Abstract:
A sample analyzer with fixed and variable indexing that is structured and arranged to align reaction vessels, e.g., cuvettes, at a pre-determined, fixed point while maintaining a positional sequence using variable indexing. Variable indexing allows cuvettes to be presented to multiple, fixed point resources at multiple occasions in a systematic progression in a highly efficient manner. The presentation of cuvettes to multiple, fixed point resources at multiple times is superior to existing indexing.

Description:
BACKGROUND OF THE INVENTION 
       [0001]    The present invention relates to sample analyzers and more particularly to sample analyzers that are adapted for improved reliability and reduced cost by using variable increment indexing. 
         [0002]    In general, a sample analyzer automates a series of activities to determine the concentration or some other property of one or more analytes in one or more samples. An “assay” is typically executed in a reaction vessel or “cuvette”. Typically, the assay process involves one or more of the following steps: addition of sample to cuvette, addition of one or more reagents to cuvette, mixing of cuvette contents, incubation of cuvette contents, detection of the resultant reaction at one or more points in time, and so forth. The sequence and timing of these critical activities differ for different assays in order to optimize analytical performance of each assay type. Variable “execution templates” result in more complex analyzer architectures in order to support variations when multiple assay types are intermixed in a single processor. 
         [0003]    Automated sample analyzers are designed to provide high throughput in an efficient footprint. For example, U.S. Pat. No. 5,352,612 to Huber, et al. discloses a sample analyzer having a movable sample support, e.g., a processor wheel, that includes an indexing drive. The indexing drive is adapted to advance the sample support a fixed distance based on the summation of one or more increments. For simplicity and by convention, an increment can refer to the time to increment, i.e., advance, rotate, shift, and the like, or to the increment distance or amount associated with moving a cuvette from a first cuvette holder position to a second cuvette holder position. Discrete equipment units are positioned around the periphery of the processor wheel at pre-determined cuvette holder positions to optimize the throughput. 
         [0004]    More particularly, the processor wheel is rotated so that each cuvette disposed in the wheel advances stepwise around the periphery of the wheel in predefined sets of increments in accordance with a pre-established time schedule. According to the teachings of the Huber patent, each set of increments comprises plural discrete increments. In one embodiment, there are two increments. The first increment of the set corresponds to the total number of cuvette holder positions in the processor wheel (n) plus one, which is to say, n+1. For example, if the processor wheel has 90 cuvette holder positions, i.e., n=90, then the first integer of the set of increments is 91. As a result, the increment always results in a complete revolution of the processor wheel plus one. The second increment of the set also results in another complete revolution of the processor wheel plus a number of additional cuvette holder positions that are determined formulaically. 
         [0005]    The usefulness of the Huber processor, however, is restricted in that individual reaction vessels are presented to resources that are disposed around the periphery of the processor wheel in a fixed temporal pattern. Because of this limitation, relatively complex mechanisms are required, to process a given assay in other than a fixed template. Accordingly, it would be desirable to provide a simple and reliable sample analyzer that enables efficient processing of a multiplicity of assays having variable protocols or “execution templates”. To enable this functionality, it would be desirable to provide a sample analyzer that allows variable incrementing, rather than the fixed incrementing taught by Huber. 
       SUMMARY OF THE INVENTION 
       [0006]    A sample analyzer with fixed and variable indexing is disclosed. The analyzer is structured and arranged to align reaction vessels, e.g., cuvettes, at a pre-determined, fixed point while maintaining a positional sequence using variable indexing. Variable indexing allows cuvettes to be presented to multiple, fixed point resources at multiple occasions in a systematic progression in a highly efficient manner. The presentation of cuvettes to multiple, fixed point resources at multiple times is superior to existing indexing. 
     
