Note: Descriptions are shown in the official language in which they were submitted.
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METHOD AND SYSTEM FOR SAMPLE TESTING
Cross-reference to Related Applications
[0001] This is a continuation-in-part application of International Application
No.
PCT/CA2005/000567, filed April 15, 2004, which claims priority from U.S.
Provisional
Application No. 60/562,851 and U.S. Provisional Application No. 60/648,225,
each of which is
incorporated herein by reference in its entirety.
Field of the Invention
[0002] The invention relates generally to the field of task management. In
particular, the
invention relates to an integrated system and method for orchestrating the
testing of samples.
Background of the Invention
[00031 Testing of samples, especially chemical testing for screening compounds
that satisfy
certain properties, often requires a large number of tests. Often, a large
number of samples are
involved. Each sample may require several tests or assays to be conducted
thereon. Test
results in one test sometimes may determine whether.subsequent tests will be
required. For
example, as is often the case, only a small number of screened compounds can
meet the
selection criteria. Current laboratory processes are not ideally suited for
such screening
processes. Some of these reasons are as follows:
[0004] 1) Large number of assays: Typically the screening process requires a
number of
assays to be run on candidate compounds, to test for various properties.
[0005] 2) Time consuming assays/tests: Many assays such as liquid
chromatography mass
spectrometer etc. typically require extensive time for processing samples and
acquiring data
and are therefore rate limiting steps.
[00061 3) Data Qualit: The results from the tests need to be of high quality
in order to
allow for well-informed decisions. The analytical confidence in prior art
methods may be low
because of discontinuous steps in experimentation, and because data was
obtained by different
groups.
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[00071 4) Cqpital Intensive Equipment: The equipment necessary to perform
certain assays
is very capital intensive. Many large organizations have numerous labs in one
or more
locations. As such, the requirement for multiple equipment or instrumentation
further increases
these costs.
[0008] In addition to the above issues, it is known to run the various assays
in parallel as
opposed to a serial manner. In the serial approach, the assays are linked
successively with a
pre-set selection criteria. Thus, a particular test will be conducted if a
prior test result provides
an acceptable result. The parallel approach comprises running multiple assays
simultaneously.
Although the latter approach may save time, it results in additional expense
since tests are
conducted on various compounds that may have been withdrawn from consideration
for other
reasons (i.e. due to failure of another assay etc.).
[0009] The foregoing creates challenges and constraints for a method and
system for
screening drugs. It is an object of the present invention to mitigate or
obviate at least one of the
above mentioned disadvantages.
Summary of Invention
=' '' '[001'01' The invention provides a system and method for testing samples
and, in one- 6 I
embodiment, a system for directing and coordinating the operations of hardware
components
and performance of tasks of laboratory personnel. The system includes a user
interface for
receiving requests from one or more users. Each request comprises a list of
one or more
samples to be tested and specifies one or more tests to be conducted on each
sample. The
system also includes a sample preparation station for maintaining a library of
all received
samples and creating a sublibrary of samples based on the test(s) to be
conducted. The system
directs hardware components and laboratory personnel (collectively, laboratory
resources) to
conduct the requested tests and reports test results to the user(s) who have
requested the test(s).
[0011] Optionally, the user can specify, in the request, a test strategy to
conduct tests in
parallel, in series, or a combination thereof. The test strategy can also
include branching
conditions to specify the parameters for promoting a sample on to subsequent
tests or which
subsequent tests to conduct depending on the results of prior tests. The
system may generate an
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order for conducting the tests based on the test strategy and/or branching
conditions specified
and direct laboratory resou.rces to conduct each requested test following the
order generated.
[0012] In another feature, the system permits dynamic preparation of
sublibraries. For
example, upon completion of a given test on a given sample, the system may
direct the sample
preparation station to create a further sublibrary, including such sample, for
a subsequent test.
In this way, sublibraries are created including only those samples that are
promoted for further
testing. In one aspect, the creation of the further sublibrary can be started
as soon as one
sample from the previous sublibrary is ready to be promoted. In this way,
sublibraries can be
generated dynamically in response to test results of individual samples
without waiting for all
samples or a sublibrary to be tested.
[0013] In other aspects the invention provides various combinations and
subsets of the
aspects described above.
,,:. . ..
Brief Descrintion of Drawin2s
[0014] For the purposes of description, but not of limitation, the foregoing
and otlidr' ~
aspects of the invention are explained in greater detail with reference to the
accompapying
drawings,'in~which:
[0015] Figure 1 shows schematically major components of an orchestrated
laboratory
system and their organization within the system;
[0016] Figure 2 illustrates schematically a reformatter for use in the
orchestrated laboratory
system shown in Figure 1;
[0017] Figure 3 shows schematically an assay station for use in the
orchestrated laboratory
system shown in Figure 1;
[0018] Figure 4 provides an overview of a software system, i.e., the software
portion of the
system of Figure 1;
[0019] Figure 5 shows an exemplary screen display that a user of the system of
Figure 1
can use to define a screening process;
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[0020] Figure 5A shows another exemplary screen display that a user of the
system of
Figure 1 can use to define a screening process;
[0021] Figure 6 illustrates a orchestrated testing environment supported by
the system
shown in Figure 1;
[0022] Figure 7 shows schematically a laboratory workflow employed in the
system shown
in Figure 1;
[0023] Figure 8 illustrates a test strategy that runs a combination of
parallel and serial tests;
[0024] Figure 9 shows an exemplary screen display for a user to confirm or
modify a
decision whether to promote a compound for conducting another test;
[0025] Figure 10 is a flow chart of an orchestrated laboratory process that is
implemented
by the system shown in Figure 4;
[0026] Figure 11A is an exemplary screen display that provides detailed status
and.
summary infornlation related to a user request;
[0027] Figure 11B is an exemplary 'screen display showing more detailed
informat2bn when
a user selects an actuatable area of the screen shown in Figure 11A;
[0028] Figure 12 shows an exemplary testing time allocation followed by the
software
system shown in Figure 4;
[00291 Figure 13A illustrates schematically a process of performing an assay
in the
orchestrated testing environment shown in Figure 6; and
[0030] Figure 13B shows steps of the process of Figure 13A in a flowchart
format.
Detailed Description of the Invention
[0031] The description which follows and the embodiments described therein are
provided
by way of illustration of an example, or examples, of particular embodiments
of the principles
of the present invention. These examples are provided for the purposes of
explanation, and not
limitation, of those principles and of the invention. In the description which
follows, like parts
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are marked throughout the specification and the drawings with the same
respective reference
numerals.
[0032] In one aspect, the present invention relates to a system and method for
the
orchestration of testing samples. Although the example of chemical or drug
testing is used to
illustrate the invention, it will be understood that the invention is not
limited to such application
and may be equally used for any other purposes such as stress testing or
nondestructive testing
of finished products in a quality control procedure. In general, the invention
can be adapted to
coordinate or orchestrate any testing protocol.
[0033] In the embodiment of the invention described herein, examples of
chemical testing
are provided wherein chemical samples are deposited tested using conunonly
known microtitre
plates. Such plates are transported to the test or assay station, which
includes the required
equipment, apparatus or personnel for conducting the desired test or assay.
