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Some understanding of diagnostic tests for pulmonary embolism

Mac Gillavry, M.R.

Publication date2001

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Citation for published version (APA):Mac Gillavry, M. R. (2001). Some understanding of diagnostic tests for pulmonary embolism.

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CHAPTER 7

Sensitivity and specificity of non-invasive diagnostic tests for pulmonary embolism vary across clinical

subgroups

Melvin R. Mac Gillavry1,2, Jeroen G. Lijmer1, IenekeJ. C. Hartmann3, Dees P. M. Brandjes2,4, Harry R. Büller4, Patrick M. M. Bossuyt1, Martin H. Prins',

on behalf of the ANTELOPE-Study Group

'Department of Clinical Epidemiology and Biostatistics, Academic Medical Center, Amsterdam;

depar tment of Internal Medicine, Slotervaart Hospital, Amsterdam; depa r tmen t of Radiology, University Medical Center, Utrecht; Department of Vascular Medicine, Academic Medical Center,

Amsterdam, The Netherlands

submitted for publication

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Abstract

Background It is usually taken for granted that the accuracy of a new test for pulmonary embolism is seen as a test characteristic, not susceptible to clinical variation. To assess the validity of this practice, we explored the effect of patient characteristics on the sensitivity and specificity of three new non- or minimally invasive tests: the D-dimer assay, spiral computed tomography (CT) and a clinical probability estimate.

Methods Data were obtained in a prospective multi-center study in patients with suspected pulmonary embolism (n=627). Subgroups were predefined, based on patient characteristics: demographics, symptoms, risk factors and co-morbid conditions. In each subgroup sensitivity and specificity of the tests under study were deter-mined by a blinded comparison of test results with the findings after lung scintig-raphy or pulmonary angiography (the conjoint reference standard).

Results The sensitivity of the D-dimer assay differed significantly between patients who had recently undergone surgery as compared to those who had not (97 versus 75%, respectively). The specificity of the D-dimer assay was affected by various co-morbid conditions. The sensitivity of the spiral CT differed significantly between users and non-users of oral contraceptives (95 versus 59%, respectively). The specificity of the clinical probability estimate was not identical for patients with chest pain and those without (10 versus 21%, respectively).

Conclusion The sensitivity and specificity of new tests for pulmonary embolism display sub-stantial variation across clinical subgroups of patients.

Sensitivity and specificity of tests vary across clinical subgroups 65

Introduction

The conventional diagnostic tests for pulmonary embolism - ventilation-per-fusion scintigraphy and pulmonary angiography - have well-known limitations. Lung scan results are inconclusive in about 50% of the patients. Clinicians are reluctant to perform angiography due to its invasiveness. In many hospitals these techniques are not directly available (1-3). To reduce the need for these conven-tional tests, several new, non- or minimally invasive tests, have been proposed (4). These include D-dimer assays, compression ultrasonography and spiral com-puted tomography (CT). The interest for the potential role of clinical judgement in the diagnosis of pulmonary embolism has also been revived (5, 6).

Estimates of the accuracy of these new tests have been reported. If satisfactory, these estimates usually serve as the basis for widespread clinical introduction without an explicit exploration of their constancy across subgroups of patients with different clinical characteristics. This practice assumes that diagnostic accu-racy is a fixed property of a test, independent of clinical characteristics of the patients. The latter assumption has been proven incorrect for a number of diag-nostic tests, of which exercise tests in the diagnosis of ischaemic heart disease are the best-documented examples (7-9). If the new tests for pulmonary embolism also show variation in test accuracy, it is very plausible that this could have clini-cal consequences.

We explored differences in sensitivity and specificity of three new diagnostic tests for pulmonary embolism associated with patient characteristics by analyz-ing data from a diagnostic study in consecutive patients with suspected pulmo-nary embolism. The tests under evaluation were the D-dimer assay, spiral CT and a clinical probability estimate of pulmonary embolism.

Methods

Patients Data were obtained in a prospective study in six Dutch teaching hospitals (10). From May 1997 through March 1998, consecutive in- and outpatients with a clinical suspicion of pulmonary embolism were eligible for the study. Patients were excluded if they were younger than 18 years of age, were pregnant, had already undergone objective diagnostic tests for pulmonary embolism, had an indication for acute thrombolytic therapy, or if there was an expected inability to complete the study protocol within 48 hours of presentation. The Institutional Review Boards of all participating hospitals approved the study protocol. Each included patient gave written informed consent.

