The landscape of reported VUS in multi-gene panel and genomic testing: Time for a change.

PURPOSE: Variants of uncertain significance (VUS) are a common result of diagnostic genetic testing and can be difficult to manage with potential misinterpretation and downstream costs, including time investment by clinicians. We investigated the rate of VUS reported on diagnostic testing via multi-gene panels (MGPs) and exome and genome sequencing (ES/GS) to measure the magnitude of uncertain results and explore ways to reduce their potentially detrimental impact. METHODS: Rates of inconclusive results due to VUS were collected from over 1.5 million sequencing test results from 19 clinical laboratories in North America from 2020 to 2021. RESULTS: We found a lower rate of inconclusive test results due to VUSs from ES/GS (22.5%) compared with MGPs (32.6%; P < .0001). For MGPs, the rate of inconclusive results correlated with panel size. The use of trios reduced inconclusive rates (18.9% vs 27.6%; P < .0001), whereas the use of GS compared with ES had no impact (22.2% vs 22.6%; P = ns). CONCLUSION: The high rate of VUS observed in diagnostic MGP testing warrants examining current variant reporting practices. We propose several approaches to reduce reported VUS rates, while directing clinician resources toward important VUS follow-up.

A Machine Learning Methodology for Identification and Triage of Heart Failure Exacerbations.

Inadequate at-home management and self-awareness of heart failure (HF) exacerbations are known to be leading causes of the greater than 1 million estimated HF-related hospitalizations in the USA alone. Most current at-home HF management protocols include paper guidelines or exploratory health applications that lack rigor and validation at the level of the individual patient. We report on a novel triage methodology that uses machine learning predictions for real-time detection and assessment of exacerbations. Medical specialist opinions on statistically and clinically comprehensive, simulated patient cases were used to train and validate prediction algorithms. Model performance was assessed by comparison to physician panel consensus in a representative, out-of-sample validation set of 100 vignettes. Algorithm prediction accuracy and safety indicators surpassed all individual specialists in identifying consensus opinion on existence/severity of exacerbations and appropriate treatment response. The algorithms also scored the highest sensitivity, specificity, and PPV when assessing the need for emergency care. Here we develop a machine-learning approach for providing real-time decision support to adults diagnosed with congestive heart failure. The algorithm achieves higher exacerbation and triage classification performance than any individual physician when compared to physician consensus opinion.

Automatically disambiguating medical acronyms with ontology-aware deep learning.

Modern machine learning (ML) technologies have great promise for automating diverse clinical and research workflows; however, training them requires extensive hand-labelled datasets. Disambiguating abbreviations is important for automated clinical note processing; however, broad deployment of ML for this task is restricted by the scarcity and imbalance of labeled training data. In this work we present a method that improves a model's ability to generalize through novel data augmentation techniques that utilizes information from biomedical ontologies in the form of related medical concepts, as well as global context information within the medical note. We train our model on a public dataset (MIMIC III) and test its performance on automatically generated and hand-labelled datasets from different sources (MIMIC III, CASI, i2b2). Together, these techniques boost the accuracy of abbreviation disambiguation by up to 17% on hand-labeled data, without sacrificing performance on a held-out test set from MIMIC III.

Trends in Treatment for Patients Hospitalized with Heart Failure with Preserved Ejection Fraction Before and After Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT).

The TOPCAT trial investigated spironolactone vs placebo in patients with heart failure with preserved ejection fraction (HFpEF). Although the primary endpoint was not statistically significant, treatment with spironolactone did reduce heart failure hospitalizations compared with placebo. TOPCAT's impact on prescribing patterns in the United States is not well-characterized. We performed a retrospective analysis of discharge prescribing data in the Get With The Guidelines-Heart Failure Registry among patients with left ventricular ejection fraction ≥50% discharged between January 2009 and December 2016 to assess prescribing trends upon dissemination of TOPCAT results. Of 142,201 patients included in the study, 18,581 (13.1%) were prescribed mineralocorticoid receptor antagonists (MRAs) at discharge. Compared with those not prescribed MRAs, patients discharged on MRAs were generally younger (75 vs 78 years), and report white race (76.7% vs 72.0%), more likely to have had prior heart failure hospitalizations (75.5% vs 65.7%), lower brain natriuretic peptide levels (492 vs 545 pg/mL), but similar serum creatinine levels (1.2 vs 1.2 mg/dL) upon admission. MRA prescribing modestly increased over time (p <0.0001), without significant change in the overall trend of prescribing rate for MRAs after TOPCAT results were presented (p =0.17). In conclusion, our findings suggest that for patients with HFpEF, the use of MRAs at hospital discharge is low, with only modest increases over time and no discernible change in the rate of MRA use after the TOPCAT results were released. There remains an important need for more clinical trials to better establish the efficacy and safety of MRAs for the treatment of HFpEF.