    
     
       DESCRIPTION OF THE DRAWINGS 
         [0007]    The invention will be more fully understood by reference to the following Detailed Description of the invention in conjunction with the Drawings, of which: 
           [0008]      FIG. 1  shows an illustrative schematic of a 95-position sample analyzer in accordance with the present invention; 
           [0009]      FIG. 2  shows platform resource timing options for a 95-position, 1 position per index sample analyzer in accordance with the prior art; 
           [0010]      FIG. 3  shows platform resource timing options for a 95-position, 1 position per index sample analyzer having plural detectors in accordance with the prior art; 
           [0011]      FIG. 4  is a schematic view of the 95-position, 1 position per index sample analyzer of  FIG. 3 ; 
           [0012]      FIG. 5  shows resource timing options for a 95-position, 26 position per index sample analyzer in accordance with the prior art; 
           [0013]      FIG. 6  shows resource timing options for a 95-position, 121 position per index sample analyzer in accordance with the prior art; 
           [0014]      FIG. 7  is a schematic view of the platform described in  FIGS. 5 and 6 ; 
           [0015]      FIG. 8  shows resource timing options for 95-position, 121 position per index sample analyzer that includes a divided incremental index in accordance with the present invention; 
           [0016]      FIG. 9  shows timing options for 95-position, 121 position per index sample analyzer that includes a divided incremental index with a single, fixed point resource in accordance with the present invention; 
           [0017]      FIG. 10  shows details of timing options for 95-position, net 121 position per index sample analyzer that includes a divided incremental index with a single, fixed point resource in accordance with the present invention; and 
           [0018]      FIG. 11  shows additional details of timing options for 95-position, net 121 position per index sample analyzer that includes a divided incremental index with a single, fixed point resource in accordance with the present invention. 
       
    
    