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Diagnostic Investigations A detailed clinical history, clinical probability estimate, D-dimer test and a venti-lation-perfusion lung scan were performed within 24 hours of study inclusion in all patients. Spiral CT was only performed in patients with an abnormal per-fusion scan. Pulmonary angiography was performed in patients with a non-diag-nostic lung scan and in patients in whom a high probability lung scan was fol-lowed by a normal spiral CT. The maximum allowed time for completion of this diagnostic protocol was 48 hours.

Upon presentation of a patient, prior to all other diagnostic investigations, the treating physician was asked to mark a clinical probability estimate of pulmonary embolism on a visual analog scale ranging from 0 to 100 percent. This estimate had to be solely based on symptoms and signs, and results of routine tests if avail-able (arterial blood gas analysis, electrocardiogram and chest X-ray). For the pur-pose of this analysis, the estimates were afterwards dichotomized into less than 20% (designated as 'low clinical probability' and considered to exclude the dis-ease) or greater than or equal to 20%. This cut-off point was chosen on the basis of previous literature (5, 11).

Directly after study inclusion and prior to or within 24 hours of the start of heparin therapy, the whole blood SimpliRED® D-dimer test (Agen Biomedical Ltd, Brisbane, Australia) was performed. At each center, a limited number of trained investigators performed the D-dimer test, as described elsewhere (12). The test result is abnormal when agglutination of red cells becomes visible on the test slide within two minutes, reflecting a D-dimer concentration of 0.20 mg/1 or above. The test result was recorded without knowledge of the outcome of the other diagnostic investigations.

Spiral CT angiography was performed during a 32-second single breath hold. If patients were very dyspneic, scanning was performed during shallow breath-ing. The chest was scanned in a caudocranial direction over a 16-cm distance, from the upper level of the diaphragm to a level slightly above the aortic arch (5 mm collimation, pitch of 1, 120 kV, 200-250 mAs). Image acquisition was started 20 seconds after intravenous injection of 900 mg/s of iodine for 40 sec-onds. Images were reconstructed at 2 mm intervals and interpreted independ-ently on a viewing station by two experienced radiologists. In case of disagree-ment, the independent interpretation of a third radiologist was considered decisive. Pulmonary embolism was considered to be present if in case of a well opacified vessel there was an intraluminal filling defect on more than one slice in the absence of artefacts. A filling defect could be seen as complete occlusion of the vessel, an eccentric partial filling defect or a partial central filling defect sur-rounded by contrast agent. A CT scan without any filling defects was considered negative for pulmonary embolism (13).

A six-view perfusion lung scintigraphy was obtained after the administration of 100 Mbq of ""Technetium-labelled macro-aggregates of albumin. If segmental

Sensitivity and specificity of tests vary across clinical subgroups 67

or larger perfusion defects were seen, ventilation lung scintigraphy was added using81 "Krypton gas. A panel of experienced nuclear medicine physicians inter-preted all lung scans by using a lung segment reference chart and reached final classifications by consensus. The lung scans were classified according to previ-ously described criteria as normal (no perfusion defects), high probability (at least one segmental or larger perfusion defect with locally normal ventilation) or non-diagnostic (ventilation-perfusion abnormalities not meeting the criteria for normal or high probability) (14, 15).

Pulmonary angiography was performed using a digital subtraction technique with the catheter positioned selectively in the right and left pulmonary artery and was interpreted independently by two radiologists according to accepted criteria (16). If there was no consensus, the independent interpretation of a third reader was considered decisive.

All lung scans and pulmonary angiograms were interpreted without knowl-edge of the clinical probability estimate or the results of the D-dimer test and, if applicable, the spiral CT. Patients were classified as having pulmonary embolism in case of a high probability lung scan or abnormal angiogram, while the diagno-sis was refuted if the lung scan or angiogram was normal.

Data Analysis We restricted our subgroup analysis to patient characteristics that can be obtained by either medical history or physical examination. The following patient characteristics were taken into consideration: age (ordered categories based on quartiles), sex, referral population (in- versus outpatients), duration of symptoms (ordered categories based on quartiles), symptoms of deep vein thrombosis, recent onset or worsening of cough, recent onset or worsening of dyspnea, haemoptysis, chest pain (categorized into pleuritic pain, non-pleuritic pain and no pain), fever (body temperature > 37.7 C), tachycardia (heartrate > 100 beats/min.), surgery or trauma within 3 months of presentation, immobi-lization for at least 3 consecutive days within the previous 4 weeks, active cancer (diagnosed or treated within the previous 6 months), use of oral contraceptives at the time of inclusion and previous episode of venous thromboembolism (deep vein thrombosis or pulmonary embolism) or a family history of this clinical entity.

