Input: What are some fields in which the inverse problem is encountered?

Context:
\section{Introduction}
Given a data set and a model with some unknown parameters, the inverse problem aims to find the values of the model parameters that best fit the data.
In this work, in which we focus on systems of interacting elements,
 the inverse problem concerns  the statistical inference
 of the underling interaction network and of its coupling coefficients from observed data on the dynamics  of the system.
 Versions of this problem are encountered in physics, biology (e.g., \cite{Balakrishnan11,Ekeberg13,Christoph14}), social sciences and finance (e.g.,\cite{Mastromatteo12,yamanaka_15}), neuroscience (e.g., \cite{Schneidman06,Roudi09a,tyrcha_13}), just to cite a few, and are becoming more and more important due to the increase in the amount of data available from these fields.\\
 \indent
 A standard approach used in statistical inference is to predict the interaction couplings by maximizing the likelihood function.
 This technique, however, requires the evaluation of the

   partition function that, in the most general case, concerns a number of computations scaling exponentially with the system size.

    Boltzmann machine learning uses Monte Carlo sampling to compute the gradients of the Log-likelihood looking for stationary points \cite{Murphy12} but this method is computationally manageable only for small systems. A series of faster approximations, such as naive mean-field, independent-pair approximation \cite{Roudi09a, Roudi09b}, inversion of TAP equations \cite{Kappen98,Tanaka98}, small correlations expansion \cite{Sessak09}, adaptive TAP \cite{Opper01}, adaptive  cluster expansion \cite{Cocco12} or Bethe approximations \cite{Ricci-Tersenghi12, Nguyen12}  have, then, been developed. These techniques take as input means and correlations of observed variables and most of them assume a fully connected graph as underlying connectivity network, or expand  around it by perturbative dilution.  In most cases, network reconstruction turns out to  be not accurate for small data sizes and/or when couplings are  strong or, else, if the original interaction network is sparse.\\
\indent
 A further method, substantially improving performances for small data, is the so-called Pseudo-Likelyhood Method (PLM) \cite{Ravikumar10}. In Ref. \cite{Aurell12} Aurell and Ekeberg performed a comparison between PLM and some of the just mentioned mean-field-based algorithms on the pairwise interacting Ising-spin  ($\sigma = \pm 1$) model, showing how PLM performs sensitively better, especially on sparse graphs and in the high-coupling limit, i.e., for low temperature.

 In this work, we aim at performing statistical inference  on a model whose interacting variables are continuous $XY$ spins, i.e., $\sigma \equiv \left(\cos \phi,\sin \phi\right)$ with $\phi \in [0, 2\pi )$. The developed tools can, actually, be also straightforward applied  to the $p$-clock model  \cite{Potts52} where the phase $\phi$ takes discretely equispaced $p$ values  in the $2 \pi$ interval, $\phi_a =  a 2 \pi/p$, with $a= 0,1,\dots,p-1$. The $p$-clock model, else called vector Potts model, gives a hierarchy of discretization of the $XY$ model as $p$ increases. For $p=2$, one recovers the Ising model, for $p=4$ the Ashkin-Teller model \cite{Ashkin43}, for $p=6$ the ice-type model \cite{Pauling35,Baxter82} and the eight-vertex model \cite{Sutherland70,Fan70,Baxter71} for $p=8$.
It turns out to be very useful also for numerical implementations of the continuous $XY$ model.
Recent analysis on the multi-body $XY$ model has shown that for a limited number of discrete phase values ($p\sim 16, 32$) the thermodynamic critical properties of the $p\to\infty$ $XY$ limit are promptly recovered \cite{Marruzzo15, Marruzzo16}.
Our main motivation to study statistical inference is that these kind of models have recently turned out to be rather useful in describing the behavior of optical systems,
including standard mode-locking lasers \cite{Gordon02,Gat04,Angelani07,Marruzzo15} and random lasers \cite{Angelani06a,Leuzzi09a,Antenucci15a,Antenucci15b,Marruzzo16}.
In particular, the inverse problem on the pairwise XY model analyzed here might be of help in recovering images from light propagated through random media.

      This paper is organized as follows: in Sec. \ref{sec:model} we introduce the general model  and we discuss its  derivation also  as a model for light transmission through random scattering media.
    In Sec. \ref{sec:plm} we introduce the PLM with $l_2$ regularization  and with decimation, two variants of the PLM respectively introduced in Ref. \cite{Wainwright06} and \cite{Aurell12} for the inverse Ising problem.
    Here, we analyze these techniques for continuous $XY$ spins and we test them on thermalized data generated by Exchange Monte Carlo numerical simulations of the original model dynamics. In Sec. \ref{sec:res_reg} we  present the results related to the PLM-$l_2$. In Sec. \ref{sec:res_dec} the results related to the PLM with decimation are reported and its performances are compared to the PLM-$l_2$ and to a variational mean-field method analyzed in Ref. \cite{Tyagi15}. In Sec. \ref{sec:conc}, we outline conclusive remarks and perspectives.

        \section{The leading $XY$ model}
      \label{sec:model}
 The leading model we are considering is defined, for a system of $N$ angular $XY$ variables, by the Hamiltonian
 \begin{equation}
  \mathcal{H} = - \sum_{ik}^{1,N} J_{ik} \cos{\left(\phi_i-\phi_k\right)}
  \label{eq:HXY}

  \end{equation}

  The $XY$ model is well known in statistical mechanics, displaying important physical
  insights, starting from the Berezinskii-Kosterlitz-Thouless
  transition in two dimensions\cite{Berezinskii70,Berezinskii71,Kosterlitz72} and moving to, e.g., the
  transition of liquid helium to its superfluid state \cite{Brezin82}, the roughening transition of the interface of a crystal in equilibrium with its vapor \cite{Cardy96}. In presence of disorder and frustration \cite{Villain77,Fradkin78} the model has been adopted to describe synchronization problems as the Kuramoto model \cite{Kuramoto75} and in the theoretical modeling of Josephson junction arrays \cite{Teitel83a,Teitel83b} and arrays of coupled lasers \cite{Nixon13}.
  Besides several derivations and implementations of the model in quantum and classical physics, equilibrium or out of equilibrium, ordered or fully frustrated systems, Eq. (\ref{eq:HXY}), in its generic form,
  has found applications also in other fields. A rather fascinating example being the behavior of starlings flocks  \cite{Reynolds87,Deneubourg89,Huth90,Vicsek95, Cavagna13}.
  Our interest on the $XY$ model resides, though, in optics. Phasor and phase models with pairwise and  multi-body interaction terms can, indeed, describe the behavior of electromagnetic modes in both linear and nonlinear optical systems in the analysis of problems such as light propagation and lasing \cite{Gordon02, Antenucci15c, Antenucci15d}. As couplings are strongly frustrated, these models turn out to be especially useful to the study of optical properties in random media \cite{Antenucci15a,Antenucci15b}, as in the noticeable case of random lasers \cite{Wiersma08,Andreasen11,Antenucci15e}  and they might as well be applied to linear scattering problems, e.g., propagation of waves in opaque systems or disordered fibers.

  \subsection{A propagating wave model}
  We briefly mention a derivation of the model as a proxy for the propagation of light through random linear media.
 Scattering of light is held responsible to obstruct our view and make objects opaque. Light rays, once that they enter the material, only exit  after getting scattered multiple times within the material. In such a disordered medium, both the direction and the phase of the propagating waves are random. Transmitted light
 yields a disordered interference pattern typically  having low intensity, random phase and almost no resolution, called a speckle. Nevertheless, in recent years it has been realized that disorder is rather a blessing in disguise \cite{Vellekoop07,Vellekoop08a,Vellekoop08b}. Several experiments have made it possible to control the behavior of light and other optical processes in a given random disordered medium,
 by exploiting, e.g.,  the tools developed for wavefront shaping to control the propagation of light and to engineer the confinement of light \cite{Yilmaz13,Riboli14}.
 \\
 \indent
 In a linear dielectric medium, light propagation can be described through a part of the scattering matrix, the transmission matrix $\mathbb{T}$, linking the outgoing to the incoming fields.
 Consider the case in which there are $N_I$ incoming channels and $N_O$ outgoing ones; we can indicate with $E^{\rm in,out}_k$ the input/output electromagnetic field phasors of channel $k$. In the most general case, i.e., without making any particular assumptions on the field polarizations, each light mode and its polarization polarization state can be represented by means of the $4$-dimensional Stokes vector. Each $ t_{ki}$ element of $\mathbb{T}$, thus, is a $4 \times 4$ M{\"u}ller matrix. If, on the other hand, we know that the source is polarized and the observation is made on the same polarization, one can use a scalar model and adopt Jones calculus \cite{Goodman85,Popoff10a,Akbulut11}:
   \begin{eqnarray}
 E^{\rm out}_k = \sum_{i=1}^{N_I}  t_{ki} E^{\rm in}_i \qquad \forall~ k=1,\ldots,N_O
 \label{eq:transm}
 \end{eqnarray}
  We recall that the elements of the transmission matrix are random complex coefficients\cite{Popoff10a}. For the case of completely unpolarized modes, we can also use a scalar model similar to Eq. \eqref{eq:transm}, but whose variables are  the intensities of the outgoing/incoming fields, rather than the fields themselves.\\
In the following, for simplicity, we will consider Eq. (\ref{eq:transm}) as our starting point,
where $E^{\rm out}_k$, $E^{\rm in}_i$ and $t_{ki}$ are all complex scalars.
If Eq. \eqref{eq:transm} holds for any $k$, we can write:
  \begin{eqnarray}
  \int \prod_{k=1}^{N_O} dE^{\rm out}_k \prod_{k=1}^{N_O}\delta\left(E^{\rm out}_k - \sum_{j=1}^{N_I}  t_{kj} E^{\rm in}_j \right) = 1
  \nonumber
  \\
  \label{eq:deltas}
  \end{eqnarray}

