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\title[A new mathematical model for verifying the Navier-Stokes compatibility of 4D flow MRI data]{ A new mathematical model for verifying the Navier-Stokes compatibility of 4D flow MRI} |
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%\author[Jeremías Garay Labra] |
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%{Jeremías Garay Labra} |
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\institute[University of Groningen] |
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{ |
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Bernoulli Institute\\ |
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Faculty of Sciences and Engineering\\ |
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University of Groningen\\[0.5cm] |
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%\includegraphics[height=1.5cm]{Imagenes/escudoU2014.pdf} |
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% \includegraphics[height=1cm]{Imagenes/fcfm.png} \\[0.5cm] |
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Jeremías Garay Labra \emph{join with} Hernan Mella, Julio Sotelo, Sergio Uribe, Cristobal Bertoglio and Joaquin Mura.} |
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\date{\today} |
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\begin{document} |
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\frame{\titlepage} |
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% \onslide<1-> |
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\begin{frame} |
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\frametitle{Index} |
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\tableofcontents |
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\end{frame} |
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\section[4D flow MRI]{4D flow MRI} |
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\begin{frame} |
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\frametitle{4D flow MRI} |
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\begin{columns}[c] |
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\column{.5\textwidth} % Left column and width |
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\footnotesize |
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\begin{itemize} |
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\item<2-> Full 3D coverage of the region of interest |
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\item<3-> Rich post-proccesing: derived parameters |
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\end{itemize} |
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\onslide<4-> Disadvantages: |
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\begin{itemize} |
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\item<5-> Long scan time |
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\end{itemize} |
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\column{.54\textwidth} % Right column and width |
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\onslide<1-> |
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\begin{figure}[!hbtp] |
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\begin{center} |
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\includegraphics[height=0.9\textwidth]{images/4dflow.png} |
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\caption{\footnotesize 4D flow MRI of a human thorax} |
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\end{center} |
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\end{figure} |
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\end{columns} |
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\end{frame} |
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\begin{frame} |
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\frametitle{4D flow MRI} |
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\footnotesize |
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\onslide<1-> Strategies: |
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\begin{itemize} |
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\item<2-> modest spatial resolutions $ \sim (2.5 \times 2.5 \times 2.5 \ mm^3)$ |
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\item<3-> partial data coverage |
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\end{itemize} |
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\begin{columns}[c] |
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\column{.4\textwidth} % Right column and width |
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\onslide<4-> |
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\footnotesize |
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\begin{figure}[!hbtp] |
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\begin{center} |
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\includegraphics[height=0.25\textwidth]{images/channel_noise.png} \\ |
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(a) Noise |
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%\caption{Noise} |
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\end{center} |
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\end{figure} |
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\column{.4\textwidth} % Right column and width |
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\onslide<5-> |
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\footnotesize |
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\begin{figure}[!hbtp] |
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\begin{center} |
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\includegraphics[height=0.25\textwidth]{images/channel_aliasing.png}\\ |
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(b) Aliasing |
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%\caption{Aliasing} |
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\end{center} |
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\end{figure} |
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\column{.4\textwidth} % Right column and width |
