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Background: Transcranial Doppler ultrasound (TCD) and magnetic resonance angiography (MRA) can identify intracranial atherosclerosis but have not been rigorously validated against the gold standard, catheter angiography. The WASID trial (Warfarin Aspirin Symptomatic Intracranial Disease) required performance of angiography to verify the presence of intracranial stenosis, allowing for prospective evaluation of TCD and MRA. The aims of Stroke Outcomes and Neuroimaging of Intracranial Atherosclerosis (SONIA) trial were to define abnormalities on TCD/MRA to see how well they identify 50 to 99% intracranial stenosis of large proximal arteries on catheter angiography.
Study Design: SONIA standardized the performance and interpretation of TCD, MRA, and angiography. Study-wide cutpoints defining positive TCD/MRA were used. Hard copy TCD/MRA were centrally read, blind to the results of angiography.
Results: SONIA enrolled 407 patients at 46 sites in the United States. For prospectively tested noninvasive test cutpoints, positive predictive values (PPVs) and negative predictive values (NPVs) were TCD, PPV 36% (95% CI: 27 to 46); NPV, 86% (95% CI: 81 to 89); MRA, PPV 59% (95% CI: 54 to 65); NPV, 91% (95% CI: 89 to 93). For cutpoints modified to maximize PPV, they were TCD, PPV 50% (95% CI: 36 to 64), NPV 85% (95% CI: 81 to 88); MRA PPV 66% (95% CI: 58 to 73), NPV 87% (95% CI: 85 to 89). For each test, a characteristic performance curve showing how the predictive values vary with a changing test cutpoint was obtained.
Conclusions: Both transcranial Doppler ultrasound and magnetic resonance angiography noninvasively identify 50 to 99% intracranial large vessel stenoses with substantial negative predictive value. The Stroke Outcomes and Neuroimaging of Intracranial Atherosclerosis trial methods allow transcranial Doppler ultrasound and magnetic resonance angiography to reliably exclude the presence of intracranial stenosis. Abnormal findings on transcranial Doppler ultrasound or magnetic resonance angiography require a confirmatory test such as angiography to reliably identify stenosis.

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Letters to the Editor
25 November 2007
Reply from the authors
Edward Feldmann, MD, Brown University School of Medicine
On behalf of the SONIA Steering Committee and the SONIA Investigators.

We thank Martí-Fàbregas et al for their comments on our publication of the SONIA trial.

We agree that the positive predictive value was much lower than the negative predictive value for MRA and TCD identification of intracranial stenosis. The word "disappointingly" may not be appropriate in this setting. Positive predictive value is proportional to the prevalence of disease. The prevalence of intracranial atherosclerosis in the population we evaluated was relatively low, thereby setting the stage for the detection of a low positive predictive value. Clearly, low positive predictive value does not obviate the utility of the tests as they appear to reliably exclude disease and function as excellent screening tests.

We agree that requiring two noninvasive tests as abnormal might increase positive predictive value. We specifically excluded this approach in the SONIA trial as it would have introduced bias into our results. It was our impression that without complete control of ordering a diagnostic test, local investigators would be substantially more likely to order a second noninvasive test in patients whose first noninvasive test was positive. Therefore, this would bias the sample and not provide an appropriate forum for assessing how noninvasive test combinations perform. An additional reason for not considering the combination of two tests is because of the unblinding that may occur in the performance of the second test.

We agree that the timing of test performance may be important because of recanalization of emboli leading to false positive results. We will re-analyze our data in this regard and see if the time of testing had an effect on positive predictive value. We will analyze only noninvasive tests performed after one week after the onset of symptoms.

We suspect that given the way patients are typically evaluated at the sites in the SONIA trial, however, the sample size would likely be small as most patients are tested rather quickly after the onset of symptoms.

Disclosure: Some or all of the authors have given expert testimony related to the subject of the article to which this correspondence refers.

25 November 2007
The Stroke Outcomes and Neuroimaging of Intracranial Atherosclerosis (SONIA) Trial
Joan Martí-Fàbregas, Department of Neurology, Hospital de la Santa Creu i Sant Pau
Sergi Martínez-Ramírez, Josep-Lluis Martí-Vilalta

We congratulate Feldmann et al. on their study concerning the Stroke Outcomes and Neuroimaging of Intracranial Atherosclerosis (SONIA) trial. [1] Although the negative predictive value (NPV) for the Magnetic Resonance Angiography (MRA) and Transcranial Doppler (TCD) were high (91% for MRA and 86% for TCD), the positive predictive value (PPV) for both tests were disappointingly low (59% and 36%, respectively).

We conducted a trial comparing aspirin to anticoagulants in the prevention of vascular events in patients with symptomatic stenosis of the middle cerebral artery (MCA). [2] We included patients only when two of the three non-invasive (MRA, TCD or CT- angiography) tests indicated the diagnosis of MCA stenosis greater than 50%. We think it would be beneficial to re-analyze the SONIA data comparing the diagnostic results of MRA and TCD with conventional angiography when both non-invasive tests are abnormal (both of them instead of anyone of them). We believe this would provide higher and more reliable PPV.

In addition, when the tests are performed is important. In our study, to minimize the risk of misdiagnosing a MCA stenosis instead of a recanalizing embolus, we accepted the abnormal results only when they were obtained a minimum of seven days after the onset of stroke.

We would like to know when the tests of the SONIA study were obtained. If the results were obtained within a few days after stroke, this could be a source of misclassification. To improve the PPV, it seems prudent to exclude patients in whom the tests were obtained within the first week after the onset of symptoms.


1. Feldmann E, Wilterdink JL, Kosinski A, et al. The stroke outcomes and neuroimaging of intracranial atherosclerosis (sonia) trial. Neurology 2007;68:2099-2106.

2. Marti-Fabregas J, Cocho D, Marti-Vilalta JL, et al. Aspirin or anticoagulants in stenosis of the middle cerebral artery: A randomized trial. Cerebrovasc Dis. 2006;22:162-169.

Disclosure: The authors report no conflicts of interest.

Information & Authors


Published In

Volume 68Number 24June 12, 2007
Pages: 2099-2106
PubMed: 17409371

Publication History

Published online: April 4, 2007
Published in print: June 12, 2007


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Affiliations & Disclosures

M. I. Chimowitz, MB, ChB
The Stroke Outcomes and Neuroimaging of Intracranial Atherosclerosis (SONIA) Trial Investigators


Address correspondence and reprint requests to Dr. Edward Feldmann Department of Clinical Neurosciences, Brown University School of Medicine, 110 Lockwood Street, Suite 324, Providence, RI 02903 [email protected]

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