All Publications

  • Imputing Gene Expression to Maximize Platform Compatibility. Bioinformatics Zhou, W., Han, L., Altman, R. B. 2016


    Microarray measurements of gene expression constitute a large fraction of publicly shared biological data, and are available in the Gene Expression Omnibus (GEO). Many studies use GEO data to shape hypotheses and improve statistical power. Within GEO, the Affymetrix HG-U133A and HG-U133 Plus 2.0 are the two most commonly used microarray platforms for human samples; the HG-U133 Plus 2.0 platform contains 54 220 probes and the HG-U133A array contains a proper subset (21 722 probes). When different platforms are involved, the subset of common genes is most easily compared. This approach results in the exclusion of substantial measured data and can limit downstream analysis. To predict the expression values for the genes unique to the HG-U133 Plus 2.0 platform, we constructed a series of gene expression inference models based on genes common to both platforms. Our model predicts gene expression values that are within the variability observed in controlled replicate studies and are highly correlated with measured data. Using six previously published studies, we also demonstrate the improved performance of the enlarged feature space generated by our model in downstream analysis.The gene inference model described in this paper is available as a R package (affyImpute), which can be downloaded at information: Supplementary data are available at Bioinformatics online.

    View details for PubMedID 27797771

  • Predicting hospital visits from geo-tagged Internet search logs. AMIA Joint Summits on Translational Science proceedings. AMIA Joint Summits on Translational Science Agarwal, V., Han, L., Madan, I., Saluja, S., Shidham, A., Shah, N. H. 2016; 2016: 15-24


    The steady rise in healthcare costs has deprived over 45 million Americans of healthcare services (1, 2) and has encouraged healthcare providers to look for opportunities to improve their operational efficiency. Prior studies have shown that evidence of healthcare seeking intent in Internet searches correlates well with healthcare resource utilization. Given the ubiquitous nature of mobile Internet search, we hypothesized that analyzing geo-tagged mobile search logs could enable us to machine-learn predictors of future patient visits. Using a de-identified dataset of geo-tagged mobile Internet search logs, we mined text and location patterns that are predictors of healthcare resource utilization and built statistical models that predict the probability of a user's future visit to a medical facility. Our efforts will enable the development of innovative methods for modeling and optimizing the use of healthcare resources-a crucial prerequisite for securing healthcare access for everyone in the days to come.

    View details for PubMedID 27570641

  • Mechanical alternans is associated with mortality in acute hospitalized heart failure: prospective mechanical alternans study (MAS). Circulation. Arrhythmia and electrophysiology Kim, R., Cingolani, O., Wittstein, I., Mclean, R., Han, L., Cheng, K., Robinson, E., Brinker, J., Schulman, S. S., Berger, R. D., Henrikson, C. A., Tereshchenko, L. G. 2014; 7 (2): 259-266


    Acute hospitalized heart failure (AHHF) is associated with 40% to 50% risk of death or rehospitalization within 6 months after discharge. Timely (before hospital discharge) risk stratification of patients with AHHF is crucial. We hypothesized that mechanical alternans (MA) and T-wave alternans (TWA) are associated with postdischarge outcomes in patients with AHHF.A prospective cohort study was conducted in the intensive cardiac care unit and enrolled 133 patients (59.6±15.7 years; 65% men) admitted with AHHF. Surface ECG and peripheral arterial blood pressure waveform via arterial line were recorded continuously during the intensive cardiac care unit stay. MA and TWA were measured by enhanced modified moving average method. All-cause death or heart transplant served as a combined primary end point. MA was observed in 28 patients (25%), whereas TWA was detected in 33 patients (33%). If present, MA was tightly coupled with TWA. Mean TWA amplitude was larger in patients with both TWA and MA when compared with patients with lone TWA (median, 37 [interquartile range, 26-61] versus 22 [21-23] μV; P=0.045). After a median of 10-month postdischarge, 42 (38%) patients died and 2 had heart transplants. MA was associated with the primary end point in univariable Cox model (hazard ratio, 1.84; 95% confidence interval, 1.00-3.40; P=0.05) and after adjustment for left ventricular ejection fraction, New York Heart Association HF class, and implanted implantable cardioverter defibrillator/cardiac resynchronization therapy defibrillator (hazard ratio, 2.12 95% confidence interval, 1.13-3.98; P=0.020). TWA without consideration of simultaneous MA was not significantly associated with primary end point (hazard ratio, 1.42; 95% confidence interval, 0.77-2.64; P=0.260).MA is independently associated with outcomes in AHHF.URL: Unique identifier: NCT01557465.

