Letters
with autistic disorder, leading to a relatively small cumulative rate of 0.277%. In a recent report, Surén et al4 examined the association between maternal use of folic acid supplements and the risk of ASD in offspring based on data from another Scandinavian country; of the 270 children that had a diagnosis of ASD, less than half (n = 114) were diagnosed with autistic disorder. This suggests that there would be large number of patients with a broader diagnosis of ASD in the study cohort of Sandin and colleagues1 that should be sufficient for statistical analysis and could be studied to draw a more robust conclusion. Lei Feng, MB, PhD Author Affiliation: Department of Psychological Medicine, National University of Singapore, Singapore. Corresponding Author: Lei Feng, MB, PhD, National University of Singapore, NUHS Tower Block, 1 E Kent Ridge Rd, Singapore, Singapore 119228 (pcmfl@nus .edu.sg). Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and reported receiving grants from the Alice Lim Memorial Fund and the National University of Singapore. 1. Sandin S, Nygren KG, Iliadou A, Hultman CM, Reichenberg A. Autism and mental retardation among offspring born after in vitro fertilization. JAMA. 2013;310(1):75-84. 2. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Washington, DC: American Psychiatric Publishing; 2013. 3. Cedars MI. In vitro fertilization and risk of autistic disorder and mental retardation. JAMA. 2013;310(1):42-43. 4. Surén P, Roth C, Bresnahan M, et al. Association between maternal use of folic acid supplements and risk of autism spectrum disorders in children. JAMA. 2013;309(6):570-577.
In Reply Our study focused on the narrow category of autistic disorder (infantile/childhood autism) and on mental retardation. We did not examine whether IVF was related to other diagnoses within the ASD category. The focus on autistic disorder was implemented to maximize diagnostic consistency across classification schemes and increase accuracy.1 Including ASDs in the outcome could potentially introduce residual confounding or confounding by calendar time because until 1999, only diagnoses obtained from hospitalized patients were reported to the Swedish registry. Information about diagnosis in outpatient clinics (where less severe cases of autism are most likely to be managed) was only introduced later. Also, recent modifications introduced to the diagnostic criteria for ASDs in the DSM-5 have been shown to result in a more stringent diagnostic threshold that excludes a substantial portion of individuals with ASDs other than autistic disorder.2 Dr Feng points out that there should be sufficient power to analyze ASDs. The issue of power, however, should be weighed against diagnostic specificity. We agree with Feng that studying ASDs is of great importance. We found no association between IVF and autistic disorder after adjustment for confounding factors. One could speculate about the results if the outcome of ASD was ana-
lyzed. If, as Feng suggests, autistic disorder and ASD share origins, then the results for spectrum disorders should be identical to those obtained for autistic disorder (ie, no association), and it would have been possible to conclude that the results are robust to diagnostic classification. However, if the results were different (ie, an observed association between spectrum disorders and IVF), then the results could be interpreted as either residual confounding or due to differences in origin between the autistic disorder and the spectrum cases. However, it would be impossible to show which of these 2 interpretations is the most valid. Like Feng, we look forward to future studies examining possible issues related to autism origin, phenotypic heterogeneity, and diagnostic specificity in relation to IVF treatments. Sven Sandin, MSc Christina Hultman, PhD Abraham Reichenberg, PhD Author Affiliations: Institute of Psychiatry, King’s College London, London, England (Sandin, Reichenberg); Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden (Hultman). Corresponding Author: Sven Sandi, MSc, Institute of Psychiatry, King’s College De Crespigny Park, London SE5 8AF, England ([email protected]). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. 1. Hultman CM, Sandin S, Levine SZ, Lichtenstein P, Reichenberg A. Advancing paternal age and risk of autism: new evidence from a population-based study and a meta-analysis of epidemiological studies. Mol Psychiatry. 2011;16(12):1203-1212. 2. McPartland JC, Reichow B, Volkmar FR. Sensitivity and specificity of proposed DSM-5 diagnostic criteria for autism spectrum disorder. J Am Acad Child Adolesc Psychiatry. 2012;51(4):368-383.
