correspondence
We concur that preventing of a cryptococcal disease with targeted pre-ART cryptococcal antigen screening in patients with CD4 cell counts lower than 100 per cubic millimeter is preferable to treating meningitis.3 Cryptococcal antigen screening is probably cost-saving.4,5 Our randomized clinical trial (ClinicalTrials.gov number, NCT01535469) in Uganda is testing broad implementation of World Health Organization recommendations for cryptococcal screening. David R. Boulware, M.D., M.P.H. University of Minnesota Minneapolis, MN [email protected]
David B. Meya, M.Med. Infectious Disease Institute Kampala, Uganda
Since publication of their article, the authors report no further potential conflict of interest. 1. Rolfes MA, Hullsiek KH, Rhein J, et al. The effect of thera-
peutic lumbar punctures on acute mortality from cryptococcal meningitis. Clin Infect Dis 2014 July 23 (Epub ahead of print). 2. Boulware DR, Stauffer WM, Hendel-Paterson BR, et al. Maltreatment of Strongyloides infection: case series and worldwide physicians-in-training survey. Am J Med 2007;120:545.e1-545.e8. 3. Meya DB, Manabe YC, Castelnuovo B, et al. Cost-effectiveness of serum cryptococcal antigen screening to prevent deaths among HIV-infected persons with a CD4+ cell count ≤100 cells/ μL who start HIV therapy in resource-limited settings. Clin Infect Dis 2010;51:448-55. 4. Rajasingham R, Meya DB, Boulware DR. Integrating cryptococcal antigen screening and pre-emptive treatment into routine HIV care. J Acquir Immune Defic Syndr 2012;59(5):e85-e91. 5. Jarvis JN, Harrison TS, Lawn SD, Meintjes G, Wood R, Cleary S. Cost effectiveness of cryptococcal antigen screening as a strategy to prevent HIV-associated cryptococcal meningitis in South Africa. PLoS One 2013;8(7):e69288. DOI: 10.1056/NEJMc1409052
Antidepressant Use in Pregnancy and the Risk of Cardiac Defects To the Editor: Congenital heart disease can have devastating consequences, even in patients with simple defects.1-3 Huybrechts et al. (June 19 issue)4 suggest that the risk of cardiac malformations in children of mothers receiving antidepressants is low. It is interesting that in the unadjusted analysis, the relative risk of cardiac malformations is increased by 25% among infants exposed to antidepressants. However, after adjustment for multiple factors, this association was lost. Thus, the key to applying these results to clinical practice is to understand the methods that were used. Such factors as misclassification resulting from the low adherence to antidepressant use and the lack of data on spontaneous or medical terminations have the potential to bias the results. Information on missing data is lacking, especially in measurements that were used to construct the propensity scores, and such missing data would automatically exclude patients from the analysis, introducing bias. Although we agree with the authors that a risk– benefit decision should be made in treating patients with severe depression, caution should be taken in overinterpreting the data and declaring antidepressants to be safe during pregnancy,
which may promote liberal use and perhaps an increase in malformations, both cardiac and noncardiac. Aleksander Kempny, M.D. Lorna Swan, M.B., Ch.B., M.D. Konstantinos Dimopoulos, M.D., Ph.D. Royal Brompton Hospital London, United Kingdom
[email protected] No potential conflict of interest relevant to this letter was reported. 1. Brickner ME, Hillis LD, Lange RA. Congenital heart disease
in adults: first of two parts. N Engl J Med 2000;342:256-63.
2. Brickner ME, Hillis LD, Lange RA. Congenital heart disease
in adults: second of two parts. N Engl J Med 2000;342:334-42.
