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1.  Physician Decision-Making And Trends In Use Of Cardiac Stress Testing To Diagnose Coronary Heart Disease In The United States, 1993–2010 
Annals of internal medicine  2014;161(7):482-490.
Cardiac stress testing, particularly with imaging, has been the focus of debates about rising health care costs, inappropriate use, and patient safety in the context of radiation exposure.
To determine whether U.S. trends in cardiac stress test use may be attributable to population shifts in demographics, risk factors, and provider characteristics and evaluate whether racial/ethnic disparities exist in physician decision making.
Analyses of repeated cross-sectional data.
National Ambulatory Medical Care Survey and National Hospital Ambulatory Medical Care Survey (1993 to 2010).
Adults without coronary heart disease.
Cardiac stress test referrals and inappropriate use.
Between 1993 to 1995 and 2008 to 2010, the annual number of U.S. ambulatory visits in which a cardiac stress test was ordered or performed increased from 28 per 10 000 visits to 45 per 10 000 visits. No trend was found toward more frequent testing after adjustment for patient characteristics, risk factors, and provider characteristics (P = 0.134). Cardiac stress tests with imaging comprised a growing portion of all tests, increasing from 59% in 1993 to 1995 to 87% in 2008 to 2010. At least 34.6% were probably inappropriate, with associated annual costs and harms of $501 million and 491 future cases of cancer. Authors found no evidence of a lower likelihood of black patients receiving a cardiac stress test (odds ratio, 0.91 [95% CI, 0.69 to 1.21]) than white patients, although some evidence of disparity in Hispanic patients was found (odds ratio, 0.75 [CI, 0.55 to 1.02]).
Cross-sectional design with limited clinical data.
National growth in cardiac stress test use can largely be explained by population and provider characteristics, but use of imaging cannot. Physician decision making about cardiac stress test use does not seem to contribute to racial/ethnic disparities in cardiovascular disease.
PMCID: PMC4335355  PMID: 25285541
2.  Cancer therapy-induced autonomic dysfunction in early breast cancer: Implications for aerobic exercise training 
International journal of cardiology  2013;171(2):e50-e51.
PMCID: PMC4116686  PMID: 24365613
Exercise; Breast cancer; Autonomic function; Cardiovascular disease; Cardiotoxicity
3.  The utility of data-driven feature selection: Re: Chu et al. 2012☆ 
NeuroImage  2013;84:1107-1110.
The recent Chu et al. (2012) manuscript discusses two key findings regarding feature selection (FS): (1) data driven FS was no better than using whole brain voxel data and (2) a priori biological knowledge was effective to guide FS. Use of FS is highly relevant in neuroimaging-based machine learning, as the number of attributes can greatly exceed the number of exemplars. We strongly endorse their demonstration of both of these findings, and we provide additional important practical and theoretical arguments as to why, in their case, the data-driven FS methods they implemented did not result in improved accuracy. Further, we emphasize that the data-driven FS methods they tested performed approximately as well as the all-voxel case. We discuss why a sparse model may be favored over a complex one with similar performance. We caution readers that the findings in the Chu et al. report should not be generalized to all data-driven FS methods.
PMCID: PMC4251655  PMID: 23891886
Feature selection; Machine learning; Neuroimaging
4.  Balancing Clinical and Pathologic Relevence in the Machine Learning Diagnosis of Epilepsy 
The application of machine learning to epilepsy can be used both to develop clinically useful computer-aided diagnostic tools, and to reveal pathologically relevant insights into the disease. Such studies most frequently use neurologically normal patients as the control group to maximize the pathologic insight yielded from the model. This practice yields potentially inflated accuracy because the groups are quite dissimilar. A few manuscripts, however, opt to mimic the clinical comparison of epilepsy to non-epileptic seizures, an approach we believe to be more clinically realistic. In this manuscript, we describe the relative merits of each control group. We demonstrate that in our clinical quality FDG-PET database the performance achieved was similar using each control group. Based on these results, we find that the choice of control group likely does not hinder the reported performance. We argue that clinically applicable computer-aided diagnostic tools for epilepsy must directly address the clinical challenge of distinguishing patients with epilepsy from those with non-epileptic seizures.
PMCID: PMC4188528  PMID: 25302313
controls; FDG-PET; epilepsy; non-epileptic seizures; machine learning; neuroimaging
5.  Impact of choice of imaging modality accompanying outpatient exercise stress testing on outcomes and resource use after revascularization for acute coronary syndromes 
American heart journal  2013;166(4):10.1016/j.ahj.2013.07.020.
