Published online February 1, 2007
PEDIATRICS Vol. 119 No. 2 February 2007, pp. 415 (doi:10.1542/peds.2006-3310)

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LETTER TO THE EDITOR

False-positive Results in Expanded Newborn Screening: In Reply

Beth A. Tarini, MD
Division of General Pediatrics
University of Michigan
Ann Arbor, MI 48103-0456

Dimitri A. Christakis, MD, MPH
General Pediatrics
University of Washington
Seattle, WA 98115-8160

H. Gilbert Welch, MD, MPH
Department of Veterans Affairs
Veterans Affairs Outcomes Group
White River Junction, VT 05009

Dr Hanley is troubled that we did not adequately acknowledge the morbidity and mortality prevented by newborn screening. We agree with him that newborn screening for diseases such as phenylketonuria has saved lives. However, our concern is not about phenylketonuria screening but the proliferation of newborn screening for other disorders and the ensuing problem of false-positive results. Although Dr Hanley is correct that higher specificity is possible with tandem mass spectrometry, this does not invalidate the basic point: the more tests one performs, the more likely a false-positive result will occur. This fundamental relationship has been well understood for years.¹ We contend that the attendant consequences are real and include psychological, medical, and financial effects.

Dr Hanley is also concerned that we "fret" about pseudodisease (the detection of an abnormality that will never become clinically apparent). Pediatricians are justified in fretting about pseudodisease, because it leads to unnecessary and potentially harmful treatment. At the turn of the century, we mistakenly believed that large thymuses put infants at risk for sudden death and, thus, irradiated thousands of them,² which caused many individuals to develop breast and thyroid cancer later in life.^3,4 Although this was not the primary focus of our article, we are concerned that some of the disorders detected by newborn screening may, in fact, represent pseudodisease. In the past 3 months, population-based research has demonstrated a lack of apparent morbidity for 2 disorders included in state newborn screening panels: 3-methylcrotonyl-coenzyme A carboxylase deficiency⁵ and short-chain acyl-coenzyme A dehydrogenase deficiency.⁶

Finally, Dr Hanley's comment that we endorse "a natural experiment ... to determine how many deaths/brain-damaged children emerge" suggests confusion about the term. A natural experiment simply makes use of the variability that already exists in practice and has existed for >40 years. Comparing the incidence in one group of states that screen for a disorder with the incidence in another group of states that do not screen for it (but instead make the diagnosis clinically) is a quick way to begin to assess the extent of pseudodisease. Such a study is not ethically indefensible, because it does not entail withholding resources that have already been allocated to children and their families. In fact, we argue that it would be indefensible not to begin to assess the outcomes associated with existing and variable newborn screening policies. The past successes of newborn screening neither guarantee the future success of screening for different disorders nor obviate the need for a critical examination of the potential consequences, good and bad, before adding new tests to newborn screening panels.

REFERENCES

1. Gordis L. Epidemiology. 3rd ed. Philadelphia, PA: Elsevier; 2004
2. Jacobs MT, Frush DP, Donnelly LF. The right place at the wrong time: historical perspective of the relation of the thymus gland and pediatric radiology. Radiology. 1999;210 :11 –16[Free Full Text]
3. Hildreth NG, Shore RE, Dvoretsky PM. The risk of breast cancer after irradiation of the thymus in infancy. N Engl J Med. 1989;321 :1281 –1284[Abstract]
4. Refetoff S, Harrison J, Karanfilski BT, Kaplan EL, De Groot LJ, Bekerman C. Continuing occurrence of thyroid carcinoma after irradiation to the neck in infancy and childhood. N Engl J Med. 1975;292 :171 –175[Web of Science][Medline]
5. Stadler SC, Polanetz R, Maier EM, et al. Newborn screening for 3-methylcrotonyl-CoA carboxylase deficiency: population heterogeneity of MCCA and MCCB mutations and impact on risk assessment. Hum Mutat. 2006;27 :748 –759[CrossRef][Web of Science][Medline]
6. van Maldegem BT, Duran M, Wanders RJ, et al. Clinical, biochemical, and genetic heterogeneity in short-chain acyl-coenzyme A dehydrogenase deficiency. JAMA. 2006;296 :943 –952[Abstract/Free Full Text]

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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 Tarini, B. A. Articles by Welch, H. G. Search for Related Content PubMed PubMed Citation Articles by Tarini, B. A. Articles by Welch, H. G. Related Collections Office Practice Social Bookmarking                         What's this?