prompt_front: Now, answer the following question based on the text below, only give me the answer and do not output any other words.

Question: What types of data did the authors use in their experiments?

Read the following text and answer briefly.

Context 1: \section{Introduction}
\label{sec:introduction}

Probabilistic models have proven to be very useful in a lot of applications in signal processing where signal estimation is needed \cite{rabiner1989tutorial,arulampalam2002tutorial,ji2008bayesian}  Some of their advantages are that 1) they force the designer to specify all the assumptions of the model, 2) they provide a clear separation between the model and the algorithm used to solve it, and 3) they usually provide some measure of uncertainty about the estimation 

On the other hand, adaptive filtering is a standard approach in estimation problems when the input is received as a stream of data that is potentially non-stationary  This approach is widely understood and applied to several problems such as echo cancellation \cite{gilloire1992adaptive}, noise cancellation \cite{nelson1991active}, and channel equalization \cite{falconer2002frequency} 

Although these two approaches share some underlying relations, there are very few connections in the literature  The first important attempt in the signal processing community to relate these two fields was the connection between a linear Gaussian state-space model (i e  Kalman filter) and the RLS filter, by Sayed and Kailath \cite{sayed1994state} and then by Haykin \emph{et al } \cite{haykin1997adaptive}  The RLS adaptive filtering algorithm emerges naturally when one defines a particular state-space model (SSM) and then performs exact inference in that model  This approach was later exploited in \cite{van2012kernel} to design a kernel RLS algorithm based on Gaussian processes 

A first attempt to approximate the LMS filter from a probabilistic perspective was presented in \cite{park2014probabilistic}, focusing on a kernel-based implementation  The algorithm of \cite{park2014probabilistic} makes use of a Maximum a Posteriori (MAP) estimate as an approximation for the predictive step  However, this approximation does not preserve the estimate of the uncertainty in each step, therefore degrading the performance of the algorithm 

In this work, we provide a similar connection between state-space models and least-mean-squares (LMS)  Our approach is based on approximating the posterior distribution with an isotropic Gaussian distribution  We show how the computation of this approximated posterior leads to a linear-complexity algorithm, comparable to the standard LMS  Similar approaches have already been developed for a variety of problems such as channel equalization using recurrent RBF neural networks \cite{cid1994recurrent}, or Bayesian forecasting \cite{harrison1999bayesian}  Here, we show the usefulness of this probabilistic approach for adaptive filtering 

The probabilistic perspective we adopt throughout this work presents two main advantages  Firstly, a novel LMS algorithm with adaptable step size emerges naturally with this approach, making it suitable for both stationary and non-stationary environments  The proposed algorithm has less free parameters than previous LMS algorithms with variable step size \cite{kwong1992variable,aboulnasr1997robust,shin2004variable}, and its parameters are easier to be tuned w r t  these algorithms and standard LMS  Secondly, the use of a probabilistic model provides us with an estimate of the error variance, which is useful in many applications 

Experiments with simulated and real data show the advantages of the presented approach with respect to previous works  However, we remark that the main contribution of this paper is that it opens the door to introduce more Bayesian machine learning techniques, such as variational inference and Monte Carlo sampling methods \cite{barber2012bayesian}, to adaptive filtering \\


\section{Probabilistic Model}

Throughout this work, we assume the observation model to be linear-Gaussian with the following distribution,

\begin{equation}
p(y_k|{\bf w}_k) = \mathcal{N}(y_k;{\bf x}_k^T {\bf w}_k , \sigma_n^2),
\label{eq:mess_eq}
\end{equation}
where  $\sigma_n^2$ is the variance of the observation noise, ${\bf x}_k$ is the regression vector and ${\bf w}_k$ is the parameter vector to be sequentially estimated, both $M$-dimensional column vectors 


In a non-stationary scenario, ${\bf w}_k$ follows a dynamic process  In particular, we consider a diffusion process (random-walk model) with variance $\sigma_d^2$ for this parameter vector:


\begin{equation}
p({\bf w}_k|{\bf w}_{k-1})= \mathcal{N}({\bf w}_k;{\bf w}_{k-1}, \sigma_d^2 {\bf I}),
\label{eq:trans_eq}
\end{equation}
where $\bf I$ denotes the identity matrix  In order to initiate the recursion, we assume the following prior distribution on ${\bf w}_k$

\begin{equation}
p({\bf w}_0)= \mathcal{N}({\bf w}_0;0, \sigma_d^2{\bf I}) \nonumber
\end{equation}

\section{Exact inference in this model: Revisiting the RLS filter}

Given the described probabilistic SSM, we would like to infer the posterior probability distribution $p({\bf w}_k|y_{1:k})$ 
Since all involved distributions are Gaussian, one can perform exact inference, leveraging the probability rules in a straightforward manner  The resulting probability distribution is
\begin{equation}
p({\bf w}_k|y_{1:k}) =  \mathcal{N}({\bf w}_k;{\bf\boldsymbol\mu}_{k}, \boldsymbol\Sigma_{k}), \nonumber
\end{equation}
in which the mean vector ${\bf\boldsymbol\mu}_{k}$ is given by
\begin{equation}
{\bf\boldsymbol\mu}_k = {\bf\boldsymbol\mu}_{k-1} + {\bf K}_k (y_k - {\bf x}_k^T {\bf\boldsymbol\mu}_{k-1}){\bf x}_k, \nonumber
\end{equation}
where we have introduced the auxiliary variable
\begin{equation}
{\bf K}_k = \frac{ \left(\boldsymbol\Sigma_{k-1} + \sigma_d^2 {\bf I}\right)}{{\bf x}_k^T  \left(\boldsymbol\Sigma_{k-1} + \sigma_d^2 {\bf I}\right)  {\bf x}_k + \sigma_n^2}, \nonumber
\end{equation}
and the covariance matrix $\boldsymbol\Sigma_k$ is obtained as
\begin{equation}
\boldsymbol\Sigma_k = \left( {\bf I} -  {\bf K}_k{\bf x}_k {\bf x}_k^T \right) ( \boldsymbol\Sigma_{k-1} +\sigma_d^2), \nonumber
\end{equation}
Note that the mode of $p({\bf w}_k|y_{1:k})$, i e  the maximum-a-posteriori estimate (MAP), coincides with the RLS adaptive rule
\begin{equation}
{{\bf w}}_k^{(RLS)} = {{\bf w}}_{k-1}^{(RLS)} + {\bf K}_k (y_k - {\bf x}_k^T {{\bf w}}_{k-1}^{(RLS)}){\bf x}_k  
\label{eq:prob_rls}
\end{equation}
This rule is similar to the one introduced in \cite{haykin1997adaptive} 

Finally, note that the covariance matrix $\boldsymbol\Sigma_k$ is a measure of the uncertainty of the estimate ${\bf w}_k$ conditioned on the observed data $y_{1:k}$  Nevertheless, for many applications a single scalar summarizing the variance of the estimate could prove to be sufficiently useful  In the next section, we show how such a scalar is obtained naturally when $p({\bf w}_k|y_{1:k})$ is approximated with an isotropic Gaussian distribution  We also show that this approximation leads to an LMS-like estimation 
 


\section{Approximating the posterior distribution: LMS filter }

The proposed approach consists in approximating the posterior distribution $p({\bf w}_k|y_{1:k})$, in general a multivariate Gaussian distribution with a full covariance matrix, by an isotropic spherical Gaussian distribution 

\begin{equation}
\label{eq:aprox_post}
\hat{p}({\bf w}_{k}|y_{1:k})=\mathcal{N}({\bf w}_{k};{\bf \hat{\boldsymbol\mu}}_{k}, \hat{\sigma}_{k}^2 {\bf I} ) 
\end{equation}

In order to estimate the mean and covariance of the approximate distribution $\hat{p}({\bf w}_{k}|y_{1:k})$, we propose to select those that minimize the Kullback-Leibler divergence with respect to the original distribution, i e , 

\begin{equation}
\{\hat{\boldsymbol\mu}_k,\hat{\sigma}_k\}=\arg \displaystyle{  \min_{\hat{\boldsymbol\mu}_k,\hat{\sigma}_k}} \{ D_{KL}\left(p({\bf w}_{k}|y_{1:k}))\| \hat{p}({\bf w}_{k}|y_{1:k})\right) \}  \nonumber
\end{equation}

The derivation of the corresponding minimization problem can be found in Appendix A  In particular, the optimal mean and the covariance are found as
\begin{equation}
{\hat{\boldsymbol\mu}}_{k} = {\boldsymbol\mu}_{k};~~~~~~ \hat{\sigma}_{k}^2 = \frac{{\sf Tr}\{ \boldsymbol\Sigma_k\} }{M} 
\label{eq:sigma_hat}
\end{equation}


We now show that by using \eqref{eq:aprox_post} in the recursive predictive and filtering expressions we obtain an LMS-like adaptive rule  First, let us assume that we have an approximate posterior distribution at $k-1$, $\hat{p}({\bf w}_{k-1}|y_{1:k-1}) =  \mathcal{N}({\bf w}_{k-1};\hat{\bf\boldsymbol\mu}_{k-1}, \hat{\sigma}_{k-1}^2 {\bf I} )$  Since all involved distributions are Gaussian, the predictive distribution
is obtained as %
\begin{eqnarray}
\hat{p}({\bf w}_k|y_{1:k-1}) &=& \int p({\bf w}_k|{\bf w}_{k-1}) \hat{p}({\bf w}_{k-1}|y_{1:k-1}) d{\bf w}_{k-1} \nonumber\\
&=& \mathcal{N}({\bf w}_k;{\bf\boldsymbol\mu}_{k|k-1}, \boldsymbol\Sigma_{k|k-1}), 
\label{eq:approx_pred}
\end{eqnarray}
where the mean vector and covariance matrix are given by
\begin{eqnarray}
\hat{\bf\boldsymbol\mu}_{k|k-1} &=& \hat{\bf\boldsymbol\mu}_{k-1} \nonumber \\
\hat{\boldsymbol\Sigma}_{k|k-1} &=& (\hat{\sigma}_{k-1}^2 + \sigma_d^2 ){\bf I}\nonumber 
\end{eqnarray}

