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JACC Cardiovasc Imaging. Author manuscript; available in PMC Jun 1, 2012.
Published in final edited form as:
PMCID: PMC3319749
NIHMSID: NIHMS366525
Do imaging studies performed in physician offices increase downstream utilization? An empiric analysis of cardiac stress testing with imaging
Jersey Chen, MD, MPH,* Reza Fazel, MD, MSc, Joseph S. Ross, MD, MHS, Robert L. McNamara, MD, MHS,* Andrew J. Einstein, MD, PhD,§ Mouaz Al-Mallah, MD,|| Harlan M. Krumholz, MD, SM,* and Brahmajee K. Nallamothu, MD, MPH#
*Section of Cardiovascular Medicine, Department of Medicine, Yale University School of Medicine, New Haven, CT
Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, GA
Department of Internal Medicine, Yale University School of Medicine, New Haven, CT
§Department of Medicine, Cardiology Division, and Department of Radiology, Columbia University College of Physicians and Surgeons, New York, NY
||Department of Cardiology, Wayne State University, Detroit, MI and King Abdul-Aziz Cardiac Center, Riyadh, Kingdom of Saudi Arabia
Robert Wood Johnson Clinical Scholars Program, Department of Medicine, the Section of Health Policy and Administration, Department of Epidemiology and Public Health, Yale University School of Medicine, and the Center for Outcomes Research and Evaluation, Yale– New Haven Hospital — all in New Haven, CT
#Veterans Affairs Ann Arbor Health Services Research and Development Center of Excellence, and the University of Michigan Division of Cardiovascular Medicine, both in Ann Arbor, MI
Address for correspondence: Jersey Chen, Yale University School of Medicine, 333 Cedar Street, New Haven CT 06520; (p) 203-785-4127, (f) 203-785-7144; jersey.chen/at/yale.edu
Objective
To compare patterns of downstream testing and procedures after stress testing with imaging performed at physician offices versus at hospital-outpatient facilities.
Background
Stress testing with imaging has grown dramatically in recent years, but whether the location of where the test is performed correlates with different patterns for subsequent cardiac testing and procedures is unknown.
Methods
We identified 82,178 adults with private health insurance from 2005–2007 who underwent ambulatory myocardial perfusion imaging (MPI) or stress echocardiography (SE). Subsequent MPI, SE, cardiac catheterization or revascularization within 6 months were compared between physician office and hospital-outpatient settings.
Results
Overall, 84.5% of MPI and 84.9% of SE were performed in physician offices. The proportion of patients who underwent subsequent MPI, SE or cardiac catheterization was not statistically different between physician office and hospital-outpatient settings for MPI (14.2% v 14.1%, p=0.80) or SE (7.9% v 8.6%, p=0.21). However, patients with physician-office imaging had slightly higher rates of repeat MPI within 6 months compared with hospital-outpatient imaging for both index MPI (3.5% v 2.0%, p<0.001) and SE (3.4% v 2.1%, p<0.001), and slightly lower rates of cardiac catheterization after index MPI (11.5% v 12.3, p=0.01) and SE (4.5% v 7.0%, p<0.001). Differences in 6-month utilization were observed across the 5 healthcare markets after index MPI but not after index SE.
Conclusions
Physician office imaging is associated with slightly higher repeat MPI and fewer cardiac catheterizations than hospital outpatient imaging, but no overall difference in the proportion of patients undergoing additional further testing or procedures. While regional variation exists, especially for MPI, the relationship between physician-office location of stress testing with imaging and greater downstream resource utilization appears modest.
Keywords: myocardial perfusion imaging, stress echocardiography, health services research, physician office imaging, health policy
Health policymakers have long been concerned about the role physician office testing has played in the rapid increase in volume of imaging studies.13 During the past decade, the number of imaging studies performed in physician offices increased faster than other venues, such as hospital-outpatient facilities.4 This has been particularly notable for cardiovascular studies, which represent the largest share of non-radiology physician office testing at ~$3 billion in annual healthcare costs.4 The expansion of physician office testing for cardiovascular studies is largely due to stress testing with imaging,5, 6 which has recently prompted reductions in reimbursement for these studies.7, 8 The implications of these changes for imaging with cardiac stress testing are profound—anticipated decreases in practice revenue are already forcing mergers between cardiology practices as well as with hospitals and health systems.9
Yet our understanding of the downstream effects of physician office imaging for stress testing is limited. On the one hand, we know that an individual diagnostic test often leads to a “cascade” of additional tests and procedures.10, 11 If this is the case, patients undergoing imaging in physician offices may be more likely to be normal studies without need for additional testing or procedures. On the other hand, if more physician office studies were equivocal due to differences in quality, or if physician office readers had lower thresholds to call abnormal studies, the use of subsequent testing can conceivably be higher in physician offices. That some physicians with in-office imaging facilities may also have a financial incentive for referring patients for repeat testing may potentially lead to increased downstream testing.
