Letters
In Reply We want to thank Huang and Subak for their interest in Author Affiliations: Diabetes Centre, Isala Clinics, Zwolle, the Netherlands
our study.1 They state that we should not have made strong con-
clusions concerning nonefficacy based on results extending out-
side the present study and that we performed an underpowered
study with methodological limitations and unsuccessful random-
ization. We respectfully disagree with all their statements.
We do agree with their last sentence “broad conclusions about
nonefficacy of device-guided breathing are not supported by this
study alone.” Nonefficacy was also the result of 2 other trials per-
formed by our research group.2,3 A recent meta-analysis, specifi-
cally in studies with sufficient methodological quality, confirmed
that there is no evidence for short-term effects on blood pressure.4
Furthermore, there is absence of evidence for long-term blood
pressure effects.4 The absence of short-term and long-term ef-
fects, let alone cardiovascular end points, justifies our conclusion.
Consistent short-term benefits should first be established. It is not
up to us to prove nonefficacy, there should be evidence for effi-
cacy, not the other way around.
Our study was not underpowered by definition.1 Power is
defined a priori and is not based on confidence intervals of re-
sults. The sample size was based on the maximum standard
deviation derived from our 2 previous trials and on a pre-
defined clinical relevant margin.2,3 We admitted that the pre-
defined clinical relevant margin was subject to debate. If we
look at “power afterwards,” we were not able to exclude a clini-
cal relevant negative effect of using the device. The upper limit
(potential beneficial effect) of the 95% confidence interval was
6.5 mm Hg, well below the predefined relevancy margin.
Randomization was not unsuccessful, and the assumption
should be categorized as a type 1 error. Baseline differences are
judged on their relevancy, and we normally appose them to
P values in baseline tables.5 There was 1 significant difference
out of many baseline variables. This hemoglobin A1c baseline dif-
ference could hardly be seen as a proxy for (in)compliance. The
analyses adjusting for baseline differences and subgroup analy-
sis in compliant patients were consistent with the main results,
further undermining the validity of their assumption.
We hope to clarify the indistinctness regarding the ad-
equacy of the control group. Our 2 previous trials used a rea-
sonable control group4—music therapy. Indeed, next to slow-
ing breathing frequency, the device could also exert effects on
blood pressure through relaxing or listening to music. The sham
device has the highest methodological quality because the pri-
mary mechanism through which the device should exert its
effects on blood pressure, and for which it is marketed, is low-
ering of breathing frequency. This methodological qualifica-
tion is in line with a previous editorial by Parati and Carretta.6
Device-guided breathing should not be advised for hyper-
tension treatment because evidence with sufficient method-
ological quality is absent. If Huang and Subak still doubt the
adequacy of the control group, we hope they agree that if the
device exerts effects through listening to music, it would be
better to advise patients to listen to music instead of advising
them to buy an expensive device.
Gijs W. D. Landman, MD, PhD
Kornelis J. J. van Hateren, MD
Nanne Kleefstra, MD, PhD
638 JAMA Internal Medicine April 2014 Volume 174, Number 4
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(Landman, van Hateren, Kleefstra); Department of Internal Medicine, University
Medical Center Groningen, Groningen, the Netherlands (Kleefstra); Langerhans
Medical Research Group, Zwolle, the Netherlands (Kleefstra).
Corresponding Author: Gijs W. D. Landman, MD, PhD, Diabetes Centre, Isala
Clinics, PO Box 10400, 8000 G K Zwolle, the Netherlands (g.w.d.landman
@isala.nl).
Conflict of Interest Disclosures: None reported.
1. Landman GW, Drion I, van Hateren KJ, et al. Device-guided breathing as
treatment for hypertension in type 2 diabetes mellitus: a randomized,
double-blind, sham-controlled trial. JAMA Intern Med. 2013;173(14):1346-1350.
