Abstract:
A method for operating a mass spectrometer so as to detect or quantify analytes, comprises: (a) identifying a selected-reaction-monitoring (SRM) transition to be used for each respective analyte; (b) determining a time duration required for a fragmentation reaction corresponding to each identified transition to proceed to a threshold percentage of completion; and (c) for each analyte, performing the steps of (i) isolating ions corresponding to a precursor-ion mass-to-charge (m/z) ratio of the respective transition; (ii) fragmenting the respective isolated ions in one of two fragmentation cells or fragmentation cell portions; and (ii) mass analyzing for fragment ions corresponding to a product-ion m/z ratio of the respective transition, wherein, for each analyte, the fragmentation cell or fragmentation cell portion that is used for fragmenting the isolated ions is determined from the time duration determined for the respective analyte.

Description:
FIELD OF THE INVENTION 
       [0001]    This invention relates generally to mass spectrometry and mass spectrometers and, in particular, to methods and apparatus for conducting multiple selected reaction monitoring procedures so as to analyze for the presence of and, optionally, the quantity of, each of a plurality of analytes. 
       BACKGROUND OF THE INVENTION 
       [0002]    The constant evolution of analytical instrumentation consists in achieving faster data acquisition and improved instrument sensitivity. In the field of mass spectrometry, structural elucidation of ionized molecules is often carried out using a tandem mass spectrometer, where a particular precursor ion is selected at the first stage of analysis or in the first mass analyzer (MS-1), the precursor ions are subjected to fragmentation (e.g. in a collision cell), and the resulting fragment (product) ions are transported for analysis in the second stage or second mass analyzer (MS-2). The method can be extended to provide fragmentation of a selected fragment, and so on, with analysis of the resulting fragments for each generation. This is typically referred to as MS n  spectrometry, with n indicating the number of steps of mass analysis and the number of generations of ions. Accordingly, MS 2  corresponds to two stages of mass analysis with two generations of ions analyzed (precursor and products). As but one non-limiting example, tandem mass spectrometry is frequently employed to determine peptide amino acid sequences in biological samples. This information can then be used to identify peptides and proteins. 
         [0003]    The procedure of performing tandem mass spectrometry so as to identify a particular analyte is sometimes referred to as selected reaction monitoring (SRM). The act of observing the presence of a particular fragment ion (of a certain product-ion mass-to-charge ratio, m/z) that is generated by fragmentation of a particular chosen and isolated precursor ion (of a certain pre-determined precursor-ion m/z) is, in many instances, powerful evidence of the presence of a particular analyte. The generation of a particular product ion by fragmentation of a selected precursor ion is often referred to as an SRM “transition”. For samples that represent complex mixtures of analytes, each SRM experiment may correspond to an analysis for the presence of and, optionally, the quantity of a particular respective analyte. 
         [0004]    A relatively new analysis technique, known as “SWATH MS” has been described for proteome analysis by Gillet et al. (Gillet et al., 2012, Targeted Data Extraction of the MS/MS Spectra Generated by Data-independent Acquisition: A New Concept for Consistent and Accurate Proteome Analysis, Mol. Cell Proteomics 11(6):O111.016717. DOI: 10.1074/mcp.O111.016717.). In the SWATH MS technique, fragment ion spectra are obtained during repeated cycling through sever consecutive precursor isolation windows (swaths). For example, Gillet et al. describe using 32 such precursor isolation windows, each such window 25 Da wide. Such SWATH MS acquisition setup generates, in a single sample injection, time-resolved fragment ion spectra for all the analytes detectable within precursor-ion range m/z range and a user-defined retention time window. The SWATH MS technique also employs a novel data analysis strategy that fundamentally differs from earlier database search approaches. Although Gillet et al. originally described SWATH MS experiments performed using a quadrupole-quadrupole time-of-flight (QqTOF) mass spectrometer system, this data analysis technique may also be employed on a triple-quadrupole mass spectrometer system as illustrated in  FIG. 1A  described below. 
         [0005]      FIG. 1A  depicts the components of a conventional mass spectrometer system  1  that may be employed for tandem mass spectrometry. It will be understood that certain features and configurations of the mass spectrometer system  1  are presented by way of illustrative examples, and should not be construed as limiting the implementation of the present teachings in or to a specific environment. An ion source, which may take the form of an electrospray ion source  5 , generates ions from an analyte material supplied from a sample inlet. For example, the sample inlet may be an outlet end of a chromatographic column, such as liquid or gas chromatograph (not depicted), from which an eluate is supplied to the ion source. The ions are transported from ion source chamber  10  that, for an electrospray source, will typically be held at or near atmospheric pressure, through several intermediate chambers  20 ,  25  and  30  of successively lower pressure, to a vacuum chamber  35 . The high vacuum chamber  35  houses a quadrupole mass filter (QMF)  51 , an ion reaction cell  52  (such as a collision or fragmentation cell) and a mass analyzer  40 . Efficient transport of ions from ion source  5  to the vacuum chamber  35  is facilitated by a number of ion optic components, including quadrupole radio-frequency (RF) ion guides  45  and  50 , octopole RF ion guide  55 , skimmer  60 , and electrostatic lenses  65  and  70 . Ions may be transported between ion source chamber  10  and first intermediate chamber  20  through an ion transfer tube  75  that is heated to evaporate residual solvent and break up solvent-analyte clusters. Intermediate chambers  20 ,  25  and  30  and high-vacuum chamber  35  are evacuated by a suitable arrangement of pumps to maintain the pressures therein at the desired values. In one example, intermediate chamber  20  communicates with a port of a mechanical pump (not depicted), and intermediate pressure chambers  25  and  30  and high-vacuum chamber  35  communicate with corresponding ports of a multistage, multiport turbomolecular pump (also not depicted). 
         [0006]    Electrodes  80  and  85  (which may take the form of conventional plate lenses) positioned axially outward from the mass analyzer  40  may be used in the generation of a potential well for axial confinement of ions, and also to effect controlled gating of ions into the interior volume of the mass analyzer  40 . The mass analyzer  40 , which may comprise a quadrupole ion trap, a quadrupole mass filter, a time-of-flight analyzer, a magnetic sector mass analyzer, an electrostatic trap, or any other form of mass analyzer, is provided with at least one detector  49  that generates a signal representative of the abundance of ions that exit the mass analyzer. If the mass analyzer  40  is provided as a quadrupole mass filter, then a detector at detector position as shown in  FIG. 1A  will generally be employed so as to receive and detect those ions which selectively completely pass through the mass analyzer  40  from an entrance end to an exit end. If, alternatively, the mass analyzer  40  is provided as a linear ion trap or other form of mass analyzer, then one or more detectors at alternative detector positions may be employed. 
         [0007]    Ions enter an inlet end of the mass analyzer  40  as a continuous or quasi-continuous beam after first passing, in the illustrated conventional apparatus, through a quadrupole mass filter (QMF)  51  and an ion reaction cell  52 . The QMF  51  may take the form of a conventional multipole structure operable to selectively transmit ions within an m/z range determined by the applied RF and DC voltages. The reaction cell  52  may also be constructed as a conventional multipole structure to which an RF voltage is applied to provide radial confinement. The reaction cell may be employed, in conventional fashion, as a collision cell for fragmentation of ions. In such operation, the interior of the cell  52  is pressurized with a suitable collision gas, and the kinetic energies of ions entering the collision cell  52  may be regulated by adjusting DC offset voltages applied to QMF  51 , collision cell  52  and lens  53 . 
         [0008]    The mass spectrometer system  1  shown in  FIG. 1A  may operate as a conventional triple quadrupole mass spectrometer, wherein ions are selectively transmitted by QMF  51 , fragmented in the ion reaction cell  52  (employed as a collision cell), and wherein the resultant product ions are mass analyzed so as to generate a product-ion mass spectrum by mass analyzer  40  and detector  49 . Samples may be analyzed using standard techniques employed in triple quadrupole mass spectrometry, such as precursor ion scanning, product ion scanning, single- or multiple reaction monitoring, and neutral loss monitoring, by applying (either in a fixed or temporally scanned manner) appropriately tuned RF and DC voltages to QMF  51  and mass analyzer  40 . The operation of the various components of the mass spectrometer systems may be directed by a controller or a control and data system  15 , which will typically consist of a combination of general-purpose and specialized processors, application-specific circuitry, and software and firmware instructions. The control and data system  15  may also provide data acquisition and post-acquisition data processing services. 
         [0009]      FIG. 1B  is a more-detailed depiction of the ion reaction cell  52  showing an entrance electrode  53  disposed at an entrance end  58   a  of the device and an exit electrode  80  disposed at an exit end  58   b . As illustrated, the ion reaction cell comprises a radio-frequency (RF) multipole device—specifically, in this example, a quadrupole—comprising four elongated and substantially parallel rod electrodes arranged as a pair of first rod electrodes  61  and a pair of second rod electrodes  62 . The leftmost diagram of  FIG. 1B  provides a longitudinal view and the rightmost diagram provides a transverse cross-sectional view, respectively, of the ion reaction cell  52 . Note that only one of the rod electrodes  62  is shown, since the view of the second rod electrode  62  is blocked in the depicted view. The four rod electrodes define an axis  59  of the device that is, parallel to the rod electrodes  62 ,  61  and that is centrally located between the rod electrodes; in other words, the four rod electrodes  62 ,  61  are equidistantly radially disposed about the axis  59 . 
         [0010]    Although the reaction cell  52  shown in  FIG. 1B  is illustrated with straight, parallel rod electrodes, alternative reaction cell configurations are known in which the electrodes are curved. Although the reaction cell  52  is shown with four rods so as to generate an RF quadrupolar electric field, the reaction cell may alternatively comprise six (6) rods, eight (8) rods, or even more rods so as to generate a hexapolar, octopolar, or higher-order electric field respectively. The rod electrodes may be contained within a housing  57  which serves to contain a collision gas used for collision induced dissociation of precursor ions introduced into a trapping volume  12  between the rod electrodes  62 ,  61  through an entrance end  58   a.    
         [0011]      FIG. 1C  schematically illustrates typical basic electrical connections for the rod electrodes  62 ,  61 . RF modulated potentials provided by power supply  250  are applied to points A and B, which are electrically connected to electrodes  62  and electrodes  61 , respectively. The electrode of each pair of electrodes—that is, the pair of electrodes  62  and the pair of electrodes  61 —are diametrically opposed to one another with respect to the ion occupation volume  12  that surrounds the longitudinal axis  59 . The phase of the RF voltage applied to one of the pairs of electrodes is exactly out of phase with the phase applied to the other pair of electrodes. 
