Patent Publication Number: US-11023679-B2

Title: Apparatus and method for automatically mapping verbatim narratives to terms in a terminology dictionary

Description:
BACKGROUND 
     Clinical trials are used to determine whether a drug or device under test is safe and effective. One type of data that clinical trials collect is information about adverse events, which are any untoward medical occurrences experienced by a patient or clinical trial subject that may not necessarily have a causal relationship to the treatment being tested. These adverse events are often recorded using verbatim narratives that vary from person to person and from trial to trial. Another type of data that clinical trials collect is concomitant medications (often called “con-meds”) narratives, which are descriptions of a drug or biological product, other than the drug under study, taken by a subject during the clinical trial. 
     Because one of the main purposes of a clinical trial is to test the safety of a drug or device, knowledge about con-meds and adverse events that are temporarily associated with the investigational treatment is very important, as is classifying the con-meds and adverse events. However, even though there are dictionaries that catalog con-meds and adverse events, mapping a verbatim narrative to a standardized term or entry in such a dictionary is not always performed in a consistent manner, resulting in incoherent analyses of the con-meds or adverse events. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         FIG. 1  is a flowchart showing a method for automatically mapping an adverse event narrative to a term in a medical terminology dictionary, according to an embodiment of the present invention; 
         FIG. 2A  is a block diagram of a system for automatically mapping an adverse event narrative to a term in a medical terminology dictionary, according to an embodiment of the present invention; 
         FIG. 2B  is a block diagram of the natural language processor of  FIG. 2A , according to an embodiment of the present invention; 
         FIGS. 3A and 3B  are flowcharts showing methods for automatically mapping a con-med narrative to a term in a drug terminology dictionary, according to embodiments of the present invention; and 
         FIG. 4  is a block diagram of a system for automatically mapping a con-med narrative to a term in a drug terminology dictionary, according to an embodiment of the present invention. 
     
    
    
     Where considered appropriate, reference numerals may be repeated among the drawings to indicate corresponding or analogous elements. Moreover, some of the blocks depicted in the drawings may be combined into a single function. 
     DETAILED DESCRIPTION 
     In the following detailed description, numerous specific details are set forth in order to provide a thorough understanding of embodiments of the invention. However, it will be understood by those of ordinary skill in the art that the embodiments of the present invention may be practiced without these specific details. In other instances, well-known methods, procedures, components, and circuits have not been described in detail so as not to obscure the present invention. 
     Many types of clinical trial data, such as blood pressure and heart rate, may be recorded as numbers, the range of which is often known very well. Such data may be tabulated and thereafter analyzed fairly easily to determine whether a drug is safe and effective. In contrast, an adverse event (“AE”) that occurs during a clinical trial is generally recorded as a text or verbatim narrative, in a format that may differ from one recorder (e.g., patient, doctor, nurse, technician, etc.) to another and may even differ by the same recorder at a different time. Such differences may be as simple as spelling differences, which may be caused by typographical errors or that some words are spelled differently in different geographic areas. One example is “diarrhea,” which may be misspelled (e.g., diarrea) or may be spelled differently in different countries (e.g., in the United Kingdom it is spelled “diarrhoea”). Other times, the same condition is described by its symptoms rather than a specific name. So “diarrhea” may be described as “loose stools,” “Soft bowels,” “soft stools,” “Loose bowel movements,” etc., and each of these words may be capitalized, may appear in singular or plural, or may be misspelled. 
     Similarly, con-med narratives may be recorded during a clinical trial to indicate medications other than the drug under test that the patient or subject is taking. Such narratives may include the brand name of the con-med, e.g., Lipitor®, the generic version of the drug or the active ingredient, e.g., atorvastatin, or a combination of one of these names with the salt or ester of the active ingredient, e.g., atorvastatin calcium. Sometimes, the drug name is accompanied by the dosage, e.g., 80 mg, and sometimes the drug delivery vehicle appears in the narrative, e.g., tablet. 
     There are currently standard dictionaries of terms for adverse events and drugs. The dictionary for adverse events, called the Medical Dictionary for Regulatory Activities (MedDRA®), is developed by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) and includes standard terminology for medical, health-related, and regulatory concepts pertaining to medical products for human use. MedDRA is arranged in a hierarchy of five levels—SOC (System Organ Class), HLGT (High Level Group Term), HLT (High Level Term), PT (Preferred Term), and LLT (Lowest Level Term). Of the five levels, PTs and LLTs are more relevant for the purposes of this patent application. A PT is a distinct descriptor (i.e., a single medical concept) for a symptom, sign, disease, diagnosis, therapeutic indication, investigation, surgical, or medical procedure, and medical, social, or family history characteristic. An LLT is generally more specific than a PT and is linked to only one PT. An LLT may be identical to the PT, a sub-element of the PT (e.g., PT “Contusion” and LLTs “Bruising of face” and “Bruising of leg”), a synonym (e.g., PT “Arthritis” and LLT “Joint inflammation”) or a quasi-synonym (e.g., PT “Otitis externa” and LLT “Bilateral otitis externa”) of the PT, or a lexical variant of the PT (e.g., PT “Acquired immunodeficiency syndrome” and LLT “AIDS”). An LLT may also be a more colloquial way of saying the PT (e.g., PT “Nasopharyngitis” and LLT “cold”). 
     MedDRA includes about 75,000 unique LLTs and PTs. It is estimated that more than 10 million adverse event records have been collected over time using Medidata&#39;s clinical trial software. A human looking at these records may be able to standardize or map some of these millions of records to the 75,000 MedDRA terms. But that requires training, diligence, consistency, patience, time, and money. And if more than one person is used to standardize these records (which is very likely), differences between the people adds another chance for error or inconsistency. 
     Analogously, there is a dictionary for drugs, called the World Health Organization Drug Dictionary (WHODD or WHO Drug Dictionary), maintained by the Uppsala Monitoring Center. Like MedDRA, WHODD also includes a hierarchical classification system, which categorizes drugs according to the organ or system on which they act and their therapeutic, pharmacological, and chemical properties. Similar to the LLT in MedDRA, the WHODD&#39;s lowest level includes proprietary drug codes that identify the generic name or the trade name (TN), e.g., LIPITOR® or TYLENOL®. The proprietary drug code is an eleven-digit number that includes a six-digit “Drecno” (short for “Drug Record Number”) for the active ingredient(s), a two-digit Sequence Number 1 identifying the salt or ester of the active ingredient, and a three-digit Sequence Number 2 identifying the trade name. For example, the Drecno 013261 is associated with the active ingredient atorvastatin. The drug code for generic atorvastatin is 013261 01 001 (which is the analog in WHODD to the Preferred Term in MedDRA) and the drug code for Lipitor is 013261 02 016. WHODD includes about 49,000 unique Drecnos. 
     It is often desirable to technically analyze the occurrences and types of adverse events and con-meds, for example, to better understand the effects of a drug or device under test. This analysis is often difficult, because adverse event and con-med narratives do not have standard formats. Attempts have been made to address the problem of analyzing unstructured narratives, for example by using a technical solution such as automating the standardization, coding, or mapping of these verbatim adverse event and con-med narratives to MedDRA terms or WHODD Drecnos. Medidata CODER®, an Internet-based enterprise coding solution, uses an auto-mapping algorithm based on exact string matching (i.e., if the AE narrative exactly matches the MedDRA term). This may work in about 60% of the adverse event narratives, but human intervention is needed to code the remaining 40% of the records. For con-med narratives, CODER will try to match the trade name or generic name and then map it to the corresponding drug code. This may work in less than about 60% of the con-med narratives. Below are examples of human-coded mappings from CODER: 
     
