Abstract:
A method and system in a computing environment for documenting mutation observations is provided. The method includes receiving mutation information, disassembling the mutation information into discrete elements and storing the discrete elements A method and system for presenting mutations is also provided. The method includes obtaining discrete elements for a mutation, obtaining a standard for presenting the mutation and assembling the mutation presentation utilizing the discrete elements and the standard of presentation.

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
       [0001]    This application is a continuation of and claims priority from pending U.S. application Ser. No. 10/679,900, filed Oct. 6, 2003, and entitled “Computerized System and Method for Documenting and Presenting Mutation Observations. Application Ser. No. 10/679,900 is incorporated by reference in its entirety. 
     
    
     TECHNICAL FIELD 
       [0002]    The present invention relates generally to the field of computer software. More particularly, the invention relates to a computerized system and method for documenting and presenting mutation observations. 
       BACKGROUND OF THE INVENTION 
       [0003]    In recent years, genetic information has become increasingly available through research efforts such as this Human Genome Project. Currently, there are clinical diagnostic tests for more than 900 genes. Each gene may have multiple identified mutations. As the results of the Human Genome Project are used to identify additional genes involved in disease or clinical response, the number of clinically relevant gene targets for diagnostic testing will increase significantly. Furthermore, the increasing use of DNA sequencing as a diagnostic tool will lead to identification of more mutations. 
         [0004]    The Human Genome Association (HUGO) has published a standard approach for describing DNA mutations. However, this standard has not been widely adopted. Many clinicians and researchers use approaches to describe mutations that differ from this published standard. Their approach is considered a user-preferred standard and has meaning within their group but differs from the published standard of HUGO. 
         [0005]    While there are known programs that document mutation results, these programs do not store templates describing one or more standards nor do these programs use templates to store and present discrete values captured during the documentation of mutation observations. 
         [0006]    Accordingly, there is a need for a system and method for documenting mutation observation and mutation results so the observations and results can be presented using published standards or user-preferred standards. There is also a need for a system and method of documenting mutations that flexibly and efficient exchanges and aggregates mutation data. 
       SUMMARY OF THE INVENTION 
       [0007]    In one aspect of the present invention, a method and system in a computing environment for documenting mutation observations is provided. The method receives mutation information and disassembles the mutation information into discrete elements. The method then stores the discrete elements. The discrete elements of the mutation may be stored such that the elements can be used to present the mutation using both user-preferred and published standards. 
         [0008]    In another aspect of the present invention, a method and system in a computing environment for presenting mutations is provided. The method obtains discrete elements of a mutation and obtains a standard for presenting the mutation information. The method assembles the mutation presentation utilizing the discrete elements and the standard of presentation. The standards may be user-preferred standards or published standards. 
     
    
     
       BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS 
         [0009]    The present invention is described in detail below with reference to the attached drawing figures, wherein: 
           [0010]      FIG. 1  is a block diagram of a computing system in accordance with an embodiment of the present invention; 
           [0011]      FIG. 2  is a flow chart representative of a computer program for documenting mutations in accordance with an embodiment of the present invention; 
           [0012]      FIG. 3  is a flow chart representative of a computer program for presenting mutations in accordance with an embodiment of the present invention; 
           [0013]      FIG. 4  is a screen shot illustrating an exemplary implementation of documenting DNA mutations in accordance with an embodiment of the present invention; 
           [0014]      FIG. 5  is a screen shot illustrating an exemplary implementation of documenting DNA mutations in accordance with an embodiment of the present invention; and 
           [0015]      FIG. 6  is a screen shot illustrating an exemplary implementation of documenting DNA mutations in accordance with an embodiment of the present invention. 
       
