Patent Application
20070250462
Genetic diagnosis and counseling has been greatly advanced in the past several years by the development of more elegant and efficient screening methods. For example, application of nucleic acid-based testing technologies such as PCR-based amplification and microarray-based analysis as made generating results of a genetic test more affordable and much less complex than in prior years. There are many commercially available genetic tests which allow one to screen for the presence or absence of many mutations (e.g., 20-40 mutations), and require non-invasive biological samples as starting material (e.g., a buccal swab). Because the tests are simple, and the results generated easily, clinics and hospitals are beginning to move these testing activities “in-house”.
Interpretation of the results of such genetic tests can be complex, particularly in the context of evaluating the risk that a carrier subject will have a child who will be affected by a genetic disease. Because there is a general misperception by the lay public that a “negative” result for the presence of a mutation associated with a genetic disease is indicative of zero risk of having an affected child, reporting the results in an “positive/negative” format is not sufficient. Proper genetic counseling should instead include advising the patient with a negative mutation analysis that, for example, risk is not non-zero, but is instead adjusted downward. A further complicating factor is that many clinicians have difficulty in understanding or appreciating the complexity of analysis of genetic test results, and as a result must refer the patient(s) to a professional with genetic counseling expertise.
Recently, there has been a significant increase in demand for genetic screens for cystic fibrosis (CF). This explosion followed the recommendation by the American College of Medical Genetics (ACMG) and the American College of Obstetricians and Gynecologists (ACOG) that obstetricians in the U.S. nationwide offer preconception and prenatal carrier screening for cystic fibrosis (CF) to all patients regardless of race, ethnicity, or demographics. As with many other genetic diseases, it is best to screen for CF carrier status in partners during preconception pregnancy planning, or as early as possible in pregnancy or in the newborn. CF screening helps prospective parents know if they are carriers and if their unborn child is at risk for the disease. A CF screen of an infant can also help new parents provide the best health care and supportive environment for children who have the disease but have not yet developed symptoms, particularly since early intervention has been shown to improve outcomes for these patients.
Well over 1,000 known different mutations of the cystic fibrosis transmembrane regulator (CFTR) gene are known, which mutations may contribute to the disease. In 2001, ACOG set a minimum standard that tests should screen for the 25 most common mutations of the CFTR gene plus a few variations. “Partial panel” tests usually identify 80% to 90% of Caucasian carriers, depending on how many of the mutations are included; the sensitivity of a partial-panel test is generally even greater for Ashkenazi Jews, but quite a bit lower for those of Hispanic, African, or Asian descent because of the different mutation frequencies within each of these ethnic groups. Some currently available CF genetic screens detect 40 mutations and 4 variants.
However, as noted above, interpretation of such genetic screens can be complicated. For example, since not all possible mutations are evaluated in partial-panel screening tests (such as described above for CF), failure to detect a mutation does not equate to zero risk. Furthermore, a patient's ethnicity and family history affect carrier risk or disease risk.
In short, genetic screens such as those for CFTR mutation analysis, are high-complexity laboratory procedures normally involving sophisticated molecular biology and human genetics expertise. The advent of population carrier screening for CFTR mutations has added, and will continue to add, an extremely large test volume to a procedure of such high complexity and sophistication, a situation unprecedented in the field of laboratory medicine. For at least these reasons, such testing should be performed by laboratories possessing the requisite expertise, experience, and physical resources.
The ACMG has recommended that any laboratory embarking on CF population carrier screening must be able to comply with the stringent quality assurance guidelines specified in the ACMG and CAP checklists and the report of the NIH-DOE Task Force on Genetic Testing, and must participate in the CAP/ACMG quality assurance and proficiency testing programs. The ACMG has also recommended that equal attention must be paid to pre- and postanalytic aspects of testing (e.g., appropriateness of test ordering, interpretation, reporting, and counseling) as to the laboratory test panel itself. Various test results will particularly generate the need for genetic counseling. Such results will include, for example, (1) the identification of positive/negative couples who may request additional mutation analyses or counseling to clarify their residual risk, (2) individuals who have a family history of CF, (3) otherwise healthy males who carry mutations or variants associated with infertility, and (4) positive/positive couples. It is important that individuals and couples receive accurate information about risks, prognostic factors, and range of options available to allow for fully informed decision-making.
However, not all hospitals or clinics have the resources to staff a board-certified genetics counselor on staff, or to have a sufficient number of such counselors to handle the increase in demand for interpretation of genetic screen results. Indeed, while the need exists, the volume of tests at any one site may not justify the expense of a certified molecular geneticist. As a result, interpretation of genetic screen results presents at least one bottle-neck to providing patients with the information they need.
Literature
US Published Application No. US 2002/0052761; U.S. Pat. Nos. U.S. Pat. No. 6,482,156; U.S. Pat. No. 6,246,975; U.S. Pat. No. 6,113,540; U.S. Pat. No. 6,022,315; U.S. Pat. No. 5,868,669; U.S. Pat. No. 5,724,968; U.S. Pat. No. 5,711,297.
Grody et al.” Laboratory Standards and Guidelines for Population-based Cystic Fibrosis Carrier Screening”, Genetics in Medicine, March/April 2001, Vol. 3 No. 2: 149-154.
Computer-based methods and systems for facilitating assessment of results of genetic screening tests are provided. The methods and systems can be implemented to, for example, facilitate a risk assessment revision for a subject who may be a carrier of a genetic disease or facilitate a diagnosis of a genetic disease.
Exemplary embodiments of the invention are disclosed herein.
It is emphasized that, according to common practice, the various features of the drawings are not necessarily to-scale, and dimensions of the various features are arbitrarily expanded or reduced for clarity. Included in the drawings are the following figures:
The present application includes an Appendix inserted after the claims, which Appendix contains the following tables:
Table—INTERPRETIVE MASTER REPORTING LIST;
CFITC—Table 1, CFITC—Table 2, CFITC—Table 3 and CFITC—Table 4;
CFIIC—Table 1, CFIIC—Table 2, and CFIIC—Table 3;
CFITD—Table 1, CFITD—Table 2, and CFITD—Table 3; and
CFIID—Table 1, CFIID—Table 2, and CFIID—Table 3.
