Letters to the Editor
Am. J. Hum. Genet. 50:438-439, 1992
General Population Screening for Cystic Fibrosis Is Premature To the Editor:
At the recent International Congress of Human Genetics (ICHG) meeting in Washington, DC, the topic of carrier screening for cystic fibrosis (CF) in the general U.S. population was intensively discussed. Two developments are of note: (1) Investigators at a major medical genetics center indicated their intention to begin offering CF carrier screening to couples who come in for counseling for other purposes, most commonly advanced maternal age. (2) A commercial supplier of DNA diagnostic services suggested that, with their test now approaching 90% detection, "this new test may be of interest to ANYONE who has not yet completed their reproductive plans" (emphasis from original). Soon after the gene associated with CF was identified, The American Society of Human Genetics (ASHG) issued a statement that routine screening in the general population was not the standard of care (Caskey et al. 1990), and a subsequent National Institutes of Health (NIH)-sponsored meeting produced a document suggesting that general screening would be premature until the detection rate reached 90%-95% and pilot projects could be carried out to assess the potential pitfalls of counseling for a disease with such a variable phenotype (National Institutes of Health 1990). The ASHG established an ad hoc committee on CF carrier screening, which formally endorsed the NIH statement. After some initial delay, the NIH, with leadership from the National Center for Human Genome Research, vigorously took up the cause of 438
pilot-project support, and the first set of pilot projects has just been funded. We are concerned that the recent developments at the ICHG meeting place this carefully reasoned plan in jeopardy. While modest improvements in carrierdetection sensitivity have occurred, other thorny aspects of the provision of carrier screening to couples without a family history of CF have not advanced significantly in the past 2 years in the United States. Most notable, an effective means of educating couples about the clinical course of CF has not been developed. This will be a major challenge, as the range of severity of CF is great. This is not Tay-Sachs disease, where the outlook for meaningful childhood development is nil. Individuals with CF commonly live to adulthood; there is every indication that survival will continue to improve; and the possibility of breakthroughs in therapy is greater now than at any time in the past. Adequate counseling will need to convey all of these nuances to couples for whom CF is an abstraction, not a reality. Even experienced genetic centers may find this difficult, especially in the context of an already established pregnancy. As pointed out in the original statement (National Institutes of Health 1990), carrier screening prior to the onset of pregnancy preserves more options for couples found to be at risk. The ASHG ad hoc committee on CF carrier screening will meet in February 1992 to reconsider the ASHG position and decide whether changes should be made. In the meantime, the undersigned individuals would like to restate the view that CF carrier screening is not now the standard of care for couples with no family history of the disease. Centers which decide to offer
Letters to the Editor
439
carrier testing at this time ought to consider themselves as undertaking research projects and should therefore endeavor to collect rigorous data about patient understanding and decision outcomes. Centers and individual physicians not comfortable with the provision of such services at the present time should feel no obligation to initiate them. LESLIE BIESECKER, * BARBARA BOWLES-BIESECKER, * FRANCIS COLLINS,* MICHAEL KABACK,t and BENJAMIN WILFONDt *Departments of Internal Medicine, Pediatrics, and Human Genetics, University of Michigan, Ann Arbor;
Table I
tDepartment of Pediatrics, University of California,
NOTE. -If A is the rate of carrier detection in step 1 and if B is the rate of carrier detection in step 2, then the rate for detection of couples at risk is the detection where both couples have positive tests in step 1 (A2) plus the detection where one partner is positive in step 1 and one partner is negative in step 1 [2A(1 - A)] times the fraction of this group where the partner with a negative test would be identified with the step 2 method (B - A / 1 - A). Thus the detection rate for couples at risk is A2+2A(1 -A)[(B-A)/(1 -A)] = A2 + 2A(B - A).