    View details for DOI 10.1161/CIRCEP.113.000958

    View details for PubMedID 24585716

  • Repolarization lability measured on 10-second ECG by spatial TT' angle: Reproducibility and agreement with QT variability. Journal of electrocardiology Feeny, A., Han, L., Tereshchenko, L. G. 2014


    Reproducibility of spatial TT' angle on the 10-second ECG and its agreement with QT variability has not been previously studied.We analyzed 2 randomly selected 10-second segments within 3-minute resting orthogonal ECG in 172 healthy IDEAL study participants (age 38.1±15.2years, 50% male, 94% white). Repolarization lability was measured by the QT variance (QTV), short-term QT variability (STV(QT)), and spatial TT' angle. Bland-Altman analysis was used to assess the agreement between different log-transformed metrics of repolarization lability, and to assess the reproducibility.The heart rate showed a very high reproducibility (bias 0.14%, Lin's rho_c=0.99). As expected, noise suppression by averaging improves reproducibility. Agreement between two 10-second LogQTV was poor (bias -0.04; 95% limits of agreement [-1.89; 1.81]), while LogSTV(QT) (0.04 [-1.01; 1.10]), and especially LogTT' angle (-0.009 [-0.84; 0.82]) was better.TT' angle is a satisfactory reproducible metric of repolarization lability on the 10-second ECG.

    View details for DOI 10.1016/j.jelectrocard.2014.06.003

    View details for PubMedID 25012076

  • Complex assessment of the temporal lability of repolarization. International journal of cardiology Han, L., Cheng, A., Sur, S., Tomaselli, G. F., Berger, R. D., Tereshchenko, L. G. 2013; 166 (2): 543-545

    View details for DOI 10.1016/j.ijcard.2012.09.189

    View details for PubMedID 23084544

  • ELECTRICAL REMODELING PREDICTS RISK OF SUDDEN CARDIAC DEATH IN ASYMPTOMATIC ADULTS JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Tereshchenko, L., Arking, D., Sotoodehnia, N., Zhang, Y., Han, L., Berger, R., Tomaselli, G., Siscovick, D., Post, W., Coresh, J., Guallar, E., Soliman, E. 2013; 61 (10): E1340-E1340
  • Comparison of Sum Absolute QRST Integral, and Temporal Variability in Depolarization and Repolarization, Measured by Dynamic Vectorcardiography Approach, in Healthy Men and Women PLOS ONE Sur, S., Han, L., Tereshchenko, L. G. 2013; 8 (2)


    Recently we showed the predictive value of sum absolute QRST integral (SAI QRST) and repolarization lability for risk stratification of sudden cardiac death (SCD) in heart failure patients. The goal of this study was to compare SAI QRST and metrics of depolarization and repolarization variability in healthy men and women.Orthogonal ECGs were recorded at rest for 10 minutes in 160 healthy men and women (mean age 39.6±14.6, 80 men). Mean spatial TT' angle, and normalized variances of T loop area, of spatial T vector amplitude, of QT interval and Tpeak-Tend area were measured for assessment of repolarization lability. Normalized variances of spatial QRS vector and QRS loop area characterized variability of depolarization. In addition, variability indices (VI) were calculated to adjust for normalized heart rate variance. SAI QRST was measured as the averaged arithmetic sum of areas under the QRST curve.Men were characterized by shorter QTc (430.3±21.7 vs. 444.7±22.2 ms; P<0.0001) and larger SAI QRST (282.1±66.7 vs. 204.9±58.5 mV*ms; P<0.0001). Repolarization lability negatively correlated with spatial T vector amplitude. Adjusted by normalized heart rate variance, QT variability index was significantly higher in women than in men (-1.54±0.38 vs. -1.70±0.33; P?=?0.017). However, in multivariate logistic regression after adjustment for body surface area, QTc, and spatial T vector amplitude, healthy men had 1.5-3 fold higher probability of having larger repolarization lability, as compared to healthy women (T vector amplitude variability index odds ratio 3.88 (95%CI 1.4-11.1; P?=?0.012).Healthy men more likely than women have larger repolarization lability.

