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PLOS One logoLink to PLOS One
. 2023 Mar 9;18(3):e0280752. doi: 10.1371/journal.pone.0280752

Clinical criteria to exclude acute vascular pathology on CT angiogram in patients with dizziness

Long H Tu 1,*, Ajay Malhotra 1, Arjun K Venkatesh 2, Richard A Taylor 2, Kevin N Sheth 3, Reza Yaesoubi 4, Howard P Forman 1, Soundari Sureshanand 5, Dhasakumar Navaratnam 3
Editor: Tatsushi Mutoh6
PMCID: PMC9997874  PMID: 36893103

Abstract

Background

Patients presenting to the emergency department (ED) with dizziness may be imaged via CTA head and neck to detect acute vascular pathology including large vessel occlusion. We identify commonly documented clinical variables which could delineate dizzy patients with near zero risk of acute vascular abnormality on CTA.

Methods

We performed a cross-sectional analysis of adult ED encounters with chief complaint of dizziness and CTA head and neck imaging at three EDs between 1/1/2014-12/31/2017. A decision rule was derived to exclude acute vascular pathology tested on a separate validation cohort; sensitivity analysis was performed using dizzy “stroke code” presentations.

Results

Testing, validation, and sensitivity analysis cohorts were composed of 1072, 357, and 81 cases with 41, 6, and 12 instances of acute vascular pathology respectively. The decision rule had the following features: no past medical history of stroke, arterial dissection, or transient ischemic attack (including unexplained aphasia, incoordination, or ataxia); no history of coronary artery disease, diabetes, migraines, current/long-term smoker, and current/long-term anti-coagulation or anti-platelet medication use. In the derivation phase, the rule had a sensitivity of 100% (95% CI: 0.91–1.00), specificity of 59% (95% CI: 0.56–0.62), and negative predictive value of 100% (95% CI: 0.99–1.00). In the validation phase, the rule had a sensitivity of 100% (95% CI: 0.61–1.00), specificity of 53% (95% CI: 0.48–0.58), and negative predictive value of 100% (95% CI: 0.98–1.00). The rule performed similarly on dizzy stroke codes and was more sensitive/predictive than all NIHSS cut-offs. CTAs for dizziness might be avoidable in 52% (95% CI: 0.47–0.57) of cases.

Conclusions

A collection of clinical factors may be able to “exclude” acute vascular pathology in up to half of patients imaged by CTA for dizziness. These findings require further development and prospective validation, though could improve the evaluation of dizzy patients in the ED.

Introduction

Posterior circulation stroke in patients presenting with dizziness is difficult to diagnose–delayed or missed diagnosis may occur in 37% of such cases on first medical contact [1]. An underlying ischemic stroke is present in 3–5% of patients presenting dizziness to the emergency department (ED) [2]. Large vessel occlusion (LVO) is the underlying etiology in approximately a third of posterior circulation ischemic strokes [3, 4]. LVO is therefore expected in ~1% of dizzy patients presenting to the ED. The National Institutes of Health Stroke Scale (NIHSS) is the most commonly used predictor in pre-hospital/pre-CTA risk assessment for LVO, however even a NIHSS of zero does not guarantee absence of LVO [5, 6].

Stroke or vessel occlusion with low NIHSS is more common in the posterior circulation and with non-focal presentations such as dizziness [5, 7]. Other acute vascular pathologies detectable on CTA include dissection and medium/small vessel occlusion; rarely, even ruptured aneurysm may initially present as dizziness [2, 810]. The early detection of these abnormalities may also impact patient management [11]. Therefore, predictive tools used to reassure against the need for emergent CTA or pre-hospital diversion to centers with endovascular capability would ideally consider these entities as well. In the absence of vessel abnormalities on CTA, underlying stroke is better detected by MRI or specialized bedside maneuvers [2, 12, 13]. Excluding the need for CTA may improve diagnosis by facilitating triage to these more sensitive modalities.

We hypothesize that there is a collection of clinical variables that can delineate a subpopulation of dizzy patients in whom there is a near zero probability of acute vascular pathology detectable on CTA. Such a collection of variables could form the basis of a decision rule guiding the selection of patients for CTA versus alternative testing. In this study, we perform a retrospective analysis to derive a decision rule excluding vascular pathology in dizzy ED patients. We then validate the rule on a temporally separate validation cohort and assess applicability to a similar group of “stroke code” presentations with dizziness. We compare performance to the NIHSS and estimate the proportion of CTA exams which are potentially avoidable.

Methods

Setting and design

We performed a cross-sectional analysis based on adult patient visits to one of three EDs in a healthcare system between 1/1/2014-12/31/2017. The first ED is a comprehensive stroke center, the second is a primary stroke center, the last is a smaller community ED. Adult (age ≥18 years) patient encounters with a chief complaint of dizziness who received CTA head and neck imaging were included for the analysis. Adult “stroke code” encounters during the same time period, with NIHSS ≤ 7 and a positive review of systems for dizziness were also obtained for a sensitivity analysis in patients presenting within the treatment window with high suspicion of stroke. An NIHSS cut off 7 was chosen based on prior literature showing that patients with NIHSS > 7 have greater risk of LVO, independent of presenting with dizziness [6, 14]. Additional details of patient eligibility for CTA imaging are provided in Item 1 in S1 File.

The study was approved by the Yale University IRB with consent waived. The decision rule was developed with reference to the transparent reporting of a multivariable prediction model for individual prognosis or diagnosis (TRIPOD) guidelines [15].

