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Stroke. 2008;39:2902-2909
Published online before print July 24, 2008, doi: 10.1161/STROKEAHA.107.511261
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(Stroke. 2008;39:2902.)
© 2008 American Heart Association, Inc.

Progress Review

Blood Biomarkers in the Diagnosis of Ischemic Stroke

A Systematic Review

William Whiteley, MRCP; Mei-Chiun Tseng, PhD Peter Sandercock, FRCPE

From the Division of Clinical Neurosciences (W.N.W., P.S.), University of Edinburgh, UK; and National Sun Yat-Sen University (M.-C.T.), Taiwan.

Correspondence to W.N. Whiteley, MRCP, Department of Clinical Neurosciences, Western General Hospital, Edinburgh EH4 2XU, UK. E-mail william.whiteley{at}ed.ac.uk


*    Abstract
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Background and Purpose— The diagnosis of ischemic stroke can be difficult. CT may be normal in the early stages of ischemic stroke or in patients with minor symptoms and MR is not always possible. Many blood markers have been proposed for the diagnosis of stroke in the acute setting.

Methods and Results— We have systematically reviewed the diagnostic literature and found 21 studies testing 58 single biomarkers and 7 panels of several biomarkers. Although all show either a high sensitivity or specificity, there are limitations in the design and reporting of all the studies that mean no biomarker can be recommended for use in clinical practice.

Conclusions— We make recommendations for the design and reporting of studies of diagnostic blood biomarkers in stroke.


Key Words: biomarker • stroke • hemorrhagic stroke • ischemic stroke • diagnosis


*    Introduction
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A rapid blood test to confirm a clinical and imaging diagnosis of ischemic stroke (or to aid risk stratification in confirmed cases), based on a simple and low-cost near-patient technology, would be extremely useful. At the moment, the diagnosis of ischemic stroke is based on an experienced stroke clinician’s examination of the patient, supplemented by the results of brain imaging. However, in people who suddenly become unwell with a suspected stroke, the clinical assessment within the first hours is not always straightforward. Many patients with acute stroke are not assessed by a stroke specialist; the initial evaluation is often performed by a family practitioner, paramedic, or triage nurse. For those assessed in hospital, interpretation of brain imaging appearances can be difficult, as computerized tomography (CT) is often normal after the onset of ischemia and may remain normal in patients with mild ischemic strokes. MRI, though undoubtedly more sensitive in detecting ischemia than CT, especially in the diagnosis of mild stroke,1 is still not 100% sensitive or specific. MRI may not be feasible in acutely ill patients because they are restless, have a contraindication to MRI, or MRI may not be immediately available.

Achieving an accurate diagnosis quickly in patients with suspected acute stroke is extremely important. Patients with ischemic stroke, even with relatively mild symptoms, may be eligible for intravenous thrombolysis or other means of brain reperfusion if treatment can be started within a few hours of symptom onset. Patients who are not suitable for such acute treatments are at risk of early recurrent stroke; 8% of high risk patients have a recurrent stroke within the first 2 days.2 Prompt initiation of secondary preventative treatment can substantially reduce the risk of further stroke.

The development of blood biomarkers for ischemic stroke faces difficulties. The blood-brain barrier slows the release of brain tissue proteins into blood after stroke, delaying the release of glial and neuronal proteins. Many potential blood markers of cerebral ischemia and inflammation are found in other conditions that may mimic stroke, such as severe myocardial infarction and brain infection. Also, the volume of damaged tissue may not correlate with disability; small volumes of tissue damaged by ischemia in an "eloquent" area of the brain may lead to a more disabling deficit than a large volume of brain damaged by stroke in another part of the brain.

There has been a substantial investment in translational medical research programs to discover new diagnostic markers. We therefore felt that a systematic review of published reports to assess the accuracy of blood markers for the diagnosis of ischemic stroke was both relevant and timely. We aimed to describe the methodological quality of the studies, to compare the accuracy of diagnostic markers, and assess the extent to which methodological weaknesses might have biased diagnostic test accuracy.


*    Methods
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 *Methods
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Study Identification
We searched Medline and EMBASE from 1966 to March 15, 2007 for all studies of the use of diagnostic blood biomarkers in stroke. We maximized retrieval by searching using both generic biomarker terms and individual biomarkers (and their synonyms) obtained from a previous search of the literature.3–6 The search strategy included 13 terms for ischemic stroke, 4 for generic biomarkers, and 780 specific biomarker terms. Diagnostic studies were identified by searching for the words "sensitivity," "specificity," "likelihood ratio," or "diagnosis" in the title or abstract and keywords. The full search strategy is listed in the supplemental materials (available online at http://stroke.ahajournals.org). The search was not restricted by language.

We searched the reference lists of relevant papers, conference abstract books and our personal files. We also searched the internet for patents (using www.freepatentsonline.com and www.google.com) and papers citing each relevant paper with the Google Scholar tool (http://scholar.google.com/).

Studies were eligible for inclusion if they examined the ability of a single or several venous blood (not CSF) markers to discriminate between patients with ischemic stroke and a group without stroke (either controls without disease, stroke mimics, or other neurological diseases), or between ischemic and hemorrhagic stroke, where a cutoff value for the test had been calculated (or arbitrarily set) and there was sufficient information to fill a 2x2 contingency table. There was no minimum sample size for study inclusion. Both conference abstracts and published articles were included.

Data Extraction
Two authors (W.W. and M.T.) reviewed the list of titles and abstracts of potentially relevant articles independently; we then obtained full copies of articles meeting our eligibility criteria, and 2 authors independently extracted data from the eligible papers. Any disagreements were resolved by discussion. We assessed the quality of the study reports with a modified QUADAS instrument7 (web supplement). Where more than one cohort was examined within a study, the results for each cohort were extracted separately.

Statistical Analysis
We calculated 95% confidence intervals for the estimates of sensitivity and specificity in each cohort.8 We made no attempt to assess for publication bias, although this probably exists, as there are currently no well established methods to assess the scale and direction of this form of bias in studies of diagnostic test accuracy.9


*    Results
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The MEDLINE/Embase search identified 3093 studies. A further 8 were found through reading conference reports and the reference lists of relevant articles. All the abstracts were read, and 70 publications were read in full. Twenty-one publications were relevant to the review—6 conference abstracts10–15 and 15 articles16–30 (supplemental materials).

Methodological Assessment
We used a modified QUADAS instrument to assess the quality of the reports of diagnostic biomarkers. The performance of blood biomarkers was examined in patients with suspected stroke—the clinical scenario for any stroke test—in 4/21 studies.14,25,27,31 The remaining studies compared cohorts of patients with a diagnosis of stroke with a control group. The sensitivity and sensitivity of a biomarker with a prespecified threshold for a positive test was examined in 6/2114,16,21,23,24,29 studies. The remainder derived a diagnostic threshold cut-off value from the cohort examined. Of the 15 studies that used a data-dependent cutoff, none validated the sensitivity estimates in a separate cohort. Only 2/2120,22 studies reported that the assessment of biomarker diagnostic accuracy was performed blinded to stroke status. All diagnoses of stroke appeared to be blinded to biomarker status.

The clinical comparisons in each study were different. Some studies classified TIA as an acute ischemic stroke10,15,17–19,30 though others did not.16,25,27 However the number of patients symptomatic at the time blood was drawn was not defined, and there were no explicit means of measuring recovery at 24 hours. Most studies classified a patient as having a definite ischemic stroke only if they had both appropriate symptoms and a visible appropriate lesion on imaging, even though it is well recognized that many patients with definite stroke can have initially normal neuroimaging. Six studies classified subarachnoid hemorrhage (which generally has a very different clinical presentation to acute stroke) as a hemorrhagic stroke15,17–19,28 though most did not. Only one study14 examined a cohort of suspected stroke patients, and compared the performance of a panel of biomarkers to another assessment method (in this case a triage nurse)—both performed with a similar sensitivity and specificity.