Breast Cancer Screening Recommendations To the Editor When discussing results of mammography screening trials, Dr Marmot1 concluded that “Meta-analysis of these trials with 13 years of follow-up estimated a 20% reduction in breast cancer mortality among women invited for screening.” This meta-analysis2 was based on 11 randomized controlled trials, most of them undertaken before the era of modern adjuvant systemic therapy for breast cancer. Marmot failed to point out that adjuvant systemic therapy will substantially reduce the benefit of mammography screening. Indeed, as the overall treatment of breast cancer improves, the benefit of screening will diminish. It is therefore important to note that in the 3 more recent trials included in the meta-analysis (Canadian National Breast Screening Study-1 and -2 and the UK Age trial),3-5 when adjuvant systemic therapy was widely available, mammography screening had no significant benefit in reducing breast cancer mortality. Moreover, population-based studies also suggest that the benefit of mammography screening has diminished over time as better breast cancer adjuvant systemic treatments have been introduced. Thus, the meta-analysis substantially overestimates the benefit of mammography screening in the population today when adjuvant systemic therapy is widely used. Ismail Jatoi, MD, PhD
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JAMA November 20, 2013 Volume 310, Number 19
Copyright 2013 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a University of Tasmania User on 05/21/2015
2101
Letters
Author Affiliation: Division of Surgical Oncology, University of Texas Health Science Center, San Antonio. Corresponding Author: Ismail Jatoi, MD, PhD, University of Texas Health Science Center, 7703 Floyd Curl Dr, Mail Code 7738, San Antonio, TX 78229 ([email protected]).
Michael G. Marmot, MBBS, MPH, PhD
Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.
Author Affiliation: Department of Epidemiology and Public Health, Institute of Health Equity at University College, London, England.
1. Marmot MG. Sorting through the arguments on breast screening. JAMA. 2013;309(24):2553-2554.
Corresponding Author: Michael G. Marmot, MBBS, MPH, PhD, University College of London, 1-19 Torrington Pl, London WC1E 7HB, England (m.marmot @ucl.ac.uk).
2. Independent UK Panel on Breast Cancer Screening. The benefits and harms of breast cancer screening: an independent review. Lancet. 2012;380(9855): 1778-1786. 3. Miller AB, To T, Baines CJ, Wall C. Canadian National Breast Screening Study-2: 13-year results of a randomized trial in women aged 50-59 years. J Natl Cancer Inst. 2000;92(18):1490-1499. 4. Miller AB, To T, Baines CJ, Wall C. The Canadian National Breast Screening Study-1: breast cancer mortality after 11 to 16 years of follow-up: a randomized screening trial of mammography in women age 40 to 49 years. Ann Intern Med. 2002;137(5 part 1):305-312. 5. Moss SM, Cuckle H, Evans A, Johns L, Waller M, Bobrow L; Trial Management Group. Effect of mammographic screening from age 40 years on breast cancer mortality at 10 years’ follow-up: a randomised controlled trial. Lancet. 2006;368(9552):2053-2060.