Data collection

Established vascular risk factors for stroke/LVO were identified based on a review of major recent literature and used to inform the first phase of feature selection [1620] [Item 2 in S1 File]. Clinical data expected to be available at the time of an imaging order were extracted from the electronic medical record database (EPIC)–including but not limited to recognized risk factors. Demographic information, past medical history (PMH), review of systems (ROS), and physical exam (PE) findings were obtained. Past medical history data also captured categories of medication use, smoking, and other substance use. Physical exam findings included systems-based exam findings as well as NIHSS and Glasgow Coma Scale data. All associated CTA head and neck exam reports were obtained.

Case categorization

CTA head and neck exam reports were categorized based on the presence of acute vascular abnormality. Acute vascular pathology was defined as large vessel occlusion, smaller arterial or venous occlusion, non-occlusive dissection, and aneurysm or other vascular lesion with hemorrhage. Operational definition of LVO is provided in Item 3 in S1 File. Various etiologies were included to account for the possibility that some patients with dizziness who do not have LVO may have other acute pathology whose acute management would be altered if detected on CTA. A decision rule excluding LVO but missing other entities requiring acute intervention would be less clinically useful. Age indeterminate though potentially acute findings were categorized as “positive” cases; this categorization was performed to maximize sensitivity even at the cost of potentially reduced specificity.

Feature coding and missing data

One-hot encoding was used to covert PMH data into categorical variables. Instead of grouping past medical history elements into categories (e.g., history of cancer or history of diabetes), specific diagnosis codes were included, to assess differential risk that may arise from different severity or manifestations of medical conditions. ROS and PE findings were represented by two binary variables, one representing occurrence of a “pertinent positive” (e.g., positive review of systems for headache) the other when occurring as a “pertinent negative” (e.g., negative review of systems for nausea). Absent or missing documentation was therefore represented as a null value for both pertinent positive and pertinent negative variables. Numerical values (e.g., age, pain rating) were coded as continuous variables. Additional details of feature encoding are given in Item 4 in S1 File.

Feature selection

The study population was split into training and validation cohorts consisting of the first 75% and last 25% of included patient encounters, respectively (corresponding to encounters before and after 14:27 on 5/12/2017). Features that were rarely documented in the medical record and therefore impractical for use in a decision rule were excluded. We initially assessed the 200 most documented PMH features, 100 most commonly ROS features, all numerical vital signs, and the 100 most commonly PE features; these were drawn from an initial pool of 1500, 186, and 266 of PMH, ROS, and PE features and covered 74.5%, 96.9%, and 97.5% of instances of documentation in these categories respectively. Features were then filtered to remove those with low relationship to the target variable based on Chi-Squared test, leaving the 100 highest ranked features.

Decision rule derivation via sequential covering

A decision tree was generated of sufficient depth to categorize all cases using the CART (Classification and Regression Trees) algorithm. Features were also ranked on random forest (Gini) importance to assess ability to separate positive and negative cases not just in the single tree, but across an ensemble of trees [21]; we used 100 trees, each with access to all top 100 Chi-Squared ranked features and allowed sufficient depth to categorize all cases. Features were then extracted to a decision rule in two phases. First, established vascular risk factors with high Gini importance (rank ≤ 5) were added to the list. Second, other (less-recognized) potential predictors were identified, based on highest Gini importance and location on the decision path predicting the largest leaf node without acute findings. Continuous variables were required to have a monotonic relationship with the target variable for inclusion, to account for the potential bias of Gini criteria toward high cardinality features [22]. Each time a feature was added to the list in either phase, the decision tree was re-created using cases not excluded by the evolving decision rule. Gini importance and decision tree structure were therefore used to obtain a list of features accounting for all positive instances of the target variable (i.e., via sequential covering [23]). Lastly, features on the list describing differing manifestations of a single condition were grouped into clinically coherent categories to arrive at the final decision rule. See Item 5 in S1 File for a schematic of this process.

Decision rule validation and sensitivity analysis

The decision rule was applied to the temporally separated testing cohort, with performance compared to the NIHSS. A sensitivity analysis for hyperacute presentations was also performed, by applying the rule to “stroke code” presentations with dizziness (within the review of systems) and a NIHSS ≤ 7.

Performance measures and statistical analysis

Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated, with 95% confidence intervals (CI) using the Wilson score method [24]. The proportion of patients predicted to have a negative exam (potentially avoidable CTAs) was also reported with 95% CI using Wilson score [24].

Software tools

Data management, coding, and analysis were done with Python (Version 3.7; Python Software Foundation; Delaware, US) in the PyCharm Integrated Development Environment (Version 2020.2.2; JetBrains; Prague, Czech Republic). Statistical and data analytic packages included pandas, sklearn, dtreeviz, and tableone [25]. Manual review and categorization of CTA findings was performed in Microsoft Excel (Version 2203; Microsoft; Redmond, Washington, US).

Results

Case characteristics (training and testing cohort)

During the study period, 15,483 adult patients presented to the ED with a chief complaint of dizziness. Of these, 1,429 (9.2%), received a CTA head and neck exam, and were included for analysis. Review of CTA head and neck results revealed 47 (3.3%) cases of acute vascular pathology (n = 31, 2.2% for LVO only) [Fig 1]. This set of cases was used to produce the training and validation cohorts. Demographic and clinical characteristics of patients with and without acute vascular pathology are provided in Table 1. Details of the positive cases are given in Item 6 in S1 File.

