A statistical method for adjusting covariates in linkage analysis with sib pairs

BACKGROUND: We propose a statistical method that includes the use of longitudinal regression models and estimation procedures for adjusting for covariate effects in applying the Haseman-Elston (HE) method for linkage analysis. Our methodology, which uses the covariate adjusted trait, contains three steps: a) modelling the covariate-adjusted population means of quantitative traits through regression; b) estimating the value of covariate-adjusted quantitative traits; and c) evaluating the linkage between the adjusted trait values and the markers based on alleles shared identically by descent. RESULTS: We applied our adjusted HE method and the standard HE method in S.A.G.E. to the sib-pair subset of the Framingham Heart Study distributed by Genetic Analysis Workshop 13 with systolic blood pressure as the quantitative trait. Both methods gave similar patterns for the LOD scores, and exhibited highest multipoint LOD scores near location 70 cM of chromosome 12. CONCLUSION: The adjusted HE method has two major advantages over the standard HE method used in S.A.G.E.: a) it has the capability to handle longitudinal data; b) it provides a more natural approach for adjusting the repeatedly measured covariates from each subject

Measuring the Performance of Online Distributed Team Innovation (Learning) Services

Copyright c○2004 by the authors. Leifer et al.: Measuring the Performance of Online Distributed Team Innovation

Prospective Evaluation of the Influence of Iterative Reconstruction on the Reproducibility of Coronary Calcium Quantification in Reduced Radiation Dose 320 Detector Row CT.

BACKGROUND: Coronary artery calcium (CAC) predicts coronary heart disease events and is important for individualized cardiac risk assessment. This report assesses the interscan variability of CT for coronary calcium quantification using image acquisition with standard and reduced radiation dose protocols and whether the use of reduced radiation dose acquisition with iterative reconstruction (IR; reduced-dose/IR ) allows for similar image quality and reproducibility when compared to standard radiation dose acquisition with filtered back projection (FBP; standard-dose/FBP ) on 320-detector row computed tomography (320-CT). METHODS: 200 consecutive patients (60 ± 9 years, 59% male) prospectively underwent two standard- and two reduced-dose acquisitions (800 total scans, 1600 reconstructions) using 320 slice CT and 120 kV tube voltage. Automated tube current modulation was used and for reduced-dose scans, prescribed tube current was lowered by 70%. Image noise and Agatston scores were determined and compared. RESULTS: Regarding stratification by Agatston score categories (0, 1-10, 11-100, 101-400, \u3e400), reduced-dose/IR versus standard-dose/FBP had excellent agreement at 89% (95% CI: 86-92%) with kappa 0.86 (95% CI: 0.81-0.90). Standard-dose/FBP rescan agreement was 93% (95% CI: 89-96%) with kappa = 0.91 (95% CI: 0.86-0.95) while reduced-dose/IR rescan agreement was similar at 91% (95% CI: 87-94%) with kappa 0.88 (95% CI: 0.83-0.93). Image noise was significantly higher but clinically acceptable for reduced-dose/IR (18 Hounsfield Unit [HU] mean) compared to standard-dose/FBP (16 HU; p \u3c 0.0001). Median radiation exposure was 74% lower for reduced- (0.37 mSv) versus standard-dose (1.4 mSv) acquisitions. CONCLUSION: Rescan agreement was excellent for reduced-dose image acquisition with iterative reconstruction and standard-dose acquisition with filtered back projection for the quantification of coronary calcium by CT. These methods make it possible to reduce radiation exposure by 74%. CLINICAL TRIAL REGISTRATION: URL: https://clinicaltrials.gov/ct2/show/NCT01621594. UNIQUE IDENTIFIER: NCT01621594

Statins and Exercise Training Response in Heart Failure Patients: Insights From HF-ACTION.

