Model for spectral and chromatographic data

Details Model for spectral and chromatographic data Model for spectral and chromatographic data

2001-05-25

2002-11-26

Assouad, Patrick (Department: 2857)

Data processing: measuring, calibrating, or testing

Measurement system

Measured signal processing

C250S281000, C250S282000, C702S028000, C702S181000

Reexamination Certificate

active

06487523

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates generally to the evaluation of objects using spectral data, and more particularly, but not exclusively, to a method for evaluating spectrum data to determine whether samples include a particular characteristic.
BACKGROUND OF THE INVENTION
As used herein, the term “indexed data set” or “spectrum” refers to a collection of measured values (“responses”) where each response is related to one or more of its neighbor elements. The relationship between the one or more neighbor elements may be, for example, categorical, spatial, or temporal. In addition, the relationship may be explicitly stated or implicitly understood from knowing the type of response data and/or how such data were obtained. When a unique index, either one-dimensional or multi-dimensional, is assigned (implicitly or explicitly) to each response, the data are considered indexed. One-dimensional indexed data is defined as data in ordered pairs (index value, response). The index values represent values of a parameter such as time, distance, frequency, or category; the response values can include but are not limited to signal intensity, particle or item counts, or concentration measurements. A multi-dimensional indexed data set or spectrum is also ordered data, but with each response indexed to a value for each dimension of a multi-dimensional array. Thus a two-dimensional index has a unique row and column address for each response (index value1, index value2, response).
Spectral/chromatographic data (as that produced by matrix-assisted laser desorption/ionization-mass spectrometry (MALDI-MS) or gas chromatography) is gathered and analyzed to characterize samples. For example, such data sets may be analyzed in an attempt to determine whether or not a known substance is present in the sample. In other applications, the data may be analyzed in an attempt to evaluate whether a chemical or biological process is performing within acceptable bounds. Some existing methods for analysis include pattern recognition techniques and visual interpretation of spectrum plots. Many techniques use principal components analysis, including partial least squares and principal component regression methods.
The identification and/or characterization of significant or useful features in the analysis of indexed data is a classic problem. Often this problem is reduced to separating the desired signal from undesired noise by, for example, identifying peaks that may be of interest. For indexed data, each of such peaks appears as a deviation, that is to say a rise and a fall (or fall and rise), in the responses over consecutive indices. However, background noise can also result in such deviations of responses leading, for example, to the identification of false peaks in indexed data.
Traditionally, peak detection has been based upon identifying responses above a threshold value. Whether this peak detection has been performed manually or by use of an automated tool, threshold selection has been a critical function that has resisted an objectively optimal solution. Thus such previously known methods for threshold selection typically require arbitrary and subjective operator/analyst-dependent decision-making and are therefore an art. The effectiveness of such artful decision-making using these known traditional methods, and peak detection as a result, is also affected by signal-to-noise ratio, signal drift, and other variations in the baseline signal. Consequently, the operator/analyst often has had to apply several thresholds to the responses over different regions of indices to capture as much signal as possible. This approach has been shown to yield results that are not reproducible, to cause substantial signal loss, and to be subject to operator/analyst uncertainty.
An example of the problems with traditional peak detection and characterization algorithms and methods is illustrated by the development of statistical analysis methods for MALDI-MS. The MALDI-MS process begins with an analyte of interest placed on a sample plate and mixed with a matrix. The matrix is a compound selected to absorb specific wavelengths of light that are emitted by a selected laser. Light from the laser is then directed at the analyte mixture causing the matrix material to become ionized. This ionization of the matrix material, in turn, ionizes some molecules of the analyte which become analyte ions
100
(FIG.
1
). A charge is applied just beyond the source region to extract ions into flight tube
102
and at a detector
104
to attract analyte ions
100
, where detector
104
measures the ionic charge that arrives over a time interval. This measure of charge is converted to an abundance of ions, and the measured flight time of each packet of ions is converted to a mass/charge (m/z) ratio based on flight time measurements of 2-3 known analytes. Since ions
100
arrive at detector
104
in a dispersed packet that spans multiple sampling intervals, ions
100
are binned and counted over several m/z units as illustrated in FIG.
2
.
Currently used algorithms require an operator/analyst to specify a detection threshold
200
for the intensities observed so that only peaks
202
that exceed this specified threshold will be detected and characterized. This procedure for setting the detection threshold appears conceptually appealing and suggests that m/z values for which no ions are present will be read as having a baseline relative abundance, while m/z values for which ions are present will result in a peak. However, as a result of this procedure, peaks
202
that are detected for a specific analyte are not only dependent on the MALDI-MS instrument used but also on the skill of the operator/analyst in setting the detection threshold
200
used for the analysis. If such a user-defined threshold
200
is too low, noise might erroneously be characterized as a peak; whereas if threshold
200
is too high, small peaks might erroneously be ignored as noise. Thus the manual setting of detection threshold
200
introduces variability that makes accurate statistical characterization of MALDI-MS spectra difficult. In addition, baseline noise is not constant over the entire data collection window and such variability decreases even further the effectiveness of current peak detection algorithms based on baseline thresholding. Also related to the problem of distinguishing signals from noise is the bounding uncertainty of the signal. It is well known that replicate analyses of a given sample often produce slightly different indexed data due to instrument variability and other factors not tied to an operator/analyst.
The related disclosures cited above provide improved methods of identifying significant features of test spectra. There remains, however, a need for improved methods of testing samples using peak indices and characteristics that are discovered using such techniques. Such applications include qualitative analysis (wherein one attempts to determine whether a sample does or does not contain a particular substance) and process control (wherein one attempts to detect at what point in time a process degrades to an unacceptable state).
The goal of process control in this context is to take sample spectra at given time epochs, and based on those spectra, to determine when the process begins to degrade or fail (i.e., becomes “out of control”). Several techniques have been developed for control of analytical processes. Many of these methods take a series of sample spectra and compare each to the statistical distribution of a reference spectrum to determine if that spectrum falls inside or outside the expected range of variation for an under-control process. Such methods are useful for identifying dramatic changes in a monitored process, but they are generally deficient when processes undergo gradual or subtle changes over time.
An often-used process control method in chemometrics is the Hotelling T
2
chart operating on principal components of the original spectrum/chromatogram. (See, e.g., Russell, E. L.; Chiang, L. H.; Braatz, R. D

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