San Diego; and tDepartment of Pediatrics and Program in Medical Ethics, University of Wisconsin, Madison References
Caskey CT, Kaback MM, Beaudet AL (1990) The American Society of Human Genetics statement on cystic fibrosis. Am J Hum Genet 46:393 National Institutes of Health (1990) Statement from the National Institutes of Health workshop on population screening for the cystic fibrosis gene. N Engl J Med 323: 70-71 i 1992 by The American Society of Human Genetics. All rights reserved. 0002-9297/ 92/5002-0022$02.00
Am. J. Hum. Genet. 50:439-440, 1992
Advantages of a Two-Step Laboratory Approach for Cystic Fibrosis Carrier Screening To the Editor: In trying to devise efficient and economical methods for carrier screening for cystic fibrosis (CF), we have considered a two-step laboratory strategy for testing
couples. The rationale would be to test both partners for fewer mutations (perhaps only the AFS08 mutation at present) in a first step and then to test only partners of identified carriers for additional mutations (perhaps four or five mutations at present). Depending on the rate of carrier detection in step 1, this would mean that only 1 in 30-40 samples need be tested in step 2, thus reducing the total number of mutational analyses to be performed by about 80%. It is remarkable that the ability to detect couples at risk of bearing
Detection Rates for Couples at Risk for Bearing a Child with CF
MUTATION DETECTION FOR STEP 2 MUTATION DETECTION FOR STEP 1 .70 .75 .80 .85 .90 .95 .98
.49 .70 .75 . ............... .80 .......................... .85 .......................... .90 .......................... .95 .......................... .98 ..........................
.56 .56
.72
.63 .64 .64
.77 .84 .78 .86 .80 .88 .94 .81 .89 .81.95 .90 .96 .90
.70 .71 .72
.88 .91 .93
.96
an affected child is very little affected by studying fewer mutations in the first step, as shown in table 1. For example, our data suggest that analysis of AFS08 alone detects 75% of non-Ashkenazic Caucasian carriers, while analysis for the G542X, G551D, R553X, and N1303K mutations in addition detects rv85% of carriers (Ng et al. 1991). Using these numbers, testing only for AF508 in the first of a two-step strategy would detect only 1% less of the couples at risk of CF, compared with testing AFS08 plus four or five other mutations on all samples (71% vs. 72%). A review of the information in the table indicates that a two-step strategy offers major advantages. Whatever the time and effort available, it is far more beneficial to test more mutations on samples from partners of known carriers than to test an increasing number of mutations on all
samples. The difference between the proportion of at-risk couples detected by a two-step strategy and the proportion detected by applying the more extensive methodology of step 2 to every sample is equal to the square of the difference in the rates for step 1 and step 2. Thus, if (step 2 = .85) minus (step 1 = .75) = .10, then the difference in detection of carrier couples is .102 or .01 when the two-step strategy is compared with testing all samples with the methodology of step 2. If (step 2 = .95) minus (step 1 = .75) = .20, then the difference in detection of carrier couples is .202 or .04. As the detection rate for step 2 increases, it
Am. J. Hum. Genet. 50:438-439, 1992
General Population Screening for Cystic Fibrosis Is Premature To the Editor:
At the recent International Congress of Human Genetics (ICHG) meeting in Washington, DC, the topic of carrier screening for cystic fibrosis (CF) in the general U.S. population was intensively discussed. Two developments are of note: (1) Investigators at a major medical genetics center indicated their intention to begin offering CF carrier screening to couples who come in for counseling for other purposes, most commonly advanced maternal age. (2) A commercial supplier of DNA diagnostic services suggested that, with their test now approaching 90% detection, "this new test may be of interest to ANYONE who has not yet completed their reproductive plans" (emphasis from original). Soon after the gene associated with CF was identified, The American Society of Human Genetics (ASHG) issued a statement that routine screening in the general population was not the standard of care (Caskey et al. 1990), and a subsequent National Institutes of Health (NIH)-sponsored meeting produced a document suggesting that general screening would be premature until the detection rate reached 90%-95% and pilot projects could be carried out to assess the potential pitfalls of counseling for a disease with such a variable phenotype (National Institutes of Health 1990). The ASHG established an ad hoc committee on CF carrier screening, which formally endorsed the NIH statement. After some initial delay, the NIH, with leadership from the National Center for Human Genome Research, vigorously took up the cause of 438