 Observed data are a noisy representation of the true values of the fields. Therefore, in inference problems it is statistically more meaningful to take that noise into account in a probabilistic way,
 rather than looking  at the precise solutions of the exact equations (whose parameters are unknown).
 To this aim we can introduce Gaussian distributions whose limit for zero variance are the Dirac deltas in Eq. (\ref{eq:deltas}).
 Moreover, we move to consider the ensemble of all possible solutions of Eq. (\ref{eq:transm}) at given $\mathbb{T}$, looking at  all configurations of input fields. We, thus, define the function:

   \begin{eqnarray}
  Z &\equiv &\int_{{\cal S}_{\rm in}} \prod_{j=1}^{N_I}  dE^{\rm in}_j \int_{{\cal S}_{\rm out}}\prod_{k=1}^{N_O} dE^{\rm out}_k
  \label{def:Z}
\\
    \times
  &&\prod_{k=1}^{N_O}
   \frac{1}{\sqrt{2\pi \Delta^2}}  \exp\left\{-\frac{1}{2 \Delta^2}\left|
  E^{\rm out}_k -\sum_{j=1}^{N_I}  t_{kj} E^{\rm in}_j\right|^2
\right\}
\nonumber
 \end{eqnarray}
   We stress that the integral of Eq. \eqref{def:Z} is not exactly a Gaussian integral. Indeed, starting from Eq. \eqref{eq:deltas}, two constraints on the electromagnetic field intensities must be taken into account.

  The space of solutions is  delimited by the total power ${\cal P}$ received by system, i.e.,
  ${\cal S}_{\rm in}: \{E^{\rm in} |\sum_k I^{\rm in}_k = \mathcal{P}\}$, also implying  a constraint on the total amount of energy that is transmitted through the medium, i. e.,
  ${\cal S}_{\rm out}:\{E^{\rm out} |\sum_k I^{\rm out}_k=c\mathcal{P}\}$, where the attenuation factor  $c<1$ accounts for total losses.
  As we will see more in details in the following, being interested in inferring the transmission matrix through the PLM, we can omit to explicitly include these terms in Eq. \eqref{eq:H_J} since they do not depend on $\mathbb{T}$ not adding any information on the gradients with respect to the elements of $\mathbb{T}$.

 Taking the same number of incoming and outcoming channels, $N_I=N_O=N/2$, and  ordering the input fields in the first $N/2$ mode indices and the output fields in the last $N/2$ indices, we can drop the ``in'' and ``out'' superscripts and formally write $Z$  as a partition function
    \begin{eqnarray}
        \label{eq:z}
 && Z =\int_{\mathcal S} \prod_{j=1}^{N} dE_j \left(   \frac{1}{\sqrt{2\pi \Delta^2}} \right)^{N/2}
 \hspace*{-.4cm} \exp\left\{
  -\frac{ {\cal H} [\{E\};\mathbb{T}] }{2\Delta^2}
  \right\}
  \\
&&{\cal H} [\{E\};\mathbb{T}] =
-  \sum_{k=1}^{N/2}\sum_{j=N/2+1}^{N} \left[E^*_j t_{jk} E_k + E_j t^*_{kj} E_k^*
\right]
 \nonumber
\\
&&\qquad\qquad \qquad + \sum_{j=N/2+1}^{N} |E_j|^2+ \sum_{k,l}^{1,N/2}E_k
U_{kl} E_l^*
 \nonumber
 \\
 \label{eq:H_J}
 &&\hspace*{1.88cm } = - \sum_{nm}^{1,N} E_n J_{nm} E_m^*
 \end{eqnarray}
 where ${\cal H}$ is a real-valued function by construction, we have introduced the effective input-input coupling matrix
\begin{equation}
U_{kl} \equiv \sum_{j=N/2+1}^{N}t^*_{lj} t_{jk}
 \label{def:U}
 \end{equation}
 and the whole interaction matrix reads (here $\mathbb{T} \equiv \{ t_{jk} \}$)
 \begin{equation}
 \label{def:J}
 \mathbb J\equiv \left(\begin{array}{ccc|ccc}
 \phantom{()}&\phantom{()}&\phantom{()}&\phantom{()}&\phantom{()}&\phantom{()}\\
 \phantom{()}&-\mathbb{U} \phantom{()}&\phantom{()}&\phantom{()}&{\mathbb{T}}&\phantom{()}\\
\phantom{()}&\phantom{()}&\phantom{()}&\phantom{()}&\phantom{()}&\phantom{()}\\
 \hline
\phantom{()}&\phantom{()}&\phantom{()}&\phantom{()}&\phantom{()}&\phantom{()}\\
 \phantom{()}& \mathbb   T^\dagger&\phantom{()}&\phantom{()}& - \mathbb{I} &\phantom{()}\\
\phantom{a}&\phantom{a}&\phantom{a}&\phantom{a}&\phantom{a}&\phantom{a}\\
 \end{array}\right)
 \end{equation}

 Determining the electromagnetic complex amplitude configurations that minimize the {\em cost function} ${\cal H}$, Eq.  (\ref{eq:H_J}),  means to maximize the overall distribution peaked around the solutions of the transmission Eqs. (\ref{eq:transm}). As the variance $\Delta^2\to 0$, eventually, the initial set of Eqs. (\ref{eq:transm}) are recovered. The ${\cal H}$ function, thus, plays the role of an Hamiltonian and  $\Delta^2$ the role of a noise-inducing temperature. The exact numerical problem corresponds to the zero temperature limit of the statistical mechanical problem. Working with real data, though, which are noisy, a finite ``temperature''
  allows for a better representation of the ensemble of solutions to the sets of equations of continuous variables.

  Now, we can express every phasor in Eq. \eqref{eq:z}  as $E_k = A_k e^{\imath \phi_k}$. As a working hypothesis we will consider the intensities $A_k^2$ as either homogeneous or as \textit{quenched} with respect to phases.
The first condition occurs, for instance, to the input intensities $|E^{\rm in}_k|$ produced by a phase-only spatial light modulator (SLM) with homogeneous illumination \cite{Popoff11}.
With \textit{quenched} here we mean, instead, that the intensity of each mode is the same for every solution of Eq. \eqref{eq:transm} at fixed $\mathbb T$.
We stress that, including intensities in the model does not preclude the inference analysis but it is out of the focus of the present work and will be considered elsewhere.

If all intensities are uniform in input and in output, this amount to a constant rescaling for each one of the four sectors of matrix $\mathbb J$ in Eq. (\ref{def:J}) that will not change the properties of the matrices.
For instance, if the original transmission matrix is unitary, so it will be the rescaled one and the matrix $\mathbb U$ will be  diagonal.
Otherwise, if intensities are \textit{quenched}, i.e., they can be considered as constants in Eq. (\ref{eq:transm}),
they are inhomogeneous with respect to phases. The generic Hamiltonian element will, therefore, rescale as
  \begin{eqnarray}
  E^*_n J_{nm} E_m = J_{nm} A_n A_m e^{\imath (\phi_n-\phi_m)} \to J_{nm} e^{\imath (\phi_n-\phi_m)}
  \nonumber
  \end{eqnarray}
  and the properties of the original  $J_{nm}$ components are not conserved  in the rescaled one. In particular, we have no argument, anymore, to possibly set the rescaled $U_{nm}\propto \delta_{nm}$.
  Eventually, we end up with the complex couplings $XY$ model, whose real-valued Hamiltonian is written as
 \begin{eqnarray}
  \mathcal{H}& = &  - \frac{1}{2} \sum_{nm} J_{nm} e^{-\imath (\phi_n - \phi_m)}  + \mbox{c.c.}
    \label{eq:h_im}
\\    &=&  - \frac{1}{2} \sum_{nm} \left[J^R_{nm} \cos(\phi_n - \phi_m)+
  J^I_{nm}\sin (\phi_n - \phi_m)\right]
  \nonumber
 \end{eqnarray}
where $J_{nm}^R$ and $J_{nm}^I$ are the real and imaginary parts of $J_{nm}$. Being $\mathbb J$  Hermitian, $J^R_{nm}=J^R_{mn}$ is symmetric and $J_{nm}^I=-J_{mn}^I$ is skew-symmetric.

\begin{comment}
\textcolor{red}{
F: comment about quenched:
I think that to obtain the XY model, it is not necessary that the intensities are strictly quenched (that is also a quite unfeasible situation, I guess).
Indeed eq (2) does not deal with the dynamics of the modes, but just connect the in and out ones.
For this, what it is necessary to have the XY model, it is that the intensities are always the same on the different samples
(so that the matrix $t_{ij}$ is the same for different phase data). If the intensities are fixed, then they can be incorporated in $t_{ij}$ and eq (2) can be written just for phases as described. \\
}
\end{comment}