       
         
           
               
               
               
               
             
               
                   
               
               
                 Verbatim 
                 Assigned Term 
                 Assigned Code 
                 Drecno 
               
               
                   
               
             
            
               
                 atorvastatine 
                 atorvastatin 
                 013261 01 001 
                 013261 
               
               
                 atorvastatin 
                 atorvastatin 
                 013261 01 001 
                 013261 
               
               
                 Lipitor 
                 atorvastatin 
                 013261 01 001 
                 013261 
               
               
                 Lipitor 20 MG 
                 Lipitor 
                 013261 01 014 
                 013261 
               
               
                 Neustatin-A 
                 Neustatin A 
                 013261 02 001 
                 013261 
               
               
                 ES Tylenol 
                 Tylenol Extra Strength 
                 000200 01 461 
                 000200 
               
               
                 Tylenol 
                 Tylenol/00020001/ 
                 000200 01 005 
                 000200 
               
               
                 acetaminpohene 
                 Acetaminophen 
                 000200 01 009 
                 000200 
               
               
                   
               
            
           
         
       
     
     Faced with this technical problem, the inventors have developed an improved system and method for standardizing, mapping, or coding the verbatim narratives that up until now have been coded by humans. This involves taking the verbatim narratives database and the mappings that have already been performed in CODER and technically processing the narratives using natural language processing and/or applying probabilistic models to the verbatim narratives. 
     Reference is now made to  FIG. 1 , which shows flowchart  100  comprising a method for automatically mapping an AE narrative to a term in a medical terminology dictionary, according to an embodiment of the present invention. In operation  103 , AE narrative  101  may be pre-processed by removing capitalization, leading and trailing spaces, extra spaces (e.g., double spaces to single spaces), and/or surrounding quotation marks. (Pre-processing in this fashion may not be necessary at this point, but may be performed later as part of cleaning, as described below.) Operation  105  asks whether the pre-processed narrative matches a term in a medical terminology dictionary, such as MedDRA. A match may be determined using a hash table or a Python dictionary. If there is a match, then the narrative is mapped in operation  199  to that term. If not, then the system will search a medical coding decision database, such as Medidata CODER, in operation  110  and ask whether the pre-processed narrative matches a term in that database. A match here may also be determined using a hash table or Python dictionary. If there is a match, then since the medical coding decision database term already corresponds (or is already mapped) to a term in the medical terminology dictionary, AE narrative  101  can be mapped in operation  199  to the term in the medical terminology dictionary to which AE narrative  101  was most frequently mapped in the medical coding decision database. 
     If the pre-processed narrative does not match a term in the medical coding decision database (i.e., the answer to operation  110  is “NO”), then the system will begin natural language processing of the narrative to try to match it to a term in the medical terminology dictionary or medical coding decision database that has also been natural-language processed. One way of executing this is to create a “processed database” that includes versions of the terms in the medical terminology dictionary and medical coding decision database that have been processed to varying degrees. Such processing, shown in operation  120 , may consist of cleaning, sorting, and stemming as described below. 
     In operation  121 , the term may be cleaned. Cleaning may involve removing punctuation; removing numbers, measurements, and units such as: ×2, 2×2, #5, +2, 2+, 10, 5.25, (1), g, kg, mg, gm, gram, umol, mmol, kmol, ml, dl, /, %, percent, meter, m, mm, km, cm, lb, pound, in, inch, inches, feet, foot, ft, degree, °, ° C., ° F., cel, celsius, celcius, centigrade, fahrenheit, farenheit, hour, hr, h, minute, min, m, second, sec, s, bpm, etc.; removing stop words (common words that are often insignificant) such as: on, at, of, in, a, the, my, her, his, had, has, have, patient, etc.; and expanding abbreviations such as: r/t→related to, d/t→due to, l and lt→left, r and rt→right, b/l→bilateral, incr→increase, decr→decrease, susp and sus→suspected, and abd and abdo→abdominal. Cleaning may also include removing capitalization, leading and trailing spaces, extra spaces (e.g., double spaces to single spaces), and/or surrounding quotation marks, to the extent not already performed. The cleaned version of the term is then added to the processed database in operation  128 . An example of a term in CODER that may be cleaned is “serum glucose (increase) 189 mg/dl.” After cleaning, this becomes “serum glucose increase.” 
     In operation  122 , the cleaned term may be sorted and then added to the processed database in operation  128 . Sorting involves normalizing the order of the words in the narrative. One type of normalization is putting the words in alphabetical order, but other sort orders may be used. Thus, sorting the cleaned term “serum glucose increase” alphabetically yields “glucose increase serum.” 
     In operation  123 , the cleaned term may be stemmed and then added to the processed database in operation  128 . Stemming involves removing meaningless lexical variations, relative to the medical terminology dictionary. One method of stemming uses the Porter Algorithm, which involves (1) removing plurals and -ed or -ing suffixes; (2) changing a terminal y to an i when there is another vowel in the stem; (3) mapping double suffixes to single ones, e.g., -ization→-ize; -ational→-ate; -fulness→-ful; etc.; (4) removing suffixes, -ful, -ness etc.; (5) removing -al, -ant, -ence, etc.; and (6) removing a final -e. Examples of the results of the Porter Algorithm are “chest soreness” becomes “chest sore” and “colonic polyps” becomes “colon polyp.” Using the previous example, stemming the cleaned term “serum glucose increase” yields “serum glucos increas.” 
     In operation  124 , the cleaned term may be stemmed AND then sorted and then added to the processed database in operation  128 . Using the previous example, stemming and sorting the cleaned term “serum glucose increase” yields “glucos increas serum.” 