In Reply The suggestion that modern treatment, especially adjuvant systemic therapy, might render breast cancer screening unnecessary was put to the Independent UK Panel on Breast Cancer Screening by expert witnesses, as was the counter view that breast cancer screening, by achieving earlier diagnosis, could make systemic therapy more effective. This issue was discussed in the full report in which the Panel concluded that there was no convincing evidence that one or the other view was more likely to be correct.1 Given the uncertainty, the benefits of treatment and screening are best viewed as independent. The dates when the trials were conducted does not provide convincing evidence. Dr Jatoi refers to “later trials,” the Canadian National Breast Screening Study-1 and -22,3 and the UK Age trial,4 showing less benefit. But the Canadian trials were started in 1980, similar to the Swedish trials included in the meta-analysis that were started in 1976 to 1982. Jatoi is correct that the UK Age trial did start 10 years later (in 1990). But the risk reduction of 17% in that trial was little different from the 20% risk reduction derived from the meta-analysis of all 11 trials. Jatoi is more convinced by the observational studies than am I. The Panel read much of this extensive literature and took evidence from several of the leading authors.1 The Panel noted the fierce controversy that surrounds studies that compare areas or examine time trends (in large measure because of the unresolved biases in comparisons) and due to questions over how assumptions were made. The contemporary case-control studies, in general, show larger beneficial effects of screening than do the older trials. Similarly, incidence-based mortality studies show breast cancer screening to be effective. But the Panel was not convinced that these modern studies were free of bias. Hence, the Panel relied on the trials as providing more reliable evidence for an estimate of mortality reduction. That said, the obser-
2102
vational studies support the hypothesis that screening continues to be beneficial in an era of improved treatment.
Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and reported being the chair of the Independent UK Panel on Breast Screening. 1. Independent UK Panel on Breast Cancer Screening. The benefits and harms of breast cancer screening: an independent review. http://www.cancerresearchuk.org /prod_consump/groups/cr_common/@nre/@hea/documents/generalcontent /ibsr-fullreport.pdf. Accessibility verified October 18, 2013. 2. Miller AB, To T, Baines CJ, Wall C. The Canadian National Breast Screening Study-1: breast cancer mortality after 11 to 16 years of follow-up: a randomized screening trial of mammography in women age 40 to 49 years. Ann Intern Med. 2002;137(5 part 1):305-312. 3. Miller AB, To T, Baines CJ, Wall C. Canadian National Breast Screening Study-2: 13-year results of a randomized trial in women aged 50-59 years. J Natl Cancer Inst. 2000;92(18):1490-1499. 4. Moss SM, Cuckle H, Evans A, Johns L, Waller M, Bobrow L; Trial Management Group. Effect of mammographic screening from age 40 years on breast cancer mortality at 10 years’ follow-up: a randomised controlled trial. Lancet. 2006;368(9552):2053-2060.
CORRECTION Incorrect Word in Results Section: In the Original Investigation entitled “Views of US Physicians About Controlling Health Care Costs” published in the July 24/31, 2013, issue of JAMA (2013;310[4]:380-388. doi:10.1001/jama.2013.8278), the wrong word was used in the Results section. In the second paragraph under “Professional Role in Cost-Containment and Cost-Consciousness Scale,” the final sentence should have read, “However, an equal majority (85%) disagreed …” (instead of “agreed”). This article was corrected online.
Guidelines for Letters Letters discussing a recent JAMA article should be submitted within 4 weeks of the article's publication in print. Letters received after 4 weeks will rarely be considered. Letters should not exceed 400 words of text and 5 references and may have no more than 3 authors. Letters reporting original research should not exceed 600 words of text and 6 references and may have no more than 5 authors. They may include up to 2 tables or figures but online supplementary material is not allowed. All letters should include a word count. Letters must not duplicate other material published or submitted for publication. Letters not meeting these specifications are generally not considered. Letters being considered for publication ordinarily will be sent to the authors of the JAMA article, who will be given the opportunity to reply. Letters will be published at the discretion of the editors and are subject to abridgement and editing. Further instructions can be found at http://jama.com/public /InstructionsForAuthors.aspx. A signed statement for authorship criteria and responsibility, financial disclosure, copyright transfer, and acknowledgment and the ICMJE Form for Disclosure of Potential Conflicts of Interest are required before publication. Letters should be submitted via the JAMA online submission and review system at http: //manuscripts.jama.com. For technical assistance, please contact [email protected]. Section Editor: Jody W. Zylke, MD, Senior Editor.
