Patent Application
20150278470
The invention relates to the field of clinical decision support where an estimation value of thrombosis risk of a patient is calculated based on patient-specific input features.
Computer-based clinical decision support systems (CDSSs) are defined as “any software designed to directly aid in clinical decision making in which characteristics of individual patients are matched to a computerized knowledge base for the purpose of generating patient-specific assessments or recommendations that are then presented to clinicians for consideration and decision making”. Clinical decision support systems have been promoted for their potential to improve the quality of health care by supporting clinical decision making.
Deep vein thrombosis is a wide spread problem in the western world. Large portions of the population are at increased risk of thrombosis, e.g. the elderly, people who travel, and patients that undergo orthopedic surgery. People at risk can be put on preventive anticoagulant treatment, but the risk of bleeding (1-3% per year), and issues of cost and inconvenience speak against this. It would therefore be desirable to have a more patient-specific measure to estimate the personal thrombosis risk and facilitate an informed choice on whether or not to treat. Unfortunately, with current clinical screening techniques and available methodologies, high risk individuals, which should receive anticoagulants, are not easily recognized and events are not accurately predicted. One of the main reasons that this continues to be the case is that the vast majority of patients who suffer from thrombosis, those without obvious genetic defects, have blood coagulation systems that are not clinically identified as abnormal by routine screening tools and factor assays. Identification of individuals who are at risk for venous thrombosis is an area of research that could benefit from innovative technical methods.
Uncertainty about the patient specific risk of thrombosis causes unnecessary thromboses in patients at high risk (of thrombosis) who do not receive anticoagulant treatment. On the other hand, this uncertainty can result in bleeding in patients at relatively low risk who do receive unnecessary anticoagulant treatment. Most conventional clinical decision support systems are adapted to estimate thrombosis risk based on a number of clinical risk factors. A number of clinical risk factors such as immobility and contraceptive use have been identified (for patients without obvious genetic defects), but these are not sufficient for screening purposes. In practice, as described in Durieux et al.: “A Clinical Decision Support System for Prevention of Venous Thromboembolism”, guidelines based on clinical risk factors are used. A conceptually different world compared to clinical risk factors based stratification is disclosed in the US 2009/0298103 A1 where a single simulation of a protein based measurement, i.e. the thrombin generation assay, is linked to thrombotic risk. However the above approaches are not sufficiently specific for screening of thrombosis because the number of patients wrongfully classified is still high using the currently available methods.
It is an object of the invention to provide a clinical decision support system with increased accuracy for of person specific thrombosis risk estimation.
This object is achieved by an apparatus as claimed in claim 1, a method as claimed in claim 9, and by a computer program product as claimed in claim 15. Accordingly, two conceptually different worlds of clinical risk factors and molecular markers are combined. This proposed combination is non-trivial to make and requires a significant effort of machine learning and data driven approaches. The smallest set of risk factors and protein concentrations that together have an optimal predictive value for thrombosis risk are selected and a numerical algorithm is created that translates the numerical value of the chosen factors and concentrations to a single numerical value specifying thrombotic risk. Thereby, accuracy of person specific thrombosis risk estimation can be increased substantially, especially within the increased risk subgroup of patients with at least one known clinical risk factor present. This subgroup involves (among others) patients that are hospitalized, are pregnant or are (start) using oral contraceptives and thus receive attention of a physician. In this context, the proposed solution helps the physician to stratify the patients that are treated or examined for conditions that are known to increase thrombosis risk, into high and low risk categories. Specifically, the proposed solution may be used to decide, per patient, whether or not to administer anticoagulant treatment based on estimated thrombosis risk.
The term “molecular marker” is intended here to include any use of the presence or concentration of a biomolecule or part of a biomolecule, e.g., a protein or a polynucleid acid as an indicator of a patient phenotype. Such presence or concentration may be measured directly in e.g. a blood or tissue sample, or as a (possibly dynamic) measurement of the molecule in a functional test like real-time quantitative polymerase chain reaction (PCR) or the thrombin generation assay.
According to a first aspect, at least one molecular marker may be selected from a concentration of coagulation protein FVIII in blood, a concentration of coagulation protein FXI in blood, and a concentration of coagulation protein TFPI in blood. Based on patient datasets obtained from a clinical study, these types of protein concentrations have turned out to serve as reliable indicators of thrombotic risk.
