1. Introduction
Every year, 15 million people worldwide suffer a stroke, resulting in 5 million deaths and 5 million individuals with significant disabilities for the remainder of their lives [
1]. In 2021, it was estimated that 795,000 people in the United States would experience a stroke, with 85% of cases being ischemic [
2]. The underlying causes of acute ischemic stroke (AIS) are not always easily identified. Nevertheless, the identification of its etiology is crucial for the management of patients, given that it is a leading cause of morbidity and mortality on a global scale. The etiology of AIS is diagnosed based on a combination of analytical and clinical parameters, cardiological testing, and parameters derived from qualitative analysis of radiological images. The TOAST (Trial of Org 10172 in Acute Stroke Treatment) criteria were developed to determine the origin of thrombi causing AIS and divide their probable etiology into five different groups: cardioembolic, atherothrombotic, lacunar infarct, unusual origin, and indetermined origin [
3]. Whilst the diagnosis of a lacunar or unusual stroke is relatively straightforward, the classification of an AIS as either a cardioembolic or atherothrombotic event is not always straightforward and is of significant clinical importance. In the context of secondary prevention management, patients with an atheromatous etiology will typically be administered antiplatelet therapy, whereas those with a cardioembolic origin will generally be provided with anticoagulant therapy. In many cases, patients may exhibit features associated with both etiological groups, resulting in an unknown etiology, or an “indetermined” classification according to the TOAST criteria. This hinders the formulation of effective secondary prevention strategies for these patients.
Furthermore, the molecular composition of a thrombus varies depending on the underlying cause [
4,
5]. Thrombi of atherothrombotic origin contain a greater proportion of red blood cells in comparison to those resulting from other etiologies classified within the TOAST system. In contrast, thrombi of cardiogenic origin exhibit a higher proportion of fibrin and platelets compared to those caused by other factors [
6,
7,
8]. This difference in molecular composition may therefore be a reason for a potentially different radiological behavior of these two types of thrombi. There have been reports of radiological differences between cardioembolic and atherothrombotic thrombi. The thrombi of cardioembolic origin have been shown to exhibit greater density and attenuation on Non-Contrast Computed Tomography (NCCT) [
9,
10]. This finding indicates that the radiological manifestation of the thrombus is contingent on its molecular composition and, consequently, its origin. Nevertheless, despite the molecular and radiological differences observed, no molecular or radiological criterion related to clots is utilized in the classification of the etiology of acute AIS.
Radiomics is a field of radiology that focuses on the extraction and analysis of a large number of quantitative data from radiological images that correlate with the underlying pathophysiology [
11]. Numerous studies have been conducted on this tool, with a particular focus on oncological pathology. These studies have demonstrated a correlation between radiomic data and various molecular patterns, genetic mutations, and other biological phenomena. However, recent studies using this technique outside oncological settings, particularly for neurologic diseases, have become increasingly common [
12]. Given the established differences in the molecular composition and radiological appearance of thrombi between etiologies of AIS, radiomics may provide further insight into these differences by analyzing quantitative data from images of thrombi. There are already a few recently published articles showing that radiomic data can provide important information to determine the different origins of thrombi in patients with AIS [
13,
14].
The hypothesis of this study is that the different molecular composition of thrombi of atherothrombotic and cardioembolic origin will result in a disparate radiomic pattern of thrombi from these two etiology groups on brain NCCT. This may provide valuable information in determining the etiology of AIS. Therefore, the objective of this article is to employ a machine learning model based on radiomic data obtained from thrombi in NCCT scans of patients with AIS, for the purpose of classifying them as cardioembolic or atherothrombotic etiology.
4. Discussion
The present study has demonstrated the capacity of radiomics to differentiate between cardioembolic and atherothrombotic thrombi. The molecular differences between these two types of clots also reflect a difference in imaging representation, thus establishing a correlation between the RF of NCCT images and the atherothrombotic and cardioembolic etiology of AIS. A total of 845 RFs were analyzed; however, only a subset of 10 RFs that were statistically associated with these two etiological groups (p < 0.05) were selected for further investigation. Multivariate analysis revealed no statistically significant association between these two etiologies of AIS and the clinical variables investigated, including clot density, arterial hypertension, dyslipidemia, diabetes mellitus, smoking, alcoholism, drug use, age, and sex (p-value > 0.05). Three predictive models were developed: one based on RF alone, one based on clinical variables alone, and a third model based on the combination of RF with clinical variables. An automatic classifier based on neural networks (Neural Network) has been used. The radiomic model performed very well, with an AUC of 0.842, an accuracy of 0.902, a Se of 0.833, and a Sp of 0.931. The model’s performance, as measured by Cohen’s Kappa index (K = 76.43%), demonstrated substantial agreement with the TOAST criteria, which are recognized as the gold standard for the etiological classification of AIS. However, when clinical variables were introduced into the model, its predictive performance was found to deteriorate, with the clinical model demonstrating the most unfavorable outcomes.
