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Title: Interpretable reduced-order modeling with time-scale separation Interpretable reduced-order modeling with time-scale separation
Publish Date: 7 March 2023
Author List: Sebastian Kaltenbach (from CSE-Lab, ETH Zurich, Harvard SEAS), Phaedon-Stelios Koutsourelakis (from CSE-Lab, ETH Zurich, Harvard SEAS), Petros Koumoutsakos (from CSE-Lab, ETH Zurich, Harvard SEAS), Harvard Seas (from CSE-Lab, ETH Zurich, Harvard SEAS)

Figure

FIG  5  Comparison between the phase-space of the reference solution (left) and the phase-space of the predictions
FIG  7  Comparison between predictions and reference solutions for a new initial condition fort = 1 25, 3 75, 7 5, 12 5, 20, 30  (from left to right and top to down) We note that with longer prediction time the uncertainty bounds increases Despite the chaotic nature of the KS equation, the predictive posterior mean is close to the reference solution for t ≤ 12 5

abstract

Partial Differential Equations (PDEs) with high dimensionality are commonly encountered in computational physics and engineering  However, finding solutions for these PDEs can be computationally expensive, making model-order reduction crucial  We propose such a data-driven scheme that automates the identification of the time-scales involved and, can produce stable predictions forward in time as well as under different initial conditions not included in the training data 
To this end, we combine a non-linear autoencoder architecture with a time-continuous model for the latent dynamics in the complex space  It readily allows for the inclusion of sparse and irregularly sampled training data  The learned, latent dynamics are interpretable and reveal the different temporal scales involved 
We show that this data-driven scheme can automatically learn the independent processes that decompose a system of linear ODEs along the eigenvectors of the system's matrix  Apart from this, we demonstrate the applicability of the proposed framework in a hidden Markov Model and the (discretized) Kuramoto-Shivashinsky (KS) equation 
Additionally, we propose a probabilistic version, which captures predictive uncertainties and further improves upon the results of the deterministic framework 

INTRODUCTION

High-fidelity simulations of critical phenomena such as ocean dynamics and epidemics have become essential for decision-making  They are based on physically-motivated PDEs expressing system dynamics that span multiple spatiotemporal scales and which necessitate cumbersome computations   In recent years there is increased attention to the development of data-driven models that can accelerate the solution of these PDEs as well as reveal salient, lower-dimensional features that control the long-term evolution 
In most cases, data-driven reduced-order models are not interpretable  In particular, models based on neural networks despite good predictive capabilities , they offer a black-box description of the system dynamics  A possible remedy is applying a symbolic regression to the learned neural network representation , but this adds additional computational cost due to the two-step procedure 
A number of frameworks such as SINDy allows to learn interpretable dynamics but it relies on the a-priori availability of lower-dimensional descriptors and of time-derivatives which can be very noisy for both simulation and experimental data  Other frameworks are tailored to specific problems such as molecular dynamics  
Here, we present a framework that only needs the value of the observables, and not their derivatives, as training data and is capable of identifying interpretable latent dynamics  The deployment of interpretable latent dynamics ensures that conservation of important properties of that are reflected in the reduced-order model  
The present method is related to approaches based on the Koopman-operator extended Dynamic Mode Decomposition (eDMD) but uses continuous complex-valued latent space dynamics and only requires one scalar variable per latent dimension to describe the latent space dynamics  Therefore we do not have to enforce any parametrizations on the Koopman matrix  
The time-continuous formulation moreover allows to incorporate sparse and irregularly sampled training data and fast generation of predictions after the training phase  By using a complex-valued latent space we can also incorporate harmonic effects and reduce the number of latent variables needed  Linear and non-linear autoencoders are used to map the observed, high-dimensional time-series to the lower-dimensional, latent representation and we identify simultaneously the autoencoder as well as the latent dynamics by optimizing a combined loss function 
Hence the to tasks of dimensionality reduction and discovery of the reduced dynamics are unified while other frameworks treat the two parts separately   Apart from using an architecture based on autoencoders to identify the latent space, projection-based methods could also be employed   We are also proposing a probabilistic version of our algorithm ) that makes use of probabilistic Slow Feature Analysis  
This allows for a latent representation that arart from being time-continuous, can quantify the predictive uncertainty and hierarchically decompose the dynamics into their pertinent scales while promoting the discovery of slow processes that control the system's evolution over long time horizons  The rest of the paper is structured as follows: We introduce the methodological framework as well as algorithmic details in section II 
Particular focus is paid on the interpretability of the inferred lower-dimensional dynamics  In section III we present three numerical illustrations, i e  a system of linear ODEs, a hidden Markov Model and the discretized KS-equation  We then present in section IV the probabilistic extension of the framework and apply it to the KS-equation 
We conclude with a summary and a short discussion about possible next steps  We introduce the autoencoders deployed in this work, followed by the interpretable latent space dynamic and discuss the training process  We consider data from high-dimensional time series x n ∈ R f with n = 1,    , T   We remark that the intervals between the different states do not need to be uniformly spaced 