Association of Implantable Device Measured Physical Activity With Hospitalization for Heart Failure.

OBJECTIVES: The purpose of this study was to evaluate the association of physical activity (PA) level and longitudinal PA trajectory with a composite heart failure hospitalization and mortality endpoint over a 5-year follow-up period following implantation. BACKGROUND: Low device measured PA early after implantation of an implantable cardioverter-defibrillator (ICD) or cardiac resynchronization therapy defibrillator (CRT-D) is associated with poor outcomes. METHODS: We linked daily PA data from the Boston Scientific ALTITUDE dataset of patients with ICD or CRT-D implantation to Medicare claims data. We used a joint model to investigate the association of the composite endpoint with 1) the time-varying point estimate of PA and 2) the time-varying trajectory/slope of PA during follow-up. RESULTS: Among 20,927 patients with median activity level 85 min/day, 14.1% and 49.6% experienced the composite endpoint at 1 and 5 years. Adjusted joint model results showed that there was a 1.13 (95% confidence interval: 1.12 to 1.13)-fold increase in the hazard of the composite endpoint for 75 min of daily PA relative to 85 min of PA; and a within-patient 10-min decrease in average daily PA over an 8-week period from 85 to 75 min was associated with a hazard ratio of 4.02 (95% confidence interval: 3.82 to 4.22) for the composite endpoint. CONCLUSIONS: Patients with large decreases in PA have significantly higher risk of experiencing heart failure hospitalization or death. PA data from implantable devices may identify patients before clinical decompensation.

Are existing and emerging biomarkers associated with cardiorespiratory fitness in patients with chronic heart failure?

BACKGROUND: Cardiorespiratory fitness (CRF) is closely linked to health status and clinical outcomes in heart failure (HF) patients. We aimed to test whether biomarkers can reflect CRF and its change over time. METHODS: This post hoc analysis used data from ambulatory cohorts of heart failure with reduced ejection fraction (HFrEF) (IRONOUT) and heart failure with preserved ejection fraction (HFpEF) (RELAX). Cardiopulmonary exercise testing, 6-minute walk distance (6MWD), and serum biomarkers were measured at baseline and 16- or 24-week follow-up (for IRONOUT and RELAX respectively). Biomarkers included N-terminal pro-B-type natriuretic peptide (NT-proBNP), soluble ST2, growth differentiation factor-15, and Galectin-3. RESULTS: Analysis included 225 patients with HFrEF and 216 with HFpEF. Baseline peak VO2, VE/VCO2 slope, and 6MWD showed a mild correlation with the doubling of all 4 tested biomarkers in HFrEF and HFpEF. Following multivariable adjustment (including all biomarkers), the only significant association between change in biomarker and functional parameter in HFrEF was change in NT-proBNP and change in VE/VCO2 slope (3.596% increase per doubling, 95% CI 0.779-6.492, P = .012). In HFpEF, a decrease in peak VO2 was associated with an increase in NT-proBNP (-0.726 mL/min/kg per doubling, 95% CI -1.100 to -0.353, P < .001), and a decrease in 6MWD was associated with an increase in growth differentiation factor-15 (-31.606 m per doubling, 95% CI -61.404 to -1.809, P = .038). CONCLUSIONS: In these ambulatory trial cohorts, NT-proBNP was associated with baseline and change in CRF in HFrEF and HFpEF. In contrast, novel biomarkers do not appear suitable as a reliable surrogate for serial assessment of exercise capacity in HF patients given lack of consistent independent association with CRF beyond traditional risk factors and NT-proBNP.

Rhythm Control Versus Rate Control in Patients With Atrial Fibrillation and Heart Failure With Preserved Ejection Fraction: Insights From Get With The Guidelines-Heart Failure.