Figure 1 shows
schematically, the architecture of an orchestrated laboratory system 100,
including a number of,,i
hardware co,rnponents. Each hardware component may have its own automation
software. =:3
Conceptually,'orche =strated laboratory system 100 may be considered to
consist of ha'rdware; ! t i
. . , ' f .:.;' . .. . ) ~ , = , . = =I" =
laboratory personnel, automation software and communication components and all
infrastructure, equipfnent, software, etc. required to operate such
components. The operation of
these components, including the performance of tasks by laboratory personnel
are orchestrated
by a central process integration server.
[0034] Figure 1 shows hardware components 102, software components 104 and
Communication components 106 of system 100. The hardware components 102
provides
hardware resources such as workstations for performing the various experiment
processes
required by the system. The coordination of operations and processes between
the hardware
components is provided by software components 104, which may also coordinate
execution of
laboratory functions. Laboratory personnel may interact with the software and
the hardware
components to provide, where necessary, the operational support and equipment
management.
The communication components 106 coordinate information flow and processing of
data,
including, for example, data processing, storage and retrieval, as well as
user communication.
The hardware components may have multiple basic units, each of which can be
combined for
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parallelization of processes, utilizing a common container/carrier for the
samples. The modular
design of system 100 permits the addition of further hardware components as
necessary or
desirable, or substituting of existing components.
[0035] By way of example, Figure 1 shows three hardware components. However,
as
explained above, the system 100 is not restricted to these three hardware
components. In fact,
the hardware, although shown and conceptually divided into different
components, may all be
enclosed in one enclosure and may share physical platforms or spaces when
conducting
experiments or performing sample preparation or analysis. The hardware
components shown
in Figure 1 may, for example, include a sample preparation station such as a
reformatter 108 for
preparing samples for each requested assay, an assay station 110 for
conducting assays and
collecting data obtained from such assays, and an analyzer station 112 for
analyzing samples
and collecting data from such analysis.
[0036] The communication components include a data processing module 114 for,
processingand analyzing data obtaiiied from the various tests and coordinating
the flowt.of data.
through the system as will. be described in greater detail below: The user
communication
subsystem ~ 116 provides services allowing a user to interact with the system.
Users of the :;=,
system may be scientists, laboratory technicians, facility staff or other
department or institution
personnel. In general, a user may be anyone that interfaces with the system to
conduct tests on
samples or access test data. This will assume that the users have any required
security
clearances to access the system. The user communication subsystem 116 may also
include a
display termina1118 for providing system status information, such as
availability of hardware
resources, status of experiments, test results or other relevant information
to a user. The system
may also include an administration workstation 120, allowing a user to
interact with the system,
so that the user may, for example, control the operation of the system, the
workflow executed
by the system, or monitor the progress of various experiments performed by the
hardware
resources. In addition, the system may also provide remote access to a user in
the fornl of an
information portal 122. The information portal 122 provides the remote display
of a user
interface that provides a user with status and other information and allows a
user to access the
system using the user's own computer resources. User's own computer resources
may include
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a computer workstation, a terminal, or a handheld computer, among others,
which may or may
not have the same operating system used by the user communication subsystem
116.
[0037] The software components 104 include a process integration server 124,
which
coordinates and orchestrates the operation of laboratory resources including
hardware
components and/or laboratory personnel. The software components may also
include various
instrument automation components. For each hardware component, there can be
provided a
corresponding software component for the automation and control thereof. There
can also be a
corresponding data acquisition module for each of the hardware components for
acquiring data
for the test conducted and coordinating the data flow.
[0038] As will be described below, the software components 104 also may
include a
scheduler (not shown in Figure 1) that determines an order to run each of the
experiments
according to test plans or criteria provided by users.
[0039] Geiierally, when requesting testing of a sample, the user provides the
sample to a
laboratory, 'for'conducting~plarined tests. Samples provided by users are
maintained in a sample
library. Sublibraries of samples are then p'repared, based on the teststo be
conducted. That is,~;
one or more saiYiples onwhich a giveii test is to be condueted are.grouped
into a sublibrary. Inu
a preferred embodiment, each sublibrary may comprise samples on one or more
microtitre
plates as known in the art. The wells of such plates contain a volume of the
desired samples.
As will be appreciated by persons skilled in the art, microtitre plates are
designed with an array
of wells (each adapted to receive a small volume of sample). In the result,
the location of each
sample on the plate can be specifically assigned, or mapped, to a particular
well. This
facilitates the traclcing of a sample as it passes through required testing
steps. This is further
described below.
[0040] Figure 2 illustrates schematically a reformatter 108 that stores the
sample library
and creates any needed sublibraries. Typically, a reformatter 108 includes
robotic control and
automation devices, liquid handling devices, sample storage unit and sample
processing unit.
These main components provide the necessary functions of sample preparation
and processing,
namely, preparation and processing of samples for experiments from a pool of
samples, such as
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a sample library, and creation of a sublibrary ("reformatting"), including
plate replication,
dilutions, additions, sealing and labeling, among others.
[0041] The reformatter 108 shown in,Figure 2 may be provided with a controlled
environment space, such as a refrigerated incubator or a refrigerated storage
126, for storing
samples. Robotic plate handling devices, such as robot arm 128, facilitate
automated plate
handling, and in particular, provide the capability of moving automatically a
sample plate from
refrigerated storage 126 to different locations, such as a lid park (not
shown) for de-lidding, or
a deck or plate platform 130 of liquid handler 132 for further liquid
handling. Liquid handler
132 enables the system to replicate these plates when needed. Liquid handler
132 in general
automates liquid handling such as reagent addition, dilution, transfer and
dispensing.
[0042] The plates used in the system are uniquely identified so that the
location and status
of each plates can be determined, preferably in real time. To accomplish this,
each plate may
be provided with an identification device such as a bar code label or RF
(radio frequency) chip
etc. Various other devices will be known too. In conjunction with such
identification devices.
The various stations of the system (including,-reformatter etc.) may include a
reader to read the
, .,. . , ,
identification device and to identify, the plates. ; Such readers can also be
connected to thei
process integration server so that the location and/or status of each plate
can be tracked and
monitored. As mentioned above, each sample well on a plate can be specifically
mapped.
Thus, by tracking each plate, specific information concerning such sample
maybe tracked.
[0043] Figure 3 shows schematically an assay station 110. In general, assay
station 110
may be a multifunctional workcell that is capable of conducting one or more
experiments. The
assay station 110 may preferably include one or more movers 134 to relocate
microtitre plates
to different instruments/stations 136 within the cell. Movers 134 may comprise
robotic devices
to minimize human intervention. An assay station 110 may have its own liquid
handlers (not
shown) to supplenient the needs of, for exanlple, reagent dilution, transfer
and dispensing while
experiments are conducted within the unit. The assay station preferably also
may include plate
identification means (such as the readers mentioned above). The assay station
110 may also
have other laboratory process accessories, such as components for maintaining
temperature of
the samples or for providing agitation of sample plate holders etc.
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[0044] Assay station 110 is preferably enclosed for safety, reliability and
protection from
the external environment. Figure 3 shows an example of an enclosure shell 138,
with
transparent windows 140 for easy monitoring. Assay station 110 is designed to
have a
minimized footprint by maximizing the utilizable space. Preferably, assay
station 110 is self-
contained and small enough to be easily relocated.
