Systematic review and meta-analysis of strategies for the diagnosis of
http://www.100md.com
《英国医生杂志》
1 Emergency Department, Centre Hospitalier Universitaire, 49033 Angers cedex 01, France, 2 Department of Clinical Epidemiology, INSERM U 729, Université Paris V, Assistance Publique Hopitaux de Paris, H?pital Européen Georges Pompidou, Paris, France, 3 Department of Respiratory and Intensive Care, Université Paris V
Correspondence to: G Meyer, Service de Pneumologie-soins intensifs, H?pital Européen Georges Pompidou, 20 rue Leblanc, 75015 Paris, France guy.meyer@hop.egp.ap-hop-paris.fr
Objectives To assess the likelihood ratios of diagnostic strategies for pulmonary embolism and to determine their clinical application according to pretest probability.
Data sources Medline, Embase, and Pascal Biomed and manual search for articles published from January 1990 to September 2003.
Study selection Studies that evaluated diagnostic tests for confirmation or exclusion of pulmonary embolism.
Data extracted Positive likelihood ratios for strategies that confirmed a diagnosis of pulmonary embolism and negative likelihood ratios for diagnostic strategies that excluded a diagnosis of pulmonary embolism.
Data synthesis 48 of 1012 articles were included. Positive likelihood ratios for diagnostic tests were: high probability ventilation perfusion lung scan 18.3 (95% confidence interval 10.3 to 32.5), spiral computed tomography 24.1 (12.4 to 46.7), and ultrasonography of leg veins 16.2 (5.6 to 46.7). In patients with a moderate or high pretest probability, these findings are associated with a greater than 85% post-test probability of pulmonary embolism. Negative likelihood ratios were: normal or near normal appearance on lung scan 0.05 (0.03 to 0.10), a negative result on spiral computed tomography along with a negative result on ultrasonography 0.04 (0.03 to 0.06), and a D-dimer concentration < 500 μg/l measured by quantitative enzyme linked immunosorbent assay 0.08 (0.04 to 0.18). In patients with a low or moderate pretest probability, these findings were associated with a post-test probability of pulmonary embolism below 5%. Spiral computed tomography alone, a low probability ventilation perfusion lung scan, magnetic resonance angiography, a quantitative latex D-dimer test, and haemagglutination D-dimers had higher negative likelihood ratios and can therefore only exclude pulmonary embolism in patients with a low pretest probability.
Conclusions The accuracy of tests for suspected pulmonary embolism varies greatly, but it is possible to estimate the range of pretest probabilities over which each test or strategy can confirm or rule out pulmonary embolism.
Pulmonary embolism is a common and serious disease. Clinical signs and symptoms allow the clinician to determine the pretest probability of someone having pulmonary embolism (the clinical probability) but are insufficient to diagnose or rule out the condition.1 Laboratory tests and imaging are thus required in all patients with suspected pulmonary embolism.2 Since 1990 a large number of diagnostic tests and strategies have been evaluated for pulmonary embolism. As the design, clinical setting, and reference methods differ between studies, the diagnostic value of most tests may seem inconsistent. Although several reviews have been published on this topic,1-3 systematic reviews that may clarify the role of the different diagnostic tests are lacking.
We carried out a systematic review to assess the likelihood ratios of the diagnostic tests used for suspected pulmonary embolism. For clinical purposes, we estimated the range of pretest probabilities over which each test can accurately confirm or exclude pulmonary embolism.
Materials and methods
We searched Medline, Embase, and Pascal Biomed for studies published from January 1990 to September 2003 using the search terms ((pulmonary embol* or pulmonary thromboembol*) and (diagnosis or diagnostic) and (angiography or arteriography or (follow adj up) or followup or (management adj stud*)) and (PY = 1990-2003) and (study or studies or trial) and (LA = ENGLISH). We also manually searched published bibliographies and our own personal libraries. We retained only studies published in English. We excluded s, editorials, reviews, case reports, and case series.
Data selection
Two reviewers (PMR, GM) independently selected potentially relevant studies. Studies were included if they evaluated tests or strategies aimed at confirming or excluding pulmonary embolism (confirmation or exclusion diagnostic strategies, respectively) and they met the following criteria: the reference method was pulmonary angiography for confirmation strategies and clinical follow-up or pulmonary angiography for exclusion strategies; the study was prospective; participants were recruited consecutively; and the test being evaluated and the reference test were interpreted independently.