Because physician office imaging may impact overall resource utilization to an even greater extent than previously thought, as a first step we sought to describe differences in patterns of downstream testing and procedures for cardiac stress testing. Using administrative data from a large cohort of insured adults, we compared the subsequent use of cardiac imaging and procedures for patients with initial imaging stress tests performed in physician offices as compared with those performed at hospital-based outpatient facilities for two imaging modalities– myocardial perfusion imaging (MPI) and stress echocardiography (SE).
The study cohort consisted of privately-insured adults with healthcare benefits administered by United Healthcare (UHC), one of the largest private healthcare insurance carriers in the United States. Adults 18 years of age and older who were alive and continuously enrolled in a health plan administered by UHC between January 1, 2005 and December 31, 2007 were identified from 5 healthcare markets (Arizona, Dallas, Orlando, South Florida, and Wisconsin) that were selected based on the stability of the enrollment population, similarity of insurance products, and to provide geographic diversity across the United States.
UHC administrative claims contain information on the age and sex of patients along with the type, indication, and location of medical services performed. Patients with MPI or SE studies were identified on the basis of Current Procedural Terminology (CPT) codes listed in the Appendix. Test indications were recorded at the discretion of the ordering clinician, and classified by International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes. The location of cardiac imaging was classified as: 1) physician office; 2) hospital-outpatient (i.e. performed in hospital facilities for non-hospitalized patients); and 3) hospital-inpatient (i.e. performed in hospital facilities for hospitalized patients). Because individuals who underwent stress testing with imaging in hospital inpatient settings were more likely to have suffered from acute events and thus clinically different from typical patients imaged in non-hospitalized settings, our study only evaluated patients undergoing testing in physician offices or hospital-based outpatient facilities.
The study population consisted of adults age 18 years and older who were continuously insured by UHC over the 3 year period. For each patient, the first (“index”) MPI or SE test performed during the study period was identified. MPI includes planar, single photon emission computed tomography (SPECT) and positron emission tomography (PET) studies. The proportion of patients with subsequent MPI or SE performed within 6 months after the index stress test was calculated. Because a goal of the analysis was to assess whether repeat imaging was performed as an alternative to cardiac catheterization, rates of re-imaging excluded MPI and SE studies performed after cardiac catheterization or revascularization procedures. Because Medicare rules allow SPECT studies to be billed once regardless of 1- or 2-day protocols, MPI claims on adjacent days were considered as separate studies. Rates of cardiac procedures performed within 6 months of index stress testing were also calculated for diagnostic cardiac catheterization, percutaneous coronary intervention (PCI), and coronary artery bypass grafting (CABG) surgery. Because CPT codes for cardiac CT only became effective on January 1, 2006 and the number of cardiac CT studies in our study was relatively small (n=475), our analysis did not evaluate this modality. MPI or SE performed in the hospital within 6 months of the initial index stress test were excluded as these studies may have been performed due to a change in clinical status. We excluded patients with an index MPI or SE study performed within 90 days after cardiac catheterization, PCI or CABG, as these studies were unlikely performed for de novo evaluation of ischemia. Patients with both MPI and SE during same day were excluded (n=64) because of an inability to determine which study was performed first. If a diagnostic cardiac catheterization was performed on the same day as a MPI (n=113) or SE (n=34) study, it was assumed that the imaging study was performed prior to the procedure.
