Patent Application
20190046123
The present invention mainly falls within the field of medical devices. In particular, it is focused on modelling and prediction systems applied to neurological diseases and, more specifically, the prediction of migraine attacks with the goal of becoming more effective at reducing pain with pharmacological treatments.
Migraines are a type of headache that is characterised by a pain with a number of characteristics defined by: duration between 4 and 72 hours, moderate-severe intensity, worsens with exercise, throbbing, interrupts the activity of the patient and is usually accompanied by symptoms such as nausea, vomiting, photophobia and/or phonophobia. Today, migraines are a very significant public health problem due to the high prevalence thereof which brings with it a significant burden for patients, families and society. Migraines are considered one of the most debilitating pathologies with significant consequences on social and work activities (absenteeism and reduced productivity at work) and, therefore, a high socioeconomic cost (Linde M, Rastenyte D, Ruiz de la Torre E, et al. The cost of headache disorders in Europe: The Eurolight project. European journal of neurology: the official journal of the European Federation of Neurological Societies. 2012; 19(5):703-711).
In treating migraine pain, it is known that early treatment is much more effective, since once the central sensitisation of the trigeminal nerve is produced, within the pain cycle, it is much more complicated to stop. Thus, the fundamental objective in the clinical practise is to treat the pain before this central sensitisation takes place. Consequently, it is recommended that the patient take analgesics as soon as the pain begins, with the aim of stopping the migraine attack, since if the medication is taken too late, it tends to not be effective.
Published studies show that the dopaminergic antagonist, domperidone (Waelkens J. Dopamine blockade with domperidone: Bridge between prophylactic and abortive treatment of migraine? A dose-finding study. Cephalalgia. 1984; 4(2):85-90), and triptan, naratriptan (Luciani R, Carter D, Mannix L, Hemphill M, Diamond M, Cady R. Prevention of migraine during prodrome with naratriptan. Cephalalgia. 2000; 20(2):122-126), drugs used in the acute phase, can make the pain go away when they are administered early, in the prodrome. The prediction based on prodromal symptoms by patients themselves can have a number of limitations, since the prodromal symptoms have a variable time horizon, meaning, the patient does not know exactly when the pain will occur, the symptoms are very unspecific (changes in mood, appetite, sleep pattern, etc.), they can happen to them in any other situation and they are not very precise (Becker W J. The premonitory phase of migraine and migraine management. Cephalalgia. 2013; 33(13):1117-1121; Rossi P, Ambrosini A, Buzzi M G. Prodromes and predictors of migraine attack. Funct Neurol. 2005; 20(4):185-191; Giffin N J, Ruggiero L, Lipton R B, et al. Premonitory symptoms in migraine: An electronic diary study. Neurology. 2003; 60(6):935-940). Thus, we may be less effective when reducing pain or deciding to take a medicinal product when a migraine is not going to occur.
For this reason, by objectively knowing that when the patient is going to have pain before they suffer from it (prediction), it will be possible to not only provide treatment that is early but also one that is better targeted; by knowing when the pain could occur and, knowing the action mechanism of the drug, the most convenient treatment for the patient can be chosen, since by knowing when the pain will occur, the action mechanism of the drug can be seen and the most convenient treatment can be considered. The method proposed in the present invention enables the pain of the patient to be predicted and the treatment to be more effective.
In the state of the art, the involvement of the autonomic nervous system (ANS) in the migraine is notable, demonstrating that there is a dysautonomic dysfunction, which manifests as an alteration of the variables controlled by it in the migraine patient and that it is involved both in the genesis and in the persistence of the migraine.
There are still many unknowns regarding the nature of said dysautonomia of the migraine patient, in particular, it is unknown if it is the cause or consequence of it, considering it simply as an epiphenomenon. The clinical studies that evaluate the autonomic function in patients with migraines have showed differing results (Gass J J, Glaros A G. Autonomic dysregulation in headache patients. Appl Psychophysiol Biofeedback. 2013; 38(4):257-263; Mosek A, Novak V, Opfer-Gehrking T L, Swanson J W, Low P A. Autonomic dysfunction in migraineurs. Headache: The Journal of Head and Face Pain. 1999; 39(2):108-117; Sanya E, Brown C, Wilmowsky C, NeundOrfer B, Hilz M. Impairment of parasympathetic baroreflex responses in migraine patients. Acta Neurol Scand. 2005; 111(2):102-107 and Benjelloun H, Birouk N, Slaoui I, et al. Autonomic profile of patients with migraine. Neurophysiol Clin. 2005; 35(4):127-134), which describe a hypofunction and hyperfunction of both the sympathetic and parasympathetic systems.