  \section{Pseudolikelihood Maximization}
  \label{sec:plm}
The inverse problem consists in the reconstruction of the parameters $J_{nm}$ of the Hamiltonian, Eq. (\ref{eq:h_im}).
Given a set of $M$ data configurations of $N$ spins
 $\bm\sigma = \{ \cos \phi_i^{(\mu)},\sin \phi_i^{(\mu)} \}$, $i = 1,\dots,N$ and $\mu=1,\dots,M$, we want to \emph{infer} the couplings:
 \begin{eqnarray}
\bm \sigma  \rightarrow  \mathbb{J}
\nonumber
 \end{eqnarray}
 With this purpose in mind,
 in the rest of this section we implement the working equations for the techniques used.
 In order to test our methods, we generate the input data, i.e., the configurations, by Monte-Carlo simulations of the model.
 The joint probability distribution of the $N$ variables $\bm{\phi}\equiv\{\phi_1,\dots,\phi_N\}$, follows the Gibbs-Boltzmann distribution:
 \begin{equation}\label{eq:p_xy}
 P(\bm{\phi}) = \frac{1}{Z} e^{-\beta \mathcal{H\left(\bm{\phi}\right)}} \quad \mbox{ where } \quad Z = \int \prod_{k=1}^N d\phi_k  e^{-\beta \mathcal{H\left(\bm{\phi}\right)}}
 \end{equation}
 and where we denote $\beta=\left( 2\Delta^2 \right)^{-1}$ with respect to Eq. (\ref{def:Z}) formalism.
 In order to stick to usual statistical inference notation, in the following we will rescale the couplings by a factor $\beta / 2$: $\beta J_{ij}/2 \rightarrow J_{ij}$.
 The main idea of the PLM is to work with the conditional probability distribution of one variable $\phi_i$ given all other variables,
 $\bm{\phi}_{\backslash i}$:

  \begin{eqnarray}
	\nonumber
   P(\phi_i | \bm{\phi}_{\backslash i}) &=& \frac{1}{Z_i} \exp \left \{ {H_i^x (\bm{\phi}_{\backslash i})
  	\cos \phi_i + H_i^y (\bm{\phi}_{\backslash i}) \sin \phi_i } \right \}
	\\
 \label{eq:marginal_xy}
	&=&\frac{e^{H_i(\bm{\phi}_{\backslash i}) \cos{\left(\phi_i-\alpha_i(\bm{\phi}_{\backslash i})\right)}}}{2 \pi I_0(H_i)}
  \end{eqnarray}
  where $H_i^x$ and $H_i^y$ are defined as
   \begin{eqnarray}
   H_i^x (\bm{\phi}_{\backslash i})  &=& \sum_{j (\neq i)} J^R_{ij} \cos \phi_j  - \sum_{j  (\neq i) } J_{ij}^{I} \sin \phi_j \phantom{+  h^R_i} \label{eq:26} \\
   H_i^y  (\bm{\phi}_{\backslash i})  &=&  \sum_{j  (\neq i)} J^R_{ij}  \sin \phi_j  + \sum_{j  (\neq i) } J_{ij}^{I}   \cos \phi_j \phantom{ + h_i^{I} }\label{eq:27}
   \end{eqnarray}
and $H_i= \sqrt{(H_i^x)^2 + (H_i^y)^2}$, $\alpha_i = \arctan H_i^y/H_i^x$   and we introduced the modified Bessel function of the first kind:
  \begin{equation}
  \nonumber
   I_k(x) = \frac{1}{2 \pi}\int_{0}^{2 \pi} d \phi e^{x \cos{ \phi}}\cos{k \phi}
  \end{equation}

   Given $M$ observation samples $\bm{\phi}^{(\mu)}=\{\phi^\mu_1,\ldots,\phi^\mu_N\}$, $\mu = 1,\dots, M$, the
   pseudo-loglikelihood for the variable $i$ is given by the logarithm of Eq. (\ref{eq:marginal_xy}),
   \begin{eqnarray}
   \label{eq:L_i}
   L_i &=& \frac{1}{M}  \sum_{\mu = 1}^M  \ln P(\phi_i^{(\mu)}|\bm{\phi}^{(\mu)}_{\backslash i})
   \\
   \nonumber
   & =&  \frac{1}{M}  \sum_{\mu = 1}^M  \left[ H_i^{(\mu)} \cos( \phi_i^{(\mu)} - \alpha_i^{(\mu)}) - \ln  2 \pi I_0\left(H_i^{(\mu)}\right)\right] \, .
    \end{eqnarray}
The underlying idea of PLM is that an approximation of the true parameters of the model is obtained for values that maximize the functions $L_i$.
The specific maximization scheme differentiates the different techniques.

   \subsection{PLM with $l_2$ regularization}
   Especially for the case of sparse graphs, it is useful to add a regularizer, which prevents the maximization routine to move towards high values of
   $J_{ij}$ and $h_i$ without converging. We will adopt an $l_2$ regularization so that the Pseudolikelihood function (PLF) at site $i$  reads:
   \begin{equation}\label{eq:plf_i}
  {\cal L}_i = L_i
  - \lambda \sum_{i \neq j} \left(J_{ij}^R\right)^2 - \lambda \sum_{i \neq j} \left(J_{ij}^I\right)^2
   \end{equation}
   with $\lambda>0$.
   Note that the values of $\lambda$ have to be chosen arbitrarily, but not too large, in order not to overcome $L_i$.
   The standard implementation of the PLM consists in maximizing each ${\cal L}_i$, for $i=1\dots N$, separately. The expected values of the couplings are then:
   \begin{equation}
   \{ J_{i j}^*\}_{j\in \partial i} :=  \mbox{arg max}_{ \{ J_{ij} \}}
    \left[{\cal L}_i\right]
   \end{equation}
   In this way, we obtain two estimates for the coupling $J_{ij}$, one from maximization of ${\cal L}_i$, $J_{ij}^{(i)}$, and another one from ${\cal L}_j$, say $J_{ij}^{(j)}$.
    Since the original Hamiltonian of the $XY$ model is Hermitian, we know that the real part of the couplings is symmetric while the imaginary part is skew-symmetric.

     The final estimate for $J_{ij}$ can then be obtained  averaging the two results:

   \begin{equation}\label{eq:symm}
   J_{ij}^{\rm inferred} = \frac{J_{ij}^{(i)} + \bar{J}_{ij}^{(j)}}{2}
   \end{equation}
   where with $\bar{J}$ we indicate the complex conjugate.
   It is worth noting that the pseudolikelihood $L_i$, Eq. \eqref{eq:L_i}, is characterized by the
   following properties: (i) the normalization term of Eq.\eqref{eq:marginal_xy} can be
   computed analytically at odd with the {\em full} likelihood case that
   in general require a computational time which scales exponentially
   with the size of the systems; (ii) the $\ell_2$-regularized pseudolikelihood
   defined in Eq.\eqref{eq:plf_i} is strictly concave (i.e. it has a single
   maximizer)\cite{Ravikumar10}; (iii) it is consistent, i.e. if $M$ samples are
   generated by a model $P(\phi | J*)$ the maximizer tends to $J*$
   for $M\rightarrow\infty$\cite{besag1975}. Note also that (iii) guarantees that
   $|J^{(i)}_{ij}-J^{(j)}_{ij}| \rightarrow 0$ for $M\rightarrow \infty$.
   In Secs. \ref{sec:res_reg}, \ref{sec:res_dec}
   we report the results obtained and we analyze the performances of the PLM having taken the configurations from Monte-Carlo simulations of models whose details are known.

   \subsection{PLM with decimation}
   Even though the PLM with $l_2$-regularization allows to dwell the inference towards the low temperature region and in the low sampling case with better performances that mean-field methods, in some situations some couplings are overestimated and not at all symmetric. Moreover, in the technique there is the bias of the $l_2$ regularizer.
   Trying to overcome these problems, Decelle and Ricci-Tersenghi introduced a new method \cite{Decelle14}, known as PLM + decimation: the algorithm maximizes the sum of the $L_i$,
   \begin{eqnarray}
    {\cal L}\equiv \frac{1}{N}\sum_{i=1}^N \mbox{L}_i
    \end{eqnarray}
    and, then, it recursively set to zero couplings which are estimated very small. We expect that as long as we are setting to zero couplings that are unnecessary to fit the data, there should be not much changing on ${\cal L}$. Keeping on with decimation, a point is reached where ${\cal L}$ decreases abruptly indicating  that relevant couplings are being decimated and under-fitting is taking place.
   Let us define  by $x$  the fraction of non-decimated couplings. To have a quantitative measure for the halt criterion of the decimation process, a tilted ${\cal L}$ is defined as,
   \begin{eqnarray}
  \mathcal{L}_t &\equiv& \mathcal{L}  - x \mathcal{L}_{\textup{max}} - (1-x) \mathcal{L}_{\textup{min}} \label{$t$PLF}
   \end{eqnarray}
   where
   \begin{itemize}
   \item $\mathcal{L}_{\textup{min}}$ is the pseudolikelyhood of a model with independent variables. In the XY case: $\mathcal{L}_{\textup{min}}=-\ln{2 \pi}$.
   \item
   $\mathcal{L}_{\textup{max}}$ is the pseudolikelyhood in the fully-connected model and it is maximized over all the $N(N-1)/2$ possible couplings.
   \end{itemize}
   At the first step, when $x=1$, $\mathcal{L}$ takes value $\mathcal{L}_{\rm max}$ and  $\mathcal{L}_t=0$. On the last step, for an empty graph, i.e., $x=0$, $\mathcal{L}$ takes the value $\mathcal{L}_{\rm min}$ and, hence, again $\mathcal{L}_t =0$.
   In the intermediate steps, during the decimation procedure, as $x$ is decreasing from $1$ to $0$, one observes firstly that $\mathcal{L}_t$ increases linearly and, then, it displays an abrupt decrease indicating that from this point on relevant couplings are being decimated\cite{Decelle14}. In Fig. \ref{Jor1-$t$PLF} we give an instance of this behavior for the 2D short-range XY model with ordered couplings. We notice that the maximum point of $\mathcal{L}_t$ coincides with the minimum point of the reconstruction error, the latter defined as
   \begin{eqnarray}\label{eq:errj}
   \mbox{err}_J \equiv \sqrt{\frac{\sum_{i<j} (J^{\rm inferred}_{ij} -J^{\rm true}_{ij})^2}{N(N-1)/2}} \label{err}
   \end{eqnarray}
  We stress that the ${\cal L}_t$ maximum is obtained ignoring the underlying graph, while the err$_J$ minimum can be evaluated once the true graph has been reconstructed.

     \begin{figure}[t!]
   	\centering
   	\includegraphics[width=1\linewidth]{Jor1_dec_tPLF_new.eps}
   	\caption{The tilted likelyhood ${\cal L}_t$ curve and the reconstruction error vs the number of decimated couplings  for an ordered, real-valued J on 2D XY model with $N=64$ spins. The peak of ${\cal L}_t$ coincides with the dip of the error.}
   	\label{Jor1-$t$PLF}
   \end{figure}

   In the next sections we will show the results obtained on the  $XY$ model analyzing the performances of the two methods and comparing them also with a mean-field method \cite{Tyagi15}.