Autoencoder

A core assumption of the method is that each high-dimensional state x n can be compressed to a lower-dimensional representation z n ∈ C c with c << f   We identify this lower-dimensional representation by an autoencoder consisiting of a parameterized encoder and decoder  The encoder maps the high-dimensional representation to the latent space as:
The latent space is complex-valued  The decoder reconstructs the high-dimensional representation based on the latent variables as: We denote the parameters of the encoder as well as the decoder by θ  As discussed later in Section II C, both set of parameters are optimized simultaneously during training and therefore there is no need for differentiating them 

Interpretable Latent Space Dynamics

We employ a propagator in the latent space to capture the reduced-order dynamics of the system  In contrast to other time-extended variational autoencoder frameworks, our representation uses complex valued latent variables  In addition the latent variables are treated independently  The latter feature enables us to have an interpretable latent dynamics as well as a model that is especially suitable for being trained in the Small Data regime due to the small number of required parameters 
This is in contrast to temporal propagators such as LSTMs   For each dimension i of the latent variable z we are using the following continuous ODE in the complex plane: By solving this ODE, we can define the operator: Interpretable reduced-order modeling with time-scale separation Here, λ is a vector containing all the individual λ's and ∆t n indicates the time-step between the latent states 
The symbol is used to indicate a component-wise multiplication  We remark that the latent variables and the parameter governing the temporal evolution are complex numbers and their role in describing the system dynamics is similar to that of an eigenvalue  The real part is associated with growth and decay whereas the imaginary part is representing the periodic component 
This approach has similarities with the Koopman-operator based methods and the extended dynamic mode decomposition   In contrast to the methods mentioned before we are using a continuous formulation in the latent space that allows us to incorporate scarce and irregularly sampled training data and directly rely on complex numbers in the latent space 

Training and Predictions

We optimize a loss function that combines both a reconstruction loss as well as a loss associated with the error of our learned propagator in the latent space: (5) We note that we could directly incorporate mini-batch training by only taking the summation over a subset of the N available training data 
For new predictions of unseen states, we use the encoder to generate a latent representations which is then advanced in time by the learned propagator  At a designated time step we are using the decoder to reconstruct the high-dimensional solution  We applied our algorithm to three systems  First, we show that the algorithm is capable of exactly reproducing the solution of a linear ODE and to identify its eigenvalues 
Afterwards we are applying the framework to a high-dimensional process generated by a complex latent dynamics, which is correctly identified  As a final test case, we are applying the algorithm to a Kuramoto Shivashinski (KS) equation  Interpretable reduced-order modeling with time-scale separation

Linear ODE

We are considering a two-dimensional ODE system for x = y 1 y 2 : Based on the obtained training data we run our algorithm using a linear encoder and decoder structure as well as two latent variables z  The loss function was optimized using the Adam algorithm   As we consider a linear ODE we can analytically compute the eigenvalues involved and compare it with the parameters λ identified by our algorithm 
We observe in Figure that the algorithm was able to recover the correct values, i e  the eigenvalues 7 and 3 of the given linear ODE  The system does not have a periodic component and the two imaginary parts correctly go to zero, whereas the real parts converge to the reference value  Moreover we are also able to identify for the linear mapping between our latent variables z and the training data a matrix consisting of a multiple of the eigenvectors (1,1) and (1,-1) and thus the correct solution 
This example was chosen to show that the algorithm is able to quickly identify the exact solution of a linear ODE in terms of its linearly independent components 