Exercise stress testing is commonly obtained after percutaneous coronary intervention (PCI) performed for acute coronary syndromes (ACS). We compared the relationships between exercise echocardiography and nuclear testing after ACS-related PCI on outcomes and resource use.
Longitudinal observational study using fee-for-service Medicare claims to identify patients undergoing outpatient exercise stress testing with imaging within 15 months after PCI performed for ACS between 2003 and 2004.
Of 63,100 patients undergoing stress testing 3 to 15 months post-PCI, 31,731 (50.3%) underwent an exercise stress test with imaging. Among 29,279 patients undergoing exercise stress testing with imaging, 15.5% received echocardiography. Echocardiography recipients had higher rates of repeat stress testing (adjusted hazard ratio [HR] 2.60, CI 2.19–3.10) compared with those undergoing nuclear imaging in the 90 days after testing, but lower rates of revascularization (adjusted HR 0.87, CI 0.76–0.98) and coronary angiography (adjusted HR 0.88, CI 0.80–0.97). None of these differences persisted subsequent to 90 days after stress testing. Rates of death and readmission for myocardial infarction rates were similar. Total Medicare payments were lower initially after echocardiography (incremental difference $498, CI 488–507), an effect attributed primarily to lower reimbursement for the stress test itself, but not significantly different after 14 months after testing.
In this study using administrative data, echocardiography recipients initially had fewer invasive procedures but higher rates of repeat testing than nuclear testing recipients. However, these differences between echo and nuclear testing did not persist over longer time frames.
PMCID: PMC3874387  PMID: 24093861
6.  Modulation of Circulating Angiogenic Factors and Tumor Biology by Aerobic Training in Breast Cancer Patients Receiving Neoadjuvant Chemotherapy 
Aerobic exercise training (AET) is an effective adjunct therapy to attenuate the adverse side-effects of adjuvant chemotherapy in women with early breast cancer. Whether AET interacts with the antitumor efficacy of chemotherapy has received scant attention. We carried out a pilot study to explore the effects of AET in combination with neoadjuvant doxorubicin–cyclophosphamide (AC+AET), relative to AC alone, on: (i) host physiology [exercise capacity (VO2 peak), brachial artery flow-mediated dilation (BA-FMD)], (ii) host-related circulating factors [circulating endothelial progenitor cells (CEP) cytokines and angiogenic factors (CAF)], and (iii) tumor phenotype [tumor blood flow (15O–water PET), tissue markers (hypoxia and proliferation), and gene expression] in 20 women with operable breast cancer. AET consisted of three supervised cycle ergometry sessions/week at 60% to 100% of VO2 peak, 30 to 45 min/session, for 12 weeks. There was significant time × group interactions for VO2 peak and BA-FMD, favoring the AC+AET group (P < 0.001 and P = 0.07, respectively). These changes were accompanied by significant time × group interactions in CEPs and select CAFs [placenta growth factor, interleukin (IL)-1β, and IL-2], also favoring the AC+AET group (P < 0.05). 15O–water positron emission tomography (PET) imaging revealed a 38%decrease in tumor blood flow in the AC+AET group. There were no differences in any tumor tissue markers (P > 0.05). Whole-genome microarray tumor analysis revealed significant differential modulation of 57 pathways (P < 0.01), including many that converge on NF-κB. Data from this exploratory study provide initial evidence that AET can modulate several host- and tumor-related pathways during standard chemotherapy. The biologic and clinical implications remain to be determined.
PMCID: PMC3800005  PMID: 23842792
7.  Comparison of Transcatheter and Surgical Aortic Valve Replacement in Severe Aortic Stenosis: A Longitudinal Study of Echo Parameters in Cohort A of the PARTNER Trial 
To compare echocardiographic findings in patients with critical aortic stenosis following surgical (SAVR) or transcatheter aortic valve replacement (TAVR
The Placement of Aortic Transcatheter Valves trial randomized patients 1:1 to SAVR or TAVR
Echocardiograms were obtained at baseline, discharge, 30 days, 6 months, 1 year, and 2 years post procedure and analyzed in a core laboratory. For the analysis of post-implant variables, the first interpretable study (≤ 6 mos) was used.
