Divergence Prior and Vessel-tree Reconstruction
We propose a new geometric regularization principle for reconstructing vector fields based on prior knowledge about their divergence. As one important example of this general idea, we focus on vector fields modelling blood flow pattern that should be divergent in arteries and convergent in veins. We show that this previously ignored regularization constraint can significantly improve the quality of vessel tree reconstruction particularly around bifurcations where non-zero divergence is concentrated. Our divergence prior is critical for resolving (binary) sign ambiguity in flow orientations produced by standard vessel filters, e.g. Frangi. Our vessel tree centerline reconstruction combines divergence constraints with robust curvature regularization. Our unsupervised method can reconstruct complete vessel trees with near-capillary details on synthetic and real 3D volumes.
1 Background on vessel detection
There is a large body of prior work on estimation of vessels in computer vision and biomedical imaging communities . Typically, pixel-level detection of tubular structures is based on multiscale eigen analysis of raw intensity Hessians developed by Frangi et al.  and other research groups . At any given point (pixel/voxel) such vessel enhancement filters output tubularness measure and estimates of vessel’s scale and orientation, which describes the flow direction upto to a sign. While such local analysis of Hessians is very useful, simple thresholding of points with large-enough vesselness measure is often unreliable as a method for computing vessel tree structure. While thresholding works well for detecting relatively large vessels, detection of smaller vessels is complicated by noise, partial voluming, and outliers (e.g. ring artifacts). More importantly, standard tubular filters exhibit signal loss at vessel bifurcations as those do not look like tubes.
Regularization methods can address vessel continuation problems due to noise, outliers, and signal loss at thinner parts and bifurcations. We propose a new regularization prior based on knowledge of the flow pattern divergence. This prior is critical for disambiguating flow directions, which provide important cues about the vessel tree structure. Next subsections outline existing regularization methods for vessel reconstruction and motivate our approach.
It may be also interesting to apply deep learning to vessel tree detection, but neural network training is problematic since vessel tree ground truth is practically impossible in real 3D data. Practical weakly-supervised training may require regularized loss functions  appropriate for vessel tree detection. While our regularization methodology may help to design such losses, we leave this for future work.
1.1 Vessel representation: centerline or segment
Two common approaches to representing vessels in reconstruction methods are volumetric binary mask and centerline. Volumetric mask is typical for techniques directly computing vessel segmentation, i.e. binary labeling of pixels/voxels. In contrast, centerline is a 1D abstraction of the vessel. But, if combined with information about vessel radii, it is easy to obtain a volumetric mask or segmentation from the vessel’s centerline, e.g. using MAT . Vice versa, centerline could be estimated from the vessel’s binary mask using skeletonization algorithms.
In the context of regularization methods for vessel reconstruction, centerline representation offers significant advantages since powerful higher-order regularizers are easier to apply to 1D structures. For example, centerline’s curvature can be regularized , while conceptually comparable regularization for vessel segmentation requires optimization of Gaussian or minimum curvature of the vessel’s surface with no known practical algorithms. In general, curvature remains a challenging regularization criteria for surfaces [24, 27, 13, 23, 20]. Alternatively, some vessel segmentation methods use simpler first-order regularizers producing minimal surfaces. While tractable, such regularizers impose a wrong prior for surfaces of thin structures due to their bias to compact blob shapes (a.k.a. shrinking bias).
1.2 Towards whole tree centerline
Many vessel reconstruction methods directly compute centerlines of different types that can be informaly defined as simplified (e.g. regularized) 1D representation of the blood flow pathlines. For example, A/B shortest path methods reqire a user to specify two end points of a vessel and apply Dijkstra to find an optimal pathline on a graph with edge weights based on vesselness measure.
Interactive A/B methods are not practical for large vessel tree reconstraction problems. While it is OK to ask a user to identify the tree root, manual identification of all the end points (leaves) is infeasible. There are tracing techniques  designed to trace vessel tree from a given root based on vesselness measures and some local continuation heuristics. Our evaluations on synthetic data with groud truth show that local tracing methods do not work well for large trees with many thin vessels even if we use the ground truth to provide all tree leaves as extra seeds in addition to the root.
Our goal is unsupervised reconstruction of the whole vessel tree centerline. We optimize a global objective function for a field of centerline tangents. Such objectives can combine vesselness measure as unary potentials with different regularization constraints addressing centerline completion. Related prior work using centerline curvature regularization is reviewed in the next subsection.