     DETAILED DESCRIPTION 
       [0019]    A method of controlling a sample analyzer using variable increment indexing and a sample analyzer having a variable indexing capability are disclosed. Inclusion of variable increment indexing enables more efficient use of resources, especially resources that are disposed or accessible only at fixed point locations such as sample probe stations, reagent probe stations, cuvette loading and unloading stations, detection stations, and the like. Before discussing the method and apparatus, the advantages of variable increment indexing will be illustrated. 
         [0020]    Resource timing options for a simple indexing 95-position platform and for a 95-position platform having a more complex index pattern are shown, respectively, in  FIG. 2  and  FIG. 5 . In  FIG. 2 , the indexing increment is fixed at one cuvette holder position per index, which is to say that each indexing event corresponds to the processor wheel advancing but a single increment to the next, adjacent position. As a result, during a complete cycle, resources that are disposed or only accessible at a single fixed point are only accessible by a given cuvette once. The opportunity to access a resource does not recur until the processor wheel has made a complete revolution; after all 95 indexing events. 
         [0021]    In the example presented in  FIG. 2 , a detector resource  20  is only accessible once per cycle. If more frequent access to a detector is desired or required, then redundant detector resources  21 ,  22 ,  23 ,  24 , and  25  must be added at various positions about the periphery of the wheel as shown in  FIG. 3  and in reaction ring schematic in  FIG. 4 . Thus, incremental indexing from one cuvette holder position to an adjacent cuvette holder position is extremely limiting and can become expensive. 
         [0022]    In contrast,  FIG. 5  shows fixed increment indexing in which the indexing increment is greater than one (1) but less than the total number of cuvette holder positions in the cuvette holding ring. For illustrative purposes only, the resource timing chart in  FIG. 5  is for a 95-position sample analyzer with a fixed, 26 positions per index increment. 
         [0023]    As shown in  FIG. 5 , when a correct combination of index size relative to the number of cuvette holder positions is selected, the reaction cuvette is brought proximate to, but not exactly to, the fixed location at various times  31  during the fixed indexing. For example, assuming that access to a detector resource is required at various and multiple times throughout the cycle,  FIG. 5  illustrates that there are several opportunities  31  in the region of cuvette holder positions  29 - 34  for detector access to the cuvette. Although more accessible than the example presented by  FIG. 2 , a complex, multi-axis detector mechanism would be required to access the reaction cuvette at any one of cuvette holder positions  29 - 34  in this instance. 
         [0024]    The same or similar indexing pattern can be achieved by indexing one full revolution in addition to the given indexing increment as illustrated in  FIG. 6 . For this example, the indexing increment is 95+26=121. This may have application for use with detector types that are capable of measuring a cuvette while in motion. A schematic view of such a reaction ring illustrating the close positioning of the cuvette at multiple cuvette positions  31  (ring positions  29 - 34 ) is shown in  FIG. 7 . 
         [0025]    Although various fixed increment indexing schemes using an indexing increment size that exceeds the total number of ring holding positions may provide more potential opportunities or options for delivering a cuvette of interest to a particular resource disposed at a discrete ring position, a fixed indexing increment still limits the efficiency and throughput of the system analyzer, especially when resources are at fixed positions. 
       Method and Advantages of Providing Variable Increment Indexing 
       [0026]    The disclosed method includes periodically dividing an otherwise fixed indexing increment to generate a plurality of (e.g., two or three) intermediate indexing increments of variable incremental lengths, the sum of which still equals the fixed indexing increment, e.g., 121 positions per increment. For the purpose of this disclosure and with respect to  FIG. 8 , the first intermediate indexing increment  36  in the illustrative embodiment is equal to ten ring positions from a starting ring position  33 . The choice of ten as the first intermediate indexing increment is arbitrary. Because the fixed indexing increment exceeds the total number of cuvette holding ring positions, the first intermediate indexing increment  36  can actually correspond either to a ten ring position increment or to a 105 ring position increment (95+10). 
         [0027]      FIG. 8  illustrates the benefit of dividing the total indexing increment into two or more intermediate indexing increments. Indeed, as shown in  FIG. 8 , providing intermediate indexing increments  36  further increases the number of available or potential options or opportunities. This is true for groups of opportunities  34 , such as for an angular reagent arm (between ring positions  65  and  77 ), as well as for fixed resources having a discrete, fixed point ring position such as a detector proximate ring position  29  (reference number  35  in  FIG. 8 ). 
         [0028]    Indeed, as shown in  FIG. 9 , including a first intermediate indexing increment of ten ring positions generates multiple instances  37  within the approximately 1300 second cycle when a reaction cuvette of interest passes the detector (at fixed point ring position  29 ). The number of opportunities or options  37  can be further and advantageously utilized, by varying the first intermediate indexing increment at discrete times during the approximately 1300 second cycle. As a result, as shown in  FIG. 10 , more reaction cuvettes of interest can access the detector (at fixed point ring position  29 ) as described in greater detail below. 
         [0029]    By further sub-dividing the first intermediate indexing increment  36  into sub-increments, one can optimize use of a discrete, fixed point resource, such as a detector. For ease of description, we will assume that the detector is fixedly disposed on the sample analyzer at ring position  29  and, moreover, that the sum of the sub-increments making up the first intermediate indexing increment is ten ring positions, realizing that just about any integer could be chosen. 
         [0030]    Table I summarizes intermediate indexing increments having variable indexing sub-increment lengths for six possible opportunities to access a detector at ring position  29 . Reference number  51  in  FIG. 11  corresponds to a cuvette containing a prepared sample (Detect 1 ) that has incubated for approximately seven and a half minutes (437 seconds versus a nominal time of 450 seconds) and that is ready for concentration measurement. Detect 2  (reference number  52  in  FIG. 11 ) corresponds to a cuvette containing a prepared sample that has incubated for approximately ten minutes (596 seconds versus a nominal time of 600 seconds) and that is ready for concentration measurement. Detect 4  (reference number  53  in  FIG. 11 ) corresponds to a cuvette containing a prepared sample that has incubated for approximately 15 minutes (912 seconds versus a nominal time of 900 seconds) and that is ready for concentration measurement. Detect 6  (reference number  54  in  FIG. 11 ) corresponds to a cuvette containing a prepared sample that has incubated for approximately 20 minutes (1229 seconds versus a nominal time of 1200 seconds) and that is ready for concentration measurement and so on. 
         [0000]    
       
         
               
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                 TABLE I 
               
               
                   
               
               
                   
                   
                 INDEX TO 
                 SUPPLEMENTAL 
                   
                   
               
               
                   
                   
                 RING 
                 INDEXING 
                 END OF 
                 NOMINAL 
               
               
                   
                 START RING 
                 POSITION 29 
                 INCREMENT 
                 INDEX RING 
                 TIME 
               
               
                 READ TAG 
                 POSITION 
                 (N) 
                 (M) 
                 POSITION 
                 (sec.) 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 Detect1 
                 20 
                 9 
                 1 
                 30 
                 437.4 
               
               
                 Detect2 
                 21 
                 8 
                 2 
                 31 
                 595.8 
               
