WO2006/019349 PCT/SE2005/001191 Measurement system for determining analyte information of a test sample The present invention relates to a measurement system and in particular to a measurement system for determining analyte 5 information of a test sample of unknown composition. Many of the types of measurement instrument that are employed in measurement systems tend to have a random drift in their output. This drift may typically occur with age or as a 10 result of an abnormal, often temporary, operating condition. It is therefore important that such a measurement instrument is periodically controlled in order to ensure the validity of the analyte information provided by the measurement system in which the instrument is employed. 15 It is known from, for example WO 04/027404, that spectral measuring instruments of the same type (so called 'satellite' instruments) may be standardized against a single instrument of that same type (so called 'master' instrument) so that a 20 measurement made on any satellite instrument will be the same as if made on the master instrument. To achieve this WO 04/027404 discloses a portable device for use in the standardization of each satellite measurement instrument. The portable device comprises a reference sample holder 25 collocated with an information unit which may be read by a satellite instrument when the holder is introduced into the satellite instrument. Information, typically including a spectrum, regarding measurements made on the reference sample by the master measuring instrument is held in the information 30 unit and transferred automatically to a satellite instrument. This information, together with information derived from measurements on the reference sample by the satellite instrument, is employed to generate a standardization model for the satellite instrument. The standardization model may 35 then be employed in a mathematical transformation of subsequent measurements made by the satellite instrument on WO2006/019349 PCT/SE2005/001191 2 unknown samples to ones that would have been made on the master instrument. However, there remain many other types of measurement 5 instrument where standardization to a master instrument is inappropriate but where confidence in the accuracy of the measurement results produced by a measurement system incorporating the instrument is still desirable. 10 One such type of instrument is a chemical assay measurement instrument. This type of instrument is often used to make routine chemical assays of an unknown test sample such as a food or a feed sample or a pharmaceutical sample. One such instrument operates according to the Kjeldahl method and is 15 employed to provide, for example, information on the amount of nitrogen, and optionally from this an amount of protein, in a test sample. Other such instruments are known which operate according to well established measurement methodologies in order to measure, for example, a fat or 20 fiber content of a sample. These types of measurement instruments are not normally standardized against a measurement that was made on a master instrument of the same type. However, it is still desirable 25 to in some way calibrate the measurement instrument. To this end it is known to provide a stoichiometric reference sample, the composition of which known directly. This reference sample may, for example, be provided to a user of the measurement system pre-weighed, in an ampoule or a user may 30 be required to manually weigh the stoichiometric material in order to create the reference sample. The results of measurements on this reference sample by a particular chemical assay measurement instrument are then correlated by the measurement system with information that indicates an 35 expected measurement results for that sample. This information is typically in the form of a data sheet or other printed material that is separate from the reference WO2006/019349 PCT/SE2005/001191 3 sample and that identifies the chemical composition of the sample and possibly its weight. This information is then manually entered by a user into the measurement system that may then be configured to automatically compute an expected 5 amount of one or more analyte. There exists considerable potential of error in this process; printed matter may be lost or confused; or incorrect data may be accidentally entered into the system. 10 It is an aim of the present invention to alleviate at least some of the aforementioned problems. Accordingly there is provided a measurement system as described in and characterized by the present Claim 1. By 15 having a data processing means that is operable to process data read from an information unit of a reference sample holder when the holder is received in the system then information about the reference sample, such as composition and weight or an expected amount of analyte, that was 20 obtained using a second, different, preferably direct, measurement methodology may be quickly, accurately and automatically transferred into the system where it may be employed in a comparison of expected analyte information with analyte information obtained using the system in order to, 25 for example, verify the correct operation of the measurement system. These and other advantages will be made apparent from a consideration of exemplary embodiments of the present invention that will now be described with reference to the 30 drawings of the accompanying figures, of which: Fig. 1 shows schematically a first embodiment of a measurement system according to the present invention; Fig. 2 shows schematically a digestion tube for a reference sample usable in the measurement system of Fig. 1; WO2006/019349 PCT/SE2005/001191 4 Fig. 3 shows schematically a second embodiment of a measurement system according to the present invention; and Fig. 4 shows schematically a portable holder according to the present invention usable with the system of Fig. 3. 