Note: Descriptions are shown in the official language in which they were submitted.
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SYSTEMS, METHODS AND HITS FOR REMOTE GENETIC
ANALYSIS AND CONSULTATION
FIELD OF THE INVENTION
This invention concerns systems and methods to simplify and improve
genetic testing, analysis and consultation including the capability to permit
the
sampling and testing of genetic source material to occur at a different
location from
the analysis of the results and the preparation of consultative reports based
on the
results.
BACKGROUND
Molecular diagnostics involves the characterization of human disease by
examining nucleic acids, both DNA and RNA, which are the template for all
proteins that mediate disease. Currently, molecular diagnostics involves the
use of a
variety of technical approaches to extract, modify, and analyze DNA for
changes
inherent to the nucleotide sequence that make up the genome. These changes,
called
mutations or polymorphisms, are the basis for determination of who we are as
humans and the differences between us, some of which give rise to disease.
Generally, most genetic tests involve five primary steps or processes:
1) specimen procurement; 2) nucleic acid purification; 3) genetic chemistry;
4) interpretation of data; and 5) reporting results of the interpretation.
While there
are four categories of genetic testing, including (1) constitutional or
inherited
disorders; (2) acquired disease, such as cancer; (3) infectious disease; and
(4)
disease of genetic predisposition, the level of technical skill to perform the
test as
well as medical expertise to interpret this information into usable results
are
different.
While there has been a marked increase in the number of genetic tests
available, the majority of existing tests are for rare and highly esoteric
types of
diseases. The complexity and the historic high costs of each test have driven
the
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majority of genetic testing to be performed at a relatively small number of
centralized laboratories. Other than specimen procurement, which is typically
performed locally in a laboratory, hospital or physician office, these
centralized
laboratories perform all of the required genetic testing steps within their
laboratory
location. This invention aims to make cost effective, state-of the-art genetic
tests
available to smaller, less sophisticated laboratories, such as those found in
hospitals
and physicians' offices.
SUMMARY OF THE INVENTION
To bring sophisticated genetic testing to locations previously thought to be
unsuited to support such services, the invention divides the various steps in
genetic
tests into those performed at the site near where the sample is collected, and
those
related to where the test is interpreted. A telemedicine model is employed, so
that
the test results are transmitted to a central location where the testing
expertise
resides.
Specifically, the invention involves systems and methods to simplify and
improve the genetic testing process to permit the secure and effective testing
of
genetic source material to occur at different locations from the analysis of
the
results and the preparation of interpretive genetic testing reports thereby
permitting
such tests to be performed by more clinical laboratories. The invention also
involves the gathering of additional information on the patient as well as
systems
and methods to use such information in conjunction with the genetic testing
results
to provide more thorough and useful physician and patient results and
feedback.
The invention may be embodied as a controlled system of computerized
hardware, software, communications links, genetic and medical expertise and
quality control to ensure test and report accuracy, quality and patient
privacy. This
could include systems and methods which employ networked, computerized
equipment for all or part of the processes of specimen procurement and nucleic
acid purification; genetic chemistry; data collection; data verification; data
transmission; interpretation of data; and reporting results of the
interpretation. The
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particular selection of network hardware or software is not critical to the
scope of
the invention, except as specifically described below.
One aspect of the invention is a specially designed genetic testing kit
(including an improvement of existing kits) that can accommodate a variety of
specimen procurement types and includes components for both the nucleic acid
extraction and the gene chemistry required for genetic testing. In a preferred
embodiment, the nucleic acid extraction is enhanced to increase the likelihood
of a
high quantity of input DNA sample from only a minimal sample specimen. In .
another preferred embodiment, the nucleic acid extraction instructions are
enhanced
to perform the assay based on the use of a rapid extraction method. In yet
another
preferred embodiment, the kit simplifies the (PCR or non-PCR) genetic
chemistry
steps of the genetic testing protocol through better controls of the assay and
simplification of the operation of the protocol. On manner of accomplishing
this
result is selection of equipment and configuration of the assay (e.g.,
arrangement of
stacking racks and other kit elements) to make following the instructions
easier. In
another preferred embodiment, the kit improves upon the non-PCR genetic
chemistry technology by implementing one or more of the following: (i)
configuring the assembly of the various reagent mixes; (ii) prealiquoting the
controls into the respective wells for the user; and (iii) improving the
controls by
basing the controls on the use of genomic DNA.
Another aspect of the invention is a genetic test data gathering process and
system that can, either automatically or initiated by a remote site or central
location,
gather from a remote site database all relevant genetic data generated through
genetic chemistry, such as both PCR genetic data and/or non-PCR genetic data.
Another aspect of the invention is a genetic test data gathering process or
system that, based on the genetic test requested and other relevant factors,
determines patient and other relevant information to gather or request
regarding the
patient. Such data could include, but not be limited to: patient billing
information;
other patient genetic data; standard medical record data; physical
characterizations
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of the patient's state of health, past laboratory test, physical exam or
specialized
studies; commentary from qualified medical professionals and other information
relevant to the patient's family history and genealogy; information regarding
the
patient's environmental context (e.g., where they live, environmental
effectors such
as hazardous material exposures and climatic factors); and any other
information
that, when correlated with the genotype data, improve the process of genomic
testing as compared to consideration of such data in isolation. In a preferred
embodiment, the process or system can (automatically or as initiated by the
remote
site or central location) gather or parse from any remote site database all
relevant
genetic data from whatever other genetic technology data that are available
(e.g.,
photographic or digital images data from colorimetric, fluorometric,
radioisotopic
or other evoked biomolecular signal outputs). In another preferred embodiment,
the
process or system can (either automatically or as initiated by the remote site
or
central location) automatically gather or parse relevant patient data from the
remote
site databases to the extent such information is available. In another
preferred
embodiment, the process or system makes requests from the test requester
(e.g.,
physician) and/or the relevant patient data, in the form of system generated
written
consent forms, a form filled out on the Internet, or an email to the testing
facility, or
any other equivalent data gathering technique. In another preferred
embodiment, the
process or system may gather the raw or unprocessed relevant patient data when
other necessary elements of data are ready to be transmitted.