We excluded retrospective studies; follow-up studies with more than 5% of patients lost to follow-up or those that used additional imaging to pulmonary angiography in patients with a negative experimental test result; studies in which crude data could not be extracted for the calculation of positive and negative likelihood ratios; and studies that had specific populations. Each study was graded according to the reference method and the characteristics of the patients (see table A on bmj.com). For studies with multiple publications, we used data from the most recent publication.
Data extraction
Two investigators (PMR, GM) independently ed data on the design; study size; setting; characteristics of the patients; type of reference standard; and the number of true positive, true negative, false positive, and false negative test results.
When we used follow-up as the reference method, we considered all the patients with a negative test result to have a false negative result if they developed deep vein thrombosis or pulmonary embolism during the three month follow-up period. We classified deaths believed to be caused by pulmonary embolism as thromboembolic events. When we could not extract data from published articles, we contacted the authors. Discrepancies in data ion between investigators were resolved by a third author (PD).
Fig 1 Positive likelihood ratios (squares) and 95% confidence intervals for strategies used to confirm a diagnosis of pulmonary embolism. Size of square is related to variance of study. Broken line represents pooled positive likelihood ratio, and limits of diamond represents 95% confidence intervals of pooled ratios
Statistical analysis
We calculated the positive likelihood ratio for confirmation diagnostic strategies and the negative likelihood ratio for exclusion diagnostic strategies. We used the adjusted Wald method to calculate 95% confidence intervals.4 Summary estimates of the likelihood ratios were calculated as a weighted average, and we calculated the confidence intervals using the DerSimonian and Laird random effects method.5 Homogeneity tests were carried out to evaluate the consistency of findings across the studies. We used Cochran's Q heterogeneity statistic and the quantity I2 to determine the percentage of total variation across the studies due to heterogeneity rather than to chance.6 When I2 was more than 0%, we explored possible reasons for heterogeneity, such as patient populations (selected or unselected patients) and the nature of the reference method (angiography or composite reference standard), using subgroup analysis based on the three categories for study quality (see table A on bmj.com).
Analyses were carried out in STATA (release 6).
Clinical practice perspectives
We considered that a confirmation strategy was accurate enough to diagnose pulmonary embolism when the post-test probability was above 85%, and that an exclusion strategy was accurate enough to exclude pulmonary embolism when the post-test probability was below 5%.3 We used Bayes's theorem to calculate the probability of pulmonary embolism, conditioned by the likelihood ratio as a function of the pretest probability.7
Results
We identified 1012 potentially eligible articles. After scanning the s and titles we screened 93 for possible retrieval. We selected 66 articles for more detailed evaluation; 48 of these were included in the final analysis (see figure on bmj.com).8-55 The studies totalled 11 004 patients with suspected pulmonary embolism. The condition was confirmed in 3329 patients and excluded in 7675 (prevalence 30%). We did not analyse studies that used electron beam computed tomography as this technique is no longer used.8 9 See tables B-D on bmj.com for characteristics of the included studies.
Confirmation diagnostic strategies
Table 1 and figure 1 summarise the confirmation diagnostic strategies and their pooled positive likelihood ratios.
Table 1 Summary of studies evaluating tests or strategies aimed at confirming pulmonary embolism
Two studies evaluated lung scintigraphy.10 11 The prospective investigation of pulmonary embolism diagnosis study assessed the performances of ventilation and perfusion lung scans.10 Miniati et al studied the value of a perfusion lung scan without ventilation.11 We were unable to pool the results of these two studies as they used different diagnostic criteria and evaluated two different techniques.
We found significant heterogeneity among the five studies on magnetic resonance angiography.24-28
Exclusion diagnostic strategies
Table 2 and figure 2 summarise the exclusion diagnostic strategies and their pooled negative likelihood ratios.
