Letters
would have attenuated any relationships we found between perioperative AF and stroke, and would therefore have biased our study toward the null hypothesis. We agree with Dr Tricoci that the different strengths of association between perioperative AF and stroke after cardiac vs noncardiac surgery may be partly attributable to unmeasured differences in antithrombotic drug use in these 2 populations. Because patients undergoing cardiac surgery often have coronary or valvular disease, they may have received more intensive medical management of vascular risk factors and this may have attenuated the relationship between perioperative AF and subsequent stroke in comparison with the noncardiac surgery group. We also agree that further research is indicated to better identify predictors of stroke in patients with perioperative AF and determine the risks and benefits of anticoagulant therapy in this population. Gino Gialdini, MD Prashant D. Bhave, MD Hooman Kamel, MD Author Affiliations: Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York, New York (Gialdini); Division of Cardiology, University of Iowa Carver College of Medicine, Iowa City (Bhave); Department of Neurology, Weill Cornell Medical College, New York, New York (Kamel). Corresponding Author: Hooman Kamel, MD, Department of Neurology, Weill Cornell Medical College, 407 E 61st St, New York, NY 10065 (hok9010@med .cornell.edu). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Kamel reported serving on a medical advisory board and a speakers bureau for Genentech. No other disclosures were reported. 1. Bhave PD, Goldman LE, Vittinghoff E, Maselli J, Auerbach A. Incidence, predictors, and outcomes associated with postoperative atrial fibrillation after major noncardiac surgery. Am Heart J. 2012;164(6):918-924.
Colorectal Cancer and the Effect of Flexible Sigmoidoscopy Screening To the Editor In the study of flexible sigmoidoscopy screening and colorectal cancer incidence and mortality by Dr Holme and colleagues,1 the authors reported adjusted analyses of results without reporting either the measured results or the implications of their adjustments. Based on the data available in the article, the relative risk for colorectal cancer mortality in the screening vs control groups is 0.82 (95% CI, 0.63-1.06) and the rate ratio is 0.80 (95% CI, 0.61-1.04); neither are statistically significant. The relative risk for all-cause mortality is 1.07 (95% CI, 1.02-1.12) and the rate ratio is 1.05 (95% CI, 1.00-1.10); both are statistically significant increases. The relative risk for colorectal cancer incidence in the screening vs control groups is 0.89 (95% CI, 0.77-1.02) and the rate ratio is 0.88 (95% CI, 0.77-1.01); these are much smaller than the reported adjusted outcomes. The authors’ apparent post hoc age adjustment changes the trial results from net harm of screening (significant increase in all-cause mortality) to net benefit (significant decreases in colorectal cancer mortality and incidence). This adjustment is difficult to embrace.
The first cohort was randomized in 1998 and the second by 2001. The 20022 and 20033 articles from this trial make no mention of an age disparity and the 20094 article explicitly states that “the two groups were similar in the distribution of age.” After 11 years of follow up, has an age disparity been discovered? More attention should be given to the measured results of the previously specified outcomes. Reporting only post hoc– adjusted results does not seem valid, especially when it creates a reversal in the statistical significance of the outcomes. Andrew W. Swartz, MD Author Affiliation: Yukon Kuskokwim Health Corporation, Bethel, Alaska. Corresponding Author: Andrew W. Swartz, MD, Yukon Kuskokwim Health Corporation, 6306 Tay Circle, Anchorage, AK 99502 ([email protected]). Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and reported that he has a sole proprietor software company through which he has created a custom endoscopy image processing program used exclusively by his affiliated institution. 1. Holme Ø, Løberg M, Kalager M, et al. Effect of flexible sigmoidoscopy screening on colorectal cancer incidence and mortality: a randomized clinical trial. JAMA. 2014;312(6):606-615. 2. Bretthauer M, Gondal G, Larsen K, et al. Design, organization and management of a controlled population screening study for detection of colorectal neoplasia: attendance rates in the NORCCAP study (Norwegian Colorectal Cancer Prevention). Scand J Gastroenterol. 2002;37(5):568-573. 3. Gondal G, Grotmol T, Hofstad B, Bretthauer M, Eide TJ, Hoff G. The Norwegian Colorectal Cancer Prevention (NORCCAP) screening study: baseline findings and implementations for clinical work-up in age groups 50-64 years. Scand J Gastroenterol. 2003;38(6):635-642. 4. Hoff G, Grotmol T, Skovlund E, et al Risk of colorectal cancer seven years after flexible sigmoidoscopy screening: randomised controlled trial [published online May 29, 2009]. BMJ. doi:10.1136/bmj.b1846.
