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lenge antibody levels developed signs of otitis me-dia. In a similar study, Buchman et al8_{reported that}

25% of normal adult volunteers developed otitis me-dia by 4 days after experimental influenza A infec-tion. McBride et al9_{studied 32 adult volunteers after}

experimental rhinovirus infection; 75% developed clinical illness and 80% of them had eustachian tube dysfunction by 2 days after infection. Clinical trials of active and passive immunization suggest that pre-venting respiratory virus infection could decrease the frequency of AOM. Two controlled clinical trials in day care centers reported reduced rates of AOM among children who received influenza A immuni-zation.10,11 _{Results from another controlled trial}

showed that recipients of high-dose RSV immune globulin had significantly fewer episodes of AOM than controls and no episodes of RSV-associated AOM.12_{Observational studies have associated}

respi-ratory virus infection with poor response to antibi-otics or development of persistent middle ear effu-sion. Chonmaitree et al reported that 50% of children with MEF positive for virus and bacteria failed to clear bacteria after 2 to 4 days of antimicrobial ther-apy compared with only 13% positive for bacteria alone.13_{Others have also reported an association}

be-tween respiratory virus infection or isolation of re-spiratory viruses from MEF and poor response to antibiotic treatment.14,15 _{The current report by}

Pit-ka¨ranta et al did not find an association between virus infection and response to antimicrobial therapy or outcome of AOM, based on a follow-up examina-tion 2 weeks after diagnosis and initiaexamina-tion of therapy. Although the conclusion that otitis media in chil-dren is largely the result of viral respiratory tract infection clearly has merit, it is not clear how this conclusion should affect management of patients, especially the decision to use antibiotics. The fact that respiratory viral infections lead to signs of AOM may well explain why a recent meta-analysis of random-ized, controlled clinical trials of antibiotics for AOM showed only a modest advantage for treated pa-tients.16 _{Selective use of antibiotics in children with}

AOM is being advocated by those who see reduction in the overall use of antibiotics for acute respiratory infections as an important component of efforts to combat the growing threat of antibiotic resistance.16,17

However, those who favor treatment of all patients with AOM point out that clinical findings which can be used to select the patients who will not require antibiotic treatment have not been identified, and that withholding treatment will lead to increased risk of more serious complications such as mastoiditis.18

One could ask whether serious efforts have been made to identify patients who would do well with-out antibiotic treatment. Clinical studies that com-bine careful initial evaluation of local and systemic signs at the time of diagnosis, selection of some patients for no antibiotics based on study criteria and reevaluation of treated and untreated patients after 48 to 72 hours might provide answers. No one would advocate antibiotic treatment of all children with other types of respiratory illness that are largely due to viral infection. The knowledge that otitis media is also largely the result of viral infection should lead to

investigation of approaches to management that in-clude withholding antibiotics from some patients.

Robert F. Pass, MD

Department of Pediatrics School of Medicine

Division of Infectious Diseases University of Alabama at Birmingham Birmingham, AL 35233

REFERENCES

1. Pitka¨ranta A, Virolainen A, Jero J, Arruda E, Hayden FG. Detection of rhinovirus, respiratory syncytial virus, and coronavrius infections in acute otitis media by reverse transcriptase polymerase chain reaction.

Pediatrics.1998;102:000 – 000

2. Chonmaitree T, Howie V, Truant A. Presence of respiratory viruses in middle ear fluids and nasal wash specimens from children with acute otitis media.Pediatrics.1986;77:698 –702

3. Ruuskanen O, Arola M, Putto-Laurila A, et al. Acute otitis media and respiratory virus infections.Pediatr Infect Dis J.1989;8:94 –99 4. Ruuskanen O, Arola M, Heikkinen T, Ziegler T. Viruses in acute otitis

media: increasing evidence for clinical significance.Pediatr Infect Dis J.

1991;10:425– 427

5. Okamoto Y, Kudo K, Ishikawa K, et al. Presence of respiratory syncytial virus genomic sequences in middle ear fluid and its relationship to expression of cytokines and cell adhesion molecules.J Infect Dis.1993; 168:1277–1281

6. Uhari M, Hietala J, Tuokko H. Risk of acute otitis media in relation to the viral etiology of infections in children.Clin Infect Dis.1995;20:521–524 7. Doyle WJ, Buchman CA, Skoner DP, Seroky JT, Hayden F, Fireman P.

Nasal and otologic effects of experimental influenza A virus infection.