Definitions
“Carrier” (or “carrier subject”) generally refers to an individual who does not display any detectable or significant symptoms of a genetic disease, but harbors the gene (or genes) for a genetic disease, and can pass the disease-causing gene (or genes) to offspring.
“Carrier risk” is used herein to refer to the risk that a carrier will have offspring affected by the genetic disease for which the subject is a carrier.
“Diagnosis” as used herein is meant a positive or negative indication as to whether a patient has, or is at risk of developing, a disease or one or more symptoms of such a disease. A genetic diagnosis is a diagnosis based at least upon detection of the presence or absence of a gene mutation (or variant) that is indicative of a disease (e.g., cystic fibrosis, Huntingto's disease, etc.).
Before additional disclosure of embodiments of the present invention is provided, it is to be understood that this invention is not limited to particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.
Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limits of that range is also specifically disclosed. Each smaller range between any stated value or intervening value in a stated range and any other stated or intervening value in that stated range is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included or excluded in the range, and each range where either, neither or both limits are included in the smaller ranges is also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the invention.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, some potential and preferred methods and materials are now described.
All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited. It is understood that the present disclosure supersedes any disclosure of an incorporated publication to the extent there is a contradiction.
It must be noted that as used herein and in the appended claims, the singular forms “a”, “an”, and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a tag” includes a plurality of such tags and reference to “the compound” includes reference to one or more compounds and equivalents thereof known to those skilled in the art, and so forth.
It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as “solely”, “only” and the like in connection with the recitation of claim elements, or the use of a “negative” limitation.
The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed.
Computer-based methods and systems for facilitating assessment of results of genetic screening tests are provided. The methods and systems can be implemented to, for example, facilitate a risk assessment revision for a subject who may be a carrier of a genetic disease or facilitate a diagnosis of a genetic disease.
Various exemplary embodiments are described herein. For example, in one exemplary embodiment the methods and systems feature a computerized method of interpretation of genetic test data of a patient comprising receiving patient data; receiving genetic test result data for at least a first allele; generating a flag configuration from the patient data and at least first allele data; and generating a report based on the flag configuration; wherein the report provides an interpretation of genetic test data for a patient. In related exemplary embodiments, receiving genetic test result data further comprises receiving genetic result data for a second allele, and the flag configuration is generated from the patient data, the first allele data, and the second allele data. In further related exemplary embodiments, receiving patient data comprises one or more of receiving patient ethnicity data; receiving personal history data; and receiving family history data; wherein the flag configuration generated includes the patient ethnicity data, personal history data and family history data. In further related exemplary embodiments, said generating a report comprises comparing the flag configuration to a table of defined flag configurations having an associated message code to identify a matching flag configuration; and entering the message code of the matching flag configuration for inclusion of associated text in the report. In related exemplary embodiments, when comparing the flag configuration to the defined flag configurations does not identify a matching flag configuration, no report is generated and is optionally not generated until and/or after manual intervention is completed.
In another exemplary embodiment, a system for analysis of genetic test data is described which system comprises a computing environment; an input device, connected to the computing environment, to receive data from a user, wherein the data received includes patient data and genetic test result data for at least a first allele; an output device, connected to the computing environment, to provide information to the user; and a computer readable storage medium having stored thereon at least one algorithm to provide for generation of a flag configuration from the patient data and the genetic test result data, and comparison of the flag configuration to a table containing defined flag configurations having associated message codes, wherein when the flag configuration generated from the patient data and the genetic test result data matches a defined flag configuration in the table, the associated message code is identified for use in generation of a report; wherein the system provides results that can be used for generation of a report providing an analysis of genetic test data of a patient. In related exemplary embodiments, the computing environment comprises a local computer local to the user and a remote computer at a site remote to the user, wherein the local computer and the remote computer are connected through a network, and wherein the computer readable storage medium is provided on the remote computer.
In another exemplary embodiment, an automated genetic test result interpretation system is provided, which comprises a communications network; a server connected to the communications network; a client computer connected to the communications network; and at least one algorithm executed based on patient data and genetic test result data, to provide for generation of a flag configuration from the patient data and the genetic test result data, and comparison of the flag configuration to a table containing defined flag configurations having associated message codes, wherein when the flag configuration generated from the patient data and the genetic test result data matches a defined flag configuration in the table, the associated message code is identified for use in populating a field of a report. In related exemplary embodiments, the communications network comprises the Internet.
Also described is a computer readable medium comprising a program stored thereon, wherein the program provides for execution of one or more algorithms to execute the methods described herein.
Further details will now be provided.
Genetic Test Platforms and Exemplary Genetic Screens Amenable to Implementation
The methods and systems described herein can be adapted for use in conjunction with any genetic test platform of interest. By “platform” or “genetic test platform” is meant any assay format that provides information about the presence or absence of a mutant allele associated with a disease of interest (e.g., cystic fibrosis). Such assays are generally nucleic-acid based, and involve the detection of the presence or absence of a mutant allele associated with a disease of interest, including determining whether the mutation occurs on one or both alleles.
Exemplary platforms include nucleic acid-based assays involving arrays (especially microarrays), beads, and the like. Exemplary assays for nucleic acid-based detection usually involve some form of nucleic acid amplification (e.g., by polymerase chain reaction (PCR)), and analysis of an amplification product for the presence or absence of a sequence associated with a mutant gene. Exemplary assays include, but are not limited to, INNO-LiPA (Innogenetics, Gent Belgium), InPlex™ (Third Wave Technologies, WI USA), Signature CF (Ambion Diagnostics, Austin Tex. USA)and Tag-It™ (Tm Bioscience Corporation (Toronto, Canada)) assays.
Any genetic screen, particularly one which requires interpretation of results requires consideration of several factors to provide assessment of carrier risk or of diagnosis and/or risk of disease severity (e.g., genetic tests for which a meaningful interpretation requires more than a positive/negative result of the assay). Genetic diseases of particular interest for which genetic screens are available and can be readily adapted to assessment according to the methods and systems described herein include cystic fibrosis (CF), fragile X, Huntington disease, and open neural tube defects.