Nine studies16,18–20,23,25–27,30 reported the delay between symptom onset and blood taking for biomarkers—the range was between 30 minutes and 5 days after stroke. Four16,23,25,26 only examined diagnostic performance within the first 24 hours of symptom onset. One study27 reported the sensitivity of a biomarker panel for a diagnosis of stroke at different time points, though there was no clear relationship between the delay to blood taking and sensitivity.

Markers Measured
The 21 studies tested 58 single biomarkers and 7 panels made up of several markers. The exact number of cohorts, and therefore the total number of patients involved, is difficult to calculate as some studies examine part cohorts from other studies included in the review (supplemental materials). The estimated upper limit is 2928 stroke patients and 1569 controls in 24 cohorts. There was sufficient information to extract 2x2 tables on 21 markers for the diagnosis of ischemic stroke versus not stroke or control (Figure 1). Of these markers, 5 had reported sensitivities over 90% (NDKA, PARK7, UFD-1, NMDA receptor [NR] 2 fragment, NR2A/B antibodies), and 14 had a specificity more than 90% (PARK 7/ RNA-BP, UFDP, NDKA, GSTP, ischemia modified albumin [IMA], visin like protein [VLP-1], beta globin DNA, NR2 fragments, S100 beta, FABP, neurone specific enolase [NSE], NR2A/2B Ab, myelin basic protein [MBP], and thrombomodulin). For 5 biomarkers (S100 beta, MBP, thrombomodulin, NSE, and beta globin DNA) the specificity was defined by a 95% or 98% reference interval in subjects without disease. Five markers were tested in more than one cohort of patients, though only NSE and S100 beta were tested by different research groups. Only S100 beta was tested in different cohorts of patients using the same cutoff for a postive result (0.02 µg/L). Information about 5 panels of markers was extracted (Figure 2); in no case was the regression equation given for the marker panel (ie, the formula which permits a calculation of the probability of stroke if the results of the individual component biomarker tests are known). No panel of markers was validated in an independent cohort of patients.


Figure 1511261
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  		Figure 1. Sensitivity and specificity of individual blood biomarkers, for the diagnosis of stroke (ischemic or any stroke) with 95% confidence intervals.


Figure 2511261
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  		Figure 2. Sensitivity and specificity for blood biomarker models, for the diagnosis of stroke, with 95% confidence intervals.

Chiefly as a result of the very substantial clinical heterogeneity of the populations studied and heterogeneity of results, we did not perform a meta-analysis to derive an overall summary receiver operator curve for any of the individual markers or any of the panels of markers. Plots of sensitivity and specificity against study quality and types of control showed no clear relationship (data not shown).

Six individual markers and 2 panels of markers were assessed in 5 studies to determine the ability of blood biomarkers to distinguish between ischemic and hemorrhagic stroke. There was sufficient information to extract 2x2 tables on 6 markers and 4 panels (Figure 3). Most studies used the diagnosis of hemorrhagic stroke as the diagnosis of interest in a population of hemorrhagic and ischemic stroke patients. Two11,17 reported a positive test as a diagnosis of ischemic stroke in a mixed population, both with a high sensitivity and specificity. No single marker or panel of markers was reported in more than one cohort of patients.


Figure 3511261
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  		Figure 3. Sensitivity and specificity of biomarkers for the diagnoisis of hemorrhagic stroke in studies of patients with hemorrhagic and ischemic stroke, with 95% confidence intervals.


*    Discussion
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 up arrowResults
 *Discussion
down arrowReferences
 
We set out to assess the utility of blood biomarker tests for improving the diagnosis of ischemic stroke in the acute phase. Most of the studies in this review reported biomarkers with high sensitivity and specificity which, if confirmed in validation studies, could be useful in clinical practice. However, all the blood biomarker studies had weaknesses in their methodology, which may explain the very high specificity and sensitivities reported. The main problems identified in the this review were: small sample size; poor choice of reference standard (lesions required on imaging rather than clinical diagnosis supported by imaging); poor choice of controls (rarely reflecting the clinical setting in which the test would be used); data-dependent thresholds; and lack of validation.

Recommendations for Design of Diagnostic Blood Biomarkers Studies
The important diagnostic questions in the management of acute ischemic stroke can be summarized as follows:

Diagnosis of Stroke in the Emergency Department Before Scanning or Expert Assessment
If a test is designed for the diagnosis of ischemic stroke in unselected patients by clinicians in an emergency setting, then cohorts of suspected stroke patients for biomarker development or validation should be recruited by clinicians in the emergency department. In this systematic review, only 114 attempted this explicitly; 3 other studies examined suspected stroke patients13,25,27 though it is unclear from the reports whether nonexpert clinicans recruited patients, and they also used healthy controls. Studies should evaluate whether biomarker tests perform better than the clinical judgment of nonexpert clinicians or prehospital screening tools such as the FAS test.32 Two useful tests for conditions other than stroke that are used in a similar setting are BNP for exclusion of diagnosis of congestive cardiac failure and D-dimer for the exclusion of a diagnosis of PE. Both are very sensitive. BNP has a sensitivity range between 68% to 98%33 and D-dimer ELISA has a sensitivity of 96%.34 D-dimer is used as part of a diagnostic algorithm that includes an initial assessment of the clinical probability of PE by means of a validated scale; biomarkers of stroke could be most useful when combined either with clinical judgment alone or with clinical judgment plus brain imaging.

Differentiating Hemorrhagic From Ischemic Stroke Before Brain Imaging
A blood test that aims to differentiate between patients with hemorrhagic and ischemic stroke would be of greatest utility before brain imaging (eg, during ambulance transfer to hospital). In studies to evaluate such a test, patients should be recruited at the earliest possible opportunity and before brain imaging is ordered. CT is a rapid test and is very good at identifying acute intracranial hemorrhage, so a biomarker test is likely to be redundant after imaging has been performed. However, in the studies in this review, which compared diagnostic test accuracy for distinguishing ischemic from hemorrhagic strokes, there were no patients in whom stroke was suspected, who turned out to have an alternative diagnosis on imaging. Hence the cohorts were too highly selected to be useful to assess the diagnostic utility of biomarkers in this particular setting.

Supporting a Diagnosis of Ischemic Stroke in Patients With Normal CT Brain
Most suspected stroke patients have a brain CT as their first investigation. When CT is normal, clinicians are often uncertain whether the diagnosis of stroke is secure enough to justify thrombolysis or the use of aggressive stroke preventative treatments. In patients with clinical symptoms of stroke, but a normal CT brain scan, a blood biomarker could perform well, as ischemic stroke may be the condition most likely to lead to a rise in specific proteins. Studies evaluating a blood biomarker in this setting should recruit patients in whom the clinicians are uncertain about the appearance of an imaging test, with blood drawn immediately after the CT. If more advanced CT and MR methods become easier in the emergency department, the diagnostic performance of blood biomarkers should be compared with these techniques.

Short-Term Prognosis After Nondisabling Stroke or TIA
In patients with nondisabling stroke or TIA, short-term prognosis has a major influence on patient management: it informs decisions about admission to hospital, the intensity and speed of investigation, and the likelihood of successful early discharge. In this context, studies of diagnostic test accuracy should identify whether patients were still symptomatic when they were first assessed and how their recovery was measured. In patients with very short-duration symptoms, imaging tests are much less likely to give positive confirmation, so the place of imaging as part of the reference standard diagnosis of stroke or transient ischemic attack (TIA) is altered, though imaging remains of value to exclude stroke mimics. In this context, expert clinicial assessment and detailed clinical follow-up to detect recurrent clinical events are the key methodological determinants.

It is very difficult to define a test which can act as a reference standard test for the diagnosis of stroke; it is recognized that CT, MR, and even autopsy may be "negative," even in patients considered to have a clinically definite acute stroke by all other criteria. Therefore the reference standard for a diagnosis of ischemic stroke remains a diagnosis by an expert clinician, based on the initial clinical features, supported by appropriate imaging, and the patient’s subsequent clinical course, with perhaps the need for repeated imaging on follow-up.