OBJECTIVES: The aim of this study was to assess for a treatment interaction between statin use and exercise training (ET) response. BACKGROUND: Recent data suggest that statins may attenuate ET response, but limited data exist in patients with heart failure (HF). METHODS: HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training) was a randomized trial of 2,331 patients with chronic HF with ejection fraction ≤35% who were randomized to usual care with or without ET. We evaluated whether there was a treatment interaction between statins and ET response for the change in quality of life and aerobic capacity (peak oxygen consumption and 6-min walk distance) from baseline to 3 months. We also assessed for a treatment interaction among atorvastatin, simvastatin, and pravastatin and change in these endpoints with ET. Multiple linear regression analyses were performed for each endpoint, adjusting for baseline covariates. RESULTS: Of 2,331 patients in the HF-ACTION trial, 1,353 (58%) were prescribed statins at baseline. Patients treated with statins were more likely to be older men with ischemic HF etiology but had similar use of renin angiotensin system blockers and beta-blockers. There was no evidence of a treatment interaction between statin use and ET on changes in quality of life or exercise capacity, nor was there evidence of differential association between statin type and ET response for these endpoints (all p values \u3e0.05). CONCLUSIONS: In a large chronic HF cohort, there was no evidence of a treatment interaction between statin use and short-term change in aerobic capacity and quality of life with ET. These findings contrast with recent reports of an attenuation in ET response with statins in a different population, highlighting the need for future prospective studies. (Exercise Training Program to Improve Clinical Outcomes in Individuals With Congestive Heart Failure; NCT00047437)

Rationale and design of the GUIDE-IT study: Guiding Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure.

OBJECTIVES: The GUIDE-IT (Guiding Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure) study is designed to determine the safety, efficacy, and cost-effectiveness of a strategy of adjusting therapy with the goal of achieving and maintaining a target N-terminal pro-B-type natriuretic peptide (NT-proBNP) level of BACKGROUND: Elevations in natriuretic peptide (NP) levels provide key prognostic information in patients with HF. Therapies proven to improve outcomes in patients with HF are generally associated with decreasing levels of NPs, and observational data show that decreases in NP levels over time are associated with favorable outcomes. Results from smaller prospective, randomized studies of this strategy thus far have been mixed, and current guidelines do not recommend serial measurement of NP levels to guide therapy in patients with HF. METHODS: GUIDE-IT is a prospective, randomized, controlled, unblinded, multicenter clinical trial designed to randomize approximately 1,100 high-risk subjects with systolic HF (left ventricular ejection fraction ≤40%) to either usual care (optimized guideline-recommended therapy) or a strategy of adjusting therapy with the goal of achieving and maintaining a target NT-proBNP level of CONCLUSIONS: The GUIDE-IT study is designed to definitively assess the effects of an NP-guided strategy in high-risk patients with systolic HF on clinically relevant endpoints of mortality, hospitalization, quality of life, and medical resource use. (Guiding Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure [GUIDE-IT]; NCT01685840)

Effect of Natriuretic Peptide-Guided Therapy on Hospitalization or Cardiovascular Mortality in High-Risk Patients With Heart Failure and Reduced Ejection Fraction: A Randomized Clinical Trial.