   \section{Inferred couplings with PLM-$l_2$}
    \label{sec:res_reg}
    \subsection{$XY$ model with real-valued couplings}

    In order to obtain the vector of couplings, $J_{ij}^{\rm inferred}$ the function $-\mathcal{L}_i$ is minimized through the vector of derivatives ${\partial \mathcal{L}_i}/\partial J_{ij}$. The process is repeated for all the couplings obtaining then a fully connected adjacency matrix. The results here presented are obtained with $\lambda = 0.01$.
   For the minimization we have used the MATLAB routine \emph{minFunc\_2012}\cite{min_func}.

      \begin{figure}[t!]
    	\centering
    	\includegraphics[width=1\linewidth]{Jor11_2D_l2_JR_soJR_TPJR}
    	\caption{Top panels: instances of single site coupling reconstruction for the case of $N=64$ XY spins on a 2D lattice with ordered $J$ (left column) and bimodal distributed $J$ (right column).

    	Bottom panels: sorted couplings.}
    	\label{PL-Jor1}
    \end{figure}

To produce the data by means of numerical Monte Carlo simulations a system with $N=64$  spin variables  is considered on a deterministic 2D lattice with periodic boundary conditions.
Each spin has then connectivity $4$, i.e., we expect to infer an adjacency matrix with $N c = 256$ couplings different from zero.
The dynamics of the simulated model is based on the Metropolis algorithm and parallel tempering\cite{earl05} is used to speed up the thermalization of the system.
The thermalization is tested looking at the average energy over logarithmic time windows and
the acquisition of independent configurations
starts only after the system is well thermalized.

   For the values of the couplings we considered two cases: an ordered case, indicated in the figure as  $J$ ordered (e.g., left column of Fig. \ref{PL-Jor1}) where the couplings can take values $J_{ij}=0,J$, with $J=1$,
   and a quenched disordered case, indicated in the figures as  $J$ disordered (e.g., right column of Fig. \ref{PL-Jor1})
   where the couplings can take also  negative values, i.e.,
    $J_{ij}=0,J,-J$, with a certain probability.  The results here presented were obtained with bimodal distributed $J$s:

    $P(J_{ij}=J)=P(J_{ij}=-J)=1/2$.  The performances of the PLM have shown not to depend on $P(J)$.

    We recall that in Sec. \ref{sec:plm} we used the temperature-rescaled notation, i.e., $J_{ij}$ stands for $J_{ij}/T$.

    To analyze the performances of the PLM, in Fig. \ref{PL-Jor1} the inferred couplings, $\mathbb{J}^R_{\rm inf}$, are shown on top of the original couplings,  $\mathbb{J}^R_{\rm true}$.
     The first figure (from top) in the left column shows  the $\mathbb{J}^R_{\rm inf}$ (black) and the $\mathbb{J}^R_{\rm tru}$ (green) for a given spin
     at temperature $T/J=0.7$ and number of samples  $M=1024$. PLM appears to reconstruct the correct couplings, though zero couplings are always given a small inferred non-zero value.
     In the left column of Fig.  \ref{PL-Jor1},  both the $\mathbb{J}^R_{\rm{inf}}$ and the $\mathbb{J}^R_{\rm{tru}}$ are sorted in decreasing order and plotted on top of each other.
     We can clearly see that $\mathbb{J}^R_{\rm inf}$ reproduces the expected step function. Even though the jump is smeared, the difference between inferred couplings corresponding to the set of non-zero couplings
     and to the set of zero couplings can be clearly appreciated.
     Similarly, the plots in the right column of Fig. \ref{PL-Jor1} show the results obtained for the case with  bimodal disordered couplings, for the same working temperature and number of samples.
     In particular, note that the algorithm infers half positive and half negative couplings, as expected.

\begin{figure}
\centering
\includegraphics[width=1\linewidth]{Jor11_2D_l2_errJ_varT_varM}
\caption{Reconstruction error $\mbox{err}_J$, cf. Eq. (\ref{eq:errj}), plotted as a function of temperature (left) for three values of the number of samples $M$ and  as a function $M$ (right) for three values of temperature in the ordered system, i.e., $J_{ij}=0,1$.
The system size is $N=64$.}
\label{PL-err-Jor1}
\end{figure}

In order to analyze the effects of the number of samples and of the temperature regimes, we plot in Fig. \ref{PL-err-Jor1} the reconstruction error, Eq. (\ref{err}), as a function of temperature for three different sample sizes $M=64,128$ and $512$.
The error is seen to sharply rise al low temperature, incidentally, in the ordered case, for  $T<T_c \sim 0.893$, which is the Kosterlitz-Thouless transition temperature of the 2XY model\cite{Olsson92}.
 However, we can see that if only $M=64$ samples are considered, $\mbox{err}_J$ remains high independently on the working temperature.
 In the right plot of Fig. \ref{PL-err-Jor1},  $\mbox{err}_J$ is plotted as a function of $M$ for three different working temperatures $T/J=0.4,0.7$ and $1.3$. As we expect,
 $\mbox{err}_J$  decreases as $M$ increases. This effect was observed also with mean-field inference techniques on the same model\cite{Tyagi15}.

To better understand the performances of the algorithms, in Fig. \ref{PL-varTP-Jor1} we show several True Positive (TP) curves obtained for various values of $M$ at three different temperatures $T$. As $M$ is large and/or temperature is not too small,  we are able to reconstruct correctly all the couplings present in the system (see bottom plots).
The True Positive curve displays how many times the inference method finds a true link of the original network  as a function of the index of the vector of sorted absolute value of reconstructed couplings $J_{ij}^{\rm inf}$.
The index $n_{(ij)}$ represents the related spin couples $(ij)$. The TP curve is obtained as follows:
first  the values $|J^{\rm inf}_{ij}|$ are sorted in descending order and  the spin pairs $(ij)$ are ordered according to the sorting position of $|J^{\rm inf}_{ij}|$. Then,
     	a cycle over the ordered set of pairs $(ij)$, indexed by $n_{(ij)}$, is performed, comparing with the original network coupling $J^{\rm true}_{ij}$ and verifying whether it is zero or not. The true positive curve is computed as
\begin{equation}
\mbox{TP}[n_{(ij)}]= \frac{\mbox{TP}\left[n_{(ij)}-1\right] (n_{ij}-1)+ 1 -\delta_{J^{\rm true}_{ij},0}}{n_{(ij)}}
\end{equation}
As far as $J^{\rm true}_{ij} \neq 0$, TP$=1$. As soon as the true coupling of a given $(ij)$ couple in the sorted list is zero, the TP curve departs from one.
In our case, where the connectivity per spin of the original system is  $c=4$ and there are $N=64$ spins, we know that we will have  $256$ non-zero couplings.
     	If the inverse problem is successful, hence, we expect a steep decrease of the TP curve when  $n_{ij}=256$ is overcome.