Fig 1. Flow of patients to categorization of acute vascular abnormality on CTA and subsequent temporal separation of cases into a training and validation cohort.

Fig 1

Table 1. Demographic and characteristics of cases with and without acute vascular pathology.

Characteristic Overall No Acute Vascular Pathology Acute Vascular Pathology P-Value
Total Number of Cases 1429 1382 47
Large Vessel Occlusion (LVO) 31 (2.2) 31 (66.0)
Demographic Features
Age, mean (SD) 63.8 (15.6) 63.6 (15.6) 67.7 (15.1) 0.079
Male 565 (39.5) 542 (39.2) 23 (48.9) 0.235
Ethnicity—Hispanic or Latino 189 (13.2) 185 (13.4) 4 (8.5) 0.452
Race—American Indian or Alaska Native 2 (0.1) 2 (0.1) 0 1
Race—Asian 31 (2.2) 31 (2.2) 0 0.622
Race—Black or African American 270 (18.9) 259 (18.7) 11 (23.4) 0.539
Race—Native Hawaiian or Other Pacific Islander 6 (0.4) 6 (0.4) 1
Race—White or Caucasian 975 (68.2) 943 (68.2) 32 (68.1) 0.891
Smoking—Active 173 (12.1) 167 (12.1) 6 (12.8) 0.931
Smoking—Former 560 (39.2) 539 (39.0) 21 (44.7) 0.527
Past Medical History
Coronary atherosclerosis of native coronary artery 17 (1.2) 14 (1.0) 3 (6.4) 0.016
Presence of coronary angioplasty implant and graft 35 (2.4) 31 (2.2) 4 (8.5)
Atherosclerotic heart disease of native coronary artery without angina pectoris 106 (7.4) 98 (7.1) 8 (17.0) 0.019
Atrial fibrillation 29 (2.0) 27 (2.0) 2 (4.3) 0.247
Cerebral infarction, unspecified 40 (2.8) 35 (2.5) 5 (10.6) 0.009
Dissection of vertebral artery 9 (0.6) 1 (0.1) 8 (17.0) <0.001
Occlusion and stenosis of carotid artery without mention of cerebral infarction 10 (0.7) 7 (0.5) 3 (6.4) 0.003
Transient ischemic attack (TIA), and cerebral infarction without residual deficits 24 (1.7) 20 (1.4) 4 (8.5) 0.007
Personal history of transient ischemic attack (TIA), and cerebral infarction without residual deficits 94 (6.6) 89 (6.4) 5 (10.6) 0.231
Essential (primary) hypertension 599 (41.9) 577 (41.8) 22 (46.8) 0.589
Hyperlipidemia, unspecified 276 (19.3) 262 (19.0) 14 (29.8) 0.097
Type 2 diabetes mellitus without complications 178 (12.5) 169 (12.2) 9 (19.1) 0.235
Migraine, unspecified, not intractable, without status migrainosus 22 (1.5) 21 (1.5) 1 (2.1) 0.524
Migraine, unspecified, without mention of intractable migraine without mention of status migrainosus 12 (0.8) 10 (0.7) 2 (4.3) 0.057
Morbid obesity 7 (0.5) 6 (0.4) 1 (2.1) 0.209
Long term (current) use of anticoagulants 90 (6.3) 81 (5.9) 9 (19.1) 0.002
Long term (current) use of antithrombotics/antiplatelets 27 (1.9) 23 (1.7) 4 (8.5) 0.01
Long term (current) use of aspirin 173 (12.1) 158 (11.4) 15 (31.9) <0.001

Unless otherwise specified, values are given as No. (%). Clinical characteristics that are known risk factors and that were the most commonly document features used for decision rule derivation are shown. Further details regarding the definition of current/former smoking and “long term” use of medications are given in Item 7 in S1 File.

The 75/25 temporal split of the study population into training and validation cohorts generated with data sets with 1072 and 357 cases, respectively. There were 41 cases of acute vascular pathology in the training set and 6 in the validation set (28 and 3 cases of LVO respectively) [Fig 1].

Decision rule list

Generation of a decision rule from the training cohort resulted in a collection of 23 features delineating a subset of encounters with zero cases of acute pathology. Summarizing these into clinical categories, we arrive at a decision rule predicting absence of acute vascular pathology in patients without a history of any of the following: stroke/transient ischemic attack (TIA), unexplained speech difficulty/ataxia or visual disturbances (i.e., possible prior stroke/TIA), dissection, coronary artery disease, diabetes, migraines, active/long-term smoking, and current long-term anti-platelet or anti-coagulant use [Table 2].

Table 2. List of features, summarized into clinical categories.