The methods and systems described herein can be readily adapted to facilitate analysis of genetic tests of any of a variety of mutant genes associated with a disease of interest. The methods and systems described herein are primarily exemplified by genetic screens involving assessing the presence of a mutation on both alleles. However, it is to be understood that the methods can also be used in facilitating assessment of carrier risk and/or diagnosis for diseases on which assessment of only a single allele is necessary, as in autosomal disorders (e.g., an X-linked disorder (e.g., in males), or a Y-linked disorder). The sequences of mutant genes associated with various genetic diseases have been identified and are known in the art. For example, a database devoted to the collection of mutations in the CFTR gene is maintained by the laboratory of Lap-Chee Tsui on behalf of the international Cystic Fibrosis genetics research community, and is available on-line at www.genet.sickkids.on.ca/cftr/.
Methods for manual interpretation of results of genetic screens for these genetic diseases and others are known in the art. For example, CF screens and methods for manual interpretation of such genetic screens are described in, for example, American College of Medical Genetics “Technical Standards and Guidelines for CFTR Mutation Testing” (2005) (www.acmg.net/Pages/ACMG_Activities/stds-2002/cf.htm); The American College of Obstetrics and Gynecologists, “Prenatal and Preconceptional Carrier Screening for Genetic Diseases in Individuals of Eastern European Jewish Descent, (August 2004) ACOG Committee Opinion No. 298 104:425-8, each of which are incorporated herein by reference in its entirety), and, where appropriate, information relating to risk assessment and diagnosis can be readily incorporated into the methods and systems of the invention as exemplified herein.
Methods of Genetic Screen Data Analysis
The methods and systems of the invention generally involve execution of algorithms to facilitate analysis of genetic test results in the context of assessing carrier risk or diagnosis of a genetic disorder.
The methods and systems of the invention are exemplified by a web-based ordering and reporting system, referred to as FocusLink™, which is described in more detail in the Example section below. In this exemplary system, the client (e.g., a lab technician, health professional, or other user) collects selected patient risk assessment data (e.g., ethnicity, personal history, family history). After performing a CF genetic screen in their laboratory on a platform of interest, the client uses FocusLink™ to order platform-specific interpretation services. The client enters the patient risk assessment data and genetic test result information.
The data input by the user is transmitted via the internet off-site (e.g., to Focus Technologies) and processed to provide an electronically-generated interpretive report. This interpretive report is normally subjected to certain quality control parameters by a reviewer, which reviewer is, or is or under the supervision of, a board-certified geneticist, and released for the client. Under certain circumstances, described below in more detail, providing results from which a report can be generated requires manual intervention. Once released, the output is then transmitted via the Internet back to the client. The final report, which contains the interpretive report, can be generated at the client-side, as in the embodiment of the Example below, or can be generated at the reviewer side. The methods and systems described herein can provide for an interpretive report of a genetic screen within 24 hours of receipt of the data in the program (e.g., in FocusLink™). A program can also provide for triggering creation of an invoice for order and corresponding service requested and rendered.
As will be readily appreciated by one of ordinary skill in the art, the FocusLink™ embodiment is but one example of how the methods and systems of the invention can be implemented and application. The methods and systems will now be described more generally and in more detail.
User-Side Data Entry
For clarity, it should be noted that the “user”, which is used interchangeably with “client”, is meant to refer to a person who at least provides for data input, and may be the same person to whom results and/or a report is transmitted, in the methods and systems described herein. In some embodiments the person who inputs the data, and the person who receives the results and/or report may be different persons, but are both referred to as “users” or “clients” herein to avoid confusion. In certain embodiments, e.g., where the methods are completely executed on a single computer, the user or client provides for data input and review of data output. In embodiments where the user only executes a portion of the method, the individual who, after computerized data processing according to the methods of the invention, reviews data output (e.g., results prior to release to provide a complete report, a complete, or reviews an “incomplete” report and provides for manual intervention and completion of an interpretive report) is referred to herein as a “reviewer”. The reviewer may be located at a location remote to the user (e.g., at a service provided separate from a healthcare facility where a user may be located). In this context of a genetic test screen, the reviewer is normally a certified geneticist or under the supervision of a certified geneticist, as may be required by government regulations or laws.
In each of the embodiments exemplified in
After the Allele 2 data is entered, then the user requests a report. Although not shown in the figures, the program can allow the user to review the data entered prior to requesting the report. In addition, it should be noted that the order of entry of data is arbitrary, and may be re-ordered as desired and compatible with the methods and systems described herein.
The data input by the user can then be processed on the same computer as used for data entry, or can be transmitted for processing to a computer at a remote site. Transmission can be accomplished via the internet, an intranet, and the like.
Processing of Data
The data input by the user (e.g., “responses” to the various queries) is then processed and a report generated from the processed data. All or a portion of the data processing and/or report generation can be carried our either at a computer local or remote to the client. For example, the responses can be transmitted to a remote site for data processing, and the processed data released back to the client, and the report generated from the processed data at the client-side.
The flag configuration thus represents a particular combination of responses, where each flag in the flag configuration defines a different response to a query. The flag configuration is then compared to defined flag configurations in a table. The table provides flag configurations for which a message code has been assigned.
As exemplified in
In
In either the carrier or diagnostic aspects, Allele 1 data is received. If Allele 1 is positive for a gene mutation, and the mutation as a variant of interest (i.e., a variant that is indicative of changed carrier or disease risk), then the program receives variant data. These steps are repeated for Allele 2 data. In another embodiment, as illustrated in
The program then generates a flag configuration from the data (i.e., the responses to the queries) using flags defined for each response. As discussed above, “flag configuration” as used herein refers to an ordered string of flags, where each flag defines a response to a query, and the order of flags in the flag configuration corresponds to the order of responses. The flags can be ordered in the flag configuration in the order in which the corresponding responses are entered, or can be ordered in numerical order according to the number of a test code assigned to each query or data type. A “test code” as used herein refers to a code assigned to a type of data entered, e.g., Personal History, Ethnicity, Family History, Allele 1, Allele 2, Variant (of Allele 1 and/or Allele 2), and the like.
The generated flag configurations are then compared to a table having flag configurations that correspond to a particular message code. If a match if found between the generated flag configuration and a flag configuration defined in the table, then the corresponding message code is assigned to the order, the results released, and the report generated. If there is no match, then manual completion of the report is required.