Only some studies have evaluated the changes between the baseline situation and the symptomatic period in the migraine patient, among which are notable: Duru M, Melek I, Seyfeli E, et al. QTc dispersion and p-wave dispersion during migraine attacks. Cephalalgia. 2006; 26(6): 672-677, which shows the association in the migraine attack with an increase of QTc interval of the electrocardiogram signal and dispersion of the P-wave in pain-free periods, the studies performed by Ordás C M, Cuadrado M L, Rodríguez-Cambrón A B, Casas-Limón J, del Prado N, Porta-Etessam J. Increase in body temperature during migraine attacks. Pain Medicine. 2013; 14(8):1260-1264 y Porta-Etessam J, Cuadrado M L, Rodriguez-Gomez O, Valencia C, Garcia-Ptacek S. Hypothermia during migraine attacks. Cephalalgia. 2010; 30(11):1406-1407. also being notable, where a case of a patient with hypothermia and another with hyperthermia during the pain period is described. In a study by Dr. Seçil (Seçil Y, Ünde C, Beckmann Y Y, Bozkaya Y T, Özerkan F, Başoğlu M. Blood pressure changes in migraine patients before, during and after migraine attacks. Pain practice. 2010; 10(3):222-227) a tendency towards diastolic hypertension was observed. In relation to the state of the art relating to the changes that occur at an electroencephalographic level the studies by Bjork are notable (Bjørk M, Sand T. Quantitative EEG power and asymmetry increase 36 h before a migraine attack. Cephalalgia. 2008; 28(9):960-968) which demonstrate a slower and more asymmetrical activity before the start of the pain also in relation to the duration of the attack and the intensity.
Nevertheless, none of these studies present the results for continuous outpatient monitoring in real time during the pre-migraine period, the migraine phase and the post-migraine period, nor do they apply pain prediction algorithms.
Meanwhile the patent application WO03063684 (Geatz M, Roiger R.) proposes the use of a system and a method for predicting the symptoms through physiological variables with applications to diseases of different natures, one of these being migraines. However, the proposed methodology has a high level of abstraction, not technically motivating the selection of variables for a certain pathology.
Other patent applications also describe, but in a more detailed manner, closed-loop control systems with applications for, in this case, diabetes (ES2334733) and epilepsy (US2011270095). However, none of these propose adaptive techniques when faced with data loss in order to make a robust system.
The application TW201023087 mentions the use of a network of sensors in order to predict, apart from not mentioning the industrial application, the claims are based on the efficient consumption and on the handling of the data acquisition through knowledge of the state of the prediction.
Moreover, the U.S. Pat. No. 8,123,683, which refers to headaches in general, has the goal of detecting the type of headache produced; this is achieved by grouping different triggers that the patient can indicate to the system. Nevertheless, said document only claims the classification of the attack and not the prediction thereof.
In the industrial field, several mobile applications have been developed that act as calendars and classifiers for migraines (Migraine Buddy, My Migraine Triggers™ and My Migraines); nevertheless, none of these is used to predict attacks in real time, and they do not perform outpatient monitoring of biometric variables.
In conclusion, none of these documents propose:
A system that implements an expert prediction-improving module for eliminating false detections that could be considered as false positives.
Preliminary results performed by the authors of the present invention confirm the following technological advantages:
The invention has the object of predicting migraine attacks in real time through a prediction method that is robust and adaptive with regards to data and/or sensor losses, and which uses non-invasive outpatient monitoring of biometric variables of the patient and environmental variables. To do so, a hierarchical system of prediction models according to the set of sensors available at all times is defined, adapted to each patient.
The invention is made up of a method for predicting migraines in real time.
The method is structured in three steps (Data acquisition, Training and validation of the migraine models and Prediction in real time) which in turn are subdivided into different modules.