Broad Clinical Category Features
Adult ED patient presenting with a chief complaint of dizziness
    • Excluding those who may have an alternative indication for neurovascular imaging, aside from dizziness
Inclusion Criteria: Adult ED patients with chief complaint of dizziness.
Exclusion Criteria: Other chief complaints, where dizziness is not the predominant concern, though may be an associated symptom (e.g., focal neurologic deficit, trauma, headache)
No PMH of cerebrovascular event, specifically:
    • Dissection, stroke, or TIA (unexplained dysarthria/aphasia, ataxia, incoordination, and visual disturbances)
1. PMH–Dissection of vertebral artery
2. PMH–Transient ischemic attack (TIA), and cerebral infarction without residual deficits
3. PMH–Other cerebral infarction
4. PMH–Aphasia
5. PMH–Dysarthria and anarthria
6. PMH–Ataxic gait
7. PMH–Ataxia, unspecified
8. PMH–Lack of coordination
9. PMH–Other lack of coordination
10. PMH–Visual Disturbances
No PMH of specific vascular risk factors:
    • Coronary artery disease, diabetes, and current/long-term smoking, and migraines
11. PMH—Coronary atherosclerosis of native coronary artery
12. PMH—Atherosclerotic heart disease of native coronary artery without angina pectoris
13. PMH—Presence of aortocoronary bypass graft
14. PMH—Type II or unspecified type diabetes mellitus without mention of complication, not stated as uncontrolled
15. PMH—Encounter for long-term (current) use of insulin
16. PMH—Long term (current) use of insulin
17. PMH—Nicotine dependence, cigarettes, uncomplicated
18. Smoking–active
19. PMH—Migraine, unspecified, without mention of intractable migraine without mention of status migrainosus
20. PMH—Migraine, unspecified, not intractable, without status migrainosus
No current specific long-term medication use:
    • Anticoagulation or anti-platelet agents
21. PMH—Encounter for long-term (current) use of aspirin
22. PMH—Long term (current) use of antithrombotics/antiplatelets
23. PMH—Long term (current) use of anticoagulants

23 features were iteratively extracted from the training dataset, which together predict absence of acute vascular pathology in patients presenting to the ED with dizziness. Along with study inclusion/exclusion criteria, these are grouped in four broad groups. Further details regarding the definition of current/former smoking and “long term” use of medications are given in Item 7 in S1 File.

Decision rule performance

In the derivation phase, the rule applied to 603 of 1072 (56%) cases, excluding all 41 cases of pathology (28 cases of LVO). In the derivation set, the rule had a sensitivity of 100% (95% CI: 0.91–1.00), specificity of 59% (95% CI: 0.56–0.62), positive predictive value of 9% (95% CI: 0.07–0.12), and negative predictive value of 100% (95% CI: 0.99–1.00). A two-by-two table of patients excluded (vs. not excluded) by the decision rule and those with (vs. without) acute vascular pathology in the derivation phase is given in Item 8 in S1 File.

Application of the decision rule to the validation cohort predicted absence of acute vascular pathology in 185 of 357 (52%) cases, excluding all 6 cases of pathology (3 cases of LVO). This corresponds to a sensitivity of 100.0% (95% CI: 0.61–1.00), specificity of 53% (95% CI: 0.48–0.58), positive predictive value of 4% (95% CI: 0.02–0.07), and negative predictive value of 100% (95% CI: 0.98–1.00). The proportion of patients with near-zero risk and potentially avoidable CTAs was 52% (CI: 0.47–0.57).

The separate cohort used for sensitivity analysis (“stroke codes,” dizziness, NIHSS ≤ 7) consisted of 81 cases with 12 acute vascular findings (10 LVO). Application of the decision rule predicted absence of acute pathology in 35 patients (43%), excluding all cases of acute pathology. Sensitivity was 1.00 (95% CI: 0.76–1.00), specificity 0.51 (95% CI: 0.39–0.62), positive predictive value 26% (95% CI: 0.16–0.40), and negative predictive value was 100% (95% CI: 0.90–1.00). The proportion of dizzy “stroke code” presents with near-zero risk and potentially avoidable CTAs was 43% (95% CI: 0.33–0.54).

Performance of the decision rule in the validation phase compared to NIHSS cut-offs is given in Table 3. Results of the derivation phase and sensitivity analysis are provided separately [Item 9 in S1 File]. Details of NIHSS documentation and performance are given in the Item 10 in S1 File.

Table 3. NIHSS and decision rule performance.

Test Sensitivity Specificity Positive Predictive Value (PPV) Negative Predictive Value (NPV) Predicted Negative (PN)
NIHSS ≤ 8 0.00 (0.00–0.43) 0.03 (0.01–0.11) 0.00 (0.00–0.06) 0.29 (0.08–0.64) 0.10 (0.05–0.20)
NIHSS ≤ 7 0.00 (0.00–0.43) 0.03 (0.01–0.11) 0.00 (0.00–0.06) 0.29 (0.08–0.64) 0.10 (0.05–0.20)
NIHSS ≤ 6 0.00 (0.00–0.43) 0.05 (0.02–0.13) 0.00 (0.00–0.06) 0.38 (0.14–0.69) 0.12 (0.06–0.22)
NIHSS ≤ 5 0.20 (0.04–0.62) 0.08 (0.04–0.18) 0.02 (0.00–0.09) 0.56 (0.27–0.81) 0.13 (0.07–0.23)
NIHSS ≤ 4 0.20 (0.04–0.62) 0.10 (0.05–0.18) 0.02 (0.00–0.09) 0.60 (0.31–0.83) 0.15 (0.08–0.25)
NIHSS ≤ 3 0.20 (0.04–0.62) 0.13 (0.07–0.23) 0.02 (0.00–0.10) 0.67 (0.39–0.86) 0.18 (0.11–0.29)
NIHSS ≤ 2 0.40 (0.12–0.77) 0.18 (0.10–0.29) 0.04 (0.01–0.13) 0.79 (0.52–0.92) 0.21 (0.13–0.32)
NIHSS ≤ 1 0.40 (0.12–0.77) 0.29 (0.19–0.41) 0.04 (0.01–0.15) 0.86 (0.65–0.95) 0.31 (0.22–0.43)
NIHSS = 0 0.60 (0.23–0.88) 0.53 (0.41–0.65) 0.09 (0.03–0.24) 0.94 (0.81–0.98) 0.52 (0.40–0.64)
Decision Rule (validation) 1.00 (0.61–1.00) 0.53 (0.48–0.58) 0.04 (0.02–0.07) 1.00 (0.98–1.00) 0.52 (0.47–0.57)

Sensitivity and specificity of NIHSS cut-offs (0–8) and the clinical decision rule, when applied to the validation cohort. 95% confidence intervals are listed in parentheses. The clinical decision rule had higher sensitivity, specificity, and NPV than all cut-off values of the NIHSS; it also identified a larger proportion of patients (predicted negative) in whom CTA might be avoidable.