In Fig. \ref{PL-varTP-Jor1}
it is  shown that,  almost independently of $T/J$, the TP score improves as $M$ increases. Results are plotted for three different temperatures, $T=0.4,1$ and $2.2$, with increasing number of samples $M = 64, 128,512$ and $1024$ (clockwise).
We can clearly appreciate the improvement in temperature if the size of the data-set is not very large: for small $M$, $T=0.4$ performs better.
When $M$ is high enough (e.g., $M=1024$), instead, the TP curves do not appear to be strongly influenced by the temperature.

\begin{figure}[t!]
	\centering
	\includegraphics[width=1\linewidth]{Jor11_2D_l2_TPJR_varT_varM}
	\caption{TP  curves  for 2D short-range ordered $XY$ model with $N=64$ spins at three different values of $T/J$ with increasing - clockwise from top - $M$.}
	\label{PL-varTP-Jor1}
\end{figure}

\subsection{$XY$ model with complex-valued couplings}
For the complex $XY$ we have to contemporary  infer $2$ apart coupling matrices,  $J^R_{i j}$ and $J^I_{i j}$.  As before, a system of $N=64$ spins is considered on a 2D lattice.
For the couplings we have considered both ordered and bimodal disordered cases.
In Fig. \ref{PL-Jor3}, a single row of the matrix $J$ (top) and the whole sorted couplings (bottom) are displayed for the ordered model (same legend as in Fig. \ref{PL-Jor1}) for the real, $J^R$ (left column), and the imaginary part, $J^I$.

\begin{figure}[t!]
	\centering
\includegraphics[width=1\linewidth]{Jor3_l2_JRJI_soJRJI_TPJRJI}
	\caption{Results related to the ordered complex XY model with $N=64$ spins on a  2D lattice. Top: instances of  single site reconstruction for the real, JR (left column), and
		the imaginary, JI (right column), part of $J_{ij}$. Bottom: sorted values of JR (left) and JI (right).}

	\label{PL-Jor3}
\end{figure}

  \section{PLM with Decimation}
 \label{sec:res_dec}

\begin{figure}[t!]
   	\centering
   	\includegraphics[width=1\linewidth]{Jor1_dec_tPLF_varT_varM}
    	\caption{Tilted Pseudolikelyhood, ${\cal L}_t$, plotted as a function of decimated couplings. Top: Different ${\cal L}_t$ curves obtained for different values of $M$ plotted on top of each other. Here $T=1.3$. The black line indicates the expected number of decimated couplings, $x^*=(N (N-1) - N c)/2=1888$. As we can see, as $M$ increases, the maximum point of ${\cal L}_t$ approaches $x^*$. Bottom: Different ${\cal L}_t$ curves obtained for different values of T with $M=2048$. We can see that, with this value of $M$, no differences can be appreciated on the maximum points of the different  ${\cal L}_t$ curves.}
   	\label{var-$t$PLF}
   \end{figure}

\begin{figure}[t!]
    \centering
    \includegraphics[width=1\linewidth]{Jor1_dec_tPLF_peak_statistics_varM_prob.eps}
    	\caption{Number of most likely decimated couplings, estimated by the maximum point of $\mathcal{L}_t$, as a function of the number of samples $M$. We can clearly see that the maximum point of $\mathcal{L}_t$ tends toward $x^*$, which is the right expected number of zero couplings in the system.}
    	\label{PLF_peak_statistics}
    \end{figure}

      For the ordered real-valued XY model we show in Fig. \ref{var-$t$PLF}, top panel, the outcome on the tilted pseudolikelyhood, $\mathcal{L}_t$ Eq. \eqref{$t$PLF}, of the progressive decimation: from a fully connected lattice  down to an empty lattice. The figure shows the behaviour of $\mathcal{L}_t$ for three different data sizes $M$. A clear data size dependence of the maximum point of  $\mathcal{L}_t$, signalling the most likely value for decimation, is shown. For small $M$ the most likely number of  couplings is overestimated and for increasing $M$ it tends to the true value, as displayed in Fig. \ref{PLF_peak_statistics}.  In the bottom panel of Fig. \ref{var-$t$PLF} we display instead different
 $\mathcal{L}_t$ curves obtained for three different values of $T$.
  Even though the values of $\mathcal{L}_t$ decrease with increasing temperature, the value of the most likely number of decimated couplings appears to be quite independent on $T$ with $M=2048$ number of samples.
In Fig. \ref{fig:Lt_complex} we eventually display the tilted pseudolikelyhood for a 2D network with complex valued ordered couplings, where the decimation of the real and imaginary coupling matrices proceeds in parallel, that is,
when a real coupling is small enough to be decimated its imaginary part is also decimated, and vice versa.
One can see that though the apart errors for the real and imaginary parts are different in absolute values, they display the same dip, to be compared with the maximum point of $\mathcal{L}_t$.

       \begin{figure}[t!]
    	\centering
      	\includegraphics[width=1\linewidth]{Jor3_dec_tPLF_new}
      	\caption{Tilted Pseudolikelyhood, ${\cal L}_t$, plotted with the reconstruction errors for the XY model with $N=64$ spins on a 2D lattice. These results refer to the case of  ordered and complex valued couplings. The full (red) line indicates ${\cal L}_t$. The dashed (green)
      		and the dotted (blue) lines show the reconstruction errors (Eq. \eqref{eq:errj}) obtained for the real and the imaginary couplings respectively. We can see that both ${\rm err_{JR}}$ and ${\rm err_{JI}}$ have a minimum at $x^*$.}
          	\label{fig:Lt_complex}
    \end{figure}

\begin{figure}[t!]
   	\centering
   	\includegraphics[width=1\linewidth]{Jor1_dec_JR_soJR_TPJR}
   	\caption{XY model on a 2D lattice with $N=64$ sites and real valued couplings. The graphs show the inferred (dashed black lines) and true couplings (full green lines) plotted on top of each other. The left and right columns refer to the
   		 cases of ordered and bimodal disordered couplings, respectively. Top figures: single site reconstruction, i.e., one row of the matrix $J$. Bottom figures: couplings are plotted sorted in descending order.}
   	\label{Jor1_dec}
   \end{figure}

\begin{figure}[t!]
    	\centering
    	\includegraphics[width=1\linewidth]{Jor3_dec_JRJI_soJRJI_TPJRJI}
    	\caption{XY model on a 2D lattice with $N=64$ sites and ordered complex-valued couplings.
    		The inferred and true couplings are plotted on top of each other. The left and right columns show the real and imaginary parts, respectively, of the couplings. Top figures refer to a single site reconstruction, i.e., one row of the matrix $J$. Bottom figures report the couplings sorted in descending order.}
    	\label{Jor3_dec}
    \end{figure}

       \begin{figure}[t!]
     	\centering
     	\includegraphics[width=1\linewidth]{MF_PL_Jor1_2D_TPJR_varT}
     	\caption{True Positive curves obtained with the three techniques: PLM with decimation, (blue) dotted line,  PLM with $l_2$ regularization, (greed) dashed line, and mean-field, (red) full line.  These results refer to real valued ordered couplings with $N=64$ spins on a 2D lattice. The temperature is here $T=0.7$ while the four graphs refer to different sample sizes: $M$ increases clockwise.}
     	\label{MF_PL_TP}
     \end{figure}

    \begin{figure}[t!]
    	\centering
    	\includegraphics[width=1\linewidth]{MF_PL_Jor1_2D_errJ_varT_varM}
    	\caption{Variation of reconstruction error, ${\rm err_J}$, with respect to temperature as obtained with the three different techniques, see Fig. \ref{MF_PL_TP}, for four different sample size:  clockwise from top   $M=512,1024, 2048$ and $4096$.}
    	\label{MF_PL_err}
    \end{figure}

     Once the most likely network has been identified through the decimation procedure, we perform the same analysis displayed in Fig. \ref{Jor1_dec}  for ordered and then quenched disordered real-valued couplings
and in Fig. \ref{Jor3_dec} for  complex-valued ordered couplings.  In comparison to the results shown in Sec. \ref{sec:res_reg},
  the PLM with decimation leads to rather cleaner results. In Figs. \ref{MF_PL_err} and \ref{MF_PL_TP} we compare the performances of the PLM with decimation in respect to ones of the PLM with $l_2$-regularization. These two techniques are also analysed in respect to a mean-field technique previously implemented on the same XY systems\cite{Tyagi15}.

    For what concerns the network of connecting links, in Fig. \ref{MF_PL_TP} we compare the TP curves obtained with the three techniques. The results refer to the case of ordered and real valued couplings, but similar behaviours were obtained for the other cases analysed.
  The four graphs are related to different sample sizes, with $M$ increasing clockwise. When $M$ is high enough, all techniques reproduce the true network.
  However, for lower values of $M$ the performances of the PLM with $l_2$ regularization and with decimation drastically overcome those ones of the previous mean field technique.
  In particular, for $M=256$ the PLM techniques still reproduce the original network while the mean-field method fails to find more than half of the couplings.
  When $M=128$, the network is clearly reconstructed only through the PLM with decimation while the PLM with $l_2$ regularization underestimates the couplings.
  Furthermore, we notice that the PLM method with decimation is able to clearly infer the network of interaction even when $M=N$ signalling that it could be considered also in the under-sampling regime $M<N$.

In Fig. \ref{MF_PL_err} we compare the temperature behaviour of the reconstruction error.
In can be observed that for all temperatures and for all sample sizes  the reconstruction error, ${\rm err_J}$, (plotted here in log-scale) obtained with the PLM+decimation is always smaller than
that one obtained with the other techniques. The temperature behaviour of ${\rm err_J}$ agrees with the one already observed for Ising spins in \cite{Nguyen12b} and for XY spins  in \cite{Tyagi15} with a mean-field approach:  ${\rm err_J}$ displays a minimum around $T\simeq 1$ and then it increases for very lower $T$; however,
 the error obtained with the PLM with decimation is several times smaller  than the error estimated by the other methods.

     \section{Conclusions}
     \label{sec:conc}

Different statistical inference methods have been applied to the inverse problem of the XY model.
After a short review of techniques based on pseudo-likelihood and their formal generalization to the model we have tested their performances against data generated by means of Monte Carlo numerical simulations of known instances
with diluted, sparse, interactions.

The main outcome is that the best performances are obtained by means of the  pseudo-likelihood method combined with decimation. Putting to zero (i.e., decimating) very weak bonds, this technique turns out to be very precise for  problems whose real underlying interaction network is sparse, i.e., the number of couplings per variable does not scale with number of variables.
The PLM + decimation method is compared to the PLM + regularization method, with $\ell_2$ regularization and to a mean-field-based method. The behavior of the quality of the network reconstruction is analyzed by looking at the overall sorted couplings and at the single site couplings, comparing them with the real network, and at the true positive curves in all three approaches. In the PLM +decimation method, moreover, the identification of the number of decimated bonds at which the tilted pseudo-likelihood is maximum allows for a precise estimate of the total number of bonds. Concerning this technique, it is also shown that the network with the most likely number of bonds is also the one of least reconstruction error, where not only the prediction of the presence of a bond is estimated but also its value.

