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EDITORIALS: Nicholas J Wald and Joan K Morris Neonatal screening for cystic fibrosis BMJ 1998; 316: 404-405 [Full text]

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Stronger evidence in support of neonatal screening for cystic fibrosis

Philip M Farrell   (25 August 1998)

Stronger evidence in support of neonatal screening for cystic fibrosis

Philip M Farrell   (1 September 1998)

Stronger evidence in support of neonatal screening for cystic fibrosis 25 August 1998
Philip M Farrell Send response to journal: Re: Stronger evidence in support of neonatal screening for cystic fibrosis	EDITOR--Although Professor Wald and Ms. Morris (1) appear to have examined carefully our article entitled "Nutritional Benefits of Neonatal Screening for Cystic Fibrosis" (2), they misunderstood some key points and failed to interpret the potentially great advantages of preventing malnutrition in CF. They comment that our "study design is an ingenious one, but the analysis of the results is problematic." Ironically, the most "ingenious" feature is the very element they criticize in their comment that "a difficulty that is not discussed in the report is that the data in children under 4 years are subject to selection bias." This issue of "selection bias" was one of the critical challenges we overcame during design of our study. In essence, our randomization protocol was designed to include a screened group and a standard diagnosis (control) group generated as a result of signs and symptoms of CF, a positive family history, or unblinding the computer-stored screening test results at four years of age. Most significantly, once the controls were completely identified by the unblinding process, their anthropometric indices of nutritional status from birth forward were obtained by review of records and were incorporated into a "what if analysis," i.e., a statistical analysis to determine how the total control group would have compared with the screened group if all patients had been identified from birth. Unfortunately, although this was explicitly described in the original version of our N Eng J Med manuscript, final editing led to deletion of the "what if analysis," but it revealed that the statistically significant differences persisted. In addition, Wald and Morris ask for "a separate analysis restricted to follow up after the first four years." We completed the unblinding of controls last April and accumulated sufficient data to show that significant differences persist. More specifically, we have shown that if this analysis starts at 4 years of age, the proportion of CF patients with heights above the 10th percentile remains significantly greater in the screened group (p=0.042). Finally, their comment that "this trial provides no evidence of any benefit of screening" is inappropriate because not only are the nutritional advantages obvious from our study, but psychological, genetic counseling, and potential pulmonary benefits are also evident (3-5), as emphasized by those expressing positive views about screening in the 8 August BMJ issue. Professor Dodge's comments about "steadily improving" prognosis/treatment and his recommendation that "cystic fibrosis should be added to diseases sought in all newborn babies" are supported by accumulating evidence. Therefore, we strongly disagree with the concern implied by Wald and Morris that "early knowledge of a serious disorder will cause more harm than good if there is no effective remedy." In fact, our assessment demonstrates convincingly that malnutrition can be prevented with early diagnosis through neonatal screening, and very few physicians caring for CF patients doubt the effectiveness of current respiratory disease intervention strategies. Philip M. Farrell, M.D., Ph.D. (on behalf of the Wisconsin CF Neonatal Screening Group) Professor of Pediatrics and Dean University of Wisconsin Medical School Madison, WI, USA 53706 1. Wald NJ and Morris JK. Neonatal screening for cystic fibrosis. BMJ 1998; 316:404-405. 2. Farrell PM, Kosorok MR, Laxova A, et al. Nutritional benefits of neonatal screening for cystic fibrosis. N Engl J Med 1997; 337:963-969. 3. Baroni MA, Anderson YE, and Mischler EH. Cystic fibrosis newborn screening. Impact on early screening results on parenting stress. Ped Nurs 1997;23:143-151. 4. Farrell PM, Shen G, Splaingard M., et al. Acquisiton of Pseudomonas aeruginosa in children with cystic fibrosis. Pediatr 1997; 100. URL:http://www.pediatrics.org/cgi/content/full/100/5/e/2. 5. Mischler EH, Wilfond BS, Reiser C, et al. Cystic fibrosis newborn screening: impact on reproductive decision making and implications for genetic counseling. Pediatr 1998; 102:44-52.
