Variability in Cardiac Stress Test Interpretation: Agreement between Enrollment Sites and Core Laboratories in the Global ISCHEMIA Trial

Abstract

Background

Cardiac stress testing is a cornerstone of risk stratification and management in patients with chronic coronary disease (CCD), yet the consistency and accuracy of its interpretation remain poorly defined. This analysis evaluated variation in the interpretation of myocardial ischemia between enrollment sites and core laboratories in the ISCHEMIA trial.

Methods

ISCHEMIA was a global (37 countries, 2012–2018) randomized trial of an initial invasive versus conservative strategy in patients with CCD and moderate or severe ischemia. This analysis included participants with site-interpreted qualifying stress tests—nuclear, echocardiography (echo), cardiac magnetic resonance (CMR), or exercise tolerance test (ETT)—and independent core laboratory adjudication. Core laboratories, serving as the reference standard, reinterpreted tests blinded to site results. A trinary outcome variable (site underestimation, concordance, or overestimation) was defined by comparing site-determined ischemia levels to standardized core lab assessments. Adjusted mixed-effects logistic regression models with random site intercepts assessed variability.

Results

Among 6,971 participants (mean age 62.8 years; 73% men), site interpretations showed 0% no/mild (by design), 43% moderate, and 57% severe ischemia. Core labs reclassified these as 8% none, 11% mild, 30% moderate, and 51% severe ischemia. For the imaging modalities, median site-core lab agreement rates were ~55%; nearly 25% of site-classified moderate/severe cases were downgraded to no or mild ischemia by core labs. Adjusted MORs for site overestimation were 2.36 (95% CI: 2.02–2.82; nuclear), 1.98 (95% CI: 1.62–2.60; echo), 1.89 (95% CI: 1.0–5.41; CMR), and 2.15 (95% CI: 1.76–2.79; ETT). Adjusted MORs for underestimation ranged from 1.25 to 1.77.

Conclusions

In ISCHEMIA, enrollment sites frequently overestimated or underestimated the severity of myocardial ischemia compared with core laboratory assessments, highlighting the need for strategies to improve the consistency and accuracy of stress testing interpretation in patients with CCD.

INTRODUCTION

Noninvasive cardiac stress testing is foundational to the diagnosis, prognostication, and management of chronic coronary disease (CCD). Clinical guidelines emphasize its role in risk stratification based upon associations between stress test findings and subsequent clinical events reported by expert, high-volume centers.^1–4 In 2006, amidst rapid increases in the use of stress testing, the ACC-Duke Think Tank on Quality in Cardiovascular Imaging highlighted key elements of stress test quality, including appropriateness, image acquisition, interpretation, and reporting.⁵ Around that time, a slew of appropriate use criteria documents were published along with standardized image acquisition protocols and reporting recommendations.^6–13 To date, the quality component associated with interpretation has rarely been studied.

To address this gap in knowledge, we leveraged data from the International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA), in which both enrollment sites and core laboratories independently interpreted multiple major cardiac stress testing modalities.¹⁴ This dual-interpretation framework provides a unique opportunity to measure how frequently site-based assessments of ischemia deviated from standardized adjudications in routine clinical practice.

METHODS

Study Population

The ISCHEMIA trial design, patient characteristics, and primary results have been previously described, and all supporting ISCHEMIA trial data for this study are available online on BioLINCC.^{14, 15} This secondary analysis of de-identified data was conducted within the established regulatory framework of the original ISCHEMIA trial, which was approved by the institutional review boards at each participating site, and all participants provided written informed consent. Briefly, ISCHEMIA was an open-label trial of patients with CCD and moderate or severe ischemia randomized to either an initial conservative strategy of guideline-directed medical therapy alone or an initial invasive strategy of angiography with coronary revascularization, if feasible, in addition to guideline-directed medical therapy. The prerequisites for site qualification in the ISCHEMIA trial included access to a ≥ 64-slice CT scanner, and the ability to perform stress testing with either nuclear myocardial perfusion imaging (MPI)—single photon emission computer tomography (SPECT) or positron emission tomography (PET)—stress echocardiography (echo), cardiac magnetic resonance imaging (CMR), or exercise tolerance test (ETT). Attenuation correction was encouraged for SPECT MPI and contrast imaging was recommended for stress echocardiography. Clinical sites were given autonomy to decide which stress test modalities they used for recruitment.

ISCHEMIA participants were recruited after undergoing cardiac stress testing for clinical indications with site interpretations demonstrating at least moderate ischemia, except for ETT, in which severe ischemia was required. Separate core laboratories were designated for each of the four stress test modalities and provided feedback to sites on their interpretations during the enrollment period. While the original ISCHEMIA protocol mandated core lab confirmation of at least moderate ischemia prior to randomization, this was changed on January 6^th, 2014, to improve recruitment efficiency by enabling sites to enroll patients based upon their interpretations alone.

This analysis leveraged data from all studies provided to the core laboratories for interpretation (n=8518), but excluded those in which the site’s interpretation of ischemia severity was not able to be determined (n=1247), those without a core lab estimate of ischemia severity (n=136), and those where the core lab deemed the study to be uninterpretable (n=164), resulting in a final cohort of 6971 studies.

Interpretation of Stress Testing

During the onboarding process, sites were trained by the core laboratories on the trial-specified enrollment definitions of at least moderate ischemia specific to each imaging modality (Table 1). Given the study’s inclusion criteria, site training focused upon distinguishing at least moderate from mild ischemia, with less attention in distinguishing moderate from severe ischemia. Core laboratories independently adjudicated the qualifying stress tests, blinded to all site (including site-level interpretations) and patient data, except sex. Core labs then independently categorized the severity of ischemia as no, mild, moderate, or severe, based upon contemporary societal definitions.¹⁶ Sites were permitted to submit borderline cases for core laboratory review before enrolling a participant, but such studies were not included in these analyses. When sufficient data were present, the imaging coordinating center abstracted sites’ ischemia severity determinations from their clinical reports using detailed data (e.g., segment-level findings) to map their findings to the trial-specified definitions of ischemia. Otherwise, the severity level recorded in the site report’s conclusion was used.

Table 1: Definitions of Myocardial Ischemia Severity Used in the ISCHEMIA Trial, Stratified by Stress Test Modality.

Thresholds shown were applied by core labs for adjudication of ischemia.

Modality	No Ischemia	Mild Ischemia	Moderate Ischemia	Severe Ischemia
Nuclear Perfusion (SPECT/PET)	0–4% ischemic myocardium	5–9% ischemic myocardium	10–14% ischemic myocardium	≥15% ischemic myocardium
Echocardiography	No new segments with induced severe HK/AK	<3 new segments with induced severe HK/AK	3 new segments with induced severe HK/AK	≥4 new segments with induced severe HK/AK
Cardiac Magnetic Resonance	No segments with inducible perfusion deficit	≤3/32 segments (<12.5%) with inducible perfusion deficit	4–7/32 segments (≥12.5%) with inducible perfusion deficit	≥8/32 segments (≥25%) with inducible perfusion deficit
Stress ECG (ETT)	Normal	ST depression ≥1 mm in at least 2 leads	Satisfying either ECG or functional capacity criteria for “Severe Ischemia”	All the following: Clinical history of typical angina or typical angina during the exercise test Absence of resting ST-segment depression ≥1.0 mm or confounders that render exercise ECG non-interpretable (LBBB, LVH with repolarization, pacemaker, etc.) As compared to the baseline tracing, either of the following: Additional exercise-induced horizontal or downsloping ST-segment depression ≥1.5 mm in 2 leads or ≥2.0 mm in any lead ST-segment elevation ≥1 mm in an area not known to be infarcted. Either of the following: Workload at which ST-segment criteria are met is not to exceed completion of stage 2 of a standard Bruce protocol or 7 METs if a non-Bruce protocol is used ST segment criteria are met at <75% of the maximum predicted HR Anatomic eligibility must be confirmed

Abbreviations: ECG = electrocardiogram, ETT = exercise tolerance test, HK = hypokinesis, AK = akinesis, LBBB = left bundle branch block, LVH = left ventricular hypertrophy, MPHR = maximum predicted heart rate, PET = Positron Emission Tomography, SPECT = Single-Photon Emission Computed Tomography.

The categories of ischemia according to modality are shown in Table 1. The threshold for moderate ischemia was selected to achieve a projected rate of cardiovascular death or MI of at least 5% per year.¹⁶ For nuclear MPI, moderate ischemia was defined as ≥ 10% and severe ischemia as ≥ 15% ischemic myocardium with lesser degrees of myocardial ischemia graded as mild (5–9%) or none (< 5%). For stress echocardiography, stress-induced severe hypokinesis or akinesis in 3/16 segments was classified as moderate and ≥ 4/16 segments as severe ischemia, although the core lab could also classify the magnitude of ischemia as mild (1–2 segments) or none (0 segments).