     Performing operations  121 - 124  on the terms in the medical technology dictionary and medical coding decision database yields a processed database of alternative terms used for matching. Thus, using the previous example of CODER term “serum glucose (increase) 189 mg/dl,” the terms “serum glucose increase,” “glucose increase serum,” “serum glucos increas,” and “glucos increas serum” may be added to the processed database as related to “serum glucose (increase) 189 mg/dl.” For completeness, the processed database may contain both the alternative versions created in operation  120  as well as the original terms from the medical terminology dictionary and medical coding decision database, because a processed narrative may match the original terms or the alternative versions. Moreover, because “serum glucose (increase) 189 mg/dl” has been assigned to the MedDRA term “blood glucose increased,” the alternative versions may also be assigned to that MedDRA term. 
     Once the terms in the medical technology dictionary and medical coding decision database have been natural-language processed, the AE narrative (or the pre-processed narrative) may be subjected to a series of natural language processing operations itself. After each operation, the further processed narrative is compared to the processed database to determine if a match can be made, as described below. 
     In operation  131 , the narrative may be cleaned in the same fashion the medical terminology dictionary or medical coding decision database term was cleaned in operation  121 . The cleaned narrative may then be compared in operation  138  to the terms in the processed database. If there is a match in operation  190 , then the process ends in operation  199  by mapping the narrative to the term in the medical terminology dictionary that corresponds to the matched term in the processed database. Thus, cleaning the narrative “Patient has a cold.” yields “cold” (stop words “patient,” “has,” and “a” are removed, as is the period), which matches LLT “cold” in MedDRA. 
     If cleaning the narrative does not result in a match (arrow  140 ), then in operation  132  the cleaned narrative may be sorted in the same manner as in operation  122 . The cleaned and sorted narrative may then be compared in operation  138  to the terms in the processed database. If there is a match in operation  190 , then the process ends in operation  199  by mapping the narrative to the term in the medical terminology dictionary that corresponds to the matched term in the processed database. For example, pre-processing AE narrative “Unruptured cerebral aneurysm” yields “unruptured cerebral aneurysm,” and sorting yields “aneurysm cerebral unruptured.” This matches one of the processed terms for the MedDRA LLT “Aneurysm cerebral (unruptured),” which had been processed in operation  120  to yield the corresponding term “aneurysm cerebral unruptured” (pre-processing to remove capitals and cleaning to remove the parentheses). Thus the narrative “Unruptured cerebral aneurysm” may be mapped to “Aneurysm cerebral (unruptured)” in operation  199 . 
     If cleaning and sorting the narrative does not result in a match (arrow  140 ), then in operation  133  the cleaned narrative may be stemmed in the same manner as in operation  123 . The cleaned and stemmed narrative may then be compared in operation  138  to the terms in the processed database. If there is a match in operation  190 , then the process ends in operation  199  by mapping the narrative to the term in the medical terminology dictionary that corresponds to the matched term in the processed database. For example, pre-processing AE narrative “ABDOMINAL BLOATNESS” yields “abdominal bloatness,” sorting yields “abdominal bloatness” (no change), and stemming yields “abdomin bloat.” This matches one of the processed terms for the MedDRA LLT “Abdominal bloating,” which had been processed in operation  120  to yield the corresponding term “abdomin bloat” (pre-processing to remove capitals and stemming to remove the “al” and “ing”). Thus the narrative “ABDOMINAL BLOATNESS” may be mapped to “Abdominal bloating” in operation  199 . 
     If cleaning and stemming the narrative does not result in a match (arrow  140 ), then in operation  134  the cleaned narrative may be stemmed and sorted in the same manner as in operation  124 . The cleaned, stemmed, and sorted narrative may then be compared in operation  138  to the terms in the processed database. If there is a match in operation  190 , then the process ends in operation  199  by mapping the narrative to the term in the medical terminology dictionary that corresponds to the matched term in the processed database. For example, pre-processing AE narrative “Enlarged Pituitary Gland” yields “enlarged pituitary gland,” stemming produces “enlarg pituitari gland,” and sorting produces “enlarg gland pituitari.” This matches one of the processed terms for the MedDRA LLT “Pituitary gland enlargement,” which had been processed in operation  120  to yield the corresponding term “enlarg gland pituitari” (pre-processing to remove capitals, stemming to change the “y” to an “i” and remove the “ement,” and sorting to reorder the words alphabetically). Thus the narrative “Enlarged Pituitary Gland” may be mapped to “Pituitary gland enlargement” in operation  199 . 
     If cleaning, sorting, stemming, and stemming+sorting do not result in a match, then in operation  135 , the cleaned and stemmed narrative may be assigned stemmed synonyms or have terms deleted, followed by sorting if needed. Synonyms and deletions may be algorithmically derived from the medical coding decision database (e.g., Medidata CODER) to learn what words human CODER users consider to have the same meaning or are unnecessary, respectively. One way to determine synonyms and deletions is by taking the difference between the verbatim term and the term assigned by the human CODER users. In other words, synonyms and deletions may be determined by stripping whichever words are in common between the verbatim term and the assigned term. For example, if the verbatim narrative is “lower extremity edema” and the assigned term in CODER is “leg edema,” stripping the common word “edema” leads to the synonym “lower extremity” for “leg.” Other synonyms may include corrections for misspelled words, e.g., “heart” for “haert” or “increased” for “inceased.” Similarly, if the verbatim narrative is “very tense” and the assigned term in CODER is “tense,” stripping the common word “tense” leads to the conclusion that “very” is not relevant in some cases and can be discarded and considered a deletion word. Other possible deletion words may be “intermittent,” “occasional,” or “mild.” All synonyms and deletions may be stemmed prior to use on the cleaned and stemmed verbatim narratives in operation  135 . 
     One algorithm that may be used to determine synonyms and deletions is as follows:
         a. Tokenize the cleaned and stemmed narrative. “Tokenizing” means reducing a string to a list of words. For example, the cleaned and stemmed narrative “skin thicken inject site” would become the following list of tokens: [“skin,” “thicken,” “inject,” “site” ];   b. For each token t i  in t 1  . . . t n , e.g., [“skin,” “thicken,” “inject,” “site” ], look up t i  in the list of synonyms and deletions:
           i. If t i  exists, replace it with the first synonym or delete it. Then sort and check for a match in MedDRA. If a match exists, output;   ii. If another synonym exists for t i , replace it again or delete it. Then sort and check again for a match in MedDRA. If a match exists, output;   iii. Repeat for t i+1  . . . t n .   
               

