Abstract
Background
Direct endoluminal imaging, such as with our previously described microangioscope, is an emerging adjunct in endovascular cerebral aneurysm management that enables clinicians to delineate between thrombi and visualize neoepithelialization after stent placement with high resolution. The present study sought to study flow diversion in vivo under direct endoluminal imaging, and to validate our findings with histopathology.
Methods
In a rabbit model, we implanted each left common carotid artery with a shielded flow diverter (FD) (Medtronic Pipeline Vantage) and nonshielded FD (Medtronic Pipeline Flex) in the right common carotid artery. We studied 9 animals in 3 groups: (1) no periprocedural antiplatelet therapy, (2) aspirin 81 mg daily, and (3) aspirin 81 mg and clopidogrel 75 mg daily. FD thrombosis, stenosis, malapposition, and neoepithelialization were all evaluated by diagnostic cerebral angiography and microangioscopy after 30 days. Diagnostic cerebral angiography and angioscopic video were analyzed by independent evaluators and compared with histopathologic analysis.
Results
In the aspirin and dual antiplatelet therapy groups, there were no significant observed differences in stent thrombosis, stenosis, malapposition, or neoepithelialization between the shielded and non‐shielded FD groups. There was significantly more thrombus formation in Group 1. Neointimal thickness as measured by the microangioscope was highly correlated with histology (r = 0.72; P = 0.016). Interrater agreement of microangioscope videos was highest for FD thrombosis and stenosis.
Conclusion
In‐stent thrombosis, stenosis, malapposition, and neopithelialization demonstrated no significant difference between shielded and non‐shielded FDs. Microangioscopy measurements for neointimal thickness were highly correlated with pathology and may be a helpful adjunct to diagnostic cerebral angiography in FD follow‐up.
Keywords: angiography, angioscopy, flow diversion, flow diverter, microangioscope, microangioscopy
Nonstandard Abbreviations and Acronyms
- CCA
common carotid artery
- DSA
digital subtraction angiography
- FD
flow diverter
- PED
pipeline embolization device
- PO
per os
Clinical Perspective
What Is New?
The microangioscope is a high‐resolution imaging device that allows real‐time visualization of the vasculature during neurointerventional procedures.
The ability of the microangioscope to evaluate clot formation, in‐stent stenosis, and endothelialization after flow diversion has not been studied.
The microangioscope was given moderate reliability scores for the evaluation of stenosis and thrombosis, and was less consistent in visualization of calcification, endothelial coverage, and flow diverter wall apposition.
What Are the Clinical Implications?
The microangioscope is a promising modality for neurointerventionalists to visualize endoluminal characteristics in an accurate and minimally invasive manner.
Further studies and development are necessary to support the microangioscope as a practical complement to angiographic imaging.
A microangioscope is a high‐resolution imaging tool with wide potential applications in neurointerventional surgery. 1 It provides real‐time visualization of the vasculature during endovascular procedures, enabling physicians to assess the aneurysm, identify thrombus, and evaluate recently deployed flow diverter stents. The images obtained through microangioscopy, when combined with digital subtraction angiography (DSA), can provide complementary information for treatment planning, including the selection of endovascular devices and early troubleshooting. 2
In our previous study, we evaluated different interventional applications and found that the microangioscope visualization capabilities have advantages over conventional angiography in the following areas: In vascular diagnostics, microangioscopy can identify and distinguish between clots of different compositions, identify plaques in vessels with various characteristics, inspect vessel wall injuries, and assess the apposition and endothelialization of flow‐diverters.
Thus, in a follow‐up study, we sought to assess the utility of the microangioscope to evaluate clot formation, in‐stent stenosis, and endothelialization after flow diversion using a rabbit model.
Methods
Animal Procedures
Data are available upon request to the corresponding author. Five‐ to 8‐month‐old New Zealand White rabbits of both sexes and weighing 3.5 to 4 kg were used in this study. All procedures were approved by the Institutional Animal Care and Use Committee, under Protocol #2011099 and conducted under the National Institutes of Health guidelines for the care and use of laboratory animals. Prototype microangioscopes, not yet commercially available, were used for intravascular visualization (Vena Medical, Kitchener, ON). The development of the microangioscope and technologic background have been previously described. 1
Nine animals were included in this study and divided into 3 groups (N = 3 per group). Group 1 received no antiplatelet therapy. Group 2 received aspirin 5 mg/kg PO every day for 17 days beginning 2 days prior to the initial procedure. Group 3 animals received aspirin 5 mg/kg and clopidogrel 75 mg/kg PO every day for 17 days beginning 2 days prior to the initial procedure.