Only patients in whom the diagnosis of pulmonary embolism was confirmed or refuted per protocol were included in the analysis. The sensitivity, specificity and corresponding exact 95% confidence intervals (CI) were calculated for the tests under study in each subgroup. The Cochran-Armitage test for trend was used to examine differences in sensitivities and specificities between the sub-groups defined by age and duration of symptoms. The Chi-square test was used to examine these differences across the three categories of chest-pain. For all other comparisons, Fisher's exact test was applied. Taking into account multiplie-

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ity of comparisons, a strict two-tailed p-value < 0.01 was considered to indicate a statistically significant difference. Analyses were performed with statistical soft-ware (SPSS; version 9.0).

Results

A total of 1162 consecutive patients with clinically suspected pulmonary embo-lism were screened, of whom 179 had to be excluded on the basis of one of the predefined criteria (10). Of the 983 eligible patients, 627 (64%) gave informed consent. A reference diagnosis regarding the absence or presence of pulmonary embolism could not be reached in 110 of these 627 patients due to withdrawal of informed consent, clear evidence for an alternative diagnosis, medical reasons or technical failure. This left a total of 517 patients for final analysis. Their clinical characteristics were similar to those of the 110 patients who were not included in the analysis (Table 7.1).

Table 7.1 Clinical characteristics of the 51 7 study patients and the 110 patients who were excluded from the final analysis

Study Excluded patients patients (n=517) (n=110)

Male 215 (42%) 55 (50%) Mean age, years (SD) 51 (18) 61 (17) Outpatients 417 (81%) 73 (66%) Median duration of symptoms, days (IQR) 3 (1-9) 3 (1-10) Symptoms of DVT 31 (6%) 12 (11%) Fever 108 (22%) 32 (30%) Cough 170 (33%) 40 (36%) Dyspnea 358 (69%) 84 (76%) Haemoptysis 31 (6%) 7 (6%) Pleuritic chest pain 280 (55%) 54 (49%) Non-pleuritic chest pain 130 (25%) 23 (21%) Tachycardia 65 (13%) 21 (19%) Cancer 50 (10%) 21 (20%) Surgery 85 (1 7%) 26 (24%) Trauma 30 (6%) 8 (7%) Immobilization 78 (15%) 22 (20%) Use of oral contraceptives 92 (31%) 6 (11%) Previous VTE 73 (14%) 25 (23%) Family history of VTE 105 (23%) 17 (19%)

IQR = interquartile range; DVT = deep vein thrombosis; VTE = venous thromboembolism

Sensitivity and specificity of tests vary across clinical subgroups 69

The sensitivity and specificity of the D-dimer test, spiral CT and the clinical probability estimate in the total group and in subgroups of patients defined by various patient characteristics are shown in Table 7.2. To preserve conciseness, data are not shown for the subgroups in which differences in test accuracy did not differ significantly.

D-dimer test results were available in 497 (96%) of the 517 study patients. The D-dimer test was not performed in the 20 remaining patients due to logistic rea-sons. The sensitivity was significantly higher in patients who had recently under-gone surgery as compared to those without this feature. Across the respective subgroups, specificity was significantly lower in elderly patients, in inpatients and in patients with fever, tachycardia, cancer and immobilization. In women who used oral contraceptives the specificity was statistically significant higher than in those not using oral contraceptives. The other patient characteristics showed no effect on the sensitivity and specificity of the D-dimer test.

A spiral CT result was available in 230 of the 274 patients in whom it was indi-cated per-protocol. Spiral CT was not performed in 36 patients due to logistic reasons. Results were inconclusive in 8 patients. In 29 other patients spiral CT results were also available, although the test was not indicated per-protocol (nor-mal perfusion scan). Hence, the overall and subgroup estimates of accuracy could be calculated in a total of 259 patients. The sensitivity was statistically significant higher in users of oral contraceptives as compared to non-users. The sensitivity and specificity of the spiral CT showed no variation across the other subgroups.