Another aspect of the invention is a genetic test data verification subprocess
or subsystem that determines the suitability of the genetic testing
information
gathered by the genetic test data gathering process or system. For example,
this may
involve determination if other relevant patient data gathered by the genetic
test data
gathering process or system is adequate, complete and otherwise ready for
transmission. In another example, the system or process may generate a report
at a
remote site location that explains any data errors or inconsistencies and
recommendations for corrections, if the relevant patient data gathered by the
genetic
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test data gathering process or system is not adequate, complete and otherwise
ready
for transmission.
Another aspect of the invention is a data transmission preparation
subprocess or subsystem that prepares for electronic transmission of some or
all
relevant patient data that has been verified by the genetic test data
verification
process or system. In one preferred embodiment, prior to transmission, all
information identifying the patient is masked and/or encrypted to prevent
patient
identification. In another preferred embodiment, prior to transmission, the
subsystem or subprocess separates all data gathered into a plurality of two
files. For
example, one file could contain non-confidential information identifying the
patient
and another file could contain other confidential information but not patient
identifying information. One or both of these files could be encrypted by the
system. In another preferred embodiment, prior to transmission, all data
gathered is
simply encrypted without substantial further modification.
Another aspect of the invention is a data transmission subprocess or
subsystem that transmits all data gathered to a central location. The data
transmission may be initiated by the remote location or by the central
location. In
either case, separate files generated and/or encrypted as described above may
be
transmitted at different times and/or in different communication channels
(e.g., one
or mole virtual private networks) could be employed for separate files). It is
preferred but not required to assemble data into batches for fast and
efficient
transmission to the central location.
Another aspect of the invention is, at a central location, an interpretation
process or system that receives patient information electronically and
performs an
initial validation of the information. For example, a preliminary genetic
testing
diagnosis may be performed for review and validation by a qualified health
professional. It is preferred that, following preliminary genetic testing
diagnosis, the
interpretation process or system will then include automatic review and
analysis of
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the genetic test results (in combination with all other relevant patient
information),
including review and validation by a qualified health professional.
In another preferred embodiment, an expert system generates natural
language explanations regarding particular genetic tests. These explanations
may be
used for various purposes, including (without limitation): imparting the
appropriate
clinical application and significance of such tests; providing answers to
specific
queries about the use of such tests; and providing formal, context-specific
interpretation of results of such tests when they have been applied to
individuals.
A preferred (but not required) embodiment of the expert system comprises
one or more of the following components:
a) An expert database containing up-to-date knowledge about
relevant genetic conditions. This subjects of such knowledge could be:
abnormalities arising from the human body's expression of certain genetic
patterns; the underlying mechanism that causes such expression; the impact
of human states such as genotype, gender and age on the likelihood and
degree of expression of these abnormalities; the impact of medications,
treatments, diets, and life choices on the likelihood and degree of expression
of these abnormalities; recommended adjustments to standard care practices
deemed or believed advisable due to such expression; recommended general
health practices for those with the potential for expressing such
abnormalities; recommendations for further testing to more completely
characterize any genetic explanation for an abnormality; and health-related
recommendations for relatives of individuals with known genotypes.
b) An interface to an electronic system that has access to
requests for explanations about genetic tests, abnormalities expressed by
genetic abnormalities, and the effect of life states, practices, and choices
on
the likely expression of these abnormalities.
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c) An interface to an electronic system that contains
demographic information and specific state information regarding
individuals being tested for genetic abnormalities and their resulting
genotype determined by this testing.
d) A data storage subsystem that temporarily holds information
that has been passed to the interfaces described above, and makes it
available to the control mechanism described below.
e) A control mechanism that inspects the contents of the data
storage subsystem and, based on the contents, assembles appropriate data
from the expert database into a coherent explanation or interpretation.
f) A display and/or reporting output module for rendering the
output of the database so that is viewable or made part of a printable report.
In one preferred embodiment, the expert database is divided into logical
compartments that correspond to relevant elements of a genetic testing
ontology for
each particular genetic test. In another preferred embodiment, the information
stored in one or more logical compartments includes variable components that
can
be rendered or not rendered as output, depending on state information
pertaining to
the subject being tested, and under the control of the control mechanism
described
above. In another preferred embodiment, the expert database allows a content
expert (such as a genetic counselor) to add information to one or more of the
compartments and thus make such information available for inclusion in
explanations and interpretations, without the need of additional intervention
by
computer programming personnel.
Another aspect of the invention is a reporting subprocess or subsystem that,
following the interpretation of testing, automatically generates a report of
the
interpretive genetic test results in medical terms. It is preferred but not
required to
additionally include a comprehensive report containing the interpretive
genetic test
results that states in medical and/or genetic terms the result of the analytic
test, and
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further comprises a comment section that may contain at least some of a
statement
that recognizes the patients contextual information and what impact if any the
genotype for the disease being tested has on this contextual data; a statement
concerning disease risk, the modification of that risk given the genotype
result, and
the contextual data (given that such a risk modification is known); and a
statement
of the implications that may exist for therapy or prognosis. In a preferred
embodiment, information (including the reports described above) may be entered
into a database that may be accessed only at the remote testing site, using
any
electronic or other technique (e.g., password-type authorization, over the
Internet,
using direct dial-up, and so on). In another preferred embodiment, the central
location transmits the reports to the remote location (or the patient) either
by hard
copy or electronic document transmission techniques (e.g., email with or
without
document attachments).
Another aspect of the invention is a consolidated test kit for gene based
testing. The consolidated test kit aids laboratories in ° the
performance of the
technical aspects of a genetic test by providing convenience, ease of use and
improvements in the quality of the genetic test results. The kit may be used
by itself
or as part of an integrated genetic testing system that includes Internet
based
consultation and reporting. The integration of the respective materials and
reagents,
as well as with improvements in the testing procedure into a consolidated kit,
enables performance of these specialized laboratory tests in a majority of
clinical
laboratory settings. A simplified process of specimen procurement, nucleic
acid
purification, genetic chemistry and other steps leading up to the
interpretation of the
test to a point where no specialized training or unique laboratory skills are
required,
collectively provide the to perform these tests at a much larger number of
laboratories, and hence at places closer to the point of care. This will
improve both
the availability of these healthcare 'services and their cost effectiveness.