5 Referring now to Fig. 1, a measurement system 2 of the Kjeldahl type is illustrated schematically. The system 2 is here shown to comprise three functional units 4,6,8 which may be separate as in the present embodiment or may, for example, be contained in a single housing. Whatever the arrangement of 10 units 4,6,8 these together form a Kjeldahl measurement instrument 10 that is operably connectable to a data processor 12. This data processor 12 may also be contained within the same housing as the other functional units 4,6,8 and may be provided in permanent connection with the 15 instrument 10. The first unit 4 is a pre-treatment unit and typically comprises a heating block 14 having a number, such as twenty, receptacles that are here illustrated as cylindrical bores 14a, each for holding a digestion tube, at least one of which 20 will be of the type that is to be described in relation to Fig. 2. A nitrogen containing test or reference sample of known weight may be transformed into ammonium ions within this unit 4. Typically the unit 4 operates by so called 'digestion' whereby the sample is contained within the 25 digestion tube in the presence of an acidic reagent and a catalyst and is then heated by the heating block 14, normally to temperatures of 300-600 0 C for periods of up to say two hours. The second unit 6 is a distillation unit in which the digested sample undergoes dilution, alkali addition and 30 distillation, such as steam distillation. The third unit 8 is a determination unit in which test or reference measurement data on the distillate is generated by a one of a number of known measurement methodologies, such as gravimetrically, volumetrically, chromatographically or, as in the present 35 example, titrimetrically using so called acid-base titration.
WO2006/019349 PCT/SE2005/001191 5 The data processor 12 of the present embodiment comprises a calculations unit 12a, a screen 12b and a user input 12c, such as a keypad and is an integral unit of the measurement system 2. It will be appreciated that the data processor 12 5 may be realized in a number of known and uninventive ways, such as by means of a suitably programmed personal computer configured with interfaces for data communication with the system 2. The calculations unit 12a is, in the present embodiment, provided with a working access to a mathematical 10 algorithm for the calculation of the nitrogen content (%N), as analyte information, using the test- or reference measurement data resulting from the titration. The system 2 as is so far described is well known in the art and is commercially available, such as the KjelTec TM product 15 range that is available from FOSS Analytical AB, Hoganas, Sweden. The operating principles of such a system 2 are more fully described in, for example US 6,287,868, the contents of which is incorporated herein by reference. Also included in the system 2 according to the present 20 invention is a further functional unit that is configured as a reader 16 shown in Fig. 1 for reading information from an information unit of a portable holder shown in Fig. 2. The reader 16 is, in the present example, collocated with the distillation unit 6 and is operably connected to the data 25 processor 12 to permit data transfer there between. Considering now Fig. 2, a portable holder 18 is here illustrated as comprising a digestion tube 20 and an information unit 22 attached to a side wall of the tube 20. In the present example the tube 20 is provided with a 30 removable lid 24 for sealing a predetermined amount of a known reference sample 26 into the tube 20 until use. This facilitates the storage of the reference sample 26 and helps assure the integrity of the reference sample 26. The information unit 22 comprises a remotely addressable memory 35 28 for holding analyte information data, such as weight, WO2006/019349 PCT/SE2005/001191 6 composition or expected amounts of analyte, regarding the reference sample 26 that was obtained by a second, different measurement methodology. Coupled to this memory 28 is an antenna 30 by which the data may by wirelessly transmitted to 5 and from the memory 28, such as by radio frequency (RF) transmissions. In use the information unit 22 is energized upon receipt of an appropriate wireless transmission from the reader 16 of the measurement system 2 and returns data to the reader 16 in 10 the form of an appropriate wireless transmission. The reader 16 then operates to convert this transmission to a data signal usable by the data processing means 12. According to the present example the reference sample 26 comprises a stoichiometric compound of known weight. In the 15 present embodiment data indicating the identity of the compound and the weight of the reference sample is transmitted to the information unit 22 and stored in its memory 28 together with an allowable measurement tolerance for the measurement instrument 10. The digestion tube 20 is 20 then sealed by means of the lid 24 and shipped to an end user having a measurement system 2 in need of calibration. During a calibration procedure the digestion tube 20 is unsealed and placed in the measurement system 2. For example the reference sample may be an amino acid if the whole 25 analysis procedure, including digestion is to be verified or it may be an ammonium salt if only the distillation and subsequent quantification is to be verified. The calibration procedure may be initiated on the measurement system 2 via the user input 12c, or may be initiated automatically by data 30 elements returned to the reader 16 from the information unit 22. The determination unit 8 of the measurement system 2 is then operated to perform an analysis, here by titration. The reference measurement data from the determination unit 8 is WO2006/019349 