    View details for DOI 10.1371/journal.pone.0057175

    View details for Web of Science ID 000316658800087

    View details for PubMedID 23451181

  • ECG Marker of Adverse Electrical Remodeling Post-Myocardial Infarction Predicts Outcomes in MADIT II Study PLOS ONE Tereshchenko, L. G., McNitt, S., Han, L., Berger, R. D., Zareba, W. 2012; 7 (12)


    Post-myocardial infarction (MI) structural remodeling is characterized by left ventricular dilatation, fibrosis, and hypertrophy of the non-infarcted myocardium.The goal of our study was to quantify post-MI electrical remodeling by measuring the sum absolute QRST integral (SAI QRST). We hypothesized that adverse electrical remodeling predicts outcomes in MADIT II study participants.Baseline orthogonal ECGs of 750 MADIT II study participants (448 [59.7%] ICD arm) were analyzed. SAI QRST was measured as the arithmetic sum of absolute QRST integrals over all three orthogonal ECG leads. The primary endpoint was defined as sudden cardiac death (SCD) or sustained ventricular tachycardia (VT)/ventricular fibrillation (VF) with appropriate ICD therapies. All-cause mortality served as a secondary endpoint.Adverse electrical remodeling in post-MI patients was characterized by wide QRS, increased magnitudes of spatial QRS and T vectors, J-point deviation, and QTc prolongation. In multivariable Cox regression analysis after adjustment for age, QRS duration, atrial fibrillation, New York Heart Association heart failure class and blood urea nitrogen, SAI QRST predicted SCD/VT/VF (HR 1.33 per 100 mV*ms (95%CI 1.11-1.59); P = 0.002), and all-cause death (HR 1.27 per 100 mV*ms (95%CI 1.03-1.55), P = 0.022) in both arms. No interaction with therapy arm and bundle branch block (BBB) status was found.In MADIT II patients, increased SAI QRST is associated with increased risk of sustained VT/VF with appropriate ICD therapies and all-cause death in both ICD and in conventional medical therapy arms, and in patients with and without BBB. Further studies of SAI QRST are warranted.

    View details for DOI 10.1371/journal.pone.0051812

    View details for Web of Science ID 000312386800089

    View details for PubMedID 23251630

  • QT variability paradox after premature ventricular contraction in patients with structural heart disease and ventricular arrhythmias JOURNAL OF ELECTROCARDIOLOGY Das, D., Han, L., Berger, R. D., Tereshchenko, L. G. 2012; 45 (6): 652-657


    Increased repolarization lability is known to be associated with the risk of ventricular tachycardia (VT)/ventricular fibrillation (VF). Premature ventricular contractions (PVCs) are excluded from the analysis of QT variability. However, QT dynamics after PVCs is poorly understood.We analyzed data of 33 patients with structural heart disease (mean age 60.5 ± 12.1; 24 (73%) men; 26 (79%) whites; 22 (67%) ischemic cardiomyopathy) and single-chamber ICD implanted for primary (28 patients, 85%) or secondary prevention of SCD. Arrhythmia group comprised 16 patients with VT/VF/death outcomes. Alive patients (n = 17) without VT/VF served as controls. The baseline far-field (FF) ICD electrogram (EGM) was recorded at rest. RR and QT intervals of 15 sinus beats before and after PVC in 33 patients were analyzed. The prematurity index, C(i)Mean(RR), where C(i) is coupling interval, was used to select the most premature PVC. QT variability index (QTVI) was calculated. Difference in QTVI was calculated as QTVI(diff) = QTVI(after)-QTVI(before.)In paired analysis QTVI significantly increased after PVC in controls (0.64 ± 1.02 vs. 0.26 ± 1.15; P = 0.046), but decreased in patients in the arrhythmia group (0.16 ± 0.85 vs. 0.43 ± 0.84; P = 0.190). QTVI(diff) was significantly lower in patients with VT/VF, as compared to controls (-0.197 ± 0.650 vs. 0.207 ± 0.723; P=0.030). In multivariate logistic regression after adjustment for the type of cardiomyopathy and NYHA class the decrease in QTVI after PVC was associated with increased risk of VT/VF (OR 9.24; 95% CI 1.11-76.82; P=0.040).Elevated at baseline QTVI is decreased during first 15 beats after PVC in patients at risk for VT/VF.