According to a second aspect which can be combined with the above first aspect, at least one clinical risk factor may be selected from immobilization within a first predetermined time period, surgery within a second predetermined time period, family history of venous thrombosis, pregnancy or puerperium with a third predetermined time period, current use of estrogens, and obesity. In a specific example, the first predetermined time period may correspond to at least three months, the second predetermined time period may correspond to one month, and the third predetermined time period may correspond to at least three months. These clinical risk factors have been selected based on the above patient datasets of the specific clinical study as most reliable in combination with the above specific protein concentrations.
According to a third aspect which can be combined with the above first or second aspect, the estimation value of thrombotic risk may be compared with a predetermined threshold value in order to classify the estimation value based on the comparison result. Thereby, decision making by a clinician can be supported by classifying patients into groups of predetermined risk levels, e.g., high and low thrombotic risk.
According to a specific implementation of the third aspect, a user may be allowed to input or disable the predetermined threshold value. Thereby, the decision support mechanism can be adapted based on the needs of the user (i.e. clinician).
According to a fourth aspect which can be combined with any one of the above first to third aspects, an optimization mechanism may be provided for applying a learning process through an optimization procedure based on a dataset stored in a database so as to minimize a prediction error. This allows continuous adaptation of the clinical decision support mechanism to new datasets of new patients or to specific datasets of individual patients.
According to a specific implementation of the fourth aspect, the dataset may be divided into a training set, a validation set and a test set, wherein the training set and the validation set may be used to select a type of machine learning function and a set of model parameters used for optimizing classifiers, wherein the optimized classifiers may be used for obtaining the patient-specific input features, and wherein the test set may be used for monitoring the estimation value for patients of the test set based on the obtained input features. This measure allows specific trimming of the input features of the clinical decision support system to a data set obtained from a specific group of patients to thereby further enhance reliability of risk estimation.
According to another embodiment said processor is adapted to calculate a deep vein thrombosis (DVT) risk score, representing an estimation value of thrombosis risk of a patient, based on clinical risk factors, single nucleotide polymorphisms (SNPs) and protein levels. This DVT risk score shows significant improvement in terms of sensitivity/specificity over known methods that calculate a DVT risk score without protein levels.
It is noted that the apparatus may be implemented as a discrete hardware circuitry with discrete hardware components, as an integrated chip, as an arrangement of chip modules, or as a signal processing device or chip controlled by a software routine or program stored in a memory, written on a computer readable medium, or downloaded from a network, such as the Internet.
It shall be understood that the apparatus of claim 1, the method of claim 9, and the computer program product of claim 15 have similar and/or identical preferred embodiments, in particular, as defined in the dependent claims.
It shall be understood that a preferred embodiment of the invention can also be any combination of the dependent claims with the respective independent claim.
These and other aspects of the invention will be apparent from and elucidated with reference to the embodiments described hereinafter.
In the drawings:
Embodiments are now described based on a computerized clinical decision support system for predicting thrombosis risk based on a combined consideration of clinical risk factors and molecular markers, e.g., protein concentrations.
The data interface 10 may be a classical user interface for allowing interaction between a user and the clinical decision support system, or a direct link to a central computer database or electronic patient record. In either case, the data interface 10 is adapted to collect at least some of the following input features on a patient at the date on which the clinical decision support system is used to assess thrombosis risk:
immobilization (plaster cast, extended bed rest at home for at least 4 days, hospitalization) within the last three months (e.g. “1” for true, “0” for false);
surgery within the last month (e.g. “1” for true, “0” for false);
family history of venous thrombosis (considered positive if at least one parent, brother, or sister experienced venous thrombosis (e.g. “1” for true, “0” for false));
pregnancy or puerperium within the last three months (e.g. “1” for true, “0” for false);
current use of estrogens (oral contraceptives or hormone replacement therapy (e.g. “1” for true, “0” for false));
obesity (body mass index over 30 (e.g. “1” for true, “0” for false));
concentration (U/mL) of the coagulation protein FVIII in blood;
concentration (U/mL) of the coagulation protein FXI in blood; and
concentration (ng/ml) of the coagulation protein TFPI in blood.
In the above, the units and possible numerical values for each input feature are given for clarity, but the choice of specific units is not essential.