In the Data acquisition step, the biometric (d1) and environmental (d5) variables, the subjective sensation of pain of the patient during the migraine (d2), information about the activity of the patient that could affect the migraine episodes (d3) and the clinical data of the patient (d4) are recorded. The set of this data is transmitted from the monitoring equipment to cloud servers. Said low-cost equipment for monitoring biometric variables has batteries with a limited duration; nevertheless, they have enough processing ability so that, by being aware of the state of the prediction, they are able to decide when to temporarily pause the outpatient monitoring and thus reduce the consumption of the batteries thereof.
The Training and Validation step of the models is carried out in servers, which is external equipment with large computational capacities. The data (d1 and d2) is used, in a first instance, for the creation of migraine models personalised for each patient that will be used in real time in the third step, for the prediction of the migraine attack. This last step, Prediction in real time of the migraine attack, is performed in a feedback loop starting from the input data (d1, d3-d5). The prediction based on environmental data (d5), activity data (d3) and clinical data (d4) will be used in the module of the decision system (7).
The steps to be followed in each step and the way in which each module intervenes are described below.
The method for predicting a migraine attack that is presented in the invention implies the use of the following multisource data:
a) Pre-Processing Modules of the Signal (1, 1-2 and 2).
The data gathered by the wireless monitoring systems can suffer losses due to the cessation of wireless communication or to sensor failures. In order to repair the signal losses in these time intervals, signal regeneration techniques are applied in the module (1) for automatic signal regeneration based on the statistical behaviour thereof. Before repair, the calculation of the secondary variables (hs1-3) is also performed in this module. In this module, apart from calculating the secondary variables and repairing lost data, the synchronisation of the data is also performed in order to adjust the sampling rates of the different signals. The result from the module (1) is the signal (b), which has two types of different signals, those of biometric origin (b[1]) and those of environmental origin (b[2]). Thus, b=b[1]∪b[2].
The module (1-2) is responsible for calculating derived variables (c) and extracting knowledge by means of Machine Learning techniques and is executed parallel to the module (1). The derived variables are features of the primary biometric variables (al1-5) and secondary biometric variables (hs1-3) and of the overall environmental variables (a1-4) and local environmental variables (al1-5). These chosen features can be different for each patient, and the study of which ones are better is automated for each of them. These features can be temporal variables (hd(t)) or specific values (figures of merit, hD). The most common features that are looked for in these signals are: energy from the signal, energy in a band of interest of the signal, moving average, maximum, minimum and average values, etc. The features that vary in time hd={hd1(t), h2(t), . . . , hdH(t)}, will be used in the module (3) for training models. Note that, although no explicit reference is made, the derived signals are the signal (c) and they include those of biometric origin (c[1]) and those of environmental origin (c[2]). Thus, c=c[1]∪c[2]. The features (hD) are calculated and they use the module which, together with the activity data (d3) and clinical data (d4) of the patient, give rise to the signal (g). The signal (g) is the result of applying fuzzy logic techniques, which will provide classification criteria to help improve the prediction of the expert system (7).
Signal regeneration and the calculation of derived variables are also applied to the environmental data (d5). Like the biometric variables, migraine prediction models will be trained with the repaired environmental data (b[2]) and with derived environmental data (c[2]).
These modules are very important since the validity of the obtained models (d) depends on the quality of the data.
In order to calculate the models, the output signal is needed, which is the pain signal. The supervision module of the pain (2) consists of reading the recordings of the subjective pain of the patient. This module generates a synthetic curve of the pain by means of a bilateral Gaussian fit of the pain evolution points marked by the patient (d2). This evolution is recorded as whole values without upper or lower limits, which represent relative changes with respect to the last moment marked. This unlimited scale, compared to others that are limited, enables a more accurate curve of the evolution of the pain of the patient to be generated. Given that they do not know a priori when the maximum pain thereof is reached or how much it is, this method prevents having a curve with saturated values at the maximum of a supposed limited traditional scale. The result from the module (2) is a signal (a) relativised at the maximum value thereof with the aim of normalizing all the migraine recordings of the patient. The synthesised symptomatic pain curve (a) is described by the parameters {(μ1, σ1), (μ2, σ2)} that make up the semi-Gaussian ones. The module (2), as well as the collection of pain data (d2) is only performed not in real time, for creating the models.