Background Limited data exist to guide treatment for patients with heart failure with preserved ejection fraction and atrial fibrillation, including the important decision regarding rate versus rhythm control. Methods and Results We analyzed the Get With The Guidelines-Heart Failure (GWTG-HF) registry linked to Medicare claims data from 2008 to 2014 to describe current treatments for rate versus rhythm control and subsequent outcomes in patients with heart failure with preserved ejection fraction and atrial fibrillation using inverse probability weighted analysis. Rhythm control was defined as use of an antiarrhythmic medication, cardioversion, or AF ablation or surgery. Rate control was defined as use of any combination of ß-blocker, calcium channel blocker, and digoxin without evidence of rhythm control. Among 15 682 fee-for-service Medicare patients, at the time of discharge, 1857 were treated with rhythm control and 13 825 with rate control, with minimal differences in baseline characteristics between groups. There was higher all-cause death at 1 year in the rate control compared with the rhythm control group (37.5% and 30.8%, respectively, P<0.01). The lower 1-year all-cause death in the rhythm control group remained after risk adjustment (adjusted hazard ratio, 0.86; 95% CI, 0.75-0.98; P=0.02). Conclusions Rhythm control in patients aged 65 and older with heart failure with preserved ejection fraction and AF was associated with a lower risk of 1 year all-cause mortality. Future prospective randomized studies are needed to explore this potential benefit.

VarSight: prioritizing clinically reported variants with binary classification algorithms.

BACKGROUND: When applying genomic medicine to a rare disease patient, the primary goal is to identify one or more genomic variants that may explain the patient's phenotypes. Typically, this is done through annotation, filtering, and then prioritization of variants for manual curation. However, prioritization of variants in rare disease patients remains a challenging task due to the high degree of variability in phenotype presentation and molecular source of disease. Thus, methods that can identify and/or prioritize variants to be clinically reported in the presence of such variability are of critical importance. METHODS: We tested the application of classification algorithms that ingest variant annotations along with phenotype information for predicting whether a variant will ultimately be clinically reported and returned to a patient. To test the classifiers, we performed a retrospective study on variants that were clinically reported to 237 patients in the Undiagnosed Diseases Network. RESULTS: We treated the classifiers as variant prioritization systems and compared them to four variant prioritization algorithms and two single-measure controls. We showed that the trained classifiers outperformed all other tested methods with the best classifiers ranking 72% of all reported variants and 94% of reported pathogenic variants in the top 20. CONCLUSIONS: We demonstrated how freely available binary classification algorithms can be used to prioritize variants even in the presence of real-world variability. Furthermore, these classifiers outperformed all other tested methods, suggesting that they may be well suited for working with real rare disease patient datasets.

Trends in cardiorespiratory fitness: The evolution of exercise treadmill testing at a single Academic Medical Center from 1970 to 2012.

OBJECTIVE: To identify temporal trends in the use of exercise treadmill testing (ETT) and cardiorespiratory fitness (CRF) estimated by ETT in metabolic equivalents (METs). PATIENTS AND METHODS: We compiled an ETT database of all available treadmill tests-including those with concomitant stress echocardiography and nuclear perfusion imaging studies-performed at Duke University Hospital from January 1, 1970- December 31, 2012. Six different ramp protocols were used in these combined modalities. CRF at maximal exertion was estimated using established metrics. Eligible patients were required to have no missing data on maximal treadmill speed, grade, and protocol. RESULTS: The most commonly used ETT protocol was the Bruce (n = 28,877), followed by manual test (n = 7390). Since the 1980's, the use of ETT for clinical purposes declined substantially; there was a decreased trend in utilization of 9.4% over the decades 1990-1999 and 2000-2009. When standard protocol (Bruce) was assessed in isolation, trends in CRF decreased progressively from 1970 to 2012 (mean METs (standard deviation): 11.7 (4.3) to 10.5 (3.5)). After adjusting for baseline comorbidities, the trend was reduced to a lesser degree. CONCLUSIONS: The use of ETT at our institution has declined over time, perhaps due to changes in clinical practice. In patients undergoing ETT using the standard Bruce protocol, CRF decreased progressively over the last five decades. Future studies are needed to clarify the etiology of the decrease in use of such a powerful predictor of clinical outcomes in our medical care environment.

High-Density Lipoprotein Particle Subfractions in Heart Failure With Preserved or Reduced Ejection Fraction.