Both groups showed a decrease in aortic valve gradients and increase in effective orifice area (EOA) (p < 0.0001) which remained stable over 2 years. Compared to SAVR, TAVR resulted in: larger indexed EOA (p = 0.038), less prosthesis-patient mismatch (p = 0.019), and more total and paravalvular aortic regurgitation (AR) (p < 0.0001). Baseline echocardiographic univariate predictors of death were: lower peak transaortic gradient in TAVR patients; low left ventricular diastolic volume (LVDV), low stroke volume, and greater severity of mitral regurgitation in SAVR patients. Post-implantation echocardiographic univariate predictors of death were: larger LVDV, systolic volume (LVSV) and EOA, decreased ejection fraction, and greater AR in TAVR patients; smaller LVSV and LVDV, low stroke volume, smaller EOA and prosthesis-patient mismatch in SAVR patients.
Patients randomized to either SAVR or TAVR experience enduring, significant reductions in transaortic gradients and increase in EOA. Compared to SAVR, TAVR patients had higher indexed EOA, lower prosthesis-patient mismatch and more AR. Univariate predictors of death for the TAVR group and SAVR groups differed and may allow future refinement in patient selection.
PMCID: PMC3931006  PMID: 23623915
transcatheter aortic valve replacement; aortic stenosis; echocardiography
8.  The Influence of Adjuvant Therapy on Cardiorespiratory Fitness in Early-Stage Breast Cancer Seven Years After Diagnosis: The Cooper Center Longitudinal Study 
We examined cardiorespiratory fitness (CRF) levels in early-stage breast cancer patients and determined whether CRF differs as a function of adjuvant therapy regimen.
Patients and methods
A total of 180 early breast cancer patients representing three treatment groups (surgery only, single-modality adjuvant therapy, and multi-modality adjuvant therapy) in the Cooper Center Longitudinal Study (CCLS) were studied. A non-cancer control group (n=180) matched by sex, age, and date of the CCLS visit were included. All subjects underwent an incremental exercise tolerance test to symptom limitation to assess CRF (i.e., peak METs and time to exhaustion).
The mean time from breast cancer diagnosis to exercise tolerance testing was 7.4 ± 6.2 years. In adjusted analyses, time to exhaustion and peak METs were incrementally impaired with the addition of surgery, single-modality, and multi-modality adjuvant therapy compared to matched controls (p=0.006 and p=0.028, respectively). CRF was lowest in the multi-modality group compared to all other groups (all p’s <0.05).
Despite being seven years post diagnosis, asymptomatic early breast cancer survivors have marked reductions in CRF. Patients treated with multi-modal adjuvant therapy have the greatest impairment in CRF.
PMCID: PMC3640334  PMID: 23504137
cardiorespiratory fitness; cardiovascular risk; adjuvant therapy; breast cancer
9.  Use of Stress Testing and Diagnostic Catheterization after Coronary Stenting: Association of Site-level Patterns with Patient Characteristics and Outcomes in 247,052 Medicare Beneficiaries 
To determine diagnostic testing patterns after percutaneous coronary intervention (PCI).
Little is known about patterns of diagnostic testing after PCI in the U.S. or the relationship of these patterns with clinical outcomes.
We linked Centers for Medicare & Medicaid Services inpatient and outpatient claims to the National Cardiovascular Data Registry® CathPCI Registry® data from 2005–2007. Hospital quartiles of the cumulative incidence of diagnostic testing use within 12 and 24 months post-PCI were compared for patient characteristics, repeat revascularization, acute myocardial infarction (AMI), and death.
A total of 247,052 patients underwent PCI at 656 institutions. Patient and site characteristics were similar across testing use quartiles. There was a 9% and 20% higher adjusted risk of repeat revascularization in Quartile 3 and Quartile 4 (highest testing rate), respectively, when compared to Quartile 1 (lowest testing rate) (p=0.020 and <0.0001, respectively). The adjusted risk for death or AMI did not differ among quartiles.
While patient characteristics were largely independent of rates of post-PCI testing, higher testing rates was not associated with lower risks of myocardial infarction or death, but repeat revascularization was significantly higher at these sites. Additional studies should examine whether increased testing is a marker for improved quality of post-PCI care or simply increased healthcare utilization.
PMCID: PMC3962793  PMID: 23727207
stress testing; diagnostic catheterization; site-level patterns; patient outcomes
10.  Analysis of Early Hypertension and Clinical Outcome With Bevacizumab: Results From Seven Phase III Studies 
The Oncologist  2013;18(3):273-280.
To assess the prognostic and predictive value of bevacizumab-related hypertension, hypertension and efficacy outcomes for seven company-sponsored placebo-controlled phase III studies of bevacizumab were analyzed. Early treatment-related BP increases were not found to have general prognostic importance for patients with advanced cancer.