         [0012]    In known fashion, application of RF potentials to the rod electrodes  62 ,  61  as discussed above produces an electric field pseudo-potential well about and in close proximity to the central axis  59 . In operation, ion lenses or electrodes, including entrance electrode  53 , exit electrode  80  and possibly others (not shown in  FIG. 1C ) are used to propel ions into the entrance end  58   a  ( FIG. 1B ) of the multipolar rod set (e.g., rod electrodes  62 ,  61 ) defined by a set of first ends of the plurality of rods. The presence of the RF-generated pseudo-potential well causes the ions to remain in an ion trapping volume in the vicinity of the axis  59  as these ions progress through the reaction cell from the entrance end  58   a  to an exit end  58   b  of the multipolar rod set. 
         [0013]    The ion trapping volume does not have sharp boundaries that can be precisely located. In any event, however, the true trapping volume lies approximately within the region  12  denoted by lines connecting the innermost points of the four rod electrodes. Thus the region  12  can be considered to comprise a practical trapping volume that is defined by the electrodes themselves such that the true trapping volume resides within the practical trapping volume  12 . Both the practical trapping volume and the true trapping volume are elongated parallel to the axis  59  between the entrance end  58   a  and the exit end  58   b . The entrance and exit ends  58   a ,  58   b  are defined by the ends of the rod electrodes  62 ,  61 . The ion trapping produced by the application of the RF field is effective in directions that are radial to the axis  59  (that, is within transverse cross-sectional planes such as the one illustrated on the right-hand side of  FIG. 1B ). In some instances, ions may be temporarily trapped along the dimension parallel to or along the axis  59 . 
         [0014]    In some instances, the elevated collision gas pressure within a collision cell can cause product ions that have been formed in the collision cell to drain out of the cell slowly or possibly even stall within the collision cell as a result of their very low velocity after many collisions with neutral gas molecules. The resulting lengthened ion clear-out time can cause experimental difficulties when several ion pairs (i.e., parent/products) are being measured in rapid succession. U.S. Pat. No. 5,847,386, in the names of inventors Thomson et al., describes several apparatus configurations that are designed to reduce this problem through the provision of an electric field that is parallel to the device axis within the space between the elongated electrodes. 
         [0015]    Another apparatus configuration described in the aforementioned U.S. Pat. No. 5,847,386 includes segmented rods, wherein different DC offset voltages are applied between adjacent segments such that ions within the interior volume experience a stepped DC electrical potential in a direction from the entrance end to the exit end. For example,  FIG. 1D  illustrates a collision cell or reaction cell  152  in which the rods  62  and the rods  61  (as shown in and previously described in reference to  FIG. 1B ) are replaced by series of rod segments  161  and  162 , respectively. Each of the segments  161  is supplied with the same RF voltage and each segments  162  is supplied with the same phase-shifted RF voltage from power supply  250  via a set of isolating capacitors (not illustrated), but each is supplied with a different DC voltage. 
         [0016]    U.S. Pat. No. 7,675,031, in the names of inventors Konicek et al. and assigned to the assignee of the present invention, describes an alternative apparatus configuration to address the problem of slowed ion movement through a collision cell. Konicek et al. teaches the use of auxiliary electrodes for creating drag fields within the cell interior volume. The auxiliary electrodes may be provided as arrays of finger electrodes for insertion between main RF electrodes (e.g., the rod electrodes  62 ,  61  shown in  FIG. 1B ) of a multipole device. The finger electrodes may be provided on thin substrate material such as printed circuit board material. A progressive range of voltages can be applied along lengths of the auxiliary electrodes by implementing a voltage divider that utilizes static resisters interconnecting individual finger electrodes of the arrays. Dynamic voltage variations may be applied to individual finger electrodes or to groups of the finger electrodes. 
         [0017]      FIG. 1E  shows a simplified depiction of one exemplary configuration taught in U.S. Pat. No. 7,675,031. The leftmost view of  FIG. 1E  is a longitudinal view of the apparatus  252  showing, very schematically, the disposition of auxiliary electrodes  54   a - 54   d , which may be configured with one or more terminal finger electrodes, between the main rod electrodes  62 ,  61 , wherein these rod electrodes are as shown in  FIG. 1B . The rightmost view of  FIG. 1E  is a transverse cross-sectional view which more accurately show how the auxiliary electrodes  54   a - 54   d  are disposed between adjacent pairs of the main rod electrodes. The auxiliary electrodes can occupy positions that generally define planes that, if extended, intersect on the central axis  59 . These planes can be positioned between adjacent RF rod electrodes at about equal distances from the main RF electrodes of the multipole ion guide device where the quadrupolar fields are substantially zero or close to zero, for example. Thus, the configured arrays of finger electrodes  71  can lie generally in these planes of zero potential or close to zero potential so as to minimize interference with the quadrupolar fields. The array of auxiliary electrodes and finger electrodes can also be adapted for use with curved quadrupolar configurations such as the configuration shown in  FIG. 1D . 
         [0018]      FIG. 2A  illustrates a simplified depiction of one exemplary configuration taught in U.S. Pat. No. 7,675,031. The configuration includes auxiliary electrodes  54   a ,  54   b ,  54   c ,  54   d  that are configured with one or more finger electrodes  71  and that are designed to be disposed between adjacent pairs of main rod electrodes  61 ,  62 . The relative positioning of the main rod electrodes  61 ,  62  and auxiliary electrodes  54   a ,  54   b ,  54   c ,  54   d  in  FIG. 2A  is somewhat exploded for improved illustration. The auxiliary electrodes can occupy positions that generally define planes whose extensions intersect on the central axis  59 , as shown by the directional arrow as referenced by the Roman Numeral III and as also shown in  FIG. 1E . These planes can be positioned between adjacent RF rod electrodes  61 ,  62  at about equal distances from the main RF electrodes of the electrode set where the quadrupolar fields are substantially zero or close to zero, for example. Thus, the configured arrays of finger electrodes  71  can lie generally in these planes of zero potential or close to zero potential so as to minimize interference with the quadrupolar fields. The right-hand side of  FIG. 1E  shows and end view perspective of the configuration of  FIG. 2A , illustrating how the radial inner edges  64   a ,  64   b ,  64   c , and  64   d  (see also  FIG. 2A ) of the finger electrodes  71  may be positioned relative to the main rod electrodes  61  and  62 . 
         [0019]    Turning back to  FIG. 2A , each electrode of the array of finger electrodes  71  may be connected to an adjacent finger electrode  71  by a predetermined resistive element  74  (e.g., a resistor) and in some instances, a predetermined capacitor  77 . The desired resistors  74  set up respective voltage dividers along lengths of the auxiliary electrodes  54   a ,  54   b ,  54   c ,  54   d . The resultant voltages on the array of finger electrodes  71  thus form a range of voltages, often a range of step-wise monotonic voltages. The voltages create a voltage gradient parallel to the axis  59  that urges ions through the reaction cell  52  from the entrance end  58   a  to the exit end  58   b . In the examples shown in  FIGS. 2A-2B , the voltages applied to the auxiliary electrodes often comprise static voltages, and the resistors often comprise static resistive elements. The capacitors  77  reduce an RF voltage coupling effect in which the RF voltages applied to the main RF rod electrodes  61 ,  62  typically couple to and heat the auxiliary electrodes  54   a ,  54   b ,  54   c ,  54   d  during operation of the RF rod electrodes  61 ,  62 . 
         [0020]    In an alternative configuration taught in U.S. Pat. No. 7,675,031 and as shown in  FIG. 2B , one or more of the auxiliary electrodes can be provided by an auxiliary electrode array, as shown generally designated by the reference numeral  130 , which has dynamic voltages individually applied to one or more of the array of finger electrodes  71 . In this alternative configuration, the controller  15  may include or be augmented by computer controlled voltage supplies  83 ,  84 ,  85 , which may take the form of Digital-to-Analogue Converters (DACs). There may be as many of these computer controlled voltage supplies  83 ,  84 ,  85  as there are finger electrodes  71  in an array, and that each computer controlled voltage supply may be connected to and control a voltage of a respective finger electrode  71  for the array. 
         [0021]    As shown in  FIG. 2B , and as briefly discussed above, the auxiliary electrode  130 , may as one arrangement, have designed voltages applied by a combination of dynamic computer controlled voltage supplies  83 ,  84 ,  85  and voltage dividers in the form of static resistors  74  so as to form an overall monotonically progressive range of voltages along a length of a multipole device. In such a configuration, the magnitude and range of voltages may be adjusted and changed to meet the needs of a particular sample or set of target ions to be analyzed. As also shown in  FIG. 2B , capacitors  77  may be connected between adjacent finger electrodes  71 . 
         [0022]      FIG. 2B  also shows in detail, the configuration of a radially inner edge  88  that is similar to the radially inner edges  64   a ,  64   b ,  64   c ,  64   d , described above for  FIG. 2A . The radially inner edge  88  includes a central portion  91  that may be metalized or otherwise provided with a conductive material, tapered portions  92  that straddle the central portion  91 , and a recessed gap portion  93 . The central portions  91  may be metalized in a manner that connects metallization on both the front and the back of the auxiliary electrode array  130  for each of the finger electrodes  71  of the array of finger electrodes. As an innermost extent of the auxiliary electrode  130 , the central portion  91  presents the DC electrical potential in close proximity to the ion path. Gaps  96  including recessed gap portions  93  are needed between metallization of the finger electrodes  71  in order to provide an electrical barrier between respective finger electrodes. 
         [0023]    A structural element for receiving and supporting metallization may be a substrate  99 , as shown in  FIG. 2B , of any printed circuit board (PCB) material, such as, but not limited to, fiberglass, that can be formed, bent, cut, or otherwise shaped to any desired configuration so as to be integrated into the working embodiments of the present invention. Although  FIG. 2B  shows the substrate as being substantially flat and having straight edges, it is to be understood that the substrates and the arrays of finger electrodes thereon may be shaped with curved edges and/or rounded surfaces. Substrates that are shaped and metalized in this way are relatively easy to manufacture. Thus, auxiliary electrodes in accordance with embodiments of the present invention may be configured for placement between curved main rod electrodes of curved multipoles. 