Hidden multiscale dynamics

We consider eight-dimensional synthetic time series data produced by an underlying twodimensional complex valued process  In particular, the data points x are generated by first solving for the temporal evolution for the two complex-valued processes p 1 and p 2 and than mapping to the eight-dimensional space by using a randomly sampled linear mapping W  
One of the two processes used to generate the data is chosen to be much slower than the other one and both processes have a periodic component  dp 2 dt = (−0 9 + 1 5i)p 2 (8) As training data we consider 40 time series with 150 data points each, obtained by simulating the described processes for a maximum of t = 15 s and then sampling from the obtained data points 
Hence the training data consists of: • 40 time-series • with each consisting 150 observations of the x at a uniform time-step ∆t = 0 0025 The autoencoder obtained consists of one linear layer for both the decoder as well as the encoder  The model is trained for 5000 iterations using the Adam optimizer and a learning rate of 10 −3  
The results for the convergence of the parameters λ 1 and λ 2 can be found in Figure   We note that the process which is slower decaying and thus more responsible for the long-term evolution of the system has a higher convergence rate than the faster process  With the obtained parameters λ as well as the trained autoencoder, we compute predictions based on the last time step used for training, i e  we apply the encoder to obtain our latent representation and than use the latent dynamics to advance the latent representation in time 
Afterwards, we employ the decoder to reconstruct the full high-dimensional system  The results can be found in Figure and show very good agreement between predictions and reference data  This example shows that our model is successfully able to carry out dimensionality reduction and moreover indicates that the convergence rate between latent processes can be different 
The latter is relevant when training models as for accurate predictions all latent processes and their dynamics should be converged 

Kuramoto-Sivashinsky

Finally, we applied our algorithm to the KS equation and aim to identify a reduced-order model for the solution u(y, t): We employed periodic boundary conditions, µ = 1 and a domain size y ∈ [0, 22]  For this domain-size, the KS-equation exhibits a structurally stable chaotic attractor as discussed in The black lines divides the area for which training data was given from the area without raining data 
;   The equation is discretized in space using a discretization step of 22 64 resulting in a state vector x of dimension 64 and a nonlinear system of coupled ODEs  This is solved using a stiff fourth-order solver  We employed a non-linear encoder and decoder with four fully-connected layers each and ReLU-activation functions as well as Dropout Layers between the fully-connected layers 
We trained the model for 200000 iterations using Adam and a learning rate of 5 • 10 4 and assuming a five-dimensional latent space  We obtained the λ's in Figure   Four latent variables have λ's close to zero and thus a slow temporal dynamic that is responsible for the long-term evolution whereas one latent variable is quickly decaying 
Based on the obtained parameters, we do predictions based on an unseen initial condition not contained in the training data  We are able to reconstruct the correct phase space based on our predictions despite only using a very limited amount of training data  The results for the phase space can be seen in Figure  
Although the small-scale fluctuations in the temporal dynamics are not well captured, the model identifies the correct manifold which has a good accuracy compared to the reference solution  All phase-spaces were obtained by using a finite-difference operator on the data or predictions  These results are in accordance Interpretable reduced-order modeling with time-scale separation with whose LSTM-based temporal dynamic model was also able to find the correct phase space but not to track the actual dynamics for long-term predictions 
Our model is not able to account for noise in the temporal evolution and thus dealing with chaotic, small-scale fluctuations is challenging  We believe that a probabilistic version of our algorithm could be advantageous here  This section contains a fully probabilistic formulation for the deterministic model discussed before 
We replace the Autoencoder with a Variational Autoencoder and the ODE in the latent space with a SDE  The loss function which we optimize is the Evidence-Lower Bound (ELBO) 