A clinical probability estimate was available in 413 (80%) of the 517 study patients. In the remaining 104 patients the estimate was not obtained before the results of the ventilation-perfusion scan were known. These patients were there-fore excluded from further analysis. The sensitivity showed no statistically signif-icant variation across subgroups. The specificity was significantly lower in patients with pleuritic chest pain as compared to those with non-pleuritic chest pain and no pain. Across the other subgroups no variation in the specificity of the clinical probability estimate was detected.

Discussion

Our analysis demonstrated variation in the sensitivity and specificity of non-invasive tests for pulmonary embolism across a number of subgroups defined by patient characteristics.

A biological explanation for the observed variation in test sensitivity between different types of patients can be found in the notion that a disease state is sel-dom truly dichotomous, to be classified as present or absent. Diseases often cover a spectrum of conditions, ranging from mild to severe forms. It has been demon-strated that test characteristics in patients with severe symptoms differ from

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Table 7.2 Sensitivity and specificity of the D-dimer test, spiral CT and clinical probability estimate in the total group and in various clinical subgroups

Patients PE Sensitivity Specificity No. % % (95%CI) % (95%CI)

D-dimer test Total group 497 31 80 (74-86) 62 (57-67) Age (years) < 3 6 124 22 74 (54-89) 78 (69-86)# 36-50 124 22 78 (58-91) 60 (49-70) 51-65 125 30 78 (62-90) 58 (47-68) >65 124 51 84 (73-92) 43 (30-56) Referral population inpatient 95 41 90 (76-97) 39 (27-53)# outpatient 402 29 77 (69-84) 66 (60-71) Fever yes 100 34 79 (62-91) 46 (33-58)* no 373 31 80 (73-88) 65 (59-70) Tachycardia yes 63 38 71 (49-87) 39 (23-55)# no 429 30 82 (75-88) 65 (59-70) Cancer yes 49 41 90 (68-99) 38 (21-58)* no 418 29 77 (70-85) 64 (58-69) Surgery yes 83 39 97 (84-100)* 47 (33-62) no 414 30 75 (68-83) 64 (59-70) Immobilization yes 75 45 94 (80-99) 27 (14-43)# no 419 28 75 (68-83) 66 (61-72) Oral contraceptives yes 88 26 87 (66-97) 79 (67-88)# no 201 27 78 (64-88) 57 (48-65)

Spiral CT Total group 259 50 69 (61-76) 86 (80-92) Oral contraceptives yes 44 48 95 (76-100)# 87 (66-97) no 109 45 59 (44-73) 85 (73-93)

Clinical Probability Estimate

Total group 413 31 91 (85-96) 17 (12-21) Chest pain pleuritic 231 33 90 (80-95) 10 (6-16)# non-pleuritic 100 19 95 (74-100) 27 (18-38) no 79 39 94 (79-99) 21 (11-35)

PE = pulmonary embolism. Statistically significance of differences in sensitivity and/or specificity across subgroups is indicated; * p

Sensitivity and specificity of tests vary across clinical subgroups 71

those with limited symptoms (17). Patients with more severe disease (more extensive, more symptoms) are usually easier to identify with diagnostic tests, whose sensitivity will be higher.

The higher sensitivity of D-dimer testing in patients who had recently under-gone surgery may be explained by the fact that this condition is a predisposing factor for pulmonary embolism, associated with more extensive disease. Alterna-tively, this condition may lead to increased fibrin formation and degradation and thus higher plasma D-dimer levels irrespective of the presence or absence of pul-monary embolism. If so, this will increase the likelihood of obtaining D-dimer levels above the cut-off point and sensitivity will be higher.

The higher sensitivity of spiral CT in users of oral contraceptives, considered to be a risk factor of pulmonary embolism, is not easily explained but may also be due to an association with more extensive disease.

A biological explanation for the observed variation in test specificity is to be found in the intrinsic heterogeneity in tested patients that do not have the target disease. This group of non-diseased' has a mix of other conditions responsible for the symptoms that led to the ordering of the test, including various co-mor-bid conditions. These may differentially influence test specificity. In other words, the conditions that are responsible for the symptoms differ in their potency to cause false-positive test results.