1.3 Curvature regularization for centerline
Curvature, a second-order smoothness term, is a natural regularizer for thin structures. In general, curvature was studied for image segmentation [24, 27, 25, 5, 13, 23, 20, 17], for stereo or multi-view-reconstruction [16, 22, 30], connectivity measures in analysis of diffusion MRI , for tubular structures extraction , for inpainting [2, 6] and edge completion [11, 29, 1].
Olsson et al.  propose curvature approximation for surface fitting regularization. Their framework employs tangential approximation of surfaces. The authors assume that the data points are noisy readings of the surface. The method estimates local surface patches, which are parametrized by a tangent plane. It is assumed that the distance from the data point to its tangent plane is a surface norm. That implicitly defines the point of tangency.
Assume there is a smooth curve, see Fig. 1. Points and on the curve and tangents and at these points are given. Then the integrals of curvature is estimated by
where is the distance between point and the tangent line at point represented by collinear vector .  explores properties of these approximations and argues
is a better regularizer, where we used a symmetric version of integral in (2).
Marin et al.  generalized this surface fitting problems to detection problems where majority of the data points, e.g. image pixels, do not belong to a thin structure. In order to do that they introduced binary variables in their energy indicating if a data point belongs to the thin structure. One of their applications is vessel detection. The proposed vessel-tree extraction system includes vessel enhancment filtering, non-maximum suppresion for data reduction, tangent approximation of vessels’ centerline and minimum spanning tree for topology extraction. Assuming that detection variables are computed, the tangent approximation of vessels’ centerline is found by minimizing energy
where summations are over detected vessel points, is the original data point’s location, is the tangent vector at point , the denoised point location is constraint to be the closest point on tangent line at , and is the neighbourhood system. The curvature term in the energy makes the tangents “collapse” onto one-dimensional centerline as in Fig. 3(a,c). But the same figures also show artifacts around bifurcations where undesired triangular structures forms indicating unoriented tangent model limitations.
Our experiments employs the same components as in . Our work focuses on analysis of failure cases and improvement of the regularization stage for tangent approximation. In particular we will show the drawbacks of curvature models (1-3) in the context of vessel tree extraction and propose a solution leading to significant improvement of the results.
1.4 Our contributions and motivation
|(a) divergent vessels (arteries)||(b) inconsistent divergence||(c) convergent vessels (veins)|
This work addresses an important limitatation of vessel tree reconstruction methods due to sign ambiguity in vessel orientation produced by local vesselness filters, e.g. Frangi. This orientation is described by the smallest eigen vector of the local intensity Hessian, but its sign is ambiguous. Thus, the actial flow directions are not known, eventhough they are an important reconstruction cue particualrly at bifurcations. This binary direction ambiguity can be resolved only by looking at the global configuration of vessel orientations (tangents) allowing to determine a consistent flow pattern.
We propose a divergence prior for disambiguating the global flow pattern over the vessel tree, see Figure 2. This prior can be imposed as a regularization constraint for a vector field of oriented unit tangents for vessel pathlines. We penalize negative (or positive) divergence for such unit tangent flow to enforce a consistent flow pattern111This divergence constraint is specific to unit tangent flow. Note that divergence for consistent blood flow velocities is zero even at bifurcations assuming incompressible blood. . The summary of our contributions:
Prior knowledge about divergence is generally useful for vector field inference. We propose a way to evaluate divergence for sparsely sampled vector fields via pairwise potentials. This makes divergence constraints amenable to a wide range of optimization methods for disrcrete of continuous hidden variables.
As an important application, we show that known divergence can disambiguate vessel directions produced by standard vessel filters, e.g. Frangi . This requires estimation of binary “sign” variables. The constraint penalizing positive (or negative) divergence is non-submodular, but it is well optimized by TRWS .
To estimate vessel tree centerline, divergence constraint can be combined with robust oriented curvature regularization for pathline tangents. Additional options include outlier/detection variables  and/or tree structure completion techniques, e.g. using MST.
We provide extensive quantitative validation on synthetic vessel data, as well as qualitative results on real high-resolution volumes.
The paper is organized as follows. Section 2 introduces oriented vessel pathline tangents and discusses their curvature-based regularization. It is clear that orientation of the flow at the bifurcations is important, e.g. see Fig.3. Section 3 introduces our divergence prior and methods for enforcing it in the context of vessel tree centerline estimation. The last sections presents our experimental results.