    View details for DOI 10.1016/j.jelectrocard.2012.07.016

    View details for Web of Science ID 000310763300021

    View details for PubMedID 22995383

  • Intracardiac J-point elevation before the onset of polymorphic ventricular tachycardia and ventricular fibrillation in patients with an implantable cardioverter-defibrillator HEART RHYTHM Tereshchenko, L. G., McCabe, A., Han, L., Sur, S., Huang, T., Marine, J. E., Cheng, A., Spragg, D. D., Sinha, S., Calkins, H., Stein, K., Tomaselli, G. F., Berger, R. D. 2012; 9 (10): 1594-1602


    The clinical importance of the J-point elevation on electrocardiogram is controversial.To study intracardiac J-point amplitude before ventricular arrhythmia.Baseline 12-lead electrocardiogram and far-field right ventricular intracardiac implantable cardioverter-defibrillator electrograms were recorded at rest in 494 patients (mean age 60.4 ± 13.1 years; 360 [72.9%] men) with structural heart disease (278 [56.3%] ischemic cardiomyopathy) who received primary (463 [93.9%] patients) or secondary prevention implantable cardioverter-defibrillator. Ten-second intracardiac far-field electrograms before the onset of arrhythmia were compared with the baseline. The J-point amplitude was measured on the baseline 12-lead surface electrocardiogram and the intracardiac far-field electrogram. The relative J-point amplitude was calculated as the ratio of J-point amplitude to peak-to-peak R-wave.The paired t test showed that the relative intracardiac J-point amplitude was significantly higher before polymorphic ventricular tachycardia/ventricular fibrillation (VF) onset (0.28 ± 0.08 vs -0.19 ± 0.39; P = .012) than at baseline. In a mixed-effects logistic regression model, adjusted for multiple episodes per patient, each 10% increase in relative J-point amplitude increased the odds of having ventricular tachycardia/VF by 13% (odds ratio 1.13 [95% confidence interval 1.07-1.19]; P < .0001) and increased the odds of having polymorphic ventricular tachycardia/VF by 27% (odds ratio 1.27 [95% confidence interval 1.11-1.46]; P = .001).The relative intracardiac J-point amplitude is augmented immediately before the onset of polymorphic ventricular tachycardia/VF in patients with structural heart disease.

    View details for DOI 10.1016/j.hrthm.2012.06.036

    View details for Web of Science ID 000309292600005

    View details for PubMedID 22750217

  • Predictive Value of Beat-to-Beat QT Variability Index Across the Continuum of Left Ventricular Dysfunction Competing Risks of Noncardiac or Cardiovascular Death and Sudden or Nonsudden Cardiac Death CIRCULATION-ARRHYTHMIA AND ELECTROPHYSIOLOGY Tereshchenko, L. G., Cygankiewicz, I., McNitt, S., Vazquez, R., Bayes-Genis, A., Han, L., Sur, S., Couderc, J., Berger, R. D., de Luna, A. B., Zareba, W. 2012; 5 (4): 719-727