Based on at least some of the above input features, the processor 20 calculates a numerical function of the above list of numerical inputs by applying the clinical decision support algorithm. This numerical function returns a number, i.e. risk score (R), between zero and one, where zero is the lowest possible thrombosis risk indication and one is the highest. This numerical output may be shown directly on the user interface 30 and/or may be compared to a threshold (T) between zero and one. If the risk score exceeds the threshold T, anti-coagulant therapy is indicated for the patient for whom the values have been entered into the calculation. Otherwise, preventive anti-coagulation therapy is indicated as not advisable. The choice of T, which can be set as a fixed value in the system or tuned by the user at the user interface 30, determines the balance between sensitivity and specificity of the clinical decision support system. Low values for T will infer a bias towards the indication of high risk, which leads to few false negatives (high sensitivity) but increases the number of false positives (low specificity or overtreatment). High values for T give the opposite effect and tends to undertreatment. The specific choice of T is the responsibility of the user, e.g. clinician, and may be the subject of a clinical study, but is not further discussed here.
The clinical decision support system may be implemented as a software application on a computer (system) that can be accessed by a clinician who needs to make a decision about patients' anticoagulation treatment. Optionally, the software application of the clinical decision support system may be integrated (e.g. as a plug-in) in an existing hospital information management system.
The interpretative clinical decision support algorithm may be a complex mathematical function that takes numerical (or Boolean) values for the above nine input features as input, uses these in a series of non-linear calculations and returns a numerical value between zero and one, where higher values represent a higher risk of thrombosis. The numerical function consists of one or a combination of classifier functions that are common in the field of machine learning, such as neural network functions or support vector machines or Bayesian network. These classifiers are optimized by the optimization unit 40 based on the database 50 of subjects, i.e. thrombosis patients and healthy controls for whom numerical values for the aforementioned nine input features are available. Optimization of the optimization unit 40 involves tuning the parameters of the classifier functions in such a way that the correlation between calculated risk score on the subjects in the database and recorded occurrence of thrombosis is maximized. The optimization process constitutes a significant effort that requires a strong experience in and understanding of the field of machine learning and numerical optimization. The process is further strongly dependent on the quality of the underlying database 50.
Then, in step S204, the procedure checks whether risk calculation has been requested by the user (e.g. through clicking on a respective button at the user interface 30). If not, the systems repeats the above steps S201 to S203 to allow an update of the input features or simply repeats step S204 until risk calculation is requested. I.e., the “No” branch arrow of step S204 can simply point back to the top of step S204 and needs not go back to step S201. If the request is detected in step S204, clinical decision support algorithm is called in step S205 (e.g. by the processor 20) to calculate a risk score based on the input features gathered in the previous steps.
In the subsequent step S206, it is checked if the threshold (T) has been enabled. If not, the procedure branches to step S209 and the calculated risk score is shown as a number or another graphical representation e.g. on a computer screen or other output medium of the user interface 30 before the procedure ends in step S210. Otherwise, if the procedure detects in step S206 that the threshold has not been disabled, the risk score is compared in step S207 to the threshold and classified based on the result of comparison. Finally, in step S208 a classification of ‘high thrombosis risk’ or ‘low thrombosis risk’ is made visible e.g. on the screen of the user interface 30 dependent on whether the risk score is higher or lower than the threshold. Optionally, a numerical and/or graphical comparison between the threshold value and the risk score should be shown along with the classification.
According to a modification of the first embodiment, the risk score could be calculated continuously (instead of upon request). This could also be done with some of the missing input parameters. In that case, a range of possible risk scores (e.g., indicated by a minimum risk estimation and maximum risk estimation) is provided as output, e.g., based on an uncertainty in the calculation.
In the following, an optimization of the clinical decision support algorithm is described based on a second embodiment.
The required data set of the database 50 may be derived from a data collection based on an extensive questionnaire on many potential risk factors for venous thrombosis. More specifically, the data collection may involve information (e.g. clinical risk factors) obtained from a questionnaire and clinical assays (e.g. activity or antigen-based assays of protein concentrations) as described in the respective assay protocols.