2 Bifurcations and curvature
2.1 Oriented curvature constraint
Previous works [21, 23, 17] ignored orientations of tangent vectors . Equations (1)–(4) do not depend on orientations of . In practice, the orientations of vectors are arbitrarily defined. Ingnoring the orientations in energy (4) results in significant “triangle” artifacts around bifurcation, see Fig. 3(a,c). Consider an illustrative example in Fig. 5(a). Each of three tangents interacts with the other two. The prior knowledge about blood flow pattern dictates that among those three tangents there should be one incoming and one outcoming. Introduction of orientations allows us to distinguish the incoming/outcoming tangents and subsequently inactivate one of the interactions, see Fig. 5(b), resulting in disappearance of these artifacts.
In order to introduce oriented curvature we introduce a new vector field , which we call oriented. Then, we introduce energy by replacing curvature term in energy (4) with a new oriented curvature as follows
and is the dot product of and and is a positive threshold discussed in Fig. 6.
The connection between oriented field and is
where binary variables flip or preserve the arbitrarily defined orientations of .
2.2 Curvature and orientation ambiguity
Introduction of orientated curvature resolves triangle artifacts, see Fig. 3(b,d). However, the orientations are not known in advance. For example, Frangi filter  defines a tangent as a unit eigen vector of a special matrix. The unit eigen vectors are defined up to orientation, which is chosen arbitrarily. One may propose to treat energy (5) as a function of tangent orientations via relationship (7) as follows
However, energy (8) is under-constrained because it allows multiple equally good solutions, see Fig. 5(b) and (c). The example in (b) shows a divergent pattern while (c) shows a convergent pattern suggesting artery/vein ambiguity. Unfortunately, energy (8) does not enforce consistent flow pattern across the vessel tree resulting in a mix of divergent and convergent bifurcations as in Fig. 2(b). Real data experiments confirm this conclusion, see Fig. 7(a).
Thus, oriented curvature model (5) has a significant problem. While it can resolve “triangle artifacts” at bifurcations, see Fig.3, it will break the wrong sides of the triangles at many bifurcations where it estimates the flow pattern incorrectly and then give the incorrect estimation of centerline, see Fig.8(a). Below we introduce our divergence prior directly enforcing consistent flow pattern over the vessel tree.
|(a) oriented curvature only (8)|
|(b) with divergence prior (11)|
3 Divergence constraint
3.1 Estimating divergence
Figure 9 describes our (finite element) model for estimating divergence of a sparse vector field defined for a finite set of points . We extrapolate the vector field over the whole domain assuming constancy of the vectors on the interior of the Voronoi cells for , see Fig.9(a). Thus, vectors change only in the (narrow) region around the cell facets where all non-zero divergence is concentrated. To compute the integral of divergence in the area between two neighboring points , see Fig.9(b), we estimate flux of the extrapolated vector field over -thin box around facet
where is the outward unit normal of the box and is the facet’s area. Then, divergence theorem implies the following formula for the integral of divergence of the vector field inside box
where we ignore only infinitesimally negligible term.
|(a) tangent vectors at convergence for energy (5)|
|(b) tangent vectors at convergence for energy (10)|
|(a) Voronoi cells for and facet|
|(b) -thin box around facet|
3.2 Oriented centerline estimation
Constraints for divergence in the regions between neighbors in Delaugney triangulation of can be combined with in (5) to obtain the following joint energy for estimating oriented centerline tangents
where the negative part operator encourages divergent flow pattern as in Fig.2(a). Alternatively, one can use to encourage a convergent flow pattern as in Fig.2(c). This joint energy for oriented centerline estimation combines Frangi measurements, centerline curvature regularity, and consistency of the flow pattern, see Fig.7(b). Note that specific value of facet size in (9) had a negligible effect in our centerline estimation tests as it only changes a relative weight of the divergence penalty at any given location. For simplicity, one may use for all .
We iterate TRWS  for optimizing non-submodular energy for binary “sign” disambiguation variables
Note that the divergence constraint in joint energy (10) resolves the problem of under-constrained objective (5) discussed at the end of Section 2. Since the flow pattern consistency is enforced, optimization of (10) should lead to a consistent resolution of triangle artifacts at bifurcations. see Fig.8(b). Our experimental results support this claim.
