Diagnostic systems and methods

Abstract

To provide diagnostic systems and methods for performing a plurality of different molecular assays to a plurality of samples.SOLUTION: An automatic method for analyzing a plurality of samples comprises the steps of, within the housing of a self-contained diagnostic system: (a) loading the diagnostic system with the plurality of samples, (b) performing a first assay to a first sample subset of the plurality of samples after the step (a); and (c) performing a second assay to a second sample subset of the plurality of samples concurrently with the step (b).SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] This application incorporates by reference in its entirety U.S. Provisional Application No. 61 / 784,994, filed March 14, 2013.

[0002] The present disclosure relates to diagnostic systems and methods for performing multiple different molecular assays on multiple samples, and in particular to molecular assays that comprise target nucleic acid amplification reactions. [Background technology]

[0003] It should be noted that any reference discussed or referred to herein is not an admission that it is prior art to the claimed invention.

[0004] Molecular assays are nucleic acid-based tests used in clinical diagnostics, screening, monitoring, industrial and environmental testing, health science research, and other applications to detect the presence or quantity of an analyte of interest in a sample, such as a microorganism or virus, or to detect genetic abnormalities or mutations in an organism. Molecular assays that allow for quantification can enable practitioners to better calculate the extent of infection or disease and determine the status of disease over time. Quantitative molecular assays are also useful for monitoring the effectiveness of therapy. Various known molecular assays can be employed to detect various diagnostic indicators.

[0005] Molecular assays generally involve multiple steps leading to the detection or quantification of a target nucleic acid in a sample. The targeted nucleic acid often contains a region specific to an identifiable "group" of organisms or viruses, where the group is defined by at least one shared sequence of nucleic acid that is common to all members of the group and specific to the group in the particular sample being assayed. Examples of nucleic acid-based detection methods are disclosed by Kohne, U.S. Patent No. 4,851,330, and Hogan et al., U.S. Patent No. 5,541,308.

[0006] Most molecular assays include a detection step in which the sample is exposed to detection probes or amplification primers that are designed or selected to exhibit specificity under particular conditions of use for nucleic acid sequences belonging to the organism or virus of interest. The detection probes or amplification primers can be labeled for detection with reporter moieties such as chemiluminescent or fluorescent agents, or intercalating dyes can be used to indiscriminately detect the presence of double-stranded nucleic acids in the sample. See, for example, U.S. Patent No. 5,538,848 to Livak et al., U.S. Patent No. 5,541,308 to Hogan et al., and U.S. Patent No. 5,541,308 to Tyagi et al. See, for example, U.S. Patent No. 5,925,517 to Higuchi et al., U.S. Patent No. 5,994,056 to Higuchi, U.S. Patent No. 6,174,670 to Wittwer et al., U.S. Patent No. 6,326,145 to Whitcombe et al., and U.S. Patent No. 6,569,627 to Wittwer et al. To make nucleic acids available for hybridization of detection probes or amplification primers, cells can be lysed or permeabilized by a variety of known techniques, including chemical (e.g., detergents), mechanical (e.g., sonication), and / or thermal procedures. See, e.g., Clark et al. See U.S. Patent No. 5,786,208 to A. et al.

[0007] Before or after exposing the target nucleic acid to the detection probe or amplification primer, the target nucleic acid can be immobilized on a solid support (e.g., particles or beads comprising a magnetically responsive material) that directly or indirectly binds the target nucleic acid. A solid-phase extraction method for directly binding nucleic acids to silica beads in the presence of a chaotropic agent is described by Boom et al. in U.S. Pat. No. 5,234,864. An example of indirect immobilization is described in Weisburg et al. in U.S. Pat. No. 6,534,273, which discloses the use of a capture probe that binds to the target nucleic acid under a first set of sample conditions and to an oligonucleotide covalently bound to the solid support under a second set of sample conditions. If the solid support comprises magnetically responsive particles or beads, a magnet can be used to attract the solid support to the side of the receptacle containing the solid support. Once the immobilized target nucleic acid is isolated within the receptacle, the isolated target nucleic acid can be separated from at least a portion of the fluid contents of the sample by, for example, contacting and aspirating the fluid contents of the receptacle with a robotic pipettor or other material transfer device. See, e.g., U.S. Patent No. 6,605,213 to Ammann et al. One or more wash steps with a buffer solution or water may be performed to further purify the isolated nucleic acid.

[0008] To increase the sensitivity of the assay, the target nucleic acid can be amplified by nucleic acid amplification reactions, many of which are well known in the art. Known methods of amplification include polymerase chain reaction ("PCR") (see, e.g., U.S. Pat. Nos. 4,683,195, 4,683,202, and 4,800,159 to Mullis et al., and Mullis et al., "Methods in Enzymology," 155:335-350 (1987)), strand displacement amplification ("SDA") (see, e.g., Walker, "PCR Methods and Applications," 3:25-30 (1993); Walker et al., "Nucleic Acids Res." 20:1691-1996 (1992); and Walker et al., "Proc. Natl. Acad. Sci. 89:392-396 (1991)), ligase chain reaction ("LCR") (see, e.g., U.S. Pat. No. 5,427,930 to Birkenmeyer and U.S. Pat. No. 5,686,272 to Carrino et al.), and transcription-based amplification methods (see, e.g., U.S. Pat. No. 5,437,990 to Boothroyd et al., U.S. Pat. Nos. 5,399,491 and 5,480,784 to Kacian et al., U.S. Pat. No. 5,409,818 to Davey et al., U.S. Pat. No. 5,130,238 to Malek et al., and International Publication Nos. WO 88 / 01302 and WO 88 / 10315 to Gingeras et al.). A review of many amplification reactions, including PCR and transcription-mediated amplification ("TMA"), is provided in Lee et al., Nucleic Acid Amplification Technologies (BioTechnology Books) (1997).

[0009] PCR is the oldest and most common form of amplification. Like other amplification methods, PCR amplifies one or more copies of a region of nucleic acid by several orders of magnitude, generating thousands to millions of copies of a specific nucleic acid sequence. PCR has a wide range of applications in clinical and biological research laboratories. The uses of this technique are numerous and well known at this time, so they will not be enumerated in this patent application.

[0010] PCR employs thermocycling, which consists of repeated cycles of heating and cooling the reaction mixture. The reaction is generally initiated using primers (short DNA fragments containing sequences complementary to the target nucleic acid region), along with enzymes and additional reaction materials. Once initiated, the replicated nucleic acid can be used as additional templates in an amplification reaction, thereby leading to exponential amplification of the target nucleic acid sequence.

[0011] Because the probe hybridizes with the targeted sequence, the intensity of the signal associated with the probe is proportional to the amount of target nucleic acid sequence present in the sample. Therefore, by periodically measuring the signal indicating the presence of the amplicon during the amplification process, the growth of the amplicon over time can be detected. Based on the data collected during this "real-time" monitoring of the amplification process, the amount of target nucleic acid originally present in the sample can be confirmed. In some contexts, collecting data in "real time" means collecting data while a reaction or other process is ongoing, as opposed to collecting data at the completion of the reaction or process. Systems and methods for real-time detection, processing real-time data, and confirming nucleic acid levels are disclosed, for example, by Lair et al. in U.S. Patent No. 7,932,081.

[0012] To detect different nucleic acids within a single assay, separate probes may be designed or selected to hybridize separately with different nucleic acids, and the probes may contain reporter moieties that can be differentiated from one another. See, for example, U.S. Patent No. 5,538,848 to Livak et al., U.S. Patent No. 5,925,517 to Tyagi et al., U.S. Patent No. 5,928,862 to Morrison, U.S. Patent No. 5,691,146 to Mayrand, and U.S. Patent No. 5,928,862 to Becker et al. For example, different probes designed or selected to hybridize with different targets may have fluorophores that emit fluorescence at a predetermined wavelength when exposed to excitation light of a specified excitation wavelength. Assays for detecting different target nucleic acids can be performed in parallel by alternately exposing sample materials to different excitation wavelengths for each target nucleic acid during a real-time monitoring process and detecting the level of fluorescence at the wavelength of interest corresponding to the probe. Parallel processing can be performed using different signal detection devices configured to periodically measure signal emissions during the amplification process, with the different signal detection devices configured to generate excitation signals of different wavelengths and measure emission signals of different wavelengths. [Prior art documents] [Patent documents]

[0013] [Patent Document 1] U.S. Patent No. 4,851,330 [Patent Document 2] U.S. Patent No. 5,541,308 [Patent Document 3] U.S. Patent No. 5,538,848 [Patent Document 4] U.S. Patent No. 5,541,308 [Patent Document 5] U.S. Patent No. 5,925,517 [Patent Document 6] U.S. Patent No. 5,994,056 [Patent Document 7] U.S. Patent No. 6,174,670 [Patent Document 8] U.S. Patent No. 6,326,145 [Patent Document 9] U.S. Patent No. 6,569,627 [Patent Document 10] U.S. Patent No. 5,786,208 Summary of the Invention [Means for solving the problem]

[0014] Aspects of the present disclosure are embodied in, among other things, systems, devices, and processes that enhance the functionality of a diagnostic first module by supporting processing capabilities not available in the base first module or in existing modules within the base first module. In one embodiment, the system, device, and process expands the functionality of a nucleic acid diagnostic first module by supporting PCR assay processing and analysis capabilities in addition to isothermal amplification processing and analysis capabilities. A second module is operably linked to the base first module to expand the overall system capabilities of the diagnostic system. The provision of this expansion module, when incorporated, grants sample / answer capabilities to a single automated instrument that can automatically perform both thermal cycling and isothermal amplification assays and may incorporate endpoint and real-time formats using chemiluminescent and / or fluorescent labels.

[0015] In some embodiments, a diagnostic system can be configured to perform a first nucleic acid amplification reaction and a second nucleic acid amplification reaction different from the first nucleic acid amplification reaction. The diagnostic system includes at least one bulk reagent container compartment configured to store at least a first bulk reagent container including a first bulk reagent for performing a sample preparation process and a second bulk reagent container including a second bulk reagent for performing the first nucleic acid amplification reaction. The at least one bulk reagent container compartment is further configured to store a unit dose reagent compartment configured to store at least one unit dose reagent pack including a plurality of unit dose reagents for performing the second nucleic acid amplification reaction. The diagnostic system is configured to perform a sample preparation process on a first subset of a plurality of samples provided to the diagnostic system using the first bulk reagent. The diagnostic system is also configured to perform a first nucleic acid amplification reaction on the first subset of the plurality of samples using the second bulk reagent. The diagnostic system is also configured to perform a second nucleic acid amplification reaction on a second subset of the plurality of samples using the plurality of unit dose reagents.

[0016] In some embodiments, an automated method for analyzing a plurality of samples includes performing a first assay on a first sample subset of the plurality of samples. The first assay comprises a first reaction using a first unit-dose reagent. The method also includes performing a second assay on a second sample subset of the plurality of samples. The second assay comprises a second reaction using (a) a second unit-dose reagent different from the first unit-dose reagent and (b) at least one of the first bulk reagents. The steps of performing the first assay and performing the second assay occur within the same diagnostic system, which stores the first unit-dose reagent, the second unit-dose reagent, and at least one of the first bulk reagent.

[0017] In one exemplary embodiment, a base first module comprises a dual-format molecular diagnostic instrument designed to perform specific target amplification assays utilizing chemiluminescence and fluorescence detection technologies for both qualitative and real-time quantitative assays. With the addition of a second module, additional automated assays, such as PCR assays, can be performed (combined) with the assays performed by the base first module to achieve similar throughput to that achieved by the base first module.

[0018] In one exemplary embodiment, the second module includes a thermal cycler with real-time fluorescence detection capabilities, a reagent pack storage bay that allows loading and refrigerated storage of new reagent packs containing reagents (e.g., PCR reagents), an additional disposable pipette tip tray, PCR and assay-specific reagents, one or more pipettor systems for performing assay steps required for PCR or other reactions, and / or a receptacle transporter. The second module may rely on the base first module for other processing steps such as sample loading, sample preparation, target capture, and addition of elution for subsequent PCR assays, thus further leveraging those capabilities of the base first module and supporting additional processing and detection capabilities without requiring sample loading and preparation functionality to be built into the second module.

[0019] Aspects of the present disclosure are embodied in a second module for enhancing the capabilities of the first module, including a first material transfer device configured to process material in each of a plurality of receptacles and to dispense material into each receptacle, and a receptacle transfer device configured to move the receptacles within the first module. The second module is configured to be coupled to or decoupled from the first module and comprises a container transporter configured to transport at least one container from a location in the second module to a location in the first module accessible to the first material transfer device for transferring material from the container to a receptacle in the first module; a receptacle distribution module configured to receive a receptacle from the receptacle transfer device of the first module, transfer the receptacle into the second module, and move the receptacle between different locations in the first module; and a second material transfer device configured to dispense material into or remove material from a receptacle in the second module.

[0020] According to some aspects of the present disclosure, the receptacle distribution module includes a receptacle distributor configured to move a receptacle onto the receptacle distributor at a first location on the second module, transport the receptacle from the first location to a second location on the second module different from the first location, and remove the receptacle from the receptacle distributor at the second location on the second module. The receptacle handover device can be configured to receive the receptacle from the receptacle transport device of the first module and reposition the receptacle for presentation to the receptacle distributor to be moved by the receptacle distributor from the receptacle handover device onto the receptacle distributor.

[0021] According to some aspects of the present disclosure, the receptacle distributor is configured to rotate about an axis of rotation and move the receptacles carried thereby in an arcuate path between locations within the second module. Other configurations for moving the receptacles between locations within the second module are also contemplated. Thus, the present disclosure is not limited to receptacle distributors that rotate about an axis of rotation.

[0022] According to some aspects of the present disclosure, the second module further includes a receptacle storage station for holding one or more receptacles to be transferred from the first module to the second module, the receptacle storage station being arranged in a configuration corresponding to the arcuate path of the receptacle distributor.

[0023] According to some aspects of the disclosure, the receptacle distributor is configured to vertically move receptacles carried thereby between different vertically disposed locations within the second module.

[0024] According to some aspects of the disclosure, the receptacle handover device is configured to rotate between a first position for receiving a receptacle from a receptacle transfer device of a first module and a second position for presenting the receptacle to a receptacle dispenser.

[0025] According to some aspects of the present disclosure, the second module further includes a container compartment configured to hold one or more fluid containers. In certain embodiments, the container compartment can be a container drawer configured to be moved between an open position and a closed position and, when moved to the closed position, to place at least one fluid container in an operable position relative to the container carrier so that the container can be transported from the container compartment into the first module by the container carrier. In alternative embodiments, the container compartment can include a door with a sliding tray configured to be moved between an open position and a closed position and, when moved to the closed position, to place at least one fluid container in an operable position relative to the container carrier so that the container can be transported from the container compartment into the first module by the container carrier.

[0026] According to some aspects of the present disclosure, the second module further includes a container carriage configured to carry one or more containers and to be movable with the container compartment, and further configured to be engaged by the container transporter such that when the container compartment is in a closed position, the container transporter is operable to move the container carriage and one or more containers carried thereby from the container compartment into the first module.

[0027] According to some aspects of the present disclosure, the second module further includes a carriage transporter and a carriage lock. The carriage transporter is movable with the container receptacle and configured to transport the container carriage between a first position when the container receptacle is in an open position and a second position when the container receptacle is in a closed position. The carriage lock is configured to lock the container carriage to the carriage transporter when the carriage transporter is in the first position and to release the container from the carriage transporter when the carriage transporter is in the second position, allowing the container carriage to be removed from the carriage transporter by the container transporter.

[0028] According to some aspects of the present disclosure, the container transporter includes a track extending from the container compartment into the first module, a carriage hook configured to engage the container carriage when the container compartment is in a closed position, and a motorized carriage hook drive system configured to move the carriage hook along the carriage track.

[0029] According to some aspects of the present disclosure, a motorized carriage hook drive system includes a motor and a belt driven by the motor and coupled to the carriage hook.

[0030] According to some aspects of the present disclosure, the processing device further comprises one or more position sensors disposed at one or more locations along the track to detect the position of the carriage on the track.

[0031] According to some aspects of the present disclosure, the second module further includes a reagent pack exchanger including a pack input device and a pack storage compartment. The pack input device is configured to allow an operator to install or remove a reagent pack containing at least one reagent into or from the second module. The pack storage compartment is configured to hold multiple reagent packs until the reagent packs are needed for processing in the second module. The receptacle distribution module is further configured to move the reagent packs between the pack input device and the pack storage compartment.

[0032] According to some aspects of the present disclosure, the second module further includes one or more reagent pack loading stations, each configured to hold a reagent pack in a manner that allows a second material transfer device to transfer material to or from the reagent pack. Thus, in some embodiments, the reagent pack loading stations are configured to change the orientation of the reagent pack from an initial loading position to a position aligned with the second material transfer device.

[0033] According to some aspects of the present disclosure, the second module further includes a charged field generator operably associated with at least one of the pack input device, the pack storage compartment, and the reagent pack loading station, and configured to generate an electrostatic force to position and retain reagents present in reagent packs held in the pack input device or the pack storage compartment. In related aspects, the charged field generator is mounted below at least one of the pack input device, the pack storage compartment, and the reagent pack loading station such that an electromagnetic force, when present, is applied to or adjacent to the bottom of one or more wells of the reagent pack.

[0034] According to some aspects of the present disclosure, the pack loading device includes a reagent pack carousel rotatable about a rotation axis, the pack carousel including a plurality of reagent pack stations, each configured to hold a reagent pack arranged around the rotation axis.

[0035] According to some aspects of the present disclosure, the pack carousel is disposed within a compartment, such as a drawer, that is movable between an open position that provides access to the pack carousel and a closed position that closes access to the pack carousel. The pack carousel can also be accessed through an access panel that exposes a slidable tray on which the pack carousel is mounted.

[0036] According to some aspects of the present disclosure, the second module further includes a code reader operatively disposed relative to the pack input device and configured to read a machine-readable code on each reagent pack transported within the pack input device, hi some embodiments, the code reader reads the machine-readable code on an individual reagent pack in close proximity to the code reader.

[0037] According to some aspects of the present disclosure, the second module further includes a pack storage carousel disposed within the pack storage compartment, the pack storage carousel being rotatable about an axis of rotation and including a plurality of reagent pack stations, each configured to hold a reagent pack disposed about the axis of rotation.

[0038] According to some aspects of the present disclosure, the reagent pack stations of the pack storage carousel are arranged on two or more levels of the second module.

[0039] According to some aspects of the present disclosure, the second module further includes a cooling system for maintaining the storage compartment below ambient temperature.

[0040] According to some aspects of the present disclosure, the second material transfer device includes a robotic pipettor having a pipettor probe, and the second module further includes one or more disposable tip compartments configured to hold a plurality of disposable tips configured to be mounted on the pipettor probe of the robotic pipettor.

[0041] According to some aspects of the present disclosure, the second module further includes a cap / vial tray configured to hold a plurality of process vials and / or associated caps. Each cap is configured to couple to and close an associated vial. The vials are accessible by a robotic pipettor to dispense process materials into the vials, and the associated caps are accessible by the robotic pipettor to move each cap into its associated vial to form a cap / vial assembly. The robotic pipettor is configured to move the cap / vial assembly from the cap / vial tray to another location on the second module.

[0042] According to some aspects of the present disclosure, the second module further includes a centrifuge, and the robotic pipettor is configured to transfer the cap / vial assemblies from the cap / vial tray to the centrifuge.

[0043] According to some aspects of the present disclosure, the second module further includes a thermacycler configured to hold a plurality of cap / vial assemblies and expose the contents of the plurality of cap / vial assemblies to cyclically varying temperatures, and a robotic vial transfer pipetter configured to move the cap / vial assemblies from the centrifuge to the thermacycler.

[0044] According to some aspects of the present disclosure, the second module further comprises one or more magnetic receptacles holding slots configured to hold receptacles to be transferred from the first module to the second module, each magnetic receptacle holding slot comprising a magnet and configured to attract magnetic particles contained within the receptacle from solution in the fluid contents of the receptacle to a wall of the receptacle.

[0045] According to some aspects of the present disclosure, the first module and the second module are configured to perform a nucleic acid amplification reaction.

[0046] According to some aspects of the present disclosure, the nucleic acid amplification reactions performed in the first module and the second module are different types of amplification reactions.

[0047] According to some aspects of the present disclosure, the nucleic acid amplification reaction performed in the first module comprises a reaction nucleic acid that is qualitatively monitored, and the amplification reaction performed in the second module comprises a reaction that is quantitatively monitored.

[0048] According to some aspects of the present disclosure, the nucleic acid amplification reaction performed in the second module comprises a reaction that is monitored in real time.

[0049] According to some aspects of the present disclosure, the nucleic acid amplification reaction performed in the first module is an isothermal reaction and the nucleic acid amplification reaction performed in the second module comprises the use of the polymerase chain reaction.