The message codes are provided for particular response combinations (e.g., flag configurations) in the table as deemed practical. For example, in carrier screening analysis if Allele 1 and Allele 2 data are negative for mutations, then the carrier risk is based on family history and ethnicity. If family history is negative (or assumed negative, if, not provided or not solicited), then an electronic report can be readily generated based on population-based carrier risk from the ethnicity response. For example, if a flag configuration indicates a Personal History and Family History that are Negative, Not Solicited, or Not Provided; a Negative result for both Allele 1 and Allele 2, and thus Variant N/A, the flag configuration has an assigned a message code, and a report generated provides a Revised Carrier Risk based on population risk according to the Ethnicity response flag (e.g., Not solicited, non-Hispanic Caucasian, Ashkenazi Jewish, Hispanic American, African American, Asian American, Complex, or Not provided).
If family history is positive, then, where possible, a report can be generated with carrier risk based on family history. In certain embodiments, it may be desirable for an indication of positive family history to have no match with response combinations (e.g., flag configurations) having a pre-assigned message code, and thus require manual intervention for completion. In other embodiments, a message code can be provided for flag configurations indicative of particular relatedness data indicating the relation of the affected family member(s) to the patient.
In some embodiments of carrier screening analysis, where at least one allele is positive for a mutation, carrier risk is based on the presence of the mutation, or a particular variant of a mutation. In some embodiments, where at least one allele is positive for a mutation, the carrier risk is based on the presence of the mutation or a particular variant of the mutation without adjusting carrier risk for ethnicity or family history data. In some embodiment, where both alleles are positive for a mutation, it may be desirable to require manual completion of the report. For example, in the specific example provided, if the flag configuration indicates a positive Family History, then manual completion is required. Also in the specific example provided, if a flag configuration indicates both Allele 1 and Allele 2 has a non-Delta F508 mutation mutation, then manual completion is required.
In general, if a combination of response to the queries (e.g., a flag configuration) do not correspond to a specific reflex message code (e.g., which contains a particular reporting message which provide information about revised carrier risk or diagnosis), then the order remains as pending, release does not occur, and no report is generated. Manual intervention is thus required for completion of the report and release to the client. Alternatively, a particular combination of responses could instead be associated with an “alert” in the definitions table, which then highlights an order as requiring manual intervention for report completion.
An algorithm is then executed on the flag configuration to generate a report, where different flag configurations are assigned to different report codes. The report codes correspond to selected text, which is then used to populate one or more report fields of a report.
It will be appreciated that the methods and systems can be readily modified to provide additional message codes for additional responses (e.g., flag configurations), so that more reports can be generated completely electronically. However, such may not be desired, e.g., in view of the number of message codes required, and/or the probability of rare response combinations (e.g., flag configurations) occurring, making it impractical from a business standpoint). Alternatively or in addition, manual intervention by the reviewer may be desired in particular situations, where it may be desirable to convey additional information in the report that may be unique to a patient's genetic screen results.
Reports
A “report” as described herein is an electronic or tangible document which is composed of report elements that provide information of interest relating to the genetic screen and its results. A report can be completely or partially electronically generated, and can include all or a portion of the details of the genetic test data (e.g., platform, test type), patient data (e.g., ethnicity, family history, personal history), and genetic test result data (e.g., data for one or both alleles (allele 1 data and allele 2 data), which generally includes data indicating the presence or absence of a gene mutation, which may include information about variants of the gene mutation).
Reports are generally generated after release of processing results as described in the methods herein. If processing does not provide for a message code for an interpretive report field (as a result of a response combination failing to match defined response combinations in a table associating response combinations with message codes), then release is not possible, and report generation is not possible, without manual intervention to complete the interpretive report field(s). Alternatively, processed results that lack one or more fields can be associated with an alert to distinguish such situations from processed results that contain all fields and can thus be released. In some embodiments, the computerized methods include an algorithm to direct sorting of processed results that are suitable for quality control review and release (i.e., can provide for generation of a final report) and those that require manual intervention for completion, and can be stored at least temporarily in separate databases where desired. Such sorting can facilitate production of reports.
Where government regulations or other restrictions apply (e.g., requirements by health, malpractice, or liability insurance), all results, whether generated wholly or partially electronically, are subjected to a quality control routine prior to release to the user.
A “report field ”, which may also be referred to as a “report element”, is a portion of a report that corresponds to input or output data. Examples of such report fields include a genetic test data fields (e.g., platform field, test type field), patient data fields (e.g., ethnicity field, family history field, personal history field), and genetic test result data fields (e.g., allele 1 data field, allele 2 data field, which can be for one or both alleles (allele 1 data and allele 2 data), which generally includes data indicating the presence or absence of a gene mutation, which may include information about variants of the gene mutation). Other report fields can include recommendations, which are provided in the report as a recommendation field, which can be part of an interpretive report field.
In general, the reports are generated by population of report fields with data that correspond to the data entered or a result obtained by execution of algorithm(s) on responses provided by a client, according to the methods described herein.
As noted above, the reports can be partially or completely electronically generated. Routine Carrier Screening and Routine Diagnostic interpretive report fields of a report can be completely electronically generated, with review by or under the supervision of a board-certified geneticist.
As noted above, processed results that require manual completion can contain an alert (e.g., text, symbol, color-coding, and the like) which prompts manual intervention by a reviewer to review and complete the report (e.g., edit the text in-the report, delete the report and generate a completely manual report, etc.). The alert can be generated in response to a key code (e.g., request for a diagnostic interpretive report), a flag (e.g., positive family history; presence of at least one allele having a mutation that has variants relevant to analysis of risk assessment), and/or a flag configuration (e.g., an indication of the presence of mutant genes on both alleles). In the context of CF genetic screens, alerts for manual intervention in report completion can be provided for, for example, a positive Family History (which can require review of relatedness of the affected family member(s)); the presence of a R117H mutation (which mutation has several variants (polyT tract variants designated as 5T, 7T, and 9T, where the presence of 5T is indicative of a higher carrier risk than the presence of 7T or 9T); the presence of mutations on both alleles; or when a diagnostic test is requested. Alternatively, rather than provide such an alert, such processed results can simply be held as “pending” and cannot be released until manual intervention is provided.