In Reply Dr Swartz is concerned because the effect estimates reported in our study were standardized by age group (classified as 50-54 vs 55-64 years) and because previously published articles from the Norwegian Colorectal Cancer Prevention (NORCCAP) trial did not standardize for age. Previous articles included only the 55- to 64-year age group (or only the screening group) and therefore had no need to consider this issue. Our article is the first to report results for the 50- to 54-year-old age group (including the control group), and therefore we had to consider the different age distribution between the screening and control groups in the analysis. Because of the uneven ratio between screening and control individuals in the 55- to 64-year group compared with the 50- to 54-year group (1:3 vs 1:5.4, respectively), individuals in the control group were on average younger than in the screening groups (56.1 and 56.9 years, respectively). As a result, a valid analysis of the trial data could not ignore the variable age group. To understand our approach, consider both age groups separately. Because of the randomized design, treatment effects are unconfounded within both the 50- to 54-year and the 55- to 64-year groups. However, pooling both age groups into a single unadjusted analysis may introduce confounding by age group.
jama.com
JAMA December 10, 2014 Volume 312, Number 22
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a Ndsu Library Periodicals User on 06/03/2015
2411
Letters
Table. Colorectal Cancer Incidence, Mortality, and All-Cause Mortality by Age Group Cases, No. Screening
Person-Time, y
Control
Screening
Control
Nonstandardized RR (95% CI)
Unadjusted HR (95% CI)
Age-Standardized RR (95% CI)
Age-Adjusted HR (95% CI)
0.80 (0.70-0.92)
0.80 (0.70-0.92)
0.73 (0.56-0.94)
0.73 (0.56-0.94)
0.97 (0.93-1.02)
0.97 (0.93-1.02)
Colorectal cancer incidence by age group, y 50-54
40
315
69 960
373 671
0.68 (0.48-0.94)
55-64
213
771
151 469
454 536
0.83 (0.71-0.97)
0.68 (0.49-0.94) 0.83 (0.71-0.96)
50-64
253
1086
221 429
828 207
0.88 (0.77-1.01)a
0.86 (0.75-0.98)a
0.74 (0.40-1.35)
Colorectal cancer mortality by age group, y 50-54
12
87
70 166
374 762
0.74 (0.37-1.35)
55-64
59
243
152 511
457 241
0.73 (0.54-0.97)
0.73 (0.55-0.97)
50-64
71
330
222 677
832 003
0.80 (0.61-1.04)a
0.79 (0.61-1.02)a
50-54
427
2387
70 166
374 762
0.96 (0.86-1.06)
0.96 (0.86-1.05)
55-64
1756
5375
152 511
457 241
0.98 (0.93-1.03)
0.98 (0.93-1.03)
50-64
2183
7762
222 677
832 003
1.05 (1.00-1.10)a
1.04 (0.99-1.09)a
All-cause mortality by age group, y
Abbreviations: HR, hazard ratio; RR, rate ratio. a
Indicated results are biased.
The Table displays the rate ratios and hazard ratios for the 2 age groups separately and combined. For example, the rate ratio of colorectal cancer incidence is 0.68 in the 50- to 54-year age group and 0.83 in the 55- to 64-year age group. However, for the 2 age groups combined, the nonstandardized (unadjusted) rate ratio is 0.88, which is higher than the agespecific analyses and obviously incorrect. This artifact is well known in the meta-analysis of randomized trials and the reason why individual data from different trials cannot be naively pooled into a single data set. Rather, effect estimates are obtained separately in each trial and then pooled into a single measure. That is approximately what we did via standardization by age group. The Table shows that standardization (using the screening group as the standard) or age adjustment via a Cox model provide similar results. Øyvind Holme, MD Magnus Loberg, MD Mette Kalager, MD, PhD Author Affiliations: Institute of Health and Society, University of Oslo, Oslo, Norway. Corresponding Author: Øyvind Holme, MD, Institute of Health and Society, University of Oslo and Sorlandet Hospital Kristiansand, Postboks 416, 4604 Kristiansand, Norway ([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.