Statistical Analysis
We first report descriptive statistics regarding the total number of MPI and SE studies by imaging location and patient distribution by healthcare market. We examined differences in indications for the index MPI or SE study between patients with physician office or hospital outpatient imaging. We then examined use of subsequent non-invasive cardiac imaging tests (MPI, SE) and invasive cardiac procedures (diagnostic cardiac catheterization, PCI, CABG) within 6 months of an index stress test, and compared their use between patients with index testing in physician office or hospital outpatient settings. Analyses were performed separately for MPI and SE. Differences across categorical variables were tested by the chi-squared test, and differences across continuous variables were tested by the t-test. Logistic regression models with Huber-White robust estimators12 were used to evaluate the relationship between physician office location and outcomes of downstream testing and revascularization, adjusting for age, sex, and indications for stress testing. The regression models also included indicator variables for the 5 markets to account for regional differences in patient characteristics or propensity for downstream testing or procedures. Exploratory subgroup analyses were performed stratifying patients on presence of known CAD (as determined by ICD-9-CM codes for history of coronary artery disease, myocardial infarction, unstable angina, ischemic heart disease, or remote PCI or CABG). To maintain adequate sample size, these analyses were limited to patients who underwent MPI as the index study. All statistical analyses were conducted using Stata version 11 (StataCorp, College Station, Texas).
Study Oversight
This study was investigator-initiated, and the authors were responsible for its design and the creation of the manuscript. The authors had complete control of the data and independently conducted the analysis. No external funding was provided for this study, and there was no need to obtain approval from UHC prior to its submission for publication.
The study population consisted of 82,178 adults continuously enrolled in UHC health insurance programs who underwent a MPI or SE study in the ambulatory setting. A total of 63,245 patients underwent an index MPI study with 53,421 (84.5%) performed in physician offices and 9,824 (15.5%) performed in hospital outpatient facilities. The mean patient age was 56.6 years (standard deviation [SD] 10.9, range 18 to 96 years) and 45.2% of these patients were female. A higher proportion of MPIs were billed by cardiologists in physician offices compared with hospital outpatient facilities (83.1% v 34.3%, p<0.001). A total of 18,933 patients underwent index SE with 16,080 (84.9%) performed in physician offices and 2,853 (15.1%) performed in hospital outpatient locations. The mean patient age was 52.3 years (SD 10.7, range 18 to 94 years) and 54.3% were female. Cardiologists billed for the majority of both physician office and hospital outpatient SEs, with a higher proportion for the former (91.9% v 82.8%, p<0.001). (Table 1)
Table 1
Table 1
Enrollee characteristics
For MPI, patients who underwent physician office imaging were more likely to have indications of CAD (32.0% v 14.7%, p<0.001) and abnormal electrocardiogram (26.6% v 11.3%, p<0.001) compared with patients with hospital outpatient imaging, and less likely to have indications of chest pain or angina (42.5% v 59.8%, p<0.001). (Table 1) For SE, patients with physician office imaging were less likely to have indications of chest pain or angina compared with those imaged in hospital outpatient facilities (47.7% v 58.1%, p<0.001), and more likely to have valve abnormalities (17.6% v 7.0%, p<0.001) or palpitations (10.1% v 5.1%, p<0.001) compared with patients with hospital outpatient SE.
For patients who underwent MPI in physician offices, the proportion of individuals undergoing additional non-invasive imaging (MPI or SE) or cardiac catheterization within 6 months was not significantly different than patients with MPI performed in hospital outpatient facilities (14.2% v 14.1%, p=0.80; adjusted odds ratio [AOR]=1.03, p=0.39). (Table 2) However, there were differences in the composition of repeat testing and procedure use. The proportion of patients who underwent repeat MPI within 6 months was higher for patients with index MPI performed in physician offices compared with hospital outpatient facilities (3.5% v 2.0%, p<0.001; AOR=1.39, p<0.001) with 66.5% of these second MPI studies billed by the same laboratory. In contrast, physician office imaging was associated with a lower need for subsequent SE (0.4% v 0.8%, p<0.001; AOR=0.58, p<0.001) compared with hospital outpatient facilities. The proportion of patients undergoing cardiac catheterization was lower for patients in physician offices (11.5% v 12.3%, p=0.01) but this difference was not statistically significant in the adjusted analyses (AOR=0.99, p=0.72). No significant difference in revascularization after MPI was observed between patients imaged in physician offices compared with hospital outpatient facilities (4.0% v 4.1%, p=0.65; AOR=0.99, p=0.93)
Table 2
Table 2
Use of non-invasive cardiac imaging and procedures after index myocardial perfusion imaging or stress echocardiography study
For the 18,933 patients who underwent index SE, the proportion of patients who underwent additional non-invasive imaging or cardiac catheterization within 6 months was not significantly different between those performed in physician offices and hospital outpatient facilities (7.9% v 8.6%, p=0.21; AOR=1.03, p=0.74) (Table 2) However, the proportion of SE patients who underwent MPI imaging within 6 months was higher for those imaged in physician offices than hospital outpatient facilities (3.4% v 2.1%, p<0.001, AOR=1.38, p=0.03). Use of repeat SE was not significantly different between the two locations (1.0% v 0.7%, p=0.07; AOR=1.36, p=0.19). The proportion of patients undergoing cardiac catheterization was lower for patients with index SE in physician offices (4.5% v 7.0%, p<0.001) with a trend also present in the adjusted analyses (AOR=0.84, p=0.07). The proportion of patients who underwent revascularization was lower for patients with index SE in physician offices (1.8% v 2.4%, p=0.04) but not in adjusted analyses (AOR=0.92, p=0.62).
