The d-dimer test for deep venous thrombosis: gold standards and bias in negative predictive value

Because venous ultrasound (US) fails to fully image the calf veins, there is the potential for US gold standard studies to classify patients with calf deep venous thrombosis (DVT) in the nondiseased category, causing bias in test index calculations. A false increase in negative predictive value (NPV) is especially likely because calf DVT false-negative tests will be counted in the numerator along with the true-negative tests in NPV calculations. We verified the presence and magnitude of this bias for the d-dimer test.

We abstracted data on overall (calf and thigh) and thigh-only test sensitivity, specificity, and NPV from the six English language studies published between March 1995 and October 2001 that compared d-dimer to a gold standard (GS) capable of imaging both thigh and calf veins and that also stratified results by thigh and calf location. Thigh specificity and NPV were calculated classifying calf DVT patients as free of disease.

The six studies included 81-214 participants and provided 26 comparisons of 16 different d-dimer assays to the GS. Thigh sensitivity was higher than overall sensitivity in 22 of 26 comparisons (range, -0.3 to 8.6); thigh specificity was lower than overall specificity in all comparisons (range, -0.7 to -7.8); and thigh NPV was higher than overall NPV in 22 of 26 comparisons and unchanged in 4 comparisons (range, 0.0-9.2). NPV was >95% in 20 of the thigh results but >95% in only 8 of the overall results.

Different GS can produce clinically significant differences in test indices. Care must be taken in interpreting DVT studies that evaluate d-dimer as a rule-out test and that use US as a GS, because missed calf DVT can falsely increase the NPV.