[0050] Aspects of the present disclosure are further embodied in an automated system capable of performing multiple molecular assays on a single sample, the system including a sample input portal configured to receive a sample contained in one or more receptacles, a sample preparation module configured to prepare the sample provided to the sample input portal for a nucleic acid amplification reaction, a first module configured to perform an isothermal nucleic acid amplification assay with the sample, a second module configured to perform a temperature cycling nucleic acid amplification assay with the sample, and a transport mechanism configured to provide automated transport of the one or more receptacles containing the sample between the sample input portal, the sample preparation module, the first module, and the second module.

[0051] According to some aspects of the present disclosure, the automated system further comprises a material transfer device configured to access the sample when present in the second module, the first module, or the second module.

[0052] According to some aspects of the present disclosure, the system further includes a reagent storage compartment configured to hold a plurality of reagent containers, the reagent storage compartment being maintained at a temperature below ambient temperature.

[0053] According to some aspects of the present disclosure, the system further includes a reagent container transport mechanism configured to transport one or more reagent containers between the reagent storage compartment and a location in a separate second module.

[0054] According to some aspects of the present disclosure, the reagent container transport mechanism is configured to transport reagent containers within the second module and to transport receptacles within the second module.

[0055] Some aspects of the present disclosure are embodied in a method for improved thermal cycling of low-volume nucleic acid amplification reaction mixtures, the method including combining a fluid sample and one or more amplification reaction reagents together in a reaction receptacle using an automated pipettor, transporting the reaction receptacle to a centrifuge using the automated pipettor, centrifuging the fluid contents of the reaction receptacle, automatically removing the reaction receptacle from the centrifuge after centrifugation and placing the reaction receptacle in a thermacycler, and exposing the fluid contents of the reaction receptacle to one or more temperature cycles in the thermacycler.

[0056] According to some aspects of the present disclosure, the reaction receptacle is removed from the centrifuge and transported to the thermacycler using a vial transfer arm.

[0057] According to some aspects of the present disclosure, a reaction receptacle is placed into a centrifuge at a first location, and the reaction receptacle is removed from the centrifuge at a second, different location.

[0058] According to some aspects of the present disclosure, the method further includes a second automated pipettor that automatically removes the reaction receptacle from the centrifuge after centrifugation and places the reaction receptacle in a thermacycler.

[0059] According to some aspects of the present disclosure, the receptacle is sealed with a cap prior to transporting the sealed receptacle to a centrifuge.

[0060] According to some aspects of the present disclosure, the automated pipettor carries a cap to the receptacle and seals the receptacle by coupling the cap to the receptacle.

[0061] Some aspects of the present disclosure are embodied in an improved method for preparing multiple different nucleic acid reaction mixtures within the workflow of an automated molecular instrument. The method includes providing two or more reaction receptacles, providing two or more unit-dose reagent containers, each corresponding to a separate reaction receptacle, and each containing nucleic acid amplification reagent specific to one or more target nucleic acids, providing a receptacle containing a first bulk reagent, and combining at least a portion of the sample, at least a portion of the unit-dose reagent, and at least a portion of the bulk reagent in each of the two or more reaction receptacles. After combination, each reaction receptacle contains a different sample, a different unit-dose reagent, and the same first bulk reagent.

[0062] According to a further aspect of the present disclosure, the method further comprises a receptacle containing a second bulk reagent, the second bulk reagent being dispensed into each of the two or more unit dose reagent containers prior to combining at least a portion of the sample with at least a portion of the unit dose reagent and at least a portion of the bulk reagent in each of the two or more reaction receptacles.

[0063] According to some aspects of the present disclosure, the second bulk reagent comprises a reconstitution reagent.

[0064] According to some aspects of the present disclosure, the method further includes transporting each of the two or more reaction receptacles to a heater, such as a heated incubator or heating plate, to perform a nucleic acid amplification assay.

[0065] Other features and characteristics of the present disclosure, as well as its method of operation, associated elements of construction and combination of parts, and economies of manufacture, will become more apparent from a consideration of the following description and appended claims, taken in conjunction with the accompanying drawings (like reference numerals designate corresponding parts in the various views), all of which form a part of this specification.

[0066] The present invention provides, for example, the following: (Item 1) 1. A diagnostic system configured to perform a first nucleic acid amplification reaction and a second nucleic acid amplification reaction different from the first nucleic acid amplification reaction, at least one bulk reagent container compartment, at least one first bulk reagent container containing at least one first bulk reagent for performing a sample preparation process using a first subset and a second subset of the plurality of samples provided to the diagnostic system; at least one second bulk reagent container containing a second bulk reagent for conducting the first nucleic acid amplification reaction; at least one bulk reagent container compartment configured to store a unit-dose reagent compartment configured to store at least one unit-dose reagent pack comprising a plurality of unit-dose reagents for performing the second nucleic acid amplification reaction; Equipped with The diagnostic system comprises: performing the sample preparation process on a first subset and a second subset of the plurality of samples using the at least one first bulk reagent; performing the first nucleic acid amplification reaction on a first subset of the plurality of samples using the second bulk reagent; performing the second nucleic acid amplification reaction on a second subset of the plurality of samples using the plurality of unit dose reagents; A diagnostic system configured to: (Item 2) 2. The diagnostic system of item 1, wherein a first module performs the first nucleic acid amplification reaction and a second module performs the second nucleic acid amplification reaction. (Item 3) Item 3. The diagnostic system of item 2, wherein the first module is integrated with the second module. (Item 4) 3. The diagnostic system of claim 2, wherein the second module is configured to be selectively operably coupled to the first module. (Item 5) Item 5. The diagnostic system of item 4, wherein the at least one bulk reagent container compartment comprises a first bulk reagent container compartment in the first module configured to store the at least one first bulk reagent container, and the unit dose reagent compartment is in the second module. (Item 6) 6. The diagnostic system of claim 5, wherein the first bulk reagent container compartment stores the at least one first bulk reagent container, and the at least one first bulk reagent comprises a target capture reagent. (Item 7) 3. The diagnostic system of claim 2, wherein the at least one bulk reagent container compartment comprises a first bulk reagent container compartment within the first module configured to store the at least one first bulk reagent container. (Item 8) 8. The diagnostic system of claim 7, wherein the first bulk reagent container compartment stores the at least one first bulk reagent container, and the at least one first bulk reagent comprises a target capture reagent. (Item 9) 9. The diagnostic system of any one of items 7-8, wherein the at least one bulk reagent container compartment further comprises a second bulk reagent container compartment within the first module configured to store the second bulk reagent container. (Item 10) 10. The diagnostic system of any one of items 7-9, wherein the second bulk reagent container compartment stores the second bulk reagent container. (Item 11) 11. The diagnostic system of any one of items 7-10, wherein the at least one bulk reagent container compartment further comprises a second bulk reagent container compartment configured to store a third bulk reagent container comprising a third bulk reagent within the second module. (Item 12) 12. The diagnostic system of claim 11, wherein the third bulk reagent container compartment stores the third bulk reagent container, the third bulk reagent comprising a reconstitution reagent. (Item 13) 13. The diagnostic system of any one of items 11-12, wherein the second bulk reagent container compartment is further configured to store a fourth bulk reagent container comprising a fourth bulk reagent. (Item 14) 14. The diagnostic system of claim 13, wherein the second bulk reagent container compartment stores the fourth bulk reagent container, the fourth bulk reagent comprising at least one of an elution buffer and an oil. (Item 15) 15. The diagnostic system of any one of items 1-14, wherein the unit dose reagent compartment stores a first unit dose reagent pack comprising a plurality of first unit dose reagents for targeting a first nucleic acid, and a second unit dose reagent pack comprising a plurality of second unit dose reagents for targeting a second nucleic acid different from the first nucleic acid. (Item 16) 16. The diagnostic system of claim 15, wherein the first unit-dose reagent comprises at least one of a polymerase and a nucleoside triphosphate for performing the second nucleic acid amplification reaction, and the second unit-dose reagent comprises at least one of a polymerase and a nucleoside triphosphate for performing the second nucleic acid amplification reaction. (Item 17) 17. The diagnostic system of any one of items 1-16, further comprising a dispenser configured to move a unit dose reagent pack stored in the unit dose reagent compartment to a location accessible to a material transfer device configured to aspirate a reconstituted form of at least one of the plurality of unit dose reagents. (Item 18) 18. The diagnostic system of any one of items 1-17, wherein the second nucleic acid amplification reaction is an isothermal reaction. (Item 19) 18. The diagnostic system of any one of items 1-17, wherein the second nucleic acid amplification reaction involves temperature cycling. (Item 20) 20. The diagnostic system of any one of items 1-17 and 19, wherein the second nucleic acid amplification reaction is a polymerase chain reaction (PCR). (Item 21) 21. The diagnostic system of any one of items 1-20, wherein the unit dose reagent compartment stores at least one unit dose reagent pack comprising a plurality of lyophilized unit dose reagents. (Item 22) 22. The diagnostic system of any one of items 1-21, wherein the first nucleic acid amplification reaction is an isothermal nucleic acid amplification reaction. (Item 23) 23. The diagnostic system of any one of items 1-22, wherein the first nucleic acid amplification reaction is transcription-mediated amplification (TMA), nucleic acid sequence-based amplification (NASBA), or strand displacement amplification (SDA). (Item 24) 22. The diagnostic system of any one of items 1-21, wherein the first nucleic acid amplification reaction involves temperature cycling. (Item 25) 25. The diagnostic system of any one of items 1-24, wherein the at least one first bulk reagent comprises a solid support for directly or indirectly immobilizing a target nucleic acid. (Item 26) 26. The diagnostic system of any one of items 25, wherein the solid support is magnetically responsive. (Item 27) 27. The diagnostic system of any one of items 1-26, wherein the at least one first bulk reagent comprises a first sample processing reagent and a second sample processing reagent, and the diagnostic system is configured to perform a sample preparation process on a first subset of the plurality of samples using the first sample processing reagent and to perform a sample preparation process on a second subset of the plurality of samples using the second sample processing reagent. (Item 28) 29. The diagnostic system of any one of items 1-28, wherein the diagnostic system is configured to simultaneously perform the first nucleic acid amplification reaction and the second nucleic acid amplification reaction. (Item 29) 1. An automated method for analyzing a plurality of samples, comprising: performing a first assay on a first sample subset of the plurality of samples, the first assay comprising a first reaction using a first unit dose reagent; simultaneously performing a second assay on a second sample subset of the plurality of samples, the second assay comprising a second reaction using at least one of: (a) a second unit dose reagent different from the first unit dose reagent; and (b) a first bulk reagent; Including, An automated method wherein the steps of performing the first assay and performing the second assay occur within the same diagnostic system that stores the first unit dose reagent and at least one of the second unit dose reagent and the first bulk reagent. (Item 30) 30. The automated method of claim 29, wherein the first assay further comprises preparing the first sample subset using a second bulk reagent, and the second assay further comprises preparing the second sample subset using at least one of the second bulk reagent and the third bulk reagent. (Item 31) 31. The automated method of any one of items 29-30, wherein preparing the first sample subset comprises isolating and purifying a first target nucleic acid for the first assay, and preparing the second sample subset comprises isolating and purifying a second target nucleic acid for the second assay. (Item 32) 32. The automated method of any one of items 30-31, wherein at least one of the second bulk reagent and the third bulk reagent comprises a solid support for directly or indirectly immobilizing either a first or second target nucleic acid present in the first and second sample subsets. (Item 33) 33. The automated method of claim 32, wherein the solid support is magnetically responsive. (Item 34) 34. The automated method of any one of items 29-33, wherein the second bulk reagent does not comprise components necessary to carry out the first and second reactions. (Item 35) 35. The automated method of any one of items 29-34, further comprising coordinating a first schedule for performing the first assay and a second schedule for performing the second assay such that use of resources of the diagnostic system is maximized and the time for performing the first assay and the time for performing the second assay is minimized. (Item 36) 36. The automated method of any one of items 29-35, wherein the second reaction uses the second unit dose reagent. (Item 37) 36. The automated method of any one of items 29-35, wherein the second reaction uses the first bulk reagent. (Item 38) 38. The automated method of any one of items 29-35 and 37, wherein the second reaction does not use a unit dose reagent. (Item 39) 39. The automated method of any one of items 29-38, wherein the first sample subset and the second sample subset comprise different samples. (Item 40) 39. The automated method of any one of items 29-38, wherein the first sample subset and the second sample subset comprise identical samples. (Item 41) 41. The automated method of any one of items 29-40, wherein the first reaction is a first nucleic acid amplification reaction. (Item 42) 42. The automated method of claim 41, wherein the first nucleic acid amplification reaction involves temperature cycling. (Item 43) 43. The automated method of any one of items 41-42, wherein the first unit-dose reagent comprises components for performing the first nucleic acid amplification reaction. (Item 44) 44. The automated method of claim 43, wherein the components comprise at least one of a polymerase and a nucleoside triphosphate. (Item 45) 45. The automated method of any one of items 29-44, wherein the second reaction is a second nucleic acid amplification reaction. (Item 46) 46. ​​The automated method of claim 45, wherein the second nucleic acid amplification reaction involves temperature cycling. (Item 47) 46. ​​The automated method of claim 45, wherein the second nucleic acid amplification reaction is an isothermal reaction. (Item 48) 48. The automated method of any one of items 45-47, wherein the second unit-dose reagent comprises components for performing the second nucleic acid amplification reaction. (Item 49) 49. The automated method of claim 48, wherein the components comprise at least one of a polymerase and a nucleoside triphosphate. (Item 50) 50. The automated method of items 29-49, wherein the first assay does not use the second unit dose reagent and the first bulk reagent. (Item 51) 51. The automated method of any one of items 29-50, wherein the second reaction is different from the first reaction. (Item 52) 52. The automated method of any one of items 29-51, wherein the diagnostic system is a self-contained appliance and the automated method is performed within an enclosure of the self-contained appliance. (Item 53) 1. A diagnostic system comprising: a first module configured to perform a first nucleic acid amplification reaction; a second module configured to perform a second nucleic acid amplification reaction different from the first nucleic acid amplification reaction; Equipped with The second module comprises: a container transporter configured to transport at least one container from the second module to a location within the first module accessible to a first material transfer device configured to transfer material from the container to a receptacle within the first module; a receptacle distribution system configured to transfer the receptacle from the receptacle transfer device of the first module to a location within the second module; a second material transfer device configured to dispense or remove a material into or from the receptacle in the second module; A diagnostic system comprising: (Item 54) Item 54. The diagnostic system of item 53, wherein the second module is configured to be selectively operably coupled to the first module. (Item 55) Item 54. The diagnostic system of item 53, wherein the first module is integral with the second module. (Item 56) The receptacle dispensing system comprises: a receptacle distributor configured to move the receptacle within the second module; a receptacle transfer device configured to receive the receptacle from the receptacle transfer device of the first module and reposition the receptacle to a location accessible to the receptacle distributor; 56. The diagnostic system according to any one of items 53 to 55, comprising: (Item 57) Item 57. The diagnostic system of item 56, wherein the receptacle distributor is configured to rotate about an axis of rotation, thereby moving the carried receptacles in an arcuate path between locations within the second module. (Item 58) Item 58. The processing module of item 57, further comprising a receptacle storage station for holding one or more receptacles to be transferred from the first module to the second module, the receptacle storage station arranged in a configuration corresponding to the arcuate path of the receptacle distributor. (Item 59) 59. The diagnostic system of any one of items 56-58, wherein the receptacle distributor is configured to move vertically such that the receptacles carried thereby can be moved between different vertically disposed locations within the second module. (Item 60) 59. The diagnostic system of any one of items 56-58, wherein the receptacle handover device is configured to rotate between a first position for receiving the receptacle from a receptacle transfer device of the first module and a second position for presenting the receptacle to the receptacle distributor. (Item 61) A diagnostic system as described in any one of items 56-60, wherein the second module further comprises a bulk reagent container compartment configured to hold one or more bulk reagent containers, the bulk reagent container compartment being configured to move between an open position and a closed position and, when moved to the closed position, to position at least one bulk reagent container in an operable location relative to the container transporter so that the at least one bulk reagent container can be transported from the container compartment to the first module by the container transporter. (Item 62) Item 62. The diagnostic system of item 61, wherein the second module further comprises a container carriage configured to carry one or more bulk reagent containers and to be movable together with the bulk reagent container compartment, and further configured to be engaged by the container carrier such that when the bulk reagent container compartment is in the closed position, the container carrier is operable to move the container carriage and one or more bulk reagent containers carried thereby from the bulk reagent container compartment to the first module. (Item 63) The second module further comprises: a container carriage transporter movable with the bulk reagent container compartment and configured to transport the container carriage between a first position when the bulk reagent container compartment is in the open position and a second position when the bulk reagent container compartment is in the closed position; a carriage lock configured to lock the container carriage to the carriage transporter when the carriage transporter is in the first position, and to release the container from the carriage transporter when the carriage transporter is in the second position, allowing the container carriage to be removed from the carriage transporter by the container transporter; Item 63. The diagnostic system of item 62, comprising: (Item 64) The container carrier includes: a track extending from the bulk reagent container compartment into the first module; a carriage hook configured to engage the container carriage when the bulk reagent container compartment is in the closed position; a motorized carriage hook drive configured to translate the carriage hook along the carriage track; 64. The diagnostic system according to any one of items 62-63, comprising: (Item 65) The motorized carriage hook drive system includes: A motor; a belt driven by the motor and connected to the carriage hook; Item 65. The diagnostic system of item 64, comprising: (Item 66) 66. The diagnostic system of any one of items 64-65, wherein the second module further comprises one or more position sensors positioned at one or more locations along the track to detect the position of the carriage on the track. (Item 67) the second module further comprises a reagent pack exchanger; The reagent pack exchanger includes: a reagent pack input device configured to allow a user to install a reagent pack containing at least one reagent into the second module or remove a reagent pack from the second module; a reagent pack storage compartment configured to store a plurality of reagent packs until needed for processing in the second module; Equipped with 67. The diagnostic system of any one of items 53-66, wherein the receptacle dispensing module is further configured to move reagent packs between the reagent pack input device and the reagent pack storage compartment. (Item 68) Item 68. The diagnostic system of item 67, wherein the second module further comprises an electrostatic generator operably associated with at least one of the reagent pack input device and the reagent pack storage compartment and configured to generate an electrostatic charge for positioning and retaining reagents present in a reagent pack held in the reagent pack input device or the reagent pack storage compartment. (Item 69) The diagnostic system of any one of items 67-68, wherein the second module further comprises one or more reagent pack loading stations, each configured to hold a reagent pack in a location that enables the second material transfer device to transfer materials to and from the reagent pack. (Item 70) 70. The diagnostic system of any one of items 67-69, wherein the reagent pack input device comprises a unit-dose reagent pack carousel rotatable about an axis of rotation, the reagent pack carousel including a plurality of reagent pack stations, each configured to hold a reagent pack arranged around the axis of rotation. (Item 71) Item 71. The diagnostic system of item 70, wherein the reagent pack carousel is disposed within a compartment that is movable between an open position that provides access to the reagent pack carousel and a closed position that closes access to the reagent pack carousel. (Item 72) A diagnostic system described in any one of items 67-71, wherein the second module further comprises a code reader operably arranged relative to the reagent pack input device and configured to read a machine-readable code on each reagent pack transported within the reagent pack input device. (Item 73) The diagnostic system of any one of items 67-71, wherein the second module further comprises a reagent pack storage carousel positioned within the reagent pack storage compartment, the reagent pack storage carousel being rotatable about a rotation axis, and the reagent pack storage carousel including a plurality of reagent pack stations, each configured to hold a reagent pack arranged around the rotation axis. (Item 74) 73. The diagnostic system of any one of items 67-72, wherein the reagent pack stations of the reagent pack storage carousel are arranged on two or more levels. (Item 75) 73. The diagnostic system of any one of items 67-72, wherein the second module further comprises a cooling system for maintaining the reagent pack storage compartment below ambient temperature. (Item 76) 76. The diagnostic system of any one of items 53-75, wherein the second material transfer device comprises a robotic pipetter having a pipetter probe, and the second module further comprises one or more disposable tip compartments configured to hold a plurality of disposable tips configured to be mounted on the pipetter probe of the robotic pipetter. (Item 77) Item 77. The diagnostic system of item 76, wherein the second module further comprises a cap / vial compartment configured to hold a plurality of processing vials and / or associated caps, each cap configured to couple to and close an associated vial, the vials accessible by the robotic pipettor to dispense processing materials into the vials, the associated caps accessible by the robotic pipettor to move each cap into its associated vial and form a cap / vial assembly, and the robotic pipettor configured to move the cap / vial assembly from the cap / vial compartment to another location on the second module. (Item 78) Item 78. The diagnostic system of item 77, wherein the second module further comprises a centrifuge, and the robotic pipetter is configured to move the cap / vial assembly from the cap / vial compartment to the centrifuge. (Item 79) The second module further comprises: a thermacycler configured to hold a plurality of cap / vial assemblies and expose the contents of the plurality of cap / vial assemblies to cyclically varying temperatures; a robotic vial transfer arm configured to move a cap / vial assembly from the centrifuge to the thermacycler; Item 79. The diagnostic system of item 78, comprising: (Item 80) The diagnostic system of any one of items 53-79, wherein the second module further comprises a magnetic receptacle having a slot configured to hold a receptacle to be transferred from the first module to the second module, the magnetic receptacle comprising a magnet and configured to attract magnetic particles contained within the receptacle from a solution in the fluid contents of the receptacle to a wall of the receptacle. (Item 81) 81. The diagnostic system of any one of items 53-80, wherein the first nucleic acid amplification reaction comprises a qualitative reaction and the second nucleic acid amplification reaction comprises a quantitative reaction. (Item 82) 82. The diagnostic system of claim 81, wherein the second nucleic acid amplification reaction comprises a reaction monitored in real time. (Item 83) 83. The diagnostic system of any one of items 81-82, wherein the first nucleic acid amplification reaction is an isothermal reaction and the second nucleic acid amplification reaction comprises a polymerase chain reaction (PCR). (Item 84) 1. An automated system configured to perform a plurality of molecular assays, comprising: (a) a sample entry portal configured to receive a plurality of samples contained within individual receptacles; (b) a sample processing module configured to prepare a plurality of samples provided to the sample input portal for at least one of a first nucleic acid amplification reaction and a second nucleic acid amplification reaction; (c) a first module configured to perform the first nucleic acid amplification reaction using a first subset of samples of the plurality of samples; (d) a second module configured to simultaneously perform a second nucleic acid amplification reaction using a second subset of samples of the plurality of samples, wherein the first and second subsets of samples are different; and (e) a transport system configured to transport the plurality of samples between components of the automated system for performing the molecular assays; and An automated system comprising: (Item 85) 85. The automated system of claim 84, wherein the first nucleic acid amplification reaction is an isothermal nucleic acid reaction. (Item 86) 86. The automated system of claim 85, wherein the first nucleic acid amplification reaction is transcription-mediated amplification (TMA), nucleic acid sequence-based amplification (NASBA), or strand displacement amplification (SDA). (Item 87) 87. The automated system of any one of items 84-86, wherein the second nucleic acid amplification reaction involves temperature cycling. (Item 88) 88. The automated system of claim 87, wherein the second nucleic acid amplification reaction is a polymerase chain reaction (PCR). (Item 89) The automated system of any one of items 84-88, wherein the second module further comprises a reagent storage compartment configured to hold a plurality of reagent containers, the reagent storage compartment being maintained at a temperature below ambient temperature. (Item 90) Item 90. The automated system of item 89, wherein the second module further comprises a reagent container transporter configured to transport one or more bulk reagent containers between the reagent storage compartment and a separate location within the first module. (Item 91) 91. The automated system of any one of items 84-90, wherein the first module is integral with the second module. (Item 92) 91. The automated system of any one of items 84-90, wherein the second module is configured to be selectively operably coupled to the first module. (Item 93) 1. A method for thermal cycling of a nucleic acid amplification reaction mixture, comprising: (a) combining a fluid sample and one or more nucleic acid amplification reaction reagents together in a reaction receptacle using an automated pipettor; (b) subjecting the fluid sample to centrifugation; (c) automatically, after centrifugation, removing the reaction receptacle from the centrifuge and placing the reaction receptacle in a thermacycler; (d) exposing the fluid contents of said reaction receptacle to temperature cycling in one or more of said thermacyclers; Including, the reaction receptacle is transferred to the centrifuge using the automated pipettor; The method includes placing the reaction receptacle in the centrifuge at a first location and removing the reaction receptacle from the centrifuge at a second, different location. Item 94. The method of item 93, further comprising a receptacle transport arm, wherein the receptacle transport arm automatically removes the reaction receptacle from the centrifuge after centrifugation and places the reaction receptacle in the thermacycler. (Item 95) Item 95. The method of item 94, wherein the receptacle transport arm lacks the ability to provide material transfer using a pipette tip. (Item 96) 1. A method for preparing a plurality of different nucleic acid reaction mixtures within the workflow of said automated molecular instrument, comprising: (a) combining in a first reaction receptacle a portion of a first sample and a portion of a first unit dose reagent for a first assay, the first unit dose reagent contained in a first unit dose reagent container, and a portion of a bulk reagent contained in a bulk reagent container; (b) combining in a second reaction receptacle a portion of a second sample different from the first sample, a portion of a second unit dose reagent for a second assay different from the first assay, the second unit dose contained in a second unit dose reagent container, and a second portion of the bulk reagent contained in the bulk reagent container; A method comprising: (Item 97) Item 97. The method of item 96, further comprising, prior to steps (a) and (b), dispensing a portion of a second bulk reagent into each of the first and second unit-dose reagent containers. (Item 98) 98. The method of claim 97, wherein the second bulk reagent comprises a reconstitution reagent. (Item 99) 99. The method of any one of items 96-98, further comprising transporting the first and second reaction receptacles to a heated incubator and conducting a nucleic acid amplification reaction. (Item 100) 99. The method of claim 98, further comprising, prior to steps (a) and (b), dispensing a portion of a third bulk reagent comprising a solid support into each of the first and second samples, wherein the solid support immobilizes nucleic acids in the first and second samples. (Item 101) 101. The method of claim 100, further comprising isolating the solid supports in the first and second reaction receptacles and removing non-immobilized components of the first and second samples, thereby purifying the nucleic acids in the first and second samples. (Item 102) 102. The method of claim 101, wherein the solid support is magnetically responsive and the solid supports of the first and second samples are exposed to a magnetic field prior to removal of non-immobilized components of the first and second samples. (Item 103) 1. A diagnostic system configured to perform a first nucleic acid amplification reaction, comprising: a unit dose reagent compartment configured to store at least one unit dose pack comprising a plurality of wells each containing a lyophilized unit dose reagent; an electrostatic generator configured to apply an electrostatic charge that positions and holds each lyophilized unit dose reagent at the bottom of each individual well of said at least one unit dose pack; A diagnostic system comprising: (Item 104) 104. The diagnostic system of claim 103, wherein the electrostatic generator is configured to apply the electrostatic charge to the lyophilized unit dose reagent upon reconstitution. The accompanying drawings, which are incorporated in and form a part of this specification, illustrate various non-limiting embodiments of the present disclosure, in which common reference numbers indicate identical or functionally similar elements. [Brief explanation of the drawings]