Thus the methods and systems of the invention can provide for both wholly electronically-generated carrier reports, as well as partially electronic, at least partially manual reports for complex presentations (e.g., for reports for certain types of carriers and for certain types of diagnostic reports, where desired).
The various data relating to different report fields may appear in the report in the same of adjacent report regions of the report, or may be distributed over different, discontinuous portions of the report. In addition, the same or similar data may be repeated in different report fields as may be helpful in reading, analysis, or understanding the report or its implications. The following are exemplary report fields and data which may be included in the reports generated by the methods and systems described herein.
Testing Facility
The report can include information about the testing facility, which information is relevant to the hospital, clinic, or lab in which the genetic screen was conducted. This information can include one or more details relating to, for example, the name and location of the testing facility, the identity of the lab technician who conducted the assay and/or who entered the input data, the date and time the assay was conducted and/or analyzed, the location where the sample and/or result data is stored, the lot number of the reagents (e.g., kit, etc.) used in the assay, and the like. Report fields with this information can generally be populated using information provided by the user.
Order Data
The order data in the report can include information relevant to the particular order requested by the user. This can include Procedure code(s) (which generally also include a short descriptor assigned to the procedure code) to identify the platform used and the test type (carrier or diagnostic) desired. Procedure code(s) can be accompanied by a pre-assigned description. The order data can also include the name of the user entering the data, and can further include the date and time of data entry. This order data can also include an order number, which can be assigned to facilitate report tracking and, where desired, invoicing. Report fields with order data information can generally be can be populated using data entered by the user, which can be selected from among pre-scripted selections (e.g., using a drop-down menu).
Service Provider
The report can include information about the service provider, which may be located outside the healthcare facility at which the user is located, or within the healthcare facility. Examples of such information can include the name and location of the service provider, the name of the reviewer, and where necessary or desired the name of the certified geneticist. Report fields with this information can generally be populated using data entered by the user, which can be selected from among pre-scripted selections (e.g., using a drop-down menu). Other service provider information in the report can include contact information for technical information about the result and/or about the interpretive report.
Patient Data
The patient data can include patient data relevant to genetic screening, which data has been subjected to the algorithms described herein to generate a report and can include ethnicity, family history (which may include data about relatedness of any affected family member(s)), and personal history. Ethnicity and family history data can be particularly relevant in a report for carrier screening, e.g., where both alleles are negative for a mutation. The report can also include administrative patient data (that is, data that is not essential to the analysis of genetic test results), such as information to identify the patient (e.g., name, patient date of birth (DOB), gender, mailing and/or residence address, medical record number (MRN), room and/or bed number in a healthcare facility), insurance information, and the like), the name of the patient's physician or other health professional who ordered the genetic test and, if different from the ordering physician, the name of a staff physician who is responsible for the patient's care (e.g., primary care physician). Report fields with this information can generally be populated using data entered by the user.
Genetic Screen
The genetic screen information (which may also be referred to as a genetic test information) refer to the information relevant to the genetic screen used and the results obtained from the genetic screen. This information can thus include the number of mutations analyzed; the names of the mutations analyzed (e.g., in the context of CF, “Delta 1507”); and text indicating whether the mutations screened include those recommended for analysis by a professional organization (e.g., ACOG, ACMG, ACHG, etc.). Report fields with this information can generally be populated automatically based on the information provided with respect to the platform data, which may be entered as order data above.
The portion of the report indicating the genetic screen information can also include the results of the genetic screen conducted as entered by the user relating to the presence or absence of a mutant gene. This information can include the name of the gene screened; the presence or absence of a mutation detected on a first allele and, where desired, presence or absence of a mutation detected on a second allele; the identity of any mutation detected (e.g., in the context of CFTR gene analysis, ΔF508); and identity of a mutation variant detected if applicable (e.g., in the context of CFTR gene analysis, R117H, intron 8-5T/7T). The presence of a mutation and/or variant can be indicated simply by providing the name of the mutation. Report fields with this information can generally be population using information entered by the user.
Sample Data
The sample data can provide information about the biological sample analyzed in the genetic screen such as the source of biological sample obtained from the patient (e.g., blood, buccal swab, mouthwashing, cord blood, unknown, etc.) and the date and time collected. Report fields with this information can generally be populated using data entered by the user, some of which may be provided as pre-scripted selections (e.g., using a drop-down menu).
Interpretive Report
The interpretive report portion of the report includes information generated after processing of the data as described herein. As described in more detail below, the interpretive report can further include information of particular relevance to the data processing, such as Indication (e.g., Carrier Screening or Diagnosis) and genetic test result (e.g., “Negative for mutations tested”). It will be appreciated that interpretive report will vary according to the analysis requested (e.g., carrier or diagnostic).
The interpretive report can include, for example, Indication (e.g., carrier screening, diagnosis of a symptom associated with CF, etc.); Family History Details (which, when positive, can include narrative describing the relatedness of the affected family member(s)); Prior Carrier Risk (e.g., based solely on population risk, e.g., based solely on population risk according to patient's ethnicity or Prior Diagnosis (if any based on, e.g., symptoms);); Result of genetic screen (e.g., “Negative for mutations tested”), Revised Carrier Risk or Revised Diagnosis (or “Diagnosis”); Interpretation; and, optionally, Recommendation(s). Exemplary Recommendations are described below in more detail.
The Revised Carrier Risk, Revised Diagnosis (or “Diagnosis), and Interpretation are portion of report that are generated as a result of processing of the data according to the methods and systems described herein. For example, as set out in the Example below, if processing of the data provided by the user generates a response combination (e.g., flag configuration) which is assigned a corresponding message code, then the text of that message code appears in the Interpretation. Also, since generation of the report can require manual intervention, the Interpretation can be composed of text elements that are partially or completely auto-populated, or which are completely or partially manually generated.
Recommendations
The Interpretation portion of the report can include a Recommendation(s). This recommendation can be assigned to a particular response combination (e.g., flag configuration) for automatic inclusion in a report, or can be generated by manual intervention (e.g., in response to an alert). For example, in the context of a carrier risk analysis, exemplary recommendations can include, but are not necessarily limited to:
In the context of diagnostic assays, recommendations can include recommendations for validation of diagnosis by other methods, suggestions for possible supportive or therapeutic intervention, and the like.