Machine learning methods are black box methods that exploit the patterns that may be hidden in the numerical values of the data to predict an output. Each method constructs a mathematical function that takes observed quantities (like protein concentrations) and qualities (like immobilization) as inputs, and produces an output that predicts a certain desired feature. Such a function is defined through its structure (e.g. a neural network function) and the numerical value of the function parameters (e.g. the weights in a neural network). The combination of function structure, parameter values and numerical inputs produce an output feature which may be binary (e.g. thrombosis vs. no thrombosis), or continuous (e.g. probability of thrombosis). The specific type of method that is used in the second embodiment is the support vector machine (SVM), an often used method in the field of machine learning (see e.g. Cristianini et al.: “An Introduction to Support Vector Machines and Other Kernel-based Learning Methods”, Cambridge University Press, 2000 for more details). A hidden pattern is ‘learned’ directly from the data, generally without concern for the identity (e.g. biological meaning) of the various inputs. Learning proceeds through an optimization procedure, where the prediction error (i.e. some numerical measure of the discrepancy between predicted model output and observations) is minimized. There are many optimization or error minimization routines which all involve the variation of the mathematical function's parameters to find that set of parameter values that produces the lowest prediction error. A wide literature exists on machine learning techniques and optimization methods. For a more in-depth view, it is referred to Kuncheva: “Combining Pattern Classifiers: Methods and Algorithms”, Wiley-Blackwell 2004.
A classifier is a specific class of black box model, the output of which is the class or label of a data element, where each element is described by a number of numerical features. The data elements in the present embodiments are human subjects for whom a number of clinical features are known through measurement or anamnesis. The class is binary: thrombosis patient or control subject. The classifier is trained on the dataset of the database 50 which contains each participant's numerical features and the corresponding label.
After the start of the optimization procedure in step S300, the dataset of the database 50 is divided in step S301 into three equally sized sets, called training set, validation set and test set, each containing the same ratio of cases to controls. In step S302, the training set is used for training or parameter tuning, i.e. search for that set of parameter values that minimizes the prediction, or in this case classification error. Most machine learning methods suffer from so-called ‘overfitting’, where the method's performance on the training set is much better than its performance on new data that has not been used for training Therefore, in step S303, a separate validation set is used to test whether such over-fitting occurs. The combination of training and validation data allows to find that type of machine learning function and choice of model parameters that is able to grasp the true pattern that hides in the (training) data, yet is still sufficiently general to predict well on the separate validation data and thus on future data as well. The thus optimized classifiers are used in step S304 to make a prediction on each of the patients in the test set, which has remained unused throughout the foregoing optimization steps. The quality of this prediction (e.g. in terms of sensitivity and specificity) is the final test of the validity of the selected classifier. The test set is selected at random to obtain solid statistics.
The steps S301 to S303 described the selection of an optimal classifier based on a train and validation subset of a database. Through permutation of the subjects in the train and the validation set (swapping patients between the two sets) in step S305 it is possible to create an ensemble of classifiers, each classifier corresponding to one specific permutation of train and validation subjects. Such an ensemble is used as a voting system. This means that each classifier in the ensemble assigns a label to the same object, e.g. ‘control subject’ or ‘thrombosis patient’. The label that turns up most often is assumed to be the correct one, and the fraction of votes that support this label are used as a confidence score: if all classifiers in the ensemble vote for thrombosis, it is 100% sure that the participant will get thrombosis, whereas a fifty-fifty distribution of the votes makes the classification no better than a coin flip. The risk score (R) is compared to a threshold (T), where a score that exceeds the threshold indicates a case and a score below the threshold indicates a control subject.
When the optimal classifier on the complete set of features has been found in step S305, the relative importance of each input feature in the classifier is analyzed in step S306. The selected subjects in the train and validation set are now used to select those features that contribute most to a correct classification. To achieve this, the following input reduction procedure is executed in step S306 for each of the optimized classifiers:
For each input feature i to the classifier
As the number of input features in the classifier reduces, the prediction error rises. Thus, there is always a trade-off between good prediction ability and conciseness of the set of input features used. The above reduction procedure is used to deduce a selection of overall most predictive features. It is performed for each aforementioned (random) division of the complete database into a train, validation and test set. In step S307, for each division, the classifier is reduced to ten input features, and each remaining input feature is marked. Then, in step S309, the number of times each input feature remains in the ‘top ten’ is counted and this count is used to rank the input features from most predictive (part of the top ten most often) to least predictive. Finally, the most predictive input features are used for risk calculation in the clinical decision support algorithm of the processor 20 and the procedure ends in step S310.
Hence, the optimization procedure of the second embodiment can be used to regularly update the clinical decision support algorithm of the processor 20 based on new patient data in the database 50.