[0067] [Figure 1] FIG. 1 is a perspective view of a diagnostic system including a first module and a second module, according to one embodiment. [Figure 2] FIG. 2 is a perspective view of a multiple receptacle device (“MRD”) according to one embodiment. [Figure 3] FIG. 3 is a partial bottom view of the MRD of FIG. [Figure 4] FIG. 4 is a top plan view of a first module of a diagnostic system, according to an embodiment. [Figure 5] FIG. 5 is an exploded top plan view of a first module and a second module, according to an embodiment. [Figure 6] FIG. 6 is a top plan view of the amplification processing deck of the second module, according to one embodiment. [Figure 7] FIG. 7 is a partial front perspective view of the second module with the bulk reagent container compartment in an open position, according to an embodiment. [Figure 8]FIG. 8 is a partial top plan view of the second module and the first module showing the bulk reagent container compartment in a closed position according to an embodiment. [Figure 9] FIG. 9 is a top perspective view of the bulk reagent container compartment and bulk reagent container transporter of the second module, with the bulk reagent container compartment in an open position, according to an embodiment. [Figure 10] FIG. 10 is a top perspective view of the bulk reagent container compartment and bulk reagent container transporter of the second module, with the bulk reagent container compartment in a closed position and an elution container being transported to the end of the bulk reagent container transporter, according to an embodiment. [Figure 11] FIG. 11 is a partial cross-sectional view of a bulk reagent container compartment, with the bulk reagent container compartment in an open position, according to an embodiment. [Figure 12] FIG. 12 is a partial cross-sectional view of a bulk reagent container compartment and bulk reagent container transporter, with the bulk reagent container compartment in a closed position, according to an embodiment. [Figure 13] FIG. 13 is a partial end view of a bulk reagent container compartment, with the bulk reagent container compartment in a closed position, according to an embodiment. [Figure 14] FIG. 14 is a top perspective view of the receptacle processing deck of the second module, according to an embodiment. [Figure 15] FIG. 15 is a partial front perspective view of the second module with the carousel compartment of the reagent pack changer in an open position, according to an embodiment. [Figure 16] FIG. 16 is a partial top perspective view of a puck carousel compartment according to one embodiment. [Figure 17] FIG. 17 is a partial side perspective view of a puck carousel compartment according to one embodiment. [Figure 18] FIG. 18 is a cross-sectional rear perspective view of an alternative embodiment of a reagent pack exchanger and reagent pack storage compartment. [Figure 19] FIG. 19 is a top perspective view of a reagent pack embodying aspects of the present disclosure, according to an embodiment. [Figure 20] 20 is a top perspective cross-sectional view of the reagent pack taken along line XX-XX in FIG. 19 according to an embodiment. [Figure 21] FIG. 21 is a perspective view of a robotic pipettor of the second module, according to one embodiment. [Figure 22] FIG. 22 is a perspective view of a material transfer pipettor of a robotic pipettor, according to one embodiment. [Figure 23] FIG. 23 is an exploded perspective view of a process vial, a process vial cap, and a pipetter probe, according to an embodiment. [Figure 24] FIG. 24 is a transverse cross-section of a process vial and a process vial cap positioned within a process vial well and a cap well, respectively, of a process cap / vial compartment tray, according to one embodiment. [Figure 25] FIG. 25 is a cross-sectional view of a process vial cap being removed from a cap well and inserted into a process vial, with the process vial disposed in the process vial well, according to an embodiment. [Figure 26] FIG. 26 is an exploded perspective view of an alternative embodiment of a process vial, a process vial cap, and a pipetter probe. [Figure 27] FIG. 27 is a top perspective view of an embodiment of a receptacle distribution module of the second module. [Figure 28] FIG. 28 is a bottom perspective view of a receptacle dispensing module, according to an embodiment. [Figure 29] FIG. 29 is a perspective view of an embodiment of a dispenser head of a rotary dispenser of a receptacle dispensing module with the receptacle hook in a retracted position. [Figure 30] FIG. 30 is a perspective view of a dispenser head with a receptacle hook in an extended position, according to an embodiment. [Figure 31]FIG. 31 is an opposite perspective view of a dispenser head according to an embodiment. [Figure 32] FIG. 32 is a cross-sectional view of a rotary dispenser with a reagent pack disposed therein, according to an embodiment. [Figure 33] FIG. 33 is a transverse cross section of a rotary distributor with an MRD disposed therein, according to an embodiment. [Figure 34] FIG. 34 is a top front perspective view of an embodiment of a dispenser movement system of a receptacle dispensing module. [Figure 35] FIG. 35 is a top rear perspective view of the dispenser movement system. [Figure 36] FIG. 36 is a top plan view of an embodiment of the magnetic elution slot and reagent pack loading station of the second module. [Figure 37] FIG. 37 is a front-end perspective view of a magnetic elution slot and reagent pack loading station, according to an embodiment. [Figure 38] FIG. 38 is a rear perspective view of a magnetic elution slot and reagent pack loading station, according to an embodiment. [Figure 39] 39 and 40 are perspective views of an embodiment of a second modular MRD delivery device. [Figure 40] 39 and 40 are perspective views of an embodiment of a second modular MRD delivery device. [Figure 41] FIG. 41 is a flow diagram illustrating steps of a sample eluate preparation process, according to an embodiment. [Figure 42] FIG. 42 is a flow diagram illustrating steps in a reaction mixture preparation process, according to an embodiment. [Figure 43] FIG. 43 is a flow diagram illustrating steps in a process for performing an automated nucleic acid amplification reaction, such as PCR, according to one embodiment. [Figure 44] FIG. 44 is a flow diagram illustrating a method of using a diagnostic system according to one such embodiment. DETAILED DESCRIPTION OF THE INVENTION

[0068] The features and advantages of the present disclosure will become more apparent from the following detailed description when considered in conjunction with the drawings, in which like reference numbers generally indicate identical, functionally similar, and / or structurally similar elements.

[0069] Unless otherwise defined, all technical terms, notations, and other scientific or technical terms used herein generally have the same meaning as understood by those skilled in the art to which this disclosure belongs. Many of the techniques and procedures described or referenced herein are well known and generally employed by those skilled in the art using conventional methodologies. Procedures involving the use of commercially available kits and reagents, as appropriate, are generally performed according to manufacturer-defined protocols and / or parameters unless otherwise noted. All patents, applications, published applications, and other publications referenced herein are incorporated by reference in their entirety. If a definition set forth in this section contradicts or otherwise conflicts with a definition set forth in a patent, application, published application, or other publication incorporated by reference herein, the definition set forth in this section shall take precedence over the definition incorporated by reference herein.

[0070] References herein to "one embodiment," "an embodiment," "a further embodiment," "an exemplary embodiment," "some aspects," "further aspects," "aspects," and the like indicate that the described embodiment may include a particular feature, structure, or characteristic, but not all embodiments necessarily include that particular feature, structure, or characteristic. Moreover, such phrases do not necessarily refer to the same embodiment. Furthermore, when a particular feature, structure, or characteristic is described in connection with one embodiment, such feature, structure, or characteristic is also described in connection with other embodiments, whether or not explicitly described.

[0071] As used herein, "a" or "an" means "at least one" or "one or more."

[0072] As used herein, a "sample" refers to any material suspected of containing a virus or organism of interest, or alternatively, any material suspected of containing a nucleic acid of interest, such as a nucleic acid derived from a virus or organism of interest, or a nucleic acid suspected of having a genetic abnormality or mutation. The material may be, for example, a blood or urogenital sample, a buffered medium containing a sample, a medium containing a lysing agent for releasing the sample and nucleic acid belonging to the virus or organism, or an unprocessed clinical sample, such as a medium containing nucleic acid derived from a virus or organism that has been isolated and / or purified in a reaction receptacle or on a reaction material or device. For this reason, the term "sample" will be understood to mean a specimen in its raw form or at any stage of processing to release, isolate, and purify nucleic acid derived from the virus or organism. Thus, reference to a "sample" can refer to a material suspected of containing nucleic acid derived from a virus or organism at different stages of processing and is not limited to the initial form of the material.

[0073] The present description may use relative spatial and / or orientation terminology when describing the position and / or orientation of components, devices, locations, features, or portions thereof. Unless otherwise stated or indicated by the context of the description, such terms, including but not limited to, top, bottom, above, below, under, above, upper, lower, left, right, inside, outside, medial, lateral, proximal, distal, front, back, next to, adjacent, between, horizontal, vertical, diagonal, longitudinal, transverse, etc., are used for convenience in referring to such components, devices, locations, features, or portions thereof in the drawings and are not intended to be limiting.

[0074] The headings used in this application are intended merely to direct the reader's attention to various aspects of the disclosed system. The headings are not intended to limit the disclosed and claimed invention. Similarly, headings are not intended to suggest that a material, feature, aspect, method, or procedure described in one section does not apply to another section. Thus, a description of a material, feature, aspect, method, or procedure described in one section is intended to apply to other sections.

[0075] Nucleic Acid Diagnostic Assays Aspects of the present disclosure involve diagnostic systems and methods that can be used in conjunction with nucleic acid diagnostic assays, including "real-time" and "endpoint" amplification assays.

[0076] Real-time amplification assays can be used to determine the presence and amount of target nucleic acids in a sample, such as those derived from pathogenic organisms (e.g., bacteria, fungi, or protozoa) or viruses. Therefore, real-time amplification assays are often referred to as quantitative assays. By determining the amount of target nucleic acid in a sample, a practitioner can estimate the amount or number of organisms or viruses in the sample. In one application, real-time amplification assays may be used to screen blood or blood products intended for transfusion for blood-borne pathogens such as hepatitis C virus (HCV) and human immunodeficiency virus (HIV). In another application, real-time assays may be used to monitor the effectiveness of treatment regimens in patients infected with pathogenic organisms or viruses or suffering from diseases characterized by abnormal or mutant gene expression. Real-time amplification assays may also be used for diagnostic purposes and in gene expression determination. An exemplary system and method for performing real-time amplification assays is disclosed in U.S. Patent No. 7,897,337 to Macioszek et al.

[0077] In addition to implementing embodiments of the present disclosure in conjunction with real-time amplification assays, they may also be implemented in conjunction with endpoint amplification assays. In endpoint amplification assays, the presence of an amplification product containing a target sequence or its complement is determined upon completion of the amplification procedure. Thus, endpoint amplification assays are often referred to as qualitative assays, in that such assays do not indicate the amount of target analyte present, but provide a qualitative indication of the presence or absence of the target analyte. Exemplary systems and methods for endpoint detection are disclosed in U.S. Patent No. 6,335,166 to Ammann et al. Determination may occur in a detection station that is integrated with or external to the incubator in which the amplification reaction occurs. In contrast, in "real-time" amplification assays, the amount of amplification product containing the target sequence or its complement is determined during the amplification procedure. In real-time amplification assays, the concentration of the target nucleic acid can be determined by calculating the rate at which the target sequence is amplified from the acquired data, using data acquired by periodically measuring a signal that is a function of the amount of amplification product in the sample containing the target sequence or its complement. An example of such a real-time amplification assay is described in US Pat. No. 8,615,368 to Light II et al.

[0078] In an exemplary real-time amplification assay, the interactive label includes a fluorescent moiety, or other emission moiety, and a quencher moiety, such as 4-(4-dimethylaminophenylazo)benzoic acid (DABCYL). When excited by light energy at an appropriate excitation wavelength, the fluorescent moiety emits light energy (i.e., fluorescence) at a specific emission wavelength. When the fluorescent moiety and quencher moiety are held in close proximity, the light energy emitted by the fluorescent moiety is absorbed by the quencher moiety. However, when the probe hybridizes to nucleic acid present in the sample, the fluorescent and quencher moieties are separated from each other, and the light energy emitted by the fluorescent moiety can be detected. Fluorescent moieties with different and distinguishable excitation and emission wavelengths are often combined with different probes. Different probes can be added to a sample, and the presence and amount of target nucleic acid associated with each probe can be determined by alternately exposing the sample to light energy at different excitation wavelengths and measuring light emission from the sample at different wavelengths corresponding to the different fluorescent moieties. In another embodiment, different fluorescent moieties with the same excitation wavelength but different and distinguishable emission wavelengths are combined with different probes, and the presence and amount of target nucleic acid associated with each probe can be determined by exposing the sample to specific wavelength light energy, and measuring light emission from the sample at the different wavelengths corresponding to the different fluorescent moieties.

[0079] A variety of different label probes and probe mechanisms are known in the art, including those in which the probe does not hybridize with the target sequence.See, for example, U.S. Patent No. 5,846,717 to Brow et al. and U.S. Patent Application Publication No. 2013 / 0109588 to Chun et al. Some embodiments of the present disclosure work regardless of the specific labeling method used, provided that the moiety to be detected can be excited by a specific wavelength of light and emits a distinguishable emission spectrum.

[0080] When nucleic acid amplification reactions are used to increase the amount of a target sequence and / or its complement present in a sample prior to detection, it is desirable to include a "control" to ensure that amplification occurs. See, for example, the amplification control described by Wang in U.S. Pat. No. 5,476,774. Such a control can be a known nucleic acid sequence unrelated to the sequence of interest. A probe (i.e., a control probe) specific for the control sequence and having a unique fluorescent dye (i.e., a control dye) and quencher combination is added to the sample along with one or more amplification reagents required to amplify the control sequence and the target sequence. After exposing the sample to appropriate amplification conditions, the sample is alternately exposed to light energy at different excitation wavelengths (including the excitation wavelength for the control dye), and emitted light is detected. Detection of emitted light at a wavelength corresponding to the control dye confirms successful amplification (i.e., the control sequence has actually been amplified), and therefore, any failure to detect emitted light corresponding to the probe for the target sequence is unlikely to be due to amplification failure. Conversely, failure to detect emitted light from the control dye may indicate a failure of amplification and therefore call into question the results from the assay. Alternatively, failure to detect emitted light may be due to a malfunction or degradation of the mechanical and / or electrical performance of the instrument for detecting emitted light.

[0081] In some embodiments, assays performed according to the descriptions herein employ techniques such as target capture, reverse transcription, and real-time polymerase chain reaction to capture, amplify, and detect nucleic acids from target organisms in patient samples. The combination of reverse transcription and PCR is abbreviated as "RT-PCR." Below is a generalized assay process description of different techniques that can be implemented according to aspects of the present disclosure.

[0082] Target capture processes isolate target (e.g., virus, bacteria, fungi, protozoa, mammalian cells, etc.) nucleic acids and purify them for amplification. Target organisms, which may be present in various biological matrices such as urine or blood, can be lysed by a target capture reagent ("TCR"), thereby liberating the nucleic acids. In one approach, a capture oligonucleotide probe hybridizes with the target nucleic acid. The capture probe / target nucleic acid complex is attached to magnetic particles in the TCR through nucleic acid hybridization. Exemplary disclosures for carrying out these methods are provided by U.S. Patent Nos. 6,140,678, 5,234,809, 5,693,785, and 5,973,138, and European Patent No. 0389063. The magnetic particles are pulled to one side of a container by a magnet, isolated, and potential inhibitors are washed away (multiple wash cycles may be performed), thereby providing the target nucleic acid. Hogan et al. provides an exemplary disclosure of this protocol in U.S. Patent No. 7,172,863. See also International Publication No. WO2003 / 097808 to Fort et al. If the target capture process is specific to the target nucleic acid, the target nucleic acid will primarily remain after the purification step. As a result, target capture can enrich various sample types, significantly reduce inhibition rates, and increase assay sensitivity. Exemplary methods of target nucleic acid capture are disclosed, for example, in U.S. Patent No. 5,234,864 to Boom et al., U.S. Patent No. 5,705,628 to Hawkins, U.S. Patent No. 5,750,338 to Collins et al., and U.S. Patent No. 6,534,273 to Weisburg et al.