               
                 Detect3 
                 22 
                 7 
                 3 
                 32 
                 754.2 
               
               
                 Detect4 
                 23 
                 6 
                 4 
                 33 
                 912.6 
               
               
                 Detect5 
                 24 
                 5 
                 5 
                 34 
                 1071.0 
               
               
                 Detect6 
                 25 
                 4 
                 6 
                 35 
                 1229.4 
               
               
                   
               
             
          
         
       
     
         [0031]    According to the method of the present invention, indexing increments having first intermediate indexing increments  36  with variable indexing sub-increment lengths are automatically initiated once a cuvette containing a prepared sample is properly incubated and ready for measurement by the detector. The first sub-increment (corresponding to column three in Table I (N)) is adapted to transport the cuvette containing the prepared and incubated sample from a starting ring position  33  ( FIG. 8 ) to the fixed point detector (ring position  29 ). 
         [0032]    For example, referring to Table I, from starting ring position  20  (point  51  in  FIG. 11 ), a cuvette can be indexed nine ring positions to the fixed point detector at ring position  29 , which ring position is also referred to as an interim index ring position. From starting ring position  21  (point  52  in  FIG. 11 ), a cuvette can be indexed eight ring positions to interim index ring position  29  (point  55   b  in  FIG. 11 ). From starting ring position  23  (point  53  in  FIG. 11 ), a cuvette can be indexed six ring positions to interim index ring position  29  (point  55   c  in  FIG. 11 ). From starting ring position  25  (point  54  in  FIG. 11 ), a cuvette can be indexed four ring positions to interim index ring position  29  (point  55   d  in  FIG. 11 ). 
         [0033]    In the example presented, the first sub-increments (N) of nine, eight, six, and four, respectively, are variable indexing increments that are greater than or equal to zero (0) and less than or equal to the first intermediate indexing increment. The first sub-increment (N) event includes transport of the cuvette to the fixed point detector at interim index ring position  29  and, optionally, can also include transfer of the cuvette from the cuvette holding ring to the detector or to a transfer wheel associated with the detector, for measurement. Preferably, transport of the cuvette to interim index ring position  29  occurs prior to the cuvette holding ring completing a first indexing revolution about its axis. However, transport of the cuvette to interim index ring position  29  (points  55   a - 55   d ) may also occur after the cuvette holding ring completes an indexing revolution about its axis. 
         [0034]    The second sub-increment index (corresponding to column four in Table I (M)) corresponds to the supplemental indexing increment to the end position to which the cuvette would otherwise have been indexed but for the first sub-increment index. Accordingly, the second sub-increment index (M) is equal to the mathematical difference between the first intermediate indexing increment, which, for this example, is equal to 10, and the first sub-increment index (N), or M=10-N. The second sub-increment index (M) refers to a further, supplemental increment necessary to transport the cuvette containing the measured sample from interim index ring position (points  55   a - 55   d ), e.g., the fixed point detector (at ring position  29 ), to the end ring position  36  (in  FIG. 8 ) of first intermediate indexing increment. The second sub-increment index (corresponding to column four in Table I) is used to account for the variable indexing increments, to synchronize the system. 
         [0035]    For example, referring to Table I and  FIG. 11 , when a reaction cuvette located at starting ring position  23  (point  53  in  FIG. 11 ) is properly incubated and ready for measurement of its concentration, the first intermediate indexing increment can be automatically sub-divided. The first sub-increment  59 , which is six, is designed to transport a cuvette to interim index ring position  29  (point  55   c  in  FIG. 11 ). Subsequently, the second indexing sub-increment  60  needed to complete the first intermediate indexing increment of ten and to transport the cuvette from interim index ring position  29  (point  55   c ) to the end position  36   b  (at ring position  33  (23+10)) is four (33−29). 
         [0036]    When a reaction cuvette located at starting ring position  25  (point  54  in  FIG. 11 ) is properly incubated and ready for measurement of its concentration, the first intermediate indexing increment can, instead, be automatically further sub-divided. The first sub-increment  62 , which is four, is designed to transport a cuvette to interim index ring position  29  (point  55   d  in  FIG. 11 ). Subsequently, the second indexing sub-increment  64  needed to complete the first intermediate indexing increment of ten and to transport the cuvette from interim index ring position  29  (point  55   d ) to the end position  36   c  (at ring position  35  (25+10)) is six (35−29). 