In this review, we found validation studies were limited. Only a few studies examined the same diagnostic threshold for a marker in more than one cohort. In one set of papers, different diagnostic thresholds have been calculated in different cohorts for the same biomarker to optimize sensitivity and specificity by ROC analysis, though the same diagnostic threshold was not examined in more than one cohort.15,18,19

It has been proposed that biomarker development should take a linear path; identification of blood biomarker candidates either in animal or human models, before testing them in cohorts of stroke patients versus normal controls, before testing them in cohorts of suspected stroke patients.3,35 However, when considering the various "-omic" approaches to discovery of biomarker candidates, there are compelling reasons to use cohorts of patients with suspected disease (after all this is the context that the test will be used in) for the discovery phase.

The biomarkers identified in this review are expressed in diverse cell types and part of many different cellular processes (Table 2). Some proteins are found mainly in the nervous system: B-type neurotrophic growth factor, S100 beta, myelin basic protein, neurone specific enolase, and visin like protein; others indicate endothelial processes: matrix metalloproteinase-9, thrombomodulin, vascular cell adhesion molecule, and von Willebrand factor. Some are not clearly linked to stroke pathogenesis, such as acrolein, nucleoside disphosphate kinase, antibodies to NR2A/2B, and glutathione S transferase. Two studies have examined RNA expression in peripheral blood leukocytes36,37 soon after stroke. The results of prediction analysis for microarrays (PAM) algorithm were different in the two studies; of a PAM gene list of 22 in one study and 29 in the other there was overlap only of N-acetyl neuraminate pyruvate lyase.

This review has a number of shortcomings. The absence of a suitable sensitive yet specific search strategy for diagnostic tests hampers the systematic review process. Searching the "gray" literature is very difficult to perform comprehensively, so it is likely that there are unpublished reports of biomarker sensitivity and specificity that have not been identified. In this study, the assessment of report quality was necessarily limited, as many of the studies were conference abstracts, with limited space to report the details of the methods of their studies. It is likely that the timing of sampling after stroke onset will affect the performance of a blood biomarker test; in these studies, it was not possible to analyze this because of a paucity of data.

We have demonstrated that the design of and reporting of studies of blood biomarkers for the diagnosis of ischemic stroke could be improved (Table 1). There are a number of blood biomarkers that perform impressively well in their development cohorts, however all of them need to be examined in unselected cohorts of patients with suspected stroke. None can be recommended yet for use in routine clinical practice. Down


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  		Table 1. Recommendations for Good Quality Studies of Blood Biomarkers for Acute Stroke Diagnosis


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  		Table 2. Main Biological Action of Biomarkers Described