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\onslide<6-> |
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\footnotesize |
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\begin{figure}[!hbtp] |
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\begin{center} |
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\includegraphics[height=0.25\textwidth]{images/channel_under.png}\\ |
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(c) Undersampling |
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%\caption{Aliasing} |
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\end{center} |
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\end{figure} |
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\end{columns} |
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\vspace{0.5cm} |
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\onslide<7-> Typical quality estimators: SNR, VNR, peak flows/velocities, mass conservation (zero divergence) |
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\vspace{0.5cm} |
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\onslide<8-> This work $\longrightarrow$ \textbf{conservation of linear momentum} (Navier-Stokes compatibility). |
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\end{frame} |
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\section[]{The corrector field} |
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\begin{frame} |
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\frametitle{The corrector field} |
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\begin{center} |
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Methodology |
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\end{center} |
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\end{frame} |
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\begin{frame} |
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\frametitle{The corrector field} |
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\footnotesize |
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\onslide<1-> We assume a perfect physical velocity field $\vec{u}$ |
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\onslide<2-> \begin{eqnarray*} |
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\rho \frac{\partial \vec{u}}{\partial t} + \rho \big ( \vec{u} \cdot \nabla \big) \vec{u} - \mu \Delta \vec{u} + \nabla p = 0 \quad \text{in} \quad \Omega \label{eq:NSmom} |
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\end{eqnarray*} |
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\onslide<3-> And a corrector field $\vec{w}$ which satisfies: |
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\onslide<4-> \begin{align} |
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\vec{u} & = \vec{u}_{meas} + \vec{w} \quad \text{in} \quad \Omega \label{eq:corrector}\\ |
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\nabla \cdot \vec w & = 0 \quad \text{in} \quad \Omega \label{eq:correctorDiv} \\ |
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\vec w & = \vec 0 \quad \text{on} \quad \partial \Omega \label{eq:correctorBC} |
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\end{align} |
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\onslide<5-> The corrector field $\vec{w}$ measures the level of agreedment of the 4D flow measures respect to the Navier-Stokes equations. |
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\end{frame} |
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\begin{frame} |
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\frametitle{The corrector field: Continuum problem} |
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\footnotesize |
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\onslide<1-> Applying the decomposition $\vec{u} = \vec{u}_{meas} + \vec{w}$ into the original equation and writing a variational problem for $\vec w$ we have:\\[0.2cm] |
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Find $(\vec w(t) ,p(t)) \in H^1_0(\Omega)\times L^2(\Omega)$ such that: |
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\onslide<2-> \begin{equation*} |
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\int_{\Omega} \rho \frac{\partial \vec{w}}{\partial t} \cdot \vec{v} + \rho \big ( ( \vec{u}_{meas} + \vec w) \cdot \nabla \big) \vec{w} \cdot \vec{v} + \rho \big ( \vec{w} \cdot \nabla \big) \vec{u}_{meas} \cdot \vec{v} + \mu \nabla \vec{w} : \nabla \vec{v} - p \nabla \cdot \vec{v} + q \nabla \cdot \vec{w} \notag |
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\end{equation*} |
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\begin{equation*} |
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= - \int_{\Omega} \rho \frac{\partial \vec{u}_{meas}}{\partial t} \cdot \vec{v} + \rho \big ( \vec{u}_{meas} \cdot \nabla \big) \vec{u}_{meas} \cdot \vec{v} + \mu \nabla \vec{u}_{meas} : \nabla \vec{v} + q \nabla \cdot \vec{u}_{meas} |
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\end{equation*} |
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\vspace{0.2cm} |
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\onslide<3-> or in simple terms: |
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\onslide<4-> \begin{equation*} |
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A(\vec w,p;\vec v ,q ) = \mathcal{L} (\vec v) |
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\end{equation*} |
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for all $(\vec v,q) \in H^1_0(\Omega) \times L^2(\Omega)$. |
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\end{frame} |
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\begin{frame} |
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\frametitle{The corrector field: Discrete problem} |
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\footnotesize |
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\onslide<1-> In the Discrete, we can write the problem as follows: |
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\onslide<2-> \begin{equation} |