       Other Known Methods/Apparatus for Generating Axial or Drag Fields in a Collision Cell 
       [0024]    Reference is next made to  FIGS. 8A-8D , which show a known modified quadrupole rod set  700  which is modified according to the teachings provided in U.S. Pat. No. 5,847,386 in the names of inventors Thomson et al. The quadrupole rod set  700  comprises a first pair of rods consisting of rods  701  and a second pair of rods consisting of rods  708 , both sets of rods equally tapered. The rods  701  of one pair are oriented so that the wide ends  702  of the rods are at the entrance  703  to the interior volume of the rod set, and the narrow ends  704  are at the exit end  705  of the rod set. The rods  708  of the other pair are oriented so that their wide ends  709  are at the exit end  705  of the interior volume and so that their narrow ends  710  are at the entrance  703 . The rods define a central longitudinal axis  707 . 
         [0025]    Each of the rods of  701  and the rods  708  are electrically connected together, with an RF potential applied to each pair (through isolation capacitors C 2 ) by an RF generator  711 . A separate DC voltage is applied to each pair, e.g. voltage V 1  to the rods  701  and voltage V 2  to the rods  708 , by DC voltage sources  712   a  and  712   b . The supplied DC voltages provide an axial potential (i.e. a potential on the axis  707 ) which is different at one end from that at the other end. Thus, an axial field is created along the axis  707 . Although a quadrupole rod set is illustrated, the general principles of operation of the modified rod set  700  may be applied to multipole rod sets comprising more than four rods. 
         [0026]      FIG. 9  is a side view of two rods of another known rod set configuration  720  as taught in the aforementioned U.S. Pat. No. 5,847,386 and that may be employed to generate an axial field along a central axis  727  of the rod set. The rods are of the rod set  720  are all the same diameter but are oriented such that, at an entrance end  723  of the apparatus, the ends  726  of a first pair of rods, comprising rods  721 , are located closer to the central axis  727  than are the opposite ends  724  of the rods  721 . In other words, the rods  721  diverge away from the central axis  727  in a direction from the entrance end  723  to the exit end  725  of the quadrupole apparatus. A second pair of rods, comprising rods  728 , are oriented such that, at the entrance end  723 , the ends  722  are further from the central axis  727  than are the opposite ends  724  of those same rods. Thus, the rods  728  of the second pair converge towards the axis  727  in a direction from the entrance end  723  to the exit end  725 . Note that, as in all the other accompanying drawings, the illustration of the rod set  720  is not drawn to scale and thus sizes and angles are exaggerated for clarity. 
         [0027]    An alternative non-parallel multipole rod configuration has been described in U.S. Pat. No. 7,985,951 in the name of inventors Okumura et al. and in U.S. Patent Publication No. 2011/0049360 in the name of inventor Schoen. In the above-described rod set  720  ( FIG. 9 ), one set of rods diverges away from a central axis in a direction from an entrance end to an exit end and the other rod set converges towards the central axis in the same direction. In contrast, in the RF-only multipole apparatuses (not illustrated herein) taught in U.S. Pat. No. 7,985,951 and U.S. Publ. No. 2011/0049360, the surfaces of all rods diverge away from the central axis in the direction from the entrance to the exit end. The divergence of the rod surfaces away from the central axis may alternatively be described as an increase in an inscribed radius, r 0  (the radius of a circle lying in a radial plane of the multipole that is tangent to the rod inner surfaces), in the same direction. The increase of the inscribed radius, r 0 , may be most simply accomplished by tilting the long axes of a set of right-circular cylindrical rods such the rod axes diverge from the apparatus central axis in the direction from the entrance to the exit end. The increase of the inscribed radius may also be accomplished by tapering the rods. The divergence of the rod surfaces away from the central axis in the direction of ion travel produces a pseudo-potential gradient that urges ions towards the exit end of the multipole device. This effect may increase the rate at which ions are transported through the multipole device and prevent stalling and unintended trapping of ions. Moreover, by increasing r 0  from the inlet end to the exit end of an RF multipole, the value of the Mathieu parameter q of an ion is progressively reduced in the direction of ion travel, resulting in a reduced effective low-mass cutoff and the availability of greater numbers of low-m/z fragment ions for mass analysis. 
         [0028]    Similar to the electrical connections shown in  FIG. 8B , the rods of  721  of the first rod pair are electrically connected together and the rods of the other (not-illustrated) pair are connected together, with an RF potential applied to each pair by an RF generator. A separate DC voltage is applied to each pair. The supplied DC voltages provide an axial potential (i.e. a potential on the axis  727 ) which is different at one end from that at the other end. Although a quadrupole rod set is illustrated, the general principles of operation of the modified rod set  720  may be applied to multipole rod sets comprising more than four rods. 
         [0029]      FIG. 10  is an end view of a known quadrupole apparatus  730  comprising a set of auxiliary rods or electrodes as taught in the aforementioned U.S. Pat. No. 5,847,386. The four small auxiliary electrodes or rods  732   a - 732   d  are mounted parallel to one another and to the quadrupole rods  731 ,  738  in the spaces between the quadrupole rods. Each of the auxiliary rods  732   a - 732   d  has an insulating core  733  with a surface layer of resistive material  734 . A voltage applied between the two ends of each auxiliary rod causes a current to flow in the resistive layer, establishing a potential gradient from one end to the other. With all four auxiliary rods connected in parallel, i.e. with the same voltage difference between the ends of the auxiliary rods, the fields generated contribute to the electric field on the central axis  737  of the quadrupole, establishing an axial field or gradient. 
         [0030]      FIG. 11  is a side view of another known quadrupole apparatus comprising a set of auxiliary rod electrodes as taught in the aforementioned U.S. Pat. No. 5,847,386. Although the apparatus  740  that is schematically illustrated in  FIG. 11  comprises four auxiliary rods, only two such auxiliary rods  742   a - 742   b  are shown for clarity. In contrast to the orientation of the auxiliary rods  732   a - 732   d  shown in  FIG. 10 , in which all rods are parallel to the central axis defined by quadrupole rods, the auxiliary rods of the apparatus  740  are tilted, so that they are closer to the central axis  747 , as defined by the parallel quadrupole rods  741  and  748 , at one end  743  than at the other end  745  of the apparatus. Since the auxiliary rods are closer to the axis at end  743  than at end  745 , the potential at end  743  is more affected by the potential on the auxiliary rods than at the other end  745 . As a result, an axial potential is generated which varies uniformly from one end to the other since the auxiliary rods are straight. The potential can be made to vary in a non-linear fashion if the auxiliary rods  742   a - 742   b  are curved. 
         [0031]    The apparatuses described above, comprising conductive rods (either tilted or tapered quadrupole rod electrodes or tilted conductive auxiliary rod electrodes) having different static DC voltages applied to respective different pairs of rods, may disadvantageously give rise to a quadrupole DC field along the central axis. The effect of such a DC field on the properties of an RF-only ion guide may be summarized as the introduction of mass discrimination, whereby the range of ionic mass-to-charge ratios ions that can be transported through a quadrupole ion guide apparatus is reduced. U.S. Pat. No. 6,163,032, in the name of inventor Rockwood, therefore taught the use ion guides in which the number of electrodes are doubled to thereby use symmetry to cancel the undesirable DC quadrupole field. An example of one such apparatus taught in U.S. Pat. No. 6,163,032 is illustrated herewith as  FIG. 12 . 
         [0032]    The modified quadrupole system  750  schematically illustrated in  FIG. 12  has twice the number of electrodes  751  than a standard quadrupole system. In the illustrated embodiment, the quadrupole electrode pairs  752  taper in opposite directions. One electrode  751  of the electrode pair  752  tapers from its widest cross section beginning at an arbitrarily selected first end  753  of the system  750  down to its narrowest cross section ending at a second end  755  of the system  750 . The other electrode  751  of the electrode pair  752  tapers in the opposite direction and has its narrowest cross section at the first end  753  and widens out to its widest cross section at the second end  755  of the system. 
         [0033]    Each electrode  751  of the electrode pair  752  has applied thereto a radio frequency (RF) voltage and a direct current (DC) voltage. Both electrodes  751  of an electrode pair  752  have a same RF voltage applied thereto. However, while electrodes  751  within a same electrode pair have the same polarity, adjacent electrode pairs  752  have applied thereto RF voltages which are always opposite in polarity. 
         [0034]    In contrast, DC voltages are applied in order to generate an axial DC electrical field. In order to create an electrical potential between the first end  753  and the second end  755 , one electrode  751  of each pair  752  always has a first DC voltage applied thereto, whereas the other electrode of the electrode pair always has a second applied DC voltage. All electrodes  751  having a same cross section width at the first end have the same DC voltage applied thereto in order to generate the axial DC field gradient required to accelerate ions. 
         [0035]      FIGS. 13A and 13B  schematically illustrate a side view and a cross sectional view of a single rod of a quadrupole or multipole rod set that is modified so as to enable generation of an axial field according to a further teaching of the aforementioned U.S. Pat. No. 5,847,386. Rod  760  is formed as an insulating ceramic tube  762  having on its exterior surface a pair of end metal bands  764  which are highly conductive. Bands  764  are separated by an exterior resistive outer surface coating  766 . The inside of tube  762  is coated with conductive metal  768 . The wall of tube  762  is relatively thin, e.g. about 0.5 mm to 1.0 mm. 
         [0036]    In operation of a multipole apparatus comprising rods  760 , a DC voltage difference indicated by V 1  is connected to the resistive surface  176  by the two metal bands  174 , while the RF from a power supply is connected to the interior conductive metal surface  178 . The high resistivity of outer surface  176  restricts the electrons in the outer surface from responding to the RF (which is at a frequency of about 1.0 MHz), and therefore the RF is able to pass through the resistive surface with little attenuation. At the same time voltage source VI establishes a DC gradient along the length of the rod  170 , again establishing an axial DC field. 
