1953 is Vol 43) Dr Tribiano, a practicing pediatrician at the Methodist Hospital in Brooklyn, New York, reports the unusual case of an 8year-old boy who sustained and survived 4 episodes of pneumococcal meningitis over a 5-year period caused by different serotyes of Streptoccocus pneumoniae (6, 19, 21, and untypable). He notes the important difference between relapsing and recurring bacterial meningitis, the possibility of either occurring only since the introduction of antibiotic therapy, and the absence of previous reports of true, recurrent bacterial meningitis in childhood. With the 20-20 vision of hindsight, and the knowledge afforded by 50 years of medical advances, the patient’s problem undoubtedly was a permanent breech in the integrity of the skull and meninges occasioned by a fall from a third-story window 13 months before the first episode of pneumococcal meningitis at 34 months of age. (Dr Tribiano suspected this). The immediate reactions of this 2003 reader are: (1) we take for granted the privileged position of medicine that only 50 years later would offer exquisite imaging modalities, successful vaccines, antimicrobial prophylaxis, and innovative neurosurgery in this case; and (2) how myopic will our current approaches seem 50 years from now? Sarah S. Long, MD Section of Infectious Diseases St. Christopher’s Hospital for Children Philadelphia, PA 19134 YMPD223 10.1067/mpd.2003.223

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