Model Structure

We postulate the following relations for our probabilistic model using an Ornstein-Uhlenbeck (OU) for each dimension i of the latent space and a Wiener process W t in the latent space: We again assume that the latent variables z t are complex-valued and a priori independent  Complex variables were chosen as their evolution includes a harmonic components which are observed in many physical systems 
We assume an initial conditions z 0,i ∼ CN (0, σ 2 0,i )  The total parameters associated with the latent space dynamics of our model are thus {σ 2 0,i , σ 2 i , λ i } c i=1 and will be denoted by θ together with all parameters responsible for the decoder mapping G (see next section)  These parameters along with the state variables z t have to be inferred from the data x t  
Based on probabilistic Slow Feature Analysis (SFA) , we set σ 2 i = 2; (λ j ) and σ 2 0,i = 1  As a consequence, a priori, the latent dynamics are stationary  A derivation and reasoning for this choice can be found in Appendix A  Hence the only independent parameters are the λ i , the imaginary part of which can account for periodic effects in the latent dynamics 

Variational Autoencoder

We employ a variational autoencoder to account for a probabilistic mappings from the lower-dimensional representation z n to the high-dimensional system x n   In particular we are employing a probabilistic decoder The encoder is used to infer the state variables z based on the given data and thus defined in the inference and learning section 

Inference and Learning

Given the probabilistic relations , our goal is to infer the latent variables z 0:T as well as all model parameters θ  We follow a hybrid Bayesian approach in which the posterior of the state variables is approximated using amortized Variational Inference and Maximum-A-Posteriori (MAP) point-estimates for θ are computed 
The application of Bayes' rule for each data sequence x 0:T leads to the following posterior: where p(θ) denotes the prior on the model parameters  In the context of variational inference, we use the following factorization of the approximate posterior i e  we infer only the mean µ and variance σ for each state variable based on the given data points 
This conditional density used for inference is the encoder-counterpart to the probabilistic decoder defined in the section before  It can be readily shown that the optimal parameter values are found by maximizing the Evidence Lower Bound (ELBO) F(q φ (z 0:T ), θ) which is derived in Appendix B  We compute Monte Carlo estimates of the gradient of the ELBO with respect to φ and θ with the help of the reparametrization trick and carry out stochastic optimization with the ADAM algorithm  

Results for the probabilistic extension

We applied our probabilistic version to the KS-equation  We used the same settings as for the deterministic approach but considered up to 10 complex latent variables  The obtained λ's are in Figure   The probabilistic model allows us to quantify the uncertainty in predictions  In Figure predictions for various time-steps and the respective uncertainty bounds are shown for an unseen initial condition 
Due to the chaotic nature of the KS-equation and the small amount of training data, the underlying linear dynamic of our model is only able to capture the full dynamics for a limited time horizon  Fortunately, due to the probabilistic approach the model is capable of capturing chaotic fluctuations with increasingly wide uncertainty bounds 
We also computed the phase space representation for the KS-equation based on the predictions obtained by our model and compare it with the reference solution  The probabilistic model identifies the correct manifold with a better accuracy than the deterministic model  As some of the small-scale fluctuations are accounted as noise, the resulting manifold is more concentrated at the origin and the obtained values are slightly smaller than the reference manifold although their shape is very similar 
Context 2: Thalassaemia minor | definition of Thalassaemia minor by Medical dictionary
Thalassaemia minor | definition of Thalassaemia minor by Medical dictionary
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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
Context 3: Margaret Way (b  Brisbane d  Cleveland, Queensland, Australia ) was an Australian writer of romance novels and women's fiction  A prolific author, Way wrote more than 120 novels since 1970, many through Mills & Boon, a romance imprint of British publisher Harlequin UK Ltd , owned by Harlequin Enterprises 

Biography
Before her marriage, she was a well-known pianist, teacher, vocal coach and accompanist  She began writing when her son, Laurence Way, was born, a friend took a pile of Mills & Boon books to her, she read all and decided that she also could write these types of novels



ground_truth: The paper was published on 7 March 2023.

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 are thalassemias classified?

Read the following text and answer briefly.