Periprocedural animal care was provided by a veterinary team, according to previously published protocols. 2 The right femoral artery was exposed by direct cut‐down and then accessed via micropuncture technique with insertion of a Terumo slender 5F dilator into the artery. Under fluoroscopic guidance, a Phenom 27 and 21 microcatheter (Medtronic Neurovascular, Minneapolis, MN) were advanced over a Synchro standard microwire into the right and left common carotid artery (CCA), respectively. A pipeline embolization device (PED, Medtronic) was then deployed using standard technique. Each animal was used as an internal control: in the right CCA, a PED Flex (no coating) was deployed via Phenom 27, and in the left CCA, a PED Vantage with Shield technology (covalently bonded synthetic phosphorylcholine biocompatible polymer 3 ) was deployed via Phenom 21. Baseline and immediate postdeployment angiography (DSA) were performed to provide a baseline image for the vessel and assess immediate device placement and complications such as thrombus formation. Different antiplatelet regimens and devices were used to explore the sensitivity of the microangioscope to detect thrombotic events.
At 30 days, follow‐up angiography was performed in all animals using the same techniques mentioned previously from a left femoral artery cut‐down. A 5F Envoy guiding catheter was advanced over a Synchro standard microwire into right and left CCA. The microangioscope was then forwarded to visualize the endothelization and other intraluminal changes. As previously described, continuous high‐flow irrigation (50 mL/min) was performed to allow for visualization. On completion of the study, the animals were euthanized under anesthesia. Further details about animal research methodology (according to Animal Research: Reporting of In Vivo Experiments guidelines; https://arriveguidelines.org/).
Histologic Analysis
Standard hematoxylin and eosin staining was conducted to evaluate tissue samples by an outside pathology service provided by the sponsor in graded fashion. The assessment included the examination of endothelial cell growth, thrombus formation, and gross pathology.
Evaluation and Statistical Analysis
Three independent evaluators (board‐certified neuroradiologist or interventional neuroradiologists) assessed the microangioscope video in several domains applicable to flow diversion treatment. These were: presence of luminal thrombus, calcification, endothelial coverage, in‐stent stenosis, and device wall apposition. These same factors were independently evaluated by gold standard histology and diagnostic angiography as well. The scoring guidelines were as follows. Malapposition (0–5): Full contact (0), 80% stent contact (1), 60% vessel stent contact (2), 40% vessel‐stent contact (3), 20% vessel‐stent contact (4), no contact (5). Thrombosis (0–4): none (0), minimal focal (1), mild multifocal (2), moderate, regionally diffuse (4), severe, marked diffuse or total luminal occlusion (4). Endothelial coverage (0–4): absence of endothelium (0), <25% of luminal surface covered (1), 25%–50% of luminal surface covered (2), 51%–74% of luminal surface covered (3), >75% of luminal surface covered (4). Neointimal thickness (0–3): absent to focal interstitial fibrin, minimal spotting of fibrin, generally consistent with background levels (0), <10% of artery circumference showing interstitial fibrin (1), 10%–25% of artery circumference showing interstitial fibrin (2), >25% of the artery circumference showing interstitial fibrin (3). Stenosis (0–4): absence of plaque and no luminal stenosis (0), plaque with 20%–49% stenosis (1), plaque with 50%–69% stenosis (2), plaque with 70%–99% stenosis (3), complete occlusion of the lumen (4). Microangioscope videos with annotation from prior experiments were used to train the evaluators (Video S1).
Statistical analysis was performed in RStudio for typical descriptive statistics; mean ratings are displayed as standard deviation (SD). Interrater reliability was calculated with intraclass correlation coefficient statistic. The intraclass correlation coefficient, a widely used reliability index for interrater reliability analyses, was used to evaluate the factors listed previously across all modalities (DSA, histology, microangioscope). The intraclass correlation coefficient values were evaluated as follows: values >0.9 indicated excellent reliability, values 0.75–0.9 indicated good reliability, and values 0.5–0.75 indicated moderate reliability. 4
Results
A total of 9 rabbits underwent device implantation in the study. Implantation was successful in the right CCA in 9/9 (100%) of rabbits and left CCA in 9/9 (100%) rabbits (Figure 1). All 9 animals were recovered and survived for 1 month postimplantation. After 30 days, all animals underwent follow‐up angiography (DSA) with microangioscopy, followed by tissue harvest and gross/histologic pathology. Examples of microangioscope‐derived images including stent endothelialization, thromboses, and perforant backflow are available at Figure 2.