     In the above example, no matches are found in this step.
         c. Repeat step b for each token plus its neighbor, e.g., [“skin thicken,” “thicken inject,” “inject site” ];       

     In the above example, no outputs are produced from this step.
         d. Repeat step b for each token plus its two following neighbors, e.g., [“skin thicken inject,” “thicken inject site” ];       

     In the above example, no matches are found in this step.
         e. Next, swap out tokens separated by another token. For each token in t 1  . . . t n , e.g., [“skin,” “thicken,” “inject,” “site” ], look up t i  in the list of synonyms and deletions:
           i. If t i  exists, replace it with the first synonym or delete it. For example, “skin” is deleted resulting in the following list of tokens: [“ ”, “thicken,” “inject,” “site” ].   ii. For each token in t 1+1  . . . t n , e.g., [“thicken,” “inject,” “site” ], look up t j  in the list of synonyms and deletions:
               If t j  exists, replace it with the first synonym or delete it. Then sort and check for match in MedDRA. If a match exists, output. For example, replacing the word “thicken” with the synonym “fibrosi” produces the following list of tokens: [“ ”, “fibrosi,” “inject,” “site” ]. Sorting has no effect, and the concatenation of the list of strings produces “fibrosi inject site,” which matches the cleaned, stemmed, and sorted MedDRA term “injection site fibrosis” (i.e., “fibrosi inject site”).   If another synonym or deletion exists for the same token, replace it again or delete it. Then sort and check again for a match in MedDRA. If a match exists, output. For example, the token “thicken” can also be replaced with the synonym “calcif,” producing the following list of tokens: [“ ”, “calcif,” “inject,” “site” ]. Again, sorting has no effect, and the concatenation of the list of strings produces “calcif inject site,” which matches the cleaned, stemmed, and sorted MedDRA term “injection site calcification” (i.e., “calcif inject site”). The token “thicken” can also be replaced with “hypertrophi” or “sclerosi” to find a match in MedDRA.   Repeat for t i+2 . In the example provided, no other matches are found by replacing “inject” or “site” when “skin” has been deleted;   
               iii. If another synonym exists for t i , replace it again and repeat step ii. In the example provided, no matches are found when “skin” is replaced with a synonym.   
           f. Of all “synonymous” verbatim narratives that found a match in the steps above, select the one that is associated with the highest CODER edit rate, i.e., the one that uses synonyms or deletions that are most frequently observed in CODER (i.e., weighted by its observed frequency). This can be calculated according to the following equation:       

     
       
         
           
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     Note that for matches from Step e. where more than one synonym or deletion has been used, the average CODER edit rate is calculated. An example of this weight calculation is as follows: if “skin” is observed in 10 terms in the CODER database, and 5 of those terms are associated with a MedDRA dictionary term that does not contain “skin,” then the average CODER edit rate for the deletion of “skin” would be 50%. In the example provided, “fibrosi inject site” is associated with the highest average CODER edit rate and thus the associated MedDRA term is assigned. 
     An example showing operations  131 - 135  is the mapping of the verbatim narrative “SKIN THICKENING AT INJECTION SITE.” Pre-processing the narrative in operation  103  yields “skin thickening at injection site,” which is not a match. Cleaning in operation  131  yields “skin thickening injection site,” and sorting the cleaned narrative in operation  132  yields “injection site skin thickening,” neither of which is a match. Stemming the cleaned narrative in operation  133  produces “skin thicken inject site,” which is not a match. Stemming+sorting the cleaned narrative in operation  134  produces “inject site skin thicken,” which is still not mappable to MedDRA or CODER. Returning to the cleaned and stemmed narrative (output of operation  133 ) “skin thicken inject site,” substituting in operation  135  the stemmed synonym “fibrosi” (i.e., root of “fibrosis”) for “skin thicken” yields “fibrosi inject site.” Sorting has no effect. This matches one of the processed terms for the MedDRA LLT “Fibrosis injection site,” which had been processed in operation  120  to yield the corresponding term “fibrosi inject site” (pre-processing to remove capitals, stemming to remove the “s” and “ion”). Thus the narrative “SKIN THICKENING AT INJECTION SITE” may be mapped to “Fibrosis injection site” in operation  199 . 
     Besides the operations shown in  FIG. 1 , other operations or series of operations may be used to automatically map a verbatim narrative to a term in a terminology dictionary. As stated above, pre-processing operation  103  may be performed as part of the cleaning operations (e.g., operation  131 ) rather than at the beginning. In addition, not every one of operations  131  to  135  needs to be used to map a narrative. As was discussed, the narrative may be mapped after one or two or three of the operations. Also, processing operation  120  (to develop the processed database) may be performed all at once on both the medical terminology dictionary and the medical coding decision database or it may be performed in stages (e.g., clean the database terms, then clean the narrative, then compare the cleaned narrative to the cleaned database terms, and, if no match, then go to the sorting steps, etc.). In some embodiments, to save processing time and power, the order of the operations may be important—cleaning, then sorting, then stemming and sorting, then applying synonyms and deletions. In other embodiments, the actual order of the operations in the flowchart may not be critical. 
     In some embodiments, splitting may be used as another natural language processing operation. This may occur if two or more adverse events are reported in the same string. In that case, the two (or more) verbatim narratives may be split on the following punctuation marks: ; −, ([+and the following terms: secondary to, due to, related to, and, with. Each split may then be cleaned as previously described. Some examples of verbatim narratives (left) that have been mapped to MedDRA terms (right) via splitting are:
         abdominal cramping and bloating→abdominal cramp, bloating   tooth infection (root canal)→tooth infection, root canal   hematoma right hip (after fall)→hematoma, fall   ((right leg pain)) secondary to fracture→leg pain, fracture   headache, vomit→headache, vomiting   lower gi bleed, coumadin toxicity, “deconditioned state”→gi bleed, drug toxicity, general physical health deterioration   skin dryness/puffiness around eyes→dry skin, tissue puffing   indigestion with heartburn→indigestion, heartburn   general deterioration with weakness, fatigue, dizziness, nausea→general physical health deterioration, weakness, fatigue, dizziness, nausea
 