From \eqref{eq:approx_pred}, the posterior distribution at time $k$ can be computed using Bayes' Theorem and standard Gaussian manipulations (see for instance \cite[Ch  4]{murphy2012machine})  Then, we approximate the posterior $p({\bf w}_k|y_{1:k})$ with an isotropic Gaussian,
\begin{equation}
\hat{p}({\bf w}_k|y_{1:k}) =  \mathcal{N}({\bf w}_k ; {\hat{\boldsymbol\mu}}_{k}, \hat{\sigma}_k^2 {\bf I} ),\nonumber
\end{equation}
where 
\begin{eqnarray}
{\hat{\boldsymbol\mu}}_{k} &= & {\hat{\boldsymbol\mu}}_{k-1}+ \frac{ (\hat{\sigma}_{k-1}^2+ \sigma_d^2)  }{(\hat{\sigma}_{k-1}^2+ \sigma_d^2)  \|{\bf x}_k\|^2 + \sigma_n^2} (y_k - {\bf x}_k^T {\hat{\boldsymbol\mu}}_{k-1}){\bf x}_k  \nonumber  \\
&=& {\hat{\boldsymbol\mu}}_{k-1}+ \eta_k (y_k - {\bf x}_k^T {\hat{\boldsymbol\mu}}_{k-1}){\bf x}_k   
\label{eq:prob_lms}
\end{eqnarray}
Note that, instead of a gain matrix ${\bf K}_k$ as in Eq ~\eqref{eq:prob_rls}, we now have a scalar gain $\eta_k$ that operates as a variable step size 


Finally, to obtain the posterior variance, which is our measure of uncertainty, we apply \eqref{eq:sigma_hat} and the trick ${\sf Tr}\{{\bf x}_k{\bf x}_k^T\}= {\bf x}_k^T{\bf x}_k= \|{\bf x}_k \|^2$,

\begin{eqnarray}
\hat{\sigma}_k^2 &=& \frac{{\sf Tr}(\boldsymbol\Sigma_k)}{M} \\
&=& \frac{1}{M}{\sf Tr}\left\{ \left( {\bf I} -  \eta_k {\bf x}_k {\bf x}_k^T \right) (\hat{\sigma}_{k-1}^2 +\sigma_d^2)\right\} \\
&=& \left(1 - \frac{\eta_k \|{\bf x}_k\|^2}{M}\right)(\hat{\sigma}_{k-1}^2 +\sigma_d^2) 
\label{eq:sig_k}
\end{eqnarray}
If MAP estimation is performed, we obtain  an adaptable step-size LMS estimation

\begin{equation}
{\bf w}_{k}^{(LMS)} = {\bf w}_{k-1}^{(LMS)} + \eta_k (y_k - {\bf x}_k^T {\bf w}_{k-1}^{(LMS)}){\bf x}_k, 	
\label{eq:lms}
\end{equation}
with
\begin{equation}
\eta_k = \frac{ (\hat{\sigma}_{k-1}^2+ \sigma_d^2)  }{(\hat{\sigma}_{k-1}^2+ \sigma_d^2)  \|{\bf x}_k\|^2 + \sigma_n^2} \nonumber
\end{equation}
At this point, several interesting remarks can be made:

\begin{itemize}

\item The adaptive rule \eqref{eq:lms} has linear complexity since it does not require us to compute the full matrix $\boldsymbol\Sigma_k$ 

\item For a stationary model, we have $\sigma_d^2=0$ in \eqref{eq:prob_lms} and \eqref{eq:sig_k}  In this case, the algorithm remains valid and both the step size and the error variance, $\hat{\sigma}_{k}$, vanish over time $k$  

\item Finally, the proposed adaptable step-size LMS has only two parameters, $\sigma_d^2$ and $\sigma_n^2$, (and only one, $\sigma_n^2$, in stationary scenarios) in contrast to other variable step-size algorithms \cite{kwong1992variable,aboulnasr1997robust,shin2004variable}  More interestingly, both $\sigma_d^2$ and $\sigma_n^2$ have a clear underlying physical meaning, and they can be estimated in many cases  We will comment more about this in the next section  
\end{itemize}



\section{Experiments}
\label{sec:experiments}

We evaluate the performance of the proposed algorithm in both stationary and tracking experiments  In the first experiment, we estimate a fixed vector ${\bf w}^{o}$ of dimension $M=50$  The entries of the vector are independently and uniformly chosen in the range $[-1,1]$  Then, the vector is normalized so that $\|{\bf w}^o\|=1$  Regressors $\boldsymbol{x}_{k}$ are zero-mean Gaussian vectors with identity covariance matrix  The additive noise variance is such that the SNR is $20$ dB  We compare our algorithm with standard RLS and three other LMS-based algorithms: LMS, NLMS \cite{sayed2008adaptive}, VSS-LMS \cite{shin2004variable} \footnote{The used parameters for each algorithm are: for RLS $\lambda=1$, $\epsilon^{-1}=0 01$; for LMS $\mu=0 01$; for NLMS $\mu=0 5$; and for VSS-LMS $\mu_{max}=1$, $\alpha=0 95$, $C=1e-4$ } The probabilistic LMS algorithm in \cite{park2014probabilistic} is not simulated because it is not suitable for stationary environments 

In stationary environments, the proposed algorithm has only one parameter, $\sigma^2_n$  We simulate both the scenario where we have perfectly knowledge of the amount of noise (probLMS1) and the case where the value $\sigma^2_n$ is $100$ times smaller than the actual value (probLMS2)  The Mean-Square Deviation (${\sf MSD} = {\mathbb E} \| {\bf w}_0 - {\bf w}_k \|^2$), averaged out over $50$ independent simulations, is presented in Fig  \ref{fig:msd_statationary} 



\begin{figure}[htb]
\centering
\begin{minipage}[b]{\linewidth}
  \centering
  \centerline{\includegraphics[width=\textwidth]{results_stationary_MSD}}
\end{minipage}
\caption{Performance in terms of MSD of probabilistic LMS with both optimal (probLMS1) and suboptimal (probLMS2) compared to LMS, NLMS, VS-LMS, and RLS }
\label{fig:msd_statationary}
\end{figure}

The performance of probabilistic LMS is close to RLS (obviously at a much lower computational cost) and largely outperforms previous variable step-size LMS algorithms proposed in the literature  Note that, when the model is stationary, i e  $\sigma^2_d=0$ in \eqref{eq:trans_eq},  both the uncertainty $\hat{\sigma}^2_k$, and the adaptive step size $\eta_k$, vanish over time  This implies that the error tends to zero when $k$ goes to infinity  Fig  \ref{fig:msd_statationary} also shows that the proposed approach is not very sensitive to a bad choice of its only parameter, as demonstrated by the good results of probLMS2, which uses a $\sigma^2_n$ that is $100$ times smaller than the optimal value  


\begin{figure}[htb]
\centering
\begin{minipage}[b]{\linewidth}
  \centering
  \centerline{\includegraphics[width=\textwidth]{fig2_final}}
\end{minipage}
\caption{Real part of one coefficient of the measured and estimated channel in experiment two  The shaded area represents two standard deviations from the prediction {(the mean of the posterior distribution)} }
\label{fig_2}
\end{figure}


\begin{table}[ht]
\begin{footnotesize}
\setlength{\tabcolsep}{2pt}
\def1 5mm{1 5mm}
\begin{center}
\begin{tabular}{|l@{\hspace{1 5mm}}|c@{\hspace{1 5mm}}|c@{\hspace{1 5mm}}|c@{\hspace{1 5mm}}|c@{\hspace{1 5mm}}|c@{\hspace{1 5mm}}|c@{\hspace{1 5mm}}|}
\hline
Method &  LMS &  NLMS & LMS-2013 & VSSNLMS & probLMS & RLS \\
\hline
\hline
MSD (dB) &-28 45 &-21 07 &-14 36 &-26 90 &-28 36 &-25 97\\
\hline                                                                     
\end{tabular}
\end{center}
\caption{Steady-state MSD of the different algorithms for the tracking of a real MISO channel }
\label{tab:table_MSD}
\end{footnotesize}

\end{table}
\newpage
In a second experiment, we test the tracking capabilities of the proposed algorithm with {real} data of a wireless MISO channel acquired in a realistic indoor scenario  More details on the setup can be found in \cite{gutierrez2011frequency}  Fig  \ref{fig_2} shows the real part of one of the channels, and the estimate of the proposed algorithm  The shaded area represents the estimated uncertainty for each prediction, i e  $\hat{\mu}_k\pm2\hat{\sigma}_k$  Since the experimental setup does not allow us to obtain the optimal values for the parameters, we fix these parameters to their values that optimize the steady-state mean square deviation (MSD)  \hbox{Table \ref{tab:table_MSD}} shows this steady-state MSD of the estimate of the MISO channel with different methods  As can be seen, the best tracking performance is obtained by standard LMS and the proposed method  





\section{Conclusions and Opened Extensions}
\label{sec:conclusions}

{We have presented a probabilistic interpretation of the least-mean-square filter  The resulting algorithm is an adaptable step-size LMS that performs well both in stationary and tracking scenarios  Moreover, it has fewer free parameters than previous approaches and these parameters have a clear physical meaning  Finally, as stated in the introduction, one of the advantages of having a probabilistic model is that it is easily extensible:}

\begin{itemize}
\item If, instead of using an isotropic Gaussian distribution in the approximation, we used a Gaussian with diagonal covariance matrix, we would obtain a similar algorithm with different step sizes and measures of uncertainty, for each component of ${\bf w}_k$  Although this model can be more descriptive, it needs more parameters to be tuned, and the parallelism with LMS vanishes 
\item Similarly, if we substitute the transition model of \eqref{eq:trans_eq} by an Ornstein-Uhlenbeck process, 

\begin{equation}
p({\bf w}_k|{\bf w}_{k-1})= \mathcal{N}({\bf w}_k;\lambda {\bf w}_{k-1}, \sigma_d^2), \nonumber
\label{eq:trans_eq_lambda}
\end{equation}
a similar algorithm is obtained but with a forgetting factor $\lambda$ multiplying ${\bf w}_{k-1}^{(LMS)}$ in \eqref{eq:lms}  This algorithm may have improved performance under such a kind of autoregresive dynamics of ${\bf w}_{k}$, though, again, the connection with standard LMS becomes dimmer 