Discussion

In this study, we used retrospective data and a sequential covering approach to derive a decision rule excluding large vessel occlusion and other vascular pathology in patients presenting with dizziness. The resultant rule consists of well-recognized vascular risk factors and as well as other features identified based on random forest importance. The decision rule predicts absence of acute vascular pathology in patients who do not have any of the following past medical history features:

Stroke/transient ischemic attack (TIA), unexplained speech difficulty/ataxia or visual disturbances (i.e., possible prior stroke/TIA), dissection, coronary artery disease, diabetes, migraines, active/long-term smoking, and current long-term anti-platelet or anti-coagulant use. See Fig 2 for a visual representation of the rule.

Fig 2. Visualization of a potential decision rule to exclude acute vascular pathology in adult ED patients with chief complaint of dizziness.

Fig 2

Clinical criteria are grouped into closely related categories. Further development and validation are needed prior to application in clinical contexts.

In the testing cohort, the decision rule excluded acute vascular pathology with 100% sensitivity and 53% specificity, The rule was more sensitive than conventionally used NIHSS thresholds (NIHSS ≤ 7), as well as NIHSS = 0. Similar performance of the rule, 100% sensitivity and 51% specificity, was seen when applied to “stroke code” presentations with dizziness and with relatively lower risk of anterior circulation LVO (NIHSS ≤ 7). High sensitivity suggests utility as a “rule out” tool; non-applicability of the rule does necessarily indicate need for CTA or presence of underlying pathology. The decision rule applied to 52% of cases in the validation cohort and 43% of cases in the sensitivity analysis, suggesting that nearly half of CTA head and neck examinations might be avoidable, if such a tool were sufficiently reassuring to defer neurovascular imaging.

Dizziness is a non-specific symptom that accompanies a wide range of neurologic, cardiovascular, psychiatric, and other disease processes [2]. In this study, we focused on those patients in whom dizziness is the presenting complaint, and in whom there may be no alternative presentations warranting neurovascular evaluation. For example, patients who are dizzy in the setting of trauma or thunderclap headache would receive neurovascular evaluation for other reasons.

Our decision rule suggests that documented (otherwise unexplained) speech, coordination, and vision abnormalities be considered potential prior stroke or TIA for the purposes of risk stratification. This would be consistent with prior research showing that as many as 90% of posterior circulation TIAs may be misdiagnosed on first medical contact [26]. Among established vascular risk factors, smoking status and diabetes were included in the decision rule; hypertension and hyperlipidemia were conspicuously absent. It is conceivable that these or other risk factors for stroke would provide predictive value if the rule were updated or validated with additional data sets. Medical history elements seemed to be much more strongly predictive than review of system or physical exam findings, which may reflect the pre-selection of ED visits with dizziness as a primary concern. A notable difference between the risk factors highlighted by our study and existing predictive tools is the inclusion of migraine history as a predictive factor. Migraine with aura is a well-described, though perhaps underappreciated, risk factor for both dissection and stroke [2729]. Our study suggests potential value within prediction tools alongside more established vascular disease processes.

Prior research suggests that vascular imaging to evaluate for large vessel occlusion may be cost-effective in acute minor stroke patients even when the risk of LVO is low (0.2%) [30]. Predictive tools for vascular pathology in stroke need to have near-perfect sensitivity to appropriately defer neurovascular evaluation. The collection of risk factors highlighted by our study suggests that subpopulations of patients with dizziness may exist with near-zero risk for pathology detectable on CTA. None of the patients excluded by the decision rule (in the training, validation, or sensitivity analysis cohorts) had an acute abnormality on CTA. Future research could assess the potential role of such a decision rule in conjunction with existing bedside exams and risk stratification tools.

Strokes in the posterior circulation are less often caused by LVO than by cardiac embolism or lacunar mechanism [3]. The decision rule developed in this work may assist in distinguishing underlying etiologies by excluding patients with stenotic atherosclerosis/vasculopathy who subsequently develop vessel occlusion. CTA is less sensitive for subtle ischemic events that arise from distal embolic and other etiologies [2]. Patients with minimal risk for LVO, but still suspected to have stroke might could be prioritized for more sensitive MRI, HINTS (head impulse, nystagmus, and test of skew), or subspecialist consultation. Vascular imaging could be deferred in this cohort and performed only if alternative indications arise.

