AUTOMATION OF ACQUISITION, ANALYSIS AND ELECTRONIC DELIVERY OF EXPERIMENTAL DATA

Abstract: A system is disclosed that is primarily meant to interface with laboratory instrumentation to acquire experimental data, process the data into a format suitable for electronic transmission, and finally transmit the experimental data to submitting persons. In the exemplary embodiment, a system is described to automatically acquire high-resolution electrospray ionization mass spectra with a commercial Fourier transform ion cyclotron resonance mass spectrometer. Upon injection of each sample, an autosampler transmits a contact closure signal to mass spectrometer to initiate data acquisition. A software package is then used off-line to accept a sample list with input information for each of the samples. Then for each of the samples, the software automatically processes and interprets the acquired data. Finally, the system prints the spectra, peak lists, exact mass reports, and e-mails the exact-mass reports to the submitting persons.

Description: AUTOMATION OF ACQUISITION, ANALYSIS AND ELECTRONIC DELIVERY OF EXPERIMENTAL DATA TECHNICAL FIELD This invention relates generally to a method of automating the acquisition, analysis, and electronic delivery of experimental data, and more particularly, to a device which interfaces between a measurement instrument and an electronic network to convert the output data from the measurement instrument to a form suitable for electronic transmission. BACKGROUND ART This invention relates in general to a method of automating the acquisition, analysis, and electronic delivery of experimental data, and more particularly, to a device which interfaces between a measurement instrument and an electronic network to convert the output data from the measurement instrument to a form suitable for electronic transmission. Disclosed as an illustrative embodiment is a Fourier transform ion cyclotron resonance mass spectrometer (FTICR MS) system capable of delivering results in electronic form to submitting chemists. The apparatus and method of analysis and delivery described herein as the illustrative embodiment are enhancements of the techniques that are referred to in the literature relating to mass spectrometry. The analysis of ions by mass spectrometers is important, as mass spectrometers are instruments that are used to determine the chemical structures of molecules. In these instruments, molecules become positively or negatively charged in an ionization source and the masses of the resultant ions are determined in vacuum by a mass analyzer that measures their mass/charge (m/z) ratio. Mass analyzers come in a variety of types, including magnetic field (B) , combined (double-focusing) electrical (E) and magnetic field (B) , quadrupole (Q) , ion cyclotron resonance (ICR) , quadrupole ion storage trap, and time-of-flight (TOF) mass analyzers. Each mass spectrometric method has a unique set of attributes . Generally, ion cyclotron resonance spectrometers operate by storing ions in "traps" and manipulating the ions by using DC and RF electric fields in a series of carefully timed events. The underlying principle of the ICR is that ions move in a circular path in a magnetic field. The cyclotron frequency of the ion's circular motion is mass dependent. By measuring the cyclotron frequency, one can determine an ion's mass. The working equation for ICR can be easily found by equating the centripetal force with the Lorentz force experienced by an ion in a magnetic field: (mv 2 ) /r = evB Solving now for the angular frequency omega, (omega) = (v/r) = (eB) / m A group of ions of the same mass-to-charge ratio will have the same cyclotron frequency, by they will be moving independently and out-of-phase at roughly thermal energies. If an excitation pulse is applied at the cyclotron frequency, the "resonant" ions will absorb energy and be brought into phase with the excitation pulse. As ions absorb energy, the size of their orbit also increases. The packet of ions passes close to the receiver plates in the ICR cell and induces image currents that can be amplified and digitized. The signal induced in the receiver plates depends on the number of ions and their distance from the receiver plates . If several different masses are present, then one must apply an excitation pulse that contains components at all of the cyclotron frequencies. This is done, for example, by using a rapid frequency sweep, an impulse excitation, or a tailored waveform. The image currents induced in the receiver plates will contain frequency components from all the mass-to-charge ratios. The various frequencies and their relative abundances can be extracted mathematically by using a Fourier transform. A Fourier transform converts a time-domain signal (the image currents) to a