The behavior of the inference quality in temperature and in the size of data samples is also investigated, basically confirming the low $T$ behavior hinted by Nguyen and Berg \cite{Nguyen12b} for the Ising model. In temperature, in particular, the reconstruction error curve displays a minimum at a low temperature, close to the critical point in those cases in which a critical behavior occurs, and a sharp increase as temperature goes to zero. The decimation method, once again, appears to enhance this minimum of the reconstruction error of almost an order of magnitude with respect to other methods.

The techniques displayed and the results obtained in this work can be of use in any of the many systems whose theoretical representation is given by Eq. \eqref{eq:HXY} or Eq. \eqref{eq:h_im}, some of which are recalled in Sec. \ref{sec:model}. In particular, a possible application can be the field of light waves propagation through random media and the corresponding problem of the  reconstruction of an object seen through an opaque medium or a disordered optical fiber \cite{Vellekoop07,Vellekoop08a,Vellekoop08b, Popoff10a,Akbulut11,Popoff11,Yilmaz13,Riboli14}.

Answer: Physics, biology, social sciences, finance, and neuroscience are some fields in which the inverse problem is encountered.


Input: How does the performance of the PLM with decimation compare to other methods?

Answer: It outperforms mean-field methods and the PLM with $l_2$ regularization in terms of reconstruction error and true positive rate.


Input: What are the symptoms of vitamin K deficiency?