In a further embodiment, splitting may be performed on the front end by the user instead of after operation  131 .
       

     Testing by the inventors on AE narratives has been favorable. The performance was evaluated on a validation set consisting of 227 clinical studies with 64,042 verbatim adverse event narratives where the MedDRA (human) coding was hidden. This set comprised 22,267 unique validation verbatim adverse event narratives. The coverage rate, which is the percent of verbatim adverse event narratives auto mapped to MedDRA, was 95.8%. This compares to about 60% for the CODER algorithm. The accuracy rate, which is the percent of mapped terms that agree with the MedDRA term, was 97.2%. This compares to 96.3% for human coders at drug sponsors. These reported rates are based on a 5% trimmed mean over all studies. The speed at which a single verbatim narrative was mapped to MedDRA was 4 milliseconds on average, using multiprocessing. This performance was consistent across drug sponsors and various study-level features, including therapeutic area, clinical trial phase, and medical indication. 
     Reference is made to  FIG. 2A , which is a block diagram of a system  200  for automatically mapping an adverse event narrative to a term in a medical terminology dictionary, according to an embodiment of the present invention. System  200  comprises auto coder  210 , medical terminology dictionary  230 , and medical coding decision database  240 . Auto coder  210  includes pre-processor  203 , natural language processor  220 , and comparator  250 . Auto coder  210  takes AE narrative  101  and produces a mapped term  299 , using terms or entries from medical terminology dictionary  230  and medical coding decision database  240 . Comparator  250  is used to determine if AE narrative  101  (processed via pre-processor  203  to remove capitals, leading and trailing spaces, multiple spaces, and/or surrounding quotation marks) matches a term in medical terminology dictionary  230 . Such comparison may be made using a hash table or Python dictionary. If such a match can be made, the term is output via arrow  255  as mapped term  299 . If such a match cannot be made, comparator  250  may be used to determine if the pre-processed narrative matches a term in medical coding decision database  240 . If such a match can be made (again using a hash table or Python dictionary, for example), the term in medical terminology dictionary  230  that corresponds (or is already mapped) to the term in medical coding decision database  240  is output via arrow  255  as mapped term  299 . If this match cannot be made, the (pre-processed) AE narrative may be further processed using natural language processor  220  via arrow  258 , as was described in relation to flowchart  100 . An example of medical terminology dictionary  230  is MedDRA, and an example of medical coding decision database  240  is Medidata CODER. 
       FIG. 2B  is a block diagram of natural language processor  220 , according to an embodiment of the present invention. Natural language processor  220  has two main functions: (1) processing terms in medical terminology dictionary  230  and medical coding decision database  240  to produce a processed database and (2) processing the narrative in a variety of ways and comparing the results with terms in the processed database. The first processing function occurs in term processor  225 , which includes cleaner  221 , sorter  222 , stemmer  223 , stemmer+sorter  224 , and processed database  228 . The second processing function uses cleaner  231 , sorter  232 , stemmer  233 , stemmer+sorter  234 , and synonym/deletion assigner  235  (collectively called “subprocessors”). 
     Processing terms using term processor  225  includes cleaning the medical terminology dictionary and medical coding decision database terms in cleaner  221  as described above with respect to operation  121  and adding the cleaned terms to processed database  228 . The cleaned terms may be sorted using sorter  222  as in operation  122 , and the sorted, cleaned terms may be added to processed database  228 . The cleaned terms may also be stemmed using stemmer  223  as in operation  123 , and the stemmed, cleaned terms may be added to processed database  228 . Finally, the cleaned terms may be stemmed+sorted using stemmer+sorter  224  as in operation  124 , and the stemmed+sorted and cleaned terms may be added to processed database  228 . Processed database  228  thus includes alternative versions of original terms in the medical terminology dictionary and medical coding decision database and, for completeness, may contain the original terms themselves to facilitate matching to processed narratives. 
     Such matching may occur as follows. After AE narrative  101  is pre-processed in pre-processor  203  ( FIG. 2A ) to remove capitals, leading and trailing spaces, multiple spaces, and/or surrounding quotation marks, the narrative may be input to cleaner  231  via arrow  258  and cleaned as described above with respect to operation  131 . The cleaned narrative may then be compared using comparator  238  to the terms in processed database  228 . If there is a match, comparator  238  outputs mapped term  299 . If there is no match, the cleaned narrative goes through the other subprocessors -sorter  232 , stemmer  233 , stemmer+sorter  234 , and synonym/deletion assigner  235 . The functions of these subprocessors were described above with respect to operations  132 - 135 , respectively. The output of each subprocessor may be compared using comparator  238  to the terms in processed database  228 . If there is a match, comparator  238  outputs mapped term  299 . If there is no match in one subprocessor, then the cleaned narrative proceeds to the next subprocessor to see if there is a match, in which case comparator  238  outputs mapped term  299 . 
     The parts and blocks shown in  FIGS. 2A and 2B  are examples of parts that may comprise system  200  and natural language processor  220  and do not limit the parts or modules that may be included in or connected to or associated with these systems and their components. Pre-processor  203  may not be used prior to comparator  250  and instead may be part of cleaner  231 . As stated above, natural language processor  220  may not be needed in certain operations, or may just be used to generate the processed database. Similarly, not all of the subprocessors may be needed to map the AE narrative to mapped term  299 . Also, while two comparators  250  and  238  are shown in  FIGS. 2A and 2B , there may only be a single comparator used in both the auto coder and the natural language processor. Moreover, while comparator  238  is shown in  FIG. 2B  as being part of natural language processor  220 , comparator  238  may be a separate component. In addition, a comparator may include a module that performs comparisons, and other modules may select a term that is a match and map the narrative to the mapped term. The blocks shown within the dashed lines of natural language processor  220  may reside in different physical “boxes” or devices, and the connections between them may be wired or wireless, via physically close connections or over a network. 
     Reference is now made to  FIGS. 3A and 3B , which are flowcharts  300 ,  350  showing methods for automatically mapping a con-med narrative to a term in a drug terminology dictionary, according to embodiments of the present invention. 