3. Kempny A, Dimopoulos K, Uebing A, et al. Reference values
for exercise limitations among adults with congenital heart disease: relation to activities of daily life-single centre experience and review of published data. Eur Heart J 2012;33:1386-96. 4. Huybrechts KF, Palmsten K, Avorn J, et al. Antidepressant use in pregnancy and the risk of cardiac defects. N Engl J Med 2014;370:2397-407. DOI: 10.1056/NEJMc1409203
To the Editor: The study by Huybrechts et al. raises several methodologic issues, which could explain the inconsistencies with other published studies. Cardiac defects were identified at 1 to
n engl j med 371;12 nejm.org september 18, 2014
The New England Journal of Medicine Downloaded from nejm.org at UNIVERSITY OF WATERLOO on February 10, 2015. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
1167
The
n e w e ng l a n d j o u r na l
of
m e dic i n e
3 months after birth, leading to underascertainment of outcome in administrative databases as a result of delayed reporting or detection. Furthermore, codes for birth defects in the United States from the International Classification of Diseases, Ninth Revision, are not reliable.1 In addition, rates of birth defects and rates of prematurity are highly correlated. Given that the use of antidepressants during pregnancy has been linked to prematurity,2 the exclusion of some cardiac defects associated with prematurity resulted in selective exclusion of defects in the antidepressant group, leading to underestimation. The algorithm that was used to estimate gestational age had low validity3 and was less accurate for premature deliveries, which are more prevalent among women taking antidepressants.2 This would be expected to result in exposure misclassification and underestimation of the risks associated with antidepressant use. Also surprising was the report that only 17 to 21% of the subcohort of depressed women used antidepressants. These women had recurrent diagnoses of depression and were taking many other antipsychotic drugs but no antidepressants. This finding is inconsistent with U.S. data showing that 37% of depressed people are taking antidepressants,4 a prevalence that is probably higher among Medicaid recipients. Anick Bérard, Ph.D. Sonia Chaabane, M.Sc. Takoua Boukhris, M.Sc.
Our study replicated the strength of associations between well-known risk factors and cardiac malformations, providing reassurance that these outcomes were well captured. Our findings were not changed by the extension of the follow-up period to 1 year or the correction of the findings for possible outcome misclassification informed by the positive predictive values estimated in an internal validation study.1 Since we sought to examine the teratogenic effects of antidepressant medications in otherwise normal deliveries, we excluded prematurity-related cardiac defects, though this is an important consideration. We agree with Kempny et al. that misclassification of antidepressant use is theoretically possible, since filling a prescription does not guarantee that the medication was taken as prescribed. However, in secondary analyses, we included only women who had refilled a prescription during the first trimester, and this did not alter the findings. For long-term use of medication, misclassification of the start of pregnancy by a few weeks has little effect on measures of exposure according to trimester.2 Although Bérard et al. suggest that the rate of antidepressant use in our cohort was lower than they would expect, the proportion of women in our cohort taking antidepressants was consistent with reports in other populations.3,4 Many women discontinue antidepressants when planning a pregnancy or early in pregnancy,5 so such use in this group is expected to be lower than that in the general population. University of Montreal Montreal, QC, Canada Differences in rates of termination of [email protected] nancies triggered by a prenatal diagnosis of a Dr. Bérard reports being a consultant for plaintiffs in litigacardiac malformation between treated and untion involving antidepressants and birth defects. No other potreated women with depression would have to tential conflict of interest relevant to this letter was reported. have been implausibly large for this factor to 1. Holmes LB, Westgate MN. Using ICD-9 codes to establish prevalence of malformations in newborn infants. Birth Defects explain our findings. (For details, see the SupRes A Clin Mol Teratol 2012;94:208-14. plementary Appendix, available with the full text 2. Huybrechts KF, Sanghani RS, Avorn J, Urato AC. Preterm birth of our article at NEJM.org.) This would also not and antidepressant medication use during pregnancy: a systemexplain differences from previous studies that atic review and meta-analysis. PLoS One 2014;9(3):e92778. 3. Margulis AV, Setoguchi S, Mittleman MA, Glynn RJ, Dor- were also restricted to live births. muth CR, Hernández-Díaz S. Algorithms to estimate the beginPoor documentation of other chronic health ning of pregnancy in administrative databases. Pharmacoepideconditions among patients taking antidepresmiol Drug Saf 2013;22:16-24. 4. Pratt LA, Brody DJ, Gu Q. Antidepressant use in persons sants is not a likely explanation, since more seaged 12 and over: United States, 2005-2008. NCHS Data Brief verely depressed patients have higher rates of 2011;76:1-8. recorded comorbidities. The association between DOI: 10.1056/NEJMc1409203 antidepressant use and cardiac defects was progressively attenuated by increasing adjustment The authors reply: The authors of both letters for an imbalance in the characteristics of paraise relevant concerns about misclassification. tients taking antidepressants and those who are
1168
n engl j med 371;12 nejm.org september 18, 2014
The New England Journal of Medicine Downloaded from nejm.org at UNIVERSITY OF WATERLOO on February 10, 2015. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
correspondence
not. This suggests that differences with previous studies may be explained by residual confounding in those studies. Our study addresses only one piece of the complex risk–benefit equation of antidepressant use in pregnancy, during which other risks associated with antidepressant use have been well documented. Our findings certainly do not justify incautious use of such drugs in these patients. Krista F. Huybrechts, Ph.D. Harvard Medical School Boston, MA
[email protected]
Sonia Hernández-Díaz, M.D., Dr.P.H. Harvard School of Public Health Boston, MA
Jerry Avorn, M.D.