Ann Otol Rhinol Laryngol.1994;103:59 – 69

8. Buchman CA, Doyle WJ, Skoner DP, et al. Influenza A virus-induced acute otitis media.J Infect Dis.1995;172:1348 –1351

9. McBride TP, Doyle WJ, Hayden FG, Gwaltney JM. Alterations of the eustachian tube, middle ear, and nose in rhinovirus infection.Arch Otolaryngol Head Neck Surg.1989;115:1054 –1059

10. Heikkinen T, Ruuskanen O, Waris M, Ziegler T, Arola M, Halonen P. Influenza vaccination in the prevention of acute otitis media in children.

Am J Dis Child.1991;145:445– 448

11. Clements DA, Langdon L, Bland C, Walter E. Influenza A vaccine decreases the incidence of otitis media in 6- to 30-month-old children in day care.Arch Pediatr Adolesc Med.1995;149:1113–1117

12. Simoes EAF, Groothuis JR, Tristram DA, et al. Respiratory syncytial virus-enriched globulin for the prevention of acute otitis media in high-risk children.J Pediatr.1996;129:214 –219

13. Chonmaitree T, Owen MJ, Howie VM. Respiratory viruses interfere with bacteriologic response to antibiotic in children with acute otitis media.J Infect Dis.1990;162:546 –549

14. Arola M, Ziegler T, Ruuskanen O. Respiratory virus infection as a cause of prolonged symptoms in acute otitis media.J Pediatr.1990;116:697–701 15. Sung B, Chonmaitree T, Broemeling LD, et al. Association of rhinovirus infection with poor bacteriologic outcome of bacterial-viral otitis media.

Clin Infect Dis.1993;17:38 – 42

16. Del Mar C, Glasziou P, Hayem M. Are antibiotics indicated as initial treatment for children with acute otitis media? A meta-analysis.Br Med J.1997;314:1526 –1529

17. Froom J, Culpepper L, Jacobs M, et al. Antimicrobials for acute otitis media? A review from the International Primary Care Network.Br Med J.1997;315:98 –102

18. Klein JO, Bluestone CD. Management of otitis media in the era of managed care. In: Aronoff SC, Hughes WT, Kohl S, Wald ER, eds.

Advances in Pediatric Infectious Diseases, XII.Chicago, IL: Mosby-Year Book, Inc; 1997:351–386

Proprietary Products and Research:

The Proponents’ View

ABBREVIATIONS. NICU, neonatal intensive care unit; APACHE, Acute Physiology and Chronic Health Evaluation; PRISM, Pediatric Risk of Mortality score; PICUES, Pediatric Intensive Care Unit Evaluations.

COMMENTARIES 401

at Viet Nam:AAP Sponsored on August 30, 2020

www.aappublications.org/news

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A

ll branches of science are grappling with commercialization and its effects on discov-ery, academic discourse, and publication.1,2

The recent commentary by Kanter3_{raises important}

issues, for which the author should be congratulated. However, we do not believe that it presents a bal-anced view of the pros and cons of commercial fund-ing in developfund-ing and maintainfund-ing clinical scorfund-ing systems. Dr Kanter’s commentary cites other com-mentariesthat efforts to seek independent verification seem disappointing but provides no data. The prop-osition is open to investigation. Good policy de-mands accurate evaluation of the facts.

The first point to stress is that comparisons of outcomes that do not measure and adjust for dif-ferences in prior risk are scientifically untenable. For example, it is inappropriate to compare the management and outcomes of ventilated neonates without objectively assessing their severity of ill-ness. However, such assessments can not be made without blood gas machines, which may use tech-nology protected by patent. Should we therefore suppress all publications that incorporate blood gas measurements? If not, would it not be a double standard to suppress publications using scoring systems if some of their components are similarly protected?

Kanter quotes the International Committee of Medical Journal Editors which, in describing the cri-teria for disclosing methods, stated that scientific manuscripts should “identify methods . . . and pro-cedures in sufficient detail to allow other workers to reproduce the results . . . [and] . . . describe statistical methods with enough detail to enable a reader with access to the original data to verify the reported results.”4_{He then stakes out his own more restrictive}

interpretation.

Perhaps we need a more balanced perspective in which we demand sufficient guarantees. In the blood gas machine example, we can demand that the ana-lyzer is accurate, by objective corroboration of its performance, without demanding that its makers compromise their ability to finance its continued pro-duction by revealing commercial secrets. The same may be true of clinical scoring systems, if their mak-ers have chosen the option of commercial funding to maintain their development. Rather than focus on the coefficients of logistic equations in clinical scor-ing systems, we should focus on the required level of disclosure. Disclosures of performance are manda-tory, but disclosure of proprietary information is not required. There is a risk of discriminating against legitimate commercially supported research. Some examples illustrate this:

1. Withholding of nonscore information.In our re-search comparing outcomes and practice varia-tions among neonatal intensive care units

(NICUs) and pediatric intensive care units, we must regularly withhold the identity of the par-ticipating sites. To accomplish this, we may have to suppress displays of sample sizes and standard errors of the mean and race and other equally identifiable characteristics. Given an explanation of these legitimate needs for confidentiality, we have never had any editorial challenges.