     In operation  305 , con-med narrative  301  may be cleaned by removing leading and trailing spaces, multiple spaces, and single and double quotation marks and making all verbatim narratives lower case. In operation  310 , the entries in the drug terminology dictionary, such as WHODD, may be cleaned in the same way (drug trade names are often partially or fully capitalized, so cleaning normalizes these variations). Operation  315  asks whether the cleaned narrative matches a term in the cleaned drug terminology dictionary, such as an active ingredient or a trade name. As with the AE narratives, a match may be determined using a hash table or a Python dictionary. If there is a match to an active ingredient, then the narrative is mapped in operation  399  to that term (or to the Drecno associated with the active ingredient). If there is a match to a drug trade name, then the narrative is mapped to the active ingredient or Drecno that corresponds to the trade name (e.g., atorvastatin for Lipitor®). 
     If there is no match, then in operation  320 , the entries in a medical coding decision database, such as Medidata CODER, may be cleaned in the same way that the WHODD terms were cleaned. The system will then search the medical coding decision database in operation  325  and ask whether the cleaned con-med narrative matches a term (active ingredient or drug trade name) in the cleaned medical coding decision database. A match here may also be determined using a hash table or Python dictionary. If there is a match, then since the medical coding decision database term already corresponds (or is already mapped) to a term in the drug terminology dictionary, con-med narrative  301  can be mapped in operation  399  to the term (e.g., active ingredient or Drecno) in the drug terminology dictionary to which con-med narrative  301  was most frequently mapped in the medical coding decision database. The cleaning steps in operations  310 ,  320  (and possibly  305 ) may be considered to be a type of natural language processing as described in the text accompanying  FIG. 1 . 
     Instead of performing operations  310  and  320  in the order shown in  FIG. 3A ,  FIG. 3B  shows that both the drug terminology and the medical coding decision databases may be cleaned and the cleaned terms added to a processed database in operation  355 , and the cleaned terms may be associated with an active ingredient or Drecno from the drug terminology dictionary. Then there may be a need for only a single matching operation, such as operation  360 , instead of operations  315  and  325 , in which the cleaned narrative is matched against a term in the processed database. If so, then con-med narrative  301  may be mapped to the active ingredient or Drecno that corresponds to such term. 
     In developing this invention, the inventors have processed the con-med data from Medidata CODER as follows. The raw CODER data included over 3.4 million con-med observations from nearly 1100 clinical studies. The data are then split into two subsets—a training set and a validation set. The training set contains approximately 2.21 million observations (approximately ⅔ of the observations) from 786 studies and the validation set includes approximately 1.10 million observations from 260 studies. 
     Within the Medidata CODER training set the mappings from con-med narratives to Drecnos exhibit a high degree of consistency among different (human) coders, especially for narratives that occur most frequently. So, there is confidence that the assigned Drecnos provide an accurate “ground truth” against which to benchmark standardization methods. For narratives that have been assigned to multiple Drecnos, however, another method is needed to resolve conflicting mappings. For these narratives, the Drecno that is selected is the one that was assigned in the plurality of the mappings. If there is more than one mapping that meets this criterion (i.e., if there is a “tie” between mappings), a weight is assigned that is inversely proportional to the number of ways the tie was split. For example, mappings for narratives with a two-way tie would receive each receive a 50 percent weight when evaluating accuracy. 
     However, the Drecnos with a plurality of mappings may still be incorrect, especially for narratives that occur infrequently. Since fewer coders have encountered these narratives, any one coder&#39;s mapping decision carries greater influence. These observations necessarily comprise a small portion of the dataset and hence likely have a limited impact. For example, narratives that occur 10 or fewer times represent less than one percent of the training data. In addition, narratives for drugs with ambiguous trade names can be assigned to two or more Drecnos, each of which is plausibly correct. Choosing the Drecno with a plurality of mappings in these situations potentially biases statistics evaluating the accuracy of standardization techniques. The inventors determined that disagreement was most prevalent among infrequently occurring narratives and nearly non-existent among narratives that occur very frequently. Accordingly, any bias introduced from ambiguous trade names is likely very limited. 
     As stated above, one way of mapping in operation  399  in the situation in which the narrative matches the medical coding decision database is to assign the Drecno that was selected for a plurality of observations in the training data set. In the event of a tie, the method described above could be used. Alternatively, in the event of a tie, a Drecno may not be assigned and mapping may be deferred to operation  330 . 
     Thus, if con-med narrative  301  does not match a term in the medical coding decision database (i.e., the answer to operation  325  is “NO”) or if there is a tie among more than one Drecno, then the system will apply a probabilistic model to con-med narrative  301 . In operation  330 , such probabilistic model may be a Naïve Bayes classifier or model. Three types of Naïve Bayes classifiers are described with respect to operation  330 , Naïve Bayes with Words; Naïve Bayes with n-Grams of Letters; and Naïve Bayes with Priors, but other classifiers may also be used. 
     The Naïve Bayes classifier is a model known for its simplicity, scalability, and predictive power. In the Naïve Bayes Model with Words, feature vectors of word frequencies are constructed and it is assumed that the class conditional features follow a multinomial distribution. Features are assumed to be independent conditional on the class, and the Drecno is selected that maximizes the posterior distribution. If x i  is the frequency of the i th  feature in a new narrative (one that does not appear in the CODER training set), then the narratives are classified according to: 
                       y   ^     =             arg   ⁢           ⁢   max                 k   ∈   1     ,   2   ,     …   ⁢           ⁢   K             ⁢     p   ⁡     (     C   k     )       ⁢         (       ∑   i     ⁢     x   i       )     !         Π   i     ⁢       x   i     !         ⁢     Π   i     ⁢     p   ik     x   i                     =             arg   ⁢           ⁢   max                 k   ∈   1     ,   2   ,     …   ⁢           ⁢   K             ⁢     p   ⁡     (     C   k     )       ⁢     Π   i     ⁢     p   ik     x   i                     =             arg   ⁢           ⁢   max                 k   ∈   1     ,   2   ,     …   ⁢           ⁢   K             ⁢     p   ⁡     (     C   k     )       ⁢         Π   i     ⁡     [         N   ik     +   1           N   k     +     |   V   |       ]         x   i                 ⁢                 
where N ik  is the number of times the i th  feature occurs in class k in the training set, N k =Σ j∈k N jk  is the sum of all feature frequencies in class k, and |V| is the number of unique features in the training set. This model may be estimated with Laplace smoothing to allow the assignment of non-zero probabilities to features not observed in the training set. (This equation is applicable to all the Naïve Bayes models, not just Naïve Bayes with Words.)
 