Table 2 Summary of studies evaluating tests or strategies aimed at excluding pulmonary embolism
Fig 2 Negative likelihood ratios (squares) and 95% confidence intervals for strategies used to exclude a diagnosis of pulmonary embolism. Size of square related to variance of study. Broken line represents pooled negative likelihood ratio, and limits of diamond represents 95% confidence intervals of pooled ratios
Nine studies analysed the value of a negative result on spiral computed tomography for excluding pulmonary embolism; however, one used a specific definition for negative results.37 We detected significant heterogeneity in the study group, but not in the two grade A studies.12 13
We found heterogeneity in the group of ultrasonography studies. Five of the six studies were carried out in patients with a non-diagnostic ventilation and perfusion lung scan and one in patients selected on the basis of clinical probability and D-dimer testing.18-21 42 43 Wells et al studied the negative diagnostic value of serial ultrasonography after a non-diagnostic ventilation and perfusion lung scan.44
Table 2 and figure 3 summarise the studies that evaluated D-dimers for the exclusion of pulmonary embolism (see also table D on bmj.com). In the analysis we included 12 studies that evaluated three different quantitative D-dimer enzyme linked immunosorbent assays, including two classic microplate methods45-50 53 and one rapid quantitative method.34 41 43 51 52 One study used a different cut-off threshold so we excluded it from the calculation of summary negative likelihood ratios.53 We detected significant heterogeneity in the study group, but we found no heterogeneity in the grade B 34 41 45 46 or grade C studies.43 47-52
Fig 3 Negative likelihood ratios (squares) and 95% confidence intervals for strategies used to exclude a diagnosis of pulmonary embolism on basis of D-dimer tests. Size of square is related to variance of study. Broken line represents pooled negative likelihood ratio, and limits of diamond represent 95% confidence interval of pooled negative likelihood ratio
Studies that used seven different quantitative D-dimer latex agglutination assays met our inclusion criteria.13 36 49 50 53 55 Two studies evaluated several latex D-dimer tests in the same patients so we excluded them from the calculation of summary negative likelihood ratios.49 50 One study used a different cut-off value so we excluded that from the calculation of the summary negative likelihood ratios too.53 Three studies could be pooled.13 36 55
Two studies that evaluated a semiquantitative agglutination latex assay had significant heterogeneity.49 54 A whole blood agglutination D-dimer assay was evaluated in three studies, with no significant heterogeneity.31 35 51
Clinical practice perspectives
For each strategy we calculated the post-test probability as a function of the pretest probability (figs 4 and 5). For each diagnostic strategy we express the accuracy of diagnostic decisions as a function of the pretest probability (fig 6).
Fig 4 Post-test probability according to pre-test probability and pooled values (solid line) or limits of 95% confidence intervals (broken lines) of the positive likelihood ratio
Fig 5 Post-test probability according to pre-test probability and pooled values (solid line) or limit of 95% confidence intervals (broken lines) of the negative likelihood ratio
Fig 6 Diagnostic tests for pulmonary embolism that allow accurate exclusion (post-test probability <5%) and accurate confirmation of the condition (post-test probability >85%) for three levels of clinical probability. Pulmonary angiography is reference method and is supposed to rule in or rule out pulmonary embolism for all values of clinical probability
Relation to pretest probability
Confirmation of pulmonary embolism
In patients with a high pretest probability; a positive result with spiral computed tomography, ultrasonography, echocardiography, or magnetic resonance angiography; or a high probability ventilation perfusion lung scan are associated with a post-test probability of over 85%, allowing pulmonary embolism to be accurately diagnosed. Patients with a moderate pretest probability require additional imaging after a positive echocardiography result. In patients with a low pretest probability, the post-test probability was below 85% for all tests and therefore further investigations would be needed to confirm pulmonary embolism (fig 6).
Exclusion of pulmonary embolism
In patients with a low clinical probability; negative test results for D-dimers or with spiral computed tomography or magnetic resonance angiography; or a normal or low probability lung scan are associated with a post-test probability of below 5%. In this situation, additional testing would not be needed to rule out pulmonary embolism. Conversely, patients with a negative echocardiography result and a normal venous ultrasonography result would require additional testing to rule out pulmonary embolism, even when the clinical probability was low. In patients with a moderate pretest probability, a negative quantitative D-dimer enzyme linked immunosorbent assay result, a normal or near normal lung scan, or a combination of normal spiral computed tomography results and normal venous ultrasonography results accurately exclude pulmonary embolism. In patients with a high pretest probability, the residual post-test probability remained above 5% for all diagnostic tests (fig 6). In these patients, additional testing would be required to confidently exclude pulmonary embolism.