Since publication of their article, the authors report no further potential conflict of interest. 1. Palmsten K, Huybrechts KF, Kowal MK, Mogun H, Hernán-
dez-Díaz S. Validity of maternal and infant outcomes within nationwide Medicaid data. Pharmacoepidemiol Drug Saf 2014; 23:646-55. 2. Toh S, Mitchell AA, Werler MM, Hernández-Díaz S. Sensitivity and specificity of computerized algorithms to classify gestational periods in the absence of information on date of conception. Am J Epidemiol 2008;167:633-40. 3. Cooper WO, Willy ME, Pont SJ, Ray WA. Increasing use of antidepressants in pregnancy. Am J Obstet Gynecol 2007; 196(6):544.e1-545.e1. 4. Mitchell AA, Gilboa SM, Werler MM, Kelley KE, Louik C, Hernandez-Diaz S. Medication use during pregnancy, with particular focus on prescription drugs: 1976-2008. Am J Obstet Gynecol 2011;205(1):51.e1-58.e1. 5. Huybrechts KF, Palmsten K, Mogun H, et al. National trends in antidepressant medication treatment among publicly insured pregnant women. Gen Hosp Psychiatry 2013;35:265-71. DOI: 10.1056/NEJMc1409203
Harvard Medical School Boston, MA
Diagnostic Clinical Genome and Exome Sequencing To the Editor: Biesecker and Green (June 19 issue)1 mention the recommendations by the American College of Medical Genetics and Genomics (ACMG) for laboratories to report incidental findings in clinical genome and exome sequencing (CGES) in a total of 56 genes (which, when mutated, cause an aggregate total of 24 disorders). Most of these conditions are associated with cancer or death from cardiovascular causes.2 Instead of focusing on relatively rare but treatable high-impact diseases, we suggest a greater focus on genetic causes of perhaps less threatening but treatable disorders that require specific treatments. Examples include diabetes caused by mutated HNF1A, with its strong response to sulfonylurea derivatives; sitosterolemia, with its strong response to ezetimibe and a specific diet; and Liddle’s syndrome, a genetic form of pseudo-aldosteronism, which can be treated with triamterene. The knowledge that a genetic mutation is the cause of treatable disease has direct consequences. Early case finding and screening might provide early and probably better, more specific treatment. We therefore suggest that the list of reported genetic conditions be expanded to genetic causes of diseases requiring specific treatments.
Jan Westerink, M.D., Ph.D. Frank L.J. Visseren, M.D., Ph.D. Wilko Spiering, M.D., Ph.D. University Medical Center Utrecht Utrecht, the Netherlands [email protected] No potential conflict of interest relevant to this letter was reported. 1. Biesecker LG, Green RC. Diagnostic clinical genome and
exome sequencing. N Engl J Med 2014;370:2418-25.