2. Logtenberg SJ, Kleefstra N, Houweling ST, Groenier KH, Bilo HJ. Effect of
device-guided breathing exercises on blood pressure in hypertensive patients
with type 2 diabetes mellitus: a randomized controlled trial. J Hypertens.
2007;25(1):241-246.
3. Altena MR, Kleefstra N, Logtenberg SJ, Groenier KH, Houweling ST, Bilo HJ.
Effect of device-guided breathing exercises on blood pressure in patients with
hypertension: a randomized controlled trial. Blood Press. 2009;18(5):273-279.
4. Mahtani KR, Nunan D, Heneghan CJ. Device-guided breathing exercises in
the control of human blood pressure: systematic review and meta-analysis.
J Hypertens. 2012;30(5):852-860.
5. Baseline data. CONSORT Statement website. http://www.consort-statement
.org/resources/database/evidence-underpinning-consort/baseline-data/.
Accessed January 29, 2014.
6. Parati G, Carretta R. Device-guided slow breathing as a non-pharmacological
approach to antihypertensive treatment: efficacy, problems and perspectives.
J Hypertens. 2007;25(1):57-61.
“Expert Opinion” Software for Medical Diagnosis
and Treatment
To the Editor The article by Meyer et al1 and the accompanying
Invited Commentary2 in the August 23, 2013, issue of JAMA In-
ternal Medicine bring up important issues. The study found that
practicing internists had significant difficulty making even rela-
tively easy diagnoses. However, perhaps even more worri-
some is that the confidence level of the physicians was not
much lower when they were wrong than when they were cor-
rect in their diagnosis. Further, probably, because of this un-
justified confidence, they did not seek second opinions or con-
sultations.
Dhaliwal2 discusses the use of computers to assist in
diagnosis. He mentions attempts to create software that can
answer medical questions clearly and succinctly or software
that monitors the electronic health record and offers appro-
priate medical updates of issues the computer algorithm
determines the physician is dealing with.
I would like to add another suggestion. The American
Medical Association (AMA) or other professional organiza-
tions should organize a group of interested physicians and
software engineers to design and implement web-based
software that uses “evidence-based guidelines” or other
“best practice” documents to interpret medical information
provided by physicians in a user-friendly interactive way
and then give them guidance in diagnosing and treating
patients.
With this software, health care providers could enter
pertinent computer-requested information and obtain an
“opinion” based on the knowledge of the best experts in the
area. This type of decision-making software offers the
potential of more accurate diagnoses and better patient
management.
jamainternalmedicine.com

The database created by the software would be very use-
ful for research. The software could also have an associated
electronic “bulletin board” where people could post ques-
tions, comments, and improvement suggestions. Further, sym-
posia on medical decision-making software should be incor-
porated into annual professional meetings. Procedures such
as these would continually improve the software as well as the
underlying practice guidelines and lead to better patient out-
comes with more efficient resource utilization.
Designing good software is a complicated process. It must
account for many combinations of data, including data er-
rors, and then make pragmatic decisions. There are few such
programs presently available.3 Perhaps the AMA could take on
the responsibility of evaluating, certifying, and implement-
ing decision-making medical software.
Robert M. Ross, MD
Author Affiliation: Department of Medicine, Baylor College of Medicine,
Houston, Texas.
Corresponding Author: Robert M. Ross, MD, Department of Medicine, Baylor
College of Medicine, 3333 Richmond Ave, Second Floor, Houston, TX 77098
(rross@bcm.edu).
Conflict of Interest Disclosures: None reported.
1. Meyer AN, Payne VL, Meeks DW, Rao R, Singh H. Physicians’ diagnostic
accuracy, confidence, and resource requests: a vignette study. JAMA Intern Med.
2013;173(21):1952-1958.
2. Dhaliwal G. Known unknowns and unknown unknowns at the point of care.
JAMA Intern Med. 2013;173(21):1959-1961.
3. Ross RM, Corry DB. Software for interpreting cardiopulmonary exercise
tests. BMC Pulm Med. 2007;7:15.