Supplemental Methods
MEDLINE Search Strategy

  1. cerebrovascular disorders/ or basal ganglia cerebrovascular disease/ or exp brain ischemia/ or carotid artery diseases/ or carotid artery thrombosis/ or carotid stenosis/ or cerebrovascular accident/ or exp brain infarction/ or exp hypoxia-ischemia, brain/ or exp intracranial arterial diseases/ or exp "intracranial embolism and thrombosis"/
  2. ([brain or cerebr$ or cerebell$ or vertebrobasil$ or hemispher$ or intracran$ or intracerebral or infratentorial or supratentorial or middle cerebr$ or mca$ or anterior circulation] adj5 [isch?emi$ or infarct$ or thrombo$ or emboli$ or occlus$ or hypoxi$]).tw.
  3. (isch?emi$ adj6 [stroke$ or apoplex$ or cerebral vasc$ or cerebrovasc$ or cva or attack$]).tw.
  4. 1 or 2 or 3
  5. exp biological markers/
  6. biomarker$.tw.
  7. ([biochemical or clinical or immun$ or laboratory or biological$ or serum or surrogate or viral] adj6 marker$).tw.
  8. ([blood or plasma] adj6 marker$).tw.
  9. 5 or 6 or 7 or 8
  10. Fructose-Bisphosphate Aldolase/ or activins/ or inhibin-beta subunits/ or Inhibins/ or Adiponectin/ or Antiplasmin/ or {alpha}-Macroglobulins/ or alpha 1-antichymotrypsin/ or alpha 1-antitrypsin/ or Orosomucoid/ or Peptidyl-Dipeptidase A/ or Fibroblast Growth Factor 2/ or angiotensins/ or angiotensin i/ or angiotensin ii/ or angiotensin iii/ or Antithrombin III/ or apolipoproteins/ or apolipoproteins a/ or apolipoprotein a-i/ or apolipoprotein a-ii/ or apolipoproteins b/ or apolipoprotein b-48/ or apolipoprotein b-100/ or apolipoproteins c/ or apolipoprotein c-i/ or apolipoprotein c-ii/ or apolipoproteins d/ or apolipoproteins e/ or apolipoprotein e2/ or apolipoprotein e3/ or apolipoprotein e4/ or beta 2-Glycoprotein I/ or Natriuretic Peptide, Brain/ or Brain-Derived Neurotrophic Factor/ or caspases, effector/ or caspase 3/ or caspase 6/ or caspase 7/ or caspase 14/ or Cathepsin B/ or antigens, cd40/ or cd40 ligand/ or Ceruloplasmin/ or Chitinase/ or Cholesterol Ester Transfer Proteins/ or Chromogranin A/ or Clusterin/ or Fibronectins/ or Chimerin Proteins/ or Chimerin 1/ or complement system proteins/ or anaphylatoxins/ or complement activating enzymes/ or complement c1/ or complement c2/ or complement c3/ or complement c4/ or complement c5/ or complement c6/ or complement c7/ or complement c8/ or complement c9/ or complement factor b/ or complement inactivator proteins/ or complement membrane attack complex/ or properdin/ or C-Reactive Protein/ or Fibrin Fibrinogen Degradation Products/ or phosphopyruvate hydratase/ or {tau}-crystallins/ or cell adhesion molecules/ or antigens, cd22/ or antigens, cd24/ or antigens, cd31/ or antigens, cd146/ or antigens, cd164/ or cadherins/ or carcinoembryonic antigen/ or cd4 immunoadhesins/ or cell adhesion molecules, neuronal/ or integrin alpha beta2/ or intercellular adhesion molecule-1/ or receptors, lymphocyte homing/ or selectins/ or vascular cell adhesion molecule-1/ or endothelins/ or endothelin-1/ or endothelin-2/ or endothelin-3/ or Erythropoietin/ or E-Selectin/ or Factor XI/ or Factor IX/ or Factor XII/ or Factor V/ or Factor VII/ or Factor VIII/ or Factor X/ or Factor XIIa/ or exp Interleukins/ or exp Fibrinogen/ or Antigens, CD95/ or exp Ferritins/ or fibrinopeptide a/ or fibrinopeptide b/ or exp Fibronectins/ or exp Follistatin-Related Proteins/ or exp Follistatin/ or exp Fatty Acids, Nonesterified/ or exp Glial Fibrillary Acidic Protein/ or exp Glutathione Transferase/ or Granulocyte-Macrophage Colony-Stimulating Factor/ or exp Selectins/ or Platelet Glycoprotein GPIIb-IIIa Complex/ or growth hormone/ or human growth hormone/ or exp Haptoglobins/ or Hemopexin/ or Heparin Cofactor II/ or exp Intercellular Adhesion Molecule-1/ or exp Immunoglobulin G/ or Laminin/ or Leptin/ or Macrophage Colony-Stimulating Factor/ or Malondialdehyde/ or exp matrix metalloproteinases, secreted/ or exp Monocyte Chemoattractant Proteins/ or Myelin Basic Proteins/ or Peroxidase/ or exp S100 Proteins/ or Neurotrophin 3/ or 9 Nitric Oxide/ or Nucleoside-Diphosphate Kinase/ or Aryldialkylphosphatase/ or Phosphoglycerate Mutase/ or Pregnancy-Associated Plasma Protein-A/ or Plasminogen Activator Inhibitor 1/ or Plasminogen/ or Plasminogen Activator Inhibitor 2/ or Platelet Activating Factor/ or Antigens, CD31/ or Platelet-Derived Growth Factor/ or Platelet Factor 4/ or Protein C/ or Protein S/ or Prothrombin/ or Resistin/ or Plasminogen Inactivators/ or Platelet Activation/ or tau Proteins/ or Thrombin/ or Thrombomodulin/ or Thromboplastin/ or TUMOR NECROSIS FACTOR-ALPHA/ or Transforming Growth Factor beta/ or Vascular Endothelial Growth Factor A/ or Vitronectin/ or von Willebrand Factor/
  11. (Aldolase A or aldolase b or aldolase c or fructose bisphosphonate aldolase or activin$ or inhibin$ or adiponectin or adipocyte specific secretory protein or gelatin binding protein or adipocyte complement related protein or alpha 2 antiplasmin or Alpha-2-antiplasmin precursor or Alpha-2-AP or Alpha-2-PI or Alpha-2-plasmin inhibitor or pigment epithelium derived factor or plasmin inhibitor alpha 2 or {alpha}-macroglobulin$ or alpha 2 mol/L or antichymotrypsin or alpha 1-antichymotrypsin or alpha 1-antitrypsin or Seromucoid or serum sialomucin or alpha 1-acid glycoprotein or alpha 1-acid seromucoid or a 1-acid seromucoid or acid alpha 1-glycoprotein or alpha 1 -acid glycoprotein or alpha 1-acid glycoprotein acute phase or alpha 1-glycoprotein acid or angiotensin converting enzyme or cd143 or cd143 or kininase ii or angiotensin i-converting enzyme or carboxycathepsin or dipeptidyl peptidase a or kininase a or ACE or kininase 2 or Dipeptidyl carboxypeptidase I or basic fibroblast growth factor or fibroblast growth factor, basic or hbgf-2 or cartilage-derived growth factor or class ii heparin-binding growth factor or fgf-2 or fgf2 or fibroblast growth factor-2 or heparin-binding growth factor class ii or prostate epithelial cell growth factor or prostatropin or Fibroblast Growth Factor 2 or heparin-binding growth factor 2 or angiotensin$ or antithrombin ii or heparin cofactor i or at iii or antithrombin iii, human plasma or antithrombin iii-alpha or atenativ or baxter brand of antithrombin or bayer brand of antithrombin or factor xa inhibitor or grifols brand of antithrombin or heparin cofactor i or pharmacia brand of antithrombin or thrombate iii or antithrombin 3 or antithrombin-3 or antithrombin iii or apolipoprotein$ or beta 2 glycoprotein$ or beta 2-Glycoprotein I or brain natriuretic peptide or nesiritide or b-type natriuretic peptide or bnp gene product or bnp-32 or brain natriuretic peptide-32 or natrecor or natriuretic factor-32 or natriuretic peptide type-b or type-b natriuretic peptide or ventricular natriuretic peptide, b-type or Brain-Derived Neurotrophic Factor or casp3 or apopain or caspase-3 or procaspase-3 or procaspase-3 or caspase 3 or cathepsin b-like activity or cathepsin b-like proteinase or cathepsin b1 or cathepsin b or amyloid precursor protein secretase or endoglin$ or CD105 or cd40 or Bp50 or caeruloplasmin or caeruloplasmin or ferroxidase or ceruloplasmin ferroxidase or ceruloplasmin oxidase or ferroxidase i or alpha 2 -ceruloplasmin or endochitinase or chitinase$ or chitotriosidase or cholesterol ester transport protein or cetp or cholesteryl ester exchange protein or cholesteryl ester transfer protein or parathyroid secretory protein or secretory protein i, parathyroid gland or Chromogranin A or pancreastatin or parastatin or Pituitary secretory protein I or vasostatin or apoj protein or apolipoprotein j or complement lysis inhibitor or complement-associated protein sp-40,40 or ionizing radiation-induced protein-8 or mac393 antigen or sgp-2 protein or sp 40,40 protein or sulfated glycoprotein 2 or sulfated glycoprotein-2 or trpm-2 protein or testosterone-repressed prostate message-2 protein or x-ray-inducible protein 8 or xip8 protein or aging-associated protein 4 or Complement cytolysis inhibitor or clusterin or cold-insoluble globulins or lets proteins or fibronectin or opsonic glycoprotein or opsonic alpha 2 sb glycoprotein or alpha 2-surface binding glycoprotein or c-fibronectin or c fibronectin or cellular fibronectin or {alpha}-1 chimerin or {alpha}-2 chimerin or {alpha}-chimerin or arhgap2 protein or n-chimerin or rhogap2 protein or chimaerin 1 or {alpha}-1 chimaerin or {alpha}-2 chimaerin or {alpha}-chimaerin or alpha1-chimaerin or n-chimaerin or chimerin or chimerin$ or collagen synthesis byproduct or complement or c reactive protein or c-reactive protein or CRP or antithrombin vi or fibrin degradation products or fibrin fibrinogen split products or Fibrin Fibrinogen Degradation Products or D-dimer or D dimer or enolase or neuron-specific enolase or 2-phospho-d-glycerate hydrolase or cobalt enolase or nervous system-specific enolase or non-neuronal enolase or alpha, {alpha}-enolase or βenolase or gamma, {gamma}-enolase or Phosphopyruvate Hydratase or Neuron specific enolase or Neurone specific enolase or Neurone-specific enolase or endothelial protein c receptor or endothelial cell protein c receptor or protein c receptor or centrocyclin or CD201 antigen or antigens, cd106 or cd106 antigens or vcam-1 or cd106 antigen or incam-110 or inducible cell adhesion molecule 110 or vascular cell adhesion molecule or big endothelin or big endothelin-1 or et-1 endothelin-1 or endothelin type 1 or endothelin, big or preproendothelin or preproendothelin-1 or proendothelin 1 to 38 or proendothelin-1 precursor or Erythropoietin or antigens, cd62e or cd62e antigens or e selectin or elam-1 or endothelial leukocyte adhesion molecule-1 or lecam-2 or cd62e antigen or endothelial leukocyte adhesion molecule 1 or e-selectin or selectin e or autoprothrombin ii or christmas factor or coagulation