|A systematic review of the literature examining the diagnostic efficacy of measurement of fractionated plasma free metanephrines in the biochemical diagnosis of pheochromocytoma
|Sawka A M, Prebtani A P, Thabane L, Gafni A, Levine M, Young W F
This review assessed the diagnostic accuracy of fractionated plasma free metanephrine measurements in the diagnosis of pheochromocytoma. The review concluded that a negative test result is effective in ruling out pheochromocytoma whereas a positive test result only moderately increases suspicion, particularly in low-risk individuals. The review was well conducted and the authors' conclusions appear reliable. However, only three studies were included.
To determine the diagnostic accuracy of measurements of fractionated plasma metanephrines for the detection of pheochromocytoma (adrenal pheochromocytomas and extra-adrenal paragangliomas).
MEDLINE (from 1989 to February 2003), the Cochrane Database of Systematic Reviews, ACP Journal Club (from September 1991 to October 2002), DARE, a controlled clinical trials database, Cancerlit (from 1975 to 2002), HealthSTAR (from 1975 to December 2002) and CINAHL (from 1982 to February 2003) were searched. No language restrictions were applied and the search terms were reported in full in the article. In addition, ISI Web of Science was searched for any study citing the Lenders methodological article, and abstract books of the 82nd to 84th annual meetings of the Endocrine Society (from 2000 to 2002) were handsearched. The authors also included updated unpublished data provided by study authors.
Study designs of evaluations included in the review
The studies had to include a minimum of 10 patients with and 10 participants without pheochromocytoma and also report a 'Methods' section to be eligible for inclusion. Prospective and retrospective studies were included.
Specific interventions included in the review
Studies evaluating the measurement of fractionated plasma free metanephrines using the Lenders method (see Other Publications of Related Interest no.1) for the purpose of diagnostic testing were eligible for inclusion. Plasma metanephrine measurements conducted in clonidine-suppression or glucagon-stimulation tests were excluded.
The upper limit of a laboratory reference range was used to define a positive test. For a test to be considered positive, either a free metanephrine or a free normetanephrine fraction value had to be above the reference range.
Reference standard test against which the new test was compared
No inclusion criteria for the reference standard were specified. Two of the three included studies used histology to confirm pheochromocytoma in patients testing positive; in one of these studies patients testing negative also received histological testing, while in the other such patients were subject to alternative diagnostic investigations. In the remaining included study, patients testing positive received histology or imaging investigations and those testing negative received imaging, pathological examination or 2 years of follow-up.
Participants included in the review
Studies of adults were eligible for inclusion. Studies in which more than one third of participants were under 18 years, or which focused on end-stage renal disease, were excluded. The studies were required to include a minimum of 10 participants with pheochromocytoma (or paraganglioma) and 10 participants without this diagnosis. The characteristics of the participants without pheochromocytoma varied between studies: in one study the majority of participants without pheochromocytoma had a genetic predisposition to the disease, whilst in another study all patients without pheochromocytoma had an adrenal abnormality.
Outcomes assessed in the review
The studies had to report new data on the sensitivity and specificity of fractionated plasma metanephrine measurements to be included in the review. The review reported 2x2 data, sensitivity, specificity, and positive and negative likelihood ratios (LRs), along with 95% confidence intervals (CIs), for each included study.
How were decisions on the relevance of primary studies made?
Two reviewers independently screened titles and abstracts obtained from the search, and all articles deemed potentially relevant by either were retrieved. Both reviewers agreed on studies to be included after a review of the full-text articles.
Assessment of study quality
The quality of the reporting of the included studies was assessed against the Standards for the Reporting of Diagnostic Accuracy Studies (STARD) guidelines (see Other Publications of Related Interest no.2). Some of the elements of methodological quality assessed were: use of an appropriate spectrum of participants; blinded interpretation of the test results; consecutive participant recruitment; prospective or retrospective data collection; universal application of the reference standard; and use of the index text result to determine application of the reference standard. Two reviewers independently assessed methodological and reporting quality. A kappa statistic was calculated to measure agreement between the two reviewers.
Two reviewers independently extracted data from the included studies in duplicate, and the final data used were determined by consensus. LRs were calculated for each study. Ninety-five per cent CIs were calculated using Wilson's method. When the LRs included a zero cell, the score method was used to calculate 95% CIs.