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
       [0016]    The present invention provides a method and system for documenting and representing mutation observations using one or more standard notations.  FIG. 1  illustrates an example of a computing system environment  20  on which the invention may be implemented. The medical information computing system environment  20  is only one example of a suitable computing environment and is not intended to suggest any limitation as to the scope of use or functionality of the invention. Neither should the computing environment  20  be interpreted as having any dependency or requirement relating to any one or combination of components illustrated in the exemplary environment  20 . 
         [0017]    The invention is operational with numerous other general purpose or special purpose computing system environments or configurations. Examples of well-known computing systems, environments, and/or configurations that may be suitable for use with the invention include, but are not limited to, personal computers, server computers, hand-held or laptop devices, multiprocessor systems, microprocessor-based systems, network PCs, minicomputers, mainframe computers, distributed computing environments that include any of the above systems or devices, and the like. 
         [0018]    The invention may be described in the general context of computer-executable instructions, such as program modules, being executed by a computer. Generally, program modules include, but are not limited to, routines, programs, objects, components, data structures that perform particular tasks or implement particular abstract data types. The invention may also be practiced in distributed computing environments where tasks are performed by remote processing devices that are linked through a communications network. In a distributed computing environment, program modules may be located in both local and remote computer storage media, including memory storage devices. 
         [0019]    With reference to  FIG. 1 , an exemplary system for implementing the invention includes a general purpose computing device in the form of server  22 . Components of server  22  may include, but are not limited to, a processing unit, internal system memory, and a suitable system bus for coupling various system components, including database cluster  24  to the control server  22 . The system bus may be any of several types of bus structures, including a memory bus or memory controller, a peripheral bus, and a local bus using any of a variety of bus architectures. By way of example, and not limitation, such architectures include Industry Standard Architecture (ISA) bus, Micro Channel Architecture (MCA) bus, Enhanced ISA (EISA) bus, Video Electronic Standards Association (VESA) local bus, and Peripheral Component Interconnect (PCI) bus, also known as Mezzanine bus. 
         [0020]    Server  22  typically includes therein or has access to a variety of computer readable media, for instance, database cluster  24 . Computer readable media can be any available media that can be accessed by server  22 , and includes both volatile and nonvolatile media, removable and nonremovable media. By way of example, and not limitation, computer readable media may comprise computer storage media and communication media. Computer storage media includes both volatile and nonvolatile, removable and nonremovable media implemented in any method or technology for storage of information, such as computer readable instructions, data structures, program modules or other data. Computer storage media includes, but is not limited to, RAM, ROM, EEPROM, flash memory or other memory technology, CD-ROM, digital versatile disks (DVD), or other optical disk storage, magnetic cassettes, magnetic tape, magnetic disk storage, or other magnetic storage devices, or any other medium which can be used to store the desired information and which can be accessed by server  22 . Communication media typically embodies computer readable instructions, data structures, program modules, or other data in a modulated data signal, such as a carrier wave or other transport mechanism, and includes any information delivery media. The term “modulated data signal” means a signal that has one or more of its characteristics set or changed in such a manner as to encode information in the signal. By way of example, and not limitation, communication media includes wired media, such as a wired network or direct-wired connection, and wireless media such as acoustic, RF, infrared and other wireless media. Combinations of any of the above should also be included within the scope of computer readable media. 
         [0021]    The computer storage media, including database cluster  24 , discussed above and illustrated in  FIG. 1 , provide storage of computer readable instructions, data structures, program modules, and other data for server  22 . 
         [0022]    Server  22  may operate in a computer network  26  using logical connections to one or more remote computers  28 . Remote computers  28  can be located at a variety of locations in a medical environment and/or a laboratory setting, for example, but not limited to, hospitals, other inpatient settings, a clinician&#39;s office, ambulatory settings, diagnostic labs, research laboratories, research facilities, and a patient&#39;s home environment. Clinicians include, but are not limited to, the treating physician, researchers, geneticists, laboratory technicians, specialists such as surgeons, radiologists and cardiologists, laboratory technicians, researchers, physician&#39;s assistants, nurse practitioners, nurses, nurse&#39;s aides, pharmacists, microbiologists, and the like. The remote computers may also be physically located in non-traditional medical care environments so that the entire health care community is capable of integration on the network. Remote computers  28  may be a personal computer, server, router, a network PC, a peer device, other common network node or the like, and may include some or all of the elements described above relative to server  22 . Computer network  26  may be a local area network (LAN) and/or a wide area network (WAN), but may also include other networks. Such networking environments are commonplace in offices, enterprise-wide computer networks, intranets and the Internet. When utilized in a WAN networking environment, server  22  may include a modem or other means for establishing communications over the WAN, such as the Internet. In a networked environment, program modules or portions thereof may be stored in server  22 , or database cluster  24 , or on any of the remote computers  28 . For example, and not limitation, various application programs may reside on the memory associated with any one or all of remote computers  28 . It will be appreciated that the network connections shown are exemplary and other means of establishing a communications link between the computers may be used. 