Figure 1.
Carotid angiography. A, B, PED Flex (no coating) was deployed in the right CCA, and PED Vantage with Shield technology in the left CCA. C, Control carotid angiography 30 days after demonstrates the right CCA fully patent. CCA indicates common carotid artery; PED, pipeline embolization device.
Figure 2.
Microangioscope‐derived still images. A, B Metal stent, view from inside, without endothelialization: inner surface appears reflective and shiny, in contrast to the greyish, darker appearance of the endothelialized stent (B). C, Free in‐stent thrombus. D, Backflow from perforating arteries through stent cells.
Videos of the microangioscopic video and DSA were assessed and scored by 3 reviewers across 5 domains for a total of 270 scores. Intraclass correlation for these scores is shown in Figure 3. The mean scores given across 5 domains (malapposition, thrombosis, endothelial coverage, neointimal thickness, and in‐stent stenosis) are demonstrated in Figure 4. Individual differences among raters for each imaging modality were quantified by 1‐way agreement single score intraclass correlation (Table S1). Individual rater scores are available in Tables S2–S4. Spearman correlation between imaging modality and used scales are available in Tables S5 and S6.
Figure 3.
Interrater correlation showed a significant level of agreement between reviewer scores for the stenosis digital subtraction angiography (DSA) scores, stenosis angioscope scores, neointimal thickness DSA scores, thrombosis DSA scores, and thrombosis angioscope scores. There was no significant agreement between reviewers for the other imaging methods/scales.
Figure 4.
Histologic, angiographic, and microangioscope evaluations scores across various factors (malapposition, thrombosis, endothelial coverage, neointimal thickness, and stenosis). On the left, the 3 groups are shown (aspirin [ASA] only, aspirin+clopidogrel, and control). Across both the Vantage and Flex devices, no significant differences were seen across the domains as assessed by any of the 3 modalities. Correlation analysis by modality showed significant correlation for stenosis scores between digital subtraction angiography (DSA) and angioscope, as well as between DSA and histology. Scores were significantly correlated for neointimal thickness between angioscope and histology. Single score intraclass correlation also showed significant intramodality agreement for stenosis scores between DSA, angioscope, and histology. All other modality combinations were not significantly correlated with each other for the measured scales.
Overall, the interclass correlation coefficient showed a high level of reliability between reviewers for DSA scores for the stenosis and thrombosis; moderate reliability for microangioscope scores of thrombosis and stenosis. Poor reliability was found for other imaging methods and scales.
There was no significant difference in the histology, DSA scores, or microangioscope scores between the PED Vantage and PED Flex flow diverter types for the 3 treatment groups: aspirin, aspirin/clopidogrel, or control.
Correlation analysis by modality showed significant correlation for stenosis scores between DSA and microangioscope, as well as between DSA and histology. For neointimal thickness, microangioscope and histology scores were significantly correlated. Single score intraclass correlation also showed significant intramodality agreement for stenosis scores between DSA, microangioscope, and histology. All other modality combinations were not significantly correlated with each other for the measured scales.
Example video clips of the microangioscope visualizing each factor are available (Video S2).