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A_{k}(\vec w,p;\vec v ,q ) + \color{blue}{S^{press}_{k}(\vec w,p;\vec v ,q)} + \color{red}{S^{conv}_{k}(\vec w;\vec v)} \color{black}{ = \mathcal{L}_j (\vec v)} |
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\label{eq:Corrector_discrete} |
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\end{equation} |
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\begin{itemize} |
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\small |
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\item<3-> $ |
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A_{k}(\vec w,p;\vec v ,q ) := \int_{\Omega} \frac{\rho}{\tau} \vec{w} \cdot \vec{v} + \rho \big ( ( \vec{u}_{meas}^k + \vec{w}^{k-1} ) \cdot \nabla \big) \vec{w} \cdot \vec{v} + \rho \big ( \vec{w} \cdot \nabla \big) \vec{u}_{meas}^k \cdot \vec{v} + \mu \nabla \vec{w} : \nabla \vec{v} - p \nabla \cdot \vec{v} + q \nabla \cdot \vec{w} |
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$ \vspace{0.2cm} |
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\item<3-> $ \mathcal{L}_j (\vec v) := \int_{\Omega} \frac{\rho}{\tau} \vec{w}^{k-1} \cdot \vec{v} + \mathcal{\ell}_j (\vec v,q) $ |
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\vspace{0.2cm} |
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\item<4-> \color{blue}$ |
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S^{press}_{k}(\vec w,p;\vec v ,q) := \delta \sum_{K \in \Omega}\int_{K} \frac{h_j^2}{\mu} \bigg ( \rho \big ( (\vec u^k_{meas} + \vec w^{k-1}) \cdot \nabla \big) \vec{w} + \rho \big ( \vec{w} \cdot \nabla \big) \vec{u}_{meas}^k + \nabla p \bigg) \cdot \notag \bigg ( \rho \big ( (\vec u^k_{meas} + \vec w^{k-1}) \cdot \nabla \big) \vec{v} + \rho \big ( \vec{v} \cdot \nabla \big) \vec{u}_{meas}^k + \nabla q \bigg ) |
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$ |
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\vspace{0.2cm} |
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\item<5-> \color{red}$ |
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S^{conv}_{k}(\vec w;\vec v) := \int_{\Omega} \frac{\rho}{2} \ \big( \nabla \cdot (\vec u^k_{meas} + \vec w^{k-1}) \big) \ \vec{w} \cdot \vec{v} |
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$ \vspace{0.2cm} |
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\end{itemize} |
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\end{frame} |
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\begin{frame} |
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\frametitle{The corrector field: Well-posedness} |
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\footnotesize |
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\onslide<1-> |
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\begin{theorem} |
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There exists a unique solution of Problem (\ref{eq:Corrector_discrete}) under the condition: $$\rho/\tau + C_\Omega^{-2} \mu/2 - \rho 3 \| \nabla\vec u_{meas}^k\|_\infty > 0$$ for all $k>0$. |
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\end{theorem} |
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\onslide<2-> |
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We can furthermore prove the following energy balance: |
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\onslide<3-> |
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\begin{theorem} For $(\vec w^k ,p^k)$ solution of Problem (\ref{eq:Corrector_discrete}), with $\ell_j(\vec v,q)=0$ it holds |
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\begin{equation*}\label{eq:energy} |
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\| \vec w^k \|^2_{L_2(\Omega)} \leq \| \vec w^{k-1} \|^2_{L_2(\Omega)} |
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\end{equation*} |
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under the condition |
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\begin{equation*}\label{eq:condstab} |
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\mu \geq C_\Omega^2 \rho \| \nabla \vec u_{meas}^k\|_\infty |
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\end{equation*} |
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\end{theorem} |
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\end{frame} |
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\section[Synthetic data]{Experiments using synthetic data } |
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\begin{frame} |
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\frametitle{Experiments} |
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\begin{center} |
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Experiments using synthetic data |
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\end{center} |
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\end{frame} |
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\begin{frame} |
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\frametitle{Numerical tests} |
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\onslide<1-> |
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\footnotesize |
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\begin{columns}[c] |
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\column{.4\textwidth} % Right column and width |
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\footnotesize |
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Simulated channel flow as measurements (Stokes flow) |
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\column{.5\textwidth} % Right column and width |
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\footnotesize |
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\begin{figure}[!hbtp] |
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\begin{center} |
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\includegraphics[height=0.35\textwidth]{images/cilinder_2.png}\\ |
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(b) Channel mesh |
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%\caption{Aliasing} |