\item As in \cite{park2014probabilistic}, the measurement model \eqref{eq:mess_eq} can be changed to obtain similar adaptive algorithms for classification, ordinal regression, and Dirichlet regression for compositional data  

\item A similar approximation technique could be applied to more complex dynamical models, i e  switching dynamical models \cite{barber2010graphical}  The derivation of efficient adaptive algorithms that explicitly take into account a switch in the dynamics of the parameters of interest is a non-trivial and open problem, though the proposed approach could be useful 

\item Finally, like standard LMS, this algorithm can be kernelized for its application in estimation under non-linear scenarios 

\end{itemize}


\begin{appendices}

\section{KL divergence between a general gaussian distribution and an isotropic gaussian}
\label{sec:kl}

 We want to approximate  $p_{{\bf x}_1}(x) = \mathcal{N}({\bf x}; \boldsymbol\mu_1,\boldsymbol\Sigma_1)$ by $p_{{\bf x}_2}({\bf x}) = \mathcal{N}({\bf x}; \boldsymbol\mu_2,\sigma_2^2 {\bf I})$  In order to do so, we have to compute the parameters of $p_{{\bf x}_2}({\bf x})$, $\boldsymbol\mu_2$ and $\sigma_2^2$, that minimize the following Kullback-Leibler divergence,

\begin{eqnarray}
D_{KL}(p_{{\bf x}_1}\| p_{{\bf x}_2}) &=&\int_{-\infty}^{\infty} p_{{\bf x}_1}({\bf x}) \ln{\frac{p_{{\bf x}_1}({\bf x})}{p_{{\bf x}_2}({\bf x})}}d{\bf x} \nonumber  \\
&= &  \frac{1}{2} \{ -M + {\sf Tr}(\sigma_2^{-2} {\bf I}\cdot \boldsymbol\Sigma_1^{-1})  \nonumber \\
  & &  + (\boldsymbol\mu_2 - \boldsymbol\mu_1 )^T \sigma^{-2}_2{\bf I} (\boldsymbol\mu_2 - \boldsymbol\mu_1 )  \nonumber \\
 & &   +  \ln \frac{{\sigma_2^2}^M}{\det\boldsymbol\Sigma_1} \}   
\label{eq:divergence}
\end{eqnarray}
Using symmetry arguments, we obtain 
\begin{equation}
\boldsymbol\mu_2^{*} =\arg \displaystyle{  \min_{\boldsymbol\mu_2}} \{ D_{KL}(p_{{\bf x}_1}\| p_{{\bf x}_2}) \} = \boldsymbol\mu_1 
\end{equation}
Then, \eqref{eq:divergence} gets simplified into 

\begin{eqnarray}
D_{KL}(p_{{\bf x}_1}\| p_{{\bf x}_2}) = \frac{1}{2}\lbrace { -M + {\sf Tr}(\frac{\boldsymbol\Sigma_1}{\sigma_2^{2}}) + \ln \frac{\sigma_2^{2M}}{\det\boldsymbol\Sigma_1}}\rbrace 
\end{eqnarray}
The variance $\sigma_2^2$ is computed in order to minimize this Kullback-Leibler divergence as

\begin{eqnarray}
\sigma_2^{2*} &=& \arg\min_{\sigma_2^2} D_{KL}(P_{x_1}\| P_{x_2}) \nonumber \\
 &=& \arg\min_{\sigma_2^2}\{ \sigma_2^{-2}{\sf Tr}\{\boldsymbol\Sigma_1\} + M\ln \sigma_2^{2} \}  
\end{eqnarray}
Deriving and making it equal zero leads to

\begin{equation}
\frac{\partial}{\partial \sigma_2^2} \left[ \frac{{\sf Tr}\{\boldsymbol\Sigma_1\}}{\sigma_2^{2}} + M \ln \sigma_2^{2} \right] = \left  {\frac{M}{\sigma_2^{2}}-\frac{{\sf Tr}\{\boldsymbol\Sigma_1\}}{(\sigma_2^{2})^2}}\right|_{\sigma_2^{2}=\sigma_2^{2*}}\left  =0 \right   
\nonumber
\end{equation}
Finally, since the divergence has a single extremum in $R_+$,
\begin{equation}
\sigma_2^{2*} = \frac{{\sf Tr}\{\boldsymbol\Sigma_1\}}{M} 
\end{equation}