This step is performed offline, not in real time. During the training step, the patient is monitored for a period of time wherein a number of migraines (T) that is sufficient to train the models is recorded. These modelling algorithms generate a prediction curve (ŷ) for each migraine starting from the multisource data collected. During training, the curve resulting from the models (signal d in
where y is the calculated symptomatic curve (signal a) marked by the patient, and ŷ is the prediction.
a) Training Module (3)
For each one of the recorded migraines a model is trained. The migraine models are created with the module (3). In order to create the migraine models, the repaired biometric signals (b[1]), those derived with temporal variation (c[1]) and the synthetic pain curve (a) are used. In the training the search for the prediction horizon that best adapts to each patient will be performed. The method evaluates different modelling techniques or algorithms; unlike the patent proposed by Geatz M. and Rolger R., which is only based on Artificial Neural Networks, our proposal and prior work have demonstrated that different modelling techniques must be evaluated for each patient, and the best of them all must be chosen. The models are or are not linear functions and have the primary biometric signals, secondary biometric signals or one of the calculated features as input variables (all of them being included in the variable sets b[1] and c[1]), and the result of which is a prediction (d) of the evolution of the migraine attack at a given horizon.
ŷ(t)=f({h1(t),h2(t), . . . ,hs1(t), . . . ,hs3(t),hd1(t), . . . hdH(t)}) Equation 2:
Equation 2 represents the predicted symptomatic curve ŷ(t) as a function of the primary (h), secondary (hs) or derived (hd) biometric variables that vary in time, all of them being contained in the signal (b[1]).
Some modelling diagrams or valid algorithms that are used successfully are: State-Space Equations, Artificial Neural Networks or Genetic Programming. The following is an example of a generic equation (Equation 3) from a state-space system of order nx:
x[k+1]=Ax[k]+Bu[k]+w[k]
y[k]=Cx[k]+Du[k]+v[k] Equation 3:
Where y[k] is the output at the moment k, which depends on the current state, x[k], and a matrix, C. The order of the system, nx, is determined by the dimension of x[k]. The variable v[k] is the innovation or unexplained portion that is added to the prediction, ideally white noise uncorrelated with the input variables, u[k]. The output can also depend on the inputs at that same moment, through the vector D, which is weighted by the input variable vector, u[k]. The following state of the method is defined by the equality of x[k+1]. The dependency between states is weighted by the state transition matrix (A), while the weight matrix of the variables (B) sets the dependence on the entry variables, u[k]. w[k] is, ideally, white noise uncorrelated with the current state, and is the unexplained portion or error that occurs when passing from one state to another.
This invention proposes the creation of different models for different input variable sets with the aim of subsequently developing a hierarchy for selecting models according to the sensors or variables available. This hierarchy lies underneath the idea of creating a robust method, which is tolerant to errors and to partial sensor failure. At the end of the Training step, Md different trained models are had and for each different combination of biometric input variables, with d=1, 2, . . . , N. N can be one or several migraines. The amount of models Md created depends on the type of algorithm selected and the parameters thereof.
Another set of models (independent from the biometric variables) is also trained with the use of the environmental variables (sets b[2] and c[2]). The prediction models based on environmental variables are coarse-grained models, and they have less temporal definition than the predictions based on biometric variables; for this reason, these predictions will only be used in the decision module (7).
b) Validation Module and Selection of Models (4 and 4-1).
The module (4) searches for the best models to predict the migraines of the patient by using Cross Validation techniques. Each model Md,i (obtained from the set Md), with i=1, . . . , d, is validated by predicting the remaining migraines not used in the Nth combination that created said model. The validations are performed in a prediction horizon that does not necessarily coincide with that which trained the model, otherwise it will search for the one further away with better prediction results.
The validation implies checking how each of these models adjusts (according to the fit) to the prediction of other migraines. The results of this module (e) is a set of models that will be ranked and stored in the module (4-1) in order to give as a final result a batch or set of the Mbest models (signal f) that best predict the migraines of the patient in question, if Md>1. The selection criteria are: the prediction horizon, the robustness of the model when faced with sensor failure or saturation of the signal and the complexity or order of the model. The selection of a set of models, instead of only one, gives greater stability to the method and mitigates the use of models with overfitting.
For each different combination of input biometric variables (b[1] and c[1]), a batch of models is finally had. The same process is followed for the environmental variables (b[2] and c[2]).