[0083] After completion of the target capture process, the magnetic particles onto which the target nucleic acid is immobilized are resuspended with 20-60 μL of wash solution, e.g., containing low-salt buffer or water. This will dehybridize the target nucleic acid from the magnetic particles, and in the presence of a strong magnet, 5-50 μL of purified nucleic acid can be recovered as input to the amplification process.

[0084] Reverse transcription and PCR can be optimized to be performed in a single receptacle using common reagents as a one-step process. This method provides a highly sensitive means for detecting low-abundance RNA, and although it is not necessarily quantitative, specific controls can be included in the experiment if quantitative results are desired. (The reverse transcription step is not required if the target nucleic acid is DNA.) In an exemplary implementation, before performing the real-time PCR reaction, the RNA is incubated with a retroviral enzyme (reverse transcriptase) under oil at 42°C for approximately 30 minutes. This process generates a single-stranded DNA copy of the RNA target sequence. If the goal is to copy all RNA present in the source material into DNA, a non-specific primer or primer set is used. In the case of mRNA with polyadenylated (polyA) ends, oligo-dT primers can be used. Alternatively, a collection of randomized hexanucleotide primers can be used to ensure that there will be a primer complementary to each of the messages. When only one RNA target is sought, a sequence-specific primer complementary to the 3' end of the desired amplification product is used. RNase H is used to degrade the RNA molecule contained in the hybrid RNA-DNA duplex so that the DNA strand is available to direct second-strand synthesis. The single-stranded DNA thus generated can serve as a template for PCR, using sequence-specific primers to amplify the region of interest.

[0085] The polymerase is inactive at low temperatures and can be heat-activated at 95°C for several minutes (e.g., about 10 minutes) before initiating PCR. While both reactions occur inside a thermocycler (i.e., a module configured to expose the contents of a receptacle to temperature cycling between two or more different temperatures), real-time PCR requires precise / rapid thermal cycling between denaturation (about 95°C), annealing (about 55°C), and synthesis (about 72°C) temperatures. Fluorescence monitoring occurs during each cycle or at other predetermined intervals at one or more color wavelengths associated with one or more probes adapted to detect one or more target analytes. PCR components may include, for example, forward and reverse primers and a fluorogenic probe containing a reporter fluorescent dye at the 5' end and a quencher dye at the 3' end. (See, e.g., Holland et al., Proc. Natl. Acad. Sci. USA, 88(16):7276-7280 (1991).) During PCR, nucleic acid primers hybridize to opposite strands of a target nucleic acid and are oriented with their 3' ends facing each other so that synthesis by a nucleic acid polymerizing enzyme, such as a DNA polymerase, extends across the segment of nucleic acid between them. The probe is intact, but the proximity of the quencher dye to the reporter dye significantly reduces the fluorescence emitted by the reporter dye. During amplification, if the target nucleic acid is present, the fluorogenic probe anneals downstream of one of the primer positions and is cleaved by the 5' nuclease activity of the polymerizing enzyme during primer extension. Cleavage of the probe separates the reporter dye from the quencher dye, thus making the reporter dye signal detectable, and removes the probe from the target strand, allowing primer extension to continue to the end of the template strand.

[0086] A single PCR synthesis will result in a new strand of non-deterministic length that, like the parent strand, can hybridize with primers upon denaturation and annealing. These products accumulate arithmetically with each subsequence cycle of denaturation, annealing with primers, and synthesis. Two cycles of denaturation, annealing, and synthesis produce two single-stranded products that together constitute a discrete double-stranded product exactly the length between the primer ends. Each strand of this discrete product is complementary to one of the two primers and can therefore serve as a template in the subsequent cycle. The amount of this product doubles with each subsequent cycle of synthesis, denaturation, and annealing. This means that 30 cycles will produce 2 strands of the discrete product. 28 This would accumulate exponentially, resulting in a 270,000,000-fold amplification.

[0087] Multiple Receptacle Devices 2 illustrates one embodiment of an MRD 160 that includes a plurality, preferably five, individual receptacles or tubes 162. The receptacles 162 are formed with open top and closed bottom ends (preferably in the form of cylindrical tubes) and are interconnected by connecting rib structures 164 that define downwardly facing shoulders extending longitudinally along both sides of the MRD 160.

[0088] Alternatively, a receptacle may be any container suitable for holding a fluid or liquid, including, for example, a cuvette, a beaker, a well in a microtiter plate, a test tube, and in some embodiments, a pipette tip. Unless expressly stated or indicated otherwise by context, descriptions of an MRD or a receptacle for an MRD are exemplary and should not be construed as limiting the scope of the disclosure, and aspects of the disclosure are applicable to any suitable "receptacle."

[0089] The MRD 160, in one embodiment, is formed from injection-molded polypropylene, such as that sold by Montell Polyolefins (Wilmington, Delaware) (product number PD701NW) or Huntsman (product number P5M6K-048). In an alternative embodiment, the receptacles 162 of the MRDs are removably secured to one another by means such as, for example, a sample tube rack or other holding structure.

[0090] An arc-shaped shielding structure 169 can be provided at one end of the MRD 160. An MRD manipulation structure 166 extends from the shielding structure 169. In one embodiment, the manipulation structure 166 is configured to be engaged by an extendable and retractable hook of a receptacle distributor or transport mechanism for moving the MRD 160 between different components of a first module of a diagnostic system. An exemplary transport mechanism compatible with the MRD 160 is disclosed by Ammann et al. in U.S. Pat. No. 6,335,166. In one embodiment, the transport mechanism engages the manipulation structure 166 from an underside of the manipulation structure, as indicated by arrow 60. In one embodiment, the MRD manipulation structure 166 includes a plate 168 extending laterally from the shielding structure 169 with a piece 167 extending perpendicularly at the opposite end of the plate 168. Gusset walls 165 may extend downwardly from side plates 168 between shielding structure 169 and vertical pieces 167 .

[0091] As shown in FIG. 3 , shielding structure 169 and vertical piece 167 have convex surfaces facing each other. However, this is just one way shielding structure 169 and vertical piece 167 may be configured. MRD 160 may be engaged by receptacle distributors, transport mechanisms, and other components by moving an engaging member, such as an extendable and retractable hook, laterally (in direction “A”) into the space between shielding structure 169 and vertical piece 167. The convex surfaces of shielding structure 169 and vertical piece 167 provide a wider entry point for the engaging member to undergo lateral relative movement into the space between shielding structure 169 and vertical piece 167. Of course, because the engaging member is robotically controlled, it should be understood that the convex surfaces are merely a design option of this embodiment and that surfaces of other shapes are also contemplated.

[0092] Indicator receiving structure 174 having a flat indicia receiving surface 175 may be provided at the end of MRD 160 opposite shielding structure 169 and MRD handling structure 166. Human and / or machine readable indicia, such as a scannable bar code, may be placed on surface 175 to provide identifying and instructional information regarding MRD 160.

[0093] Further details regarding an exemplary MRD160 are disclosed in US Pat. No. 6,086,827 to Horner et al.

[0094] Diagnostic Systems FIG. 1 illustrates a diagnostic system 10, according to one embodiment. The diagnostic system 10 can be configured to perform multiple different molecular assays on multiple samples. In some embodiments, the diagnostic system 10 can be configured to perform different target nucleic acid amplification reactions. For example, the diagnostic system 10 can be configured to perform a first target nucleic acid amplification reaction on a first subset of the multiple samples and a second, different target nucleic acid amplification reaction on a second subset of the multiple samples.

[0095] In some embodiments, the diagnostic system 10 comprises a first module 100 configured to perform at least one of the steps of a first target nucleic acid amplification reaction and a second module 400 configured to perform at least one of the steps of a second target nucleic acid amplification reaction.

[0096] In some embodiments, the diagnostic system 10 is an integrated, self-contained structure, where the first module 100 is selectively coupled to the second module 400 and cannot be decoupled therefrom.

[0097] In some embodiments, the diagnostic system 10 is configured such that the first module 100 can be selectively operably coupled to the second module 400, and the first module 100 can be selectively decoupled from the second module 400. In some embodiments, the first module 100 can be selectively coupled to the second module 400 using, for example, mechanical fasteners (e.g., bolts or screws), clamps, any combination thereof, or any other suitable attachment device. In some embodiments, suitable power and / or data lines are provided between the second module 400 and the first module 100. For example, in embodiments in which the first module 100 can be selectively coupled to the second module 400, the second module 400 can expand the overall system capabilities of a diagnostic system that includes only the first module 100 previously purchased by a customer.

[0098] The configurations and functions of the first module 100 and the second module 400 according to various embodiments are described below.

[0099] First Module A first module 100, in which embodiments of the present disclosure may be implemented, is shown diagrammatically in plan view in FIG. 4 and designated by reference numeral 100. First module 100 includes various devices configured to receive one or more reaction receptacles (described in more detail below) within each of which one or more steps of a multi-step nucleic acid test (NAT) designed to detect viruses or organisms (e.g., bacteria, fungi, or protozoa) are performed. First module 100 can include a receptacle-receiving component configured to receive and hold the one or more reaction receptacles and, in some cases, perform a process on the contents of the receptacle. Exemplary processes include, but are not limited to, adding and / or removing substances from a reaction receptacle, such as sample fluid, reagents (e.g., target capture reagents, amplification reagents, buffers, oils, labels, probes, or any other reagents), agitating the receptacle to mix its contents, maintaining and / or altering the temperature of the contents of the reaction receptacle, heating or cooling the contents of the reaction receptacle, altering the concentration of one or more components of the contents of the reaction receptacle, separating or isolating components of the contents of the reaction receptacle, detecting electromagnetic signal emissions (e.g., light) from the contents of the reaction receptacle, deactivating or stopping a reaction in progress, or any combination of two or more such processes.

[0100] In some embodiments, first module 100 may include a receptacle loading device 102 that includes structure for receiving and holding one or more empty reaction receptacles before the receptacles are used to perform one or more process steps of NAT. Receptacle loading device 102 may comprise a compartment, e.g., a drawer or cabinet, that can be opened and loaded with multiple receptacles and that can include a receptacle feeding device for moving the receptacles, e.g., one or more at a time, to a receptacle pick-up location. In some embodiments, the receptacle pick-up location includes a registered or known location of the receptacle to facilitate removal of the receptacle by a receptacle dispenser.

[0101] In some embodiments, first module 100 may further include one or more bulk reagent container compartments configured to store one or more bulk containers that hold bulk reagents or that hold waste materials. In some embodiments, the bulk reagents include fluids such as water, buffer solutions, target capture reagents, nucleic acid amplification reagents, etc. In some embodiments, the bulk reagent container compartments may be configured to maintain the contents of such containers at a defined storage temperature and / or agitate such containers to maintain the contents of the containers in solution or suspension.

[0102] In some embodiments, the first module 100 comprises a first bulk reagent container compartment configured to store at least one bulk container holding nucleic acid amplification reagents, e.g., reagents for performing TMA, and a separate second bulk reagent container compartment configured to store at least one bulk container holding sample preparation reagents, e.g., target capture reagents. In some embodiments, the first module 100 comprises a bulk reagent container compartment that stores both bulk containers holding nucleic acid amplification reagents and bulk containers holding sample preparation reagents, e.g., target capture reagents. In some embodiments, the bulk reagent container compartment configured to store at least one bulk container can be a compartment that houses a mixer, e.g., an orbital mixer configured to transport containers holding sample preparation reagents, e.g., target capture reagents. In some embodiments, one or more bulk container compartments can comprise a holding structure for transporting and agitating containers (e.g., containers of TCRs with magnetically responsive solid supports). U.S. Provisional Application No. 61 / 783,670 to Buse et al., entitled "Apparatus for Indexing and Agitating Fluid Containers," filed March 14, 2013, which is commonly owned with this specification, discloses exemplary retention structures. In some embodiments, one or more bulk container compartments comprise a slidable tray defining at least one recess configured to receive individual bulk containers in close proximity.

[0103] In some embodiments, one or more of the bulk reagent container compartments of the first module 100 can be configured to store at least two containers containing sample preparation reagents, such as target capture reagents. In some embodiments, each target capture reagent is specific to a particular assay type (i.e., target nucleic acid), nucleic acid type (e.g., RNA or DNA), and / or sample type (e.g., feces, urine, blood, etc.). For example, the target capture reagent can comprise a probe having a region specific to the target nucleic acid. See, e.g., U.S. Patent No. 6,534,273 to Weisburg et al.

[0104] First module 100 may further include a sample loading device configured to receive and hold containers, such as test tubes, containing samples. First module 100 may also include one or more material transfer devices for transferring fluids, e.g., sample fluids, reagents, bulk fluids, waste fluids, etc., to and from reaction receptacles and / or other containers. In some embodiments, the material transfer device may comprise one or more robotic pipettors configured for controlled and automated movement and access to reaction receptacles, bulk containers holding reagents, and containers holding samples. In some embodiments, the material transfer device may also include a fluid dispenser, e.g., a nozzle, disposed within another device and connected by suitable fluid conduits to a container, e.g., a bulk container holding reagents, and to a pump or other device for effecting fluid transfer from the container to the dispenser.

[0105] In some embodiments, first module 100 may further include multiple loading stations, such as loading stations 104, 106, 108 depicted in FIG. 4 , configured to receive racks and other forms of holders for carrying sample receptacles and various reagent containers that can be accessed by material transfer devices. Examples of loading stations and receptacle holders that can be used in conjunction with embodiments are shown and described in U.S. Patent No. 8,309,036 to Clark et al. In certain embodiments in which first module 100 comprises a platform for performing NAT, the reaction reagents may include target capture reagents, lysis reagents, nucleic acid amplification reagents (e.g., polymerase and nucleoside triphosphates required for amplification), and / or nucleic acid detection reagents, such as detectable probes or intercalating dyes.

[0106] In some embodiments, first module 100 may further include a temperature gradient station 110 configured to hold one or more reaction receptacles in an environment maintained above ambient temperature so as to elevate the temperature of the contents of the receptacles. An exemplary temperature gradient station is disclosed in U.S. Patent No. 8,192,992 to Ammann et al.

[0107] In some embodiments, the first module 100 may further include one or more heater modules. The illustrated first module 100 includes three heated incubators 112, 114, and 116, each configured to receive multiple reaction receptacles and maintain the receptacles in an elevated temperature environment. Exemplary incubators are disclosed by U.S. Patent No. 7,964,413 to Macioszek et al. and U.S. Patent Application Publication No. 2012 / 0221252 to Heinzet al. The heater module may alternatively be a heating plate. In some embodiments, it is possible to have a heater module configured with one or more heated incubators and one or more heating plates.

[0108] In certain embodiments in which first module 100 comprises a platform for performing NAT, the first module may also include sample processing components, such as magnetic separation wash stations 118, 120, adapted to separate or isolate target nucleic acids immobilized on magnetically responsive solid supports from the remaining contents of the receptacle. Exemplary magnetic separation wash stations are disclosed by Hagen et al., U.S. Patent Application Publication No. 2010 / 0288395, and Ammann et al., U.S. Patent No. 6,605,213.

[0109] Although not illustrated in the plan view of first module 100, first module 100 may, in some embodiments, include one or more material transfer devices, such as robotic pipettors. Figure 21, a perspective view of a robotic pipettor of second module 400, illustrates at least one method for configuring a material transfer device for first module 100.

[0110] In some embodiments, the first module 100 may further include a cooling module 122 adapted to receive one or more reaction receptacles and maintain the receptacles at a temperature below the ambient temperature environment so as to reduce the temperature of the contents of the receptacles.

[0111] Also, in some embodiments, first module 100 may include detector 124 configured to receive reaction receptacles and detect signals (e.g., optical signals) emitted by the contents of the reaction receptacles. In one implementation, detector 124 may comprise a luminometer for detecting luminescence signals emitted by the contents of the receptacles and / or a fluorometer for detecting fluorescent emissions. First module 100 may also include one or more signal detection devices, such as fluorometers, coupled to one or more of incubators 112, 114, 116 and preferably configured and controlled to detect signals emitted by the contents of receptacles contained within the incubators at defined periodic intervals while a process, such as nucleic acid amplification, is occurring within the reaction receptacles. An exemplary luminometer and an exemplary fluorometer are disclosed by Macioszek et al. in U.S. Pat. No. 7,964,413, and another exemplary fluorometer is disclosed by Heinz et al. in U.S. Patent Application Publication No. 2012 / 0221252.

[0112] First module 100 further includes a receptacle transfer device, which in the illustrated embodiment comprises a receptacle distributor 150. Components of first module 100, such as incubators 112, 114, 116, loading stations 104, 106, 108, temperature gradient station 110, washing stations 118, 120, and cooling module 122, may also include receptacle transfer portals through which receptacles can be inserted into or removed from the individual components. Each component may or may not include an openable door covering its receptacle portal. Receptacle distributor 150 is configured to move receptacles between various components, retrieve receptacles from components, and place receptacles into components. In one exemplary embodiment, receptacle dispenser 150 includes a receptacle dispense head 152 configured to move in an X direction along a transport track assembly 154, rotate in a theta (Θ) direction, and move receptacles in an R direction into and out of receptacle dispense head 152 and one of the components of first module 100. An exemplary receptacle dispenser is disclosed by Hagen et al. in U.S. Patent Application Publication No. 2012 / 0128451.

[0113] Second Module Aspects of the present disclosure are embodied in a second module 400 of a diagnostic system. In some embodiments, the second module 400 is integral with the first module 100, as described above, while in other embodiments, the second module 400 may be selectively operably coupled to the first module 100. In some embodiments, the first module 100 to which the second module 400 may be operably coupled includes a molecular instrument, such as, for example, the Panther® instrument system available from Hologic, Inc.

[0114] In one exemplary embodiment, second module 400 is configured to perform a nucleic acid amplification reaction, e.g., PCR, and in certain embodiments, measure fluorescence in real time (i.e., as the amplification reaction occurs). A controller commands the components of first module 100 and second module 400 to perform the assay steps. In one exemplary embodiment, first module 100 houses a computer and all the fluids, reagents, consumables, and mechanical modules required to perform a given amplification-based assay, such as an assay based on a transcription-based amplification method, e.g., TMA or nucleic acid sequence-based amplification (NASBA). (TMA methods are described by Kacian et al. in U.S. Pat. Nos. 5,399,491 and 5,480,784, and NASBA methods are described by Davey et al. in U.S. Pat. No. 5,409,818 and Malek et al. in U.S. Pat. No. 5,409,818.) (As described by U.S. Patent No. 5,130,238 to W. et al.). As previously mentioned, the controller may comprise a computer, preferably capable of supporting LIS ("Laboratory Information System") connectivity as well as remote user access. In some embodiments, the second module 400 stores component modules that enable a second amplification assay, melt analysis, and, optionally, additional functionality. Other components may include a printer and an optional uninterruptible power supply.

[0115] Embodiments of the general configuration of second module 400 are shown in Figures 1, 5, 6, and 14. Figure 1 is a perspective view of diagnostic system 10 including second module 400 and first module 100. Figure 5 is a top plan view of second module 400 separated from first module 100. Figure 6 is a top plan view of amplification processing deck 430 of second module 400, e.g., a deck containing components for performing PCR. Figure 14 is a top plan view of receptacle processing deck 600 of second module 400. 1, 5, 6, and 14, components of second module 400 may include, for example, a material transfer device (e.g., robotic pipettor 402), a thermacycler / signal detector 432, tip compartments 580 (e.g., two or more) configured to contain trays of disposable tips for the pipettors, processing cap / vial compartments 440 (e.g., two or more) configured to contain trays of disposable processing vials and associated caps, bulk reagent container compartment 500, bulk reagent container transporter 550, receptacle handoff device 602, and In the exemplary embodiment shown, the system may include a receptacle dispensing system comprising a receptacle dispenser 312 comprising a rotary dispenser, MRD storage units 608, 610, 612 configured to store MRDs 160, magnetic elution slots 620 (e.g., two or more), a waste bin access door 652, a waste bin 652, a centrifuge 588, a reagent pack exchanger 700, a reagent pack loading station (e.g., two or more) 640, and a compartment 590 configured to store accessories including, for example, consumables, output cards, and / or post-processing cap / vial assemblies.