For CMR, perfusion and wall motion abnormalities were considered. Perfusion was adjudicated using a 32-segment model, in which each of the standard 16 American Heart Association segments was subdivided transmurally into an endocardial and epicardial half. This granularity allowed for the conversion of perfusion defects into a percentage of total myocardium, with each individual sub-segment representing approximately 3.125% of the myocardial mass. For perfusion, ≥12.5% (4–7 of 32 subsegments) ischemic myocardium was considered moderate and ≥ 25% (≥ 8 subsegments) was considered severe, whereas <12.5% was considered mild and the absence of any perfusion defect was classified as no ischemia.

For ETT, 4 criteria were required prior to enrollment, including history of stable or exercise limiting angina, absence of baseline ECG abnormalities precluding interpretation of ST segment changes, horizontal or downsloping ST segment changes, and exercise metabolic equivalents. As described in the supplement, an expanded definition of moderate ischemia was allowed for MPI and stress echo, but this only encompassed 1% of enrolled participants.

Statistical Analysis

Overall agreement between site and core laboratory assessments was categorized as a trinary variable—site underestimation, concordance, or overestimation—based upon core lab assessments of none, mild, moderate, or severe ischemia; stratified by stress modality (nuclear, echo, CMR, and ETT). To examine variability across sites within each imaging modality, two series of mixed effects logistic regression models were fit, one for sites underestimating and a one for sites overestimating ischemic severity by at least one category compared with the core lab assessment. All models included random intercepts for site to account for clustering of patients within sites and to estimate between-site variation. In each series, the first model included no fixed effects, providing an estimate of “unadjusted” site variation. For screened patients who were not enrolled, only age, sex, and site were available. The second model included adjustment for patient age and sex, and a third model adjusted for age, sex and geographic region. These models were fit on the entire cohort of 6971 ISCHEMIA participants with site and core lab interpretations. We further evaluated the impact of additional patient factors by repeating the above models with a final step that included characteristics collected only after randomization. These sequential models were constructed as follows: first with no adjustment, then cumulatively adjusting for (1) age and sex, (2) BMI, (3) diabetes, prior myocardial infarction, prior PCI, prior CABG, heart failure, and the Seattle Angina Questionnaire-7 Summary score, and lastly (4) geographic region.

From all models, we converted the between-site variance estimates to median odds ratios (MOR). The MOR represents the median odds of underestimating or overestimating ischemia severity in statistically identical patients tested at one random site vs. another, after adjusting for patient covariates.¹⁷ Higher MOR values suggest greater variability across institutions. For example, an MOR of 2.0 means that, for two identical patients seen at two randomly selected hospitals, the odds of one hospital underestimating or overestimating ischemia severity are, on average, twice that of the other hospital. In contrast, an MOR of 1.0 would indicate no difference in site-level interpretations as compared with the core labs. Finally, the distribution of sites’ rates of underestimation, concordance, and overestimation were described using Sankey diagrams and box plots. The box plots were generated using mixed effects multinomial logistic regression models of the trinary outcome with a random effect for site and a fixed effect for geographic region. All analyses were stratified by imaging modality and performed using SAS version 9.4 (SAS Institute, Cary, NC) and R version 4.3.3.¹⁸

RESULTS

Study Population

Among 6971 patients, the mean age was 62.8 ± 9.8 years, and 73.4% were male. Recruitment was global—across 320 clinical sites and 37 countries—with participants from Asia (34.2%), Europe (31.2%), North America (25.5%), Latin America (7.3%), and other regions (1.8%). Of those enrolled, 36.7% had a history of diabetes, and 16.3% had a prior myocardial infarction (Table 2). Nuclear MPI was the most frequently utilized stress test (45.6%), followed by ETT (32.7%), stress echocardiography (19.1%), and CMR (2.6%). Figure 1 depicts the site volume-adjusted rates of ischemia severity overestimation and underestimation stratified by modality.

Table 2: Baseline Patient Characteristics.

All enrolled patients in the ISCHEMIA trial with both an enrollment site and a core laboratory cardiac stress test interpretation.

Characteristic	Distribution of Characteristic	Concordance Rates by Characteristic
		Site Underestimated	Concordant	Site Overestimated
All patients	6971 (100.0%)	9.4%	61.6%	29.1%
Region
Asia	2387 (34.2%)	3.9%	70.7%	25.4%
Europe	2175 (31.2%)	9.9%	55.6%	34.4%
Latin America	506 (7.3%)	17.2%	62.1%	20.8%
North America	1776 (25.5%)	13.5%	56.2%	30.3%
Other	127 (1.8%)	15.0%	63.8%	21.3%
Age
<55	1357 (19.5%)	7.5%	64.4%	28.1%
55 to 64	2505 (35.9%)	7.9%	63.0%	29.1%
65 to 74	2317 (33.2%)	11.0%	59.9%	29.1%
>=75	792 (11.4%)	12.4%	57.1%	30.6%
Sex
Male	5118 (73.4%)	9.9%	63.3%	26.7%
Female	1853 (26.6%)	7.9%	56.6%	35.5%
Diabetes
Yes	2557 (36.7%)	9.9%	64.8%	25.3%
No	4413 (63.3%)	9.1%	59.7%	31.2%
Prior MI
Yes	1122 (16.3%)	14.1%	56.0%	29.9%
No	5777 (83.7%)	8.5%	62.7%	28.8%
CCTA results
Disease >=70%	3305 (47.4%)	11.9%	72.5%	15.6%
No disease >= 70%	911 (13.1%)	5.9%	58.8%	35.2%
Not evaluable	800 (11.5%)	7.4%	60.6%	32.0%
CCTA not performed	1955 (28.0%)	7.5%	44.8%	47.7%
Stress test modality
Nuclear (PET/SPECT)	3181 (45.6%)	15.2%	52.5%	32.3%
ECHO	1332 (19.1%)	9.5%	60.4%	30.0%
CMR	181 (2.6%)	24.3%	55.2%	20.4%
ETT	2277 (32.7%)	0.0%	75.3%	24.7%
Nuclear imaging modality
SPECT Sodium Iodide	2319 (72.9%)	15.2%	53.2%	31.6%
SPECT Solid State	611 (19.2%)	15.2%	50.2%	34.5%
PET/CT	100 (3.1%)	22.0%	66.0%	12.0%
PET standalone	5 (0.2%)	0.0%	60.0%	40.0%
Not specified	146 (4.6%)	10.3%	41.8%	47.9%
Echo: contrast used
Yes	517 (38.9%)	9.1%	66.0%	25.0%
No	812 (61.1%)	9.9%	57.0%	33.1%
Site assessment of ischemia
Moderate	2982 (42.8%)	21.9%	46.3%	31.8%
Severe	3989 (57.2%)	0.0%	73.0%	27.0%
Core lab assessment of ischemia
None	544 (7.8%)	0.0%	0.0%	100.0%
Mild	782 (11.2%)	0.0%	0.0%	100.0%
Moderate	2082 (29.9%)	0.0%	66.3%	33.7%
Severe	3563 (51.1%)	18.3%	81.7%	0.0%

Abbreviations: CCTA = coronary computed tomography angiography, CMR = cardiac magnetic resonance, CT = computed tomography, ECHO = electrocardiogram, ETT = exercise tolerance test, MI = myocardial infarction PET = Positron Emission Tomography, SPECT = Single-Photon Emission Computed Tomography.

Figure 1: Stress Testing in the ISCHEMIA Trial.

This figure depicts site-level variability in the interpretation of myocardial ischemia severity, stratified by stress test modality, based on core laboratory adjudication. Estimated rates of overestimation and underestimation are shown for 286 participating sites and are adjusted to account for unstable estimates in low-volume centers.

Abbreviations: CMR = cardiac magnetic resonance, ECHO = echocardiogram, ETT = exercise tolerance test

Nuclear MPI

Among 3181 patients enrolled following nuclear stress testing, 72.9% underwent SPECT with sodium iodide detectors, 19.2% SPECT with solid-state detectors, 3.1% PET/CT, and 0.2% standalone PET; 4.6% were unspecified (Table 2). While clinical sites interpreted 78.3% of studies as moderate and 21.7% as severe ischemia, the core lab’s independent interpretation reclassified these as 11.4% with no ischemia, 16.4% mild, 41.7% moderate, and 30.5% severe (Figure 2); comparative site versus core lab interpretation rates across all modalities and sub-modalities are detailed in Table S1. Notably, SPECT studies were more frequently downgraded to no or mild ischemia compared with PET studies (27.7% vs. 11.4%; Figure 3)

Figure 2: Site vs. Core Laboratory Interpretation of Myocardial Ischemia Severity.

Plots illustrate the flow of ischemia severity assessments from site-level interpretation (left-sided rows) to core laboratory adjudication (right-sided rows) across the four stress testing modalities used in the ISCHEMIA trial.

Abbreviations: CMR = cardiac magnetic resonance, ECHO = echocardiogram, ETT = exercise tolerance test

Figure 3: Imaging Stress Tests Reclassified as No or Mild Myocardial Ischemia.

Percentage of cardiac stress imaging tests initially classified as moderate or severe ischemia by enrollment sites with subsequent core lab adjudication of no or mild myocardial ischemia.

Abbreviations: CMR = cardiac magnetic resonance, echo = echocardiogram, PET = Positron Emission Tomography, SPECT = Single-Photon Emission Computed Tomography.