Routine Depression Screening for Patients With Diabetes To the Editor Ms Ducat and colleagues1 recommended routinely screening patients with diabetes for depression. They cited the American Diabetes Association (ADA) standards of 2412
care2 to support this recommendation. However, neither the ADA standards nor Ducat et al cite any evidence from randomized clinical trials (RCTs) that screening for depression would reduce the burden of depression among patients with diabetes. No appropriately designed and well-conducted trials in such patients or any other patient group have demonstrated that sc reening for depression improves depression outcomes when patients who are screened and provided quality depression care are compared with patients who are not screened but who may be identified as depressed via other mechanisms, such as self-report or clinician recognition, and receive similar depression care if identified as depressed.3,4 It should not be assumed, without evidence, that depression screening would benefit patients. Available screening tools tend to have high false-positive rates when used with patients not already identified as depressed or receiving treatment for depression. Standard depression treatments tend to benefit patients with high levels of depressive symptoms but may not provide substantive benefits to patients with less severe symptoms who would not be identified without the use of a screening questionnaire.3 Depression screening could unintentionally harm some patients. Some patients who receive antidepressant medication following a positive depression screen result and assessment will not benefit but will experience unpleasant, and in some cases dangerous, adverse effects. In addition, for some patients not otherwise concerned about their mental health, a positive screen result may undermine their sense of wellbeing and could function as a nocebo, by which the suggestion of impairment may lead to the development or worsening of symptoms.3
JAMA December 10, 2014 Volume 312, Number 22
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a Ndsu Library Periodicals User on 06/03/2015
jama.com
would have attenuated any relationships we found between perioperative AF and stroke, and would therefore have biased our study toward the null hypothesis. We agree with Dr Tricoci that the different strengths of association between perioperative AF and stroke after cardiac vs noncardiac surgery may be partly attributable to unmeasured differences in antithrombotic drug use in these 2 populations. Because patients undergoing cardiac surgery often have coronary or valvular disease, they may have received more intensive medical management of vascular risk factors and this may have attenuated the relationship between perioperative AF and subsequent stroke in comparison with the noncardiac surgery group. We also agree that further research is indicated to better identify predictors of stroke in patients with perioperative AF and determine the risks and benefits of anticoagulant therapy in this population. Gino Gialdini, MD Prashant D. Bhave, MD Hooman Kamel, MD Author Affiliations: Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York, New York (Gialdini); Division of Cardiology, University of Iowa Carver College of Medicine, Iowa City (Bhave); Department of Neurology, Weill Cornell Medical College, New York, New York (Kamel). Corresponding Author: Hooman Kamel, MD, Department of Neurology, Weill Cornell Medical College, 407 E 61st St, New York, NY 10065 (hok9010@med .cornell.edu). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Kamel reported serving on a medical advisory board and a speakers bureau for Genentech. No other disclosures were reported. 1. Bhave PD, Goldman LE, Vittinghoff E, Maselli J, Auerbach A. Incidence, predictors, and outcomes associated with postoperative atrial fibrillation after major noncardiac surgery. Am Heart J. 2012;164(6):918-924.