Limitations

Our study has some limitations. The first of these is the retrospective nature of data collection. Documentation in ED medical records is known to be inconsistent [31], which limits incorporation of predictive factors not appearing in the medical chart. Decision rule performance would also be impacted by medical history elements which may be present but not documented. Prospective and external validation would help address these limitations. Our data precede the COVID-19 pandemic; therefore, any potential thromboembolic risk from COVID-19 infection or related to rare vaccination side effects [32] are not captured. This possibility could be incorporated in future studies. Considering age-indeterminate findings on CTA to be potentially acute allowed us to err on the side of maximizing sensitivity, though could have reduced specificity for detection of acute abnormality. The consideration of a large and varied set of features allowed us to identify risk factors which may have been underappreciated, though could also reduce generalizability. The derivation of predictive tools for dizzy patients is complicated by the low prevalence of acute abnormality on imaging and therefore fewer positive events. We expect the need to refine the decision rule and estimates of performance with subsequent work using additional datasets. Most of the study limitations would have reduced the ability to identify patients at low risk; yet, we still found that half of patients may not have required CTA.

Conclusion

Our study suggests that a collection of clinical variables may delineate a sizeable subpopulation of dizzy patients receiving CTA in whom there is a near zero risk of acute vascular pathology including LVO. A decision rule composed of these predominantly well-recognized risk factors could apply to as many as half of patients currently evaluated by head and neck CTA. Further development and validation of this predictive tool would help guide efficient diagnosis and management of dizzy patients in the emergency department.

Supporting information

S1 File

(DOCX)

Data Availability

Deposited files can be found at: DOI 10.17605/OSF.IO/HWUK2.

Funding Statement

This work was supported by grant UL TR001863 from the National Center for Advancing Translational Science. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Decision Letter 0

Tatsushi Mutoh

8 Nov 2022

PONE-D-22-23945Clinical Criteria to Exclude Acute Vascular Pathology on CT Angiogram in Patients with DizzinessPLOS ONE

Dear Dr. Tu,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

==============================

ACADEMIC EDITOR: All issues raised by expert reviewers are required. I recommend inclusion of criteria on how to judje application of contrast CTA head and neck exam (clinical values of biochemical data on renal function, etc.) to 3 institutes studied in supplementary data. I understand CTA is easy to test in ED in the US; however in some other countries (e.g., Germany, Japan), non-contrast MR diffusion images (<30sec) and MRA (~30 min) could be proceeded to detect LVO in the posterior circulation for EVT. 

 Please include the following items when submitting your revised manuscript:

  • A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

  • A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

  • An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

==============================

Please submit your revised manuscript by Dec 23 2022 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Tatsushi Mutoh

Academic Editor

PLOS ONE

Journal Requirements:

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf   

2. Thank you for stating the following in the Competing Interests section:

“I have read the journal's policy and the authors of this manuscript have the following competing interests: LT reported receiving royalties for 2 textbooks, Search Pattern: A Systematic Approach to Diagnostic Imaging (2020) and A Brief Guide to the Neuroradiology Fellowship (2021), and was a student in the Yale University Investigative Medicine Program, which receives funding from the National Center for Advancing Translational Science, a component of the National Institutes of Health (NIH). KS reported receiving grants from Hyperfine during the conduct of the study and from the NIH, American Heart Association, and Biogen outside the submitted work. KS also reported receiving personal fees from Zoll (data and safety monitoring board chair), Alva Equity, and Cerovasc outside the submitted work. AV reported receiving grants from the US Centers for Medicare and Medicaid Services, Moore Foundation, American College of Radiology, and American College of Emergency Physicians outside the submitted work. No other disclosures were reported. The contents of this work are solely the responsibility of the authors and do not necessarily represent the official view of the NIH.”

Please confirm that this does not alter your adherence to all PLOS ONE policies on sharing data and materials, by including the following statement: "This does not alter our adherence to  PLOS ONE policies on sharing data and materials.” (as detailed online in our guide for authors http://journals.plos.org/plosone/s/competing-interests).  If there are restrictions on sharing of data and/or materials, please state these. Please note that we cannot proceed with consideration of your article until this information has been declared.

Please include your updated Competing Interests statement in your cover letter; we will change the online submission form on your behalf.

3.  Please include your full ethics statement in the ‘Methods’ section of your manuscript file. In your statement, please include the full name of the IRB or ethics committee who approved or waived your study, as well as whether or not you obtained informed written or verbal consent. If consent was waived for your study, please include this information in your statement as well.

4. We note that you have stated that you will provide repository information for your data at acceptance. Should your manuscript be accepted for publication, we will hold it until you provide the relevant accession numbers or DOIs necessary to access your data. If you wish to make changes to your Data Availability statement, please describe these changes in your cover letter and we will update your Data Availability statement to reflect the information you provide.

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6. Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

********** 

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: I Don't Know

********** 

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: No

Reviewer #2: Yes

********** 

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

********** 

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The paper entilted "Clinical Criteria to Exclude Acute Vascular Pathology on CT Angiogram in Patients with

Dizziness" is well written. I have no concern about the methods, results, and data interpretations. There is only one minor issue need the authors to revise:

“Review of system” was incorrectly abbreviated as “PE” in the paragraph of data collection.

Reviewer #2: The purpose of this retrospective cross-sectional study was to identify a subpopulation of dizzy patients with near zero probability of acute vascular pathology detectable on CTA. The authors created a decision rule consisting of clinical factors that could exclude all cases of acute vascular pathology on CTA. The proposed sensitivity of the decision rule (100%) appears to be better than that of any thresholds of NIHSS scores up to 8 points.

This study documents interesting features concerning that as many as half of currently conducted head and neck CTA was avoidable.

I agree with the authors that this decision rule which was made to maximize sensitivity can potentially be a useful rule-out tool to detect dizzy patients who don’t need to undergo CTA, with future research assessment.

However, I have some suggestions for clarifying some aspects of the manuscript.

Specific points to be addressed are as follows.