Stronger evidence in support of neonatal screening for cystic fibrosis 1 September 1998
Philip M Farrell Send response to journal: Re: Stronger evidence in support of neonatal screening for cystic fibrosis	EDITOR--Although Professor Wald and Ms. Morris (1) appear to have examined carefully our article entitled "Nutritional Benefits of Neonatal Screening for Cystic Fibrosis" (2), they misunderstood some key points and failed to interpret the potentially great advantages of preventing malnutrition in CF. They comment that our "study design is an ingenious one, but the analysis of the results is problematic." Ironically, the most "ingenious" feature is the very element they criticize in their comment that "a difficulty that is not discussed in the report is that the data in children under 4 years are subject to selection bias." This issue of "selection bias" was one of the critical challenges we overcame during design of our study. In essence, our randomization protocol was designed to include a screened group and a standard diagnosis (control) group generated as a result of signs and symptoms of CF, a positive family history, or unblinding the computer-stored screening test results at four years of age. Most significantly, once the controls were completely identified by the unblinding process, their anthropometric indices of nutritional status from birth forward were obtained by review of records and were incorporated into a "what if analysis," i.e., a statistical analysis to determine how the total control group would have compared with the screened group if all patients had been identified from birth. Unfortunately, although this was explicitly described in the original version of our N Eng J Med manuscript, final editing led to deletion of the "what if analysis," but it revealed that the statistically significant differences persisted. In addition, Wald and Morris ask for "a separate analysis restricted to follow up after the first four years." We completed the unblinding of controls last April and accumulated sufficient data to show that significant differences persist. More specifically, we have shown that if this analysis starts at 4 years of age, the proportion of CF patients with heights above the 10th percentile remains significantly greater in the screened group (p=0.042). Finally, their comment that "this trial provides no evidence of any benefit of screening" is inappropriate because not only are the nutritional advantages obvious from our study, but psychological, genetic counseling, and potential pulmonary benefits are also evident (3-5), as emphasized by those expressing positive views about screening in the 8 August BMJ issue. Professor Dodge's comments about "steadily improving" prognosis/treatment and his recommendation that "cystic fibrosis should be added to diseases sought in all newborn babies" are supported by accumulating evidence. Therefore, we strongly disagree with the concern implied by Wald and Morris that "early knowledge of a serious disorder will cause more harm than good if there is no effective remedy." In fact, our assessment demonstrates convincingly that malnutrition can be prevented with early diagnosis through neonatal screening, and very few physicians caring for CF patients doubt the effectiveness of current respiratory disease intervention strategies. Philip M. Farrell, M.D., Ph.D. (on behalf of the Wisconsin CF Neonatal Screening Group) Professor of Pediatrics and Dean University of Wisconsin Medical School Madison, WI, USA 53706 1. Wald NJ and Morris JK. Neonatal screening for cystic fibrosis. BMJ 1998; 316:404-405. 2. Farrell PM, Kosorok MR, Laxova A, et al. Nutritional benefits of neonatal screening for cystic fibrosis. N Engl J Med 1997; 337:963-969. 3. Baroni MA, Anderson YE, and Mischler EH. Cystic fibrosis newborn screening. Impact on early screening results on parenting stress. Ped Nurs 1997;23:143-151. 4. Farrell PM, Shen G, Splaingard M., et al. Acquisiton of Pseudomonas aeruginosa in children with cystic fibrosis. Pediatr 1997; 100. URL:http://www.pediatrics.org/cgi/content/full/100/5/e/2. 5. Mischler EH, Wilfond BS, Reiser C, et al. Cystic fibrosis newborn screening: impact on reproductive decision making and implications for genetic counseling. Pediatr 1998; 102:44-52.