BACKGROUND: Circulating high-density lipoprotein particle (HDL-P) subfractions impact atherogenesis, inflammation, and endothelial function, all of which are implicated in the pathobiology of heart failure (HF). OBJECTIVES: The authors sought to identify key differences in plasma HDL-P subfractions between patients with HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF) to determine their prognostic utility. METHODS: Patients with HFrEF (n = 782), HFpEF (n = 1,004), and no HF (n = 4,742) were identified in the CATHGEN (Catheterization Genetics) biorepository of sequential patients undergoing cardiac catheterization. Nuclear magnetic resonance-based lipoprotein profiling was performed on frozen fasting plasma obtained at catheterization. The authors used multivariable analysis of covariance to compare high-density lipoprotein particle (HDL-P) subfractions across groups, and Cox proportional hazards modeling to determine associations between HDL-P subfractions and time to death or major adverse cardiac events. RESULTS: Mean HDL-P size was greater in HFrEF than HFpEF, both of which were greater than in no HF (all 2-way p < 0.0001). By contrast, concentrations of small HDL-P and total HDL-P were lesser in HFrEF than HFpEF, which were both lesser than no HF (all 2-way p ≤ 0.0002). In both HFrEF and HFpEF, total HDL-P and small HDL-P were inversely associated with time to adverse events. These findings persisted after adjustment for 14 clinical covariates (including high-density lipoprotein cholesterol content, coronary artery disease, and the inflammatory biomarker GlycA), and in sensitivity analyses featuring alternate left ventricular ejection fraction definitions, or stricter inclusion criteria with diastolic dysfunction or left ventricular end-diastolic pressure thresholds. CONCLUSIONS: In the largest analysis of HDL-P subfractions in HF to date, derangements in HDL-P subfractions were identified that were more severe in HFrEF than HFpEF and were independently associated with adverse outcomes. These data may help refine risk assessment and provide new insights into the complex interaction of HDL and HF pathophysiology.

Bulked-Segregant Analysis Coupled to Whole Genome Sequencing (BSA-Seq) for Rapid Gene Cloning in Maize.

Forward genetics remains a powerful method for revealing the genes underpinning organismal form and function, and for revealing how these genes are tied together in gene networks. In maize, forward genetics has been tremendously successful, but the size and complexity of the maize genome made identifying mutant genes an often arduous process with traditional methods. The next generation sequencing revolution has allowed for the gene cloning process to be significantly accelerated in many organisms, even when genomes are large and complex. Here, we describe a bulked-segregant analysis sequencing (BSA-Seq) protocol for cloning mutant genes in maize. Our simple strategy can be used to quickly identify a mapping interval and candidate single nucleotide polymorphisms (SNPs) from whole genome sequencing of pooled F2 individuals. We employed this strategy to identify narrow odd dwarf as an enhancer of teosinte branched1, and to identify a new allele of defective kernel1 Our method provides a quick, simple way to clone genes in maize.

Relation of Early Repolarization (J Point Elevation) to Mortality in Blacks (from the Jackson Heart Study).

Conflicting data exist regarding the associations of early repolarization (ER) with electrocardiogram (ECG) and clinical outcomes in blacks. We examined the association of ER defined by J point elevation (JPE) and all-cause mortality, and heart failure (HF) hospitalization in blacks in the Jackson Heart Study (JHS) cohort. We included JHS participants with ECGs from the baseline visit coding JPE and excluded participants with paced rhythms or QRS duration ≥120 ms. We compared the cumulative incidence of 10-year all-cause mortality and 8-year HF hospitalization by presence of JPE ≥0.1 mV in any ECG lead at baseline using Kaplan-Meier estimates and multivariable Cox models. Of the 4,978 participants, 1,410 (28%) had JPE at baseline: anterior leads 97.8%, lateral leads 8.3%, and inferior leads 2.9%. Compared with participants without JPE, those with JPE were younger, more likely to be male and current smokers, and less likely to have hypertension. Over a median follow-up of 8 years, there were no significant differences in the cumulative incidence or multivariable-adjusted hazards of all-cause mortality or HF hospitalization in participants with and without JPE in any lead (adjusted hazard ratio 0.97, 95% confidence interval 0.89 to 1.52, and adjusted hazard ratio 1.18, 95% confidence interval 0.9 to 1.54, respectively). Of the 2,523 participants who completed Exam 3 without JPE at baseline, 246 (10%) developed JPE over follow-up. In conclusion, JPE on ECG was not associated with long-term mortality or HF hospitalization in a large prospective black community cohort, suggesting that ER may represent a benign ECG finding in blacks.

Use of Mineralocorticoid Receptor Antagonists in Patients With Heart Failure and Comorbid Diabetes Mellitus or Chronic Kidney Disease.