Context 3:  She began to write and promote her country with her stories set in Australia  She sold her first novels in 1970  Margaret Way lives with her family in her native Brisbane  Beginning in 2013, Margaret began to self-publish, releasing her first "e-book" mid-July 

Margaret died on the 10th of August 2022 in Cleveland, Queensland 

Bibliography

Single Novels
King Country (1970)
Blaze of Silk (1970)
The Time of the Jacaranda (1970)
Bauhinia Junction (1971)
Man from Bahl Bahla (1971)
Summer Magic (1971)
Return to Belle Amber (1971)
Ring of Jade (1972)
Copper Moon (1972)
Rainbow Bird (1972)
Man Like Daintree (1972)
Noonfire (1972)
Storm Over Mandargi (1973)
Wind River (1973)
Love Theme (1974)
McCabe's Kingdom (1974)
Sweet Sundown (1974)
Reeds of Honey (1975)
Storm Flower (1975)
Lesson in Loving (1975)
Flight into Yesterday (1976)
Red Cliffs of Malpara (1976)
Man on Half-moon (1976)
Swan's Reach (1976)
Mutiny in Paradise (1977)
One Way Ticket (1977)
Portrait of Jaime (1977)
Black Ingo (1977)
Awakening Flame (1978)
Wild Swan (1978)
Ring of Fire (1978)
Wake the Sleeping Tiger (1978)
Valley of the Moon (1979)
White Magnolia (1979)
Winds of Heaven (1979)
Blue Lotus (1979)
Butterfly and the Baron (1979)
Golden Puma (1980)
Temple of Fire (1980)
Lord of the High Valley (1980)
Flamingo Park (1980)
North of Capricorn (1981)
Season for Change (1981)
Shadow Dance (1981)
McIvor Affair (1981)
Home to Morning Star (1981)
Broken Rhapsody (1982)
The Silver Veil (1982)
Spellbound (1982)
Hunter's Moon (1982)
Girl at Cobalt Creek (1983)
No Alternative (1983)
House of Memories (1983)
Almost a Stranger (1984)
A place called Rambulara (1984)
Fallen Idol (1984)
Hunt the Sun (1985)
Eagle's Ridge (1985)
The Tiger's Cage (1986)
Innocent in Eden (1986)
Diamond Valley (1986)
Morning Glory (1988)
Devil Moon (1988)
Mowana Magic (1988)
Hungry Heart (1988)
Rise of an Eagle (1988)
One Fateful Summer (1993)
The Carradine Brand (1994)
Holding on to Alex (1997)
The Australian Heiress (1997)
Claiming His Child (1999)
The Cattleman's Bride (2000)
The Cattle Baron (2001)
The Husbands of the Outback (2001)
Secrets of the Outback (2002)
With This Ring (2003)
Innocent Mistress (2004)
Cattle Rancher, Convenient Wife (2007)
Outback Marriages (2007)
Promoted: Nanny to Wife (2007)
Cattle Rancher, Secret Son (2007)
Genni's Dilemma (2008)
Bride At Briar Ridge (2009)
Outback Heiress, Surprise Proposal (2009)
Cattle Baron, Nanny Needed (2009)

Legends of the Outback Series
Mail Order Marriage (1999)
The Bridesmaid's Wedding (2000)
The English Bride (2000)
A Wife at Kimbara (2000)

Koomera Crossing Series
Sarah's Baby (2003)
Runaway Wife (2003)
Outback Bridegroom (2003)
Outback Surrender (2003)
Home to Eden (2004)

McIvor Sisters Series
The Outback Engagement (2005)
Marriage at Murraree (2005)

Men Of The Outback Series
The Cattleman (2006)
The Cattle Baron's Bride (2006)
Her Outback Protector (2006)
The Horseman (2006)

Outback Marriages Series
Outback Man Seeks Wife (2007)
Cattle Rancher, Convenient Wife (2007)

Barons of the Outback Series Multi-Author
Wedding At Wangaree Valley (2008)
Bride At Briar's Ridge (2008)

Family Ties Multi-Author
Once Burned (1995)

Hitched! Multi-Author
A Faulkner Possession (1996)

Simply the Best Multi-Author
Georgia and the Tycoon (1997)

The Big Event Multi-Author
Beresford's Bride (1998)

Guardian Angels Multi-Author
Gabriel's Mission (1998)

Australians Series Multi-Author
7  Her Outback Man (1998)
17



ground_truth: According to the globin that is affected (alpha or beta).

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: When did Margaret Way start self-publishing her books as e-books?

Read the following text and answer briefly.