    The goal of the present study was to determine the predictive value of beat-to-beat QT variability in heart failure patients across the continuum of left ventricular dysfunction.Beat-to-beat QT variability index (QTVI), log-transformed heart rate variance, normalized QT variance, and coherence between heart rate variability and QT variability have been measured at rest during sinus rhythm in 533 participants of the Muerte Subita en Insuficiencia Cardiaca heart failure study (mean age, 63.1±11.7; men, 70.6%; left ventricular ejection fraction >35% in 254 [48%]) and in 181 healthy participants from the Intercity Digital Electrocardiogram Alliance database. During a median of 3.7 years of follow-up, 116 patients died, 52 from sudden cardiac death (SCD). In multivariate competing risk analyses, the highest QTVI quartile was associated with cardiovascular death (subhazard ratio, 1.67 [95% CI, 1.14-2.47]; P=0.009) and, in particular, with non-SCD (subhazard ratio, 2.91 [1.69-5.01]; P<0.001). Elevated QTVI separated 97.5% of healthy individuals from subjects at risk for cardiovascular (subhazard ratio, 1.57 [1.04-2.35]; P=0.031) and non-SCD in multivariate competing risk model (subhazard ratio, 2.58 [1.13-3.78]; P=0.001). No interaction between QTVI and left ventricular ejection fraction was found. QTVI predicted neither noncardiac death (P=0.546) nor SCD (P=0.945). Decreased heart rate variability rather than increased QT variability was the reason for increased QTVI in the present study.Increased QTVI because of depressed heart rate variability predicts cardiovascular mortality and non-SCD but neither SCD nor extracardiac mortality in heart failure across the continuum of left ventricular dysfunction. Abnormally augmented QTVI separates 97.5% of healthy individuals from heart failure patients at risk.

    View details for DOI 10.1161/CIRCEP.112.970541

    View details for Web of Science ID 000313584500020

    View details for PubMedID 22730411

  • Antiarrhythmic Effect of Reverse Electrical Remodeling Associated with Cardiac Resynchronization Therapy PACE-PACING AND CLINICAL ELECTROPHYSIOLOGY Tereshchenko, L. G., Henrikson, C. A., Stempniewicz, P., Han, L., Berger, R. D. 2011; 34 (3): 357-364


    Antiarrhythmic and proarrhythmic effects of cardiac resynchronization therapy (CRT) remain controversial. We hypothesized that reverse electrical remodeling (RER) with CRT is associated with reduced frequency of ventricular tachyarrhythmias (VTs).The width of native and paced QRS was measured in lead II electrocardiogram before and 13 ± 7 months after implantation of a CRT defibrillator device in 69 patients (mean age 66.3 ± 13.9; 39 males [83%]) with bundle branch block (BBB) (41 patients with left BBB and three patients with bifascicular block) or nonspecific intraventricular conduction delay (25 patients, 36%), and New York Heart Association class III-IV heart failure. Biventricular pacing was inhibited for 10 seconds to record native QRS. RER was defined as a decrease in the native QRS duration ?10 ms compared to preimplant. Patients were followed prospectively 24 ± 13 months after assessment for electrical remodeling.RER was observed in 22 patients (32%), among whom QRS duration decreased by 30.9 ± 14.1 ms (P < 0.00001) with similar heart rate and QRS morphology. Native QRS duration increased by 10.3 ± 16.6 ms in the other 47 patients (68%) (P = 0.0001). Baseline mean ejection fraction did not differ between patients with and those without RER (24.9 ± 10.0 vs 24.2 ± 8.6%, NS). During 2 ± 1 years of further follow-up, 19 patients had VTs and 12 patients died. RER was associated with a fourfold decrease in the risk of death or sustained VTs requiring appropriate implantable cardioverter-defibrillator therapies, whichever came first (hazard ratio 0.25; 95% confidence interval 0.08-0.85; P = 0.026).RER of the native conduction with CRT is associated with decreased mortality and antiarrhythmic effect of CRT.