Note: The % data label on the y-axis refers to the overall percentage of studies reclassified by the core lab for each imaging modality.

Across all nuclear stress testing, the median estimated rate between clinical sites and the core lab on ischemia severity was 54.7% (IQR: 47.1% – 59.5%), ranging from 15% – 75% across individual sites (Figure 4). Sites were more likely to overestimate ischemia grade (median: 28.8%; IQR: 22.0% – 39.2%) than to underestimate it (median: 14.9%; IQR: 13.1% – 17.3%). The unadjusted MOR for overestimation was 2.44 (95% CI: 2.09 – 2.92), compared to 1.78 (95% CI: 1.55 – 2.09) for underestimation (Figure 5).

Figure 4: Agreement Between Enrollment Sites and Core Laboratory Assessment of Ischemia Severity Stratified by Stress Test Modality.

Boxplots illustrate the distribution of agreement rates (percentages) between individual enrollment sites and their respective core laboratories, categorized by imaging modality: nuclear imaging, echocardiography (Echo), cardiovascular magnetic resonance (CMR), and exercise tolerance test (ETT). Data are presented in three categories: site underestimation of ischemia severity, concordant assessments, and site overestimation of ischemia severity. Median agreement percentages and interquartile ranges (IQR) are reported for each modality, demonstrating variability across modalities and sites. For example, while the median site submitting nuclear stress tests was estimated to be concordant with the core lab 54.7% of the time (IQR 47.1, 59.5), one site was estimated to be concordant roughly 15% of the time.

Abbreviations: CMR = cardiac magnetic resonance, ECHO = echocardiogram, ETT = exercise tolerance test

Figure 5: Median Odds Ratios for Site Underestimate and Overestimate Across Imaging Modalities.

Median odds ratio of an enrollment site underestimating and overestimating the severity of myocardial ischemia on a cardiac stress test compared to a concordant read with a core lab, stratified by modality.

Abbreviations: CMR = cardiac magnetic resonance, ECHO = echocardiogram, ETT = exercise tolerance test

Note: The median odds ratio (MOR) quantifies between-site interpretive variability. An MOR of 1.0 indicates no difference between sites, while higher values reflect greater variability. For example, an MOR of 2.0 means the odds of underestimating or overestimating ischemia severity are, on average, twofold higher at one randomly selected site versus another for identical patients

In the subgroup of PET MPI, clinical sites reported 74.3% as moderate and 25.7% as severe, whereas the core lab classified 1.9% as showing no ischemia, 9.5% mild, 44.8% moderate, and 43.8% as severe (Table S2). The median agreement increased to 66% (IQR: 60.6% – 66.4%; Figure S1), PET MPI demonstrated the lowest rate, across all modalities, of site overestimation (median: 11.9%; IQR 11.2% – 13.8%; Figure S1), and site underestimation increased (median: 22.5%; IQR 21.9% – 23.5%; Figure S1). Further details regarding PET, sodium iodide, and solid-state SPECT MPI are provided in the supplement (Figure S2). Additionally, analyses adjusting for additional patient characteristics in the randomized population showed findings consistent with unadjusted results (Figures S3 and S4).

Stress Echocardiography

Of the 1332 participants enrolled with stress echocardiography, clinical sites interpreted 30.1% as moderate and 69.9% as severe ischemia. In comparison, core lab interpretation identified 5.0% with no ischemia, 10.2% mild, 27.4% moderate, and 57.4% severe ischemia (Figure 2). Notably, non-contrast studies were more frequently reclassified as no or mild ischemia compared to contrast-enhanced echo studies (17.7% vs. 11%, Figure 3).

The median agreement rate for stress echo was 56.6% (IQR: 45.4% – 66.1%; Figure 4). Among all modalities, echo demonstrated the highest tendency for site overestimation (median: 33.4%; IQR 21.8% – 48.6%; Figure 4). The MOR for overestimation was 2.09 (95% CI: 1.68 – 2.78), while the MOR for underestimation was 1.54 (95% CI: 1.06 – 2.21; Figure 5); these remained stable after multivariable adjustment.

In the subgroup using contrast (38.9% of studies), the site-reported rates of moderate (26.7%) and severe (73.3%) ischemia were reclassified by the core lab as 3.5% with no ischemia, 7.5% mild, 25.7% moderate, and 63.3% severe ischemia (Table S2). The median agreement increased to 68.5% (IQR: 59.3% – 71.1%; Figure S1), site overestimation of ischemia decreased (median: 22.5%; IQR 19.6% – 32.1%; Figure S1), and stress echo demonstrated the lowest rate, across all modalities, of site underestimation (median: 8.6%; IQR 6.2% – 9.1%; Figure S1). The MOR for overestimation in contrast studies was 1.75 (95% CI: 1.20 – 2.92), and 1.83 (95% CI: 1.13 – 3.57) for underestimation (Figure S2).

Cardiac MRI

Of the 181 participants who underwent CMR, clinical sites interpreted 50.3% of cases as moderate and 49.7% as severe ischemia. The core lab’s interpretation of these same studies identified 4.4% with no ischemia, 7.7% mild, 25.4% moderate, and 62.4% severe ischemia (Figure 2). Consequently, 12.2% of CMR studies were reclassified by the core lab as showing no or mild ischemia (Figure 3).

The median agreement rate for CMR was 54.1% (IQR: 53.0% – 57.2%: Figure 4). Along with PET, CMR was the only modality in which sites were more likely to underestimate ischemia severity (median 25.2%; IQR 19.5% – 26.9%) than to overestimate it (median 19.4%; IQR 17.7% – 23.9%; Figure 4). The unadjusted MOR for site overestimation was 1.98 (95% CI: 1.0 – 5.88) and 1.26 (95% CI: 1.0 – 2.50; Figure 5) for underestimation; these values remained stable after multivariable adjustment.

Non-imaging ETT

Clinical sites submitted 2277 ETTs, all of which were categorized as severe ischemia per study inclusion requirements. Core lab reassessment, however, identified 4.7% with no evidence of ischemia, 4.8% mild, 15.2% moderate, and 75.3% severe ischemia (Figure 2). Compared with other stress test modalities, ETT demonstrated the highest median agreement at 69.4% (IQR: 59.2% – 77.6%; Figure 4). The median rate at which a site overestimated ischemia severity was 30.6% (IQR: 22.4% – 40.8%; Figure 4), with an unadjusted MOR of 2.43 (95% CI: 1.97 – 3.21); these findings remained consistent after multivariable adjustment (Figure 5).

DISCUSSION

Leveraging the unique opportunity afforded by the ISCHEMIA trial—where site interpretations and expert core lab adjudications could be directly compared across multiple modalities of stress testing—we found substantial variability in interpretation of ischemic burden. For imaging-based tests, nearly 1 in 4 studies interpreted by sites as at least moderate ischemia were downgraded by core labs to no or mild ischemia. While the median agreement rates were similar across modalities (~55%), PET MPI, CMR, and contrast-enhanced echo demonstrated lower rates of overestimation and fewer reclassifications to lower-severity categories (Table S3).

Early reports of stress echocardiography and SPECT reproducibility were mixed. Initially thought to have high intra- and interobserver reproducibility, subsequent studies would conclude only fair inter-institutional agreement (kappa 0.37), emphasizing the need for better image quality, standardized digital processing, and uniform reading criteria.^19–21 In 2006 and 2009, the ACC–Duke quality statements on cardiovascular imaging identified interpretive variability as a primary threat to diagnostic integrity, recommending systematic internal or external reviews.^{5, 22}

These long-standing concerns are challenged by a small data set from the only core laboratory with metrics available regarding internal reliability. The ISCHEMIA stress echocardiography core lab demonstrated 100% interobserver agreement when expert readers stratified studies into binary categories (“negative” vs. “positive” or “mild/no” vs. “moderate/severe” ischemia).²³ Although our analyses evaluate concordance across a more granular spectrum of ischemia, these discrepancies highlight several key takeaways: experienced observers with standardized approaches can achieve minimal variability, the trial’s reference standard is exceptionally stable, and the translation of these standards into routine clinical site interpretation remains a source of significant diagnostic variance.

In the original ISCHEMIA trial, the severity of myocardial ischemia, aggregated across all stress testing modalities, did not correlate with the estimated 5-year event rate. However, recent data from Kwong et al. demonstrate that ischemia severity adjudicated specifically by the CMR core laboratory was associated with 4-year cumulative event rates across all trial endpoints—a correlation not observed in a pooled cohort of SPECT and echo studies.²⁴ Furthermore, patients with no or mild ischemia on CMR experienced zero primary endpoint events over four years, which was not true for SPECT/echo. These pooled modalities also had higher rates of trial exclusion due to insufficient ischemia determined by the core lab or nonobstructive disease on CCTA. These findings suggest that the lower overestimation rates observed with CMR in our study translate into superior prognostic accuracy and more appropriate utilization of invasive procedures; although, the small sample size and low event rate in the CMR group warrant cautious interpretation.