JAMA November 20, 2013 Volume 310, Number 19
Copyright 2013 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a University of Tasmania User on 05/21/2015
jama.com
with autistic disorder, leading to a relatively small cumulative rate of 0.277%. In a recent report, Surén et al4 examined the association between maternal use of folic acid supplements and the risk of ASD in offspring based on data from another Scandinavian country; of the 270 children that had a diagnosis of ASD, less than half (n = 114) were diagnosed with autistic disorder. This suggests that there would be large number of patients with a broader diagnosis of ASD in the study cohort of Sandin and colleagues1 that should be sufficient for statistical analysis and could be studied to draw a more robust conclusion. Lei Feng, MB, PhD Author Affiliation: Department of Psychological Medicine, National University of Singapore, Singapore. Corresponding Author: Lei Feng, MB, PhD, National University of Singapore, NUHS Tower Block, 1 E Kent Ridge Rd, Singapore, Singapore 119228 (pcmfl@nus .edu.sg). Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and reported receiving grants from the Alice Lim Memorial Fund and the National University of Singapore. 1. Sandin S, Nygren KG, Iliadou A, Hultman CM, Reichenberg A. Autism and mental retardation among offspring born after in vitro fertilization. JAMA. 2013;310(1):75-84. 2. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Washington, DC: American Psychiatric Publishing; 2013. 3. Cedars MI. In vitro fertilization and risk of autistic disorder and mental retardation. JAMA. 2013;310(1):42-43. 4. Surén P, Roth C, Bresnahan M, et al. Association between maternal use of folic acid supplements and risk of autism spectrum disorders in children. JAMA. 2013;309(6):570-577.
In Reply Our study focused on the narrow category of autistic disorder (infantile/childhood autism) and on mental retardation. We did not examine whether IVF was related to other diagnoses within the ASD category. The focus on autistic disorder was implemented to maximize diagnostic consistency across classification schemes and increase accuracy.1 Including ASDs in the outcome could potentially introduce residual confounding or confounding by calendar time because until 1999, only diagnoses obtained from hospitalized patients were reported to the Swedish registry. Information about diagnosis in outpatient clinics (where less severe cases of autism are most likely to be managed) was only introduced later. Also, recent modifications introduced to the diagnostic criteria for ASDs in the DSM-5 have been shown to result in a more stringent diagnostic threshold that excludes a substantial portion of individuals with ASDs other than autistic disorder.2 Dr Feng points out that there should be sufficient power to analyze ASDs. The issue of power, however, should be weighed against diagnostic specificity. We agree with Feng that studying ASDs is of great importance. We found no association between IVF and autistic disorder after adjustment for confounding factors. One could speculate about the results if the outcome of ASD was ana-
lyzed. If, as Feng suggests, autistic disorder and ASD share origins, then the results for spectrum disorders should be identical to those obtained for autistic disorder (ie, no association), and it would have been possible to conclude that the results are robust to diagnostic classification. However, if the results were different (ie, an observed association between spectrum disorders and IVF), then the results could be interpreted as either residual confounding or due to differences in origin between the autistic disorder and the spectrum cases. However, it would be impossible to show which of these 2 interpretations is the most valid. Like Feng, we look forward to future studies examining possible issues related to autism origin, phenotypic heterogeneity, and diagnostic specificity in relation to IVF treatments. Sven Sandin, MSc Christina Hultman, PhD Abraham Reichenberg, PhD Author Affiliations: Institute of Psychiatry, King’s College London, London, England (Sandin, Reichenberg); Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden (Hultman). Corresponding Author: Sven Sandi, MSc, Institute of Psychiatry, King’s College De Crespigny Park, London SE5 8AF, England ([email protected]). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. 1. Hultman CM, Sandin S, Levine SZ, Lichtenstein P, Reichenberg A. Advancing paternal age and risk of autism: new evidence from a population-based study and a meta-analysis of epidemiological studies. Mol Psychiatry. 2011;16(12):1203-1212. 2. McPartland JC, Reichow B, Volkmar FR. Sensitivity and specificity of proposed DSM-5 diagnostic criteria for autism spectrum disorder. J Am Acad Child Adolesc Psychiatry. 2012;51(4):368-383.