Methods of synthesis
How were the studies combined?
The LRs were pooled using a random-effects model. The authors attempted to construct a funnel plot to assess publication bias.
How were differences between studies investigated?
The chi-squared test (Q statistic) was used to assess between-study heterogeneity. Separate analyses were performed for all pheochromocytomas and for sporadic pheochromocytomas (those without genetic predisposition).
Results of the review
Three studies were included in the review: one prospective, one retrospective and one unknown.
Methodological limitations were noted in all studies: no study had blinded interpretation of the test results, consecutive recruitment was reported in only one study, and in only one other study was a histological reference standard applied universally to all participants. The kappa statistic, measuring agreement between reviewers on the assessment of methodological quality, ranged from 0.60 to 0.82 across the included studies.
The sensitivity ranged from 96% (specificity 85%) to 100% (specificity 100%) and the specificity from 85% (sensitivity 96%) to 100% (sensitivity 100%). The pooled positive LR was 7.86 (95% CI: 5.17, 11.94) and the pooled negative LR was 0.02 (95% CI 0.01, 0.04). Significant between-study heterogeneity was observed for the positive LRs (P=0.017).
The sensitivity ranged from 97% (specificity 84%) to 100% (specificity 100%) and the specificity from 82% (sensitivity 99%) to 100% (sensitivity 100%). The pooled positive LR was 5.82 (95% CI: 4.81, 7.05) and the pooled negative LR ratio was 0.02 (95% CI 0.01, 0.07). No significant between-study heterogeneity was observed.
The funnel plot was uninterpretable because of the small number of included studies and, therefore, the presence of publication bias could not be assessed.
A negative plasma fractionated free metanephrine result is effective in ruling out pheochromocytoma, while a positive test result only moderately increases suspicion of disease, particularly when testing for sporadic pheochromocytoma.
This review addressed a clearly stated question, which was further defined by appropriate inclusion criteria. A thorough literature search, with no language restrictions, was conducted and reported, and an attempt was made to assess publication bias using a funnel plot. However, the funnel plot was uninterpretable because of the small number of studies identified and, therefore, it was not possible to assess publication bias. Attempts to identify unpublished data were limited. The methodological quality of the included studies was assessed using appropriate criteria for diagnostic studies. The review methodology was clearly reported, and appropriate measures were taken to minimise the introduction of error or reviewer bias.
Sufficient detail of the included studies, as well as methodological limitations, was reported in the text. In addition, limitations of the review itself were fully discussed. Despite the inclusion of only three studies, the methods used to generate pooled estimates of diagnostic outcome measures were appropriate and clearly reported. The authors' conclusions follow from the results presented.
Implications of the review for practice and research
Practice: The authors stated that clinicians should assess the relative likelihood of pheochromocytoma in each case, in order to determine whether or not to test. A positive test result in a high-risk individual (e.g. genetically pre-disposed or with known adrenal mass characteristic of pheochromocytoma), or a negative test result in a low-risk individual (e.g. patient with refractory hypertension), is useful for ruling in or ruling out disease, respectively. However, a negative result in a high-risk individual or a positive result in a low-risk individual should be interpreted with caution.
Research: The authors stated that research to validate newer assays (e.g. liquid chromatography with tandem mass spectrometry) in clinical patient populations is needed.
Sawka A M, Prebtani A P, Thabane L, Gafni A, Levine M, Young W F. A systematic review of the literature examining the diagnostic efficacy of measurement of fractionated plasma free metanephrines in the biochemical diagnosis of pheochromocytoma. BMC Endocrine Disorders 2004; 4:2
Other publications of related interest
1. Lenders JW, Eisenhofer G, Armando I, Keiser HR, Goldstein DS, Kopin IJ. Determination of metanephrines in plasma by liquid chromatography within electrochemical detection. Clin Chem 1993;39:97-103. 2. Bossuyt PM, Reitsma JB, Bruns DE, Gatsonis CA, Glasziou PP, Irwig LM, et al. Towards complete and accurate reporting of studies of diagnostic accuracy: the STARD Initiative. Ann Intern Med 2003;138:40-4.
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This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.