Other features
It will be readily appreciated that the reports can include all or some of the elements above, with the proviso that the report generally includes at least the elements sufficient to provide the analysis requested by the user (e.g., information relevant to providing a carrier risk assessment (or revised carrier risk assessment) or diagnosis as requested by the user).
It will also be readily appreciated that the reports can include additional elements or modified elements. For example, where electronic, the report can contain hyperlinks which point to internal or external databases which provide more detailed information about selected elements of the report. For example, the genetic test platform report element can include a hyperlink to a website of the manufacturer of the genetic test platform. The patient data element of the report can include a hyperlink to an electronic patient record, or a site for accessing such a patient record, which patient record is maintained in a confidential database. This latter embodiment may be of particular interest in an in-hospital system or -in-clinic setting.
Computer-Based Systems and Methods
The methods and systems described herein can be implemented in numerous ways. In one embodiment of particular interest, the methods involve use of a communications infrastructure, for example the internet. Several embodiments of the invention are discussed below. It is also to be understood that the present invention may be implemented in various forms of hardware, software, firmware, processors, or a combination thereof. The methods and systems described herein can be implemented as a combination of hardware and software. The software can be implemented as an application program tangibly embodied on a program storage device, or different portions of the software implemented in the user's computing environment (e.g., as an applet) and on the reviewer's computing environment, where the reviewer may be located at a remote site associated (e.g., at a service provider's facility).
For example, during or after data input by the user, portions of the data processing can be performed in the user-side computing environment. For example, the user-side computing environment can be programmed to provide for defined test codes to denote platform, carrier/diagnostic test, or both; processing of data using defined flags, and/or generation of flag configurations, where the responses are transmitted as processed or partially processed responses to the reviewer's computing environment in the form of test code and flag configurations for subsequent execution of one or more algorithms to provide a results and/or generate a report in the reviewer's computing environment.
The application program for executing the algorithms described herein may be uploaded to, and executed by, a machine comprising any suitable architecture. In general, the machine involves a computer platform having hardware such as one or more central processing units (CPU), a random access memory (RAM), and input/output (I/O) interface(s). The computer platform also includes an operating system and microinstruction code. The various processes and functions described herein may either be part of the microinstruction code or part of the application program (or a combination thereof) which is executed via the operating system. In addition, various other peripheral devices may be connected to the computer platform such as an additional data storage device and a printing device.
As a computer system, the system generally includes a processor unit. The processor unit operates to receive information, which generally includes genetic test data (e.g., platform, test type), patient data (e.g., ethnicity, family history, personal history), and genetic test result data (e.g., data for one or both alleles (allele 1 data and allele 2 data), which generally includes data indicating the presence or absence of a gene mutation, which may include information about variants of the gene mutation). This information received can be stored at least temporarily in a database, and data analyzed to generate a report as described above.
Part or all of the input and output data can also be sent electronically; certain output data (e.g., reports) can be sent electronically or telephonically (e.g., by facsimile, e.g., using devices such as fax back). Exemplary output receiving devices can include a display element, a printer, a facsimile device and the like. Electronic forms of transmission and/or display can include email, interactive television, and the like. In an embodiment of particular interest, all or a portion of the input data and/or all or a portion of the output data (e.g., usually at least the final report) are maintained on a web server for access, preferably confidential access, with typical browsers. The data may be accessed or sent to health professionals as desired. The input and output data, including all or a portion of the final report, can be used to populate a patient's medical record which may exist in a confidential database at the healthcare facility.
A system for use in the methods described herein generally includes at least one computer processor (e.g., where the method is carried out in its entirety at a single site) or at least two networked computer processors (e.g., where data is to be input by a user (also referred to herein as a “client”) and transmitted to a remote site to a second computer processor for analysis, where the first and second computer processors are connected by a network, e.g., via an intranet or internet). The system can also include a user component(s) for input; and a reviewer component(s) for review of data, generated reports, and manual intervention. Additional components of the system can include a server component(s); and a database(s) for storing data (e.g., as in a database of report elements, e.g., interpretive report elements, or a relational database (RDB) which can include data input by the user and data output. The computer processors can be processors that are typically found in personal desktop computers (e.g., IBM, Dell, Macintosh), portable computers, mainframes, minicomputers, or other computing devices.
The networked client/server architecture can be selected as desired, and can be, for example, a classic two or three tier client server model. A relational database management system (RDMS), either as part of an application server component or as a separate component (RDB machine) provides the interface to the database.
In one embodiment, the architecture is provided as a database-centric client/server architecture, in which the client application generally requests services from the application server which makes requests to the database (or the database server) to populate the report with the various report elements as required, particularly the interpretive report elements, especially the interpretation text and alerts. The server(s) (e.g., either as part of the application server machine or a separate RDB/relational database machine) responds to the client's requests.
The input client components can be complete, stand-alone personal computers offering a full range of power and features to run applications. The client component usually operates under any desired operating system and includes a communication element (e.g., a modem or other hardware for connecting to a network), one or more input devices (e.g., a keyboard, mouse, keypad, or other device used to transfer information or commands), a storage element (e.g., a hard drive or other computer-readable, computer-writable storage medium), and a display element (e.g., a monitor, television, LCD, LED, or other display device that conveys information to the user). The user enters input commands into the computer processor through an input device. Generally, the user interface is a graphical user interface (GUI) written for web browser applications.
The server component(s) can be a personal computer, a minicomputer, or a mainframe and offers data management, information sharing between clients, network administration and security. The application and any databases used can be on the same or different servers.
Other computing arrangements for the client and server(s), including processing on a single machine such as a mainframe, a collection of machines, or other suitable configuration are contemplated. In general, the client and server machines work together to accomplish the processing of the present invention.
Where used, the database(s) is usually connected to the database server component and can be any device which will hold data. For example, the database can be a any magnetic or optical storing device for a computer (e.g., CDROM, internal hard drive, tape drive). The database can be located remote to the server component (with access via a network, modem, etc.) or locally to the server component.