frequency- domain spectrum (the mass spectrum) . The background pressure of an FTICR should be kept very low to minimize ion-molecule reactions and ion-neutral collisions that damp the coherent ion motion. A variety of external ion source designs have been developed to deal with this problem. Most FTICR mass spectrometers uses superconducting magnets, which provide a relatively stable calibration over a long period of time. Although some mass accuracy can be obtained without internal calibration, mass accuracy and resolution are inversely proportional to m/z and the most accurate mass measurements benefit from an internal calibrant . While the conventional methods of FTICR spectroscopy have been described, several examples of automated analysis and results delivery exist in the prior art. Galle et al U.S. Patent No. 4,844,887 discloses an automatic analysis apparatus for performing chemical analysis on a plurality of sample liquids. The device includes a sample delivery pump for precisely dispensing the sample liquid into a reaction cuvette and a reagent delivery pump for dispensing a precise amount of the reagent into the reaction cuvette. The sample liquid and the reagent together form a test liquid. The test liquid passes along a plurality of photometering sections for performing a plurality of photomeric and/or nephelometric and/or flourometric measurements. While the apparatus of Galle et al does describe an apparatus that automatically analyzes samples, no means for the integration of an electronic results delivery system is described. MacPhail U.S. Patent No. 5,089,956 relates to a method for distributing documents that have a directed relationship within an information processing system. A user indicates to the system which document is to be distributed to one or more recipients. The system then builds the necessary structures to transmit the document to the recipients. While the method of MacPhail teaches the delivery of documents, there is no mention of integration with any type of instrumentation. Furthermore, unlike the present invention, the method of MacPhail cannot generate the distributed document . Hager et al U.S. Patent No. 5,247,661 discloses a method and apparatus to automatically distribute an electronic document to a preselected list of recipients. The selected document is identified and a document profile is created consisting of the technical or functional area disclosed within the document . The document profile is then used to determine a preselected group of recipients. The system of Hager et al simply distributes documents to appropriate recipients based on embedded data. It is not capable of interfacing with instrumentation or generating the document itself . Kitain et al U.S. Patent No. 5,864,871 is directed to an integrated computer-implemented corporate information delivery system. An integral database stores research reports produced by and received electronically from brokerage firms. Authorization information (entitlements) specifies who is authorized to access each research report . A delivery module allows a user to submit a query and receive results listing research reports and corporate information the user is entitled to that satisfy the query. The query results may be delivered via the Internet . The system of Kitain et al is directed largely towards the financial and investment markets, and therefore, is not meant to be interfaced with any type of instrumentation. Furthermore, it merely searches a database of existing documents, it is not capable of actually generating the document. Toga U.S. Patent No. 5,987,504 describes a method for delivering data. A request is placed by a user for a particular data file, along with a storage location. A storage location may be, for example, an e-mail address. In response to the request, the system delivers the data to the storage location. The advantage of the system is a queuing type process wherein the delivery of data is postponed until network traffic lowers. Such a system does not allow interfacing with any type or instrumentation, nor is it capable of automatically creating the data document from collected data. Frantz U.S. Patent No. 6,003,070 teaches a device that is either integral or peripheral to equipment that requires monitoring and maintenance. The device converts status signals from the equipment into an e-mail message that is sent to the technician at a remote location. Further, the device can then convert the e-mail instructions from the technician into commands for the equipment. While this device does create the sent e-mail, it creates very simple messages indicative of the equipment status- -there is no type of measurement or analysis involved. SUMMARY OF THE INVENTION Analytical instrumentation is well known to be generally very expensive