We found regional differences in subsequent 6-month rates of MPI, SE, and cardiac catheterization among patients with an index MPI. Most notably for in South Florida physician office imaging was associated with lower utilization (8.2% v 12.2%, p<0.001) when compared with the overall cohort. This was predominately driven by lower repeat MPI (1.7% v 5.0%, p<0.001) and not explained by differential use of cardiac catheterization (p=0.39). Subsequent 6-month rates of MPI, SE, and cardiac catheterization was higher for physician-office imaging in Dallas (19.1% v 16.8%, p=0.03), Orlando (15.1% v 12.9%, p=0.03), and Wisconsin (15.7% v. 13.9%, p=0.02) but not significantly different for Arizona (15.6% v 14.3%, p=0.20). In contrast to MPI, there were no significant differences for SE across regions in 6-month rates of MPI, SE, and cardiac catheterization between physician office and hospital outpatient imaging (p>0.47).
In secondary analyses among patients undergoing index MPI, there were 18,811 patients presumably with known CAD and 44,434 patients without known CAD. In logistic regression analyses, patients without known CAD in physician offices were significantly more likely to undergo subsequent imaging (odd ratio[OR]=1.22, p=0.009), cardiac catheterization (OR=1.14, p<0.002), or revascularization (OR=1.21, p=0.016) compared with patients initially imaged in hospital facilities. In contrast, patients with known CAD and MPI in physician offices did not differ in odds of subsequent imaging (OR=0.96, p=0.76) compared with patients imaged in hospital facilities, and had lower odds of cardiac catheterization (OR=0.64, p<0.001) or revascularization (OR=0.71, p<0.001)”
This study provides a contemporary assessment of patterns of downstream testing and procedures according to location of the initial imaging cardiac stress testing. While the overall proportion of patients undergoing additional tests and procedures (MPI, SE or cardiac catheterization) was similar regardless of physician office or hospital outpatient setting of the index stress test, patients who underwent MPI or SE in physician offices were more likely to undergo repeat non-invasive imaging with MPI rather than be referred directly for cardiac catheterization.
While several studies have implied that physician office imaging is a major contributor to the growth of non-invasive imaging,4, 5 there has been little investigation into whether physician office imaging is associated with differences in the use of downstream testing and procedures. Several reasons may potentially explain why repeat MPI was performed more often (and cardiac catheterization less often) among patients initially imaged in physician offices. Convenience of referral may be a factor if it is for physicians to refer patients with equivocal studies for repeat imaging rather than suffer the additional burden for scheduling for cardiac catheterization outside of the office. Alternatively, different levels of study quality or the presence of imaging artifacts may be responsible for the additional imaging associated with physician offices. For example, if physicians were able to personally view stress test images, if he or she may be more likely to conclude that a suspected abnormality is an artifact, leading to repeat imaging with changes to technique rather than direct referral to cardiac catheterization.13 There also may be differences between laboratories in the rate that studies are reported as equivocal or in the thresholds for abnormal non-imaging results that lead to further testing (such as ischemic ECG changes or symptoms in the setting of normal imaging). Financial incentives for repeating stress testing with imaging may also play a role, given that many of the subsequent studies would also be performed in physician offices, generating more revenue for the physician.