Discussion
Main Findings
This study demonstrated the feasibility of incorporating microangioscopy during flow diversion treatment procedures. The microangioscope was used at multiple steps during the treatment – predeployment evaluation of the vessel, postdeployment, and follow‐up. The easily interpretable images provided by the microangioscope were used to evaluate clinically relevant end points. The assessment was benchmarked against histology and diagnostic cerebral angiography, which are the overall and in vivo gold standards. Interrater correlation showed a significant level of agreement between reviewer scores for the stenosis DSA scores, stenosis microangioscope scores, neointimal thickness DSA scores, thrombosis DSA scores, and thrombosis microangioscope scores. There was no significant agreement between reviewers for the other imaging methods/scales. There was no significant difference in the histology, DSA scores, or microangioscope scores between the Vantage and Flex diverter types for the 3 treatment groups: aspirin, aspirin/clopidogrel, or control. This could be explained by minor differences in rabbit hematology and rheology compared to humans. Additionally, the time frame we selected might not be rapid enough to demonstrate differences, as rabbits are known to endothelialize stent struts very rapidly, by the second week after implantation. 5 An alternate explanation is that the difference between the groups may not exist. The CICAFLOW study presented similar evidence that the integration of flow diverters into the arterial wall is comparable between coated devices and uncoated devices, regardless of the antiplatelet regimen. 6 Finally, a potential explanation may stem from the current resolution limitations of the microangioscope, which may not be adequate. Additionally, the small sample size (n = 3) and the histology technique employed might not be sufficiently sensitive to detect the minor differences.
Correlation analysis by modality showed a significant correlation for stenosis scores between DSA and microangioscopy, as well as between DSA and histology. For neointimal thickness, microangioscope and histology scores were significantly correlated. This has potential clinical use in guiding dual antiplatelet therapy. For example, a patient with complete neointimal covering of the device may no longer require antiplatelet therapy, as has been recently demonstrated in stent‐assisted coiling. 7 Single‐score intraclass correlations also showed significant intramodality agreement for stenosis scores between DSA, microangioscopy, and histology. No other modality combinations were significantly correlated with each other on the measured scales.
This study demonstrated the feasibility of incorporating microangioscopy during flow‐diversion treatment procedures and follow‐up. The easily interpretable images provided an easy evaluation of stent‐wall apposition and vessel coverage that was similar in several domains to histology and DSA.
From Angioscopy to Microangioscopy
Neurointerventional practice saw the introduction of angioscopy in the evaluation of carotid disease. Kuroda studied the accuracy of angioscopy in detecting atherosclerotic changes, such as plaque, ulcer, and mural thrombus, in the extracranial carotid and compared these with angiographic and operative findings. 8 A few years later it was used as an adjunct to stent placement for an extracranial internal carotid artery aneurysm. 9 They noted at the time that the angioscope confirmed correct stent placement and normal endothelialization. Although these were useful end points, translation to the cerebrovasculature has been limited by the large size of the device and lack of flexibility/trackability. The novel microangioscope overcomes these limitations, while maintaining viable imaging resolution.
Current Challenges in Flow Diversion
Flow diversion is now a dominant force in the treatment of intracranial aneurysms. However, several challenges and unanswered questions remain in the course of treatment. First, we do not necessarily know when the device has healed (ie, fully endothelialized). Aneurysm occlusion is used as a proxy, but these 2 end points are not equivalent. Second, in the case of persistent aneurysm filling, it is unclear when to place a second device. Third, in the case of persistent aneurysm filling, we do not know when it is safe to reduce dual antiplatelet therapy. Fourth, in high‐risk thrombotic scenarios (ruptured aneurysms, large jailed branch vessel 10 ), our detection of microthrombi is limited to what is visible on fluoroscopy/angiography. Lastly, as suggested by Shapiro et al, 11 visualization of local geometrical inhomogeneities in the overlapping devices can be evaluated, which is particularly important to the telescoping constructs used in challenging aneurysms. It remains to be seen whether “live” intravascular imaging, whether by microangioscopy or optical coherence tomography (OCT), may provide diagnostic assistance in such cases.
Lessons From Optical Coherence Tomography
This microangioscope has undergone several iterations to reach the current level of resolution and miniaturization. 1 , 2 Although angioscopy is well established for coronary indications, the current technology to navigate the neurovasculature is emerging. The advantage of any direct endoluminal imaging modality is the detailed inspection of the intravascular anatomy and device deployment while balancing the need for flow arrest for adequate visualization.