[0045] An analyzer station 112 may be provided for analyzing the test results
and
collecting experimental data. For example, analyzer station 112 may be a high
throughput
liquid chromatography mass spectrometry (LC-MS) workstation. Such a
workstation enables
its users to automatically analyze a large number of microtitre plate samples
at high speed with
LC-MS technology. Samples from microtitre plates may be injected at random
into an LC-MS
at high speeds. Instruments such as an automated incubator (controlled
environment) can also
be used to supply these plates at random with high speed to an auto-sampler
(not shown) that
will inject samples into an LC-MS workstation. A data acquisition unit (not
shown) connected
to analyzer station 112 captures data generated by, analyzer station 112, such
as a high
throughput LC-MS workstation, and transmits the captured data to process
integration server
124 for further processing.
[0046] Figure 4 provides an overview of a software system 400, i.e., the
automation
software portion and IT software portion of the system 100 in more detail. The
software
system 400 provides the control and integration of the operation of hardware
components and
the testing processes utilizing these hardware components. Among other things,
the software
system 400 coordinates and manages laboratory workflow, directs laboratory
resources to
initiate assays requested by researchers, tracks and manages data to
facilitate monitoring of
workflows, receives and processes user requests and reports to users upon
completion of
requested testing. Necessary data processing capability and user control as
well as means for
communication between a user and the system 400, and between the hardware
components and
the software system 400, are also provided.
[0047] The software system 400 has a number of components to provide its
functionality.
The process integration server 124 provides the function of orchestration.
Other components
may include network messaging module 402, data warehouse 404, information
services module
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406, process scheduler 408, instrument cell subsystem 410 for each of the
reformatter 108,
assay station 110 and analyzer station 112, decision module 420, workflow
interface subsystem
422 and analytics module 424.
[0048] In general, messages are generated and exchanged for establishing
communication
between and among the process integration server 124 and various data
processing and logic
process units. For example, the network messaging module 402 exchanges
messages with
various hardware subsystems to control start, stop, operations of the
hardware, data collection,
and to monitor hardware subsystems. The network messaging module 402 also
exchanges
messages with user communication subsystem 116 for receiving inputs from and
communicating output to users. These messages may be in the form of any
network messages
conforming to a suitable protocol or protocols, such as web service messages
in http (hypertext
transfer protocol) format, or electronic control signals if a hardware unit is
directly controllable
by software system 400.
[0049] Data warehouse 404 is a data depository: Data warehouse 404 may consist
of one
database or several integrated databases, stored on'one' storage medium, or
several different
storage media, or any suitable storage or memoiy means: Data warehouse 404
stores data as
acquired from each workcell during experiments or upon completion of
experiments. A
complete audit trail of each experiment may be collected at each hardware unit
and archived in
data warehouse 404. Such audit data may include, for example, the location of
a sample and
the time the sample stayed at that location, the test conditions of an
experiment conducted on a
sample at a workstation, status information of a hardware unit when conducting
an experiment,
among others. Processed data, i.e., data generated from a data analysis
operation on raw data,
are also stored in data warehouse 404. For easy storage and retrieval as well
as for access
control, the database may be a secure SQL database. A laboratory information
management
system (LIMS) may also be provided with the database to provide further
integration and
unification of data acquired in any given screening campaign or in multiple
screening
campaigns. Alternatively, there may be provided an interface for exchanging
data with an
external LIMS.
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[0050] Information services module 406 is a subsystem that provides software
services
allowing the communication between users and the system 400. Users of the
orchestrated
laboratory system 100 and the software system 400 may include researchers,
scientists,
laboratory personnel, facility staff and facility managers. Information
services module 406 is
responsible for providing a user interface, such as a graphical user
interface, to allow users to
communicate with the system. The user interface may be accessible remotely, no
matter where
a user is located. Such user interfaces may be provided, for example, by Web-
browser-based
software applications, software applications resident on either a fixed or
wireless mobile
networked computing device, or a display terminal directly controlled by
information services
module 406. Input can be entered by a user through the user interface.
Information services
module 406 can request data from data warehouse 404 and present the data in a
suitable format
for user review. Status information, such as progress of experiments, can be
sent to users as
system messages or may be communicated to users on display terminal 118 or
information
portal 122. Information services module 406 may further distinguish the types
of data and their
respective intended user and present the data differently so as to tailor the
portal presentation
specific to users' particular roles within a laboratory. F.or example,
information regarding
status of various instruments, including assays being run on instruments or
workstations, may
be delivered to users by network messaging module 402 on information portal
122, without any
restriction. On the other hand, test plans and modifications thereof may be
delivered to
scientists in a trusted fashion, requiring user authentication.
[0051] Figure 5 shows one example of a data entry form produced by information
services
module 406. This data entry form may be presented to a user as a web page
formatted on a
display terminal 118. This way, a user can access the system any time and from
any location.
The data entry form can be used by a user, such as a researcher, to define a
job request, in this
case, a compound screening campaign. A user starts by providing a list of
compounds to be
tested. The user also identifies the tests to be conducted on each sample.
Each assay is
associated with specific experimental procedures, which may be either provided
by the user or
established by the testing facility. Figure 5 shows a series of assays to be
run in a screening
campaign. As will be appreciated, a screening campaign serves to identify
compounds that
possess certain pre-selected properties. A test acceptance criteria, or hurdle
property, is
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assigned to, or associated with each assay. Through the data entry form, the
user can associate
with each assay a single test acceptance criteria, a number of test acceptance
criteria, or an
acceptable range or ranges, for determining whether the compound passes or
fails the assay.
The user may pick the order in which each assay is run, for example, in order
of priority.
Alternatively, the user may specify interdependencies of the assays, in which
case, the software
system 400 determines a sequence to run the assays. The user may also specify
a condition to
terminate the testing process, for example, when one of the assays fails.
These criteria are
entered into the system and saved to data warehouse 404 as a test plan.
[0052] The entry form 500 shown in Figure 5 allows a user to define a series
of assays that
need to be run in sequence. Appropriate hurdle rates for each assay can be
selected. In this
example, six selectable assay entry cells 502 are provided (with the first
three being labeled).
A user can select, for example, from a drop-down list 504 in each assay entry
cell a desired
assay or manually enter an assay to be conducted. A test acceptance criteria
is selected or
entered in the acceptance criteria box 506. After, test acceptance criteria
for the desired number
of assays are entered, the user can request the system 400 to schedule the
screening campaign
by pressing a"Start the Campaign" button 508, or using other suitable means.
Process
integration server 124 uses the information provided by the user in this user
request to schedule
and coordinate the tests or assays on each of the compounds as requested by
the user.
[0053] Although Figure 5 shows only test acceptance criteria as "hurdles",
test acceptance
criteria may also be a range or ranges. Figure 5A shows another exemplary
screen display that
allows a user to submit ajob request. The user requests three assays to be
performed on a list of
compounds specified in a compound list data file 510. Instead of a single
"hurdle", a user can
specify an acceptance range 512 for each assay. If the test result of a
compound falls within the
specified range, the compound passes the test. Otherwise, the compound fails.