C) Step of Prediction in Real Time. Expert System
This step is performed in a loop in real time and the data can continue to be sent to the servers, or not. If it is sent, a control in real time of the state of the patient can be had, and in the case of false negatives, there would be records to be able to confirm how said errors occurred. With the batch of models of each patient the prediction of the migraine attack is performed by using the primary, secondary and/or derived biometric variables. The steps in which the prediction is performed are detailed below.
a) System for Selecting Models Depending on the Sensors (SMDS2) (5)
This model provides robustness to the method by adaptation, and not by redundancy or a high amount of trained models. The migraines of each patient can be defined by a set of variables (v1, v1=b∪c) different from that of another patient; furthermore, in an outpatient monitoring context, the error of the sensors due to unavailability or saturation is a recurring problem. In this scenario, a hierarchy or criteria is defined for selecting models is defined per patient and depends on the input variables that are necessary and available. This adaptation is what makes the method robust.
After the validation and selection of the models of a patient the input variables that best define their migraines then are known. In this case, the models that are chosen and have that combination of variables as an input are used ({Mbest, v1}). If, due to an error or breakage, one of the necessary sensors is not available, the next set of models with better fit and that do not depend on said sensor is used ({Mbest, v2}).
This module, therefore, indicates the set of models of the module (4-1) to be used (6) both for the biometric variables and the environmental variables.
b) Prediction and Linear Combination of Models (6)
By using the models obtained from (5) and with the biometric signals (b[1] and c[1]), the prediction of the migraine will be performed. The prediction horizon is the best one that can be obtained with each model. Each one of the models from the batch (5) performs a prediction on the data from the necessary biometric variables (b[1] and c[1]). In total Mbest predictions are had. The final result is a linear combination (p) of all these predictions. Since prediction models are also trained through the environmental variables, they are also used to make predictions, for which reason the signal (p) is the union of the average predictions obtained with the biometric inputs (p[1]) and the environmental inputs (p[1]). Thus, p=p[1]∪p[2].
c) Correction and Fit of the Prediction (7)
With the aim of obtaining the best predictions, this module performs a correction of the prediction (p[1]) through the biometric variables (b[1] and c[1]), removing false data points from said signal. The false data points are detected by defining level and time thresholds.
Furthermore, in this module decisions are taken on the prediction through another prediction (p[2]) made with the second set of variables (g) comprising: the environmental variables (b[2]) and (c[2]), the information obtained with the data mining and fuzzy logic techniques on the features of the biometric and environmental variables, and the activity and clinical data of the patient. These decisions are weightings or weights for the prediction. The result is double, on one hand a prediction curve for a given horizon, and on the other a warning signal of the beginning of pain with a probability of occurrence.
The environmental variables generate longer-term predictions with less precision, but they serve as contrast to the prediction performed with the biometric variables. These contrasts or decisions are carried out with fuzzy logic techniques trained beforehand for the patient in the module (1-2). This module presents the corrected, fitted and contrasted prediction (p) at the output (i) thereof. It returns, apart from the prediction, a decision of at what moment and with which probability the pain will occur.
d) Actuator (8)
The actuator is the last module of the method, it is a man-machine interface (8), and it re-supplies the patient with the prediction that was made and corrected (i). In this manner the patient can take the medication with enough time for it to take effect and have complete effectiveness before the pain appears. The prediction also arrives at the devices for monitoring biometric and local environmental variables so that they can evaluate whether to stop, or not, the monitoring during a known period of time. The interface will be the mobile application that gathers information from the activity of the patient, since the patient will have it with them at all times.
The novelty of this invention is rooted in the following technical characteristics:
The following drawings illustrate the preceding description:
The monitoring implies the recording of a sufficient number of migraines for the training step. In order to train the modelling algorithms, it is considered that the training can be sufficient as of 10 migraine episodes (the monitoring time generally oscillates between 4 and 6 weeks). One possible way of proceeding to acquire data is described below in an indicative and non-exhaustive manner.
The monitoring of the biometric variables (d1) is carried out with commercial outpatient monitoring devices. The ECG sensor can have as many derivations as desired, but having only three electrodes is enough to extract the HR (hs1); in this case, they will be placed on the precordial horizontal plane in derivations V3, V4 and V5. The EDA sensor (h1) placed in the arm acts to measure the relative variations in perspiration; like the superficial temperature sensor (h2), placed as close as possible to the armpit. One way of acquiring the SpO2 (h3) and the PPG (h4) is by means of the use of an oximetry clip placed on a finger. The EEG electrodes will be placed on the occipital area, in the reference points OZ, O1 and O2 (according to the international system 10-20). The PTT will be calculated through the ECG and PPG signals and by applying one of the bibliographical methods (Yoon Y, Cho JungH, Yoon Gilwon, Non-constrained Blood Pressure Monitoring Using ECG and PPG for Personal Healthcare. 2009; 33(4):261-266). The HR can be calculated in intervals of 20 seconds with a 10 second overlap. The qEEG is the energy of the Alpha, Beta, Gamma, Delta and Theta bands in 20 second intervals without overlap.