         [0023]    A user may enter commands and information into server  22  or convey the commands and information to the server  22  via remote computers  28  through input devices, such as keyboards, pointing devices, commonly referred to as a mouse, trackball, or touch pad. Other input devices may include a microphone, satellite dish, scanner, or the like. Server  22  and/or remote computers  28  may have any sort of display device, for instance, a monitor. In addition to a monitor, server  22  and/or computers  28  may also include other peripheral output devices, such as speakers and printers. 
         [0024]    Although many other internal components of server  22  and computers  28  are not shown, those of ordinary skill in the art will appreciate that such components and their interconnection are well known. Accordingly, additional details concerning the internal construction of server  22  and computer  28  need not be disclosed in connection with the present invention. 
         [0025]    As contemplated by the language above, the method and system of the present invention may be implemented on a stand-alone desktop, personal computer or any other computing device used in a medical environment, solitary research lab or any of a number of other locations. 
         [0026]    With reference to  FIG. 2 , a method  200  for documenting mutations is provided. Mutations may be documented for any organism. For example, mutations may be documented for humans, animals, vertebrates, invertebrates, plants, viruses, bacteria, fungi, prokaryotes, eukaryotes, and protista. A user seeks to document a particular mutation. The mutation to be documented may be obtained in any number of ways. In one embodiment, the mutation information is obtained from genetic testing. In another embodiment, the mutation to be documented is selected from a list of reference content in the database. A mutation, as used herein, is a permanent and heritable change to a DNA, which may also be represented in terms of the effects that a given mutation has on an RNA or protein molecule. DNA sequences may vary among individuals. These differences are called mutations and are the result of changes in the native genetic sequence due to substitutions, insertions, deletions, inversions, duplications, translocations and complex rearrangements. 
         [0027]    At block  202 , the system receives a query for a particular genetic information sequence. The query may be made by the user or initiated by the system in response to a clinical event or any of a number of events or activities. At block  204 , the system provides a list of known mutations for the particular genetic information sequence. The list of mutations provided by the system may be for any genetic sequence, including, but not limited to, genes, proteins, and any known DNA and RNA sequences. There may be numerous known mutations for any particular gene, protein or sequence. For example, the sequence of nucleotides for a particular gene may vary between individuals. 
         [0028]    The list of known mutations is displayed using a user interface. The user interface window presents a graphical user interface of the conventional kind for selecting a mutation from a comprehensive list. The list may include the common name for the mutation or any of a number of other formats that identify the mutation. These mutations may be presented in terms of the DNA alteration or in terms of the effects of the mutation on the RNA or protein sequence. 
         [0029]    At block  206 , if the mutation to be documented is available on the list of known mutations, the mutation is selected from the list. The selection is received at block  208 . The mutation may be selected from the list of mutations displayed on the user interface in a variety of ways using any of a number of input devices and techniques. 
         [0030]    If the mutation to be documented is not available in the list of known mutations at block  206 , then the system obtains and displays the reference sequence for the particular genetic sequence at block  214 . For example, if the sequenced genetic information is a gene, the ordered sequence of the nucleotides of the gene is displayed. If the genetic information is a protein sequence, the ordered sequences of the amino acids of the protein may be displayed. In one embodiment, the reference sequence is displayed using a sequence editor. From the sequence editor, a user can quickly and easily document mutations that are not presented on the list of known mutations. The mutation type is received at block  216  preferably from the user&#39;s selection. Types of mutations that may be documented, include, but are not limited to: substitutions, insertions, deletions, inversions, duplications, translocations and complex rearrangements. 
         [0031]    At block  218 , the observed mutation value is received preferably in response to the user&#39;s input. The sequence in the sequence editor may be dynamically modified to input the mutation information using the sequence editor. For example, a user may make edits such as, additions, deletions, and modifications, relative to the reference sequence in the sequence editor. The system may then disassemble the mutation information into discrete elements directly from the sequence editor and/or dynamically display the edits as entries in data entry fields. Mutation information may also be directly entered into the data entry fields. For example, if the mutation is a substitution, the system provides data entry fields for the user to enter the position of the substitution relative to the reference sequence, a data entry field for the native value of the genetic sequence and a data entry field for the observed value of the substitution. If the mutation is an insertion, the system provides data entry fields for the starting position of the insertion relative to the reference sequence, the length of the insertion and the specific sequence being inserted into the reference sequence. If the mutation is a deletion, the system provides data entry fields for the entry of the starting position of the deletion within the reference sequence and the ending position of the deletion within the reference sequence. For inversions, the system provides data entry fields including the starting position of the inversion within the reference sequence and the ending position of the inversion within the reference sequence. Additional fields and types of fields may be used to capture mutation information. 
         [0032]    At block  210 , the system disassembles the mutation into discrete elements. The discrete elements of the mutation are stored at block  212 . By way of example, Table 1 illustrates the type and structure of data stored at block. The elements may be stored in a relational database, in an extensible markup language (XML) format or any of a number of other manners. 
         [0000]    
       