Hypertension is associated with antivascular endothelial growth factor treatment, but the clinical implications of hypertension are uncertain. To assess the prognostic and predictive value of bevacizumab-related hypertension, a comprehensive analysis of whether hypertension and efficacy outcomes are associated was conducted on seven company-sponsored placebo-controlled phase III studies of bevacizumab.
Patient-specific data were available from 6,486 patients with metastatic colorectal, breast, non-small cell lung, pancreatic, and renal cell cancers. Primary hypertension endpoint was a blood pressure (BP) increase of >20 mmHg systolic or >10 mmHg diastolic within the first 60 days of treatment. Additional endpoints included other predefined thresholds of change in BP and severity of hypertension graded using the National Cancer Institute's Common Terminology Criteria for Adverse Events. To analyze the general prognostic importance of an early BP increase, multivariate Cox regression models were used to assess the correlation between BP changes and progression-free (PFS) and overall survival (OS) outcomes in the control groups. To analyze whether early BP increases could predict for benefit from bevacizumab, similar analyses were conducted in the bevacizumab-treated and control groups.
In six of seven studies, early BP increase was neither predictive of clinical benefit from bevacizumab nor prognostic for the course of the disease. For study AVF2107g, early increased BP was associated with longer PFS and OS times in the bevacizumab group but shorter OS time in the control group.
Early treatment-related BP increases do not predict clinical benefit from bevacizumab based on PFS or OS outcomes. BP increases do not appear to have general prognostic importance for patients with advanced cancer.
PMCID: PMC3607523  PMID: 23485622
Bevacizumab; Hypertension; Clinical outcome; Prognostic factor; Predictive factor
11.  Low Diagnostic Yield of Elective Coronary Angiography 
The New England journal of medicine  2010;362(10):886-895.
Guidelines for triaging patients for cardiac catheterization recommend a risk assessment and noninvasive testing. We determined patterns of noninvasive testing and the diagnostic yield of catheterization among patients with suspected coronary artery disease in a contemporary national sample.
From January 2004 through April 2008, at 663 hospitals in the American College of Cardiology National Cardiovascular Data Registry, we identified patients without known coronary artery disease who were undergoing elective catheterization. The patients’ demographic characteristics, risk factors, and symptoms and the results of noninvasive testing were correlated with the presence of obstructive coronary artery disease, which was defined as stenosis of 50% or more of the diameter of the left main coronary artery or stenosis of 70% or more of the diameter of a major epicardial vessel.
A total of 398,978 patients were included in the study. The median age was 61 years; 52.7% of the patients were men, 26.0% had diabetes, and 69.6% had hypertension. Noninvasive testing was performed in 83.9% of the patients. At catheterization, 149,739 patients (37.6%) had obstructive coronary artery disease. No coronary artery disease (defined as <20% stenosis in all vessels) was reported in 39.2% of the patients. Independent predictors of obstructive coronary artery disease included male sex (odds ratio, 2.70; 95% confidence interval [CI], 2.64 to 2.76), older age (odds ratio per 5-year increment, 1.29; 95% CI, 1.28 to 1.30), presence of insulin-dependent diabetes (odds ratio, 2.14; 95% CI, 2.07 to 2.21), and presence of dyslipidemia (odds ratio, 1.62; 95% CI, 1.57 to 1.67). Patients with a positive result on a noninvasive test were moderately more likely to have obstructive coronary artery disease than those who did not undergo any testing (41.0% vs. 35.0%; P<0.001; adjusted odds ratio, 1.28; 95% CI, 1.19 to 1.37).
In this study, slightly more than one third of patients without known disease who underwent elective cardiac catheterization had obstructive coronary artery disease. Better strategies for risk stratification are needed to inform decisions and to increase the diagnostic yield of cardiac catheterization in routine clinical practice.
PMCID: PMC3920593  PMID: 20220183
12.  Downstream Testing and Subsequent Procedures After Coronary Computed Tomographic Angiography Following Coronary Stenting in Patients ≥65 Years of Age 
The American journal of cardiology  2012;110(6):776-783.