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BRIEF DESCRIPTION OF THE DRAWINGS
The accompanying drawings show a particular embodiment of the
invention as an example, and are not intended to limit the scope of the
invention.
For example, while the invention is shown and described in schematic terms,
many
aspects of the invention may be performed by computer hardware or software in
any
combination.
Figure 1 is a schematic diagram of one embodiment of the invention.
Figure 2 is a schematic diagram of an operational scheme for genetic testing
in accordance with the invention.
Figure 3 is a schematic diagram of a genetic test kit.
Figure 4 is a schematic diagram of a portion of a genetic test kit.
Figure 5 is a schematic diagram of a portion of a genetic test kit.
Figure 6 is a schematic diagram of a portion of a genetic test kit.
Figure 7 is a schematic diagram of a portion of a genetic test kit.
Figure 8 is a schematic diagram of a portion of a genetic test kit.
Figure 9 is a schematic diagram of a portion of a genetic test kit.
Figure 10 is a schematic diagram of a portion of a genetic test kit.
Figure 11 is a schematic representation of a screen shot of an embodiment
of the invention.
Figure 12 is a schematic diagram of one aspect of the invention.
Figure 13 is a schematic representation of a screen shot of an embodiment
of the invention.
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Figure 14 is a schematic diagram of one aspect of the invention.
Figure 15 is a schematic representation of a screen shot of an embodiment
of the invention.
Figure 16 is a schematic representation of a screen shot of an embodiment
of the invention.
Figure 17 is a schematic representation of a screen shot of an embodiment
of the invention.
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DETAILED DESCRIPTION
Figure 1 is a schematic view of one preferred embodiment of the invention.
In general functional terms, the system comprises eight major components:
specimen procurement; nucleic acid purification; genetic chemistry; data
collection;
raw data detection and verification; transmission; interpretation; and
reporting. The
system may comprise discrete sub-systems, each dedicated to a single
functional
component, or a fully integrated system. Similarly, any or all of the
individual
components may be integrated into sub-systems. Thus, the following description
should not necessarily be understood to define any physical or functional
separation
of the components, except as specifically described and required.
In general terms, Figure 1 shows a remote genetic testing system 100,
comprising a clinical laboratory-based genetic testing system 200, a data
collection
system 300, a data transmission system 400, a computer network (shown by way
of
example only as the Internet) 500, a central data analysis/interpretation
system 600,
an expert database 650 and report data 700. Shown schematically as lightning
bolts
are conventional networking hardware and software as required to connect the
various components of remote genetic testing system 100 together, according to
known techniques not relevant to the scope of the invention.
T'he remote clinical laboratory-based genetic testing system 200
schematically comprises several subsystems, specifically specimen procurement
subsystem 210, nucleic acid purification subsystem 220, genetic chemistry
subsystem 230, and analytic technology subsystem 240. These are described in
more detail below.
Figure 2 schematically shows the genetic testing operational scheme of the
invention and how the invention provides a local laboratory with the
capabilities to
perform genetic tests. In general terms, this involves the processes of
nucleic acid
extraction, gene chemistry and analysis of the test result. These steps are
illustrated
as separate and distinct because the invention improves upon this situation in
that
the collective steps can be reduced to a kit.
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Figure 3 illustrates one embodiment of the genetic test kit. In general terms,
the kits includes are the reagents and materials necessary to execute the
technical
aspects of a genetic test from a single protocol. As illustrated in Figures 3-
10, one
version of the genetic test kit includes the extraction rack and reagent
elements for
DNA extraction, the reaction rack including the components of the gene
chemistry
Invader in a newly organized presentation to make simpler the process of
assembling the reaction components, the reaction plate and template guide and
the
corresponding replacement disposable plastic supplies. The last component of
the
test kit is the protocol book that describes each of the steps in the
technical aspects
of the test, as well as for the initiation and completion of the data
transmission steps
of the system.
Figure 12 is a schematic of the overall architecture of the telemedicine
process of the invention. The process of data collection from the analytic
instrument
occurs first at the computer of the remote site 400. Data is transmitted
through the
Internet via a process that is both secure and involves data that is encoded
or
dispersed in such as way as to render the patient information de-identified,
410. The
transmitted analytic and patient specific demographic data is encrypted (e.g.,
128-
bit encryption or as otherwise desired) and unencrypted at the system firewall
420
and is collected at the central computer 430 which in turn provides the prompt
to
the persons interpreting the transmitted results to work on those data files.
A
qualified health care professional 440 interprets the data with the aid of the
expert
database 450. The completed test result is transmitted back to the site where
the test
was performed and printed or in some way distributed electronically to the
requestors of the tests 460.
The expert system database 650 used in the interpretation of the genetic
tests consists of electronic platform such as a software data processing
program
with large amounts of abstracted medical information pertaining to aspects of
genetic test interpretation. This may include subjects as the application of
these tests
to medical conditions, risk assessment, other contributing genes and
therapeutic
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options for the medical condition. The initiation of a specific test and the
subsequent transmission of that data registers as a need to sort the database,
so that
the interpreter is presented with only a subset of the interpreted options.
The system
provides the preferred combination of comments in an assembled natural
language
paragraph. Such a selection of the comment for a given analytic test result is
driven
from a priori knowledge provided through the Internet by the remote testing
lab.
The creation of the semi-automated test interpretation is confirmed, rejected
or
modified by the interposed physician test interpreter.
Figures 15-17 show possible reports created consequent to the transmission
of the test data.
Specimen Procurement
°The specimens to be tested shall be obtained from the patient in an
environment most convenient to the patient, such as a hospital or physician's
office.
The invention may include the provision of a kit, which may use existing
technologies, along with all the necessary instructions and controls, to allow
laboratory technicians to expertly obtain specimen samples necessary for the
relevant genetic test to be performed.
Nucleic Acid Purification
Isolation of genetic materials) suitable for sensitive diagnostic tests
requires DNA and RNA that has been separated (purified) from their cellular
context and other contaminants contained in the blood, cells, tissue or body
fluid
samples. Ideally, such processes are performed in a clinical laboratory in or
near the
clinic in which procurement of the sample from the patient occurs.
