. 2013 Nov;9(4):340–352. doi: 10.2174/1573403X10666140214122633

Table 5.

General pro’s and con’s of studies conducted aiming to find ischemic stroke etiology biomarkers.

Strenghts	Shortcommings
Some published studies include large cohorts (n>200 patients). The great majority of studied biomarkers for stroke etiology can be easily determined in blood samples. The most promising biomarkers are related to specific chronic condition prior to brain artery occlusion (i.e. cardiac dysfunctions or insufficiency). Some biomarkers, especially when combined, have showed high sensitivity and specificity for cardioembolic stroke i.e D-dimer & BNP combination [24], NT-proBNP [27], etc Some biomarkers have been proven to clear up undetermined strokes, i.e D-dimer & BNP combination [24] or a panel including 40 genes expression profile [77]. Most of those studies show optimal cutoff points for the studied biomarkers and perform logistic regression models to find out if a biomarker might independently predict cardioembolic stroke. Some of the markers may be determined some days after the acute event and still have an acceptable predictive value. Relevant clinical decisions may be done using these markers (i.e. to shift antiplatelet to anticoagulant regime).	There is currently no “gold-standard” to define the exact etiology/mechanism of stroke. Some underlying conditions i.e. inflammation, endothelial damage are common among different stroke etiologies, making some of the biomarkers unspecific. The clot formation usually occurs hours before sample collection. Therefore, a biomarker specifically related to this event might be partly cleared from circulation at that time. Most of times samples are taken after 4.5 hours, thus currently the great majority of the studied biomarkers might not be useful during acute phases. Most published studies do not report temporal profiles of the biomarker after stroke onset and among etiologies, therefore the ideal time point of the biomarker to be used remains elusive. Biomarker studies, especially those with small sample size, do not show a biomarker cutoff point and a logistic regression analysis nor other statistical metrics (i.e. IDI). Cardioembolic related biomarkers might be also associated with the cardiovascular disorders originating the index stroke. Ongoing therapies prior to stroke onset are not always taken into account in patient’s selection criteria. Previous anticoagulation or antiplatelet therapies might influence biomarker levels. Clinical models are not always adjusted by NIHSS and infarct size. As CE stroke is more pronounced than other etiologies it might be a confounder to be taken into account.

Strenghts

Shortcommings

Some published studies include large cohorts (n>200 patients).
The great majority of studied biomarkers for stroke etiology can be easily determined in blood samples.
The most promising biomarkers are related to specific chronic condition prior to brain artery occlusion (i.e. cardiac dysfunctions or insufficiency).
Some biomarkers, especially when combined, have showed high sensitivity and specificity for cardioembolic stroke i.e D-dimer & BNP combination [24], NT-proBNP [27], etc
Some biomarkers have been proven to clear up undetermined strokes, i.e D-dimer & BNP combination [24] or a panel including 40 genes expression profile [77].
Most of those studies show optimal cutoff points for the studied biomarkers and perform logistic regression models to find out if a biomarker might independently predict cardioembolic stroke.
Some of the markers may be determined some days after the acute event and still have an acceptable predictive value.
Relevant clinical decisions may be done using these markers (i.e. to shift antiplatelet to anticoagulant regime).

There is currently no “gold-standard” to define the exact etiology/mechanism of stroke.
Some underlying conditions i.e. inflammation, endothelial damage are common among different stroke etiologies, making some of the biomarkers unspecific.
The clot formation usually occurs hours before sample collection. Therefore, a biomarker specifically related to this event might be partly cleared from circulation at that time.
Most of times samples are taken after 4.5 hours, thus currently the great majority of the studied biomarkers might not be useful during acute phases.
Most published studies do not report temporal profiles of the biomarker after stroke onset and among etiologies, therefore the ideal time point of the biomarker to be used remains elusive.
Biomarker studies, especially those with small sample size, do not show a biomarker cutoff point and a logistic regression analysis nor other statistical metrics (i.e. IDI).
Cardioembolic related biomarkers might be also associated with the cardiovascular disorders originating the index stroke.
Ongoing therapies prior to stroke onset are not always taken into account in patient’s selection criteria. Previous anticoagulation or antiplatelet therapies might influence biomarker levels.
Clinical models are not always adjusted by NIHSS and infarct size. As CE stroke is more pronounced than other etiologies it might be a confounder to be taken into account.