factor ix or ptc or plasma thromboplastin component or blood coagulation factor ix or factor ix complex or factor ix fraction or coagulation factor xi or plasma thromboplastin antecedent or blood coagulation factor xi or coagulation factor xii or hageman factor or blood coagulation factor xii or coagulation factor v or proaccelerin or ac globulin or blood coagulation factor v or factor pi or factor v or factor ix or factor xii or factor xi or coagulation factor vii or proconvertin or stable factor or blood coagulation factor vii or factor vii or antihemophilic factor or coagulation factor viii or factor viii clotting antigen or factor viii coagulant antigen or factor viii procoagulant activity or thromboplastinogen or blood coagulation factor viii or f viii-c or factor viii-heavy chain or factor viiic or hemofil or hemofil hm or hemofil m or hemophil or humate-p or hyate-c or hyatt-c or monoclate or factor viii or autoprothrombin iii or coagulation factor x or stuart factor or stuart-prower factor or blood coagulation factor x or stuart prower factor or factor vii activating protease or coagulation factor xiia or factor xii, activated or activated factor xii or blood coagulation factor xii, activated or hageman-factor fragments or prekallikrein activator or factor xiia or interleukin or fibrinogen or coagulation factor i or factor i or blood coagulation factor i or {gamma}-fibrinogen or apo-1 antigen or apoptosis antigen 1 or cd95 antigens or receptors, fas or tumor necrosis factor receptor superfamily, member 6 or fas antigens or fas receptors or cd95 antigen or tnfrsf6 receptor or fas antigen or fas receptor or basic isoferritin or ferritin or isoferritin or isoferritin, basic or fibrinopeptide or cold-insoluble globulins or lets proteins or fibronectin or opsonic glycoprotein or opsonic alpha 2 sb glycoprotein or alpha 2-surface binding glycoprotein or activin-binding protein or follistatin or fatty acids, free or free fatty acids or nefa or glial fibrillary acidic protein or GFAP or glial intermediate filament protein or astroprotein or gfa-protein or glial fibrillary acid protein or glutathione s-alkyltransferase or glutathione s-aryltransferase or glutathione s-epoxidetransferase or ligandins or s-hydroxyalkyl glutathione lyase or glutathione organic nitrate ester reductase or glutathione s-transferase or glutathione s-transferase 3 or glutathione s-transferase a or glutathione s-transferase b or glutathione s-transferase c or glutathione s-transferase iii or glutathione s-transferase p or glutathione transferase e or glutathione transferase mu or glutathione transferases or heme transfer protein or ligandin or b-glutathione-s-transferase or csf-gm or colony-stimulating factor, granulocyte-macrophage or gm-csf or histamine-producing cell-stimulating factor or csf-2 or tc-gm-csf or tumor-cell human gm colony-stimulating factor or granulocyte macrophage colony stimulating factor or antigens, cd62p or cd62p antigens or gmp-140 or lecam-3 or p selectin or platelet {alpha}-granule membrane protein or cd62p antigen or padgem or antigens, cd62l or cd62l antigens or lecam-1 or cd62l antigen or l selectin or lam-1 or leu-8 antigen or leukocyte adhesion molecule, lam-1 or mel-14 antigen or tq1 antigen or antigens, cd62e or cd62e antigens or e selectin or elam-1v or endothelial leukocyte adhesion molecule-1 or lecam-2 or cd62e antigen or endothelial leukocyte adhesion molecule 1 or gp130 or sgp130 or interleukin 11 receptor or gpiib-iiia receptors or integrin alphaiibbeta3 or glycoproteins iib-iiia or integrin {alpha}-iib β3 or pituitary growth hormone or somatotropin or growth hormone, pituitary or haptoglobin or hemopexin or hemopexin or heparin cofactor ii or antigens, cd54 or cd54 antigens or icam-1 or cd54 antigen or intercellular adhesion molecule 1 or gamma globulin, 7s or igg or allerglobuline or igg t or igg1 or igg2 or igg2a or igg2b or igg3 or igg4 or immunoglobulin gt or polyglobin or immunoglobulin g or insulin or ischemia modified albumin or merosin or glycoprotein gp-2 or laminin m or laminin m chain or laminin or leptin or ob protein or obese protein or ob gene product or obese gene product or lipoprotein associated phospholipase or lipoprotein lipase or csf-1 or csf-m or colony-stimulating factor 1 or colony-stimulating factor, macrophage or m-csf or macrophage colony stimulating factor or malonaldehyde or propanedial or malonylaldehyde or malonyldialdehyde or sodium malondialdehyde or Malondialdehyde or interstitial collagenase or mmp-1 metalloproteinase or mmp1 metalloproteinase or matrix metalloproteinase-1 or promatrix metalloproteinase-1 or promatrixmetalloproteinase-1 or prommp-1 or matrix metalloproteinase 1 or gelatinase a or 72-kda gelatinase or 72-kda type iv collagenase or mmp-2 metalloproteinase or mmp2 metalloproteinase or matrix metalloproteinase-2 or matrix metalloproteinase 2 or stromelysin 1 or transin or mmp-3 metalloproteinase or mmp3 metalloproteinase or stromelysin or matrix metalloproteinase 3 or gelatinase b or 92-kda gelatinase or 92-kda type iv collagenase or mmp-9 metalloproteinase or mmp9 metalloproteinase or matrix metalloproteinase-9 or matrix metalloproteinase 9 or metallopeptidase 9 or monocyte chemoattractant protein-1 or myelin basic protein or encephalitogenic basic proteins or basic protein, encephalitogenic or basic proteins, encephalitogenic or encephalitogenic basic protein or neuritogenic protein or protein, encephalitogenic basic or proteins, encephalitogenic basic or myeloperoxidase or hemi-myeloperoxidase or Peroxidase or antigen s 100 or nerve tissue protein s 100 or s-100 protein or s100 protein family or s 100 or ngf-2 or nerve growth factor 2 or neurotrophin 3 or neutrophil gelatinase associated lipocalin or neutrophil protease 4 or deoxynucleoside diphosphate kinases or gdp kinase or nucleoside diphosphokinases or nucleoside-diphosphate kinases or oxidized ldl or osteoprotogerin or aryl-dialkyl phosphatase or arylalkylphosphatase or homocysteine thiolactone hydrolase or opa anhydrase or oph enzyme or organophosphorus acid anhydrase or organophosphorus acid anhydrolase or organophosphorus acid hydrolase or organophosphorus hydrolase or paraoxonase or paraoxonase-1 or paraoxonase-2 or glycerate 3 to 2-phosphomutase or phosphoglyceromutase or phosphoglycerate phosphomutase or phosphoglycerate mutase or papp-a or igfbp-4 metalloproteinase or igfbp-4 protease or igfbp-4-specific proteinase or insulin-like growth factor-dependent igf binding protein-4 protease or insulin-like-growth factor binding protein-4 protease or papp-alpha or pregnancy associated alpha plasma protein or pregnancy-associated {alpha}-plasma protein or pregnancy associated plasma protein a or profibrinolysin or glu-plasminogen or glutamic acid 1-plasminogen or glutamyl plasminogen or agepc or acetyl glyceryl ether phosphorylcholine or paf-acether or phosphorylcholine, acetyl glyceryl ether or 1-alkyl-2-acetyl-sn-glycerophosphocholine or platelet aggregating factor or platelet aggregation enhancing factor or platelet-activating substance or thrombocyte aggregating activity or platelet activating factor or cd31 antigens or pecam-1 or platelet endothelial cell adhesion molecule-1 or cd31 antigen or platelet derived microvesicles or platelet derived growth factor or antiheparin factor or pf 4 or heparin neutralizing protein or pf4 or {gamma}-thromboglobulin or prorenin or Protein C or Protein S or Protein Z or coagulation factor ii or factor ii or blood coagulation factor ii or differentiation reversal factor or prothrombin or adipocyte cysteine-rich secreted protein fizz3 or resistin or receptor of AGE or RAGE or receptor of advanced glycation end products or secretagogin or plasminogen activator inhibitors or bae-pai or endothelial plasminogen activator inhibitors or placental plasminogen activator inhibitors or plasminogen activator inhibitors, endothelial or plasminogen activator inhibitors, placental or platelet activation or PARK 7 or SCD40L or Tau or thrombase or thrombinar or thrombostat or {alpha}-thrombin or beta,{gamma}-thrombin or βthrombin or {gamma}-thrombin or thrombin or thrombin-antithrombin complex or Thrombomodulin or antigens, cd142 or cd142 antigens or coagulation factor iii or factor iii or tissue factor or tissue thromboplastin or blood coagulation factor iii or coagulin or glomerular procoagulant activity or prothrombinase or tissue factor procoagulant or urothromboplastin or thromboplastin or tissue factor pathway inhibitor or tissue inhibitor of metalloproteinase or cachectin or tnf-alpha or tumor necrosis factor ligand superfamily member 2 or cachectin-tumor necrosis factor or tnf superfamily, member 2 or tumor necrosis factor or bone-derived transforming growth factor or platelet transforming growth factor or tgf-beta or milk growth factor or tgfbeta or Transforming Growth Factor beta or ubiquitin fusion degradation protein 1 or Vascular Endothelial Growth Factor A or vascular endothelial growth factor or vascular endothelial growth factor-a or gd-vegf or glioma-derived vascular endothelial cell growth factor or vegf or vegf-a or vascular permeability factor or vasculotropin or vitronectin or factor viii-related antigen or f viii-vwf or factor viiir-ag or factor viiir-rco or plasma factor viii complex or ristocetin cofactor or ristocetin-willebrand factor or vwf ag or von willebrand factor type iib or von willebrand protein or von Willebrand Factor).tw.
  12. 10 or 11
  13. (12 and 4) not (4 and 9)
  14. (alzheimer$ or coronary or fibrillation or cardiac or cardio$ or cadasil or diabetes or tumor ot tumor or trauma$ or angina or dement$ or child$ or pediatr$ or paediatr$ or newborn$).ti.
  15. 14 and stroke.ti.
  16. 14 not 15
  17. 13 not 16
  18. limit 17 to humans