1) Abstract (conclusion):

It is questionable to conclude that, "A collection of clinical factors may be able to “exclude” acute vascular pathology in up to half of the patients presenting to the ED with dizziness" since this study has excluded dizzy patients not receiving CTA head and neck, and targets acute vascular pathology detected on CTA. I recommend that the authors should tone down the statement as written in the discussion/conclusion of the manuscript and clarify that "acute vascular pathology” means that detectable on CTA.

2) Methods:

(3rd Para) Data Collection

(2nd page of the methods, 1st line) The authors wrote that “review of systems (PE)”, but isn’t it ROS?

3) Results:

(3rd Para) Decision Rule Performance

(4th page of the results, 5th line) The authors described the sensitivity and specificity of the decision rules applied in the derivation phase cohort. Since the rule was composed of negative forms and made as exclusion criteria, sensitivity and specificity seem complicated at first sight. Adding the conventional two-by-two table of patients with/without acute vascular pathology on CTA and patients included in the rules (low risk)/NOT included in the rules (NOT low risk), as Supplemental data would be helpful for readers.

4)Table1, Table2:

There are some criteria with “long-term”, such as long-term smoking, and long-term medication use. How long do you define the length of “long-term”? Please describe.

5)Table 3:

The table compares the sensitivity and specificity of NIHSS and the clinical decision rule when applied to the validation cohort. However, the performance of the decision rule during the derivation phase and sensitivity analysis are also added. I think that those are not appropriate to add in parallel in this table since they are applied in the different cohorts. I would recommend the values of NIHSS and validation cohort and those of derived phase and sensitivity analysis are presented separately.

********** 

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

**********

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

PLoS One. 2023 Mar 9;18(3):e0280752. doi: 10.1371/journal.pone.0280752.r002

Author response to Decision Letter 0


25 Nov 2022

*The following has been uploaded as a file with the revision, pasted below from Word file.*

We would first like to thank the academic editor and reviewers for their thorough and insightful comments. We have addressed all suggestions, and are amenable to further revisions should they help clarify this work.

ONE-D-22-23945

Clinical Criteria to Exclude Acute Vascular Pathology on CT Angiogram in Patients with Dizziness

PLOS ONE

Dear Dr. Tu,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

==============================

ACADEMIC EDITOR: All issues raised by expert reviewers are required. I recommend inclusion of criteria on how to judje application of contrast CTA head and neck exam (clinical values of biochemical data on renal function, etc.) to 3 institutes studied in supplementary data. I understand CTA is easy to test in ED in the US; however in some other countries (e.g., Germany, Japan), non-contrast MR diffusion images (<30sec) and MRA (~30 min) could be proceeded to detect LVO in the posterior circulation for EVT.

Thank you so much for this thoughtful perspective. We have elaborated on the selection of patients for contrast CTA head and neck, including with regard to renal function. We very much agree that where available, non-contrast MR diffusion and/or MRA offers the potential for alternative workflows – we have also provided additional discussion on these scenarios. The additions are within S1 Supporting Information and referenced in Methods (Setting and Design). The Supporting Information is re-numbered/reformatted throughout.

Please include the following items when submitting your revised manuscript:

• A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

==============================

Please submit your revised manuscript by Dec 23 2022 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Tatsushi Mutoh

Academic Editor

PLOS ONE

Journal Requirements:

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

Done. Thank you.

2. Thank you for stating the following in the Competing Interests section:

“I have read the journal's policy and the authors of this manuscript have the following competing interests: LT reported receiving royalties for 2 textbooks, Search Pattern: A Systematic Approach to Diagnostic Imaging (2020) and A Brief Guide to the Neuroradiology Fellowship (2021), and was a student in the Yale University Investigative Medicine Program, which receives funding from the National Center for Advancing Translational Science, a component of the National Institutes of Health (NIH). KS reported receiving grants from Hyperfine during the conduct of the study and from the NIH, American Heart Association, and Biogen outside the submitted work. KS also reported receiving personal fees from Zoll (data and safety monitoring board chair), Alva Equity, and Cerovasc outside the submitted work. AV reported receiving grants from the US Centers for Medicare and Medicaid Services, Moore Foundation, American College of Radiology, and American College of Emergency Physicians outside the submitted work. No other disclosures were reported. The contents of this work are solely the responsibility of the authors and do not necessarily represent the official view of the NIH.”

Please confirm that this does not alter your adherence to all PLOS ONE policies on sharing data and materials, by including the following statement: "This does not alter our adherence to PLOS ONE policies on sharing data and materials.” (as detailed online in our guide for authors http://journals.plos.org/plosone/s/competing-interests). If there are restrictions on sharing of data and/or materials, please state these. Please note that we cannot proceed with consideration of your article until this information has been declared.

Please include your updated Competing Interests statement in your cover letter; we will change the online submission form on your behalf.

We have added the relevant statement. Updated Competing Interests are included in the cover letter.

3. Please include your full ethics statement in the ‘Methods’ section of your manuscript file. In your statement, please include the full name of the IRB or ethics committee who approved or waived your study, as well as whether or not you obtained informed written or verbal consent. If consent was waived for your study, please include this information in your statement as well.

Done. Thank you.

4. We note that you have stated that you will provide repository information for your data at acceptance. Should your manuscript be accepted for publication, we will hold it until you provide the relevant accession numbers or DOIs necessary to access your data. If you wish to make changes to your Data Availability statement, please describe these changes in your cover letter and we will update your Data Availability statement to reflect the information you provide.