At the same time that the biometric variables (d1) are recorded, the local and overall environmental variables (d5) are recorded. The overall environmental variables are taken from the geographic area corresponding to the location of the patient, and a national weather service can be used. The local environmental variables are monitored through a weather station that is always near the patient. The good synchronisation of all the data must be taken into account; to do so, a smartphone can be used to capture all the weather data. The subjective sensation of the pain (d2) is recorded through a mobile application. The patient indicates the beginning and end of the pain, as well as the subjective evolution thereof. With the same mobile application, the activity of the patient (d3) is recorded, and furthermore, there is knowledge of some of their clinical data (d4) relevant for the study, such as weight, age, gender or diseases related to migraines. All the data (d1-d5) collected during the training step is pre-processed (1 and 1-2) and used to train migraine models in (3).
Both the training of the models, and the validation (4), are performed not in real time in high-capacity computing equipment. The result of the training step is a set of models that is different for each possible combination of variables. (f). The models are trained by means of supervised techniques, where the inputs are the processed variables, and the output to be fitted is the subjective pain of the patient pre-processed in (2). Models will be trained for all the possible combinations of input variables. In validation, the best ones will be ranked and chosen to be used in the prediction step in real time.
In the prediction step in real time, the system for selecting models depending on the sensors (5) is used to select the variables of interest of each patient and the hierarchical set of models (f-2) depending on the sensors available. To do so, the state of the sensors must be known at all times, and if there are any that are not available, the models will be changed. Once the chosen models are had, these are applied one by one to the input variables, giving rise to a set of predictions; the final prediction (p) is calculated in (6) like the linear combination of said predictions. The horizon in which the prediction is performed will depend on the quality of the model obtained, for example 30 minutes. The module for correction and fit of the prediction (7) removes the false prediction points according to criteria of duration and degree of detection; thus, possible false alarms are able to be eliminated. Furthermore, decision criteria (g) are applied in order to weight the answer. The prediction obtained from the biometric variables is weighted by the decision criteria. These weightings are the result of the fuzzy logic algorithms that, based on the knowledge of the environmental variables and of the activity of the patient, regulate the prediction, for example lessening or increasing the levels thereof. Finally, the prediction (i) is transmitted to the patient through the actuator module (8, the mobile phone) so that it can move up the ingestion of the medicinal product against the migraine pain, before it begins.
The retraining of the models can be carried out automatically in a transition period in which it is still in the real-time prediction step, but the set of models of the patient starts to be updated. The retraining will be necessary when the patient finds that the predictions are no longer correct or a clinical evaluation considers it appropriate. In real time, the patients will not mark the evolution of their pain (d2) for which reason the only record of errors in the prediction that can be had will be the one of the false positives (migraines that were not detected).
The hardware of the monitoring devices must have enough computational capacity to be able to sample the variables at the sampling rate required and send the data wirelessly. The capacity to stop monitoring when they are aware of the state of the prediction must also be supported by the hardware and the firmware of the devices.
The present invention has application in the field of medical devices for the early alert of migraine pain. The network of electronic outpatient health monitoring devices approved for medical use is increasingly widespread and established; furthermore, the portability thereof and the duration of the batteries thereof keeps increasing. The machine-man interface for alerting patients is performed through a smartphone terminal, which is common today. For all of this, the present invention can have an immediate use in monitoring migraine patients in order to predict their attacks.
This invention enables those suffering from migraines to perform the earlier ingestion of the medication against migraine pain so that it has a complete effect and they are able to thus prevent the painful phase of the migraine. The use of this method increases the quality of life of the patients, as well as reduces the direct and indirect costs that the disease causes worldwide.
| Number | Date | Country | Kind |
|---|---|---|---|
| P201600158 | Feb 2016 | ES | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/ES2017/070004 | 1/3/2017 | WO | 00 |