Any convenient nucleic acid purification method is suitable for use with the
invention, but a preferred method is provided by Gentra Systems, Inc. of
Minneapolis, Minnesota. Alternative nucleic acid extraction systems or
methods,
such as those commercialized by Qiagen N.V., Xtrana, Inc., and others are also
equivalent, as are those that perform similar results but have not yet been
developed
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or commercialized. Specific details of the Gentra Systems, Inc. technology is
described in relevant portions of the following documents (the entire contents
of
which are incorporated by reference), which are provided as an example of the
products and processes to be used at the on site DNA extraction stage of the
process:
~ US Patent 5,973,137 entitled "LOW PH RNA ISOLATION REAGENTS,
METHOD,.AND KIT"
~ International Patent Publication WO00066267A1 entitled "PREVENTING
CROSS-CONTAMINATION IN A MULTI-WELL PLATE"
~ International Patent Publication W000049557A2 entitled "COMPUTER-
M'LEMENTED NUCLEIC ACID ISOLATION METHOD AND
APPARATUS"
~ International Patent Publication W009938962A3 entitled
"COMPOSITIONS AND METHODS FOR USING A LYSING MATRIX
FOR ISOLATING DNA"
~ International Patent Publication W009939010A1 entitled "ELUTING
REAGENTS, METHODS AND KITS FOR ISOLATING DNA"
~ International Patent Publication W009913976A1 entitled
"APPARATUSES AND METHODS FOR ISOLATING NUCLEIC ACID"
The kit included with the invention may also include existing technologies,
along with all the necessary instructions and controls, to allow laboratory
technicians to expertly perform the nucleic acid purification from the
specimen
sample.
Genetic Chemistry
Doctors and patients benefit by having the genetic chemistry (manipulation
and amplification) portion of the genetic testing process performed on site
within a
clinical laboratory in or near the health care setting where the patient
sample is
collected and extracted (procured). On site sample procurement, extraction,
amplification or some other means of genetic manipulation reduces the risks
and
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costs associated with shipping samples to a remote location and enhances the
timeliness of the results.
Possible generic chemistry techniques suitable for use with the invention
include a variety of well-known, commercially available PCR (Polymerase Chain
Reaction) approaches, including: (a) those known by the tradename
LIGHTCYCLER from Roche Laboratories (b) those known by the tradename
LABMAP from Luminex Corporation; and (c) those known by the tradename
ESENSOR from Motorola, Inc. Other suitable approaches include the microarray
technology commercially available from a variety of sources, including the
system
known by the tradename INFiNITI from AutoGenomics, Inc.
In one embodiment the preferred gene chemistry strategy employs a non-
PCR approach which may be simpler for operators to use. The application of
this
gene chemistry to the invention involves the integration of the assembly of
the
reaction components, comprised of the sample control DNA admixed separately
with a master reagent into a microwell incubation plate all within the
confines of
the kit. Additionally, the system employs the use of the analytic instrument,
a
fluorometer, which carnes out the incubation as well as serves as the
interface with
the Internet based controlling software. The use of the this gene chemistry
includes,
but is not limited to the detection of genetic test data from a solution based
reaction
andlor a fluorescent reported on a solid support such as a microarray. In each
case,
the data created by this gene chemistry is entered into the system and
interpreted
after its transport through the Internet.
Other suitable non-PCR approaches are commercially available from Third
Wave Technologies, Inc. of Madison, Wisconsin USA under the tradename
INVADER~ and described in relevant portions of the following documents (the
entire contents of which are incorporated by reference):
~ United States Patent 6,214,545 entitled "POLYMORPHISM ANALYSIS
BY NUCLEIC ACID STRUCTURE PROBING"
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~ United States Patent 6,210,~~0 entitled "POLYMORPHISM ANALYSIS
BY NUCLEIC ACID STRUCTURE PROBING WITH STRUCTURE-
BRIDGING OLIGONUCLEOTIDES"
~ United States Patent 6,194,149 entitled, "TARGET-DEPENDENT
REACTIONS USING STRUCTURE-BRIDGING
OLIGONUCLEOTIDES"
In addition to allowing the laboratory technicians to expertly perform the
nucleic acid purification from the specimen sample, the kit provided as part
of the
invention also allows laboratory technicians to perform the genetic chemistry
steps
at their location.
Gathering of Additional Genetic Information
In addition to the typical genetic chemistry processes described above for
gene amplification or some other means of genetic manipulation, the invention
could also use any of a series of analytic technologies to create raw or non-
interpreted test data. These technologies may include agarose and
polyacrylamide
gel electrophoresis, capillary electrophoresis, fiberoptic sensor devices,
planar wave
guide sensing devices, DNA microarrays, micromechanical biosensors, non-array
based chip sensors, real-time fluorescence detectors, digital image capture,
fluorometers, and the like, all according to known principles.
It should be noted that the collection of components described above is only
one preferred embodiment of the invention. The full scope of the invention
includes
any integrated genetic testing system 200, including (without limitation) the
system
disclosed in US Patent 6,054,277 ~ entitled "INTEGRATED MICROCHIP
GENETIC TESTING SYSTEM," the entire contents of which is incorporated by
reference.
Integrated Kit
As illustrated in Figures 3-10, in a preferred aspect of the invention an
integrated genetic test kit is employed to organize and simplify the technical
and
operational aspect of the steps required to perform most molecular genetic
assays.
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In general terms, the primary components of such an embodiment are a
specialized
package that contains the reagents and the disposable materials to perform a
DNA
or RNA based test. These tests could include any of a series of localized gene
sequence alterations including detection of nucleotide substations through
mutation,
single nucleotide polymorphisms and small nucleotide deletions or insertions.
The
package may include a series of devices to house the various reagents used in
each
of the test procedures including (without limitation): devices for the
collection of
specialized specimens, materials for sample labeling, forms for test
requisition, and
specialized "racks" for guiding the procedure for nucleic acid extraction and
gene
chemistry.
The component nature of the test kit enables it to be assembled from a
variety of supplier sources and compiled at a single site before being shipped
to the
requesting laboratory, or it can be shipped directly to the performing lab and
quickly
assembled on-site, usually by fitting the respective components in their
designated
places in the kit box.