Breast Cancer Screening Recommendations To the Editor When discussing results of mammography screening trials, Dr Marmot1 concluded that “Meta-analysis of these trials with 13 years of follow-up estimated a 20% reduction in breast cancer mortality among women invited for screening.” This meta-analysis2 was based on 11 randomized controlled trials, most of them undertaken before the era of modern adjuvant systemic therapy for breast cancer. Marmot failed to point out that adjuvant systemic therapy will substantially reduce the benefit of mammography screening. Indeed, as the overall treatment of breast cancer improves, the benefit of screening will diminish. It is therefore important to note that in the 3 more recent trials included in the meta-analysis (Canadian National Breast Screening Study-1 and -2 and the UK Age trial),3-5 when adjuvant systemic therapy was widely available, mammography screening had no significant benefit in reducing breast cancer mortality. Moreover, population-based studies also suggest that the benefit of mammography screening has diminished over time as better breast cancer adjuvant systemic treatments have been introduced. Thus, the meta-analysis substantially overestimates the benefit of mammography screening in the population today when adjuvant systemic therapy is widely used. Ismail Jatoi, MD, PhD
jama.com
JAMA November 20, 2013 Volume 310, Number 19
Copyright 2013 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a University of Tasmania User on 05/21/2015
2101
Letters
Author Affiliation: Division of Surgical Oncology, University of Texas Health Science Center, San Antonio. Corresponding Author: Ismail Jatoi, MD, PhD, University of Texas Health Science Center, 7703 Floyd Curl Dr, Mail Code 7738, San Antonio, TX 78229 ([email protected]).
Michael G. Marmot, MBBS, MPH, PhD
Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.
Author Affiliation: Department of Epidemiology and Public Health, Institute of Health Equity at University College, London, England.
1. Marmot MG. Sorting through the arguments on breast screening. JAMA. 2013;309(24):2553-2554.
Corresponding Author: Michael G. Marmot, MBBS, MPH, PhD, University College of London, 1-19 Torrington Pl, London WC1E 7HB, England (m.marmot @ucl.ac.uk).
2. Independent UK Panel on Breast Cancer Screening. The benefits and harms of breast cancer screening: an independent review. Lancet. 2012;380(9855): 1778-1786. 3. Miller AB, To T, Baines CJ, Wall C. Canadian National Breast Screening Study-2: 13-year results of a randomized trial in women aged 50-59 years. J Natl Cancer Inst. 2000;92(18):1490-1499. 4. Miller AB, To T, Baines CJ, Wall C. The Canadian National Breast Screening Study-1: breast cancer mortality after 11 to 16 years of follow-up: a randomized screening trial of mammography in women age 40 to 49 years. Ann Intern Med. 2002;137(5 part 1):305-312. 5. Moss SM, Cuckle H, Evans A, Johns L, Waller M, Bobrow L; Trial Management Group. Effect of mammographic screening from age 40 years on breast cancer mortality at 10 years’ follow-up: a randomised controlled trial. Lancet. 2006;368(9552):2053-2060.
