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An expert system (PERFEX) developed for the computer-assisted interpretation of myocardial perfusion SPECT studies is now becoming widely available. To date, a systematic validation of the diagnostic performance of this expert system for the interpretation of myocardial perfusion SPECT studies has not been reported.To validate PERFEX's ability to detect and locate coronary artery disease (CAD), we analyzed 655 stress/rest myocardial perfusion prospective SPECT studies in patients who also underwent coronary angiography. The patient population comprised CAD patients (n = 480) and healthy volunteers (n = 175) (449 men, 206 women). Data from 461 other patient studies were used to implement and refine 253 heuristic rules that best correlated the presence and location of left ventricular myocardial perfusion defects on SPECT studies with angiographically detected CAD and with human expert visual interpretations. Myocardial perfusion defects were automatically identified as segments with counts below sex-matched normal limits. PERFEX uses the certainty of the location, size, shape, and reversibility of the perfusion defects to infer the certainty of the presence and location of CAD. The visual interpretations of tomograms and polar maps, vessel stenosis from coronary angiography, and PERFEX interpretations were all accessed automatically from databases and were used to automatically generate comparisons between diagnostic approaches.Using the physician's reading as a gold standard, PERFEX's sensitivity and specificity levels for detection and localization of disease were, respectively, 83% and 73% for CAD, 76% and 66% for the left anterior descending artery, 90% and 70% for the left circumflex artery, and 74% and 79% for the right coronary artery. These results were extracted from a receiver operating characteristic curve using the average optimal input certainty factor.This study shows that the diagnostic performance of PERFEX for interpreting myocardial perfusion SPECT studies is comparable with that of nuclear medicine experts in detecting and locating CAD.