BACKGROUND: Perceived risks of hyperkalemia and acute renal insufficiency may limit use of mineralocorticoid receptor antagonist (MRA) therapy in patients with heart failure, especially those with diabetes mellitus or chronic kidney disease. METHODS AND RESULTS: Using clinical registry data linked to Medicare claims, we analyzed patients hospitalized with heart failure between 2005 and 2013 with a history of diabetes mellitus or chronic kidney disease. We stratified patients by MRA use at discharge. We used inverse probability-weighted proportional hazards models to assess associations between MRA therapy and 30-day, 1-year, and 3-year mortality, all-cause readmission, and readmission for heart failure, hyperkalemia, and acute renal insufficiency. We performed interaction analyses for differential effects on 3-year outcomes for reduced, borderline, and preserved ejection fraction. Of 16 848 patients, 12.3% received MRA therapy at discharge. Higher serum creatinine was associated with lower odds of MRA use (odds ratio, 0.66; 95% confidence interval, 0.61-0.71); serum potassium was not (odds ratio, 1.00; 95% confidence interval, 0.90-1.11). There was no mortality difference between groups. MRA therapy was associated with greater risks of readmission for hyperkalemia and acute renal insufficiency and lower risks of long-term all-cause readmission. Patients on MRA therapy with borderline or preserved ejection fraction had greater risks of readmission for hyperkalemia (P=0.02) and acute renal insufficiency (P<0.001); patients with reduced ejection fraction did not. CONCLUSIONS: Among patients with heart failure and diabetes mellitus or chronic kidney disease, MRA use was associated with lower risk of all-cause readmission despite greater risk of hyperkalemia and acute renal insufficiency.

Accelerometer-Measured Daily Activity in Heart Failure With Preserved Ejection Fraction: Clinical Correlates and Association With Standard Heart Failure Severity Indices.

BACKGROUND: Daily physical activity assessed by accelerometers represents a novel method to assess the impact of interventions on heart failure (HF) patients' functional status. We hypothesized that daily activity varies by patient characteristics and correlates with established measures of HF severity in HF with preserved ejection fraction. METHODS AND RESULTS: In this ancillary study of the NEAT-HFpEF trial (Nitrate's Effects on Activity Tolerance in HF With Preserved Ejection Fraction), average daily accelerometer units (ADAU) and hours active per day were assessed during a 14-day period before starting isosorbide mononitrate or placebo (n=110). Baseline ADAU was negatively associated with age, female sex, height, and body mass index, and these variables accounted for 28% of the variability in ADAU (P<0.007 for all). Adjusting for these factors, patients with lower ADAU were more likely to have had an HF hospitalization, orthopnea, diabetes mellitus and anemia, be treated with ß-blockers, have higher ejection fraction, relative wall thickness and left atrial volume, and worse New York Heart Association class, HF-specific quality of life scores, 6-minute walk distance, and NT-proBNP (N-terminal pro-B-type natriuretic peptide; P<0.05 for all). Associations between hours active per day and clinical characteristics were similar. Relative to baseline, there were no significant associations between changes in ADAU or hours active per day and changes in standard functional assessments (New York Heart Association, quality of life, 6-minute walk distance, and NT-proBNP) with isosorbide mononitrate. CONCLUSIONS: Daily activity is a measure of HF-related and global functional status in HF with preserved ejection fraction. As compared with intermittently assessed standard HF assessments, change in daily activity may provide unique information about the impact of HF interventions on functional status. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov/. Unique identifier: NCT02053493.

Trajectory of Congestion Metrics by Ejection Fraction in Patients With Acute Heart Failure (from the Heart Failure Network).

Differences in the clinical course of congestion by underlying ejection fraction (EF) have not been well-characterized in acute heart failure (AHF). A post hoc analysis was performed using pooled data from the Diuretic Optimization Strategies Evaluation in Acute Heart Failure, Cardiorenal Rescue Study in Acute Decompensated Heart Failure, and Renal Optimization Strategies Evaluation in Acute Heart Failure trials. All patients were admitted for a primary diagnosis of AHF. Patients were grouped as reduced EF ≤40%, borderline 40% < EF < 50%, or preserved EF ≥50%. Multivariable Cox regression analysis was used to assess the association among measures of congestion and the composite of unscheduled outpatient visits, rehospitalization, or death. Mean age was 68 ± 13 years and 74% were male. Patients with a preserved EF were older, more likely to be female, less likely to have an ischemic etiology of HF, and had a higher prevalence of atrial fibrillation/flutter and chronic obstructive pulmonary disease. Compared with patients with a reduced EF, preserved EF patients had lower amino-terminal pro-b-type natriuretic peptide levels at baseline (i.e., reduced: 5,998 pg/ml [3,009 to 11,414] vs borderline: 4,420 pg/ml [1,740 to 8,057] vs preserved: 3,272 pg/ml [1,687 to 6,536]) and experienced smaller changes during hospitalization. In general, there were few differences between EF groups in the clinical course of congestion as measured by signs and symptoms of HF, body weight change, and net fluid loss. After adjusting for potential confounders, a greater improvement in global visual analog scale was associated with lower risk of unscheduled outpatient visits, rehospitalization, or death at day 60 (hazard ratio 0.94 per 10 mm increase, 95% confidence interval 0.89 to 0.995). This relation did not differ by EF (p = 0.54). In conclusion, among patients hospitalized for AHF, there were few differences in the in-hospital trajectory or prognostic value of routine markers of congestion by EF.