EMBASE Search Strategy

  1. cerebral artery disease/ or cerebrovascular accident/ or stroke/ or vertebrobasilar insufficiency/ or wallenberg syndrome/ or exp brain infarction/ or exp brain ischemia/ or exp occlusive cerebrovascular disease/ or cerbrovascular disease/ or exp carotid artery diseases/
  2. ([brain or cerebr$ or cerebell$ or vertebrobasil$ or hemispher$ or intracran$ or intracerebral or infratentorial or supratentorial or middle cerebr$ or mca$ or anterior circulation] adj5 [isch?emi$ or infarct$ or thrombo$ or emboli$ or occlus$ or hypoxi$]).tw.
  3. (isch?emi$ adj6 [stroke$ or apoplex$ or cerebral vasc$ or cerebrovasc$ or cva or attack$]).tw.
  4. 1 or 2 or 3
  5. disease Marker/ or biochemical marker/ or biological marker/ or molecular marker/ or marker/
  6. biomarker$.tw.
  7. ([biochemical or clinical or immun$ or laboratory or biological$ or serum or surrogate or viral] adj6 marker$).tw.
  8. ([blood or plasma] adj6 marker$).tw.
  9. (Aldolase A or aldolase b or aldolase c or fructose bisphosphonate aldolase or activin$ or inhibin$ or adiponectin or adipocyte specific secretory protein or gelatin binding protein or adipocyte complement related protein or alpha 2 antiplasmin or Alpha-2-antiplasmin precursor or Alpha-2-AP or Alpha-2-PI or Alpha-2-plasmin inhibitor or pigment epithelium derived factor or plasmin inhibitor alpha 2 or {alpha}-macroglobulin$ or alpha 2 mol/L or antichymotrypsin or alpha 1-antichymotrypsin or alpha 1-antitrypsin or Seromucoid or serum sialomucin or alpha 1-acid glycoprotein or alpha 1-acid seromucoid or a 1-acid seromucoid or acid alpha 1-glycoprotein or alpha 1-acid glycoprotein or alpha 1-acid glycoprotein acute phase or alpha 1-glycoprotein acid or angiotensin converting enzyme or cd143 or cd143 or kininase ii or angiotensin i-converting enzyme or carboxycathepsin or dipeptidyl peptidase a or kininase a or ACE or kininase 2 or Dipeptidyl carboxypeptidase I or basic fibroblast growth factor or fibroblast growth factor, basic or hbgf-2 or cartilage-derived growth factor or class ii heparin-binding growth factor or fgf-2 or fgf2 or fibroblast growth factor-2 or heparin-binding growth factor class ii or prostate epithelial cell growth factor or prostatropin or Fibroblast Growth Factor 2 or heparin-binding growth factor 2 or angiotensin$ or antithrombin ii or heparin cofactor i or at iii or antithrombin iii, human plasma or antithrombin iii-alpha or atenativ or baxter brand of antithrombin or bayer brand of antithrombin or factor xa inhibitor or grifols brand of antithrombin or heparin cofactor i or pharmacia brand of antithrombin or thrombate iii or antithrombin 3 or antithrombin-3 or antithrombin iii or apolipoprotein$ or beta 2 glycoprotein$ or beta 2-Glycoprotein I or brain natriuretic peptide or nesiritide or b-type natriuretic peptide or bnp gene product or bnp-32 or brain natriuretic peptide-32 or natrecor or natriuretic factor-32 or natriuretic peptide type-b or type-b natriuretic peptide or ventricular natriuretic peptide, b-type or Brain-Derived Neurotrophic Factor or casp3 or apopain or caspase-3 or procaspase-3 or procaspase-3 or caspase 3 or cathepsin b-like activity or cathepsin b-like proteinase or cathepsin b1 or cathepsin b or amyloid precursor protein secretase or endoglin$ or CD105 or cd40 or Bp50 or caeruloplasmin or caeruloplasmin or ferroxidase or ceruloplasmin ferroxidase or ceruloplasmin oxidase or ferroxidase i or alpha 2 -ceruloplasmin or endochitinase or chitinase$ or chitotriosidase or cholesterol ester transport protein or cetp or cholesteryl ester exchange protein or cholesteryl ester transfer protein or parathyroid secretory protein or secretory protein i, parathyroid gland or Chromogranin A or pancreastatin or parastatin or Pituitary secretory protein I or vasostatin or apoj protein or apolipoprotein j or complement lysis inhibitor or complement-associated protein sp-40,40 or ionizing radiation-induced protein-8 or mac393 antigen or sgp-2 protein or sp 40,40 protein or sulfated glycoprotein 2 or sulfated glycoprotein-2 or trpm-2 protein or testosterone-repressed prostate message-2 protein or x-ray-inducible protein 8 or xip8 protein or aging-associated protein 4 or Complement cytolysis inhibitor or clusterin or cold-insoluble globulins or lets proteins or fibronectin or opsonic glycoprotein or opsonic alpha 2 sb glycoprotein or alpha 2-surface binding glycoprotein or c-fibronectin or c fibronectin or cellular fibronectin or {alpha}-1 chimerin or {alpha}-2 chimerin or {alpha}-chimerin or arhgap2 protein or n-chimerin or rhogap2 protein or chimaerin 1 or {alpha}-1 chimaerin or {alpha}-2 chimaerin or {alpha}-chimaerin or alpha1-chimaerin or n-chimaerin or chimerin or chimerin$ or collagen synthesis byproduct or complement or c reactive protein or c-reactive protein or CRP or antithrombin vi or fibrin degradation products or fibrin fibrinogen split products or Fibrin Fibrinogen Degradation Products or D-dimer or D dimer or enolase or neuron-specific enolase or 2-phospho-d-glycerate hydrolase or cobalt enolase or nervous system-specific enolase or non-neuronal enolase or alpha, {alpha}-enolase or βenolase or gamma, {gamma}-enolase or Phosphopyruvate Hydratase or Neuron specific enolase or Neurone specific enolase or Neurone-specific enolase or endothelial protein c receptor or endothelial cell protein c receptor or protein c receptor or centrocyclin or CD201 antigen or antigens, cd106 or cd106 antigens or vcam-1 or cd106 antigen or incam-110 or inducible cell adhesion molecule 110 or vascular cell adhesion molecule or big endothelin or big endothelin-1 or et-1 endothelin-1 or endothelin type 1 or endothelin, big or preproendothelin or preproendothelin-1 or proendothelin 1 to 38 or proendothelin-1 precursor or Erythropoietin or antigens, cd62e or cd62e antigens or e selectin or elam-1 or endothelial leukocyte adhesion molecule-1 or lecam-2 or cd62e antigen or endothelial leukocyte adhesion molecule 1 or e-selectin or selectin e or autoprothrombin ii or christmas factor or coagulation factor ix or ptc or plasma thromboplastin component or blood coagulation factor ix or factor ix complex or factor ix fraction or coagulation factor xi or plasma thromboplastin antecedent or blood coagulation factor xi or coagulation factor xii or hageman factor or blood coagulation factor xii or coagulation factor v or proaccelerin or ac globulin or blood coagulation factor v or factor pi or factor v or factor ix or factor xii or factor xi or coagulation factor vii or proconvertin or stable factor or blood coagulation factor vii or factor vii or antihemophilic factor or coagulation factor viii or factor viii clotting antigen or factor viii coagulant antigen or factor viii procoagulant activity or thromboplastinogen or blood coagulation factor viii or f viii-c or factor viii-heavy chain or factor viiic or hemofil or hemofil hm or hemofil m or hemophil or humate-p or hyate-c or hyatt-c or monoclate or factor viii or autoprothrombin iii or coagulation factor x or stuart factor or stuart-prower factor or blood coagulation factor x or stuart prower factor or factor vii activating protease or coagulation factor xiia or factor xii, activated or activated factor xii or blood coagulation factor xii, activated or hageman-factor fragments or prekallikrein activator or factor xiia or interleukin or fibrinogen or coagulation factor i or factor i or blood coagulation factor i or {gamma}-fibrinogen or apo-1 antigen or apoptosis antigen 1 or cd95 antigens or receptors, fas or tumor necrosis factor receptor superfamily, member 6 or fas antigens or fas receptors or cd95 antigen or tnfrsf6 receptor or fas antigen or fas receptor or basic isoferritin or ferritin or isoferritin or isoferritin, basic or fibrinopeptide or cold-insoluble globulins or lets proteins or fibronectin or opsonic glycoprotein or opsonic alpha 2 sb glycoprotein or alpha 2-surface binding glycoprotein or activin-binding protein or follistatin or fatty acids, free or free fatty acids or nefa or glial fibrillary acidic protein or GFAP or glial intermediate filament protein or astroprotein or gfa-protein or glial fibrillary acid protein or glutathione s-alkyltransferase or glutathione s-aryltransferase or glutathione s-epoxidetransferase or ligandins or s-hydroxyalkyl glutathione lyase or glutathione organic nitrate ester reductase or glutathione s-transferase or glutathione s-transferase 3 or glutathione s-transferase a or glutathione s-transferase b or glutathione s-transferase c or glutathione s-transferase iii or glutathione s-transferase p or glutathione transferase e or glutathione transferase mu or glutathione transferases or heme transfer protein or ligandin or b-glutathione-s-transferase or csf-gm or colony-stimulating factor, granulocyte-macrophage or gm-csf or histamine-producing cell-stimulating factor or csf-2 or tc-gm-csf or tumor-cell human gm colony-stimulating factor or granulocyte macrophage colony stimulating factor or antigens, cd62p or cd62p antigens or gmp-140 or lecam-3 or p selectin or platelet {alpha}-granule membrane protein or cd62p antigen or padgem or antigens, cd62l or cd62l antigens or lecam-1 or cd62l antigen or l selectin or lam-1 or leu-8 antigen or leukocyte adhesion molecule, lam-1 or mel-14 antigen or tq1 antigen or antigens, cd62e or cd62e antigens or e selectin or elam-1v or endothelial leukocyte adhesion molecule-1 or lecam-2 or cd62e antigen or endothelial leukocyte adhesion molecule 1 