A natural robustification of the ordinary instrumental variables estimator.

Instrumental variables estimators are designed to provide consistent parameter estimates for linear regression models when some covariates are correlated with the error term. We propose a new robust instrumental variables estimator (RIV) which is a natural robustification of the ordinary instrumental variables estimator (OIV). Specifically, we construct RIV using a robust multivariate location and scatter S-estimator to robustify the solution of the estimating equations that define OIV. RIV is computationally inexpensive and readily available for applications through the R-library riv. It has attractive robustness and asymptotic properties, including high resilience to outliers, bounded influence function, consistency under weak distributional assumptions, asymptotic normality under mild regularity conditions, and equivariance. We further endow RIV with an iterative algorithm which allows for the estimation of models with endogenous continuous covariates and exogenous dummy covariates. We study the performance of RIV when the data contains outliers using an extensive Monte Carlo simulation study and by applying it to a limited-access dataset from the Framingham Heart Study-Cohort to estimate the effect of long-term systolic blood pressure on left atrial size.

MRM-based multiplexed quantitation of 67 putative cardiovascular disease biomarkers in human plasma.

A highly-multiplexed MRM-based assay for determination of cardiovascular disease (CVD) status and disease classification has been developed for clinical research. A high-flow system using ultra-high performance LC and an Agilent 6490 triple quadrupole mass spectrometer, equipped with an ion funnel, provided ease of use and increased the robustness of the assay. The assay uses 135 stable isotope-labeled peptide standards for the quantitation of 67 putative biomarkers of CVD in tryptic digests of whole plasma in a 30-min assay. Eighty-five analyses of the same sample showed no loss of sensitivity (<20% CV for 134/135 peptides) and no loss of retention time accuracy (<0.5% CV for all peptides). The maximum linear dynamic range of the MRM assays ranged from 10(3) -10(5) for 106 of the assays. Excellent linear responses (r >0.98) were obtained for 117 of the 135 peptide targets with attomole level limits of quantitation (<20% CV and accuracy 80-120%) for 81 of the 135 peptides. The assay presented in this study is easy to use, robust, sensitive, and has high-throughput capabilities through short analysis time and complete automated sample preparation. It is therefore well suited for CVD biomarker validation and discovery in plasma.

Proteomic signatures in plasma during early acute renal allograft rejection.

Acute graft rejection is an important clinical problem in renal transplantation and an adverse predictor for long term graft survival. Plasma biomarkers may offer an important option for post-transplant monitoring and permit timely and effective therapeutic intervention to minimize graft damage. This case-control discovery study (n = 32) used isobaric tagging for relative and absolute protein quantification (iTRAQ) technology to quantitate plasma protein relative concentrations in precise cohorts of patients with and without biopsy-confirmed acute rejection (BCAR). Plasma samples were depleted of the 14 most abundant plasma proteins to enhance detection sensitivity. A total of 18 plasma proteins that encompassed processes related to inflammation, complement activation, blood coagulation, and wound repair exhibited significantly different relative concentrations between patient cohorts with and without BCAR (p value <0.05). Twelve proteins with a fold-change >or=1.15 were selected for diagnostic purposes: seven were increased (titin, lipopolysaccharide-binding protein, peptidase inhibitor 16, complement factor D, mannose-binding lectin, protein Z-dependent protease and beta(2)-microglobulin) and five were decreased (kininogen-1, afamin, serine protease inhibitor, phosphatidylcholine-sterol acyltransferase, and sex hormone-binding globulin) in patients with BCAR. The first three principal components of these proteins showed clear separation of cohorts with and without BCAR. Performance improved with the inclusion of sequential proteins, reaching a primary asymptote after the first three (titin, kininogen-1, and lipopolysaccharide-binding protein). Longitudinal monitoring over the first 3 months post-transplant based on ratios of these three proteins showed clear discrimination between the two patient cohorts at time of rejection. The score then declined to baseline following treatment and resolution of the rejection episode and remained comparable between cases and controls throughout the period of quiescent follow-up. Results were validated using ELISA where possible, and initial cross-validation estimated a sensitivity of 80% and specificity of 90% for classification of BCAR based on a four-protein ELISA classifier. This study provides evidence that protein concentrations in plasma may provide a relevant measure for the occurrence of BCAR and offers a potential tool for immunologic monitoring.

Diagnostic performance of high-definition coronary computed tomography angiography performed with multiple radiation dose reduction strategies.

BACKGROUND: Numerous radiation dose reduction measures have been proposed for coronary computed tomographic angiography (CCTA). Although these techniques allow for imaging with reduced radiation, it is unknown whether diagnostic performance is maintained. A new high-definition CCTA (HD-CCTA) allows higher spatial resolution, reduced image noise, and lower radiation doses. OBJECTIVES: The aim of this study was to determine the diagnostic performance of HD-CCTA, in combination with multiple radiation dose reduction strategies, for the detection of obstructive coronary artery disease. METHODS: Consecutive patients (N = 43, aged 60 ± 10 years, 83% male) with chest pain and referred for quantitative coronary angiography (QCA) underwent HD-CCTA with radiation dose reduction measures, including prospective electrocardiographic triggering, reduction of additional tube on-time, and minimization of tube voltage and current. Intraluminal diameter stenosis ≥ 50% was considered significant. QCA served as the reference standard. The area under the receiver-operating-characteristic curve (AUC) was used to evaluate diagnostic accuracy. RESULTS: All scans demonstrated diagnostic image quality, with 99% (543/548) of included coronary segments interpretable by HD-CCTA. Median effective radiation dose was 2.8 mSv (interquartile range, 1.3-3.9). The AUC for the per-patient assessment for stenosis ≥ 50% was 0.90 (95% confidence interval [CI], 0.77-0.96), with sensitivity of 95% (95% CI, 85%-100%), specificity of 79% (95% CI, 63%-95%), positive predictive value of 78% (95% CI, 61%-95%), and negative predictive value of 95% (95% CI, 85%-100%). CONCLUSIONS: Compared with QCA, HD-CCTA with multiple dose reduction measures resulted in low radiation doses and high diagnostic accuracy to detect and exclude obstructive coronary artery disease.