Differences in pre-test probability for CAD may also explain our findings; if patients who undergo physician office imaging were at lower average risk for CAD, physicians may (appropriately) prefer repeat imaging than invasive procedures that entail a risk for complications. The results of our adjusted analyses demonstrate a similar revascularization rate for patients referred to physician office imaging centers; however, this may be confounded by the fact that physician-office testing was associated with fewer diagnostic cardiac catheterizations — a precursor to revascularization. Future studies using clinical data are needed to examine differences in baseline clinical risk and test appropriateness of patients who undergo physician-office imaging compared with other locations.
While we did not find downstream utilization to be different between physician-office and hospital outpatient imaging in the overall cohort, there were some differences across regions for MPI. It is unclear why South Florida differed from the other regions by having lower repeat MPI after index MPI associated with physician-office imaging, but does not appear due to increased substitution by cardiac catheterization. Dallas, Orlando and Wisconsin had slightly higher 6-month rates of MPI/SE/cardiac catheterization associated with physician office imaging, but the magnitude was modest (<2.3%). There are several speculative reasons for these regional differences, such as variation in patient risk, imaging quality, or practice patterns across markets. Although all of these may play a role, further investigation will be needed to better understand these differences. Investigating this phenomenon, using clinical data, may yield insights on the feasibility of reducing regional differences in downstream testing between physician-office and hospital outpatient centers.
Our findings suggests that subsequent utilization for patients with suspected (but not known) CAD was higher for physician offices compared with hospital-based facilities. Potential interpretations of this utilization pattern are that: 1) among patients with suspected but not known CAD, clinicians referred higher risk patients to cardiologists who had in-office imaging available, and referred lower risk patients to hospital facilities; or 2) patients without known CAD interpreted in physician offices were more likely to be read as abnormal, resulting in additional imaging and procedure use; or 3) patients with known CAD imaged in physician offices were more often referred for disease surveillance, resulting similar or fewer subsequent tests and procedures compared with patients imaged in hospital facilities. Future studies with clinical data would better differentiating between these potential explanations. However, we note that 91.5% of patients with “known CAD” in this cohort had ICD-9-CM codes of 414—a code often used as a “rule-out CAD” indication. Since this code may be a potentially unreliable indicator of known CAD, this analysis should be considered hypothesis-generating for future studies using clinical data.
Our findings should provide some reassurance to policymakers that physician office imaging has a limited impact on subsequent resource utilization when compared with imaging performed at hospital outpatient facilities. First, we note that the proportion of patients who subsequently underwent MPI, SE or cardiac catheterization was similar across the two settings— the main difference was the allocation between non-invasive and invasive testing. Furthermore, even when we found discrepancies, the absolute difference in use of repeat imaging or cardiac catheterization between the two groups was small— up to ~2.5 percentage points. While there was a preference for physician offices to slightly favor additional imaging, this level of difference implies a modest effect on overall costs. Furthermore, particular patients may have benefited from a practice pattern of repeat imaging, if this strategy helps selected patients avoid the risks of invasive angiography. For example, in a large MPI registry 7.4% of studies were interpreted as equivocal for ischemia and had higher cardiac event rates than those with normal or near normal studies.14 If repeat imaging can shift patients from equivocal status, physicians may choose to a non-invasive approach as an alternative to invasive coronary angiography. Because recent studies have demonstrated that a substantial proportion of coronary angiograms do not reveal significant flow-limiting disease,15 judicious use of imaging may potentially reduce the need for diagnostic cardiac catheterizations that ultimately do not lead to revascularization, reducing the risk of complications from the procedure and its associated costs.
Ultimately, the availability of physician office imaging raises complex issues for policy-makers. The ready availability of physician office testing could lead to increased utilization, which may indicate less efficient care. However, our findings suggest that physician office cardiac imaging only has a modest association with additional subsequent testing. While these findings should be considered as hypothesis-generating for future studies, our study suggests that concerns regarding physician office imaging in terms of follow-up utilization may be not be as great as some fear. This data informs the current debate regarding current efforts to restrict outpatient imaging using ionizing radiation by non-radiologists. 16, 17
The primary limitation of this study is that with administrative billing data alone we were unable to determine the appropriateness of stress testing, or the reason for repeat testing, or adjust for clinical factors other than patient demographics or test indications. Test indications may have also been selected to maximize reimbursement rather than reflect the most appropriate clinical situation. While clinical data (especially imaging results) would be preferred, only administrative datasets currently provides sufficiently large numbers of laboratories required to make comparisons between physician office versus other locations. For example, the clinically-rich SPARC imaging registry18 consists of 41 sites, compared with 4,244 physician office and 1,906 hospital outpatient sites in our study.