A Novel Protein Glycan-Derived Inflammation Biomarker Independently Predicts Cardiovascular Disease and Modifies the Association of HDL Subclasses with Mortality.

BACKGROUND: Evidence suggests that systemic inflammation may adversely impact HDL function. In this study we sought to evaluate the independent and incremental predictive performance of GlycA-a novel serum inflammatory biomarker that is an aggregate measure of enzymatically glycosylated acute phase proteins-and HDL subclasses on adverse events in a retrospective observational study of a secondary prevention population and to understand a priori defined potential interactions between GlycA and HDL subclasses. METHODS: GlycA and HDL subclasses were measured using proton nuclear magnetic resonance spectroscopy in 7617 individuals in the CATHGEN (CATHeterization GENetics) cardiac catheterization biorepository. RESULTS: GlycA was associated with presence [odds ratio (OR) 1.07 (1.02-1.13), P = 0.01] and extent [OR 1.08 (1.03, 1.12) P < 0.0005] of coronary artery disease and with all-cause mortality [hazard ratio (HR) 1.34 (1.29-1.39), P < 0.0001], cardiovascular mortality [1.37 (1.30-1.45), P < 0.0001] and noncardiovascular mortality [1.46 (1.39-1.54) P < 0.0001] in models adjusted for 10 cardiovascular risk factors. GlycA and smaller HDL subclasses had independent but opposite effects on mortality risk prediction, with smaller HDL subclasses being protective [HR 0.69 (0.66-0.72), P < 0.0001]. There was an interaction between GlycA and smaller HDL subclasses-increasing GlycA concentrations attenuated the inverse association of smaller HDL subclasses with mortality. Adding GlycA and smaller HDL subclasses into the GRACE (Global Registry of Acute Coronary Events) and Framingham Heart Study Risk Scores improved mortality risk prediction, discrimination and reclassification. CONCLUSIONS: These findings highlight the interaction of systemic inflammation and HDL with clinical outcomes and may increase precision for clinical risk assessment in secondary prevention populations.

Implications of Using Different Definitions on Outcomes in Worsening Heart Failure.

BACKGROUND: In-hospital worsening heart failure (WHF) is an important event that has inconsistent definitions used across trials. We used data from 2 acute heart failure (HF) trials from the National Institutes of Health HF Network, DOSE (Diuretic Optimization Strategies Evaluation) and ROSE (Renal Optimization Strategies), to understand event rates associated with different WHF definitions. METHODS AND RESULTS: We pooled data from 668 patients in DOSE and ROSE and assessed the relationship between WHF and the composite end point of rehospitalization, emergency room visits for HF, and mortality through 60 days. We also assessed for a differential relationship between the timing of WHF development and outcomes. The overall incidence of WHF was 14.6% (24.1% in DOSE, 6.3% in ROSE, and 5.0% in DOSE using the ROSE definition). WHF was associated with an increase in the composite end point (hazard ratio [HR], 1.64; 95% confidence interval [CI], 1.11-2.42; P=0.01). However, the association between WHF and outcomes was significantly stronger in ROSE than in DOSE (HR, 2.67; 95% CI, 1.45-4.91; P<0.01 and HR, 1.28; 95% CI, 0.79-2.08; P=0.31, respectively). Development of WHF between baseline to 24 hours compared with 24 to 48 hours or 48 to 72 hours demonstrated a trend toward improved outcomes (HR, 0.49; 95% CI, 0.21-1.17; P=0.11 and HR, 0.45; 95% CI, 0.20-1.04; P=0.06, respectively). CONCLUSIONS: A WHF definition that excluded the intensification of diuretics resulted in a lower event rate but a stronger association with outcomes. These data support the need for continued efforts to standardize WHF definitions in clinical trials. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00577135 (DOSE) and NCT01132846 (ROSE).