         
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 1 
               
               
                   
               
               
                   
                 Molecule 
                 Genetic 
                   
                   
                   
                   
                   
                 Native 
                   
               
               
                 ID 
                 Type 
                 Sequence 
                 Type 
                 Start 
                 Length 
                 End 
                 Ref Seq 
                 Value 
                 Observed 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 1 
                 cDNA 
                 CFTR 
                 Sub 
                 3978 
                   
                 3978 
                 NM_000492 
                 G 
                 A 
               
               
                 2 
                 cDNA 
                 CFTR 
                 Sub 
                 15 
                   
                 15 
                 NM_000492 
                 A 
                 C 
               
               
                 3 
                 cDNA 
                 HADHA 
                 Ins 
                 2162 
                 1 
                   
                 NM_000182 
                 — 
                 C 
               
               
                 4 
                 cDNA 
                 ACADM 
                 Del 
                 1293 
                 4 
                 1296 
                 NM_000016 
                 TTAT 
                 — 
               
               
                   
               
             
          
         
       
     
         [0033]    The discrete elements may also include the molecule type such as genomic DNA, cDNA, RNA or a protein. Genomic DNA and all other DNA is composed of nucleotides in a specific order. The nucleotides that make DNA include adenine (A), guanine (G), cytosine (C) and thymine (T). The ordered sequence of nucleotides at a specific location in the genome which encodes a functional product, either protein or RNA, is a gene 
         [0034]    A protein is a large molecule composed of amino acids in a specific order. There are twenty naturally occurring amino acids that can be used to make a protein. The order of the amino acids is determined by the base sequence of the nucleotides of the gene coding for the protein. 
         [0035]    RNA molecules are composed of strands of nucleotides much like genomic DNA. However, the nucleotides that makeup RNA include adenine (A), guanine (G), cytosine (C) and uracil (U). There are several classes of ribonucleic acids (RNA) including messenger RNA (mRNA), transfer RNA (tRNA), ribosomal RNA and other RNAs serving a different purpose. 
         [0036]    Complementary DNA (cDNA) is DNA that has synthesized from a messenger RNA template corresponding to expressed sequences of genomic DNA. Complementary DNA is also composed of multiple nucleotides, A, T, C and G, in a specific order but lacks the intronic sequences found in genomic DNA. 
         [0037]    The discrete elements also include the type of mutation (Type) such as a substitution (Sub), insertion (Ins), deletion (Del), inversion (Inv), duplication, translocation and complex rearrangement and the particular sequenced genetic information for which the mutation is to be documented. For example, when a user selects a mutation from a predefined list of mutations, the discrete information can be managed as reference content through association with a concept identifier with attributes that define the type, start, length, end and reference sequence ID. 
         [0038]    Other discrete elements include a unique mutation identification value identifying the mutation (ID), a reference sequence identification value identifying the reference sequence (e.g. Gene Bank ID number), an identification value for identifying the individual being tested, the starting position of the mutation within the reference sequence, the ending position within the reference sequence, the length of an insertion, the native value of the sequenced genetic information, and the observed value of the mutation being documented. For example, in Table 1, a substitution mutation for cDNA is documented for the particular genetic sequence for the CFTR gene. The identification value for the reference sequence is 3978 NM — 000492 and the mutation identification value is “1”. The starting position for the substitution within the reference sequence is 3978 and the ending position is also 3978. The native value for the CFTR gene at the 3978 position is “G”. The observed value of the nucleotide at the 3978 position of the substitution mutation is “T”. A variety of other discrete values relating to the mutation may also be documented as needed. 
         [0039]    With reference to  FIG. 3 , a method  300  of providing mutation observations using preferred or published standards is shown. The system receives a query for a mutation presentation at block  302 . At block  304 , the system obtains the stored discrete values for the mutation. 
         [0040]    At block  306 , the system obtains the user-preferred standard or published standard for presenting the mutation. In one embodiment, the published standards and preferred standards are obtained from a relational database (or other storage type) containing the information in Table 2 below. The exemplary database contains the preferred standards for more than one user. Table 2 contains information regarding published and preferred standards for presenting a substitution mutation. 
         [0000]    
       