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\end{center} |
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\end{figure} |
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\end{columns} |
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\vspace{0.2cm} |
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%\onslide<1-> We tested the corrector using CFD simulations as a measurements, in the following testcases: |
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%\onslide<2-> |
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%\begin{itemize} |
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%\item Womersley flow in a cilinder |
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%\item Navier-Stokes simulations in an aortic mesh |
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%\end{itemize} |
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\onslide<2-> Afterwards, perturbations were added: |
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\begin{itemize} |
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\item<3-> velocity aliasing (varying the $venc$ parameter) |
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\item<4-> additive noise (setting SNR in decibels) |
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\item<5-> simulated k-space undersampling (compressed sensing for the reconstruction) |
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\end{itemize} |
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%\onslide<7-> All simulations were done using a stabilized finite element method implemented in FEniCS. Afterwards, all numerical simulations were interpolated into a voxel-type structured mesh |
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\end{frame} |
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% |
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%\begin{frame} |
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% \frametitle{Numerical tests: channel} |
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%\begin{columns}[c] |
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%\column{.6\textwidth} % Left column and width |
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%\footnotesize |
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%\textbf{Channel:} |
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%\begin{itemize} |
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%\item Convective term was neglected |
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%\item Non-slip condition at walls |
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%\item Oscilatory pressure at $\Gamma_{inlet}$ |
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%\end{itemize} |
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%\column{.5\textwidth} % Right column and width |
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%\footnotesize |
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%\begin{figure}[!hbtp] |
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% \begin{center} |
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% \includegraphics[height=1.0\textwidth]{images/cilinder.png} |
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% \caption{3D channel mesh} |
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% \end{center} |
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% \end{figure} |
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%\end{columns} |
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%\end{frame} |
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% |
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\begin{frame} |
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\frametitle{Numerical tests} |
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\begin{center} |
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Results |
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\end{center} |
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\end{frame} |
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\begin{frame} |
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\frametitle{Aliasing and noise} |
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\footnotesize |
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\onslide<1-> For comparison we defined a perfect corrector field as: $\delta \vec u = \vec u_{ref} - \vec u_{meas}$ |
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\onslide<2-> |
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\begin{figure}[!hbtp] |
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\begin{center} |
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\includegraphics[height=0.45\textwidth]{images/channel_ppt_1.png} |
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\caption{\small Fields for the channel: $(SNR,venc) = (\infty,120\%)$. $\vec{w} \times 200$} |
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\end{center} |
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\end{figure} |
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\end{frame} |
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\begin{frame} |
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\frametitle{Aliasing and noise} |
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\footnotesize |
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For comparison we defined a perfect corrector field as: $\delta \vec u = \vec u_{ref} - \vec u_{meas}$ |
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\begin{figure}[!hbtp] |
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\begin{center} |
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\includegraphics[height=0.45\textwidth]{images/channel_ppt_2.png} |
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\caption{\small Fields for the channel: $(SNR,venc) = (\infty,80\%)$. $\vec{w} \times 4$ } |
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%\caption{\small Different perturbation scenarios. $(\infty , 120 \%)$: $\vec{w} \times 200$, $(10 \ dB , 120 \%)$: $\delta \vec{u}, \vec{w} \times 4$, rest: $\vec{w} \times 4$ } |
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\end{center} |