Context:
Vitamin K - Wikipedia
(Redirected from Vitamin k)
This article needs more medical references for verification or relies too heavily on primary sources. Please review the contents of the article and add the appropriate references if you can. Unsourced or poorly sourced material may be challenged and removed. (November 2015)
This article is about the family of vitamers. For vitamin K1 the form usually used as a supplement, see Phytomenadione.
Vitamin K structures. MK-4 and MK-7 are both subtypes of K2.
Vitamin K deficiency, Warfarin overdose
Vitamin K is a group of structurally similar, fat-soluble vitamins the human body requires for complete synthesis of certain proteins that are prerequisites for blood coagulation and which the body also needs for controlling binding of calcium in bones and other tissues. The vitamin K-related modification of the proteins allows them to bind calcium ions, which they cannot do otherwise. Without vitamin K, blood coagulation is seriously impaired, and uncontrolled bleeding occurs. Low levels of vitamin K also weaken bones and promote calcification of arteries and other soft tissues[citation needed].
Chemically, the vitamin K family comprises 2-methyl-1,4-naphthoquinone (3-) derivatives. Vitamin K includes two natural vitamers: vitamin K1 and vitamin K2.[1] Vitamin K2, in turn, consists of a number of related chemical subtypes, with differing lengths of carbon side chains made of isoprenoid groups of atoms.
Vitamin K1, also known as phylloquinone, is made by plants, and is found in highest amounts in green leafy vegetables because it is directly involved in photosynthesis. It may be thought of as the plant form of vitamin K. It is active as a vitamin in animals and performs the classic functions of vitamin K, including its activity in the production of blood-clotting proteins. Animals may also convert it to vitamin K2.
Bacteria in the gut flora can also convert K1 into vitamin K2. In addition, bacteria typically lengthen the isoprenoid side chain of vitamin K2 to produce a range of vitamin K2 forms, most notably the MK-7 to MK-11 homologues of vitamin K2. All forms of K2 other than MK-4 can only be produced by bacteria, which use these forms in anaerobic respiration. The MK-7 and other bacterially derived forms of vitamin K2 exhibit vitamin K activity in animals, but MK-7's extra utility over MK-4, if any, is unclear and is a matter of investigation.
Three synthetic types of vitamin K are known: vitamins K3, K4, and K5. Although the natural K1 and all K2 homologues and synthetic K4 and K5 have proven nontoxic, the synthetic form K3 (menadione) has shown toxicity.[2]
1.2 Cardiovascular health
1.4 Coumarin poisoning
4.1 Conversion of vitamin K1 to vitamin K2
4.2 Vitamin K2
6 Absorption and dietary need
7 Dietary reference intake
10 Biochemistry
10.1 Function in animals
10.2 Gamma-carboxyglutamate proteins
10.3 Methods of assessment
10.4 Function in bacteria
11 Injection in newborns
11.3 Controversy
A review of 2014 concluded that there is positive evidence that monotherapy using MK-4, one of the forms of Vitamin K2, reduces fracture incidence in post-menopausal women with osteoporosis, and suggested further research on the combined use of MK-4 with bisphosphonates. In contrast, an earlier review article of 2013 concluded that there is no good evidence that vitamin K supplementation helps prevent osteoporosis or fractures in postmenopausal women.[3]
A Cochrane systematic review of 2006 suggested that supplementation with Vitamin K1 and with MK4 reduces bone loss; in particular, a strong effect of MK-4 on incident fractures among Japanese patients was emphasized.[4]
A review article of 2016 suggested to consider, as one of several measures for bone health, increasing the intake of foods rich in vitamins K1 and K2.[5]
Cardiovascular health[edit]
Adequate intake of vitamin K is associated with the inhibition of arterial calcification and stiffening,[6] but there have been few interventional studies and no good evidence that vitamin K supplementation is of any benefit in the primary prevention of cardiovascular disease.[7]
One 10-year population study, the Rotterdam Study, did show a clear and significant inverse relationship between the highest intake levels of menaquinone (mainly MK-4 from eggs and meat, and MK-8 and MK-9 from cheese) and cardiovascular disease and all-cause mortality in older men and women.[8]
Vitamin K has been promoted in supplement form with claims it can slow tumor growth; there is however no good medical evidence that supports such claims.[9]
Coumarin poisoning[edit]
Vitamin K is part of the suggested treatment regime for poisoning by rodenticide (coumarin poisoning).[10]
Although allergic reaction from supplementation is possible, no known toxicity is associated with high doses of the phylloquinone (vitamin K1) or menaquinone (vitamin K2) forms of vitamin K, so no tolerable upper intake level (UL) has been set.[11]
Blood clotting (coagulation) studies in humans using 45 mg per day of vitamin K2 (as MK-4)[12] and even up to 135 mg per day (45 mg three times daily) of K2 (as MK-4),[13] showed no increase in blood clot risk. Even doses in rats as high as 250 mg/kg, body weight did not alter the tendency for blood-clot formation to occur.[14]
Unlike the safe natural forms of vitamin K1 and vitamin K2 and their various isomers, a synthetic form of vitamin K, vitamin K3 (menadione), is demonstrably toxic at high levels. The U.S. FDA has banned this form from over-the-counter sale in the United States because large doses have been shown to cause allergic reactions, hemolytic anemia, and cytotoxicity in liver cells.[2]
Phylloquinone (K1)[15][16] or menaquinone (K2) are capable of reversing the anticoagulant activity of the anticoagulant warfarin (tradename Coumadin). Warfarin works by blocking recycling of vitamin K, so that the body and tissues have lower levels of active vitamin K, and thus a deficiency of vitamin K.
Supplemental vitamin K (for which oral dosing is often more active than injectable dosing in human adults) reverses the vitamin K deficiency caused by warfarin, and therefore reduces the intended anticoagulant action of warfarin and related drugs.[17] Sometimes small amounts of vitamin K are given orally to patients taking warfarin so that the action of the drug is more predictable.[17] The proper anticoagulant action of the drug is a function of vitamin K intake and drug dose, and due to differing absorption must be individualized for each patient.[citation needed] The action of warfarin and vitamin K both require two to five days after dosing to have maximum effect, and neither warfarin or vitamin K shows much effect in the first 24 hours after they are given.[18]
The newer anticoagulants dabigatran and rivaroxaban have different mechanisms of action that do not interact with vitamin K, and may be taken with supplemental vitamin K.[19][20]
Vitamin K2 (menaquinone). In menaquinone, the side chain is composed of a varying number of isoprenoid residues. The most common number of these residues is four, since animal enzymes normally produce menaquinone-4 from plant phylloquinone.
A sample of phytomenadione for injection, also called phylloquinone
The three synthetic forms of vitamin K are vitamins K3 (menadione), K4, and K5, which are used in many areas, including the pet food industry (vitamin K3) and to inhibit fungal growth (vitamin K5).[21]
Conversion of vitamin K1 to vitamin K2[edit]
Vitamin K1 (phylloquinone) – both forms of the vitamin contain a functional naphthoquinone ring and an aliphatic side chain. Phylloquinone has a phytyl side chain.
The MK-4 form of vitamin K2 is produced by conversion of vitamin K1 in the testes, pancreas, and arterial walls.[22] While major questions still surround the biochemical pathway for this transformation, the conversion is not dependent on gut bacteria, as it occurs in germ-free rats[23][24] and in parenterally-administered K1 in rats.[25][26] In fact, tissues that accumulate high amounts of MK-4 have a remarkable capacity to convert up to 90% of the available K1 into MK-4.[27][28] There is evidence that the conversion proceeds by removal of the phytyl tail of K1 to produce menadione as an intermediate, which is then condensed with an activated geranylgeranyl moiety (see also prenylation) to produce vitamin K2 in the MK-4 (menatetrione) form.[29]
Vitamin K2[edit]
Main article: Vitamin K2
Vitamin K2 (menaquinone) includes several subtypes. The two subtypes most studied are menaquinone-4 (menatetrenone, MK-4) and menaquinone-7 (MK-7).
Vitamin K1, the precursor of most vitamin K in nature, is a stereoisomer of phylloquinone, an important chemical in green plants, where it functions as an electron acceptor in photosystem I during photosynthesis. For this reason, vitamin K1 is found in large quantities in the photosynthetic tissues of plants (green leaves, and dark green leafy vegetables such as romaine lettuce, kale and spinach), but it occurs in far smaller quantities in other plant tissues (roots, fruits, etc.). Iceberg lettuce contains relatively little. The function of phylloquinone in plants appears to have no resemblance to its later metabolic and biochemical function (as "vitamin K") in animals, where it performs a completely different biochemical reaction.
Vitamin K (in animals) is involved in the carboxylation of certain glutamate residues in proteins to form gamma-carboxyglutamate (Gla) residues. The modified residues are often (but not always) situated within specific protein domains called Gla domains. Gla residues are usually involved in binding calcium, and are essential for the biological activity of all known Gla proteins.[30]
At this time[update], 17 human proteins with Gla domains have been discovered, and they play key roles in the regulation of three physiological processes:
Blood coagulation: prothrombin (factor II), factors VII, IX, and X, and proteins C, S, and Z[31]
Bone metabolism: osteocalcin, also called bone Gla protein (BGP), matrix Gla protein (MGP),[32] periostin,[33] and the recently discovered Gla-rich protein (GRP).[34][35]
Vascular biology: growth arrest-specific protein 6 (Gas6)[36]
Unknown function: proline-rich γ-carboxyglutamyl proteins (PRGPs) 1 and 2, and transmembrane γ-carboxy glutamyl proteins (TMGs) 3 and 4.[37]
Like other lipid-soluble vitamins (A, D and E), vitamin K is stored in the fatty tissue of the human body.
Absorption and dietary need[edit]
Previous theory held that dietary deficiency is extremely rare unless the small intestine was heavily damaged, resulting in malabsorption of the molecule. Another at-risk group for deficiency were those subject to decreased production of K2 by normal intestinal microbiota, as seen in broad spectrum antibiotic use.[38] Taking broad-spectrum antibiotics can reduce vitamin K production in the gut by nearly 74% in people compared with those not taking these antibiotics.[39] Diets low in vitamin K also decrease the body's vitamin K concentration.[40] Those with chronic kidney disease are at risk for vitamin K deficiency, as well as vitamin D deficiency, and particularly those with the apoE4 genotype.[41] Additionally, in the elderly there is a reduction in vitamin K2 production.[42]
The National Academy of Medicine (NAM) updated an estimate of what constitutes an adequate intake (AI) for vitamin K in 2001. The NAM does not distinguish between K1 and K2 – both are counted as vitamin K. At that time there was not sufficient evidence to set the more rigorous estimated average requirement (EAR) or recommended dietary allowance (RDA) given for most of the essential vitamins and minerals. The current daily AIs for vitamin K for adult women and men are 90 μg and 120 μg respectively. The AI for pregnancy and lactation is 90 μg. For infants up to 12 months the AI is 2–2.5 μg, and for children aged 1 to 18 years the AI increases with age from 30 to 75 μg. As for safety, the FNB also sets tolerable upper intake levels (known as ULs) for vitamins and minerals when evidence is sufficient. In the case of vitamin K no UL is set, as evidence for adverse effects is not sufficient. Collectively EARs, RDAs, AIs and ULs are referred to as dietary reference intakes.[43] The European Food Safety Authority reviewed the same safety question and did not set an UL.[44]
For U.S. food and dietary supplement labeling purposes, the amount in a serving is expressed as a percentage of daily value (%DV). For vitamin K labeling purposes the daily value was 80 μg, but as of May 2016 it has been revised upwards to 120 μg. A table of the pre-change adult daily values is provided at reference daily intake. Food and supplement companies have until 28 July 2018 to comply with the change.
See also: Vitamin K2 § Dietary sources
K1 (μg)[45]
Kale, cooked
Collards, cooked
Collards, raw
Swiss chard, cooked
Swiss chard, raw
Turnip greens, raw
Romaine lettuce, raw
Table from "Important information to know when you are taking: Warfarin (Coumadin) and Vitamin K", Clinical Center, National Institutes of Health Drug Nutrient Interaction Task Force.[46]
Vitamin K1 is found chiefly in leafy green vegetables such as dandelion greens (which contain 778.4 μg per 100 g, or 741% of the recommended daily amount), spinach, swiss chard, lettuce and Brassica vegetables (such as cabbage, kale, cauliflower, broccoli, and brussels sprouts) and often the absorption is greater when accompanied by fats such as butter or oils; some fruits, such as avocados, kiwifruit and grapes, are also high in vitamin K. By way of reference, two tablespoons of parsley contains 153% of the recommended daily amount of vitamin K.[47] Some vegetable oils, notably soybean oil, contain vitamin K, but at levels that would require relatively large calorie consumption to meet the USDA-recommended levels.[48] colonic bacteria synthesize a significant portion of humans' vitamin K needs; newborns often receive a vitamin K shot at birth to tide them over until their colons become colonized at five to seven days of age from the consumption of breast milk.
The tight binding of vitamin K1 to thylakoid membranes in chloroplasts makes it less bioavailable. For example, cooked spinach has a 5% bioavailability of phylloquinone, however, fat added to it increases bioavailability to 13% due to the increased solubility of vitamin K in fat.[49]
Main article: Vitamin K deficiency