Context 3:  Master of Maramba (2001)
19  Outback Fire (2001)
22  Mistaken Mistress (2002)
24  Outback Angel (2002)
33  The Australian Tycoon's Proposal (2004)
35  His Heiress Wife (2004)

Marrying the Boss Series Multi-Author
Boardroom Proposal (1999)

Contract Brides Series Multi-Author
Strategy for Marriage (2002)

Everlasting Love Series Multi-Author
Hidden Legacy (2008)

Diamond Brides Series Multi-Author
The Australian's Society Bride (2008)

Collections
Summer Magic / Ring of Jade / Noonfire (1981)
Wife at Kimbara / Bridesmaid's Wedding (2005)

Omnibus in Collaboration
Pretty Witch / Without Any Amazement / Storm Over Mandargi (1977) (with Lucy Gillen and Margaret Malcolm)
Dear Caliban / Heart of the Eagle / Swans' Reach (1978) (with Jane Donnelly and Elizabeth Graham)
The Bonds of Matrimony / Dragon Island / Reeds of Honey (1979) (with Elizabeth Hunter and Henrietta Reid)
The Man Outside / Castles in Spain / McCabe's Kingdom (1979) (with Jane Donnelly and Rebecca Stratton)
Winds From The Sea / Island of Darkness / Wind River (1979) (with Margaret Pargeter and Rebecca Stratton)
Moorland Magic / Tree of Idleness / Sweet Sundown (1980) (with Elizabeth Ashton and Elizabeth Hunter)
The Shifting Sands / Portrait of Jaime / Touched by Fire (1982) (with Jane Donnelly and Kay Thorpe)
Head of Chancery / Wild Heart / One-Way Ticket (1986) (with Betty Beaty and Doris Smith)
Heart of the Scorpion / The Winds of Heaven / Sweet Compulsion (1987) (with Janice Gray and Victoria Woolf)
One Brief Sweet Hour / Once More With Feeling / Blue Lotus (1990) (with Jane Arbor and Natalie Sparks)
Marry Me Cowboy (1995) (with Janet Dailey, Susan Fox and Anne McAllister)
Husbands on Horseback (1996) (with Diana Palmer)
Wedlocked (1999) (with Day Leclaire and Anne McAllister)
Mistletoe Magic (1999) (with Betty Neels and Rebecca Winters)
The Australians (2000) (with Helen Bianchin and Miranda Lee)
Weddings Down Under (2001) (with Helen Bianchin and Jessica Hart)
Outback Husbands (2002) (with Marion Lennox)
The Mother's Day Collection (2002) (with Helen Dickson and Kate Hoffmann)
Australian Nights (2003) (with Miranda Lee)
Outback Weddings (2003) (with Barbara Hannay)
Australian Playboys (2003) (with Helen Bianchin and Marion Lennox)
Australian Tycoons (2004) (with Emma Darcy and Marion Lennox)
A Mother's Day Gift (2004) (with Anne Ashley and Lucy Monroe)
White Wedding (2004) (with Judy Christenberry and Jessica Steele)
A Christmas Engagement (2004) (with Sara Craven and Jessica Matthews)
A Very Special Mother's Day (2005) (with Anne Herries)
All I Want for Christmas    (2005) (with Betty Neels and Jessica Steele)
The Mills and Boon Collection (2006) (with Caroline Anderson and Penny Jordan)
Outback Desire (2006) (with Emma Darcy and Carol Marinelli)
To Mum, with Love (2006) (with Rebecca Winters)
Australian Heroes (2007) (with Marion Lennox and Fiona McArthur)
Tall, Dark and Sexy (2008) (with Caroline Anderson and Helen Bianchin)
The Boss's Proposal (2008) (with Jessica Steele and Patricia Thayer)
Island Heat / Outback Man Seeks Wife / Prince's Forbidden Virgin / One Night Before Marriage / Their Lost-and-found Family / Single Dad's Marriage Wish (2008) (with Robyn Donald, Marion Lennox, Carol Marinelli, Sarah Mayberry and Anne Oliver)
Australian Billionaires (2009) (with Jennie Adams and Amy Andrews)
Cattle Baron : Nanny Needed / Bachelor Dad on Her Doorstep (2009) (with Michelle Douglas)

External links
Margaret Way at Harlequin Enterprises Ltd

Australian romantic fiction writers
Australian women novelists
Living people
Year of birth missing (living people)
Women romantic fiction writers



ground_truth: Margaret Way started self-publishing her books as e-books in 2013.