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\end{figure} |
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\end{frame} |
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\begin{frame} |
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\frametitle{Aliasing and noise} |
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\footnotesize |
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For comparison we defined a perfect corrector field as: $\delta \vec u = \vec u_{ref} - \vec u_{meas}$ |
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\begin{figure}[!hbtp] |
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\begin{center} |
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\includegraphics[height=0.45\textwidth]{images/channel_ppt_3.png} |
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\caption{\small Fields for the channel: $(SNR,venc) = (10 \ dB,120\%)$. $\delta \vec{u}, \vec{w} \times 4$} |
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%\caption{\small Different perturbation scenarios. $(\infty , 120 \%)$: $\vec{w} \times 200$, $(10 \ dB , 120 \%)$: $\delta \vec{u}, \vec{w} \times 4$, rest: $\vec{w} \times 4$ } |
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\end{center} |
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\end{figure} |
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\end{frame} |
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\begin{frame} |
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\frametitle{Aliasing and noise} |
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\footnotesize |
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For comparison we defined a perfect corrector field as: $\delta \vec u = \vec u_{ref} - \vec u_{meas}$ |
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\begin{figure}[!hbtp] |
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\begin{center} |
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\includegraphics[height=0.45\textwidth]{images/channel_ppt_4.png} |
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\caption{\small Fields for the channel: $(SNR,venc) = (10 \ dB,80\%)$. $\vec{w} \times 4$} |
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%\caption{\small Different perturbation scenarios. $(\infty , 120 \%)$: $\vec{w} \times 200$, $(10 \ dB , 120 \%)$: $\delta \vec{u}, \vec{w} \times 4$, rest: $\vec{w} \times 4$ } |
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\end{center} |
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\end{figure} |
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|
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\end{frame} |
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|
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|
||||
|
||||
\begin{frame} |
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\frametitle{Aliasing and noise} |
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\footnotesize |
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|
||||
\begin{figure}[!hbtp] |
||||
\begin{center} |
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\includegraphics[height=0.5\textwidth]{images/channel_curves_SNRinf.png} |
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\caption{ \footnotesize Evolution of the $L-2$ norms of the components of $\vec w$} |
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\end{center} |
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\end{figure} |
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|
||||
|
||||
\end{frame} |
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|
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|
||||
\begin{frame} |
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\frametitle{Aliasing and noise} |
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\footnotesize |
||||
|
||||
\begin{figure}[!hbtp] |
||||
\begin{center} |
||||
\includegraphics[height=0.5\textwidth]{images/channel_curves_SNR10.png} |
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\caption{ \footnotesize Evolution of the $L-2$ norms of the components of $\vec w$} |
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\end{center} |
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\end{figure} |
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|
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|
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\end{frame} |
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|
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|
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|
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|
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\begin{frame} |
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\frametitle{Undersampling} |
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\footnotesize |
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|
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\begin{figure}[!hbtp] |
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\begin{center} |
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\includegraphics[height=0.6\textwidth]{images/histo_channel.png} |
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\caption{ \footnotesize Histograms of different undersampling rates for the channel} |
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\end{center} |
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\end{figure} |
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|
||||
\end{frame} |
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|
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|
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|
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|
||||
%\begin{frame} |
||||
% \frametitle{Results for channel: undersampling} |
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%\footnotesize |
||||
% |
||||
%\begin{figure}[!hbtp] |
||||
% \begin{center} |
||||
% \includegraphics[height=0.6\textwidth]{images/undersampling_press.png} |
||||
%\caption{ \footnotesize Different undersampling rates for the channel} |