\end{appendices}

\vfill
\clearpage

\bibliographystyle{IEEEbib}

Context 3: Thalassaemia minor | definition of Thalassaemia minor by Medical dictionary
Thalassaemia minor | definition of Thalassaemia minor by Medical dictionary
https://medical-dictionary thefreedictionary com/Thalassaemia+minor
(redirected from Thalassaemia minor)
Related to Thalassaemia minor: thalassaemia major
Thalassemia describes a group of inherited disorders characterized by reduced or absent amounts of hemoglobin, the oxygen-carrying protein inside the red blood cells  There are two basic groups of thalassemia disorders: alpha thalassemia and beta thalassemia  These conditions cause varying degrees of anemia, which can range from insignificant to life threatening 
All types of thalassemias are considered quantitative diseases of hemoglobin, because the quantity of hemoglobin produced is reduced or absent  Usual adult hemoglobin is made up of three components: alpha globin, beta globin, and heme  Thalassemias are classified according to the globin that is affected, hence the names alpha and beta thalassemia  Although both classes of thalassemia affect the same protein, the alpha and beta thalassemias are distinct diseases that affect the body in different ways 
Beta thalassemia may be the most best-known type of thalassemia and is also called Cooley's anemia  It is caused by a change in the gene for the beta globin component of hemoglobin  Beta thalassemia causes variable anemia that can range from moderate to severe, depending in part on the exact genetic change underlying the disease  Beta thalassemia can be classified based on clinical symptoms  Beta thalassemia major usually causes severe anemia that can occur within months after birth  If left untreated, severe anemia can result in insufficient growth and development, as well as other common physical complications that can lead to a dramatically decreased life-expectancy  Fortunately, in developed countries beta thalassemia is usually identified by screening in the newborn period, before symptoms have developed  Children who are identified early can be started on ongoing blood transfusion therapy as needed  Although transfusion therapy prevents many of the complications of severe anemia, the body is unable to eliminate the excess iron contained in the transfused blood  Over time, the excess iron deposits in tissues and organs, resulting in damage and organ failure  Another medication must be administered to help the body eliminate the excess iron and prevent iron-over-load complications  Beta thalassemia intermedia describes the disease in individuals who have moderate anemia that only requires blood transfusions intermittently, if at all 
Alpha thalassemia is the result of changes in the genes for the alpha globin component of hemoglobin  There are two main types of alpha thalassemia disease: hemoglobin H disease and alpha thalassemia major  The two diseases are quite different from beta thalassemia as well as from one another  Individuals with hemoglobin H disease can experience events of hemolytic anemia—anemia caused by the rapid breakdown of the red blood cells  These events are thought to be triggered by various environmental causes, such as infection and/or exposure to certain chemicals  Hemoglobin H disease is in most cases milder than beta thalassemia  It does not generally require transfusion therapy  Alpha thalassemia major is a very serious disease that results in severe anemia that begins even before birth  Most affected babies do not survive to be born or die shortly after birth 
The thalassemias are among the most common genetic diseases worldwide  Both alpha and beta thalassemia have been described in individuals of almost every ancestry, but the conditions are more common among certain ethnic groups  Unaffected carriers of all types of thalassemia traits do not experience health problems  In fact, the thalassemia trait is protective against malaria, a disease caused by blood-borne parasites transmitted through mosquito bites  According to a widely accepted theory, most genetic changes—mutations—that cause thalassemia occurred multiple generations ago  Coincidentally, these mutations increased the likelihood that carriers would survive malaria infection  Survivors passed the mutation onto their offspring, and the trait became established throughout areas where malaria is common  As populations migrated, so did the thalassemia traits 
Beta thalassemia trait is seen most commonly in people with the following ancestry: Mediterranean (including North African, and particularly Italian and Greek), Middle Eastern, Indian, African, Chinese, and Southeast Asian (including Vietnamese, Laotian, Thai, Singaporean, Filipino, Cambodian, Malaysian, Burmese, and Indonesian)  Alpha-thalassemia trait is seen with increased frequency in the same ethnic groups  However, there are different types of alpha thalassemia traits within these populations  The frequency of hemoglobin H disease and alpha thalassemia major depends on the type of alpha thalassemia trait  The populations in which alpha thalassemia diseases are most common include Southeast Asians and Chinese (particularly Southern Chinese) 
It is difficult to obtain accurate prevalence figures for various types of thalassemia within different populations  This difficulty arises due to testing limitations in determining exact genetic diagnoses, as well as the fact that many studies have focused on small, biased hospital populations 
Two studies reflect prevalence figures that can be helpful counseling families and determining who to screen for beta thalassemia  Between the years of 1990 and 1996, the State of California screened more than 3 1 million infants born in the state for beta thalassemia  Approximately 1 in 114,000 infants had beta thalassemia major, with prevalence rates being highest among Asian Indians (about one in 4,000), Southeast Asians (about one in 10,000), and Middle Easterners (about one in 7,000)  Another type of beta thalassemia disease, E/beta thalassemia, was represented in approximately one in 110,000 births, all of which occurred in families of Southeast Asian ancestry  Among Southeast Asians, the prevalence of E/beta thalassemia was approximately one in 2,600 births  This is in keeping with the observation that hemoglobin E trait carrier rates are relatively high within the Southeast Asian population: 16% in a study of 768 immigrants to California, and up to 25% in some specific Southeast Asian populations such as Cambodians  While these California studies address some of the limitations of earlier population studies, the pattern observed in California is expected to be different in other areas of the United States and the world  For example, Italians are underrepresented in this population when compared to the population of the East Coast of the United States 
Determining prevalence figures for alpha thalassemia is even more difficult due to increased limitations in diagnostic testing  All types of alpha thalassemia disease are most common among people of Southeast Asian and Chinese descent, for reasons that become clearer with an understanding of the underlying genetics of alpha thalassemia  One study of 500 pregnant women in Northern Thailand estimated a frequency of one in 500 pregnancies affected by alpha thalassemia major, for example  Prevalence of alpha thalassemia disease is significantly lower in the United States primarily because of immigration patterns; although at least one state, California, has observed growing hemoglobin H disease incidence rates that are high enough to justify universal newborn screening for the condition 
Humans normally make several types of the oxygen-carrying protein hemoglobin  An individual's stage in development determines whether he or she makes primarily embryonic, fetal, or adult hemoglobins  All types of hemoglobin are made of three components: heme, alpha (or alpha-like) globin, and beta (or beta-like) globin  All types of thalassemia are caused by changes in either the alpha- or beta-globin gene  These changes cause little or no globin to be produced  The thalassemias are, therefore, considered quantitative hemoglobin diseases  All types of thalassemias are recessively inherited, meaning that a genetic change must be inherited from both the mother and the father  The severity of the disease is influenced by the exact thalassemia mutations inherited, as well as other genetic and environmental factors  There are rare exceptions, notably with beta thalassemia, where globin gene mutations exhibit a dominant pattern of inheritance in which only one gene needs to be altered in order to see disease expression  Scientists continue to study the causes  For instance, a new mutation for alpha-thalassemia was discovered for the first time among Iranian patients in 2004 
BETA-THALASSEMIA  Most individuals have two normal copies of the beta globin gene, which is located on chromosome 11 and makes the beta globin component of normal adult hemoglobin, hemoglobin A  There are approximately 100 genetic mutations that have been described that cause beta thalassemia, designated as either beta0 or beta + mutations  No beta globin is produced with a beta0 mutation, and only a small fraction of the normal amount of beta globin is produced with a beta + mutation 
When an individual has one normal beta globin gene and one with a beta thalassemia mutation, he or she is said to carry the beta thalassemia trait  Beta thalassemia trait, like other hemoglobin traits, is protective against malaria infection  Trait status is generally thought not to cause health problems, although some women with beta thalassemia trait may have an increased tendency toward anemia during pregnancy 
When two members of a couple carry the beta thalassemia trait, there is a 25% chance that each of their children will inherit beta thalassemia disease by inheriting two beta thalassemia mutations, one from each parent  The clinical severity of the beta thalassemia disease—whether an individual has beta thalassemia intermedia or beta thalassemia major—will depend largely on whether the mutations inherited are beta0 thalassemia or beta + thalassemia mutations  Two beta0 mutations generally lead to beta thalassemia major, and two beta+ thalassemia mutations generally lead to beta thalassemia intermedia  Inheritance of one beta0 and one beta + thalassemia mutation tends to be less predictable 
Although relatively uncommon, there are other thalassemia-like mutations that can affect the beta globin gene  Hemoglobin E is the result of a substitution of a single nucleotide  This change results in a structurally altered hemoglobin that is produced in decreased amounts  Therefore, hemoglobin E is unique in that it is both a quantitative (i e  thalassemia-like) and qualitative trait  When co-inherited with a beta thalassemia trait, it causes a disease that is almost indistinguishable from beta thalassemia disease  Large deletions around and including the beta globin gene can lead to delta/beta thalassemia or hereditary persistence of fetal hemoglobin (HPFH)  Interestingly, delta/beta thalassemia trait behaves very similarly to beta thalassemia trait in its clinical manifestations  However, HPFH trait does not tend to cause hemoglobin disease when co-inherited with a second thalassemia or other beta globin mutation 
ALPHA-THALASSEMIA  Most individuals have four normal copies of the alpha globin gene, two copies on each chromosome 16  These genes make the alpha globin component of normal adult hemoglobin, which is called hemoglobin A  Alpha globin is also a component of fetal hemoglobin and the other major adult hemoglobin called hemoglobin A2  Mutations of the alpha globin genes are usually deletions of the gene, resulting in absent production of alpha globin  Since there are four genes (instead of the usual two) to consider when looking at alpha globin gene inheritance, there are several alpha globin types that are possible 
Absence of one alpha globin gene leads to a condition known as silent alpha thalassemia trait  This condition causes no health problems and can be detected only by special genetic testing  Alpha thalassemia trait occurs when two alpha globin genes are missing  This can occur in two ways  The genes may be deleted from the same chromosome, causing the 'cis' type of alpha thalassemia trait  Alternately, they may be deleted from different chromosomes, causing the 'trans' type of alpha thalassemia trait  In both instances, there are no associated health problems, although the trait status may be detected by more routine blood screening 
Hemoglobin H disease results from the deletion of three alpha globin genes, such that there is only one functioning gene  Typically, this can occur when one parent carries the silent alpha thalassemia trait, and the other parent carries the 'cis' type of the alpha thalassemia trait  In this situation, there is a 25% chance for hemoglobin H disease in each of such a couple's children 
Hemoglobin H disease-like symptoms can also be a part of a unique condition called alpha thalassemia mental retardation syndrome  Alpha thalassemia mental retardation syndrome can be caused by a deletion of a significant amount of chromosome 16, affecting the alpha globin genes  This is usually not inherited, but rather occurs sporadically in the affected individual  Affected individuals have mild hemoglobin H disease, mild-to-moderate mental retardation, and characteristic facial features  This syndrome can also occur as a sex-linked form in which a mutation is inherited in a particular gene on the X-chromosome  This gene influences alpha globin production, as well as various other developmental processes  Individuals affected with this form of the syndrome tend to have more severe mental retardation, delayed development, nearly absent speech, characteristic facial features, and genital-urinary abnormalities  The remaining discussion will focus only on aspects of hemoglobin H disease 