Where used in the system and methods, the database can be a relational database that is organized and accessed according to relationships between data items. The relational database is generally composed of a plurality of tables (entities). The rows of a table represent records (collections of information about separate items) and the columns represent fields (particular attributes of a record). In its simplest conception, the relational database is a collection of data entries that “relate” to each other through at least one common field.
Additional workstations equipped with computers and printers may be used at point of service to enter data and, in some embodiments, generate appropriate reports, if desired. The computer(s) can have a shortcut (e.g., on the desktop) to launch the application to facilitate initiation of data entry, transmission, analysis, report receipt, etc. as desired.
Computer-Readable Storage Media
The invention also contemplates a computer-readable storage medium (e.g. CD-ROM, memory key, flash memory card, diskette, etc.) having stored thereon a program which, when executed in a computing environment, provides for implementation of algorithms to carry out all or a portion of the methods of analysis of genetic test results as described herein. Where the computer-readable medium contains a complete program for carrying out the methods described herein, the program includes program instructions for collecting, analyzing and generating output, and generally includes computer readable code devices for interacting with a user as described herein, processing that data in conjunction with analytical information, and generating unique printed or electronic media for that user.
Where the storage medium provides a program which provides for implementation of a portion of the methods described herein (e.g., the user-side aspect of the methods (e.g., data input, report receipt capabilities, etc.)), the program provides for transmission of data input by the user (e.g., via the internet, via an intranet, etc.) to a computing environment at a remote site. Processing or completion of processing of the data is carried out at the remote site to generate a report. After review of the report, and completion of any needed manual intervention, to provide a complete report, the complete report is then transmitted back to the user as an electronic document or printed document (e.g., fax or mailed paper report). The storage medium containing a program according to the invention can be packaged with instructions (e.g., for program installation, use, etc.) recorded on a suitable substrate or a web address where such instructions may be obtained. The computer-readable storage medium can also be provided in combination with one or more reagents for carrying out a genetic test (e.g., primers, probes, arrays, or other genetic test kit components).
The following examples are put forth so as to further provide those of ordinary skill in the art a disclosure and description of how to make and use various aspects of the present invention, and are not intended to limit the scope of what is regarded as the invention, nor are they intended to represent that the examples below are all or the only actual reduction to practice.
The methods and systems of the invention are exemplified by a web-based ordering and reporting system, referred to as FocusLink™. In this system, the client (e.g., a lab technician, health professional, or other user) collects selected patient risk assessment data (e.g., ethnicity, personal history, family history). After performing a CF genetic screen in their laboratory on a platform of interest, the client uses FocusLink™ to order platform-specific interpretation services. The client enters the patient risk assessment data and genetic test result information. The data is transmitted via the internet off-site (e.g., to Focus Technologies) and processed to provide an electronically-generated interpretive report. This interpretive report is then subjected to certain quality control parameters by a reviewer, which reviewer is, or is or under the supervision of, a board-certified geneticist, and released for the client. Under certain circumstances, described below in more detail, the electronically-generated report requires manual intervention for preparation of a complete report; after report completion in this case, the report is then released. Once the report is released, it is then transmitted via the Internet back to the client. This can provide for an interpretive report of a CF genetic screen within 24 hours of receipt of the data in FocusLink™. A unit code also triggers creation of an invoice for the client for the service rendered.
The present example provides for 50 interpretive ” Routine Carrier” reports, and 50 “Routine Diagnostic” reports, where such routine reports can be generated completely electronically.
FocusLink™ thus can alleviate internal and external concern about “incomplete” test offering (e.g., test results without appropriate interpretation), delivers patient and platform-specific reports, and provides a service that is platform-neutral (i.e., the service can be used regardless of the type of platform in which the genetic screen was conducted),
In this example, selection of a procedure from a list of procedures provides for a predetermined set of assumptions and a predetermined set of queries for the user, which are designed to help reduce the amount of data that needs to be entered and user error. The user can select either “CF GENOMEX INTERP, CARRIER (TagIt), which is indicative of both the TagIt™ 40+4 test platform and the test type “carrier”, “CF GENOMEX INTERP, DIAGNOSTIC (TagIt), which is indicative of both the TagIt™ 40+4 test platform and the test type “diagnostic”,“CF GENOMEX INTERP, CARRIER (InPlex), which is indicative of both the InPlex, Invader™-based platform and the test type “carrier” or “CF GENOMEX INTERP, DIAGNOSTIC (InPlex), which is indicative of both the InPlex, Invader™-based platform and the test type “diagnostic”.
Furthermore, in this example, if the user selects a carrier test, then the program assumes the patient's personal history is negative or assumed negative; if a diagnostic test is selected, then the program assumes the patient's personal history is positive (or assumed positive). However, the program can still contain queries for this information regardless of whether a carrier or diagnostic procedure is requested.
The user is then subjected to a series of queries (under the heading “Questions and Answers”).
The data is then transmitted via the internet to a remote server, where the data is then processed.
Data processing involves 1) Accessioning the order into the Laboratory Information System, 2), Building the accessions(s) on a worklist (CFIIC, CFIID, CFITC, CFITD) and 3) Result entry and release) During Result entry, each accessions results are evaluated as defined in the Interpretive Reporting Master List (Table 1 of the Appendix). In the program,, as shown in the Master List, each possible response for each Test Code is defined by a “flag” (e.g., if the response to Ethnicity is African America, then the test code 8045 in the CFITC worklist is defined by “A”). The responses are then loaded to generate a flag configuration, and the flag configuration compared to determine if it matches a flag configuration assigned to a message code (“MC”). If there is a match, then the appropriate corresponding message code will be assigned to the accession of the order, and the order will remain on the pending list until released. If there is no match, then the order remains on the pending list, and manual intervention is required for completion. An accession that is incomplete after processing and on the pending list cannot be released until after manual intervention to provide an interpretive message. Attempts to manually release such an accession will result in the message ALL RESULTS NOT ENTERED.
The Interpretive Reporting Master List lists the definitions for each of the four types of procedures that can be requested (CFITC, CFITD, CFIIC and CFIID). Each definition contains all of the possible values where a reflex will occur. The table below provides a key to this master list.
Thus, depending on the procedure selected by the client (CFITC, CFITD, CFIIC and CFIID), during the result entry process, each accessions' results (the client responses) will be processed according to the algorithms set forth in this master list. The flag configurations are then processed to generate a report.