or gp130 or sgp130 or interleukin 11 receptor or gpiib-iiia receptors or integrin alphaiibbeta3 or glycoproteins iib-iiia or integrin {alpha}-iib β3 or pituitary growth hormone or somatotropin or growth hormone, pituitary or haptoglobin or hemopexin or hemopexin or heparin cofactor ii or antigens, cd54 or cd54 antigens or icam-1 or cd54 antigen or intercellular adhesion molecule 1 or gamma globulin, 7s or igg or allerglobuline or igg t or igg1 or igg2 or igg2a or igg2b or igg3 or igg4 or immunoglobulin gt or polyglobin or immunoglobulin g or insulin or ischemia modified albumin or merosin or glycoprotein gp-2 or laminin m or laminin m chain or laminin or leptin or ob protein or obese protein or ob gene product or obese gene product or lipoprotein associated phospholipase or lipoprotein lipase or csf-1 or csf-m or colony-stimulating factor 1 or colony-stimulating factor, macrophage or m-csf or macrophage colony stimulating factor or malonaldehyde or propanedial or malonylaldehyde or malonyldialdehyde or sodium malondialdehyde or Malondialdehyde or interstitial collagenase or mmp-1 metalloproteinase or mmp1 metalloproteinase or matrix metalloproteinase-1 or promatrix metalloproteinase-1 or promatrixmetalloproteinase-1 or prommp-1 or matrix metalloproteinase 1 or gelatinase a or 72-kda gelatinase or 72-kda type iv collagenase or mmp-2 metalloproteinase or mmp2 metalloproteinase or matrix metalloproteinase-2 or matrix metalloproteinase 2 or stromelysin 1 or transin or mmp-3 metalloproteinase or mmp3 metalloproteinase or stromelysin or matrix metalloproteinase 3 or gelatinase b or 92-kda gelatinase or 92-kda type iv collagenase or mmp-9 metalloproteinase or mmp9 metalloproteinase or matrix metalloproteinase-9 or matrix metalloproteinase 9 or metallopeptidase 9 or monocyte chemoattractant protein-1 or myelin basic protein or encephalitogenic basic proteins or basic protein, encephalitogenic or basic proteins, encephalitogenic or encephalitogenic basic protein or neuritogenic protein or protein, encephalitogenic basic or proteins, encephalitogenic basic or myeloperoxidase or hemi-myeloperoxidase or Peroxidase or antigen s 100 or nerve tissue protein s 100 or s-100 protein or s100 protein family or s 100 or ngf-2 or nerve growth factor 2 or neurotrophin 3 or neutrophil gelatinase associated lipocalin or neutrophil protease 4 or deoxynucleoside diphosphate kinases or gdp kinase or nucleoside diphosphokinases or nucleoside-diphosphate kinases or oxidized ldl or osteoprotogerin or aryl-dialkyl phosphatase or arylalkylphosphatase or homocysteine thiolactone hydrolase or opa anhydrase or oph enzyme or organophosphorus acid anhydrase or organophosphorus acid anhydrolase or organophosphorus acid hydrolase or organophosphorus hydrolase or paraoxonase or paraoxonase-1 or paraoxonase-2 or glycerate 3 to 2-phosphomutase or phosphoglyceromutase or phosphoglycerate phosphomutase or phosphoglycerate mutase or papp-a or igfbp-4 metalloproteinase or igfbp-4 protease or igfbp-4-specific proteinase or insulin-like growth factor-dependent igf binding protein-4 protease or insulin-like-growth factor binding protein-4 protease or papp-alpha or pregnancy associated alpha plasma protein or pregnancy-associated {alpha}-plasma protein or pregnancy associated plasma protein a or profibrinolysin or glu-plasminogen or glutamic acid 1-plasminogen or glutamyl plasminogen or agepc or acetyl glyceryl ether phosphorylcholine or paf-acether or phosphorylcholine, acetyl glyceryl ether or 1-alkyl-2-acetyl-sn-glycerophosphocholine or platelet aggregating factor or platelet aggregation enhancing factor or platelet-activating substance or thrombocyte aggregating activity or platelet activating factor or cd31 antigens or pecam-1 or platelet endothelial cell adhesion molecule-1 or cd31 antigen or platelet derived microvesicles or platelet derived growth factor or antiheparin factor or pf 4 or heparin neutralizing protein or pf4 or {gamma}-thromboglobulin or prorenin or Protein C or Protein S or Protein Z or coagulation factor ii or factor ii or blood coagulation factor ii or differentiation reversal factor or prothrombin or adipocyte cysteine-rich secreted protein fizz3 or resistin or receptor of AGE or RAGE or receptor of advanced glycation end products or secretagogin or plasminogen activator inhibitors or bae-pai or endothelial plasminogen activator inhibitors or placental plasminogen activator inhibitors or plasminogen activator inhibitors, endothelial or plasminogen activator inhibitors, placental or platelet activation or PARK 7 or SCD40L or Tau or thrombase or thrombinar or thrombostat or {alpha}-thrombin or beta,{gamma}-thrombin or βthrombin or {gamma}-thrombin or thrombin or thrombin-antithrombin complex or Thrombomodulin or antigens, cd142 or cd142 antigens or coagulation factor iii or factor iii or tissue factor or tissue thromboplastin or blood coagulation factor iii or coagulin or glomerular procoagulant activity or prothrombinase or tissue factor procoagulant or urothromboplastin or thromboplastin or tissue factor pathway inhibitor or tissue inhibitor of metalloproteinase or cachectin or tnf-alpha or tumor necrosis factor ligand superfamily member 2 or cachectin-tumor necrosis factor or tnf superfamily, member 2 or tumor necrosis factor or bone-derived transforming growth factor or platelet transforming growth factor or tgf-beta or milk growth factor or tgfbeta or Transforming Growth Factor beta or ubiquitin fusion degradation protein 1 or Vascular Endothelial Growth Factor A or vascular endothelial growth factor or vascular endothelial growth factor-a or gd-vegf or glioma-derived vascular endothelial cell growth factor or vegf or vegf-a or vascular permeability factor or vasculotropin or vitronectin or factor viii-related antigen or f viii-vwf or factor viiir-ag or factor viiir-rco or plasma factor viii complex or ristocetin cofactor or ristocetin-willebrand factor or vwf ag or von willebrand factor type iib or von willebrand protein or von Willebrand Factor).tw.
  10. Fructose Bisphosphate Aldolase/ or ACTIVIN A/ or ACTIVIN/ or INHIBIN A/ or INHIBIN/ or INHIBIN B/ or ADIPONECTIN/ or ANTIPLASMIN/ or ALPHA 2 ANTIPLASMIN/ or Alpha 2 Macroglobulin/ or Chymotrypsin A/ or Alpha 1 Antitrypsin/ or OROSOMUCOID/ or Dipeptidyl Carboxypeptidase/ or Fibroblast Growth Factor 2/ or ANGIOTENSIN I/ or ANGIOTENSIN/ or ANGIOTENSIN BLOOD LEVEL/ or ANGIOTENSIN II/ or Antithrombin III/ or exp Apolipoprotein/ or Beta2 Glycoprotein 1/ or exp Brain Natriuretic Peptide/ or Brain Derived Neurotrophic Factor/ or exp CASPASE/ or Cathepsin B/ or CD40 LIGAND/ or CD40 ANTIGEN/ or exp CERULOPLASMIN BLOOD LEVEL/ or exp CERULOPLASMIN/ or CHITINASE/ or Cholesterol Ester Transfer Protein/ or Chromogranin A/ or exp CLUSTERIN/ or Fibronectin/ or Chimerin/ or exp COMPLEMENT/ or COMPLEMENT BLOOD LEVEL/ or Anaphylatoxin/ or PROPERDIN/ or C Reactive Protein/ or Fibrin Degradation Product/ or Enolase/ or TAU PROTEIN/ or Cell Adhesion Molecule/ or Cd22 Antigen/ or Cd24 Antigen/ or Cd31 Antigen/ or antigens, cd164/ or Cadherin/ or Carcinoembryonic Antigen/ or Cd4 Immunoglobulin/ or Nerve Cell Adhesion Molecule/ or Integrin/ or Intercellular Adhesion Molecule 1/ or Homing Receptor/ or Selectin/ or Vascular Cell Adhesion Molecule 1/ or ENDOTHELIN 2/ or BIG ENDOTHELIN 2/ or ENDOTHELIN 1/ or BIG ENDOTHELIN 1/ or ENDOTHELIN 3/ or ENDOTHELIN/ or ERYTHROPOIETIN/ or P SELECTIN GLYCOPROTEIN LIGAND 1/ or L SELECTIN/ or SELECTIN/ or exp Blood Clotting Factor/ or exp Cytokine/ or exp Fibrinogen/ or Antigens, CD95/ or exp Ferritin/ or fibrinopeptide a/ or fibrinopeptide b/ or exp Fibronectins/ or exp Follistatin-Related Proteins/ or exp Follistatin/ or exp Fatty Acids, Nonesterified/ or exp Glial Fibrillary Acidic Protein/ or exp Glutathione Transferase/ or Granulocyte-Macrophage Colony-Stimulating Factor/ or exp Selectins/ or Platelet Glycoprotein GPIIb-IIIa Complex/ or growth hormone/ or human growth hormone/ or exp Haptoglobins/ or Hemopexin/ or Heparin Cofactor II/ or exp Intercellular Adhesion Molecule-1/ or exp Immunoglobulin G/ or Laminin/ or Leptin/ or Macrophage Colony-Stimulating Factor/ or Malondialdehyde/ or exp Matrix Metalloproteinase/ or exp Monocyte Chemoattractant Proteins/ or Myelin Basic Proteins/ or Peroxidase/ or exp S100 Proteins/ or Neurotrophin 3/ or 9 Nitric Oxide/ or Nucleoside-Diphosphate Kinase/ or Aryldialkylphosphatase/ or Phosphoglycerate Mutase/ or Pregnancy-Associated Plasma Protein-A/ or Plasminogen Activator Inhibitor 1/ or Plasminogen/ or Plasminogen Activator Inhibitor 2/ or Platelet Activating Factor/ or Antigens, CD31/ or Platelet-Derived Growth Factor/ or Platelet Factor 4/ or Protein C/ or Protein S/ or Prothrombin/ or Resistin/ or Plasminogen Inactivators/ or Platelet Activation/ or tau Proteins/ or Thrombin/ or Thrombomodulin/ or Thromboplastin/ or TUMOR NECROSIS FACTOR-ALPHA/ or Transforming Growth Factor beta/ or Vascular Endothelial Growth Factor A/ or Vitronectin/ or von Willebrand Factor/ or Tissue Plasminogen Activator/ec [Endogenous Compound]
  11. 5 or 6 or 7 or 8 or 9 or 10
  12. 4 and 11
  13. (alzheimer$ or coronary or fibrillation or cardiac or cardio$ or cadasil or diabetes or tumor ot tumor or trauma$ or angina or dement$ or child$ or pediatr$ or paediatr$ or newborn$). m_titl.
  14. stroke.m_titl.
  15. 13 not 14
  16. 12 not 15
  17. limit 16 to human
  18. (diagnos$ or sensitivity or specificity or odds ratio or likelihood ratio or LR).tw.
  19. 17 and 18