The patterns of interpretive variability here mirror established diagnostic performance data from previous meta-analyses.²⁵ Higher-resolution modalities, such as PET and CMR, which typically demonstrate superior specificity, showed the lowest rates of core lab downgrading. In fact, PET and CMR were the only modalities where sites were more likely to underestimate ischemia severity. Conversely, modalities with traditionally lower pooled specificities—SPECT, non-contrast stress echo, and ETT—exhibited consistently higher rates of overestimation. These findings align with a recent position statement from the American Society of Nuclear Cardiology recommending PET MPI with myocardial blood flow as the preferred modality for patients needing MPI.²⁶

Aside from the differences in technical quality, there are several other potential explanations for the observed interpretive variability. PET and CMR are more prevalent at leading cardiovascular centers, which may correlate with higher interpretive skill. Additionally, while site onboarding emphasized the threshold for moderate ischemia, the distinction between moderate and severe was less prioritized. Our goal, however, was not to assess whether sites could match a core lab under ideal training conditions, but rather to evaluate agreement in usual care. Given that ISCHEMIA sites were pre-screened for quality, encouraged to follow best practices, received training on ischemia grading, and only submitted tests showing at least moderate disease—a fraction of all stress testing performed—these findings likely underestimate the degree of interpretive variation in routine clinical practice.

Designing Future Clinical Trials

Our findings offer critical lessons for future trial design. ISCHEMIA’s inclusion of diverse stress test modalities reflects real-world practice—a decision that favored pragmatism and generalizability. While it is conceivable restricting enrollment to more advanced imaging modalities (e.g. PET or CMR) might have recruited a more phenotypically homogenous population, it would have been more costly, time-consuming, and much less representative of current diagnostic practices. Ultimately, no single imaging modality was immune to site-core lab discordance.

Standardized core lab adjudication remains a formidable challenge. Logistically, real-time review of eligibility constrains recruitment. Indeed, the ISCHEMIA workflow was modified from requiring core lab confirmation of ischemia prior to randomization to relying upon site-based interpretations to improve efficiency. Financially and technically, core labs are resource intensive, and while the core lab is often treated as the gold standard, concerns remain as to which interpretation is correct. Clinical sites may receive an underappreciated benefit from additional clinical context, and core labs may be subject to expectancy bias. Future trials will need to weigh such costs against the benefits of consistent, potentially more accurate, interpretations based upon the study’s goals. For example, core labs may provide superior risk-stratification and characterization of participants for study inclusion, subgroup analyses, or mechanistic insight necessary to explain treatment effects that may justify their inherent cost and complexity. Conversely, for pragmatic trials relying on site-based interpretations, those investigators might consider validating a representative subset of studies through a core lab to ensure participating sites are not diagnostic outliers. Indeed, prior to the initiation of ISCHEMIA, potential clinical sites submitted two qualification stress echoes (one with moderate/severe ischemia and one with mild ischemia) for core lab interpretation with a reported concordance of 81%;²⁷ this is similar to the overall 84.8% agreement rate observed in this analysis when results are dichotomized into “at least moderate” versus “mild/none,” demonstrating longitudinal consistency.

Inaccurate assessments of ischemia lead to inappropriate management. The persistent and substantial variability noted here suggest efforts, such as certification processes, appropriate use criteria, standardized image acquisition protocols and reporting, have been insufficient to ensure consistent, accurate study interpretation in routine practice.^28–30 Professional societies should consider developing additional strategies to improve consistency, such as mandatory use of attenuation correction, implementing routine over-reads—particularly for junior staff—prospectively testing artificial intelligence protocols, and stress test laboratories should consider investing in high-resolution modalities when feasible.

LIMITATIONS

These findings should be interpreted within the context of several limitations. First, the generalizability of the observed variability may be constrained due to the careful selection process of clinical sites in ISCHEMIA. Second, while some patients were excluded due to missing site-level interpretations, this was primarily an administrative rather than a clinical issue and is unlikely to have introduced significant selection bias. Third, clinical data for enrolled but non-randomized patients were limited, and core labs—by design—were blinded to the supplemental clinical information typically available to interpreting physicians.

Furthermore, because ISCHEMIA specifically targeted patients with at least moderate ischemia, our analysis is innately limited in its ability to fully characterize site-level underestimation (e.g. assessing cases where a site interpreted a study as mild, but a core lab would have interpreted it as moderate or severe). While it is plausible sites might over-call ischemia to meet recruitment goals, the requirement for core lab adjudication may have conversely deterred the enrollment of such borderline cases. Nevertheless, this analysis highlights a substantial discrepancy between routine clinical practice and these standardized trial benchmarks which is not only a central issue in clinical trial recruitment but also patient care; one which warrants further research to better understand potential opportunities to improve diagnostic accuracy.

CONCLUSIONS

Accurate and consistent interpretation of cardiac stress testing is a cornerstone of high-quality cardiovascular care, directly guiding the management of patients with CCD. In this analysis of the ISCHEMIA trial, comparison between enrollment sites and expert core laboratories reveals marked interpretive variability across all stress testing modalities. These findings highlight a critical gap between routine clinical practice and standardized benchmarks. To ensure diagnostic integrity of cardiac testing, novel strategies—including mandatory minimum technology standards, systematic over-reads, investment in imaging infrastructure, and the prospective testing of artificial intelligence—must be explored to improve the consistency and accuracy of interpretations.

Supplementary Material

Figures S1–4

Tables S1–3

Appendices S1–2

What is Known:

• Cardiac stress testing is central to management of chronic coronary disease, but variability in interpretation has not been well defined.

What the Study Adds:

• In the ISCHEMIA trial, enrollment site interpretation of stress testing frequently differed from core laboratory assessments, achieving only ~55% concordance across modalities. Additionally, nearly one in four site-classified moderate/severe cases were reclassified as showing no or mild ischemia by the core labs. These findings highlight the need for strategies to improve consistency and accuracy in stress test interpretation.

ABBREVIATIONS

CABG

coronary artery bypass grafting

CCD

chronic coronary disease

CCTA

coronary computed tomography angiography

CMR

cardiac magnetic resonance

Echo

echocardiography

ETT

exercise tolerance test

ISCHEMIA

International Study of Comparative Health Effectiveness with Medical and Invasive Approaches

MOR

median odds ratio

MPI

myocardial perfusion imaging

PCI

percutaneous coronary intervention

PET

positron emission tomography

SPECT

single photon emission computed tomography

Appendix I: ISCHEMIA Research Group

Kreton Mavromatis

Jason Linefsky

Todd Miller

Subhash Banerjee

Jonathan D. Newman

Robert M. Donnino

Muhamed Saric

Khaled Abdul-Nour

Peter H. Stone

James J. Jang

Gennie Yee

Steven Weitz

Suzanne Arnold

James Henry O’Keefe, Jr

Michael D. Shapiro

Steven A. Fein

Mikhail T. Torosoff

Radmila Lyubarova

Sulagna Mookherjee

Krzysztof Drzymalski

Edward O. McFalls

Santiago A. Garcia

Stefan C. Bertog

Rizwan A. Siddiqui

Areef Ishani

Ronnell A. Hansen

Michel Georges Khouri

Jonathan L. Goldberg

Richard Goldweit

Ronny A. Cohen

Brooks Mirrer

Victor Navarro

David E. Winchester

Marvin Kronenberg

Christopher McFarren

John F. Heitner

Ira M. Dauber

Charles Cannan

Sriram Sudarshan

Puja K. Mehta

Michael McDaniel

Stamatios Lerakis

Arshed Quyyumi

Nanette K. Wenger

Chester M. Hedgepeth

Heather Hurlburt

Alan Rosen

Zakir Sahul

Steve Leung

Hassan Reda

Khaled Ziada

Sampoornima Setty

Rajat S. Barua

Fadi Hage

James E. Davies

Massoud Leesar

Jaekyeong Heo

Amy Iskandrian

Firas Al Solaiman

Satinder Singh

Khaled Dajani

Mohammad El-Hajjar

Paul Der Mesropian

Joseph Sacco

Brian McCandless

Marisa Orgera

Mandeep S. Sidhu

Imran Arif

Hanan Kerr

Jorge F. Trejo (Gutierrez)

