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. Purpose: Quantifying stenosis in cardiac computed tomography angiography (CTA) images remains a difficult task, as image noise and cardiac motion can degrade image quality and distort underlying anatomic information. The purpose of this study was to develop a computational framework to objectively assess the precision of quantifying coronary stenosis in cardiac CTA. Approach: The framework used models of coronary vessels and plaques, asymmetric motion point spread functions, CT image blur (task-based modulation transfer functions) and noise (noise-power spectrums), and an automated maximum-likelihood estimator implemented as a matched template squared-difference operator. These factors were integrated into an estimability index ( ) as a task-based measure of image quality in cardiac CTA. The index was applied to assess how well it can to predict the quality of 132 clinical cases selected from the Prospective Multicenter Imaging Study for Evaluation of Chest Pain trial. The cases were divided into two cohorts, high quality and low quality, based on clinical scores and the concordance of clinical evaluations of cases by experienced cardiac imagers. The framework was also used to ascertain protocol factors for CTA Biomarker initiative of the Quantitative Imaging Biomarker Alliance (QIBA). Results: The index categorized the patient datasets with an area under the curve of 0.985, an accuracy of 0.977, and an optimal threshold of 25.58 corresponding to a stenosis estimation precision (standard deviation) of 3.91%. Data resampling and training–test validation methods demonstrated stable classifier thresholds and receiver operating curve performance. The framework was successfully applicable to the QIBA objective. Conclusions: A computational framework to objectively quantify stenosis estimation task performance was successfully implemented and was reflective of clinical results in the context of a prominent clinical trial with diverse sites, readers, scanners, acquisition protocols, and patients. It also demonstrated the potential for prospective optimization of imaging protocols toward targeted precision and measurement consistency in cardiac CT images.