Average diets are usually not lacking in vitamin K, and primary deficiency is rare in healthy adults. Newborn infants are at an increased risk of deficiency. Other populations with an increased prevalence of vitamin K deficiency include those who suffer from liver damage or disease (e.g. alcoholics), cystic fibrosis, or inflammatory bowel diseases, or have recently had abdominal surgeries. Secondary vitamin K deficiency can occur in people with bulimia, those on stringent diets, and those taking anticoagulants. Other drugs associated with vitamin K deficiency include salicylates, barbiturates, and cefamandole, although the mechanisms are still unknown. Vitamin K1 deficiency can result in coagulopathy, a bleeding disorder.[50]Symptoms of K1 deficiency include anemia, bruising, nosebleeds and bleeding of the gums in both sexes, and heavy menstrual bleeding in women.
Osteoporosis[51][52] and coronary heart disease[53][54] are strongly associated with lower levels of K2 (menaquinone). Vitamin K2 (as menaquinones MK-4 through MK-10) intake level is inversely related to severe aortic calcification and all-cause mortality.[8]
Function in animals[edit]
Mechanism of action of vitamin K1.
The function of vitamin K2 in the animal cell is to add a carboxylic acid functional group to a glutamate (Glu) amino acid residue in a protein, to form a gamma-carboxyglutamate (Gla) residue. This is a somewhat uncommon posttranslational modification of the protein, which is then known as a "Gla protein". The presence of two −COOH (carboxylic acid) groups on the same carbon in the gamma-carboxyglutamate residue allows it to chelate calcium ions. The binding of calcium ions in this way very often triggers the function or binding of Gla-protein enzymes, such as the so-called vitamin K-dependent clotting factors discussed below.
Within the cell, vitamin K undergoes electron reduction to a reduced form called vitamin K hydroquinone, catalyzed by the enzyme vitamin K epoxide reductase (VKOR).[55] Another enzyme then oxidizes vitamin K hydroquinone to allow carboxylation of Glu to Gla; this enzyme is called gamma-glutamyl carboxylase[56][57] or the vitamin K-dependent carboxylase. The carboxylation reaction only proceeds if the carboxylase enzyme is able to oxidize vitamin K hydroquinone to vitamin K epoxide at the same time. The carboxylation and epoxidation reactions are said to be coupled. Vitamin K epoxide is then reconverted to vitamin K by VKOR. The reduction and subsequent reoxidation of vitamin K coupled with carboxylation of Glu is called the vitamin K cycle.[58] Humans are rarely deficient in vitamin K1 because, in part, vitamin K1 is continuously recycled in cells.[59]
Warfarin and other 4-hydroxycoumarins block the action of VKOR.[60] This results in decreased concentrations of vitamin K and vitamin K hydroquinone in tissues, such that the carboxylation reaction catalyzed by the glutamyl carboxylase is inefficient. This results in the production of clotting factors with inadequate Gla. Without Gla on the amino termini of these factors, they no longer bind stably to the blood vessel endothelium and cannot activate clotting to allow formation of a clot during tissue injury. As it is impossible to predict what dose of warfarin will give the desired degree of clotting suppression, warfarin treatment must be carefully monitored to avoid overdose.
Gamma-carboxyglutamate proteins[edit]
Main article: Gla domain
The following human Gla-containing proteins ("Gla proteins") have been characterized to the level of primary structure: blood coagulation factors II (prothrombin), VII, IX, and X, anticoagulant proteins C and S, and the factor X-targeting protein Z. The bone Gla protein osteocalcin, the calcification-inhibiting matrix Gla protein (MGP), the cell growth regulating growth arrest specific gene 6 protein (Gas6), and the four transmembrane Gla proteins (TMGPs), the function of which is at present unknown. Gas6 can function as a growth factor to activate the Axl receptor tyrosine kinase and stimulate cell proliferation or prevent apoptosis in some cells. In all cases in which their function was known, the presence of the Gla residues in these proteins turned out to be essential for functional activity.
Gla proteins are known to occur in a wide variety of vertebrates: mammals, birds, reptiles, and fish. The venom of a number of Australian snakes acts by activating the human blood-clotting system. In some cases, activation is accomplished by snake Gla-containing enzymes that bind to the endothelium of human blood vessels and catalyze the conversion of procoagulant clotting factors into activated ones, leading to unwanted and potentially deadly clotting.
Another interesting class of invertebrate Gla-containing proteins is synthesized by the fish-hunting snail Conus geographus.[61] These snails produce a venom containing hundreds of neuroactive peptides, or conotoxins, which is sufficiently toxic to kill an adult human. Several of the conotoxins contain two to five Gla residues.[62]
Methods of assessment[edit]
Vitamin K status can be assessed by:
The prothrombin time (PT) test measures the time required for blood to clot. A blood sample is mixed with citric acid and put in a fibrometer; delayed clot formation indicates a deficiency. This test is insensitive to mild deficiency, as the values do not change until the concentration of prothrombin in the blood has declined by at least 50%.[63]
Undercarboxylated prothrombin (PIVKA-II); in a study of 53 newborns, found "PT (prothrombin time) is a less sensitive marker than PIVKA II",[64] and as indicated above, PT is unable to detect subclinical deficiencies that can be detected with PIVKA-II testing.
Plasma phylloquinone was found to be positively correlated with phylloquinone intake in elderly British women, but not men,[65] but an article by Schurgers et al. reported no correlation between FFQ[further explanation needed] and plasma phylloquinone.[66]
Urinary γ-carboxyglutamic acid responds to changes in dietary vitamin K intake. Several days are required before any change can be observed. In a study by Booth et al., increases of phylloquinone intakes from 100 μg to between 377 and 417 μg for five days did not induce a significant change. Response may be age-specific.[67]
Undercarboxylated osteocalcin (UcOc) levels have been inversely correlated with stores of vitamin K[68] and bone strength in developing rat tibiae. Another study following 78 post-menopausal Korean women found a supplement regimen of vitamins K and D, and calcium, but not a regimen of vitamin D and calcium, was inversely correlated with reduced UcOc levels.[69]
Function in bacteria[edit]
Many bacteria, such as Escherichia coli found in the large intestine, can synthesize vitamin K2 (menaquinone-7 or MK-7, up to MK-11),[70] but not vitamin K1 (phylloquinone). In these bacteria, menaquinone transfers two electrons between two different small molecules, during oxygen-independent metabolic energy production processes (anaerobic respiration).[71] For example, a small molecule with an excess of electrons (also called an electron donor) such as lactate, formate, or NADH, with the help of an enzyme, passes two electrons to menaquinone. The menaquinone, with the help of another enzyme, then transfers these two electrons to a suitable oxidant, such fumarate or nitrate (also called an electron acceptor). Adding two electrons to fumarate or nitrate converts the molecule to succinate or nitrite plus water, respectively.
Some of these reactions generate a cellular energy source, ATP, in a manner similar to eukaryotic cell aerobic respiration, except the final electron acceptor is not molecular oxygen, but fumarate or nitrate. In aerobic respiration, the final oxidant is molecular oxygen (O2), which accepts four electrons from an electron donor such as NADH to be converted to water. E. coli, as facultative anaerobes, can carry out both aerobic respiration and menaquinone-mediated anaerobic respiration.
Injection in newborns[edit]
The blood clotting factors of newborn babies are roughly 30–60% that of adult values; this may be due to the reduced synthesis of precursor proteins and the sterility of their guts. Human milk contains 1–4 μg/L of vitamin K1, while formula-derived milk can contain up to 100 μg/L in supplemented formulas. Vitamin K2 concentrations in human milk appear to be much lower than those of vitamin K1. Occurrence of vitamin K deficiency bleeding in the first week of the infant's life is estimated at 0.25–1.7%, with a prevalence of 2–10 cases per 100,000 births.[72] Premature babies have even lower levels of the vitamin, so they are at a higher risk from this deficiency.
Bleeding in infants due to vitamin K deficiency can be severe, leading to hospitalization, blood transfusions, brain damage, and death. Supplementation can prevent most cases of vitamin K deficiency bleeding in the newborn. Intramuscular administration is more effective in preventing late vitamin K deficiency bleeding than oral administration.[73][74]
As a result of the occurrences of vitamin K deficiency bleeding, the Committee on Nutrition of the American Academy of Pediatrics has recommended 0.5–1 mg of vitamin K1 be administered to all newborns shortly after birth.[74]
In the UK vitamin K supplementation is recommended for all newborns within the first 24 hours.[75] This is usually given as a single intramuscular injection of 1 mg shortly after birth but as a second-line option can be given by three oral doses over the first month.[76]
Controversy arose in the early 1990s regarding this practice, when two studies suggested a relationship between parenteral administration of vitamin K and childhood cancer,[77] however, poor methods and small sample sizes led to the discrediting of these studies, and a review of the evidence published in 2000 by Ross and Davies found no link between the two.[78] Doctors reported emerging concerns in 2013,[79] after treating children for serious bleeding problems. They cited lack-of newborn vitamin K administration, as the reason that the problems occurred, and recommended that breastfed babies could have an increased risk unless they receive a preventative dose.
In the early 1930s, Danish scientist Henrik Dam investigated the role of cholesterol by feeding chickens a cholesterol-depleted diet.[80] He initially replicated experiments reported by scientists at the Ontario Agricultural College (OAC).[81] McFarlane, Graham and Richardson, working on the chick feed program at OAC, had used chloroform to remove all fat from chick chow. They noticed that chicks fed only fat-depleted chow developed hemorrhages and started bleeding from tag sites.[82] Dam found that these defects could not be restored by adding purified cholesterol to the diet. It appeared that – together with the cholesterol – a second compound had been extracted from the food, and this compound was called the coagulation vitamin. The new vitamin received the letter K because the initial discoveries were reported in a German journal, in which it was designated as Koagulationsvitamin. Edward Adelbert Doisy of Saint Louis University did much of the research that led to the discovery of the structure and chemical nature of vitamin K.[83] Dam and Doisy shared the 1943 Nobel Prize for medicine for their work on vitamin K (K1 and K2) published in 1939. Several laboratories synthesized the compound(s) in 1939.[84]
For several decades, the vitamin K-deficient chick model was the only method of quantifying vitamin K in various foods: the chicks were made vitamin K-deficient and subsequently fed with known amounts of vitamin K-containing food. The extent to which blood coagulation was restored by the diet was taken as a measure for its vitamin K content. Three groups of physicians independently found this: Biochemical Institute, University of Copenhagen (Dam and Johannes Glavind), University of Iowa Department of Pathology (Emory Warner, Kenneth Brinkhous, and Harry Pratt Smith), and the Mayo Clinic (Hugh Butt, Albert Snell, and Arnold Osterberg).[85]
The first published report of successful treatment with vitamin K of life-threatening hemorrhage in a jaundiced patient with prothrombin deficiency was made in 1938 by Smith, Warner, and Brinkhous.[86]
The precise function of vitamin K was not discovered until 1974, when three laboratories (Stenflo et al.,[87] Nelsestuen et al.,[88] and Magnusson et al.[89]) isolated the vitamin K-dependent coagulation factor prothrombin (factor II) from cows that received a high dose of a vitamin K antagonist, warfarin. It was shown that, while warfarin-treated cows had a form of prothrombin that contained 10 glutamate (Glu) amino acid residues near the amino terminus of this protein, the normal (untreated) cows contained 10 unusual residues that were chemically identified as γ-carboxyglutamate (Gla). The extra carboxyl group in Gla made clear that vitamin K plays a role in a carboxylation reaction during which Glu is converted into Gla.
The biochemistry of how vitamin K is used to convert Glu to Gla has been elucidated over the past thirty years in academic laboratories throughout the world.
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Rhéaume-Bleue, Kate (2012). Vitamin K2 and the Calcium Paradox. John Wiley & Sons, Canada. ISBN 1-118-06572-7. External links[edit]
"Vitamin K: Another Reason to Eat Your Greens". v
TPP / ThDP (B1)
FMN, FAD (B2)
NAD+, NADH, NADP+, NADPH (B3)
Coenzyme A (B5)
PLP / P5P (B6)
THFA / H4FA, DHFA / H2FA, MTHF (B9)
AdoCbl, MeCbl (B12)
Phylloquinone (K1), Menaquinone (K2)
non-vitamins
Coenzyme B
Heme / Haem (A, B, C, O)
Molybdopterin/Molybdenum cofactor
THMPT / H4MPT
Fe2+, Fe3+
vitamins: see vitamins
Antihemorrhagics (B02)
(coagulation)
Phytomenadione (K1)
Menadione (K3)
intrinsic: IX/Nonacog alfa
VIII/Moroctocog alfa/Turoctocog alfa
extrinsic: VII/Eptacog alfa
common: X
II/Thrombin
I/Fibrinogen
XIII/Catridecacog
combinations: Prothrombin complex concentrate (II, VII, IX, X, protein C and S)
Carbazochrome
thrombopoietin receptor agonist (Romiplostim
Eltrombopag)
Tetragalacturonic acid hydroxymethylester
Epinephrine/Adrenalone
amino acids (Aminocaproic acid
Aminomethylbenzoic acid)
serpins (Aprotinin
Alfa1 antitrypsin
Camostat).

Answer: Symptoms of vitamin K deficiency include anemia, bruising, nosebleeds, bleeding of the gums, and heavy menstrual bleeding in women.