         [0037]    The inventors, Crawford et al., of U.S. Pat. No. 7,064,322 considered that multipole devices that use high resistance multipole rods may be prone to the phenomenon “RF droop” (i.e., areas of reduced RF). The inventors considered that this phenomenon may cause ions to become stalled (and/or filtered) as they are transported through such an ion guide. To counteract this disadvantageous property, the U.S. Pat. No. 7,064,322 teaches the use, in multipole devices, of rods exemplified by the schematic illustration in  FIG. 14  herein, wherein each of the rods of the multipole device may be described as containing an inner conductive element  778 , an outer resistive element  774 , and an insulative element  776  between the inner element  778  and outer element  774 . The elements are coaxially arranged along the length of each rod to provide a rod that can be thought of as a coaxial capacitor containing a resistive outer coating. The inner element  778  may optionally be centrally located in the rod (as shown in the uppermost rod of  FIG. 14 ) or optionally present as a layer upon a central core  772  of the rod that provides structural strength (as shown in the lowermost rod of  FIG. 14 ). According to the teachings of U.S. Pat. No. 7,064,322, the insulation and resistive layers do not need to go all the way around the rod, but can be limited to the surface of the rod which influences the ion beam. 
         [0038]      FIG. 14  also illustrates exemplary electrical connections between a pair of quadrupole rods  771 , such as a pair of rods diametrically opposed to one another across a central axis, according to the teachings of U.S. Pat. No. 7,064,322. In the illustrated embodiment, the resistive element  774  and the conductive element  778  of a rod are electrically connected with each other at one end of the rod. Resistive elements  774  and conductive elements  778  of each of the rods of the rod pair are connected at the same end to the same DC voltage source  773  and the same RF source  775 . Likewise, the resistive elements and conductive elements of each of the rods of the other pair of rods (not illustrated in  FIG. 14 ) are connected at the same end to the DC voltage source  773  and the same RF source  775 . Resistive element  774  and not conductive element  778  of each rod is connected to DC voltage source  779  and RF source  777  at the other end of each rod. The DC voltage sources  773  and  779  typically supply different DC voltages to the ends of the rods, thereby providing a voltage gradient along the rod. The RF voltage supplied to the ends of each one of the pair of rods  771  by RF sources  775  and  777  is typically in phase, and the RF voltage supplied to the ends of each of the other pair of rods (not shown) by RF sources  775  and  777  is typically in phase. As is known for other multipole devices, the RF voltages supplied to the illustrated rods  771  may be 180 degrees out of phase with that supplied to the other pair of rods. 
         [0039]    The inventor, Crawford, of U.S. Pat. No. 7,564,025 determined that a much simpler rod design could be employed in a multipole ion guide device as shown in  FIG. 15 , in which no conductor is required in the rods and both RF and DC voltages are applied to a resistive material. The accompanying  FIG. 15  shows a schematic view of an exemplary rod  780  according to the teachings of U.S. Pat. No. 7,564,025. The rod  780 , which need not be cylindrical in cross section, comprises an optional insulating core rod  782  with a resistive coating  786 . The resistive coating  786  is usually of small thickness compared with the diameter of core rod  782 . The resistive coating  786  need not coat the entire surface of the core rod  782 . However, according to the teachings of U.S. Pat. No. 7,564,025, the surface of the rod that faces the axis of the containing multipole device should be covered by the resistive coating. 
         [0040]      FIG. 16  is a perspective view of a known ring pole ion transport apparatus as taught in U.S. Pat. No. 6,417,511 in the name of inventor Russ I V et al. The ion transport apparatus  790  illustrated in  FIG. 14  comprises a multipole portion  792  and a ring stack portion  794  and has an input end  793  for accepting analyte ions and an output end  795 . The ring stack portion  794  extends inside and outside the multipole portion  792 , thereby essentially overlapping the multipole portion  792 . 
         [0041]    The multipole portion  792  of the apparatus  790  comprises a plurality of rods or poles  796  that are grouped together in a spaced apart relationship. The rods  796  may be either parallel or non-parallel to the central axis  797 . Further, the rods  796  may have a parallel portion and/or a nonparallel portion. The central axis  797  may be linear or nonlinear, or may have a linear portion and/or a nonlinear portion. The ring stack portion  794  comprises a plurality of rings  798  in a spaced apart stacked relationship distributed along the central axis  797 . Each ring  798  of the ring stack portion  794  may comprise a thin, conductive plate. Alternatively, each ring  798  may comprise a thin, nonconductive plate with a conductive coating. Each ring has a generally centrally located inner through-hole  799  to allow passage of ions therethrough. Further, each ring  798  has a plurality of spaced apart through-holes  791 , each through hole  791  being dimensioned, positioned and aligned to receive one of the plurality of rods  796  of the multipole portion  792 . 
         [0042]    In operation, a radio frequency (RF) power source (not shown) is applied to the multipole portion  792  while a direct current (DC) voltage source (not shown) is applied to the ring stack portion  794 , such that a respective DC voltage difference is set up between each pair of adjacent rings. The RF power source produces an RF electromagnetic field that functions to “guide” or compress the analyte ions toward a generally centrally located longitudinal axis  797  of the ring pole ion guide  790 . The analyte ions, under the influence of the RF power source, travel through the ring pole ion guide  790  in a collimated trajectory, or “beam”. The DC voltage source produces an axial electric field that imparts an accelerating force to the analyte ions. The axial field essentially “pushes” the ions in the transport direction (from the input end  793  to the output end  795 ) along the central axis  797 . Therefore, the multipole portion  792  and its associated RF power source operate in conjunction with the ring stack portion  794  and its associated DC voltage source to simultaneously guide and transport analyte ions from the input end  793  to the output end  795  of the ring pole ion guide  790 . 
       New Requirements to Achieve Fast SRM on a Triple Quadrupole 
       [0043]    Fast SRM on a triple quadrupole mass spectrometer such as illustrated in  FIG. 1A  is a relatively new design goal where the desire is to achieve 500 SRM transitions or more per second. Many presently existing collision cells a purposely designed for high sensitivity. Such designs typically require long internal path lengths and multiple collision conditions that favor complex multistep reaction pathways. Unfortunately, using such a cell that is optimized for sensitivity, the total time required from the selection of a new precursor ion with Q 1  to the observation of a stable product signal from Q 3  can easily exceed the 2 millisecond total time available for monitoring a specific transition. Even the addition of an axial field (e.g., by employing configurations as shown in  FIGS. 1D-1E ,  FIGS. 2A-2B ,  FIGS. 8A-8D ,  FIGS. 9-12 ,  FIGS. 13A-B  or  FIGS. 14-15 ) has not proven to be especially useful. Indeed, some reactions have been observed that require 50 milliseconds to reach equilibrium using a collision cell optimized for sensitivity. The operation of such cells may be made faster by employing lower collision pressures and increased RF voltages, but even under these conditions, 0.5 milliseconds may be required to achieve equilibrium. 
         [0044]    An alternative design that favors fast reaction pathways is needed for fast SRM. Such a cell may employ a short path length, preferably with an axial field that favors facile reactions that will not require more than a few hundred microseconds to complete. Therefore, fast ion transit times will be acceptable in such shorter cells. However, these short-cell designs will not provide the highest sensitivity in cases where speed is not required. Therefore, the inventors have determined that a two-collision-cell apparatus may be advantageously employed. 
       SUMMARY OF THE INVENTION 
       [0045]    To address the above-identified needs in the art, the inventors here disclose mass spectrometer designs that incorporate either multiple separate collision cells or else a single collision cell having multiple segments, wherein the mass spectrometer system has the capability of dynamically choosing the appropriate collision cell or collision cell segment that is suitable for particular experimental requirements. According to some embodiments, a first collision cell (a “long” collision cell) has a length that is greater than the length of a second collision cell (a “short” collision cell). Note that the terms “first collision cell” and “second collision cell”, as used herein, are used to identify and distinguish individual collision cell components and are not intended to imply any particular spatial order, unless otherwise stated. Note also that the terms “collision cell” and “fragmentation cell” are used synonymously herein. 
         [0046]    The short collision cell is utilized for conducting fragmentation reactions that require a short time duration to proceed to effective completion under given conditions of collision cell pressure and precursor ion kinetic energy, where “effective completion” corresponds to a certain threshold percentage of precursor ions being fragmented during the reaction. The threshold percentage that corresponds to effective completion may vary according to the requirement of each experimenter or analyst and may depend, at least in part, on whether analytes are quantified, as opposed to merely detected, as well as the quantity of analyte molecules present in a sample or the level of analytical sensitivity required. In some instances, effective completion of a fragmentation reaction may correspond to greater than 50% fragmentation of precursor ions (i.e., a threshold percentage of 50%). In other instances effective completion may correspond to greater than 60%, 67%, 70%, 75%, 80%, 90%, 95%, or 99% fragmentation of precursor ions. 
         [0047]    The phrase “short time duration” refers to a time duration (for reaction effective completion) that is less than an experimentally specified threshold time. In some instances or for some fragmentation reactions, the threshold time may be set as long as 10 msec (e.g., ten milliseconds); in other words, in such instances, the short collision cell would be used if the fragmentation reaction proceeds to effective completion in less than 10 msec. In other instances, the threshold time may be 5 msec or 10 msec. In other instances, the threshold time may be as short as 500 μsec (microseconds), 250 μsec, or 100 μsec. The threshold time may be specified in accordance with an experimental goal of achieving a certain average rate of experimentally observed transitions per second, such as at least 250 transitions per second or, more preferably, 500 transitions per second. 
         [0048]    References to “high pressure” or “relatively high pressure”, as used herein in reference to mass spectrometer internal pressures, refer to pressures suitable for fragmentation reactions by the process of collision induced dissociation in the range of about 0.5 mtorr to about 5 mtorr. Similarly, references to a collision cell being “pressurized, as used below refer to an internal gas pressure within a collision cell in the same range—that is, about 0.5 mtorr to about 5 mtorr. 
         [0049]    The long collision cell is utilized either for conducting fragmentation reactions that require a time duration for effective completion that is longer than or equal to the threshold time or for conducting fragmentation reactions when high-sensitivity detection of the fragments is required (i.e., when detection of fragments is required at fragment abundances below a threshold limit of detection or when quantification of fragment abundances is required at fragment abundances below a threshold limit of quantification). 
         [0050]    According to some embodiments in accordance with the present teachings, the long collision cell is not pressurized during the course of fragmentation reactions that occur primarily within the short collision cell, and is operated, in the unpressurized state, as a simple ion transfer device either to or from the short collision cell device. During operation according to other embodiments in accordance with the present teachings, the long collision cell remains pressurized during the course of fragmentation reactions that occur primarily within the short collision cell, and precursor or product ions are transferred through the long collision cell (either to or from the short collision cell, respectively) by application of an axial or drag field within the long collision cell. According to some other embodiments in accordance with the present teachings, the short collision cell is not pressurized during the course of fragmentation reactions that occur primarily within the long collision cell, and is operated as a simple ion transfer device either to or from the long collision cell. According to yet other embodiments in accordance with the present teachings, the short collision cell remains pressurized during the course of fragmentation reactions that occur primarily within the long collision cell, and precursor or product ions are transferred through the short collision cell (either to or from the long collision cell, respectively) by application of an axial or drag field within the short collision cell. 