Limited data are available on the use of coronary computed tomography angiography (CCTA) in patients who have received percutaneous coronary intervention (PCI). To evaluate patterns of cardiac testing including CCTA after PCI, we created a retrospective observational data set linking the National Cardiovascular Data Registry® CathPCI Registry® baseline data with longitudinal inpatient and outpatient Medicare claims data for patients who received coronary stenting between November 1, 2005 and December 31, 2007. Among 192,009 PCI patients (median age 74 years), the first test after coronary stenting was CCTA for 553 (0.3%), stress testing for 89,900 (46.8%), and coronary angiography for 22,308 (11.6%); 79,248 (41.3%) had no further testing. Patients referred to CCTA first had generally similar or lower baseline risk than those referred for stress testing or catheterization first. Compared to patients with stress testing first after PCI, patients who underwent CCTA first had higher unadjusted rates of subsequent noninvasive testing (10% vs. 3%), catheterization (26% vs. 15%), and revascularization (13% vs. 8%) within 90 days of initial post-PCI testing (p<0.0001 for all). In conclusion, despite similar or lesser risk profiles, patients initially evaluated with CCTA after PCI had more downstream testing and revascularization than patients initially evaluated with stress testing. It is unclear whether these differences derive from patient selection, the performance of CCTA relative to other testing strategies, or the association of early CCTA adoption with distinct patterns of care.
PMCID: PMC3915770  PMID: 22651883
coronary computed tomography angiography; percutaneous coronary intervention; patterns of care
13.  Patterns of Stress Testing and Diagnostic Catheterization after Coronary Stenting in 250,350 Medicare Beneficiaries 
Patterns of non-invasive stress test (ST) and invasive coronary angiography (CA) utilization after percutaneous coronary intervention (PCI) are not well described in older populations.
Methods and Results
We linked National Cardiovascular Data Registry® CathPCI Registry® data with longitudinal Medicare claims data for 250,350 patients undergoing PCI from 2005 to 2007 and described subsequent testing and outcomes. Between 60 days post-PCI and end of follow-up (median 24 months), 49% (n=122,894) received stress testing first, 10% (n=25,512) underwent invasive CA first, and 41% (n=101,944) had no testing (NT). A number of clinical risk factors at time of index PCI were associated with decreased likelihood of downstream testing (ST or CA, p<0.05 for all), including older age (HR 0.784 per 10 year increase), male sex (HR 0.946), heart failure (HR 0.925), diabetes (HR 0.954), smoking (HR 0.804), and renal failure (HR 0.880). Fifteen percent of patients with ST first proceeded to subsequent CA within 90 days of testing (n=18,472/101,884); of these, 48% (n=8831) underwent revascularization within 90 days, compared to 53% (n=13,316) of CA first patients (p<0.0001).
In this descriptive analysis, stress testing and invasive CA were common in older patients after PCI. Paradoxically, patients with higher-risk features at baseline were less likely to undergo post-PCI testing. The revascularization yield was low on patients referred for ST after PCI, with only 9% undergoing revascularization within 90 days.
PMCID: PMC3915772  PMID: 23074343
non-invasive stress test; coronary angiography; percutaneous coronary intervention; clinical outcomes
14.  The Potential Role of Aerobic Exercise to Modulate Cardiotoxicity of Molecularly Targeted Cancer Therapeutics 
The Oncologist  2013;18(2):221-231.
This article reviews the molecular signaling of antiangiogenic and HER2-directed therapies that may underpin cardiac toxicity and the hypothesized cardioprotective properties of aerobic exercise.
Molecularly targeted therapeutics (MTT) are the future of cancer systemic therapy. They have already moved from palliative therapy for advanced solid malignancies into the setting of curative-intent treatment for early-stage disease. Cardiotoxicity is a frequent and potentially serious adverse complication of some targeted therapies, leading to a broad range of potentially life-threatening complications, therapy discontinuation, and poor quality of life. Low-cost pleiotropic interventions are therefore urgently required to effectively prevent and/or treat MTT-induced cardiotoxicity. Aerobic exercise therapy has the unique capacity to modulate, without toxicity, multiple gene expression pathways in several organ systems, including a plethora of cardiac-specific molecular and cell-signaling pathways implicated in MTT-induced cardiac toxicity. In this review, we examine the molecular signaling of antiangiogenic and HER2-directed therapies that may underpin cardiac toxicity and the hypothesized molecular mechanisms underlying the cardioprotective properties of aerobic exercise. It is hoped that this knowledge can be used to maximize the benefits of small molecule inhibitors, while minimizing cardiac damage in patients with solid malignancies.
PMCID: PMC3579607  PMID: 23335619
Exercise; Cardiotoxicity; Molecular therapeutics; Solid malignancies
15.  Sex‐Based Differences in Outcomes After Percutaneous Coronary Intervention for Acute Myocardial Infarction: A Report From TRANSLATE‐ACS 
Data regarding sex‐based outcomes after percutaneous coronary intervention (PCI) for myocardial infarction are mixed. We sought to examine whether sex differences in outcomes exist in contemporary practice.