PCT/SE2005/001191 7 passed to the calculations unit 12a which operates as it would for a test sample to process the measurement data and determine thereby constituent information of the reference sample 24 as an amount of nitrogen present in the reference 5 sample 24. The calculations unit 12a also operates during this calibration procedure to receive information from the reader 16 that in the present embodiment indicates the chemical formula and the weight of the reference sample 26 and to 10 process this information to generate corresponding expected analyte information, being here an expected amount of nitrogen present in the reference sample 26. It will be appreciated that the expected amount of nitrogen, determined essentially as it would have been determined by the 15 calculations unit 12a, may be stored directly in the information unit 22 as expected analyte information and accessed by the calculations unit 12a. This would serve to reduce the processing burden on the unit 12a. The unit 12a is programmed to then perform a comparison of 20 the determined amount of nitrogen with the expected amount in order obtain an indication of the numerical difference there between. A signal indicative of the same is subsequently originated. In the present embodiment this signal is then compared with a signal from the reader 16 indicating the 25 allowable measurement tolerance and a further signal is originated within the system 2. This further signal is, in the present embodiment, used to inhibit the future operation of the measurement system 2 to measure test and/or reference samples when the comparison shows the difference to lie 30 outside the allowable tolerance. The further signal may, for example, be employed within the data processor 12 in order to generate a warning message on the screen 12c and to lock the operation of the calculations unit 12a to prevent a determination of an amount of nitrogen in a test sample. The 35 calculations unit 12a may be temporarily unlocked automatically in response to the user or the information unit WO2006/019349 PCT/SE2005/001191 8 22 input indicating a calibration procedure so as to enable an amount of nitrogen in a reference sample 26 to be determined. The operation of the measurement system 2 to measure test 5 samples may be reinstated when the results of a subsequent calibration procedure indicates the operation of the instrument 10 to be within the allowable tolerance. Additionally or alternatively, the calculations unit 12a may be configured to store reference analyte information for 10 further processing. This information may, for example, be automatically transformed into a calibration function which relates expected reference analyte information to corresponding actual reference analyte information as determined by the system 2 for a number of reference samples 15 having different amounts of the analyte present. This function (or data that may be employed in an automatic calculation of the function) may then be stored in an addressable memory included in the data processor 12, for use in the subsequent operation of the system 2. Such use may, 20 for example, include the operation of the calculations unit 12a to carry out a mathematical transformation of test sample measurement data in accordance with the calibration function so as to provide 'corrected' test results. This then advantageously provides for an automatic standardization of 25 all members of a group of like measurement systems. Consider now a second embodiment of the present invention as illustrated in Fig. 3 in which a functional block diagram is depicted of a measurement system 32 including a measurement instrument in the form of a flow cytometer type cell counter 30 34. This measurement instrument 34 may be considered to comprise three functional units, 40,42,44 that in the present embodiment are shown as being contained within a single housing of the instrument 34. The first unit 40 is a sample preparation unit comprising a sample intake 36, such as a 35 pipette, and transport system 38. The sample intake 36 is WO2006/019349 PCT/SE2005/001191 9 operable to remove an amount of a liquid from a sample holder 48, such as a vial, test tube or other liquid container, into the instrument 34. Essentially the transport system 38 may be considered to operate to mix the amount of liquid with 5 a fluorescent marker dye for highlighting the specific cells or bacteria to be counted to produce a test sample. The system then provides a heated test sample to an optical unit 42. The optical unit 42 basically comprises a light source for exciting fluorescence and a cooperating detector (neither 10 shown) for detecting the amplitude of the so excited fluorescence to generate test measurement data. An analysis and control unit 44 includes a data processor 46 that is configured to receive the test measurement data from the detector and to process this to determine constituent 15 information of the test sample, being here the number of cells or bacteria of interest present in the test sample. This first measurement methodology provides a so-called indirect determination of the number of particles of interest since the amount of total luminescence is measured which is 20 then related to the number of particles. Such a measurement instrument 34 as so far described is well known in the art, and is, for example, commercially available from FOSS A/S Hillered, Denmark, where it is marketed as FOSSOMATIC m 25 Included in the system 32 according to the present invention is a reader 50 for reading information from an information unit of a portable holder shown in Fig. 4 which is devised in a manner similar to the holder 18 of Fig. 2. The reader 50 is operably connected to the analysis and control unit 44 to 30 permit data transfer there between, said data being usable within the data processor 46.