2. Green RC, Berg JS, Grody WW, et al. ACMG recommenda-
tions for reporting of incidental findings in clinical exome and genome sequencing. Genet Med 2013;15:565-74. DOI: 10.1056/NEJMc1408914
To the Editor: Biesecker and Green inform clinicians about indications for and limitations of CGES, and they offer concise, practical guidance on its effective and appropriate implementation. They do not discuss genetic counseling,1 a crucial element in implementing CGES. Genetic counselors are specialists with expertise in obtaining thorough, targeted family histories; identifying and addressing ethical issues (e.g., informed consent and communicating with at-risk family members) and psychosocial issues (e.g., guilt and fatalism) that are commonly attendant
n engl j med 371;12 nejm.org september 18, 2014
The New England Journal of Medicine Downloaded from nejm.org at UNIVERSITY OF WATERLOO on February 10, 2015. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
1169
We concur that preventing of a cryptococcal disease with targeted pre-ART cryptococcal antigen screening in patients with CD4 cell counts lower than 100 per cubic millimeter is preferable to treating meningitis.3 Cryptococcal antigen screening is probably cost-saving.4,5 Our randomized clinical trial (ClinicalTrials.gov number, NCT01535469) in Uganda is testing broad implementation of World Health Organization recommendations for cryptococcal screening. David R. Boulware, M.D., M.P.H. University of Minnesota Minneapolis, MN [email protected]
David B. Meya, M.Med. Infectious Disease Institute Kampala, Uganda
Since publication of their article, the authors report no further potential conflict of interest. 1. Rolfes MA, Hullsiek KH, Rhein J, et al. The effect of thera-
peutic lumbar punctures on acute mortality from cryptococcal meningitis. Clin Infect Dis 2014 July 23 (Epub ahead of print). 2. Boulware DR, Stauffer WM, Hendel-Paterson BR, et al. Maltreatment of Strongyloides infection: case series and worldwide physicians-in-training survey. Am J Med 2007;120:545.e1-545.e8. 3. Meya DB, Manabe YC, Castelnuovo B, et al. Cost-effectiveness of serum cryptococcal antigen screening to prevent deaths among HIV-infected persons with a CD4+ cell count ≤100 cells/ μL who start HIV therapy in resource-limited settings. Clin Infect Dis 2010;51:448-55. 4. Rajasingham R, Meya DB, Boulware DR. Integrating cryptococcal antigen screening and pre-emptive treatment into routine HIV care. J Acquir Immune Defic Syndr 2012;59(5):e85-e91. 5. Jarvis JN, Harrison TS, Lawn SD, Meintjes G, Wood R, Cleary S. Cost effectiveness of cryptococcal antigen screening as a strategy to prevent HIV-associated cryptococcal meningitis in South Africa. PLoS One 2013;8(7):e69288. DOI: 10.1056/NEJMc1409052
Antidepressant Use in Pregnancy and the Risk of Cardiac Defects To the Editor: Congenital heart disease can have devastating consequences, even in patients with simple defects.1-3 Huybrechts et al. (June 19 issue)4 suggest that the risk of cardiac malformations in children of mothers receiving antidepressants is low. It is interesting that in the unadjusted analysis, the relative risk of cardiac malformations is increased by 25% among infants exposed to antidepressants. However, after adjustment for multiple factors, this association was lost. Thus, the key to applying these results to clinical practice is to understand the methods that were used. Such factors as misclassification resulting from the low adherence to antidepressant use and the lack of data on spontaneous or medical terminations have the potential to bias the results. Information on missing data is lacking, especially in measurements that were used to construct the propensity scores, and such missing data would automatically exclude patients from the analysis, introducing bias. Although we agree with the authors that a risk– benefit decision should be made in treating patients with severe depression, caution should be taken in overinterpreting the data and declaring antidepressants to be safe during pregnancy,
which may promote liberal use and perhaps an increase in malformations, both cardiac and noncardiac. Aleksander Kempny, M.D. Lorna Swan, M.B., Ch.B., M.D. Konstantinos Dimopoulos, M.D., Ph.D. Royal Brompton Hospital London, United Kingdom
[email protected] No potential conflict of interest relevant to this letter was reported. 1. Brickner ME, Hillis LD, Lange RA. Congenital heart disease
in adults: first of two parts. N Engl J Med 2000;342:256-63.
2. Brickner ME, Hillis LD, Lange RA. Congenital heart disease
in adults: second of two parts. N Engl J Med 2000;342:334-42.