Methods and Results
We examined acute myocardial infarction patients undergoing PCI between April 2010 and October 2012 at 210 US hospitals participating in the Treatment with Adenosine Diphosphate Receptor Inhibitors: Longitudinal Assessment of Treatment Patterns and Events after Acute Coronary Syndrome (TRANSLATE‐ACS) observational study. Outcomes included 1‐year risk of major adverse cardiac events and bleeding according to Global Utilization of Strategies To Open Occluded Arteries (GUSTO) and Bleeding Academic Research Consortium (BARC) definitions. Among 6218 patients, 27.5% (n=1712) were female. Compared with men, women were older, had more comorbidities, and had lower functional status. Use of multivessel PCI and drug‐eluting stents was similar between sexes, while women received less prasugrel. Unadjusted cumulative incidence of 1‐year major adverse cardiac events was higher for women than for men (15.7% versus 13.6%, P=0.02), but female sex was no longer associated with higher incidence of major adverse cardiac events after multivariable adjustment (hazard ratio 0.98, 95% CI 0.83 to 1.15). Female sex was associated with higher risks of post‐PCI GUSTO bleeding (9.1% versus 5.7%, P<0.0001) and postdischarge BARC bleeding (39.6% versus 27.9%, P<0.0001). Differences persisted after adjustment (GUSTO: hazard ratio 1.32, 95% CI 1.06 to 1.64; BARC: incidence rate ratio 1.42, 95% CI 1.27 to 1.56).
Female and male myocardial infarction patients undergoing PCI differ regarding demographic, clinical, and treatment profiles. These differences appear to explain the higher observed major adverse cardiac event rate but not higher adjusted bleeding risk for women versus men.
PMCID: PMC3959683  PMID: 24510115
acute myocardial infarction; major adverse cardiac events; percutaneous coronary intervention; sex‐based outcomes
16.  Downstream Procedures and Outcomes After Stress Testing For Suspected Coronary Artery Disease in the United States 
American heart journal  2012;163(3):10.1016/j.ahj.2011.11.022.
Millions of Americans with suspected coronary artery disease undergo non-invasive cardiac stress testing annually. Downstream procedures and subsequent outcomes among symptomatic patients without known coronary disease referred for stress testing are not well characterized in contemporary community practice.
We examined administrative insurance billing data from a national insurance provider from November 2004 through June 2007. After excluding patients with prior cardiac disease or chest pain evaluation, we identified 80,676 people age 40–64 years with outpatient cardiac stress testing within 30 days after an office visit for chest pain. We evaluated rates of invasive coronary angiography, coronary revascularization, and cardiovascular events after stress testing.
Within 60 days, only 8.8% of stress test patients underwent cardiac catheterization and only 2.7% underwent revascularization; within one year only 0.5% suffered death, myocardial infarction, or stroke. There were marked geographic variations in one-year rates of catheterization (3.8–14.8%) and revascularization (1.2–3.0%) across 20 hospital referral regions.
In this large national cohort of middle-aged patients without previously coded cardiac diagnosis who were referred for stress testing after outpatient chest pain evaluation, few proceeded to invasive angiography or revascularization, and subsequent cardiovascular events were infrequent.
PMCID: PMC3886123  PMID: 22424017
17.  Method for Simultaneous fMRI/EEG Data Collection during a Focused Attention Suggestion for Differential Thermal Sensation 
In the present work, we demonstrate a method for concurrent collection of EEG/fMRI data. In our setup, EEG data are collected using a high-density 256-channel sensor net. The EEG amplifier itself is contained in a field isolation containment system (FICS), and MRI clock signals are synchronized with EEG data collection for subsequent MR artifact characterization and removal. We demonstrate this method first for resting state data collection. Thereafter, we demonstrate a protocol for EEG/fMRI data recording, while subjects listen to a tape asking them to visualize that their left hand is immersed in a cold-water bath and referred to, here, as the cold glove paradigm. Thermal differentials between each hand are measured throughout EEG/fMRI data collection using an MR compatible temperature sensor that we developed for this purpose. We collect cold glove EEG/fMRI data along with simultaneous differential hand temperature measurements both before and after hypnotic induction. Between pre and post sessions, single modality EEG data are collected during the hypnotic induction and depth assessment process. Our representative results demonstrate that significant changes in the EEG power spectrum can be measured during hypnotic induction, and that hand temperature changes during the cold glove paradigm can be detected rapidly using our MR compatible differential thermometry device.