    View details for DOI 10.1111/j.1540-8159.2010.02974.x

    View details for Web of Science ID 000288918300017

    View details for PubMedID 21091740

  • Lability of R- and T-wave peaks in three-dimensional electrocardiograms in implantable cardioverter defibrillator patients with ventricular tachyarrhythmia during follow-up Han, L., Tereshchenko, L. G. CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS. 2010: 577-582


    From experiments, we know that the heterogeneity of action potential duration and morphology is an important mechanism of ventricular tachyarrhythmia. Electrocardiogram (ECG) markers of repolarization lability are known; however, lability of depolarization has not been systematically studied. We propose a novel method for the assessment of variability of both depolarization and repolarization phases of the cardiac cycle.Baseline orthogonal ECGs of 81 patients (mean ± SD age, 56 ± 13 years; 61 male [75%]) with structural heart disease and implanted single-chamber implantable cardioverter defibrillator (ICD) were analyzed. Clean 30-beat intervals with absence of premature beats were then selected. Baseline wandering was corrected before analysis. Peaks of R wave and peaks of T wave were detected for each beat, and the axis magnitude was calculated. The peaks were plotted to show clouds of peaks and then used to construct a convex hull, and the volumes of the R peaks cloud and T peaks cloud and ratio of volumes were calculated.During a mean (SD) follow-up period of 13 (10) months, 9 of the 81 patients had sustained ventricular tachycardia or ventricular fibrillation (VT/VF) and received appropriate ICD therapies. All ICD events were adjudicated by three independent electrophysiologists. There was no statistically significant difference in the volume of T-wave peaks or R-wave peaks between patients with and without VT or VF during follow-up; however, R/T peaks cloud volume ratio was significantly lower in patients with subsequent VT/VF (22.4 ± 25.4 versus 13.1 ± 7.9, P = .024).Larger volume of T peaks cloud, measured during 30 beats of three-dimensional ECG, is associated with higher risk of sustained ventricular tachyarrhythmias and appropriate ICD therapies. New method to assess temporal variability of repolarization in three-dimensional ECGs by measuring volume of peak clouds shows potential for further exploration for VT/VF risk stratification.

    View details for DOI 10.1016/j.jelectrocard.2010.05.011

    View details for Web of Science ID 000284514700016

    View details for PubMedID 20655057

  • Beat-to-beat three-dimensional ECG variability predicts ventricular arrhythmia in ICD recipients HEART RHYTHM Tereshchenko, L. G., Han, L., Cheng, A., Marine, J. E., Spragg, D. D., Sinha, S., Dalal, D., Calkins, H., Tomaselli, G. F., Berger, R. D. 2010; 7 (11): 1606-1613


    Methodological difficulties associated with QT measurements prompt the search for new electrocardiographic markers of repolarization heterogeneity.We hypothesized that beat-to-beat 3-dimensional vectorcardiogram variability predicts ventricular arrhythmia (VA) in patients with structural heart disease, left ventricular systolic dysfunction, and implanted implantable cardioverter-defibrillators (ICDs).Baseline orthogonal electrocardiograms were recorded in 414 patients with structural heart disease (mean age 59.4 ± 12.0; 280 white [68%] and 134 black [32%]) at rest before implantation of ICD for primary prevention of sudden cardiac death. R and T peaks of 30 consecutive sinus beats were plotted in 3 dimensions to form an R peaks cloud and a T peaks cloud. The volume of the peaks cloud was calculated as the volume within the convex hull. Patients were followed up for at least 6 months; sustained VA with appropriate ICD therapies served as an end point.During a mean follow-up time of 18.4 ± 12.5 months, 61 of the 414 patients (14.73% or 9.6% per person-year of follow-up) experienced sustained VA with appropriate ICD therapies: 41 of them were white and 20 were black. In the multivariate Cox model that included inducibility of VA and use of beta-blockers, the highest tertile of T/R peaks cloud volume ratio significantly predicted VA (hazard ratio 1.68, 95% confidence interval 1.01 to 2.80; P = .046) in all patients. T peaks cloud volume and T/R peaks cloud volume ratio were significantly smaller in black subjects (median 0.09 [interquartile range 0.04 to 0.15] vs. median 0.11 [interquartile range 0.06 to 0.22], P = .002).A relatively large T peaks cloud volume is associated with increased risk of VA in patients with structural heart disease and systolic dysfunction.

    View details for DOI 10.1016/j.hrthm.2010.08.022

    View details for Web of Science ID 000283648200019

    View details for PubMedID 20816873