equipment. Thus, many researchers are limited in their access to higher-level instruments, and therefore, the vital results that could be garnered are sometimes unavailable. This, combined with bourgeoning levels of research in many areas of science and technology create a need for a system that makes analytical instrumentation available to a wide variety of researchers in a timely, effective fashion. Described herein is a system that interfaces with an analytical instrument, e.g., a mass spectrometer, and electronically receives requests for analyses from submitting persons, and then upon completion of analysis, proceeds to electronically deliver the results to the submitting person. Thus, many researchers can gain easy, effective access to instrumentation that normally would not be available. The illustrative embodiment discussed herein involves the use of a mass spectrometer. Fourier transform ion cyclotron resonance mass spectrometry (FTICR MS) has been shown to be a powerful technique for obtaining high-resolution exact-mass MS and MS n data over the whole mass range of the spectrum. The resolving power in FTICR MS increases linearly with increasing applied magnetic field with corresponding improvements in mass accuracy and signal-to-noise ratio. These desirable features can be routinely achieved with modern instruments equipped with high-field superconducting magnets. Even though very powerful data systems are used for data acquisition and data processing, electrospray ionization (ESI) FTICR experiments are generally conducted manually where single samples are infused one at a time. With this manual approach, the analysis of large numbers of samples is very time consuming, manpower inefficient, and hence not very cost effective. At most facilities, chemists submit numerous samples of synthetic and natural origin to the analytical mass spectrometry laboratory for exact-mass measurements to confirm elemental formulas and thereby chemical structures. Often, for a variety of reasons, these materials failed to produce useful results by microanalysis . Many of these materials are pharmaceuticals and natural products and are very polar and thermally unstable and ESI is the ionization mode of choice for their analysis. To analyze the large numbers of samples efficiently under high-resolution exact-mass conditions, novel automation methods are disclosed to automatically acquire, process, interpret, and electronically deliver the ESI FTICR MS data. Described herein are the hardware and software details of an embodiment of such a system presently in routine use, using e-mail as the delivery system, that completely integrates the automatic acquisition, processing, and interpretation of batches of FTICR MS data. Those knowledgeable in the art will recognize that the delivery system could take the form of the creation of a web page, a voice-mail message, an alpha-numeric page and compatible pager, or the like. Furthermore, the instrumentation need not be of the type described, but may take the form of any type of common laboratory instrumentation. With the exemplary package described herein, total automation is achieved for high-resolution exact-mass ESI FTICR MS data from the point of downloading sample information from a corporate database to the electronic delivery of the exact- mass report to the requesting chemist. Therefore, it is an object of this invention to provide electronic delivery of experimental results to submitting persons. Furthermore, it is an object of this invention to provide an apparatus to interface with an instrument to acquire experimental results and convert these results into electronic form suitable for transmittal . Further, it is an object of this invention to greatly automate the tedious process of acquiring experimental results. These and other objects will become apparent to one skilled in the art upon reviewing the following diagrams and description. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 depicts a flow diagram of the system in an FTICR MS configuration and e-mailing capabilities ; FIG. 2 is an example of an acquired spectrum of a mixture of three halogenated pharmaceuticals; and FIG. 3 is an example of experimental results that could be e- mailed to a submitting chemist. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT For the purposes of complete disclosure, the experimental configuration used in the preferred embodiment will be briefly described. Referring to FIG. 1, The FTICR mass spectrometer 101 used was equipped with a passively shielded 9.4 tesla superconducting magnet (160 mm diameter bore) , an external Analytica ESI source with APIlOO controller, a Hewlett-Packard Model 1100 HPLC system (Degasser, Pump, Diode Array Detector, Autosampler, Hand-Held Controller) , and a UNIX based Silicon Graphics 02 Workstation data system 105. The external ESI source was operated with a grounded capillary sprayer needle mounted approximately 45° off-axis with nitrogen nebulizing gas at ambient temperature and 30 lb/in 2 and with nitrogen drying gas heated to 130 °C and flow rate of 20 L/h. The transfer capillary voltage was 2056 V on the source side and 90 V on the analyzer side. The skimmer voltage was 1.7 V. A hexapole ion guide in the external ESI source was used as an external trap to accumulate ions for times ranging from 0.5 to 5.0 s before transfer to the FTICR MS INFINITY analyzer cell. The transfer of ions from the ESI source hexapole ion guide to the analyzer cell is accomplished by electrostatic ion optics. To trap the ions in the FTICR MS analyzer cell, the Sidekick ion accumulation method and occasionally gated trapping (with and without trapping gas) were used. Switching between Sidekick and gated trapping simply involved changing the values of electrostatic elements in the FTICR MS Infinity analyzer cell under computer control and varying the timing of these voltage changes, also under computer control. Typically 512 K data points were acquired. For low molecular weight pharmaceutical molecules of interest, resolving powers of 50,000 (FWHM) and absolute mass accuracies of <1.0 mmu (millimass unit) were routinely achieved. The instrument was calibrated with Csl, poly (ethylene glycol) bis (carboxymethyl) ether (average Mn ,- 600) or a peptide mixture containing angiotensin I and II, bradykinin, substance P, gramacidin, bombesin, actinomycin D, leucine enkephalin, and melittin. The stability of the instrument is remarkable in that mass accuracies <1.0 mmu can be achieved for a number of days without retuning and recalibrating the instrument. For this reason, external calibration was used for all measurements but the reference standard was run at the beginning and end of the series of samples to verify the stability and reproducibility of the measurements . The carrier solvent used was 1 : 1 water :acetonitrile (W:ACN) with a flow rate of 50 m /min. To illustrate the automation methodology, a mixture of halogenated pharmaceuticals was analyzed which included chlorothiazide (C7 H6 N3 04 S2 Cl, MW 294.9488), chloramphenicol (Cll H12 N2 05 C12 , MW 322.0123), and dibromotyrosine (C9 H9 N03 Br2 , MW 336.8949). In addition, nearly 700 proprietary samples were analyzed with the automation instrumentation and the performance statistics for them were evaluated. A PC 114 was used to download sample information from a corporate database 114 and to communicate with the Silicon Graphics Workstation 105 through the corporate intranet. PC programs 106 to download and transfer the sample information were written in Visual Basic. Data processing 107 using this sample information was performed under control of a script written in Tcl/Tk (Tool command language/Toolkit) . Tcl/Tk is a platform independent, extendable, and embeddable programming language that was linked to the FTICR MS processing software ("processing software") . This link was accomplished by extending the Tel scripting language with built-in commands that allow access to the processing software command interpreter, enabling all commands to be executed from within Tel scripts. Further versatility was added by creating built-in Tel commands to permit access to all processing software data parameters, as well as the raw and processed data vectors. In essence, the processing software could be controlled completely by the Tel script . The Tel scripts can also obtain information f om the processing software, either directly via the built-in commands described above, or by causing the processing software to write data (i.e., peak lists) to a file on disk which could then be accessed by the Tel script. Again referring to FIG. 1, the system can be divided into two sections, one dealing with data acquisition and the other dealing with data processing. Each section can function independently to acquire or process a batch of data. The autosampler, within the FTICR MS 101, upon injecting a 5 mL sample for flow injection analysis into the ESI source of the FTICR MS sends a TTL trigger 104 to the mass spectrometer 101 to initiate data acquisition after a preset delay time 103 necessary for the sample to flow into the ESI source, typically about 30 s. The pretuned and precalibrated instrument acquires and sums 30 spectra for a total acquisition time of about 30 s. This raw time- domain data 102 is stored for future processing. After a total time of approximately 2.0 min the next sample is injected. This later delay of about 1.0 min is used to clean the autosampler, tubing and source of any residual analyte, consequently cross contamination of later samples is reduced. This process is repeated until