The present findings are consistent with those reported in two other articles published on the subject of the prediction of the etiology of AIS. Chen et al. obtained an AUC of 0.9018 and an accuracy of 0.8929 in differentiating between cardioembolic and atherothrombotic etiology using radiomic features based on CTA images [
13]. The most notable difference between the two studies is the source of the radiomic data. In the present work, the radiomic data are obtained from the NCCT, while in the referenced article, they are obtained from the CTA. A further distinction between our work and the referenced article is that we perform a semi-automatic segmentation, while they employed a manual segmentation. The semi-automated segmentation performed is based on automatic edge detection, with the radiologist responsible for ensuring that the segmentation includes as much of the thrombus area as possible. In patients with an arterial clot visible on NCCT, the contrast between the region of interest and the rest of the brain parenchyma is sufficiently remarkable to be easily detected by the automatic edge detection method, with the radiologist only intervening to accept or correct the segmentation performed. This made the segmentation faster and included the entire thrombi. Finally, the aforementioned article does not incorporate clinical variables within the radiomic analysis, in contrast to the approach employed in the present article.
Regarding the other published article, Jiang J et al. obtained an AUC of 0.838 in predicting the cardioembolic etiology of AIS in a sample of 403 patients, also using manual segmentation. They used NCCT-based radiomic features of patients with AIS [
14]. As far as this article is concerned, the main difference lies in the fact that in our case, we are trying to predict both etiological atherothrombotic and cardioembolic groups, instead of limiting ourselves to predicting only one of them. The segmentation process is also manual, as described by Chen et al. Furthermore, this article makes no mention of clinical variables in the context of radiomic analysis. On the other hand, the images used in this case are also from NCCT, which also gives good results in predicting the cardioembolic group, supporting our findings that there is a correlation between the radiomic data obtained from NCCT and the etiology of thromboembolic events in patients with AIS. Therefore, this article also concluded that radiomics could be helpful in determining the etiology of AIS.
Determining the etiology of AIS is crucial for effective therapeutic management and early implementation of appropriate secondary prevention measures [
27]. The classification of a stroke as lacunar or of infrequent etiology using the TOAST (Trial of Org 10172 in Acute Stroke Treatment) criteria is well-protocolized. However, in cases of cardioembolic and atherothrombotic etiology, the boundaries may be less clearly defined, resulting in a significant number of patients being labeled as having an “undetermined etiology”. In other cases, the information for etiology determination is only available after the acute onset of stroke, leading to delayed identification of the cause of AIS. The intention of this study is to utilize radiomics in order to provide additional information that will assist in the classification of patients who meet the criteria for both etiological groups, or whose etiology has been incompletely studied (classified as “indetermined” according to the TOAST criteria). However, thrombi of atherothrombotic and cardioembolic origin exhibit divergent molecular compositions [
5,
6,
7,
8], yet these specific molecular data remain inaccessible in the acute care setting for these patients. Conversely, radiomic data derived from NCCT are obtainable early in the management of patients with AIS. The present study makes a significant contribution to the extant literature by demonstrating that radiomics also has the capacity to differentiate thrombi of atherothrombotic origin from those of cardioembolic origin. These findings may assist in the timely and accurate diagnosis of the etiology of stroke in such patients.
Regarding the limitations of our study, the first one is that it is a retrospective study. In this regard, since there is not much literature available, we believe that the first step to investigate whether radiomics can contribute something to the diagnosis of the etiology of AIS is to perform a retrospective study, as it is the one that involves the least ethical conflicts, as well as not delaying or altering the usual management of these patients. Having shown that the association appears to exist with a retrospective study, we believe that the next step is to confirm these findings with a prospective study. Another classic limitation of radiomic studies is external validity. In our case, images from two different CT scanners of the same make and model were used. In this sense, it is necessary to include images from scanners of different manufacturers and from other hospitals to increase the external validity of these studies. For this reason, we believe that multicenter studies are also needed, because single-center studies seem to show that such an association exists. Finally, another limitation of radiomic studies is the difference in methodology between study groups in data processing and analysis of radiomic variables. In this case, it is necessary to publish in detail the steps carried out in order to increase the available bibliography in this field and to share methodologies that can be reproduced by other research groups, with the aim of unifying the analytical processes as much as possible. In terms of specific limitations of our study, it is important to note that we had a lower number of subjects in comparison to previous studies. This may limit the applicability of the study to clinical practice. Furthermore, the study exclusively includes patients with visible thrombus on NCCT, thereby limiting the generalizability of the results to those patients in whom the thrombus is not visible on NCCT. In our case, in addition to a significantly shorter recruitment period, the fact that only patients with a clot visible on NCCT and pure occlusion of the distal ICA or proximal branches of the MCA were selected meant that the N was not higher. With this in mind, a sampling method recommended for low N studies was used (LOOCV). Further patient recruitment is needed to increase the sample size and to include other patient groups not analyzed in the current article. The incorporation of additional imaging techniques and biomarkers may also result in an increase in the number of patients [
28]. With regard to the segmentation process, no study of interobserver variability has been conducted. Instead, the segmentations have been reviewed by a group of neuroradiologists who are experts in diagnosis and interventional procedures. Lastly, it is important to note that patient medication and thrombus age have not been considered in the present study, nor in any previously published research. These factors may vary in both etiological groups. In this regard, the relationship between antiplatelet and anticoagulant therapy, which could have the capacity to modify the composition of thrombus, has not been evaluated. This limitation has also been identified in the previously published studies, and it is recommended that it be explored in future research.