Gerald Fletcher

Gary E. Lane

Lynn M. Neeson

Pragnesh P. Parikh

Peter M. Pollak

Brian P. Shapiro

Kevin Landolfo

Anthony Gemignani

Daniel O’Rourke

Judith L. Meadows

Jason T. Call

Joseph Hannan

Robert Bojar

Deepti Kumar

John Mukai

Edward T. Martin

Gabriel Vorobiof

Alec Moorman

Scott Kinlay

Robert J. Hamburger

Thomas P. Rocco

Deepak L. Bhatt

Kevin Croce

Jacquelyn A Quin

Jati Anumpa

Marco Zenati

David P Faxon

Glenn Rayos

Ashraf Seedhom

Lance Sullenberger

Gregory Kumkumian

Steven P. Sedlis

Robert M. Donnino

Jeffrey Lorin

Jacqueline E. Tamis-Holland

Robert Kornberg

Robert Leber

Souheil Saba

Michael W. Lee

Delano R. Small

Wassim Nona

Patrick B. Alexander

Iram Rehman

Umesh Badami

Kevin Marzo

Inga H. Robbins

Howard A. Levite

Sanjay Shetty

Mayuri Patel

Glenn S. Hamroff

Raymond W. Little

Brandi D. Zimbelman

Charles Y. Lui

Brigham R. Smith

Daniel P. Vezina

Lillian L. Khor

Josephine D. Abraham

David A. Bull

Stephen H. McKellar

David Booth

John Kotter

Ahmed Abdel-Latif

Bob Hu

Arthur J. Labovitz

Michael Berlowitz

Philip Rogal

Fadi Matar

Christiano Caldeira

Fatima Rodriguez

Ingela Schnittger

William F. Fearon

Prakash Deedwania

Kiran Reddy

Joseph Sweeny

Christopher Spizzieri

Claudia P Hochberg

William D. Salerno

Ray Wyman

Amer Zarka

Anil V. Shah

Thomas Haldis

Jeffrey A. Kohn

Saket Girotra

Omar Almousalli

Mayil S. Krishnam

Jeffrey C. Milliken

Pranav M. Patel

Arnold H. Seto

Kevin T. Harley

Michael A. Gibson

Byron J. Allen

Rita Coram

Sabu Thomas

Ronald G Schwartz

Wei Chen

Mahfouz El Shahawy

James Stafford

William B. Abernethy

Andrew Zurick

Thomas M. Meyer

Ronald G. Morford

Bruce Rutkin

Sabahat Bokhari

Seth I. Sokol

Jay Meisner

Ihab Hamzeh

Arunima Misra

Matthew Wall Jr.

Veronica Lenges De Rosen

Mahboob Alam

Michael C. Turner

Thomas J. Mulhearn

Arnold P. Good

Nicolas W. Shammas

Robert Chilton

Patricia K. Nguyen

Matthew Jezior

Paul C. Gordon

Thomas Crain

Robert Stenberg

Ronald P. Pedalino

Joseph Wiesel

George J. Juang

Mohammed Al-Amoodi

David Wohns

Ellis W. Lader

Michael Mumma

Lekshmi Dharmarajan

Joseph F.X. McGarvey Jr

Thomas R. Downes

Gary J. Luckasen

Benjamin Cheong

Srinivasa Potluri

Ronald A. Mastouri

Jeffery A. Breall

George E. Revtyak

Jonathan W. Bazeley

Dayuan Li

Kenneth Giedd

Wayne Old

Francis Burt

Kozhaya Sokhon

Deepika Gopal

Uma S. Valeti

Jon Kobashigawa

Sajeev Chakanalil Govindan

Rajesh Gopalan Nair

Cholenahally Nanjappa Manjunath

Nagaraja Moorthy

Satvic Cholenahally Manjunath

Suryaprakash Narayanappa

Neeraj Pandit

Ranjit Kumar Nath

S.K. Dwivedi

V.S. Narain

Sharad Chandra

Gurpreet S. Wander

Rohit Tandon

Sarju Ralhan

Naved Aslam

Abhishek Goyal

G. Karthikeyan

S. Ramakrishnan

Sandeep Seth

Rakesh Yadav

Sandeep Singh

Ambuj Roy

Neeraj Parakh

Sunil Kumar Verma

Rajiv Narang

Sundeep Mishra

Nitish Naik

Gautam Sharma

Shiv Kumar Choudhary

Chetan Patel

Gurpreet Gulati

Sanjeev Sharma

V K Bahl

Anoop Mathew

Eapen Punnoose

Siddharth Gadage

Tapan Umesh Pillay

Santhosh Satheesh

Atul Mathur

Johann Christopher

Rajeev Menon

Nirmal Kumar

Abraham Oomman

Robert Mao

Hilda Solomon

Sajeeda Parveen Khan

Purvez Grant

Ranjan Kachru

Ajit Kumar VK

Sanjay Ganapathi

Jayakumar K

Harikrishnan Sivadasanpillai

Bijulal Sasidharan

Kapilamoorthy TR

Praneeth Polamuri

Upendra Kaul

Keith AA Fox

Kathryn Carruthers

Ahmed Elghamaz

Sothinathan Gurunathan

Nikolaos Karogiannis

Benoy N Shah

Richard HJ Trimlett

Michael B Rubens

Edward D Nicol

Tarun K Mittal

Reinette Hampson

Reto Andreas Gamma

Mark A de Belder

Jeet Thambyrajah

Thuraia Nageh

John R Davies

Steven J. Lindsay

John Kurian

Haqeel Jamil

Osama Raheem

Angela Hoye

Patrick Donnelly

Bernardas Valecka

Anoop Chauhan

Craig Barr

Khaled Alfakih

Jonathan Byrne

Ian Webb

Peter Henriksen

Peter OKane

Ramesh de Silva

Dwayne S. G. Conway

Alexander A Sirker

Stephen P Hoole

Fraser N. Witherow

Nicola Johnston

Mark Harbinson

Simon Walsh

Hanna Douglas

Matthew Luckie

Jolanta Sobolewska

Paramjit Jeetley

Niket Patel

Tushar Kotecha

Christopher Travill

Iqbal Karimullah

Mahmud Al-Bustami

Denise Braganza

Robert Henderson

Kate Pointon

Surendra Naik

Thomas Mathew

Colin Berry

Damien Collison

Giles Roditi

Andrew J Moriarty

Jason D. Glover

Jiwan Pradhan

Mikhail Ghada

Darrel P. Francis

Vladimir Dzavik

Ariel Diaz

Philippe Rheault

Miguel Barrero

Carl-Éric Gagné

Yanek Pépin-Dubois

Ricardo Costa

Ying Tung Sia

Catherine Lemay

Alejandro Gisbert

Pierre Gervais

Alain Rheault

Denis Carl Phaneuf

Gilbert Gosselin

Pallav Garg

Renee C. Hessian

Rob S. Beanlands

Richard F. Davies

Asim N. Cheema

Akshay Bagai

Ron Wald

Shaun Goodman

John Joseph Graham

Mark Peterson

Chi-Ming Chow

Beth Abramson

Asim Nazir Cheema

Mohammad Tariq Vakani

James Cha

Andrew G Howarth

Graham Wong

Amar Uxa

Paul Galiwango

Saleem Kassam

Ashok Mukherjee

A. Joseph Ricci

Andy Lam

Shamir Mehta

Jacob Udell

Philippe Généreux

Adnan Hameed

Ledjalem Daba

Whady Hueb

Paulo Cury Rezende

Alexandre Ciappina Hueb

Paola Emanuela Poggio Smanio

Alexandre Schaan de Quadros

Renato Abdala Karam Kalil

José Luiz da Costa Vieira

Gabriel Grossmann

Pedro Píccaro de Oliveira

Leonardo Bridi

Simone Savaris

João V Vitola

Rodrigo J Cerci

Fabio R Farias

Miguel M Fernandes

José Antonio Marin-Neto

André Schmidt

Moysés de Oliveira Lima Filho

Ricardo Mendes Oliveira

João Reynaldo Abbud Chierice

Carísi A. Polanczyk

Mariana V. Furtado

Luis F. Smidt

Antonio Carlos Carvalho

Gustavo Pucci

Flavio Lyra

Alvaro Rabelo Alves Junior

Marianna D. A. Dracoulakis

Rodolfo G. S. D Lima

Estevao Figueiredo

Paulo Ricardo Caramori

Rogerio Tumelero

Frederico Dall’Orto

Claudio T. Mesquita

Alexandre S. Colafranseschi

Amarino C. Oliveira Jr.

Luiz A. Carvalho

Isabella C. Palazzo

Andre S. Sousa

Expedito Eustáquio Ribeiro da Silva

Pedro Gabriel Melo de Barros e Silva

Luciana de Pádua Silva Baptista

Marcelo Jamus Rodrigues

Marcos Valério Coimbra de Resende

Jose Francisco Saraiva

Costantino Costantini

Witold Ruzyllo

Marcin Demkow

Radoslaw Pracon

Cezary Kepka

Anna Teresinska

Karolina Kryczka

Jan Henzel

Mateusz Solecki

Edyta Kaczmarska

Tomasz Mazurek

Jaroslaw Drozdz

Bartosz Czarniak

Malgorzata Frach (formerly Stasiak)