pilot-project support, and the first set of pilot projects has just been funded. We are concerned that the recent developments at the ICHG meeting place this carefully reasoned plan in jeopardy. While modest improvements in carrierdetection sensitivity have occurred, other thorny aspects of the provision of carrier screening to couples without a family history of CF have not advanced significantly in the past 2 years in the United States. Most notable, an effective means of educating couples about the clinical course of CF has not been developed. This will be a major challenge, as the range of severity of CF is great. This is not Tay-Sachs disease, where the outlook for meaningful childhood development is nil. Individuals with CF commonly live to adulthood; there is every indication that survival will continue to improve; and the possibility of breakthroughs in therapy is greater now than at any time in the past. Adequate counseling will need to convey all of these nuances to couples for whom CF is an abstraction, not a reality. Even experienced genetic centers may find this difficult, especially in the context of an already established pregnancy. As pointed out in the original statement (National Institutes of Health 1990), carrier screening prior to the onset of pregnancy preserves more options for couples found to be at risk. The ASHG ad hoc committee on CF carrier screening will meet in February 1992 to reconsider the ASHG position and decide whether changes should be made. In the meantime, the undersigned individuals would like to restate the view that CF carrier screening is not now the standard of care for couples with no family history of the disease. Centers which decide to offer
Letters to the Editor
439
carrier testing at this time ought to consider themselves as undertaking research projects and should therefore endeavor to collect rigorous data about patient understanding and decision outcomes. Centers and individual physicians not comfortable with the provision of such services at the present time should feel no obligation to initiate them. LESLIE BIESECKER, * BARBARA BOWLES-BIESECKER, * FRANCIS COLLINS,* MICHAEL KABACK,t and BENJAMIN WILFONDt *Departments of Internal Medicine, Pediatrics, and Human Genetics, University of Michigan, Ann Arbor;
Table I
tDepartment of Pediatrics, University of California,
NOTE. -If A is the rate of carrier detection in step 1 and if B is the rate of carrier detection in step 2, then the rate for detection of couples at risk is the detection where both couples have positive tests in step 1 (A2) plus the detection where one partner is positive in step 1 and one partner is negative in step 1 [2A(1 - A)] times the fraction of this group where the partner with a negative test would be identified with the step 2 method (B - A / 1 - A). Thus the detection rate for couples at risk is A2+2A(1 -A)[(B-A)/(1 -A)] = A2 + 2A(B - A).
San Diego; and tDepartment of Pediatrics and Program in Medical Ethics, University of Wisconsin, Madison References
Caskey CT, Kaback MM, Beaudet AL (1990) The American Society of Human Genetics statement on cystic fibrosis. Am J Hum Genet 46:393 National Institutes of Health (1990) Statement from the National Institutes of Health workshop on population screening for the cystic fibrosis gene. N Engl J Med 323: 70-71 i 1992 by The American Society of Human Genetics. All rights reserved. 0002-9297/ 92/5002-0022$02.00
Am. J. Hum. Genet. 50:439-440, 1992
Advantages of a Two-Step Laboratory Approach for Cystic Fibrosis Carrier Screening To the Editor: In trying to devise efficient and economical methods for carrier screening for cystic fibrosis (CF), we have considered a two-step laboratory strategy for testing
couples. The rationale would be to test both partners for fewer mutations (perhaps only the AFS08 mutation at present) in a first step and then to test only partners of identified carriers for additional mutations (perhaps four or five mutations at present). Depending on the rate of carrier detection in step 1, this would mean that only 1 in 30-40 samples need be tested in step 2, thus reducing the total number of mutational analyses to be performed by about 80%. It is remarkable that the ability to detect couples at risk of bearing
Detection Rates for Couples at Risk for Bearing a Child with CF
MUTATION DETECTION FOR STEP 2 MUTATION DETECTION FOR STEP 1 .70 .75 .80 .85 .90 .95 .98
.49 .70 .75 . ............... .80 .......................... .85 .......................... .90 .......................... .95 .......................... .98 ..........................
.56 .56
.72
.63 .64 .64
.77 .84 .78 .86 .80 .88 .94 .81 .89 .81.95 .90 .96 .90
.70 .71 .72
.88 .91 .93
.96
an affected child is very little affected by studying fewer mutations in the first step, as shown in table 1. For example, our data suggest that analysis of AFS08 alone detects 75% of non-Ashkenazic Caucasian carriers, while analysis for the G542X, G551D, R553X, and N1303K mutations in addition detects rv85% of carriers (Ng et al. 1991). Using these numbers, testing only for AF508 in the first of a two-step strategy would detect only 1% less of the couples at risk of CF, compared with testing AFS08 plus four or five other mutations on all samples (71% vs. 72%). A review of the information in the table indicates that a two-step strategy offers major advantages. Whatever the time and effort available, it is far more beneficial to test more mutations on samples from partners of known carriers than to test an increasing number of mutations on all
samples. The difference between the proportion of at-risk couples detected by a two-step strategy and the proportion detected by applying the more extensive methodology of step 2 to every sample is equal to the square of the difference in the rates for step 1 and step 2. Thus, if (step 2 = .85) minus (step 1 = .75) = .10, then the difference in detection of carrier couples is .102 or .01 when the two-step strategy is compared with testing all samples with the methodology of step 2. If (step 2 = .95) minus (step 1 = .75) = .20, then the difference in detection of carrier couples is .202 or .04. As the detection rate for step 2 increases, it