         
               
               
               
               
               
             
           
               
                 TABLE 2 
               
               
                   
               
               
                 User 
                 Position 1 
                 Position 2 
                 Position 3 
                 Position 4 
               
               
                   
               
             
             
               
                 Published Standard 
                 RefSeq Position 
                 Normal value 
                 Link symbol 
                 Observed value 
               
               
                 User 1 
                 Normal value 
                 RefSeq Position 
                 Observed Value 
               
               
                 User 2 
                 RefSeq Position 
                 Observed Value 
               
               
                   
               
             
          
         
       
     
         [0041]    In Table 2, the published standards for presenting a substitution mutation provide information about the mutation in four positions. Position 1 is the position within the reference sequence (RefSeq Position) at which the substitution value occurs. Position 2 is the native value (e.g. nucleotide(s) or amino acid(s)) of the sequenced genetic information. Position 3 is a link symbol such as “&gt;” and Position 4 is the observed value (e.g. nucleotide(s) or amino acid(s)) of the mutation. However, the preferred standards for viewing a mutation for User 1 provide information regarding the mutation only in three positions. Position 1 is the native value (e.g. nucleotide(s) or amino acid(s)) of the sequenced genetic information. Position 2 is the position within the reference sequence of the substitution and Position 3 is the observed value of the mutation (e.g. nucleotide(s) or amino acid(s)). 
         [0042]    Notably, the information regarding published and preferred standards may be obtained from any number of sources. Further, the published and preferred standards may be stored in different databases and formats. 
         [0043]    At block  308 , the system assembles the mutation presentation by using the discrete values as directed by the preferred or published standard. At block  310 , the system delivers the mutation presentation. 
         [0044]    With reference to  FIG. 2 , by way of an example to demonstrate the operation of the present invention, documentation of a Cystic Fibrosis genetic test result for patient John Doe is demonstrated. First, at block  202 , the system is queried for known mutations for Cystic Fibrosis. The genetic results indicate that the patient has a deletion of nucleotides 1652-1655 in the Cystic Fibrosis gene which results in the deletion of phenalanine (F) at position 508 of the protein sequence (D F508). The system is configured to present this and other mutations in terms of the resulting amino acid substitutions. With reference to  FIG. 4 , a screen shot  400  of a list of current mutations  404  for the Cystic Fibrosis gene  402  is shown. The DF508 mutation is listed. The user selects the DF508 mutation to be documented. With reference back to  FIG. 2 , the system receives the user&#39;s selection of the known mutation (DF508) from the list at block  208 . The system disassembles the DF508 results into discrete values at block  210 , and, at block  212 , stores this information. 
         [0045]    With reference to  FIG. 3 , later, if the clinician wants to view the mutation using the preferred standards of the presentation, the system receives the query for the mutation at block  302 . At block  304 , the system obtains the stored discrete values and at block  306  the system obtains the user&#39;s preferred standards. At block  308 , the system assembles the discrete values as directed by the preference. At block  310 , the system delivers the mutation presentation to the user. The user&#39;s preferred standards for presentation of a substitution mutation are: type of mutation, Native Value; Location within the Reference Sequence; Observed Value or lack of observed value. In this instance, the preferred presentation of the DF508 mutation del 1652-1655 would be “del F508”. 