In Reply The suggestion that modern treatment, especially adjuvant systemic therapy, might render breast cancer screening unnecessary was put to the Independent UK Panel on Breast Cancer Screening by expert witnesses, as was the counter view that breast cancer screening, by achieving earlier diagnosis, could make systemic therapy more effective. This issue was discussed in the full report in which the Panel concluded that there was no convincing evidence that one or the other view was more likely to be correct.1 Given the uncertainty, the benefits of treatment and screening are best viewed as independent. The dates when the trials were conducted does not provide convincing evidence. Dr Jatoi refers to “later trials,” the Canadian National Breast Screening Study-1 and -22,3 and the UK Age trial,4 showing less benefit. But the Canadian trials were started in 1980, similar to the Swedish trials included in the meta-analysis that were started in 1976 to 1982. Jatoi is correct that the UK Age trial did start 10 years later (in 1990). But the risk reduction of 17% in that trial was little different from the 20% risk reduction derived from the meta-analysis of all 11 trials. Jatoi is more convinced by the observational studies than am I. The Panel read much of this extensive literature and took evidence from several of the leading authors.1 The Panel noted the fierce controversy that surrounds studies that compare areas or examine time trends (in large measure because of the unresolved biases in comparisons) and due to questions over how assumptions were made. The contemporary case-control studies, in general, show larger beneficial effects of screening than do the older trials. Similarly, incidence-based mortality studies show breast cancer screening to be effective. But the Panel was not convinced that these modern studies were free of bias. Hence, the Panel relied on the trials as providing more reliable evidence for an estimate of mortality reduction. That said, the obser-
2102
vational studies support the hypothesis that screening continues to be beneficial in an era of improved treatment.
Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and reported being the chair of the Independent UK Panel on Breast Screening. 1. Independent UK Panel on Breast Cancer Screening. The benefits and harms of breast cancer screening: an independent review. http://www.cancerresearchuk.org /prod_consump/groups/cr_common/@nre/@hea/documents/generalcontent /ibsr-fullreport.pdf. Accessibility verified October 18, 2013. 2. Miller AB, To T, Baines CJ, Wall C. The Canadian National Breast Screening Study-1: breast cancer mortality after 11 to 16 years of follow-up: a randomized screening trial of mammography in women age 40 to 49 years. Ann Intern Med. 2002;137(5 part 1):305-312. 3. Miller AB, To T, Baines CJ, Wall C. Canadian National Breast Screening Study-2: 13-year results of a randomized trial in women aged 50-59 years. J Natl Cancer Inst. 2000;92(18):1490-1499. 4. Moss SM, Cuckle H, Evans A, Johns L, Waller M, Bobrow L; Trial Management Group. Effect of mammographic screening from age 40 years on breast cancer mortality at 10 years’ follow-up: a randomised controlled trial. Lancet. 2006;368(9552):2053-2060.
CORRECTION Incorrect Word in Results Section: In the Original Investigation entitled “Views of US Physicians About Controlling Health Care Costs” published in the July 24/31, 2013, issue of JAMA (2013;310[4]:380-388. doi:10.1001/jama.2013.8278), the wrong word was used in the Results section. In the second paragraph under “Professional Role in Cost-Containment and Cost-Consciousness Scale,” the final sentence should have read, “However, an equal majority (85%) disagreed …” (instead of “agreed”). This article was corrected online.
Guidelines for Letters Letters discussing a recent JAMA article should be submitted within 4 weeks of the article's publication in print. Letters received after 4 weeks will rarely be considered. Letters should not exceed 400 words of text and 5 references and may have no more than 3 authors. Letters reporting original research should not exceed 600 words of text and 6 references and may have no more than 5 authors. They may include up to 2 tables or figures but online supplementary material is not allowed. All letters should include a word count. Letters must not duplicate other material published or submitted for publication. Letters not meeting these specifications are generally not considered. Letters being considered for publication ordinarily will be sent to the authors of the JAMA article, who will be given the opportunity to reply. Letters will be published at the discretion of the editors and are subject to abridgement and editing. Further instructions can be found at http://jama.com/public /InstructionsForAuthors.aspx. A signed statement for authorship criteria and responsibility, financial disclosure, copyright transfer, and acknowledgment and the ICMJE Form for Disclosure of Potential Conflicts of Interest are required before publication. Letters should be submitted via the JAMA online submission and review system at http: //manuscripts.jama.com. For technical assistance, please contact [email protected]. Section Editor: Jody W. Zylke, MD, Senior Editor.
JAMA November 20, 2013 Volume 310, Number 19
Copyright 2013 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a University of Tasmania User on 05/21/2015
jama.com
![[Breast cancer screening].](/assets/img/hold.png)