         [0037]    For the two exemplary cases described immediately above, the variable second indexing sub-increment  60  and  64  includes transport of the reaction cuvette to the normal end position  36   b  and  36   c.  Optionally, prior to the variable second indexing sub-increment, the cuvette could be transferred from the detector back to the cuvette holding ring. 
         [0038]    Although the above description positions reaction cuvettes for transfer to and from a detector or detection while remaining on the processing wheel, e.g., to detect the results of a chemistry reaction of the contents of the cuvette, those skilled in the art can appreciate that there are other operations that can be performed either on or outside of the cuvette processing wheel. For example, transferring cuvettes to and from a resource that is outside of or remote from the cuvette holding ring, e.g., an aliquot wheel or other device, can also be used to improve throughput and efficiency. 
         [0039]    In a manner similar to that previously described hereinabove, additional transfers can be executed by dividing the indexing increment into a plurality of (two or three) intermediate indexing increments. 
       Sample Analyzer 
       [0040]    Having described a method for optimizing multiple sample analyses by using variable indexing, a sample analyzer and controller for the same will be described. Sample analyzers and the discrete resources used by sample analyzers are well-known to the art and will not be described in detail except in relation to the variable indexing attribute. 
         [0041]    A sample analyzer embodiment in accordance with the present invention is shown in  FIG. 1 . The embodied sample analyzer  10  includes at least one reaction cuvette holding ring  40 , at least one reagent storing ring  50 , a sample holding ring  70 , a nephelometry or photometry position  90 , and an additional detector position  15 . 
         [0042]    The embodiment shown in  FIG. 1  includes, inter alia, a fixed reagent transfer arm (R 1 ) at a first reagent transfer position  11  (at ring position  9 ), an angular reagent transfer arm (R 2 ) at a plurality of second reagent transfer positions  12  (generally between ring positions  60  and  78 ), a reaction cuvette loading position  13  (at ring position  51 ), a reaction cuvette unloading position  16  (at ring position  85 ), a sample transfer arm  14  (at ring position  0 ), and a detector position  15  (at ring position  29 ). Optionally or alternatively, the embodiment shown in  FIG. 1  can include, inter alia, a first angular reagent transfer arm (R 1 ) at a plurality of first reagent transfer positions, a second angular reagent transfer arm at a plurality of second reagent transfer positions, a reaction cuvette loading position, a sample (or aliquot) transfer position, and a detector position. 
         [0043]    The cuvette holding ring(s)  40  include an annular structure or wheel that is independently rotatable about a first axis  5 . Each cuvette holding ring  40  is structured and arranged to include a plurality of cuvette holding positions (not shown) for holding reaction vessels, i.e., cuvettes. For this disclosure, the number of cuvette holding positions is 95 although other numbers are envisioned. The cuvette holding ring(s)  40  is coupled to a motor (not shown) and a controller  100 . The controller  100  is adapted to operate the motor to produce a desired indexing rate. The motor is structured and arranged to rotate the cuvette holding ring  40  about the first axis  5 . 
         [0044]    Reaction cuvettes for holding at least one of a sample and reagent are loaded or inserted into empty cuvette holder positions in the cuvette holding ring(s)  40  at the cuvette loading position  13  using a cuvette transferring device. The controller  100  is adapted to present an empty cuvette holding position at the cuvette loading position  13  and to load or insert an unused and sanitary cuvette into the empty cuvette holding position. 
         [0045]    Reaction cuvettes that have been tested are unloaded or otherwise removed from the cuvette holding ring(s)  40  at the cuvette unloading position  16  using a cuvette transferring device and properly disposed of. The controller  100  is adapted to present a used and measured reaction cuvette at the cuvette unloading position  16  and to unload or remove the reaction cuvette and its contents from the cuvette holding ring  40 . 
         [0046]    The reagent storing ring(s)  50  includes an independently rotatable annular device or wheel that is concentric and coaxial with the wheel of the cuvette holding ring  40 . The reagent storing ring  50  is coupled to a motor (not shown) and to the controller  100 . The controller  100  is adapted to operate the motor to rotate the reagent storing ring(s)  50  to present a discrete vessel containing a known reagent to a desired location. The motor is structured and arranged to rotate the reagent storing ring  50  about the first axis  5 . 