[0116] As shown in FIG. 1 , components may be located on different levels or decks arranged vertically throughout module 400. In some embodiments, material transfer and handling device 402 can be a robotic pipettor 402, as shown in FIG. 1 . Robotic pipettor 402 is located near the top of second module 400, and in some embodiments, above all other components. The depicted configuration represents just a single embodiment. The vertical order of decks and components may vary according to the intended use of diagnostic system 10. In the depicted embodiment, below robotic pipettor 402, amplification processing deck 430 includes bulk reagent container compartment 500 and bulk reagent container transporter 520, centrifuge 588, the top of the thermacycler / signal detector 432, tip compartment 580, and processing cap / vial compartment 440. Below the amplification processing deck 430, the receptacle processing deck 600 includes a receptacle transfer device 602, a rotary distributor 312, MRD storage units 608, 610, 612, a magnetic elution slot 620, a reagent pack exchanger 700, and a reagent pack loading station 640. As can be seen in Figure 6, the magnetic elution slot 620 and the reagent pack loading station 640 on the receptacle processing deck 600 are accessible by the robotic pipettor 402 through gaps between the modules of the amplification processing deck 430.

[0117] The receptacle distribution system, comprising a receptacle handover device 602 and a rotary distributor 312, is configured to receive a receptacle or a group of receptacles (e.g., MRD 160) from a receptacle transport device (e.g., receptacle distributor 150) of a first module 100, transfer the receptacles to a second module 400, and move the receptacles to different positions within the second module 400. The rotary distributor 312 and the receptacle handover device 602 are shown diagrammatically in FIG. 14. Further details regarding these components are described below.

[0118] In some embodiments, the second module 400 is operably positioned adjacent to the first module 100, and the bulk reagent container compartment 500 extends into the first module 100 so that the elution containers 502, 504 can be transported by a bulk reagent container transporter 550 from the bulk reagent container compartment 500 to a position within the first module 100 where a material transfer device, e.g., a robotic pipetter, within the first module 100 can access the containers 502, 504.

[0119] In some embodiments, the second module 400 is generally self-supporting relative to the first module 100 so that the second module / first module assembly is not over-constrained. Thus, in some embodiments, the second module 400 does not include any feet that contact the ground surface directly below the second module and support some or all of the module's weight. In some embodiments, if the second module 400 includes its own rigid feet (e.g., two, three, or four feet), the feet of the first module 100 and the feet of the second module 400 may create an over-constrained geometry. In this case, all feet of the second module 400 and the first module 100 would be carefully leveled relative to each other to ensure that the assembly is level and that excessive stress is not applied to the attachment points between the second module 400 and the first module 100. To avoid such potentially over-constrained geometries, the second module 400, in some embodiments, is cantilevered from the first module 100, where the first module foot can support the additional weight of the second module. In some embodiments, a portion of the weight of the second module 400 may be supported from the first module 100 by a single foot on the far end of the second module 400.

[0120] In some embodiments, the second module 400 and the first module 100 are mounted to an integral frame.

[0121] In some embodiments, the interface between the second module 400 and the first module 100 is blocked and sealed, if possible, to prevent airflow between the two modules. An existing air inlet on the side of the first module 100 facing the second module 400 may be conducted to a fresh air source through the second module 400. The sidewall of the second module 400 facing the first module 100 may be covered by a panel to block airflow into the first module 100. Such a panel may include openings, cable routing, etc. for transferring receptacles or containers between the second module 400 and the first module 100, as needed.

[0122] The components of an exemplary embodiment of the second module 400 are described below.

[0123] Reagent Pack In some embodiments, amplification and other reagents may be provided in second module 400 in lyophilized form in a reagent pack comprising a cartridge containing wells in which the lyophilized reagents can be reconstituted. An example of a cartridge that may be used in this embodiment is described in U.S. Provisional Application No. 61 / 782,320, "Systems, (Both of these cartridges are identified by reference number 500 in FIGS. 10A and 10B.) Reagent packs are further stored within the second module 400 and, in some embodiments, configured to be moved within the second module 400 by the dispenser 312 and inserted into and removed from the reagent pack exchanger 700.

[0124] Details of a reagent pack 760, according to one embodiment, are shown in FIGS. 19 and 20. The reagent pack 760 may include multiple mixing wells 762, each containing a lyophilized unit-dose of an assay-specific reagent 768, which may be in pellet form. (As used herein, "unit dose" or "unitized" means an amount or concentration of a reagent sufficient to perform one or more steps of a single assay for a single sample.) In some embodiments, the unit-dose reagent 768 comprises components for performing a nucleic acid amplification reaction. For example, the nucleic acid amplification reaction components can be a polymerase, a nucleoside triphosphate, or any other suitable components. In the illustrated embodiment, the reagent pack 760 includes ten mixing wells 762. However, in some embodiments, the reagent pack 760 may include more or fewer than ten mixing wells. Each mixing well 762 of a single reagent pack 760 may hold the same reagent, or the wells 762 may hold different reagents, or some wells 762 may hold the same reagent and some may hold different reagents. Exemplary assay-specific reagents 768 retained within reagent pack 760 include unitized reagents for performing a single amplification reaction, e.g., PCR, and / or sample-based detection reaction. Such reagents may be specific for one target nucleic acid or multiple different target nucleic acids. For example, the multiple different target nucleic acids may be part of a respiratory panel, and the unitized reagents may be specific for Flu A, Flu B, RSV, parainfluenza 1, 2, and 3, human metapneumovirus, adenovirus, HI, H3, 2009, or other viruses. suffices to perform PCR reactions targeting H1N1 and / or Tamiflu resistance. In certain embodiments, each reagent pellet 768 is retained at the bottom of its associated mixing well 762 using an electrostatic charge imparted to the pellet 768 and / or the mixing well 762. In other embodiments, each reagent pellet 768 is retained at the bottom of its associated mixing well 762 using one or more physical features present within the mixing well 762, such as those disclosed in U.S. Provisional Application No. 61 / 782,320 to Knight et al.

[0125] In some embodiments, the mixing well 762 is covered by a pierceable foil 766 adhered to the top of the reagent pack 760. The foil 766 can be pierced by a pipette tip 584 to allow a reconstitution agent or other substance to be dispensed into the mixing well 762 and to allow a reconstitution reagent to be aspirated from the mixing well 762.

[0126] In some embodiments, the reagent pack 760 further includes a manipulation structure 764, e.g., a manipulation hook, similar to the manipulation structure 166 of the MRD 160 and configured to be engageable by a manipulation structure, e.g., a hook, of the rotary distributor 312. The reagent pack 760 may include a rear recess 770 configured to align the reagent pack within a reagent pack carrier, as described below.

[0127] Tip Compartment As shown in FIGS. 1, 5, and 6, tip compartment 580 is configured to hold trays 582 of disposable pipette tips in a manner that allows tips held in drawer 580 to be accessed by robotic pipettor 402. In the illustrated embodiment, second module 400 includes two tip compartments 580, each configured to hold up to three trays 582 of disposable pipette tips. Compartments 580 may be configured to receive commercially available trays of disposable pipette tips. Exemplary commercially available pipette tips and trays are available from TECAN (TECAN US Inc., Research Triangle Park, North Carolina). Such tips are available in various volume capacities, and each tip may be conductive to facilitate capacitive liquid level sensing and tip presence detection, as is known in the art. An exemplary tray holds 96 pipette tips.

[0128] The tip compartment 580 is configured to be accessible by an operator for reloading of the trays 582. In certain contemplated embodiments, the tip compartment 580 comprises a drawer configured to slide out from the second module 400, allowing an operator to place tip trays 582 into the drawer 580 and remove empty trays from the drawer 580. A door or cover panel, part of either each drawer 580 or the housing of the diagnostic system 10, opens to access each tip compartment 580 behind it. The door or cover panel may provide an aesthetically pleasing appearance to the front of the second module 400. A manual or automatic lock controlled by the system controller may be provided to prevent the compartment 580 from opening when the second module 400 is operating, and in some embodiments, a visual and / or audible warning signal may be provided to indicate that the compartment 580 is not properly closed. In an alternative embodiment, compartment 580 includes an access door and a slidable tray configured to slide out of the second module, thereby providing loading access to the operator.

[0129] Material Transfer and Handling Systems 1, 21, and 22, the material transfer and handling system 402, e.g., a robotic pipettor, is a dual-arm system including a front arm 408 and a rear arm 416. However, other robotic pipettor and handling configurations are contemplated, and the depicted embodiment is exemplary only. The material transfer and handling system 402 can be configured to dispense and / or aspirate materials into and / or from containers, receptacles, wells, etc., within the second module 400. In the exemplary embodiment, the front arm 408 includes a material transfer pipettor 410 configured to aspirate and dispense fluids and includes a pump, e.g., an integrated syringe pump, while the rear arm 416 includes a vial transfer arm 418 and does not perform material transfer. The robotic pipettor system 402 comprises a Cartesian gantry assembly with two lateral tracks 404, 406, a rear arm longitudinal track 420, and a front arm longitudinal track 412. The designations "longitudinal" and "lateral" are merely to distinguish between two sets of tracks, which may be orthogonal to one another; otherwise, the designations are arbitrary.

[0130] The material transfer pipettor 410 may be driven back and forth along the front arm longitudinal track 412 by a belt, drive screw, or other motion transmission device coupled to a motor, and the vial transfer arm 418 may be driven back and forth along the rear arm longitudinal track 420 by a belt, drive screw, or other motion transmission device coupled to a motor. The front arm longitudinal track 412 may be driven back and forth along the lateral tracks 404, 406 by a belt, drive screw, or other motion transmission device coupled to a motor, and the rear arm longitudinal track 420 may be driven back and forth along the lateral tracks 404, 406 by a belt, drive screw, or other motion transmission device coupled to a motor. The material transfer pipettor 410 and the vial transfer arm 418 include a probe that is driven along the Z-axis, i.e., vertical axis, by, for example, a motor coupled to the probe by, for example, a gear, rack and pinion, lead screw, or other suitable device. The motor may be under the control of a system controller. The motors may be stepper motors and may include rotary encoders for controlling and monitoring the position of the tracks or pipettors coupled thereto. Each track has a home sensor (or limit switch) for indicating when the material transfer pipettor 410 or vial transfer arm 418 is in one or more designated positions, such as a designated "home" position. Similarly, each device may have a vertical home sensor for indicating when the probe is in one or more designated vertical positions, such as a designated vertical "home" position. Such sensors for indicating home position may include optical sensors (e.g., slotted optical sensors), proximity sensors, magnetic sensors, capacitive sensors, etc.

[0131] In one exemplary embodiment, the material transfer pipettor 410 is configured to receive a TECAN 1 mL disposable pipette tip by inserting its probe into the disposable pipette tip; the interference fit between the probe and the pipette tip frictionally secures the pipette tip to the end of the probe. The front arm 408 and material transfer pipettor 410 are configured to access at least a portion of both the amplification processing deck 430 and the receptacle processing deck 600 on the second module 400. The material transfer pipettor 410 may include integrated tip sensing to confirm the presence or absence of a disposable pipette tip, capacitive level sensing to detect contact by the pipette tip with the surface of the fluid contents of a fluid reaction receptacle or other container and determine the level of the fluid contents based on the detected vertical position of the pipettor, and pressure sensing to sense pressure fluctuations within the material transfer system during fluid dispensing or aspiration. The material transfer pipettor 410 is capable of transferring fluids, caps, or cap / processing vial assemblies, such as those described below.

[0132] Vial transfer arm 418 is a "pick and place" device configured to pick up cap / vial assemblies by inserting its probe into the cap coupled to the vial, as described below.

[0133] Pipette Pump In an exemplary embodiment, the pump for the material transfer pipettor 410 includes a ceramic piston driven by a servo motor and lead screw. The servo motor is controlled by a system controller, and the device may include rotary encoder feedback to the system controller and a home sensor for monitoring the position of the piston. The syringe may have a volume of 0.5 to 3 mL (preferably 1.05 mL) and, in certain embodiments, is ceramic. The pump is preferably capable of dispensing very small volumes (5 μL) of fluid with a + / - 5% coefficient of variation (CV) measured over 30 discrete dispenses. To achieve this performance, in certain embodiments, the pump includes a solenoid valve to release pressure at the end of the stroke, ensuring consistent fluid shear. Processing Cap / Vial Assembly

[0134] Generally, the processing vials provide receptacles for containing reaction fluids for performing PCR or other processes. Caps are configured to be placed in or on the vials in an automated manner to close the vials. In some embodiments, the caps are configured to receive the end of the vial transfer arm 418 using a friction fit so that the transfer arm 418 can then pick up the cap and place it in or on the vial. The cap and vial are configured to lock together such that once the cap is placed in or on the vial, they interlock and form a cap / vial assembly. A robotic pipettor, with the probe of the transfer arm 418 inserted into the cap, can then pick up the cap / vial assembly and transfer it from one location 400 to another within the second module. Exemplary caps and processing vials are disclosed, for example, by Knight et al., U.S. Provisional Application No. 61 / 782,320.

[0135] Details of an exemplary embodiment of a process vial 464, a process vial cap 476, and a vial transfer arm probe 422 are shown in Figures 23-26.

[0136] 23-25, the processing vial 464 may have a conical shape and an open top end 465 surrounded by a locking collar 466. Side through-holes 468 are formed through the locking collar 466 at diametrically opposed locations. A latch hook 472 is located above each through-hole 468.

[0137] The process vial cap 476 has an open top end 478 and a closed bottom end 480. An annular collar 482 extends about the cap 476 at a location between the top end 478 and the bottom end 480. The collar 482 of the vial 476 seats on top of the thermacycler when the vial 476 is installed therein, ensuring a close fit of the vial within the well of the thermacycler. An exemplary thermacycler for use with the process vial 476 is disclosed by Buse et al. in U.S. Patent Application Publication No. 2014 / 0038192. The lower portion of the cap 476 directly below the collar 482 defines a plug that fits within the open top end 465 of the process vial 464. The plug is sized to fit within the process vial 464 using an interference friction fit. A latch collar 484 extends about the cap 476 at a location below the collar 482. Sealing rings 486, 488 extend about the cap 476 at a location below the latch collar 484.

[0138] 24 and 25 show, in cross section, a process vial cap 464 initially held in a cap well 490 of a cap / vial tray 460, and a process vial 464 held in a vial well 474 of the cap / vial tray 460. After fluid is dispensed into the process vial 464 (connected to a robotic pipettor) with a disposable pipette tip 584, the process vial 464 is capped with a process vial cap 476 by inserting the closed lower end 480 of the cap 476 into the open upper end 465 of the vial 464 until the bottom surface of the collar 482 of the cap 476 abuts the top surface of the locking collar 466 of the vial 464. The latch collar 484 of the cap 476 snaps beneath the latch hook 472 of the vial 464, securing the cap 476 to the vial 464. The cap 476 and vial 464 are then locked together, and the cap / vial assembly may be picked up and moved by the pipettor. The cap / vial assembly can be removed from the pipettor probe 422 by an extraction device that engages the rim 479 surrounding the open end 478 and pulls the cap / vial assembly away from the probe 422. The sealing rings 486, 488 of the cap 476 preferably have an outer diameter slightly larger than the inner diameter of the upper portion of the vial 464, thereby forming a tight seal between the cap 476 and the vial 464 because the cap and vial are made, at least in part, from a material that is resilient, such as a suitable plastic.

[0139] An alternative process cap / vial assembly is shown in FIG. 26, which is an exploded perspective view of a process vial 670 and a process vial cap 660. The process vial cap 660 includes a closed lower end 662, a tapered opening 668, and a latch collar 664 having latch fingers 666. The vial 670 includes a locking collar 672 that surrounds the open upper end of the vial 670 and collar 674. The collar 674 of the vial 670 seats on top of the thermacycler when the vial 670 is installed therein, ensuring a close fit of the vial into the well of the thermacycler. After fluid is dispensed into vial 670, the vial is capped by first inserting pipettor probe 422 into the tapered opening 668 of process vial cap 660, frictionally securing cap 660 to pipettor probe 422, and then using the pipettor to pick up cap 660 and insert the closed lower end 662 of cap 660 into the open upper end of vial 670 until latch fingers 666 snap into locking engagement onto locking collar 672 of vial 670. Cap 660 and vial 670 are then locked together, and the cap / vial assembly may be picked up and moved by the pipettor. The cap / vial assembly can be removed from probe 422 by an extraction device that engages rim 669 surrounding opening 668 and pulls the cap / vial assembly away from probe 422.

[0140] The second module 400 may also include a "vial present" sensor. The vial present sensor is used as a process control measure to verify whether a vial is attached to a cap. The material transfer pipettor 410 (front arm 408) and the vial transfer arm 418 (rear arm 416) will detect when a cap is attached to the arm. One way the material transfer pipettor 410 or the vial transfer arm 418 detects when a cap is present is by a strip sleeve on the probe 422. When a cap is picked up by the probe, the upper rim of the cap pushes up against the sleeve, causing it to elevate (e.g., a few millimeters), and this movement can be detected by a sensor. However, pipettors often cannot detect when a vial is attached to a cap. In one exemplary embodiment, the vial present sensor is an optical sensor (or sensors) that either arm 408, 416 may move over / through as it transports capped vials into and out of the centrifuge 588. The vial presence sensor will trigger on a vial (if present) as the arm moves past the sensor.

[0141] Bulk reagent container compartment and bulk reagent container carrier In one exemplary embodiment, bulk reagent container compartment 500 is configured to hold multiple bulk reagent containers. Each bulk reagent container can hold reagents for use in multiple reaction receptacles. In some embodiments, the bulk reagent containers are bottles or any other containers suitable for containing reagents in bulk. In some embodiments, the bulk reagents in the bulk reagent containers can include sample preparation reagents (e.g., target capture reagents (TCRs), wash solutions, elution reagents, or any other sample preparation reagents), reconstitution reagents, or any other required bulk reagents. In some embodiments, the bulk reagent containers hold a quantity of bulk reagent sufficient to perform between about 50 and 2000 assays. In some embodiments, the bulk reagent containers hold a quantity of bulk reagent sufficient to perform between about 250 and 1000 assays. In some embodiments, the bulk reagent containers hold a quantity of bulk reagent sufficient to perform less than about 250 assays or more than about 1000 assays. In some embodiments, the bulk reagents are for performing isothermal nucleic acid amplification reactions, e.g., transcription-based amplification reactions such as TMA.

[0142] In some embodiments, bulk reagent container compartment 500 can be configured to hold two elution buffer containers, two oil containers, and four reconstitution fluid containers. Bulk reagent container compartment 500 may be opened and loaded with containers by an operator. For example, bulk reagent container compartment 500 may be a drawer that is slid out of the main body of diagnostic system 10. In some embodiments, once closed, bulk reagent container transporter 550 moves elution buffer containers into first module 100 to a location where a material transfer mechanism, e.g., a robotic pipetter, can access the containers. In some embodiments, bulk oil and bulk reconstitution fluid containers remain within bulk reagent container compartment 500, where they are accessible to material transfer pipetter 410.

[0143] Containers carried on the bulk reagent container compartment 500 may be identified by a machine-readable code such as RFID. An indicator panel 507 with visible (e.g., red and green LEDs) and / or audible indicators provides feedback to the operator regarding container status.

[0144] Bulk reagent container compartment 500 and bulk reagent container transporter 550 are shown in FIGS. 5-10. In some embodiments, bulk reagent container compartment 500 is located on amplification processing deck 430 adjacent tip compartment 580 and may be accessed from the front of second module 400. Bulk reagent container compartment 500 may be pulled out to allow an operator to place into drawer 500 two containers 502, 504 containing elution buffer and several bulk containers or other types of fluid containers containing other reagents, such as oil or reconstitution buffer. The number of containers accommodated by drawer 500 is dictated by considerations of the intended processing volume and the desired time period between required restorage of supply volumes.

[0145] A door or cover panel, which may be part of the bulk reagent container compartment 500 or the housing of the diagnostic system 10, may be opened to access the bulk reagent container compartment 500 behind it. The door or cover panel may provide an aesthetically pleasing appearance to the front of the second module 400. An automatic lock, controlled by the system controller, may be provided to prevent the bulk reagent container compartment 500 from being pulled open when the second module 400 is in operation. In some embodiments, a visual and / or audible warning signal may be provided to indicate that the bulk reagent container compartment 500 is not properly closed.

[0146] When the bulk reagent container compartment 500 is closed, the containers 502, 504 are moved to the distal end of the drawer 500 where they are positioned in operable engagement with a bulk reagent container transporter 550 that extends laterally from the end of the drawer 500 into the first module 100. In response to the closure of the bulk reagent container compartment 500, the bulk reagent container transporter 550 is activated and moves the containers 502, 504 into the first module 100 to a position where the containers 502, 504 may be accessed by a robotic pipettor of the first module 100. The bulk reagent container transporter 550 may be activated manually by an operator (e.g., by depressing a button or switch) or automatically by a system controller in response to receiving a load signal indicating that the bulk reagent container compartment 500 is fully closed, thereby placing the containers 502, 504 in an operable position relative to the bulk reagent container transporter 550.

[0147] Details of bulk reagent container compartment 500 are shown in Figures 9-13. In some embodiments, bulk reagent container compartment 500 includes a container tray 506 configured to hold a plurality of reagent containers and a container carriage 512 disposed at an end of container tray 506 and configured to carry elution reagent containers 502, 504. In some embodiments, container tray 506 and container carriage 512 are movable along a track 508 between an extraction position as shown in Figure 9 (see also Figure 7) and a closed position as shown in Figure 10 (see also Figure 8).