Colorectal Cancer and the Effect of Flexible Sigmoidoscopy Screening To the Editor In the study of flexible sigmoidoscopy screening and colorectal cancer incidence and mortality by Dr Holme and colleagues,1 the authors reported adjusted analyses of results without reporting either the measured results or the implications of their adjustments. Based on the data available in the article, the relative risk for colorectal cancer mortality in the screening vs control groups is 0.82 (95% CI, 0.63-1.06) and the rate ratio is 0.80 (95% CI, 0.61-1.04); neither are statistically significant. The relative risk for all-cause mortality is 1.07 (95% CI, 1.02-1.12) and the rate ratio is 1.05 (95% CI, 1.00-1.10); both are statistically significant increases. The relative risk for colorectal cancer incidence in the screening vs control groups is 0.89 (95% CI, 0.77-1.02) and the rate ratio is 0.88 (95% CI, 0.77-1.01); these are much smaller than the reported adjusted outcomes. The authors’ apparent post hoc age adjustment changes the trial results from net harm of screening (significant increase in all-cause mortality) to net benefit (significant decreases in colorectal cancer mortality and incidence). This adjustment is difficult to embrace.
The first cohort was randomized in 1998 and the second by 2001. The 20022 and 20033 articles from this trial make no mention of an age disparity and the 20094 article explicitly states that “the two groups were similar in the distribution of age.” After 11 years of follow up, has an age disparity been discovered? More attention should be given to the measured results of the previously specified outcomes. Reporting only post hoc– adjusted results does not seem valid, especially when it creates a reversal in the statistical significance of the outcomes. Andrew W. Swartz, MD Author Affiliation: Yukon Kuskokwim Health Corporation, Bethel, Alaska. Corresponding Author: Andrew W. Swartz, MD, Yukon Kuskokwim Health Corporation, 6306 Tay Circle, Anchorage, AK 99502 ([email protected]). Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and reported that he has a sole proprietor software company through which he has created a custom endoscopy image processing program used exclusively by his affiliated institution. 1. Holme Ø, Løberg M, Kalager M, et al. Effect of flexible sigmoidoscopy screening on colorectal cancer incidence and mortality: a randomized clinical trial. JAMA. 2014;312(6):606-615. 2. Bretthauer M, Gondal G, Larsen K, et al. Design, organization and management of a controlled population screening study for detection of colorectal neoplasia: attendance rates in the NORCCAP study (Norwegian Colorectal Cancer Prevention). Scand J Gastroenterol. 2002;37(5):568-573. 3. Gondal G, Grotmol T, Hofstad B, Bretthauer M, Eide TJ, Hoff G. The Norwegian Colorectal Cancer Prevention (NORCCAP) screening study: baseline findings and implementations for clinical work-up in age groups 50-64 years. Scand J Gastroenterol. 2003;38(6):635-642. 4. Hoff G, Grotmol T, Skovlund E, et al Risk of colorectal cancer seven years after flexible sigmoidoscopy screening: randomised controlled trial [published online May 29, 2009]. BMJ. doi:10.1136/bmj.b1846.
In Reply Dr Swartz is concerned because the effect estimates reported in our study were standardized by age group (classified as 50-54 vs 55-64 years) and because previously published articles from the Norwegian Colorectal Cancer Prevention (NORCCAP) trial did not standardize for age. Previous articles included only the 55- to 64-year age group (or only the screening group) and therefore had no need to consider this issue. Our article is the first to report results for the 50- to 54-year-old age group (including the control group), and therefore we had to consider the different age distribution between the screening and control groups in the analysis. Because of the uneven ratio between screening and control individuals in the 55- to 64-year group compared with the 50- to 54-year group (1:3 vs 1:5.4, respectively), individuals in the control group were on average younger than in the screening groups (56.1 and 56.9 years, respectively). As a result, a valid analysis of the trial data could not ignore the variable age group. To understand our approach, consider both age groups separately. Because of the randomized design, treatment effects are unconfounded within both the 50- to 54-year and the 55- to 64-year groups. However, pooling both age groups into a single unadjusted analysis may introduce confounding by age group.