         [0051]    According to other embodiments, a single collision cell may be partitioned into a plurality of separate segments, each such segment comprising its own respective gas supply, lens and voltage control. The partitioned device may be considered to be an adjustable pressure and length collision cell. Collision cells in accordance with the present teachings may employ multiple rods. However, in alternative embodiments, alternative ion-confining technologies may be employed, such as, but not limited to, stacked rings and lossy dielectric tubes. 
         [0052]    According to a first aspect of the present teachings, there is disclosed a mass spectrometer system comprising: (a) an ion source configured to receive a sample from a sample inlet; (b) a mass filter configured to receive the ions from the ion source; (c) a mass analyzer including a detector configured to separate ions in accordance with their mass-to-charge ratios and detect the separated ions; (d) a first and a second ion fragmentation cell disposed along an ion pathway between the mass filter and the mass analyzer, the first ion fragmentation cell configured to receive ions from the mass filter, the second ion fragmentation cell configured to receive ions from the first ion fragmentation cell and to outlet ions to the mass analyzer, each fragmentation cell comprising: (d1) a set of multipole rod electrodes; (d2) a housing enclosing the set of multipole rod electrodes; and (d3) a gas inlet fluidically coupled to a source of a collision gas and to an interior of the housing; (e) at least one radio-frequency (RF) voltage source electrically coupled to the set of multipole rod electrodes of each of the first and second ion fragmentation cells; and (f) at least one direct current (DC) voltage source electrically coupled to the mass filter, wherein a length, L 2 , of the second ion fragmentation cell is less than a length, L 1 , of the first ion fragmentation cell. 
         [0053]    According to a second aspect of the present teachings, there is disclosed a mass spectrometer system comprising: (a) an ion source configured to receive a sample from a sample inlet; (b) a mass filter configured to receive the ions from the ion source; (c) a mass analyzer including a detector configured to separate ions in accordance with their mass-to-charge ratios and detect the separated ions; (c) a first ion fragmentation cell configured to receive ions from the mass filter and comprising a gas inlet fluidically coupled to a source of a collision gas and to an interior of the first ion fragmentation cell; (d) a second ion fragmentation cell configured to receive ions from the first ion fragmentation cell and to outlet ions to the mass analyzer, the second ion fragmentation cell comprising: (d1) a tube comprising a resistive material; (d2) a set of multipole rod electrodes disposed exteriorly to the tube; and (d3) a gas inlet fluidically coupled to a source of a collision gas and to an interior of the tube; (e) at least one radio-frequency (RF) voltage source electrically coupled to the set of multipole rod electrodes; and (f) at least one direct current (DC) voltage source electrically coupled to the mass filter and electrically coupled to the tube so as to apply an electrical potential gradient across a length of the tube, wherein a length, L 2 , of the second ion fragmentation cell is less than a length, L 1 , of the first ion fragmentation cell. 
         [0054]    According to a third aspect of the present teachings, there is disclosed a mass spectrometer system comprising: (a) an ion source configured to receive a sample from a sample inlet; (b) a mass filter configured to receive the ions from the ion source; (c) a mass analyzer including a detector configured to separate ions in accordance with their mass-to-charge ratios and detect the separated ions; (d) an ion fragmentation cell configured to receive ions from the mass filter and to outlet fragment ions to the mass analyzer, the ion fragmentation cell comprising: (d1) a set of multipole rod electrodes; (d2) a housing enclosing the set of multipole rod electrodes and comprising a housing interior, an ion inlet and an ion outlet; (d3) a set of partitions within the housing separating the housing interior into a plurality of compartments, each partition comprising an aperture disposed along an ion pathway between the ion inlet and ion outlet; and (d4) a plurality of gas inlets, each gas inlet fluidically coupled to a source of a collision gas and to a respective compartment and having a respective inlet shutoff valve; (e) at least one radio-frequency (RF) voltage source electrically coupled to the set of multipole rod electrodes; (f) at least one direct current (DC) voltage source electrically coupled to the mass filter; and (g) a controller electrically coupled to each inlet shutoff valve and each vent shutoff valve, the controller configured to independently control the pressure of collision gas within each compartment. 
         [0055]    According to another aspect of the present teachings, a method for operating a mass spectrometer so as to detect a presence of or a quantity of each of one or more analytes of a sample is disclosed, wherein the method comprises: (a) for each of the one or more analytes, identifying one or more selected-reaction-monitoring (SRM) transitions to be used for detecting the presence or quantity of the respective analyte; (b) for each of the one or more identified SRM transitions, determining a time duration required for a fragmentation reaction corresponding to the respective SRM transition to proceed to a certain threshold percentage of completion; (c) ionizing the sample in an ionization source of the mass spectrometer so as to produce one or more populations of first-generation ions; and (d) for each of the one or more identified SRM transitions, performing the steps of: (d1) isolating a sub-population of a one of the one or more populations of first-generation ions corresponding to a precursor-ion mass-to-charge (m/z) ratio associated with the respective SRM transition; (d2) fragmenting the respective isolated sub-population of ions in a one of two fragmentation cells of the mass spectrometer so as to produce a respective population of fragment ions; and (d3) analyzing, with a mass analyzer of the mass spectrometer, for the presence or quantity, among the respective fragment ions, of ions corresponding to a product-ion m/z ratio associated with the respective SRM transition, wherein, for each identified SRM transition, the fragmentation cell that is used for fragmenting the isolated sub-population of ions corresponding to the respective precursor-ion m/z ratio is determined from the time duration determined for the respective identified SRM transition. 
         [0056]    According to yet another aspect of the present teachings, a method for operating a mass spectrometer so as to detect a presence of or a quantity of one or more analytes of a sample is disclosed, wherein the method comprises: (a) for each of the one or more analytes, identifying one or more selected-reaction-monitoring (SRM) transitions to be used for detecting the presence or quantity of the respective analyte; (b) for each of the one or more identified SRM transitions, determining a time duration required for a fragmentation step corresponding to the identified SRM transition to proceed to a certain threshold percentage of completion; (c) ionizing the sample in an ionization source of the mass spectrometer so as to produce one or more populations of first-generation ions; and (d) for each of the one or more identified SRM transitions, performing the steps of: (d1) isolating a sub-population of the one or more populations of first-generation ions corresponding to a precursor-ion mass-to-charge (m/z) ratio associated with the respective SRM transition; (d2) fragmenting the respective isolated sub-population of ions in a one of two portions of a partitioned fragmentation cell of the mass spectrometer so as to produce a respective population of fragment ions; and (d3) analyzing, with a mass analyzer of the mass spectrometer, for the presence or quantity, among the respective fragment ions, of ions corresponding to a product-ion m/z ratio associated with the respective SRM transition, wherein, for each identified SRM transition, the portion of the partitioned fragmentation cell that is used for fragmenting the isolated sub-population of ions corresponding to the respective precursor-ion m/z ratio is determined from the time duration determined for the respective identified SRM transition. 
         [0057]    According to still yet another aspect of the present teachings, a method for operating a mass spectrometer so as to detect a presence of or a quantity of each of one or more analytes of a sample is disclosed, wherein the method comprises: (a) for each of the one or more analytes, identifying one or more selected-reaction-monitoring (SRM) transitions to be used for detecting the presence or quantity of the respective analyte; (b) for each of the one or more identified SRM transitions, determining a required limit of detection or a required limit of quantification of fragment ions corresponding to the respective SRM transition; (c) ionizing the sample in an ionization source of the mass spectrometer so as to produce one or more populations of first-generation ions; and (d) for each of the one or more identified SRM transitions, performing the steps of: (d1) isolating a sub-population of a one of the one or more populations of first-generation ions corresponding to a precursor-ion mass-to-charge (m/z) ratio associated with the respective SRM transition; (d2) fragmenting the respective isolated sub-population of ions in a one of two fragmentation cells of the mass spectrometer so as to produce a respective population of fragment ions; and (d3) analyzing, with a mass analyzer of the mass spectrometer, for the presence or quantity, among the respective fragment ions, of ions corresponding to a product-ion m/z ratio associated with the respective SRM transition, wherein, for each identified SRM transition, the fragmentation cell that is used for fragmenting the isolated sub-population of ions corresponding to the respective precursor-ion m/z ratio is determined from the required limit of detection or the required limit of quantification of fragment ions corresponding to the respective SRM transition. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0058]    The above noted and various other aspects of the present invention will become apparent from the following description which is given by way of example only and with reference to the accompanying drawings, not drawn to scale, in which: 
           [0059]      FIG. 1A  is a schematic diagram showing components of a conventional mass spectrometer system; 
           [0060]      FIG. 1B  is a schematic illustration of a conventional quadrupolar collision or reaction cell; 
           [0061]      FIG. 1C  is a schematic diagram of typical electrical connections for a quadrupolar collision cell or reaction cell; 
           [0062]      FIG. 1D  is a schematic illustration of a known segmented quadrupolar collision or reaction cell; 
           [0063]      FIG. 1E  is a schematic illustration of a known alternative quadrupolar collision or reaction cell that includes auxiliary electrodes; 
           [0064]      FIG. 2A  is a diagrammatic perspective view of a known multipole ion guide comprising rod electrodes and auxiliary electrodes; 
           [0065]      FIG. 2B  is diagrammatic top view of a known auxiliary electrode structure as may be employed in the multipole ion guide of  FIG. 2A ; 
           [0066]      FIG. 3  is a schematic illustration of a portion of a first mass spectrometer system in accordance with the present teachings; 
           [0067]      FIG. 4A  is a schematic illustration of a partitioned ion fragmentation cell in accordance with the present teachings; 
           [0068]      FIG. 4B  is a schematic illustration of the structure of a partition as may be employed in the partitioned ion fragmentation cell of  FIG. 4A ; 
           [0069]      FIG. 4C  is a schematic illustration of structure of another partition as may be employed in the partitioned ion fragmentation cell of  FIG. 4A ; 
           [0070]      FIG. 5  is a schematic illustration of a portion of another mass spectrometer system in accordance with the present teachings; 
           [0071]      FIG. 6  is a schematic illustration of a portion of still another mass spectrometer system in accordance with the present teachings; 
           [0072]      FIG. 7  is a flow chart of a method for performing mass spectrometric analyses in accordance with the present teachings; 
           [0073]      FIG. 8A  is side view of a known configuration of two rods of a tapered rod set for use in generating an axial field along a central axis of a quadrupole apparatus of a mass spectrometer; 
           [0074]      FIG. 8B  is an end view of the entrance end of the known rod set configuration of  FIG. 8A ; 
           [0075]      FIG. 8C  is a cross-sectional view at the center of the known rod set configuration of  FIG. 8A ; 
           [0076]      FIG. 8D  is an end view of the exit end of the known rod set configuration of  FIG. 8A ; 
           [0077]      FIG. 9  is a side view of two rods of another known rod set configuration for use in generating an axial field along a central axis of a quadrupole apparatus of a mass spectrometer; 
           [0078]      FIG. 10  is an end view of a known quadrupole apparatus comprising a set of auxiliary resistive rods for use in generating an axial field along a central axis of a quadrupole apparatus of a mass spectrometer; 
           [0079]      FIG. 11  is a side view of a known quadrupole apparatus comprising a set of angled conductive auxiliary rod electrodes for use in generating an axial field along a central axis of a quadrupole apparatus of a mass spectrometer; 
           [0080]      FIG. 12  is a perspective view of a known configuration of quadrupole electrodes for use in generating an axial field along a central axis of a quadrupole apparatus of a mass spectrometer, wherein the electrodes of the quadrupole apparatus are disposed in tapered electrode pairs; 
           [0081]      FIG. 13A  is a side view of a single rod of a quadrupole or multipole rod set that is modified in a known fashion for use in generating an axial field along a central axis of a quadrupole or other multipole apparatus of a mass spectrometer; 
           [0082]      FIG. 13B  is a cross-sectional view at the center of the rod of  FIG. 13A ; 
           [0083]      FIG. 14  is a schematic view of two rods of a multipole ion guide apparatus that comprises, in a known fashion, conductive, resistive and insulating layers and showing a known configuration of electrical connections between even-numbered or odd-numbered rods; 
           [0084]      FIG. 15  is a schematic is a schematic view of two rods of a multipole ion guide apparatus that comprises, in a known fashion, a resistive coating on an insulating core; 
           [0085]      FIG. 16  is a perspective view of a known ring pole ion transport apparatus capable of generating an axial field directed along a central axis of the apparatus; and 
           [0086]      FIG. 17  is a schematic depiction of a focused gas flow employed in lieu of a short collision cell, the focused gas flow generated by passing a flow of the gas through a curved multichannel plate apparatus. 