3. Kempny A, Dimopoulos K, Uebing A, et al. Reference values
for exercise limitations among adults with congenital heart disease: relation to activities of daily life-single centre experience and review of published data. Eur Heart J 2012;33:1386-96. 4. Huybrechts KF, Palmsten K, Avorn J, et al. Antidepressant use in pregnancy and the risk of cardiac defects. N Engl J Med 2014;370:2397-407. DOI: 10.1056/NEJMc1409203
To the Editor: The study by Huybrechts et al. raises several methodologic issues, which could explain the inconsistencies with other published studies. Cardiac defects were identified at 1 to
n engl j med 371;12 nejm.org september 18, 2014
The New England Journal of Medicine Downloaded from nejm.org at UNIVERSITY OF WATERLOO on February 10, 2015. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
1167
The
n e w e ng l a n d j o u r na l
of
m e dic i n e
3 months after birth, leading to underascertainment of outcome in administrative databases as a result of delayed reporting or detection. Furthermore, codes for birth defects in the United States from the International Classification of Diseases, Ninth Revision, are not reliable.1 In addition, rates of birth defects and rates of prematurity are highly correlated. Given that the use of antidepressants during pregnancy has been linked to prematurity,2 the exclusion of some cardiac defects associated with prematurity resulted in selective exclusion of defects in the antidepressant group, leading to underestimation. The algorithm that was used to estimate gestational age had low validity3 and was less accurate for premature deliveries, which are more prevalent among women taking antidepressants.2 This would be expected to result in exposure misclassification and underestimation of the risks associated with antidepressant use. Also surprising was the report that only 17 to 21% of the subcohort of depressed women used antidepressants. These women had recurrent diagnoses of depression and were taking many other antipsychotic drugs but no antidepressants. This finding is inconsistent with U.S. data showing that 37% of depressed people are taking antidepressants,4 a prevalence that is probably higher among Medicaid recipients. Anick Bérard, Ph.D. Sonia Chaabane, M.Sc. Takoua Boukhris, M.Sc.
Our study replicated the strength of associations between well-known risk factors and cardiac malformations, providing reassurance that these outcomes were well captured. Our findings were not changed by the extension of the follow-up period to 1 year or the correction of the findings for possible outcome misclassification informed by the positive predictive values estimated in an internal validation study.1 Since we sought to examine the teratogenic effects of antidepressant medications in otherwise normal deliveries, we excluded prematurity-related cardiac defects, though this is an important consideration. We agree with Kempny et al. that misclassification of antidepressant use is theoretically possible, since filling a prescription does not guarantee that the medication was taken as prescribed. However, in secondary analyses, we included only women who had refilled a prescription during the first trimester, and this did not alter the findings. For long-term use of medication, misclassification of the start of pregnancy by a few weeks has little effect on measures of exposure according to trimester.2 Although Bérard et al. suggest that the rate of antidepressant use in our cohort was lower than they would expect, the proportion of women in our cohort taking antidepressants was consistent with reports in other populations.3,4 Many women discontinue antidepressants when planning a pregnancy or early in pregnancy,5 so such use in this group is expected to be lower than that in the general population. University of Montreal Montreal, QC, Canada Differences in rates of termination of [email protected] nancies triggered by a prenatal diagnosis of a Dr. Bérard reports being a consultant for plaintiffs in litigacardiac malformation between treated and untion involving antidepressants and birth defects. No other potreated women with depression would have to tential conflict of interest relevant to this letter was reported. have been implausibly large for this factor to 1. Holmes LB, Westgate MN. Using ICD-9 codes to establish prevalence of malformations in newborn infants. Birth Defects explain our findings. (For details, see the SupRes A Clin Mol Teratol 2012;94:208-14. plementary Appendix, available with the full text 2. Huybrechts KF, Sanghani RS, Avorn J, Urato AC. Preterm birth of our article at NEJM.org.) This would also not and antidepressant medication use during pregnancy: a systemexplain differences from previous studies that atic review and meta-analysis. PLoS One 2014;9(3):e92778. 3. Margulis AV, Setoguchi S, Mittleman MA, Glynn RJ, Dor- were also restricted to live births. muth CR, Hernández-Díaz S. Algorithms to estimate the beginPoor documentation of other chronic health ning of pregnancy in administrative databases. Pharmacoepideconditions among patients taking antidepresmiol Drug Saf 2013;22:16-24. 4. Pratt LA, Brody DJ, Gu Q. Antidepressant use in persons sants is not a likely explanation, since more seaged 12 and over: United States, 2005-2008. NCHS Data Brief verely depressed patients have higher rates of 2011;76:1-8. recorded comorbidities. The association between DOI: 10.1056/NEJMc1409203 antidepressant use and cardiac defects was progressively attenuated by increasing adjustment The authors reply: The authors of both letters for an imbalance in the characteristics of paraise relevant concerns about misclassification. tients taking antidepressants and those who are
1168
n engl j med 371;12 nejm.org september 18, 2014
The New England Journal of Medicine Downloaded from nejm.org at UNIVERSITY OF WATERLOO on February 10, 2015. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
correspondence
not. This suggests that differences with previous studies may be explained by residual confounding in those studies. Our study addresses only one piece of the complex risk–benefit equation of antidepressant use in pregnancy, during which other risks associated with antidepressant use have been well documented. Our findings certainly do not justify incautious use of such drugs in these patients. Krista F. Huybrechts, Ph.D. Harvard Medical School Boston, MA
[email protected]
Sonia Hernández-Díaz, M.D., Dr.P.H. Harvard School of Public Health Boston, MA
Jerry Avorn, M.D.