[0148] Container carriage 512 is carried on a carriage transporter 522 configured to be movable along track 508 along with container tray 506. As shown in Figures 11 and 12, carriage transporter 522 includes horizontal carriage rails 524 and 526, respectively, that engage rail slots 514, 516 formed in container carriage 512 and retain container carriage 512 within carriage transporter 522.

[0149] The bulk reagent container compartment 500 is configured to allow an operator to place reagent containers 502, 504 into the container carriage 512 when the drawer is in the open position, as shown in Figures 7 and 9. Upon closing of the drawer to the position shown in Figures 8 and 10, the reagent container carriage 512 is released from the carriage transporter 522 and can be engaged by the bulk reagent container transporter 550 to pull the carriage 512 to a lateral position relative to the track 508 of the container tray 506, as shown in Figure 10. In this manner, bulk reagents can be transferred from the second module 400 to the first module 100.

[0150] More specifically, the carriage transporter 522 moves along the track 508 as the container tray 506 is moved to the open or closed position. As shown in FIG. 11 , the carriage transporter 522 is configured to pivot about a pivot pin 534 and includes a pivoting carriage lock 532 including a locking leg 536 that extends upward through an opening 528 formed in the bottom of the carriage transporter 522 and into a lock recess 520 formed in the bottom of the container carriage 512. A trigger leg 538 extends below the carriage transporter 522. As the container tray 506 is moved to the closed position (left in FIG. 11 ), the trigger leg 538 of the pivoting carriage lock 532 engages the lock trigger 510 protruding upward from the track 508, thereby pivoting the carriage lock 532 counterclockwise and removing the ends of the locking legs 536 from the lock recesses 520 of the container carriage 512, as shown in FIG. 12 . Once the trigger leg 538 is removed from the lock recesses 520, the container carriage 512 and the containers 502, 504 carried therein can slide laterally from the carriage transporter 522 onto the bulk reagent container transporter 550.

[0151] The bulk reagent container transporter 550 includes a motorized carriage transport mechanism for moving the container carriage 512 and the containers 502, 504. In one exemplary embodiment, as shown in Figures 9, 10, and 13, the carriage transporter includes a motor 552, a continuous belt 554 disposed over the output shaft of the motor, and an idler wheel 556 located on the opposite end of the container transporter 550 from the motor 552. The motor 552 may include a stepper motor and may include a rotary encoder for monitoring and controlling the position of the motor via control signals and feedback data.

[0152] The carriage transport mechanism further includes a slide 558 with a carriage hook 564 extending therefrom. A belt 554 is attached to a portion of the slide 558 such that movement of the belt by the motor 552 causes corresponding translation of the slide 558 in one direction or the other along the transporter 550.

[0153] 12 and 13, the container tray 506 is moved to the closed position, where the trigger leg 538 of the pivoting carriage lock 532 engages the lock trigger 510, disengaging the locking leg 536 from the lock recess 520 and passing the carriage hook 564 through a carriage hook slot 530 formed in the carriage transporter 522 and engaging a hook catch 518 formed in the container carriage 512. The slide 558 and carriage hook 564 may then be translated laterally along the container transporter 550 by the belt 554 to pull the container carriage 512 from the carriage transporter 522 and onto the bulk reagent container transporter 550. As shown in FIG. 11, the bulk reagent container transporter includes carriage rails 566 , 568 that will engage with rail slots 514 , 516 , respectively, of the container carriage 512 as the container carriage 512 is pulled onto the bulk reagent container transporter 550 .

[0154] 13, a home flag 560 protrudes from the slide 558 and engages a slotted optical sensor 562, indicating that the slide 558 and carriage hook 564 are in the fully extended position shown in FIG. 13. A second slotted optical sensor 570 is provided closer to the motor 552 (see FIG. 9). The second optical sensor 570 is engaged by the home flag 560 when the slide 558 and hook 564 are in the fully retracted position, as shown in FIG. 9. Signals from the sensors 562, 570 are communicated to a system controller to monitor the position of the slide 558. Alternatively, the bulk reagent container transporter 550 may include a limit switch (e.g., a contact switch) for stopping the operational movement of the slide 558 in the fully extended and / or fully retracted positions, for example, by generating a stop signal that is communicated to the controller, which then sends a stop command or terminates power to the motor 552. Still, other types of sensors may also be used to indicate the extend and retract stop positions, including proximity sensors, magnetic sensors, capacitive sensors, etc.

[0155] Cycler / Signal Detector The cycler deck 430 includes a cycler 432, such as a Thermacycler. The cycler 432 is used in nucleic acid amplification reactions, and the choice of cycler type depends on the nature of the amplification reaction intended to be performed on the second module 400. For purposes of this disclosure, the use of a Thermacycler is illustrated. However, it should be understood that the cycler type incorporated into the second module 400 depends on the amplification reaction intended to be performed on the second module 400.

[0156] An exemplary embodiment of the thermacycler 432 is disclosed by U.S. Patent Application Publication No. 2014 / 0038192 to Buse et al. An exemplary embodiment of the signal detector 432 is disclosed by Hagen et al., filed March 7, 2014, which is commonly owned herewith. et al., U.S. Patent Application No. 14 / 200,460, entitled "Indexing Signal Detection Module."

[0157] In certain embodiments, the thermacycler can have different thermal zones. Such thermacyclers allow the system to run separate assays under different conditions. For example, in a two-zone thermacycler, a first assay can be run under a first set of time and temperature conditions, and a second assay can be run under a second set of time and temperature conditions. It is contemplated that a multi-zone thermacycler can have two, three, four, five, or even six or more separate thermal zones. Generally, to the extent that a multi-zone thermacycler is implemented in a system, the number of zones for the multi-zone thermacycler is equally divisible into 96 (i.e., 2, 4, 6, 8, etc.).

[0158] centrifuge As shown in FIGS. 1, 5, and 6, the centrifuge 588 can be located on the amplification processing deck 430 of the second module 400. In one exemplary embodiment, the centrifuge 588 will centrifuge one or more (in one embodiment, up to five) capped processing vials 464, 670 at a time. In the exemplary embodiment, each vial is centrifuged prior to PCR to ensure that the sample material is concentrated within the bottom of the processing vial 464, 670 and to remove any air bubbles from the contents of the vial 464, 670, which may affect heat transfer and optical transmission quality. The material transfer pipettor 410 of the front arm 408 places the capped vial 464, 670 into the centrifuge 588 at an access port indicated by reference numeral 589. After centrifugation is complete, the vial transfer arm 418 of the rear arm 416 removes the capped vial 464, 670 from the centrifuge 588 at an access port indicated by reference numeral 587 and places it in the thermacycler 432. In one embodiment, the centrifuge configuration (e.g., by providing separate ports 587, 589) allows the material transfer pipettor 410 (front arm 408) and the vial transfer arm 418 (rear arm 416) to simultaneously load / unload the capped vials 464, 670 without interfering with each other. Thus, in one embodiment, the centrifuge not only performs the function of centrifuging its loaded vials, but also functions as a vial transport mechanism by transporting the capped vials 464, 670 from a position 589 accessible to the material transfer pipettor 410 to a position 587 accessible to the vial transfer arm 418. In one embodiment, material transfer pipettor 410 is disabled to access location 587 and vial transfer arm 418 is disabled to access location 589 .

[0159] Additionally, centrifuge 588 may be configured to track the position of a loaded vial within the centrifuge and determine when a vial is positioned at either of access ports 587, 589. For example, the turntable or other rotating structure on which the loaded vial is centrifuged may be driven by a stepper motor, which may include a rotary encoder for precise movement of the turntable and tracked motor count, and / or the turntable or rotating structure may include a rotational position indicator, such as a home flag sensor, configured to indicate one or more rotational positions or reference points.

[0160] In one exemplary embodiment, the maximum rotation speed of the centrifuge is 3000 revolutions per minute, although other rotation speeds are contemplated based, among other things, on the composition of the solution being centrifuged and the time period required to provide proper centrifugation.

[0161] Receptacle distribution system and rotary distributor In one embodiment, the receptacle dispenser comprises a rotary dispenser configured to move a receptacle onto the receptacle dispenser at a first location on the second module, transport the receptacle from the first location to a second location on the second module different from the first location, and remove the receptacle from the receptacle dispenser at the second location on the second module. In an exemplary embodiment, the rotary dispenser of the receptacle dispenser system not only comprises a robotic pipettor, such as the aforementioned material transfer and handling device 402 or other material transfer device comprising a vial transfer arm supported on a structure for automatically moving the pipettor in different Cartesian directions (i.e., x, y, z directions), but is also a three-axis robot designed to transport MRDs 160 and reagent packs 760 between different components of the second module 400. In one exemplary embodiment, the rotary dispenser 312 functions by a hook and rail system in which extendable and retractable hooks push or pull the MRD 160 or reagent pack 760 into or from the dispenser head of the rotary dispenser 312. Within the dispenser head, the MRD 160 or reagent pack 760 is supported and guided by rails and wall features within the head. The rotational position of the dispenser head is controlled and monitored by a rotary encoder on the motor and has a home sensor for position feedback. The dispenser hooks may be belt-driven with home and end-of-travel sensors (e.g., slotted optical sensors, limit switches, etc.). The rotary dispenser 312 is also configured for motorized vertical (or z-axis) movement of the dispenser head for vertical translation of the MRD 160 or reagent pack 760. In one exemplary embodiment, the rotary dispenser 312 is configured to allow at least 100 mm of z-axis travel. The dispenser head may include an MRD / reagent pack presence / absence sensor within the head. In one exemplary embodiment, the rotary distributor is configured to transfer MRDs 160 between any two modules of the second module 400 in four seconds or less. In an embodiment, each axis can make a full forward movement in about one second or less.

[0162] Details of an exemplary receptacle dispensing system are shown in Figures 27 and 28. In the illustrated embodiment, receptacle dispensing system 200 includes a frame 202 with legs 203, 204, and 205 extending between a bottom panel 208 and a top panel 206. A receptacle transfer station 602 is mounted on a transfer station bracket 606 attached to the bottom panel 208 of frame 202, as discussed further below. A magnetic elution slot 620 and a reagent pack loading station 640 are supported on brackets 642 attached to legs 204 and 205 of frame 202, as discussed further below. A rotary distributor 312 is supported on first and second upright walls 218, 220 within frame 202.

[0163] Details of the exemplary rotary dispenser 312 are shown in Figures 29-31. The illustrated rotary dispenser 312 includes a dispenser head 314 that defines a partial enclosure for holding an MRD 160 or a reagent pack 760, and a receptacle hook 318 that is configured to engage with the manipulation structure 166 of the MRD 160 or the manipulation hook 764 of the reagent pack 760.

[0164] The hook actuator system 316 linearly translates the receptacle hook 318 relative to the dispenser head 314 between an extended position, as illustrated in FIG. 30, and a retracted position, as illustrated in FIG. 29. The illustrated hook actuator system 316 includes a hook carriage 320 to which the receptacle hook 318 is attached. A drive belt 344 is attached to the hook carriage 320 by a screw and bracket, shown at 322. The drive belt 344 is carried on a drive wheel 334 and idler wheels 336, 338, 340, 342. While illustrated using a drive belt-based system, it should be understood that other mechanisms, such as screw drive systems and linear piston actuators, are equally suitable for the hook actuator system.

[0165] 31 , which is a perspective view of the opposite side of the distributor head 314, a drive belt motor 370 having a rotary encoder 372 is attached to the distributor head 314. The drive belt motor 370 is coupled to a drive wheel 334 that drives a drive belt 344 of the hook actuator system 316.

[0166] The hook actuator system 316 can include a belt tensioner 346 for maintaining the proper tension in the belt 344. The belt tensioner 346 includes a pivoting idler wheel bracket 348 to which the idler wheel 336 is attached and which is pivotally attached to the distributor head 314 by a pivot screw 352. A slot 350 is formed in the end of the pivoting idler wheel bracket 348, and a position lock screw 354 extends through the slot 350 into the distributor head 314. A spring 356 bears against a portion of the pivoting idler wheel bracket 348. The tension in the belt 344 can be adjusted by relaxing the position lock screw 354, thereby allowing the spring 356 to drive the pivoting idler wheel bracket 348, thus urging the idler wheel 336 upward and creating the proper tension in the drive belt 344. Once the proper tension is achieved in the drive belt 344, the position lock screw 354 can then be retightened.

[0167] Hook carriage 320 includes a rail channel 324 that translates along a hook carriage guide rail 330 that is attached to an upper interior portion of dispenser head 314. Receptacle hook 318 is attached to a mount 326 that is disposed between rail channel 324 and hook 318.

[0168] A hook home sensor, such as a slotted optical sensor or limit switch, may be provided to indicate when the hook 318 is in the retracted, or "home," position when a sensor flag extending from the mount 326 extends into the slotted optical sensor. Other types of sensors, such as proximity, magnetic, or capacitive sensors, may also be used to indicate home position. The receptacle hook 318 and hook carriage 320 are operably coupled for electronic communication with the rest of the rotary distributor 312 using a flexible cable 366 attached to one end of the hook carriage 320 and to a printed circuit board or other connector located on the distributor head 314. Strain buffers 368 and 369 may be provided to secure the flexible cable 366 to the distributor head 314 and hook carriage 320, respectively.

[0169] 32 illustrates the manner in which reagent packs 760 may be transported within module 400 using rotating dispenser 312. As shown in FIG. 32, rotating dispenser 312 may be configured to receive and hold reagent packs 760 that are pulled into dispenser 312 by the operating hooks of rotating dispenser 312, with the bottom edge 765 of pack 760 supported on rails 373 formed on the interior wall of dispenser 312.

[0170] Similarly, Figure 33 illustrates the manner in which MRDs 160 may be carried within module 400 by rotary distributor 312. As shown in Figure 33, rotary distributor 312 may be configured to receive and hold MRDs 160, which are pulled into distributor 312 by operating hooks of rotary distributor 312, with connecting rib structures 164 of MRDs 160 supported on rails 373 formed on the interior walls of distributor 312.

[0171] Receptacle dispensing system 200 includes a dispenser movement device configured to move dispenser head 314 in a circular path or a vertical linear path. More specifically, in one exemplary embodiment, dispenser movement device includes rotary drive system 212 configured to move dispenser head 314 in a circular path and lift system 230 configured to move dispenser head 314 vertically.

[0172] Details of an exemplary rotary drive system 212 are shown in Figures 27, 28, 34, and 35. While it is contemplated that in certain embodiments, rotary drive system 212 is configured to freely rotate 360°, it should be understood that in at least some embodiments, rotary drive system 212 is configured to rotate 180° between two distinct loading positions.

[0173] The first and second upright walls 218, 220, on which the distributor head 314 is supported, are mounted on a turntable 214, which is mounted for rotation about its central axis on the bottom panel 208 of the frame 202. A motor 222, having a rotary drive 224, such as a rotary drive gear, attached to and extending above the bottom panel 208, engages peripheral teeth of the turntable 214 such that motorized rotation of the motor 222 results in rotation of the turntable 214 and the first and second upright walls 218, 220 and distributor head 314 supported thereon. While illustrated as having teeth configured to interengage, it should be understood that the rotary drive 224 and the turntable 214 can also interengage without having toothed components. In such an embodiment, the rotary drive and the turntable can both be wheels with rubberized outer surfaces to facilitate traction. Rotational motor 222 is preferably a stepper motor for providing precise control of the rotation of turntable 214 and preferably includes a rotary encoder 223 for providing rotational position feedback to a control system controlling rotational motor 222. Other means for rotatably coupling distributor head 314 to motor 222 are also encompassed within the present disclosure, including, for example, a belt and pulley, a gear train comprising one or more gears, a drive shaft and worm gear, etc.

[0174] As shown in FIG. 35 , a position sensor 226, which may comprise a slotted optical sensor including an optical transmitter-receiver pair, provides a rotational position feedback signal for the wheel 214. The optical sensor 226 may be configured to detect the passage of one or more position flags on the wheel 214 to indicate one or more specific rotational positions. The sensor 226 includes protrusions or portions located above and below the wheel 214, and the position flags may therefore include one or more openings (e.g., 227) formed through the wheel. The passage of an opening between the portions of the sensor 226 located above and below the wheel 214 completes an optical signal transmission between the transmitter and receiver portions of the sensor 226, thus generating a signal corresponding to the passage of the opening. Other types of sensors, including proximity sensors, magnetic sensors, capacitive sensors, etc., may also be used to indicate specific rotational positions.

[0175] A second optical sensor 228 may be provided below the turntable 214. The sensor 228 may comprise a slotted optical sensor including an optical transmitter-receiver pair to detect the passage of one or more sensor flags (not shown) extending beneath the turntable 214 to indicate rotational position. Other types of sensors may also be used to indicate home position, including proximity sensors, magnetic sensors, capacitive sensors, etc.

[0176] Details of the distributor lift system 230 are primarily shown in FIG. 35. The depicted lift system 230 includes a threaded rod 232 extending upward from the turntable 214 through a motor 234 and female screw drive 236 mounted to the distributor head 314 (see also FIG. 31). Rotation of the female screw drive 236 by the motor 234 translates the threaded rod 232 up and down relative to the motor and distributor head 314 to which it is attached. A guide rail 238 extends vertically from one edge of the second upright wall 220, and the motor 234 is connected to the guide rail 238 by a rail connection 240. Alternatives to the threaded rod and female screw drive for vertically moving the distributor head 314 are also encompassed by the present disclosure, including, for example, a rack and pinion or belt drive system.

[0177] 27, 28, and 34, the sensor 246 extends below the dispenser head 314. As the dispenser head 314 is lowered by the lifting system 230, a separate protrusion of the sensor 246 extends into an opening 216 formed in the turntable 214. The sensor 246 may be a slotted optical sensor, with the protrusion forming a transmitter-receiver pair. The optical signal between the spaced apart protrusions is broken when the protrusion enters the opening 216, thereby sending a signal to the control system that the dispenser head 314 is in its lowest position. Other types of sensors may also be used to indicate the down position of the dispenser head 314, including, for example, a proximity sensor, a magnetic sensor, a capacitive sensor, etc.

[0178] Data and power are communicated between the rotary distributor 312 and the modules 400 using a coiled cable 244 that may accommodate rotation of the rotary distributor 312 relative to the frame 202 by, for example, 180 degrees in either direction.

[0179] To transfer the MRD 160, the dispenser head 314 is rotated a few degrees by the rotary drive system 212 of the rotary dispenser 312, the hook 318 is extended by the hook actuator system 316, and the head 314 is rotated in the opposite direction to engage the operating structure 166 of the MRD 160. The dispenser hook 318 is then retracted, and the MRD 160 is coupled to the dispenser head 314. Similarly, to transfer a reagent pack 760, the dispenser head 314 is rotated a few degrees by the rotary drive system 212, the hook is extended by the hook actuator system 316, and the head 314 is then rotated in the opposite direction to engage the operating hook 764 of the reagent pack 760. The dispenser hook 318 is then retracted, and the reagent pack 760 is pulled into the dispenser head 314.

[0180] Receptacle handover device Receptacle handover device 602 is configured to transfer receptacles, such as MRD 160, between receptacle distributor 150 of first module 100 and rotary distributor 312 of second module 400. Both receptacle distributor 150 of first module 100 and rotary distributor 312 of second module 400 use hooks or other similar devices to manipulate MRD 160 and engage with operating structure 166 of MRD 160. Thus, after MRD 160 is disengaged by receptacle distributor 150 of first module 100, MRD 160 is positioned and oriented in a manner to present operating structure 166 to rotary distributor 312 of second module 400. Handover device 602 performs this function.

[0181] Details of the transfer device 602 are shown in Figures 27, 28, 39, and 40. The receptacle transfer device 602 includes a receptacle yoke 604 configured to receive and hold an MRD 160 installed in the yoke 604 by the receptacle distributor 150 of the first module 100. The yoke 604 is mounted on a transfer device bracket 606 attached to and extending from the bottom panel 208 of the frame 202 for rotation about a vertical axis of rotation. In one exemplary embodiment, the yoke 604 is coupled to a transfer device motor 680 attached to the bracket 606. The motor 680 may be a stepper motor for precise motion control and may include a rotary encoder 682 for providing rotational position feedback of the receptacle yoke 604 to a controller. Sensor 684, which may be a slotted optical sensor with an optical transmitter-receiver pair, is mounted to bracket 606 and detects a home flag 686 extending from yoke 604 to provide rotational position feedback. Other types of sensors may also be used to provide position or orientation feedback, including proximity sensors, magnetic sensors, capacitive sensors, etc. After MRD 160 is installed in yoke 604 by receptacle distributor 150 of first module 100 and receptacle distributor 150 disengages MRD 160, housing 604 is rotated to present operating structure 166 of MRD 160 to rotary distributor 312 of second module 400.

[0182] Alternatively, the transfer device 602 may be passively actuated by the rotary distributor 312. For example, the transfer device rotation may be tied to the rotation of the rotary distributor 312 (e.g., via a cable, belt, gears, or other means) such that when the rotary distributor 312 rotates to the transfer position, the transfer device 602 will be spun to face the rotary distributor 312. When the rotary distributor 312 rotates away from the transfer device 602, the transfer device 602 will rotate back toward the receptacle distributor 150 of the first module 100.