       
    
    
     DETAILED DESCRIPTION 
       [0087]    The following description is presented to enable any person skilled in the art to make and use the invention, and is provided in the context of a particular application and its requirements. Various modifications to the described embodiments will be readily apparent to those skilled in the art and the generic principles herein may be applied to other embodiments. Thus, the present invention is not intended to be limited to the embodiments and examples shown but is to be accorded the widest possible scope in accordance with the features and principles shown and described. The reader should be aware that, throughout this document, the term “DC” is used in accordance with its general usage in the art so as to mean “non oscillatory” without necessary implication of the existence of an associated electrical current. Thus, the usage of the terms “DC voltage”, “DC voltage source”, “DC power supply”, “DC potential” etc. in this document are not, unless otherwise noted, intended to necessarily imply the generation or existence of an electrical current in response to the “DC voltage” or “DC potential” or to imply the provision of an electrical current by a “DC voltage source” or a “DC power supply”. As used in the art and as used herein unless otherwise noted, the term “DC” is made in reference to electrical potentials (and not electrical current) so as to distinguish from radio-frequency (RF) potentials. A “DC” electrical potential, as commonly used in the art and as used herein, may be static but is not necessarily so. The particular features and advantages of the invention will become more apparent with reference to the appended  FIGS. 1-17 , taken in conjunction with the following description. 
         [0088]      FIG. 3  illustrates a portion of a mass spectrometer system  307  in accordance with the present teachings. The system  307  illustrated in  FIG. 3  is modified from a conventional triple quadrupole configuration (e.g., the configuration illustrated as system  1  in  FIG. 1A ) by incorporation of a secondary collision cell  352  that is, with respect to pathway  69  of ions through the mass spectrometer, in line with and downstream from the collision cell  52 . The additional collision cell  352  is disposed between the previously-described collision cell  52  and the mass analyzer  40 . The collision cell  52  comprises a length, L 1  and the additional collision cell  352  comprises a length L 2 , where L 2 &lt;L 1 . These lengths are taken along the ion pathway  69  between the between the ion inlet and the ion outlet of each cell. It should be noted that like reference numbers in  FIG. 1A  and  FIG. 3  denote like components and that additional components of the system that are disposed to the left of the electrostatic lens  70  have been omitted from  FIG. 3  for clarity. Such omitted components may be but are not necessarily configured identically to the configuration illustrated in  FIG. 1A . 
         [0089]    According to the exemplary configuration illustrated in  FIG. 3 , the secondary collision cell  352  includes a multipole  360  (which, preferably, is a quadrupole) which is contained within an enclosure  353  and which is operated in RF-only mode. A suitable inert gas which is provided into the enclosure  353  through a second gas inlet  6  provides neutral molecules that may absorb the kinetic energy of ions upon colliding with the ions. An additional ion lens  56  is disposed between the collision cell  52  and the secondary collision cell  352 . An electrical potential difference between ion lens  53  and ion lens  56 , disposed at opposite ends of collision cell  52  urges ions through the collision cell  52 . Likewise, an electrical potential difference between ion lens  56  and ion lens  80 , disposed at opposite ends of the secondary collision cell, propels the ions through the secondary collision cell  352 . 
         [0090]    According to the exemplary configuration, illustrated in  FIG. 3 , the secondary collision cell  352  is structurally similar to the collision cell  52  except that is shorter in length as measured along the ion pathway  69  of ions towards the detector  49 . The secondary collision cell  352  may thus be referred to as a “short” collision cell whereas the collision cell  52  may be referred to as a “long” collision cell. Preferably, the long and short collisions cells are configured so as to operate independently of one another. Accordingly, the electrical potential difference between the lens  53  and ion lens  56  preferably may be controlled independently of the electrical potential difference between ion lens  56  and ion lens  80 . Further, each collision cell comprises its own respective collision gas inlet  6  and, optionally, its own collision gas vent  27 , such that the pressure of a collision gas within each cell may be independently controlled by means of independent gas introduction and venting. Although not specifically illustrated, each vent  27  may be provided with a respective independently-controlled valve to enable control of gas venting from each respective collision cell. In various embodiments, either the collision cell  352  or the collision cell  52  (or both) may be supplemented by auxiliary electrodes as illustrated in  FIGS. 2A-2B  that, in operation, may be used to generate a DC drag field within the associated collision cell for urging ions to flow through the collision gas in the direction of the ion pathway  69 . 
         [0091]    The independent operation of the two collision cells  52 ,  352  ( FIG. 3 ) enables different ion fragmentation conditions to be applied to each cell. Generally, the residence time of a packet of ions within the short collision cell  352  will be shorter than the residence time of a packet of ions within the long collision cell  52 . In this sense, the term “packet” refers to a collection of precursor ions that enter a collision cell within a certain restricted time range as well as to any product ions generated from those precursor ions within the collision cell. Also, the term “residence time” refers to the average time duration between the introduction of the collection of precursor ions into the collision cell and the exit of the respective packet of ions from the collision cell. Because of the different residence times associated with the two collision cells, the short collision cell  352  is efficient for conducting a series of fragmentation reactions that are kinetically relatively fast. However, the short collision cell may be unsuitable for conducting fragmentation reactions that are kinetically relatively slow, since such reactions may not proceed to completion in the short collision cell. For such slower reactions, the long collision cell  52  may be employed. In operation, only one of the two collision cells will be employed for ion fragmentation at any particular time. The unused collision cell at any such time is generally used as a pass through cell or simple ion guide by maintaining the interior of the unused cell at a high vacuum. 
         [0092]    If a mass spectrometer is to be employed for conducting a plurality of SRM experiments including transitions comprising a range of fragmentation kinetics, then the system illustrated in  FIG. 3  may be extended by the provision of additional collision cells—for example, a third and possibly subsequent collision cells—comprising different respective lengths along the ion pathway  69 . In such a configuration, the length of each cell is inversely related to the speed of fragmentation reactions to be conducted within it. Alternatively, a single collision cell may be employed in a similar fashion by the provision of internal partitions as schematically illustrated by the collision cell  252  in accordance with the present teachings shown in  FIG. 4A . The single, integrated collision cell  252  illustrated in  FIG. 4A  comprises a single set of rods  61 ,  62  (rods  62  not shown in  FIG. 4A —see  FIG. 1E  for positions) within a single housing  57 . The collision cell  252  further comprises one or more internal partitions  221  that divide the interior of the single collision cell into two or more internal compartments  240 . Each such compartment comprises its own respective independently controllable collision gas inlet  6  and collision gas vent  27  such that the pressure of a collision gas within each compartment may be independently controlled by means of independent gas introduction and venting. Although not specifically illustrated, each vent  27  may be provided with a respective independently-controlled valve to enable control of gas venting from each respective compartment. 
         [0093]    The internal partitions  221  of the partitioned collision cell  252  serve to isolate the introduced collision gas to a desired compartment or multiple-compartment portion of the collision cell. The collision gas may be introduced into the desired compartment or compartments by choosing which gas inlet  6  (or inlets) through which the collision gas is introduced. Valves (not shown) provided with collision gas vents  27  of the compartment or compartments that are to receive the collision gas may be maintained in a closed position so as to retain the collision gas in those compartments. At the same time, valves provided with collision gas vents  27  of other compartments may be maintained in open position so that those latter compartments are maintained under high vacuum by the mass spectrometer vacuum system. By such operation, the collision cell may be partitioned into both a “short portion” and a “long portion” whereby the relative lengths of the long and short portions (along the ion pathway  69 ) are variable. 