[0054] Through similar user interfaces, a user can also define or specify a
test strategy for
testing the compounds specified. This can be achieved through specifying
interdependencies of
the assays to be conducted. For example, the user can specify a sequence or
order to perform the
assays, as shown in Figures 5 and 5A. One assay is conducted only after the
completion of prior
assays in the sequence. The user can also explicitly specify that these assays
are all to be
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conducted in parallel or request parallel testing by specifying that the
assays are all independent of
each other. A test strategy can include any combinations of serial or parallel
testing. The user can
also specify a branching relationship between assays, i.e., wherein the test
result of an assay
determines the subsequent assay(s) to be performed on a compound. For example,
the user may
specify that one subsequent assay is to be performed only if the result of the
current assay is within
a particular range and another subsequent assay will be performed instead if
the result of the
current assay is outside the range. The user, of course, can also define a
test strategy that includes
a hierarchy or decision tree, combining parallel, serial and branching
decisions. An example of a
test strategy is shown in Figure 8, which will be described later.
[0055] Referring to an embodiment of the invention as shown in Figure 4,
corresponding to
each hardware unit, such as reformatter 108, assay station 110, and analyzer
station 112, there
is an instrument cell subsystem 410. The hardware instrument cell and its
software instrument
cell subsystem together constitute a laboratory instrument subsystem. Each
laboratory
instrument subsystem may operate independently at the instrument level,
controlled by its own
automation software subsystem. These laboratory instrument subsystems
communicate with
the process integration server 124 through the network messaging module 402 so
that
information at each laboratory instrument subsystem, such as instrument
status, test conditions,
test results, sample information, can be communicated or transmitted to the
integration server
124 and any instructions from the process integration server 124 to any of the
laboratory
instrument subsystems can be similarly transmitted.
[0056] The software portion, namely, instrument cell subsystem 410, controls
and monitors
the operation of the corresponding hardware unit and is responsible for the
automated
operation, or "walk-away" operation, of each hardware unit. An experiment is
set up by
supplying the required samples and the requisite instructions on experimental
procedures to be
carried out. This allows instructions to be sent to the required laboratory
resource to start a test
procedure. Once a procedure is started, the instrument cell subsystem 410 is
responsible for
directing the corresponding hardware instrument to carry out the steps without
human
intervention.
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[0057] Acquisition of experiment data can be automated. A hardware instrument
may be
provided with its own dedicated detection units and data acquisition software.
The software
application may be executing on a processor physically located in the vicinity
of the hardware
unit, or may be executing on a processor remote from the hardware unit, such
as a central
computer located in a control room. The hardware unit may also be serviced by
a generic
software application that is designed for servicing all hardware units
operated by a laboratory.
Instrument cell subsystem 410 may also be responsible for capturing data from
the experiment
or samples, if the hardware instrument is not equipped with its data
acquisition software.
[0058] Figure 4 shows the details of one embodiment of an instrument cell
subsystem 410
for a reformatter, namely the reformatter subsystem 412. The reformatter
subsystem 412 has a
robotic control module 414 for controlling at least one of the robotic device,
such as a robot
arm 128, a liquid handling module 416 for controlling the liquid handling
devices, namely
liquid handler 132, and a laboratory process module 418 for performing
laboratory processes,
such as controlling sample temperature or labeling and sealing sample
containers. Where an
identification means, such as a bar code reader, is provided; laboratory
process module 418 is
also responsible for "checking in" and "checking out" sample plates and
thereby enabling the
system 100 to track the movement of each of the sample plates within the
system.
[0059] Instrument cell subsystems for other instrument cells may have a
similar structure,
although it will be appreciated that the function of each instrument cell
subsystem will vary.
For other types of workcells, other software modules may be required. For
example, for an
analyzer station 112, there will be a data acquisition module. If the analyzer
station 112 has its
own dedicated data acquisition software application, the data acquisition
module will only be
responsible for interfacing the dedicated data acquisition software
application with process
integration server 124; otherwise, the data acquisition module will also be
responsible for
interacting with data acquisition devices of the analyzer station 112 to
capture data and transmit
the captured data to integration server 124.
[0060] Process scheduler 408 is a software service subsystem that applies
laboratory
experiment rules to the construction of a laboratory workflow strategy. A
scientist or
researcher submits a user request to the system 400 through a user interface
provided by the
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system 400. The user request generally includes a test plan, which includes a
list of one or
more samples to be tested as well as an indication of one or more assays or
analyses (i.e., tests)
to be conducted on each sample. The test plan may also include a test
strategy. The user can
specify a test strategy to conduct tests in parallel, in serial, or in a
combination thereof.
Branching conditions can also be specified. The scheduler 408 analyzes the
test plan and
determines an order of running all assays in the specified set of assays. An
example of a test
strategy is provided in Figure 8, as will be described in detail later.
[0061] Alternatively, test strategy may be implicitly specified through
interdependencies
and priorities of the assays. For example, for a process screening for
desirable pharmaceutical
components, it may be desirable to run all toxic assays first. Any compound
that fails a toxic
assay may be rejected immediately. The process scheduler 408 may schedule to
run all toxic
assays in parallel and as the first step in a series of tests.
[0062] Running one assay may require a series of steps such as reformatting
samples,
conducting experiments on the samples, and analyzing experimental results to
cap'ture data+.,
Laboratory resources required for each step of an assay as well as time
required are generally
known in advance. This information may be stored in a memory means accessible
to.scheduler
408 or in a permanent storage device, such as a hard disk. Based on the assays
requested by a
user, the scheduler 408 may also develop a list of required instrument units,
as well as the
required laboratory personnel, for performing the tests.
{0063] Decision module 420 is a software service subsystem that examines
information
obtained from laboratory instrument subsystems, by way of their software
service components
or instrument cell subsystem 410 provided by process integration server 124.
Decision module
420 applies heuristics to the determination of adjustments to subsequent
laboratory process
flows orchestrated with the process integration server 124.
[0064] For example, a user can specify a test acceptance criteria, or "hurdle
property", for
"promoting" a sample to the next scheduled assay. Failing a single test
acceptance criteria may
eliminate a compound immediately, without the need of continuing with other
assays. Other
heuristic methods can be used, such as passing control samples (such as test
markers or
"canaries") through to subsequent tests, or basing the hurdle rate on the
capacity of the
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downstream devices. A test acceptance criteria may also be cumulative in that
only after failing
a number of similar hurdle properties will the compound be eliminated. The
decision module
420 can make the decision automatically to determine whether to permit the
compound to
proceed (or, to be "promoted") to the next assay. This allows the automatic
running of all
assays once the samples are provided to the system 100. Alternatively, the
researcher can
choose to be advised on the status of each test so that a decision can be made
on the hurdle
property while the results are being reported (as described further below).
[0065] Workflow interface subsystem 422 is a subsystem that provides software
services
allowing laboratory personnel and research scientists to interact with the
system, monitor the
process of each experiment, monitor the status of the laboratory instruments,
and initiate,
modify or execute laboratory processes. To the extent that some elements of
the orchestrated
laboratory flow process are performed by laboratory personnel, and not
laboratory instrument
subsystems, inherent in such a configuration is the communication with such
personnel by the
orchestration components and the process integration server, during the course
of initiating,
adjusting, and executing the laboratory process. The communication may be in
the forrn-of e-
inail messages, notification messages on a computer display, status indication
displayed in a
message window, an audio message or any other suitable form.
[0066] Once an assay is completed for a compound, the decision module 420 of
the
software system 400 makes a decision as to whether the compound should be
promoted. A
message is then sent to the laboratory resources scheduled for the next step.