all the samples placed in the autosampler within FTICR MS 101 are run. A maximum of 100 samples can be run in one batch with the Hewlett-Packard Model 1100 Autosampler. The data reduction, analysis, and e-mailing steps described below are automatically repeated for all the samples analyzed in a given batch. With regard to sample list generation, sample information is downloaded directly from a corporate database 116 and a sample list 110 is automatically generated on a PC 114 in spreadsheet format or a like compatible format. The sample list 110 is transferred as a tab delimited text file or like compatible format through the corporate intranet or other electronic network to the Silicon Graphics Workstation 105. The sample list 110 information (chemist name, notebook number, request number, predicted elemental formula, autosampler vial number, MS log book number) is used as header information for all generated reports and the predicted elemental formula is used for mass spectral interpretation. Each component predicted to be present in a sample is entered individually as a separate line entry in the sample list with the same vial number. With respect to the raw data reduction, the raw summed time- domain spectra 102 are automatically processed by preset operating parameters. The processes 108 are apodization of the time-domain data, generally selected as a centered sine bell function, fast Fourier transform with zero filling, frequency to mass conversion, and peak picking. Options for automatic printout via printer 111 of the spectrum 112 and peak list are available. On to data correlation and interpretation, this module 109 compares the exact masses from the list of picked peaks with those of the possible molecular ion adducts predicted to be formed from the expected elemental formula indicated in the sample list 110 for the sample,. An option for automatic printout via printer 111 of the exact-mass report is available. Also, a summary report of the test results for all the samples is generated automatically for bookkeeping purposes . Lastly, there is the e-mailing of exact-mass report 113. An alias file is set up to link submitter names with their e-mail addresses. The Tcl/Tk macro calls up an e-mail macro which attaches the exact-mass report as a text file and transmits it to the submitting chemists 117 via the corporate intranet server 115. FIG. 2 is an example of an automatically acquired spectrum of a mixture of three halogenated pharmaceuticals in the ESI negative ion mode. Note that the exact masses and isotopic distributions are consistent with the predicted values for all the abundant ions. Exemplary peaks 201, 202, 203 correspond to mass values on the mass/charge x-axis 204 and their high relative intensity on the y- axis 205. FIG. 3 illustrates a typical e-mailed exact-mass report using Novell GroupWise as displayed in Microsoft Notepad for the spectrum illustrated in Figure 2. The report lists for the given analyte 307, the name 304, charge 305, and exact-mass 306 of the predicted molecular ion adduct, the correlated observed mass 308, the mass error in mmu 309 and ppm 310 and the relative intensity of the ion 311. Only consistent results are e-mailed, as indicated by flag 312. Absence of the predicted exact-mass indicates inconsistent (absolute mass error .3 mmu) or inconclusive (insufficient signal) results. Exemplary adduct values 301, 302, 303 correspond to peak values 201, 202, 203 on FIG. 2. What has been disclosed is batch processing package for automated acquisition, processing, interpretation, and e-mailing of high-resolution exact-mass ESI data acquired by direct infusion on a commercial high-field 9.4 tesla FTICR mass spectrometer. This package permits reliable unattended operation of the instrument for large numbers of samples and the efficient acquisition and analysis of the data, thereby increasing the productivity of the system. Typically with this system, resolving powers >50,000 (FWHM) and mass measurement errors approximately 1.0 mmu and/or approximately 1.0 ppm are routinely achieved with ions of moderate abundance for pharmaceuticals with molecular weights ranging from 250 to 700 Da with external calibration. Future extensions of the software include automated sequential acquisition, processing, and e-mailing of MS, MS n , and LC/MS data for both electrospray and atmospheric pressure chemical ionization modes (with either internal or external calibration) and automated instrument shut-down. While the foregoing embodiment of the invention has been set forth in considerable detail for the purposes of making a complete disclosure of the invention, it will be apparent to those of skill in the art that numerous changes may be made in such details without departing from the spirit and the principles of the invention.