2. Replication by authorized researchers. Kanter dismisses the remarkable compromise offered by APACHE Medical Systems,5_{and Pediatric Risk of}

Mortality (PRISM III),6 _{decrying elitist groups}

with secret information. The issue for a score is its performance; its validity and reliability in field use, not its internal mechanics. Disclosure of lo-gistic regression coefficients has nothing to do with replicating the score in a new population. Under the APACHE Medical Systems and PRISM III compromises, other researchers are welcome to perform such replications. The expectation that they be legitimate, qualified researchers is reason-able. In our experience, interested and knowl-edgeable readers can fail in applying even the openly published Score for Neonatal Acute Phys-iology (SNAP) scoring system7 _{and original}

PRISM score8_{when they don’t communicate with}

the original authors9,10 _{compared with}

indepen-dent researchers who do collaborate.11_{PRISM III}

algorithms are currently approved for replication studies in regional population studies in Australia and England, without cost to the researchers. 3. General versus specific methods. Hosmer and

Lemeshow12 _{extensively describe approaches to}

statistical model-building and argue that many equivalent models might derive from the same data. If the issue is performance and fit of the model, independent researchers can assess this using their own alternative models. How much detail in specific methodology is required when the general methods are readily accessible? 4. Unauthorized variants. There are other issues

that relate to the need to protect scoring systems. Standardized scoring methods permit fair com-parisons between patients, institutions, countries, and over time. Public domain scores are subject to local modification, a problem that fragmented se-verity measurement in adult intensive care.13,14

This cacophony of variants leads to a generalized loss of value of all scores.

5. Availability of research funds. Pragmatically, federal funding for health services research in the United States has been decimated15_and

commer-cial support is often the only option. Indeed re-searchers involved in measuring severity of illness have received the clear message that any research with commercial potential has an exceedingly low funding priority. Commercialization may be the only way that score development, validation, and recalibration, all expensive activities, are sup-ported. Such activities have even been encouraged by the federal government, both by direct encour-agement and federal Small Business Innovation Research (SBIR) grants.

Received for publication Mar 16, 1998; accepted May 13, 1998.

Address correspondence to: Douglas K. Richardson, MD, MBA, Beth Israel Deaconess Medical Center, Department of Neonatology, 330 Brookline Ave, Boston MA 02115.

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Journal editors must take a pragmatic approach to evaluating the publication of scores and indexes. Editors must demand standards score performance,16

and protect the confidential material involved in the review process, as well as protect the review process itself. The compromise worked out by APACHE III and by PRISM III of allowing researchers to have the internal equations to assess its performance without revealing the internal scoring publicly may be a rea-sonable balance. The consequences of losing any ex-ternal review of the scoring systems, or worse, losing the scoring systems themselves if financial support can not be found to sustain them, may be a much greater risk to the scientific community.

Perhaps commercialization would be more accept-able if the organizations that administer the profits from scoring systems were constituted so that the profits had to be ploughed back into their continued development and not for personal gain. The fees of the Vermont Oxford Neonatal Network17 _{and the}

Pediatric Intensive Care Unit Evaluations (PICUES), which uses PRISM III algorithms are managed in this way, and without this membership support, they could not continue their pioneering and important function. However, let no one underestimate the dif-ficulty of developing and maintaining scoring sys-tems18_{without generating a regular income.}

It seems that Dr Kanter’s logic is amenable to scientific investigation. Test the proprietor’s claim that permits use of algorithms in scientific docu-ments. Document the occasions that research “can only be discussed by a small exclusive group pos-sessing secret information . . . ” Investigate the pro-posal that studies using proprietary information could have been conducted without proprietary in-formation. Prove the argument that the loss of search using proprietary information would not re-sult in a substantial loss to the research and general community.

The opinion pieces have already been written. Dr Kanter’s hypothesis should be tested.