Discussion
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Correspondence to: G Meyer, Service de Pneumologie-soins intensifs, H?pital Européen Georges Pompidou, 20 rue Leblanc, 75015 Paris, France guy.meyer@hop.egp.ap-hop-paris.fr
Objectives To assess the likelihood ratios of diagnostic strategies for pulmonary embolism and to determine their clinical application according to pretest probability.
Data sources Medline, Embase, and Pascal Biomed and manual search for articles published from January 1990 to September 2003.
Study selection Studies that evaluated diagnostic tests for confirmation or exclusion of pulmonary embolism.
Data extracted Positive likelihood ratios for strategies that confirmed a diagnosis of pulmonary embolism and negative likelihood ratios for diagnostic strategies that excluded a diagnosis of pulmonary embolism.
Data synthesis 48 of 1012 articles were included. Positive likelihood ratios for diagnostic tests were: high probability ventilation perfusion lung scan 18.3 (95% confidence interval 10.3 to 32.5), spiral computed tomography 24.1 (12.4 to 46.7), and ultrasonography of leg veins 16.2 (5.6 to 46.7). In patients with a moderate or high pretest probability, these findings are associated with a greater than 85% post-test probability of pulmonary embolism. Negative likelihood ratios were: normal or near normal appearance on lung scan 0.05 (0.03 to 0.10), a negative result on spiral computed tomography along with a negative result on ultrasonography 0.04 (0.03 to 0.06), and a D-dimer concentration < 500 μg/l measured by quantitative enzyme linked immunosorbent assay 0.08 (0.04 to 0.18). In patients with a low or moderate pretest probability, these findings were associated with a post-test probability of pulmonary embolism below 5%. Spiral computed tomography alone, a low probability ventilation perfusion lung scan, magnetic resonance angiography, a quantitative latex D-dimer test, and haemagglutination D-dimers had higher negative likelihood ratios and can therefore only exclude pulmonary embolism in patients with a low pretest probability.
Conclusions The accuracy of tests for suspected pulmonary embolism varies greatly, but it is possible to estimate the range of pretest probabilities over which each test or strategy can confirm or rule out pulmonary embolism.
Pulmonary embolism is a common and serious disease. Clinical signs and symptoms allow the clinician to determine the pretest probability of someone having pulmonary embolism (the clinical probability) but are insufficient to diagnose or rule out the condition.1 Laboratory tests and imaging are thus required in all patients with suspected pulmonary embolism.2 Since 1990 a large number of diagnostic tests and strategies have been evaluated for pulmonary embolism. As the design, clinical setting, and reference methods differ between studies, the diagnostic value of most tests may seem inconsistent. Although several reviews have been published on this topic,1-3 systematic reviews that may clarify the role of the different diagnostic tests are lacking.
We carried out a systematic review to assess the likelihood ratios of the diagnostic tests used for suspected pulmonary embolism. For clinical purposes, we estimated the range of pretest probabilities over which each test can accurately confirm or exclude pulmonary embolism.
Materials and methods
We searched Medline, Embase, and Pascal Biomed for studies published from January 1990 to September 2003 using the search terms ((pulmonary embol* or pulmonary thromboembol*) and (diagnosis or diagnostic) and (angiography or arteriography or (follow adj up) or followup or (management adj stud*)) and (PY = 1990-2003) and (study or studies or trial) and (LA = ENGLISH). We also manually searched published bibliographies and our own personal libraries. We retained only studies published in English. We excluded s, editorials, reviews, case reports, and case series.
Data selection
Two reviewers (PMR, GM) independently selected potentially relevant studies. Studies were included if they evaluated tests or strategies aimed at confirming or excluding pulmonary embolism (confirmation or exclusion diagnostic strategies, respectively) and they met the following criteria: the reference method was pulmonary angiography for confirmation strategies and clinical follow-up or pulmonary angiography for exclusion strategies; the study was prospective; participants were recruited consecutively; and the test being evaluated and the reference test were interpreted independently.