The next step may
be further compound detection, other experiments, or sample preparation, for
example. If the
hardware resource for the next step is completely automated, the message may
be in the form
of a control signal to conunence operation of the hardware unit. If the
hardware resource for
the next step is not completely automated, the message may be an e-mail
message sent to a
laboratory technician or a test facility staff responsible for the hardware
unit so that that person
may take the necessary steps to commence the operation of the hardware unit to
start the next
step. In case where the compound is not promoted, there may not be any further
steps to be
perfonned on the compound. This lielps to reduce the number of unnecessary
testing and
thereby speed up the screening process.
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[00671 Results analysis module 424 provides the necessary data analysis
services and is
part of the data processing module 114. Data generated by hardware units and
acquired by
their associated data acquisition software applications are analyzed by the
results analysis
nlodule 424. Results analysis module 424 typically has a statistics component
for extracting
statistical information from raw data. It may also have graphing components
for visually
presenting data. Data may be analyzed as the experiment is being conducted,
for example, by
periodically polling the hardware instrument for new data, or upon completion
of the
experiment. Results analysis module 424 may also process data in real-time and
provide feed-
back to the hardware unit for optimizing compound detection and data
acquisition. For
example, results analysis module 424 may analyze data streams from a LC-MS
workstation,
locate signal peaks, and provide feed-back to the LC-MS workstation so the
detection
parameters may be optimized in real-time. Results analysis module 424 may be
custom
prograinmed for those specific experiments conducted in a laboratory, or may
be adapted from
commercially available data analysis soflware. Results analysis module 424 may
also make. . :..
experiment results available to users, laboratory personnel, or othters for
viewing and process:
decision-making.
[0068] In another embodiment, orchestration software system 400 interconnects
~experiment .
instruments to support an orchestrated testing environment 600 as illustrated
in Figure 6.
Central to this environment is interchange hub 602, or discovery bus, which
comprises an
interchange over which all the elements of orchestrated testing environment
600 interrelate and
which helps create a communication envirorunent in which people, hardware
instrumentation
and software applications interact. The bus is logical or conceptual, rather
than a physical bus
such as a computer's bus or a telecommunication network. For example, in an
orchestrated
laboratory system, the bus may represent LANs and protocols, with which
computer systems
communicate. The bus may also represent messaging to and from laboratory
personnel. In
general, messages are sent to interchange hub 602 for the intended recipient
to piclc up and act
upon. The bus is a link within the orchestrated testing environment 600 that
allows each
elements of the environment to communicate with other elements.
[0069] Each self-contained, automated laboratory instrument, such as the
reformatter, work
cell tc., constitutes an individual laboratory service process. Laboratory
instruments 604
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interacts with each other and other elements in the orchestrated testing
environment 600
through interchange hub 602. For example, laboratory personnel 606 interact
with process
integration server 124 through interchange hub 602 in the form of e-mail
messages and data
entry forms. Network messaging module 402 enables the initiation and
completion of test
procedures conducted by workcells, such as sample transfer 608, sample
preparation and
testing 610 and sample analysis 612. Communication may be in the form of web
messages
delivered to interchange hub 602, which messages are then processed by process
integration
server 124 and delivered to their respective destinations for further
processing. A web portal
614 (or a display terminal, not shown in Figure 6) is attached to interchange
hub 602 for
allowing a user, laboratory personnel, or others to monitor the progress of
experiments. A user
may also use web portal 614 to access the system to control the progress of
the experiments,
such as to pass or fail a compound for a particular assay, or series of assays
based on results
received from the system.
[0070] Orchestration software system 400 interconnects the individual
laboratory
instruments to provide an integrated laboratory environment 600. The
laboratory process flow
is determined aiid adjusted by the process integration server 124 according to
data received
from individual laboratory instrument systems. These data are obtained as
these systems
perform their assigned test procedures following the process flow.
[0071] The environment 600 may be supported by custom software. Conveniently,
commercially available software also may be used, with only necessary custom
programming
to integrate the commercially available software. For example, BizTalkTM
commercially
available from Microsoft Corporation may be used to perform some of the
fi.inctions required
by process integration server 124 or workflow interface subsystem 422.
[0072) Figure 7 provides an example of a laboratory worlcflow. Here, a
laboratory
workflow refers to the flow of samples and data through the orchestrated
laboratory system 100
as well as human interaction with the samples and data. The workflow 700 shown
in Figure 7
may include, for example, the steps of sending and receiving an assay request
702, identifying a
compound 704, commencing an assay 706, capturing data 708, returning assay
results 710,
assigning assay results 712, and saving assay results 714.
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[0073] At the step of sending and receiving assay request 702, a laboratory
staff member,
for example, starts the workflow by sending an operation request. The request
may also be sent
automatically by the system. For example, when samples are delivered to a
workcell, such as
an LC-MS workstation for purity assay, upon checking in of the samples using a
barcode
reader, an XML form is sent from the LC-MS workstation and received by process
integration
server 124. The process integration server 124 uses the message to identify
the compound to
be tested at the step of identifying compound 704 and the assay requested in
order to schedule
and instruct the appropriate workcell for performing the assay. At the step of
commencing
assay 706, a message (for example, in XML format) is sent to an appropriate
hardware unit,
such as assay station 110 to commence the requested assay. Data is captured
during the
performance of the assay at the step of capturing data 708 where possible.
Certain data may
only be collected upon completion of experiment. When all data are collected,
assay results are
returned from the hardware units to process integration server at a step of
returning assay
results 710. The returned assay results are assigned to the compound, namely
associated with
the compound, at the assigning assay results 712 step. The assay results,
associated with the
compound, are next stored in data warehouse 404 for later retrieval or further
processing. Once
such a generic workflow is defined, it may be repeatedly executed by the
hardware and
software components of the orchestrated laboratory system 100.
[0074] Referring to Figure 8, running assays in a combination of parallel and
serial steps is
described using the exemplary process shown. A total of five assays are shown.
In this
example, successful completion of first assay 802 determines whether to run
the rest of the
assays. The next group, second, third and fourth assays 804, are independent
of each other and
therefore are run in parallel. Running assays in parallel helps to maximize
utilization of
hardware resources such as workcells and instruments and reduce their idle
time. Upon
completion of second, third and fourth assays 804, results of each assay are
evaluated to
determine whether to promote all or only some of the samples. At decision
point 806, such
decision may be made by the system or by a user. Only the samples that pass
all the assays,
namely first assay 802 at the first serial step and second, third and fourth
assays 804 at the
parallel step, will be "promoted" to the next serial step i.e., advance to the
next step for the fifth
assay 808. If a compound is not to be advanced as determined by the system,
preferably, the
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system sends a message to the user and requests the user to review the
decision. The user can
either confirm or override the decision.
[0075] Figure 9 shows an exemplary screen display 900 from which the user may
enter or
modify a decision as to whether to pass a compound for a purity assay. The
exemplary screen
display 900 shows the purity results for a number of compounds. Each compound
sample has a
designated compound serial number so the system can track and store results of
each assay on
each compound sample. The test acceptance criteria, i.e., test cut-off, in
this case is set at 80%.
From exemplary screen display 900, it can be seen that several compounds have
passed the
assay, as indicated by a checked checkbox 902 shown next to the corresponding
serial number.