OCT, on the other hand, is an indirect endoluminal imaging device adapted from the interventional cardiology domain with increasing neurointerventional applications. Several key preclinical studies have demonstrated their potential use in the treatment of cerebral aneurysms. Thorell et al described one of the first accounts of OCT for monitoring in‐situ aneurysm healing after coil embolization in a canine model. 12 More recently, King et al usedd OCT to assess malapposition of flow diverters with high sensitivity and specificity in predicting delayed aneurysm occlusion. 13 Until recently, the limitations of this technology have included device size and maximal tissue penetration of near‐infrared light of 3 mm. 14 However, with high‐frequency OCT device miniaturization and flexibility have taken several leaps forward, now as small as 1.2F and able to navigate a tortuous brachiocephalic artery in a porcine model. 15
Thus, both direct and indirect endoluminal imaging devices have great potential as adjuncts in cerebral aneurysm treatment. Particularly in flow diversion, these devices can delineate important factors that aid in predicting early aneurysm occlusion, such as stent‐wall apposition and neoendothelialization. 15
Clinical Applications of the Microangioscope
Endovascular intracranial imaging with the microangioscope presents promising prospects for research, teaching, and various clinical applications including diagnosis and interventional procedures. Employing this technique in research would enable the observation of current and new endovascular tools in vivo during application and follow‐up, thereby enhancing comprehension of their mechanisms of action and biological reactions, such as endothelialization after stent deployment and aneurysms coiling. In some cases, a microangioscope may serve as a substitute for control angiography studies or aid in cases of uncertain imaging. This technique could be invaluable for monitoring the healing process in animal experiments over an extended period, eliminating the need for repeated angiography or even euthanasia.
This noninvasive technique may also play a role in the lab training of physicians who are new to applying endovascular devices. Clinical results in flow diverter surgery depend on sizing and accurate placement of the flow diverter, while avoiding twisting or overextension. Both manually driven complications can be detected through control microangioscope inspection.
From a clinical perspective, with further advances in imaging quality, we see the microangioscope as a practical, easy‐to‐use adjunct to angiography before, during, and after a procedure. Vessels branching from the neck, partial occlusions, or dissections are a few complications that direct visual inspection with a microangioscope may help with. Another possible application might be in cerebral atherosclerotic disease, where a microangioscope might help visualize plaque, its structure, and branches (perforators) in proximity and assist with interventional strategies.
Future Directions
Future studies may assess the safety and quality of the microangioscope as it relates to in vivo clinical translation. Pairing the microangioscope with other imaging modalities, such as OCT, may be explored, as complementary imaging may provide superior diagnostic accuracy and treatment outcomes. The ability for the microangioscope to aid in visualization in real time during common cerebrovascular procedures, such as flow diverter placement and carotid disease evaluation may also be investigated.
Limitations
Limitations specific to the microangioscope were discussed in our original proof‐of‐concept study and apply to other angioscopes as well. 1 , 16 These include the necessity for flow arrest for visualization, which may promote prolonged ischemia via balloon occlusion, and the microangioscope's inability to see beyond the pathology of interest. Limitations of the present study include a small sample size of 3 reviewers. Additionally, the quantified observations were made in the left and right CCA of rabbits. Although the rabbit carotid artery model has been extensively validated in aneurysm research due to its representative vessel size and features, additional procedures must validate the microangioscope in vivo prior to clinical translation. 17 Our animal model did not harbor aneurysms, which may have impacted the rate of endothelialization of the flow diverting device (FDD), because of “perfect” wall apposition. Lastly, there is a known difference in healing and thrombosis rates between humans and rabbits. Though they are known to be similar, this may limit the translation of our results to the clinical setting.
Conclusions
The microangioscope is a feasible and useful adjunct in flow diversion treatments. It provides information on thrombus formation, calcification, in stent stenosis, and endothelialization that correlate well with histologic and angiographic findings.
Sources of Funding
The study was funded by Medtronic and outcome measures were independently assessed by the physician and the laboratory pathologist (blinded to device type). The independent physicians are also funded by the National Institute of Health. Additional device support was from Vena Medical, manufacturers of the Vena MicroAngioscope used in the study. The study was supported by the Joe Niekro Foundation.
Disclosure
Phillip Cooper and Michael Phillips are employees of Vena Medical. Peter Kan is a stockholder in Vena Medical. Peter Kan is a consultant for Stryker Neurovascular and Cerenovus. Oscar Bolanos and Richard Forrest Duncan are employees of Medtronic and stockholders in Medtronic.
Supporting information
Supplementary Video 1. Video used to train the evaluators the microangioscope, with sample clips taken from prior experiments.
Supplementary Video 2. Example of the microangioscope video showing findings across 5 domains (stenosis, neointimal thickness, endothelial coverage, thrombosis, and malapposition) in this experiment. Clips are included across multiple animal subjects.