Alpha thalassemia major results from the deletion of all four alpha globin genes, such that there are no functioning alpha globin genes  This can occur when both parents carry the 'cis' type of the alpha thalassemia trait  In this situation, there is a 25% chance for alpha thalassemia major in each of such a couple's children 
Beta thalassemia major is characterized by severe anemia that can begin months after birth  In the United States and other developed countries beta thalassemia is identified and treated early and effectively  Therefore, the following discussion of symptoms applies primarily to affected individuals in the past and unfortunately in some underdeveloped countries now  If untreated, beta thalassemia major can lead to severe lethargy, paleness, and delays in growth and development  The body attempts to compensate by producing more blood, which is made inside the bones in the marrow  However, this is ineffective without the needed genetic instructions to make enough functioning hemoglobin  Instead, obvious bone expansion and changes occur that cause characteristic facial and other changes in appearance, as well as increased risk of fractures  Severe anemia taxes other organs in the body—such as the heart, spleen, and liver—which must work harder than usual  This can lead to heart failure, as well as enlargement and other problems of the liver and spleen  When untreated, beta thalassemia major generally results in childhood death, usually due to heart failure  In 2004, the first known heart attack associated with beta thalassemia major was reported  Fortunately, in developed countries diagnosis is usually made early, often before symptoms have begun  This allows for treatment with blood transfusion therapy, which can prevent most of the complications of the severe anemia caused by beta thalassemia major  Individuals with beta thalassemia intermedia have a more moderate anemia that may only require treatment with transfusion intermittently, such as when infections occur and stress the body  As a person with beta thalassemia intermedia gets older, however, the need for blood transfusions may increase to the point that they are required on a regular basis  When this occurs their disease becomes more similar to beta thalassemia major  Other genetic and environmental factors can influence the course of the disease as well  For example, co-inheritance of one or two alpha thalassemia mutations can tend to ameliorate some of the symptoms of beta thalassemia disease, which result in part from an imbalance in the amount of alpha- and beta-globin present in the red blood cells 
Hemoglobin h disease
Absence of three alpha globin genes causes an imbalance of alpha and beta globin proteins in the red blood cells  The excess beta globin proteins tend to come together to form hemoglobin H, which is unable to release oxygen to the tissues  In addition, hemoglobin H tends to precipitate out in the cells, causing damage to the red blood cell membrane  When affected individuals are exposed to certain drugs and chemicals known to make the membrane more fragile, the cells are thought to become vulnerable to breakdown in large numbers, a complication called hemolytic anemia  Fever and infection are also considered to be triggers of hemolytic anemia in hemoglobin H disease  This can result in fatigue, paleness, and a yellow discoloration of the skin and whites of eyes called jaundice  Usually, the anemia is mild enough not to require treatment  Severe anemia events may require blood transfusion, however, and are usually accompanied by such other symptoms as dark feces or urine and abdominal or back pain  These events are uncommon in hemoglobin H disease, although they occur more frequently in a more serious type of hemoglobin H disease called hemoglobin H/Constant Spring disease  Individuals effected with this type of hemoglobin H disease are also more likely to have enlargement of and other problems with the spleen 
Alpha thalassemia major
Because alpha globin is a necessary component of all major hemoglobins and some minor hemoglobins, absence of all functioning alpha globin genes leads to serious medical consequences that begin even before birth  Affected fetuses develop severe anemia as early as the first trimester of pregnancy  The placenta, heart, liver, spleen, and adrenal glands may all become enlarged  Fluid can begin collecting throughout the body as early as the start of the second trimester, causing damage to developing tissues and organs  Growth retardation is also common  Affected fetuses usually miscarry or die shortly after birth  In addition, women carrying affected fetuses are at increased risk of developing complications of pregnancy and delivery  Up to 80% of such women develop toxemia, a disturbance of metabolism that can potentially lead to convulsions and coma  Other maternal complications include premature delivery and increased rates of delivery by cesarean section, as well as hemorrhage after delivery 
Thalassemia may be suspected if an individual shows signs that are suggestive of the disease  In all cases, however, laboratory diagnosis is essential to confirm the exact diagnosis and to allow for the provision of accurate genetic counseling about recurrence risks and testing options for parents and affected individuals  Screening is likewise recommended to determine trait status for individuals of high-risk ethnic groups 
The following tests are used to screen for thalassemia disease and/or trait:
hemoglobin electrophoresis with quantitative hemoglobin A2 and hemoglobin F
free erythrocyte-protoporphyrin (or ferritin or other studies of serum iron levels)
A complete blood count will identify low levels of hemoglobin, small red blood cells, and other red blood cell abnormalities that are characteristic of a thalassemia diagnosis  Since thalassemia trait can sometimes be difficult to distinguish from iron deficiency, tests to evaluate iron levels are important  A hemoglobin electrophoresis is a test that can help identify the types and quantities of hemoglobin made by an individual  This test uses an electric field applied across a slab of gel-like material  Hemoglobins migrate through this gel at various rates and to specific locations, depending on their size, shape, and electrical charge  Isoelectric focusing and high-performance liquid chromatography (HPLC) use similar principles to separate hemoglobins and can be used instead of or in various combinations with hemoglobin electrophoresis to determine the types and quantities of hemoglobin present  Hemoglobin electrophoresis results are usually within the normal range for all types of alpha thalassemia  However, hemoglobin A2 levels and sometimes hemoglobin F levels are elevated when beta thalassemia disease or trait is present  Hemoglobin electrophoresis can also detect structurally abnormal hemoglobins that may be co-inherited with a thalassemia trait to cause thalassemia disease (i e , hemoglobin E) or other types of hemoglobin disease (i e , sickle hemoglobin)  Sometimes DNA testing is needed in addition to the above screening tests  This can be performed to help confirm the diagnosis and establish the exact genetic type of thalassemia 
Diagnosis of thalassemia can occur under various circumstances and at various ages  Several states offer thalassemia screening as part of the usual battery of blood tests done for newborns  This allows for early identification and treatment  Thalassemia can be identified before birth through the use of prenatal diagnosis  Chorionic villus sampling (CVS) can be offered as early as 10 weeks of pregnancy and involves removing a sample of the placenta made by the baby and testing the cells  CVS carries a risk of causing a miscarriage that is between 0 5%-1%  Amniocentesis is generally offered between 15 and 22 weeks of pregnancy, but can sometimes be offered earlier  Two to three tablespoons of the fluid surrounding the baby is removed  This fluid contains fetal cells that can be tested  The risk of miscarriage associated with amniocentesis ranges from 0 33-0 5%  Pregnant woman and couples may choose prenatal testing in order to prepare for the birth of a baby that may have thalassemia  Alternately, knowing the diagnosis during pregnancy allows for the option of pregnancy termination  Preimplantation genetic diagnosis (PGD) is a relatively new technique that involves in-vitro fertilization followed by genetic testing of one cell from each developing embryo  Only the embryos unaffected by sickle cell disease are transferred back into the uterus  PGD is currently available on a research basis only and is relatively expensive 
Individuals with beta thalassemia major receive regular blood transfusions, usually on a monthly basis  This helps prevent severe anemia and allows for more normal growth and development  Transfusion therapy does have limitations, however  Individuals can develop reactions to certain proteins in the blood—called a transfusion reaction  This can make locating appropriately matched donor blood more difficult  Although blood supplies in the United States are very safe, particularly relative to the past and to other areas of the world, there remains an increased risk of exposure to such blood-borne infections as hepatitis  Additionally, the body is not able to get rid of the excess iron that accompanies each transfusion  An additional medication called desferoxamine is administered, usually five nights per week over a period of several hours, using an automatic pump that can be used during sleep or taken anywhere the person goes  This medication is able to bind to the excess iron, which can then be eliminated through urine  If desferoxamine is not used regularly or is unavailable, iron overload can develop and cause tissue damage and organ damage and failure  The heart, liver, and endocrine organs are particularly vulnerable  Desferoxamine itself may rarely produce allergic or toxic side effects, including hearing damage  Signs of desferoxamine toxicity are screened for and generally develop in individuals who overuse the medication when body iron levels are sufficiently low  Overall, however, transfusion and desferoxamine therapy have increased the life expectancy of individuals with the most severe types of beta thalassemia major to the 4th or 5th decade  This can be expected to improve with time and increased developments in treatment, as well as for those with more mild forms of the disease 
New treatments offer additional options for some individuals with beta thalassemia major  There are various medications that target the production of red blood cells (i e  erythropoeitin) or fetal hemoglobin (i e  hydroxyurea and butyrate)  Their effectiveness in ameliorating the severity of beta thalassemia is currently being investigated  Another promising new treatment is bone marrow transplantation, in which the bone marrow of an affected individual is replaced with the bone marrow of an unaffected donor  If successful, this treatment can provide a cure  However, there is an approximately 10-15% chance the procedure could be unsuccessful (i e  the thalassemia returns); result in complications (i e  graft-versus-host disease); or result in death  The risk for specific individuals depends on current health status, age, and other factors  Because of the risks involved and the fact that beta thalassemia is a treatable condition, transplant physicians require a brother or sister donor who has an identically matched tissue type, called HLA type  HLA type refers to the unique set of proteins present on each individual's cells, which allows the immune system to recognize "self" from "foreign " HLA type is genetically determined, so there is a 25% chance for two siblings to be a match  Transplant physicians and researchers are also investigating ways to improve the safety and effectiveness of bone marrow transplantation  Using newborn sibling umbilical cord blood—the blood from the placenta that is otherwise discarded after birth but contains cells that can go on to make bone marrow—seems to provide a safer and perhaps more effective source of donor cells  Donors and recipients may not have to be perfect HLA matches for a successful transplant using cord blood cells  Trials are also underway to determine the effectiveness of "partial transplants," in which a safer transplant procedure is used to replace only a percentage of the affected individual's bone marrow  Other possible treatments on the horizon may include gene therapy techniques aimed at increasing the amount of normal hemoglobin the body is able to make 
Hemoglobin H disease is a relatively mild form of thalassemia that may go unrecognized  It is not generally considered a condition that will reduce one's life expectancy  Education is an important part of managing the health of an individual with hemoglobin H disease  It is important to be able to recognize the signs of severe anemia that require medical attention  It is also important to be aware of the medications, chemicals, and other exposures to avoid due to the theoretical risk they pose of causing a severe anemia event  When severe anemia occurs, it is treated with blood transfusion therapy  For individuals with hemoglobin H disease, this is rarely required  For those with the hemoglobin H/Constant Spring form of the disease, the need for transfusions may be intermittent or ongoing, perhaps on a monthly basis and requiring desferoxamine treatment  Individuals with this more severe form of the disease may also have an increased chance of requiring removal of an enlarged and/or overactive spleen 