Modified QUADAS Questionnaire

  1. Is the reference standard likely to correctly classify the target condition?
       Yes: Expert clinical opinion supported by neuroimaging.
       No: No imaging, no expert opinion on stroke diagnosis.

  2. Did patients receive the same reference standard regardless of the index test result?
       Yes: All patients had reference standard. If "normal controls" recruited, some description of how stroke was excluded in the ‘normal’ cohort is necessary.
       No: Some patients who had the biomarker test did not have a sensible reference standard (ie, expert clinical opinion+ imaging).

  3. Was the reference standard independent of the index test?
       Yes: The biomarker status was not used to make a diagnosis of stroke.
       No: The biomarker status could be used to make a diagnosis of stroke.

  4. Were the index test results interpreted without knowledge of the results of the reference standard?
       Yes: The report mentions that assessors of biomarker status are blinded to stroke status.
       No: If the report states that the assessor of biomarker status had knowledge of stroke status.

  5. Were the reference standard results interpreted without knowledge of the results of the index test?
       Yes: Either the report mentions the diagnosis was collected before the blood marker was measured or there is mention of blinding.
       No: The reporter of the diagnostic study (expert or radiologist) has access to biomarker status.

  6. Were withdrawals from the study explained?
       Yes: All patients who enter the study complete it, or there is explanation of why some patients do not make it to analysis.
       No: Patients missing from final analysis without explanation.

  7. Was a cut-off established before the study was started?
       Yes: A cut-off was taken either from the literature or in a clearly defined pilot study before the analysis of the main data.
       No: Not true.

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  		Table I. Included Studies


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  		Table I. Continued


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  		Table II. Modified QUADAS Instrument to Assess Quality of Reporting


*    Acknowledgments
 
We are grateful for the helpful comments and discussions from Joanna Wardlaw, Carl Counsell, Rustam Al-Shahi Salman, Francesca Chappel, and Steff Lewis.

Sources of Funding

William Whiteley holds a Clinical Academic Training Fellowship from the Chief Scientist’s Office, Scottish Executive.

Disclosures

None.

Received December 3, 2007; revision received January 22, 2008; accepted January 30, 2008.


*    References
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 *References
 
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