We excluded retrospective studies; follow-up studies with more than 5% of patients lost to follow-up or those that used additional imaging to pulmonary angiography in patients with a negative experimental test result; studies in which crude data could not be extracted for the calculation of positive and negative likelihood ratios; and studies that had specific populations. Each study was graded according to the reference method and the characteristics of the patients (see table A on bmj.com). For studies with multiple publications, we used data from the most recent publication.
Data extraction
Two investigators (PMR, GM) independently ed data on the design; study size; setting; characteristics of the patients; type of reference standard; and the number of true positive, true negative, false positive, and false negative test results.
When we used follow-up as the reference method, we considered all the patients with a negative test result to have a false negative result if they developed deep vein thrombosis or pulmonary embolism during the three month follow-up period. We classified deaths believed to be caused by pulmonary embolism as thromboembolic events. When we could not extract data from published articles, we contacted the authors. Discrepancies in data ion between investigators were resolved by a third author (PD).
Fig 1 Positive likelihood ratios (squares) and 95% confidence intervals for strategies used to confirm a diagnosis of pulmonary embolism. Size of square is related to variance of study. Broken line represents pooled positive likelihood ratio, and limits of diamond represents 95% confidence intervals of pooled ratios
Statistical analysis
We calculated the positive likelihood ratio for confirmation diagnostic strategies and the negative likelihood ratio for exclusion diagnostic strategies. We used the adjusted Wald method to calculate 95% confidence intervals.4 Summary estimates of the likelihood ratios were calculated as a weighted average, and we calculated the confidence intervals using the DerSimonian and Laird random effects method.5 Homogeneity tests were carried out to evaluate the consistency of findings across the studies. We used Cochran's Q heterogeneity statistic and the quantity I2 to determine the percentage of total variation across the studies due to heterogeneity rather than to chance.6 When I2 was more than 0%, we explored possible reasons for heterogeneity, such as patient populations (selected or unselected patients) and the nature of the reference method (angiography or composite reference standard), using subgroup analysis based on the three categories for study quality (see table A on bmj.com).
Analyses were carried out in STATA (release 6).
Clinical practice perspectives
We considered that a confirmation strategy was accurate enough to diagnose pulmonary embolism when the post-test probability was above 85%, and that an exclusion strategy was accurate enough to exclude pulmonary embolism when the post-test probability was below 5%.3 We used Bayes's theorem to calculate the probability of pulmonary embolism, conditioned by the likelihood ratio as a function of the pretest probability.7
Results
We identified 1012 potentially eligible articles. After scanning the s and titles we screened 93 for possible retrieval. We selected 66 articles for more detailed evaluation; 48 of these were included in the final analysis (see figure on bmj.com).8-55 The studies totalled 11 004 patients with suspected pulmonary embolism. The condition was confirmed in 3329 patients and excluded in 7675 (prevalence 30%). We did not analyse studies that used electron beam computed tomography as this technique is no longer used.8 9 See tables B-D on bmj.com for characteristics of the included studies.
Confirmation diagnostic strategies
Table 1 and figure 1 summarise the confirmation diagnostic strategies and their pooled positive likelihood ratios.
Table 1 Summary of studies evaluating tests or strategies aimed at confirming pulmonary embolism
Two studies evaluated lung scintigraphy.10 11 The prospective investigation of pulmonary embolism diagnosis study assessed the performances of ventilation and perfusion lung scans.10 Miniati et al studied the value of a perfusion lung scan without ventilation.11 We were unable to pool the results of these two studies as they used different diagnostic criteria and evaluated two different techniques.
We found significant heterogeneity among the five studies on magnetic resonance angiography.24-28
Exclusion diagnostic strategies
Table 2 and figure 2 summarise the exclusion diagnostic strategies and their pooled negative likelihood ratios.