In Reply While we agree with Dr Ross that software that uses
evidence-based or best-practice suggestions could provide di-
agnostic guidance to physicians, we would like to first recog-
nize the currently established body of work on diagnostic de-
cision support systems that could be leveraged for this purpose.
For example, the American Medical Association previously
sponsored the dissemination of one of these tools, DXplain,1
and several recent reviews on diagnostic decision-making soft-
ware highlight opportunities for the field.2 Also, we agree it
would be helpful to get more physician professional societies
and medical meetings to be inclusive of discussions of these
systems, although forums such as the Society to Improve Di-
agnosis in Medicine (http://www.improvediagnosis.com) and
the Diagnostic Error in Medicine annual meetings have re-
cently begun to provide this platform.
We also agree that more advanced and more user friendly
systems could provide better cognitive support to physi-
cians. It is well accepted that information processing during
brief physician encounters is challenging and should be sup-
ported by better technology. However, widespread adoption
of diagnostic decision support systems has not occurred for
many reasons.3 It has been challenging to implement some of
these systems within the frontlines of busy clinical care envi-
ronments, and inaccurate and incomplete data gathering4 can
jeopardize the usefulness of these systems. In addition, and
perhaps more importantly, in our study we found that physi-
cians did not opt to use clinical decision support when they
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Letters
were offered the choice to do so.5 Thus, additional strategies
will be needed to address factors such as overconfidence that
play a role here, otherwise physicians may not realize when
they need help from these systems and will not use them no
matter how well they are designed.
Thus, designing and implementing good software will need
to be accompanied by strategies to integrate the software with
clinicians’ workflow. Multifaceted sociotechnical approaches6
could be used to guide the successful implementation and use
of these software systems to improve the diagnostic process.
Hardeep Singh, MD, MPH
Ashley N. D. Meyer, PhD
Author Affiliations: Houston VA Health Services Research and Development
Center for Innovations in Quality, Effectiveness, and Safety, Michael E. DeBakey
Veterans Affairs Medical Center, Houston, Texas (Singh, Meyer); Section of
Health Services Research, Department of Medicine, Baylor College of Medicine,
Houston, Texas (Singh, Meyer).
Corresponding Author: Hardeep Singh, MD, MPH, VA Medical Center (152),
2002 Holcombe Blvd, Houston, TX 77030 (hardeeps@bcm.edu).
Conflict of Interest Disclosures: None reported.
Funding/Support: This project is supported with resources and the use of
facilities at the Houston VA Health Services Research and Development Center
for Innovations in Quality, Effectiveness, and Safety (CIN 13-413) at the Michael
E. DeBakey VA Medical Center, Houston, Texas.
Role of the Sponsor: The sponsor had no role in the preparation, review, or
approval of the manuscript and the decision to submit the manuscript for
publication.
Disclaimer: The views expressed in this article are those of the authors and do
not necessarily represent the views of the Department of Veterans Affairs.
1. Massachusetts General Hospital Laboratory of Computer Science. DXplain:
using decision support to help explain clinical manifestations of disease. 2013.
http://www.lcs.mgh.harvard.edu/projects/dxplain.html. Accessed December 8,
2013.
2. Bond WF, Schwartz LM, Weaver KR, Levick D, Giuliano M, Graber ML.
Differential diagnosis generators: an evaluation of currently available computer
programs. J Gen Intern Med. 2012;27(2):213-219.
3. Miller RA, Masarie FE Jr. The demise of the “Greek Oracle” model for medical
diagnostic systems. Methods Inf Med. 1990;29(1):1-2.
4. Singh H, Giardina TD, Meyer AN, Forjuoh SN, Reis MD, Thomas EJ. Types and
origins of diagnostic errors in primary care settings. JAMA Intern Med.
2013;173(6):418-425.