Others have unchecked checkbox 904, indicating that the compounds failed the
assay. The
system 400 makes the initial decision whether a compound passes an assay based
on the test
acceptance criteria associated with the assay. A compound having the checkbox
checked
passes and will advance to the next assay. A compound having its checkbox
unchecked may
not advance to the next assay. If the'test plan specifies that a compound will
be eliminated
immediately upon failing the assay, the unchecked compound will be eliminated
from all
subsequent assays. If the test plan specifies that a compound will be
eliminated if it fails
certain number of assays or a set of specified assays, the decision module 420
will determine
whether the compound has failed the pre-determined number of assays or all of
the assays in
the specified set and decide whether to eliminate the compound from further
screening.
However, preferably, the system 400 sends a notification message to a user and
requests the
user to review and confirm the system decision. The user may access the system
through
information portal 122, for example. A web page that is shown in Figure 9 can
be provided.
The user may uncheck a checked checkbox 902 or check an unchecked checkbox 904
to
override the system decision. After a user is satisfied which compounds should
pass or fail the
assay, the user press the confirmation button 906 labeled "Send CutOff
Approval" to confirm
the system decision or to commit the changes just made.
[0076] In operation, a user submits a user request for running a number of
assays on a list
of compounds to the system 100 through a user interface. Optionally, the
scheduler 408
analyzes the user request to generate an order to run these assays on each of
the compounds.
Upon confirmation or notification that compound samples are arrived at the
laboratory,
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instructions are sent to the reformatter 108 to reformat plates, namely, to
create a sublibrary
from the library of samples, for conducting the first assay. The status of the
laboratory
resources and each sample as well as the data generated from the tests are
monitored and
stored. At the completion of each assay conducted on each sample, the decision
module 420
may compare test results with a test acceptance criterion, if one is supplied
by the user. If the
test results are within acceptable range as compared with the test acceptance
criterion, the
compound being tested is to be "promoted", i.e., to be further tested. If so,
instructions are sent
to reformatter to reformat the compound for the next assay. Otherwise, a
message may be sent
to the user so the user can determine whether the compound is to be to
promoted. These steps
are repeated until all compounds specified in the user requests are tested.
[0077] Referring to Figure 10, there is shown a diagram in flowchart format an
orchestrated
laboratory process 1000. This represents a process for screening compounds
from a list of
compounds. This process implements dynamic scheduling. Instead of scheduling
all assays in
advance, this process schedules each assay only.as necessary, namely only if
the assay is to be
conducted on the compound, depending on' results of prior assays requested by
the user.
[0078] The process has the following steps: obtaining test plan 1002,
obtaining samples
1004, initiating sample preparation 1006, initiating experiment procedures
1008, data
acquisition 1010, performing data analysis 1012, optionally presenting test
results 1014 to a
user of the system, deciding compounds promotion 1016, making subsequent assay
decision
1018, and process termination 1020.
[0079] The process starts by obtaining a test plan related to the screening
campaign at an
obtaining test plan 1002 step. The test plan may be one entered by a user in
the user request, or
modified from a previous test plan. As described earlier, a test plan
identifies a list of samples
or compounds, a set of assays for each compound and optionally a test
strategy. The test
strategy may request that the assays be run in parallel, in serial, in a
combination of parallel or
serial, or including branching conditions. Test procedures and experiment
protocols may also
be defined or specified. The test plan is retrieved at the obtaining test plan
1002 step.
[0080] When determining next the samples of compounds required, the scheduler
408
analyses the test plan (or test plans if there are more than one user request
outstanding), and
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determines an order to conduct the assays. As will be appreciated, if a
sequential order is
provided in the test plan, the integration server 124 simply follows the order
in scheduling the
assays. Once an assay to be performed is determined, the required compounds or
samples can
also be determined by identifying all samples for the assay from the test plan
or plans. In
general, if a decision tree is specified, the decision tree provides an order
to conduct the assays.
If no order is specified, or if at one stage, parallel testing is requested,
then these assays can be
perfonned in parallel, namely, performed in any time sequence. If not
sufficient hardware units
are available for testing all samples, a round robin order, or any other
suitable order, may be
selected by the system for parallel testing. In any case, the system will
first select an assay for
testing, based on the test strategy, or decision tree, provided in the user
request, namely the test
plan. If a priority is specified, assays having the same priority are
scheduled together, starting
from the highest priority. Optionally, the system may also poll the required
hardware units or
examine the schedule information of the required hardware unit to determine
whether all these
hardware units required for conducting the chosen assay will be available. If
any of them will
not be available when required, the system may attempt to schedule next assay
until an assay
can be scheduled. As described above, once the chosen assay is determined,
samples are
selected and provided to reformatter 108.
. 5, .
[0081] Referring to Figure 10, having retrieved a pre-defined test plan, the
system 400, at
an obtaining samples 1004 step, confirms that samples have arrived and placed
in one of
reformatter 108. Samples may be selected from a master library and placed in
reformatter 108
by laboratory personnel for creating a sublibrary. Alternatively, samples can
be selected by
robotic devices and transported to reformatter 108 automatically. Selected
samples may be
identified by labeling means such as barcode labeling the compound in the
master library and
the samples or plates holding the samples. Where only plate labeling is
labeled, sample in each
well of the plate can be mapped to the compound selected from the master
library for
identification and tracking purposes.
[0082] Upon confirmation that samples are in reformatter 108, process
integration server
124 sends a web service message to the instrument cell subsystem 410
responsible for
reformatter 108. The instrument cell subsystem 410 instructs reformatter 108
or a laboratory
technician to start the reformatter 108 to prepare sample plates for the
requested assays at an
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initiating sample preparation 1006 step. Reformatter 108, through its
instrument cell subsystem
410, informs process integration server 124 when sample preparation is
completed. In a semi-
automated system, process integration server 124 sends an e-mail message to
laboratory
personnel, updates the status information presented in information portal 122,
or otherwise
notifies the laboratory technician of the completion of sample preparation so
that the laboratory
technician may transport the prepared samples to assay station 110 for
testing. If barcode or
other labeling technology is used, a bar code reader may be employed to check
in and check out
the samples. Process integration server 124 may then record the location of
each sample, thus
providing location tracking of each of the samples as they move from hardware
unit to
hardware unit. In an automated system, process integration server 124 directs
a transport
system to move the prepared samples from reformatter 108 to assay station 110
and records the
movement and location of each sample.
[0083] Experiments are conducted at assay station 110. An instrument cell
subsystem 410
responsible for assay station 110 is iristructed by proces'integration server
124 to start the
experiments at an initiating experiment procedures' 1008 step. Experiment
procedures specified
in the test plan or steps in the protocol selected for the test, plan are
followed by instruments and
devices of assay station 110, such as robotic devices and liquid handling
devices, in an
automated fashion. Upon completion of all procedures, the instrument cell
subsystem 410
notifies process integration server 124 by sending a notification message, for
example. Again,
in a semi-automated system, process integration server 124 may notify a
laboratory technician
or a researcher of the completion of the experiment by sending an e-mail
message, updating the
status information presented in information portal 122, or by employing some
other suitable
means. The e-mail message may simply provide status information. It may also
include an
experiment report to provide more detailed information about the assay or
experiment
completed. Any other suitable audio or visual means may be utilized to provide
the
notification.