Table 2 Summary of studies evaluating tests or strategies aimed at excluding pulmonary embolism
Fig 2 Negative likelihood ratios (squares) and 95% confidence intervals for strategies used to exclude a diagnosis of pulmonary embolism. Size of square related to variance of study. Broken line represents pooled negative likelihood ratio, and limits of diamond represents 95% confidence intervals of pooled ratios
Nine studies analysed the value of a negative result on spiral computed tomography for excluding pulmonary embolism; however, one used a specific definition for negative results.37 We detected significant heterogeneity in the study group, but not in the two grade A studies.12 13
We found heterogeneity in the group of ultrasonography studies. Five of the six studies were carried out in patients with a non-diagnostic ventilation and perfusion lung scan and one in patients selected on the basis of clinical probability and D-dimer testing.18-21 42 43 Wells et al studied the negative diagnostic value of serial ultrasonography after a non-diagnostic ventilation and perfusion lung scan.44
Table 2 and figure 3 summarise the studies that evaluated D-dimers for the exclusion of pulmonary embolism (see also table D on bmj.com). In the analysis we included 12 studies that evaluated three different quantitative D-dimer enzyme linked immunosorbent assays, including two classic microplate methods45-50 53 and one rapid quantitative method.34 41 43 51 52 One study used a different cut-off threshold so we excluded it from the calculation of summary negative likelihood ratios.53 We detected significant heterogeneity in the study group, but we found no heterogeneity in the grade B 34 41 45 46 or grade C studies.43 47-52
Fig 3 Negative likelihood ratios (squares) and 95% confidence intervals for strategies used to exclude a diagnosis of pulmonary embolism on basis of D-dimer tests. Size of square is related to variance of study. Broken line represents pooled negative likelihood ratio, and limits of diamond represent 95% confidence interval of pooled negative likelihood ratio
Studies that used seven different quantitative D-dimer latex agglutination assays met our inclusion criteria.13 36 49 50 53 55 Two studies evaluated several latex D-dimer tests in the same patients so we excluded them from the calculation of summary negative likelihood ratios.49 50 One study used a different cut-off value so we excluded that from the calculation of the summary negative likelihood ratios too.53 Three studies could be pooled.13 36 55
Two studies that evaluated a semiquantitative agglutination latex assay had significant heterogeneity.49 54 A whole blood agglutination D-dimer assay was evaluated in three studies, with no significant heterogeneity.31 35 51
Clinical practice perspectives
For each strategy we calculated the post-test probability as a function of the pretest probability (figs 4 and 5). For each diagnostic strategy we express the accuracy of diagnostic decisions as a function of the pretest probability (fig 6).
Fig 4 Post-test probability according to pre-test probability and pooled values (solid line) or limits of 95% confidence intervals (broken lines) of the positive likelihood ratio
Fig 5 Post-test probability according to pre-test probability and pooled values (solid line) or limit of 95% confidence intervals (broken lines) of the negative likelihood ratio
Fig 6 Diagnostic tests for pulmonary embolism that allow accurate exclusion (post-test probability <5%) and accurate confirmation of the condition (post-test probability >85%) for three levels of clinical probability. Pulmonary angiography is reference method and is supposed to rule in or rule out pulmonary embolism for all values of clinical probability
Relation to pretest probability
Confirmation of pulmonary embolism
In patients with a high pretest probability; a positive result with spiral computed tomography, ultrasonography, echocardiography, or magnetic resonance angiography; or a high probability ventilation perfusion lung scan are associated with a post-test probability of over 85%, allowing pulmonary embolism to be accurately diagnosed. Patients with a moderate pretest probability require additional imaging after a positive echocardiography result. In patients with a low pretest probability, the post-test probability was below 85% for all tests and therefore further investigations would be needed to confirm pulmonary embolism (fig 6).
Exclusion of pulmonary embolism
In patients with a low clinical probability; negative test results for D-dimers or with spiral computed tomography or magnetic resonance angiography; or a normal or low probability lung scan are associated with a post-test probability of below 5%. In this situation, additional testing would not be needed to rule out pulmonary embolism. Conversely, patients with a negative echocardiography result and a normal venous ultrasonography result would require additional testing to rule out pulmonary embolism, even when the clinical probability was low. In patients with a moderate pretest probability, a negative quantitative D-dimer enzyme linked immunosorbent assay result, a normal or near normal lung scan, or a combination of normal spiral computed tomography results and normal venous ultrasonography results accurately exclude pulmonary embolism. In patients with a high pretest probability, the residual post-test probability remained above 5% for all diagnostic tests (fig 6). In these patients, additional testing would be required to confidently exclude pulmonary embolism.
Discussion
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