5. Meyer AN, Payne VL, Meeks DW, Rao R, Singh H. Physicians’ diagnostic
accuracy, confidence, and resource requests: a vignette study. JAMA Intern Med.
2013;173(21):1952-1958.
6. Sittig DF, Singh H. A new sociotechnical model for studying health
information technology in complex adaptive healthcare systems. Qual Saf
Health Care. 2010;19(suppl 3):i68-i74.
In Reply Dr Ross proposes the adoption of software that inter-
prets physician-selected data and provides guidance derived
from high-quality information sources. Currently web-based
differential diagnosis generators such as Isabel, VisualDx, and
DXplain do that to some degree.1
At issue is the uptake of such assistance. As the recent
JAMA Internal Medicine studies elegantly demonstrated, lack
of time and overconfidence are major barriers to physicians’
seeking assistance from knowledge sources and decision
support.2,3 It takes so much time to enter information once into
the medical record that physicians are understandably disin-
clined to enter the same information again into another pro-
JAMA Internal Medicine April 2014 Volume 174, Number 4 639
 Letters
gram (eg, PubMed, diagnostic support, Google). The key to har-
nessing any software program’s potential is to have it detect,
extract, and interpret the relevant variables from the elec-
tronic medical record (and other inputs) without interrupt-
ing physician workflow.
Societies and organizations that shift from the business of
generating guidelines to the business of delivering guide-
lines’ most relevant content at the right place and the right time,
and in the most brain- and workflow-friendly way, will have
the greatest potential to bring best practices to the bedside.
I share Dr Ross’ optimism that well-designed software will
have an increasing role in improving our diagnostic and thera-
peutic performance and therefore should garner increased at-
tention and academic credit.
Gurpreet Dhaliwal, MD
Author Affiliations: Department of Medicine, University of California, San
Francisco; Medical Service, San Francisco Veterans Affairs Medical Center, San
Francisco, California.
Corresponding Author: Gurpreet Dhaliwal, MD, Department of Medicine,
University of California, San Francisco, San Francisco VA Medical Center, 4150
Clement St (111), San Francisco, CA 94131 (gurpreet.dhaliwal@ucsf.edu).
Conflict of Interest Disclosures: None reported.
1. Bond WF, Schwartz LM, Weaver KR, Levick D, Giuliano M, Graber ML.
Differential diagnosis generators: an evaluation of currently available computer
programs. J Gen Intern Med. 2012;27(2):213-219.
2. Meyer AN, Payne VL, Meeks DW, Rao R, Singh H. Physicians’ diagnostic
accuracy, confidence, and resource requests: a vignette study. JAMA Intern Med.
2013;173(21):1952-1958.
3. Cook DA, Sorensen KJ, Wilkinson JM, Berger RA. Barriers and decisions when
answering clinical questions at the point of care: a grounded theory study. JAMA
Intern Med. 2013;173(21):1962-1969.
Antihypertensive Medications and Breast Cancer Risk
To the Editor We read with great interest the article published
in JAMA Internal Medicine titled “Use of Antihypertensive
Medications and Breast Cancer Risk Among Women Aged 55
to 74 Years” by Li et al.1 The study provided further evidence
that long-term current use of calcium channel blockers is as-
sociated with an increased risk of breast cancer. Moreover, the
data revealed that a reduction in breast cancer risk was asso-
ciated with long-term use of angiotensin-converting enzyme
inhibitors. We appreciate the authors’ extraordinary contri-
bution, which provides us with a basis for further investiga-
tion of the effects of antihypertensive medications on breast
cancer risk. Nonetheless, there are several major points that
need further discussion with respect to this article.