The kit may also include a detailed procedure manual that combines what
may otherwise be separate protocols into an integrated document. This
procedure
manual rnay employ specialized instructions to communicate a complex procedure
into a straightforward recipe that may be followed by relatively untrained
and/or
inexperienced personnel. The procedure manual may also include instructions on
accessing and using several electronic tools (such as those that may be
available on
a website) to simplify the process of making calculations for reagent volumes,
estimating time, and other aspects of the procedure. The procedure manual may
also
include forms for gathering patient specific information that will enhance the
value
of the interpretative genetic test report.
Another preferred embodiment concerns the manner of labeling elemental
components in the kit for the purpose of quality control and tracking of
reagent lot
numbers and outdates. The labeling, along with the design of the respective
racks
and materials, make possible the restocking of the kit through an
electronically
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registered supply chain monitoring system. The integration of the physical kit
with
the labeling of the elemental components and the linkage of said elements to
an
electronic supply and information management monitoring system is all intended
to
make for a higher quality test and the subsequent medical interpretation of
the test
results into a report for patient care.
The high quality of the data generated from the invention is intended to
enhance the interpretation of the genetic test data into a series of reports.
One
embodiment of the invention is where it is used as part of a more
comprehensive
genetic testing system, where the invention facilitates the extraction of the
sample-
derived nucleic acid and the gene chemistry steps as well as the presentation
of the
results through a fluorometer interfaced with a computer and connected to the
Internet. The invention can be used with a fluorometer or similar bioanalytic
instrument that generates results analyzed locally, i.e. on-site , or as part
of an
integrated genetic testing system that includes transmission of various types
of data
to a remote computer and database, where a qualified healthcare professional
provides the expert interpretation and composition of the various reports.
Through
that same system, namely a secured Internet portal, the invention is used to
monitor
quality control of the test results being produced, to track inventory of the
kit
elements, and access to essential information such as material safety data,
storage
and outdating of the reagents. In this regard is it possible, but not
required, for the
kit to contain an attached or embedded device to record and store information
about
components of the kit. For example, in one possible embodiment an EPROM or
similar data recording device may collect sensory information about the
storage and
or transport condition of the kit during assembly, shipment or storage, and
such
information may be incorporated into the operation of the invention.
Preferred embodiments of the invention comprise a test kit box, made of
paper or plastic, that has exterior labeling of the genetic test kit. The
interior of the
kit box includes a series of compartments to contain each of, but not limited
to, the
following test kit components. First, there is a compartment, such as a
rectangular
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space, to contain a variety of disposable materials used in the processing of
sample,
extracted DNA and in the set up of the gene chemistry. Typical materials would
include, but not be limited to: boxes of disposable pipet tips, transfer
pipets; and a ,
supply of additional microcentrifuge tubes. The number of prepackaged
materials
supplied is proportionate to the intended number of tests in each kit. The kit
boxes
are configurable for convenient sizes of batches of individual tests, but
typically are
in sizes of 24, 48 and 60 tests.
The inside cover of the kit box may have a movable flap of material, which
when deployed serves as a shelf onto which the procedure manual is supported.
The
flap of material may be fastened to the inside cover in a number of ways, but
include a flap attached by means of hook and loop fastener or reusable
adhesive, or
it may precut to enable it to be clipped or simply punched out of the cover
material.
A second compartment in the kit box contains a variable series of
specialized racks. In one embodiment, there are two separate racks, one for
the
operational steps of nucleic acid extraction, and one for the assembly of the
gene
chemistry reactions. The racks are constructed from any material (such as
paper or
plastic or equivalent) and in their most basic form are comprised of a
rectangular
support with holes on one face into which are placed tubes to hold the
samples) at
the various steps of their processing. The design of the racks is such that
they can be
used within the space of the larger kit box, or removed and used as a separate
element. The sizes of the holes is significant in the design to hold specific
types of
tubes, i.e., glass vacuum tubes for blood collection, microcentrifuge tubes
for
sample processing, etc. The placement of the holes is significant to the use
of a
multichannel pipeting instrument, such that the center-to-center distance
between
holes corresponds to the same between two adjacent pipet tips. The distance
between adjacent holes in this dimension is related to the distance between
adjacent
rows of holes in a second dimension. This inter-row distance is a design
feature to
permit the snap tops of the tubes not to overlap and to make easier the
removal of
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individual tubes from the rack. Other features of the general design are
described in
the specific racks that are part of the invention.
Another specific component is a rack designed to simplify the operational
steps in extracting DNA from a sample of blood by means of a technique
referred to
a capture matrix columns. The basic design of the rack places a series of
tubes in
vertically oriented rows with the intent of processing individual samples
horizontally across rows. Each row has holes containing the series of tubes
for the
capture matrix column extraction procedure, where each row is intended for a
separate step in the technical procedure. The rack can be modified to
accommodate
various manufacturers' extraction systems. One preferred embodiment is that
designed for the extraction system of Gentra Systems, Inc. known by the
tradename
GENERATION CAPTURE COLUMN SYSTEM. In this case, the first row, left
side of the rack, which may be labeled as "Patient Samples," holds a set of 8
standard adult size vacuum blood tubes. The second row is designated for the
column tubes of the extraction system and is labeled as "Buffy Coat." A third
row
also contains a set of extraction system column tubes and is labeled as
"Wash." A
fourth row contains another set of tubes and is labeled as "Elution and Wash."
A
fifth and final row contains a set of standard 1.5 mL microcentrifuge tubes
and is
labeled as "Elution and DNA." As described above, both the spacing between the
rows of tubes and between the individual tube holes within each row is set to
simplify the processing of specimens in a left to right orientation according
to the
instructions in the protocol book. At the top of the rack are two additional
holes to
place the respective "Wash" and "Elution" solutions that are added to the
tubes in
the respective rows.
Another component is a mixing rack. One embodiment of the mixing rack
is a rectangular cardboard box of appropriate dimensions, with holes punched
into
the top face in a pattern that serves to fulfill the functions listed below.
Another
embodiment is a printed face-plate, made of paper, plastic or other printable
material that overlies an insulated or non-insulated plastic or paper rack
with either
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a matrix of correctly spaced and sized holes or with only the specific holes
needed
for the function of the device.
This rack is designed to simplify the operational steps in preparation of the
master mixes) and control DNA samples that that are essential reagents in the
preferred non-PCR approach commercially available from Third Wave
Technologies, Inc. of Madison, Wisconsin USA under the tradename INVADER.