Claims: CLAIMS : We claim: 1. A method for providing experimental results to submitting persons comprising the steps of: receiving a request for experimental data from a submitting person; executing said request; and electronically delivering results of said request to said submitting person. 2. A method according to claim 1, wherein said request comprises identification data for said submitting person. 3. A method according to claim 1, wherein said request comprises delivery destination data for said submitting person. 4. A method according to claim 1, wherein said request comprises preferred delivery method data for said submitting person. 5. A method according to claim 4 wherein said data indicates delivery of said results via e-mail. 6. A method according to claim 4 wherein said data indicates delivery of said results via creation of a web page. 7. A method according to claim 4 wherein said data indicates delivery of said results via a pager. 8. A method according to claim 4 wherein said data indicates delivery of said results via voice mail. 9. A method according to claim 1, further comprising the step providing a user database . 10. A method according to claim 9 wherein said database comprises entitlements for submitting persons. 11. A method according to claim 10, wherein said step of executing comprises the steps of: comparing said request to said entitlements; and fulfilling said request based on said comparing. 12. A method according to claim 1 further comprising the step of encrypting said results for security during transmission. 13. A method for automated analysis and delivery of results to submitting persons comprising the steps of: receiving a request for experimental data from a submitting person; analyzing said request to determine parameters of said request; interfacing with a measurement instrument to perform analysis wherein said analysis generates said requested experimental data; processing said experimental data into a form suitable for electronic transmission; and electronically transmitting said experimental data to said submitting person. 14. A method according to claim 13, wherein said request comprises identification data for said submitting person. 15. A method according to claim 13, wherein said request comprises delivery destination data for said submitting person. 16. A method according to claim 13, wherein said request comprises preferred delivery method data for said submitting person. 17. A method according to claim 16 wherein said data indicates delivery of said results via e-mail. 18. A method according to claim 16 wherein said data indicates delivery of said results via creation of a web page. 19. A method according to claim 16 wherein said data indicates delivery of said results via a pager. 20. A method according to claim 16 wherein said data indicates delivery of said results via voice mail. 21. A method according to claim 13 wherein said request is received by e-mail 22. A method according to claim 13 wherein said request is received by telephone . 23. A method according to claim 13 wherein said request is received by an interactive voice response system. 2 . A method according to claim 13 wherein said request is received by a web page. 25. A method according to claim 13, further comprising the step providing a user database . 26 . A method according to claim 25 wherein said database comprises entitlements for submitting persons. 27. A method according to claim 26 wherein said step of analyzing comprises the step of comparing said parameters of said request to said entitlements. 28. A device for use with a measurement instrument, comprising; receive means for receiving requests for experimental data from submitting persons ,- interface means for interfacing with a measurement instrument to effect analysis, wherein said analysis generates said requested experimental data; acquisition means for electronically acquiring said experimental data from said measurement instrument; process means for processing said experimental data into a format suitable for electronic transmittal; and transmission means, coupled to said process means, for receiving and electronically transmitting said processed experimental data to said submitting persons . 29 . An apparatus according to claim 28 wherein said receive means receives requests comprising identification data for said submitting person. 30. An apparatus according to claim 28 wherein said receive means receives requests comprising delivery destination data for said submitting person. 31. An apparatus according to claim 28 wherein said receive means receives requests comprising preferred delivery method data for said submitting person. 32. An apparatus according to claim 31 wherein said data indicates delivery of said results via e-mail. 33. An apparatus according to claim 31 wherein said data indicates delivery of said results via creation of a web page. 34. An apparatus according to claim 31 wherein said data indicates delivery of said results via a pager. 35. An apparatus according to claim 31 wherein said data indicates delivery of said results via voice mail . 36. An apparatus according to claim 28 wherein said receive means receives requests by e-mail. 37. An apparatus according to claim 28 wherein said receive means receives requests by telephone. 38. An apparatus according to claim 28 wherein said receive means receives requests by an interactive voice response system. 39. An apparatus according to claim 28 wherein said receive means receives requests by a web page. 40. An apparatus according to claim 28, further comprising database means for storing submitting person information. 41. An apparatus according to claim 40 wherein user identification data is stored in said database means. 42. An apparatus according to claim 40 wherein said user delivery destination data stored in said database. 43. An apparatus according to claim 40 wherein said user delivery method data is stored in said database. 44. An apparatus according to claim 40 wherein said database comprises submitting user entitlement data.

Inventors: HUANG NELSON, KRUPPA GARY, SIEGEL MARSHALL MAYER, HUANG, NELSON, KRUPPA, GARY, SIEGEL, MARSHALL, MAYER
Applicants: BRUKER DALTONICS INC, BRUKER DALTONICS, INC.
Application year: 2001
Main classification: G06F17
IPC codes: G01D1, G06F17