It has been well documented that host factors (eg, alcohol or
tobacco use), confounding with other pharmacologic exposures
(eg, aspirin), and comorbid medical conditions (eg, system inflam-
mation or heart disease) are associated with cancer risk.2,3 In the
study by Li et al,1 the authors used polytomous logistic regression
to calculate odds ratios and their associated 95% confidence in-
tervals to compare patients with breast cancer with controls. The
models are adjusted for age, reference year, county, race/ethnicity,
and recency of alcohol use (Tables 2, 3, and 4). However, many
other important factors were not included in the analysis (eg, his-
tory of heart disease). This brings up the possibility that the cur-
rent study is not likely to accurately establish the association be-
640 JAMA Internal Medicine April 2014 Volume 174, Number 4
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tween antihypertensive medications and breast cancer risk. More-
over, long-term hypertension exposure could be associated with
increased cancer risk as it is associated with cellular senescence,
telomere shortening, and inhibition of apoptosis.4 However, in
the study of Li et al,1 the authors did not separate the indepen-
dent effects of the condition of hypertension itself (varying lev-
els of severity) and treatment in the form of antihypertensive
medications on the risk of breast cancer. Furthermore, the dose-
response relationship of antihypertensive medications exposure
on subgroups of patients has yet not been explored in their study.1
The carcinogenic potential of antihypertensive medications
has been debated for nearly 40 years.5 However, despite the ap-
parent widespread use of antihypertensive drugs, the current data
are limited. Many publications were not subjected to the usual
stringency of phase 1 to 3 clinical trials, and most were not pro-
spective or randomized. Do antihypertensive medications influ-
ence breast cancer risk? Prospective randomized clinical trials may
provide the only way to overcome the selection and ascertainment
bias and answer this question more accurately.
Yi Ji, MD, PhD
Siyuan Chen, MD, PhD
Author Affiliations: Division of Oncology, Department of Pediatric Surgery,
West China Hospital of Sichuan University, Chengdu, China (Ji); Intensive Care
Unit, West China Hospital of Sichuan University, Chengdu, China (Chen).
Corresponding Author: Yi Ji, MD, PhD, Division of Oncology, Department of
Pediatric Surgery, West China Hospital of Sichuan University, 37 Guo-Xue-Xiang,
Chengdu 610041, China (jijiyuanyuan@163.com).
Conflict of Interest Disclosures: None reported.
1. Li CI, Daling JR, Tang MT, Haugen KL, Porter PL, Malone KE. Use of
antihypertensive medications and breast cancer risk among women aged 55 to
74 years. JAMA Intern Med. 2013;173(17):1629-1637.
2. Bangalore S, Kumar S, Kjeldsen SE, et al. Antihypertensive drugs and risk of
cancer: network meta-analyses and trial sequential analyses of 324,168
participants from randomised trials. Lancet Oncol. 2011;12(1):65-82.
3. Fung TT, Hu FB, Hankinson SE, Willett WC, Holmes MD. Low-carbohydrate
diets, dietary approaches to stop hypertension-style diets, and the risk of
postmenopausal breast cancer. Am J Epidemiol. 2011;174(6):652-660.
4. Hamet P, Richard L, Dam TV, et al. Apoptosis in target organs of
hypertension. Hypertension. 1995;26(4):642-648.
5. Boston Collaborative Drug Surveillance Program. Reserpine and breast
cancer. Lancet. 1974;2(7882):669-671.
To the Editor In their article, Li and colleagues1 assess the as-
sociation between antihypertensive medication use and in-
creased breast cancer risk in women aged 55 to 74 years. They
conclude that only continued use of calcium channel block-
ers for 10 years or more was significantly associated with a
higher risk of breast cancer. However, we query the lack of sig-
nificant results in their study concerning β-blocker use and
breast cancer risk. The potential effect of β-blocker use on the
risk of cancer is an important issue, and we believe that the
results deserve to be reported stratified by β-adrenergic re-
ceptor (AR) antagonist subtype.
Published data indicate that β2-AR signaling plays the most
prominent role in breast tumor regulation and that the rela-
tive effects of β1-selective and β1/β2-nonselective antagonists
are different.2 In vitro, in vivo, and preclinical models show
that propranolol (β 2 -AR) can specifically inhibit stress-
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