Douglas Richardson, MD, MBA

Joint Program in Neonatology

(Beth Israel Deaconess Medical Center, Brigham and Women’s Hospital, Children’s Hospital and Harvard Medical School)

Maternal and Child Health Harvard School of Public Health Boston, MA 02215

William O. Tarnow-Mordi, MB, ChB

Neonatal Medicine and Perinatal Epidemiology Department of Child Health

University of Dundee and Ninewells Hospital and Medical School

Dundee, United Kingdom DD1 9SY

Murray M. Pollack, MD

Department of Pediatrics

George Washington University School of Medicine Critical Care Medicine

Children’s National Medical Center Washington, DC 20010

ACKNOWLEDGMENTS

Dr Richardson is the principal developer of the Score for Neo-natal Acute Physiology (SNAP), a public domain illness severity score for neonatal intensive care.6_{Dr Richardson, at Beth Israel}

Deaconess Medical Center, and colleagues at Kaiser Permanente Division of Research (Dr Gabriel Escobar) and at the University of British Columbia (Dr Shoo Lee) have recently announced the availability of SNAP-II, a simplified version of SNAP that will be licensed for commercial use, but available to researchers. Dr Tar-now-Mordi is the principal developer of the Clinical Risk Index for Babies (CRIB), a public domain mortality risk score for very pre-mature babies (,1500 g,#31 weeks’ gestation).19_{He is Director of}

the nonprofit International Neonatal Network, a volunteer collab-oration of NICUs in 28 countries that shares information on NICU outcomes. Dr Pollack is the principal developer of the Pediatric Risk of Mortality (PRISM) score, a mortality risk scale for pediatric intensive care units.5,7 _{He is Director of the Pediatric Intensive}

Care Unit Evaluations (PICUES) Program. This program is based in the Children’s Research Institute of the Children’s National Medical Center, a not-for-profit organization. Children’s Research Institute holds all patents and copyrights related to this program.

REFERENCES

1. Blumenthal D. Academic-industry relations in the life of sciences.

JAMA.1992;268:3344 –3349

2. Intellectual Property Restrictions on Access to and Use of Research Tools in Biomedical Research.http://www.nih.gov/welcome/forum/ April 24, 1998

3. Kanter RK. Research publications involving proprietary products: sci-ence, news, or advertising?Pediatrics.1998;101:468 – 470

4. International Committee of Medical Journal Editors. Uniform require-ments for manuscripts submitted to biomedical journals.N Engl J Med.

1997;336:309 –315

5. Knaus WA, LaRosa JC, Marks RD, et al. The value of commercial funding in health services research: the case of the APACHE III meth-odology.Health Serv Res.1994;28:673– 678

6. Pollack MM, Patel KM, Ruttimann UE. PRISM III: an updated pediatric risk of mortality score.Crit Care Med.1996;24:743–752

7. Richardson DK, Gray JE, McCormick MC, Workman-Daniels K, Gold-mann D. Score for Neonatal Acute Physiology (SNAP): validation of a new physiology-based severity of illness index. Pediatrics. 1993;91: 617– 623

8. Pollack MM, Ruttimann UE, Getson PR. The Pediatric Risk of Mortality (PRISM) Score.Crit Care Med.1988;16:1110 –1116

9. Rautonen J, Makela A, Boyd H, et al. CRIB and SNAP: assessing the risk of death for preterm neonates.Lancet.1994;343:1272–1273

10. Richardson DK, McCormick MC, Gray JE, et al. CRIB and SNAP.Lancet.

1994;344:124 –125

11. Escobar GJ, Fischer A, Li DK, et al. Score for neonatal acute physiology: validation in three Kaiser Permanente neonatal intensive care units.

Pediatrics.1995;96:918 –922

12. Hosmer DW, Lemeshow S.Applied Logistic Regression.New York, NY: John Wiley and Sons; 1989

13. Le Gall JR, Loirat P, Alperovitch A, et al. A simplified acute physiology score for ICU patients.Crit Care Med.1984;12:975–977

14. Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II: a severity of disease classification system.Crit Care Med.1985;13:818 – 829 15. Deyo RA, Psaty BM, Simon G, Wagner EH, Omenn GS. The messenger under attack—intimidation of researchers by special-interest groups.

N Engl J Med.1997;336:1176 –1180

16. Angus DC, Pinsky MR. Risk prediction: judging the judges.Intensive Care Med.1997;23:363–365

17. Horbar JD. The Vermont Oxford Neonatal Network: integrating re-search and clinical practice to improve the quality of medical care.

Semin Perinatol.1995;19:124 –131

18. Richardson DK, Tarnow-Mordi WO, Escobar GJ. Neonatal illness se-verity scores: can they predict mortality and morbidity?Clin Perinatol.

1998. In press. 1998

19. International Neonatal Network. The CRIB (Clinical Risk Index for Babies) score: a tool for assessing initial risk and comparing perfor-mance of neonatal intensive care units.Lancet.1993;342:193–198

COMMENTARIES 403

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DOI: 10.1542/peds.102.2.401

1998;102;401

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Proprietary Products and Research: The Proponents' View

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Proprietary Products and Research: The Proponents' View

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