Konrad Szymczyk

Iwona Niedzwiecka

Sebastian Sobczak

Tomasz Ciurus

Piotr Jakubowski

Magdalena Misztal-Teodorczyk

Dawid Teodorczyk

Aleksandra Fratczak

Marcin Szkopiak

Patrycja Lebioda

Michal Wlodarczyk

Anna Plachcinska

Jacek Kusmierek

Magdalena Miller

Halina Marciniak

Karolina Wojtczak-Soska

Katarzyna Łuczak

Tomasz Tarchalski

Anna Cichocka-Radwan

Grazyna Anna Szulczyk

Adam Witkowski

Krzysztof Kukuła

Małgorzta Celińska-Spodar

Joanna Zalewska

Grzegorz Gajos

Krzysztof Bury

Piotr Pruszczyk

Marek Roik

Krystyna Łoboz-Grudzień

Leszek Sokalski

Barbara Brzezińska

Maciej Lesiak

Magdalena Łanocha

Krzysztof W. Reczuch

Zbigniew Kalarus

Andrzej Swiatkowski

Mariola Szulik

Wlodzimierz J. Musial

Leo Bockeria

Karen Petrosyan

Tatiana Trifonova

Alexander M. Chernyavskiy

Evgeniy I. Kretov

Igor O. Grazhdankin

Leonid L. Bershtein

Sergey A. Sayganov

Anastasia M. Kuzmina-Krutetskaya

Elizaveta V. Zbyshevskaya

Nana O. Katamadze

Elena A. Demchenko

Pavel S. Kozlov

Vikentiy Y. Kozulin

Ekaterina I. Lubinskaya

Jose Lopez-Sendon

Almudena Castro

Elena Refoyo Salicio

Gabriela Guzman

Gabriel Galeote

Silvia Valbuena

Jesús Peteiro

María Dolores Martínez-Ruíz

Ruth Pérez-Fernández

José J Cuenca-Castillo

Xacobe Flores-Ríos

Óscar Prada-Delgado

Gonzalo Barge-Caballero

Jose Ramon Gonzalez Juanatey

Miguel Souto Bayarri

Virginia Pubull Nuñez

Raymundo Ocaranza Sanchez

Belen Cid Alvarez

Carlos Peña Gil

Amparo Martinez Monzonis

Alessandro Sionis

Montserrat Vila Perales

Josep Maria Padró

Antonio Serra Peñaranda

Joan García Picart

Antonino Ginel Iglesias

Xavier Garcia-Moll Marimon

Guillem Pons Lladó

Francesc Carreras Costa

Vicente Miro

Jose L Diez

Pilar Calvillo

F. Marin Ortuño

M. Valdés Chávarri

A. Tello Montolliu

E. Pinar Bermudez

G. De La Morena

Montserrat Gracida Blancas

Jose Enrique Castillo Luena

Francisco Fernandez-Aviles

Jiyan Chen

Yongjian Wu

Yitong Ma

Yining Yang

Zheng Ji

Xinchun Yang

Wenhua Lin

Hesong Zeng

Xin Fu

Songtao Wang

Gong Cheng

Yulan Zhao

Xuehua Fang

Qiutang Zeng

Xi Su

Qingxian Li

Shao-ping Nie

Qin Yu

Jian’an Wang

Shuyang Zhang

Zhenyu Liu

Aldo P. Maggioni

Gian Piero Perna

Marco Marini

Gabriele Gabrielli

Stefano Provasoli

Edoardo Verna

Lorenzo Monti

Barbara Nardi

Antonio Di Chiara

Andrea Mortara

Marcello Galvani

Filippo Ottani

Marco Sicuro

Paolo Calabro

Tiziana Formisano

Giuseppe Tarantini

Umberto Cucchini

Anto Luigi Andres

Emanuela Racca

Carlo Briguori

Roberto Amati

William Vergoni

Aldo Russo

Raffaele Fanelli

Kian-Keong Poh

Ping Chai

Titus Lau

Joshua P. Loh

Edgar L. Tay

Kristine Teoh

Lynette L. Teo

Ching-Ching Ong

Raymond C. Wong

Poay-Huan Loh

Theodoros Kofidis

Wan Xian Chan

Koo Hui Chan

David Foo

Jason Loh Kwok Kong

Ching Min Er

Fahim Haider Jafary

Terrance Chua

Juergen Stumpf

Klaus Matschke

Gregor Simonis

Clemens T. Kadalie

Udo Sechtem

P. Christian Schulze

Bjoern Goebel

Karsten Lenk

Georg Nickenig

Herwig Schuchlenz

Stefan Weikl

Irene Marthe Lang

Kurt Huber

Gabriele, Jakl-Kotauschek

Matyas Keltai

Andras Vertes

Albert Varga

Geza Fontos

Bela Merkely

Gabor Kerecsen

Sasa Hinic

Marija Zdravkovic

Vladan Mudrenovic

Bogdan Crnokrak

Branko D. Beleslin

Nikola N. Boskovic

Marija T. Petrovic

Milan R. Dobric

Zeljko Z. Markovic

Ana S. Mladenovic

Nada Cemerlic-Adjic

Goran Davidović

Rada Vučić

Milica Nikola Dekleva

Goran Stankovic

Svetlana Apostolovic

Jorge Escobedo

Rubén Baleón-Espinosa

Arturo S Campos-Santaolalla

Elihú Durán-Cortés

José M Flores-Palacios

Andrés García-Rincón

Moisés Jiménez-Santos

Joaquín V Peñafiel

José A. Ortega-Ramírez

Aquiles Valdespino-Estrada

Erick Alexánderson Rosas

Deirdre Murphy

Joseph B. Selvanayagam

Majo X. Joseph

Suku T. Thambar

Jamie Rankin (past)