         [0046]    However, in this example, a researcher also wants to extract CFTR mutation results from the system and aggregate those results with those of other researchers. Further, in this example, the researcher wants to transfer the results using published standards rather than clinician&#39;s preferred standards. At block  302 , the system receives the query for CFTR mutations and at block  304  obtains the stored discrete values for each CFTR mutation. At block  306 , the system obtains the published standards and assembles the discrete values as directed by the published standards for presentation. At block  310 , the system delivers the mutation presentation. According to current published standards for presentation of a deletion mutation are: Location within Reference Sequence; “del”; positions deleted. In this example, the presentation of the DF508 mutation according to published standards would be “1652delGTC”. 
         [0047]    In operation, by way of another example, a clinician receives a different Cystic Fibrosis genetic test result for patient John Doe to be documented. The sequenced genetic results indicate that the patient has a previously unknown mutation of the Cystic Fibrosis gene. With reference to  FIG. 4 , a screen shot  400  of list of mutations  404  for the Cystic Fibrosis gene  402  is shown. The unknown mutation is not in the list of known mutations. As such, the user selects sequence editor  406  to document the mutation. After receiving the selection of the sequence editor  406 , the system obtains and displays the reference sequence of the CFTR gene. 
         [0048]    With reference to  FIG. 5 , a screen shot  500  displays reference sequence  510  and data entry fields  506  for a hypothetical deletion mutation  504 . The user enters the starting position of the deletion within the reference sequence in data entry field  506  and the ending position of the deletion within the reference in data entry field. Alternatively, this information may also be entered directly into the sequence editor. For example, nucleotides “GACC”  512  from position 37 to position 40 are deleted relative to the reference sequence contained in the sequence editor. The system could utilize these edits from the sequence editor automatically or may also dynamically display the edits as data in the data entry fields  504 ,  506  and  508 . In this example, the system stores the discrete values as the CFTR gene  514 , the type of mutation  515 , the starting position of the deletion  516  within the reference sequence, the ending position 518 of the deletion within the reference sequence and an identification value identifying the reference sequence  520 . 
         [0049]    In operation by way of yet another example, a clinician receives a Cystic Fibrosis genetic test result for patient John Doe. The sequenced genetic result indicates that the patient has an unknown mutation of the Cystic Fibrosis gene. With reference to  FIG. 4 , a screen shot  400  of list of mutations  404  for the Cystic Fibrosis gene  402  is shown. The unknown mutation is not on the list of known mutations. As such, the user selects sequence editor  406  to document the mutation. After selecting the sequence editor  406 , the system obtains and displays the reference sequence of the CFTR gene. 
         [0050]    With reference to  FIG. 6 , a screen shot  600  displaying reference sequence  610  and data entry fields  606  and  608  for a substitution mutation  604  are shown. The user enters the substitution value “G” (e.g. observed nucleotide) into data entry field  606  and the position of the substitution “4” within the reference sequence in data entry field. As can be seen in the sequence editor, nucleotide “C”  612  at position “4” is substituted with the observed value “G.” The system then stores the discrete values. For example, the system stores the discrete values as the CFTR Gene  614 , the type of mutation  615 , the position of the substitution  616 , the native value  617 , the observed value  618  and an identification value identifying the reference sequence  619 . 
         [0051]    The present invention provides a method and system for documenting mutation observations. The present invention also provides a method and system for presenting mutation observations. Although the invention has been described with reference to the preferred embodiment illustrated in the attached drawing figures, it is noted that substitutions may be made and equivalents employed herein without departing form the scope of the invention as recited in the claims. For example, additional steps may be added and steps omitted without departing from the scope of the invention.