         [0047]    The reagent storing ring(s)  50  includes or is in operational communication with plural reagent arms (R 1  and R 2 ) and associated probes for aspirating reagent solution from vessels containing the reagent and for dispensing reagent solution into a reaction cuvette. At least one of the plural reagent arms is an angular reagent arm. For example, the embodiment shown in  FIG. 13  includes a fixed first reagent arm (R 1 ) for dispensing a first reagent into the reaction cuvette at a fixed point  11  and an angular second reagent arm (R 2 ) for dispensing a second reagent into the reaction cuvette. 
         [0048]    In operation, the controller  100  is adapted to move the reagent storing ring(s)  50  during increment indexing to present a vessel containing a desired reagent to one of the reagent arms (R 1 , R 2 ) and their associated probes. The controller  100  is further adapted to operate the reagent arms (R 1 , R 2 ) and their associated probes to aspirate a volume of the desired reagent from a reagent-containing vessel and to dispense the extracted volume of the desired reagent into a desired reaction cuvette. 
         [0049]    The sample holding ring  70  is structured and arranged for holding samples. The sample holding ring  70  includes an independently rotatable wheel having an axis of rotation that is parallel to the axis  5  of the cuvette holding ring  40 . The sample holding ring  70  is structured and arranged to include a sample transfer arm  14  that includes a sample probe  75 , which is adapted to aspirate a sample from a vessel containing the same and to dispense the sample into a reaction cuvette on the cuvette holding ring  40 . 
         [0050]    The sample holding ring  70  is operatively coupled to a motor (not shown) and to a controller  100 . The motor is structured and arranged to rotate the sample holding ring  70  about the second axis. The controller  100  is adapted to operate the motor to rotate the sample holding ring  70  to present a discrete vessel containing a given sample to a desired location, e.g., proximate the sample probe  75 . The controller  100  is further adapted to cause the sample probe  75  to aspirate a measured portion of the sample provided from a vessel containing the same and to dispense the sample directly into a reaction cuvette on the cuvette holding ring  40 . 
         [0051]    Nephelometry and photometry are techniques that are well known to the art for sample analysis and will not be described in detail. An optical nephelometer or photometer  90  is adapted to take readings of, e.g., scan, the contents of cuvettes residing in the cuvette holding ring  40  as the cuvette passes by the same during indexing. More specifically, each indexing is designed to exceed 360 degrees so that the optical nephelometer or photometer  90  may take readings of each cuvette during each revolution of the cuvette holding ring  40 . 
         [0052]    The embodied sample analyzer includes a controller  100  that is adapted to initiate variable incremental indexing at discrete times, to transport discrete reaction cuvettes that are awaiting an available resource that is disposed at a discrete, fixed point. More specifically, the controller  100  is adapted to divide an otherwise fixed indexing increment to generate a plurality of (e.g., two or three) intermediate indexing increments of variable incremental lengths, the sum of which still equals the fixed indexing increment, e.g.,  121  positions per increment. The method of dividing the fixed indexing increment has been described hereinabove and will not be described further. 
         [0053]    The controller  100  can be implemented as hardware or software or a combination of the two. In the case of the latter, the controller  100  includes a processing unit that is structured and arranged to execute at least one application, driver program, and the like, at least one input/output interface, and suitable memory, e.g., random access memory (RAM), for executing the at least one application, driver program, and the like, and read-only memory (ROM), for storing operational data, the at least one application, driver program, and the like. 
         [0054]    In pertinent part, the controller  100  is adapted to identify discrete cuvettes containing a sample that is prepared for processing at an available resource disposed at a fixed point and to vary the otherwise fixed indexing increment to transport the discrete cuvette to the fixed point by dividing the fixed indexing increment into a plurality of intermediate indexing increments at least two of which have variable incremental lengths. 
         [0055]    While the invention is described through the above-described exemplary embodiments, it will be understood by those of ordinary skill in the art that modifications to, and variations of, the illustrated embodiments may be made without departing from the inventive concepts disclosed herein. Accordingly, the invention should not be viewed as limited, except by the scope and spirit of the appended claims.