         [0094]    In addition to their function of constraining which compartments of the collision cell  252  are maintained with an elevated pressure of collision gas, the partitions  221  may also serve as internal electrodes capable of applying an internal drag electric field or axial electrical field within the collision cell.  FIGS. 4B-4C  illustrate two embodiments of such partitions. The partition  221 . 1  comprises a plate or vane  225  of an electrically insulating material provided with apertures  224  through which the rod electrodes  61 ,  62  pass and by which the rod electrodes may be at least partially mechanically supported. Another aperture  226  disposed centrally between the apertures  224  permits transfer of ions through the partition and, thus, between compartments  240 . An electrode  223 , which may be a separate conductive component affixed to the central portion of the insulative vane  225  or may alternatively comprise a conductive coating on the vane  225 , surrounds the aperture and is electrically coupled to a DC voltage source  43  (see  FIG. 1A ) by an electrical coupling (not shown). 
         [0095]    The partition  221 . 2  illustrated in  FIG. 4C  comprises a plate or vane  233  of an electrically conducting material (such as a metal) that is electrically coupled to the DC voltage source  43 . Thus, the plate or vane  233  is itself an electrode. An aperture  236  provided in the vane  233  permits transfer of ions through the partition  221 . 2  and, thus, between compartments  240 . Electrically insulating inserts  235  that are affixed to the plate or vane  233  are provided with apertures  234  through which the rod electrodes  61 ,  62  pass. 
         [0096]    Each compartment  240  of the collision cell  252  is bounded by either two partitions  221 , each comprising an ion aperture  226 ,  236  or by a single apertures partition and an apertured wall of the housing  57  of the collision cell. Thus each compartment  240  comprises its own respective compartment ion inlet aperture and ion outlet aperture. The collection of electrodes  223  ( FIG. 4B ) or  233  ( 4 C) and the entrance and exit lenses  53 ,  80  may be electrically coupled to a DC power supply that and electrical potential gradient may be applied along the ion path direction  69  between the compartment ion inlet aperture and the compartment ion outlet aperture of each compartment. The various electrical couplings between the partitions and between the partitions and the DC power supply may be configured as described above with regard to  FIGS. 2A-2B . 
         [0097]      FIG. 5  illustrates a portion of another mass spectrometer system in accordance with the present teachings. In similarity to the mass spectrometer system  307  illustrated in  FIG. 3 , the system  407  shown in  FIG. 5  comprises two collision cells consisting of a long collision cell  52  comprising a length, L 1  and a short collision cell  452  comprising a length L 2 , where L 2 &lt;L 1 . Each of these two collision cells comprises its own respective collision gas inlet  6  and its own collision gas vent  27  as previously described. Also, each collision cell  52 ,  452  comprises its own respective electrical connections such that the operation of each collision cell may be fully controlled, independently of the other cell. 
         [0098]    The short collision cell  452  shown in  FIG. 5  differs from the collision cell  352  shown in  FIG. 3  in that each individual multipole rod of the cell  352  is replaced, in the cell  452 , by a plurality of rod segments along the ion pathway  69  in a fashion similar to that shown in  FIG. 1D . The segmented multipolar system is indicated as segmented rod set  462 . Each multipolar segment  461  (one of which is outlined in  FIG. 5 ) consists of a set consisting of one segment of each segmented rod. For example, if the multipole rod set is a quadrupolar rod set, then each multipolar segment  461  consists of one segment of each of the four segmented rods. In operation of the collision cell  452 , each separate multipole segment may be supplied with a different DC electrical potential such that an electrical potential gradient (i.e., a drag field) is generated that urges ions through the collision cell in the direction of the arrows along ion pathway  69 . Although not specifically illustrated in  FIG. 5 , the long collision cell  52  may be segmented in a similar fashion. 
         [0099]    In alternative embodiments, the set of rods of the collision cell  452  may be replaced by a set of stacked ion plate electrodes, in a stacked-ring ion guide or ion tunnel configuration, where each plate comprises an aperture through which the ions pass. An RF voltage is applied to the plate electrodes, with alternating electrodes being supplied with voltages that are exactly out of phase. Further, the plate electrodes may be electrically coupled to a DC power supply using a voltage divider chain such that an electrical potential gradient is formed between each pair of adjacent electrodes. 
         [0100]      FIG. 6  illustrates a portion of another two-collision cell mass spectrometer system  507  in accordance with the present teachings in which a drag field is provided within the short collision cell  552  by application of voltage across the two ends of a tube  590  that comprises a lossy dielectric material. One example of such material is so called “resistive glass”. as described in U.S. Pat. No. 5,736,740 or U.S. Pat. No. 7,935,922. Suitable materials have resistivity greater than that of a perfect dialectric but significantly less than that of a metal conductor. For example, the resistive tube member  52   a  may be formed of any one of a number of materials (e.g., without limitation, doped glasses, cermets, polymers, metallic oxides, doped glasses, metal films, ferrite compounds, carbon resistive inks, etc.) having electrically resistive properties. The tube may be fabricated from the resistive material or may employ the resistive material as a coating, such as a coating of ruthenium oxide, on either the interior or exterior of a conventional glass tube or a tube formed of an insulator material. It is also possible to generate a resistive coating on a glass surface by, for example, chemical reactions (U.S. Pat. No. 7,081,618). Such tubes are commercially available, e. g. under the name FieldMaster™ from Burle Electro-Optics Inc., Sturbridge Mass. (USA). In the system  507  shown in  FIG. 6 , the multipole rod set  560  is disposed exteriorly to the resistive tube  590 . Because collision gas is supplied directly into the lumen of the resistive tube from collision gas inlet  6 , a separate housing is not required to enclose the rod set  560  which may remain under high vacuum conditions. Although not specifically illustrated in  FIG. 6 , the long collision cell  52  may employ a resistive tube in a similar fashion. 
         [0101]    During conventional operation of collision cells, precursor ions entering the cell are provided with an amount of initial kinetic energy such that is sufficient to, upon collision of these ions with molecules of collision gas, impart a sufficient amount of bond vibrational energy to the precursor ions to cause chemical bond breakage and fragmentation. In this process, a portion of the initial precursor ion kinetic energy is absorbed by the bond breakage and another portion is converted to thermal energy of gas molecules. However, there will generally be an excess of the initial precursor-ion kinetic energy that is taken up as residual kinetic energy of the fragment ions and of any unreacted precursor ions. Conventionally, the collision cell interior is provided with a sufficient pressure of a collision gas (e.g., greater or equal than 0.5 mtorr) and is of sufficient length such that such residual kinetic energy is absorbed by further (lower energy and non-reactive) collisions with the gas molecules. Thus, the gas in the collision cell not only causes precursor-ion fragmentation but also provides “collisional cooling” of the resulting fragment ions. 
         [0102]    During operation of apparatuses described herein, if fragmentation is caused to occur in a short collision cell (i.e., collision cell  352  shown in  FIG. 3 , collision cell  452  shown in  FIG. 5 , collision cell  552  shown in  FIG. 6  or one or more short compartments  240  as illustrated in the collision cell  252  of  FIG. 4A ) or in a collision cell in which the gas pressure is less than 0.5 mtorr (or both), then each fragment ion may not collide a sufficient number of gas molecules to fully damp its residual kinetic energy. In such a case, the excess kinetic energy will cause the cloud of such energetic fragment ions to occupy a wider than desirable volume about the collision cell central axis—in other words, there will be poor confinement of the energetic fragment ions to the axial region. It has been found that that, when a of collection of fragment ions of various fragment ion species is formed, the residual kinetic energy is partitioned or distributed among the species in a manner that is mass dependent. If the collection of fragment ions having the distributed excess kinetic energy is then transferred to a mass analyzer, such as mass analyzer  40  shown in  FIG. 3 , then there will be incomplete transmission of fragment ions through the mass analyzer to a detector (e.g., detector  49 ) during a mass scan, as a result of the less than optimal confinement of the fragment ions to the axial region at the time of entry into the mass analyzer. Further, the quality of the transmission will be mass dependent, thereby leading to erroneous determinations of relative abundances of fragment ions. 
         [0103]    To counteract the undesirable spectral effects of mass-dependent distribution of excess energy among fragment ions, various embodiments of methods for operating a mass spectrometer in accordance with the present teachings may employ a mass-dependent control of offset voltage between a collision cell and a subsequent mass analyzer. The offset voltage is a non-oscillatory DC electrical potential difference between the collision cell multipole rods and either an entrance lens or the quadrupole rods of the mass analyzer. The offset voltage serves to urge analyte ions along a continuous pathway through the collision cell into the mass analyzer. 
         [0104]    During a typical mass scan of the fragment ions, the RF voltage, U, and mass discriminating DC voltage, V, that are applied to the mass analyzer quadrupole rods are ramped (increased) in proportion to one another such that ions of progressively greater m/z ratios develop stable trajectories through the mass analyzer and are thus transmitted through the mass analyzer to the detector. The utilization of mass-dependent control of offset voltage, as may be required by various embodiments of methods in accordance with the present teachings, corresponds to a variation of the offset voltage in synchronicity with the ramping of the U and V voltages. By this means, the offset voltage is caused to vary such that the additional translational kinetic energy imparted by the offset voltage is at its lowest value at the time that ions having the greatest amount of excess residual kinetic energy are being transmitted by the mass analyzer and is at its greatest value at the time that ions having the least amount of excess residual kinetic energy are being so transmitted (and is at appropriate intermediate values at times when other ions are being so transmitted). The variation of mass analyzer offset voltage in this mass-dependent fashion has previously been employed in early versions of triple quadrupole mass spectrometers. 
         [0105]      FIG. 7  is a flow chart of a method in accordance with the present teachings for operating a mass spectrometer system to detect or measure particular analytes of a sample. The method  600  illustrated in  FIG. 7  assumes that the sample is analyzed by performing a pre-determined plurality of SRM transitions. The method also assumes that a mass spectrometer system either comprises two collision cells—a long cell and a short collision cell, serially arranged along an ion pathway—as illustrated, for example, in  FIG. 3 ,  FIG. 5  or  FIG. 6  or comprises a single partitioned collision cell as illustrated in  FIG. 4A . In the following discussion, the expression “first collision cell” may refer to either of the two collision cells and is not intended to imply reference to the long collision cell or to the first cell in series along the pathway. Likewise, the expression “second collision cell” refers to the collision cell that is other than the “first collision cell” and is not intended to imply reference to the short collision cell or to the second cell in series along the pathway. Further, references a portion (either a first portion or a second portion) of a partitioned collision cell refers to a set of one or more cell chambers as illustrated in  FIG. 4A  that are not separated, one from another, by any intervening chamber and that function as a unit. Generally, a partitioned cell will be apportioned, when appropriate, into exactly two portions. References to a first portion and to a second portion in the following discussion are not intended to imply which of the two portions is closest to the ion inlet to the partitioned cell; either the first or the second portion may be closest to the ion inlet. 