Another limitation is that our study is based on clinical practice patterns from 2005–2007; while this time period is contemporary, the emergence of new technologies, especially coronary computed tomography angiography, could have an impact on current practice patterns. We were also unable to assess patient clinical outcomes, such as mortality, adverse cardiac events, or quality of life. We were also unable to determine whether an indication for CAD reflected known disease or a request to “rule-out” significant disease which may differ by location. We were not able to identify patients who underwent stress testing after a recent AMI, but this would have limited impact on our findings given national trends towards early invasive therapy.19 We were not able evaluate whether the referring physician had a financial interest in the in-office imaging facility. Our study is also limited by its ability to determine how different pre-approval processes across regions affect subsequent downstream testing and procedure use. We note that the proportion of patients recorded with hypertension and diabetes was modest, and our findings may not be generalizable to higher risk populations. Lastly, this study population was limited to 5 healthcare markets and those with private health insurance; whether our findings can be extrapolated to patients in other regions, or those with different forms of health insurance is unknown.
Conclusions
Approximately 85% of ambulatory MPI and SE studies are performed in physician offices. Patients undergoing stress testing with imaging in physician offices were slightly more likely to be reimaged with MPI and slightly less likely to be referred for diagnostic cardiac catheterization than those undergoing initial testing in hospital-based facilities. The overall proportion of patients undergoing any additional testing or procedures to evaluate CAD (MPI, SE or diagnostic catheterization) was similar regardless of physician office or hospital outpatient setting.
Acknowledgments
We are grateful to Matthew J. Drawz, Tri C. Tong, James C. Dahl, and Neil C. Jensen from United Health care for their assistance with the initial preparation of data.
Sources of funding
Dr. Chen is supported by an American Heart Association Clinical Research Program Award (AHA 10CRP2640075) and an Agency for Healthcare Research and Quality Career Development Award (1K08HS018781-01). Dr. Ross is supported by the National Institute on Aging (K08 AG032886) and by the American Federation of Aging Research through the Paul B. Beeson Career Development Award Program. Dr Einstein was supported in part by an NIH K12 institutional career development award (KL2 RR024157), and by the Louis V. Gerstner, Jr. Scholars Program. Dr. Krumholz is supported by a National Heart Lung Blood Institute Cardiovascular Outcomes Center Award (1U01HL105270-01).
Abbreviations
AORadjusted odds ratio
CABGcoronary artery bypass graft
CADcoronary artery disease
CIconfidence interval
CPTCurrent Procedural Terminology
MPImyocardial perfusion imaging
ORodds ratio
PCIpercutaneous coronary intervention
PETpositron emission tomography
SEstress echocardiography
SPECTsingle photon emission computed tomography
UHCUnited Healthcare

Appendix
CPT codes for cardiac imaging tests and procedures
  • Myocardial perfusion imaging (78460–78480, 78491–78492)
  • Stress echocardiography (93350)
  • Diagnostic cardiac catheterization (93539, 93540, 93555, 93556, 93508, 93545)
  • Percutaneous coronary intervention (92973, 92974, 92980–92982, 92984–92996)
  • Coronary artery bypass grafting (33510–33519, 33521–33523, 33533–33536)
Chest pain786.5
Angina413
Abnormal electrocardiogram794.31
Dyspnea786.0
Chronic coronary artery disease (includes myocardial infarction and ischemic heart disease)410, 411, 414
Valve abnormalities424
Rhythm abnormalities427
Diabetes mellitus250
Hypertension401
Palpitations785.1
Preoperative assessmentV728.1
Footnotes
Disclosures
Dr. Krumholz reports receiving consulting fees for serving on the United Healthcare Cardiac Scientific Advisory Board. He received no fees related to this project. Dr Einstein reports having received research support from Spectrum Dynamics. No other potential conflicts of interest relevant to this article were reported by any of the authors.
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