John F. Beltrame

Graham S. Hillis

Christophe Thuaire

Téodora Dutoiu

Jean-Michel Juliard

Michel S. Slama

Rami El Mahmoud

Eric Nicollet

Pascal Goube

Gilles Barone-Rochette

Alain Furber

Loïc Bière

Aleksandras Laucevicius

Elvin Kedhi MD

Jorik Timmer

Rik Hermanides

Eliza Kaplan

Robert K. Riezebos

Pouneh Samadi

Elise van Dongen

Sander R. Niehe

Harry Suryapranata

Stijn van Vugt

Duarte Cacela

Ana Santana

Antonio Fiarresga

Lidia Sousa

Hugo Marques

Lino Patricio

Luis Bernanrdes

Pedro Rio

Ramiro Carvalho

Rui Ferreira

Tiago Silva

Ines Rodrigues

Pedro Modas

Guilherme Portugal

Jose Fragata

Fausto J. Pinto

Miguel Nobre Menezes

Guilhermina Cantinho Lopes

Ana Gomes Almeida

Pedro Canas Silva

Angelo Nobre

Ana Rita Francisco

Nuno Ferreira

Ricardo L. Lopes

Rafael Diaz

Luis Guzman

Julio César Figal

Oscar Méndiz

Claudia Cortés

Roberto René Favaloro

Carlos Alvarez

Javier Courtis

Gabriela Zeballos

Lilia Schiavi

Mariano Rubio

Caroline Alsweiler

Gerard Patrick Devlin

Raewyn Fisher

Ralph Alan Huston Stewart

Harvey Douglas White

Jocelyne Benatar

Sasko Kedev

Irena Peovska Mitevska

Elizabeta Srbinovska Kostovska

Hristo Pejkov

Claes Held

Kai Eggers

Gunnar Frostfelt

Nina Johnston

Maciej Olsowka

Axel Åkerblom

Inga Soveri

Johannes Aspberg

Rafael Beyar

Eugenia Nikolsky

Tali Sharir

Dan Elian

Arthur Kerner

Samia Massalha

Keiichi Fukuda

Shun Kohsaka

Satoshi Yasuda

Shigeyuki Nishimura

Frans Van de Werf

Kathleen Claes

Chung-Lieh Hung

Chun-Ho Yun

Charles Jia-Yin Hou

Jen-Yuan Kuo

Hung-I Yeh

Ta-Chuan Hung

Jiun-Yi Li

Chen-Yen Chien

Cheng-Ting Tsai

Chun-Chieh Liu

Fa-Chang Yu

Yueh-Hung Lin

Wei-Ren Lan

Chih-Hsuan Yen

Jui-Peng Tsai

Kuo-Tzu Sung

Mpiko Ntsekhe

Shaheen Pandie

Charle A Viljoen

Marianne De Andrade

Tiziano Moccetti

M.Grazia Rossi

Magdy Abdelhamid

Ahmed Adel

Ahmed Kamal

Hossam Mahrous

Sameh El Kaffas

Hussien El Fishawy

Calin Pop

Matei Claudia

Bogdan A. Popescu

Carmen Ginghina

Dan Deleanu

Vlad A. Iliescu

Mouaz H. Al-Mallah

Ahmed Aljzeeri

Hani Najm

Ali Alghamdi

Walter Enrique Mogrovejo Ramos

Srun Kuanprasert

Arintaya Prommintikul

Weerachai Nawarawong

Surin Woragidpoonpol

Thitipong Tepsuwan

Noppon Taksaudom

Chataroon Rimsukcharoenchai

Juntima Euathrongchit

Yutthaphan Wannasopha

Sukit Yamwong

Piyamitr Sritara

Suthara Aramcharoen

Krissada Meemuk

Ahmad Khairuddin

Hafidz Abd Hadi

Shaiful Azmi Yahaya

John Doan

Raven Lee

Risha Patel

So Yang Cho

Susan Milbrandt

Dawn Shelstad

Preeti Kamath

Ishita Tejani

Kirsten J. Quiles

Allison Schley

Heather Golden

Hermine Osseni

Charlene Wiyarand

Peter Douglass

Hayley Pomeroy

Alexandra Craft

Bethany Harvey

Olivia Anaya

Phoebe Goold

Steven Giovannone

Lori Pritchard

Rosann Gans

Paul Kennedy

Shobana Ganesan

David Schlichting

Aynun Naher

Wendy L. Stewart

Kristin M. Salmi

Debra K. Johnson

Rebekah R. Herrmann

Kristine Arges

Melissa LeFevre

Jennifer Tomfohr

Kimberly Ann Byrne

Taissa Zappernick

Sallie Canada

Meghana Kakade

Patricia Mieses

Stanley E. Cobos

Raven R. Dwyer

Dalisa Espinosa

Kirsten J. Quiles

Magdalena Rantinella

Jessica Rodriguez

Olivia Mancilla

Susan Stinson

Terry Weyand

Sherron C. Crook

Jean Ho

Saadat Khan

Mahmoud Mohamed

Mary R. Soltau

Delsa K. Rose

Rebecca J. Wimmer

Kathy E. Siegel

Susan Derbyshire

Michelle Dixon

Gerald Leonard

Ciarra Heard

Viviana Gabriel

Sukie Desire

Fauzia Rashid

Senait Asier

Keyur Patel

Jennifer Gillis

Megan Manocchia

Susan Moore

Elizabeth Congdon

Gail Brandt

Nora Marchelletta

Kristina Wippler

Kimberly E. Halverson

Christine Roraff

Jonean Thorsen

Amarachi Ojajuni

Oni Olurinde

Kamalakar Surineni

Badhma Valaiyapathi

Carol M. Kartje

Michele Rawlins

Jennifer Thomson

Mary Colleen Rogge

Julie Bunke

Kendra Unterbrink

Jacqueline Fannon

Cynthia Burman

Marcia F. Dubin

Sarah Beaudry

Stephanie A. Tirado

Janet Halliday

Pamela Julian

Stephanie, M. Lane

Jennifer L. Stanford

Patricia Arsenault

Pamela Sigel

Miriam Brooks

Ladda Douangvila

Rubine Gevorgyan

Fatima Ranjbaran

Bryn Smith

Carly Ohmart

Samantha Ly

Margot C. Quinn

Sara Temiyasathit

Jacquelyn Do

Desiree Tobin

Jennifer Langdon

Marcia Werner Bayer

Amanda O’Malley

Erin Orvis

Mandy Murphy

Ann Greenberg

Margaret Iraola

Leandro C. Maranan

Ammy Malinay

Candice P. Edillo

Ann Ostrander

Stephanie Wasmiller

Wendy Drewes

Dipti Patel

Jackie M White

Alison Hallam

Benjamin J Spooner

Linda M Hollenweger

Holly Little

Tiffany Little

Nona A Eskelson

Yvonne Taul

Caroline Rodgers

Jennifer Isaacs

Viktoria Bulkley

Renee Kaneshiro

Bonnie J. Kirby

Nhi N. Tran

Catherine Jahrsdorfer

Reem Yunis

Jhina Patro

Antonia Vega

Hugo Bloise-Adames

Santa Jimenez

Nicole Saint Vrestil

Reyna Bhandari

Danielle Schade

Roxanne Yost

Paula Beardsley

Denise Fine

Jana Tancredi

Patricia Arakelian

Susan Mathus

Deborah O’Neill

Joy Burkhardt

Suellen Hosino

Oksana A. Lubyanaya

Jose D. Salas

Maria Aguirre

Manu Dhawan

Diana Parra

Tri Tran

Katie Fowler-Lehman

Natalie Spitzer

Casey Riedberger

Catherine Weick

Kirsten J. Quiles

Carrie Drum

Kimberly Miller-Cox

Amy Ollinger

Elizabeth Capasso-Gulve

Alaine Melanie Loehr

Marlowe Mosley

Shirin Heydari

Andrea M. Lundeen

Edgar Karanjah

Wanda C. Marfori

Eduardo Hernandez-Rangel

Pam Singh

Anne Marie Webb

Ellie Fridell

Heidi Wilson

Angela Kim

Patrick Wilmot

Ramona Stevens

Loriane Black

Amber B. Hull

Olivia J. Lim

Helen C. Tucker

Natasha C. Putnam

Linda L. Hall

Tia Cauthren

Trish Tucker

Hollie Horton

Jan Orga

Joyce R. White

Cynthia Baumann

Vidya Seeratan

Magnolia Jimenez

Cidney Schultz

Jeanne Russo

Zohra Huda

Araceli Boan

Christine R Hinton

Beth A. Archer

Julia S. Dionne

Cheryl A. Allardyce

Lindsey N. Sikora

Jennifer H. Czerniak

Jennifer A. Mull

Elizabeth Ferguson

Frances Laube

Gail A Shammas

Lori Christensen

Holly Park

Joan Hecht

Davis Vo

James Hirsch

Jody Bindeman

Sara Salkind

Lori-Ann Desimone

Lina Felix-Stern

Jassira Gomes

Catherine Gordon

Aimee Mann

Theresa McCreary

Kirsten J. Quiles

Candace Gopaul

Karen Hultberg

Tauqir Huk

Afshan Hussain

Yesenia Zambrano

Sarah Medina Rodriguez

Trudie Milner

Abbey Mulder

Stacie Van Oosterhout

Martha Meyer

Nancy L. Clapp

Heather Barrentine

Jenne M. Jose

Jenne Manchery

Vera McKinney

Linda Schwarz

Scott M. Kaczkowski

Adam J. Jaskowiak

Joel Klitch

Debra Dees

Precilia Vasquez

Elise L. Hannemann

Judy Mae Foltz

Emily DeRosa

Beth Jorgenson

Joyce Riestenberg-Smith

Rebecca Bariciano

Jessica Waldron

Michelle Mayon

Gretchen Ann Peichel

Brandy Starks

Lucilla Garcia

Maria Thottam

Anjali Anand

Janitha Raj

Reshma Ravindran

VS Rajalekshmi

Nandita Nataraj

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Roma Tewari

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Sonika Gupta

Chandini Suvarna

Binoy Mannekkattukudy Kurian

Sheetal Rupesh Karwa

Suvarna Kolhe

R. J. Vindhya

Peeyush Jain

Ashok Seth

Zile Singh Meharwal

Atul Verma

Mona Bhatia

Ankush Sachdeva

Thounaojam Indira Devi

Nungshi Jungla

K. Manjula Rani

M. Sowjanya Reddy

K. Preethi

Rinu R Sidh

Vamshi Priya

Kotiboinna Preethi

Shweta Hande

Abhishek Dubey

Kavita Rawat

Vineeth CP

Manas Chacko

Suresh Babu

Sowjanya Reddy

Manjula Rani

Priyadarshani Arambam

Bebek Singh

Grace M. Young

Christopher Kinsey

Raisa Kavalakkat

Jo Evans

Ikraam Hassan

Sarah Williams

Kim Holland

Karen Swan

Bev Atkinson

Swapna Kunhunny

Craig Atkinson

Carita Krannila

Manitha Vinod

Lisa Chaytor

Leanne Cox

Julie Morrow

Kay Rowe

Stephanie Kelly

Susan Regan

Dawn Turnbull

Catherine Fleming

Arijit Ghosh

Karen Gratrix

Stephen Preston

Anne Cartwright

Abigail Knightonc

Katherine Martin

Laura Flint

James Harrison

Nicki Lakeman

Anja Ljubez

Judith Wright

Donna Exley

Mervyn Andiapen

Amy J. Richards

Lisa Wong

Melanie J. Munro

Michelle McEvoy

Caroline Brown

Thabitha Charles

Laurel Kolakaluri

Hannah Phillips

Louise Morby

Karen Hallett

Carolyn Corbett

Lynne Winstanley

Angelique Smit

Susan Gent

Nafisa Hussain

Fiona Haines

Joanne Taaffe

Jane Burton

Maria Colton

Rachel King

Ammani Brown

Andrew Docherty

Lisa McCloy

Kate Robb

Craig Paterson

Wenda Crawford

Joanne Kelly

Lorraine McGregor

Anne Mackin

Janet P Knight

Tuhina Bose

Anna Proietti

Myriam Brousseau

Magalie Corfias

Patricia Blaise

Luc Harvey

Patricia Alarie

Linda Arcand

Isabelle Roy

Estelle Montpetit

Katia Drouin

Christine Bergeron

Christine Shelley

Christine Masson

Sandy Carr

Catherine Bone

Ermina Moga

Janetta Kourzenkova

Olga Walter

Norma Hogg

Suzanne Welsh

Mohammed Hussain

Olugbenga Bello

Ishba Syed

Khrystyna Kushniriuk

Judy Otis

Rebecca Otis

Michelle M Seib

Sandra M Rivest

Rosa Sandonato

Jackie Chow

Andrew Starovoytov

Naomi Uchida

Ngaire Meadows

Nadia Asif

Suzana Tavares

Bev Bozek

Maria Shier

Lori-Ann Larmand

Amir Janmohamed

Brenda Hart

Jane Marucci

Sharon Tai

Sonya Brons

Chris Beck

Glenda Wong

Krystal Etherington

Thippeekaa Arumairajah

Maria Aprile

Sara Karlsson

Susan Webber

Chantale Mercure

Nancy Aedy

Fran Farquharson

Anam Siddiqui

Myrthes Emy Takiuti