4.1 Synthetic vessel volume
We used the modification222The implementation of  contains bugs, which were fixed. of a method generating synthetic 3D vessel tree data . The generated data consists of CT333Computer tomography-like volume and ground truth vessel centerline tree, see Fig. 11 for an example. We generate 15 artificial volumes containing synthetic vascular trees with voxel intensities in the range to . The size of voxel is mm. We use three different levels of additive Gaussian noise  with standard deviations 5, 10 and 15.
measure and estimates tangent at each voxel . Then we threshold the tubularness measure to remove background pixels. Then we use non-maximum suppression444The use of NMS is mainly for data reduction. Our method is able to work on thresholded data directly, see Fig. 3(d). (NMS) resulting in voxel set . We use 26-connected neighborhood system . Next, we optimize our new join energy (10) to disambiguate tangent orientation and estimate centerline location, see Sec. 3.2. The hyperparameters are (see energy (5)), (see energy (10)), (see equation (6)), and the maximum number of iterations is 1500 for both TRWS and Levenberg-Marquardt. Finally, we extract oriented vessel tree centerline as the minimum spanning tree of the complete graph.
We evaluate different regularization methods including energy (4) (QuaCurv), energy (10) with either quadratic curvature (OriQuaCurv) or absolute curvature (OriAbsCurv) within the system outline above. We also compare to a tracing method  and medial axis .
We adopt receiver operating characteristic (ROC) curve methodology for evaluation of our methods and . We compute recall and fall-out statistics of an extracted vessel tree for different levels of the threshold. The computed statistics define ROC curve.
While ground truth is defined by locations at bifurcations and leaves of the tree, all evaluated methods yield densly sampled points on the tree. Therefore, we resample both ground truth and reconstructed tree with step size mm. For each point on one tree, we find the nearest point on the other tree and compute the Euclidean distance. If the distance is less than voxels, this pair of points is considered a match. Here is the vessel radius at the corresponding point of the ground truth and is a matching threshold measured in voxels. The recall is
where is the number of matched points in the ground truth and is the total number of points in the ground truth. The fall-out is
where is the number of matched points in the ground truth and is the total number of points in the ground truth.
The tracing method of  requires a seed points list as an input. We generate four seed lists as described in Fig. 12. The ROC curves in Fig. 12 favour our method. Since bifurcations is only a fraction of the data, the improvements around bifurcations are largely unnoticed in these curves. Therefore, we compute the ROC curves for only bifurcation nodes. We use a bigger matching threshold voxels. The results are shown in Fig. 13 where the gap between methods is bigger. Also we compute angle errors at bifurcations, see Fig. 14 and few examples in Fig. 15.
4.2 Real vessel data
We obtained the qualitative experimental results using a real micro-CT scan of mouse’s heart as shown in Figure 16. The size of the volume is voxels. Most of the vessels are thinner than voxel size. Due to the size of the volume the problem has higher computational cost than in Sec. 4.1. We built custom GPU implementation of Levenberg-Marquardt algorithm to handle the large volume size. Figure 17 shows the reconstructed centerline. Figure 18 demostrate significant improvement of centerline estimation around bifurcations.
5 Conclusions and Future work
We propose divergence prior for vector field reconstruction problems. In the contest of vessel tree estimation, we use divergent vessel prior to estimate vessel directions disambiguating orientations produced by Frangi filter. Our method significnatly improves the accuracy of reconstruction at bifurcations reducing the corresponding angle estimation errors by about 50 percent.
There are interesting extentions for our work on estimating vessel orientations. For example, such orientations can be directly used for extracting vessel tree topology or connectivity. Instead of using standard MST on undirected graphs, e.g. as in , we can now use Chu-Liu-Edmonds algorithm [7, 8] to compute a minimum spanning arborescence (a.k.a. directed rooted tree) on a directed weighted graph where a weight of any edge estimates the length of a possible direct “vessel” connection specifically from to . Such a weight can estimate the arc length from to along a unique circle such that it contains and , it is coplanar with and , and it is tangential to . However, such constant curvature path from to works as a good estimate for a plausible vessel connection from to only if ; otherwise there should be no edge from to . This implies a directed graph since edges and will be determined by two different tangents or and two different conditions or .
We would like to thank Maria Drangova (Robarts Research Institute, London, Ontario) for providing high-resolution microscopy CT volumes with cardiac vessels. We used TRWS code by Vladimir Kolmogorov (ITS, Vienna, Austria) for efficient minimization of binary orientation variables. Marc Moreno Maza (Western University, London, Ontario) shared his expertice in high-profirmance computing allowing our efficient implementation of trust region. This research would not be possible without support by the Canadian government including Discovery and RTI programs by NSERC.
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