The basic design of the mixing rack places a sequence of the reagents that
comprise
the master mix in a series, where each sequential reagent tube, and the
appropriate
volume of reagent from that tube is added to the last tube in that series
which is
labeled as and comprises the master mix for that particular batch of tests.
Each of
the master mix series of tubes is oriented horizontally across the rack, where
each of
the tubes in that series has a color-coded cap. The color-coding of the caps
corresponds to the coloring coding and labeling on the rack. In one example,
there
are 5 reagents that make up the master mix. These reagents are placed in the 5
tubes
labeled 1,2,3,4,5. With the calculated volumes of each reagent needed to
perform a
batch of tests, the assembly of the batch's master mix will involve first the
addition
of reagent 1 (tube 1) to the master mix tube. Second, the volume of reagent 2
(tube
2) is added to the master mix tube; then 3 (tube 3) into the master mix tube;
then 4
and 5 in the same manner. The process of adding each sequential reagent to a
single
master mix tube is made simpler by using color-coded labels on the rack itself
and
on the tops of tubes with graded shading of a single color. It is preferred
that the
series of holes that hold the reagents to be combined into a common reagent
are
labeled with colors in a graduated pattern of shading. Thus, the combination
of all
lighter or darker colors are ultimately added to the lightest or darkest
colored
labeled in the series.
In a similar manner, the orientation of the DNA control tubes and the
placement of these controls in the rack correspond to the sequential addition
of
these reagents to the reaction plate in a similar orientation, and with
spacing
between those control tubes in the rack to accommodate the center-to-center
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distance between adjacent tips on a multichannel pipeting device. The design
of the
mixing rack, considering the placement of the respective tubes, the labeling
of those
tubes and their orientation within the rack as a stand alone device or in the
context
of the complete kit relates to a simple operational procedure in the kit
procedure
manual discussed in more detail below. Additionally, the determination of the
appropriate volumes of reagent that are required for a particular batch of
master mix
for a performance of a batch of genetic tests is also linked to a web based
program.
A third component of the genetic test kit is the reaction plate. The reaction
plate is the point where the DNA samples, extracted as described above, and
the
single test volume of the preferred INVADER master mix, as assembled in the
mixing rack, as well as other optional added materials comprise the set of
individual test reactions for a given genetic test or, when multiplexed
together,
multiple genetic tests. °The combination of the various volumes of the
sample and
reagents into specific reaction wells in the reaction plate can be difficult
because it
requires the pipeting of small volumes from the various sized tubes used in
DNA
extraction and INVADER master mix into very small and particularly positioned
wells manually or with automated, but handheld, pipeting devices.
To this end, the invention may also includes a device in the form of a planar
sheet of paper, plastic or similar material containing a series of small holes
that
correspond to the underlying holes in the reaction plate, into which
individual and
specific reaction component samples and controls are added.
In one embodiment, a mylar laminated paper card of dimension C x D is
labeled on one side with the numbers and lettering corresponding to one type
of
reaction, such as the gene chemistry reaction for the wild type or normal
genetic
allele of a particular genetic marker. The opposite side is labeled for the
mutant or
alternative genetic allele for the same genetic marker. Therefore, to perform
the
desired gene chemistry reaction for a specific allele, the operator merely
selects the
appropriate side of the guide and positions that side face-up against one
particular
edge of the underlying reaction plate. The holes in the guide then permit the
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alignment of the wells for the placement of each of the respective samples for
that
reaction. When the opposite side of the guide is used, the holes then align to
the
wells designated for the alternative reactions. In this device, the operator
is aided in
avoiding the placement of the wrong sample or reactant into the wrong reaction
well.
Another component of the invention is the procedure manual that describes
and illustrates each calculated and manual operation involved in the
performance
for a specific genetic test beginning with sample procurement and continuing
through the final step of how to activate the web portal for transmission of
the
results for analysis of the genetic reactions. The procedure manual is
designed to
make simpler the performance of the complete, as well as individual,
operations
required for the genetic test. The manual integrates the disparate required
operations
of different vendors' commercial products into a single document. The manual
permits the skilled but occasional operator of these genetic tests, to achieve
analytic
results from the genetic testing system comparable to those obtained by an
expert
operator of these genetic tests.
Within the design of the complete kit, the manual may be fastened by any
convenient method to the inside cover of the kit box. The kit and manual are
designed so the book may be used either on a support on the inside cover or as
an
independent stand up display of the book, using the included paper base that
holds
the two covers in a triangular prop for a bench or table top use.
There will in general be various versions of the manual based on the
specific genetic test to be performed and the commercial products used. The
organization of each version follows a format whereby each step in the
procedure is
detailed on a single page, typically on the left side of the two page open
book
format. Each operational step also presents a single or multiplexed
illustration on
the opposing page. One feature of the manual is the procedure guide bar. The
procedure guide bar consists of a complete listing of the operational steps
across the
top of the opposing two page format with an illustration of a slide bar or
forward
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pointing set of arrows that guide the user as to what are the sequential steps
in the
complete protocol, along with the details of one operational step, for each
two page
format. The particular step that is detailed on that set of pages is
highlighted in the
procedure guide bar, using the illustrative technique of magnifying the text
at that
position on the guide bar with a larger or bolder font.
As illustrated in Figure 11, in addition to the detailed instructions for the
test protocol, the manual may also describe the use of web-based tools that
may
complement the specific test protocol. These include a siilgle web page
display
listing the respective volumes of each of the reagents that make up required
mixes.
'The invention includes programming of the web page so that the operator needs
to
enter only the number of test samples intended for a particular batch run of
the
procedure. The program calculates the volumes of each reagent needed to
assemble
the master mix.
As illustrated in Figure 13, another web-based tool is a tabular display of
data fields containing information about a patient, their medical history,
pertinent
information about the genetic history and other unique demographics that aid
in the
interpretation of the genetic data created in the process of testing. This
aspect of the
invention makes simpler the process of entering patient demographic data,
essential
to the accuracy of diagnostic testing. This may be linked to a reference
genetic
database. In one embodiment, information entered into selected data fields
will lead
to a triggering of a sorting and selection function of reference information
from the
genetic database.