The lower specificity of the D-dimer test in patients with fever, tachycardia, cancer and immobilization may be due to a hypercoagulable state that increases D-dimer levels above the cut-off point of the test. These co-morbid conditions were more frequently seen in elderly patients and inpatients (data not shown), which may explain the lower specificity of D-dimer testing in these subgroups. This may also explain the higher specificity in the subgroup of oral contracep-tives users in which co-morbid conditions were less frequent. The lower specifi-city of the clinical probability estimate in patients with pleuritic chest pain may be explained by the fact that this symptom is considered typical for pulmonary embolism, but accompanies many alternative diagnoses.

For the evaluated D-dimer test in particular, our results also suggest that the subjective threshold for designating the test as abnormal varied among observers, leading to variation in the estimates of sensitivity and specificity. Although the inter-observer variability of the subjective D-dimer test was not evaluated in this study, qualitative differences across the clinical subgroups of referral population, cancer, surgery and immobilization argue for an implicit trade-off between sensi-tivity and specificity due to a shift in the subjective positivity threshold. Observ-ers may implicitly have had a lower threshold for calling the test abnormal when known risk factors of pulmonary embolism were present. In that case, sensitivity will be increased at the expense of a lower specificty. This hypothesis awaits fur-ther investigation.

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The available evidence on variability in sensitivity and specificity of these new diagnostic tests for pulmonary embolism is limited. A few studies have previously demonstrated a lower specificity of D-dimer tests in inpatients, elderly patients, immobilized patients and patients with cancer (18-21). For the other tests exam-ined here there are no data available regarding variation in test accuracy due to the examined clinical characteristics.

Two methodological aspects of our analysis should be addressed. Firstly, our results potentially suffer from a selection bias, since verification of the test result through a reference test was not possible in all included patients. It should be kept in mind that the analyzed study cohort comprised more than 80% of the ini-tially included patients, covering a broad spectrum of patients. In addition, most of the patient characteristics of the final study cohort were similar to those of the patients who were not included in the analysis. Therefore, we do consider our results applicable to patients generally encountered with clinically suspected pul-monary embolism under similar circumstances. Secondly, one could argue that some of the observed effects of patient characteristics on test accuracy are chance findings, as the number of patients in the subgroups was small and comparisons were multiple. To adjust for this, we used a strict criterion for significance.

The potential consequences of variation in sensitivity and/or specificity can be illustrated with the evaluated D-dimer assay. Suppose one uses the overall sensi-tivity (80%) and specificity (62%) of the D-dimer assay to estimate the posttest probability of pulmonary embolism after a normal test result has been obtained in a patient with tachycardia. The overall likelihood ratio of such a result is 0.3 ([1-sensitivity] / specificity). Given a pretest probability of pulmonary embolism of 0.38 in patients with tachycardia, the pretest odds is 0.61 (pretest probability / [1-pretest probability]). According to Bayes' theorem the posttest odds should equal the pretest odds times the likelihood ratio. This produces 0.18, correspond-ing to an estimated posttest probability of pulmonary embolism for a normal test result of 0.15 However, if one would repeat this calculation with the subgroup estimates of test accuracy (sensitivity 71%; specificity 39%), the posttest proba-bility has to be 0.31. Similar calculations can be performed for patients who had recently undergone surgery. Given a pretest probability of 0.39 in these patients, the estimates of the posttest probability of pulmonary embolism for a normal D-dimer result change in the opposite direction (0.16 versus 0.04. This example shows that blunt application of the overall sensitivity or specificity in Bayes' theo-rem can lead to biased (overoptimistic or too conservative) estimates of the post-test probability of pulmonary embolism.

The variability in test characteristics poses a challenge to researchers and clini-cians. If true, it has to be investigated and accounted for in the interpretation of test results. We feel that diagnostic studies should be designed with sufficient power to investigate clinically significant variability in a priori specified sub-groups.

Sensitivity and specificity of tests vary across clinical subgroups 73

To increase precision of the observed variation in the sensitivity and specificity of the evaluated tests for pulmonary embolism, investigators should be encouraged to examine and report estimates of test accuracy in prespecified clinical sub-groups within their study populations. This would allow synthesis of the available evidence in a meta-analytic fashion in order to provide subgroup estimates with large precision.

In conclusion, we have demonstrated variation in the sensitivity and specifi-city of non-invasive tests for pulmonary embolism across subgroups defined by various patient characteristics. Future evaluations of diagnostic tests for pulmo-nary embolism should examine the consistency of accuracy estimates among subgroups, as this can have clinical consequences.

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