PMCID: PMC4063545  PMID: 24429915
Behavior; Issue 83; hypnosis; EEG; fMRI; MRI; cold glove; MRI compatible; temperature sensor
19.  Cancer Therapy-Induced Cardiac Toxicity in Early Breast Cancer: Addressing the Unresolved Issues 
Circulation  2012;126(23):2749-2763.
PMCID: PMC3667651  PMID: 23212997
cardiomyopathy; cardiotoxicity; heart failure; women
20.  Cardiac imaging approaches to evaluate drug-induced myocardial dysfunction 
American heart journal  2012;164(6):846-855.
The ability to make informed benefit-risk assessments for potentially cardiotoxic new compounds is of considerable interest and importance at the public health, drug development, and individual patient levels. Cardiac imaging approaches in the evaluation of drug-induced myocardial dysfunction will likely play an increasing role. However, the optimal choice of myocardial imaging modality and the recommended frequency of monitoring are undefined. These decisions are complicated by the array of imaging techniques, which have varying sensitivities, specificities, availabilities, local expertise, safety, and costs, and by the variable time-course of tissue damage, functional myocardial depression, or recovery of function. This White Paper summarizes scientific discussions of members of the Cardiac Safety Research Consortium on the main factors to consider when selecting nonclinical and clinical cardiac function imaging techniques in drug development. We focus on 3 commonly used imaging modalities in the evaluation of cardiac function: echocardiography, magnetic resonance imaging, and radionuclide (nuclear) imaging and highlight areas for future research.
PMCID: PMC3686274  PMID: 23194484
21.  Clinical Implications of Referral Bias in the Diagnostic Performance of Exercise Testing for Coronary Artery Disease 
Exercise testing with echocardiography or myocardial perfusion imaging is widely used to risk‐stratify patients with suspected coronary artery disease. However, reports of diagnostic performance rarely adjust for referral bias, and this practice may adversely influence patient care. Therefore, we evaluated the potential impact of referral bias on diagnostic effectiveness and clinical decision‐making.
Methods and Results
Searching PubMed and EMBASE (1990–2012), 2 investigators independently evaluated eligibility and abstracted data on study characteristics and referral patterns. Diagnostic performance reported in 4 previously published meta‐analyses of exercise echocardiography and myocardial perfusion imaging was adjusted using pooled referral rates and Bayesian methods. Twenty‐one studies reported referral patterns in 49 006 patients (mean age 60.7 years, 39.6% women, and 0.8% prior history of myocardial infarction). Catheterization referral rates after normal and abnormal exercise tests were 4.0% (95% CI, 2.9% to 5.0%) and 42.5% (36.2% to 48.9%), respectively, with odds ratio for referral after an abnormal test of 14.6 (10.7 to 19.9). After adjustment for referral, exercise echocardiography sensitivity fell from 84% (80% to 89%) to 34% (27% to 41%), and specificity rose from 77% (69% to 86%) to 99% (99% to 100%). Similarly, exercise myocardial perfusion imaging sensitivity fell from 85% (81% to 88%) to 38% (31% to 44%), and specificity rose from 69% (61% to 78%) to 99% (99% to 100%). Summary receiver operating curve analysis demonstrated only modest changes in overall discriminatory power but adjusting for referral increased positive‐predictive value and reduced negative‐predictive value.
Exercise echocardiography and myocardial perfusion imaging are considerably less sensitive and more specific for coronary artery disease after adjustment for referral. Given these findings, future work should assess the comparative ability of these and other tests to rule‐in versus rule‐out coronary artery disease.
PMCID: PMC3886773  PMID: 24334965
coronary artery disease; diagnostic performance; echocardiography; exercise testing; myocardial perfusion imaging
22.  Automated Diagnosis of Epilepsy using EEG Power Spectrum 
Epilepsia  2012;53(11):e189-e192.
Interictal electroencephalography (EEG) has clinically meaningful limitations in its sensitivity and specificity in the diagnosis of epilepsy because of its dependence on the occurrence of epileptiform discharges. We have developed a computer-aided diagnostic (CAD) tool that operates on the absolute spectral energy of the routine EEG and has both substantially higher sensitivity and negative predictive value than the identification of interictal epileptiform discharges. Our approach used a multilayer perceptron to classify 156 patients admitted for video-EEG monitoring. The patient population was diagnostically diverse with 87 diagnosed with either generalized or focal seizures. The remainder was diagnosed with non-epileptic seizures. The sensitivity was 92% (95% CI: 85–97%) and the negative predictive value was 82% (95% CI: 67%–92%). We discuss how these findings suggest that this CAD can be used to supplement event-based analysis by trained epileptologists.