The following example is presented by way of illustration of the present invention, and are not intended to limit the present invention and the embodiments provided herein in any way.
In a first example which relates to thrombosis risk classification, the second embodiment explained above was applied to a clinical study of ˜500 thrombosis patients and ˜500 healthy controls, and showed that the proposed solution leads to significantly better results in terms of estimation accuracy than a ‘conventional’ approach based on clinical risk factors alone. An ensemble of support vector machines was used on the LeidenThrombophilia Study (LETS) (as described for example in van der Meer et al.: “The LeidenThrombophilia Study (LETS)”, Thromb Haemost. 1997; 78(1):631-5) in order to find a combination of known biomarkers that is able to distinguish thrombosis patients from healthy controls. Focus was directed at two different types of patient features, i.e. coagulation protein concentrations in blood and clinical risk factors that are known to relate to thrombosis. It could be shown that the predictive power of clinical risk factors alone, either as a simple risk factor count or used in a machine learning approach, can be improved by incorporation of measured coagulation protein concentrations.
A second example relates to input feature reduction. In the study, the determined most influential protein in thrombosis classification was coagulation factor VIII, followed by factor XI and TFPI (cf. Table 1 below). Classification with all clinical risk factors (for which no measurement is necessary) and these three protein concentrations achieves almost equivalent classification at AUC of 0.77. The improvement is especially clear in the increased risk population, here defined as those subjects showing one or more known clinical risk factors.
As can be gathered from
Table 1 shows a list of classifier features, sorted by the percentage of classifiers (based on different random choices of validation set) that retain the feature in the 10 features that are pruned last.
The risk of deep vein thrombosis has been evaluated by using information from the MEGA (Multiple Environment and Genetic Assessment of risk factors for venous thrombosis) study and the Leiden Thrombophilia Study (LETS). Both are case-control studies that were set up to identify risk factors for venous thrombosis that have been performed in the Netherlands (Blom, 2005, van der Meer F J, Koster T, Vandenbroucke J P, Briët E, 1997). A plethora of variables, ranging from coagulation protein levels to environmental thrombotic risk factors and genetic thrombophilia has been taken from patients with venous thrombosis and controls. For the purpose of this study, a neural networks approach (see e.g. Kuncheva, 2004) has been used in the MEGA study to estimate potential risk factors for Deep Vein Thrombosis (DVT) and their predictive value in one integrated approach. The identified combinatory risk score is validated in an internal cross-validation on the MEGA study and in an independent validation on the LETS study.
It has been shown in the past that a combination of clinical risk factors and single nucleotide polymorphisms (SNPs) allowed discrimination between high and low risk patients with an area under the Receiver Operating Characteristic (ROC) curve (AUC) of 0.82 on MEGA and 0.77 on LETS. It is now shown that through the addition of protein levels as predictive factors a significant further increase in predictive accuracy can be achieved as quantified in the AUCs of 0.87 and 0.81 respectively.
Further, four clinical risk factors that were not available for the initial study are now considered: immobilization because of plaster cast, leg injury in the past 3 months, cancer in the period from five years before to six month after the index date and travel for more than four hours in the past 2 months. The other considered risk factors were part of the initial study as well: immobilization because of extended bed rest at home for at least 4 days, hospitalization), surgery, a family history of venous thrombosis (considered positive if at least 1 parent, brother, or sister experienced venous thrombosis, pregnancy or puerperium within 3 months before the index date, or use of estrogens (oral contraceptives or hormone replacement therapy) at the index date and the presence of obesity, determined as a body mass index of 30 kg/m2 or higher).
Next to the data from the questionnaire and measured protein levels, data was available on the presence of five genetic aspects, i.e. blood group and four single nucleotide polymorphisms (SNPs) in F2 (G20210A), Fibrinogen (rs no 2066865), F11 (rs no 2036914) and F5 (FV Leiden; rs no 6025). The data further included the number of alleles that were affected per SNP.
The considered protein levels are a subset of the proteins that were included before (because of a more limited set of measurements performed in the MEGA study). They are: anti-thrombin (AT), prothrombin (factor II), factor 7 (FVII), FVIII, FIX, FX, FXI, fibrinogen and protein C (all activity measurements) and protein S (antigen measurement).