Anemia — A blood condition in which the level of hemoglobin or the number of red blood cells falls below normal values  Common symptoms include paleness, fatigue, and shortness of breath 
Bilirubin — A yellow pigment that is the end result of hemoglobin breakdown  This pigment is metabolized in the liver and excreted from the body through the bile  Bloodstream levels are normally low; however, extensive red cell destruction leads to excessive bilirubin formation and jaundice 
Bone marrow — A spongy tissue located in the hollow centers of certain bones, such as the skull and hip bones  Bone marrow is the site of blood cell generation 
Bone marrow transplantation — A medical procedure used to treat some diseases that arise from defective blood cell formation in the bone marrow  Healthy bone marrow is extracted from a donor to replace the marrow in an ailing individual  Proteins on the surface of bone marrow cells must be identical or very closely matched between a donor and the recipient 
Desferoxamine — The primary drug used in iron chelation therapy  It aids in counteracting the life-threatening buildup of iron in the body associated with long-term blood transfusions 
Globin — One of the component protein molecules found in hemoglobin  Normal adult hemoglobin has a pair each of alpha-globin and beta-globin molecules 
Heme — The iron-containing molecule in hemoglobin that serves as the site for oxygen binding 
Hemoglobin — Protein-iron compound in the blood that carries oxygen to the cells and carries carbon dioxide away from the cells 
Hemoglobin A — Normal adult hemoglobin that contains a heme molecule, two alpha-globin molecules, and two beta-globin molecules 
Hemoglobin electrophoresis — A laboratory test that separates molecules based on their size, shape, or electrical charge 
Hepatomegaly — An abnormally large liver 
HLA type — Refers to the unique set of proteins called human leukocyte antigens  These proteins are present on each individual's cell and allow the immune system to recognize 'self' from 'foreign'  HLA type is particularly important in organ and tissue transplantation 
Hydroxyurea — A drug that has been shown to induce production of fetal hemoglobin  Fetal hemoglobin has a pair of gamma-globin molecules in place of the typical beta-globins of adult hemoglobin  Higher-than-normal levels of fetal hemoglobin can ameliorate some of the symptoms of thalassemia 
Iron overload — A side effect of frequent blood transfusions in which the body accumulates abnormally high levels of iron  Iron deposits can form in organs, particularly the heart, and cause life-threatening damage 
Jaundice — Yellowing of the skin or eyes due to excess of bilirubin in the blood 
Mutation — A permanent change in the genetic material that may alter a trait or characteristic of an individual, or manifest as disease, and can be transmitted to offspring 
Placenta — The organ responsible for oxygen and nutrition exchange between a pregnant mother and her developing baby 
Red blood cell — Hemoglobin-containing blood cells that transport oxygen from the lungs to tissues  In the tissues, the red blood cells exchange their oxygen for carbon dioxide, which is brought back to the lungs to be exhaled 
Screening — Process through which carriers of a trait may be identified within a population 
Splenomegaly — Enlargement of the spleen 
Because alpha thalassemia major is most often a condition that is fatal in the prenatal or newborn period, treatment has previously been focused on identifying affected pregnancies in order to provide appropriate management to reduce potential maternal complications  Pregnancy termination provides one form of management  Increased prenatal surveillance and early treatment of maternal complications is an approach that is appropriate for mothers who wish to continue their pregnancy with the knowledge that the baby will most likely not survive  In recent years, there have been a handful of infants with this condition who have survived long-term  Most of these infants received experimental treatment including transfusions before birth, early delivery, and even bone marrow transplantation before birth, although the latter procedure has not yet been successful  For those infants that survive to delivery, there seems to be an increased risk of developmental problems and physical effects, particularly heart and genital malformations  Otherwise, their medical outlook is similar to a child with beta thalassemia major, with the important exception that ongoing, life-long blood transfusions begin right at birth 
As discussed above, the prognosis for individuals with the most serious types of thalassemia has improved drastically in the last several years following recent medical advances in transfusion, chemo-, and transplantation therapy  Advances continue and promise to improve the life expectancy and quality of life further for affected individuals 
"First Known Heart Attack Associated With Beta-thalassemia Major Reported " Heart Disease Weekly February 22, 2004: 10 
"Novel Alpha-thalassemia Mutations Identified " Hematology Week January 26, 2004: 19 
Children's Blood Foundation  333 East 38th St , Room 830, New York, NY 10016-2745  (212) 297-4336  cfg@nyh med cornell edu 
Cooley's Anemia Foundation, Inc  129-09 26th Ave  #203, Flushing, NY 11354  (800) 522-7222 or (718) 321-2873  http://www thalassemia org 
March of Dimes Birth Defects Foundation  1275 Mamaroneck Ave , White Plains, NY 10605  (888) 663-4637  resourcecenter@modimes org  http://www modimes org 
National Heart, Lung, and Blood Institute  PO Box 30105, Bethseda, MD 20824-0105  (301) 592-8573  nhlbiinfo@rover nhlbi nih gov  http://www nhlbi nih gov 
National Organization for Rare Disorders (NORD)  PO Box 8923, New Fairfield, CT 06812-8923  (203) 746-6518 or (800) 999-6673  Fax: (203) 746-6481  http://www rarediseases org 
Bojanowski J  "Alpha Thalassemia Major: The Possibility of Long-Term Survival " Pamphlet from the Northern California Comprehensive Thalassemia Center  (1999) 
Children's Hospital Oakland, Northern California Comprehensive Thalassemia Center website  http://www thalassemia com 
Cooley's Anemia Foundation, Inc  website  http://www thalassemia org/gohome html 
Joint Center for Sickle Cell and Thalassemic Disorders website  http://cancer mgh harvard edu/medOnc/sickle htm 
[thal″ah-se´me-ah]
a heterogeneous group of hereditary hemolytic anemias marked by a decreased rate of synthesis of one or more hemoglobin polypeptide chains, classified according to the chain involved (α, β, δ); the two major categories are α- and β-thalassemia 
α-thalassemia (alpha-thalassemia) that caused by diminished synthesis of alpha chains of hemoglobin  The homozygous form is incompatible with life, the stillborn infant displaying severe hydrops fetalis  The heterozygous form may be asymptomatic or marked by mild anemia 
β-thalassemia (beta-thalassemia) that caused by diminished synthesis of beta chains of hemoglobin  The homozygous form is called t  major and the heterozygous form is called t  minor 
thalassemia ma´jor the homozygous form of β-thalassemia, in which hemoglobin A is completely absent; it appears in the newborn period and is marked by hemolytic, hypochromic, microcytic anemia; hepatosplenomegaly; skeletal deformation; mongoloid facies; and cardiac enlargement 
thalassemia mi´nor the heterozygous form of β-thalassemia; it is usually asymptomatic, but there may be mild anemia 
sickle cell–thalassemia a hereditary anemia involving simultaneous heterozygosity for hemoglobin S and thalassemia 
thal·as·se·mi·a
, thalassanemia (thal'ă-sē'mē-ă, thă-las-ă-nē'mē-ă),
Any of a group of inherited disorders of hemoglobin metabolism in which there is impaired synthesis of one or more of the polypeptide chains of globin; several genetic types exist, and the corresponding clinical picture may vary from barely detectable hematologic abnormality to severe and fatal anemia 
[G  thalassa, the sea, + haima, blood]
/thal·as·se·mia/ (thal″ah-se´me-ah) a heterogeneous group of hereditary hemolytic anemias marked by a decreased rate of synthesis of one or more hemoglobin polypeptide chains, classified according to the chain involved (α, β, δ); the two major categories are α- and β-thalassemia 
α-thalassemia that caused by diminished synthesis of alpha chains of hemoglobin  The homozygous form is incompatible with life, the stillborn infant displaying severe hydrops fetalis  The heterozygous form may be asymptomatic or marked by mild anemia 
β-thalassemia that caused by diminished synthesis of beta chains of hemoglobin  The homozygous form is called t  major and the heterozygous form is called t  minor 
thalassemia ma´jor the homozygous form of &#x03B2;, in which hemoglobin A is completely absent; it appears in the newborn period and is marked by hemolytic, hypochromic, microcytic anemia, hepatosplenomegaly, skeletal deformation, mongoloid facies, and cardiac enlargement 
thalassemia mi´nor the heterozygous form of &#x03B2;, usually asymptomatic, although there is sometimes mild anemia 
(thăl′ə-sē′mē-ə)
An inherited form of anemia occurring chiefly among people of Mediterranean descent, caused by faulty synthesis of part of the hemoglobin molecule  Also called Mediterranean anemia 
thal′as·se′mic adj 
[thal′əsē′mē·ə]
Etymology: Gk, thalassa, sea, a + haima, without blood
production and hemolytic anemia characterized by microcytic, hypochromic red blood cells  Thalassemia is caused by inherited deficiency of alpha- or beta-globin synthesis  See also hemochromatosis, hemosiderosis 
Beta thalassemia, clinical thalassemia, Cooley's anemia, Mediterranean anemia, thalassemia major Hematology A group of genetic diseases by underproduction of hemoglobin due to mutations in the beta globin gene, which is more common in Mediterraneans Heredity Parents are carriers–heterozygotes; one in 4 children is homozygous for the mutation and thus has full-blown disease Clinical See Anemia  Cf Sickle cell anemia 
α-thalassemia
Hemoglobin Barts Hematology An inherited condition caused by a defect in the synthesis of the Hb α chain; Hb Barts hemoglobinopathy is characterized by the presence of 4 gamma chains; it is more common in southeast Asians; the most severe form of alpha thalassemia causes stillbirth due to hydrops fetalis Heredity Parents are carriers–heterozygotes; one in 4 children is homozygous for the mutation and thus has full-blown disease Clinical Pallor, fatiguability, FTT, fever, infections, diarrhea Management Transfusions
Thalassemia major Hematology A hemoglobinopathy caused by a defect in the synthesis of Hb β chain Clinical Pallor, fatigability, FTT, fever due to infections, diarrhea, bone deformities, hepatosplenomegaly Management Transfusions, but iron overload can damage the heart, liver, and endocrine systems, ergo iron chelation–early use of deferiprone, deferoxamine ↓ transfusion-related iron overload and may protect against DM, cardiac disease, early death
δ-thalassemia
Hematology A condition characterized by a defect of Hb A2–α2δ2; because Hb A2 comprises only 3% of the circulating Hb, even its complete absence; δ-thalassemia has little clinical or hematologic impact
γ-thalassemia
Hematology A condition characterized by a defect of gamma–γ Hb chains found in Hb F–α2γ2; because Hb F is present primarily in the fetus and newborns, it is rarely seen outside of the neonatal period, but may cause transient neonatal hemolytic anemia 
, thalassanemia (thal'ă-sē'mē-ă, -ă-să-nē'mē-ă)
Any of a group of inherited disorders of hemoglobin metabolism in which there is impaired synthesis of one or more of the polypeptide chains of globin; several genetic types exist, and the corresponding clinical picture may vary from barely detectable hematologic abnormality to severe and fatal anemia  People of Mediterranean, extraction are more often affected than others by this type of anemia 
Synonym(s): thalassaemia, thalassanaemia 
Any of a group of inherited disorders of hemoglobin metabolism with impaired synthesis of one or more polypeptide chains of globin; several genetic types exist 
<a href="https://medical-dictionary thefreedictionary com/Thalassaemia+minor">thalassemia</a>
Barts hemoglobin
beta hemoglobinopathy
beta-delta thalassemia
beta-thalassaemia
Bite Cell
black gallstone
I know of a couple, totally unrelated and unbeknownst to them, who are silent carriers of Thalassaemia minor 
Pakistan: Genetic factor: All in the genes
But, unfortunately, when one person with thalassaemia minor carrier happens to marry another with the same diagnosis, there is a strong possibility that their child would be thalassaemia major, as happened in the case of Taneja 
' My life depends upon a monthly blood transfusion '
0] thalassaemia demonstrates variable severity, ranging from a condition similar to [beta] thalassaemia minor to something approaching thalassaemia major 
A retrospective review of homozygous haemoglobin E patients
Thal, Alan P 
thalame
thalamencephalic
thalamencephalon
thalamic
thalamic fasciculus
thalamic nucleus
thalamic pain syndrome
thalamic peduncle
thalamic radiation
thalamo-
thalamocoele
thalamocortical
thalamocortical fibers
thalamogeniculate artery
thalamolenticular
thalamoperforating artery
thalamostriate radiation
thalamotuberal artery
Thalassaemia minor
thalassaemiaor Cooley's disease
thalassemic facies
thalasso-
Thalassobacter
Thalassobacter utilis
thalassoplankton
thalassoposia
thalidomide neuropathy
Thalidomider
thallium poisoning
Thalarctos
THALAS
Thalasaemia
Thalassaemia Association of Malaysia
thalassaemia major
Thalassaemias
thalassaemic
thalassanaemia
Thalassemia Action Group
Thalassemia Clinical Research Network
thalassemia syndrome