         [0106]    In the first step, step  601 , of the method  600 , the SRM transitions are divided into two groups based on the kinetics of fragmentation of the respective precursor species to be isolated as part of each SRM. For example, the division might be made with reference to a pre-determined time (e.g., number of microseconds) required for a fragmentation step to proceed to completion to a certain percentage of completion. Then, the SRM transitions requiring less time than the pre-determined number of microseconds might be assigned to a “fast fragmentation” group whereas the remaining transitions are assigned to a “slow fragmentation” group. 
         [0107]    In step  602 , the dual collision cells or the partitions of the partitioned collision cell are configured in preparation for a first mass analysis of the sample (i.e., in subsequent step  604 ). During the first mass analysis of the sample, the mass spectrometer is configured to perform the steps associated with conducting all the SRM transitions assigned to one of the groups—either the “fast fragmentation” group or the “slow fragmentation” group—that were defined in step  601 . If the mass spectrometer system comprises two collision cells, then, in step  602 , a first one of the collision cells is rendered “active” and the other one of the collision cells is rendered “inactive”. If the mass spectrometer system comprises a single partitioned collision cell, then a first portion of the collision cell is rendered “active” and the other portion of the collision cell is rendered “inactive” in step  602 . The “active” collision cell or collision cell portion the cell or portion in which controlled ion fragmentation occurs. The “inactive” collision cell or collision cell portion is employed as a pass-through cell, i.e., as a simple ion guide. According to this method, one of the collision cells or cell portions is employed for performing the fragmentation steps associated with all of the “fast fragmentation” SRMs and the other one of the collision cells or cell portions is employed for performing the fragmentation steps associated with all of the “slow fragmentation” SRMs. Therefore, the choice of cell or cell portion that is rendered “active” in this step depends on which group of transitions are to be performed in the subsequent step  604 . 
         [0108]    Rendering a cell or cell portion as “active” will generally include introducing a collision gas into the cell or cell portion and may also include configuring electrodes so as to apply a drag field or axial field within said collision cell or cell portion. Rendering a cell or cell portion as “active” may also include configuring ion lenses that are upstream (along the ion pathway) from the cell so as to introduce ions into the cell or cell portion with an initial kinetic energy. Rendering a cell or cell portion as “inactive” will generally be a series of steps that are opposite to those required to render the cell as “active”. For example, a previously introduced collision gas must be vented out of a cell or cell portion as part of the process of rendering it as “inactive”. 
         [0109]    In step  604  of the method  600  ( FIG. 7 ), a first mass spectrometric analysis of the sample is conducted. During this step, the mass spectrometer performs all of the steps associated with conducting all of the SRM transitions assigned to one of the groups—either the “fast fragmentation” group or the “slow fragmentation” group. These steps include, for each SRM transition, isolating the appropriate precursor ion, fragmenting the isolated precursor ion in the active (first) collision cell or cell portion while employing the other collision cell or cell portion as a pass-through ion guide, transferring the product ions to a mass analyzer and conducting a search for the appropriate product ion using the mass analyzer. These steps are repeated for each SRM transition in the group (as defined in step  601 ) being analyzed. The mass spectrometric analysis will generally include additional common operations, such as supplying a portion of the sample to the mass spectrometer system, and ionizing the sample or sample portion to generate the precursor ions. If the sample is provided to the mass spectrometer as a series of chromatographically separated fractions, such as by liquid chromatography or gas chromatography, etc., then the step  604  may include performing the chromatographic separation using a first portion of the sample. 
         [0110]    In step  606 , the system is reconfigured so that the second collision cell or collision cell portion is rendered active and the previously active first collision cell is rendered inactive. This step includes venting of the collision gas from the first collision cell or cell portion and supplying collision gas to the second collision cell or cell portion. Then, during subsequent step  608 , a second mass spectrometric analysis of the sample is conducted. During this step, the mass spectrometer performs all of the steps associated with conducting all of the SRM transitions assigned to the remaining group of transitions. These steps include fragmenting isolated precursor ions in the active (second) collision cell or cell portion while employing the first collision cell or cell portion as a pass-through ion guide. If the sample is provided to the mass spectrometer as a series of chromatographically separated fractions, then the step  608  may include performing the chromatographic separation a second time using a second portion of the sample. In a variation of the method  600 , the sample that is analyzed in step  608  is different from the sample that is analyzed in step  604 . 
         [0111]    If the mass spectrometer employs a partitioned collision cell such as collision cell  252  shown in  FIG. 4A , then the method  600  may be extended to include more than just two groups of SRM transitions. For example, the step  601  may be modified such that the SRM transitions of interest are divided into three groups (or any number of groups) based on fragmentation speed. The three groups may be defined as a “fast fragmentation” group, an “intermediate-speed fragmentation” group and a “slow fragmentation” group. For example, the three groups may be defined relative to a first pre-determined number of microseconds and a second pre-determined number of microseconds required for fragmentation. 
         [0112]    Because the portion of the collision cell  252  that may be rendered as “active” is variable, three different such portions may of the collision cell  252  may be defined—each portion corresponding to and employed for the fragmentation of a respective one of the divided SRM groups. For example, only the rightmost chamber  240  of fragmentation cell  252  may be employed for fragmentation of the “fast fragmentation” group of SRM transitions by supplying collision gas to only this rightmost chamber  240  while maintaining the three leftmost chambers  240  under high vacuum. Similarly, only the rightmost two chambers may be employed for fragmenting the “intermediate-speed fragmentation” group and all four chambers may be employed for fragmenting the “slow fragmentation” group. 
         [0113]    The flow chart shown in  FIG. 7  may be readily conceptually modified so as to correspond to the analysis of the “fast fragmentation”, “intermediate-speed fragmentation” and “slow fragmentation” groups of SRM transitions discussed above by adding another configuration step followed by another mass spectrometric analysis step after step  608 . More generally, the flow chart can be conceptually modified so as to accommodate analyses comprising any number, N, of groups of SRM transitions by considering the configuration and analysis steps to be iterated N times, with one iteration per SRM group. 
         [0114]      FIG. 17  depicts a portion of another system embodiment does not comprise a casing or housing capable of enclosing a pressurized collision. Instead, the known apparatus  800  comprises a curved and perforated plate  802  that is fluidically coupled to a gas inlet tube  804  at its convex side. As a result of the curvature of the perforated plate, a flow of gas  806  supplied by the gas inlet tube encounters the perforations oriented in a fashion such that each perforation diverts a respective portion of the gas flow towards a gas focal position  808  that is disposed along the pathway  810   a  of a beam of ions comprising precursor ions. 
         [0115]    In operation, the curved and perforated plate  802  ( FIG. 17 ) functions as a “gas lens” that focuses a flow of gas to a small focal region of localized high gas pressure. The restriction of the gas to a small focal position  808  along the ion beam path creates a localized region of high pressure within which the probability of ion-molecule collisions is high such that fragmentation occurs in a short time duration (i.e., less than 100 μsec and, preferably, less than 100 μsec). Upon emerging from the focal region, a precursor-containing ions  810   a  is converted to fragment-containing beam of ions  810   b . The beams of ions  810   a ,  810   b  are urged to flow along the beam direction, as indicated by arrows at the bottom of  FIG. 17 , by conventional or standard ion optics components (not illustrated). Thus, additional means for providing an axial field is not required as part of the simple apparatus  800 . Although the gas pressure is relatively high at the focal position  808 , the overall flow rate of gas supplied from the gas inlet tube  804  is sufficiently small that the gas may be readily purged from a mass spectrometer high vacuum chamber by an existing evacuation system without significant vacuum degradation. 
         [0116]    In many embodiments, the curved and perforated plate  802  may comprise an originally-flat portion of a micro-channel plate, as is often used in image intensifiers and night-vision apparatus (see, for example, U.S. Pat. No. 6,259,088). The curvature of the originally-flat portion may be induced by application of heat. The micro-channels may be generated by chemical etching after the deformation. 
       CONCLUSION 
       [0117]    The discussion included in this application is intended to serve as a basic description. Although the present invention has been described in accordance with the various embodiments shown and described, one of ordinary skill in the art will readily recognize that there could be variations to the embodiments and those variations would be within the scope of the present invention. For example, collision cell components of apparatus embodiments in accordance with the present teachings may employ any of the configurations shown in  FIGS. 1D-1E ,  FIGS. 2A-2B ,  FIGS. 8A-8D ,  FIGS. 9-12 ,  FIGS. 13A-B  or  FIGS. 14-15  and discussed in respectively associated paragraphs above for purposes of generating a drag field or axial field within the collision cell. In the case of axial field generating components, configurations or systems that employ a resistive coating or a resistive member (the coating or member provided either as part or all of a quadrupole rod or part or all of an auxiliary rod) as all or a portion of the mechanism for generating the axial field, the resistive material may be formed of any one of a number of materials (e.g., without limitation, doped glasses, cermets, polymers, metallic oxides, doped glasses, metal films, ferrite compounds, carbon resistive inks, etc.) having electrically resistive properties. A resistive ink comprising ruthenium oxide is contemplated as a suitable resistive coating material that may be applied to rods or tubes described herein. It is also possible to generate a resistive coating on a glass surface by, for example, chemical reactions (U.S. Pat. No. 7,081,618). 
         [0118]    Where reference is made in the above discussion to “quadrupole” components of collision cell components, it is to be understood that any conventional multipole rod configuration, such as a hexapole, octopole, dodecapole, etc. multipole rod configuration may be substituted for the quadrupole configuration. Further, although many of the accompanying drawings illustrate rods (either multipole rods or auxiliary rods) having circular cross sections, rods having any cross sectional shape, such as square, rectangular, oval, polygonal, etc. may alternatively be employed in various embodiments in accordance with the present teachings. 
         [0119]    The reader should be aware that the specific discussion may not explicitly describe all embodiments possible; many alternatives are implicit. Accordingly, many modifications may be made by one of ordinary skill in the art without departing from the scope of the invention. Neither the description nor the terminology is intended to limit the scope of the invention—the invention is defined only by the claims. Any patents, patent publications or other publications mentioned herein are hereby incorporated by reference in their respective entireties.