[0084] As described earlier, dedicated software or instrument cell subsystem
410
responsible for a workcell captures experiment results and transmits the
captured data to
process integration server 124 for saving to data warehouse 404. Data
acquisition 1010 is
performed either when the experiment procedures are being conducted or at the
conclusion of
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the experiment procedures, depending on the nature of assay and the experiment
procedures.
Once the results are captured, they are stored in data warehouse 404.
[0085] Next, process integration server 124 waits for results from analytics
module 424.
The results analysis module 424 polls the hardware units periodically for new
data. Once a
hardware unit has new data available, in a data analysis 1012 step, the
results analysis module
424 processes the raw data and extracts information from the data. Data
analysis operations
may include statistical analysis of the data, formatting data, i.e.,
manipulating for sharing with
other components of the system or other users, as well as preparing data for
visualization.
Results of data analysis 1012 are also stored in data warehouse 404 as the
data are processed.
[0086] At the step of presenting test results 1014, these results are
communicated to users,
such as researchers and laboratory personnel. The results may be "pushed" to
the users by
updating a status screen display constantly as results of each assay become
available; they may
also be "pulled" by users as a response to request for data or assay results.
As will be
appreciated, because the test results are communicated back to the integration
server 124 in real
time, or at least during each assay, what are available to users and therefore
can be
communicated to users are not limited to test results. As the test results are
stored for each
sample at least during each assay, the storing of test results therefore
enables the system to
provide status infornation to the user in real time. Along with the test
result, test conditions of
each experiment, such as temperature or agitation rate, can be stored. The
status information
therefore may include the assays already conducted on the sample and assays
still left to be
conducted, the test results of conducted assays, and test conditions of the
conducted assays,
among others.
[00871 At this step, status information can be communicated to a user as
requested, or
constantly communicated to the user as the information is updated. Because of
the potentially
large quantity of information associated with such a screening process, the
information can be
organized and presented in a summary form, and in a graphical format. For
example, the
results and status of the tests can be shown in a flow chart fornlat,
corresponding to the decision
tree specified by the user, as that shown in Figure 11A. Figure 11A is an
exeniplary screen
display that provides detailed status and summary information related to a
user request. This
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process has only two assays specified. The screen display shows that the first
one is completed,
and the second one is yet to start. The result box 1102 provides a summary of
total number of
compounds tested, the number of compounds that pass the test and the number of
compounds
that fail the test. It also provides hot links, or actuatable areas, for a
user to drill down, namely
to request more detailed information. For example, by selecting the actuatable
area 1104
labelled "Histogram Results", the user can request another screen that shows
the test results in
greater detail. This is shown in an exemplary screen display shown in Figure
11B. As can be
seen in Figure 11B, compounds are grouped by their results. Graphed in each
range in a pre-
determined series of ranges are compounds with test results falling in the
range. Any particular
group or range can be further examined. Figure 11B shows that one group 1106
is selected for
further examination. The group has solubility falling within the pre-
determined range [5.335,
17.783). As can be seen, 20 compounds have a solubility within this range.
Each compound,
represented by a unique compound serial number, has its solubility shown in
the result column
1108. Test results of a particular compound can also be selected and reviewed,
for example, by
entering its compound serial number in an input area 1110. As will be
understood, although
only test results are shown in this exemplary screen display, other, status
information can be
similarly presented and displayed. Further drill-down, namely, selecting a
graphical element
representing a group of samples or a sample to further explore the data at a
more detailed level,
may be similarly provided. This allows a user to track the compounds as they
are tested,
including the tracking of their physical locations as they move from hardware
unit to hardware
unit and their experiment status within the process, including the assays
conducted and the
results of each assay.
[0088] At compounds promotion 1016 step, process integration server 124
retrieves the
results of the assay and forward the results to its decision module 420. At
least the relevant test
acceptance criteria for the assay is also forwarded to or made available to
decision module 420.
The decision module 420 compares the assay results with the test acceptance
criteria to
determine whether to advance all, some or none of the compounds. A sample is
to advance if
its test results pass the associated test acceptance criteria. An advanced
compound will have
further assays performed thereon until all assays requested by the user have
been completed.
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[0089] If the test results fail the test acceptance criteria, the sample may
be eliminated from
further testing. In general, a sample is eliminated from further testing if it
fails a specified set
of tests. A special case is for the sample to fail a single test. As discussed
earlier, in general,
the decision to eliminate a sample is made accumulatively on the failure of
several tests. The
controlling factor may be the number of failed tests in the specified set of
tests or the failure of
all tests in a more confined group. How the accumulative decision is to be
made is specified by
a user, such as a scientist, when submitting a job request entry form. If a
sample is not to be
promoted, no further tests will be performed on the failed sample. The sample
can be removed
from the schedule for further testing. If so, none of the hardware components
that are
scheduled to perform further tests on the failed sample will be requested to
perform the
cancelled tests. Alternatively, a message may be sent to all such hardware
components to
explicitly cancel further testing, or to all staff members who would otherwise
test the failed
sample as scheduled. This tends to reduce the wasted time and resources spent
unnecessarily
on samples that are already known to be unsuitable.
[0090] Whatever the decision is rendered by the software system 400, the
decision may be
reviewed and modified by a user. For example, when screeniing for compounds, a
user may
review the results of current assay or all assays performed thus far and then
decide whether to
fail a compound. Test results as well as test acceptance criteria may be
reviewed along with the
machine-made decision. The results may be provided through a user interface,
such as an
information portal 122. The user may confirm the automatically rendered
decision. The user
may also use his or her own judgment to decide whether to modify, namely
manually override,
the automatically rendered decision. A user can make these modifications
through, for
example, a user screen shown in Figure 9. Alternatively, the user may also
modify the test
acceptance criteria to indirectly alter the system rendered decision. At the
step of deciding
subsequent assay 1018, process integration server 124 will terminate the
testing process, i.e.,
screening campaign, at step 1020, unless there is at least one remaining assay
to be performed
on advanced compounds.
[0091] In case a further assay is to be performed, the process returns to the
step of
obtaining samples 1004 step. Namely, process integration server 124 instructs
reformatter 108
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to prepare the requisite plates for the next assay, without including any
compounds that are
already eliminated, and the process will be repeated from there.
[0092] As can be seen, according to this process, each assay is scheduled for
a compound
only if necessary. The scheduling of the assay is dynamic in that the process
integration server
124 determines the next step and directs the laboratory resources to start the
next assay only
when test results of the current assay are known. Because test results are
communicated back
to the process integration server 124 in real time, the next assay can be
scheduled in real time
as well, upon the completion of the current assay.
[0093] Further, the scheduling can incorporate availability of laboratory
resources,
including hardware resources and laboratory personnel. In general, it tends to
be more difficult
to predict when a laboratory resource may become unavailable at the begirming
of the testing
process, which may last for several days. But, it may be more predictable
whether a laboratory
resource may become unavailable when the next assay is to be conducted, which
maybe only
several hours in the future. In addition, should a hardware resource becomes
unavailable
during an assay, dynamic scheduling also allows the screening process to be re-
scheduled,
iilstead of suspending the process until the failed hardware resource becomes
available again.