[0183] MRD storage station As shown in FIG. 14 , MRD storage stations 608, 610, 612 are located on the receptacle processing deck 600 of the second module 400 and serve as temporary locations for MRDs within the second module 400. The storage stations 608, 610, 612 include several slots 614, each configured to receive an MRD 160. The storage stations 608, 610, 612 are arranged in an arc, thereby corresponding to the rotational path of motion of the rotary distributor 312. Providing additional storage for MRDs within the second module 400 offers the advantage of improving workflow by allowing flexibility in the timing at which any particular MRD or its contents are utilized within the second module 400. This allows MRDs that may arrive later at the second module 400 to be processed out of order, for example, to address urgent laboratory needs.

[0184] While illustrated as having three MRD storage stations 608, 610, 612, it should be understood that embodiments can be constructed with two or more such storage stations. Similarly, while illustrated as configured in an arcuate arrangement, it should be understood that the distributor 312, in some embodiments, does not rotate about an arc, and that an arcuate arrangement is convenient for rotating distributor 312 embodiments. To the extent alternative configurations of distributor 312 are implemented, the MRD storage stations would similarly conform to the alternative arrangement that maximizes system workflow.

[0185] Magnetic elution slot / reagent pack loading station Magnetic elution slots 620 (two in the illustrated embodiment) and reagent pack loading stations 640 are supported on brackets 642 that are attached to frame 202. The purpose of each magnetic elution slot 620 is to hold an MRD 160 while a material transfer pipettor 410 aspirates elution fluid from a receptacle 162, applying a magnetic force to the contents of the MRD and drawing the magnetic beads to the sidewall of each receptacle 162.

[0186] Details of the magnetic elution slot 620 and the reagent pack loading station 640 are shown in Figures 36-38. Each magnetic elution slot 620 includes a block 622 having a slotted opening 624 formed therein. The MRD 160 installed in the slotted opening 624 is supported within the opening 624 by the MRD's connecting rib structure 164, which rests on top of a bracket 642. A manipulating structure 166 extends from the opening 624, and notches 632 in each side wall of the block 622 allow the hook 318 of the rotary distributor 312 to move laterally in and out of the MRD manipulating structure 166 of the MRD 160 positioned within the slotted opening 624. The top of the MRD is uncovered, thus allowing pipettor access to the receptacle 162 of the MRD 160 held within the elution slot 620. A magnet 628 is attached to or embedded in one or both of the walls defining the slotted opening 624. An individual magnet 628 may be provided for each receptacle 162 of the MRD 160, as shown in FIGS. 37 and 38, or a single magnet may be provided for a receptacle with one or more individual receptacles.

[0187] The reagent pack loading stations 640 are defined by spaced apart retention features 644 extending above the bracket 642 and backstops 646 that define the rear end of each reagent pack loading station 640. A reagent pack 760 is inserted between the retention features 644 under the side flanges and pulled into the loading station 640 until the rear end of the reagent pack 760 contacts the backstops 646.

[0188] Reagent pack dust chute The reagent pack dust chute 428 is supported on the bracket 642. In the exemplary embodiment, the reagent pack dust chute 428 includes an entrance structure defined by side walls 434, 436 and a top panel 438, through which the reagent pack 760 is inserted into the dust chute 428. The side walls 434, 436 are attached to the top of the bracket 642 and are bent or flared outward at their forward edges to provide a funnel-shaped entrance to the dust chute 428. A resilient tab 442 extends downwardly from the top panel 438.

[0189] To discard a reagent pack 760, the rotary dispenser 312 inserts the pack 760 into the dust chute 428 between the side walls 434, 436. When the reagent pack 760 is inserted into the dust chute 428, a gap exists between the top panel 438 and the top of the reagent pack 760. A resilient tab 442 bears against the top of the reagent pack 760, holding the reagent pack 760 down into the dust chute 428. The angle of the resilient tab 442 allows the reagent pack 760 to be pushed into the dust chute 428, but resists the reagent pack 760 from moving out of the dust chute.

[0190] As a subsequent reagent pack 760 is inserted into the reagent pack waste chute, it is pushed against the reagent pack 760 previously inserted into the dust chute 428, thereby pushing the previously inserted pack further into the dust chute 428. Notches 648 are formed in bracket 642 so that the previously inserted pack 760 eventually falls out of the dust chute 428 and is guided by guide ramps 444 extending downward from bracket 642 into a waste bin located below the dust chute 428.

[0191] Reagent Pack Exchanger Details of an exemplary reagent pack exchanger 700 are shown in Figures 15-17. The purpose of the reagent pack exchanger 700 is to provide fully independent reagent pack loading and test execution, whereby an operator may place a reagent pack into a reagent pack input device and / or remove a reagent pack 760 from the reagent pack input device, while the previously loaded reagent pack 760 is stored in a storage compartment, which may be temperature controlled and available for access by an instrument, independent of the status of the reagent pack input device. The reagent pack exchanger is configured to move reagent packs 760 between the reagent pack input device and the storage compartment.

[0192] As shown in FIGS. 15-17 , in one exemplary embodiment, the reagent pack input device comprises a reagent pack carousel compartment 702 that can be pulled out from the second module 400 and contains a rotatable reagent pack carousel 704. The pack carousel 704 includes several reagent pack stations 706, each adapted to receive and transport a reagent pack 760, and is defined by a radially inner divider 708 and a radially outer divider 710. As can be seen in FIGS. 15-17 , the reagent pack stations 706 of the reagent pack carousel 704 are arranged about the outer periphery of the reagent pack carousel 704, while the extended reagent pack stations 706 and the reagent packs 760 transported thereby are not radially arranged relative to the center of the reagent pack carousel 704. Each reagent pack station 706 is oriented at an angle (e.g., 5-20°) relative to a true radial orientation. This configuration of the reagent packs optimizes the placement of the reagent packs 760 on the carousel 704, thereby allowing the reagent pack carousel 704 to carry a maximum number of reagent packs 760, and provides the barcode reader 774 with access to the identifiable indicia present on each reagent pack 760.

[0193] A gap 712 between each inner divider 708-outer divider 710 pair allows an operator to insert their fingers into the gap 712 and thereby grasp the sides of the reagent pack 760 to place the reagent pack 760 in or remove the reagent pack 760 from the reagent pack station 706. Each reagent pack station 706 of the reagent pack carousel 704 also includes an alignment block 714 at the radially inner end of the reagent pack station 706. The alignment block in a rear recess 770 of the reagent pack 760 helps to maintain proper alignment and position of the reagent pack 760 in the reagent pack station 706.

[0194] In some embodiments, the reagent pack carousel compartment 702 preferably includes a carousel frame 716 disposed on tracks that allow the frame 716 to slide in and out of the module 400 as a drawer. The frame 716 includes a drawer front 720. The reagent pack carousel 704 is rotatably disposed within the frame 716, which may include a circular recess 722 shaped to match the reagent carousel 704.

[0195] The reagent pack carousel 704 is motor-driven to provide motorized rotation of the carousel. In one exemplary embodiment, the reagent pack carousel compartment 702 may include a motor (not shown) coupled to the reagent pack carousel 704, for example, by a belt and pulley arrangement (not shown), for motorized rotation of the reagent pack carousel 704. The motor may move in and out of the reagent pack carousel compartment 702, which is mounted to the reagent pack carousel frame 716 and connected to the module 400 by a flex cable. The reagent pack carousel compartment 702 may include one or more position sensors to detect when the carousel is in an open or closed position and communicate a corresponding signal to the system controller. Such sensors may include optical sensors, proximity sensors, magnetic sensors, capacitive sensors, etc.

[0196] The reagent pack carousel compartment 702 may also include a software controlled lock.

[0197] The reagent pack carousel compartment 702 may also include one or more sensors for tracking the position of the reagent pack station 706. For example, the reagent pack carousel 704 may include a home flag, such as a tab and an optical sensor, that detects the position of the tab at a defined rotational position of the reagent pack carousel 704. Other types of sensors may also be used to indicate a home position, including proximity sensors, magnetic sensors, capacitive sensors, etc. Additionally, the motor that drives the reagent pack carousel 704 may be a stepper motor that includes a rotary encoder for generating a signal corresponding to the rotational position of the reagent pack carousel 704.

[0198] The second module 400 may include a machine pack reader configured to read a machine code provided on each reagent pack 760, which provides information about the reagent pack 760, such as the identification of the assay reagents carried within the reagent pack 760, the manufacturer, lot number, expiration date, etc. The machine code may also include a unique identifier that specifically identifies that particular reagent pack 760. The machine code reader device may include a bar code reader 774 configured to read bar code indicia 772 disposed on the reagent pack 760. The bar code indicia 772 may be a two-dimensional or one-dimensional bar code. A scanning slot 718 formed in the carousel frame 716 provides an opening through which the bar code reader 774 may read the indicia 772 on the reagent pack 760. Similarly, the orientation of the reagent packs 760 transported within the pack stations 706 of the pack carousel 704 may be set at an angle relative to a true radial orientation, and the generally trapezoidal shape of the outer divider 710 creates clearance openings through which a barcode reader 774 can read barcode indicia 772 disposed on the reagent packs 760. In conjunction with a rotary encoder, the barcode reader 772 provides an indication of where each reagent pack 760 is positioned within each reagent pack station 706 of the reagent pack carousel 704. While a barcode scanner is illustrated, the use of other technologies, such as RFID and QR Codes, is also contemplated.

[0199] Each reagent pack station 706 may include a station empty barcode located on the side of each outer divider 710 that will be read by barcode reader 774 when no reagent pack 760 is positioned in the reagent pack station 706.

[0200] In another exemplary embodiment, the reagent pack input device comprises an alternate reagent pack carousel 730 shown in FIG. 18 . The reagent pack carousel 730 is not carried on a drawer that slides out of the module 400, but instead includes radially oriented reagent pack stations 732 that are arranged around the periphery of the reagent pack carousel 730 and are accessible through slots in the front of the second module 400, which may be covered by an operator-openable door. Motorized rotation of the reagent pack carousel 730 may be provided by a carousel drive system that may include a motor 734 having an output drive wheel 736 coupled to a drive pulley 739 of the carousel 730 with a drive belt 738. The motor 734 may comprise a stepper motor with a rotational encoder, and a home flag may be provided on the carousel 730 to detect and monitor the rotational position of the reagent pack carousel 730, and therefore each reagent pack station 732.

[0201] 18 also shows an exemplary embodiment of a reagent pack storage compartment, represented by reference numeral 740. Storage compartment 740 is located directly below reagent pack carousel 730. In the embodiment described above, reagent pack carousel compartment 702 would be located within module 400 above storage compartment 740 and movable relative thereto.

[0202] In some embodiments, the storage compartment 740 includes a housing 742 that defines a temperature-controlled chamber therein. The desired storage temperature can be as low as 4° C., but can also be any temperature below ambient temperature, such as 15° C. In some embodiments, the chamber of the storage compartment 740 further includes a humidity control module configured to control the humidity level of the air circulating within the temperature-controlled chamber. As part of this process, the humidity control module is optionally equipped to collect condensed water and route it outside the cooled storage area for disposal.

[0203] The housing 742 may be insulated and cooled by a Peltier device that may be mounted directly on the housing 742 or by a Peltier device coupled to heat and cool a fluid, such as water or a refrigerant, circulated around the housing 742. In one embodiment, the storage compartment 740 is cooled by two separate Peltier devices mounted directly on the housing 742, each at a different temperature or temperature range. In this embodiment, the first Peltier device is maintained at a temperature near the freezing temperature of water. The second Peltier device is provided in a location within the storage compartment 740 separate from or adjacent to the first Peltier device and is provided at a higher temperature than the first Peltier device, e.g., 15°C. The second Peltier device is in operative communication with a temperature sensor within the storage compartment 740 that is positioned near the top of the storage compartment 740. The second Peltier device will operate based on the measured temperature to maintain a predetermined temperature within the storage compartment 740. In this embodiment, a fan may be provided within storage compartment 740 to circulate air within storage compartment 740 through the fan and past the first and second Peltier devices. As air, which is held at a very low temperature, passes through the first Peltier device, it cools, thus reducing its humidity-holding capacity, and the humidity will condense on the Peltier device or another designated element. Thus, this dual Peltier device embodiment provides both a temperature- and humidity-controlled environment, which is beneficial for extending the shelf life of lyophilized reagents that are susceptible to rapid degradation in the presence of increased temperature and atmospheric humidity.

[0204] Other methods for cooling and / or dehumidifying the storage compartment 740 are also contemplated, and the present disclosure is not limited to the illustrated embodiment.

[0205] The housing 742 should include a liquid collection and / or drainage system for handling condensed liquid inside the housing 742. Such a system may include, for example, piping for directing collected condensate from the housing 742 and to a drain or evaporator.

[0206] A storage carousel 744 is rotatably mounted within the housing 742, for example, on a shaft 745. The storage carousel 744 includes a plurality of pack stations 746 arranged around its periphery and positioned on one or more levels of the carousel 744. In the illustrated embodiment, the storage carousel 744 includes pack stations 746 on two levels, one above the other.

[0207] The carousel drive can power the rotation of the storage carousel 744 within the storage compartment 740. The carousel drive may include a motor 748, which may be a stepper motor having an output drive wheel 750 coupled to a drive pulley 749 of the puck carousel 744 with a drive belt 752. The motor 748 may be located outside the housing 742 to keep heat generated by the motor 748 from heating the storage compartment 740, and the drive belt 752 may extend through an opening in the housing 742. Alternatively, the drive pulley coupled to the carousel 744 may be located outside the housing 740. The motor 748 may include a rotational encoder, and the reagent pack carousel 744 may include a home flag for monitoring the rotational position of each of the reagent pack stations 746 of the pack carousel 744.

[0208] The operation of the reagent pack exchanger 700 will now be described.

[0209] After the reagent packs 760 are placed in the reagent pack carousel 704 or reagent pack carousel 730 of the pack entry device, the barcode of each reagent pack 760 is read by a barcode reader 774, and the identification and other information provided by the barcode is associated with the particular reagent pack station 706, 732 of the reagent pack carousel 704. Alternatively, the reagent packs 760 may be scanned outside of the module 400, for example, by a manual barcode scanner, before the reagent packs 760 are placed in the pack entry device.

[0210] After a reagent pack 760 is placed in a reagent pack input device, such as the reagent pack carousel 704 or the reagent pack carousel 730, the pack carousel compartment 702 is blocked off or the door in front of the carousel access opening is closed. The rotary distributor 312 then removes one or more reagent packs 760 from the reagent pack carousel 704, 730 and moves the reagent packs 760 into pack stations 746 of the storage carousel 744 in the storage compartment 740. As shown in FIG. 16 , the carousel frame 716 of the reagent pack carousel compartment 702 includes reagent pack access slots 724 through which the rotary distributor 312 can access the manipulation hooks 764 of the reagent packs 760 positioned in the reagent pack stations 706. The rotary distributor 312 provides motorized and controlled vertical, i.e., z-axis, motion to enable the rotary distributor 312 to transfer reagent packs 760 between the reagent pack input carousels 704 or 730 to one or more levels of the storage carousel 744 of the storage compartment 740. Access to the reagent pack access slots 724 by the rotary distributor 312 is preferably controlled by a door when the reagent carousel 704 or 730 is temperature controlled.

[0211] Once a reagent pack 760 is present in the storage compartment 740, it is available to be utilized in an amplification assay, such as a PCR assay. When a sample requiring a particular assay is present, the carousel of the storage compartment 740 rotates to a position where the reagent pack 760 containing the specific unit-dose reagent for that particular assay is accessible by the carousel dispenser 312. Typically, such access will be through a door to maintain a tightly controlled temperature environment within the storage compartment 740. The dispenser 312 will access the reagent pack 760 through the door and move it to the reagent pack loading station 640 for reconstitution of one or more lyophilized reagents contained on the reagent pack 760. When the reagent pack 760 is empty, or when the reagents in one or more wells on the reagent pack 760 have been reconstituted and removed, the dispenser 312 will again move the reagent pack 760. If there is any reagent remaining in the reagent pack 760, the dispenser 312 will transfer the reagent pack 760 back to the storage compartment 740. If the reagent pack 760 no longer contains reagent or is otherwise designated as unsuitable for continued use (e.g., contaminated or expired reagent), the dispenser 312 will transfer the reagent pack 760 to either the waste chute 426 or the reagent pack input carousel 704 or 730 for removal.

[0212] A further alternative for scanning each reagent pack 760 is for the dispenser 312 to present each reagent pack 760 to a barcode scanner as each reagent pack is removed from the reagent pack input carousel and before placing the reagent pack 760 in the storage carousel 744.

[0213] Reagent identification control is maintained by monitoring the position of each reagent pack station 706, 732 on the carousels 704, 730 and each reagent pack station 746 on the storage carousel 744 after the barcode (or other machine code) is read on the reagent pack 760, and correlating the identification of the reagent pack 760 from the barcode with the location of the reagent pack station.

[0214] The reagent pack carousels 704, 730 rotate independently from the storage carousel 744 of the storage compartment 740, allowing an operator to load and unload reagent packs 760 from the reagent pack carousels 704, 730 while the module 400 (i.e., the rotary distributor 312) independently accesses the reagent packs 760 stored in the storage carousel 744 for assay processing.

[0215] The reagent pack exchanger 700 preferably stores at least 28 to 30 or more reagent packs 760.

[0216] The second module 400 may further include an electrostatic generator to apply an electrostatic charge to position and hold the lyophilized reagents 768 present in the reagent packs 760 at the bottom of their respective mixing wells 762. While the reagents 768 may be held at the bottom of their associated mixing wells 768 using a pre-applied electrostatic charge, as described above, the inclusion of a mechanism such as an electrostatic generator to actively pull the lyophilized reagents 768 to the bottom of the mixing wells 762 as the reagents are reconstituted will ensure positioning in the correct spot within the mixing well during reconstitution. In certain embodiments, the electrostatic generator is positioned below the reagent pack loading stations 640, 730. Alternatively, or in addition, an electrostatic generator may be provided in the reagent pack carousels 704, 730 present in the reagent pack loading drawers and / or the storage carousel 744 present in the storage compartment 740. In such an embodiment, providing an electrostatic generator within storage compartment 740 would have an improved electrostatic effect due to the lower temperature and humidity, so the electrostatic generator may be located below or operably coupled to reagent pack station 746 below reagent pack stations 706, 732 or reagent pack 760.

[0217] Storage / Expansion Module Details of compartment 590 for storing accessories or accommodating possible expansion of second module 400 are shown in Figures 5, 6, 14, and 15. In one exemplary embodiment, compartment 590 can store a standard 96-well plate. The plate is positioned so that both pipettor arms 408, 416 can access the 96-well plate location. The expansion space has access at the front (via a pull-out mechanism) so that an operator can unload the plate. The expansion space can also be accessed from the side of the instrument. A drive system, for example, comprising a motor-driven belt, may be provided to translate well plates or other containers or components into and out of second module 400. Compartment 590 can be utilized as an area to collect cap / vial assemblies that have undergone PCR and / or melt assays and provide the ability to perform additional assays (e.g., ELISA) on samples contained within the cap / vial assemblies. (A procedure for performing thermal melt analysis is disclosed by Wittwer et al., U.S. Pat. No. 8,343,754.) In certain embodiments, arranging the cap / vial assemblies in a 96-well plate format has advantages when further processing of the sample is desired, as the 96-well plate size is compatible with a variety of known sample processing and molecular assay instruments.

[0218] Theory of operation of the device The first module 100 is used for the sample preparation portion of the amplification assay (i.e., the minimal steps for isolating and purifying target nucleic acids that may be present in the sample). The sample and TCR, which may include a magnetically responsive solid support, are loaded onto the first module 100. Elution buffer containers 502, 504 are loaded onto the second module 400. The second module 400 then automatically moves these containers into a space within the first module 100 that can be accessed by the first module's 100 material transfer device, e.g., a reagent pipetter (not shown in FIG. 1). Through information provided to the first module 100, for example, by an operator via a user interface or through automated machine-readable information such as a barcode provided on the sample container (not shown in FIG. 1), the first module recognizes that a particular amplification assay will be initiated. To process a sample, the receptacle distributor 150 of the first module 100 pulls a new MRD 160 from the input matrix 102 and places it into a sample dispense position within the first module 100. The TCR and sample are transferred by a pipettor within the first module 100 from reagent containers and sample tubes, respectively, into each receptacle 162 of the MRD 160. The contents of the MRD 160 are then incubated at a specified temperature for a specified period of time before the MRD 160 is transferred to magnetic separation and wash stations 118, 120 for a magnetic washing procedure.