An additional component of the kit is an order pad, a convenient and simple
tool by which clinicians and patients can provide information that will be
subsequently entered into the web-based tools. One embodiment of this part of
the
invention is the listing of questions pertinent to a selection of genetic
tests, which
provide essential demographic and medical data about the patient to be tested.
When information from the order pad is entered into the web-based tool, the
genetic
database is triggered. One additional feature of the order pad is fulfillment
of the
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requirement that each genetic test used for patient care be "ordered" by a
licensed
physician. The order pad provides a convenient means to meet this compliance
regulation.
Other interior space of the kit may be filled with an insulating material such
as cellulose, plastic or other material for the purpose of surrounding the
reagent
tubes and maintain a colder, normal or heated temperature.
Data Collection
After the raw or non-interpreted genetic data and any necessary
enhancements to increase clarity is generated, it is then gathered at the
remote
location in any convenient manner by data collection system 300. In addition
to
scientific clinical data, data collection system 300 also is preferably
supplied with or
gathers relevant demographic data about the patient. Based on the genetic test
performed, the data collection system 300 gathers from the remote location, to
the
extent available, patient demographic data that enhances interpretation of the
analytic data gathered at the remote site, analyzed in the central data
analysis/interpretation system 600, and/or reported in the form of report data
700.
The relevant demographic data about the patient report could consist of, but
is not
limited to, patient identifier, gender, age, clinical history, billing
information, and
other correlative information about the patient including written or numerical
identifiers, current and historic physical characterizations of the patient's
state of
health, past laboratory, physical exam or specialized studies and commentary
from
qualified medical professionals.
An aspect of this invention is that patient demographic data may be parsed,
extracted or in some manner derived from electronic databases at or associated
with
the site where the patient interface occurs or at the site where the technical
aspects
of the test is performed. This process of deriving patient demographic
information
may involve information systems outside the system.
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Additionally, patient demographic information may be entered into the
system by the physician, nurse or laboratory technologist based on the
responses
provided on the "Genetic Test Request Pad". The Genetic Test Request Pad is a
media to convenient transcribe information pertinent to the interpretation of
the
genetic tests into the system. The information collected varies for every
test, but
may include such facts as the date of birth, gender, listed medical
conditions,
responses to specific questions relevant to the particular test at hand, and
any
additional laboratory data that may precede the application of the genetic
test. For a
single or combination of tests offered, the genetic test request pad is
customized to
include questions and demographic data pertinent to the interpretation of that
selection of tests.
Within the system, the preferred embodiment for gathering demographic
data is a simple spreadsheet with fields that permit entry of the responses to
the
questions on the Genetic Test Request Pad. This may involve the entry of data
by
any suitable technique, such as voice command, typing, touch screen, or by
selection of electronic buttons or menus.
Demographic patient data may be used in any of the following ways. First,
the data may be used to create a test identification number that links a
certain
patient with their respective analytic results. Second, the selection of
demographic
data may be used to sort interpretative information in the expert database
650.
Third, the data may be used to organize the placement of samples on the
reaction
plate.
The preferred embodiment for the data collection system uses computer
networking techniques and systems to electronically gather data with as little
human
involvement as possible. The derivation of the analytic data involves the
creation of
a software interface to an analog data source through a connected computer
which
in tum is connected to a central server at a site distant to the remote
laboratory
through the Internet. Through this interface the system can address the remote
laboratory without the aid of operator actions. One embodiment of the
invention
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includes the warm-up of the fluorometer and the ability to address that
instrument
to determine if a reaction plate incubation is ongoing. This is achieved by
means of
a software derived "scout" that queries the instrument for a variety of its
functions.
The software permits the periodic cessation of the incubation and subsequent
read
of the reaction plate to determine if that operation is complete or
incomplete. The
software interprets the control in each reaction plate to determine if an
adequate
level of fluorescence signal has been created. If the reaction is complete,
then the
system prompts the interpreter to read the plate, otherwise the plate is
returned to
the incubation mode, and the process is repeated later in time. The software
is
designed to control of the assay operations such as control of heating
sources,
mechanical movement of the plate and or plate holder, mechanical agitation of
reactions and the operation of the readout functions of the machine. The
interface
also allows us to acquire and process the numeric results after a batch of
tests are
read.
The capabilities to determine what information to gather and how such
information is gathered by the data collection system 300 is an important
embodiment of the invention.
Verification of the Genetic Testing Data
In addition to gathering data at the remote location, depending on the
preferences and capabilities of the remote location, the data collection
system 300
may also include the capability to provide mathematical representations and/or
transformations of raw and other data, for quality control or other purposes,
prior to
transmission to the central location. Specifically, the data collection system
300
may automatically perform a preliminary review of the data gathered to
determine
the existence of information necessary for the central location to complete
the
genetic test and generate useful reports and other feedback. If such review
determines insufficient or inconsistent data has been collected, the data
collection
system 300 generates a report for the remote location user identifying such
issues
along with recommendations to correct the problem. In addition to being
located at
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the data collection system 300, such capabilities could also be provided in
central
data analysis/interpretation system 600.
The invention may include verification of the completion of the amplified
genetic testing data produced on-site, with transmission of such data and
specific
patient demographic information through a proprietary hardware and software
system to a central pool of experts in diagnosis and genetics. This enhances
the
quality and the value of the test results and information provided for both
the doctor
and the patient. One possible embodiment of this aspect of the system
comprises
the generation of an e-mail or voicemail prompt to the designated expert
informing
them that test results are available for review. This prompt may be
automatically
generated when a batch of test reactions is completely received from one of
the
connected remote sites. Another optional embodiment comprises directing the
test
data to one of any number of designated expert interpreters, each of whom
would be
prompted to read the test results assigned to them.
Preparation of the Genetic Testing Data for Transmission
After gathering and verifying the genetic testing data, the data collection
system 300 prepares the genetic testing data for transmission to the central
data
analysis/interpretation system 600 for interpretations and reports. Depending
on
1) preferences or capabilities of the remote location, 2) the type of genetic
testing
data to be transmitted, and 3) the transmission system to be used, the
preparation of
the genetic testing data by the data collection system 300 for transmission
could
take alternative forms.