     This model adds flexibility to the CODER mappings in two ways. First, term-frequency feature vectors are agnostic to the order of the words in the verbatim. For example, Bayer Extra Strength and Extra Strength Bayer are treated as two distinct narratives by the CODER mapping method, but are represented by identical feature vectors. Second, a probabilistic approach is more robust to the presence of extraneous information, such as prescribed dosages. So long as the contribution to the likelihood from words related to the drug outweighs contributions related to extraneous information, the estimated model should select the correct class more often than not. In fact, if certain drugs tend to be prescribed in consistent dosages, the extraneous information may even help identify the correct class. 
     This model may be tuned by specifying the minimum number of times a feature must appear before it is included in the model. For example, if the feature need only appear once, the error rate may be as much as 18%, but if the feature appears a minimum of five times to be included in the model, the error rate decreases to about 15.5%. A value of 12 (i.e., if the feature appears a minimum of 12 times) minimizes the error rate at just under 15%. 
     Similar to the CODER mappings, the Naïve Bayes with Words for features requires an exact match to words contained in narratives in the training. So, narratives that contain words that are misspelled in ways not observed in the training data may not be matched. For example, atorvastatin may be misspelled as atorvastatine, atrovastatin, atorvastatina, atorvastatinum, etc. The second model, the Naïve Bayes Model with n-Grams of Letters, addresses the misspelling issues by identifying the portions of narratives that are in common with each other. 
     To do this, n-Grams of letters are extracted from words in the con-med narratives. For example, extracting 4-grams from the narrative atorvastatin yields the following list of partial features: ATOR, TORT, ORVA, RVAS, VAST, ASTA, STAT, TATI, ATIN. The table below shows partial feature vectors for several misspellings of atorvastatin. There is one column for each 4-gram extracted from the correctly-spelled narrative atorvastatin, where ones and zeros indicate whether the misspelled narrative has a given feature in common with the correctly spelled narrative. Overall, there is a large degree of similarity across misspellings, indicated by the lack of cells with a zero. 
     
       
         
           
               
               
               
               
               
               
               
               
               
               
             
               
                   
               
               
                 Narrative 
                 ATOR 
                 TORV 
                 ORVA 
                 RVAS 
                 VAST 
                 ASTA 
                 STAT 
                 TATI 
                 ATIN 
               
               
                   
               
             
            
               
                 atorvastatine 
                 1 
                 1 
                 1 
                 1 
                 1 
                 1 
                 1 
                 1 
                 1 
               
               
                 atrovastatin 
                 0 
                 0 
                 0 
                 0 
                 1 
                 1 
                 1 
                 1 
                 1 
               
               
                 atorvastatinum 
                 1 
                 1 
                 1 
                 1 
                 1 
                 1 
                 1 
                 1 
                 1 
               
               
                 atorvastastin 
                 1 
                 1 
                 1 
                 1 
                 1 
                 1 
                 0 
                 0 
                 0 
               
               
                 atorvostatin 
                 1 
                 1 
                 0 
                 0 
                 0 
                 0 
                 1 
                 1 
                 1 
               
               
                 atorvast[at]in 
                 1 
                 1 
                 1 
                 1 
                 1 
                 0 
                 0 
                 0 
                 0 
               
               
                 atorvastatina 
                 1 
                 1 
                 1 
                 1 
                 1 
                 1 
                 1 
                 1 
                 1 
               
               
                 atorvasterol 
                 1 
                 1 
                 1 
                 1 
                 1 
                 0 
                 0 
                 0 
                 0 
               
               
                 ato[r]vastatin 
                 0 
                 0 
                 0 
                 0 
                 1 
                 1 
                 1 
                 1 
                 1 
               
               
                 atorvast[a]stin 
                 1 
                 1 
                 1 
                 1 
                 1 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
            
           
         
       
     