For example, suppose during a purity assay, an LC-MS workstation breaks down,
the
integration server 124 can dynamically schedule and start the next assay to be
carried out if the
next assay does not require an LC-MS workstation, instead of waiting for the
current assay to
finish. Of course, it is understood that the next assay does not depend on the
result of the
current assay, though it is also possible to program the integration server
124 to ignore the
results of the current assay, if the estimated time for restoring the failed
hardware resource
exceeds certain limit. Although this example malces reference to hardware
failure, it is
understood that the same principle can be applied to unavailability of
laboratory personnel as
well.
[0094] At the end of the screening process, the network messaging module 402
may
generate a message to notify the user of the termination of the process. As
will be understood,
the process may terminate either when all requested assays are conducted or
when there are no
further assays to be conducted. Of course, a user may also decide to terminate
the process at
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any time. The notification may simply inform the user that the process is now
terminated so
that the user can request a final test report. The system 400 may also
generate a test report at
the end of the process, without being requested by the user, and send the test
report to the user,
along with the notification message. The test report may include summary
information relating
to the screening process, such as number of compounds that pass all test
criteria and the test
conditions of each assay. Further drill-down on each assay or each compound
may also be
provided in the test report, for the user to explore further the test results.
[0095] Figure 12 shows an example of applying the process shown in Figure 10
to conduct
three assays on a few hundred samples. The three assays are metabolic
stability (Human
microsomes), DDI (CYP 3A4 inhibition) and PAMPA, which are represented by
shaded areas
in the chart. As can be seen from Figure 12, the PAMPA assay and MetStab assay
require a
reformatter, an assay station and an LC-MS station, while the DDI assay
require only a,
reformatter and an assay station. Prior to running the samples on an LC-MS
station, a tuning
run,is perfarmed on the LC-MS station to tune the LC-MS station for the
compounds being,
tested. Referring to Figure 12, these three assays are all run in parallel,
without dependencies.
The chart shows that the PAMPA assay starts with reformatting (1202). .
Samples prepared by
refomatter are then run on an assay station (1204), after which the samples
are analyzed on an
LC-MS station (1206).
[0096] As can be seen in Figure 12, the LC-MS analysis does not begin
immediately after
the samples finish the tests at the workcell at the end of day one. Instead,
the LC-MS analysis
(1206) begins at day three. This is due to the tuning run, which makes the LC-
MS station
unavailable. Similarly, when conducting the MetStab assay, the LC-MS analysis
(1208) does
not begin immediately after the tests at the workcell (1210) at the end of day
two; but rather
commences only at day five, when the PAMPA assay has completed its LC-MS
analysis
operation. These resource conflicts may be planned and resolved in advance,
using a project
planning software such as Microsoft PorjectTM. Preferably, these conflicts are
resolved by
process integration server 124 when it orchestrates the operation of each
laboratory resources.
Through status tracking and monitoring, the process integration server 124
maintains a list of
availability of laboratory resources. Prior to directing the required
laboratory resources to
perform a step in an assay, the process integration server 124 determines the
availability of the
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required laboratory resource(s) and sends a message to initiate the step only
when the resource
or resources are available. Where the required laboratory resources are able
to maintain a job
queue, the process integration server 124 may also simply add the instructions
to initiate the
next test step to the queue so that the laboratory resource may start the next
step once it
becomes available.
[0097] Figure 12 also shows that reformatting for MetStab (1212) begins before
the
PAMPA assay finishes. This is an example of progressive reformatting, or
dynamic
preparation of samples. Through the communication with the process integration
server 124,
the reformatter 108 is provided with a running list of samples in a continuous
stream that have
completed the test or passed a test acceptance criteria for the PAMPA assay.
As results come
in, requests for reformatting these compounds for the subsequent assay is
added to the running
list. The reformatter 108 can start reformatting the compounds once they are
added to the
running list. Assay plates are accumulated progressively in separate temporary
storage places,
or "hotels", for each of the subsequent assays for the passed, or "promoted",
compounds.
Essentially; the reformatter 108 is engaged at a steady rate rather than in
bursts of sample
preparation.Id'le time of hardware components is minimized. Alternatively,
progressive
reformatting can also be achieved by building assay specific pick lists
dynamically at runtime::.-:
Compounds, or rather, serial numbers representing the compounds, are added to
the pick list
upon completion of experiment procedure of each sample. The pick list can be
stored
temporarily in computer memory or in a more permanent storage medium sucli as
a hard disk to
facilitate future review. The pick list is built dynamically, rather than
built at the completion of
the entire batch of samples. Instead of instructing the reformatter 108 to
start preparing plates
for the next test in advance for an estimated amount of time, the reformatter
108 also can start
reformatting plates for the next assays when the pick list has grown to
contain a pre-determined
number of compounds. This number can be provided by a user in a test plan or
may be set by a
laboratory personnel based on instrument capacity, for example. All
information on the
generation of plates is passed back to the process integration server 124. At
the completion of
preparation of plates for one of these separate assays, the reformatter 108
notifies the process
integration server 124. The process integration server 124 can subsequently
notify the
laboratories resource scheduled for the assay, either a hardware unit (in a
completely automated
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system) or a laboratory technician (in a semi-automated system), to commence
the assay. The
time the assay is commenced can be stored in data warehouse 404, to allow
users to track the
status of the assay and the screening process in real time.
[0098] In one embodiment, a process alternative to that shown in Figure 10 is
implemented
to screen compounds, namely to perform multiple assays on each candidate
compound
identified in a list of compounds. Figure 13A illustrates schematically the
steps of a process for
performing an assay as seen in the orchestrated testing environment 600 shown
in Figure 6;
Figure 13B shows steps of the process in a flowchart format.
[0099] The steps are as follows. First, at step 1302, the compounds from a
library to be
screened are delivered to the orchestrated laboratory system 100, in a set of
formatted
microtitre plates, together with the data corresponding to each of the
compounds. Next, at step
1304, reformatter 108 reformats these samples into the appropriate microtitre
plates to form a
sublibrary of samples. At step 1306, reformatted samples are transported to
the appropriate
wo rkcell or workstations for performing the assay, either by a robotic
transport device~ or
moved by a laboratory technician.
[00100] The purity assay commences at step 1308. As purity data is being
obtained,
decisions will start to be made on whether a compound passes the property
hurdle or not at step
1310. As described, the system 400 can decide whether to advance a compound
for further
testing by comparing assay results against the associated test acceptance
criteria. Scientists can
review the system decision to advance or eliminate a compound, and to confirm
or override the
decision, or vary the hurdle rates, or choose other heuristics to indirectly
decide whether to pass
compounds to the next stage.
[00101] If at least one compound passes the property hurdle, the system 400 at
step 1310
automatically starts passing information on to the reformatter 108, through
the process
integration server 124, in order to start reformatting microtitre plates for
the subsequent assay.
The reformatter 108 reformats all the passed compounds into new microtitre
plates as directed.
If the next assay is not immediately performed upon creation of the
sublibrary, the plates are
stored in standard format container temporarily, waiting to be tested.
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[001021 Various embodiments of the invention have now been described in
detail. Those
skilled in the art will appreciate that numerous modifications, adaptations
and variations may be
made to the embodiments without departing from the scope of the invention.
Since changes in and
or additions to the above-described best mode may be made without departing
from the nature,
spirit or scope of the invention, the invention is not to be limited to those
details but only by the
appended claims.