Importance: The natriuretic peptides are biochemical markers of heart failure (HF) severity and predictors of adverse outcomes. Smaller studies have evaluated adjusting HF therapy based on natriuretic peptide levels ( guided therapy ) with inconsistent results. Objective: To determine whether an amino-terminal pro-B-type natriuretic peptide (NT-proBNP)-guided treatment strategy improves clinical outcomes vs usual care in high-risk patients with HF and reduced ejection fraction (HFrEF). Design, Settings, and Participants: The Guiding Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure (GUIDE-IT) study was a randomized multicenter clinical trial conducted between January 16, 2013, and September 20, 2016, at 45 clinical sites in the United States and Canada. This study planned to randomize 1100 patients with HFrEF (ejection fraction ≤40%), elevated natriuretic peptide levels within the prior 30 days, and a history of a prior HF event (HF hospitalization or equivalent) to either an NT-proBNP-guided strategy or usual care. Interventions: Patients were randomized to either an NT-proBNP-guided strategy or usual care. Patients randomized to the guided strategy (n = 446) had HF therapy titrated with the goal of achieving a target NT-proBNP of less than 1000 pg/mL. Patients randomized to usual care (n = 448) had HF care in accordance with published guidelines, with emphasis on titration of proven neurohormonal therapies for HF. Serial measurement of NT-proBNP testing was discouraged in the usual care group. Main Outcomes and Measures: The primary end point was the composite of time-to-first HF hospitalization or cardiovascular mortality. Prespecified secondary end points included all-cause mortality, total hospitalizations for HF, days alive and not hospitalized for cardiovascular reasons, the individual components on the primary end point, and adverse events. Results: The data and safety monitoring board recommended stopping the study for futility when 894 (median age, 63 years; 286 [32%] women) of the planned 1100 patients had been enrolled with follow-up for a median of 15 months. The primary end point occurred in 164 patients (37%) in the biomarker-guided group and 164 patients (37%) in the usual care group (adjusted hazard ratio [HR], 0.98; 95% CI, 0.79-1.22; P = .88). Cardiovascular mortality was 12% (n = 53) in the biomarker-guided group and 13% (n = 57) in the usual care group (HR, 0.94; 95% CI; 0.65-1.37; P = .75). None of the secondary end points nor the decreases in the NT-proBNP levels achieved differed significantly between groups. Conclusions and Relevance: In high-risk patients with HFrEF, a strategy of NT-proBNP-guided therapy was not more effective than a usual care strategy in improving outcomes. Trial Registration: clinicaltrials.gov Identifier: NCT01685840

Teaching Innovation in Interdisciplinary Environments: Toward a Design Thinking Syllabus

An increasing number of universities offer user-centric innovation courses based on the principles of design thinking. Lecturers combine a plethora of design thinking elements in design thinking course syllabi and thereby adopt teaching styles that range from autonomy-supportive to structured. Using a balance between these two teaching styles seems most suitable to optimally engage students and provide guidance through the innovation process. To develop a syllabus for innovation courses, we draw on best practices currently being undertaken in universities worldwide and examine 11 design thinking syllabi from different departments (Engineering, Design, Business, and Information Systems). We identify 17 common and 18 unique elements of design thinking courses and related course materials. Based on our results, we propose a design thinking syllabus that includes suggestions for course objectives, course setup, assignment design, and team composition using a balance between autonomous-support and structural teaching styles

Differences in NT-proBNP Response and Prognosis in Men and Women With Heart Failure With Reduced Ejection Fraction.

Background NT-proBNP (N-terminal pro-B-type natriuretic peptide) is a prognostic biomarker in heart failure (HF) with reduced ejection fraction. However, it is unclear whether there is a sex difference in NT-proBNP response and whether the therapeutic goal of NT-proBNP ≤1000 pg/mL has equivalent prognostic value in men and women with HF with reduced ejection fraction. Methods and Results In a secondary analysis of the GUIDE-IT (Guiding Evidence Based Therapy Using Biomarker Intensified Treatment) trial we analyzed trends in NT-proBNP and goal attainment by sex. Differences in clinical characteristics, HF treatment, and time to all-cause death or HF hospitalization were compared. Landmark analysis at 3 months determined the prognostic value of early NT-proBNP goal achievement in men and women. Of the 286 (32%) women and 608 (68%) men in the GUIDE-IT trial, women were more likely to have a nonischemic cause and shorter duration of HF. Guideline-directed medical therapy was less intense over time in women. The absolute NT-proBNP values were consistently lower in women; however, the change in NT-proBNP and clinical outcomes were similar. After adjustment, women achieving the NT-proBNP goal had an 82% reduction in death or HF hospitalization compared with a 59% reduction in men. Conclusions Men and women with HF with reduced ejection fraction had a similar NT-proBNP response despite less intensive HF treatment among women. However, compared with men, the early NT-proBNP goal of ≤1000 pg/mL had greater prognostic value in women. Future efforts should be aimed at intensifying guideline-directed medical therapy in women, which may result in greater NT-proBNP reductions and improved outcomes in women with HF with reduced ejection fraction. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01685840