||||
% \end{center} |
||||
% \end{figure} |
||||
% |
||||
% |
||||
%\end{frame} |
||||
% |
||||
|
||||
|
||||
|
||||
%\begin{frame} |
||||
% \frametitle{Numerical tests: aorta} |
||||
% |
||||
%\begin{columns}[c] |
||||
%\column{.6\textwidth} % Left column and width |
||||
%\footnotesize |
||||
%\textbf{Aorta} |
||||
%\begin{itemize} |
||||
%\item a mild coartation was added in the descending aorta |
||||
%\item $u_{inlet}$ simulates a cardiac cycle |
||||
%\item 3-element Windkessel for the outlets |
||||
%\item Non-slip condition at walls |
||||
%\end{itemize} |
||||
|
||||
%\column{.5\textwidth} % Right column and width |
||||
%\footnotesize |
||||
%\begin{figure}[!hbtp] |
||||
% \begin{center} |
||||
% \includegraphics[height=1.0\textwidth]{images/aorta_blender.png} |
||||
%\caption{Aortic mesh} |
||||
% \end{center} |
||||
% \end{figure} |
||||
%\end{columns} |
||||
% |
||||
% |
||||
%\end{frame} |
||||
% |
||||
% |
||||
|
||||
|
||||
%\begin{frame} |
||||
% \frametitle{Results for aorta: aliasing and noise} |
||||
%\footnotesize |
||||
% |
||||
%\begin{figure}[!hbtp] |
||||
% \begin{center} |
||||
% \includegraphics[height=0.7\textwidth]{images/aorta_perturbation.png} |
||||
%\caption{Different perturbation scenarios for the aortic mesh} |
||||
% \end{center} |
||||
% \end{figure} |
||||
% |
||||
%\end{frame} |
||||
% |
||||
% |
||||
%\begin{frame} |
||||
% \frametitle{Results for aorta: undersampling} |
||||
%\footnotesize |
||||
% |
||||
%\begin{figure}[!hbtp] |
||||
% \begin{center} |
||||
% \includegraphics[height=0.6\textwidth]{images/histo_blender.png} |
||||
%\caption{ \footnotesize Histograms of different undersampling rates for the aortic mesh} |
||||
% \end{center} |
||||
% \end{figure} |
||||
% |
||||
%\end{frame} |
||||
% |
||||
%\begin{frame} |
||||
% \frametitle{Results for aorta: undersampling} |
||||
%\footnotesize |
||||
% |
||||
%\begin{figure}[!hbtp] |
||||
% \begin{center} |
||||
% \includegraphics[height=0.7\textwidth]{images/undersampling_blender.png} |
||||
%\caption{ \footnotesize Different undersampling rates for the aortic mesh} |
||||
% \end{center} |
||||
% \end{figure} |
||||
% |
||||
%\end{frame} |
||||
% |
||||
% |
||||
|
||||
|
||||
|
||||
\section[4D flow data]{Experiments using real 4D flow data } |
||||
|
||||
|
||||
|
||||
\begin{frame} |
||||
\frametitle{Experiments} |
||||
\begin{center} |
||||
Experiments using real 4D flow data |
||||
\end{center} |
||||
\end{frame} |
||||
|
||||
|
||||
|
||||
|
||||
\begin{frame} |
||||
\frametitle{Experiments} |
||||
\footnotesize |
||||
|
||||
\begin{columns}[c] |
||||
\column{.6\textwidth} % Left column and width |
||||
|
||||
\begin{itemize} |
||||
\item<1-> 4D flow measurements were taken from a silicon thoracic aortic phantom made of silicon. |
||||
\item<2-> A controled pump (heart rate, peak flow, stroke volume and flow waveform) |
||||
\item<3-> A stenosis of $11 \ mm$ of diameter was added in the descending aorta |
||||
\item<4-> The phantom was scanned using a clinical $1.5 \ T$ MR scanner (Philips Achieva, Best, The Netherlands) |
||||
\end{itemize} |
||||
|
||||
|
||||
\column{.5\textwidth} % Right column and width |
||||
|
||||
\begin{figure}[!hbtp] |
||||
\begin{center} |
||||
\footnotesize |
||||
\includegraphics[height=\textwidth]{images/phantom.jpg} |
||||
\caption{\footnotesize{Experiment done at the Centre of Biomedical Images (CIB) of the Catholic Unversity of Chili (PUC)}} |
||||
\end{center} |
||||
\end{figure} |
||||
|
||||
\end{columns} |
||||
|
||||
%\includemedia[width=0.6\linewidth,height=0.6\linewidth,activate=pageopen, |
||||
%passcontext, |
||||
%transparent, |
||||
%addresource=images/phantom.mp4, |
||||
%flashvars={source=images/phantom.mp4} |
||||
%]{\includegraphics[width=0.6\linewidth]{images/phantom.jpg}}{VPlayer.swf} |
||||
% |
||||
|
||||
\end{frame} |
||||
|
||||
|
||||
|
||||
|
||||
|
||||
|
||||
\begin{frame} |
||||
\frametitle{Results} |
||||
\footnotesize |
||||
|
||||
\begin{figure} |
||||
\begin{subfigure}{.31\textwidth} |
||||
\centering |
||||
% \includegraphics[trim=100 80 100 150, clip, width=1.0\textwidth]{images/u_15.png} |
||||
\caption*{(a) $\vec{u}_{meas}$} |
||||
\end{subfigure} |
||||
\begin{subfigure}{.01\textwidth} |
||||
\hfill |
||||
\end{subfigure} |
||||
\begin{subfigure}{.31\textwidth} |
||||
\centering |
||||
%\includegraphics[trim=100 80 100 150, clip, width=1.0\textwidth]{images/w_15.png} |
||||
\caption*{(b) $\vec{w}$} |
||||
\end{subfigure} |
||||
\begin{subfigure}{.01\textwidth} |
||||
\hfill |
||||
\end{subfigure} |
||||
\begin{subfigure}{.31\textwidth} |
||||
\centering |
||||
%\includegraphics[trim=100 80 100 150, clip, width=1.0\textwidth]{images/uc_15.png} |
||||
\caption*{(c) $\vec{u}_{meas}+\vec{w}$} |
||||
\end{subfigure} |
||||
\caption{Measurements, corrector fields and corrected velocities for all the cases.} |
||||
\label{fig:phantom_resolution} |
||||
\end{figure} |
||||
|
||||
\end{frame} |
||||
|
||||
|
||||
|
||||
|
||||
|
||||
\section{Conclusions} |
||||
|
||||
\begin{frame} |
||||
\frametitle{Experiments} |
||||
\begin{center} |
||||
Conclusions |
||||
\end{center} |
||||
\end{frame} |
||||
|
||||
|
||||
\begin{frame} |
||||
\frametitle{Conclusions and future work} |
||||
\footnotesize |
||||
|
||||
\onslide<1-> Potential of the new quality parameter: |
||||
|
||||
\begin{itemize} |
||||
\item<2-> Vector fields has more details |
||||
\item<3-> Artifacts recognition |
||||
\end{itemize} |
||||
|
||||
|
||||
\onslide<4-> Future: |
||||
\begin{itemize} |
||||
\item<5-> The use of the field for create new inverse problems which can be used for further accelerations |
||||
\end{itemize} |
||||
|
||||
|
||||
|
||||
\end{frame} |
||||
|
||||
|
||||
|
||||
|
||||
|
||||
\begin{frame} |
||||
\begin{center} |
||||
\huge{Thank you for your time!} |
||||
\end{center} |
||||
\end{frame} |
||||
|
||||
|
||||
|
||||
|
||||
|
||||
|
||||
|
||||
%\includegraphics<1>[height=4.5cm]{images/pat1.png} |
||||
%\includegraphics<2>[height=4.5cm]{images/pat2.png} |
||||
|
||||
|
||||
|
||||
\end{document} |
||||
|
Loading…
Reference in new issue