Leonardo Pizzol Caetano

Aline Peixoto Deiro

Alice Manica Muller

Maria Antonieta Pereira de Moraes

Bruna Maria Ascoli

Sílvia Zottis Poletti

Sandra S. Zier

Vilmar Veiga

Diego Franca da Cunha

Guilherme G Rucatti

Fernanda Igansi

Mauren P Haeffner

Viviane Almeida

Gabriela Sanchez de Souza

Mayana Almeida

Viviane dos Santos

Natalia S Oliveira

Bruna Edilena Paulino Azevedo

Marco Bizzaro Santos

Amanda Germann

Vitor Gomes

Rosa Homem

Ellen Magedanz

Rosane Laimer

Alexandre Tognon

Roberta P Santos

Mariana Yumi Okada

Ana Paula Batista

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Larissa Miranda Trama

Talita Silva

Camila Thais de Souza Ormundo

Carla Vicente

Caroline Pinheiro

Daniele Komar

Olga Walesiak

Katarzyna Malinowska

Jakub Maksym

Karolina Wojtera

Anna Fojt

Ewa Szczerba

Marta Swiderek

Ewelina Wojtala

Jaroslaw Karwowski

Andrzej Łabyk

Agnieszka Szramowska

Olga Zdończyk

Joanna Jaroch

Adam Kolodziej

Marta Marcinkiewicz-Siemion

Olga Bockeria

Zalina Kudzoeva

Nodira Aripova

Ivan A. Naryshkin

Alena Kuleshova

Dastan Malaev

Irina Subbotina

Victoria Gumerova

Olga B. Nikolaeva

Virginia Fernández-Figares, Pharm

Moisés Blanco-Calvo

Encarnación Alonso-Álvarez

Paula García-González

Jose Seijas Amigo

Ana Fernández Martínez

Begoña Igual

M. Quintana Giner

A.I. Romero Aniorte

JM. Rivera Caravaca

Olga Cañavate

Sonia Guerrero

Silvia Riera

Maria Lasala

Maria Lorenzo

Olga Sobrino

Alexandra Vazquez

Haojian Dong

Peiyu He

Chunli Xia

Junqing Yang

Qi Zhong

Yanmeng Tian

Dongze Li

Xiaomei Li

Xiang Ma

Zixiang Yu

Qian Zhao

Chunguang Li

Lei Zhang

Yu Zhao

Bolin Zhu

Mulei Chen

Hongjie Chi

Yang Wang

Jing Zhang

Rui Jing

Jingjing Liu

Qiang Zhou

Chang Xu

Zhuxi Li

Junhua Li

Luyang Xiong

Dan Gao

Dengke Jiang

Ran Leng

Xutong Wang

Qianqian Yuan

Lili Zhang

Ziliang Bai

Jianhua Li

Jie Qi

Fei Wang

Haitao Wang

Bin Yang

Zhou Yue

Zhulin Zhang

Yumei Dong

Jiajia Mao

Bin Zhang

Xiuhong Li

Xiaowei Yao

Nier Zhong

Ning Zhou

Yaping Huang

Panpan Zhou

Wei Su

Yu Kunwu

Yudong Peng

Xin Su

Chen Wang

Yunhai Zhao

Yaming Geng

Yanfu Wang

Jing-yao Fan

Si-ting Feng

Xiao Wang

Yan Yan

Hui-min Zhang

Lingping Chi

Fang Liu

Han Chen

Jun Jiang

Huajun Li

Yechen Han

Lihong Xu

Gang Chen

Rongrong Hu

Francesca Pietrucci

Anna Di Donato

Francesca Pezzetta

Valentina Casali

Chiara Attanasio

Gianpiero Leone

Francesco Pisano

Cristina Bare

Fabio Fimiani

Alberto Barioli

Federica Ramani

Fabrizio Rolfo

Cecilia Goletto

Francesca De Micco

Stefano Di Marco

Martina Tricoli

Massimo Villella

Sik-Yin V Tan

Winnie C Sia

Audrey W Leong

Li Hai Yan

Nasrul Ismail

Min Tun Kyaw

Deborah Yip

Dorit Grahl

Franziska Guenther

Kerstin Bonin

Ina Wenzelburger

Susanne Gruensfelder

Jan-Malte Sinning

Marcel Weber

Nikos Werner

Gudrun Steinmaurer

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Maximilian, Tscharre

Claudia, Wegmayrc

Bernhard, Jäger

Florian, Egger

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Zoltan Davidovits

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Gergely Ágoston

Gabor Dekany

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Jelena Djokic

Ana D. Djordjevic-Dikic

Vojislav L. Giga

Jelena J. Stepanovic

Lazar Velicki

Ljiljana Pupic

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Miroslav Stevo Martinovic

Gordana Stevanovic

Milan Dobric

Sonja Salinger Martinovic

Dragana Stanojevic

Ramon de Jesús-Pérez

María Fernanda Canales Brassetti

Diego Adrián Vences Anaya

María Pérez García

Isabel Estela Carvajal Juarez

Magdalena Madero Rovalo

Sau Lee

Prince Thomas

Melissa D Chaplin

Jeanette K. Stansborough

Marilyn Black

Michelle M. Bonner

Kim F. Ireland

Clare Venn-Edmonds

Corine Thobois

Emilie Tachot

Christophe Laure

Christel Vassaliere

Helene Abergel

Axelle Fuentes

Ludivine Eliahou

Olivier Dubourg

Pierre Michaud

Sarah Hadjih

Patricia Brito

Charles Cornet

Jeremy Rautureau

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Irma Kalibataite-Rutkauskiene

Laura Keinaite

Monika Laukyte

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Akvile Smigelskaite

Ilona Tamasauskiene

Agne Urboniene

Ilse Bouwhuis

Lia Nijmeijer

Jeannette, J. M. Schoep

Elisabeth, M. Janzen

Sandra Ahoud

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Filipa Silva

Cláudia Freixo

Inês Zimbarra Cabrita

Andreia Rocha

Francisca Patuleia Figueiras

Andreia Coelho

Marta Capinha

Maria Inês Caetano

Susana Silva

Veronica Tinnirello

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Marina Garcia

Valeria Godoy

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Leah Howell

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Marie Essermark

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Or Harel

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Adriana Anesini

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Monica Rosca

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Sarah Zahrani

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Anong Chaiyasri

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Anong Amaritakomol

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Humayrah Hashim

Jeffrey Berger

David Williams

Robert Harrington

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Erick Donato Morales Rodríguez

Pal Maurovich-Horvat

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Ramakrishnan T.

Soundarya Nayak

Stephanie C Boer

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Christian Hamm

Malte Helm

Eric Peterson

Christie Ballantyne

Karen Calfas

Mary Ann Champagne

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Philippe Menasche

Michael Davidson

Stephen Fremes

Robert Guyton

Michael Mack

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Oz Shapira

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Antonio Colombo

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Jeffrey Moses

Ken Mahaffey

Salvador Cruz-Flores

Nicholas Danchin

Eli Feen

Mario J. Garcia

Paul Hauptman

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Eugene Passamani

Ileana L. Pina

Maarten Simoons

Hicham Skali

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David Waters

Patricia Endsley

Gerard Esposito

Jeffrey Kanters

John Pownall

Dimitrios Stournaras

Matthias Friedrich

Rory Hachamovitch

Dana Oliver

Frank Harrell

Jeffrey Blume

Kerry Lee

Iftikhar Kullo

Bruce McManus

Kristin Newby

David Cohen

Raffaele Bugiardini

Deirdre Mattina

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Roy Mathew

Lawrence Friedman

Jeffrey Anderson

Jessica Berg

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C. Michael Gibson

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Nicole Deming

Jonathan Himmelfarb

Pamela Ouyang

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Ruth Kirby

Neal Jeffries

Jean E. Denaro

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Gia Cobb

Aira Contreras

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Michelle Chang

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Graceanne Wayser

Solomon Yakubov

Michelle Yee

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Isabelle Hogan

Albertina Qelaj

Charlotte Pirro

Kerrie Van Loo

Brianna Wisniewski

Margaret Gilsenan

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Patenne D. Mathews

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Mark Xavier

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Patricia Cowper

Linda Davidson-Ray

Laura Drew

Tina Harding

J David Knight

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Philip Jones

Karen Nugent

Grace Jingyan Wang

Abhinav Goyal

Holly Hetrick

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John D. Friedman

R. James Gerlach

Mark Hyun

Romalisa Miranda-Peats

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Louise Thomson

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Steven Michael

Judy Hung

Xin Zeng

Jane Eckstein

Bandula Guruge

Mary Streif

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Maria P. Corral

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Jennifer Horst

Ivana Jankovic

Maayan Konigstein

Mitchel B. Lustre

Yolayfi Peralta

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Reza Arsanjani

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Millie Gomez

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Rine Nakanishi

M. Barbara Srichai-Parsia

Eunice Yeoh

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Tauane Bello Duarte

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Julia de Aveiro Morata

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Li Li

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Qiulan Xie

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Jianxin Zhang

Lihua Zhang

Liping Zhang

Ning Zhang

Hui Zhong

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Maria Posada

Sara Fernandez

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Rafael Selgas

Ann Luyten

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Richa Bhatt

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