Cross-validation results on MEGA. Neural networks based risk scores that predict risk based on clinical risk factors, genetic effects and protein levels to risk scores based on clinical risk factors and genetic effects (without protein levels) and clinical risk scores based only on clinical risk factors were considered. The comparison is performed on the MEGA study, but otherwise in the same cross-validation setup and with the same methods as described in the initial study. The corresponding AUC's are 0.87, 0.83 and 0.78, i.e. each addition improves the accuracy of the risk score; all improvements are significant (p<0.01 in a paired t-test).
The LETS study includes four less clinical risk factors than the MEGA study, as described above with respect to the clinical risk factors. The cross-validation as performed in the previous paragraph has been repeated without these four risk factors and under the exclusion of cancer patients, who had been excluded from the LETS study as well. The AUCs on the reduced MEGA study are 0.84, 0.80 and 0.74, in the same order as in the last paragraph. Next, for each of the selections of input features (clinical risk factors with/without genetic effects with/without protein levels) one risk score on the reduced MEGA study (without divisions into train and test set as would be necessary in a cross-validation) was derived and applied this risk score without adaptation to the individuals of the LETS study. The resulting AUCs were 0.82, 0.79 and 0.74, showing that the proposed risk score can be applied on an independent study with little loss of performance, and the improvement due to the proposed inclusion of protein levels holds in an external validation.
The same methods are used in a cross-validation study within the MEGA sub-population of individuals with one or more of the aforementioned clinical risk factors present (this was done for the LETS study in the initial filing as well). The resulting AUCs were 0.86, 0.81 and 0.76 for the three scoring methods, again with lower scores for scores that consider fewer input features.
Following the same methods as described above, the importance of all features that were used as inputs to the neural networks that provide the risk score were ranked. The results are shown in Table 2. The results overlap partially with the earlier results: F8 is still by far the most predictive protein and contraceptive use, surgery, immobility and family history still score high. TFPI has not been measured in MEGA and does therefore not appear in the ranking F11 scores much lower than before.
Cross-validation on MEGA with a risk score based on all clinical risk factors, one SNP (FV Leiden) and the protein level of FVIII provides an accuracy that is only a little reduced (AUC=0.85 vs 0.87). Further addition of the SNP in fibrinogen and the protein levels of protein S and FX increase the AUC to 0.86.
As explained above a DVT risk score based on clinical risk factors, SNPs and protein levels shows significant improvement in terms of sensitivity/specificity over known methods without protein levels in an evaluation on the MEGA study. To summarize, an apparatus and method have been described for clinical decision support to identify patients at high risk of thrombosis based on a combination of clinical risk factors and molecular markers, e.g., protein concentrations. These clinical risk factors and molecular markers are combined in a machine learning based algorithm which returns an output value, relating to an estimated risk of a thrombosis event in the future.
While the invention has been illustrated and described in detail in the drawings and foregoing description, such illustration and description are to be considered illustrative or exemplary and not restrictive. The invention is not limited to the disclosed embodiment. It can be applied in any field of clinical decision support, in a situation where a decision needs to be made about whether or not to place a patient under preventive treatment. Moreover, the number and types of input features (i.e. clinical risk factors and molecular markers) are not restricted to the nine input factors mentioned in the embodiments. Based on the optimization procedure of the above examples, various other clinical risk factors or molecular markers (e.g. concentration of protein Z, C4B binding protein, fibrinogen, TAFI, Factor II, V, VII, IX, X, XII or XIII, antithrombin, protein C, protein C inhibitor, protein S or other markers) may be selected as decisive input features.
Other variations to the disclosed embodiments can be understood and effected by those skilled in the art in practicing the claimed invention, from a study of the drawings, the disclosure and the appended claims. In the claims, the word “comprising” does not exclude other elements or steps, and the indefinite article “a” or “an” does not exclude a plurality. A single processor or other unit may fulfill the functions of several items recited in the claims. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage.
The foregoing description details certain embodiments of the invention. It will be appreciated, however, that no matter how detailed the foregoing appears in text, the invention may be practiced in many ways, and is therefore not limited to the embodiments disclosed. It should be noted that the use of particular terminology when describing certain features or aspects of the invention should not be taken to imply that the terminology is being re-defined herein to be restricted to include any specific characteristics of the features or aspects of the invention with which that terminology is associated.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/IB2013/059424 | 10/17/2013 | WO | 00 |
| Number | Date | Country | |
|---|---|---|---|
| 61718242 | Oct 2012 | US |