[0219] After the target capture process, the MRD 160 is moved by the receptacle distributor 150 to an amplification reagent dispensing position within the first module 100. The material transfer device of the first module 100 then adds elution fluid to each receptacle 162 of the MRD 160, separating the target (sample) material from the magnetic particles, and the first module 100 mixes the contents of each receptacle 162 before sending the MRD 160 to the second module 400. The second module 400 places the MRD 160 into one of a series of slots configured to hold the MRD 160. Upon signaling by the system controller, the second module 400 moves the MRD 160 to the magnetic elution slot 620, separating the eluted nucleic acid material from the magnetic particles. The material transfer device 402, e.g., a robotic pipettor, then begins the amplification process. The pipettor 402 first dispenses oil into all process vials 464, 670 matrixed for use in the test. The pipettor 402 then aspirates the eluate / sample from the MRD 160 and then aspirates the reconstituted reagent solution from the reconstituted reagent cartridge or reservoir and dispenses them into the lyophilized reagent wells of the reagent pack 760. The reconstituted reagents and lyophilized amplification reagents in the reagent wells of the reagent pack 760 may be drawn into and expelled from the pipette tips one or more times to ensure proper and rapid reconstitution. The reconstituted amplification reagents are pipetted into the process vials 464, 670 and then capped. The reconstituted amplification reagents, sample, and oil may be drawn into and expelled from the pipette tips one or more times to ensure proper mixing. The capped vials 464, 670 are transported to a centrifuge and then to a thermacycler 432, such as the thermacycler 432 for PCR amplification and fluorometric detection.

[0220] The results are displayed on the instrument monitor or user interface and may either be printed or communicated to the LIS.

[0221] In certain embodiments, first module 100 is configured to perform one or more isothermal nucleic acid amplification reactions on the nucleic acid material contained within MRD 160. In one embodiment, such isothermal processes may be performed on the contents of MRD 160 before transporting MRD 160 to second module 400 and performing PCR on a portion of the MRD content material, as described above. Alternatively, after MRD 160 is processed in second module 400, a volume of eluate / sample is transported from the MRD to one or more vials 464, 670 for performing PCR or other processes that second module 400 is configured to perform. MRD 160 may be transported back to first module 100, and an isothermal nucleic acid amplification reaction may be performed on the remaining contents of MRD 160.

[0222] Example Process Details of operations and processes embodying aspects of the present disclosure are shown in the flow diagrams of Figures 41-43. The following processes are exemplary. Other processes may also be performed, and / or the processes shown herein and described below may be modified, for example, by omitting and / or reordering certain steps.

[0223] A sample eluate preparation process that may be performed using the above-described first module 100 and second module 400 is represented by flow diagram 800 in FIG. 41. In step S802 of method 800, a reaction receptacle is moved to a location where reaction materials can be added to the receptacle. See, e.g., U.S. Patent No. 8,309,036 to Clark et al. For example, receptacle distributor 150 of first module 100 moves MRD 160 from input device 102 to one of loading stations 104, 106, or 108. See, e.g., U.S. Patent Application Publication No. 2012 / 0128451 to Hagen et al.

[0224] In step S804, the material transfer device of the first module 100 transfers the reaction materials to the receptacles. See, for example, U.S. Provisional Application No. 61 / 783,670 to Buse et al. For example, the robotic pipettor of the first module 100 transfers a target capture reagent (“TCR”) (e.g., 500 μL), a sample fluid (e.g., 360 μL), and a target enhancer reagent (“TER”) (e.g., 140 μL) into each receptacle 162 of the MRD 160.

[0225] In step S806, the reaction materials added to the receptacles in step S804 are mixed, for example, the TCR, sample fluid, and TER added to receptacle 162 of MRD 160 are mixed by, for example, oscillating MRD 160 at a high frequency (e.g., 16 Hz for 60 seconds).

[0226] In step S808, the receptacle is moved into an environment that will be conducive to the desired reaction. For example, receptacle distributor 150 removes MRD 160 from loading station 104 and transfers it to one of incubators 112, 114, 116 (referred to in FIG. 41 as an AT-binding incubator, "ATB incubator") to incubate the contents of MRD 160 at a specified temperature for a specified time period (e.g., 63°C for 1800 seconds). Before moving MRD 160 to the incubator, MRD 160 may first be placed in one of temperature gradient stations 110 (e.g., 65°C for 300 seconds) to raise the temperature of MRD 160 and its contents to a temperature closer to that of the incubator to which MRD 160 will be transported, so as to minimize temperature fluctuations within the incubator.

[0227] The desired reaction may require two or more incubations at different temperatures. Thus, according to one implementation of the present disclosure, in step S810, receptacle dispenser 150 removes MRD 160 from one of the incubators and transfers MRD 160 to another incubator (referred to in FIG. 41 as a "high temperature incubator") at a different (e.g., higher or lower) temperature than the first incubator, and continues incubation of the contents of MRD 160 at the specified temperature for a specified period of time (e.g., 43.7°C for 600 seconds).

[0228] In step S812, receptacle distributor 150 removes MRD 160 from the second temperature incubator and returns MRD 160 to another incubator at a different temperature (which may be the same incubator in which MRD 160 was placed in step S808 (e.g., an "ATB incubator")).

[0229] Upon completion of the incubation step, it may be desirable to cool the temperature of the contents of the receptacle, for example, to terminate any reactions occurring within the receptacle. Thus, in one embodiment, in step S814, receptacle dispenser 150 may remove MRD 160 from the incubator and transfer MRD 160 to cooling module 122 (referred to in FIG. 41 as a "cooling ramp"), which is maintained at a predetermined temperature.

[0230] Next, assuming that the reaction taking place in the receptacle includes immobilizing the target nucleic acid on a magnetically responsive solid support, a magnetic separation procedure is performed on the contents of the receptacle. Accordingly, in step S816, the receptacle dispenser 150 removes the MRDs 160 from the cooling module 122 after a predetermined time period (e.g., 830 seconds) and transfers the MRDs 160 to a magnetic storage station equipped with a magnet for attracting the magnetically responsive solid support in each receptacle 162 to the wall of the receptacle 162 and pulling the solid support out of suspension. See, for example, U.S. Patent No. 8,276,762 to Davis et al. In step S818, after a defined time period (e.g., 300 seconds) within the magnetic storage station, receptacle dispenser 150 removes MRD 160 from the magnetic storage station and transfers MRD 160 to magnetic separation washing station 118 or 120. See, for example, U.S. Patent Application Publication No. 2010 / 0288395 to Hagen et al. In step S820, a magnetic washing procedure is performed on the contents of MRD 160 placed in magnetic washing station 118 or 120. One exemplary embodiment of the magnetic separation procedure involves several magnetic dwell times, during which the contents of the receptacle are exposed to a magnetic force for a predetermined time period; after each magnetic dwell time, the fluid contents are aspirated from the receptacle while the contents are still exposed to the magnetic force, leaving the magnetic particles in the receptacle. In one exemplary embodiment, three magnetic dwell times of 120 seconds each are performed. At the completion of each magnetic dwell time, the magnetic force is removed from the contents of the receptacle. After each magnetic dwell time, except for the final magnetic dwell time, a volume of wash fluid (e.g., 1000 μL of wash buffer) is added to the receptacle to resuspend the magnetic particles before the start of the next magnetic dwell time.

[0231] After the magnetic washing process is complete (e.g., after the final magnetic dwell time, followed by aspiration of the non-magnetic fluid contents of the receptacle), in step S822, receptacle dispenser 150 retrieves MRD 160 from magnetic separation wash station 118 or 120 and moves MRD 160 to one of loading stations 104, 106, or 108. At the loading station, a volume of elution buffer (e.g., 50-110 μL) is transferred into first module 100 by a material transfer device, such as, for example, a robotic pipetter, from one of elution containers 502, 504 transferred by bulk reagent container transporter 550 in bulk reagent container compartment 500 of second module 400.

[0232] In some embodiments, it may be desirable to heat or incubate the contents of MRD160 to improve the efficiency of nucleic acid elution.

[0233] In step S824, following the addition of the elution buffer, the contents of the MRD160 are mixed by agitating the MRD160.

[0234] In step S826, the MRD 160 is transferred from the first module 100 to the magnetic elution slot 620 in the second module 400. First, the receptacle distributor 150 of the first module 100 retrieves the MRD 160 from the loading station 104, 106, or 108 and transfers the MRD 160 to the end of the transport track assembly 154 closest to the second module 400. The dispense head 152 of the receptacle distributor 150 places the MRD into the receptacle delivery device 602 of the second module 400. The receptacle delivery device 602 then rotates the MRD 160 and presents it to the rotary distributor 312. Rotary distributor 312 engages manipulating structure 166 of MRD 160 by extending its hook 318, rotating several degrees, placing hook 318 in manipulating structure 166, then withdrawing hook 318 and pulling MRD 160 into distributor head 314 of rotary distributor 312. Rotary distributor 312 then rotates to align MRD 160 carried therein with one of magnetic elution slots 620 (or, optionally, MRD reservoir 608) of second module 400. Rotary distributor 312 then extends its hook 318, pulling MRD 160 into magnetic elution slot 620, rotating several degrees, and removing hook 318 from manipulating structure 166.

[0235] The process then proceeds to process 830 shown in FIG.

[0236] 42, a reaction mixture preparation process is represented by flow diagram 830. One or more of the steps of process 830 may proceed in parallel with one or more of the steps of process 800 shown in FIG.

[0237] In step S832, the material transfer pipettor 410 of the second module 400 picks up a disposable tip 584 from a disposable tip tray 582 carried in one of the tip compartments 580.

[0238] In step S834, the material transfer pipettor 410 transfers a quantity of oil (e.g., 15 μL) from the oil container transported in the bulk reagent container compartment 500 to one or more processing vials 464 held in the cap / vial tray 460 of the processing cap / vial compartment 440.

[0239] In step S836, the material transfer pipettor 410 moves to the dust chute 426, removes the disposable pipette tip 584 therefrom, and discards the tip into the dust chute 426. The material transfer pipettor 410 then returns to the disposable tip tray 582 and picks up another disposable pipette tip 584.

[0240] In step S838, the material transfer pipettor 410 transfers a volume of reconstitution reagent (e.g., 20 μL) from a reconstitution reagent container held in the bulk reagent container compartment 500 to the mixing well 762 of a PCR reagent pack 760 that was previously transported from the storage compartment 740 to the reagent pack loading station 640 by the rotary distributor 312. In one embodiment, before the reconstitution reagent is dispensed into the mixing well 762, the pipettor 410 performs level sensing at the foil 766 before puncturing the foil 766 with the pipette tip 584. The level sensing is performed on the foil of the reagent pack 760 to "calibrate" the height of the reagent pack 760 relative to the pipettor. Generally, the pipettor 410 is configured to extend the pipette tip to the bottom of the mixing well for more accurate reagent aspiration.

[0241] In step S840, the fluid in the mixing well 762 is mixed to dissolve the lyophilized reagent 768. In one embodiment, the material transfer pipettor 410 mixes the fluid in the mixing well 762 by alternately aspirating the fluid into the pipette tip 584 and expelling the fluid back into the well 762 one or more times to dissolve the lyophilized reagent 768.

[0242] In step S842, the material transfer pipettor 410 transfers a volume (e.g., 20 μL) of reconstituted reagent from the mixing well 762 (referred to as the "master mix" in FIG. 42) of the PCR reagent pack 760 into the vial 464. The PCR master mix provides the key components needed to perform PCR in a premixed and optimized format. Included within the master mix are Taq DNA polymerase, deoxynucleoside triphosphates (dNTPs), and magnesium chloride (MgCl). Typically, forward and reverse primers are not included.

[0243] In step S844, the material transfer pipettor 410 moves to the dust chute 426 and removes the pipettor tip 584 into the dust chute. The material transfer pipettor 410 then moves to the disposable tip tray 582 and picks up a new disposable pipette tip 584.

[0244] Block "B" in Figure 42 represents the integration of process 800 shown in Figure 41 and process 830 shown in Figure 42. MRD 160 containing a sample mixture (in this exemplary embodiment, purified in a magnetic separation procedure) and elution buffer is retained in magnetic elution slot 620, which was placed therein in step S826 of process 800. In one embodiment, MRD 160 is retained in magnetic elution slot 620 for a residence period of at least 120 seconds.

[0245] In step S846 of process 830, the material transfer pipettor 410 transfers a volume of elution solution (e.g., 5 μL) from the MRD 160 held in the elution slot 620 to the processing vial 464 to which the oil and reagent were added in steps S834 and S842, respectively.

[0246] In step S848, the material transfer pipettor 410 returns to the waste chute 426 and removes the disposable pipette tip 584 into the waste chute.

[0247] The process now proceeds to process 850 shown in FIG.

[0248] Referring to Figure 43, a process for performing an automated biological process, such as a PCR reaction, is represented by flow diagram 850. Block "C" in Figure 43 represents the integration of process 830 shown in Figure 43 and process 850 shown in Figure 43.

[0249] In step S852, the material transfer pipettor 410 picks up a process vial cap 476 from a cap well 440 of the cap / vial tray 460 (see FIG. 26, which shows a replacement cap 600 and vial 670 combination) by inserting the pipettor probe 422 (without a disposable pipette tip thereon) into the cap 476. The material transfer pipettor 410 then picks up the cap 476, which is held on the pipettor probe 422 by friction, and inserts the cap 476 into a process vial 464 held in the process vial well 474 until the cap 476 locks with the vial 464, forming a cap / vial assembly (see FIG. 25).

[0250] In step S854, the material transfer pipettor 410 transfers the cap / vial assembly, which is held by friction on the pipettor probe 422, to the centrifuge 588, where an detachment device removes the cap / vial assembly from the pipettor probe 422 and places the cap / vial assembly in the centrifuge 588.

[0251] In step 856, following a prescribed time period within the centrifuge, the vial transfer pipettor 418 inserts its pipettor probe 422 into the cap 476 of the cap / vial assembly held within the centrifuge 588, removes the cap / vial assembly from the centrifuge 588, and transfers the cap / vial assembly to an incubator module, such as the thermacycler 432. An ejection device removes the cap / vial assembly from the pipettor probe 422 of the vial transfer pipettor 418.

[0252] In step S858, an incubation process is performed. The incubation process may include PCR thermal cycling, which includes multiple cycles of temperatures varying between 95°C for denaturation, 55°C for annealing, and 72°C for synthesis. During the thermacycling process, emitted signals from the contents of the processing vial may be monitored. For example, fluorescence monitoring at one or more colored wavelengths during each PCR cycle may be measured using a signal detection device, such as a fluorometer, operably integrated with the thermacycler 432. Periodic fluorescence intensity measurements at each wavelength may be taken at regular intervals to generate fluorescence time series data for subsequent processing and analysis.

[0253] In step S860, following the PCR process of step S858, the vial transfer pipettor 418 retrieves the cap / vial assembly from the thermal cycler 432 and transfers the cap / vial assembly to the dust chute 424, where the cap / vial assembly is removed from the pipettor probe 422 into the dust chute 424, or the cap / vial assembly is transported to an output reagent pack 760 in the storage / expansion module.

[0254] In some embodiments, diagnostic system 10 can be used to perform two or more assays, including nucleic acid amplification reactions, that require different reagents, including one or more unit dose reagents. Figure 44 illustrates a method of using diagnostic system 10, including first module 100 and second module 400, according to one such embodiment.

[0255] In step 862, a plurality of samples are loaded into diagnostic system 10. A first sample subset of the plurality of samples is designated for at least one assay, and a second sample subset of the plurality of samples is designated for at least one different assay. In some embodiments, barcodes on sample receptacles indicate the appropriate assays, while in other embodiments, the assays are manually entered into the system by an operator using a user interface of diagnostic system 10.

[0256] In some embodiments, a first assay comprising a first nucleic acid amplification reaction is designated for the first sample subset. For example, the first nucleic acid amplification reaction can be a PCR, and the target nucleic acid can be, for example, a nucleic acid associated with a particular virus or organism. In some embodiments, the first nucleic acid amplification reaction uses unit-dose reagents stored and operably accessible within the diagnostic system 10. For example, the first nucleic acid amplification reaction can be a PCR or any other desired thermal cycling reaction that can be performed by the second module 400 of the diagnostic system 10.

[0257] In some embodiments, a second assay comprising a second nucleic acid amplification reaction will be designated for the second sample subset. The second nucleic acid amplification reaction may be the same or a different nucleic acid amplification reaction as the first nucleic acid amplification reaction of the first assay, although in some embodiments, the reagents used in the second nucleic acid amplification reaction may target a different nucleic acid than the target of the first reagent used in the first assay. In some embodiments, the second nucleic acid amplification reaction may be a PCR or any other desired thermal cycling reaction, for example, performed by the second module 400 of the diagnostic system 10. In some embodiments, the second nucleic acid amplification reaction may be a TMA or any other isothermal reaction, for example, performed by the first module 100 of the diagnostic system 10. The reagents used for the second assay may be unit dose reagents different from the unit dose reagents used for the first assay, bulk reagents, or both. For example, if the second nucleic acid amplification reaction is PCR, the second reagent used in the second assay can be a unit dose reagent, and if the second nucleic acid amplification reaction is TMA, the second reagent used in the second assay can be a bulk reagent. In some embodiments, the second unit dose reagent, the first bulk reagent, or both are stored and operably accessible within diagnostic system 10.

[0258] The first and second assays each have a temporal workflow schedule associated with the respective assay. In some embodiments, in step 864, the diagnostic system 10 coordinates the schedule for performing the first assay with the schedule for performing the second assay so that use of the diagnostic system's resources is maximized. For example, the first assay schedule may require the use of one of the material transfer devices, and the second assay schedule may also require the use of the same material transfer device. The diagnostic system 10 can be configured to shift one or both of the schedules so that once the first assay is completed using the material transfer device, the material transfer device can be used for the second assay. Such coordination increases throughput and minimizes processing time.

[0259] In step 866, the diagnostic system 10 performs a first assay on the first sample subset. In step 868, the diagnostic system 10 begins performing a second assay on the second sample subset. Thus, a diagnostic system 10, which stores and provides operable access to a first unit-dose reagent used in the first assay and at least one of a second unit-dose reagent or a first bulk reagent used in the second assay, performs both steps 866 and 868, according to certain embodiments. In some embodiments, step 868 begins while step 866 is being performed. That is, the diagnostic system can perform the first and second assays simultaneously. In some embodiments, where an individual assay requires a unit-dose reagent for, for example, a PCR assay, during steps 866 and 868, the diagnostic system 10 verifies whether a reagent pack 760 containing the required reagent is positioned in one of the loading stations 640. If not, the dispenser system replaces the reagent pack 706 located at the loading station 640 with a reagent pack 760 containing the unit dose reagents needed for the requested assay. In some embodiments, step 868 begins after step 866 is completed. Also, in some embodiments, step 868 can begin after step 866, but step 868 can be completed before step 866 is completed.

[0260] In some embodiments, the diagnostic system 10 can switch between steps 866 and 868. For example, the diagnostic system 10 can perform a first assay on a first sample of a first sample subset, and then perform a second assay on a first sample of a second sample subset. The diagnostic system 10 can then return to step 866 and perform a first assay on a second sample of the first sample subset.

[0261] In some embodiments, the first assay and the second assay each include preparing a separate sample subset using a second bulk reagent that is different from the first bulk reagent that may be used in the second nucleic acid amplification reaction. For example, each sample of the first and second sample subsets can be prepared according to process 800 described above with reference to FIG.

[0262] In some embodiments, the first sample subset and the second sample subset comprise different samples. In some embodiments, the first sample subset and the second sample subset comprise the same sample. In such embodiments, multiple assays, such as the first and second assays described above, are performed on the same sample.

[0263] In some embodiments, steps 866 and 868 are performed without additional equipment preparation (e.g., wiping down the equipment of diagnostic system 10), reagent preparation (replacing reagent bottles stored within diagnostic system 10), and consumable preparation (replacing empty tip trays).

[0264] Hardware and Software Aspects of the present disclosure are implemented through control and computing hardware components, user-written software, data input components, and data output components. Hardware components include computing and control modules (e.g., system controllers), such as microprocessors and computers, configured to receive one or more input values, execute one or more algorithms stored on a non-transitory, machine-readable medium (e.g., software) that provide instructions for manipulating or otherwise acting on the input values, thereby effecting calculation and / or control steps, and outputting one or more output values. Such output may be displayed or otherwise indicated to an operator to provide information, for example, regarding the status of the instrument or the process being performed thereby, or such output may comprise input to other process and / or control algorithms. Data input components comprise elements through which data is input for use by the control and computing hardware components. Such data inputs may include position sensors, motor encoders, and manual input elements such as graphic user interfaces, keyboards, touchscreens, microphones, switches, manually operated scanners, and voice-activated inputs. Data output components may include a hard drive or other storage medium, a graphic user interface, a monitor, a printer, an indicator light, or an audible signal element (e.g., a buzzer, horn, bell, etc.).

[0265] The software comprises instructions stored on a non-transitory computer-readable medium that, when executed by the control and computing hardware, cause the control and computing hardware to perform one or more automatic or semi-automatic processes.

[0266] While the present disclosure has been described and illustrated in considerable detail with reference to certain illustrative embodiments, including various combinations and subcombinations of features, those skilled in the art will readily appreciate other embodiments and variations and modifications thereof that are encompassed within the scope of the present disclosure. Moreover, the description of such embodiments, combinations, and subcombinations is not intended to convey that the present disclosure requires any features or combinations of features other than those expressly recited in the claims. Accordingly, the present disclosure is deemed to include all modifications and variations encompassed within the spirit and scope of the following appended claims.

Claims

[Claim 1] The method or reagent pack exchanger described in the specification.

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