Since publication of their article, the authors report no further potential conflict of interest. 1. Palmsten K, Huybrechts KF, Kowal MK, Mogun H, Hernán-
dez-Díaz S. Validity of maternal and infant outcomes within nationwide Medicaid data. Pharmacoepidemiol Drug Saf 2014; 23:646-55. 2. Toh S, Mitchell AA, Werler MM, Hernández-Díaz S. Sensitivity and specificity of computerized algorithms to classify gestational periods in the absence of information on date of conception. Am J Epidemiol 2008;167:633-40. 3. Cooper WO, Willy ME, Pont SJ, Ray WA. Increasing use of antidepressants in pregnancy. Am J Obstet Gynecol 2007; 196(6):544.e1-545.e1. 4. Mitchell AA, Gilboa SM, Werler MM, Kelley KE, Louik C, Hernandez-Diaz S. Medication use during pregnancy, with particular focus on prescription drugs: 1976-2008. Am J Obstet Gynecol 2011;205(1):51.e1-58.e1. 5. Huybrechts KF, Palmsten K, Mogun H, et al. National trends in antidepressant medication treatment among publicly insured pregnant women. Gen Hosp Psychiatry 2013;35:265-71. DOI: 10.1056/NEJMc1409203
Harvard Medical School Boston, MA
Diagnostic Clinical Genome and Exome Sequencing To the Editor: Biesecker and Green (June 19 issue)1 mention the recommendations by the American College of Medical Genetics and Genomics (ACMG) for laboratories to report incidental findings in clinical genome and exome sequencing (CGES) in a total of 56 genes (which, when mutated, cause an aggregate total of 24 disorders). Most of these conditions are associated with cancer or death from cardiovascular causes.2 Instead of focusing on relatively rare but treatable high-impact diseases, we suggest a greater focus on genetic causes of perhaps less threatening but treatable disorders that require specific treatments. Examples include diabetes caused by mutated HNF1A, with its strong response to sulfonylurea derivatives; sitosterolemia, with its strong response to ezetimibe and a specific diet; and Liddle’s syndrome, a genetic form of pseudo-aldosteronism, which can be treated with triamterene. The knowledge that a genetic mutation is the cause of treatable disease has direct consequences. Early case finding and screening might provide early and probably better, more specific treatment. We therefore suggest that the list of reported genetic conditions be expanded to genetic causes of diseases requiring specific treatments.
Jan Westerink, M.D., Ph.D. Frank L.J. Visseren, M.D., Ph.D. Wilko Spiering, M.D., Ph.D. University Medical Center Utrecht Utrecht, the Netherlands [email protected] No potential conflict of interest relevant to this letter was reported. 1. Biesecker LG, Green RC. Diagnostic clinical genome and
exome sequencing. N Engl J Med 2014;370:2418-25.
2. Green RC, Berg JS, Grody WW, et al. ACMG recommenda-
tions for reporting of incidental findings in clinical exome and genome sequencing. Genet Med 2013;15:565-74. DOI: 10.1056/NEJMc1408914
To the Editor: Biesecker and Green inform clinicians about indications for and limitations of CGES, and they offer concise, practical guidance on its effective and appropriate implementation. They do not discuss genetic counseling,1 a crucial element in implementing CGES. Genetic counselors are specialists with expertise in obtaining thorough, targeted family histories; identifying and addressing ethical issues (e.g., informed consent and communicating with at-risk family members) and psychosocial issues (e.g., guilt and fatalism) that are commonly attendant
n engl j med 371;12 nejm.org september 18, 2014
The New England Journal of Medicine Downloaded from nejm.org at UNIVERSITY OF WATERLOO on February 10, 2015. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
1169