WO2006/019349 PCT/SE2005/001191 10 Considering now Fig. 4, an exemplary embodiment of a portable holder 52 is shown as comprising a container 54 for a reference liquid 64. The container 54 of the present embodiment being removably located within a housing 56 so as 5 to provide, in use, an externally accessible region 58 by which liquid 64 may be removed from the container 54. In the present embodiment the housing 56 is devised to provide physical protection for the liquid container 54. This is particularly useful during transport of the holder 52 between 10 geographically dispersed sites. The housing 56 is provided with a recess 60 in which a remotely readable information unit 62, similar in function to that unit 22 of Fig. 2, may be located either fixedly or removably. The information unit 62 is configured to retain data 15 indicating an expected number of cells or bacteria of interest within the reference liquid 64 as determined according to a measurement methodology different to that employed in the measurement instrument 34 of the system 32 of Fig. 3. In a preferred solution this different measurement 20 methodology directly determines the number of particles and comprises the counting of individual cells or bacteria, such as by eye with the aid of a microscope or by the computer aided analysis of a digitised image that records the individual cells or bacteria. 25 During a calibration procedure of the system 32 the portable holder 52 is placed proximal the pipette 36 of the measurement instrument 34 so that an amount of the reference liquid 64 may be taken into the measurement instrument 34. Here it is mixed with a suitable fluorescent marker to 30 produce a reference sample for measurement in the optical unit 42 according to the measurement methodology employed on the test sample as described above and to thereby originate reference measurement data. The data processor 46 is adapted to process this reference measurement data to determine 35 reference analyte information as indicating an amount of the cells or bacteria of interest in the reference liquid 64. The WO2006/019349 PCT/SE2005/001191 11 data processor 46 then operates to compare this with the data provided from the information unit 62 indicative of corresponding expected analyte information of the reference sample, here being the expected number of cells or bacteria, 5 so as to determine whether or not the measurement instrument 34 is operating in an acceptable manner. The subsequent operation of the measurement instrument 34 may then be varied in a manner dependent on this determination, similar to the control and/or calibration of the measurement instrument 10 10 of Fig. 1 described above. In the present embodiment the samples comprise biological material. Such material typically has a limited useful lifetime, after which the cell or bacteria content becomes unreliable. It may be useful then to include in the data held 15 in the information unit 62 temporal data that may, for example, provide an indication of the useful lifetime of the reference sample material. This may be in the form of date information indicating, for example, the last date on which the reference sample should be used (so-called 'expiry 20 date'). The data processor 46 may then be programmed to determine whether or not to perform a calibration procedure or to use the results of such a procedure in dependence of this date information. Of course, such temporal data may be provided to and employed 25 in a similar manner within the measurement system 2 of Fig. 1. It will be appreciated by those skilled in the art that the portable holders 18;52 may take any form that is suitable for use with a particular measurement instrument of interest and 30 are not confined to the forms illustrated in the present embodiments.
WO2006/019349 PCT/SE2005/001191 12 It will also be appreciated that other data may be held in the information units 22;62 to be used by the system, for example in automating the operation of the measurement instrument 10;34. Such automation may involve an automatic 5 selection of on or more of an appropriate sample handling protocol, a measurement protocol, and a data processing (control or calibration for example) protocol, all based on data identifying the sample type or class. Moreover, it will be further appreciated that functions of 10 one or more functional unit may be shared with or transferred to other function units or more than one analyte may be used without departing from the invention as claimed.