Published online February 1, 2007
PEDIATRICS Vol. 119 No. 2 February 2007, pp. 414-415 (doi:10.1542/peds.2006-2710)

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LETTER TO THE EDITOR

False-positive Results in Expanded Newborn Screening

W. B. Hanley, MD
Clinical Genetics
Hospital for Sick Children
Toronto, Ontario, Canada M5G 1X8

To the Editor.—

I read with concern the article by Tarini et al,¹ which focused on estimated false-positive results from expanded newborn screening by tandem mass spectrometry (MS/MS) and the alleged damage that they would ensue. There is no mention of the mortality and morbidity that newborn screening would prevent, although the authors do admit that "some infants may benefit from expanded newborn screening." They note that the specificity of MS/MS is 99.995% to 99.5% (a marked improvement over the 92% specificity of the old bacterial inhibition assay methods of Guthrie²) and calculate that this would result in 2575 to 51 059 false-positive results in 1 year of testing in the United States. They then go on to outline purported adverse effects in this nondiseased cohort by pointing out, among other things, reports of vulnerable-child consequences. They also fret about "pseudodisease"—mild variants of inherited metabolic disease that do not need treatment. In their last paragraph they suggest that states not yet using the full panel serve as controls and make "use of the natural experiment" by deferring expansion of testing.

If the 4 million infants born annually in the United States underwent screening for the full recommended panel of 29 diseases (23 diagnosable by MS/MS and all amenable to treatment), according to extensive review by the American College of Medical Genetics³ (commissioned by the Health Resources and Services Administration), it would result in 5000 (1:800) true-positive results, which would save many lives/brains and be cost-beneficial.⁴ The problem of false-positive results is now being vigorously approached by most programs, and extensive printed and Internet material is available for the health care workers who provide prenatal and postnatal counseling.^5,6 The authors' pseudodisease fixation leads to mention of histidinemia (recognized as a nondisease in 1974⁷) and nonphenylketonuria mild hyperphenylalaninemia (well known as benign by workers in the field^8–10). It seems to me that their nontesting "natural experiment" suggestion (to determine how many deaths/brain-damaged children emerge?) would, in the current milieu, have significant medicolegal implications.

The authors seem to have joined a cadre of nonclinician academicians (including those with primary interest in bioethics,¹¹ evaluative clinical sciences, and outcomes groups with no firsthand experience in caring for [late-diagnosed] patients with inborn errors of metabolism) in criticizing this important advance. One must remind the reader that very similar criticism greeted Guthrie in 1963 when he introduced his idea of universal newborn screening for phenylketonuria. His manuscript was rejected by the first journal to which it was submitted¹² but was accepted later by Pediatrics.¹³ The article went on to be selected by Scriver¹⁴ as the most important article on genetics published by Pediatrics in its first 50 years of operation.

REFERENCES

1. Tarini BA, Christakis DA, Welch HG. State newborn screening in the tandem mass spectrometry era: more tests, more false-positive results. Pediatrics. 2006;118 :448 –456[Abstract/Free Full Text]
2. Hanley WB, Demshar H, Preston MA, et al. Newborn phenyl ketonuria (PKU) Guthrie (BIA) screening and early hospital discharge. Early Hum Dev. 1997;47 :87 –96[CrossRef][Web of Science][Medline]
3. American College of Medical Genetics. Newborn Screening: Toward a Uniform Screening Panel and System. Rockville, MD: American College of Medical Genetics; 2005
4. Schoen EJ, Baker JC, Colby CJ, To TT. Cost-benefit analysis of universal tandem mass spectrometry for newborn screening. Pediatrics. 2002;110 :781 –786[Abstract/Free Full Text]
5. American Academy of Pediatrics. Children's health topics: newborn screening. Available at: www.aap.org/healthtopics/newbornscreening.cfm. Accessed December 4, 2006
6. Ontario Ministry of Health and Long-term Care. Newborn screening: a healthy start leads to a healthier life. Available at: www.health.gov.on.ca/newbornscreening. Accessed December 4, 2006
7. Levy HL, Shih VE, Madigan PM. Routine newborn screening for histidinemia: clinical and biochemical results. N Engl J Med. 1974;291 :1214 –1219[Web of Science][Medline]
8. Levy HL, Shih VE, Karolkewicz V, et al. Persistent mild hyperphenylalaninemia in the untreated state: a prospective study. N Engl J Med. 1971;285 :424 –429[Web of Science][Medline]
9. Weglage J, Pietsch M, Feldman R, et al. Normal clinical outcome in untreated subjects with mild hyperphenylalaninemia. Pediatr Res. 2001;49 :532 –536[Web of Science][Medline]
10. Smith ML, Saltzman J, Klim P, Hanley WB, Feigenbaum A, Clarke JTR. Neuropsychological function in mild hyperphenyl alaninemia. Am J Ment Retard. 2000;105 :69 –80[CrossRef][Web of Science][Medline]
11. Botkin JR, Clayton EW, Fost NC, et al. Newborn screening technology: proceed with caution. Pediatrics. 2006;117 :1793 –1799[Free Full Text]
12. Koch JH. Robert Guthrie: The PKU Story. Pasadena, CA: Hope Publishing House; 1997
13. Guthrie R, Susi A. A simple phenylalanine method for detecting phenylketonuria in large populations of newborn infants. Pediatrics. 1963;32 :38 –43
14. Scriver CR. "A Simple Phenylalanine Method for Detecting Phenylketonuria in Large Populations of Newborn Infants," by Robert Guthrie and Ada Susi, Pediatrics, 1963;32:318–343. Pediatrics. 1998;102(1 pt 2) :236 –237

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PEDIATRICS (ISSN 1098-4275). ©2007 by the American Academy of Pediatrics

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This Article Extract Full Text (PDF) Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services E-mail this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to My File Cabinet Download to citation manager Request Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Hanley, W. B. Search for Related Content PubMed PubMed Citation Articles by Hanley, W. B. Related Collections Office Practice Social Bookmarking                         What's this?