jama.com
JAMA December 10, 2014 Volume 312, Number 22
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a Ndsu Library Periodicals User on 06/03/2015
2411
Letters
Table. Colorectal Cancer Incidence, Mortality, and All-Cause Mortality by Age Group Cases, No. Screening
Person-Time, y
Control
Screening
Control
Nonstandardized RR (95% CI)
Unadjusted HR (95% CI)
Age-Standardized RR (95% CI)
Age-Adjusted HR (95% CI)
0.80 (0.70-0.92)
0.80 (0.70-0.92)
0.73 (0.56-0.94)
0.73 (0.56-0.94)
0.97 (0.93-1.02)
0.97 (0.93-1.02)
Colorectal cancer incidence by age group, y 50-54
40
315
69 960
373 671
0.68 (0.48-0.94)
55-64
213
771
151 469
454 536
0.83 (0.71-0.97)
0.68 (0.49-0.94) 0.83 (0.71-0.96)
50-64
253
1086
221 429
828 207
0.88 (0.77-1.01)a
0.86 (0.75-0.98)a
0.74 (0.40-1.35)
Colorectal cancer mortality by age group, y 50-54
12
87
70 166
374 762
0.74 (0.37-1.35)
55-64
59
243
152 511
457 241
0.73 (0.54-0.97)
0.73 (0.55-0.97)
50-64
71
330
222 677
832 003
0.80 (0.61-1.04)a
0.79 (0.61-1.02)a
50-54
427
2387
70 166
374 762
0.96 (0.86-1.06)
0.96 (0.86-1.05)
55-64
1756
5375
152 511
457 241
0.98 (0.93-1.03)
0.98 (0.93-1.03)
50-64
2183
7762
222 677
832 003
1.05 (1.00-1.10)a
1.04 (0.99-1.09)a
All-cause mortality by age group, y
Abbreviations: HR, hazard ratio; RR, rate ratio. a
Indicated results are biased.
The Table displays the rate ratios and hazard ratios for the 2 age groups separately and combined. For example, the rate ratio of colorectal cancer incidence is 0.68 in the 50- to 54-year age group and 0.83 in the 55- to 64-year age group. However, for the 2 age groups combined, the nonstandardized (unadjusted) rate ratio is 0.88, which is higher than the agespecific analyses and obviously incorrect. This artifact is well known in the meta-analysis of randomized trials and the reason why individual data from different trials cannot be naively pooled into a single data set. Rather, effect estimates are obtained separately in each trial and then pooled into a single measure. That is approximately what we did via standardization by age group. The Table shows that standardization (using the screening group as the standard) or age adjustment via a Cox model provide similar results. Øyvind Holme, MD Magnus Loberg, MD Mette Kalager, MD, PhD Author Affiliations: Institute of Health and Society, University of Oslo, Oslo, Norway. Corresponding Author: Øyvind Holme, MD, Institute of Health and Society, University of Oslo and Sorlandet Hospital Kristiansand, Postboks 416, 4604 Kristiansand, Norway ([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.
Routine Depression Screening for Patients With Diabetes To the Editor Ms Ducat and colleagues1 recommended routinely screening patients with diabetes for depression. They cited the American Diabetes Association (ADA) standards of 2412
care2 to support this recommendation. However, neither the ADA standards nor Ducat et al cite any evidence from randomized clinical trials (RCTs) that screening for depression would reduce the burden of depression among patients with diabetes. No appropriately designed and well-conducted trials in such patients or any other patient group have demonstrated that sc reening for depression improves depression outcomes when patients who are screened and provided quality depression care are compared with patients who are not screened but who may be identified as depressed via other mechanisms, such as self-report or clinician recognition, and receive similar depression care if identified as depressed.3,4 It should not be assumed, without evidence, that depression screening would benefit patients. Available screening tools tend to have high false-positive rates when used with patients not already identified as depressed or receiving treatment for depression. Standard depression treatments tend to benefit patients with high levels of depressive symptoms but may not provide substantive benefits to patients with less severe symptoms who would not be identified without the use of a screening questionnaire.3 Depression screening could unintentionally harm some patients. Some patients who receive antidepressant medication following a positive depression screen result and assessment will not benefit but will experience unpleasant, and in some cases dangerous, adverse effects. In addition, for some patients not otherwise concerned about their mental health, a positive screen result may undermine their sense of wellbeing and could function as a nocebo, by which the suggestion of impairment may lead to the development or worsening of symptoms.3
JAMA December 10, 2014 Volume 312, Number 22
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a Ndsu Library Periodicals User on 06/03/2015
jama.com