PMCID: PMC3447367  PMID: 22967005
Epilepsy; machine learning; prediction; non-epileptic seizure; computer aided diagnostics
23.  Patterns and Predictors of Stress Testing Modality after Percutaneous Coronary Stenting: Retrospective Analysis using Data from the NCDR® 
JACC. Cardiovascular imaging  2012;5(10):969-980.
We evaluated temporal trends and geographic variation in choice of stress testing modality post-PCI, as well as associations between modality and procedure use after testing.
Stress testing is frequently performed post-PCI, but the choices amongst available modalities (electrocardiogram [ECG]-only, nuclear, or echocardiography; pharmacologic or exercise stress) and consequences of such choices are not well characterized.
CathPCI Registry® data were linked with identifiable Medicare claims to capture stress testing use between 60 and 365 days post-PCI and procedures within 90 days after testing. Testing rates and modality used were modeled based on patient, procedure, and PCI facility factors, calendar quarter, and Census Divisions using Poisson and logistic regression. Post-test procedure use was assessed using Gray’s test.
In 284,971 patients, the overall stress testing rate after PCI was 53.1 per 100 person-years. Testing rates declined from 59.3 in Quarter 1 (2006) to 47.1 in Quarter 4 (2008), but the relative use of modalities changed little. Among exercise testing recipients, adjusted proportions receiving ECG-only testing varied from 6.8%-22.8% across Census Divisions and among exercise testing recipients having an imaging test, the proportion receiving echocardiography (versus nuclear) varied from 9.4%-34.1%. Post-test procedure use varied among modalities; exercise ECG-only testing was associated with more subsequent stress testing (13.7% vs. 2.9%; p<0.001), but less catheterization (7.4% vs. 14.1%; p<0.001) than imaging-based tests.
Modest reductions in stress testing after PCI occurring between 2006 and 2008 cannot be ascribed to trends in use of any single modality. Additional research should assess whether this trend represents better patient selection for testing or administrative policies (e.g., restricted access for patients with legitimate testing needs). Geographic variation in utilization of stress modalities and differences in downstream procedure use among modalities suggest a need to identify optimal use of the different test modalities in individual patients.
PMCID: PMC3628616  PMID: 23058063
imaging; echocardiography, stress; myocardial perfusion imaging
24.  Use of the Corus® CAD Gene Expression Test for Assessment of Obstructive Coronary Artery Disease Likelihood in Symptomatic Non-Diabetic Patients 
PLoS Currents  2013;5:ecurrents.eogt.0f04f6081905998fa92b99593478aeab.
The determination of the underlying etiology of symptoms suggestive of obstructive coronary artery disease (CAD, ≥50% stenosis in a major coronary artery) is a common clinical challenge in both primary care and cardiology clinics. Usual care in low to medium risk patients often involves a family history, risk factor assessment, and then stress testing with or without non-invasive imaging. If positive, this is often followed by invasive coronary angiography (ICA). Despite extensive adoption of this usual care paradigm, more than 60% of patients referred for angiography do not have obstructive CAD. In order to robustly identify those symptomatic patients without obstructive CAD, who can avoid subsequent cardiac testing and look elsewhere for the cause of their symptoms, a recently described whole blood gene expression score (GES: Corus® CAD, CardioDx, Inc., Palo Alto, CA) has been developed and validated in two multi-center trials. This paper reviews the published literature and assessments by independent parties regarding the analytical and clinical validity as well as the clinical utility of the Corus® CAD test.
PMCID: PMC3770834  PMID: 24043473
25.  Future Directions for Cardiovascular Disease Comparative Effectiveness Research 
Comparative effectiveness research (CER) aims to provide decision-makers the evidence needed to evaluate the benefits and harms of alternative clinical management strategies. CER has become a national priority, with considerable new research funding allocated. Cardiovascular disease is a priority area for CER. This workshop report provides an overview of CER methods, with an emphasis on practical clinical trials and observational treatment comparisons. The report also details recommendations to the National Heart Lung and Blood Institute for a new framework for evidence development to foster cardiovascular CER, and specific studies to address eight clinical issues identified by the Institute of Medicine as high priorities for cardiovascular CER.
PMCID: PMC3416944  PMID: 22796257
comparative effectiveness; research methods; clinical trials

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