Thank you, yes. We will be providing repository information with acceptance.

5. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information.

We have done this. There is only one supporting information file, containing 10 items. Please feel free to edit/remove the details provided.

6. Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Done. Thank you.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

________________________________________

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: I Don't Know

________________________________________

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: No

Reviewer #2: Yes

________________________________________

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

________________________________________

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The paper entilted "Clinical Criteria to Exclude Acute Vascular Pathology on CT Angiogram in Patients with

Dizziness" is well written. I have no concern about the methods, results, and data interpretations. There is only one minor issue need the authors to revise:

“Review of system” was incorrectly abbreviated as “PE” in the paragraph of data collection.

Thank you so much for the consideration. Yes, this was an oversight. We have made the correction.

Reviewer #2: The purpose of this retrospective cross-sectional study was to identify a subpopulation of dizzy patients with near zero probability of acute vascular pathology detectable on CTA. The authors created a decision rule consisting of clinical factors that could exclude all cases of acute vascular pathology on CTA. The proposed sensitivity of the decision rule (100%) appears to be better than that of any thresholds of NIHSS scores up to 8 points.

This study documents interesting features concerning that as many as half of currently conducted head and neck CTA was avoidable.

I agree with the authors that this decision rule which was made to maximize sensitivity can potentially be a useful rule-out tool to detect dizzy patients who don’t need to undergo CTA, with future research assessment.

However, I have some suggestions for clarifying some aspects of the manuscript.

Specific points to be addressed are as follows.

1) Abstract (conclusion):

It is questionable to conclude that, "A collection of clinical factors may be able to “exclude” acute vascular pathology in up to half of the patients presenting to the ED with dizziness" since this study has excluded dizzy patients not receiving CTA head and neck, and targets acute vascular pathology detected on CTA. I recommend that the authors should tone down the statement as written in the discussion/conclusion of the manuscript and clarify that "acute vascular pathology” means that detectable on CTA.

Yes. We agree completely. The original statement was inexact. We have updated the relevant line in the abstract and clarified a similar line in the discussion/conclusion.

2) Methods:

(3rd Para) Data Collection

(2nd page of the methods, 1st line) The authors wrote that “review of systems (PE)”, but isn’t it ROS?

Yes. This was an error. Thank you. We have made the correction.

3) Results:

(3rd Para) Decision Rule Performance

(4th page of the results, 5th line) The authors described the sensitivity and specificity of the decision rules applied in the derivation phase cohort. Since the rule was composed of negative forms and made as exclusion criteria, sensitivity and specificity seem complicated at first sight. Adding the conventional two-by-two table of patients with/without acute vascular pathology on CTA and patients included in the rules (low risk)/NOT included in the rules (NOT low risk), as Supplemental data would be helpful for readers.

This is a great point. We have added such a table to S1 Supporting Information and referenced it in-text in the results.

4)Table1, Table2:

There are some criteria with “long-term”, such as long-term smoking, and long-term medication use. How long do you define the length of “long-term”? Please describe.

Thank you. We have described these designations further in S1 Supporting Information, with reference within the legends for Table 1 and Table 2. We would also like to note here that we noticed a typo in table 2 in enumerating 22 features summarized into 4 broad clinical categories. There are 23 features (two related to insulin use were previously listed on the same line) – we have made appropriate corrections in the legend/text. Please let us know if this is alright.

5)Table 3:

The table compares the sensitivity and specificity of NIHSS and the clinical decision rule when applied to the validation cohort. However, the performance of the decision rule during the derivation phase and sensitivity analysis are also added. I think that those are not appropriate to add in parallel in this table since they are applied in the different cohorts. I would recommend the values of NIHSS and validation cohort and those of derived phase and sensitivity analysis are presented separately.

Yes. We agree completely. We have removed the derivation and sensitivity analysis from this table. We have instead presented decision rule performance in the differing phases of the study in a table within the S1 Supporting Information, indicating that the measures are produced using differing patient cohorts. Thank you!

________________________________________

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Reviewer #1: No

Reviewer #2: No

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Attachment

Submitted filename: Reviewer Comments.docx

Decision Letter 1

Tatsushi Mutoh

8 Jan 2023

Clinical Criteria to Exclude Acute Vascular Pathology on CT Angiogram in Patients with Dizziness

PONE-D-22-23945R1

Dear Dr. Tu,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Tatsushi Mutoh

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

The authors have done a good job of addressing most of the comments from the reviewers.

I could only find some errors and/or corrections--please see two reviewers' comments.

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: I Don't Know

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The authors addressed all the concerns raised in the last round of review.

However, it seems that Table 3 was not revised correctly according to the suggestion from reviewer 2 (the derivation and sensitivity analysis should be removed).

Reviewer #2: Thank you for the revised manuscript. The authors answered the points raised by the reviewer.

Although I am mostly satisfied with this revision, I still find several minor corrections as follows.

1, Supporting information, item 7, line 4

There remain the words `Our stu`. Please delete them.

2, Table 3

In the rebuttal letter, the authors wrote that they had removed the derivation and sensitivity analysis from the table, but they are still in the table. Please check and correct them.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

**********

Acceptance letter

Tatsushi Mutoh

27 Feb 2023

PONE-D-22-23945R1

Clinical Criteria to Exclude Acute Vascular Pathology on CT Angiogram in Patients with Dizziness

Dear Dr. Tu:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Tatsushi Mutoh

Academic Editor

PLOS ONE


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