ground_truth: The authors used simulated data and real data from a wireless MISO channel.

prompt_front: Now, answer the following question based on the text below, only give me the answer and do not output any other words.

Question: How many massive star-forming regions were studied?

Read the following text and answer briefly.

Context 2: \section{Introduction}

Spectral line surveys have revealed that high-mass star-forming
regions are rich reservoirs of molecules from simple diatomic species
to complex and larger molecules (e g ,
\citealt{schilke1997b,hatchell1998b,comito2005,bisschop2007}) 
However, there have been rarely studies undertaken to investigate the
chemical evolution during massive star formation from the earliest
evolutionary stages, i e , from High-Mass Starless Cores (HMSCs) and
High-Mass Cores with embedded low- to intermediate-mass protostars
destined to become massive stars, via High-Mass Protostellar Objects
(HMPOs) to the final stars that are able to produce Ultracompact H{\sc
  ii} regions (UCH{\sc ii}s, see \citealt{beuther2006b} for a recent
description of the evolutionary sequence)  The first two evolutionary
stages are found within so-called Infrared Dark Clouds (IRDCs)   While
for low-mass stars the chemical evolution from early molecular
freeze-out to more evolved protostellar cores is well studied (e g ,
\citealt{bergin1997,dutrey1997,pavlyuchenkov2006,joergensen2007}),
it is far from clear whether similar evolutionary patterns are present
during massive star formation 

To better understand the chemical evolution of high-mass star-forming
regions we initiated a program to investigate the chemical properties
from IRDCs to UCH{\sc ii}s from an observational and theoretical
perspective  We start with single-dish line surveys toward a large
sample obtaining their basic characteristics, and then perform
detailed studies of selected sources using interferometers on smaller
scales  These observations are accompanied by theoretical modeling of
the chemical processes   Long-term goals are the chemical
characterization of the evolutionary sequence in massive star
formation, the development of chemical clocks, and the identification
of molecules as astrophysical tools to study the physical processes
during different evolutionary stages  Here, we present an initial
study of the reactive radical ethynyl (C$_2$H) combining single-dish
and interferometer observations with chemical modeling   Although
C$_2$H was previously observed in low-mass cores and Photon Dominated
Regions (e g , \citealt{millar1984,jansen1995}), so far it was not
systematically investigated in the framework of high-mass star
formation 

\section{Observations}
\label{obs}

The 21 massive star-forming regions were observed with the Atacama
Pathfinder Experiment (APEX) in the 875\,$\mu$m window in fall 2006 
We observed 1\,GHz from 338 to 339\,GHz and 1\,GHz in the image
sideband from 349 to 350\,GHz   The spectral resolution was
0 1\,km\,s$^{-1}$, but we smoothed the data to
$\sim$0 9\,km\,s$^{-1}$  The average system temperatures were around
200\,K, each source had on-source integration times between 5 and 16
min  The data were converted to main-beam temperatures with forward
and beam efficiencies of 0 97 and 0 73, respectively
\citep{belloche2006}  The average $1\sigma$ rms was 0 4\,K   The main
spectral features of interest are the C$_2$H lines around 349 4\,GHz
with upper level excitation energies $E_u/k$ of 42\,K (line blends of
C$_2$H$(4_{5,5}-3_{4,4})$ \& C$_2$H$(4_{5,4}-3_{4,3})$ at
349 338\,GHz, and C$_2$H$(4_{4,4}-3_{3,3})$ \&
C$_2$H$(4_{4,3}-3_{3,2})$ at 349 399\,GHz)  The beam size was $\sim
18''$ 

The original Submillimeter Array (SMA) C$_2$H data toward the
HMPO\,18089-1732 were first presented in \citet{beuther2005c}  There
we used the compact and extended configurations resulting in good
images for all spectral lines except of C$_2$H  For this project, we
re-worked on these data only using the compact configuration  Because
the C$_2$H emission is distributed on larger scales (see
\S\ref{results}), we were now able to derive a C$_2$H image  The
integration range was from 32 to 35\,km\,s$^{-1}$, and the achieved
$1\sigma$ rms of the C$_2$H image was 450\,mJy\,beam$^{-1}$   For more
details on these observations see \citet{beuther2005c} 

\section{Results}
\label{results}

The sources were selected to cover all evolutionary stages from IRDCs
via HMPOs to UCH{\sc ii}s  We derived our target list from the samples
of \citet{klein2005,fontani2005,hill2005,beltran2006}   Table
\ref{sample} lists the observed sources, their coordinates, distances,
luminosities and a first order classification into the evolutionary
sub-groups IRDCs, HMPOs and UCH{\sc ii}s based on the previously
available data  Although this classification is only based on a
limited set of data, here we are just interested in general
evolutionary trends  Hence, the division into the three main classes
is sufficient 

Figure \ref{spectra} presents sample spectra toward one source of each
evolutionary group  While we see several CH$_3$OH lines as well as
SO$_2$ and H$_2$CS toward some of the HMPOs and UCH{\sc ii}s but not
toward the IRDCs, the surprising result of this comparison is the
presence of the C$_2$H lines around 349 4\,GHz toward all source types
from young IRDCs via the HMPOs to evolved UCH{\sc ii}s   Table
\ref{sample} lists the peak brightness temperatures, the integrated
intensities and the FWHM line-widths of the C$_2$H line blend at
349 399\,GHz  The separation of the two lines of 1 375\,MHz already
corresponds to a line-width of 1 2\,km\,s$^{-1}$  We have three C$_2$H
non-detections (2 IRDCs and 1 HMPO), however, with no clear trend with
respect to the distances or the luminosities (the latter comparison is
only possible for the HMPOs)  While IRDCs are on average colder than
more evolved sources, and have lower brightness temperatures, the
non-detections are more probable due to the relatively low sensitivity
of the short observations (\S\ref{obs})  Hence, the data indicate
that the C$_2$H lines are detected independent of the evolutionary
stage of the sources in contrast to the situation with other
molecules   When comparing the line-widths between the different
sub-groups, one finds only a marginal difference between the IRDCs and
the HMPOs (the average $\Delta v$ of the two groups are 2 8 and
3 1\,km\,s$^{-1}$)   However, the UCH{\sc ii}s exhibit significantly
broader line-widths with an average value of 5 5\,km\,s$^{-1}$ 

Intrigued by this finding, we wanted to understand the C$_2$H spatial
structure during the different evolutionary stages   Therefore, we
went back to a dataset obtained with the Submillimeter Array toward
the hypercompact H{\sc ii} region IRAS\,18089-1732 with a much higher
spatial resolution of $\sim 1''$ \citep{beuther2005c}   Albeit this
hypercompact H{\sc ii} region belongs to the class of HMPOs, it is
already in a relatively evolved stage and has formed a hot core with a
rich molecular spectrum   \citet{beuther2005c} showed the spectral
detection of the C$_2$H lines toward this source, but they did not
present any spatially resolved images  To recover large-scale
structure, we restricted the data to those from the compact SMA
configuration (\S\ref{obs})  With this refinement, we were able to
produce a spatially resolved C$_2$H map of the line blend at
349 338\,GHz with an angular resolution of $2 9''\times 1 4''$
(corresponding to an average linear resolution of 7700\,AU at the
given distance of 3 6\,kpc)  Figure \ref{18089} presents the
integrated C$_2$H emission with a contour overlay of the 860\,$\mu$m
continuum source outlining the position of the massive protostar  In
contrast to almost all other molecular lines that peak along with the
dust continuum \citep{beuther2005c}, the C$_2$H emission surrounds the
continuum peak in a shell-like fashion 

\section{Discussion and Conclusions}

To understand the observations, we conducted a simple chemical
modeling of massive star-forming regions  A 1D cloud model with a mass
of 1200\,M$_\sun$, an outer radius of 0 36\,pc and a power-law density
profile ($\rho\propto r^p$ with $p=-1 5$) is the initially assumed
configuration  Three cases are studied: (1) a cold isothermal cloud
with $T=10$\,K, (2) $T=50$\,K, and (3) a warm model with a temperature
profile $T\propto r^q$ with $q=-0 4$ and a temperature at the outer
radius of 44\,K  The cloud is illuminated by the interstellar UV
radiation field (IRSF, \citealt{draine1978}) and by cosmic ray
particles (CRP)  The ISRF attenuation by single-sized $0 1\mu$m
silicate grains at a given radius is calculated in a plane-parallel
geometry following \citet{vandishoeck1988}  The CRP ionization rate is
assumed to be $1 3\times 10^{-17}$~s$^{-1}$ \citep{spitzer1968}  The
gas-grain chemical model by \citet{vasyunin2008} with the desorption
energies and surface reactions from \citet{garrod2006} is used 
Gas-phase reaction rates are taken from RATE\,06 \citep{woodall2007},
initial abundances, were adopted from the ``low metal'' set of
\citet{lee1998} 

Figure \ref{model} presents the C$_2$H abundances for the three models
at two different time steps: (a) 100\,yr, and (b) in a more evolved
stage after $5\times10^4$\,yr  The C$_2$H abundance is high toward the
core center right from the beginning of the evolution, similar to
previous models (e g , \citealt{millar1985,herbst1986,turner1999}) 
During the evolution, the C$_2$H abundance stays approximately
constant at the outer core edges, whereas it decreases by more than
three orders of magnitude in the center, except for the cold $T=10$~K
model   The C$_2$H abundance profiles for all three models show
similar behavior 

The chemical evolution of ethynyl is determined by relative removal
rates of carbon and oxygen atoms or ions into molecules like CO, OH,
H$_2$O  Light ionized hydrocarbons CH$^+_{\rm n}$ (n=2  5) are quickly
formed by radiative association of C$^+$ with H$_2$ and hydrogen
addition reactions: C$^+$ $\rightarrow$ CH$_2^+$ $\rightarrow$
CH$_3^+$ $\rightarrow$ CH$_5^+$   The protonated methane reacts with
electrons, CO, C, OH, and more complex species at later stage and
forms methane   The CH$_4$ molecules undergo reactive collisions with
C$^+$, producing C$_2$H$_2^+$ and C$_2$H$_3^+$  An alternative way to
produce C$_2$H$_2^+$ is the dissociative recombination of CH$_5^+$
into CH$_3$ followed by reactions with C$^+$   Finally, C$_2$H$_2^+$
and C$_2$H$_3^+$ dissociatively recombine into CH, C$_2$H, and
C$_2$H$_2$  The major removal for C$_2$H is either the direct
neutral-neutral reaction with O that forms CO, or the same reaction
but with heavier carbon chain ions that are formed from C$_2$H by
subsequent insertion of carbon  At later times, depletion and
gas-phase reactions with more complex species may enter into this
cycle   At the cloud edge the interstellar UV radiation
instantaneously dissociates CO despite its self-shielding,
re-enriching the gas with elemental carbon 