Supplementary Tables 1. Inter‐rater differences quantified through one way agreement single score intraclass correlation for utilized scales (stenosis, neointimal thickness, endothelial coverage, thrombosis, and malapposition) for both DSA and Angioscope.
Supplementary Tables 2. Comparison of quantified histological, DSA, and angioscope observations between Flex and Vantage flow diverter implants in left and right common carotid arteries of 30‐day survival rabbits treated with aspirin monotherapy (ASA). Parametric data analyzed with two‐sample test and nonparametric data analyzed with Wilcoxon‐rank sum (Mann‐Whitney) analysis.
Supplementary Tables 3. Comparison of quantified histological, DSA, and angioscope observations between Flex and Vantage flow diverter implants in left and right common carotid arteries of 30‐day survival rabbits treated with aspirin/plavix anticoagulation (ASA/Plavix). Parametric data analyzed with two‐sample t‐test and nonparametric data analyzed with Wilcoxon‐rank sum (Mann‐Whitney) analysis.
Supplementary Tables 4. Comparison of quantified histological, DSA, and angioscope observations between Flex and Vantage flow diverter implants in left and right common carotid arteries of longer‐term “Control” survival rabbits. Parametric data analyzed with two‐sample t‐test and nonparametric data analyzed with Wilcoxon‐rank sum (Mann‐Whitney) analysis.
Supplementary Tables 5. Spearman correlation between modality scores (DSA, Angioscope, and Histology) for utilized scales (stenosis, neointimal thickness, and malapposition). Single score intraclass correlation is provided showing intra‐modality agreement within utilized scales for all three modalities. NA indicates there is no variation within the measurement.
Supplementary Tables 6. Spearman correlation between modality scores (DSA, Angioscope, and Histology) for utilized scales (stenosis, neointimal thickness, and malapposition). Single score intraclass correlation is provided showing intra‐modality agreement within utilized scales for all three modalities. NA indicates there is no variation within the measurement.
Acknowledgments
None.
References
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Associated Data
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Supplementary Materials
Supplementary Video 1. Video used to train the evaluators the microangioscope, with sample clips taken from prior experiments.
Supplementary Video 2. Example of the microangioscope video showing findings across 5 domains (stenosis, neointimal thickness, endothelial coverage, thrombosis, and malapposition) in this experiment. Clips are included across multiple animal subjects.
Supplementary Tables 1. Inter‐rater differences quantified through one way agreement single score intraclass correlation for utilized scales (stenosis, neointimal thickness, endothelial coverage, thrombosis, and malapposition) for both DSA and Angioscope.
Supplementary Tables 2. Comparison of quantified histological, DSA, and angioscope observations between Flex and Vantage flow diverter implants in left and right common carotid arteries of 30‐day survival rabbits treated with aspirin monotherapy (ASA). Parametric data analyzed with two‐sample test and nonparametric data analyzed with Wilcoxon‐rank sum (Mann‐Whitney) analysis.
Supplementary Tables 3. Comparison of quantified histological, DSA, and angioscope observations between Flex and Vantage flow diverter implants in left and right common carotid arteries of 30‐day survival rabbits treated with aspirin/plavix anticoagulation (ASA/Plavix). Parametric data analyzed with two‐sample t‐test and nonparametric data analyzed with Wilcoxon‐rank sum (Mann‐Whitney) analysis.
Supplementary Tables 4. Comparison of quantified histological, DSA, and angioscope observations between Flex and Vantage flow diverter implants in left and right common carotid arteries of longer‐term “Control” survival rabbits. Parametric data analyzed with two‐sample t‐test and nonparametric data analyzed with Wilcoxon‐rank sum (Mann‐Whitney) analysis.
Supplementary Tables 5. Spearman correlation between modality scores (DSA, Angioscope, and Histology) for utilized scales (stenosis, neointimal thickness, and malapposition). Single score intraclass correlation is provided showing intra‐modality agreement within utilized scales for all three modalities. NA indicates there is no variation within the measurement.
Supplementary Tables 6. Spearman correlation between modality scores (DSA, Angioscope, and Histology) for utilized scales (stenosis, neointimal thickness, and malapposition). Single score intraclass correlation is provided showing intra‐modality agreement within utilized scales for all three modalities. NA indicates there is no variation within the measurement.