In general, if a flag configuration indicates a Personal History and Family History that are Negative, Not Solicited, or Not Provided; a Negative result for both Allele 1 and Allele 2, and Variant is N/A, the flag configuration is assigned a report code, and a report generated provides a Revised Carrier Risk based only on population risk according to the Ethnicity response flag (e.g., Not solicited, non-Hispanic Caucasian, Ashkenazi Jewish, Hispanic American, African American, Asian American, Complex, or Not provided).
If a flag configuration indicates that at least one allele is positive for a mutation (i.e., is not “Negative”), then a report code (also referred to as a “message code” is assigned, and a report generated based on a flag configuration composed of Personal History, Allele 1, Allele 2, and Variant data flags. In this latter example, thus, the flags for Ethnicity and Family History are not used in generating the flag configuration to identify a report code for population of an Interpretation report field.
If a flag configuration indicates a positive Family History, Personal History are any of Negative, Not Solicited, or Not Provided; and a Negative result for both Allele 1 and Allele 2 (with variant being N/A), no message code is assigned. This interpretive report will require manual intervention by the reviewer.
If a flag configuration indicates the presence of two different mutations at least one of which is R117H, and the procedure unit code corresponds to a procedures that is either a carrier screening or a diagnostic test, no message code is assigned. This will require manual intervention by the reviewer for completion of the interpretive report. If the key code is a diagnostic and a R117H mutation is present on either Allele 1 or Allele 2 or both, then an indication of disease severity can optionally be provided.
If a flag configuration indicates both Allele 1 and Allele 2 have a non-Delta F508 mutation, then the flag configuration is assigned, no message code is assigned. This will require manual intervention by the reviewer for completion of the interpretive report.
The FocusLink™ provides four different procedures for carrier screening or diagnosis using either the Invader™ or TagIt™ platforms. The flags, flag configurations, and test codes assigned to various flag configurations are provided in the Tables I in the Appendix.
For example, for the Invader™-based platform, carrier test (CFIIC), the program includes a worklist of test codes 8045-ETHNICITY, 8145-FAMHIS (Family History), 8245-PERHIST (Personal History), 9045-ALLELE1, 9046-ALLELE2, and 8345-VARIANT, with flags defined according to the responses indicated.
The flags for each test code are processed to generate a flag configuration. The flag configuration is composed of a string of flags for each test code, with the flags ordered in the string according to the test code number, i.e., so that the flags are provided in numerical order according to the test code to which they are assigned. Thus for the CFIIC example, the flags for the test codes are ordered numerically by the numbers 8045, 8145, 8245, 9045, 9046, and 8345, and a flag positioned indicative of the user's response to the corresponding data queries for Ethnicity, Family History, Personal History, Allele 1, Allele 2, and Variant, respectively. The test code 8745-INTERP (Interpretation) is added to the worklist. For example, if the user indicated African America, Negative Family History, Negative Personal History, Negative Allele 1, Negative Allele 2, and N/A for Variant, the flag configuration generated for the CFIIC worklist would be AAAAAA.
The flag configuration is then analyzed, and a report code assigned to the 87455-INTERP test code. The report codes correspond to different combination of interpretive report elements, which are then in the Interpretation report field of the report. The report codes correspond to different combinations of text for the Report Fields “Indication” (e.g., Carrier Screening, Diagnosis of a symptomatic patient”, etc.); “Result” (e.g., “Negative for mutations tested”); Recommendations; Interpretation; and a Field referred to as a “Reporting Message”, which corresponds to pre-written text, which contains the interpretive statements that apply to the combination of patient information and results of mutation analysis.
If the flag configuration indicates both allele 1 and allele 2 are negative, then a report code is assigned based on all 6 flags set out above.
For example, a CFIIC worklist having the flag configuration AAAAAA is assigned the report code #CF0005, which is associated with the following text for the Interpretation field of the report:
If a flag configuration indicates a mutation at either Allele2 or Allele2, then the program assigns a report code based on a flag configuration composed of only the Personal History flag (8245-PERHIST), Allele 1 (9045-ALLELE1), Allele 2 (9046-ALLELE2), and Variant (8345-VARIANT).
Tables are included in the Appendix as part of this specification which provide
After flag configuration analysis and assignment of report code(s), the report is generated using the report codes. The report codes direct population of the report fields of the report.
An exemplary report is provided generated from a mock order for a CFIIC procedure is provided in
The preceding merely illustrates the principles of the invention. It will be appreciated that those skilled in the art will be able to devise various arrangements which, although not explicitly described or shown herein, embody the principles of the invention and are included within its spirit and scope. Furthermore, all examples and conditional language recited herein are principally intended to aid the reader in understanding some of the principles of the invention and the concepts contributed by the inventors to furthering the art, and are to be construed as being without limitation to such specifically recited examples and conditions. Moreover, all statements herein reciting principles, aspects, and embodiments of the invention as well as specific examples thereof, are intended to encompass both structural and functional equivalents thereof. Additionally, it is intended that such equivalents include both currently known equivalents and equivalents developed in the future, e.g., any elements developed that perform substantially the same function, regardless of structure.
Furthermore, while the invention has been illustrated and described in detail in the drawings and foregoing description, the same is to be considered as illustrative and not restrictive in character, it being understood that only exemplary embodiments have been shown and described and that all changes and modifications that come within the spirit of the invention are desired to be protected. A person of ordinary skill in the computer software art is readily capable of practicing this invention based upon this detailed description of the preferred embodiment to date without undue experimentation. A person of ordinary skill in the relevant art, e.g., the computer software art, will also recognize that the architecture exemplified, user interface features, including the window navigation style, mechanism for selecting options, screen content and layouts can be organized differently on the same screen or different screens than as portrayed in the illustrations and still be within the spirit of the invention. The scope of the present invention, therefore, is not intended to be limited to the exemplary embodiments shown and described herein. Rather, the scope and spirit of present invention is embodied by the appended claims.
This application claims the benefit of U.S. Provisional Application No. 60/732,728, filed Nov. 1, 2005, which application is incorporated herein by reference in its entirety.
| Number | Date | Country | |
|---|---|---|---|
| 60732728 | Nov 2005 | US |