     Besides 4-grams, the model may use features having any letter-length of 2 or more. The 2-gram model yielded an error rate of over 13 percent, whereas the 3-gram model yielded an error rate of a little over 10%, the 4-gram model yielded an error rate of about 8.7%, and the 5-gram model yielded an error rate of a little over 9%, with longer feature-length models having even higher error rates. Thus, a 4-gram model yielded the lowest error rate, which is over 6% better than the words-based model. (The inventors selected a parameter of 15 for the minimum number of times a feature must appear before it is included in the model (as discussed above with respect to the words-based model), because more pruning reduces the number of model parameters without having a deleterious effect on the error rate.) 
     The above models are best suited for classifying new narratives that are similar to the narratives observed in historical CODER data; however, not all drugs are contained in the historical data, including (1) drugs with new trade names that are not observed in the historical data but share the same active ingredient(s) as other drugs that are observed in the historical data and (2) drugs that have entirely new active ingredient(s). 
     So, the third model, Naïve Bayes with Priors may be used. In this model, for the first group of drugs, the WHO Drug Dictionary can be used to identify all of the trade names associated with the subset of Drecnos that are observed in the historical CODER data. This information may be incorporated into the Naïve Bayes models by augmenting the CODER training data with observations from the WHO Drug Dictionary where the WHO Drug drug name is inputted as a new narrative. Conceptually, this approach is equivalent to introducing Dirichlet priors on both the class probabilities and the class-conditional feature probabilities. The weight on these priors may be increased by introducing multiple iterations of the observations from the WHO Drug Dictionary. Both the words-based model and the letters-based model benefit from such multiple iterations—with the words-based model benefiting more (reducing the error rate by almost two percentage points) with 14 iterations and the letter-based model improving by 0.8% (from 8.7 to 7.9%) when 10 iterations are included. Such an approach may also be used for the second group of drugs, those that have entirely new active ingredient(s), although it may increase the complexity of the classification task, since there are 8,917 unique Drecnos in the CODER data and 49,242 potential Drecnos to choose from in the complete WHO Drug Dictionary. 
     A further modification of the Naïve Bayes models may include using the words-based model in some cases and the letters-based model in others. More specifically, if the probability of the assigned Drecno exceeds a certain value from 0 to 1, the words-based model would be used, otherwise the letters-based model would be used. The error rate of this combined model is minimized when the value equals 0.63; thus, the words-based model would be used if the probability of the assigned class exceeds 0.63, and the letters-based model would be used the rest of the time. This reduced the error rate from 7.9% to 7.7%. 
     The letters-based Naïve Bayes model may be combined with previous mappings from CODER to improve the error rates of both approaches. For narratives that were observed in the training data, this combined approach has an error rate of 0.6%; for narratives that were not observed in the training data, the combined approach has an error rate of 35.8%. Together, the error rate over the whole validation set is 3.7%, compared to 7.9% for the letters-based Naïve Bayes model and 10.9% for the CODER mappings. 
     Besides the operations shown in  FIGS. 3A and 3B , other operations or series of operations may be used to automatically map a con-med narrative to an active ingredient in a terminology dictionary. For example, operation  325  may not be used -just the probabilistic model in operation  330  may be sufficient to map the narrative with a low error rate. Moreover, the actual order of the operations in the flowchart may not be critical. 
     Reference is now made to  FIG. 4 , which is a block diagram of a system  400  for automatically mapping a con-med narrative to a term in a drug terminology dictionary, according to an embodiment of the present invention. System  400  comprises auto coder  410 , drug terminology dictionary  430 , and medical coding decision database  440 . Auto coder  410  includes cleaners  405 ,  435 ,  445 , processed database  460 , naïve Bayes classifier  420 , and comparator  450 . Auto coder  410  takes con-med narrative  301  and produces a mapped term  499 , using terms or entries from drug terminology dictionary  430  and medical coding decision database  440 . Cleaners  435 ,  445  are used to clean (as described above with respect to operations  310 ,  320 ) terms in drug terminology dictionary  430  and medical coding decision database  440 . Cleaners  435 ,  445  (and possibly  405 ) may be considered to be a type of natural language processor as described in  FIGS. 2A and 2B . The cleaned terms are then added to processed database  460 . Comparator  450  is then used to determine if con-med narrative  301  (cleaned via cleaner  405 ) matches a term from processed database  460 . Such comparison may be made using a hash table or Python dictionary. If such a match can be made, the term is output via arrow  455  as mapped term  499 . If this match cannot be made, the cleaned con-med narrative may be input to naïve Bayes classifier  420  via arrow  458 , as was described in relation to flowcharts  300  and  350 . The naïve Bayes classifier used may be any of the models described above. An example of drug terminology dictionary  430  is WHODD, and an example of medical coding decision database  440  is Medidata CODER. 
     The parts and blocks shown in  FIG. 4  are examples of parts that may comprise system  400  and do not limit the parts or modules that may be included in or connected to or associated with this system and its components. While three cleaners  405 ,  435 ,  445  are shown, there may only be a single cleaner (or natural language processor) used for such operation. The blocks shown in auto coder  410  may reside in different physical “boxes” or devices, and the connections between them may be wired or wireless, via physically close connections or over a network. 
     One benefit of the present invention is that it automatically maps adverse event and con-med narratives to terms in the medical terminology and drug dictionaries and does so more accurately than a person can and much more quickly. The invention also provides more coverage and a lower error rate than using the medical coding decision database by itself. This leads to the production of more accurate reports from a clinical trial to a regulatory agency describing the safety of a drug or device being tested in the trial. It also allows sponsors or others to perform more robust statistical analyses involving adverse events and con-meds. 
     Aspects of the present invention may be embodied in the form of a system, a computer program product, or a method. Similarly, aspects of the present invention may be embodied as hardware, software or a combination of both. The system may provide a cloud service. Aspects of the present invention may be embodied as a computer program product saved on one or more computer-readable media in the form of computer-readable program code embodied thereon. 
     For example, the computer-readable medium may be a computer-readable signal medium or a computer-readable storage medium. A computer-readable storage medium may be, for example, an electronic, optical, magnetic, electromagnetic, infrared, or semiconductor system, apparatus, or device, or any combination thereof. 
     A computer-readable signal medium may include a propagated data signal with computer-readable program code embodied therein, for example, in baseband or as part of a carrier wave. Such a propagated signal may take any of a variety of forms, including, but not limited to, electromagnetic, optical, or any suitable combination thereof. A computer-readable signal medium may be any computer-readable medium that is not a computer-readable storage medium and that can communicate, propagate, or transport a program for use by or in connection with an instruction execution system, apparatus, or device. 
     Computer program code in embodiments of the present invention may be written in any suitable programming language. The program code may execute on a single computer or on a plurality of computers. The computer may include a processing unit in communication with a computer-usable medium, wherein the computer-usable medium contains a set of instructions, and wherein the processing unit is designed to carry out the set of instructions. 
     The above discussion is meant to be illustrative of the principles and various embodiments of the present invention. Numerous variations and modifications will become apparent to those skilled in the art once the above disclosure is fully appreciated. It is intended that the following claims be interpreted to embrace all such variations and modifications.