One alternative is for the data collection system 300 to mask all patient-
identifying information that could be used to identify the patient, which is
contrary
to desired or mandated privacy requirements, from other data related to the
genetic
test of the patient. Under this alternative, information transmitted to the
central data
analysis/interpretation system 600 does not include any information that could
identify the patient. When interpretations and reports (described below) are
returned
from central data analysis/interpretation system 600, the data collection
system 300
2~
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at the remote location could then correlate the data identifying a patient
data with
the test result at the remote site. In this manner, no genetic testing or
demographic
data positively linked to a named patient ever leaves the local clinical
laboratory.
This arrangement greatly increases the private nature of the entire remote
genetic
testing procedure.
Another alternative is for the data collection system 300 to separate the data
into two separate files that can be transmitted separated. One of the files
can include
information on the patient that is not generally viewed as confidential, such
as the
patient's name, address, job, age sex, weight and third party payer
information,
while the other file can include patient data that is confidential such as
genetic
testing data and medical history. The file containing the confidential
information
does not include any information that identifies the patient. After the data
is
separated, the two files of information can be transmitted separately,
including the
transmission of information through different transmission modalities and at
different times. Upon receipt of the two files, the central data
analysis/interpretation
system 600 can then correlate the two files to perform the required
interpretations
and analysis necessary to generate the reports (described below). Under this
alternative, the central data analysis/interpretation system 600 has all of
the
pertinent information on the patient, yet no genetic testing or other
confidential data
on a patient that could identify the patient is ever transmitted.
Another alternative is for the data collection system 300 to encrypt, using
any convenient encryption technology, any portion of the information to be
transmitted. The encrypted transmission is deciphered by the
analysis/interpretation
system 600 upon receipt.
Any or all of these data preparation alternatives may be used in any desired
combination to ensure the safe, secure and confidential transmission of the
genetic
testing data and other information from the remote location to the
analysis/interpretation system 600.
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Transmission of the Genetic Testing Data
The raw and non-interpreted, and possibly encrypted, data is then
transmitted, either automatically or initiated by an operator, to a central
data
analysis/interpretation system 600, which may be in a location different from
the
clinical laboratory that performs the testing processes described above. This
transmission may be accomplished using any convenient data transmission
scheme.
In a preferred embodiment, a remote, secure Internet portal 400 is provided
and
accessed from the clinic location. In another preferred embodiment,
conventional
application service provider architecture is used by the central data
analysis/interpretation system 600 to service an application 400 running on
the
clinic data collection system 300.
Regardless of the data transmission scheme chosen, the functions of this
component of the system include the distinct capture of the raw and non-
interpreted
analytic data and the pertinent patient demographic data. 'The transmission,
processing interpretation and report of these data, including the maintenance
of
each type of data in a secured and confidential form is an important
embodiment of
the invention. Figure 12 shows one embodiment of the invention, in which
genetic
testing information is transmitted over the Internet as a non-limiting example
of a
computer network.
Data Interpretation
Medical and genetic experts resident at a central location read and interpret
the genetic data transmitted from the remote locations and determine the
genetic
profile of the patient. In addition, the demographic information on the
patient
provided with the genetic data greatly enhances the ability of the medical and
genetic experts resident at a central location to provide additional useful
advice in
the reports to clinical professional (physician) and the patient as discussed
below.
Once the data has been interpreted, a series of reports 700 are generated and
securely transmitted back to the source clinic. While any secondary data
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transmission scheme may be used, the preferred approach is to use the same
data
transmission scheme as used to transmit the data from the source clinical
laboratory
to the central data interpretation facility, i.e., a two-way communications
scheme.
Typical contents of the reports include the analytic measurements of the
genetic tests themselves; insurance reimbursement data (e.g., recommended CPT
coding for the procedures that have been performed); and genetic counseling.
In a
preferred embodiment, both a technical report directed to the clinical
professional
(physician), arid a separate non-technical report directed to the patient, are
included.
The system may identify technical problems in the performance of the test
steps
done at the remote location that require added samples or steps to ensure a
quality
test result. Such problems may then be identified to a remote location so that
corrective actions may be taken.
Another aspect of the invention is the manner is which additional
information derived from the medical and scientific literature is incorporated
into
the construction of customized interpretations and comments. The expert
interpreter
of these tests relies in whole or in part on an integral expert system
database, which
contains large amounts of prewritten information pertaining to various
clinical and
pathologic aspects of the condition being tested. The expert system is part of
the
invention and is described in detail below.
The expert system is integral to the genetic testing system. In general terms,
the expert system is a electronic database constructed from one or more of a
variety
of commercially available software products. The database is derived from the
manual and automated review of the medical and scientific literature made
available from the variety of the public and subscription based information
search
sources. The database collates information from the various sources based on
prescribed key words that a are specific the disease, test and clinical
condition. The
database sort is modified according to the results obtained from a particular
patients
test, and in combination with the provided demographic information. Hence the
expert system contains information in excess of what is needed for any one
patient
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sample, and uses the specific results, transmitted from the remote lab to
initiate a
sort of pertinent references and comments which in turn is presented to the
expert
interpreter.
The expert system integrates with other aspects of the system at the points
involving the sorting of patient demographic and analytic data. The interface
involves the initiation of a primary sort of pertinent comments based on the
specific
analytic result from one patient. The primary sorting derives, from a large
data set, a
subset of information such as risk and therapeutic options that is based on
the
specific gene test results. When provided, the demographic data, including
information such as gender, age, medications and pre-existing medical
conditions,
initiates subsequent sorts of the database. The subsequent sorts further
reduce the
set of selected comments and references to those pertinent to all of the
provided
demographic and analytic data conditions. The result is a markedly reduced set
of
prewritten interpretations and comments that the expert can then use in the
creation
of the customized genetic test report.
The expert system 650, which is a subsystem to the complete system,
contains entries from the medical literature derived from public and
commercial
sources (such as Medline, PubMed, Compendex, GeneBank, www.genetest.com
and www.webmd.com). From searches performed within these sources, the expert
system abstracts selected information about a particular disease or genetic
condition. The expert system involves the assignment of various categories of
the
derived data that are used in the sort function. Such categories include, but
are not
limited to disease association with a particular genetic result, risk
calculations about
a diseases given a certain demographic or analytic test result, and options
for
therapy.
32