The transformation of C$_2$H into CO and other species proceeds
efficiently in dense regions, in particular in the ``warm'' model
where endothermic reactions result in rich molecular complexity of the
gas (see Fig ~\ref{model})   In contrast, in the ``cold'' 10\,K model
gas-grain interactions and surface reactions become important   As a
result, a large fraction of oxygen is locked in water ice that is hard
to desorb ($E_{\rm des} \sim 5500$~K), while half of the elemental
carbon goes to volatile methane ice ($E_{\rm des} \sim 1300$~K)  Upon
CRP heating of dust grains, this leads to much higher gas-phase
abundance of C$_2$H in the cloud core for the cold model compared to
the warm model  The effect is not that strong for less dense regions
at larger radii from the center 

Since the C$_2$H emission is anti-correlated with the dust continuum
emission in the case of IRAS\,18089-1732 (Fig \,\ref{18089}), we do
not have the H$_2$ column densities to quantitatively compare the
abundance profiles of IRAS\,18089-1732 with our model  However, data
and model allow a qualitative comparison of the spatial structures 
Estimating an exact evolutionary time for IRAS\,18089-1732 is hardly
possible, but based on the strong molecular line emission, its high
central gas temperatures and the observed outflow-disk system
\citep{beuther2004a,beuther2004b,beuther2005c}, an approximate age of
$5\times10^4$\,yr appears reasonable   Although dynamical and chemical
times are not necessarily exactly the same, in high-mass star
formation they should not differ to much: Following the models by
\citet{mckee2003} or \citet{krumholz2006b}, the luminosity rises
strongly right from the onset of collapse which can be considered as a
starting point for the chemical evolution  At the same time disks and
outflows evolve, which should hence have similar time-scales   The
diameter of the shell-like C$_2$H structure in IRAS\,18089-1732 is
$\sim 5''$ (Fig \,\ref{18089}), or $\sim$9000\,AU in radius at the
given distance of 3 6\,kpc   This value is well matched by the modeled
region with decreased C$_2$H abundance (Fig \,\ref{model})   Although
in principle optical depths and/or excitation effects could mimic the
C$_2$H morphology, we consider this as unlikely because the other
observed molecules with many different transitions all peak toward the
central submm continuum emission in IRAS\,18089-1732
\citep{beuther2005c}  Since C$_2$H is the only exception in that rich
dataset, chemical effects appear the more plausible explanation 

The fact that we see C$_2$H at the earliest and the later evolutionary
stages can be explained by the reactive nature of C$_2$H: it is
produced quickly early on and gets replenished at the core edges by
the UV photodissociation of CO  The inner ``chemical'' hole observed
toward IRAS\,18089-1732 can be explained by C$_2$H being consumed in
the chemical network forming CO and more complex molecules like larger
carbon-hydrogen complexes and/or depletion 

The data show that C$_2$H is not suited to investigate the central gas
cores in more evolved sources, however, our analysis indicates that
C$_2$H may be a suitable tracer of the earliest stages of (massive)
star formation, like N$_2$H$^+$ or NH$_3$ (e g ,
\citealt{bergin2002,tafalla2004,beuther2005a,pillai2006})  While a
spatial analysis of the line emission will give insights into the
kinematics of the gas and also the evolutionary stage from chemical
models, multiple C$_2$H lines will even allow a temperature
characterization  With its lowest $J=1-0$ transitions around 87\,GHz,
C$_2$H has easily accessible spectral lines in several bands between
the 3\,mm and 850\,$\mu$m   Furthermore, even the 349\,GHz lines
presented here have still relatively low upper level excitation
energies ($E_u/k\sim42$\,K), hence allowing to study cold cores even
at sub-millimeter wavelengths   This prediction can further be proved
via high spectral and spatial resolution observations of different
C$_2$H lines toward young IRDCs 

\acknowledgments{H B  acknowledges financial support
  by the Emmy-Noether-Programm of the Deutsche Forschungsgemeinschaft
  (DFG, grant BE2578)  }






ground_truth: 21.

prompt_front: Now, answer the following question based on the text below, only give me the answer and do not output any other words.

Question: What are the symptoms of alpha thalassemia major?

Read the following text and answer briefly.

Context 4: 
As with CPUE of all catch, there was a positive relationship between unstandardised CPUE (catch per set) of threatened and regulated species and number of hooks, but a significant negative relationship between standardised CPUE (catch per 100 hooks per set)  This was likely due to diminishing returns of adding additional hooks, and indicates that the effort for threatened and regulated species was exceeding maximum sustainable yield effort, such that increases in effort (e g  hook number) were leading to decreases in catch [28–30] 
Due to the profitability of the shark industry in Tanjung Luar, and limited adaptive capacity and willingness of shark fishers to move into other industries, it is necessary to identify practical and ethical management interventions that can improve the sustainability of the fishery whilst also mitigating the negative socio-economic consequences for coastal communities  Our findings indicate that spatiotemporal closures and restrictions on fishing effort could improve the overall catch per unit effort and sustainability of the Tanjung Luar shark fishery, and lead to positive conservation outcomes for priority species 
Since the location of shark fishing grounds plays a significant role in determining the likelihood of catching threatened species and their associated CPUE, improved marine spatial planning, with the identification of marine protected areas (MPAs) that protect critical shark habitat and shark populations, could reduce catch of species of conservation concern [31–33] and increase abundance of sharks [34, 35]  Provincial governments in West Papua and West Nusa Tenggara have already established ‘shark sanctuary’ MPAs, which protect critical shark habitat and ban shark fishing within their boundaries [16, 36], and monitoring data indicates positive impacts of shark-specific closures on shark abundance [37, 38]  Strengthening Indonesia’s existing MPA network for shark conservation, such as making all MPAs no-take zones for sharks and expanding spatial protection to critical shark habitat, including aggregation sites or pupping and nursery grounds for species of conservation concern, could have considerable conservation benefits  It should be noted, however, that MPAs may only be effective for certain species, such as those with small ranges or site-fidelity   More research is required to identify critical shark habitat and life history stages  For Tanjung Luar these efforts could focus on better understanding scalloped hammerhead (Sphyrna lewini) aggregation sites  Well-targeted spatial closures for this species could significantly reduce catch of threatened species in this fishery 
The relationships between gear type, several aspects of fishing effort (i e  hook number, engine power, number of sets, trip length), standardised CPUE of all shark species and standardised CPUE of threatened and regulated species suggest that there is an optimal effort that could increase overall CPUE of the fishery and significantly reduce fishing mortality of species of conservation concern  For example, our data suggest that CPUE peaks with low to intermediate trip lengths and gear sets, intermediate engine power and hook numbers of less than 75 per set longline  Although standardised CPUE of threatened and regulated species is also higher when fewer hooks are deployed, the catch per set and overall mortality is significantly lower  Regulations that control the number of hooks in combination with incentives for shark fishers to tightly manage the number of hooks they deploy could significantly reduce mortality of threatened and endangered species, maximise the overall CPUE of the fishery, and reduce operational costs for fishers, making shark fishing in Tanjung Luar more sustainable and more cost effective [39–41] 
Acknowledging that almost half of Tanjung Luar’s shark catch consists of CITES-listed species, developing measures that ensure both the sustainability of the fishery, and full traceability and control of onward trade, will be crucial for implementing CITES   The Indonesian government has demonstrated a strong commitment to regulating shark trade and implementing CITES [17–18], as demonstrated through several policy decisions to confer full and partial protection to CITES-listed shark and ray species (Marine Affairs and Fisheries Ministerial Decree No 4 /KEPMEN-KP/2014, Regulation No  48/PERMEN-KP/2016)  This includes zero quotas/export bans for hammerhead and oceanic whitetip sharks  However, these export bans should be considered intermediate policy measures as monitoring systems and data availability are improved, and sustainable quotas are established  This will be challenging, as shark products are often traded in large volumes of fresh and/or preserved body parts, with high morphological similarity between products from regulated species and non-regulated species  To guarantee that trade is not detrimental to the survival of species, sustainable fisheries management will need to be complemented with species-specific trade quotas  This will require catch documentation systems which trace shark products from point of catch to point of export and rapid, low-cost species identification methods 
As baseline data on shark population health are limited, and there is no standardised, fisheries-independent system for monitoring long-term changes in shark populations, indirect bio-indicators (e g  endo- and ectoparasites, [43–45]) could help to elucidate the impact of management measures on fisheries and populations of wild species  In the future, shark conservation and fisheries management could benefit from long-term monitoring of agreed indices of population abundance and health status 
These lessons may also apply to shark fisheries in other parts of the world  As sharks increasingly become the focus of global conservation efforts it should be acknowledged that species protection alone will not be enough to reduce mortality of priority species  More needs to be done to identify practical fisheries management measures that can reduce pressure on the most vulnerable species and populations, but also support sustainable use of species that are less susceptible to overfishing  Shark fishing forms an integral part of the livelihood strategies of many coastal communities [22, 23], and prohibiting catches will not necessarily lead to positive conservation outcomes [21, 46]  Management interventions must take into account local context and the motivations and well-being of fisher communities in order to be ethical, feasible and impactful 
S1 Dataset  Data of landed sharks at Tanjung Luar auction that had been used for this study 
S1 File  Questionnaires have been used to interview shark fishers, collector, traders, and processors 
We wish to acknowledge the support provided by fishers in Tanjung Luar for their great cooperation during fieldwork  We also thank I Made Dharma Aryawan, Muhsin, Abdul Kohar, and Abdurrafik for their assistance during field research, Benaya M Simeon, Peni Lestari, and Siska Agustina for helping with data processing, Ken Kassem for carefully reading the manuscript and providing useful inputs, and the anonymous reviewers for their constructive comments 
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ground_truth: Severe anemia that begins even before birth.